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  • Koskensalo, Selja (Helsingin yliopisto, 2013)
    Background and aims: The most important prognostic factor in colorectal cancer (CRC) is tumour stage. Prognosis of local tumours is good, but in tumours with lymph node or distant metastasis, the prognosis is worse. Patients with stage III (Dukes C) tumours usually receive adjuvant chemotherapy. Patients with stage IV (Dukes D) tumours cannot be treated curatively by surgery alone and usually receive chemotherapy. In stage II (Dukes B) disease, adjuvant chemotherapy is recommended for patients at risk for recurrence, such as with tumours with vascular or perineural invasion, or in cases with emergency surgery or insufficient lymph-node harvest. In order to identify better those patients requires additional prognostic factors like biomarkers. Material and methods: Clinical data came from 643 consecutive patients who underwent surgery for colorectal cancer at the Department of Surgery, Meilahti Hospital, Helsinki University Central Hospital, between 1982 and 1998. Clinical data and archival tissue specimens were available from 623 cases. For MMP-9, a validation series of 213 patients treated between 1998 and 2001 was included. Survival data came from the Population Register Centre of Finland and Statistics Finland. Tissue microarray (TMA) blocks were prepared from re-evaluated histological archive blocks. TMA slides were stained with MMP-2, MMP-7, MMP-8, MMP-9, TATI, trypsinogen-1, trypsinogen-2, p53, Ki-67, and EGFR antibodies. Correlation of immunoexpression of markers with clinicopathological variables was assessed. Survival analysis was performed by the Kaplan-Meier method, and multivariate Cox proportional hazards model. Results: Study I showed strong MMP-7 to be an independent prognostic marker for 5-year survival, but later the difference faded. In Study II, no association was observable between p53 or Ki-67 expression and survival. In Study III, TATI immunoexpression was an independent prognostic marker for improved survival, particularly in subgroups of trypsinogen-1- and trypsinogen-2-positive patients, although trypsinogen-1 and trypsinogen-2 were not prognostic factors. In Study IV, MMP-9 expression was an independent prognostic marker of favourable survival in Dukes B patients, but the validation series did not confirm these results. MMP-2 and MMP-8 immunoexpression lacked any correlation with prognosis. In Study V, EGFR+TATI+ patients had significantly better prognosis than did those with EGFR+TATI-, EGFR-TATI+, or EGFR-TATI-. Conclusion: MMP-7, MMP-9, TATI, and the TATI-EGFR combination can all serve as prognostic biomarkers in CRC.
  • Kanerva, Jukka (Helsingin yliopisto, 2002)
  • Koljonen, Virve (Helsingin yliopisto, 2004)
  • Ilmonen, Suvi (Helsingin yliopisto, 2005)
  • Taskinen, Minna (Helsingin yliopisto, 2011)
    Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma. It is an indolent and clinically heterogeneous disease, which is generally considered incurable. Currently, immunochemotherapy has significantly improved the outcome of FL patients. This is based on the combination of rituximab, a monoclonal anti-CD20 antibody, with chemotherapy, and is used at present as a standard first-line therapy in FL. Thus far, however, patients have been selected for treatment based on clinical risk factors and indices that were developed before the rituximab era. Therefore, there is a growing need to understand the molecular mechanisms underlying the disease, which would not only provide information to predict survival in the rituximab era, but also enable the design of more targeted therapeutic strategies. In this study, our aim was to identify genes predicting the outcome in FL patients treated with immunochemotherapy. Thus, we performed a cDNA microarray with 24 FL patients. When gene expression differences from diagnostic tumour samples were related to the clinical outcome, we identified novel genes with a prognostic impact on survival. The expression of selected genes was further characterized with quantitative PCR and immunohistochemistry (IHC). Interestingly, the prognostic influence of these genes was often associated with their expression in non-malignant cells instead of tumour cells. Based on the observed gene expression patterns, we analyzed the abundance and prognostic value of non-malignant immune cells in 95-98 FL patients treated with immunochemotherapy. We observed that a high content of tumour-associated macrophages was a marker of a favourable prognosis. In contrast, the accumulation of mast cells correlated with a poor outcome and was further associated with tumour vascularity. Increased microvessel density also correlated with an inferior outcome. In addition, we used the same microarray data with a systems biology approach to identify signalling pathways or groups of genes capable of separating patients with favourable or adverse outcomes. Among the transcripts, there were many genes associated with signal transducers and activators of the transcription (STAT5a) pathway. When IHC was used as validation, STAT5a expression was mostly observed in T-cells and follicular dendritic cells, and expression was found to predict a favourable outcome. In cell cultures, rituximab was observed to induce the expression of STAT5a-associated interleukins in human lymphoma cell lines, which might provide a possible link for the cross-talk between rituximab-induced FL cells and their microenvironment. In conclusion, we have demonstrated that the microenvironment has a prognostic role in FL patients treated with immunochemotherapy. The results also address the importance of re-evaluating the prognostic markers in the rituximab era of lymphoma therapies.
