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Sökning: WFRF:(Olsson Hans Dr.)

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1.
  • Tidskriftsartikel (refereegranskat)
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2.
  • Shungin, Dmitry, et al. (författare)
  • New genetic loci link adipose and insulin biology to body fat distribution.
  • 2015
  • Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
  • Tidskriftsartikel (refereegranskat)abstract
    • Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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3.
  • Forskningsöversikt (refereegranskat)
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4.
  • Aljabery, Firas (författare)
  • Staging and tumor biological mechanisms of lymph node metastasis in invasive urinary bladder cancer
  • 2017
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Aim: To study the possibility of detecting lymph node metastasis in locally advanced urinary bladder cancer (UBC) treated with radical cystectomy (RC) by using preoperative positron emission tomography/computed tomography (PET/CT) and peroperative sentinel node biopsy (SNB) technique. We also investigate the clinical significance of macrophage traits expression by cancer cells, M2-macrophage infiltration (MI) in tumor stroma and the immunohistochemical expression of biomarkers in cancer cells in relation to clinicopathologic data.Patients and Methods: We studied prospectively 122 patients with UBC, pathological stage pT1–pT4 treated with RC and pelvic lymph node dissection (PLND) during 2005–2011 at the Department of Urology, Linköping University Hospital. In the first study, we compared the results of preoperative PET/CT and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes (LNs). In the second study we investigated the value of SNB technique for detecting pathological LNs during RC in patients with UBC. W also examined the significance of the primary tumor location in the bladder in predicting the site of LN metastases, and the prognostic significance of lympho-vascular invasion (LVI) and lymph node metastasis density (LNMD) on survival. In the third study, we investigate the clinical significance of macrophage infiltration (MI) in tumor stroma and macrophage-traits expression by tumor cells. In the fourth study, we investigate the cell cycle suppression proteins p53, p21, pRb, p16, p14 ARF as well as tumors proliferative protein Ki67 and DNA repair protein ERCC1 expression in cancer cells. The results were compared with clinical and pathological characteristics and outcome.Results: Prior to RC, PET/CT was used to detect LN metastasis in 54 patients. PET/CT had 41% sensitivity, 86% specificity, 58% PPV, and 76% NPV, whereas the corresponding figures for conventional CT were 41%, 89%, 64%, and 77%. SNB was performed during RC in 103 patients. A median number of 29 (range 7–68) nodes per patient were examined. SNs were detected in 83 out of 103 patients (81%). The sensitivity and specificity for detecting metastatic disease by SNB varied among LN stations, with average values of 67% -90%. LNMD or ≥8% and LVI were significantly related to shorter survival. In 103 patients, MI was high in 33% of cases, while moderate and low infiltration occurred in 42% and 25% of tumors respectively. Patients with tumors containing high and moderate compared to low MI had low rate of LN metastases (P=0.06) and improved survival (P=0.06), although not at significant level. The expression of different tumor suppression proteins was altered in 47-91% of the patients. There were no significant association between cancer specific survival (CSS) and any of the studied biomarkers. In case of altered p14ARF, ERCC1 or p21, CSS was low in case of low p53 immunostaining but increased in case of p53 accumulation, although not at a significant level, indicating a possible protective effect of p53 accumulation in these cases.Conclusion: PET/ CT provided no improvement over conventional CT in detection and localization of regional LN metastases in bladder cancer. It is possible to detect the SN but the technique is not a reliable for perioperative localization of LN metastases; however, LVI and LNMD at a cut-off level of 8% had significant prognostic values. MI in the tumor microenvironment but not CD163 expression in tumor cells seems to be synergistic with the immune response against urinary bladder cancer. Our results further indicate that altered p53 might have protective effect on survival in case of altered p14ARF, p21, or ERCC1 indicating an interaction between these biomarkers.
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5.
  • Law, Matthew H, et al. (författare)
  • Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma.
  • 2015
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718. ; 47:9, s. 987-995
  • Tidskriftsartikel (refereegranskat)abstract
    • Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.
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6.
