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    Uncovering Therapeutic Vulnerabilities in Androgen-Independent Prostate Cancer: A Multidimensional Phenotypic and Transcriptomic Investigation of Next Generation Imipridones
    Ghamlouche, Fatima; Abou Kheir, Wassim; Daoud, Georges; Darwiche, Nadine; Abi-Habib, Ralph; Basbous, Jihane; El Hajj, Hiba; El-Sabban, Marwan; PhD; Department of Anatomy, Cell Biology and Physiological Sciences; Faculty of Medicine; American University of Beirut
    Background: Prostate cancer (PCa) remains a major cause of cancer-related mortality, particularly following progression to androgen-independent disease states characterized by therapeutic resistance, phenotypic plasticity, and reduced dependence on canonical androgen receptor signaling. These features are further supported by stem/progenitorlike subpopulations that contribute to tumor persistence, recurrence, and treatment failure. Accordingly, therapeutic strategies capable of acting independently of canonical androgen receptor signaling and targeting both bulk tumor cells and treatment-resilient stem/progenitor-like populations remain a key therapeutic priority. Imipridones are a class of small-molecule anticancer agents that have been shown to engage noncanonical mitochondrial and cellular stress pathways. The next-generation derivatives ONC206 and ONC212 were developed to improve upon the potency of the parental compound ONC201, which has demonstrated preclinical antitumor activity in advanced and treatment-resistant PCa models. Against this background, this thesis investigated the comparative anticancer effects of ONC201, ONC206, and ONC212 in androgenindependent PCa models and characterized the transcriptomic alterations induced by ONC206 and ONC212. Methods: DU145 and PC3 AIPC cells were treated with ONC201, ONC206, or ONC212, with ONC201 included as the parental comparator. Functional assays were used to assess proliferation, growth, viability, migration, invasion, cell-cycle distribution, sub-G1 accumulation, mitochondrial membrane potential- and mitochondrial mass-associated signals, and spheroid formation and growth in firstgeneration and serially propagated three-dimensional models. RNA sequencing was performed to define global and pathway-level transcriptional responses to ONC206 and ONC212. Results: Among the three imipridones, ONC212 consistently showed the greatest anticancer activity. ONC212 reduced proliferation, growth, and viability at markedly lower concentrations than ONC201 and ONC206, with growth-inhibitory effects observed at approximately 0.1 µM compared with approximately 0.5 µM ONC206 and 5 µM ONC201. ONC212 also exerted the most sustained anti-migratory activity and significantly inhibited invasion at nanomolar concentrations. In cell-cycle analyses, imipridone treatment induced time-dependent sub-G1 accumulation and cell linespecific cell-cycle redistribution, with dynamic changes across G0/G1, S, and G2/M phases. Imipridones also altered mitochondrial parameters in a cell line-specific manner. In three-dimensional models, ONC212 strongly inhibited spheroid formation and growth at concentrations approximately 50-fold and 10-fold lower than ONC201 and ONC206, respectively, supporting enhanced activity against stem/progenitor-like AIPC subpopulations. Transcriptomic profiling revealed that ONC206 and ONC212 induced overlapping but distinct gene-expression programs. Shared responses included repression of DNA replication, E2F target, and cell-cycle-associated pathways, together with enrichment of stress-response, unfolded protein response, integrated stress response, FOXO-associated, and apoptosis-related programs. Compound- and cell linespecific alterations were also observed, including stronger PERK-associated stressresponse enrichment with ONC206 treatment in PC3 cells and mitochondrial RNA metabolism-related pathway alterations associated with ONC212. Conclusion: Collectively, these findings identify ONC212 as the lead imipridone in AIPC models, combining potent inhibition of bulk tumor cell phenotypes and stem/progenitor-like spheroid-forming and growth capacity with coordinated modulation of cell-cycle, mitochondrial, and stress-response programs. These results support further mechanistic and translational investigation of next-generation imipridones, particularly ONC212, as candidate therapeutic strategies for advanced and androgen-independent PCa.
