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Jerhammar, Fredrik
Publications (10 of 19) Show all publications
Bivik Eding, C., Domer, J., Wäster, P., Jerhammar, F., Rosdahl, I. & Öllinger, K. (2015). Melanoma Growth and Progression After Ultraviolet A Irradiation: Impact of Lysosomal Exocytosis and Cathepsin Proteases. Acta Dermato-Venereologica, 95(7), 792-797
Open this publication in new window or tab >>Melanoma Growth and Progression After Ultraviolet A Irradiation: Impact of Lysosomal Exocytosis and Cathepsin Proteases
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2015 (English)In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 95, no 7, p. 792-797Article in journal (Refereed) Published
Abstract [en]

Ultraviolet (UV) irradiation is a risk factor for development of malignant melanoma. UVA-induced lysosomal exocytosis and subsequent cell growth enhancement was studied in malignant melanoma cell lines and human skin melanocytes. UVA irradiation caused plasma membrane damage that was rapidly repaired by calcium-dependent lysosomal exocytosis. Lysosomal content was released into the culture medium directly after irradiation and such conditioned media stimulated the growth of non-irradiated cell cultures. By comparing melanocytes and melanoma cells, it was found that only the melanoma cells spontaneously secreted cathepsins into the surrounding medium. Melanoma cells from a primary tumour showed pronounced invasion ability, which was prevented by addition of inhibitors of cathepsins B, D and L. Proliferation was reduced by cathepsin L inhibition in all melanoma cell lines, but did not affect melanocyte growth. In conclusion, UVA-induced release of cathepsins outside cells may be an important factor that promotes melanoma growth and progression.

Place, publisher, year, edition, pages
ACTA DERMATO-VENEREOLOGICA, 2015
Keywords
lysosome; cathepsin; UVA; exocytosis; melanocyte; melanoma
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:liu:diva-122545 (URN)10.2340/00015555-2064 (DOI)000362925500005 ()25669167 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Ostgotaregionens Cancer Foundation; Stiftelsen Olle Engkvist Byggmastare; Swedish Cancer Society; Welander-Finsen Foundation

Available from: 2015-11-06 Created: 2015-11-06 Last updated: 2017-12-01
Jerhammar, F., Johansson, A.-C., Ceder, R., Welander, J., Jansson, A., Grafstrom, R. C., . . . Roberg, K. (2014). YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer. Oral Oncology, 50(9), 832-839
Open this publication in new window or tab >>YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer
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2014 (English)In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 50, no 9, p. 832-839Article in journal (Refereed) Published
Abstract [en]

Objectives: Targeted therapy against the epidermal growth factor receptor (EGFR) only variably represents a therapeutic advance in head and neck squamous cell carcinoma (HNSCC). This study addresses the need of biomarkers of treatment response to the EGFR-targeting antibody cetuximab (Erbitux (R)). Materials and Methods: The intrinsic cetuximab sensitivity of HNSCC cell lines was assessed by a crystal violet assay. Gene copy number analysis of five resistant and five sensitive cell lines was performed using the Affymetrix SNP 6.0 platform. Quantitative real-time PCR was used for verification of selected copy number alterations and assessment of mRNA expression. The functional importance of the findings on the gene and mRNA level was investigated employing siRNA technology. The data was statistically evaluated using Mann-Whitney U-test and Spearmans correlation test. Results: Analysis of the intrinsic cetuximab sensitivity of 32 HNSCC cell lines characterized five and nine lines as cetuximab sensitive or resistant, respectively. Gene copy number analysis of five resistant versus five sensitive cell lines identified 39 amplified protein-coding genes, including YAP1, in the genomic regions 11q22.1 or 5p13-15. Assessment using qPCR verified that YAP1 amplification associated with cetuximab resistance. Amplification of YAP1 correlated to higher mRNA levels, and RNA knockdown resulted in increased cetuximab sensitivity. Assessment of several independent clinical data sets in the public domain confirmed YAP1 amplifications in multiple tumor types including HNSCC, along with highly differential expression in a subset of HNSCC patients. Conclusion: Taken together, we provide evidence that YAP1 could represent a novel biomarker gene of cetuximab resistance in HNSCC cell lines.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Head and neck cancer; SCCHN; YAP1; Predictive marker; Treatment response; Gene copy number; Drug resistance
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-110268 (URN)10.1016/j.oraloncology.2014.06.003 (DOI)000340267300011 ()24993889 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society [2008/552, 2010/545]; Ake Wiberg foundation; National board of health and welfare; Ostergotland county council; Foundation of Olle Engkvist; Swedish Cancer and Allergy Fund; Swedish Research Council; Swedish Fund for Research

