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  • Pietarinen-Runtti, Petra (Helsingin yliopisto, 2000)
  • Myllärniemi, Marjukka (Helsingin yliopisto, 1999)
  • Erkkilä, Krista (Helsingin yliopisto, 2002)
  • Liesmaa, Inka (Helsingin yliopisto, 2010)
    Accumulating evidence show that kinins, notably bradykinin (BK) and kallidin, have cardioprotective effects. To these include reduction of left ventricular hypertrophy (LVH) and progression of heart failure. The effects are mediated through two G protein-coupled receptors- bradykinin type-2 receptor (BK-2R) and bradykinin type -1 receptor (BK-1R). The widely accepted cardioprotective effects of BK-receptors relate to triggering the production and release of vasodilating nitric oxide (NO) by endothelial cells. They also exert anti-proliferative effects on fibroblasts and anti-hypertrophic effects on myocytes, and thus may play an essential role in the cardioprotective response to myocardial injury. The role for BK-1Rs in HF is based on experimental animal models, where the receptors have been linked to cardioprotective- but also to cardiotoxic -effects. The BK-1Rs are induced under inflammatory and ischemic conditions, shown in animal models; no previous reports, concerning BK-1Rs in human heart failure, have been presented. The expression of BK-2Rs is down-regulated in human end-stage heart failure. Present results showed that, in these patients, the BK-1Rs were up-regulated, suggesting that also BK-1Rs are involved in the pathogenesis of human heart failure. The receptors were localized mainly in the endothelium of intramyocardial coronary vessels, and correlated with the increased TNF-α expression in the myocardial coronary vessels. Moreover, in cultured endothelial cells, TNF-α was a potent trigger of BK-1Rs. These results suggest that cytokines may be responsible for the up-regulation of BK-1Rs in human heart failure. A linear relationship between BK-2R mRNA and protein expression in normal and failing human left ventricles implies that the BK-2Rs are regulated on the transcriptional level, at least in human myocardium. The expression of BK-2Rs correlated positively with age in normal and dilated hearts (IDC). The results suggest that human hearts adapts to age-related changes, by up-regulating the expression of cardioprotective BK-2Rs. Also, in the BK-2R promoter polymorphism -58 T/C, the C-allele was accumulated in cardiomyopathy patients which may partially explain the reduced number of BK-2Rs. Statins reduce the level of plasma cholesterol, but also exert several non-cholesterol-dependent effects. These effects were studied in human coronary arterial endothelial cells (hCAEC) and incubation with lovastatin induced both BK-1 and BK-2Rs in a time and concentration-dependent way. The induced BK-2Rs were functionally active, thus NO production and cGMP signaling was increased. Induction was abrogated by mevalonate, a direct HMG-CoA metabolite. Lovastatin is known to inhibit Rho activation, and by a selective RhoA kinase inhibitor (Y27632), a similar induction of BK-2R expression as with lovastatin. Interestingly a COX-2-inhibitor (NS398) inhibited this lovastatin-induction of BK-2Rs, suggesting that COX-2 inhibitors may affect the endothelial BK-2Rs, in a negative fashion. Hypoxia is a common denominator in HF but also in other cardiovascular diseases. An induction of BK-2Rs in mild hypoxic conditions was shown in cultured hCAECs, which was abolished by a specific BK-2R inhibitor Icatibant. These receptors were functionally active, thus BK increased and Icatibant inhibited the production of NO. In rat myocardium the expression of BK-2R was increased in the endothelium of vessels, forming at the border zone, between the scar tissue and the healthy myocardium. Moreover, in in vitro wound-healing assay, endothelial cells were cultured under hypoxic conditions and BK significantly increased the migration of these cells and as Icatibant inhibited it. These results show, that mild hypoxia triggers a temporal expression of functionally active BK-2Rs in human and rat endothelial cells, supporting a role for BK-2Rs, in hypoxia induced angiogenesis. Our and previous results show, that BK-Rs have an impact on the cardiovascular diseases. In humans, at the end stage of heart failure, the BK-2Rs are down-regulated and BK-1Rs induced. Whether the up-regulation of BK-1Rs, is a compensatory mechanism against the down-regulation of BK-2Rs, or merely reflects the end point of heart failure, remains to bee seen. In a clinical point of view, the up-regulation of BK-2Rs, under hypoxic conditions or statin treatment, suggests that, the induction of BK-2Rs is protective in cardiovascular pathologies and those treatments activating BK-2Rs, might give additional tools in treating heart failure.
