R Grénman

University of Turku, Turku, Varsinais-Suomi, Finland

Are you R Grénman?

Claim your profile

Publications (153)535.55 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Predominant causes of head and neck cancer recurrence after radiotherapy are rapid repopulation, hypoxia, fraction of cancer stem cells and intrinsic radioresistance. Currently, intrinsic radioresistance can only be assessed by ex-vivo colony assays. Besides being time-consuming, colony assays do not identify causes of intrinsic resistance. We aimed to identify a biomarker for intrinsic radioresistance to be used before start of treatment and to reveal biological processes that could be targeted to overcome intrinsic resistance. We analyzed both micro- and messenger RNA expression in a large panel of HNSCC cell lines. Expression was measured on both irradiated and unirradiated samples. Results were validated using modified cell lines and a series of laryngeal cancer patients. MiRs, mRNAs and gene sets that correlated with resistance could be identified from expression data of unirradiated cells. The presence of epithelial to mesenchymal transition (EMT) and low expression of miRs involved in the inhibition of EMT were important radioresistance determinants. This finding was validated in two independent cell line pairs, in which the induction of EMT reduced radiosensitivity. Moreover, low expression of the most important miR (miR-203) was shown to correlate with local disease recurrence after radiotherapy in a series of laryngeal cancer patients. These findings indicate that EMT and low expression of EMT-inhibiting miRs, especially miR-203, measured in pre-treatment material, causes intrinsic radioresistance of HNSCC, which could enable identification and treatment modification of radioresistant tumors. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 08/2015; DOI:10.1158/1078-0432.CCR-15-0454 · 8.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Radiotherapy remains the backbone of head and neck cancer therapy but response is sometimes impeded by tumor radioresistance. Identifying predictive biomarkers of radiotherapy response is a crucial step towards personalized therapy. The aim of this study was to explore gene expression data in search of biomarkers predictive of the response to radiotherapy in head and neck squamous cell carcinoma (HNSCC). Microarray analysis was performed on five cell lines with various intrinsic radiosensitivity, selected from a panel of 29 HNSCC cell lines. The bioinformatics approach included Gene Ontology (GO) enrichment profiling and Ingenuity Pathway Analysis (IPA). The GO-analysis detected 16 deregulated categories from which development, receptor activity and extracellular region represented the largest groups. Fourteen hub genes (CEBPA, CEBPB, CTNNB1, FN1, MYC, MYCN, PLAU, SDC4, SERPINE1, SP1, TAF4B, THBS1, TP53 and VLDLR) were identified from the IPA network analysis. The hub genes in the highest ranked network, (FN1, SERPINE1, THBS1 and VLDLR) were further subjected to qPCR analysis in the complete panel of 29 cell lines. Of these genes, high FN1 expression associated to high intrinsic radiosensitivity (p = 0.047). In conclusion, gene ontologies and hub genes of importance for intrinsic radiosensitivity were defined. The overall results suggest that FN1 should be explored as a potential novel biomarker for radioresistance.
    Cancer biology & therapy 10/2014; 10(12). DOI:10.4161/cbt.10.12.13432 · 3.07 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: OFP-12-001 Early stage oral tongue cancer: A prognostic model for survival A. Almangush*, R. Coletta, I. Bello, C. Bitu, J. Hagström, Y. Soini, P. Koivunen, R. Grénman, T. Salo, I. Leivo *Haartman Institute, Dept. of Pathology, Helsinki, Finland Objective: Oral tongue squamous cell carcinoma (OTSCC) is the most common and most aggressive cancer diagnosed within the oral cavity and characterized by poor prognosis even at early stage (cT1-2N0). We introduced a simple prognostic model for early stage OTSCC based on two well-defined histopathologic parameters, tumor budding and depth of invasion. Method: Three hundred and eleven cases treated for early stage (cT1-T2N0) OTSCC were included in this multicenter retrospective study. Tumor budding (B) and depth of invasion (D) were scored on hematoxylin-eosin stained cancer slides. The scored parameters were combined in a predictive model (BD model). Results: In the multivariate analysis, cases with high risk score (BD score 2) were showed to have more loco-regional recurrence (hazard ratio [HR], 2.49; 95 % confidence interval [CI], 1.41–4.39) and more deaths from OTSCC (HR: 6.52; 95 % CI: 2.68–15.83). Conclusion: BD model is a promising indicator for patients’ survival in early OTSCC. Early stage OTSCC cases with high BD score (score 2) might benefit from multimodality treatment. Further validation of BD model is recommended.