Influence has been studied across many different domains including sociology, statistics, marketing, network theory, psychology, social media, politics, and web search. In each of these domains, being able to measure and rank various degrees of influence has useful applications. For example, measuring influence in web search allows internet users to discover useful content more quickly. However, many of these algorithms measure influence across networks and graphs that are mathematically static. This project explores influence measurement within the context of linear time invariant (LTI) systems. While dynamical networks do have mathematical models for quantifying influence on a node-to-node basis, to the best of our knowledge, there are no proposed mathematical formulations that measure aggregate level influence across an entire dynamical network. The dynamics associated with each link, which can differ from one link to another, add additional complexity to the problem. Because of this complexity, many of the static-graph approaches used in web search do not achieve the desired outcome for dynamical networks. In this work we build upon concepts from PageRank and systems theory introduce two new methods for measuring influence within dynamical networks: 1) Dynamical Responsive Page Rank (DRPR) and 2) Aggregated Targeted Reachability (ATR). We then compare and analyze and compare results with these new methods.

Background: We aim to validate a seven-marker immunohistochemical signature, consisting of Bax, Bcl-X, PTEN, COX-2, (loss of) ß-Catenin, (loss of) MTAP and (presence of) CD20, in an independent patient cohort and test clinical feasibility. Methods: We performed staining of the mentioned antibodies in tissue of 88 primary melanomas and calculated a risk score for each patient. Data were correlated with clinical parameters and outcome (recurrence-free, distant metastasis-free and melanoma-specific survival). Results: The seven-marker signature was able to identify high-risk patients within stages IB-III melanoma patients that have a significantly higher risk of disease recurrence, metastasis, and death. In particular, the high sensitivity of relapse prediction (>94%) in sentinel negative patients (stages IB–IIC) was striking (negative predictive value of 100% for melanoma-specific survival and distant metastasis-free survival, and 97.5% for relapse-free survival). For stage III patients (positive nodal status), the negative predictive value was 100% with the seven-marker signature. Conclusions: The seven-marker signature can help to further select high-risk patients in stages IIB-C but also in earlier stages IB–IIA and be a useful tool for therapy decisions in the adjuvant and future neo-adjuvant settings. Stage III patients with measurable lymph node disease classified as high-risk with the seven-marker signature are potential candidates for neoadjuvant immunotherapy.

A discussion of offensiveness in advertising is the initial focus of this research. A review of the offensiveness, irritation, nudity, and sexual suggestiveness in advertising literature suggested that females report somewhat high arousal scores when viewing nudity but that the arousal may not necessarily be positive. The measure of contributing variables to offendedness responses was proposed using various degrees of nudity in existing advertising as the primary stimuli.

To address the unmet clinical need to eradicate treatment-resistant CD133+ cancer stems within tumors, a CSC-targeted radionuclide therapy (TRT) and companion diagnostic imaging probes were developed utilizing CD133-targeting antibodies and antibody fragments. In Chapter 1, background research providing context for the work in this Thesis is presented. In Chapter 2, a CD133-targeting antibody, RW03IgG, underwent radiolabeling with lutetium-177 to synthesize [177Lu]Lu-DOTA-RW03IgG for CD133-TRT. The CD133-TRT was evaluated for pharmacokinetics and treatment of a CD133 expressing human colorectal