Lanthanide phosphate (LnPO4) and lanthanide vanadate (LnVO4) nanoparticles (NPs) are promising platforms for theranostic applications because of their chemical stability, low solubility, low toxicity, and unique luminescence and magnetic properties. Motivated by the high radiation resistance and ability to host actinides of naturally occurring lanthanide-based compounds, LnPO4 and LnVO4 NPs were studied as radionuclide carriers for targeted radionuclide therapy using in vivoα-generators, 223Ra, 225Ac, and 227Th. The implementation of these radionuclides has shown potential for the treatment of micrometastases and solid tumors as well as challenges in the retention of decay daughters at the target site to minimize unwanted radiotoxicity. LnPO4 and LnVO4 core-shell NPs doped with either 156Eu, a “cocktail” of 85, 89Sr and 156Eu, or in vivo α-generators 223Ra, 225Ac, and 227Th were synthesized in aqueous media. In vitro retention of radionuclides was investigated by dialyzing the radionuclide-doped NPs suspensions against deionized water and quantifying the activity in dialysate aliquots over time. The crystal structure, morphology, physical stability, luminescence and magnetic properties were evaluated. Partial retention of 156Eu (~70–95%) and 85, 89Sr (>80%) was evidenced in LnPO4 core NPs, while 227Th and decay daughters were quantitatively retained in LaPO4 core + 2 shells NPs (>99%). Gd0.8Eu0.2VO4 and GdVO4 core-shell NPs showed partial retention of 223Ra (~75%), 225Ac (75–95%), 227Th (>96%), and decay daughters. Radionuclide retention was influenced by the lanthanide concentration, crystal structure, and number of shells. The partial retention of radionuclides in both LnPO4 and LnVO4 core-shell NPs may enhance the treatment efficacy while minimizing unwanted toxicity. LnVO4 core and core-shell NPs have potential as carriers of short-lived radionuclides for both diagnostic and therapeutic applications. Emission intensities were higher for LnVO4 with respect to LnPO4 NPs, whereas no significant difference was observed in the magnetic susceptibilities. GdVO4 core NPs displayed enhancement of the signal intensity in T1-weighted images. This work evidences the promising application of both LnPO4 and LnVO4 NPs as platforms for targeted radionuclide therapy and multimodal molecular imaging.

The United States increasingly has resorted to the use of Unmanned Aerial Vehicles (UAVs) for targeted killings of terrorists as a counterterrorism strategy. More states and terrorist organizations also are acquiring UAVs and this development can lead to indiscriminate and unregulated use of UAVs. Previous researchers have indicated the surveillance ability and precise weapon delivery capacity of UAVs make them a weapon of choice for U.S. counterterrorism efforts. Although the U.S. government estimated the collateral damage involved in the use of UAVs at 3-5%, nongovernmental sources put it at 25-40%. A gap exists in the current literature regarding public perception of the use of UAVs as a counterterrorism measure and how international humanitarian law (IHL) may interpret employment of UAVs. The purpose of this quantitative, cross-sectional study is to determine if a relationship exists among public support of the use of UAVs for targeted killing, attitudes towards counterterrorism, and public perceptions of IHL. An online survey was used to collect data from 104 adult participants using the convenience sampling method. Logistic regression, ANOVA, and correlational analyses helped to determine the relationships. The outcomes contributed to the existing literature by providing important data related to public perception of the use of UAVs with the potential to enhance global peace and security. The results contributed to social change initiatives through the potential to facilitate the establishment of international and domestic legal frameworks to regulate the future employment of UAVs for targeted killing.

