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Niclosamide Nanoparticles Enhance Pancreatic Cancer Sensitivity to Gemcitabine via HIF-1α Inhibition
No full textPancreatic cancer (PC) exhibits profound metabolic adaptations that support tumor progression, survival, and therapy resistance. Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of these processes, promoting metabolic reprogramming and chemoresistance. Given that mitochondrial metabolites modulate HIF-1α stability, targeting mitochondrial metabolism offers a promising therapeutic strategy. Niclosamide (Nic), a clinically approved anthelmintic, disrupts mitochondrial function but is limited by poor bioavailability. To overcome this, we developed polyanhydride-based Nic nanoparticles (NicNps) to enhance bioavailability and efficacy. NicNps impaired mitochondrial function, suppressed metabolism, downregulated HIF-1α, and inhibited growth of PC cells and orthotopic gemcitabine (Gem)-resistant mouse tumor models. Notably, NicNps combined with Gem overcame therapy resistance by synergistically reducing tumor hypoxia and HIF-1α-driven metabolic reprogramming. These findings highlight NicNps as a mitochondria-targeted, nanoparticle-based therapy that enhances Nic\u27s bioavailability while suppressing HIF-1α-driven adaptations. NicNps in combination with Gem offer a promising strategy to overcome therapy resistance and improve treatment outcomes in patients with pancreatic cancer
Optimizing Small Molecule Targeted Radionuclide Therapeutics for Enhanced Tumor Retention in Ovarian and Colorectal Cancer
No full textSmall-molecule targeted radionuclide therapeutics (TRTs) have proven effective in several malignancies by combining precise tumor targeting with rapid clearance from non-target tissues. However, many TRTs exhibit poor tumor retention, which directly limits their deliverable therapeutic radiation dose. In response, our laboratory investigated the incorporation of irreversible epoxysuccinyl-based protease inhibitors into TRTs to generate dual-targeted constructs that improve tumor retention through high molecular weight adduct formation via a cysteine protease trapping approach (CPTA).
Neurotensin receptor subtype 1 (NTS1) is a GPCR that promotes cancer cell invasion and survival through upregulation across many malignancies. Its low expression in normal tissues identifies it as a viable target for TRT development. [¹⁷⁷Lu]Lu-3BP-227 is a NTS1-TRT that demonstrated favorable tumor uptake but rapid clearance in clinical trials, motivating its optimization via the CPTA. Preliminary CPTA–NTS1-targeted agents (CPTA-NTS1TAs) achieved two- to threefold increases in tumor retention but exhibited elevated renal uptake. To mitigate off-target toxicity, this work investigated structural modifications to decouple tumor and renal retention of CPTA-NTS1TAs.
In Chapter 2, a structure-activity study evaluated linker composition within CPTA-NTS1TAs, revealing that positively charged ([¹⁷⁷Lu]Lu-8c) or flexible ([¹⁷⁷Lu]Lu-8a) linkers enhanced NTS1 targeting and retention (17.8–28% of initial uptake) compared to [¹⁷⁷Lu]Lu-3BP-227 (13 ± 2%), though renal accumulation remained high. Chapter 3 examined amino acid substitutions at the P2 position of the epoxysuccinyl inhibitor to refine enzymatic specificity and pharmacokinetics. Eight constructs demonstrated preserved NTS1 affinity, efficient internalization, and distinct high–molecular weight adduct profiles. Tyrosine substitution suggested selective cysteine protease interactions and elevated tumor uptake, and sustained retention.
Finally, Chapter 4 extended CPTA utility to a folate receptor 1 (FOLR1)–targeted system for metastatic ovarian cancer, confirming generalizability of the trapping strategy through improved tumor retention and adduct formation relative to a non-trapping control. Collectively, this work establishes the CPTA as a versatile platform for enhancing tumor retention. By bridging the pharmacokinetic gap between small molecules and macromolecular agents, it lays the foundation for developing next-generation TRTs with broader clinical applicability across solid tumors
Oncomucin-Mediated Stromal Remodeling in Pancreatic Cancer
No full textPancreatic ductal adenocarcinoma (PDA) remains one of the most lethal malignancies, in part due to its dense fibrotic stroma and immunosuppressive microenvironment. This dissertation identified cancer-associated mucins (oncoMUCs), particularly MUC4 and MUC16, as central coordinators of these phenotypes. Multiplex imaging and transcriptomic profiling revealed stage-specific clonal diversity in oncoMUC expression, with elevated MUC4 and MUC16 modulating a signaling network that regulates multiple immune checkpoints. Functional studies in murine models demonstrated that oncoMUCs converge on EGFR and UNC5B pathways to drive TIM3, VISTA, and PD-L1 expression, reinforcing immune evasion.
