Poon, Fan Fong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 109-124). / Abstract also in Chinese. / Abstract --- p.i / Acknowledgements --- p.v / Table of Content --- p.vi / List of Figures --- p.xi / List of Tables --- p.xiii / List of Abbreviations --- p.xiv / List of papers published during the study --- p.xvi / Chapter Chapter 1 --- Introduction and Aim of Study --- p.1 / Chapter 1.1 --- General Introduction --- p.1 / Chapter 1.2 --- Project objective and potential significances --- p.6 / Chapter Chapter 2 --- Literature Reviews --- p.8 / Chapter 2.1 --- Cancer genetics --- p.8 / Chapter 2.1.1 --- Oncogenes and TSGs --- p.8 / Chapter 2.1.2 --- Kundsońةs two-hit event of cancer gene --- p.9 / Chapter 2.2 --- Cancer Epigenetics --- p.9 / Chapter 2.2.1 --- Types of Epigenetic regulation --- p.10 / Chapter 2.2.2 --- DNA methylation in TSGs --- p.10 / Chapter 2.2.2.1 --- Promoter CpG island in DNA methylation --- p.10 / Chapter 2.2.2.2 --- Protection system in DNA methylation --- p.11 / Chapter 2.2.2.3 --- Transcriptional silencing by DNA methylation --- p.11 / Chapter 2.2.2.4 --- DNA methylation of TSG silencing in cancers --- p.13 / Chapter 2.2.3 --- Hypomethylation of the cancer genome --- p.14 / Chapter 2.2.4 --- Clinical relevance of cancer epigenetic --- p.14 / Chapter 2.3 --- EGFR/STAT/SOCS pathway --- p.15 / Chapter 2.3.1 --- General Introduction of the EGFR pathway --- p.15 / Chapter 2.3.2 --- EGFR survival signaling pathways --- p.16 / Chapter 2.3.3 --- EGFR/STAT/SOCS signaling --- p.17 / Chapter 2.3.4 --- EGFR/STAT/SOCS signaling and cancers --- p.18 / Chapter 2.3.4.1 --- EGF and cancers --- p.18 / Chapter 2.3.4.2 --- EGFR/STAT/SOCS pathway and cancers --- p.18 / Chapter 2.3.4.3 --- EGF survival signaling as a target for cancer therapy --- p.19 / Chapter 2.4 --- TSGs in the EGFR/STAT/SOCS pathway --- p.20 / Chapter 2.4.1 --- Suppressors of cytokine signaling (SOCS) family --- p.20 / Chapter 2.4.2 --- Signal transducers and activators of transcription (STATs) family --- p.22 / Chapter 2.4.3 --- Sprouty (SPRY) family --- p.23 / Chapter 2.4.4 --- Protein Inhibitor of Activated STAT (PIASs) family --- p.25 / Chapter 2.4.5 --- Ras and Rab Interactor (RIN) family --- p.26 / Chapter 2.4.6 --- Ras-association domain family (RASSF) --- p.26 / Chapter 2.4.7 --- Glycine N-methyltransferase (GNMT) --- p.28 / Chapter 2.5 --- Nasopharyngeal carcinoma (NPC) --- p.30 / Chapter 2.5.1 --- Epidemiology of NPC --- p.30 / Chapter 2.5.2 --- Histopathology of NPC --- p.30 / Chapter 2.5.3 --- Genetic and epigenetic alteration in NPC --- p.31 / Chapter 2.5.4 --- EGFR signaling in NPC --- p.32 / Chapter 2.6 --- Esophageal squamous cell carcinoma (ESCC) --- p.33 / Chapter 2.6.1 --- Epidemiology of ESCC --- p.34 / Chapter 2.6.2 --- Histopathology of ESCC --- p.34 / Chapter 2.6.3 --- Genetic and epigenetic alteration in ESCC --- p.35 / Chapter 2.6.4 --- EGFR signaling in ESCC --- p.36 / Chapter Chapter 3 --- Materials and Methods --- p.38 / Chapter 3.1 --- General Materials --- p.38 / Chapter 3.1.1 --- "Cell lines, tumor and normal tissue samples" --- p.38 / Chapter 3.1.2 --- Maintenance of cell lines --- p.38 / Chapter 3.1.3 --- Drugs treatment of cell lines --- p.39 / Chapter 3.1.4 --- Total RNA extraction --- p.39 / Chapter 3.1.5 --- Genomic DNA extraction --- p.40 / Chapter 3.2 --- General techniques --- p.40 / Chapter 3.2.1 --- Agarose gel electrophoresis of DNA --- p.40 / Chapter 3.2.2 --- TA cloning and blunt end cloning of PCR product --- p.40 / Chapter 3.2.3 --- Transformation of cloning products to E. coli competent cells --- p.41 / Chapter 3.2.4 --- Preparation of plasmid DNA --- p.41 / Chapter 3.2.4.1 --- Mini-prep plasmid DNA extraction --- p.41 / Chapter 3.2.4.2 --- Midi-prep of plasmid DNA --- p.42 / Chapter 3.2.5 --- Measurement of DNA or RNA concentrations --- p.42 / Chapter 3.2.6 --- DNA sequencing of plasmid DNA and PCR products --- p.42 / Chapter 3.3 --- Preparation of reagents and medium --- p.43 / Chapter 3.4 --- Semi-quatitative Reverse-Transcription (RT) PCR expression analysis --- p.44 / Chapter 3.4.1 --- Reverse transcriptin reaction --- p.44 / Chapter 3.4.2 --- Semi-quantitative RT-PCR --- p.44 / Chapter 3.4.2.1 --- Primers design --- p.44 / Chapter 3.4.2.2 --- PCR reaction --- p.46 / Chapter 3.5 --- Methylation analysis of candidate genes --- p.47 / Chapter 3.5.1 --- Bisulfite treatment of genomic DNA --- p.47 / Chapter 3.5.2 --- Methylation-specific PCR (MSP) --- p.48 / Chapter 3.5.2.1 --- Bioinformatics prediction of CpG island --- p.48 / Chapter 3.5.2.2 --- Primers design --- p.48 / Chapter 3.5.2.3 --- PCR reaction --- p.49 / Chapter 3.5.3 --- Bisulfite Genomic Sequencing (BGS) --- p.50 / Chapter 3.6 --- Construction of expression vectors of candidate genes --- p.51 / Chapter 3.6.1 --- Sub-cloning of expression vector of candidate genes --- p.51 / Chapter 3.6.1.1 --- Mouse Socsl expression vector --- p.51 / Chapter 3.6.1.2 --- SPRY1 expression vector --- p.51 / Chapter 3.6.1.3 --- GNMT expression vector --- p.52 / Chapter 3.6.2 --- Restriction digestion of cloning vectors and expression --- p.52 / Chapter 3.6.3 --- Ligation of cloning fragments --- p.53 / Chapter 3.6.4 --- Colony formation assay on monolayer culture --- p.53 / Chapter 3.6.5 --- Statistical analysis --- p.54 / Chapter Chapter 4 --- Screening of candidate TSGs in EGFR pathway --- p.55 / Chapter 5.3.3 --- Restoration of GNMT expression by pharmacological demethylation --- p.89 / Chapter 5.3.4 --- Confirmation of the methylation status of GNMT promoter by BGS --- p.90 / Chapter 5.3.5 --- Methylation status of GNMT in ESCC and NPC primary tumors --- p.90 / Chapter 5.3.6 --- GNMT inhibited the growth of tumor cells in-vitro --- p.90 / Chapter 5.3.7 --- Discussion --- p.95 / Chapter Chapter 6 --- General Discussion --- p.100 / Chapter Chapter 7 --- Summary --- p.105 / Chapter Chapter 8 --- Future Study --- p.107 / Reference --- p.109

