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THE SEX-DEPENDENT ROLE OF FORMAT IN MYOCARDIAL ISCHEMIA/REPERFUSION INJURY
No full textIschemic heart disease is a leading cause of death worldwide, most commonly manifesting as a myocardial infarction. Quick and successful restoration of blood flow can salvage viable myocardium, but reperfusion exacerbates damage, resulting in ischemia/reperfusion (I/R) injury. Notably, premenopausal women are at reduced risk for ischemic heart disease as compared to age-matched men. We and others have found that female hearts have enhanced activities of alcohol dehydrogenase 5 (ADH5) and mitochondrial aldehyde dehydrogenase (ALDH2), which metabolize formaldehyde to formate. Loss of ADH5 exacerbates I/R injury in female hearts, yet it is unclear whether loss of ADH5 is detrimental because it increases formaldehyde or reduces formate. Thus, the purpose of this study was to examine a protective role for formate in the heart. Male, female, and ovariectomized (OVX) female hearts were assessed for formaldehyde metabolism by examining the activities of ADH5 and ALDH2. Moreover, male, female, and OVX hearts were subjected to I/R injury ±30µM formate. While OVX hearts had decreased formaldehyde metabolizing capacity than intact females, formate did not rescue OVX hearts. Further, there was no difference in infarct size between intact and OVX females. As such, while estrogen may affect formaldehyde metabolism and formate production, it does not fully protect the heart through this mechanism. Male hearts also demonstrated a reduction in formaldehyde metabolism. Interestingly, formate-treated male hearts had a significant reduction of injury following ischemia and reperfusion demonstrating both a reduction in infarct size and increase in functional recovery. Formate increased protein nitrosylation in vitro and in postischemic hearts, but this effect was blocked with the non-specific nitric oxide synthase inhibitor N(gamma)-nitro-L-arginine methyl ester (L-NAME). Additionally, formate administration preserved tetrahydrobiopterin levels following I/R injury, further supporting a role for formate in supporting nitric oxide synthase function. Further, formate-induced protection from I/R injury in males could be blocked by pharmacologic nitric oxide synthase inhibition with L-NAME. Together, these findings highlight the importance of sex differences in myocardial aldehyde metabolism and identify formate as a promoter of protection. As such, exogenous formate may have translational potential for treatment of myocardial ischemic injury in humans
DESIGN AND DEVELOPMENT OF A VARIABLE-DOSING DRUG DELIVERY DEVICE WITH A NEEDLE-STICK SAFETY MECHANISM
No full textIn the realm of cancer treatment, drug doses for patients are determined by weight, while adults receive a standard dose volume. As medical care increasingly shifts from hospitals to home settings, the need for self-administration of parenteral drugs becomes more pressing. Consequently, the demand for prefilled syringes has surged recently. These syringes, which also serve as drug containers, require a more involved manufacturing process than traditional syringes. The complexity of drug filling and syringe finishing processes makes it expensive and in some cases, prohibitive to commercialize more than one dose presentation of the drug. This leads to a scarcity of drugs in prefilled syringes below adult dosages and, thus, more hospital visits for vial-based injections. Moreover, most oncology drugs in prefilled syringes incorporate safety features, such as Becton Dickinson’s UltraSafe PlusTM Passive Needle Guard, to cover the needle after injection and prevent needlestick injuries.
Therefore, the focus of this work is to develop a drug delivery device capable of administering a broad spectrum of volumes, ranging from as little as 40 μL for pediatric patients to the adult dose of 0.6 mL using the prefilled syringe that would otherwise be used for injecting only 0.6 mL. Furthermore, the device must be compatible with the UltraSafe PlusTM and activate its safety mechanism after each dosing level. The product conceived in this project meets these requirements and provides visual, audible, and tactile feedback to the user during various stages of device operation. It is also designed to minimize incidences of user errors, that could result in dosing errors. Designed for manufacturing using Injection Molding, the device has undergone Finite Element Analysis and preliminary reliability studies to verify its structural and functional integrity. The design’s viability has also been verified with a prototype that confirms the device’s functionality. A device of this kind is enabling for a number of treatments to be made available to under-served patients.