  • Mäkitie, Teemu (Helsingin yliopisto, 2001)
  • Koskinen, Walter (Helsingin yliopisto, 2006)
    Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Well-known risk factors include tobacco smoking and alcohol consumption. Overall survival has improved, but is still low especially in developing countries. One reason for this is the often advanced stage of the disease at the time of diagnosis, but also lack of reliable prognostic tools to enable individualized patient treatment to improve outcome. To date, the TNM classification still serves as the best disease evaluation criterion, although it does not take into account the molecular basis of the tumor. The need for surrogate molecular markers for more accurate disease prediction has increased research interests in this field. We investigated the prevalence, physical status, and viral load of human papillomavirus (HPV) in HNSCC to determine the impact of HPV on head and neck carcinogenesis. The prevalence and genotyping of HPV were assessed with an SPF10 PCR microtiter plate-based hybridization assay (DEIA), followed by a line probe-based genotyping assay. More than half of the patients had HPV DNA in their tumor specimens. Oncogenic HPV-16 was the most common type, and coinfections with other oncogenic and benign associated types also existed. HPV-16 viral load was unevenly distributed among different tumor sites; the tonsils harbored significantly greater amounts of virus than other sites. Episomal location of HPV-16 was associated with large tumors, and both integrated and mixed forms of viral DNA were detected. In this series, we could not show that the presence of HPV DNA correlated with survival. In addition, we investigated the prevalence and genotype of HPV in laryngeal carcinoma patients in a prospective Nordic multicenter study based on fresh-frozen laryngeal tumor samples to determine whether the tumors were HPV-associated. These patients were also examined and interviewed at diagnosis for known risk factors, such as tobacco smoking and alcohol consumption, and for several other habituations to elucidate their effects on patient survival. HPV analysis was performed with the same protocols as in the first study. Only 4% of the specimens harbored HPV DNA. Heavy drinking was associated with poor survival. Heavy drinking patients were also younger than nonheavy drinkers and had a more advanced stage of disease at diagnosis. Heavy drinkers had worse oral hygiene than nonheavy drinkers; however, poor oral hygiene did not have prognostic significance. History of chronic laryngitis, gastroesophageal reflux disease, and orogenital sex contacts were rare in this series. To clarify why vocal cord carcinomas seldom metastasize, we determined tumor lymph vessel (LVD) and blood vessel (BVD) densities in HNSCC patients. We used a novel lymphatic vessel endothelial marker (LYVE-1 antibody) to locate the lymphatic vessels in HNSCC samples and CD31 to detect the blood microvessels. We found carcinomas of the vocal cords to harbor less lymphatic and blood microvessels than carcinomas arising from sites other than vocal cords. The lymphatic and blood microvessel densities did not correlate with tumor size. High BVD was strongly correlated with high LVD. Neither BVD nor LVD showed any association with survival in our series. The immune system plays an important role in tumorigenesis, as neoplastic cells have to escape the cytotoxic lymphocytes in order to survive. Several candidate HLA class II alleles have been reported to be prognostic in cervical carcinomas, an epithelial malignancy resembling HNSCC. These alleles may have an impact on head and neck carcinomas as well. We determined HLA-DRB1* and -DQB1* alleles in HNSCC patients. Healthy organ donors served as controls. The Inno-LiPA reverse dot-blot kit was used to identify alleles in patient samples. No single haplotype was found to be predictive of either the risk for head and neck cancer, or the clinical course of the disease. However, alleles observed to be prognostic in cervical carcinomas showed a similar tendency in our series. DRB1*03 was associated with node-negative disease at diagnosis. DRB1*08 and DRB1*13 were associated with early-stage disease; DRB1*04 had a lower risk for tumor relapse; and DQB1*03 and DQB1*0502 were more frequent in controls than in patients. However, these associations reached only borderline significance in our HNSCC patients.
