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Molecular and System-Level Characterization of MMP12 Suppression in Lung Cancer: A Combined Bioinformatics and Molecular Approach
Get PDFLung cancer remains a major cause of cancer-related death, highlighting the need for new molecular targets and novel therapeutics. Matrix metalloproteinases are key regulators of invasion and microenvironment remodeling, and among them, matrix metalloproteinase-12 (MMP12) is a particularly attractive candidate whose network-level effects in cancer are still poorly defined. Herein, we applied an integrative strategy that combines bioinformatics methods with experimental validation in non-small cell lung cancer (NSCLC) cells. Protein–protein interaction (PPI) and pathway analyses of MMP12-regulated genes identified 113 downstream targets enriched in the extracellular matrix, PI3K–AKT, and immune pathways, from which an eight-gene panel (MMP12, CD44, ADAM9, NFKBIA, PSME3, SPARCL1, CCL15, and APOA1) was prioritized as a biomarker signature. Guided by these predictions, we screened a 31-compound MMP12 inhibitor library and selected five leads (C1, C7, C9, C10, and C15) for testing in H1299 cells, with C9 showing the strongest antiproliferative activity. These compounds showed antimigratory activity (C1 achieving a 90% inhibition of wound closure at its IC50 concentration), reduced clonogenic growth, cell cycle perturbation, and induction of apoptosis. Gene- and protein-expression analyses confirmed MMP12 suppression and modulation of the eight-gene panel. Upstream regulator predictions implicated reduced AKT signaling alongside an ADAM9-centered adaptive axis. Collectively, these findings highlight C1, C7, C9, C10, and C15 as promising MMP12 inhibitors, supporting their further development in preclinical lung cancer and nominating the eight-gene panel as a pharmacodynamic signature for MMP12-targeted therapies
Outcomes of the Deloyers procedure: A systematic review and meta‐analysis of proportions
Get PDFBackground Extended left hemicolectomies may result in a short transverse colon and excessive mesenteric tension, precluding a tension‐free anastomosis. The Deloyers procedure is a colonic rotation technique that facilitates anastomosis without total colectomy. This study aimed to evaluate short‐term outcomes following the Deloyers procedure in patients undergoing left‐sided colorectal resections. Methods A systematic review and meta‐analysis were conducted using PubMed, Scopus and the Cochrane Central Register to identify observational studies published up to March 2025. Continuous outcomes were pooled as means with 95% confidence intervals (CIs) and binary outcomes as proportions. Heterogeneity was assessed using the I 2 statistic and Cochrane Q‐test. All analyses were performed using R (v4.4.1). Results Thirteen studies including 287 patients undergoing the Deloyers procedure were analysed. The pooled mean operating time was 256.7 min (95% CI, 188.5–349.6), intraoperative blood loss was 327.5 mL (95% CI, 227.9–470.6) and the perioperative transfusion rate was 25% (95% CI, 16%–35%). Postoperative recovery outcomes included a mean hospital stay of 9.9 days (95% CI, 7.6–12.9), an ileus rate of 15% (95% CI, 7%–30%) and an average of 2.9 bowel movements per day (95% CI, 2.4–3.5). Reported complications included Clavien–Dindo grade I–II events in 36% of patients (95% CI, 14%–66%) and grade III–IV events in 12% (95% CI, 5%–24%). The pooled rate of surgical site infection was 13% (95% CI, 4%–34%), small bowel obstruction 6% (95% CI, 0%–35%) and anastomotic leakage 1% (95% CI, 0%–7%). The overall mortality rate was 0% (95% CI, 0%–1%), with two deaths reported in patients with significant comorbidities and advanced oncological disease. Conclusion The Deloyers procedure is a feasible surgical alternative in patients requiring extended left‐sided colectomy, providing acceptable operative times, functional recovery and complication rates. It may help avoid total colectomy in anatomically complex cases
Political Commitment and Signaling in the International Arms Trade
Get PDFThe politics of the international arms trade is a consequential yet undertheorized component of international relations, particularly with respect to our understanding of how individual states make their arms trade partnership decisions. To build upon the existing arms trade literature, this dissertation examines the international political dimensions of state-level arms trade decision-making in the post-Cold War era. Using illustrative cases of major arms acquisition decisions made in Norway, Saudi Arabia, Kuwait, and Qatar, I employ the canonical rationalist bargaining theory framework to resolve certain state-level arms acquisition behavior that is puzzling from a purely economic and national security-based perspective. First, I explore the United States' enduring post-Cold War dominance of the international arms market through the lens of Norway’s 2008 decision to purchase the American F-35 fighter jet over the Swedish JAS 39 Gripen fighter jet in a direct competition between the two aircraft. Next, I examine the tendency of certain states to amass stocks of major weapons in excess of what is required to meet genuine national security needs, as well as the costly and inefficient decision of certain states to purchase operationally