Immunotherapy has emerged as one of the four “standard” cancer therapies, alongside surgery, chemotherapy, and radiotherapy. Immune checkpoint inhibitor (ICI) therapy is an immunotherapy that blocks inhibitory immune checkpoint interactions, allowing T cells and other immune cells to kill tumor cells. In the tumor microenvironment, there is often overexpression of immune checkpoint proteins, whose binding interaction with cytotoxic T cells and other immune cells results in the dampening of the antitumor response. Programmed cell death protein 1 (PD-1) and T-lymphocyte-associated protein 4 (CTLA-4) are the two most targeted immune checkpoint proteins. Antibodies against PD-1 and CTLA-4, as well as other checkpoint proteins, are approved for clinical use as well as in clinical trials. While ICIs have changed the treatment landscape for many cancers, particularly those with significant immunogenicity, only 20-40% of patients respond to ICI therapy. Many factors are behind the lack of response and resistance, and significant efforts are aimed at improving the response to ICI therapy. One major area is modulating the gut microbiome, as it is well-established that microbial dysbiosis is associated with various human diseases. The concept is that by modulating the microbiome, we might be able to return it to a composition more similar to that seen in healthy individuals or provide microorganisms beneficial to clinical response. In the case of ICI therapy, it is proposed that there is a connection between certain microbial species and the immune system via metabolites and other signaling effects. The microbiome can be manipulated through many methods, including fecal microbiota transplantation (FMT), transferring bacterial isolates or consortia, probiotics, antibiotics, and soluble dietary fiber. For clinical insights, it is important to consider how the pre-treatment microbiome of patients may affect their response to ICI therapy, as well as how their microbiomes can be manipulated to enhance their response. Initial clinical trials have been promising, but this is an emerging field with additional work to be done. Particularly, a better understanding of the microorganisms involved in the response to ICI therapy and the mechanism by which they communicate with the immune system is essential. Future studies will need to be much larger to reduce noise between studies and to allow for emerging computational techniques to be applied.

Thesis advisor: Shih-Yuan Liu / Thesis advisor: Amir H. Hoveyda / Chapter 1. Senphos–Palladium-Catalyzed cis-Carboboration of Internal 1,3-Enynes with Carbon–Bound Boron Enolates: Reaction Development and Mechanistic Analysis. A new family of carbon-bound boron enolates (C–boron enolates) that are created through a kinetically controlled halogen exchange process between B–chlorocatecholborane and silylketene acetals is presented. These C–boron enolates are demonstrated to activate 1,3-enynes substrates in the presence of a Senphos-Pd complex to achieve carboboration reaction of an alkyne unit. This carboboration reaction produced highly substituted dienyl boron building blocks in high site-, regio-, and diastereoselectivity. A combined experimental and computational study of this carboboration reaction by Density-Functional Theory (DFT) calculations, 31P NMR study, kinetic study, Hammett analysis and Arrhenius/Eyring analysis will also be described. Mechanistic study supports a syn outer-sphere oxidative addition mechanism featuring a Pd-π-allyl intermediate followed by coordination-assisted rearrangement instead of the conventional inner-sphere β-migratory insertion mechanism. Chapter 2. trans-Hydroalkynylation of Internal 1,3-Enynes Enabled by Cooperative Catalysis. A trans-hydroalkynylation reaction of internal 1,3-enynes enabled by a cooperative catalysis system that comprises of Senphos–Pd complex, tris(pentafluorophenyl)borane, copper(I) bromide, and 2,2,6,6-tetramethylpiperidine, is described. The tris(pentafluorophenyl)borane as Lewis acid catalyst is shown to promote the reaction involving the emerging outer-sphere oxidative reaction step. This hydroalkynylation reaction affords the cross-conjugated dieneynes that serve as versatile synthons for organic synthesis. The photophysical properties of these cross-conjugated dieneynes depend on the position of electron donor/acceptor substituents along the conjugation path, as characterized by UV–vis absorption and emissions spectroscopy. Chapter 3. Senphos–Palladium/B(C6F5)3-Catalyzed trans-Hydrothiolation of 1,3-Enynes: Reaction Development and Mechanistic Analysis. A trans-hydrothiolation reaction of 1,3-enynes enabled by a cooperative catalysis system that comprises of Senphos–Pd complex and tris(pentafluorophenyl)borane is detailed. The tris(pentafluorophenyl)borane is shown to alter the reaction pathway, leading to a trans-addition product over cis-addition one. Experimental mechanistic study that includes 31P NMR, kinetic study, kinetic isotope effect (KIE) study, Hammett analysis, is consistent with a cooperative activation mechanism that features an outer-sphere protonation step. / Thesis (PhD) — Boston College, 2023. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Afin de soutenir le processus d'autogestion des personnes vivant avec la maladie de Parkinson qui tentent de mieux prendre en charge leur maladie et de maintenir une qualité de vie à domicile, cette recherche a comme objectif d'identifier les caractéristiques de messages personnalisés de conseils de santé répondant aux besoins et aux attentes de ces personnes. En nous appuyant sur la théorie de la communication multimodale développée par Bezemer et Kress (2016), cette recherche qualitative permet de décrire les éléments clés essentiels à intégrer à la conception de messages personnalisés. De plus, nous voulions examiner la perspective de professionnels de la santé travaillant avec des patients qui vivent avec la maladie de Parkinson. L'analyse des messages personnalisés de conseils de santé pour accompagner les personnes atteintes de la maladie de Parkinson dans leur processus d'autogestion est un sujet complexe mais de la plus grande importance. Selon notre recherche, les professionnels de la santé ayant pris part à un groupe de discussion démontrent de l'ingéniosité quant à la création de messages « sur mesure » ainsi qu'une ouverture à la multimodalité pour rendre les ressources significatives et personnalisées, ainsi qu'adaptables tout au long du parcours de la maladie de Parkinson. Sur le plan pratique, cette recherche a permis d'élaborer quelques recommandations visant à améliorer le contenu et la forme des messages personnalisés qui sont générés par une plateforme d'autogestion nommée eCARE-PD. Actuellement en développement, nous souhaitons que cet outil devienne essentiel et indispensable pour les patients qui recherchent une meilleure qualité de vie.