Available from: 2014-09-05 Created: 2014-09-05 Last updated: 2017-12-05
Zheng, L., Cedazo-Minguez, A., Hallbeck, M., Jerhammar, F., Hultenby, K., Marcusson, J. & Terman, A. (2013). Intracellular localization of amyloid beta peptide in SH-SY5Y neuroblastoma cells. Journal of Alzheimer's Disease, 37(4), 713-733
Open this publication in new window or tab >>Intracellular localization of amyloid beta peptide in SH-SY5Y neuroblastoma cells
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2013 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 37, no 4, p. 713-733Article in journal (Refereed) Published
Abstract [en]

Amyloid-beta peptide (A beta), the main component of Alzheimer's disease (AD) senile plaques, has been found to accumulate within the lysosomal compartment of AD neurons. We have previously shown that in differentiated SH-SY5Y neuroblastoma cells cultured under normal conditions, the majority of A beta is localized extralysosomally, while oxidative stress significantly increases intralysosomal A beta content through activation of macroautophagy. It is, however, not clear which cellular compartments contain extralysosomal A beta in intact SH-SY5Y cells, and how oxidative stress influences the distribution of extralysosomal A beta. Using confocal laser scanning microscopy and immunoelectron microscopy, we showed that in differentiated neuroblastoma cells cultured under normal conditions A beta (A beta(40), A beta(42), and A beta oligomers) is colocalized with both membrane-bound organelles (endoplasmic reticulum, Golgi complexes, multivesicular bodies/late endosomes, lysosomes, exocytotic vesicles and mitochondria) and non-membrane-bound cytosolic structures. Neuroblastoma cells stably transfected with A beta PP Swedish KM670/671NL double mutation showed enlarged amount of A beta colocalized with membrane compartments. Suppression of exocytosis by 5 nM tetanus toxin resulted in a significant increase of the amount of cytosolic A beta as well as A beta colocalized with exocytotic vesicles, endoplasmic reticulum, Golgi complexes, and lysosomes. Hyperoxia increased A beta localization in the endoplasmic reticulum, Golgi apparatus, mitochondria, and lysosomes, but not in the secretory vesicles. These results indicate that in SH-SY5Y neuroblastoma cells intracellular A beta is not preferentially localized to any particular organelle and, to a large extent, is secreted from the cells. Challenging cells to hyperoxia, exocytosis inhibition, or A beta overproduction increased intracellular A beta levels but did not dramatically changed its localization pattern.

Place, publisher, year, edition, pages
IOS Press, 2013
Keywords
Alzheimer’s disease, Amyloid β-protein, Endosomes, Exocytosis, Lysosomes
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-73411 (URN)10.3233/JAD-122455 (DOI)000325649500007 ()
Available from: 2012-01-03 Created: 2012-01-03 Last updated: 2017-12-08Bibliographically approved
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
Zheng, L., Cedazo-Minguez, A., Hallbeck, M., Jerhammar, F., Marcusson, J. & Terman, A. (2012). Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system.. Translational Neurodegeneration, 1(1), 19
Open this publication in new window or tab >>Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system.
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2012 (English)In: Translational Neurodegeneration, ISSN 2047-9158, Vol. 1, no 1, p. 19-Article in journal (Refereed) Published
Abstract [en]

Background

Amyloid beta peptide (Aβ) is the main component of extraneuronal senile plaques typical of Alzheimer’s disease (AD) brains. Although Aβ is produced by normal neurons, it is shown to accumulate in large amounts within neuronal lysosomes in AD. We have recently shown that under normal conditions the majority of Aβ is localized extralysosomally, while oxidative stress significantly increases intralysosomal Aβ content through activation of macroautophagy. It is also suggested that impaired Aβ secretion and resulting intraneuronal increase of Aβ can contribute to AD pathology. However, it is not clear how Aβ is distributed inside normal neurons, and how this distribution is effected when Aβ secretion is inhibited.

Methods

Using retinoic acid differentiated neuroblastoma cells and neonatal rat cortical neurons, we studied intracellular distribution of Aβ by double immunofluorescence microscopy for Aβ40 or Aβ42 and different organelle markers. In addition, we analysed the effect of tetanus toxin-induced exocytosis inhibition on the intracellular distribution of Aβ.