La prise en charge contemporaine du cancer repose de plus en plus sur le concept de médecine dite personnalisée qui permet, après identification des caractéristiques propres de la tumeur, d'envisager une thérapeutique adaptée à chaque patient. La meilleure connaissance de la biologie des cancers et la mise en évidence de nouvelles cibles thérapeutiques ont ainsi abouti au développement des thérapies ciblées qui vont agir sur une cible cellulaire, généralement surexprimée au niveau d'une tumeur, leur conférant une plus grande spécificité d'action tumorale et un profil d'effets indésirables moins marqué par rapport à la thérapie cytotoxique conventionnelle. Malgré les données d'efficacité clinique, rapportées sur les stratégies thérapeutiques intégrant des thérapies ciblées, on ne dispose pas, malheureusement, des études pharmaco-économiques en cancérologie surtout que ces médicaments se caractérisent par leurs coûts très élevés (exemple: bevacizumab 1000 euros/400 mg ; cetuximab 964 euros/500 mg) et doivent donc être également appréhendés dans le cadre d'études dites en condition de vie réelle. L'objectif de ce projet de recherche est donc de proposer une étude pharmaco- économique sur l'utilisation des thérapies ciblées en cancérologie. Compte tenu du large champ d'investigation, deux affections tumorales distinctes seront considérées : le cancer colorectal métastatique et le glioblastome.Le cancer colorectal fera l'objet d'une étude conduite spécifiquement au Liban et le glioblastome d'une étude en France. L'originalité de cette thèse, conduite dans le cadre d'une coopération franco-libanaise, sera également d'évaluer les impacts médico-économiques de ces nouvelles stratégies selon des perspectives d'organismes payeurs très différentes, ce qui permettra d'appréhender les éventuelles problématiques d'accès aux soins / Although cancer incidence and prevalence are increasing at an alarming rate, progress in the treatment has been slow and treatment benefits are measured in weeks to months. Following the progress in the diagnostic tools and early detection biomarkers, a number of cancer types can be detected before pathological symptoms develops and this is of great significance because individual specific treatment regimens can be designed based on the presence and stage of cancer. In the past decade, there have been considerable improvements in the way that tumors are characterized and knowledge of cancer, at the molecular level has therefore increased greatly and has shift towards the use of targeted cancer therapies that display greater sensitivity and specificity for tumor cells by blocking the activity of the molecule in the host microenvironment that supports tumor growth or inhibiting the activity of protein tyrosine kinases or signaling pathways. Unfortunately, many pharmaco-economic studies are lacking today in the oncologic field. In addition, targeted therapies are very expensive (bevacizumab costs 100 euros/400mg and cetuximab 964 euros/500 mg) and should, therefore, be analyzed in real life conditions. That’s why the main objective of this research-project is to find a pharmaco-economic method on the use of the targeted therapies in oncology. Given the wide scope of investigations, 2 different tumor pathologies will be discussed: metastatic colorectal cancer and glioblastoma. The choice between these 2 cancer types takes place in the growing role of the targeted therapies in the effectiveness and survival of patients as well as their relative costs, especially that they have in common “bevacizumab” targeting the tumor vasculature

Background and purpose. This thesis documents a program of five studies concerned with the assessment of software measurement. The goal of this program is to assist the software industry to improve the information support for managers, analysts and software engineers by providing evidence of where opportunities for improving measurement and analysis exist. Methods. The first study examined the assessment of software measurement frameworks using models of best practice based on performance/success factors. The software measurement frameworks of thirteen organisations were surveyed. The association between a factor and the outcome experienced with the organisations' frameworks was then evaluated. The subsequent studies were more info-centric and investigated using models of information quality to assess the support provided for software processes. For these studies, information quality models targeting specific software processes were developed using practitioner focus groups. The models were instantiated in survey instruments and the responses were analysed to identify opportunities to improve the information support provided. The final study compared the use of two different information quality models for the assessing and improving information support. Assessments of the same quantum of information were made using a targeted model and a generic model. The assessments were then evaluated by an expert panel in order to identify which information quality model was more effective for improvement purposes. Results. The study of performance factors for software measurement frameworks confirmed the association of some factors with success and quantified that association. In particular, it demonstrated the importance of evaluating contextual factors. The conclusion is that factor-based models may be appropriately used for risk analysis and for identifying constraints on measurement performance. Note, however, that a follow-up study showed that some initially successful frameworks subsequently failed. This implied an instability in the dependent variable, success, that could reduce the value of factor-based models for predicting success. The studies of targeted information quality models demonstrated the effectiveness of targeted assessments for identifying improvement opportunities and suggest that they are likely to be more effective for improvement purposes than using generic information quality models. The studies also showed the effectiveness of importance-performance analysis for prioritizing improvement opportunities.