  • Lyth, Johan, 1980- (författare)
  • Clinical-epidemiological studies on cutaneous malignant melanoma : A register approach
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • The incidence of cutaneous malignant melanoma (CMM) is steadily increasing. Most of the patients have thin CMM with a good prognosis and a 5-year survival of about 90%. The prognosis is highly related to tumour thickness and clinical stage at diagnosis. Effective systemic treatment for patients with metastatic disease has only recently been available. This thesis aims to increase knowledge of trends in tumour thickness, prognostic factors, socioeconomic differences and medical costs in patients with CMM.The population-based Swedish melanoma register is the main source of data in all papers in the thesis. Papers I-III include patients from all of Sweden while paper IV is delimited to the County of Östergötland. Cox regression and logistic regression are the main multivariable methods used. Paper IV is focused on stage-specific costs of CMM by comparing direct healthcare costs to a general population.For men, there has been a shift over time towards thinner tumours at diagnosis accompanied by an improved survival. Women are still diagnosed with considerably thinner tumours and they experience a better survival than men. Tumour ulceration, tumour thickness and Clark’s level of invasion all showed significant independent long-term prognostic information in T1 CMMs. By combining these factors, three distinct prognostic subgroups were identified. Lower level of education was associated with reduced CMM-specific survival, which may at least partially be attributed to a more advanced stage at diagnosis. The direct healthcare costs for CMM patients were significantly higher than for the general population, independent of clinical stage. CMM patients diagnosed in clinical stage III-IV were associated with particularly high costs.Even though the survival among Swedish patients with CMM is among the highest in the world and still seems to improve, the results of this thesis emphasise the need of improved early detection strategies. This may be of particular concern in men, older women, and groups with a low level of education. The results also imply that the costs for the management of CMM patients may be reduced if early detection efforts are successful and lead to a more favourable stage distribution. The finding of a better risk stratification of thin CMMs may help to improve the management of this large patient group.
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7.
  • Sawcer, Stephen, et al. (författare)
  • Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
  • 2011
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
  • Tidskriftsartikel (refereegranskat)abstract
    • Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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8.
  • Liedgren, Pernilla (författare)
  • Att bli, att vara och att ha varit - om ingångar i och utgångar ur Jehovas vittnen i Sverige
  • 2007
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • SummaryTo become, to be and to have been: about the  Jehovah’s WitnessesThe Watchtower Bible and Tract Society, in the following text referred to as the Jehovah’s Witnesses or “the organisation”, is a worldwide Christian organisation with about 6.7 million members. The organisation has many times, without any success so far, proclaimed Armageddon when they expect Jehovah to return to Earth. They interpret the Bible in their own, often very literal way, and require their members to live according to these interpretations. Among the consequences of this, members are forbidden to vote, to do military service or to receive blood transfusions. Apart from attending the three weekly meetings, members are expected to be active in missionary work, known as “publishing”. If a member fails to do a certain number of hours’ publishing, he or she risks being deprived of active membership statusSweden in general is considered to be a society where the population is not very religious. The formerly state-governed Lutheran church has lost its influence and the vast majority of ordinary Swedes do not visit church on other occasions than weddings, funerals or christenings. Expressing one’s own religious values has become somewhat of a private matter where publicity is seldom appreciated, which is contrary to the practice of the Jehovah’s Witnesses. This is one of the reasons why the Jehovah’s Witnesses are commonly perceived by average Swedes as a “suspicious” religious organisation.The aim and methods of the studyThis dissertation seeks to describe and investigate the entering and leaving of a highly structured and hierarchical religious community, exemplified in this case by the Jehovah’s Witnesses. What are the thoughts and aspirations of someone who is considering becoming a Jehovah’s Witness? What are the priorities and what experiences seem important when a person is going through such a process? And when this person has finally reached his or her goal of becoming a member, is it the same motivation that makes him or her stay in the organisation for longer periods of time, possibly for the rest of their lives, or does it change during the process of entering, or does this motivation change its character during the transition from entering to being a regular member?Why do some of the members change their attitude to the Jehovah’s Witnesses from rejoicing to bitterness? And how does this process of exit manifest itself? In what way is it different from the process of entry?The respondents in this study were chosen from both active members of the Jehovah’s Witnesses in Sweden and those who have left the organisation for personal reasons. Repeated interviews with ten active members of the organisation have been conducted in the course of the study and compared to equal numbers of former members. The interviews have been semi-structured to deal with questions of how a person has come into contact with the organisation; how they retrospectively