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Here, the hypoxic regulation of the PERK/ATF4/LAMP3-arm of the UPR in head and neck squamous cell carcinoma (HNSCC) was examined.MethodsLAMP3 expression was determined in patient biopsies by immunohistochemistry and correlated to clinicopathological parameters. mRNA and protein expression for PERK, ATF4 and LAMP3 was evaluated after hypoxic exposure of HNSCC cell lines.ResultsIn HNSCC patients, high LAMP3 expression correlated with N-stage (P=0.019) and the occurrence of distant metastases during follow-up (P=0.039). Patients with high LAMP3 levels had a worse metastasis-free survival (P=0.008). Intriguingly, LAMP3 expression was localized exclusively in normoxic areas of tumors and xenografts. Expression of PERK, p-PERK, p-eIF2α, ATF4 and LAMP3 was not universally induced in hypoxic HNSCC cell lines. Exposure to ER-stress stimulated PERK, ATF4 and LAMP3 expression.ConclusionLAMP3 is relevant for prognosis in HNSCC. However, the PERK/ATF4/LAMP3-arm of the UPR responds differently to hypoxia in HNSCC compared to other tumor types. Head Neck, 2014
    Head & Neck 06/2014; 37(6). DOI:10.1002/hed.23693 · 2.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Wood has been used as a model material for the development of novel fiber-reinforced composite bone substitute biomaterials. In previous studies heat treatment of wood was perceived to significantly increase the osteoconductivity of implanted wood material. AIM: The objective of this study was to examine some of the changing attributes of wood materials that may contribute to improved biological responses gained with heat treatment. METHODS: Untreated and 140 degrees C and 200 degrees C heat-treated downy birch (Betula pubescens Ehrh.) were used as the wood materials. Surface roughness and the effect of pre-measurement grinding were measured with contact and non-contact profilometry. Liquid interaction was assessed with a dipping test using two manufactured liquids (simulated blood) as well as human blood. SEM was used to visualize possible heat treatment-induced changes in the hierarchical structure of wood. RESULTS: The surface roughness was observed to significantly decrease with heat treatment. Grinding methods had more influence on the surface contour and roughness than heat treatment. The penetration of the human blood in the 200 degrees C heat-treated exceeded that in the untreated and 140 degrees C heat-treated materials. SEM showed no significant change due to heat treatment in the dry-state morphology of the wood. DISCUSSION: The results of the liquid penetration test support previous findings in literature concerning the effects of heat treatment on the biological response to implanted wood. Heat-treatment has only a marginal effect on the surface contour of wood. The highly specialized liquid conveyance system of wood may serve as a biomimetic model for the further development of tailored fiber-composite materials.
    Bio-medical materials and engineering 05/2014; 24(3):1595-607. DOI:10.3233/BME-140964 · 1.09 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The presence of hypoxia in head and neck squamous cell carcinoma (HNSCC) is associated with therapeutic resistance and increased risk of metastasis formation. alphaB-crystallin (HspB5) is a small heat shock protein, which is also associated with metastasis formation in HNSCC. In this study, we investigated whether alphaB-crystallin protein expression is increased in hypoxic areas of HNSCC biopsies and analyzed whether hypoxia induces alphaB-crystallin expression in vitro and in this way may confer hypoxic cell survival. In 38 HNSCC biopsies, the overlap between immunohistochemically stained alphaB-crystallin and pimonidazole-adducts (hypoxiamarker) was determined. Moreover, expression levels of alphaB-crystallin were analyzed in HNSCC cell lines under hypoxia and reoxygenation conditions and after exposure to reactive oxygen species (ROS) and the ROS scavenger N-acetylcysteine (NAC). siRNA-mediated knockdown was used to determine the influence of alphaB-crystallin on cell survival under hypoxic conditions. In all biopsies alphaB-crystallin was more abundantly present in hypoxic areas than in normoxic areas. Remarkably, hypoxia decreased alphaB-crystallin mRNA expression in the HNSCC cell lines. Only after reoxygenation, a condition that stimulates ROS formation, alphaB-crystallin expression was increased. alphaB-crystallin mRNA levels were also increased by extracellular ROS, and NAC abolished the reoxygenation-induced alphaB-crystallin upregulation. Moreover, it was found that decreased alphaB-crystallin levels reduced cell survival under hypoxic conditions CONCLUSIONS: We provide the first evidence that hypoxia stimulates upregulation of alphaB-crystallin in HNSCC. This upregulation was not caused by the low oxygen pressure, but more likely by ROS formation. The higher expression of alphaB-crystallin may lead to prolonged survival of these cells under hypoxic conditions.
