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Pharmacokinetics And Tissue Distribution of a Lipid-Based Extended-Release Nano-Formulation Of MO-OH-Nap Tropolone to Enhance Pulmonary Delivery for the Treatment of Pulmonary Metastatic Osteosarcoma
No full textOsteosarcoma is the most common primary bone tumor in children and adolescents. Metastasis is prevalent in 25% of patients, at diagnosis, with the lungs being the most common metastatic site. Pulmonary metastatic osteosarcoma is a significant therapeutic challenge with a 5-year survival rate of ≤30%. Patients with pulmonary metastatic disease at diagnosis receive the same standard of care as patients with local disease, which hasn’t changed over the past 30 years. The treatment and prevention of pulmonary metastatic osteosarcoma represents a significant critical and unmet need.
MO-OH-Nap tropolone is a novel small molecule with cytotoxic activity across multiple human osteosarcoma cell lines, yet poor solubility limits its clinical development. We developed a MO-OH-Nap tropolone liposomal nanoparticle formulation to enhance delivery to pulmonary tissue for the treatment of pulmonary metastatic osteosarcoma.
The nanoparticle formulation was prepared using a lipid film hydration method. Dynamic light scattering and ultra-centrifugation were used to determine the average particle size and encapsulation efficiency. The pharmacokinetics and biodistribution of MO-OH-Nap tropolone were determined in CD-1 mice following a single intraperitoneal dose of MO-OH-Nap tropolone aqueous solution or MO-OH-Nap tropolone liposomes nanoparticle formulation (5 mg/kg). Serial plasma and tissue samples were collected over 48 hours. MO-OH-Nap tropolone concentrations were determined utilizing a validated LC-MS/MS method. Phoenix® software was used to determine pharmacokinetic parameters utilizing non-compartmental analysis and a 3-compartment pharmacokinetic model to better characterize the MO-OH-Nap tropolone liposomes nanoparticle plasma and tissue concentrations. The finalized model was used to simulate different dosing regimen responses utilizing Monte Carlo simulations.
The liposomes nanoparticle average particle size was 188.3 ± 54 d.nm with 99% encapsulation efficiency. Following single dose administration in mice, MO-OH-Nap tropolone systemic drug exposure was significantly increased (~10 fold) for the nanoparticle formulation (28229 hr*ng/mL) compared to the MO-OH-Nap (2846 hr*ng/mL). The observed clearance was 184.4 mL/hr/kg for the nanoparticle formulation and 1738.6 mL/hr/kg for the drug in aqueous solution. Drug concentrations in lung tissue 24 hours post dose (165.5 ng/g) were significantly increased following nanoparticle formulation administration compared to drug in aqueous solution (1.20 ng/g, student t-test, p-value \u3c 0.001).
The developed pharmacokinetic model accurately described the plasma concentration time profile and pulmonary drug accumulation. The model revealed a biphasic absorption pattern with a rapid initial drug release followed by a sustained drug release phase, indicating the controlled release properties of the nanoparticle formulation. Monte Carlo simulation for multiple dosing scenarios identified that the 7.5 mg/kg twice-weekly regimen would significantly improve lung coverage while moderately enhancing plasma levels, aligning better with the goal of maintaining pulmonary concentrations above the IC50 for a 75% of the dosing interval of 28 days. The model\u27s fit was validated through bootstrap analysis, confirming the reliability of the pharmacokinetic parameters. Overall, this pharmacokinetic model provides critical insights into the behavior of MO-OH-Nap tropolone nanoparticle formulation, facilitating the development of effective dosing strategies for enhanced treatment of pulmonary metastatic osteosarcoma.
The developed formulation substantially increased systemic exposure and pulmonary delivery of MO-OH-Nap tropolone. Further studies will assess the safety profile of 7.5 mg/kg IP dose twice weekly, as well as evaluate efficacy in mouse models of metastatic OS
Exploration of Canine T. Cruzi Seroprevalence as a Trigger for Enhanced Human Chagas Surveillance
No full textBackground: Chagas disease, caused by the parasite Trypanosoma cruzi, is endemic in many Latin American countries and now the southern United States. An increasing number of Chagas cases in the U.S. have occurred because of autochthonous transmission and enzootic cycles involving infected wildlife and domestic animals, like canines.
Objective: This study aimed to explore canine seroprevalence as a trigger for enhanced human Chagas surveillance by describing detected U.S. T. cruzi from human and canine testing data, creating maps to explore geographic areas with potential high yield for T. cruzi surveillance via animal testing, and developing a SWOT analysis for designing a pilot surveillance program.
Methods: To calculate canine and human Chagas cumulative burden, this study examined the number of canine indirect fluorescent antibody (IFA) tests performed by the Texas Veterinary Medical Diagnostic Lab (TVMDL) and the number positive at the state level from March 1, 2019, through April 5, 2024 and looked at the number of confirmed positive human first-time donor specimens reported at the state level from 2014-2019 by The Association for the Advancement of Blood and Biotherapies (AABB) and corresponding state population from the U.S. census. A Chi-Square analysis was performed to identify overlap between human and canine Chagas blood testing data. Human and canine blood data and other risk factor data were then mapped to perform a visual comparison for geographic overlap.
