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  • Nukarinen, Eija; Lindstrom, Outi; Kuuliala, Krista; Kylänpää, Leena; Pettilä, Ville; Puolakkainen, Pauli; Kuuliala, Antti; Hamalainen, Mari; Moilanen, Eeva; Repo, Heikki; Hästbacka, Johanna (2016)
    Objectives Several biomarkers for early detection of severe acute pancreatitis (SAP) have been presented. Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) are released early in inflammation. We aimed to assess levels of MMP-7, -8, -9 and TIMP-1 in acute pancreatitis (AP) and explore their ability to detect disease severity. Our second aim was to find an association between MMPs, TIMP and creatinine. Methods We collected plasma samples for MMP-7, -8, -9 and TIMP-1 analyses from 176 patients presenting within 96 h from onset of acute pancreatitis (AP) symptoms. We used samples from 32 control subjects as comparison. The revised Atlanta Classification was utilised to assess severity of disease. Receiver operating characteristic curve analysis and Spearman's Rho-test were utilised for statistical calculations. Results Compared with controls, patients showed higher levels of all studied markers. MMP-8 was higher in moderately severe AP than in mild AP (p = 0.005) and MMP-8, -9 and TIMP-1 were higher in severe than in mild AP (p
  • Carpen, Timo; Sorsa, Timo; Jouhi, Lauri; Tervahartiala, Taina; Haglund, Caj; Syrjänen, Stina; Tarkkanen, Jussi; Mohamed, Hesham; Mäkitie, Antti; Hagström, Jaana; Mattila, Petri S. (2019)
    Background An emerging subset of oropharyngeal squamous cell carcinomas (OPSCC) is caused by HPV. HPV-positive OPSCC has a better prognosis than HPV-negative OPSCC, but other prognostic markers for these two different diseases are scarce. Our aim was to evaluate serum levels and tumor expression of matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and to assess their prognostic role in HPV-positive and HPV-negative OPSCC. Materials and methods A total of 90 consecutive OPSCC patients diagnosed and treated with curative intent at the Helsinki University Hospital between 2012 and 2016 were included. Serum samples were prospectively collected. An immunofluorometric assay and an enzyme-linked immunosorbent assay were used to determine MMP-8 and TIMP-1 serum concentrations, respectively. HPV status of the tumors was determined using a combination of HPV-DNA genotyping and p16-INK4a immunohistochemistry. The endpoints were overall survival (OS) and disease-free survival (DFS). Results High TIMP-1 serum levels were strongly and independently associated with poorer OS (adjusted HR 14.7, 95% CI 1.8-117.4, p = 0.011) and DFS (adjusted HR 8.7, 95% CI 1.3-57.1, p = 0.024) among HPV-negative patients; this association was not observed in HPV-positive OPSCC. Although TIMP-1 was immunoexpressed in the majority of the tumor tissue samples, the level of immunoexpression was not associated with prognosis, nor did MMP-8 serum levels. Conclusion Our results indicate that serum TIMP-1 levels may serve as an independent prognostic marker for HPV-negative OPSCC patients.
  • Määttä, Merita; Laurila, Henna P.; Holopainen, Saila; Aaltonen, Kaisa; Lilja-Maula, Liisa; Viitanen, Sanna; Rajamaki, Minna M. (2021)
    Background Canine idiopathic pulmonary fibrosis (CIPF) is a chronic, interstitial lung disease that mainly affects West Highland white terriers (WHWTs) and is characterized by excessive deposition of extracellular matrix (ECM) in the lung. Matrix metalloproteinases (MMPs) participate in remodeling of ECM. Objectives To compare metalloproteinase-2, -7 and -9 activities in blood or bronchoalveolar lavage fluid (BALF) samples or both of CIPF WHWTs with healthy WHWTs, healthy dogs of other breeds, and dogs with other lung diseases and determine if these MMPs could be used as diagnostic and prognostic markers for CIPF. Animals Forty-four CIPF WHWTs, 24 dogs with chronic bronchitis (CB), 17 with eosinophilic bronchopneumopathy (EBP), 10 with bacterial pneumonia, 39 healthy WHWTs, and 35 healthy dogs of other breeds. Methods Cross-sectional observational study. Pro-MMP and active MMP activities were analyzed by zymography. Results In serum, significantly higher (P <.01) pro-MMP-7 activities were observed in CIPF WHWTs compared to healthy dogs of other breeds, dogs with CB and dogs with EBP. In BALF of CIPF WHWTs, both pro-MMP-9 and pro-MMP-2 activities were significantly higher (P <.01) compared to healthy WHWTs, but these differences were not detected in plasma. The CIPF WHWTs had significantly higher (P <.05) activities of pro-MMP-9 compared to dogs with CB and of pro-MMP-2 compared to dogs with CB and EBP. No statistically significant prognostic factors were observed in CIPF WHWTs. Conclusions and clinical relevance Serum MMP-7 and BALF MMP-2 and -9 potentially may be useful diagnostic markers but not prognostic markers for CIPF.
