Lymph node metastasis is a critical prognostic factor for lung cancer. Effective therapy to control lymphatic metastasis may improve survival. The work described in this thesis focuses on the development of a microparticulate lymphatic targeting system, which can be applied as an adjuvant therapy in the control of lymphatic metastasis in lung cancer. The study shows that intrapleural administered colloidal particulates are predominantly taken up by regional lymphatic tissue in rat models including healthy rats, rats bearing orthotopic lung tumours and rats following pneumonectomy. The effect of particle size on lymphatic particle distribution was examined by intrapleural administration of 111In-aminopolystyrene beads. Approximately 2 µm is a suitable size for intrapleural lymphatic targeting. Biodegradable polylactide-co-glycolide (PLGA) microparticles containing the anticancer agent paclitaxel (PTX) were subsequently formulated in the desired size by spray drying. PLGA-PTX microspheres were incorporated into a biodegradable and biocompatible gelatin sponge matrix to form an implantable lymphatic targeted drug delivery system. The system was characterized in vitro and its lymphatic targeting ability was examined in vivo. Fluorescence labeled microspheres embedded within the sponge were selectively taken up by regional lymphatics as the sponge matrix disintegrated following intrapleural implantation. A pharmacokinetic study showed that the total PTX exposure in lymphatic tissue was dramatically higher than that achieved through intravenous administration. The peak plasma drug concentration, which governs systemic toxicity, was significantly reduced. The low but persistent detection of plasma PTX indicates that PTX was control released from the system after intrapleural implantation. In a therapeutic efficacy study performed in the H460 orthotopic lung cancer model, gelatin sponges containing PLGA-PTX microspheres were placed in the pleural cavity as an adjuvant treatment after surgical resection of the primary lung tumour. Trans-lymphatic chemotherapy resulted in a significantly lower incidence of lymphatic tumour recurrence (20%) compared to no treatment and placebo control animals (100%). PLGA-PTX microspheres were seen in regional lymphatic tissue over 4 weeks after the sponge placement. It is concluded that the trans-lymphatic targeting drug delivery system described in this thesis may improve the control of lymphatic metastasis in lung cancer.

Lymph node metastasis is a critical prognostic factor for lung cancer. Effective therapy to control lymphatic metastasis may improve survival. The work described in this thesis focuses on the development of a microparticulate lymphatic targeting system, which can be applied as an adjuvant therapy in the control of lymphatic metastasis in lung cancer. The study shows that intrapleural administered colloidal particulates are predominantly taken up by regional lymphatic tissue in rat models including healthy rats, rats bearing orthotopic lung tumours and rats following pneumonectomy. The effect of particle size on lymphatic particle distribution was examined by intrapleural administration of 111In-aminopolystyrene beads. Approximately 2 µm is a suitable size for intrapleural lymphatic targeting. Biodegradable polylactide-co-glycolide (PLGA) microparticles containing the anticancer agent paclitaxel (PTX) were subsequently formulated in the desired size by spray drying. PLGA-PTX microspheres were incorporated into a biodegradable and biocompatible gelatin sponge matrix to form an implantable lymphatic targeted drug delivery system. The system was characterized in vitro and its lymphatic targeting ability was examined in vivo. Fluorescence labeled microspheres embedded within the sponge were selectively taken up by regional lymphatics as the sponge matrix disintegrated following intrapleural implantation. A pharmacokinetic study showed that the total PTX exposure in lymphatic tissue was dramatically higher than that achieved through intravenous administration. The peak plasma drug concentration, which governs systemic toxicity, was significantly reduced. The low but persistent detection of plasma PTX indicates that PTX was control released from the system after intrapleural implantation. In a therapeutic efficacy study performed in the H460 orthotopic lung cancer model, gelatin sponges containing PLGA-PTX microspheres were placed in the pleural cavity as an adjuvant treatment after surgical resection of the primary lung tumour. Trans-lymphatic chemotherapy resulted in a significantly lower incidence of lymphatic tumour recurrence (20%) compared to no treatment and placebo control animals (100%). PLGA-PTX microspheres were seen in regional lymphatic tissue over 4 weeks after the sponge placement. It is concluded that the trans-lymphatic targeting drug delivery system described in this thesis may improve the control of lymphatic metastasis in lung cancer.

Histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated a wealth of biological effects, including anti-proliferative, anti-inflammatory, anti-parasitic, and cognition-enhancing activities. The recent FDA approvals of the inhibitors SAHA and FK-228 have validated HDACi clinical use in cutaneous T cell lymphoma, while numerous clinical trials are currently ongoing using HDACi against a variety of disease states. While the future of the HDAC field looks increasingly promising, there are lingering issues hindering broader use. Recent data point to dysregulation of specific HDAC isoforms in many disease states. However, most current HDACi are pan-inhibitors, lacking the specificity to target individual isoforms. Adding to this, there are currently 18 identified HDAC isoforms, and most lack a defined crystal structure, further complicating the task of designing isoform-specific inhibitors. Most importantly, HDACi have demonstrated a lack of efficacy against solid tumors in the clinic, a major obstacle to broader use in cancer therapy. Several of these issues could more fully be addressed through specific targeting of HDACi, and could bring HDACi into wider and more efficacious pharmaceutical use. Targeting the specific tissue or organelle where HDAC dysregulation occurs could confer greater efficacy in vivo. To this end, we have created four classes of compounds: (1) aryltriazolyl HDACi that potently inhibit HDAC activity and prostate cancer cell growth, (2) dual-targeted inhibitors of Topoisomerase II and HDAC and (3) dual-targeted inhibitors of Topoisomerase I and HDAC, both of which have potent inhibition against both target enzymes as well as cancer cell lines, and finally (4) macrocyclic HDACi that potently inhibit the growth of lung cancer cell lines and preferentially target lung tissue in vivo.

The research presented in this dissertation describes the creation and characterization of a novel antibody-vesicle conjugate modified with polyethylene glycol (PEG) that possesses enhanced binding to and uptake by inflammation-activated endothelial cells with improved storage stability and longer shelf-life and potential reduction in immunogenic potential compared to previous designs. Targeted drug delivery provides an effective means of delivering therapeutic concentrations of a drug to the site or organ of action. The drug is delivered using a niosome, a vesicle with an aqueous core and a bilayer membrane composed of non-ionic surfactants and cholesterol. Antibodies that recognize specific cell antigens are attached to the niosome to complete the targeting molecule, an immuno-niosome (IN). When functionalized PEG, a water soluble, biologically inert polymer, is attached to proteins, it can protect the protein, increasing its half-life in vivo. The immuno-niosome synthesis process is modified to include PEG incorporation into the niosome membrane, a process known as PEGylation. Since the vasculature connects the entire body, immuno-niosomes targeted to endothelial cells were used. When endothelial cells are activated during disease, stress and injury, certain receptors are expressed and upregulated. One such receptor, CD44, is upregulated in response to vascular inflammation associated with atherosclerosis. The research hypothesis is that the addition of polyethylene glycol to the drug delivery vesicle (immuno-niosome) using cyanuric chloride linking chemistry will improve colloidal stability and binding performance of the PEGylated immuno-niosomes to endothelial cell surface receptors expressed during an inflammatory response. The research presented in this dissertation provides the following evidence to support this hypothesis: Construction and characterization of a modified drug delivery vesicle using non-ionic surfactants conjugated with PEG and functionalized with antibodies against endothelial cell surface receptors (PEGylated immuno-niosomes) improves the colloidal stability over previously designed vesicles. Binding of PEGylated CD44-IN to activated endothelial cells is improved over previously designed vesicles. Binding of PEGylated CD44-IN to activated endothelial cells under physiological conditions (flow) is demonstrated. Uptake of PEGylated immuno-niosomes by activated or injured endothelial cells is demonstrated using confocal microscopy.

No description available.