  • Raj, Rahul (Helsingin yliopisto, 2014)
    Background: Prognostic models are important tools for heterogeneity adjustment in traumatic brain injury (TBI). Prognoses after TBI have been particularly challenging to predict, with limited availability of robust prognostic models. TBI patients are by definition trauma patients, and often treated in the intensive care unit (ICU). Several prognostic models for ICU and trauma patients have been developed, although their applicability in patients with TBI is uncertain. Recently, however, some new prognostic models specifically designed for patients with TBI were introduced. Still, the optimal type of prognostic model in TBI remains unknown. Aim: To investigate the applicability of different types of prognostic models in patients with TBI and to develop novel models with enhanced performance to previous models, focusing on long- term outcome prediction. Methods: Four patient databases of patients with TBI treated in the ICU were used to validate three TBI specific models, two computerized tomography (CT) scoring systems, one trauma scoring system, and three intensive care scoring systems. Models were validated by assessing their discrimination using area under the curve (AUC), calibration, and explanatory variation. Logistic regression was used for model customization and development. Models were internally validated using a resample bootstrap technique or a split-sample technique. Primary outcome was six-month mortality and unfavorable neurological outcome by the Glasgow Outcome Scale. 30-day in-hospital mortality was used for the trauma scoring system. Results: Study populations ranged from 342 to 9,915 patients. The TBI models showed the best performance with AUCs between 0.80 and 0.85, followed by the intensive care scoring systems and the CT scores with AUCs between 0.68 to 0.80 and 0.63 to 0.70, respectively. Most models showed poor calibration, although good calibration was achieved following customization. The trauma scoring system exhibited modest to good discrimination (AUC 0.76-0.89) for short-term mortality prediction, but poor calibration. Several new prognostic models, with statistically significant superior performance to previous models were created, among them a combined TBI-ICU model ( IMPACT-APACHE ) and a novel CT scoring system ( The Helsinki CT score ). Using a TBI specific model, based on admission characteristics, up to 40 % of the patient s final long-term outcome could be predicted. Conclusion: The TBI models showed superior predictive performance to the intensive care and trauma scoring systems, showing that TBI patients are a highly specific population in the trauma and ICU setting. Thus, the use of a TBI specific model is advocated in the setting of TBI. The newly proposed models were found to be significant improvements over previous models, but require external validation to show generalizability.
  • Nyman, Heidi (Helsingin yliopisto, 2010)
    Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin lymphomas. As DLBCL is characterized by heterogeneous clinical and biological features, its prognosis varies. To date, the International Prognostic Index has been the strongest predictor of outcome for DLBCL patients. However, no biological characters of the disease are taken into account. Gene expression profiling studies have identified two major cell-of-origin phenotypes in DLBCL with different prognoses, the favourable germinal centre B-cell-like (GCB) and the unfavourable activated B-cell-like (ABC) phenotypes. However, results of the prognostic impact of the immunohistochemically defined GCB and non-GCB distinction are controversial. Furthermore, since the addition of the CD20 antibody rituximab to chemotherapy has been established as the standard treatment of DLBCL, all molecular markers need to be evaluated in the post-rituximab era. In this study, we aimed to evaluate the predictive value of immunohistochemically defined cell-of-origin classification in DLBCL patients. The GCB and non-GCB phenotypes were defined according to the Hans algorithm (CD10, BCL6 and MUM1/IRF4) among 90 immunochemotherapy- and 104 chemotherapy-treated DLBCL patients. In the chemotherapy group, we observed a significant difference in survival between GCB and non-GCB patients, with a good and a poor prognosis, respectively. However, in the rituximab group, no prognostic value of the GCB phenotype was observed. Likewise, among 29 high-risk de novo DLBCL patients receiving high-dose chemotherapy and autologous stem cell transplantation, the survival of non-GCB patients was improved, but no difference in outcome was seen between GCB and non-GCB subgroups. Since the results suggested that the Hans algorithm was not applicable in immunochemotherapy-treated DLBCL patients, we aimed to further focus on algorithms based on ABC markers. We examined the modified activated B-cell-like algorithm based (MUM1/IRF4 and FOXP1), as well as a previously reported Muris algorithm (BCL2, CD10 and MUM1/IRF4) among 88 DLBCL patients uniformly treated with immunochemotherapy. Both algorithms distinguished the unfavourable ABC-like subgroup with a significantly inferior failure-free survival relative to the GCB-like DLBCL patients. Similarly, the results of the individual predictive molecular markers transcription factor FOXP1 and anti-apoptotic protein BCL2 have been inconsistent and should be assessed in immunochemotherapy-treated DLBCL patients. The markers were evaluated in a cohort of 117 patients treated with rituximab and chemotherapy. FOXP1 expression could not distinguish between patients, with favourable and those with poor outcomes. In contrast, BCL2-negative DLBCL patients had significantly superior survival relative to BCL2-positive patients. Our results indicate that the immunohistochemically defined cell-of-origin classification in DLBCL has a prognostic impact in the immunochemotherapy era, when the identifying algorithms are based on ABC-associated markers. We also propose that BCL2 negativity is predictive of a favourable outcome. Further investigational efforts are, however, warranted to identify the molecular features of DLBCL that could enable individualized cancer therapy in routine patient care.