tumor bearing mouse model. Biodistribution studies on [177Lu]Lu-DOTA-RW03IgG demonstrated notable uptake in the colorectal tumors and off-target organ uptake consistent with previously reported antibody-based TRTs. Confirmation that tumor uptake was mediated by antibody-antigen binding was verified through co-injection with an excess dose of unlabeled RW03IgG. A dose-escalation therapy trial using [177Lu]Lu-DOTA-RW03IgG for treatment of the colorectal cancer mouse model revealed a dose-dependent reduction in tumor growth rate at well-tolerated doses. The decrease in tumor growth rate observed due to [177Lu]Lu-DOTA-RW03IgG treatment, along with an improvement in overall mouse survival, demonstrate the therapeutic efficacy of CD133-TRT. Additionally, histopathological and immunohistochemical (IHC) analyses indicated low off-target organ toxicity and significant anti-tumor effects. These findings suggested the potential for enhanced overall survival benefits through multiple doses. However, results on multiple-dosed CD133-TRT on the tumor growth rate and overall mouse survival were inconclusive. In Chapter 3, an orthotopic patient-derived glioblastoma (GBM) mouse model was developed that replicates anatomical pharmacokinetic challenges and CSC populations observed in patient tumors. Stereotactic engraftment of the patient GBM cells was optimized to reproducibly deliver tumor cells to the thalamus and growth was monitored using bioluminescence imaging. Ex vivo analysis confirmed various key characteristics of patient GBM, including CD133 expression, hypercellularity, and invasiveness. Biodistribution studies on [177Lu]Lu-DOTA-RW03IgG using the PDX GBM mouse model indicate antibody-antigen driven tumor uptake, determined through co-injection an excess dose of unlabeled RW03IgG. Ex vivo autoradiography supported the biodistribution results and showed elevated uptake of [177Lu]Lu-DOTA-RW03IgG in tumor relative to non-tumor bearing brain tissue. Chapters 4 and 5 centered on the development and evaluation of companion diagnostic CD133-targeted immunoPET probes. Chapter 4 specifically explored probes derived from the full antibody, RW03IgG. The probes were synthesized by conjugating RW03IgG with DFO-NCS to produce DFO-RW03IgG at different chelator-to-antibody ratios. The various DFO-RW03IgG conjugates were then radiolabeled with zirconium-89 to obtain [89Zr]-DFO-RW03IgG. Biodistribution studies and PET imaging revealed promising tumor uptake of [89Zr]-DFO-RW03IgG, and it was observed that higher chelator-to-antibody ratios led to increased accumulation in off-target organs. Chapter 5 investigated a probe derived from an scFv-Fc fragment of RW03, [89Zr]-DFO-RW03scFv-Fc. Biodistribution studies and PET images of colorectal tumor-bearing mice administered [89Zr]-DFO-RW03scFv-Fc showed favorable tumor uptake and low off-target organ accumulation. In Chapter 6, a probe for CD133-Photoacoustic Imaging (PAI) was synthesized through conjugation of RW03IgG with IR-783, an organic dye recognized for its favorable photoacoustic properties. Challenges were encountered in isolating the product, (IR-783)-RW03IgG, at high degrees of labeling (DOL) due to product aggregation. In vitro binding assays indicated that (IR-783)-RW03IgG (DOL = 1) maintained a comparable binding affinity to native RW03IgG. In vivo, colorectal tumors in mice administered (IR-783)-RW03IgG (DOL = 1) did not exhibit significant contrast from the background tissue, and the tumor PA signal did not differ significantly compared to tumors in mice administered an IR-783 labeled isotype IgG. The results suggest that a higher concentration of dye is needed within colorectal tumors for effective tumor visualization than what was provided by IR-783-RW03IgG. Chapter 7 investigated the use of Imaging Mass Cytometry (IMC) to simultaneously visualize [177Lu]Lu-DOTA-RW03IgG and multiple tumor biomarkers in tissue specimens collected from colorectal tumor xenograft mice treated with CD133-TRT. IMC showed