Diss. (sammanfattning) Stockholm : Karolinska institutet, 2001. / Härtill 4 uppsatser.

The development of a functional vascular system is impinged upon the restructuring of a primitive vasculature into a more complex and mature vessel network via a process known as angiogenesis. Of particular importance to this vascular remodeling process is the function of the Tek/Tie-2 receptor tyrosine kinase. Mouse gene-targeting studies have shown that Tie-2 deficient embryos succumb to embryonic death at embryonic day 9.5 due to insufficient sprouting and remodeling of the primary capillary plexus. Over the years, the functions and the signaling pathways downstream of Tie-2 receptor have been elucidated; however, the repertoire of genes controlled by Tie-2 signaling leading to angiogenesis had not been studied. To identify the underlying genetic mechanisms, transcriptomes from Tie-2 wild-type (WT) and knockout (KO) embryonic day 8.5 yolk sac tissues were quantitatively analyzed using a gene expression profiling technique called Serial Analysis of Gene Expression (SAGE). Tie-2 WT and KO SAGE libraries were constructed, sequenced and compared to identify genes that were differentially expressed. A list of candidate genes was selected for further validation using semi-quantitative PCR that included 4933402E13Rik, a novel transcript encoding a protein product containing the melanoma-associated antigen (MAGE) domain. Initial characterization of 4933402E13Rik suggested a murine-specific expression profile restricted to the yolk sac, embryo, placenta, testis, endothelial and embryonic stem cells. The expression of 4933402E13Rik in mouse endothelial cells was found to be regulated by Tie-2 signaling since down-regulation of Tie-2 level via siRNA knockdown resulted in decreased 4933402E13Rik mRNA expression. In contrast, stimulation of Tie-2 in mouse endothelial cells using its ligand, Angiopoietin-1, increased 4933402E13Rik mRNA levels. Additionally, 4933402E13Rik expression was found to be modulated through epigenetics especially by histone deacetylation. Mouse endothelial cells treated with Trichostatin A, a potent inhibitor of histone deacetylase, led to an increase in the expression of 4933402E13Rik. Taken together, the results of this study shed new insight on the repertoire of genes implicated in Tie-2 signaling. The identification of 4933402E13Rik as a novel gene modulated by Tie-2 provides a new avenue of research on Tie-2 signaling that may contribute further to our understanding of vascular development.

The development of a functional vascular system is impinged upon the restructuring of a primitive vasculature into a more complex and mature vessel network via a process known as angiogenesis. Of particular importance to this vascular remodeling process is the function of the Tek/Tie-2 receptor tyrosine kinase. Mouse gene-targeting studies have shown that Tie-2 deficient embryos succumb to embryonic death at embryonic day 9.5 due to insufficient sprouting and remodeling of the primary capillary plexus. Over the years, the functions and the signaling pathways downstream of Tie-2 receptor have been elucidated; however, the repertoire of genes controlled by Tie-2 signaling leading to angiogenesis had not been studied. To identify the underlying genetic mechanisms, transcriptomes from Tie-2 wild-type (WT) and knockout (KO) embryonic day 8.5 yolk sac tissues were quantitatively analyzed using a gene expression profiling technique called Serial Analysis of Gene Expression (SAGE). Tie-2 WT and KO SAGE libraries were constructed, sequenced and compared to identify genes that were differentially expressed. A list of candidate genes was selected for further validation using semi-quantitative PCR that included 4933402E13Rik, a novel transcript encoding a protein product containing the melanoma-associated antigen (MAGE) domain. Initial characterization of 4933402E13Rik suggested a murine-specific expression profile restricted to the yolk sac, embryo, placenta, testis, endothelial and embryonic stem cells. The expression of 4933402E13Rik in mouse endothelial cells was found to be regulated by Tie-2 signaling since down-regulation of Tie-2 level via siRNA knockdown resulted in decreased 4933402E13Rik mRNA expression. In contrast, stimulation of Tie-2 in mouse endothelial cells using its ligand, Angiopoietin-1, increased 4933402E13Rik mRNA levels. Additionally, 4933402E13Rik expression was found to be modulated through epigenetics especially by histone deacetylation. Mouse endothelial cells treated with Trichostatin A, a potent inhibitor of histone deacetylase, led to an increase in the expression of 4933402E13Rik. Taken together, the results of this study shed new insight on the repertoire of genes implicated in Tie-2 signaling. The identification of 4933402E13Rik as a novel gene modulated by Tie-2 provides a new avenue of research on Tie-2 signaling that may contribute further to our understanding of vascular development.

