Thesis advisor: Charles Gallagher / Thesis advisor: Peter Krause / Drone strikes are sensational events. The United States Government uses remotely piloted aircraft (or drones) equipped with precisions weapons systems to unilaterally hunt and kill its enemies across the globe. The American public, and many around the world, are startled by the pervasiveness of American lethal force. In many ways, drone strikes are unprecedented. The technology, the frequency of use, and the geographic scope are all by-products of the twenty-first century. However, the United States government has a deep history of debating whether to kill individual enemies, and has a history of authorizing operations to do so. Beneath the rhetoric, the arguments, and the opinions that dominate drone policy today there is something missing: the history. This thesis argues that there are historical precedents for targeted killings and signature strikes in American history that predate the September 11 terrorist attacks and examining these past operations can inform modern policy. / Thesis (BA) — Boston College, 2014. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: College Honors Program. / Discipline: History.

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Doctor of Philosophy / Department of Chemistry / Santosh Aryal / Nanotechnology offers exciting options for the site-selective delivery of chemotherapeutics and diagnostic agents using nanoparticles. Varieties of organic and inorganic nanomaterials have been explored extensively as a delivery system either in the form of drug carriers or imaging agents. Successful stories include the clinical translation of anticancer nanomedicines such as PEGylated liposomal doxorubicin (DOXIL®), albumin-bound paclitaxel (Abraxane®), and polymeric micelle loaded paclitaxel (Genexol®), which are currently used in the clinic as one of the first lines for cancer chemotherapies. These conventional nanomedicines rely on passive-drug targeting taking advantage of leaky tumor vasculature, called the Enhanced Permeability and Retention (EPR) effect. However, delivering biologically active components selectively to the diseased cell, for example, cancer, is highly challenging due to the biological barriers in the body including blood pool cells/proteins, heterogeneous microenvironment, and intracellular degradation. Therefore, the goal of this dissertation is to develop nanoplatforms that can deliver the agents of interest in targeted fashion to cancer while bypassing or collaborating with the biological barriers. The design consideration of these nanoplatforms centralizes on using simple chemical reactions and cell biology to engineer nanoparticles. The presented nanoparticles were extensively studied and evaluated for their biological functions using in vitro and in vivo models. These nanoconstructs described herein address current limitations of conventional nanomedicine such as (1) the lack of understanding of the interaction of nanoparticle and biological system, and (2) the lack of an effective targeting strategy to deliver drugs to the cancer cell in the tumors. The significant findings of each system will be highlighted and discussed throughout this dissertation. Results obtained highlight key findings such as NP intracellular fate, maximized tumor accumulation, and unique pharmacokinetics could open the avenues for systemic investigations for personalized medicine and lay the foundation for nanomedicine design to accelerate clinical translation.

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Targeted school violence (TSV) in the United States is increasing, causing a loss of innocent lives and challenges for teachers and students in building rapport. In addition, TSV increases levels of anxiety and makes it difficult for parents and community members to believe students are safe while at school. Several studies have highlighted the fact that age may be a factor in school shootings, calling for future research to determine if age is indeed influential. The problem is to date age has not been established as a predictive factor, even though the extant research is beginning to identify possible variances. Guided by general strain theory and ceremonial violence, this study determined statistical significance between age and select variables in the personal, event, and ecological categories. This information could be illuminating to educators, mental health professionals, and law enforcement for threat assessment purposes. The information was gathered on all TSV members within the United States from 1966 to 2015 through archival data, and the data were analyzed using logistic regression, Pearson's correlation, and Spearman's correlation. Results indicated that, as age increases, the offenders are more likely to have a higher social status, have a mental health and criminal history, carry out their act in the afternoon, and choose a knife as a weapon. In addition, older offenders are less likely to be students and less likely to have been bullied. Implications for social change include modifications to current threat assessment protocol regarding weapon choice and previous mental health or criminal history, which could be utilized to change public policy for mandatory reporting of students identified as at risk. Also, younger offenders are being bullied more often than older offenders and this could add more awareness to antibullying program procedure and earlier mental health intervention.