    BMC Cancer 04/2014; 14(1):252. DOI:10.1186/1471-2407-14-252 · 3.36 Impact Factor
  • Radiotherapy and Oncology 01/2014; 111:S189. DOI:10.1016/S0167-8140(15)30588-0 · 4.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Kinases downstream of growth factor receptors have been implicated in radioresistance and are, therefore, attractive targets to improve radiotherapy outcome in head and neck squamous cell carcinoma (HNSCC) patients. An antibody-based array was used to quantify the expression levels of multiple phospho-kinases involved in growth factor signaling in nine untreated or irradiated HNSCC lines. Radiosensitivity was assessed with clonogenic cell survival assays and correlated with the expression levels of the phospho-kinases. Inhibitors of the kinases that were associated with radiosensitivity were tested for their ability to increase radiosensitivity in the 3 most radioresistant HNSCC lines. The basal expression of phosphorylated Yes, Src and STAT5A, and the expression after radiotherapy of phosphorylated AKT, MSK1/2, Src, Lyn, Fyn, Hck, and STAT6, were correlated with radiosensitivity in the panel of HNSCC lines. In combination with radiotherapy, inhibitors of AKT, p38 and Src Family Kinases (SFK) were variably able to reduce survival, whereas MEK1/2, STAT5 and STAT6 inhibition reduced survival in all cell lines. The combined effect of radiotherapy and the kinase inhibitors on cell survival was mostly additive, although also supra-additive effects were observed for AKT, MEK1/2, p38 and STAT5 inhibition. Kinases of the AKT, MAPK, STAT and SFK pathways correlated with radiosensitivity in a panel of HNSCC lines. Particularly inhibitors against MEK1/2, STAT5 and STAT6 were able to decrease survival in combination with radiotherapy. Hence, inhibitors against these kinases have the potential to improve radiotherapy outcome in HNSCC patients and further research is warranted to confirm this in vivo.
    Molecular Cancer 11/2013; 12(1):133. DOI:10.1186/1476-4598-12-133 · 4.26 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: This study investigated the use of 3 different established cell-sorting strategies to isolate and characterize stem cells from head and neck cancer cell lines. Methods: Five low-passage cell lines were subjected to cell sorting based on Hoechst side population, Aldefluor, and CD44 expression. Isolated cell populations were studied for gene expression, radiosensitivity, and chemosensitivity to cisplatin and paclitaxel. Results: Each sorting method identified a different set of genes associated with different gene ontology categories, with mitosis being the only common category. CD44-associated gene changes were almost exclusively associated with cell cycle and in particular mitosis. There were no significant differences in radiosensitivity or cisplatin sensitivity of stem or non-stem cells, but CD44-isolated stem cells were more resistant to paclitaxel. Conclusions: This study suggested that CD44 may be the most promising cell-sorting strategy to isolate and investigate the impact of stem cells in head and neck squamous cell cancer (HNSCC).
    Head & Neck 11/2013; 35(11). DOI:10.1002/hed.23184 · 2.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer cells can obtain their ability to invade and metastasise by undergoing epithelial-to-mesenchymal transition (EMT). Exploiting this mechanism of cellular plasticity, malignant cells can remodel their actin cytoskeleton and down-regulate proteins needed for cell-cell contacts. The mechanisms of cytoskeletal reorganisation resulting in mesenchymal morphology and increased invasive potential are poorly understood. Actin nucleating formins have been implicated as key players in EMT. Here, we analysed which formins are altered in squamous cell carcinoma related EMT. FHOD1, a poorly studied formin, appeared to be markedly upregulated upon EMT. In human tissues FHOD1 was primarily expressed in mesenchymal cells, with little expression in epithelia. However, specimens from oral squamous cell cancers demonstrated consistent FHOD1 upregulation in mesenchymally transformed cells at the invasive edge. This upregulation was confirmed in an oral squamous carcinoma model, where FHOD1 expression was markedly increased upon EMT in a PI3K signalling dependent manner. In the EMT cells FHOD1 contributed to the spindle-shaped morphology and mesenchymal F-actin organization. Furthermore, functional assays demonstrated that FHOD1 contributes to cell migration and invasion. Finally, FHOD1 depletion reduced the ability of EMT cancer cells to form invadopodia and to degrade extracellular matrix. Our results indicate that FHOD1 participates in cytoskeletal changes in EMT. In addition, we show that FHOD1 upregulation occurs during cancer cell EMT in vivo, which indicates that FHOD1 may contribute to tumour progression.