  • Mrena, Johanna (Helsingin yliopisto, 2011)
    Background and aims: Low stage and curative surgery are established factors for improved survival in gastric cancer. However, not all low-stage patients have a good prognosis. Cyclooxygenase-2 (COX-2) is known to associate with reduced survival in several cancers, and has been shown to play an important role in gastric carcinogenesis. Since new and better prognostic markers are needed for gastric cancer, we studied the prognostic significance of COX-2 and of markers that associate with COX-2 expression. We also studied markers reflecting proliferation and apoptosis, and evaluated their association with COX-2. Our purpose was to construct an accurate prognostic model by combining tissue markers and clinicopathogical factors. Materials and methods: Of 342 consecutive patients who underwent surgery for gastric cancer at Meilahti Hospital, Helsinki University Central Hospital, 337 were included in this study. Low stages I to II were represented by 141 (42%) patients, and high stages III to IV by 196 (58%). Curative surgery was performed on 176 (52%) patients. Survival data were obtained from the national registers. Slides from archive tissue blocks were prepared for immunohistochemistry by use of COX-2, human antigen R (HuR), cyclin A, matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), and Ki-67 antibodies. Immunostainings were scored by microscopy, and scores were entered into a database. Associations of tumor markers with clinicopathological factors were calculated, as well as associations with p53, p21, and results of flow cytometry from earlier studies. Survival analysis was performed by the Kaplan-Meier method, and Cox multivariate models were reconstructed. Cell culture experiments were performed to explore the effect of small interfering (si)RNA of HuR on COX-2 expression in a TMK-1 gastric cancer cell line. Results: Overall 5-year survival was 35.1%. Study I showed that COX-2 was an independent prognostic factor, and that the prognostic impact of COX-2 was more pronounced in low-stage patients. Cytoplasmic HuR expression also associated with reduced survival in gastric cancer patients in a non-independent manner. Cell culture experiments showed that HuR can regulate COX-2 expression in TMK-1 cells in vitro, with an association also between COX-2 and HuR tissue expression in a clinical material. In Study II, cyclin A was an independent prognostic factor and was associated with HuR expression in the gastric cancer material. The results of Study III showed that epithelial MMP-2 associated with survival in univariate, but not in multivariate analysis. However, MMP-9 showed no prognostic value. MMP-2 expression was associated with COX-2 expression. In Study IV, the prognostic power of COX-2 was compared with that of all tested markers associated with survival in Studies I to III, as well as with p21, p53, and flow cytometry results. COX-2 and p53 were independent prognostic factors, and COX-2 expression was associated with that of p53 and Ki-67 and also with aneuploidy. Conclusions: COX-2 is an independent prognostic factor in gastric cancer, and its prognostic power emerges especially in low stage cancer. COX-2 is regulated by HuR, and is associated with factors reflecting invasion, proliferation, and apoptosis. In an extended multivariate model, COX-2 retained its position as an independent prognosticator. COX-2 can be considered a promising new prognostic marker in gastric cancer.
