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Ansell, Anna
Publications (10 of 15) Show all publications
Ansell, A., Jedlinski, A., Johansson, A.-C. & Roberg, K. (2016). Epidermal growth factor is a biomarker for poor cetuximab response in tongue cancer cells. Journal of Oral Pathology & Medicine, 45(1), 9-16
Open this publication in new window or tab >>Epidermal growth factor is a biomarker for poor cetuximab response in tongue cancer cells
2016 (English)In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 45, no 1, p. 9-16Article in journal (Refereed) Published
Abstract [en]

Background: Epidermal growth factor receptor (EGFR) is a target for treatment in tongue cancer. Here, EGFR ligands were evaluated for their potential uses as predictive biomarkers of cetuximab treatment response.

Methods: In three tongue cancer cell lines the influences of epidermal growth factor (EGF), amphiregulin (AR), and epiregulin (EPR) on tumour cell proliferation and cetuximab response were evaluated by the addition of recombinant human (rh) proteins or the siRNA-mediated downregulation of endogenous ligand production.

Results: EGF or AR downregulation suppressed the proliferation of all investigated cell lines. Furthermore, all cell lines displayed increased cetuximab resistance upon the addition of rhEGF, whereas EGF silencing resulted in an improved cetuximab response in one cell line.

Conclusions: Our data suggest that EGF and AR are critical components of the EGFR signalling network required for full proliferative potential. Moreover, EGF is a potential predictive biomarker of poor cetuximab response and a possible treatment target.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2016
Keywords
Head and neck cancer; Tongue cancer; Erbitux; EGFR ligands; treatment response
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-100675 (URN)10.1111/jop.12310 (DOI)000369990100003 ()
Note

Funding agencies: Foundation of Ake Wiberg; Swedish Cancer Society [2008/552, 2010/545]; County Council of Ostergotland; Linkoping University Hospital; Foundation of Magnus Bergvall; Cancer Foundation of Ostergotland

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Available from: 2013-11-11 Created: 2013-11-11 Last updated: 2017-05-03
Farnebo, L., Stjernstrom, A., Fredrikson, M., Ansell, A., Garvin, S. & Thunell, L. (2015). DNA repair genes XPC, XPD, XRCC1, and XRCC3 are associated with risk and survival of squamous cell carcinoma of the head and neck. DNA Repair, 31, 64-72
Open this publication in new window or tab >>DNA repair genes XPC, XPD, XRCC1, and XRCC3 are associated with risk and survival of squamous cell carcinoma of the head and neck
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2015 (English)In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 31, p. 64-72Article in journal (Refereed) Published
Abstract [en]

Head and neck squamous cell carcinomas (HNSCC) are a heterogenous group of tumors with a high rate of early recurrences, second primary tumors, and mortality. Despite advances in diagnosis and treatment over the past decades, the overall 5-year survival rate remains around 50%. Since the head-and neck-region is continuously exposed to potentially DNA-damaging exogenous and endogenous factors, it is reasonable to expect that the DNA repair genes play a part in the development, progression, and outcome of HNSCC. The aim of this study was to investigate the SNPs XPC A499V, XPD K751Q XRCC1 R399Q and XRCC3 T241M as potential risk factors and indicators of survival among Caucasian patients. One-hundred-sixty-nine patients as well as 344 healthy controls were included and genotyped with PCR-RFLP. We showed that XPC A499V was associated with increased risk of HNSCC, especially laryngeal carcinoma. Among women, XPD K751Q was associated with increased risk of oral SCC. Furthermore, XPD homozygous mutant individuals had the shortest survival time, a survival time that increased however after full dose radiotherapy. Wild-type individuals of XRCC3 T241M demonstrated an earlier age of onset. HPV-positive never smokers had lower frequencies of p53 mutation. Among HNSCC patients, HPV-positivity was significantly associated with XRCC1 R399Q homozygous mutant genotype. Moreover, combinations of putative risk alleles seemed to act synergistically, increasing the risk of HNSCC. In conclusion, our results suggest that SNPs of the DNA repair genes XPC, XPD, XRCC1, and XRCC3 may affect risk and survival of HNSCC. (C) 2015 Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Head and neck squamous cell carcinoma; XPC; XPD; HPV; p53; Overall survival
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-120212 (URN)10.1016/j.dnarep.2015.05.003 (DOI)000357138600007 ()26001739 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society; Laryngfonden