Hyperspectral imaging (HSI) in abdominal surgery is a new non-invasive tool for the assessment of the perfusion and oxygenation of various tissues and organs. Its benefit in pancreatic surgery is still unknown. The aim of this study was to evaluate the key impact of using HSI during pancreatoduodenectomy (PD). In total, 20 consecutive patients were included. HSI was recorded during surgery as part of a pilot study approved by the local Ethics Committee. Data were collected prospectively with the TIVITA® Tissue System. Intraoperative HS images were recorded before and after gastroduodenal artery (GDA) clamping. We detected four patients with celiac artery stenosis (CAS) caused by a median arcuate ligament (MAL). In two of these patients, a reduction in liver oxygenation (StO2) was discovered 15 and 30 min after GDA clamping. The MAL was divided in these patients. HSI showed an improvement of liver StO2 after MAL division (from 61% to 73%) in one of these two patients. There was no obvious decrease in liver StO2 in the other two patients with CAS. HSI, as a non-invasive procedure, could be helpful in evaluating liver and gastric perfusion during PD, which might assist surgeons in choosing the best surgical approach and in improving patients’ outcomes.

A physiologically-based toxicokinetic and toxicodynamic (PBTK/TD) model was developed, from the open literature, to predict the toxicokinetic disposition and toxicodynamic response (acetylcholinesterase inhibition) of a ternary organophosphorus (OP) insecticide mixture: chlorpyrifos (CP), methyl parathion (MP) and parathion (P). In vivo studies were conducted in adult male Sprague-Dawley rats, orally administered one of two CP/MP/P mixtures (2.5, 0.5, 0.5 mg/kg or 5, 1, 1 mg/kg) with selected tissues (blood, brain, diaphragm, liver, lung and skeletal muscle) collected at 30min, 4, 12 and 24hr postdosing. Low dosages were studied so the mixture did not result in significant disruption of cardiovascular function nor invalidate the model’s underlying general physiological assumptions. The data were used to validate the model. CP and its metabolites (CP-oxon, 3,5,6-trichloro-2-pyridinol (TCP)), as well as MP, P and 4-nitrophenol, were quantified in the tissues of interest. Peak concentrations of CP were attained by 4hr in all tissues with the exception of the liver, whose peak occurred at 30min; MP, 30min in all tissues; P, 12hr in all tissues with the exception of the liver, 30min. This was supported by the model simulations. MP, P, and their respective oxons were below limits of quantitation for the lower dosage. No toxicokinetic interactions were observed in the present study. Cholinesterase inhibition in the tissues ranged from 11- 37% for the lower dosage, and 29-93% for the higher dosage group; with few exceptions, inhibition was generally additive and was also supported by the model simulations. This study demonstrates the utility of using previously developed individual PBTK/TD models and in vitro/in vivo data from the open literature to construct reliable mixture PBTK/TD models.

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