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The Design, Synthesis and Biological Evaluation of Novel 17β-Hydroxysteroid Dehydrogenase Modulators
Get PDFAlzheimer’s disease (AD), affecting over 55 million people globally, is projected to impact 150 million by 2050. With no cure available, current treatments mainly manage symptoms or slow disease progression. The need for therapies addressing the underlying mechanisms of AD is urgent. The primary hallmarks of AD are amyloid beta (Aβ) plaques, tau neurofibrillary tangles, mitochondrial dysfunction, and neuroinflammation, which coincide and worsen over time.
17β-Hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a mitochondrial enzyme involved in energy regulation, steroid metabolism, and cellular homeostasis, and its upregulation has been implicated in AD and various cancers. In AD, 17β-HSD10 exacerbates Aβ toxicity by binding to Aβ and disrupting neuronal function. Moreover, its overexpression, independent of Aβ interaction, contributes to reduced cellular energy and heightened cytotoxicity. These findings suggest that targeting 17β-HSD10 may offer a novel therapeutic strategy for AD, either by disrupting its Aβ interaction or inhibiting the enzyme itself.
Several small molecule chemotypes have been identified to modulate 17β-HSD10, and although varying in shape, they all struggle when it comes to their pharmacokinetic (PK) properties, which, when progressed, will limit their efficacy. Therefore, developing current chemotypes to alleviate these liabilities and identifying new chemotypes to probe the restraints of the chemical space is fundamental to progressing this research.
This work described details the design and synthesis of derivatives of AG18051, the most studied modulator of 17β-HSD10, building on prior structure-activity relationship studies to identify more potent and PK-friendly compounds. Additionally, a high-throughput screen led to the discovery of BCC0100281, a novel small molecule modulator of 17β-HSD10. A synthetic route for BCC0100281 and related derivatives was developed, followed by biological evaluation. To conclude this work, the process of virtual screening, hit evaluation, synthesis, and biological assessment will be described as a method to identify new modulator chemotypes with improved properties to be advanced in this area. The findings from this research contribute to the growing pool of potential small molecule modulators of 17β-HSD10. These molecules can be used to further investigate the relationship between 17β-HSD10 and AD (or cancer) and be developed into therapeutic candidates
AI and OT: Preparing Future-ready Practitioners
Get PDFThis is an abstract from the Spotlight on Scholarship event in 2025
Exploring Culture-Based Metacognitive Practices Among the Urban Native American Elder Population
No full textThis research utilized a “Three-Eyed Seeing” approach, which balances contributions from conventional, traditional, and local knowledge systems, to explore metacognitive practices among the urban Native American Elder population nationwide. Researchers asked the question: “What culture-based metacognitive practices do urban Native American Elders engage in?” Existing research demonstrates that metacognitive practices can be a predictor of health and prevention, and a promising approach for reducing harmful stress among Native Americans, a risk factor for brain health outcomes (e.g., cognitive decline, Alzheimer’s Disease and Related Dementias, etc.). This research aims to increase understanding of the types of metacognitive activities that are engaged in, as well as why and how these are practiced, to inform culturally relevant measures and strategies for prevention and treatment.
In partnership with the Native American Health Center, based in CA, the Nebraska Urban Indian Health Coalition, based in NE, and the Indigenous Mindfulness Coalition, based in Rhode Island, the research team purposefully recruited a regionally diverse sample (n=31), including participants age 45+ who identified as Native American and resided in the Eastern, Western, and Midwestern United States. Using Photovoice methods, participants submitted one photograph depicting a culture-based metacognitive activity and responded to related survey questions. Participants were then invited to engage in one of three focus groups to gather additional community insights (n=25). Analysis of the Photovoice and focus group data informed a typology of seven Native American culture-based metacognitive activity domains and four emergent themes reflecting the purpose and meaning associated with these practices. Participants articulated spirituality as a common thread woven throughout the seven domains of metacognitive activity. 100% of participants reported that they practice these culture-based activities regularly, with focused attention and awareness, and the expectation of a positive outcome; three characteristics described in literature as the powerful ways to train the brain or make physical changes in the structure and future functioning of the brain.
