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  • Eskelinen, Ulla (2001)
    Tutkimuksessa selvitettiin vasikoiden trakeobronkiaalihuuhtelunäytteissä esiintyviä MMP-2- ja MMP-9-tasoja sekä hengitysteiden Pasteurella-infektion yhteydessä MMP-aktiivisuuksissa tapahtuvia muutoksia. Tutkimusaineistoon kuului 11 hengitystietulehdusta sairastavaa vasikkaa sekä 6 tervettä vasikkaa sisältävä kontrolliryhmä. Vasikat valittiin ryhmiin yleistutkimuksen, verinäytetulosten ja trakeobronkiaalihuuhtelunesteen bakteriologisen tutkimuksen perusteella. Huuhtelunäytteiden gelatinolyyttisen aktiivisuuden määrittämiseen käytettiin gelatiinizymografiaa. Lisäksi gelatiinizymografialla tutkittiin, tuottaako erään tutkimusvasikan keuhkohuuhtelunäytteestä eristetty Pasteurella-bakteerikanta gelatinolyyttistä MMP:a. Kaikissa tutkituissa trakeobronkiaalihuuhtelunäytteissä havaittiin MMP-2- ja MMP-9-aktiivisuutta. Sairaiden ja terveiden vasikoiden MMP-tasojen eroja testattiin ei-parametrisella Mann-Whitney-testillä. Testattavat muuttujat olivat näytteen gelatinolyyttinen kokonaisaktiivisuus, kompleksimuodot, proMMP-9, aktiivinen MMP-9, proMMP-2 ja aktiivinen MMP-2 sekä aktiivisten MMP-muotojen prosentuaalinen osuus MMP:n kokonaistasosta. Ryhmien välillä havaittiin tilastollisesti merkitsevät eroavuudet (p<0,05) totaaliaktiivisuudessa sekä kompleksin ja MMP-2:n määrissä. Gelatinolyyttinen kokonaisaktiivisuus sekä aktiivisen MMP-2:n tasot olivat selvästi korkeampia sairailla kuin terveillä. Myös MMP-9-tasot olivat sairailla hieman korkeammat kuin terveillä, vaikka ero ei ollut tilastollisesti merkitsevä (p=0,056). Aktiivisten MMP-muotojen prosentuaalisissa osuuksissa sekä MMP-9:n ja MMP-2:n proentsyymimuotojen tasoissa ei ryhmien välillä havaittu tilastollisesti merkitseviä eroja. Pasteurella -kannan MMP-tuotannon selvittämiseksi tehty zymografia ei paljastanut bakteereista minkäänlaista gelatinolyyttistä aktiivisuutta. Pasteurellojen aiheuttama vasikoiden bronkopneumonia on kliinisesti ja taloudellisesti merkittävimpiä vasikoiden sairauksia. Taudille tyypillistä on laajojen keuhkokudoksen vaurioiden syntyminen, mikä vaikeuttaa infektiosta toipumista ja heikentää paranemisennustetta. Matriksimetalloproteinaasit ovat mm. tulehdussolujen tuottamia proteolyyttisiä entsyymejä, jotka hajottavat ekstrasellulaarista matriksia. Niiden proteolyyttisellä kapasiteetilla uskotaan olevan keskeinen rooli paitsi kudosten fysiologisessa uusiutumisessa myös erilaisten patologisten tilojen, kuten esimerkiksi eräiden hengitystiesairauksien, patogeneesissä sekä niihin liittyvien kudosvaurioiden synnyssä. Keuhkokudoksen matriksimetalloproteinaasi-aktiivisuuksien kohoaminen onkin osoittautunut hyväksi kudostuhon indikaattoriksi monissa hengityselinsairauksissa. Kirjallisuuskatsauksessa on käsitelty vasikoiden hengitystiesairauskompleksin esiintymistä, etiologiaa sekä oireita ja taudinkuvaa sekä Pasteurella-suvun tärkeimpien hengitystiepatogeenien, P. haemolytican ja P. multocidan, aiheuttamien hengitystietulehdusten erityispiirteitä ja bakteerien ominaisuuksia. Lisäksi käsitellään elimistön tulehdusvastetta ja kudosvaurioiden mekanismeja pasteurella- hengitystieinfektioissa sekä matriksimetalloproteinaasien (MMP) osuutta hengitystietulehduksen patogeneesissä.