    PLoS ONE 09/2013; 8(9):e74923. DOI:10.1371/journal.pone.0074923 · 3.23 Impact Factor
  • A Almangush · I Bello · J Hagstrom · Y Soini · P Koivunen · R Grenman · I Leivo · T Salo
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To validate the association of phosphorylated (p)AKT with lymph node metastasis in an independent, homogeneous cohort of patients with larynx cancer. Seventy-eight patients with laryngeal cancer were included. Epidermal growth factor receptor, pAKT, vimentin, E-cadherin, hypoxia, and blood vessels were visualized in biopsy material using immunohistochemistry. Positive tumor areas and spatial relationships between markers were assessed by automated image analysis. In 6 laryngeal cancer cell lines, E-cadherin and vimentin messenger RNA was quantified by real-time polymerase chain reaction and by immunohistochemistry before and after treatment with the pAKT inhibitor MK-2206. A significant correlation was found between low pAKT in the primary tumor and positive lymph node status (P=.0005). Tumors with lymph node metastases had an approximately 10-fold lower median pAKT value compared with tumors without lymph node metastases, albeit with large intertumor variations, validating our previous results. After inhibition of pAKT in laryngeal cancer cells with MK-2206, up-regulation of vimentin and a downregulation of E-cadherin occurred, consistent with epithelial-mesenchymal transition. Low pAKT expression in larynx tumors is associated with lymph node metastases. Further, inhibition of pAKT in laryngeal cancer induces epithelial-mesenchymal transition, predisposing for an increased metastatic risk.
    International journal of radiation oncology, biology, physics 07/2013; 87(2). DOI:10.1016/j.ijrobp.2013.05.046 · 4.26 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background αB-crystallin is able to modulate vascular endothelial growth factor (VEGF) secretion. In many solid tumors VEGF is associated with angiogenesis, metastasis formation and poor prognosis. We set out to assess whether αB-crystallin expression is correlated with worse prognosis and whether this is related to VEGF secretion and cell motility in head and neck squamous cell carcinoma (HNSCC). Methods αB-crystallin expression was determined immunohistochemically in tumor biopsies of 38 HNSCC patients. Locoregional control (LRC) and metastasis-free survival (MFS) of the patients were analyzed in relation to αB-crystallin expression. Additionally, the effects of αB-crystallin knockdown on VEGF secretion and cell motility were studied in vitro. Results Patients with higher staining fractions of αB-crystallin exhibited a significantly shorter MFS (Log-Rank test, p < 0.005). Under normoxic conditions αB-crystallin knockdown with two different siRNAs in a HNSCC cell line reduced VEGF secretion 1.9-fold and 2.1-fold, respectively. Under hypoxic conditions, a similar reduction of VEGF secretion was observed, 1.9-fold and 2.2-fold, respectively. The effect on cell motility was assessed by a gap closure assay, which showed that αB-crystallin knockdown decreased the rate by which HNSCC cells were able to close a gap by 1.5- to 2.0-fold. Conclusions Our data suggest that αB-crystallin expression is associated with distant metastases formation in HNSCC patients. This association might relate to the chaperone function of αB-crystallin in mediating folding and secretion of VEGF and stimulating cell migration.