This study’s results enhance scientific and academic understanding of culture-based metacognitive practices among urban Native American Elders, advancing research on the association of culture-based metacognitive practices with healthy aging and brain health promotion. One implication of this research is that participant contributions and study findings informed the preliminary adaptation of an existing evidence-based brain health instrument, the Cognitive and Leisure Activity Survey (CLAS) component of the Resilience Index, establishing a more culturally appropriate measure of ADRD risk and protective factors among AI/AN communities. The adapted survey tool will support future research and facilitate more effective and sustainable efforts for brain health promotion among Native American populations
A Replication and Extension of the Enhanced Choice Model for Children Who Exhibit Challenging Behavior
No full textRajaraman et al. (2022) first introduced the Enhanced Choice Model (ECM) as an intervention that incorporates assent within the treatment framework. Shortly after, Staubitz et al. (2022) and Rajaraman et al. (2024) added to the literature available specifically regarding the ECM. Despite the initial successes of the ECM, it has only been applied to nine individuals. Of these, only two needed some form of modification to the treatment model. The criteria for these modifications was not specified within previous literature. Therefore, the purpose of the current study was twofold. First, we extended previous research by evaluating systematic modifications to the ECM for participants for whom the original ECM procedures are not effective. These additional procedures included stepwise systematic modifications that alternated between quality of reinforcer modifications and modifying response effort needed to access reinforcement
American Society of Hematology/International Society on Thrombosis and Haemostasis 2024 Updated Guidelines for Treatment of Venous Thromboembolism in Pediatric Patients
Get PDFBACKGROUND: The American Society of Hematology (ASH) guidelines on treatment of pediatric venous thromboembolism (VTE) were published in 2018. In the last 6 years, there has been a 10-fold increase in the number of children involved in VTE treatment trials.
OBJECTIVE: The ASH Committee on Quality and Guidelines agreed to update the pediatric guidelines in conjunction with the International Society on Thrombosis and Haemostasis (ISTH). These ASH/ISTH evidence-based guidelines are intended to support patients, clinicians, and other health care professionals in the management of pediatric patients with VTE.
METHODS: ASH/ISTH formed a multidisciplinary guideline panel to minimize potential bias from conflicts of interest. An unconflicted patient representative was not identified. The University of Kansas Health System supported the guideline development process, updating or performing systematic evidence reviews up to 2024. The panel focused specifically on the 2018 questions for which there was the greatest amount of interim data. The panel used the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment.
RESULTS: The panel agreed on 20 recommendations and also provided implementation guidance on the optimal use of anticoagulants in pediatric patients. Key recommendations of these guidelines include the role of DOACs in the treatment of a variety of pediatric VTEs.
CONCLUSIONS: Further research is required. Key priorities are understanding the natural history of clinically unsuspected thrombosis across a range of patient subpopulations and obtaining real-world data on the use of DOACs in children
Assessment of Cellular Metabolism in Disease Progression and Prevention
No full textCellular metabolism is emerging as a crucial regulator of both pathological and physiological processes, critically influencing cancer progression, reproductive function and tissue remodeling. In cancer, the rewiring of metabolism supports cancer initiation, proliferation, immune evasion, metastasis and therapy resistance. Conventional cancer therapies are often hindered by resistance and relapse, highlighting the need for novel strategies to effectively treat cancers. Similarly, in ovarian physiology metabolic cues govern processes such as follicular development and luteal regression. While research over the past decade has explored some aspects of metabolic control, the complexity among these dynamic systems further demands high-resolution tools for in-depth insights. In this context, metabolomics has emerged as a robust tool that enables comprehensive profiling of metabolites, reflecting the real-time physiological state of biological systems. Metabolomics provides an unbiased functional readout of cellular phenotypes and responses to interventions with extreme accuracy and precision.
The central aim of this dissertation is to understand how metabolic reprogramming underlies tumorigenesis and reproductive physiology and to evaluate how novel drug candidates and regulatory proteins modulate these pathways. Using metabolomics, we investigate how various metabolic networks – including nucleotide metabolism, glycolysis, TCA cycle, and amino acid biosynthesis are altered in response to novel therapeutics and genetic perturbations. This work is organized into four chapters, each exploring a distinct biological context within the overarching theme of metabolic vulnerability and intervention.
In chapter 1, we use lipidomics to evaluate the impact of polymeric hydroxychloroquine on PDAC metabolism. By linking metabolic rewiring to suppression of protumorigenic lipid metabolites, this study demonstrates how metabolomics can reveal the suppression of lipid mediators following PCQ treatment, particularly in metabolically rigid tumors like PDAC. In chapter 2, we employed untargeted metabolomics to evaluate the metabolic consequences of treating OS cell lines with MO-OH-Nap tropolone. This study highlights how metabolomics can uncover context-specific vulnerabilities, guiding personalized therapeutic approaches in heterogenous tumors like osteosarcoma. Next, in chapter 3, we used metabolomics to map the metabolic reprogramming downstream of YAP and TAZ activation. This study offers novel insights into the metabolic determinants of ovarian physiology with implications for conditions like PCOS and provides detailed analysis of how transcriptional cues influence metabolic output. In chapter 4, we shift focus to transcriptional regulation of metabolism in PDAC through ELK3. Findings from this study underscore how metabolomics can uncover the metabolic consequences of transcription factor activity and identifying new targets like ELK3 for therapeutic intervention in metabolically plastic cancers such as PDAC.