Available from: 2015-07-21 Created: 2015-07-20 Last updated: 2017-12-04
Jedlinski, A., Ansell, A., Johansson, A.-C. & Roberg, K. (2013). EGFR status and EGFR ligand expression influence the treatment response of head and neck cancer cell lines. Journal of Oral Pathology & Medicine, 42(1), 26-36
Open this publication in new window or tab >>EGFR status and EGFR ligand expression influence the treatment response of head and neck cancer cell lines
2013 (English)In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 42, no 1, p. 26-36Article in journal (Refereed) Published
Abstract [en]

Background: Combination treatment (chemoradiotherapy) is the standard treatment for locally advanced head and neck squamous cell carcinoma (HNSCC); however, treatment resistance and local recurrence are significant problems. A high level of epidermal growth factor receptor (EGFR) has been associated with a more aggressive phenotype as well as decreased responsiveness to radio- or chemotherapy. We examined the role of EGFR status and EGFR ligand expression for the treatment response. Methods: Intrinsic sensitivity to radiotherapy, cisplatin, and cetuximab treatments was investigated in 25 HNSCC cell lines. EGFR gene copy number, mRNA and protein expression, EGFR and Akt phosphorylation status, and mRNA expression of the EGFR ligands were analyzed using quantitative PCR and ELISA and assessed for their impact on treatment sensitivity. Results: Different treatment modalities yielded great diversity in outcome; of note, cetuximab treatment stimulated growth in one cell line. When treatments were combined primarily additive effects were observed. While radioresistance tended to be associated with a high level of phosphorylated EGFR (pEGFR; P = 0.09), cetuximab-resistant cells had low levels of pEGFR (P = 0.13). The three most cetuximab-sensitive cell lines had high EGFR gene copy numbers. Furthermore, cetuximab treatment response was significantly correlated with epiregulin mRNA expression (r = -0.408, P = 0.043). Cisplatin-resistant tumor cells expressed significantly lower levels of EGFR protein (P = 0.04) compared to cisplatin-sensitive cells and tended to have lower levels of phosphorylated Akt (pAkt; P = 0.13) and lower expression levels of amphiregulin (P = 0.18). Conclusions: Epidermal growth factor receptor status and ligand expression influence the treatment sensitivity of HNSCC cells and may be useful as predictive markers.

Place, publisher, year, edition, pages
John Wiley and Sons, 2013
Keywords
chemoradiotherapy, EGFR, epiregulin, Erbitux (R), HB-EGF, SCCHN, TGF-a, treatment response
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-87963 (URN)10.1111/j.1600-0714.2012.01177.x (DOI)000312998500004 ()
Note

Funding Agencies|Swedish Laryng Foundation||Foundation of Olle Engkvist, Building Contractor||Linkoping University Hospital||

Available from: 2013-01-28 Created: 2013-01-28 Last updated: 2017-12-06
Ansell, A. (2013). Identification of Tumor Cell- and Stroma Derived Biomarkers of Treatment Response in Head and Neck Cancer. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Identification of Tumor Cell- and Stroma Derived Biomarkers of Treatment Response in Head and Neck Cancer
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Head and neck squamous cell carcinoma (HNSCC) poses a major health problem in the world with approximately 600 000 new cases yearly. Treatment resistance is a major problem within this patient group and despite advances in treatment strategies the overall survival rate has unfortunately not increased.

One of the major components of the tumor microenvironment is the cancer associated fibroblasts (CAFs) which can modulate the treatment sensitivity, tumor growth, and the invasive potential of tumor cells.

The aim of this thesis was to identify predictive markers for treatment response in HNSCC and to study the crosstalk between tumor cells and CAFs that may underlie treatment resistance.