Information pertaining to the design is herein owned by Congruence Medical Solutions, LLC. Inclusion of any Congruence device information in this document is not regarded as public disclosure until the month of May, 2028 per John’s Hopkins Embargo policy. Dissemination of this document is limited and subject to confidentiality agreement signed with Congruence Medical Solutions, LLC
Characteristics of Unilateral Versus Bilateral Herpes Zoster Ophthalmicus: Analysis of the American Academy of Ophthalmology Intelligent Research in Sight Registry
No full textBackground: Herpes zoster ophthalmicus (HZO) is usually a unilateral condition. Bilateral HZO cases are only rarely reported in the literature, and the proportion of HZO cases that are bilateral is unknown. Risk factors for bilateral versus unilateral HZO are also unknown.
Objective: To compare sociodemographic and clinical characteristics among patients and eyes diagnosed with unilateral versus bilateral HZO at the time of initial diagnosis.
Methods: Using data from the American Academy of Ophthalmology’s Intelligent Research in Sight (IRIS) Registry, we assembled a dataset containing HZO diagnosis date, HZO laterality (unilateral versus bilateral), patient-level demographic information, and eye-level clinical information on date of HZO diagnosis such as visual acuity (VA), intraocular pressure (IOP), ocular diagnosis codes, and medications prescribed by the ophthalmologist. Patients and eyes were diagnosed as having unilateral HZO (one eye diagnosed with HZO per patient) or bilateral HZO (both eyes diagnosed with HZO per patient) based on diagnostic code laterality. Patients with newly diagnosed HZO were identified using a three-year disease-free lookback period during which eligible patients were required to have no diagnosis of HZO in either eye; patients with HZO diagnosed in either eye during the lookback period were excluded as non-new HZO cases. Patients with HZO diagnosed toward the end of IRIS Registry observation were also excluded to prevent misclassification of unilateral versus bilateral sequential HZO. We compared sociodemographic characteristics across unilateral versus bilateral HZO patients using descriptive statistics and multivariable logistic regression adjusting for covariates. We compared eye-level clinical characteristics across unilateral HZO eyes versus the better-seeing HZO eye of bilateral HZO patients using descriptive statistics and multivariable logistic regression.
Results: A total of 62,781 eyes of 59,445 patients met study eligibility criteria and were included in the analysis. Bilateral HZO occurred in 6,672 eyes of 3,336 patients (5.6% of all HZO patients). Compared to patients with unilateral HZO, the bilateral HZO patient group had younger mean age at the time of HZO diagnosis (58.1 ± 16.4 years vs. 64.1 ± 15.8 years, p60 years at time of HZO diagnosis (OR 0.74, 95% CI 0.62 – 0.88) versus unilateral HZO patients. Multivariable logistic regression demonstrated that compared to eyes with unilateral HZO, better-seeing eyes in patients with bilateral HZO had lower odds of low vision, ocular comorbidities, or being prescribed HZO medications.