The societal burden of autoimmune diseases and donor organ transplant rejection in developed countries reflects the lack of effective immune suppressive drugs. The main objective of my thesis was to develop novel fusion proteins targeting receptors linked to autoimmunity; strategies that will allow the suppression of autoreactive cells while sparing resting lymphocytes. Interleukin (IL) 15 has been demonstrated to exert its effects mainly on activated T-cells triggered via their T-cell receptor (TCR). Since we found that the fusion of granulocyte-macrophage colony stimulating factor (GMCSF) to IL15 - aka GIFT15 - paradoxically leads to aberrant signalling downstream of the IL15R and blocks interferon (IFN)-gamma secretion in a mixed lymphocyte reaction (MLR), we hypothesized to use this fusokine in proof-of-principle cell transplantation models and shown that GIFT15 can indeed block the rejection of allogeneic and xenogeneic cells in immunocompetent mice. Additionally, we found that ex vivo GIFT15 treatment of mouse splenocytes lead to the generation of regulatory B-cells (Bregs). These Bregs express high levels of MHCII, IL10 and are capable to block antigen (Ag)-presentation in vitro as third party bystander cells. Moreover, a single injection of these GIFT15-generated Bregs in mice with pre-developed experimental autoimmune encephalomyelitis (EAE) leads to long lasting remission of disease. / Along those lines, we also found that mesenchymal stromal cells (MSCs) lead to the paracrine conversion of CCL2 to an antagonist form capable of specifically inhibiting plasma cells and activated Th17 cells. This mechanistic insight informed the design of a second class of suppression fusokine. Namely, the fusing of antagonist CCL2 to GMCSF - aka GMME1. We tested its potential use in autoimmune diseases such as EAE and rheumatoid arthritis (RA). We demonstrated that GMME1 leads to asymmetrical signalling and inhibition of plasma cells as well as Th17 EAE/RA-reactive CD4 T-cells. The net outcome of these pharmacological effects is the selective depletion of CCR2-reactive T-cells as demonstrated both in vitro and in vivo. / Overall, our data support the use of our fusion proteins as part of a powerful and specific immunosuppressive strategy either as directly injectable protein biopharmaceuticals or through the ex vivo generation of autologous Bregs in the case of GIFT15.