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    Modulation of Serotonin Signaling in a Mouse Model of Chronic Inflammatory Bowel Disease
    Al Baltaji, Nour Al Huda; Jurjus, Abdo; Hawi, Jihad; Soueid, Jihane; Daoud, Georges; Khalil, Athar; MS; Department of Anatomy, Cell Biology, and Physiological Sciences; Faculty of Medicine; American University of Beirut
    Background: Inflammatory bowel disease (IBD) is a chronic, relapsing disorder driven by epithelial barrier disruption, immune hyperactivation, and tissue remodeling. While peripheral serotonin (5-HT) contributes to the regulation of intestinal secretomotor reflexes, barrier integrity, and immune signaling, the distinct regulation between mucosal and neuronal serotonergic networks during chronic post-inflammatory remodeling remains unresolved. Methods: Twelve male C57BL/6 mice were subjected to a chronic 5-cycle dextran sulfate sodium (DSS; 1.5% w/v) regimen followed by a 10-day recovery period, while ten mice served as controls. Colonic tissue fibrosis was evaluated using Masson’s trichrome staining. Localized reactive oxygen species (ROS) were measured via in situ dihydroethidium (DHE) fluorescence. Because reference-gene stability can be altered during colitis, five candidate genes were evaluated (Gapdh, 18S, Actb, Hprt1, Tbp). Target transcript profiles (Il6, Il1b, Tgfb1, Chga, Tph1, Sert, Tubb3, Tph2, and 5-HT receptors) were subsequently analyzed by RT-qPCR and normalized to Gapdh. Quantitative dual-target indirect immunofluorescence was performed to assess the colocalization of Tph1 with the enteroendocrine marker Chga and Tph2 with the neuronal marker Tubb3. Results: Chronic colitis induced significant structural damage and a significant expansion of the fibrotic area within the submucosa and muscularis layers (p = 0.0080). ROS levels were elevated in the colitis group but did not reach statistical significance (p = 0.1773). Gapdh was identified as the most stable reference gene among the five tested candidates and was used for normalization of target gene expression. Cytokine profiling revealed upregulation of Il6 (p = 0.0267), decline of Il1b (p = 0.0004), and unchanged Tgfb1 expression. A significant downregulation of Chga (p < 0.0001), Tph1 (p = 0.0010), and Sert (p = 0.0092) was depicted in the colitis group, with a reduced Chga/DAPI-positive cell density (p = 0.0141); however, the proportion of enterochromaffin cells within the remaining endocrine pool was preserved (Tph1/Chga, p = 0.4818). In the neural compartment, Tubb3 expression (p = 0.0106) and Tubb3/DAPI-positive density (p = 0.0363) were reduced, whereas Tph2 expression (p = 0.5780) and Tph2/Tubb3 co-localization (p = 0.2096) remained unchanged. Serotonergic receptor profiling demonstrated upregulation of Htr1a (p = 0.0254), downregulation of Htr2a (p = 0.0217), Htr2b (p < 0.0001), and Htr4 (p = 0.0053), invariant Htr7 expression (p = 0.3296), and near-total loss of Htr3a (p < 0.0001) and Htr3b (p = 0.0003). Conclusion: Chronic colonic inflammation was associated with differential alterations in mucosal and enteric neural serotonergic compartments. Alterations in Chga, Tph1, and Sert reflected disruption of the mucosal enteroendocrine serotonergic compartment, whereas preservation of Tph2 and Tph2/Tubb3 suggested relative maintenance of neuronal serotonergic phenotype. Altered expression of multiple 5-HT receptors further indicates remodeling of serotonergic signaling in the inflamed colon. These findings suggest that enteric neural networks may sustain baseline serotonergic capability despite pervasive mucosal injury.