In paper I, we identified gene expression differences between one cisplatin sensitive cell line and two cisplatin resistant cell lines, by microarray analysis, and found that a high expression of matrix metalloproteinase (MMP) -7 was associated with resistance to cisplatin. In paper II, the epidermal growth factor (EGF) receptor ligands EGF, amphiregulin, and epiregulin were evaluated regarding their potential use as predictive biomarkers for cetuximab treatment response in tongue cancer cell lines and it was shown that EGF may serve as a marker for poor cetuximab response. In paper III and IV, we investigated the influence of CAFs on the proliferation, migration, gene expression, and cetuximab response of tumor cells. It was found that CAFs induced resistance to cetuximab in a MMP-dependent manner. In addition, a microarray analysis, comparing tumor cells co-cultured with CAFs and tumor cells cultured alone, revealed that CAFs induced multiple gene expression changes in tumor cells some of which are related to epithelial to mesenchymal transition. Some of these changes were found to be dependent on cell-cell contact.

Taken together, we here suggest MMP-7 and EGF to be predictive markers of cisplatin and cetuximab response, respectively. We also show that CAFs protect HNSCC cells from cetuximab treatment; however, the factor responsible for the protective effect is yet to be discovered.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. p. 89
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1382
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-100734 (URN)10.3384/diss.diva-100734 (DOI)978-91-7519-492-9 (ISBN)
Public defence
2013-11-29, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2013-11-11 Created: 2013-11-11 Last updated: 2013-11-11Bibliographically approved
Ansell, A., Kankainen, M., Jönsson, J.-I., Monni, O., Roberg, K. & Johansson, A.-C. (2013). Molecular cross-talk between head and neck squamous cell carcinoma cells and cancer-associated fibroblasts.
Open this publication in new window or tab >>Molecular cross-talk between head and neck squamous cell carcinoma cells and cancer-associated fibroblasts
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2013 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Cancer-associated fibroblasts (CAFs) are one of the main components of the tumor stroma and are known to increase tumor growth and stimulate  invasion and metastasis. Increasing evidence suggests that CAFs may also be an important determinant of the response to various treatments. In this study we aimed to characterize the molecular cross-talk between CAFs and head and neck squamous cell carcinoma (HNSCC) cells.

HNSCC cell lines were co-cultured with their patient-matched CAFs for seven days, after which the gene expression of tumor cells was investigated by Affymetrix microarray. 58 protein coding genes were found to be differentially expressed (Q≤0.05) in tumor cells cocultured with CAFs when compared to tumor cells cultured alone. The top functions of these genes were cancer, cellular movement, and embryonic development as analyzed by Ingenuity Pathway Analysis. Nine genes were upregulated by ≥1.5-fold while the expression of 35 genes was found to be reduced by ≤ 0.67-fold. Several of the differentially expressed genes have been associated with epithelial-to-mesenchymal transition (EMT). The change in the expression of POSTN, GREM1, COL1A2, VIM, and MMP7 was verified by qPCR analysis. Moreover, the influence of CAFs on the proliferation, migration and cetuximab sensitivity of tumor cells was investigated, and was found to vary among the tumor cell-CAF pairs.

In conclusion, we demonstrate that CAF-derived signals cause changes in the expression of multiple genes, several of which are associated with an EMT phenotype of tumor cells. Furthermore, CAFs modulate the proliferation, migration and cetuximab treatment response of tumor cells.

Keywords
Head and neck cancer; Tongue cancer; Erbitux; EGFR ligands; treatment response
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-100678 (URN)
Available from: 2013-11-11 Created: 2013-11-11 Last updated: 2013-11-11Bibliographically approved
Farnebo, L., Tiefenböck, K., Ansell, A., Thunell, L., Garvin, S. & Roberg, K. (2013). Strong expression of survivin is associated with positive response to radiotherapy and improved overall survival in head and neck squamous cell carcinoma patients. International Journal of Cancer, 133(8), 1994-2003
Open this publication in new window or tab >>Strong expression of survivin is associated with positive response to radiotherapy and improved overall survival in head and neck squamous cell carcinoma patients
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2013 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 8, p. 1994-2003Article in journal (Refereed) Published
Abstract [en]