Der menschliche Organismus ist zeitlebens von malignen Neoplasien bedroht, die durch lokales oder metastasiertes Wachstum lebensnotwendige Funktionen des Körpers beeinträchtigen können. Als wichtigstes Werkzeug zur Abwehr dieser Neoplasien wurde in den letzten Jahrzehnten die natürliche Immunität aufgedeckt. Besonders die Antikörper der innaten Immunität spielen eine entscheidende Rolle. BARB-4 ist ein humaner, tumorspezifischer Antikörper und Teil dieser natürlichen Immunität. Er wurde mit Hilfe der Hybridomatechnologie aus einem Patienten mit Siegelringkarzinom des Magens isoliert, und ist einer der wenigen Vertreter innater humaner IgG Antikörper. Diese Arbeit gibt einen ersten Überblick über die Bindungsspezifität und die funktionellen Eigenschaften des BARB-4-Antikörpers. In den immunhistochemischen Färbungen konnte die Tumorspezifität des Antikörpers nachgewiesen werden. Bei dem zugehörigen Antigen handelt es sich um eine Variante des TAF15, einem Protein der FET-Familie, die intrazelluläre Aufgaben bei Transkriptionsvorgängen haben, bei denen zudem aber auch eine Beteiligung an Adhäsions- und Migrationsvorgängen vermutet wird. Diese Variante ist bei malignen Zellen an der Oberfläche lokalisiert, was die Ergebnisse der Durchflußzytometrie belegen. Durch konfokale Mikroskopie mit Fluoreszenz-markiertem BARB-4 konnte diese Oberflächenbindung an Tumorzellen bestätigt werden. Im weiteren zeitlichen Verlauf konzentrierte sich der Antikörper im Zellinneren. Die Präsenz des Antikörpers führte bei Versuchen mit Tumorzellen zu einer bemerkenswerten Hemmung der Adhäsions- und Migrationsfähigkeit der Zellen. Beide stellen Schlüsseleigenschaften für die Metastasierung von Tumorzellen dar. Diese Eigenschaften könnten BARB-4 für einen möglichen, therapeutischen Einsatz zur Prävention von Tumormetastasen qualifizieren. / Throughout live, the human body is threatened by malign neoplasms whose local or metastasizing growth can restrict its essential functions. In the last decades, natural immunity was discovered as an instrumental tool in the fight against these neoplasms. Especially antibodies of the innate immune response play a central role in this defense. BARB-4 is part of this repertoire of antibodies. B-cells producing BARB-4 were isolated from a patient suffering from signet ring carcinoma, and propagated using Hybridoma-technology. While most antibodies of the innate immune response are of the IgM subclass, BARB-4 is an IgG antibody. This work offers an assessment of the specificity and functional properties of BARB-4. By using immuno-histochemistry, it couId be shown that BARB-4 specifically binds to human cancer cells. More specifically BARB-4 binds to a variant of TAF15, a member of the FET family of transcriptional regulators. TAF15 is also assumed to be involved in adhesion and cell-migration. Flow-cytometry confirmed its localization to the plasma-membrane, which is unique to this tumor-specific variant of TAF15. Subsequent confocal microscopy showed that after initial binding of TAF15, the BARB-4 antibody is internalized by the bound cancer cells. Remarkably, BARB-4 treatment of cancer cells resulted in the inhibition of their ability to adhere and migrate. As both adhesion and migration are hallmarks of metastasis in cancer cells, BARB-4 is a possible candidate for therapeutic prevention of cancer metastasis.

<p>Targeted radionuclide therapy (TRT) holds great promise for the treatment of cancer. In TRT, radioactive nuclides are delivered specifically to tumours by molecules that recognise and bind to structures overexpressed by, or specific to, cancer cells. Human epidermal growth factor receptor like protein 2 (HER-2) is an oncogene product overexpressed in e.g. urological, breast, or ovarian cancers that have been correlated to poor prognosis and resistance to hormonal therapy. There is also evidence that tumour cells retain their HER-2 overexpression in metastases.</p><p>Trastuzumab and pertuzumab are two humanised monoclonal antibodies targeting different parts of HER-2. This thesis describes the radiolabelling of these antibodies for use in TRT and diagnostics. The thesis also investigates possible methods for modifying uptake and retention of radioactivity delivered with antibodies binding to HER-2. Modification of the cellular retention of ¹²⁵I by using polyhedral boron anion based linker molecules (DABI and NBI) is investigated, and it is shown that linking ¹²⁵I to trastuzumab using DABI increases cellular accumulation of radioactivity by 33%. It is also shown that trastuzumab can be efficiently coupled to the positron emitter ⁷⁶Br by using NBI. Furthermore, it is shown that cellular uptake of ¹²⁵I can be modified by stimulating EGFR (HER-1) with EGF.</p><p>When labelled with the alpha emitter ²¹¹At, trastuzumab could specifically kill cells in vitro. This cell killing effect could be prevented by saturating the receptors of the target cells with non-radiolabelled trastuzumab.</p><p>Pertuzumab was radiolabelled with the low energy beta emitter ¹⁷⁷Lu without losing affinity or immunocompetence. [¹⁷⁷Lu]pertuzumab was specific to HER-2 in vitro and in vivo. This targeting conjugate was shown to increase median time to tumour progression in mice bearing xenografts of the radioresistant SKOV-3 cell line. </p><p>In conclusion, antibodies against HER-2, especially pertuzumab radiolabelled with ¹⁷⁷Lu, show promise as TRT agents.</p>