  • Juuti, Anne (Helsingin yliopisto, 2006)
    Background. Pancreatic cancer is one of the major causes of cancer death in the industrialised world. The overall survival of patients with ductal pancreatic adenocarcinoma is poor: 5-year survival is only 0.2 to 4%. Tumour stage and histological grade are used as prognostic markers in pancreatic cancer. However, there are differences in survival within stages and histological grades. New, additional and more accurate prognostic tools are needed. Aims. The purpose of this study was to investigate whether the tissue expression of potential and promising tumour markers p27, tenascin C, syndecan-1, COX-2 and MMP-2 are associated with clinicopathological parameters in pancreatic cancer. The expression of p27, tenascin C and syndecan-1 was also evaluated in acute and chronic pancreatitis. The main purpose in the study was to find new prognostic markers for pancreatic adenocarcinoma. Patients. The study included 147 patients with histologically verified pancreatic adenocarcinoma treated at Helsinki University Central Hospital from 1974 to1998. Methods. The expression of tumour marker antigens was demonstrated by immunohistochemistry using monoclonal antibodies against p27, syndecan-1, tenascin C, COX-2 and MMP-2. The results were compared with clinicopathological variables, i.e. age, sex, TNM stage and histological grade. Survival analyses were performed with univariate Kaplan-Meier life-tables and the log-rank test, while multivariate analyses were performed using Cox regression. Results. Pancreatic adenocarcinomas expressed p27, syndecan-1, tenascin C, COX-2 and MMP-2 in 30, 94, 92, 36 and 50% of the samples, respectively. Loss of p27 expression was associated with poor prognosis in stage I and II pancreatic cancer. Stromal syndecan-1 expression was an independent prognostic marker in pancreatic cancer, whereas epithelial syndecan-1 expression predicted better prognosis only in stage I and II disease. Tenascin C expression did not correlate with survival but was associated with differentiation. COX-2 expression was associated with poor outcome and was an independent prognostic factor. Epithelial MMP-2 correlated with poor prognosis in pancreatic cancer. Conclusion: p27 and epithelial syndecan-1 are prognostic markers in early (stage I and II) pancreatic cancer. Stromal syndecan-1, COX-2 and epithelial MMP-2 are prognostic factors in ductal pancreatic adenocarcinoma.
  • Mizohata, Kenichiro (Helsingin yliopisto, 2012)
    Elastic recoil detection analysis (ERDA) with heavy ion beams has evolved into a universal ion beam analysis (IBA) method for simultaneous analysis of almost all elements, with an essentially constant detection sensitivity. The method is based on the detection and identification of recoiling atoms that have been elastically scattered from a sample by an incident heavy ion beam. The principal characteristics of heavy-ion ERDA are outlined and illustrated using examples of data obtained with time of flight (TOF) and dE-E detector systems. The potential and limitations of the quantitative analysis were explored. For this purpose, a number of thin layer samples were measured using different projectiles and energies. Desorption of the surface materials during ERDA measurements was determined as a function of the probing ion fluence. As the differential cross-sections for scattering were enhanced for heavy projectiles, the beam dose to which the sample was exposed to during measurements was reduced by using heavy ion beams. However the higher cross-sections caused an increase of the desorption. An essential part of this study was dedicated to study those topics that limit the accuracy of the analysis in heavy ion TOF-ERDA, namely: uncertain stopping forces, quantification accuracy, irradiation induced damage, depth resolution, and the role of multiple and plural scattering. Possible approaches to improve the sample characterisation efficiency and accuracy were studied by using a gas ionisation detector. This study concentrates on the noise reduction, detection characterisation, and analysis procedures. The focus was upon the effect of the large solid angle and position sensitivity on the irradiation induced damage, depth resolution, mass resolution, and elemental sensitivity. The reliability of the concentration distributions obtained with heavy ion ERDA was strongly affected by the surface structure, surface roughness and multiple scattering. These effects were studied by comparing Monte Carlo simulations with the experimental results. The analysis procedure was developed to enable the characterisation of novel materials such as atomic layer deposited thin films and nanoparticles. Data handling and storage was improved to facilitate and speed up the analysis procedures.