The United States is experiencing a socio-demographic shift in population and education. Latinos are the fastest growing segment of the population on the national level and in higher education. The Latino student population growth rate and Latino college completion rate are not reciprocal. While Latino students are the fastest growing demographic group in higher education, they continue to have the lowest persistence and retention rates. Latino students are more at risk for dropping out of college than any other ethnic group. Latinos decreasing persistence rates have caused an academic achievement gap in higher education (Long, 2011). Literature has correlated the gap with Latinos limited IL competency and low library usage (Long, 2011).This quasi-experimental research examined the effects of a targeted information literacy (IL) instructional method on Latino community college students IL skills and library usage. The study also introduced the idea of using a connectivism based targeted instruction to influence Latinos IL skills and library usage. The intent of the study was to investigate the development of information literacy instruction (ILI) which targets Latino students and uses the principles of connectivism. Connectivism posits that students' learn by connecting to information along their personal learning networks (Siemens, 2005). Connectivism helps position the library within Latino students' personal learning networks. This positioning may increase their library usage and by extension their IL skills. Specifically, this quantitative study assessed the effect of the instruction on IL skills and library usage behavior of Latino community college students. A pretest/posttest control group design was used for this study. A sample of 92 Latino male and female students completed the pretest and posttest. They were recruited from a diverse population of community college students who were registered for Introductory English classes. Data was collected through instrumentation that included an Information Literacy Rubric, an Information Literacy Skills Test, a Library Usage Survey/Demographic Identification Form, and a Citation Analysis Form. Though two of the hypotheses were not supported, the data collected allowed the researcher to accomplish two of the purposes of this study, to design and assess a targeted ILI that increases Latino students' IL skills and library usage, and to advance the research that grounds the emerging learning theory of connectivism. The more connections students made to information sources the higher their overall IL skill score were. This data suggests that as students make connections to information resources they are learning IL skills and the more sources they connect to, the more they learn. Though TI did not emerge as the more effective method, it is effective at increasing library usage and IL skills in Latino community college students'. The results of this study may lead to a better understanding of how students acquire IL skills. Instruction has become increasingly important in librarianship and recently has even eclipsed traditional reference service. (Grassian & Kaplowitz, xix, 2009). More and more academic libraries are being held accountable for their contribution to student learning. The findings of this study provide evidence that the instructional efforts of the library are influencing student learning outcomes.

In the last decade the fight against terrorism was carried out not only by measures indicated in national criminal procedure laws or international treaties outlining measures in the fight against terrorism, but also using military forces and carrying out military measures. Thus the dissertation aims to establish when and to what extent is the international humanitarian law (hereinafter – IHL) applied in the fight against terrorism, that is, to analyze in what cases the fight against terrorism amounts to armed conflict, what is the status of terrorists taking part in the armed conflict according to IHL, and to evaluate in the light of IHL principles and rules the specific measures taken against terrorists. Firstly the dissertation analyses the question of the definition of terrorism and proposes a possible definition of this phenomenon. Further on the dissertation analyzes the instances when the IHL rules are applied in the fight against terrorism, that is, when such situation amounts to an armed conflict, and evaluates the main criteria of armed conflict – intensity and organization – and their application in the fight against terrorism. The dissertation also explores the questions of the status of terrorists taking part in an armed conflict, distinguishing those taking part in international and non-international armed conflicts, and exploring the criteria for the direct participation in hostilities for such persons. Finally, the dissertation analyzes the specific measure of... [to full text] / Pastaraisiais dešimtmečiais kovą su terorizmu pradėta vykdyti ne tik pasitelkiant nacionaliniuose baudžiamojo proceso įstatymuose ar tarptautinėse sutartyse, skirtose kovai su terorizmu, numatytas priemones, tačiau ir naudojant karines pajėgas bei atliekant karinius veiksmus. Taigi disertacijoje iškeliamas tikslas nustatyti, kada ir kokiu mastu taikoma tarptautinė humanitarinė teisė (toliau – THT) kovoje su terorizmu, tai yra, ištirti, kokiais atvejais kova su terorizmu laikytina ginkluotu konfliktu, koks yra teroristų, dalyvaujančių ginkluotame konflikte, statusas pagal THT ir atsižvelgiant į THT normas įvertinti specifines kovos priemones, naudojamas kovojant su teroristais. Pirmiausiai disertacijoje analizuojamas terorizmo apibrėžimo klausimas ir pateikiamas galimas terorizmo apibrėžimas. Toliau disertacijoje vertinama, kuriais atvejais kovojant su terorizmu bus taikomos THT normos, tai yra, kada kova su terorizmu prilygsta ginkluotam konfliktui, tiriami ginkluoto konflikto intensyvumo ir organizuotumo kriterijai ir jų taikymas kovos su terorizmu situacijose. Disertacijoje taip pat tiriama, koks yra teroristų, dalyvaujančių ginkluotame konflikte, statusas pagal THT, išskiriant tarptautiniuose ir netarptautiniuose ginkluotuose konfliktuose dalyvaujančius asmenis, taip pat išsamiai išanalizuojant asmenų tiesioginio dalyvavimo ginkluotame konflikte kriterijus. Galiausiai disertacijoje tiriama specifinė kovos su terorizmu priemonė – tikslinių nužudymų, ypač naudojant... [toliau žr. visą tekstą]