undetectable concentrations of hafnium-177 (the decay product of lutetium-177) in tumors treated with CD133-TRT. However, lutetium-176 and lutetium-175, sourced from the carrier-added [177Lu]LuCl3 used in the synthesis of [177Lu]Lu-DOTA-RW03IgG, were present at levels sufficient for IMC visualization. The distribution of lutetium-176, representing [177Lu]Lu-DOTA-RW03IgG, within tumors, was imaged concomitantly with CD133, DNA damage markers, and several additional biomarkers that describe elements of the tumor microenvironment. These collective results endorse IMC as a useful tool to assess the distribution of TRT within tumors and uncover changes to the microenvironment in response to treatment. / Thesis / Doctor of Philosophy (PhD) / Targeted radionuclide therapy (TRT) and molecular imaging strategies were developed to aid in the elimination of the rare and particularly resilient Cancer Stem Cell (CSC) population in tumors. A fully human monoclonal antibody and antibody fragments targeting CD133, a molecular biomarker for CSCs, provided the means to deliver radioactive isotopes for therapy and imaging to CD133+ cells in tumors. The therapeutic efficacy of CD133-TRT for treatment of a colorectal cell line-derived xenograft mouse model was promising, and the treatment showed uptake in orthotopic patient derived glioblastoma tumors engrafted in mice. ImmunoPET probes targeting CD133 were optimized and successfully delineated CD133 expressing tumors from background tissue, warranting further evaluation using patient-representative cancer models. A non-invasive CD133-targeting Photoacoustic Imaging (PAI) probe was synthesized through conjugation of the CD133-targeting antibody to an organic dye, IR-783, although further probe optimization is required to provide tumor contrast. Tumor specimens from mice treated with CD133-TRT were assessed by Imaging Mass Cytometry (IMC), which revealed detectable concentrations of carrier isotopes from the therapy in the tumors, implicating the discovery of a powerful new tool for multiplexed single-cell level resolution imaging for cellular-scale analysis of targeted radionuclide therapy. The CSC-therapy and select molecular imaging probes generated in this Thesis warrant further evaluation using patient-representative mouse models of cancer.

Graphen und Siliciumdioxid Nanopartikel sind als Trägersubstanz für Medikamente beim Drug Targeting von Interesse. Diese Arbeit ist eine toxikologische Untersuchung der Nanopartikel Graphen und Siliciumdioxid im Zellmodell. Dabei wurden Graphen Nanopartikel mit einer Dicke von 6 bis 8 nm und einer Breite von 15 µm verwendet. Die verwendeten Siliciumdioxid Nanopartikel waren kugelförmig und porös mit einer Partikel-Größe von 5 bis 20 nm. Die dosisabhängige Toxizität (Konzentrationen 0,01 mg/ml, 0,1 mg/ml und 1 mg/ml, Inkubation über 24 Stunden) gegenüber 5 verschiedenen Zelllinien (cerebEND, Caco-2, Hep G2, HEK-293, H441) wurde geprüft. Dabei kamen Zellviabilitätstests (CellTiter-Glo Assay, EZ4U-Test) zum Einsatz. Zudem wurde mit den Apoptose-Markern Bax und Caspase-3 auf Gen- und Proteinebene (Polymerasekettenreaktion und Western Blot) überprüft, ob eine Apoptose eingeleitet wurde. Zur Untersuchung der Zellviabilität wurde der CellTiter-Glo Assay verwendet. Für Graphen Nanopartikel zeigte sich ab einer Konzentration von 1 mg/ml bei den Zelllinien HEK-293 und H441 ein statistisch signifikanter Abfall der Zellviabilität. CerebEND und Hep G2 Zellen reagierten auf Graphen Nanopartikel ab einer Konzentration von 1 mg/ml ebenfalls mit einem deutlichen Abfall der Zellviabilität, diese Ergebnisse waren jedoch nicht statistisch signifikant. Die Zelllinie Caco-2 zeigte sich von den Graphen Nanopartikeln unbeeindruckt, es kam zu keiner statistisch signifikanten Veränderung der Zellviabilität. Siliciumdioxid Nanopartikel bewirkten ab einer Konzentration von 1 mg/ml einen statistisch signifikanten Abfall der Zellviabilität bei den Zelllinien cerebEND, HEK-293 und H441. HepG2 Zellen