Results: An inverse association was present between canine and human cumulative burden intensity. A geographic overlap existed between most states that had a positive canine IFA and positive first-time human blood donation. A similar overlap between these states and other risk factors examined was also present.
Conclusions: Although not without limitations, analysis of available human and canine blood data and other risk factors can contribute to knowledge of endemic and hyperendemic areas and influence recommendations for future surveillance program designs
Antimicrobial Activity of Gallium(III) Compounds: Pathogen-Dependent Targeting of Multiple Iron/Heme-Dependent Biological Processes
Get PDFMetals play vital roles in biological systems, with iron/heme being essential for cellular and metabolic functions necessary for survival and/or virulence in many bacterial pathogens. Given the rise of bacterial resistance to current antibiotics, there is an urgent need for the development of non-toxic and novel antibiotics that do not contribute to resistance to other antibiotics. Gallium, which mimics iron, has emerged as a promising antimicrobial agent, offering a novel approach to combat bacterial infections. Gallium does not have any known functions in biological systems. Gallium exerts its effects primarily by replacing iron in redox enzymes, effectively inhibiting bacterial growth by targeting multiple iron/heme-dependent biological processes and suppressing the development of drug resistance. The aim of this review is to highlight recent findings on the mechanisms of action of gallium and provide further insights into the development of gallium-based compounds. Understanding the mechanisms underlying gallium\u27s biological activities is crucial for designing drugs that enhance their therapeutic therapies while minimizing side effects, offering promising avenues for the treatment of infectious diseases
Healthcare Professionals\u27 Perspectives of Barriers to Cancer Care Delivery for American Indian, Rural, and Frontier Populations
Get PDFOBJECTIVE: This descriptive qualitative study sought to understand the barriers affecting cancer care delivery from the perspective of healthcare professionals (HCPs) serving American Indian (AI), rural, and frontier populations.
METHODS: One-on-one, semi-structured interviews with multidisciplinary HCPs (
RESULTS: Thematic content analysis revealed three major themes: (a) Access, (b) Time, and (c) Isolation. The themes represent the HCP perspectives of the needs and barriers of persons with cancer to whom they provide cancer care. Furthermore, these themes also reflect the barriers HCPs experience while providing cancer care to AI, rural and frontier populations.
CONCLUSIONS: This study provides preliminary evidence for the need and strong multidisciplinary support for an early palliative care intervention in rural and frontier South Dakota (SD). This intervention could support the needs of persons with advanced cancer as well as the HCPs delivering cancer care in rural settings.
INNOVATION: This study is the initial step to develop the first culturally responsive, nurse-led, early palliative care intervention for AI, rural, and frontier persons with advanced cancer in SD
Potential Prognostic Determinants for FET::CREB Fusion-Positive Intracranial Mesenchymal Tumor
Get PDFIntracranial mesenchymal tumor (IMT), FET::CREB fusion-positive is a provisional tumor type in the 2021 WHO classification of central nervous system tumors with limited information available. Herein, we describe five new IMT cases from four females and one male with three harboring an EWSR1::CREM fusion and two featuring an EWSR1::ATF1 fusion. Uniform manifold approximation and projection of DNA methylation array data placed two cases to the methylation class IMT, subclass B , one to meningioma-benign and one to meningioma-intermediate . A literature review identified 74 cases of IMTs (current five cases included) with a median age of 23 years (range 4-79 years) and a slight female predominance (female/male ratio = 1.55). Among the confirmed fusions, 25 (33.8%) featured an EWSR1::ATF1 fusion, 24 (32.4%) EWSR1::CREB1, 23 (31.1%) EWSR1::CREM, one (1.4%) FUS::CREM, and one (1.4%) EWSR1::CREB3L3. Among 66 patients with follow-up information available (median: 17 months; range: 1-158 months), 26 (39.4%) experienced progression/recurrences (median 10.5 months; range 0-120 months). Ultimately, three patients died of disease, all of whom underwent a subtotal resection for an EWSR1::ATF1 fusion-positive tumor. Outcome analysis revealed subtotal resection as an independent factor associated with a significantly shorter progression free survival (PFS; median: 12 months) compared with gross total resection (median: 60 months; p \u3c 0.001). A younger age (\u3c 14 years) was associated with a shorter PFS (median: 9 months) compared with an older age (median: 49 months; p \u3c 0.05). Infratentorial location was associated with a shorter overall survival compared with supratentorial (p \u3c 0.05). In addition, the EWSR1::ATF1 fusion appeared to be associated with a shorter overall survival compared with the other fusions (p \u3c 0.05). In conclusion, IMT is a locally aggressive tumor with a high recurrence rate. Potential risk factors include subtotal resection, younger age, infratentorial location, and possibly EWSR1::ATF1 fusion. Larger case series are needed to better define prognostic determinants in these tumors
Risk-stratified treatment for drug-susceptible pulmonary tuberculosis.