Head and neck squamous cell carcinoma (HNSCC) is a malignancy that is associated with severe mortality despite advances in therapy. Todays standard treatment most commonly includes radiotherapy, often combined with chemotherapy or surgery. There are so far no established biomarkers to predict response to radiation, and thus the aim of this study was to investigate a series of markers that could potentially identify HNSCC patients who would benefit from radiotherapy. The selected markers, both proteins (epidermal growth factor receptor, survivin and p53), and single nucleotide polymorphisms (SNPs) in the genes of XRCC3, XRCC1, XPC, XPD, MDM2, p53 and FGFR4 were correlated to the response to radiotherapy and overall survival. Investigations were performed on pretreatment tumor biopsies from patients classified as responders or nonresponders to radiotherapy. Protein expression was examined using immunohistochemistry and the genotyping of specific SNPs was analyzed using PCR-RFLP or pyrosequencing. We found that survivin expression was significantly stronger in the responder group (p = 0.003) and that patients with a strong survivin expression had a significantly better overall survival (p andlt; 0.001). Moreover, downregulation of survivin by siRNA in two HNSCC cell lines significantly decreased their sensitivity to radiation. Among the SNPs analyzed, patients with the XPD Lys751Gln SNP had a significantly shorter overall survival (p = 0.048), and patients with the FGFR4 Gly388Arg SNP had a significantly longer overall survival (p = 0.010). In conclusion, our results suggest that survivin plays an important role in the response to radiotherapy and may be a useful marker for predicting radiotherapy response in patients with HNSCC. less thanbrgreater than less thanbrgreater thanWhats new? Resistance to radiation therapy is a significant problem in the treatment of head and neck squamous cell carcinoma (HNSCC) and has created a need for the discovery of markers predictive of radiotherapy response. One promising marker is survivin, an inhibitor of apoptosis. Here, in pre-treatment biopsies from 40 patients with HNSCC, strong survivin expression was significantly associated with response to radiotherapy and increased overall survival. The data also indicate that single nucleotide polymorphisms in the genes XPD and FGFR4 are other possible predictors of overall survival after radiotherapy.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2013
Keywords
head and neck tumors, radiotherapy, survivin, single nucleotide polymorphism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-97229 (URN)10.1002/ijc.28200 (DOI)000322908600025 ()
Note

Funding Agencies|Swedish Cancer Society|2008/5522010/545|Swedish Laryng Foundation||Foundation of Ake Wiberg||County Council of Ostergotland||Research Funds of Linkoping University Hospital||

Available from: 2013-09-06 Created: 2013-09-05 Last updated: 2017-12-06
Johansson, A.-C., Ansell, A., Jerhammar, F., Bradic Lindh, M., Grenman, R., Munck-Wikland, E., . . . Roberg, K. (2012). Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase-Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells. Molecular Cancer Research, 10(9), 1158-1168
Open this publication in new window or tab >>Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase-Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells
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2012 (English)In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 10, no 9, p. 1158-1168Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-86135 (URN)10.1158/1541-7786.MCR-12-0030 (DOI)000310648300003 ()
Note

Funding Agencies|Johan and Jakob Soderberg Foundation||Foundation Olle Engqvist Byggmastare||Swedish Laryng Foundation||Borgholm Rotary Club||Swedish National Board of Health and Welfare||Lions Research Foundation||Lars Hierta Memorial Foundation||Tore Nilsson Foundation for Medical Research||Swedish Society for medical research||County Council of Ostergotland||Cancer Foundation of Ostergotland||Merck Serono||Swedish Research Council|349-2008-6578|Swedish Cancer Society|CAN 2009/1136CAN 2010/545|