redundant major weaponry from multiple international arms suppliers. To resolve instances of what I term major conventional weapons ``abundance” and ``redundancy,” I examine the emergence of these two phenomena in Saudi Arabia, Kuwait, and Qatar in the post-Cold War era. To resolve each of these three puzzles, I both theorize and demonstrate that international political considerations are often decisive in driving state-level arms trade decision-making. Specifically, I demonstrate that states engaged in the international arms trade are often motivated primarily by the need to overcome the significant credible commitment problems inherent to the buying and selling of major weapons, and by their desire to use major arms transfers to send costly and credible signals to outside audiences. When viewed in this political light, I also demonstrate that states often use major arms transfers as a deliberate foreign policy tool to manage international political relationships, which can lead to counterintuitive outcomes. Taken together, these findings shed considerable light on how the contemporary international arms market works, and on the centrality of international political considerations to our understanding of state-level arms trade decision-making. These findings also carry significant lessons and insights for principals in industry, government, and defense.Doctor of Philosoph
Cobalamin as a light-sensitive agent in targeted therapies for a range of diseases
Get PDFFor decades, scientists have invested countless hours developing targeted therapies in search of the elusive “magic bullet” of drug delivery. Many drug delivery vehicles have been tested, from nanoparticles to liposomes to cell-based carriers. Among those tested, red blood cells have emerged as a preferred carrier due to their biocompatibility, large size, and long circulation time. In combination with these vehicles, several triggers, both internal and external, for drug release have been developed. Light is one of the most commonly used release mechanisms, favored for its exquisite spatiotemporal selectivity. Due to the constraints of the therapeutic window of tissue, however, light-based therapies must be developed that respond to 600-900 nm light in order to penetrate tissue sufficiently for therapeutic application.Cobalamin (Cbl, vitamin B12) contains a light-sensitive Co-C bond and is wavelength-tunable via attachment of fluorophores of various wavelength. Herein, I describe recent advancements in Cbl-based drug delivery conducted by the Lawrence lab, including studies of membrane anchoring stability, photolytic efficiency of different alkyl groups, and in vivo tests of thrombolytic protein delivery.Doctor of Philosoph
CHARACTERIZING AND MEASURING FAMILY ENVIRONMENTS OF TRANSFEMININE ADULTS WITH HIV: A MIXED-METHODS STUDY IN SANTO DOMINGO, DOMINICAN REPUBLIC
Get PDFBackground: Research assessing how family impacts trans people’s health often operationalizes families as either accepting/supportive or rejecting. Yet nascent research finds that families’ behaviors and attitudes are more complex, often encompassing acceptance, support, and rejection simultaneously. This dissertation leveraged mixed-methods research to advance understanding of family environments experienced by transfeminine adults with HIV in the Dominican Republic (DR). Methods: In the first study, I conducted secondary analysis of qualitative in-depth interviews (n = 20) to characterize family environment typologies of transfeminine adults with HIV. In the second study, I developed the Spanish-language Transfeminine Adult Family Environment Scale (TAFES) through a multi-step process informed by individuals with lived experience and expert feedback. I assessed the construct validity of the TAFES in a sample of transfeminine adults with HIV (n = 79) with exploratory factor analyses, convergent and discriminant validity. Finally, I examined correlations between the TAFES subscales and anxiety symptoms, depressive symptoms, and recent drug use. Results: In the first study, I characterized six family environment typologies. Some form of acceptance, support, and rejection was present across most family environments, while complete rejection or acceptance was only present in two of the family environments. While several family environments included acceptance and/or support, gender affirmation from family was less commonly experienced. In the second study, I developed a 24-item measure. A 23-item TAFES with a three-factor solution (1. Gender Affirmation; 2. Rejection; 3. General Acceptance and Support) best explained the data. All subscales had high internal consistency reliability and demonstrated convergent and discriminant validity. Gender Affirmation and General Acceptance and Support were significantly negatively correlated with depressive symptoms score, while correlations between the other subscales and mental health outcomes were not significant. In both studies, gender affirmation emerged as an important construct distinct from acceptance, demonstrating that family can be perceived as accepting even when not engaging in gender affirming behaviors.Conclusions: Acceptance, support, gender affirmation, and rejection are important constructs that create a transfeminine adult’s family environment. This dissertation provides researchers with rich description of family environment typologies and a tool to measure family environments and inform future family-based interventions.Doctor of Philosoph