An in vivo study with 19 rabbits was completed. Half of the exposed rabbits had a magnetic field placed externally over their right lung. Magnetic resonance images of the lungs were acquired to determine the iron concentrations in the right and left lung of each animal. The right/left ratio increased in the middle and basal regions of the lung. With further optimization, this technique could be an effective method for targeted drug delivery. Additionally, the feasibility of increasing the length of high aspect ratio particles for improved targeted drug delivery was explored. An ultrasonic nozzle was pulsed into a large evaporation chamber. Individual particles were found to be double the original length. However, due to locally increased humidity the droplets were not dried, except with the use of an orifice to rapidly accelerate and break apart the larger droplets. The complications associated with this method make it an undesirable and unfeasible method of creating longer particles.

Many mitochondrial and chloroplast proteins are encoded in the nucleus and subsequently imported into the organelles via active protein transport systems. While usually highly specific, some proteins are dual-targeted to both organelles. In tobacco (<i>Nicotiana tabacum L.</i>), the cDNA encoding the mitochondrial isoform of NADP+-dependent isocitrate dehydrogenase (NADP+-ICDH) contains two translational ATG start sites, indicating the possibility of two tandem targeting signals. In this work the putative mitochondrial and chloroplastic targeting signals from NADP+-ICDH were fused to a yellow fluorescent protein (YFP) to generate a series of constructs and introduced into tobacco leaves by <i>Agrobacterium</i>-mediated transient transfection. The subsequent sub-cellular locations of the ICDH:YFP fusion proteins were then examined under the confocal microscope. Constructs predicted to be targeted to the chlroplast all localized to the chloroplast. However, this was not the case for constructs that were predicted to be mitochondrial targeted. While some constructs localized to mitochondria, others appeared to be chloroplast localized. This was attributed to an additional 50 amino acid residues of the mature NADP+-ICDH protein which was present in those constructs. In addition, during the process of generating these constructs our sequence analysis indicated a stop codon present at amino acid position 161 of the mature NADP+-ICDH protein from both Xanthi and Petit Havana cultivars of tobacco. This was confirmed by multiple sequencing reactions and created discrepancies with the reported sequence present in the database. The results of this study raise interesting questions with regard to the targeting and processing of NADP+-ICDH.

This research work involves multifunctional magnetically targeted drug delivery microspheres for treatment against breast cancer. A combination therapy approach was followed by encapsulating two chemotherapeutics, 5-Fluorouracil (5-Fu) and cyclophosphamide in poly(D, L-lactide-co-glycolide) (PLGA) microspheres. Magnetite nanoparticles and albumin were also incorporated in the microspheres to achieve targeted treatment. The microspheres were fabricated using oil-in-oil emulsion/solvent evaporation technique. Albumin is attracted to cancer cells and thus it is likely to draw the microspheres towards tumor cells. On application of magnetic field near tumor site, magnetites in the microspheres are likely to guide them to the region of magnetic field. This will allow release of drugs from microspheres in the cancer cells. Also the burst release of drugs and then slow release due to diffusion in the cancer cells lead to effective treatment and also limit excessive spreading of drugs in other regions of the body. Release rate study was carried out using high performance liquid chromatography (HPLC). Invitro and in-vivo study was carried out to check the efficacy of treatment. / Thesis (M.S.)--Wichita State University, College of Engineering, Dept. of Mechanical Engineering.