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    Development of an Electroactive Hydrogel Platform for Localized Drug Delivery Through Neural Interfaces
    Temsah, Hazar; Khraiche, Massoud; Beydoun, Ahmad; Karam, Pierre; Obeid, Makram; El Hajj, Albert; Khashab, Niveen; MS; BBiomedical Engineering Program; Maroun Semaan Faculty of Engineering and Architecture; Faculty of Medicine; American University of Beirut
    Drug-resistant epilepsy (DRE) affects approximately one-third of individuals with epilepsy and remains a major therapeutic challenge despite advances in pharmacological and surgical interventions. Localized, on-demand drug delivery through implantable neural interfaces has emerged as a promising strategy for improving therapeutic efficacy while minimizing systemic exposure. This thesis proposes the development of a flexible electroactive hydrogel platform capable of electrically controlled, localized delivery of the antiepileptic drug levetiracetam (LEV) for the treatment of focal epilepsy. The work combines conductive polymer technology, smart hydrogel materials, and inkjet printing to fabricate a novel neural drug-delivery interface. The platform is based on a poly(N-isopropylacrylamide) (PNIPAM) hydrogel integrated with the conductive polymer poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS), enabling both thermo-responsive behavior and electrically stimulated drug release. Flexible polycaprolactone (PCL) substrates are employed to produce biocompatible implantable electrodes using inkjet printing technology. To evaluate the therapeutic functionality of the platform, an analytical method based on high-performance liquid chromatography is developed and validated to quantify LEV release under physiological conditions. Both passive diffusion and electrically modulated drug-release profiles are investigated to determine the ability of the conductive hydrogel to provide controlled and responsive drug delivery. Finally, the therapeutic potential of localized LEV delivery is evaluated in a kainic acid-induced focal epilepsy rat model using electrocorticographic recordings to quantify seizure attenuation and establish proof of concept for future device-based therapy. This research presents an interdisciplinary approach that integrates materials science, bioelectronics, drug delivery, and microengineering to address a significant unmet clinical need in epilepsy management. The proposed electroactive neural interface establishes a foundation for future closed-loop therapeutic systems capable of simultaneously detecting seizure activity and delivering antiepileptic medication on demand. Such technology has the potential to improve seizure control, reduce systemic adverse effects, and contribute to the next generation of personalized neuromodulation therapies for patients with drug-resistant epilepsy.
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    Contribution of Nox4 to Peripheral Nerve Dysfunction in Diet-Induced Obesity
    Al Boukhari, Dania; Eid, Stéphanie; Eid, Assaad Antoine; Soueid, Jihane; El Ayoubi, Nabil; MS; Department of Anatomy, Cell Biology and Physiological Sciences; Faculty of Medicine; American University of Beirut
    Obesity is a major risk factor for peripheral neuropathy (PN), a prevalent and debilitating disorder characterized by progressive sensory and motor dysfunction. NADPH oxidase (Nox) enzymes are important sources of reactive oxygen species (ROS). Among these enzymes, Nox4 has been implicated in metabolic and diabetic complications, as well as neuropathic pain and nerve degeneration. However, the specific role of Nox4 in obesity-induced peripheral nerve dysfunction remains unclear. This study investigated whether global Nox4 deletion attenuates oxidative stress and peripheral nerve dysfunction in a high-fat diet (HFD)-induced mouse model of obesity and PN. Twelve-week-old male C57BL/6 wild-type (WT) and Nox4 knockout (KO) mice were assigned to either standard diet (10% fat) or HFD (60% fat) for 24 weeks. Metabolic phenotyping included assessments of body weight, body composition, fasting blood glucose, glucose tolerance, and insulin levels. Peripheral sensory function was assessed using thermal and mechanical sensitivity testing at early and late stages of HFD feeding. Nox isoform expression was examined in peripheral nerves and hippocampal tissue, while Nox activity and inflammatory and antioxidant markers were