Conclusion: Over 5% of HZO patients have bilateral disease. HZO eyes of bilateral cases have better VA and lower clinical severity on initial presentation than HZO eyes of unilateral cases, though the long-term clinical outcomes of bilateral HZO remain unknown. HZO patients with bilateral disease are younger than those with unilateral disease. Since older age is considered a key risk factor for developing HZO, the younger age of bilateral HZO patients may indicate they have unique patient-level differences placing them at particularly high risk for bilateral disease
IMPACT OF THE MOST COMMON HUMAN C. DIFFICILE TOXIN B SUBTYPES ON TUMORIGENESIS
No full textRecently, our laboratory established that the enteric pathogen Clostridioides difficile can be detected in a subset of human colorectal cancers and can promote tumorigenesis in mouse models in a TcdB toxin-dependent manner. Within this project, we aimed to clarify the mechanistic behavior of how C. difficile toxin B (TcdB) contributes to tumorigenesis, and hypothesized that different subtypes of TcdB would harbor different tumorigenic potential. We first utilized a screening colonoscopy cohort to determine the prevalence and TcdB subtype of asymptomatic C. difficile colonization and its association with colonic polyp status. We then performed mechanistic studies in vitro on representative strains from each major TcdB subtype to determine the potential for these strains to induce direct DNA damage via a plasmid nicking assay. Finally, we tested these strains in our germ-free ApcMin/+ mouse model to determine their tumorigenic potential, screening for microadenomas by histopathology, ROS-associated enzyme expression by qRT-PCR, and co-localization of C. difficile with hotspots of ROS and gH2AX staining by immunohistochemistry, fluorescent in situ hybridization, and immunofluorescent staining. We found that 10.59% of screening colonoscopy individuals tested positive for C. difficile 16S and 4.7% tested positive for tcdB by qPCR. Of those that tested positive for C. difficile, 6/9 had at least one adenomatous polyp at the time of screening. Utilizing a plasmid nicking assay, TcdB did not have the potential for direct genotoxicity, although one strain (Cd_3752T) secreted a molecule with restriction enzyme-like DNase activity. By qRT-PCR on midcolons of mice from our gnotobiotic mouse model, we observed an upregulation of the ROS enzymes Duox2 and Nos2 across TcdB+ C. difficile-exposed mice at 2 wk p.i., regardless of TcdB subtype, compared to sham. Additionally, in Cd_M7404 (TcdB2)-exposed mice there was an upregulation of Nox1 compared to both Cd_3752T (TcdB1) and sham mice. gH2AX staining of the normal crypts correlated significantly with microadenoma counts. Finally, preliminary RNAscope staining demonstrated spatial and expression level differences in Duox2 and Nox1 between sham and C. difficile-exposed mice. Together our data suggests that persistent colonization with most TcdB+ C. difficile strains likely promotes tumorigenesis via chronic ROS-induced DNA damage, regardless of subtype
OPTIMIZING INTERMEMBRANE DISTANCES TO ENHANCE CAR T-CELL RESPONSIVENESS
No full textChimeric Antigen Receptors (CARs) are synthetic molecules that enable T-cells to induce cytotoxicity against tumor cells following recognition of their target cell surface antigen. While this therapy has achieved durable remissions for some leukemia patients, others have relapse driven by the emergence of leukemic cells with abrogated or diminished expression of the CAR-targeted ligand. In this thesis, we leverage in-vitro, in-vivo, and in-silico experiments to advance our understanding of the relationship between CAR protein structure and the efficacy of CAR T-cells against antigen-low tumor cells.
We first assessed the impact of hinge and transmembrane domains on the sensitivity of CD22 CARs against CD22-low leukemia, revealing significantly greater cytotoxicity for CARs with a CD8α hinge as compared to an equivalent CAR with a CD28 hinge. Evaluation of the biophysical and dynamic properties of the CD8α hinge by nuclear magnetic resonance spectroscopy highlighted local structural motifs, with cis-trans isomerization of CD8α hinge prolines promoting dynamic exchange and amplifying antigen-binding effects to improve cytotoxicity.
Notably though, incorporation of a CD8α hinge does not universally result in optimal CAR cytotoxicity; a CD28 hinge boosted the activity of a CD19 CAR against CD19-low leukemia. Evaluation of the intrinsic disorder of the CD28- and CD8α-derived hinges revealed a lower intrinsic disorder and collapse of the former, suggesting that the sequence specificity of the hinge alters its length and downstream CAR responsiveness. Indeed, lower responsiveness of CD19 CARs with CD8α hinges could be overcome, both in-vitro and in-vivo, by reducing the length of the CD8α hinge, with direct consequences on the synaptic cleft distance—the distance between the T-cell and tumor cell. Using these data, we developed an in-silico model, Synaptic Alignment to Program Sensitivity (SynAPS) that predicts the maximally responsive CD8α hinge length as a function of the targeted CAR epitope. Using SynAPS, we were then able to engineer CD33-targeted CARs with optimized responsiveness to antigen-low leukemia. Together, my PhD research demonstrates the critical role of protein structure and dynamics—providing valuable insights into the molecular basis of CAR T-cell design against a wide range of novel targets