  • Hästbacka, Johanna; Freden, Filip; Hult, Maarit; Bergquist, Maria; Wilkman, Erika; Vuola, Jyrki; Sorsa, Timo; Tervahartiala, Taina; Huss, Fredrik (2015)
    Introduction Matrix metalloproteinases (MMPs) -8 and -9 are released from neutrophils in acute inflammation and may contribute to permeability changes in burn injury. In retrospective studies on sepsis, levels of MMP-8, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) differed from those of healthy controls, and TIMP-1 showed an association with outcome. Our objective was to investigate the relationship between these proteins and disease severity and outcome in burn patients. Methods In this prospective, observational, two-center study, we collected plasma samples from admission to day 21 post-burn, and burn blister fluid samples on admission. We compared MMP-8, -9, and TIMP-1 levels between TBSA20% (N = 30) injured patients and healthy controls, and between 90-day survivors and non-survivors. MMP-8, -9, and TIMP-1 levels at 24-48 hours from injury, their maximal levels, and their time-adjusted means were compared between groups. Correlations with clinical parameters and the extent of burn were analyzed. MMP-8, -9, and TIMP-1 levels in burn blister fluids were also studied. Results Plasma MMP-8 and -9 were higher in patients than in healthy controls (P20% groups. MMP-8 and -9 were not associated with clinical severity or outcome measures. TIMP-1 differed significantly between patients and controls (P20% groups (P
  • Kelppe, Jetta; Thoren, Hanna; Haglund, Caj; Sorsa, Timo; Hagström, Jaana (2021)
    Objectives Ameloblastoma is a benign, locally aggressive odontogenic tumor with high recurrence rates. Matrix metalloproteinases (MMPs) mediate extracellular integrity in normal and pathological conditions, and exert multiple functions coordinating inflammation and tumor progression. E-cadherin and beta-catenin are adherence junction molecules in cell-to-cell connections. We investigated the involvement of MMP-7, -8, -9, E-cadherin, and beta-catenin in ameloblastoma and the surrounding extracellular matrix. Material and methods Our material consisted of 30-34 tissue samples from ameloblastoma patients of Helsinki University Hospital. We used immunohistochemistry to detect the expression of the biomarkers. Two oral pathologists independently scored the immunoexpression intensities and statistical calculations were made based on the results. Results E-cadherin expression was weaker in the maxillary than in mandibular ameloblastomas. Beta-catenin was expressed in the ameloblastoma cell membranes. We detected MMP-8 and -9 expression in polymorphonuclear neutrophils in the extracellular area and these MMPs correlated positively with each other. Osteoclasts lining bone margins and multinuclear giant cells expressed MMP-9. Neither MMP-8 nor MMP-9 immunoexpression could be detected in ameloblastoma cells. MMP-7 expression was seen in some apoptotic cells. Conclusion The fact that E-cadherin immunoexpression was weaker in maxillary compared to mandibular ameloblastomas might associate to earlier recurrences. It promotes the idea of mandibular and maxillary ameloblastoma exerting differences in their biologies. We detected MMP-8 and -9 in polymorphonuclear neutrophils which relates to these MMPs participating in extracellular remodeling through a mild inflammatory process. Bone degradation around ameloblastoma may be due to MMP-9 in osteoclasts but this phenomenon might be an independent process and needs further investigations.