  • Miettinen, Pauli (Helsingin yliopisto, 2009)
    Matrix decompositions, where a given matrix is represented as a product of two other matrices, are regularly used in data mining. Most matrix decompositions have their roots in linear algebra, but the needs of data mining are not always those of linear algebra. In data mining one needs to have results that are interpretable -- and what is considered interpretable in data mining can be very different to what is considered interpretable in linear algebra. --- The purpose of this thesis is to study matrix decompositions that directly address the issue of interpretability. An example is a decomposition of binary matrices where the factor matrices are assumed to be binary and the matrix multiplication is Boolean. The restriction to binary factor matrices increases interpretability -- factor matrices are of the same type as the original matrix -- and allows the use of Boolean matrix multiplication, which is often more intuitive than normal matrix multiplication with binary matrices. Also several other decomposition methods are described, and the computational complexity of computing them is studied together with the hardness of approximating the related optimization problems. Based on these studies, algorithms for constructing the decompositions are proposed. Constructing the decompositions turns out to be computationally hard, and the proposed algorithms are mostly based on various heuristics. Nevertheless, the algorithms are shown to be capable of finding good results in empirical experiments conducted with both synthetic and real-world data.
  • Polvi-Huttunen, Silja (2015)
    This work considers learning meaningful sets of chemical reactions called pathways and groups of species called Operational Taxonomical Units (OTUs) from metagenomic data. The methods are based on Nonnegative Matrix Factorization (NMF). The rows of our data matrix correspond to metagenomic samples and columns correspond to chemical reactions present in the samples. In order to learn both pathways and OTUs as well as relationships between them, we consider ways to factorize the data matrix into three factors instead of two. Denoting the samples times reactions data matrix by V, our factorization problem setting is to find nonnegative matrices W, H and P so that V is approximately WHP. The matrix W tells what OTUs are present in each of the samples, P defines pathways as combinations of reactions while H describes what pathways are implemented by which OTUs. We first discuss two standard NMF algorithms based on different objective functions and four sparsity constrained variants. Sparsity constrained variants are designed to produce output matrices with few values significantly above zero. We are interested in sparser variants because metagenomic pathways are short, thus the method should find a representation where only a small set of reactions is present in each pathway. We describe how using a standard two-factor NMF method twice yields a three-factor representation. We briefly mention an existing method, Nonnegative Matrix Tri-factorization (NMTF), that learns all three matrices W, H and P simultaneously. However, this method applies hard orthogonality constraints, i.e. it only finds solutions where the matrices W and P are orthogonal. Because of this constraint, NMTF is not suitable in our biological problem setting. We introduce an unconstrained method called NMF3 as well as a sparsity constrained variant SNMF3 based on Sparse Nonnegative Matrix Factorization (SNMF) and show how both of these algorithms can be derived. In order to compare the different algorithms' performance, we have built two synthetic data sets. Both sets are based on human intestinal species and pathway information available in an existing biological database. One of the data matrices can be exactly factorized into the underlying matrices used to generate the data. The other data set is built through simulating a sampling process that introduces noise and strictly limits the number of observed reactions per sample. We tested factorization methods discussed in the thesis on both data sets, using 100 to 1500 samples. We compare the methods and show and discuss the results. We found differences between NMF variants that use different objective functions. Many methods perform well on our task, surprisingly even in the case where the number of pathways is greater than the number of samples. Varying the number of samples affected the results less than we expected. Instead, we found that all algorithms performed significantly better on the factorizable data than on the simulated set.We conclude that the number of available metagenomic samples does not dramatically affect the performance of the factorization methods. More important is the quality of the samples.
  • Mäkitalo, Laura (Helsingin yliopisto, 2010)
    Matrix metalloproteinases (MMPs) represent a family of 23 metalloendopeptidases, collectively capable of degrading all components of the extracellular matrix. MMPs have been implicated in several inflammatory processes such as arthritis, atherosclerosis, and even carcinomas. They are also involved in several beneficial activities such as epithelial repair. MMPs are inhibited by endogenous tissue inhibitors of matrix metalloproteinases (TIMP). In this study, MMPs were investigated in intestinal mucosa of inflammatory bowel diseases (IBD), chronic intestinal disorders. The main focus was to characterize mucosal inflammation in the intestine, but also cutaneous pyoderma gangrenosum (PG), to assess similarites with IBD inflammation. MMPs and TIMPs were mainly examined in colonic mucosa, in adult Crohn s disease (CD), and paediatric CD, ulcerative colitis (UC), and indeterminate colitis (IC). Ileal pouch mucosa of proctocolectomized paediatric onset IBD patients was also investigated to characterize pouch mucosa. The focus was on finding specific MMPs that could act as markers to differentiate between different IBD disorders, and MMPs that could be implied as markers for tissue injury, potentially serving as targets for MMP-inhibitors. All examinations were performed using immunohistochemistry. The results show that immunosuppressive agents decrease stromal expression of MMP-9 and -26 that could serve as specific targets for MMP-inhibitors in treating CD. In paediatric colonic inflammation, MMP-10 and TIMP-3 present as molecular markers for IBD inflammation, and MMP-7 for CD. MMP expression in the the pouch mucosa could not be classified as strictly IBD- or non-IBD-like. For the first time, this study describes the expression of MMP-3, -7, -9, -12, and TIMP-2 and -3 in pouch mucosa. The MMP profile in PG bears resemblance to both intestinal IBD inflammation and cutaneous inflammation. Based on the results, MMPs and their inhibitors emerge as promising tools in the differential diagnosis of IBD and characterization of the disease subtype, although further research is necessary. Furthermore, the expression of several MMPs in pouch has been described for the first time. While further research is warranted, the findings contribute to a better understanding of events occurring in IBD mucosa, as well as pyoderma gangrenosum.