Complete Mitogenome Barcoding of the Anopheles Coustani Species Complex
Get PDFCryptic anopheline species complexes pose significant obstacles to malaria eradication efforts because they potentially perpetuate residual transmission and affect vector control program design and efficacy. Members of these groups are typically morphologically indistinguishable and closely related but still genetically distinct species, which may result in phenotypic and bionomic differences such as occupying ecological niches not accessible by indoor vector control methods. A notable example is the understudied Anopheles coustani species complex, whose members typically feed outdoors on non-human hosts but have also demonstrated plasticity or shifts to human and indoor foraging behaviors and significant roles in local and residual Plasmodium falciparum transmission cycles in several southern and central African nations. The primary cryptic species identification method is DNA barcoding with COI and ITS2 sequences, which struggles with inconsistent results, unclear taxonomic boundaries within complexes, and phylogenies with low clade support due to misidentified samples and short sequence lengths. We addressed this challenge by assembling and conducting phylogenomic analyses with ten complete mitochondrial genomes of four Zambian species of the An. coustani group: An. coustani s.s., An. ziemanni, An. paludis, and An. tenebrosus. Maximum-likelihood trees clearly delineated An. paludis and An. tenebrosus but could not differentiate between An. coustani s.s. and An. ziemanni, due to specimens having <2% genetic distances. They also uncovered an unknown clade that may represent a separate unidentified species or an An. tenebrosus subgroup. These results demonstrate the need to further analyze the species boundaries within the An. coustani group and importance of integrating morphological, behavioral, ecological, and molecular species identification approaches
PRIMAL-DUAL THEORY FOR THE SUBGRADIENT METHOD IN WEAKLY-CONVEX OPTIMIZATION
Get PDFDavis at al. prove the convergence rate of the subgradient method on weakly-convex functions to be O(k^−1/4). Still, the reliable stopping criterion remained unknown. This thesis establishes several computable stopping criteria from a new equivalent dual description for the classical subgradient method. Meanwhile, it discussed that under simple assumption, the primal and dual convergence rate of the subgradient method on nonsmooth functions can increase to O(k^−1/2). Several classical optimization conditions like PL-condition and quadratic growth condition are shown to be able to satisfy such conditions. The main result can be particularly applied to solve the phase retrieval problems
MACHINE LEARNING-AIDED DIGITAL TWINS FOR DAMAGE SENSING: A MULTI-PHYSICS AND MULTI-SCALE COMPUTATIONAL FRAMEWORK USING PIEZOELECTRIC COMPOSITES
No full textFailure of composite materials is inherently a multiscale phenomenon. It is governed by damage mechanisms at the microstructural length scale of the material. These damage mechanisms determine the initiation and evolution of fracture across length scales, manifesting its effects on the structural response. This necessitates the development of a robust sensor that can quantify the characteristics of material damage. Piezoelectric composites are an obvious choice for this application due to a strong electromechanical coupling. This thesis attempts to advance our understanding of damage and develop a tool to predict it.
A micromechanical model for crack evolution in heterogeneous piezoelectric composite microstructures is developed. Crack propagation and interfacial decohesion in the presence of electro-mechanical fields are modeled by a phase-field model integrated with cohesive traction-separation laws at material interfaces. However, high gradients in the solution fields require a fine discretization of the computational domain leading to increased computational cost. The first part of the thesis implements an adaptive wavelet-enhanced hierarchical framework to improve the efficiency of the finite element solver. Numerical examples are solved to demonstrate the advantage of this technique over conventional methods.
Simulating damage in structural scale components using a high-fidelity phase field model is computationally intractable. Therefore, a generalized higher-scale continuum damage mechanics model for piezo-composite structures is introduced in the second part of the thesis. Evolution laws are formulated to model damage growth at the component scale with evolving mechanical and electrical fields. A nonlocal scheme is included in the finite element implementation to alleviate mesh dependency in the simulations. Numerical examples are solved to demonstrate the macroscopic effects of damage on the structural response.