zeigten bei 1 mg/ml Siliciumdioxid einen deutlichen aber statistisch nicht signifikanten Abfall der Zellviabilität. Die Zelllinie Caco-2 erwies sich auch bei Siliciumdioxid Nanopartikel als äußerst robust und zeigte keine statistisch signifikanten Veränderungen der Zellviabilität. Messungen der Zellviabilität auf Grundlage von Adsorptionsmessung, wie beim EZ4U-Test, hatten sich als ungeeignet erwiesen, da die Eigenfarbe der Nanopartikel Graphen und Siliciumdioxid mit dieser Messung interferierte. Zudem wurde geprüft, ob die bei einem Teil der Zelllinien eingetretene toxische Wirkung der Nanopartikel ab einer Konzentration von 1 mg/ml durch Nekrose oder durch Apoptose zustande kam. Die Polymerasekettenreaktion zeigte mit einer einzigen Ausnahme keine statistisch signifikante Erhöhung der Genexpression für Bax und Caspase-3 und gab somit auch keine Hinweise auf die Einleitung einer Apoptose. Im Western Blot zeigte sich keine statistisch signifikante Erhöhung der Proteinexpression von Bax und Caspase-3. Zudem konnte im Western Blot auch keine aktivierte Caspase-3 nachgewiesen werden. Somit lagen auf Grundlage von Polymerasekettenreaktion und Western Blot keine Hinweise auf das Eintreten einer Apoptose vor. Die toxische Wirkung der Nanopartikel Graphen und Siliciumdioxid, die bei einem Teil der Zelllinien ab einer Konzentration von 1 mg/ml nachgewiesen werden konnte, beruhte demnach auf Nekrose. / Graphene and silicon dioxide nanoparticles are of interest as drug carriers for controlled drug delivery systems. This thesis is an evaluation of the toxic properties of the nanoparticles Graphene and Silicon dioxide based on tests on cell culture. The Graphene nanoplatelets were 6 to 8 nm thick and 15 µm wide. The Silicon dioxide nanoparticles were spherical and porous with a particle size of 5 to 20 nm. The dose dependent toxicity (concentrations 0,01 mg/ml, 0,1 mg/ml und 1 mg/ml, incubation over 24 hours) was tested on 5 different cell lines (cerebEND, Caco-2, Hep G2, HEK-293, H441). I used cell viability test (CellTiter-Glo Assay, EZ4U-test). In addition, I used PCR (Polymerase chain reaction) and western blot to detect the apoptosis markers Bax and Caspase-3, to see if the nanoparticles cause an apoptosis or a necrosis. For investigating the cell viability, I used the CellTiter-Glo Assay. Graphene nanoplatelets showed from a concentration of 1 mg/ml for the cell lines HEK-293 und H441 a statistically significant decrease of cell viability. CerebEND and Hep G2 cells reacted on Graphene nanoplatelets from a concentration of 1 mg/ml with a clearly decrease in cell viability, but these results were not statistically significant. The cell line Coco-2 showed no decrease in cell viability after the incubation with Graphene nanoplatelets. Silicon dioxide nanoparticles showed from a concentration of 1 mg/ml a statistic significant decrease of cell viability in the cell lines cerebEND, HEK-293 and H441. The Hep G2 cells showed a decrease in cell viability as well, but the results were not statistically significant. The cell line Caco-2 showed no decrease in cell viability after the incubation with Silicon dioxide nanoparticles. Cell viability tests based on the messurement of adsorption like the EZ4U-test, proved not suitable for this setting, because the own color of the nanoparticles interfered with the measurement. In addition, I tested if the nanoparticles caused an apoptosis or a necrosis. The PCR showed with one exception no statistically significant increase in the gene expression of Bax and Caspase-3 and therefore no proof of apoptosis. The western blot showed no statistically significant increase in the protein expression of Bax and Caspase-3. And it detected no activated Caspase-3. There was based on PCR and western blot no sign for the cells to enter in apoptosis. The toxic properties of the nanoparticles Graphene and Silicon dioxide, that was shown in a part of the cell lines from a concentration of 1 mg/ml, was therefore based on necrosis.