assessed in the hippocampus. HFD feeding produced an obesity-associated metabolic phenotype in WT mice, including increased body weight, impaired glucose, and increased insulin levels accompanied by altered thermal and mechanical sensitivity. Nox4 deletion modified the metabolic response to HFD: KO-HFD mice exhibited lower body weight, adiposity, and plasma insulin than WT-HFD mice, despite higher fasting blood glucose and greater glucose intolerance. Nox4 deletion also produced time-dependent effect on sensory function, with early differences in thermal sensitivity that were not sustained following prolonged HFD exposure. At the molecular level, HFD and Nox4 deletion were associated with tissue- and condition-dependent alterations in Nox1 and Nox2 expression. Hippocampal Nox activity was altered across experimental groups, while IL-1β was selectively increased in KO mice while TGF-β, Nrf2, and catalase levels remained unchanged. Overall, Nox4 deletion modified metabolic, sensory, and molecular responses to chronic HFD feeding but did not provide sustained protection against HFD-associated peripheral sensory dysfunction. Despite reduced adiposity, KO-HFD mice remained metabolically and sensory impaired, indicating that the effects of Nox4 deletion extend beyond changes in body composition. Together, these findings suggest that Nox4 contributes to the response to chronic metabolic stress within a broader Nox-dependent redox network and highlights the complexity of targeting Nox4 in obesity-associated PN.
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    Firearm-Related Incidents in Lebanon (2021-2025): Temporal Trends, Circumstances, Injury Outcomes, and Socioeconomic Context (A Secondary Analysis of ISF Records)
    Barakat, Shaymaa; Al-Hajj, Samar; Ghandour, Lilian; El Asmar, Khalil; Mowafi, Hani; MS; Department of Epidemiology and Biostatistics; Faculty of Health Sciences; American University of Beirut
    Background: Firearm-related injuries and violence are a major global public health concern, contributing to mortality, disability, and social harm. In 2021, firearms accounted for approximately 47% of intentional homicides with a known mechanism worldwide. In Lebanon, national evidence remains scarce. This study aimed to describe temporal and circumstance-related patterns of recorded firearm-related incidents (FRI), their documented casualty outcomes, and their associations with area-level socioeconomic deprivation and weekend status. Methods: A secondary ecological analysis of de-identified Lebanese Internal Security Forces records from January 2021 to July 2025 was conducted. FRI were defined as firearm-discharge events regardless of injury outcome. Descriptive analyses examined temporal patterns, shooting circumstances, recorded casualties, and deprivation quartiles derived from a district-level composite index. Negative binomial regression with population-time offsets and district-clustered standard errors estimated temporal and socioeconomic associations. Results: A total of 20,784 FRI were recorded across all 26 districts of Lebanon between January 1, 2021 and July 1, 2025. The complete-year rate increased from 65.86 per 100,000 population in 2021 to 93.49 in 2023, before declining to 79.14 in 2024; the January-June rate rose from 41.20 in 2024 to 44.47 in 2025. Adjusted rates were highest in August compared to January (IRR: 1.82; 95% CI: 1.59-2.08) and were also higher on weekends and public holidays. Celebratory firing accounted for 62.02% of New Year incidents and 29.15% of examination-result incidents. Disputes represented 50.44% of all FRI and most documented casualties. The most deprived quartile had a 3.46-fold higher adjusted FRI rate than the least deprived quartile (95% CI: 1.68-7.09), and weekend patterns differed across deprivation quartiles. Because casualty documentation was incomplete, the reported injury and fatality findings represent only the outcomes recorded in the ISF data and should not be interpreted as the complete casualty burden. Conclusion: Recorded FRI in Lebanon followed distinct temporal, circumstance-related, and socioeconomic patterns. The findings point to the need for stronger multisource surveillance and targeted prevention during predictable periods of elevated recorded FRI occurrence, including measures addressing celebratory and accidental firearm discharge, conflict prevention, and structurally disadvantaged contexts.