Results

Under normal conditions, Aβ was found in the small cytoplasmic granules in both neurites and perikarya. Only minor portion of Aβ was colocalized with trans-Golgi network, Golgi-derived vesicles, early and late endosomes, lysosomes, and synaptic vesicles, while the majority of Aβ granules were not colocalized with any of these structures. Furthermore, treatment of cells with tetanus toxin significantly increased the amount of intracellular Aβ in both perikarya and neurites. Finally, we found that tetanus toxin increased the levels of intralysosomal Aβ although the majority of Aβ still remained extralysosomally.

Conclusion

Our results indicate that most Aβ is not localized to Golgi-related structures, endosomes, lysosomes secretory vesicles or other organelles, while the suppression of Aβ secretion increases intracellular intra- and extralysosomal Aβ.

Place, publisher, year, edition, pages
BioMed Central, 2012
Keywords
Alzheimer disease; Amyloid β-protein; Colocalization; Exocytosis; Immunocytochemistry; Lysosomes
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-99373 (URN)10.1186/2047-9158-1-19 (DOI)23210724 (PubMedID)2-s2.0-84875525734 (Scopus ID)
Available from: 2013-10-16 Created: 2013-10-16 Last updated: 2018-01-11Bibliographically approved
Jerhammar, F. (2012). Predictive Markers of Treatment Resistance in Head and Neck Squamous Cell Carcinoma. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Predictive Markers of Treatment Resistance in Head and Neck Squamous Cell Carcinoma
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Head and neck cancer is a common malignancy with approximately 600 000 new cases yearly. Disappointingly, the overall survival has not increased over the last decades. The concept of personalized medicine, i.e. to treat every patient with an individually planned treatment regime has gathered increased interest, but requires the establishment of novel biomarkers that can predict treatment response.

The aim of this thesis is to propose novel predictive single markers or combinations of markers of response to radiation, cisplatin and cetuximab. The general methodology is to evaluate common differences of cell lines resistant to radiation, cisplatin or cetuximab compared to sensitive counterparts.

In paper I, we analysed the expression of 14 proteins involved in growth control and/or apoptosis by western blot and related them to intrinsic radiosensitivity (IR) in nine cell lines. No factor had a significant correlation to IR on its own. A combination of EGFR, survivin, Bak, Smad4, and Hsp70 had the best correlation to IR (R=0.886, p=0.001). Additionally, we analysed the presence of p53 mutations in the cell lines. All cell lines had at least one missense, splice site or loss of transcript mutation. To be able to combine protein expression and presence of p53 mutations we created a system designated the number of negative points (NNP). With this system we could extract that expression of EGFR, survivin, and p53 missense or splice site mutations had the best correlation to IR (R=0.990, p<0.001).

In paper II we conducted a gene expression microarray analysis of three cell lines, from which common deregulations in two cisplatin resistant cell lines was compared to a cisplatin sensitive cell line. From a bioinformatic approach of gene ontology and molecular network analysis, we defined a transcriptional profile of 20 genes. Finally, key findings were analysed in a larger panel of cell lines, where high MMP-7 expression correlated with higher cisplatin resistance.

Paper III compared 4 cell lines with high IR to a radiosensitive equivalent. Using a similar bioinformatic approach as paper II, we established a transcriptional profile of 14 genes. Analysis in a larger panel of cell lines revealed that FN1 expression predicts higher IR.

Paper IV establishes the cetuximab sensitivity of 35 cell lines of which 12 were resistant and five were sensitive to cetuximab. After whole genome gene copy number analysis of five cetuximab resistant and five cetuximab sensitive cell lines, and verification of key findings in a larger cell line panel, the results show that the amplification of the YAP1 gene is coupled to cetuximab resistance.

In summary, this thesis proposes a number of novel markers of resistance to radiation, cisplatin, and cetuximab which could influence treatment choice in the future, following verifications in primary tumor material.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. p. 83
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1291
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-76152 (URN)978-91-7519-968-9 (ISBN)
Public defence
2012-04-27, Elsa Brändströmsalen, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2012-03-29Bibliographically approved
Farnebo, L., Jerhammar, F., Ceder, R., Grafström, R. C., Vainikka, L., Thunell, L., . . . Roberg, K. (2011). Combining factors on protein and gene level to predict radioresponse in head and neck cancer cell lines. Journal of Oral Pathology & Medicine, 40(10), 739-746
Open this publication in new window or tab >>Combining factors on protein and gene level to predict radioresponse in head and neck cancer cell lines
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2011 (English)In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 40, no 10, p. 739-746Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Radiotherapy is the main therapy for head and neck squamous cell carcinoma (HNSCC); however, treatment resistance and local recurrence are significant problems, highlighting the need for predictive markers. In this study, we evaluated selected proteins, mutations, and single nucleotide polymorphisms (SNPs) involved in apoptosis, cell proliferation, and DNA repair alone or combined as predictive markers for radioresponse in 42 HNSCC cell lines.