Sammanfattning Magproblem är ett utbrett besvär bland befolkningen. Detta innebär en stor fysisk men ibland också ekonomisk kostnad för individen. Denna studien sökte att öka förståelsen för hur utbrett magbesvär är bland högskolestudenter och hur de relaterar till olika livsstilsvanor. En enkät delades ut till 150 studenter. Den bestod av 13 frågor rörande magont, svullen mage, förstoppning, diarré och livsstilsvanor så som fysisk träning, rökning, alkohol, koffein, stress och livsmedelskänslighet. Deskriptiv data och skillnader mellan män och kvinnor analyserades. Statistiskt signifikanta skillnader fastslogs med Mann-Whiteys U-test. Resultaten visade att 90% rapporterade att de hade upplevt minst ett av problemen den senaste månaden minst en gång. Några av studenterna upplevde flera av symptom flera gånger i veckan. Kvinnor led av mer problem än männen: magont (p<.0001), svullnad (p<.0001) och förstoppning (p=.005). Kvinnor upplevde också mer stress under dagen än män (p<.0001) och rapporterade högre grad av livsmedelskänslighet (p=.01). Magproblem var utbrett bland högskolestudenter så även stress och livsmedelskänsligheter. Fler studier behöver göras för att fastslå de grundläggande orsakerna till magbesvären.

Obesity is a widespread problem in the United States that has profound health implications. Obesity rates also differ across different racial and ethnic groups. Among women, an important time period in their lives is the pregnancy period as gestational weight gain and postpartum weight retention may influence and contribute to noticeable differences in weight gain and retention. Maternal weight retention has implications for future health related problems and therefore needs to be addressed. One such group that is of specific interest is African Americans as data shows that obesity is more prevalent among African American adults, with the highest rates occurring in African-American women. Weight loss intervention programs for postpartum women may be useful in helping new mothers lose weight. This study was aimed at observing changes in areas such as weight loss and body image perception from a pilot-tested randomized controlled culturally tailored weight loss intervention program.

Although melanoma accounts for only 4% of skin cancers, it is responsible for 80% of deaths from skin cancers and its incidence in Caucasians has been increasing steadily during the last 30 years. So far, no treatment - except surgery at the earliest stages of the disease - has been shown to significantly improve survival. New treatments are thus clearly needed. The interest of immunologists for melanoma is based on particular features of this tumor. Rare spontaneous regressions have been described, which are possibly mediated by immune responses. Moreover, melanoma cell lines are relatively easy to obtain, providing essential tools for laboratory studies. The first melanoma vaccines involved inoculations of patients with autologous or allogeneic melanoma cells, as well as a variety of immunological adjuvants. Since the beginning of the nineties, the identification of antigens recognized on human tumors by autologous T lymphocytes has opened the way for new vaccination strategies involving molecularly defined tumor antigens. An important group of antigens recognized by T lymphocytes is encoded by “cancer-germ line genes”, which are expressed in tumors of various histological types, but are silent in normal tissues, with the exception of testis germinal cells and placental trophoblast. Since the latter do not express the HLA molecules required to present these antigens to the T lymphocytes, cancer-germ line genes encoded antigens are only present on tumors, which should limit the risk of generating autoimmune diseases as a consequence of vaccination. Therefore, these widely shared tumor specific antigens should represent good targets for the development of cancer vaccines. Our clinical research program of therapeutic vaccinations focuses on antigens encoded by the MAGE family of cancer-germ line genes. Most of the patients included in our phase I/II immunization trials had measurable metastatic melanoma. Several MAGE peptides as well as a recombinant MAGE-3 protein have been tested, while several additional trials are ongoing, including immunizations with a recombinant poxvirus coding for 2 MAGE epitopes. No major toxicity was reported. Tumor regressions have been observed in a minority of patients, mainly those who had regional or distant metastases without visceral involvement. Some of these regressions have been complete and long lasting. Although the rate of objective tumor response observed is low, it is clearly higher than the rate of spontaneous tumor regression observed in melanoma. Other immunization modes against T-cell defined epitopes are currently being explored by several groups in human clinical trials. Vaccines include peptides presented by class I or class II HLA molecules, proteins given alone or mixed with immunological adjuvants or cytokines, recombinant viral or bacterial vectors, dendritic cells and DNA encoding the antigen. Adoptive transfer of T lymphocytes selected for their capacity to recognize defined epitopes presented by the tumor represents another type of approach aiming at the destruction of the tumor by the immune system. It is difficult to predict whether and when therapeutic vaccination against cancer will reach an efficacy that will be sufficient for a standard cancer treatment. Provided their low toxicity, these vaccines should be tested in an adjuvant setting, at earlier stages of the disease.