Therapeutically, co-inhibition of oncoMUC signaling and mutant KRAS using Istradefylline and MRTX1133 significantly reduced tumor burden, suppressed checkpoint expression, and restored CD8+ T-cell function, suggesting a promising combinatorial strategy. Beyond immune modulation, this work revealed a novel role for MUC16 in extracellular matrix (ECM) remodeling. In contrast to prior assumptions that collagen is primarily stromal-derived, we showed that PDA cells produce and organize key collagen isoforms, notably Col4a2, in response to complement signaling.
MUC16-expressing cancer cells activate the complement cascade via factor D, triggering ERK and NFκB pathways in both cancer cells and fibroblasts. This promotes a fibrotic ECM and supports survival under detachment stress, aiding metastasis. Col4a2,
retained at the cancer cell surface, may function not only structurally, but also as a survival ligand via integrin-AKT signaling. Together, these findings positioned oncoMUCs as drivers of immune suppression, ECM reprogramming, and metastatic fitness.
By redefining the roles of mucins and complement in PDA, this work highlighted the tumor-intrinsic mechanisms that reshape the stroma to favor dissemination. It also established a framework for mucin-directed therapeutic strategies that address both epithelial and microenvironmental barriers to effective treatment
Unmasking B7-H3: A Spontaneous Small-Cell Lung Cancer Model Reveals its Dual Role in Tumor Progression and Immune Modulation
No full textSmall-cell lung cancer (SCLC) is an aggressive malignancy that is generally considered an immune desert. The therapeutic impact of immune checkpoint inhibitors in SCLC is modest and confined to a small population of patients. The immune checkpoint protein B7-H3 (also known as CD276) is highly expressed in SCLC; however, its functional contribution to SCLC remains unexplored. Here, to dissect tumor-intrinsic and immunomodulatory functions of B7-H3, we generated a novel genetically engineered mouse (GEM) model Rb1fl/fl; Trp53fl/fl; LSL-MycT58A; Cd276fl/fl (RPMC). Cd276 deletion significantly impaired primary tumor growth, metastatic dissemination, and reprogrammed the SCLC tumor microenvironment by increasing CD8+ T-cell infiltration and decreasing immunosuppressive myeloid populations. Loss of B7-H3 also improved responsiveness to combination therapy (cisplatin and anti-PD-L1) by modulating the anti-tumor immune response. Mechanistically, B7-H3 regulates NFIB through a CXCL11-CXCR7 feed-forward loop. To further evaluate translational implications, we tested a B7-H3 targeted antibody-drug conjugate m276-SL-PBD, which abrogated SCLC in the GEM model. Collectively, our findings establish B7-H3 as a key regulator of SCLC progression, metastatic competence, and immune escape, and highlight B7-H3-directed therapies as promising strategies for this recalcitrant disease
Understanding Agricultural Injury Burden and Prevention: Economic Costs, Military Service Factors, and Safety Training Challenges in the United States
No full textThis dissertation examines the burden, distribution, and prevention of agricultural injuries in the U.S. (United States) using a macro–meso–micro framework that links national costs, subgroup risk, and safety-training implementation. At the macro level, I estimated the annual national cost of farm-related injuries by combining Central States surveillance data from the Farm and Ranch Health and Safety Survey (FRHSS) with federal insurance and injury statistics. Self-reported injury rates among farmers and ranchers were 15.25 injuries per 100 operators (20.20 per 100 FTEs), substantially exceeding Bureau of Labor Statistics rates. When extrapolated nationally and combined with hired-worker injuries, the annual economic burden of agricultural injuries was approximately 11.6 billion after inflation adjustment, representing a notable share of U.S. gross and net farm income.
At the meso level, I used FRHSS data to describe injury patterns, work tasks, safety behaviors, and chronic health conditions among agricultural producers with prior military service in the Central States, comparing them with non-veteran peers. Veteran producers emerged as an older, high-exposure subgroup with substantial injury and chronic disease burden, underscoring the need to integrate service connected health considerations into agricultural safety and rehabilitation strategies.
At the micro level, I analyzed survey data from the University of Nebraska Medical Center (UNMC) Safety Management Survey and Feedyard 15 participants to identify motivators and barriers to implementing and sustaining safety training in cattle feedyards. Results highlighted the combined influence of management commitment, regulatory and market pressures, perceived productivity benefits, time and staffing constraints, and fit of training materials with multilingual, high-turnover workforces.