Here we developed multiple genetic systems through which genetic modifications driven by DNA breaks caused by the I-SceI nuclease can be assayed in the yeast Saccharomyces cerevisiae and in human cells. Using the delitto perfetto approach for site-directed mutagenesis in yeast, we generated isogenic strains in which we could directly compare the recombination potential of different I-SceI variants. By genetic engineering procedures, we generated constructs in human cells for testing the recombination activity of the same I-SceI variants. Both in yeast and human cells we performed gene correction experiments using oligonucleotides (oligos) following modification and/or optimization of existing gene targeting protocols and development of new ones. We demonstrated that an I-SceI nicking enzyme can stimulate recombination on the chromosome in S. cerevisiae at multiple genomic loci. We also demonstrated in yeast that an I-SceI-driven nick can activate recombination 10 kb distant from the initial site of the chromosomal lesion. Moreover we demonstrated that an I-SceI nick can stimulate recombination at the site of the nick at episomal and chromosomal loci in human cells. We showed that an I-SceI double-strand break (DSB) could trigger recombination up to 2 kb distant from the break at an episomal target locus in human cells, though the same was not observed for the nick. Overall, we demonstrated the capacity for I-SceI nick-induced recombination in yeast and human cells. Importantly, our findings reveal that the nick stimulates gene correction by oligos differently from a DSB lesion, as determined by genetic and molecular analyses in yeast and human cells. This research illustrates the promise of targeted gene correction following generation of a nick.

When planning to implement a marketing tool such as Integrated Marketing Communication (IMC) into ones company, marketers need to know what IMC means or is perceived to be in their environment. The definition of IMC is shown in the background chapter of this study and more definitions are stated in the theoretical frame chapter as well. Months of research lead to the conduction of a study, that is to test the perception of IMC in the Swedish market by sampling and sending questionnaires to Swedish marketers. Five Hypotheses were formed to test if each factor has a positive or negative relation with IMC. A questionnaire was formulated that tested all of the five main success factors (customer focus, targeted communication, customer-brand relationship, synergy and communication channels) in relation to IMC and how the Swedish marketers perceived each one of the factor’s connection to IMC. The marketers were chosen due to the fact that they would know most about IMC since it’s within the field of marketing.  It was found that Swedish marketers support 2 out of the 5 hypotheses. This means that the results showed that Swedish marketers perceive that there is a positive relationship between both channels of communication and IMC, and customer brand relationship and IMC, while targeted communication, customer focus and synergy were denied to be as positively related to IMC. This study would be of great help to a Swedish company trying to implement IMC because it gives directions to the Swedish perception of it, thereby making it more clear to know exactly what they are implementing, which help them find out in what way they should implement IMC, in order to avoid failures that could be very expensive.

Recent advancements in pharmaceutical technology based on principles of nanotechnology, polymer chemistry, and biomedical engineering have resulted in the creation of novel drug delivery systems with the potential to revolutionize current strategies in cancer chemotherapy. In oncology, realization of significant improvements in therapeutic efficacy requires minimization of drug exposure to healthy tissues and concentration of the drug within the tumor. As such, encapsulation of chemotherapeutic agents inside nanoparticles capable of enhancing tumor-targeted drug delivery is a particularly promising innovation. Yet, initial investigations into the intratumoral fate of nanomedicines have suggested that they may be heterogeneously distributed and achieve limited access to cancer cells located distant from the tumor vasculature. As such, uncovering the determinants of nanoparticle transport at the intratumoral level is critical to the development of optimized delivery vehicles capable of fully exploiting the therapeutic potential of nanomedicines. In this work, the chemotherapeutic agent, docetaxel (DTX), was incorporated into nano-sized, biocompatible PEG-b-PCL block copolymer micelles (BCMs). Encapsulation of DTX in micelles via chemical conjugation or physical entrapment resulted in a dramatic increase in drug solubility and customizable drug release rate. The use of multicellular tumor spheroids (MCTS) was established as a viable platform for assessing the efficacy and tumor tissue penetration of nanomedicines in vitro. A series of complementary assays was validated for analysis of DTX-loaded micelle (BCM+DTX) toxicity in monolayer and spheroid cultures relative to Taxotere®. Cells cultured as spheroids were less responsive to treatment relative to monolayer cultures due to mechanisms of drug resistance associated with structural and microenvironmental properties of the 3-D tissue. Computational, image-based methodologies were used to assess the spatial and temporal penetration of BCMs in spheroids and corresponding human tumor xenografts. Using this approach, the tumor penetration of micelles was found to be nanoparticle-size-, tumor tissue type- and time- dependent. Furthermore, spheroids were found to be a valuable platform for the prediction of trends in nanoparticle transport in vivo. Overall, the results reported herein serve to demonstrate important determinants of nanoparticle intratumoral transport and to establish computational in vitro and in vivo methodologies for the rational design and optimization of nanomedicines.