experienced the process of entry; the reasons for becoming a member. Questions have also been asked about life in the organisation. The group of “exiters” have also been asked about the experience of leaving, why they wanted to leave, and how this process was started and carried out.In addition to this I have analysed a four-year diary describing the time inside and the process of leaving the organisation. This has given me an extra psychological insight into the inner experience of someone who has gone through the whole process.The analysis has been done by categorising the content of the transcribed interviews. An attempt to outline a model of an entry and exit process has been made, based on ideas and interpretations presented in the interviews. The analysis of the diary has involved thorough reading, resulting in a division of it into four different parts, where each part has been given a certain key-word, signifying the author’s emotional state when writing it. A great deal of the information about the Jehovah’s Witnesses has been collected through discussion boards on the Internet, informal talks with members and ex-members, interviews with representatives of the organisations during visits to its different offices (Bethels), such as St. Petersburg, Russia, and Brooklyn, New York, USA.The contextEach organisation evolves in its own context with its own norms, roles and stories that would not survive outside it. With this as a starting point, there is a chapter dedicated to the description of the organisation’s history, structure and activities. It has been stated that the organisation’s treatment of its critical members and the strategies for recruiting new members have evolved over the years of its history. At the beginning there was an openness allowing members to be critical. As the structure of the organisation has become more rigid and formalised, the treatment of internal critics has become much less tolerated and exclusion has become a frequent option.As a rule many new members have been attracted to the organisation when (1) the day of Armageddon has been pronounced to be approaching; (2) the members of the organisation have been persecuted or threatened with persecution; and (3) the organisation has discovered a “new market”.The processes for entering and exitingHow the entering processes manifest themselves depends on whether the person has been brought up in the organisation or not. A person converting as an adult has to pass six phases before being considered a Jehovah’s Witness by the organisation. These are: Contact with the Jehovah’s Witnesses,Studying the bible with members of the organisation,Questioning,Accepting,Being active as publisher (spreading the belief),Being baptised. For a person brought up in the organisation, the process to full membership is much shorter: Upbringing in the organisation,Taking a stand on the belief,Being baptised.The exit process contains of seven phases: Different levels of doubts,Testing of doubts,Turning points,Different kinds of decisions,Different steps in executing the decisions,Floating, a period of emotional and cognitive consideration of membership and its experiences,Realtive neutrality. The process in and the process out are both slow and are accompanied with anguish and doubts. When a person is going through the process in or out of the organisation he or she experiences criticism. This is when people around the adept question the decision to continue in the process. The result of the criticism depends on where in the process the person is. If he or she is at the beginning of the process, the criticism will probably make the person insecure and the process will slow down or stop. If the criticism is pronounced in a later phase, the process will probably speed up.The norms of the organisation affect the behaviour of the members. There are techniques for inclusion that both bind members to the organisation and shield them off from the surrounding society. Examples of techniques for inclusion are the “work situation” and “closed doors”. The work situation signifies that members who do as the organisation recommends – doing simple work – often end up in the same branch of industry as many other Jehovah’s Witnesses. This often means that the person has other witnesses as workmates. If the person is unemployed or moves to another town it is easy to find a new job through connections in the organisation.Doubts and exclusions can lead to problems since they entail a risk of losing one’s job. This can also result in problems getting a new job. Jehovah’s Witnesses are not supposed to talk to excluded members, which of course mean difficulties working together. “Closed doors” means that members who do as the organisation recommends – not pursuing higher education, not engaging in civil society, working with a manual or in other way simple job, putting much time into the organisation – will, after a long life in the organisation, have problems starting a new life outside the Jehovah’s Witnesses.The language used in the organisation shows the community among the members, thus the language is one of the most important symbols. A special way of thinking is created through the language. It binds members to the organisation and sometimes it can work as a way to get back into the normative world of the organisation.Randall Collins’s (1990, 2004) thoughts about “emotional energy” have enabled an understanding of the solidarity and unity in the organisation. This also gives an understanding of the way the members treat doubting and critical members. The members who want to exit have to open up the binding/screening off. A possible way to do that is through language, to become aware of the effect the language might have. Another way is to search for emotional energy in another situation.During the exit process, shame might be of some importance. When members become aware of the shame they feel, because they perceive they are “acting a belief”, the exit process might accelerate.
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