  • Tynninen, Olli (Helsingin yliopisto, 2011)
    Gliomas are the most frequent primary brain tumours. The cardinal features of gliomas are infiltrative growth pattern and progression from low-grade tumours to a more malignant phenotype. These features of gliomas generally prevent their complete surgical excision and cause their inherent tendency to recur after initial treatment and lead to poor long-term prognosis. Increasing knowledge about the molecular biology of gliomas has produced new markers that supplement histopathological diagnostics. Molecular markers are also used to evaluate the prognosis and predict therapeutic response. The purpose of this thesis is to study molecular events involved in the malignant progression of gliomas. Gliomas are highly vascularised tumours. Contrast enhancement in magnetic resonance imaging (MRI) reflects a disrupted blood-brain barrier and is often seen in malignant gliomas. In this thesis, 62 astrocytomas, oligodendrogliomas and oligoastrocytomas were studied by MRI and immunohistochemistry. Contrast enhancement in preoperative MRI was associated with angiogenesis, tumour cell proliferation and histological grade of gliomas. Activation of oncogenes by gene amplification is a common genetic aberration in gliomas. EGFR amplification on chromosome 7p12 occurs in 30-40% of glioblastomas. PDGFRA, KIT and VEGFR2 are receptor tyrosine kinase genes located on chromosome 4q12. Amplification of these genes was studied using in situ hybridisation in the primary and recurrent astrocytomas, oligodendrogliomas and oligoastrocytomas of 87 patients. PDGFRA, KIT or VEGFR2 amplification was found in 22% of primary tumours and 36% of recurrent tumours including low-grade and malignant gliomas. The most frequent aberration was KIT amplification, which occurred in 10% of primary tumours and in 27% of recurrent tumours. The expression of ezrin, cyclooxygenase 2 (COX-2) and HuR was studied immunohistochemically in a series of primary and recurrent gliomas of 113 patients. Ezrin is a cell membrane-cytoskeleton linking-protein involved in the migration of glioma cells. The COX-2 enzyme is implicated in the carcinogenesis of epithelial neoplasms and is overexpressed in gliomas. HuR is an RNA-stabilising protein, which regulates the expression of several proteins including COX-2. Ezrin, COX-2 and HuR were associated with histological grade and the overall survival of glioma patients. However, in multivariate analysis they were not independent prognostic factors. In conclusion, these results suggest that contrast enhancement in MRI can be used as a surrogate marker for the proliferative and angiogenic potential of gliomas. Aberrations of PDGFRA, KIT and VEGFR2 genes, as well as the dysregulated expression of ezrin, COX-2 and HuR proteins, are linked to the progression of gliomas.
  • Atanasova, Nina (Helsingin yliopisto, 2013)
    Archaea are commonly found in the most extreme environments on Earth, such as geothermal hot springs, submarine hydrothermal vents and hypersaline lakes. They are also an important part of the biosphere in soils and different types of aquatic environments. Hypersaline environments in different parts of the world are dominated by extremely halophilic archaea from the family Halobacteriaceae, but contain also halophilic bacteria and the green algae Dunaliella, which is the sole primary producer in such ecosystems. Since cellular predators are nearly absent in extreme salinities, haloviruses are the main force influencing cell diversity and evolution of halophilic microorganisms. From the studied aquatic environments, hypersaline lakes and salterns contain the highest numbers of virus-like particles. A high percentage of these are considered to represent archaeal viruses. To date, only a handful of archaeal viruses have been characterized. The described ones infect extreme halophiles, hyperthermophiles, or methanogens and are most famous for having either unique virion architectures, or morphotypes resembling viruses that infect members of the other two domains. The number of viruses on the biosphere is astronomical and viruses represent the greatest genetic diversity on the Earth. However, the limited protein fold space restricts the ways viral capsids can be assembled and it has been proposed that the vast number of viruses can be organized into a limited amount of distinct morphotypes. In order to test this hypothesis, a global sampling of nine different hypersaline environments was performed. Close to 100 strains of halophilic archaea and bacteria and 49 viruses infecting them were isolated. These viruses approximately doubled the number of known archaeal viruses. The majority of the viral isolates were head-tailed myoviruses and siphoviruses and for the first time, podovirus morphology was observed for an archaeal virus. From the four isolated halophilic bacteriophages, three were head-tailed and one, designated as SSIP-1, was the first tailles icosahedral membrane-containing phage described for a halophilic bacterium. An archaeal virus with a similar morphology was also isolated. It is probable, that these two viruses belong to the structure-based lineage of PRD1-like viruses, which are considered to have a common ancestor. In addition to these well-known virus morphotypes, we isolated a group of viruses with a novel, pleomorphic morphology. The isolated four viruses were compared with the previously described pleomorphic HRPV-1, HHPV-1 and His2. These seven viruses, designated as pleolipoviruses, had similar virion architecture consisting of a membrane vesicle which encloses the ssDNA or dsDNA genome without associated nucleoproteins. Pleolipoviruses form a group of related viruses despite having different genome types and thus challenge the current classification of viruses based on similar genome types and replication mechanisms. In addition to virus morphology, we studied microbial interactions in nine hypersaline environments. One third of the isolated archaea and bacteria were found to produce antimicrobial agents called halocins. Several of the identified halocin producers were inhibiting a broad range of sensitive strains, even those belonging to a different domain of life. When virus-host interactions were studied, numerous viruses were found to infect hosts from geographically distant locations. The same observation was done for halocin production-sensitivity interactions, indicating that halophilic microorganisms are globally distributed and able to produce broad spectrum antibiotics.