Expressive writing has been linked to positive psychological and health outcomes in general and medical populations, but research examining this intervention in HIV is limited. Higher levels of emotional expression (EE) and depth processing (DP) during writing have been linked to better health status in HIV. Expressive writing has been shown to improve health-related quality of life (HRQoL) in other populations, but has not been examined in HIV. HRQoL is often compromised in HIV+ individuals and therefore improvements in this area are an appropriate goal of psychosocial interventions. This longitudinal study used HLM analyses to examine the relationship between levels of EE and DP during trauma writing and the rate of change in HRQoL over six months in an ethnically diverse sample of 106 HIV+ men and women. Three subscales of the HIV/AIDS-targeted Quality of Life measure were examined: Overall Healthy Functioing (HRQoL-Overall), Without Health Worries (HRQoL-Health), and Life Satisfaction (HRQoL-Life). All longitudinal analyses controlled for demographic (age, gender, race/ethnicity, education), medical (CD4 and VL) and psychological (stressful life events) factors. No significant effects were found for EE/DP to predict changes in HRQoL over time for the full sample. When men and women were examined separately, there was a non-significant tendency for men to decrease in HRQoL over time and for women to increase over time, and a number of EE/DP variables were significant predictors of rate of change in HRQoL. As hypothesized, for women (n = 44) higher level of Experiential Involvement DP predicted greater increase in HRQoL-Overall and HRQoL-Life, and higher negative EE also predicted greater increase in HRQoL-Life over time. Opposite of the direction hypothesized, higher Self Esteem DP predicted a lower level of increase in HRQoL-Life for women. For men (n = 62), findings appeared to be in the opposite direction of women, with greater Self Esteem DP working as a buffer to decreases in HRQoL-Life and HRQoL-Health over time. Furthermore, higher Experiential Involvement and negative EE appeared detrimental for men as both predicted greater decreases in HRQoL-Life over time and Experiential Involvement also predicted greater decreases in HRQoL-Health. Results should be interpreted with caution, as the overall slopes did not show significant change in HRQoL over time. The reasons for observed gender differences are not known. This is the first study to examine the impact of EE and DP in expressive trauma writing on HRQoL in HIV+ individuals. Implications and limitations are discussed.

Quantitative real-time PCR (QPCR) technology has been very useful for diagnosis of viral diseases. QPCR has recently reached a level of sensitivity, simplicity, and reproducibility which allows a large number of samples to be screened rapidly, make it a suitable tool for the clinical virology diagnostics. In this thesis, broadly targeted and degenerated quantitative QPCR assays were used. A somewhat novel single-tube real-time reverse transcription-polymerase chain reaction (QRT-PCR), with takes advantage of ability of rTth DNA polymerase to reverse transcribe RNA in the presence of Mn2+ at elevated temperatures and includes protection against amplimer contamination by using thermolabile UNG, was developed. A new technique for diagnostic of recent viral infection by detection of viral immunoglobulin M (IgM) was also developed. In the first paper, a sensitive single-tube QRT-PCR for detection of enteroviral RNA in patients with aseptic meningitis was presented. In the second paper, a single-serum-dilution real-time PCR-based PIA (PCR-enhanced immunoassay), called quantitative PIA (QPIA), to detect enterovirus IgM for diagnosis of EV infection in patients with aseptic meningitis, was also developed. In the third paper, a broadly targeted, simple, single tube degenerated quantitative QPCR technique for detection of JCV, BKV and SV40 DNA was developed. A conserved region of the VP2 gene of JCV, BKV and SV40 was targeted. A false positive result due to contamination with commonly used SV40 T-antigen plasmids was therefore avoided. In manuscript four, the QPIA assay provide a rational strategy for detection of EV IgM, allows the use of viral antigens isolate from newly diagnosed Type 1 diabetes patients (T1D-EV-QPIA) to measured IgM against diabetogenic viruses in serum from newly diagnosed T1D children, siblings, and healthy children. To conclude, novel broadly targeted real-time PCR methods for diagnosis of entero- and polyoma viral infections were developed.