METHODS: The expression of epidermal growth factor receptor, survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and heat shock protein 70 was analyzed by ELISA. Furthermore, mutations and SNPs in the p53 gene as well as SNPs in the MDM2, XRCC1, and XRCC3 genes were analyzed for their relation to radioresponse. To enable the evaluation of the predictive value of several factors combined, each cell line was allocated points based on the number of negative points (NNP) system, and the NNP sum was correlated with radioresponse.

RESULTS: Survivin was the only factor that alone was significantly correlated with the intrinsic radiosensitivity (r=0.36, p=0.02). The combination of survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and the p53 Arg72Pro polymorphism was found to most strongly correlate with radioresponse (r=0.553, p<0.001).

CONCLUSION: These data indicate that the intrinsic radiosensitivity of 42 HNSCC cell lines can be predicted by a panel of factors on both the protein and gene levels. Moreover, among the investigated factors, survivin was the most promising biomarker of radioresponse.

Place, publisher, year, edition, pages
John Wiley and sons, 2011
Keywords
head and neck tumors, radiotherapy, survivin, Bcl-2 family, p53 Arg72Pro
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-61585 (URN)10.1111/j.1600-0714.2011.01036.x (DOI)000296607200002 ()
Note
Funding agencies|Swedish Laryng Foundation||County Council of Ostergotland (OLL)||Swedish Cancer Foundation||Foundation of Olle Engkvist||Linkoping University Hospital||Available from: 2010-11-16 Created: 2010-11-16 Last updated: 2017-12-12Bibliographically approved
Jerhammar, F., Welander, J., Johansson, A. C., Söderkvist, P. & Roberg, K. (2011). Gene Copy Number as Predictive Marker for Cetuximab Resistance in Head and Neck Squamous Cell Carcinomas in EUROPEAN JOURNAL OF CANCER, vol 47, issue , pp S571-S571. In: EUROPEAN JOURNAL OF CANCER (pp. S571-S571). Elsevier, 47
Open this publication in new window or tab >>Gene Copy Number as Predictive Marker for Cetuximab Resistance in Head and Neck Squamous Cell Carcinomas in EUROPEAN JOURNAL OF CANCER, vol 47, issue , pp S571-S571
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2011 (English)In: EUROPEAN JOURNAL OF CANCER, Elsevier , 2011, Vol. 47, p. S571-S571Conference paper, Published paper (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
Elsevier, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71804 (URN)000295752802031 ()
Available from: 2011-11-04 Created: 2011-11-04 Last updated: 2011-11-04
Jerhammar, F., Ceder, R., Garvin, S., Grenman, R., C Grafstrom, R. & Roberg, K. (2010). Fibronectin 1 is a potential biomarker for radioresistance in head and neck squamous cell carcinoma. CANCER BIOLOGY and THERAPY, 10(12), 1244-1251
Open this publication in new window or tab >>Fibronectin 1 is a potential biomarker for radioresistance in head and neck squamous cell carcinoma
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2010 (English)In: CANCER BIOLOGY and THERAPY, ISSN 1538-4047, Vol. 10, no 12, p. 1244-1251Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Landes Bioscience, 2010
Keywords
head and neck cancer, predictive markers, radiotherapy, microarray, gene ontology, pathway analysis, fibronectin 1
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-64243 (URN)10.4161/cbt.10.12.13432 (DOI)000285388400007 ()
Available from: 2011-01-17 Created: 2011-01-17 Last updated: 2012-03-29Bibliographically approved
Jerhammar, F. & Roberg, K. (2010). Variation of intrinsic cetuximab sensitivity in head and neck squamous cell carcinomas in EJC SUPPLEMENTS, vol 8, issue 5, pp 50-50. In: EJC SUPPLEMENTS (pp. 50-50). Elsevier Science B.V., Amsterdam., 8(5)
Open this publication in new window or tab >>Variation of intrinsic cetuximab sensitivity in head and neck squamous cell carcinomas in EJC SUPPLEMENTS, vol 8, issue 5, pp 50-50
2010 (English)In: EJC SUPPLEMENTS, Elsevier Science B.V., Amsterdam. , 2010, Vol. 8, no 5, p. 50-50Conference 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-67313 (URN)000288603100187 ()
Available from: 2011-04-08 Created: 2011-04-08 Last updated: 2011-04-14
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