Syftet med studien är att se vad barn har för uppfattningar om människokroppen och hur ser vi ut på insidan samt vad barnen vet om hur magen och hjärtat fungerar. Kvalitativa intervjuer användes för att ta reda på barns uppfattningar om kroppen och tolkningar av organens funktion. I studien framgick det att, hur mycket barnen lär sig beror på intresset hos det enskilda barnet om specifika organ eller helorgansystem t.ex. magens placering och funktion hade flera barn klart för sig än hjärtats funktion. Bygger man undervisningen eller en aktivitet utifrån barnens intresse vill också barnen lära sig.

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The aim of this essay is to examine how important marketing and networking is for the meeting industry in Stockholm. The meeting industry is one of the most profitable areas of the tourism industry today and a major contributor to economic growth in Sweden. The meeting industry has grown rapidly in Sweden and Stockholm has during the last five years been one of the ten most popular congress cities in the world. This has resulted in that the city has become a strong competitor to other European cities. Stockholm International fairs are for example the largest trade fair organizer in Scandinavia and Stockholm Waterfront Congress Centre is the new arena of opportunity. However the marketing and a broad network is necessary for meeting facilities if their aim is to be successful. Marketing contributes to the meeting facilities establishment and makes it well known for the potential market, while the collaborations and relationships is important for facilitating their work. Today there is a discussion whether there has been a paradigm shift from traditional transaction marketing to relationship marketing; it means that it is more important today with relationships in all aspects and not just exchanges with unknown parties. Relationships and networks are therefore a strong key feature in the meeting industry and relationship marketing are becoming increasingly important for meeting facilities and conference industry.

The field of synthetic biology seeks to use design principles of life to create new genes, organisms and populations to both better understand biology as well as generate species with useful properties. Budding yeast has been a workhorse for synthetic biology, as well as an important model organism in the broader fields of molecular biology and genetics. This thesis aimed to create genome engineering tools for the manipulation of genomes, with direct applications in yeast. I focused developing high-throughput and highly efficient methods for making genomic modifications in yeast to allow for the generation of large libraries of precisely modified yeast genomes. By manipulation of endogenous DNA recombinases and mismatch repair enzymes in yeast, we were able to develop an oligonucleotide only method for genome engineering to generate libraries as large as 10^5 individuals with a frequency of modification as high as 1%. Additionally, we validated the use of RNA-guided CRISPR/Cas9 endonucleases to make changes in yeast genomes, resulting in frequencies of genome modification >90% in transformed populations. We further optimized this method to generate larger libraries as high as 10^5 individuals and explored a proof of concept epistasis experiment involving thermotolerance. Lastly, the propagation of changes to successive generations is useful when engineering organisms on the population level. To this end we explored the use of RNA-guided gene drives to bias inheritance in S. cerevisiae. We show that inheritance of these selfish elements can be biased to over 99% and is reversible.