  • Suomalainen, Laura (Helsingin yliopisto, 2004)
  • Pihlajoki, Marjut (Helsingin yliopisto, 2014)
    The main steroidogenic organs, adrenal cortex and ovary, arise from a common pool of progenitors in the developing embryo. Similar signaling pathways regulate the differentiation, growth, and survival of cells in these tissues. Proper development of the adrenal cortex and ovary requires precise spatiotemporal control of gene expression and apoptosis; disruption of these processes may lead to congenital disorders or malignant transformation. Earlier in vitro studies demonstrated that transcription factor GATA6 regulates the expression of multiple steroidogenic genes in the adrenal cortex. To show that GATA6 is a crucial regulator of adrenocortical development and function in vivo, we generated a mouse model in which Gata6 is conditionally deleted in steroidogenic cells. These mice exhibited a complex adrenal phenotype that includes cortical thinning, blunted aldosterone production, lack of an X-zone, impaired apoptosis, and subcapsular cell hyperplasia. These results offer genetic proof that GATA6 regulates the differentiation of steroidogenic progenitors into adrenocortical cells. Ovarian granulosa cell tumors (GCTs), the most common sex-cord stromal tumors in women, are thought to be caused by aberrant granulosa cell apoptosis during folliculogenesis. A somatic missense mutation in transcription factor FOXL2 (402C→G) is present in vast majority of human GCTs. FOXL2 plays a key role in the development and function of normal granulosa cells. Wild type (wt) FOXL2 induces GCT cell apoptosis, while mutated FOXL2 is less effective. To clarify the molecular pathogenesis of GCTs, we investigated the impact of FOXL2 and two other factors implicated in granulosa cell function, GATA4 and SMAD3, on gene expression and cell viability in GCTs. We found that these factors physically interact and that GATA4 and SMAD3 synergistically induce CCND2 promoter transactivation, which is reduced by both wt and mutated FOXL2. Finally, we demonstrated that GATA4 and SMAD3 protect GCT cells from wt FOXL2 induced apoptosis without affecting the apoptosis induced by mutated FOXL2. These findings suggest that mutated FOXL2 disrupts the balance between growth and apoptosis in granulosa cells, leading to malignant transformation. The treatment of recurrent or metastatic GCTs is challenging, and biologically targeted treatment modalities are needed. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) activates the extrinsic apoptotic pathway. Interestingly, TRAIL is able to induce apoptosis in malignant cells without affecting normal cells. Vascular endothelial growth factor (VEGF) is the key regulator of both physiological and pathological angiogenesis. Cancer cells often express VEGF receptor, and an autocrine VEGF/VEGFR signaling loop exists in several types of cancer cells. We found that GCT cells express functional TRAIL and VEGF receptors, and that treatment with TRAIL and the VEGF-binding antibody (bevacizumab) induce GCT cell apoptosis. These findings establish a preclinical basis for targeting these two pathways in the GCT treatment.