Chronic kidney disease (CKD) is a common disease that affects millions across the US and the globe. Patients with CKD experience an increased risk of venous thrombosis. Here we use two longstanding robust murine models of nephropathies in conjunction with a reliable murine model of venous thrombosis to model venous thrombosis risk in CKD. We show that in the adenine diet-induced CKD, increased concentrations of adenine in the diet result in increased histological evidence of nephropathy and increased venous thrombosis risk assessed by Inferior Vena Cava ligation. Next, we demonstrate that in unilateral ureteric obstruction models, the duration of obstruction is proportional to the nephropathies developed by histological assessment. In both models, we relate nephropathy to venous thrombosis risk. When probed for aryl hydrocarbon receptor (AHR) activation, adenine diet-induced CKD mice show increased activation assessed by nuclear translocation of the receptor. This phenotype was confirmed in vitro when treating human telomerase immortalized human umbilical endothelial cells with uremic serum. Nuclear AHR was not observed in control conditions in vivo or in vitro. Pharmacologic AHR inhibition using a novel drug, BAY Compound, and a well-known AHR inhibitor were both able to abrogate uremic activation of AHR in vitro, which was then corroborated with in vivo studies. Tissue factor (TF) and plasminogen activator inhibitor 1 (PAI-1) are prothrombogenic proteins linked to AHR activation. TF and PAI-1 showed upregulation in CKD mice which were blocked when CKD mice were given AHR inhibitor BAY Compound. This work demonstrates a unique model of venous thrombosis in CKD and suggests that AHR inhibition may be able to limit the elevated risk of venous thrombosis associated with uremia. / 2026-03-08T00:00:00Z

This dissertation contains three essays on theoretical analysis of pricing and promotional strategies. Chapter 1 serves as a brief introduction that provides a motivation and an overview of the topics covered in the subsequent chapters. In Chapter 2, we study optimal couponing strategies in a differentiated duopoly with repeat purchase. Both firms can distribute defensive coupons alone, defensive and offensive coupons together, or mass media coupons. They can also determine how many coupons to offer. Allowing consumers to change their tastes for the firms' products over time, we find that the optimal couponing strategy for the firms is to only distribute coupons to all of the customers who buy from them. The effects of intertemporally constant preferences and consumer myopia on the profitability of the optimal couponing are investigated as well. Chapter 3 examines the profitability of behavior-based price discrimination (BBPD) by duopolists producing horizontally differentiated experience goods. We consider a three-stage game in which the firms first make price discrimination decisions followed by two-stage pricing decisions. The main findings are: (i) there are two subgame perfect Nash equilibria where both firms do not collect information about consumers' purchase histories so that neither firm price discriminates and where both firms collect consumer information to practice BBPD; and (ii) BBPD is more profitable than uniform pricing if sufficiently many consumers have a poor experience with the firms' products. The asymmetric case where one firm produces experience goods and the other search goods is also investigated. Chapter 4 provides a possible explanation of the fact that one ticket price is charged for all movies (regardless of their quality) in the motion-picture industry. Considering a model a la Hotelling in which moviegoers form their beliefs about movie quality through pricing schemes to which an exhibitor commits, we characterize the conditions under which committing to uniform pricing is more profitable than committing to variable pricing. The welfare consequences of a uniform pricing commitment and some extensions of the model are discussed as well. / Ph. D.