  • Mäkinen, Laura K. (Helsingin yliopisto, 2015)
    Predicting the clinical course of an early-stage oral tongue squamous cell carcinoma (OTSCC) is challenging, as even small tumors can behave aggressively. OTSCC often metastasizes to the cervical lymph nodes, and the presence of lymph node metastasis at the time of diagnosis is considered the most important tumor-related prognostic factor in OTSCC. The mechanisms of this disease progression are poorly understood. Despite slight improvement in the prognosis of OTSCC in recent decades, the outcome of these patients is still modest. Therefore, a deeper understanding of the phenomena behind tumor progression would enable medical professionals to evaluate the aggressiveness of the disease and to adjust its treatment more effectively. The extracellular matrix and basement membrane must be broken down before a tumor can invade surrounding tissues and further spread into blood and lymph vessels. This is a process that involves various proteolytic enzymes, the most important of which are matrix metalloproteinases (MMPs). Over 25 structurally related, but genetically distinct, human MMPs have been identified and characterized: collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and other MMPs. Toll-like receptors (TLRs) are pattern-recognition molecules involved in innate immunity that are also expressed in many types of cancer. TLRs apparently play a pivotal role in malignant disease: they are related to tumor progression and, conversely, to cancer inhibition. Their expression pattern and role in oral cancer, however, remains unclear. In this thesis we studied the expression of MMPs 2, 7, 8, 9, 13, and 25 and TLRs 2, 4, 5, 7, and 9 in early-stage OTSCC. The study comprised 73 consecutive clinically T1N0M0 and T2N0M0 OTSCC patients treated at the Helsinki University Hospital, Helsinki, Finland in 1992-2002. We prepared tissue array blocks from primary tumors and immunostained them. We also used whole section slides from patients with metastasized or recurrent disease. We compared immunoexpression of MMPs and TLRs to tumor and patient characteristics as well as to patient outcomes. We also used Western immunoblot to examine TLR-2 and -4 expression in the highly invasive and aggressive HSC-3 OTSCC cell line. In addition, we studied the effect of TLR-2 and -4 antagonist GIT27 (4,5-dihydro-5-isoxasoleacetic acid) on the invasion of the HSC-3 cell line in myoma organotypic invasion assay. OTSCC tumors expressed both MMPs and TLRs. Nuclear expression of MMP-13, but not cytoplasmic expression of MMP-2, -8, and -9, associated with deeper invasion and advanced tumor size. Furthermore, high nuclear MMP-13 expression predicted poor disease-specific survival. High MMP-7 protein expression associated with the presence of occult cervical metastases, increased invasion depth, and higher tumor grade, and also predicted poor outcome. Immunostaining of MMP-25 failed to correlate with any clinical parameters. High TLR-2, -4, and -9 expression correlated with deeper tumor invasion. Cytoplasmic expression of TLR-2 and -4 also correlated significantly with higher tumor grade, whereas high TLR-5 expression associated with lower tumor grade. High expression of TLR-9 correlated with advanced tumor size. Negative or mild TLR-5 expression predicted poor disease-specific survival. OTSCC primary tumors, neck metastases and recurrent tumors expressed TLR-2, -4, and -9. TLR-2 and -4 antagonist GIT27 did not affect the invasion of the HSC-3 cell line in myoma organotypic invasion assay. Thus, TLRs may operate under a different mechanism of action depending on whether they are activated by damage-associated molecular patterns in cancer or by pathogen-associated molecular patterns in infection. Our results suggest that MMP-7 and MMP-13 in particular may have prognostic value in OTSCC. Their use as prognostic biomarkers, however, calls for further study. TLR-2, -4, and -9 seemed to predict invasive tumor growth. Primary tumors and neck metastases as well as recurrent tumors of OTSCC express these TLRs, suggesting that TLRs seem to play a role in both the development and progression of tongue carcinoma.