  • Myöhänen, Heli (Helsingin yliopisto, 2003)
  • Martelin, Eeva (Helsingin yliopisto, 2004)
  • Tojkander, Sari (Helsingin yliopisto, 2007)
    Functional loss of tumor suppressor protein p53 is a common feature in diverse human cancers. The ability of this protein to sense cellular damage and halt the progression of the cell cycle or direct the cells to apoptosis is essential in preventing tumorigenesis. Tumors having wild-type p53 also respond better to current chemotherapies. The loss of p53 function may arise from TP53 mutations or dysregulation of factors controlling its levels and activity. Probably the most significant inhibitor of p53 function is Mdm2, a protein mediating its degradation and inactivation. Clearly, the maintenance of a strictly controlled p53-Mdm2 route is of great importance in preventing neoplastic transformation. Moreover, impairing Mdm2 function could be a nongenotoxic way to increase p53 levels and activity. Understanding the precise molecular mechanisms behind p53-Mdm2 relationship is thus essential from a therapeutic point of view. The aim of this thesis study was to discover factors affecting the negative regulation of p53 by Mdm2, causing activation of p53 in stressed cells. As a model of cellular damage, we used UVC radiation, inducing a complex cellular stress pathway. Exposure to UVC, as well as to several chemotherapeutic drugs, causes robust transcriptional stress in the cells and leads to activation of p53. By using this model of cellular stress, our goal was to understand how and by which proteins p53 is regulated. Furthermore, we wanted to address whether these pathways affecting p53 function could be altered in human cancers. In the study, two different p53 pathway proteins, nucleophosmin (NPM) and promyelocytic leukemia protein (PML), were found to participate in the p53 stress response following UV stress. Subcellular translocations of these proteins were discovered rapidly after exposure to UV. The alterations in the cellular localizations were connected to transient interactions with p53 and Mdm2, implicating their significance in the regulation of p53 stress response. NPM was shown to control Mdm2-p53 interface and mediate p53 stabilization by blocking the ability of Mdm2 to promote p53 degradation. Furthermore, NPM mediated p53 stabilization upon viral insult. We further detected a connection between cellular pathways of NPM and PML, as PML was found to associate with NPM in UV-radiated cells. The observed temporal UV-induced interactions strongly imply existence of a multiprotein complex participating in the p53 response. In addition, PML controlled the UV response of NPM, its localization and complex formation with chromatin associated factors. The relevance of the UV-promoted interactions was demonstrated in studies in a human leukemia cell line, being under abnormal transcriptional repression due to expression of oncogenic PML-RARa fusion protein. Reversing the leukemic phenotype with a therapeutically significant drug was associated with similar complex formation between p53 and its partners as following UV. In conclusion, this thesis study identifies novel p53 pathway interactions associated with the recovery from UV-promoted as well as oncogenic transcriptional repression.
  • Al-Jamal, Rana'a (Helsingin yliopisto, 2011)
    Uveal melanoma (UM) is the second most common primary intraocular cancer worldwide. It is a relatively rare cancer, but still the second most common type of primary malignant melanoma in humans. UM is a slowly growing tumor, and gives rise to distant metastasis mainly to the liver via the bloodstream. About 40% of patients with UM die of metastatic disease within 10 years of diagnosis, irrespective of the type of treatment. During the last decade, two main lines of research have aimed to achieve enhanced understanding of the metastasis process and accurate prognosis of patients with UM. One emphasizes the characteristics of tumor cells, particularly their nucleoli, and markers of proliferation, and the other the characteristics of tumor blood vessels. Of several morphometric measurements, the mean diameter of the ten largest nucleoli (MLN) has become the most widely applied. A large MLN has consistently been associated with high likelihood of dying from UM. Blood vessels are of paramount importance in metastasis of UM. Different extravascular matrix patterns can be seen in UM, like loops and networks. This presence is associated with death from metastatic melanoma. However, the density of microvessels is also of prognostic importance. This study was undertaken to help understanding some histopathological factors which might contribute to developing metastasis in UM patients. Factors which could be related to tumor progression to metastasis disease, namely nucleolar size, MLN, microvascular density (MVD), cell proliferation, and The Insulin-like Growth Factor 1 Receptor(IGF-1R), were investigated. The primary aim of this thesis was to study the relationship between prognostic factors such as tumor cell nucleolar size, proliferation, extravascular matrix patterns, and dissemination of UM, and to assess to what extent there is a relationship to metastasis. The secondary goal was to develop a multivariate model which includes MLN and cell proliferation in addition to MVD, and which would fit better with population-based, melanoma-related survival data than previous models. I studied 