Get PDFThe Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54-0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07-1.91; extensive disease: HR 2.02, 95%CI 1.07-3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment
What in the Assessment Are We Doing? A Snapshot of Student Learning Assessment in Health Science Libraries
Get PDFObjective: When it comes to education and instruction, there’s no clear answer to what health science librarians/information professionals are doing in student learning assessment and if the methodologies they use are helpful and successful in receiving responses. This project looks to answer two questions: do health science librarians assess student learning in the context of health-related information literacy, and what strategies do health science librarians employ to encourage students to complete learning assessments?
Methods: A twelve-question survey was developed using the Springshare LibWizard tool. It was sent out to library listservs: MCMLA, ICON, MEDLIB-L, AAHSL (Deans/Directors), ACRL, Health Literacy, MLA Expert-Searching, and the MLA Dental caucus on December 5, 2023, and closed on December 22, 2023. Follow-up virtual interviews were completed between January and February 2024.
Results: Forty-three individuals responded to the survey, and five health science librarians participated in follow-up virtual interviews. Five themes emerged from the results: Time, Outcomes (good and bad), Experience, and Resources (tools and individuals).
Conclusions: The result from this survey provides a snapshot of student learning assessment practices used by health science librarians and how students are encouraged to complete their assessments. Librarians are delivering assessments in orientations and one-shots the most and have looked at various technologies to provide these assessments: QR codes, AI, specific online tools, and more. The authors recommend that more research in this area needs to be conducted
A Novel Interactive Video Module for Providers Improves Knowledge of Best-Practices for Treating Alcohol Use Disorder
Get PDFBackground: Despite the availability of efficacious treatment for alcohol use disorder (AUD), providers and patients are often unaware of available treatment options and how to pursue them. Prior studies have found that providers desire more training to effectively treat AUD. Our aim was to develop a standardized video to educate providers about AUD treatment.
Methods: Prospective single-center cohort study evaluating the impact of a novel, interactive educational video module (EVM) for providers about AUD treatment. The EVM discusses treatment, motivational interviewing (MI) and harm reduction strategies, and case examples. The EVM was hosted on our hospital’s website, and available to all providers (faculty, trainees, and practitioners) within the departments of internal medicine, family medicine, psychiatry, and gastroenterology/hepatology. The EVM was optional to complete, but participants were incentivized using continuing medical education (CME) credit. Pre/post surveys solicited feedback and evaluated 1) knowledge of AUD treatments, 2) comfort prescribing medications, and 3) confidence with MI. Matched responses were evaluated using paired t-tests.
Results: 45 providers participated (31 faculty, 14 trainees), reporting significant improvements in their knowledge of AUD treatment (p=0.0001), comfort in prescribing medications (p=0.0002) and using motivational interviewing techniques (p=0.003) after viewing the EVM (Figure 1). Feedback was 89% positive, 2% negative, and 9% suggested ways to improve the EVM.
Conclusion: EVM can significantly improve provider knowledge and comfort in treating AUD. Further studies are needed to evaluate if EVM can improve treatment access and patient outcomes
Thrive: Success Strategies for the Modern-Day Faculty Member
Get PDFThe THRIVE collection is intended to help faculty thrive in their roles as educators, scholars, researchers, and clinicians. Each section contains a variety of thought-provoking topics that are designed to be easily digested, guide personal reflection, and put into action. Please use the THRIVE collection to help: Individuals study topics on their own, whenever and wherever they want Peer-mentoring or other learning communities study topics in small groups Leaders and planners strategically insert faculty development into existing meetings Faculty identify campus experts for additional learning, grand rounds, etc.
If you have questions or want additional information on a topic, simply contact the article author or email [email protected]://digitalcommons.unmc.edu/facdev_books/1001/thumbnail.jp
Understanding and Mitigating the Potential Effects of Postpartum Depression on Fathers and Male Support Persons
Get PDFBackground. During the postpartum period, best practices dictate that medical professionals screen new mothers or birthing persons for anxiety and depression and direct them to the appropriate resources and services they may need. This qualitative study explored the steps being taken to identify depression and anxiety concerns in male support partners during the postpartum period and to understand what resources are being brought to their attention if depression and anxiety are identified. Methods. A convenience sample of male support persons participated in semi-structured, one-on-one interviews either in-person or over Zoom between September and October 2024. Interviews were recorded, transcribed, and cleaned for analysis. A deductive-inductive approach was used to develop a codebook and identify themes. Results. Five interviews were completed with male support persons to identify the main areas of concern among their demographic. Four themes were identified, Access, Stigma, Resources, and Community. Conclusions. Interviews provided an understanding of how and what affects male support persons’ mental health during the postpartum period. As research suggests, male support partners who experience mental health concerns may negatively impact the well-being of the mother and child. Investing in mental health services for male support persons during the postpartum period is an important area of public health