Affinity proteins constitute an important category of cancer therapeutics. Owing to properties such as high target affinity and selectivity, therapeutic proteins offer more targeted therapy than small molecule drugs. The target molecules are typically proteins that are overexpressed on the surface of tumour cells, such as membrane-bound receptors. However, these surface proteins are usually expressed in normal tissues as well, resulting in on-target off-tumour toxicity. Proteins with a higher tissue selectivity are thus needed. Here, this has been addressed by developing prodrug proteins dependent on cancer-specific proteases for activation. The prodrugs were composed of a target-binding affibody (active domain) connected to a masking affibody (masking domain) by a peptide linker including a protease substrate. The target of the prodrugs developed in this project was the HER2 receptor, which is overexpressed in several cancer types. Three prodrug candidates were developed, produced and characterised based on their ability to be activated by their respective protease. The hypothesis that the prodrugs could be activated and thus bind to HER2 in cancer cells was tested using biosensor assays, as well as preliminary cancer cell assays. One of the three candidates showed strong potential to be used as a targeted therapy for cancer treatment in the future. / Affinitetsproteiner utgör en viktig kategori av cancerläkemedel. Jämfört med småmolekylära läkemedel är affinitetsproteiner mer riktade, då de har högre affinitet och selektivitet än små molekyler. Oftast utgörs det molekylära målet av ett protein som överuttrycks på ytan av cancerceller, så som membranbundna receptorer. Dessvärre uttrycks de flesta cancerspecifika proteiner i mindre mängd även i normal vävnad. Detta leder till oönskade effekter som kan ge upphov till biverkningar. I syfte att utveckla mer vävnadsspecifika läkemedel har här affibody-baserade “prodrugs”, beroende av cancerspecifika proteaser för aktivering, tagits fram. Prodrug-proteinerna i detta projekt är riktade mot HER2-receptorn, som är överuttryckt i flera typer av cancer. Tre kandidater togs fram och utvärderades med avseende på deras förmåga att aktiveras av sina respektive proteaser. För att testa hypotesen att kandidaterna kunde binda till HER2 på cancerceller efter proteasaktivering användes biosensoranalys samt experiment med cancerceller. En av kandidaterna visade stark potential att kunna användas som ett riktat läkemedel mot cancer i framtiden.

Syftet med projektet var att utveckla en multiplexanalys för att detektera antigen från SARS-CoV-2, influensa och respiratoriskt syncytial virus genom att använda en masspektrometrisk metod som involverar antigenspecifika bindare. Bindarna klonades, renades och biotinylerades innan de användes i en analys utvecklad genom en målinriktad metod som involverade antigenerna. En slutsats som drog var att det var möjligt för Avi-märkta bindare att specifikt binda antigen-härledda peptidmål i multiplexanalysen. / The purpose of project was to develop a multiplex assay capable of detecting antigens from SARSCoV-2, influenza and respiratory syncytial virus by utilizing a mass spectrometric approach involving antigen-specific binders. Binders were cloned, purified and biotinylated before being employed in an assay developed by though a targeted method involving the antigens. It was concluded to be possible for Avi-tagged binders to specifically bind antigen-derived peptide targets in the multiplex assay.

The purpose of this literature review was to identify any adaptations that could be made to the rehabilitation process for Traumatic Transfemoral Amputees. Traumatic Transfemoral Amputation is particularly debilitating with the amputees encountering many obstacles throughout the rehabilitation process. These obstacles can prevent the return to pre-morbid functioning. With an ever-increasing number of amputees within the United States, it is imperative the rehabilitation process be addressed. This literature review addresses possible adjustments in the initial stages of rehabilitation examining the post-operative, pre-prosthetic, and prosthetic rehabilitation stage to enhance the physical functioning for the amputee. This comprehensive literature review encompassing 63 academic and medical journals analyzes the research literature regarding each of the three stages of the post-operative procedure. The literature review synthesizes the research findings to see how procedures may be adapted to reduce the risk of further co-morbidities such as loss of bone mineral density and disuse atrophy. Loss of bone mineral density and disuse atrophy are the major contributing factors to the amputees decreased mobility. Reducing this loss can be addressed within the initial post-operative, pre-prosthetic, and prosthetic rehabilitation stages. Further research is required to examine the efficacy of these alterations in relation to this specific population.