Havsplanering som sammanhållen statlig fysisk planering finns i svensk lagstiftning sedan 2014. Införandet har skapat ett förhållande där ett område i territorialhavet planeras av både stat och kommun. Ingen av planerna står över den andra i formell mening. Samtidigt bygger systemet på antaganden som skapar förutsättningar för vilken kunskap som blir legitim i planeringen. Denna studie har haft som avsikt att undersöka hur havsplaneringen konstrueras i praktiken genom samhällsstyrning och kunskapssyn med särskilt fokus på förhållandet mellan stat och kommun. Den teoretiska utgångspunkten till studien tas i samhällsstyrning genom begreppen ”government” och ”governance” samt för kunskapssynerna genom tre idealmodeller: rationell, kommunikativ och pragmatisk kunskapssyn. Metoder som används är dokumentstudier, intervjuer och observationer. Databehandlingen sker med kvalitativ innehållsanalys utifrån en tematisk kodningsmall som skapats i processen. Analysen utgår från ett analytiskt ramverk uppbyggt kring tre frågor om styrning och tre frågor om kunskapssyn. Vem ansvarar för vad? Vem fattar det slutliga beslutet? Hur ska processen gå till? Hur skapas kunskapen? Var skapas kunskapen? Varför skaps kunskapen? Studien är uppdelad i två delar, en tvärsnittsstudie och en fallstudie. Tvärsnittsstudien behandlar remissvar till den statliga offentliga utredningen ”Planering på djupet” samt promemorian ”Hushållning med havsområden”. Fallstudien består av intervjuer med planeringsaktiva från både stat och kommun i havsplaneringen i Blekinge. Intervjuerna är kompletterade med observationer från samrådsmöten och dokument tillhörande processen. Studien bekräftar att en rationell kunskapssyn är starkt förankrad i havsplaneringen. Samtidigt visas också att förhållandet är flytande och har förändrats i sökandet efter planeringens struktur. De rationella dragen var starkast i utredningsskedets tidiga del för att allt mer utmanas med kommunikativa kunskaper till de senare delarna. I fallstudien visas att när havsplaneringen ska implementeras i praktiken blir bilden mer komplex. Den rationella kunskapssynens dominans syns i en stark betoning på naturvetenskapliga data och kalkyler i planeringens underlagsmaterial. Framförallt visas detta i den statliga planeringen. I den kommunala planeringen visas en kommunikativ kunskapssyn genom inkludering av olika typer av lokal kunskap och stor vikt vid deltagandeprocesser. Kommunerna visar också drag av en pragmatisk kunskapssyn i den vikt som läggs vid planeringens innehåll och praktiska effekt framför val av processmetod. Studien har visat att under utredningsskedet diskuterades kommunens roll utifrån två linjer. En linje med naturvårdens företrädare krävde mer statlig kontroll av kommunerna. Den andra linjen värnade det kommunala planmonopolet företrädd av den kommunala sektorn. Diskussionen om gränserna för den kommunala självstyrelsen är därför fortfarande aktuell. I implementeringsskedet är kommunen och statens planer på en likvärdig nivå hierarkiskt. Otydligheten om vilken plan som ska vara styrande gör att aktörerna i sitt agerande skapar hierarkiska strukturer att förhålla sig till. I de konflikter som uppstår finns en förväntan om domstolsprövning. Vilken kunskapssyn som ska gälla och vilken kunskap som blir legitim kommer därför inte att avgöras i planeringsprocessen utan i sista hand avgöras av jurister.