167 patients with UM, who developed metastasis even after a very long time following removal of the eye, metastatic disease was the main cause of death, as documented in the Finnish Cancer Registry and on death certificates. Using an independent population-based data set, it was confirmed that MLN and extravascular matrix loops and networks were unrelated, independent predictors of survival in UM. Also, it has been found that multivariate models including MVD in addition to MLN fitted significantly better with survival data than models which excluded MVD. This supports the idea that both the characteristics of the blood vessels and the cells are important, and the future direction would be to look for the gene expression profile, whether it is associated more with MVD or MLN. The former relates to the host response to the tumor and may not be as tightly associated with the gene expression profile, yet most likely involved in the process of hematogenous metastasis. Because fresh tumor material is needed for reliable genetic analysis, such analysis could not be performed Although noninvasive detection of certain extravascular matrix patterns is now technically possible,in managing patients with UM, this study and tumor genetics suggest that such noninvasive methods will not fully capture the process of clinical metastasis. Progress in resection and biopsy techniques is likely in the near future to result in fresh material for the ophthalmic pathologist to correlate angiographic data, histopathological characteristics such as MLN, and genetic data. This study supported the theory that tumors containing epithelioid cells grow faster and have poorer prognosis when studied by cell proliferation in UM based on Ki-67 immunoreactivity. Cell proliferation index fitted best with the survival data when combined with MVD, MLN, and presence of epithelioid cells. Analogous with the finding that high MVD in primary UM is associated with shorter time to metastasis than low MVD, high MVD in hepatic metastasis tends to be associated with shorter survival after diagnosis of metastasis. Because the liver is the main organ for metastasis from UM, growth factors largely produced in the liver hepatocyte growth factor, epidermal growth factor and insulin-like growth factor-1 (IGF-1) together with their receptors may have a role in the homing and survival of metastatic cells. Therefore the association between immunoreactivity for IGF-1R in primary UM and metastatic death was studied. It was found that immunoreactivity for IGF-IR did not independently predict metastasis from primary UM in my series.
  • Vaara, Suvi (Helsingin yliopisto, 2012)
    Acute kidney injury (AKI), defined as an abrupt decrease in kidney function, is frequent among intensive care unit (ICU) patients and increases their morbidity and mortality. Severe AKI is treated with renal replacement therapy (RRT). Of all general ICU patients, 3% to 8% receive RRT for AKI. Patients with RRT have high mortality rates, up to 50% to 60%; as such, improvements in their treatment are clearly warranted. Thus, the objectives of this study were to evaluate the incidence and outcome of critically ill patients receiving RRT for AKI in Finland. The association of ICU size and presence of fluid overload at RRT initiation with outcome were investigated and the provided RRT described. Additionally, the quality of published pharmacokinetic studies in patients receiving continuous RRT was studied. The population-based incidence of RRT for AKI, the outcome of these patients, and outcome-associated factors were evaluated first in a retrospective cohort including 24 904 adult patients treated in 24 Finnish ICUs during 2007-2008, of which 1686 (6.8%) received RRT for AKI. The population-based incidence of RRT for AKI was 20 per 100 000 adults per year. The hospital mortality of RRT-treated patients was 35%, and the 6-month mortality was 49%. Patients with RRT who were treated in small central hospitals had higher crude and adjusted hospital mortality rates compared to those treated in larger hospitals. Second, a prospective cohort study included 296 adult patients with RRT in 17 Finnish ICUs over a five-month period in 2011-2012. The 90-day mortality of RRT-treated patients was 39%. Presence of fluid overload at RRT initiation was associated with an increased risk for 90-day mortality. RRT was initiated after a median of 14 hours from ICU admission in the presence of a median of three indications. Initially, 73% of the patients received continuous RRT and the used continuous RRT dose was in line with the current recommendations. Altogether 49 original publications reporting pharmacokinetic results of adult critically ill patients receiving continuous RRT were included in a systematic review. The general quality of these studies was moderate, while the reporting of RRT-related parameters remained inadequate. The used continuous RRT dose was mainly according to recommendations. In summary, the population-based incidence of RRT for AKI was broadly in line with reports from other regions. The mortality rates of these patients were high compared to other ICU-treated syndromes, but lower than previously reported for this patient group. Patients treated with RRT in small ICUs and those with fluid overload at RRT initiation demonstrated worse outcome. The reporting of parameters related to continuous RRT in pharmacokinetic studies was inadequate.