Severe Traumatic Brain Injury (sTBI) is a major cause of mortality and morbidity. At the Department of Neurosurgery Umeå University Hospital subjects with sTBI are treated with an intracranial pressure (ICP) guided therapy based on physiological principles, aiming to optimise the microcirculation of the brain so avoiding secondary brain injuries. The investigations in this thesis are unique in the sense that all patients with sTBI were treated according to the guidelines of an ICP targeted therapy based on the “Lund concept”. As the treatment is based on normalisation of the ICP, the accuracy and reliability of the measuring device is of outmost importance. Therefore the accuracy, drift, and complications related to the measuring device was prospectively studied (n=128). The drift was 0,9 ± 0,2 mmHg during a mean of 7,2 ± 0,4 days and the accuracy high. No clinical significant complications were noted. In 1997 uni- or bilateral decompressive hemi-craniectomy (DC) was introduced into the treatment guidelines. The effect of DC on the ICP and outcome was retrospectively analysed for subjects with sTBI treated 1998-2001. In the subjects who underwent DC the ICP was 36,4 mmHg immediately before and 12,6 mmHg immediately after the DC. The ICP then levelled out at just above 20 mmHg. The ICP was significant lower during the 72 hours following DC. The outcome did not differ between subjects who had undergone DC or not. Subclinical electroencephalographic seizures and status epilepticus have been reported to be common in subjects treated for traumatic brain injury (TBI). This can negatively influence the outcome giving rise to secondary brain injuries. The occurrence of seizures in subjects treated for TBI using continuous EEG monitoring was therefore prospectively studied. During 7334 hours of EEG recording in 47 patients no electroencephalographic seizures were observed. Theoretically, and based on animal studies, prostacyclin (PGI2) can improve the microcirculation of the brain, decreasing the risk for secondary ischaemic brain injury. PGI2 was introduced to the treatment in a prospective randomised double blinded study (epoprostenol 0,5 ng/kg/min). The effect of PGI1 pkt was analysed using the lactate/pyruvate ratio (L/P) measured by cerebral microdialysis in order to study the energy metabolism in the brain. The outcome was measured as Glasgow Outcome Scale (GOS) at 3 months follow-up. Forty-eight subjects were included. The L/P was pathological high during the first day, thereafter decreasing. There was no significant difference in L/P or outcome between the treated and non-treated group. At 3 months the mortality was 12,5% (95,8% was discharged alive from the ICU), and favourable outcome (GOS 4-5) was 52%. In the same study the brain injury biomarkers S-100B and NSE were followed twice a day for five days to evaluate brain injury and investigate the possible use of these biomarkers for outcome prediction. Initially the biomarkers were elevated to pathological levels which decreased over time. The biomarkers were significant elevated in subjects with Glasgow Coma Scale 3 (GCS) and GOS 1 compared with subjects with GCS 4-8 and GOS 2–5, respectively. A correlation to outcome was found but this correlation could not be used to predict clinical outcome. It is concluded that the ICP measurements are valid and the treatment protocol is a safe and solid protocol, yielding among the best reported results in the world, in regard to favourable outcome as well as in regard to mortality. Epoprostenol in the given dose was not shown to have any effects on the microdialysis parameters nor the clinical outcome. In sTBI L/P and brain injury biomarkers can not be used to predict the final outcome.

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.