MATERNAL SOCIO-ENVIRONMENTAL EXPOSURES DURING EARLY PREGNANCY AND MORTALITY AMONG CHILDREN BORN WITH CRITICAL CONGENITAL HEART DEFECTS
Get PDFBackground: Children with critical congenital heart defects (CCHDs) experience high infant mortality (~25%). While various factors like severity and prenatal diagnosis impact survival, the role of environmental exposures remain understudied. We evaluated the associations between maternal neighborhood-level socioeconomic position (nSEP) and air pollution exposure during early pregnancy and survival in children with CCHDs. Methods: Children with CCHDs in the National Birth Defects Prevention Study (1999–2011) classified as univentricular (UVHDs; more severe) or biventricular (BVHDs) were linked to vital records for 1-year and 5-year mortality. To characterize nSEP, we applied principal component analysis to construct the Neighborhood Deprivation Index (NDI) [low (reference), moderate, or high deprivation] based on maternal addresses reported via interview. To evaluate per-IQR increases in ambient air pollutants, we assigned weekly averages (gestational weeks 2-8) using the nearest air monitor ≤50 kilometers. We estimated survival probabilities and hazard ratios (HRs) with 95% confidence intervals (CIs), adjusting for maternal and infant characteristics. Results: One-year survival was high (87-92%), though lower among children with UVHDs (60-75%) than BVHDs (93-95%). Among all CCHDs, survival differed significantly by deprivation (p<0.001), with the lowest survival among those living in highdeprivation areas. Compared to living in areas characterized as having low deprivation, living in areas characterized as having high deprivation was associated with an increased risk of 1-year mortality for all CCHDs (1.18 [0.83, 1.68]) and UVHDs (1.19 [0.73, 1.95]), though non-significant. Estimates for BVHDs were null (1.01 [0.58, 1.77]). For pollutant exposures, per-IQR increases in carbon monoxide (CO) were associated with increased mortality risk (1.25-1.36) across weeks 2-8. No associations were observed among children with UVHDs, but increased mortality risk was observed among children with BVHDs for CO (1.30-1.72) and sulfur dioxide (1.37-1.38). Associations with 5-year mortality were stronger in magnitude for both exposures, with greater deprivation-related disparities among BVHDs and higher CO-related mortality in UVHDs. Conclusion: These observations suggest that the socio-environmental context during pregnancy is associated with childhood mortality risk, with differences observed across severity of CCHDs. Further research could inform underlying structural, environmental, and/or physiological factors that contribute to increased early childhood mortality.Doctor of Philosoph
Latent Confounder adjustment in Multivariate Analysis
Get PDFLatent confounding—unobserved factors that influence both covariates and outcomes—poses a fundamental challenge to valid inference in modern multivariate regression. Such confounders are pervasive in biomedical, epidemiologic, and genomic studies, where biological processes, environmental exposures, and measurement artifacts induce structured dependence across variables. When ignored, latent confounding can bias effect estimates, inflate false discoveries, and compromise replicability. Despite substantial progress in high-dimensional regression and multiple testing, general and computationally efficient methods for latent confounder adjustment remain limited, especially for correlated binary outcomes. This dissertation develops a unified theoretical and methodological foundation for latent confounder adjustment in multivariate regression and extends these ideas to continuous, binary, and high-dimensional settings. The work proceeds in three interrelated components. First, we establish a unifying latent-factor regression framework showing that several widely used approaches—such as negative-control (NC) methods, robust regression (RR), and surrogate-variable analysis (SVA)—are special cases of a general model under distinct identifiability conditions. This theoretical perspective clarifies when unbiased estimation is possible, provides sufficient conditions for identifiability, and reveals common structure among methods previously viewed as distinct. Second, we extend this framework to multivariate binary data through a generalized linear latent variable model (GLLVM), which formally characterizes identifiability under logistic links. We develop likelihood-based estimation procedures, including adaptive Gaussian quadrature and Laplace approximations, and demonstrate their effectiveness in simulation and real-world applications such as vaccine safety surveillance. Finally, motivated by modern large-scale studies, we design scalable inference algorithms for high-dimensional binary outcomes that circumvent high-dimensional integration. These include variational and Pólya–Gamma–based approximations that maintain interpretability while enabling efficient computation. Collectively, these approaches establish a continuum of accuracy–efficiency trade-offs for latent confounder adjustment in large-scale data. Across simulations and applications, the proposed methods achieve accurate, stable estimation under diverse confounding structures and substantially improve interpretability compared to standard analyses. Taken together, this work unifies disparate lines of research on latent-factor modeling and confounding adjustment, establishes general identifiability theory for multivariate regression, and delivers practical algorithms suited to modern high-dimensional biomedical data.Doctor of Philosoph