  • Linna, Milla (Helsingin yliopisto, 2014)
    The aim of this thesis was to study the impact of eating disorders on young women's reproductive and psychological health in both clinical and population-based settings. Two samples of women were utilized to meet these goals. First, women treated at the eating disorder clinic of Helsinki University Central Hospital during 1995-2010 (n=2257) were compared with matched controls drawn from the Central Population Register (n=9028). Register-based measures of general reproductive outcomes, course of pregnancy and childbirth, and perinatal health outcomes were compared across these two groups in Studies I and II. Second, twins born in Finland during 1975-1979 (FinnTwin16, n=2825 women) were assessed at the age of 22-28 years by means of a mailed questionnaire that included several measures of psychological health as well as a screen for eating disorders, followed by diagnostic interviews. Studies III-V compared the twins with a history of lifetime eating disorders with their unaffected twin sisters and healthy women to evaluate recovery rates and psychological outcomes. The probability of recovery from anorexia nervosa and bulimia nervosa in the twin sample five years after the onset of the illness was 67% and 57%, respectively. Many of the women treated for an eating disorder had experienced reproductive health problems at follow-up, but most of them had no complications in pregnancy or childbirth. In the clinical sample, an increased likelihood of remaining childless was found among women with anorexia nervosa, whereas women with bulimia nervosa were more likely to experience induced abortion, and miscarriage was common among women with binge eating disorder (BED) in comparison with the controls. Maternal anorexia nervosa and BED were related to abnormal patterns of fetal growth during pregnancy. Significantly, severe perinatal health complications were observed in women treated for anorexia nervosa or bulimia nervosa. The psychological outcomes of anorexia nervosa and bulimia nervosa were more favorable in the twin cohort than previously reported. Recovery was slow and gradual, but most women with anorexia nervosa reached the level of their unaffected twin sisters in terms of psychological health over time. The course of bulimia nervosa was marked by a more gradual easing of symptoms. Body dissatisfaction and psychosomatic symptoms seemed to be the most persistent residua of both illnesses. Overall, the outcome was poor for some, but favorable for most women with a history of eating disorders. Several reproductive health problems were observed among women who had received treatment, suggesting the need for enhanced monitoring of pregnancies among these women. However, in the twin cohort, most women with a history of eating disorders proceeded towards recovery, did not experience reproductive impairment, and, on measures of psychological health, resembled their unaffected twin sisters more closely over time.
  • Larivaara, Meri (Helsingin yliopisto, 2012)
    Since the late 1990s Russia has seen rapid social change in terms of population decline and low fertility. The health service system has been reformed. A mandatory health insurance system has been constructed and the development of the private sector has taken place. In the field of reproductive health services attitudes towards maternity care, birth control, and termination of pregnancy have undergone considerable change. At the same time new technologies have become available. Access to reliable contraception has improved and the number of induced abortions has declined, but the use of unreliable birth control methods continues to be common practice. Previous studies have reported that many patients are dissatisfied with the quality of health services in the public sector. ---- Relatively little is known about reproductive health providers' knowledge, attitudes and practices concerning family planning. Information about providers' roles in reproductive health promotion is scarce and scattered. Previous literature points to missed opportunities in reproductive health counselling and low patient involvement in clinical decision-making. The objective of this study was to increase the current understanding of the obstacles that limit the extent and effectiveness of reproductive health counselling in the public sector out-patient services in urban Russia. The specific aims were (1) to describe how the delivery of women's reproductive health services is organised in St Petersburg, (2) to analyse the challenges in women's reproductive health services as perceived by health administrators and practising gynaecologists, (3) to analyse gynaecologists' views and practices concerning preventing, planning, and monitoring pregnancy, and (4) to examine gynaecologists' perceptions of the provider-patient relationship. The data of this study are qualitative, consisting of semi-structured interviews and observations. The data were collected between January and May 2005. The data collection consisted of four parts: (1) semi-structured background interviews with administrative personnel and medical professors (N=9), and managers of women's out-patient clinics (N=9), (2) a pilot study involving observations (N=3) and semi-structured interviews (N=2) at a women's out-patient clinic, (3) observations (N=17) and semi-structured interviews (N=12) at two women's out-patient clinics, and (4) visits