Available from: 2012-12-07 Created: 2012-12-07 Last updated: 2017-12-07
Wahlström, O., Risto, O., Kalén, A., Linder, C., Ansell, A., Söderström, M. & Magnusson, P. (2011). Acidic preparations of lysed platelets up-regulate proliferative and vascular genes, and the TGFBR pathway in osteoblast-like cells in BONE, vol 48, issue , pp S118-S118. In: BONE (pp. S118-S118). Elsevier Science B.V., Amsterdam., 48
Open this publication in new window or tab >>Acidic preparations of lysed platelets up-regulate proliferative and vascular genes, and the TGFBR pathway in osteoblast-like cells in BONE, vol 48, issue , pp S118-S118
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2011 (English)In: BONE, Elsevier Science B.V., Amsterdam. , 2011, Vol. 48, p. S118-S118Conference paper, Published paper (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam., 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-68230 (URN)10.1016/j.bone.2011.03.215 (DOI)000289879800194 ()
Available from: 2011-05-13 Created: 2011-05-13 Last updated: 2013-10-23
Wahlström, O., Linder, C., Ansell, A., Kalén, A., Söderström, M. & Magnusson, P. (2011). Acidic preparations of lysed platelets upregulate proliferative pathways in osteoblast-like cells as demonstrated by genome-wide microarray analysis. Platelets, 22(6), 452-460
Open this publication in new window or tab >>Acidic preparations of lysed platelets upregulate proliferative pathways in osteoblast-like cells as demonstrated by genome-wide microarray analysis
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2011 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 22, no 6, p. 452-460Article in journal (Refereed) Published
Abstract [en]

latelets contain numerous growth factors essential for wound and fracture healing. We investigated the gene expression in human osteoblast-like cells stimulated with lysed platelets prepared in acidic, neutral, or alkaline buffers. Lysed platelets prepared in buffers at pH 5.4, 7.4, and 7.9, were added after neutralization to hFOB 1.19 cells. Genome-wide microarray analysis was performed using the Affymetrix GeneChip 7G Scanner. Biometric, cluster, and pathway analyses were performed with GeneSpring GX. Biometric analyses demonstrated that 53 genes were differentially regulated (p andlt;= 0.005, andgt;= 2-fold increase). Pathway analysis revealed 10 significant pathways of which eight are common ones regulating bone formation and cancer growth. Eleven genes were selected for quantitative real-time polymerase chain reaction (PCR) based on the microarray analysis of the lysed platelets prepared in the pH 5.4 experiments. In conclusion, acidic preparations of lysed platelet concentrates release factors essential for cell proliferation and particularly cell metabolism under hypoxic conditions. The genetic response from these factors was dominated by genes associated with the same pathways observed in bone formation and cancer growth. Activation of TGF-beta in the acidic preparation could be a stimulatory key factor of cell proliferation. These results support the hypothesis that acidification of platelets modifies the stimulatory response of mesenchymal cells in vitro, which is analogous with the observed milieu of a low pH present in wound and fracture sites, as well as in growing tumors.

Place, publisher, year, edition, pages
Informa Healthcare, 2011
Keywords
Cell proliferation, gene expression, hypoxia, platelets, TGFBR pathway
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-70115 (URN)10.3109/09537104.2011.565432 (DOI)000293600300008 ()
Note

Original Publication: Ola Wahlström, Cecilia Linder, Anna Ansell, Anders Kalén, Mats Söderström and Per Magnusson, Acidic preparations of lysed platelets upregulate proliferative pathways in osteoblast-like cells as demonstrated by genome-wide microarray analysis, 2011, Platelets, (22), 6, 452-460. http://dx.doi.org/10.3109/09537104.2011.565432 Copyright: Informa Healthcare http://informahealthcare.com/

Available from: 2011-08-19 Created: 2011-08-19 Last updated: 2017-12-08
Johansson, A., Ansell, A., Ostman, A. & Roberg, K. (2010). Cancer-associated fibroblasts desensitizes head and neck squamous cell carcinoma cells to epidermal growth factor receptor-targeted therapy in EJC SUPPLEMENTS, vol 8, issue 5, pp 134-134. In: EJC SUPPLEMENTS (pp. 134-134). Elsevier Science B.V., Amsterdam., 8(5)
Open this publication in new window or tab >>Cancer-associated fibroblasts desensitizes head and neck squamous cell carcinoma cells to epidermal growth factor receptor-targeted therapy in EJC SUPPLEMENTS, vol 8, issue 5, pp 134-134
2010 (English)In: EJC SUPPLEMENTS, Elsevier Science B.V., Amsterdam. , 2010, Vol. 8, no 5, p. 134-134Conference paper, Published paper (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam., 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67315 (URN)000288603100509 ()
Available from: 2011-04-08 Created: 2011-04-08 Last updated: 2011-04-14
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