Metabolomics has played a central role in revealing the metabolic hallmarks of disease progression, therapeutic response and genetic regulation. From targeting lipid signaling in PDAC, disrupting nucleotide metabolism in OS modulating redox and amino acid pathways in ovarian cells, to reversing glycolytic addiction through ELK3 suppression, metabolic profiling has been central to this dissertation. Collectively, this dissertation demonstrates the pivotal role of metabolic reprogramming and positions metabolomics as a cornerstone of next-generation biomedical research
Factors Associated With Tooth Loss in Periodontal Maintenance Patients: A Retrospective Study
No full textBackground. Tooth retention is related to overall health and quality of life. Thus, it is important to understand factors associated with tooth loss. The objective of this cross-sectional study was to evaluate associations between systemic and oral factors with tooth loss in a retrospective study of periodontal maintenance patients.
Methods. Periodontal maintenance patients seen in both 2013 and 2019 at the University of Nebraska Medical Center College of Dentistry were included. Demographic data, smoking status, diabetes status, periodontitis stage and extent, medication use, alveolar bone height, probing depths, and tooth mobility were recorded from the electronic dental record. Adjusted odds ratios (AORs) for tooth loss and their associated 95% confidence intervals (CIs) were derived from a logistic regression, which included age, gender, smoking status, diabetes, periodontitis stage and extent, and antidepressant usage.
Results. After adjusting for covariates, patients taking an antidepressant at baseline had 2.68 (95% CI, 1.30 to 5.50) times the odds of losing at least one tooth during the study period than patients who did not. Similarly, a higher adjusted odds of losing at least one tooth was associated with older age (in decades; AOR = 1.33; 95% CI, 1.06 to 1.66), a baseline diagnosis of diabetes (AOR = 2.55; 95% CI, 1.15 to 5.65), and higher baseline periodontitis stage (AOR = 2.66; 95% CI, 1.36 to 5.21).
Conclusion. Our study contributes evidence for the association between antidepressant usage and tooth loss in periodontal maintenance patients. In addition, age, diabetes, and periodontitis stage at baseline were associated with tooth loss. It is recommended that dentists and physicians leverage collaborative strategies to improve tooth retention in patients with periodontitis
Perceptions and Barriers of Vestibular Rehabilitation Among Occupational Therapy Practitioners
No full textBackground: Vestibular dysfunction affects 15-20% of adults annually, often impacting daily activities and quality of life (Neuhauser, 2016). While occupational therapists and occupational therapy assistants (OTs/OTAs) can address functional limitations caused by vestibular disorders, their role in vestibular rehabilitation (VR) is under-studied.
Objective: This study explored the competence and confidence of occupational therapy practitioners (OTP) in VR and identified barriers to implementation.
Methods: A cross-sectional survey was distributed to 532 OTP in the Gulf South region, with 79 responses received. The survey included questions on VR training, techniques used, barriers of implementation in practice, and educational supports. Quantitative data were analyzed descriptively, and thematic analysis was applied to open-ended responses.
Results: Of the respondents, only 37% had received formal VR training while 63% had not. Commonly used techniques in practice included static balance screens (72%), oculomotor interventions (62%), and positional vertigo screens (55%). The reported primary barrier to VR was lack of training (66%). While 53% strongly agreed that VR is within OT scope of practice, over 30% felt that entry-level OT/OTA curricula inadequately prepared practitioners for VR evaluation and treatment.
Conclusions: The findings highlight a need for enhanced VR education and training for OTP. Addressing these gaps can empower OTP to better serve clients with vestibular dysfunction, improving clients’ overall participation in meaningful activities. Further research and professional development in VR are essential to advance the vital role of OTP in this area of practice
Evaluating BMX-001 as a Selective Radioprotector for Healthy Tissue in Pelvic Cancers
No full textPelvic cancers, including rectal, anal, and prostate cancer, are relatively survivable cancers with high five-year survival rates, partially due to the addition of radiation to treatment regimens. Radiation confers excellent tumor control, but also causes damage to surrounding tissue, resulting in both short-term and long-term side effects. In a patient population that is surviving longer after treatment, limiting the impact of side effects is instrumental to improving patient quality of life. Radiation-induced ROS is instrumental in causing these side effects and provides a unique opportunity to protect healthy tissue from damage while sensitizing cancer tissue to treatment, as cancer cells thrive under levels of ROS that damage healthy cells.