  • Loponen, Jussi (Helsingin yliopisto, 2006)
    This thesis examines protein behaviours that occur during cereal fermentations. The focus is on the prolamin degradation in sourdoughs. The thesis also looks at what happens to the oat globulins during an oat bran acidification process. The cereal prolamins are unique proteins in many respects. The wheat prolamins (glutenins and gliadins) are responsible for the formation of the gluten that provides the viscoelastic properties to wheat doughs whereas the rye prolamins (secalins) are unable to develop gluten-like structures. In addition, many baking technological features, such as flavour, shelf-life and dough properties are affected by the protein degradation that might occur during processing. On the other hand, the prolamins contain protein structures that are harmful to gluten sensitive people. It is thus evident that the degradation of the prolamins in sourdough processes may be approached from various aspects. This thesis describes some of these approaches. Four different cereal fermentations were carried out. Wheat sourdough (WSD) and rye sourdough (RSD) fermentations represented traditional sourdoughs. A germinated-wheat sourdough (GWSD) was a novel sourdough type that was prepared using germinated wheat grains that had high and diverse proteolytic activities. The oat bran fermentation (OBF) represented a fermentation system that lacked functional cereal proteases. The high molecular weight glutenins and rye secalins were degraded during the WSD and RSD fermentations, respectively. It was noteworthy that in WSD only a very limited degradation of the gliadins occurred. The gliadins were, however, hydrolysed very extensively during the GWSD fermentation. No protein degradation was observable in the OBF system. Instead the acidification altered the solubility of the oat globulins and this finally led to their aggregation. This thesis confirms that the endogenous proteases of cereals hydrolyse cereal prolamins in sourdoughs. The thesis also shows that the proteolytic activity of the used cereal raw material determines the extent of proteolysis that occurs in sourdough. This means that bakers may adjust the protein degradation in their sourdoughs by selecting the raw material based on its proteolytic activity. The thesis also demonstrates that by using germinated grains, with high and diverse proteolytic activity in sourdough preparations, the prolamins can be extensively degraded. Whether such highly proteolytic food technology could be used to manufacture new gluten-free cereal-based products for gluten sensitive people remains to be solved.
  • Posio, Pekka (Helsingin yliopisto, 2012)
    The expression of pronominal subjects by independent subject pronouns is considered optional in both Peninsular Spanish (PS) and European Portuguese (EP). The present dissertation examines and compares the factors affecting the expression vs. omission of subject pronouns in these two languages. The goals are to provide and compare empirical data from PS and EP, to present a theoretical account of the findings and to deepen the understanding of factors affecting subject pronoun use in languages with variable subject expression. The theoretical framework is cognitive-functional, usage-based linguistics. The four articles of the dissertation examine data from different speech corpora. The methodology combines qualitative examination with quantitative frequency analyses. EP is shown to have a significantly higher general rate of expressed subjects than PS. In the first person singular, verb semantics affect subject expression in both languages: agentive verbs have a lower rate of expressed subjects while stative verbs have a higher rate. This tendency is connected with the focusing of attention on either the subject referent or on other participants in the event. In addition to this general tendency, subject expression in connection to the most frequently occurring verb tokens (i.e. I think , I say , I know ) deviates from the general pattern, causing differences between PS and EP. With frequently occurring verb tokens, subject expression has become formulaic, i.e. fixed as a part of the construction where it occurs. While semantics and frequency effects affect subject expression in the first person singular, the first person plural differs between PS and EP in that in PS subject expression is rare and typically restricted to hearer-exclusive reference. In EP, subject expression is found with hearer-inclusive, hearer-exclusive and impersonal reading. In all grammatical persons, the postverbal placement of subject pronouns is shown to serve both contrasting and backgrounding functions. In EP the postverbal placement is mostly restricted to certain non-productive, formulaic sequences. The study contributes to the discussion of variable subject expression in a wider typological and theoretical context. Previously null subject languages have been assumed to form a relatively homogeneous group where subject omission is the norm and expression is reserved for e.g. contrast and emphasis. It is shown that while the factors affecting subject expression may be similar, even closely related languages differ with regard to subject expression rates and subject expression in formulaic constructions.