  • Kuivanen, Tiina (Helsingin yliopisto, 2008)
    The incidence of non-melanoma skin cancer is increasing worldwide. Basal cell carcinoma followed by squamous cell carcinoma and malignant melanoma are the most frequent skin tumors. Immunosuppressed patients have an increased risk of neoplasia, of which non-melanoma skin cancer is the most common. Matrix metalloproteinases (MMPs) are proteolytic enzymes that collectively are capable of degrading virtually all components of the extracellular matrix. MMPs can also process substrates distinct from extracellular matrix proteins and influence cell proliferation, differentiation, angiogenesis, and apoptosis. MMP activity is regulated by their natural inhibitors, tissue inhibitors of metallopro-teinases (TIMPs). In this study, the expression patterns of MMPs, TIMPs, and certain cancer-related molecules were investigated in premalignant and malignant lesions of the human skin. As methods were used immunohistochemisty, in situ hybridization, and reverse transcriptase polymerase chain reaction (RT-PCR) from the cell cultures. Our aim was to evaluate the expression pattern of MMPs in extramammary Paget's disease in order to find markers for more advanced tumors, as well as to shed light on the origin of this rare neoplasm. Novel MMPs -21, -26, and -28 were studied in melanoma cell culture, in primary cutaneous melanomas, and their sentinel nodes. The MMP expression profile in keratoacanthomas and well-differentiated squamous cell carcinomas was analyzed to find markers to differentiate benign keratinocyte hyperproliferation from malignantly transformed cells. Squamous cell carcinomas of immunosuppressed organ transplant recipients were compared to squamous cell carcinomas of matched immunocompetent controls to investigate the factors explaining their more aggressive nature. We found that MMP-7 and -19 proteins are abundant in extramammary Paget's disease and that their presence may predict an underlying adenocarcinoma in these patients. In melanomas, MMP-21 was upregulated in early phases of melanoma progression, but disappeared from the more aggressive tumors with lymph node metastases. The presence of MMP-13 in primary melanomas and lymph node metastases may relate to more aggressive disease. In keratoacanthomas, the expression of MMP-7 and -9 is rare and therefore should raise a suspicion of well-differentiated squamous cell carcinomas. Furthermore, MMP-19 and p16 were observed in benign keratinocyte hyperproliferation of keratoacanthomas, whereas they were generally lost from malignant keratinocytes of SCCs. MMP-26 staining was significantly stronger in squamous cell carcinomas and Bowen s disease samples of organ transplant recipients and it may contribute to the more aggressive nature of squamous cell carcinomas in immunosuppressed patients. In addition, the staining for MMP-9 was significantly stronger in macrophages surrounding the tumors of the immunocompetent group and in neutrophils of those patients on cyclosporin medication. In conclusion, based on our studies, MMP-7 and -19 might serve as biomarkers for more aggressive extramammary Paget's disease and MMP-21 for malignant transformation of melanocytes. MMP -7, -9, and -26, however, could play an important role in the pathobiology of keratinocyte derived malignancies.