    BMC Cancer 03/2013; 13(1):128. DOI:10.1186/1471-2407-13-128 · 3.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Invasion is an important hallmark of cancer involving interactions between the tumor microenvironment and the cancer cells. Hypoxia, low oxygen level, is related to increased invasion and metastasis in many cancers. The aim was to elucidate the effect of hypoxia on invasion of oral squamous cell carcinoma cells (OSCC), and the applicability of a novel 3-dimentional myoma organotypic invasion model in hypoxia experiments. OSCC cell lines (primary oral carcinoma derived cellsUT-SCC-43A, recurrent oral carcinoma cells UT-SCC-43B and aggressive tongue carcinoma cells HSC-3) were studied for their migration and invasion capabilities under normoxia, hypoxia, and in the presence a hypoxia-mimicker cobalt chloride. As expected, the recurrent UT-SCC-43B cells were significantly more aggressive than the primary tumor derived cells. In contrast to tongue carcinoma HSC-3 cells, they only mildly responded to hypoxia in the migration or invasion assays, indicating a cell line specific response of hypoxia on the invasive potential. The modification of the organotypic human tissue-derived matrix via the removal of various yet unidentified soluble factors by rinsing the tissue resulting in stripped matrixsubstantially changed the invasion pattern of HSC-3 cells and the outcomes of hypoxic treatments. Only in the stripped tissue hypoxia significantly increased invasion, whereas in native intact tissue the induced invasion was not observed. This demonstrates the importance of the soluble factors to the invasion pattern andto the hypoxia response. A metastasis and poor prognosis marker, hypoxia-regulated lysyl oxidase (LOX), was present in the myoma tissue, but could be removed by rinsing. The inhibition of LOX resulted in a decrease in invasion area, but only very mildly in invasion depth. Thus, it may have a role in the modulation of the invasion pattern. Another hypoxia-related poor prognosis marker carbonic anhydrase 9 (CAIX) was induced in HSC-3 cells both by the hypoxic exposure andinterestingly in invading HSC-3 cells inside the tissue even in normoxic conditions. In conclusion,this suggests that the intact myoma organotypic model offersoptimally hypoxicsurroundings, thus being an excellent human tumor microenvironment mimicker.
    Experimental Cell Research 12/2012; 319(4). DOI:10.1016/j.yexcr.2012.12.010 · 3.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Only a minority of cancer patients benefits from the combination of EGFR-inhibition and radiotherapy in head and neck squamous cell carcinoma (HNSCC). A potential resistance mechanism is activation of EGFR and/or downstream pathways by stimuli in the microenvironment. The aim of this study was to find molecular targets induced by the microenvironment by determining the in vitro and in vivo expression of proteins of the EGFR-signaling network in 6 HNSCC lines. As hypoxia is an important microenvironmental parameter associated with poor outcome in solid tumors after radiotherapy, we investigated the relationship with hypoxia in vitro and in vivo. Methods Six human HNSCC cell lines were both cultured as cell lines (in vitro) and grown as xenograft tumors (in vivo). Expression levels were determined via western blot analysis and localization of markers was assessed via immunofluorescent staining. To determine the effect of hypoxia and pAKT-inhibition on cell survival, cells were incubated at 0.5% O2 and treated with MK-2206. Results We observed strong in vitro-in vivo correlations for EGFR, pEGFR and HER2 (rs=0.77, p=0.10, rs=0.89, p=0.03) and rs=0.93, p=0.02, respectively), but not for pAKT, pERK1/2 or pSTAT3 (all rs<0.55 and p>0.30). In vivo, pAKT expression was present in hypoxic cells and pAKT and hypoxia were significantly correlated (rs=0.51, p=0.04). We confirmed in vitro that hypoxia induces activation of AKT. Further, pAKT-inhibition via MK-2206 caused a significant decrease in survival in hypoxic cells (p<0.01), but not in normoxic cells. Conclusions These data suggest that (p)EGFR and HER2 expression is mostly determined by intrinsic features of the tumor cell, while the activation of downstream kinases is highly influenced by the tumor microenvironment. We show that hypoxia induces activation of AKT both in vitro and in vivo, and that hypoxic cells can be specifically targeted by pAKT-inhibition. Targeting pAKT is thus a potential way to overcome therapy resistance induced by hypoxia and improve patient outcome.