  • Melgin, Elina (Helsingin yliopisto, 2014)
    This dissertation focuses on the role of art and culture in Finland s national communication, and its impact on foreign relations during the period from 1937 to 1952. Cultural relations are examined through politically important countries: Sweden, the Soviet Union, the United States, Germany, Italy and France. At the beginning of the period covered, the Finnish state began heavily investing in communication. Culture was used in brochures, articles and documentary films, but also in international public relations. Art exhibitions, concerts and presentations were modes of cultural exchange. In addition to the Ministry of Foreign Affairs and embassies, official communication also took place through the information organizations set up by the Finnish state to support the war effort. It was possible to gain sympathy abroad through the national message veiled in the cultural context. Public diplomacy also included semi-official and private actors. The content of Finnish art and culture supported the general messages dictated by the official foreign policy. During the war, culture acted as a weapon against bolshevism. In order to highlight the originality of Finns and the Western orientation of Finnish civilisation, the message consisted of both traditional Kalevala-related art and Western European classical art. The music of Jean Sibelius, the art of Akseli Gallen-Kallela and Wäinö Aaltonen, the poetry of V.A. Koskenniemi and the designs of Alvar Aalto fit the needs of public diplomacy well. This dissertation uses the methodology of conceptual history to analyse whether Finnish national communication should be considered propaganda or public diplomacy. The propagandist role was most evident in the relationship with Germany 1941-43. When the state-run information organizations were discontinued together with censorship after the war, official national communication in Finland reverted back to the Ministry of Foreign Affairs, and the context of diplomacy. Art and culture continued to function as an important instrument of foreign relations, even during the post-war years when free expression of political opinions was more restricted. The Soviet Union built friendly relations with Finland through cultural exchange, as did the United States. In reality, it is difficult of course to separate propaganda from public diplomacy. In the context of culture, this diplomatic role was more pronounced because cultural content seldom became an object of censorship and because decision making on art and cultural content lay with the requisite cultural institutions. It should also be noted that surprisingly many of the officers in the State propaganda machinery had key roles in the domain of art. This dissertation also provides new insights into the history of communication as a profession. One of the central claims is that due to the propagandists deep cultural knowledge, art and culture were instrumental during the exceptional war period. The investment in culture during and immediately after the war strengthened national identity, and the message conveyed through cultural propaganda was canonised as an integral part of Finnish national cultural identity.
  • Kohonen, Anssi (Helsingin yliopisto, 2014)
    This thesis consists of four chapters: an introduction and three independent research papers. The red line in the thesis is to study with time series methods how financial markets propagate financial shocks both across countries and from the financial sector to the real sector of an economy. The introductory chapter presents the three main themes of the thesis contagion, volatility spillovers and real effects of uncertainty and introduces the basic models that the thesis applies. These models are structural vector autoregressive (SVAR) model and (multivariate) generalized autoregressive conditional heteroskedasticity (GARCH) model. The introduction also discusses the identification of the SVAR models which is also an important theme in the thesis. Chapter 2 considers volatility spillovers in the Eurozone during the beginning of the recent euro crisis, in the years 2010-2011. The chapter proposes a way to identify a structural model which explains volatility spillovers being a result of information asymmetries between investors. The identification of the model is based on recent ideas of using particularities of residual distribution and, as a novelty, Google trends data, not parameter restrictions, to identify a SVAR model. The empirical results confirm the existence of volatility spillovers between the euro countries of the sample (Greece, Italy, Germany, Ireland and Spain). Especially, we find that stock market volatility shocks in large countries have significant effects in all countries but those in the small countries mainly affect only other small countries. Chapter 3 extends an existing SVAR model in multiple ways to study the interdependencies between the government bond spreads over the German bond of the main crisis countries of the Eurozone (Greece, Portugal, Ireland, Spain and Italy). We are especially interested in studying the possibility of contagion of government default risk between the countries. The identification of the SVAR model is again based on non-normalities and heteroskedasticity in the residual distribution of the model. The results of the paper suggest that contagion explains a great part of the increases in the spreads during 2010-2012. However, there are substantial differences between the countries. For Ireland, Italy and Spain also the idiosyncratic risk factors seem to play an important role. Also, perhaps contrary to the common belief, there is evidence of substantial contagion from the spreads of the other countries to the Greek and Portuguese spreads. Chapter 4 considers the real economic effect of uncertainty. The data include the monthly change in the US industrial production and the monthly US stock market return. As a measure of uncertainty we consider the volatility of the stock market return, and to study its effect on the growth rate of the industrial production, we consider a bivariate vector autoregressive (VAR) model with GARCH-effect in the residuals and where volatility is allowed to affect the conditional means (GARCH-in-mean-model). The data cover the years 1919-2013, and we find that stock market volatility has a statistically significant, counter-cyclical effect on the growth rate of the industrial production.