The aim of this paper is to describe and explain how the separation between state and church effects the power relations between state and religious groups and organizations. Former state church, The Swedish church, is in this paper, not included in the definition of religious groups. The reform (“stat-kyrka reformen”) took place between 1995 and year 2000.I’m examining if religious groups had any influence on the reform. My expectation is to give a clearer picture of religious groups and its power position in Swedish politics and society. A process-tracing method is used. I use different theories, theory of power and influence and theory of collective action. The reason for the decision to separate church and state was to handle social changes such as increasing secularism, pluralism and multiculturalism. This paper can however conclude that the state, after the reform, has shown an even greater, less secular, determination to connect with religious groups. I can also conclude that these religious groups had influence on the reform itself, partly because of its power resources and partly because its ability for collective actions.

In order to make development aid more efficient, a large number of donors, including Sweden, signed the so called Paris Declaration in 2005. The Declaration gives the partner countries more responsibility for their own development and aims to make he development aid provided by donor countries more measurable. It has been referred to as a paradigm shift within this policy area due to its far‐reaching goals. The Declaration has consequences for all actors in the development aid community, and this thesis aims at outlining and analyzing the effects of the Declaration on the Swedish non‐governmental organisations which hold a frame agreement with the Swedish International Development Agency (SIDA). As an increasing part of evelopment aid is being channelled through NGOs and they hold an important role in the area, they are interesting subjects of study. The analysis is conducted from a society‐centred governance perspective, which focuses on how different actors in society shape public policy. The perspective hallenges the view on the state as dominating unilaterally and takes into account the diversity of actors involved in policy‐making, such as NGOs. The result of the study is, among other things, that the character of the relationships and interactions between Swedish NGOs and SIDA varies, and can be described as either a more traditional hierarchical model or co‐governing. Furthermore, the Paris Declaration is perceived by the NGOs as being a step in the right direction rather than a paradigm shift at all level. / För att göra utvecklingsbistånd effektivare, undertecknade ett stort antal givare, däribland Sverige, den så kallade Parisdeklarationen 2005. Deklarationen ger samarbetsländerna ett större ansvar för sin egen utveckling och syftar till att göra biståndet från givarländerna mer mätbart. Man har kallat detta ett paradigmskifte inom området på grund av sina långtgående mål. Deklarationen har konsekvenser för alla aktörer inom området utvecklingsbistånd, och denna uppsats syftar till att beskriva och analysera de effekter som deklarationen har på de svenska icke‐statliga organisationer som har ett ramavtal med SIDA. Eftersom en allt större del av utvecklingsbiståndet kanaliseras genom enskilda organisationer och de innehar en viktig roll i området, är de intressanta att studera. Analysen görs utifrån ett samhällsorienterat governance perspektiv som fokuserar på hur olika aktörer i samhället utformar den offentliga politiken. Perspektivet utmaningar uppfattningen om att staten ensidigt dominerar och tar hänsyn till mångfalden av aktörer i det politiska beslutsfattandet, till exempel icke‐statliga organisationer. Resultaten av undersökningen är bland annat att karaktären av de relationer och interaktioner mellan svenska icke‐statliga organisationer och SIDA varierar, och kan beskrivas som traditionellt hierarkisk, eller samarbetsbaserad (co‐governing). Vidare uppfattas Parisdeklarationen av icke‐statliga organisationer som ett steg i rätt riktning, snarare än ett paradigmskifte på alla nivåer.

The European Union has created a common plan regarding narcotics use and abuse within the European member states. The aim here is to reduce the supply and demand for drugs among the citizens of the Union. However, the opinions on how to achieve these goals greatly differ among member states. The range of attitudes varies from the strictly restrictive attitudes of countries such as Sweden, to the complete decriminalization of personal possession of all narcotic substances in Portugal. The purpose of this paper is therefore to study the underlying attitudes and approaches that these two countries have, and hopefully to give some light to how come there is this big difference in legal frameworks regarding a rather delicate political question. A review and analyze of the current proposition for each country regarding drug policies is the method for the paper. By interpreting the content and quoting parts of these two propositions an ideology analysis is made. The theory chapter consists of the two different philosophies of Rousseau’s theory on the social contract and the general will, as well as objectivism. These theories are used in order to make a distinction in the empirical research between attitudes towards the states’ as well as the individuals’ role in the drug policies of Sweden and Portugal. A model with the most important features of these theories is constructed and works as a base for the analysis. Overall, the results from the empirical research show that while both countries initially share the same general value towards the narcotics situation, Sweden devotes their policies more frequently towards the Rousseauian values up until the point of treating drug addicts, where they change directions and instead argue in a more objectivistic manner. On the contrary, Portugal reason in a more individualistic and objectivistic way, but change ideological paths into Rousseauianism when starting to set up aims for the treatment of addicts and offenders.