    BMC Cancer 10/2012; 12(1):463. DOI:10.1186/1471-2407-12-463 · 3.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A growing body of evidence suggests that components of the tumor microenvironment, including cancer-associated fibroblasts (CAF), may modulate the treatment sensitivity of tumor cells. Here, we investigated the possible influence of CAFs on the sensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines to cetuximab, an antagonistic epidermal growth factor receptor (EGFR) antibody. Cetuximab treatment caused a reduction in the proliferation rate of HNSCC cell lines, whereas the growth of HNSCC-derived CAF cultures was unaffected. When tumor cells were cocultured with CAFs in a transwell system, the cetuximab-induced growth inhibition was reduced, and a complete protection from growth inhibition was observed in one of the tumor cell lines investigated. Media that had been conditioned by CAFs offered protection from cetuximab treatment in a concentration-dependent manner, suggesting that the resistance to treatment was mediated by CAF-derived soluble factors. The coculture of HNSCC cell lines with CAFs resulted in an elevated expression of matrix metalloproteinase-1 (MMP-1) in both the tumor cells and CAFs. Moreover, the CAF-induced resistance was partly abolished by the presence of an MMP inhibitor. However, CAFs treated with siRNA targeting MMP-1 still protected tumor cells from cetuximab treatment, suggesting that several MMPs may cooperate to facilitate resistance or that the protective effect is mediated by another member of the MMP family. These results identify a novel CAF-dependent modulation of cetuximab sensitivity and suggest that inhibiting MMPs may improve the effects of EGFR-targeted therapy. Mol Cancer Res; 10(9); 1158-68. ©2012 AACR.
    Molecular Cancer Research 07/2012; 10(9):1158-68. DOI:10.1158/1541-7786.MCR-12-0030 · 4.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To find molecular markers from expression profiling data to predict recurrence of laryngeal cancer after radiotherapy. We generated gene expression data on pre-treatment biopsies from 52 larynx cancer patients. Patients developing a local recurrence were matched for T-stage, subsite, treatment, gender and age with non-recurrence patients. Candidate genes were then tested by immunohistochemistry on tumor material from a second series of 76 patients. Both series comprised early stage cancer treated with radiotherapy alone. Finally, gene expression data of eight larynx cancer cell lines with known radiosensitivity were analyzed. Nineteen patients with a local recurrence were matched with 33 controls. Gene sets for hypoxia, proliferation and intrinsic radiosensitivity did not correlate with recurrence, whereas expression of the putative stem cell marker CD44 did. In a supervised analysis, probes for all three splice variants of CD44 on the array appeared in the top 10 most significantly correlated with local recurrence. Immunohistochemical analysis of CD44 expression on the independent validation series confirmed CD44's predictive potential. In 8 larynx cancer cell lines, CD44 gene expression did not correlate with intrinsic radiosensitivity although it did correlate significantly with plating efficiency, consistent with a relationship with stem cell content. CD44 was the only biological factor tested which significantly correlated with response to radiotherapy in early stage larynx cancer patients, both at the mRNA and protein levels. Further studies are needed to confirm this and to assess how general these findings are for other head and neck tumor stages and sites.
    Clinical Cancer Research 11/2010; 16(21):5329-38. DOI:10.1158/1078-0432.CCR-10-0799 · 8.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Tumour-specific expression of matrix metalloproteinase (MMP)-7 has been noted in cutaneous squamous cell carcinomas (SCCs) in patients with recessive dystrophic epidermolysis bullosa (RDEB). To examine the potential role of MMP-7 in shedding of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in RDEB-associated and sporadic SCCs. Tissue microarrays of RDEB-associated SCC (n = 20), non-EB SCC (n = 60) and Bowen disease (n = 28) were immunostained for MMP-7, CD44 variant 3 (CD44v3) and HB-EGF. Shedding of HB-EGF was studied in vitro using two cutaneous SCC cell lines. Immunohistochemical analysis showed that HB-EGF was absent in tumour cells when MMP-7 and CD44v3 colocalized, and that the absence of HB-EGF was more pronounced in RDEB-associated SCCs than in non-EB SCCs. The loss of HB-EGF in MMP-7-CD44v3 double-positive areas was interpreted to indicate shedding and activation of HB-EGF; this was also detected in Bowen disease indicating its importance in the early phase of SCC development. Specific knockdown of MMP-7 expression in human cutaneous SCC cells by small interfering RNA inhibited shedding of HB-EGF and resulted in diminished activation of the EGF receptor (EGFR) and ERK1/2, and in reduced proliferation of SCC cells. These findings provide evidence for the role of MMP-7 in promoting the growth of cutaneous SCCs by shedding HB-EGF, and identify EGFR signalling as a potential therapeutic target in RDEB-associated SCC and unresectable sporadic cutaneous SCC.