Together, these studies provide updated national cost estimates, bring veteran producers into clearer focus, and identify practical levers for improving safety culture and training uptake in high-risk livestock systems. The findings offer an integrated evidence base for policymakers, insurers, veteran-serving organizations, and extension professionals seeking to reduce agricultural injury burden while supporting the long-term viability of U.S. farms and ranches
Simulating Vascular Emergencies in Robotic Surgery: Preparing OB-GYN Residents for Surgical Complications
Get PDFThis is an abstract from the Spotlight on Scholarship event in 2025
Exposure of Tracheostomy Education Well-Received During Pre-Clinical Head and Neck Physical Exam Course
Get PDFThis is an abstract from the Spotlight on Scholarship event in 2025
Combinatorial Antiviral Regimen as Strategy to Control SARS-CoV-2 Infections
No full textThe coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have impacted health of the people and economy globally. Despite multiple vaccines have been authorized for emergency use, the continuous emergence of SARS-CoV-2 variants of concern (VOCs) with enhanced infectivity and transmissibility, as well as resistance to antibody neutralization from vaccine-elicited sera and convalescent plasma, has become a major obstacle against ending the COVID-19 epidemic. Although several antivirals with SARS-CoV-2 inhibitory activity have been approved for the clinical use to treat COVID-19, only a few have shown significant clinical efficacy. Many antivirals are either less effective or may cause serious side effects or resistance and are no longer recommended for the treatment of COVID-19. Therefore, the development of potent and broad-spectrum antivirals to inhibit SARS-CoV-2 and its variants and treat COVID-19 is urgently needed.
Antiviral therapeutics can be directed at the host or at the virus. Therefore, in-depth understanding of the virus interaction with the host as well as steps of virus replication is very important. Here we provide insights into the different targets, both virus and host, and discuss the critical components. SARS-CoV-2 genome encodes two open-reading the non-structural protein 5 (NSP5) main protease (Mpro), and the NSP3 papain-like protease (PLpro). Here we screened different compounds targeting main protease (Mpro) and PLpro using high throughput antiviral assays, computational docking, enzymatic and binding assays, and cells-based assays. Similarly, we screened a potent target host protease inhibitor against SARS-CoV-2 and its variants. Mono therapeutic regimen sometimes results in the development of drug resistance strains, especially when given to immune-compromised patients. Therefore, combinatorial antiviral regimens targeting different enzymes that are essential for viral replication are important, as they have less toxicity and blunt the evolution of mutant strains. We used a combinatorial antiviral approach to investigate the synergistic effect of compounds with the previously FDA approved drugs for COVID-19 treatment like Remdesivir, Molnupiravir, and Nirmaletrelvir.
In conclusion, we identified compounds with potent antiviral activity against the SARS-CoV-2 and the latest circulating variants of SARS-CoV-2. These compounds when combined with FDA-approved antiviral drugs for for COVID-19, exhibit a synergistic/additive effect, that warrants validation of these findings in preclinical models to treat the persistent SARS-CoV-2 replication
HIV-1 Tat Induces Transient TLR4/6 downregulation in Human Microglia Cells: Implications for Neuroinflammation
Get PDFMicroglia, the resident immune cells of the central nervous system (CNS), plays a pivotal role in neuroinflammation associated with HIV infection. Toll-like receptors (TLRs) are critical innate immune sensors expressed in microglia, and their dysregulation is implicated in HIV-associated neurocognitive disorders (HAND). In this preliminary study, we examined the basal expression of TLRs and the impact of HIV-Tat on their expression using the human microglial HMC3 cell line. First, the microglial identity of HMC3 cells was confirmed by the expression of Iba1, a microglia-specific marker. RT-PCR analysis revealed basal expression of TLR2, TLR4, andTLR6, with TLR4 showing the highest expression followed by TLR6 and TLR2 under unstimulated conditions. Treatment with recombinant HIV-Tat protein (50 ng/mL) for 24 hours resulted in a significant downregulation of TLR4 mRNA levels, with a rebound at 48 hours. Upon treatment with HIV-Tat protein, TLR6 mRNA levels were also significantly downregulated at 24 hours, with a partial recovery observed by 48 hours. Heat-inactivated Tat (HI-Tat) served as a negative control and did not significantly affect TLR expression compared to untreated controls. These initial findings suggest that HIV-Tat selectively alters TLR expression in microglial cells, potentially contributing to CNS immune dysregulation during HIV infection. Further investigations involving a broader range of Tat concentrations and time points are necessary to validate and expand upon these observations.https://digitalcommons.unmc.edu/surp2025/1005/thumbnail.jp
From Classroom to Clinic: Innovative Strategies to Develop and Assess Clinical Readiness and Student Success
Get PDFClinical education readiness is a foundational expectation in physical therapist education and a core requirement of CAPTE accreditation. In response to national concerns regarding variability in student preparedness, the American Council of Academic Physical Therapy published a set of core knowledge, skills, and abilities (KSAs) that students should demonstrate prior to beginning full-time clinical experiences. Many of these KSAs emphasize competencies within the affective domain, such as adherence to professional standards and effective communication. Clinical reasoning is also highlighted as a key component essential for clinical readiness. However, these competencies are often underemphasized and difficult to assess prior to clinical placement, despite being among the most frequently cited concerns by clinical instructors. Traditional assessment tools such as written exams and group projects often fail to provide accurate, individualized insights into student readiness. There is a growing need for innovative, scalable, and validated instructional strategies that support both the development and assessment of these KSAs prior to clinical education. This session will present a comprehensive and longitudinal approach to building clinical readiness across a DPT curriculum, beginning in the first semester and culminating in Integrated Clinical Education Readiness Assessments (ICRA) before students embark on full-time clinical education experiences