The means that the Swedish State has to legitimize and standardize different perspectives of women and their sexuality is significant. Persecution of gender and sexuality is today something that can grant refugee status according to the Swedish Aliens Act. By studying the documents that forestall the amendment of the laws is it possible to unveil the concept and ideas about women sexuality that the state manifests and reproduces through these laws and official documents. The aim of this essay is to look upon the sexual policy as it occurs in official the documents that deal with lesbian refugees. The study cover and maps present research on this group of women and gives an answer to how norms about women sexuality are expressed in these documents. Throughout the survey of the research field not much previous research was found, therefore even research that only partly covers the field is included and reviewed. As method a detailed reading of the official documents and a discourse analysis with it’s emphasize on theoretical themes like gender and sexuality, lesbianism and state feminism, was made. Lesbians are missing in the official state documents and the one time the Migration Board’s documents refer to lesbians they are ascribed to as gender and not as sexuality. The essay concludes that the confusion about the category gender and the category sexuality has the result that the lesbians become invisible. Lesbians tend throughout the material to be ascribed to the category gender and gay men to the category sexuality. The standardized perspective and normative discourse that has been found in the official documents has the effect that women is looked a pound as gender and therefore, by the same logic loose their sexuality. In this way the Swedish State discriminates lesbian. Another conclusion is that the Swedish State has a somewhat ambivalence perspective on their own work on promoting gender equality.

Spiritual care in hospitals is a well-established practice in Sweden that is justified by religious freedom. Contemporary Sweden is a multicultural society with a culturally and religiously diverse population. Since 2006, a Muslim spiritual care organization has been established in co-operation with the Swedish state. This interview study with Muslim spiritual caregivers examines how Islam is being interpreted and how Muslim spiritual care in Swedish hospitals is apprehended by the informants. By approaching Islam as a discursive tradition and combining historical and ethnological methods, this study sheds light on what aspects of Islam are considered relevant in the hospital context and it examines why that is the case. The study shows that Muslim spiritual care is regarded to be a complement to other healthcare practices. To a large extent, the care is provided by supportive conversations, Islamic counseling, as well as help with religious practices and rituals. To manage a patient’s various wants and the denominational diversity, the Muslim representatives hold that they put the patient’s and the relatives’ needs and interpretations of Islam first. The study concludes that the representatives are spiritual care professionals that are loyal to the state and the secular institutions they serve. This involves staying true to ideals of cultural and religious pluralism and equality but also knowing that these principles are subordinated to the hospital’s rules. This constructs boundaries regarding how Islam is interpreted and has to be negotiated in the efforts of making Islam a natural part of the institution.

Human rights for refugees has proven to be incredibly hard to protect. The problem lies with the fact that it is the individual State that in practise will protect and guarantee human rights. However, states tend to only protect the rights of their own citizens. As refugees often have left the country where they are citizens and are currently residing in a country where they are not, they find themself in a legal limbo, making them one of the world's most vulnerable groups. Martha Finnemore & Kathryn Sikkink argued that international norms can affect a state’s national politics and that international organisations have an important role to play in that. Earlier research argued that international cooperations can influence states to change their perspective on human rights protection. To better understand this dynamic the study aimed to research if international cooperations could, through socialisation of norms, influence states to respect and protect refugee rights. The study used Turkey’s reception of refugees from Syria between the years 2011 to 2020 as a case. Sweden adopted, during 2016, a regional strategy for the Syrian crisis which led to aid projects in Turkey. The study, therefore, examines Turkey's refugee reception before and after Sweden implemented their projects in the regions. The study made three themes of rights that are specifically important for refugees which was the foundation for the analys. The results were firstly, that refugee protection in Turkey had weakened since the implementation of Sweden's aid project. The only positive change was in labour rights in which the study could find alternative explanations for that specific change. The study found no evidence that international cooperation could influence a state’s approach to human rights. More research within the field is, however, needed.

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