    British Journal of Dermatology 10/2010; 163(4):726-35. DOI:10.1111/j.1365-2133.2010.09924.x · 4.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of a long period of preoperative fasting in surgical care has been to prevent aspiration of stomach contents by reducing the risk of vomiting. This has been based on the assumption that long periods of fasting will reduce the volume and acidity of stomach contents and the risk of pneumonia caused by aspiration [1]. Children undergoing ambulatory surgery have been without fluids preoperatively for even more than 14 hours [2]. Research in the field of pediatric surgery has highlighted the need for shorter preoperative fasting periods [3], and randomized controlled trials have shown that a two-hour fast is safe and might even have a beneficial impact on the acidity of stomach contents [4] and promote emptying of the stomach [5]. Neither aspiration nor other complications related to fasting have increased, and patients have been more satisfied [6]. According to the parents, the children are less irritable and tolerate the preoperative experience better, nor do they consider the changed guidelines difficult to follow [4]. According to the present fasting guidelines, children are allowed to drink clear fluids two hours and eat solid food 4-6 hours before surgery [7, 8]. In practice, changes have been delayed because of fears related to aspiration [9], and according to recent studies, children are still often fasting preoperatively for longer periods in spite of the guidelines for shorter fasting times [10,11], although the benefits of shorter fasting times have clearly outweighed the drawbacks [12]. Pediatric tonsillectomy patients seem to fast preoperatively for as long as others in pediatric surgical care [13, 3, 14, 15], even though their postoperative fast may be several hours longer. Thus, preoperative clear fluids might help to resolve the problem of perioperative irritation and dehydration in children [16], also in pediatric tonsillectomy patients. However, one of the most common
    Ambulatory Surgery 10/2010; 16(3):75-79.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Wood is a natural fiber reinforced composite. It structurally resembles bone tissue to some extent. Specially heat-treated birch wood has been used as a model material for further development of synthetic fiber reinforced composites (FRC) for medical and dental use. In previous studies it has been shown, that heat treatment has a positive effect on the osteoconductivity of an implanted wood. In this study the effects of two different heat treatment temperatures (140 and 200 degrees C) on wood were studied in vitro. Untreated wood was used as a control material. Heat treatment induced biomechanical changes were studied with flexural and compressive tests on dry birch wood as well as on wood after 63 days of simulated body fluid (SBF) immersion. Dimensional changes, SBF sorption and hydroxylapatite type mineral formation were also assessed. The results showed that SBF immersion decreases the biomechanical performance of wood and that the heat treatment diminishes the effect of SBF immersion on biomechanical properties. With scanning electron microscopy and energy dispersive X-ray analysis it was shown that hydroxylapatite type mineral precipitation formed on the 200 degrees C heat-treated wood. An increased weight gain of the same material during SBF immersion supported this finding. The results of this study give more detailed insight of the biologically relevant changes that heat treatment induces in wood material. Furthermore the findings in this study are in line with previous in vivo studies.
    Journal of Materials Science Materials in Medicine 05/2010; 21(8):2345-54. DOI:10.1007/s10856-010-4087-4 · 2.59 Impact Factor

Publication Stats

4k Citations
535.55 Total Impact Points


  • 1986–2015
    • University of Turku
      • • Department of Medical Biochemistry and Genetics
      • • Department of Dermatology and Venereology
      • • Department of Otorhinolaryngology
      • • Department of Neurology
      Turku, Varsinais-Suomi, Finland
  • 1991–2013
    • Turku University Hospital
      • • Department of Dermatology
      • • Department of Obstetrics and Gynecology
      Turku, Province of Western Finland, Finland
  • 2001
    • University of Oulu
      • Department of Diagnostics and Oral Medicine
      Uleoborg, Northern Ostrobothnia, Finland
  • 1991–2000
    • Turku centre for biotechnology, finland
      Turku, Province of Western Finland, Finland
  • 1999
    • University of Helsinki
      • Department of Otorhinolaryngology
      Helsinki, Uusimaa, Finland
  • 1998
    • Turku PET Centre
      Turku, Varsinais-Suomi, Finland
  • 1996
    • Helsinki University Central Hospital
      • Department of Otolaryngology
      Helsinki, Province of Southern Finland, Finland
  • 1995
    • National Public Health Institute
      Helsinki, Southern Finland Province, Finland
  • 1987–1993
    • University of Michigan
      • Department of Otolaryngology - Head and Neck Surgery
      Ann Arbor, Michigan, United States