  • Rathnayake, Nilminie; Gustafsson, Anders; Norhammar, Anna; Kjellstrom, Barbro; Klinge, Bjorn; Ryden, Lars; Tervahartiala, Taina; Sorsa, Timo; PAROKRANK Steering Grp (2015)
    Background and Objective Matrix metalloproteinase (MMP) -8, -9 and myeloperoxidase (MPO) are inflammatory mediators. The potential associations between MMP-8, -9, MPO and their abilities to reflect cardiovascular risk remains to be evaluated in saliva. The objective of this study was to investigate the levels and associations of salivary MMP-8, -9, MPO and tissue inhibitors of metalloproteinase (TIMP)-1 in myocardial infarction (MI) patients and controls with or without periodontitis. Materials and Methods 200 patients with a first MI admitted to coronary care units in Sweden from May 2010 to December 2011 and 200 controls matched for age, gender, residential area and without previous MI were included. Dental examination and saliva sample collection was performed 6-10 weeks after the MI in patients and at baseline in controls. The biomarkers MMP -8, -9, MPO and TIMP-1 were analyzed by time-resolved immunofluorescence assay (IFMA), Western blot and Enzyme-Linked ImmunoSorbent Assay (ELISA). Results After compensation for gingivitis, gingival pockets and smoking, the mean salivary levels of MMP-8 (543 vs 440 ng/mL, p = 0.003) and MPO (1899 vs 1637 ng/mL, p = 0.02) were higher in non-MI subjects compared to MI patients. MMP-8, -9 and MPO correlated positively with clinical signs of gingival/periodontal inflammation while TIMP-1 correlated mainly negatively with these signs. The levels of latent and active forms of MMP-8 did not differ between the MI and non-MI groups. Additionally, MMP-8, MPO levels and MMP-8/TIMP-1 ratio were significantly higher in men compared to women with MI. Conclusions This study shows that salivary levels of the analyzed biomarkers are associated with periodontal status. However, these biomarkers could not differentiate between patients with or without a MI. These findings illustrate the importance to consider the influence of oral conditions when analyzing levels of inflammatory salivary biomarkers.
  • Bockelman, Camilla; Beilmann-Lehtonen, Ines; Kaprio, Tuomas; Koskensalo, Selja; Tervahartiala, Taina; Mustonen, Harri; Stenman, Ulf-Hakan; Sorsa, Timo; Haglund, Caj (2018)
    Background: Almost all of the extracellular matrix (ECM) components can be degraded by the endoproteinases matrix metalloproteinases (MMPs). Important regulators of MMPs, and thereby of the extracellular environment, are tissue inhibitors of metalloproteinases (TIMPs), and especially TIMP-1. Early tumor development, as well as distant metastasis, may be results of an MMP/TIMP ratio imbalance altering the ECM. MMPs are elevated in several inflammatory conditions. Our aim is to investigate the prognostic role of MMP-8, -9, and TIMP-1 in colorectal cancer (CRC) and their relationship to inflammation. Methods: We included 337 colorectal cancer patients and 47 controls undergoing surgery at Helsinki University Hospital in Finland, 1998-2011. Serum levels of MMP-8 and plasma levels of C-reactive protein (CRP) were determined with a time-resolved immunofluorometric assay (IFMA), and MMP-9 and TIMP-1 with commercial enzyme-linked immunosorbent assay (ELISA) kits. Association and correlation analyses were performed with the Mann-Whitney U, Kruskal-Wallis, and Spearman rank correlation tests. Survival curves were constructed according to the Kaplan-Meier method and compared with the log-rank test. Results: Among patients with advanced disease, serum levels of MMP-8 and TIMP-1 were elevated. CRC patients with high MMP-8 (HR (hazard ratio) 1.72, 95% confidence interval (CI) 1.17-2.52, P = 0.005) and those with high TIMP-1 (HR 1.80, 95% CI 1.23-2.64, P = 0.002) had worse prognoses. MMP-9 level failed to serve as a prognostic factor. In multivariable survival analysis, Dukes stage, and low MMP-9/TIMP-1 molar ratio (HR 0.46, 95% CI 0.33-0.98, P = 0.042) were independently predicted prognosis. A weak correlation between CRP and MMP-8 (r(S) = 0.229, P <0.001), and TIMP-1 (r(S) = 0.280, P <0.001) was noted. Among patients showing no systemic inflammatory response, MMP-8 (HR 1.66, 95% CI 1.10-2.53, P = 0.017) and TIMP-1 (HR 1.59, 95% CI 1.05-2.42, P = 0.029) were prognostic factors. Conclusions: MMP-8 and TIMP-1 in serum, but not MMP-9, identified CRC patients with bad prognosis. Among patients showing no systemic inflammatory response, MMP-8 and TIMP-1 may associate with poor prognosis.