and comparison interviews (N=4) at five women's out-patient clinics. The main method of data analysis was content analysis. The women's clinics provided a variety of services ranging from preventative gynaecological check-ups and contraceptive counselling to monitoring of pregnancies and treatment of gynaecological complaints. More than 40 per cent of the patient visits concerned monitoring pregnancy, whereas contraceptive counselling was the primary purpose of the visit in only a small number of cases. Women's clinics suffered from a low level of formal funding, which has resulted in user charges in breach of the mandatory health insurance legislation. The clinics had also developed commercial services to improve their financial situation. Many of the study participants were concerned about equal access to health services and the decline of health promotion. The gynaecologists were well-informed about the latest contraceptive methods and had a positive attitude towards promoting their use. They offered contraceptive counselling to many patients, but the coverage was not 100 per cent among women of reproductive age. The depth of contraceptive counselling varied considerably. In about two-thirds of the observed cases patient involvement was low and counselling was provider-centred, but in approximately a third of the cases patient preferences influenced the clinical decision-making process. Gynaecologists regarded the use of reliable contraception as a means of protecting future fertility and avoiding terminations and as a sign of responsible and morally respectable womanhood. Gynaecologists held a medicalised view of pregnancy planning, promoting gynaecological examinations and diagnostic tests before pregnancy. In practice they emphasised specialist knowledge and risk management in monitoring pregnancy, although they thought their work should ideally combine medical expertise and maternal caretaking. The practising gynaecologists felt that there were many gaps in the provider-patient relationship and that patients did not pay enough attention to reproductive health matters. The gynaecologists expressed patient-centred and holistic ideas about patient work in interviews, but patient involvement was limited during the observed clinical encounters. The gynaecologists emphasised medical authority in interviews, but they also wished for warm and trusting provider-patient relationships. The study results suggest that mandatory health benefit packages should be defined in detail and that reforms are needed to the compensation provided by mandatory health insurance to women's clinics. The results indicate that gynaecologists need continuing education in patient-centred counselling and treatment and in how to involve patients in clinical decision-making. The results point to several implications for future research including the need to broaden models of the provider-patient relationship to incorporate mutual liking and trust in the existing models of patient involvement.
  • Sommarhem, Antti (Helsingin yliopisto, 2007)
    Rituximab, a monoclonal antibody against B-cell specific CD20 antigen, is used for the treatment of non-Hodgkin lymphomas (NHL) and chronic lymphatic leukemia. In combination with chemotherapeutics rituximab has remarkably improved the outcome of NHL patients, but a vast variation in the lengths of remissions remains and the outcome of individual patients is difficult to predict. This thesis has searched for an explanation for this by studying the effector mechanisms of rituximab and by comparing gene expression in lymphoma tissue samples of patients with long- and short-term survival. This work demonstrated that activation of complement (C) system is in vitro more efficient effector mechanism of rituximab than cellular mechanisms or apoptosis. Activation of the C system was also shown in vivo during rituximab treatment. However, intravenously administered rituximab could not enter the cerebrospinal fluid, and neither C activation nor removal of lymphoma cells was observed in central nervous system. In vitro cytotoxicity assays showed that rituximab-induced cell killing could be markedly improved with simultaneous neutralization of the C regulatory proteins CD46 (Membrane cofactor protein), CD55 (Decay-accelerating factor), and CD59 (protectin). In a retrospective study of follicular lymphoma (FL) patients, low lymphoma tissue mRNA expressions of CD59 and CD55 were associated with a good prognosis and in a progressive flow cytometry study high expression of CD20 relative to CD55 was correlated to a longer progression free survival. Gene expression profile analysis revealed that expression of certain often cell cycle, signal transduction or immune response related genes correlate with clinical outcome of FL patients. Emphasizing the role of tumor microenvironment the best differentiating genes Smad1 and EphA1 were demonstrated to be mainly expressed in the non-malignant cells of tumors. In conclusion, this thesis shows that activation of the C system is a clinically important effector mechanism of rituximab and that microenvironment factor in tumors and expression of C regulatory proteins affect markedly the efficacy of immunochemotherapy. This data can be used to identify more accurately the patients for whom immunochemotherapy is given. It may also be beneficial in development of rituximab-containing and other monoclonal antibody therapies against cancer.