  • Hästbacka, Johanna (Helsingin yliopisto, 2013)
    The systemic levels of matrix metalloproteinases (MMPs) -7, -8 and -9 and the tissue inhibitor of metalloproteinases-1 (TIMP-1) were investigated in 877 critically ill patients. In Study I, 15 intensive care unit-(ICU) treated adult patients with secondary peritonitis were prospectively included. Peritoneal fluid, blood and urine samples were collected at the ICU after surgery. The serum and urine levels of MMP-8 were compared with those obtained from ten healthy volunteers, and were found to be significantly higher in patients. In peritoneal fluid, MMP-8 levels were significantly higher than in serum and urine. This study was the first to identify MMP-8 in the peritoneal fluid of peritonitis patients. Study II was a sub-study of the FINNSEPSIS study where patients with severe sepsis or septic shock were prospectively included in 24 Finnish ICUs. Serum samples of 248 patients were analysed for MMP-8, MMP-9 and TIMP-1 levels, that were found to be higher than those of healthy controls. MMP-8, -9 and TIMP-1 levels were compared between ICU survivors and non-survivors. Median MMP-8 (p<0.01) and TIMP-1 (p<0.001) were higher and median MMP-9 levels lower (p=0.047) in ICU non-survivors than in ICU survivors. Study III investigated MMP-7, MMP-8, MMP-9, and TIMP-1 levels on 51 patients resuscitated from cardiac arrest (CA). The patients were a subgroup of the Hypothermia After Cardiac Arrest study. Thirty patients had received mild therapeutic hypothermia treatment (MTH) and 21 non-hypothermia treatment (non-MTH). Serum samples taken at 24 and 48 hours from restoration of spontaneous circulation were analysed and compared between patients and healthy volunteers. Serum MMP and TIMP-1 levels of MTH-treated patients were compared during and after MTH with the levels of non-MTH-treated patients. MMP-8 and MMP-9 were higher in CA patients than controls. Patients receiving MTH treatment had lower median MMP-9 levels during MTH than non-MTH-treated patients (p<0.001). This is one novel potential mechanism of how MTH treatment improves outcome of CA patients. Study IV was a 563-patient sub-study of the FINNALI study that included acute respiratory failure patients at 25 Finnish ICUs. MMP-8 and TIMP-1 were analysed from blood samples taken on study admission and 48 hours thereafter. Association of MMP-8 and TIMP-1 with 90-day mortality was examined. Serum MMP-8 predicted 90-day mortality of acute respiratory failure patients poorly. Admission TIMP-1 levels were higher in non-survivors than in survivors (p<0.001).TIMP-1 was an independent predictor of 90-day mortality, with a moderate discriminative power (AUC 0.633, 95% CI 0.580- 0.686). TIMP-1 was also associated with the severity of oxygenation disturbance. Thus, TIMP-1 is a potentially useful biomarker for predicting outcome in acute respiratory failure patients.
  • Cederqvist, Katariina (Helsingin yliopisto, 2006)
    During inflammation, excess production and release of matrix proteinases, including matrix metalloproteinases (MMPs) and serine proteinases, may result in dysregulated extracellular proteolysis leading to development of tissue damage. Pulmonary inflammation may play an important role in the pathogenesis of lung injury in the preterm infant. The aims of this study were to evaluate involvement of MMPs and serine proteinase trypsin in acute and chronic lung injury in preterm infants and to study the role of these enzymes in acute lung injury by means of an animal model of hyperoxic lung injury. Molecular forms and levels of MMP-2, -8, and -9, and their specific inhibitor, tissue inhibitor of metalloproteinases (TIMP)-2, as well as trypsin were studied in tracheal aspirate fluid (TAF) samples collected from preterm infants with respiratory distress. Expression and distribution of trypsin-2 and proteinase-activated receptor 2 (PAR2) was examined in autopsy lung specimens from fetuses, from preterm infants with respiratory distress syndrome (RDS) or bronchopulmonary dysplasia (BPD), and from newborn infants without lung injury. We detected higher MMP-8 and trypsin-2 and lower TIMP-2 in TAF from preterm infants with more severe acute respiratory distress. Infants subsequently developing BPD had higher levels of MMP-8 and trypsin-2 early postnatally than did those who survived without this chronic lung injury. Immunohistochemically, trypsin-2 was mainly detectable in bronchial epithelium, but also in alveolar epithelium, and its expression was strongest in prolonged RDS. Since trypsin-2 is potent activator of PAR2, a G-protein coupled receptor involved in inflammation, we studied PAR2 expression in the lung. PAR2 co-localized with trypsin-2 in bronchoalveolar epithelium and its expression was significantly higher in bronchoalveolar epithelium in preterm infants with prolonged RDS than in newborn controls. In the experimental study, rats were exposed to >95% oxygen for 24, 48, and 60 hours, or room air. At 48 hours of hyperoxia, MMP-8 and trypsin levels sharply increased in bronchoalveolar lavage fluid, and expression of trypsin appeared in alveolar epithelium, and MMP-8 predominantly in macrophages. In conclusion, high pulmonary MMP-8 and trypsin-2 early postnatally are associated with severity of acute lung injury and subsequent development of BPD in preterm infants. In the injured preterm lung, trypsin-2 co-localizes with PAR2 in bronchoalveolar epithelium, suggesting that PAR2 activated by high levels of trypsin-2 is involved in lung inflammation associated with development of BPD. Marked increase in MMP-8 and trypsin early in the course of experimental hyperoxic lung injury suggests that these enzymes play a role in the pathogenesis of acute lung injury. Further exploration of the roles of trypsin and MMP-8 in lung injury may offer new targets for therapeutic intervention.