  • Savonius, Okko; Roine, Irmeli; Alassiri, Saeed; Tervahartiala, Taina; Helve, Otto; Fernandez, Josefina; Peltola, Heikki; Sorsa, Timo; Pelkonen, Tuula (2019)
    Background. Matrix metalloproteinases (MMPs) and myeloperoxidase (MPO) contribute to the inflammatory cascade in the cerebrospinal fluid (CSF) during bacterial meningitis. We determined levels of MPO, MMP-8, MMP-9, and tissue inhibitor of metalloproteinase- (TIMP-) 1 in the CSF of children with bacterial meningitis and investigated how these inflammatory mediators relate to each other and to the disease outcomes. Methods. Clinical data and the diagnostic CSF samples from 245 children (median age eight months) with bacterial meningitis were obtained from a clinical trial in Latin America in 1996-2003. MMP-9 levels in the CSF were assessed by zymography, while MMP-8, MPO, and TIMP-1 concentrations were determined with immunofluorometric and enzyme-linked immunosorbent assays. Results. MPO correlated positively with MMP-8 (rho 0.496, P
  • Meurman, Jukka H.; Söder, Birgitta (2022)
    The Stockholm Studies are a series of investigations started in 1985 and still ongoing. Out of 105,798 inhabitants, aged 30 and 40 years and living in the greater Stockholm area in Sweden, 3273 subjects were randomly selected. Of them, 1676 were clinically examined focusing on oral health. The subjects were then followed up using national population and health registers in order to study associations between oral health parameters and systemic health outcomes and finally death. The 35 years of observation provides unique possibilities to analyze, for example, how periodontitis links to a number of systemic health issues. The results have consequently provided numerous new associations and confirmed earlier observations on how poor oral health is associated with heart diseases and cancer.
  • Acosta, Alicia Jurado; Rysä, Jaana; Szabo, Zoltan; Moilanen, Anne-Mari; Komati, Hiba; Nemer, Mona; Ruskoaho, Heikki (2017)
    The phenylephrine-induced complex-1 (PEX1) transcription factor, also known as zinc-finger protein 260 (Zfp260), is an effector of endothelin-1 and alpha(1)-adrenergic signaling in cardiac hypertrophy. However, the role of PEX1 in transcriptional regulation of myocardial remodeling remains largely unknown. In the present study, we used PEX1 gain- and loss-of-function to examine the effects of PEX1 on left ventricular remodeling. Adenoviral constructs expressing PEX1, antisense PEX1, or LacZ were delivered by local injection into the anterior wall of the left ventricle in Sprague-Dawley rats. PEX1 overexpression led to induction of hypertrophic gene program and increased fibrosis. In agreement with this, the expression of genes involved in the fibrotic process, such as collagens I and III, matrix metalloproteinases (MMPs), fibronectin-1, transforming growth factor beta-1 and connective tissue growth factor, were significantly up-regulated following PEX1 overexpression, whereas silencing of PEX1 significantly inhibited the expression of pro-fibrotic genes and increased left ventricular ejection fraction and fractional shortening. In vitro luciferase reporter assays showed that PEX1 regulates the expression of MMP-9 by activating promoter. Furthermore, PEX1 gain- and loss-of-function experiments in rat neonatal cardiac fibroblasts and myocytes revealed that MMP-9 gene expression was affected by PEX1 predominantly in fibroblasts. Our results indicate that PEX1 is involved in regulating cardiac fibrosis and extracellular matrix turnover, particularly fibroblasts being responsible for the fibrosis-associated changes in gene expression. Furthermore, PEX1 activation of the MMP-9 promoter triggers the pro-fibrotic response directed by PEX1.