The strong electromechanical coupling in piezoelectric materials leads to the third part of the thesis which develops the digital twin of a damage sensor. This can quantitatively predict microstructural damage from the measurement of macroscopic electrical signals at predefined locations on the surface of the structure. An advanced machine learning model capable of treating history-dependent nonlocal material data is employed for this purpose. This model can replace current practices of damage sensing techniques by providing a quantitative global damage indicator in near-real time rather than a location-specific qualitative damage measure
THE INTERSECTION OF PAIN-RELATED HEALTHCARE UTILIZATION WITH NEIGHBORHOOD FACTORS IN ADULTS LIVING WITH SICKLE CELL DISEASE
No full textSickle cell disease (SCD) imposes substantial morbidity and mortality burdens, particularly affecting African American communities, with pain crises as a significant source of morbidity. This study addresses a crucial gap in the literature by examining the impact of neighborhood factors on pain management outcomes and healthcare utilization among adults with SCD. Drawing on Andersen’s Behavior Model of Health Service Use and Krieger’s Ecosocial Theory, it investigates how neighborhood characteristics influence health behaviors and outcomes. Through a systematic literature review and secondary data analysis, the study identifies neighborhood factors associated with adverse health outcomes in SCD, focusing on pain-related outcomes and utilization patterns. The findings indicate that neighborhood social adversity, such as racial residential segregation and income concentration, is correlated with increased pain medication changes and healthcare utilization. However, unexpected associations, such as decreased utilization with greater distance to care, challenge prevailing assumptions and necessitate further exploration. Despite limitations, such as the cross-sectional design and potential confounding factors, this study offers valuable insights into the intricate relationship between neighborhood context and SCD outcomes. By enhancing our understanding of these connections, this research informs targeted interventions to enhance pain management and healthcare access for individuals with SCD, thereby advancing health equity and improving patient outcomes
A THERANOSTIC APPROACH TOWARDS PROGRAMMED DEATH-LIGAND 1 (PD-L1)
No full textCancer is a highly heterogenous and complex disease. Recent advancements in understanding cancer biology have led to development of new therapies. On the forefront of new therapies is immunotherapy which helps the immune system to recognize and eliminate cancer. Programmed death-ligand 1(PD-L1) is a crucial immune checkpoint marker that inhibits anti-tumor response by engaging with its ligand, PD-1 on cytotoxic T cells. Targeting PD-1/PD-L1 axis remains avidly explored avenue clinically, however, a substantial subset of patients remains unresponsive or develop resistance. Given the intra- and inter-patient heterogeneity seen with PD-L1, accurate quantification is key to identify patients most likely to respond to PD-(L)1 targeted therapies and guiding such therapies. Molecular imaging allows non-invasive real-time mapping of its target at the whole-body level.
To allow precise quantification of PD-L1, we developed, [18F]DK222, a peptide-based positron emission tomography (PET) imaging agent. [18F]DK222 accurately measures the varying levels of PD-L1 expression across different types of tumors and changes induced by therapy. To make a versatile and clinically relevant theranostic agent, DK223, we modified DK222 to contain a chelator suitable for gallium-68 (diagnostic) and lutetium-177 (therapy) labeling. DK223 was designed for imaging and molecular radiotherapy (MRT) of PD-L1+ tumors, which represents a promising approach in cancer immunotherapy. The diagnostic arm, [68Ga]DK223, successfully detected PD-L1 expression in various cancer cell lines and xenografts, with uptake strongly correlating with PD-L1 levels. Owing to fast specific accumulation of [68Ga]DK223 in PD-L1+ lesions, it is possible to repeatedly quantify PD-L1 expression. This is particularly useful when quantifying dynamic nature of PD-L1 for patients undergoing immunotherapy. The therapeutic counterpart [177Lu]DK223 displayed potent cytotoxicity in vitro, and in vivo studies demonstrated tumor growth inhibition, particularly with fractionated [177Lu]DK223 doses. MRT with [177Lu]DK223 also increased antigen presentation via MHC-I upregulation and modulated the tumor microenvironment by reducing immunosuppressive players such as LAG-3+ immune cells. Notably, combining [177Lu]DK223 with anti-PD-1 immunotherapy showed enhanced responses, with some mice showing complete remission, suggesting a potential combination strategy for aPD-1 non-responders. This theranostic approach holds promise for personalized, image-guided radiotherapy of PD-L1-positive tumors, potentially overcoming drug resistance often seen immunotherapies