BMX-001, a superoxide dismutase mimetic with potent superoxide scavenging capabilities, is currently in clinical trials as a selective radioprotector when administered before and during radiation therapy for brain, head and neck, endometrial, rectal, and anal cancers. Existing work has established BMX-001’s efficacy as a radioprotector, but few studies have sought to elucidate its mechanism, particularly in the context of physiologically relevant doses, alternative dosing schedules, and in the context of chemotherapy alone. We hypothesize that BMX-001 acts as a chemoradioprotector not only through its activity as a superoxide dismutase mimetic but through a myriad of consequent functions, including via Nrf2 activation, alterations to protein oxidation status, and changes in methylation patterns. We confirmed that BMX-001 does not protect colorectal cancer cells in a hind flank model, and showed that BMX-001 provided robust protection against acute radiation damage in rectal tissue. We demonstrated that BMX-001 enacts chemoradioprotection of bone marrow even in mice that lack functional Nrf2. We found significant alterations in protein sulfenylation in response to BMX-001 in genes responsible for decreasing chemotherapy-induced stress in bone marrow, including CREB regulated transcription coactivator 2 (CRTC2), aldehyde dehydrogenase 7 family member A1 (ALDH7A1), and dihydropyrimidine dehydrogenase (DPYD).
For the first time, we established a novel role for BMX-001 as an agent which can reverse fibrosis, which has therapeutic relevance outside the context of radiation-induced fibrosis. We confirmed that BMX-001 can reverse prototypical markers of fibroblast activation and senescence when administered three weeks after radiation, and that it can prevent fibrosis from occurring via collagen deposition six months after radiation. We validated that BMX-001 can repair radiation-induced changes in methylation and that BMX-001 may reverse fibrosis through expression of a fibrosis-implicated gene, CaMKIIβ. These studies provide both novel functions of BMX-001 as a chemoprotector and as an agent to reverse fibrosis. These studies also provide a novel mechanism for BMX-001 outside its superoxide dismutase activity. Together, this study provides increased rationale for BMX-001’s clinical use and expands potential indications for the use of BMX-001 to maximally benefit patients
Phosphorylation Modulates the Structure and Function of Replication Protein A
No full textReplication protein A (RPA) is the major human single-stranded DNA-binding protein essential for DNA replication, recombination, and repair. As a flexible heterotrimer composed of RPA70, RPA32, and RPA14 subunits, RPA engages a broad range of DNA and protein partners and is extensively regulated by post-translational modifications, particularly phosphorylation. Although RPA has been studied for decades, a complete structural understanding of how phosphorylation modulates its dynamic architecture and functions remains incomplete. In this work, we investigated how G2-phase cell-specific phosphorylation and the DNA damage response (DDR) associated with double-strand breaks (DSBs) influence RPA structure, single-stranded DNA (ssDNA) binding, and protein-protein interactions, all of which are central to the DDR. Eleven candidate serine and threonine phosphorylation sites across RPA70 and RPA32 were mutated to glutamic acid to mimic phosphorylation, and seventeen engineered phosphomimetics were evaluated for expression and stability. Five phosphomimetic proteins were successfully purified as stable heterotrimers and used to assess how phosphorylation affects RPA’s affinity for ssDNA and RAD52, as well as its capacity to transfer ssDNA to RAD52 during homologous recombination.
To determine the structural consequences of phosphorylation, we integrated multiple biophysical approaches – including thermal denaturation, circular dichroism, small-angle X-ray scattering (SAXS), and X-ray footprinting mass spectrometry (XFMS) – to characterize each phosphomimetic in the absence and presence of ssDNA. All phosphomimetics exhibited decreased disorder and increased compaction upon ssDNA binding, as revealed by low-resolution SAXS electron density, which showed a denser, more compact molecular envelope in the presence of ssDNA. XFMS further identified residue-specific protection patterns throughout the protein, including previously unrecognized ssDNA-induced protection within RPA14 and the F domain on RPA70, suggesting a direct role for this subunit in DNA engagement and structural stabilization. Together, these findings demonstrate that phosphorylation measurably alters RPA’s structural integrity and regulatory behavior while preserving its global compaction response to ssDNA. This work advances our understanding of how RPA phosphorylation modulates DNA binding and repair functions and provides new structural insights – including an unexpected contribution from RPA14 and RPA70F – that may inform future mechanistic studies and therapeutic targeting of RPA-mediated DNA repair pathways