Phase variation of Clostridioides difficile colony morphology occurs via modulation of cell division by CmrRST, a three-component signal transduction system
Get PDFThe intestinal pathogen Clostridioides difficile is a leading cause of healthcare-associated infections globally, causing recurrent infections with significant morbidity, mortality, and economic burden. Like many bacterial species, C. difficile exists in phenotypically diverse populations that increase survival in dynamic environments. Phenotypic heterogeneity in C. difficile is largely attributed to phase variation in which inversion of a DNA sequence containing regulatory information (a “switch”) modulates the expression of adjacent genes in an ON/OFF manner. The cmr switch controls expression of cmrRST, an operon that encodes the signal transduction system CmrRST. CmrS is a histidine kinase predicted to respond to a signal, and CmrR and CmrT are transcriptional regulators that presumably coordinate responses to the CmrS-detected stimulus. Prior work established that CmrRST plays a broad role in C. difficile physiology and pathogenesis. CmrR decreases biofilm production and is required for colonization in the hamster model of acute infection. CmrT promotes rough colony development, increases surface motility, decreases swimming motility, and confers cell chaining and elongation. However, little is known about the regulatory mechanisms that govern CmrRST activity, how CmrRST functions, or the genes that are regulated by this signal transduction system to confer the observed cmr-associated phenotypes. In this work, we discover that multiple regulatory mechanisms control transcription of cmrRST. Beyond the cmr switch orientation, signaling by cyclic diguanylate monophosphate and autoregulation by CmrR positively regulate expression of the operon. We characterize the CmrR and CmrT proteins by showing that the regulators form both homo- and heterodimers in vitro and identify residues that are required for full CmrR/CmrT activity. Lastly, we determine the genes regulated by CmrR and CmrT and identify two CmrT-regulated genes which encode previously uncharacterized proteins, MrpA and MrpB, that promote rough colony development, increased surface motility, cell elongation, and decreased swimming motility. We find that MrpA interferes with typical cell division by interacting with septum site-determining protein MinD, resulting in elongated cells. We propose that CmrRST-mediated effects on cell division drive the cmr-associated colony morphology and motility differences in a manner resembling sliding motility.Doctor of Philosoph
On Grobner Bases and Their Applications
Get PDFThis thesis focuses on presenting three different and interesting applications of Grobner basis to commutative algebra, algebraic geometry, and field theory. In particular, we will begin by introducing the fundamental theory of Grobner bases followed by providing an algorithm, widely known as Buchberger's Algorithm, to compute a Grobner basis for an ideal in a polynomial ring followed by applying these concepts to 1. determine a criterion for the membership of a polynomial in the radical of an ideal in a polynomial ring,2. devise an algorithm to obtain a Grobner basis for the kernel and image of a polynomial map, and3. determine the minimal polynomial of an algebraic element over a field.Master of Scienc
Naturalistic Social Communication in Autistic Females: Identification of Speech Prosody Markers
Get PDFDifferences in prosody are considered to be a hallmark of the autism phenotype, yet the existing body of literature has yielded inconsistent results from a wide variety of methodological approaches. Additionally, very few studies characterizing prosody have included adequate samples of autistic females, making it unclear whether conclusions from prior work can be extended to this underrepresented subgroup. Recent studies have identified unique ways in which autistic females differ from peers in other domains of pragmatic language. Given the important role that prosody plays in social communication and clinical assessment, understanding prosody in autistic females is critical. The purpose of this study is to characterize speech prosody in a large, matched sample of school-aged (4 – 8 years) autistic and non-autistic males and females (N = 80, 50% female). Acoustic data (measures of pitch and rhythm) were drawn from a conversation task between a child and an experimenter, who asked the child about general topics and topics of special interest. Effects of sex, diagnosis, and conversation topic were seen across several prosodic variables. Additional effects of social measures and language ability were examined, revealing important interactions with sex and diagnostic group on prosody. These results underscore the importance of experimental design and group-specific considerations when characterizing prosody in autistic youth.Doctor of Philosoph