Skip to main content
Top
Published in: European Journal of Medical Research 1/2013

Open Access 01-12-2013 | Research

RETRACTED ARTICLE: Ferroportin in the progression and prognosis of hepatocellular carcinoma

Authors: Qin Wang, Jun Zhou, Dewu Zhong, Qunwei Wang, Jiangsheng Huang

Published in: European Journal of Medical Research | Issue 1/2013

Login to get access

Abstract

Background

Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor in men and the seventh in women and understanding the molecular mechanisms of HCC and establishing more effective therapies are critical and urgent issues. Our objective was to study the expression of ferroportin in hepatocellular carcinoma (HCC) tissue samples and the relationship between ferroportin expression and HCC characteristics.

Methods

Sixty HCC tissues and their corresponding para-cancer liver tissues (PCLT) were obtained from sixty HCC patients who had undergone hepatectomy in the Second Xiangya Hospital of Central South University. Ten normal liver tissue samples were also obtained as a control. Immunohistochemistry (IHC) was performed to analyze the ferroportin expression in HCC, and the relationship between ferroportin expression and HCC clinical pathological characteristics also was analyzed. For the evaluation of IHC results, the comprehensive scoring criteria were met according to the staining intensity and the number of positive staining cells. Western blotting was performed to detect the expression level of ferroportin in HCC cell lines.

Results

Ferroportin expression in HCC tissue was significantly lower compared to PCLT and normal liver tissue (P <0.05). Moreover, ferroportin expression was related to liver cancer cell de-differentiation, the severity degree in TNM staging, Edmondson-Steiner grading, intrahepatic metastasis and portal vein invasion. In addition, high expression of ferroportin was observed in normal human liver cell lines L02 and HL7702, whereas weak positive expression and even negative expression of ferroportin were observed in HCC cell lines FOCUS, MHCC-97H, HepG2 and SMMC-7721. Furthermore, among the four kinds of HCC cell lines, the expression level of ferroportin was the lowest in MHCC-97H cells.

Conclusions

Ferroportin expression level declines along with the progression of liver cancer, suggesting that the reduction of ferroportin may serve as an important marker for poor HCC prognosis and as a new therapeutic target.
Appendix
Available only for authorised users
Literature
1.
go back to reference Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61: 69–90. 10.3322/caac.20107CrossRefPubMed Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61: 69–90. 10.3322/caac.20107CrossRefPubMed
2.
go back to reference Parkin DM, Bray F, Ferlay J, Pisani P: Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001, 94: 153–156. 10.1002/ijc.1440CrossRefPubMed Parkin DM, Bray F, Ferlay J, Pisani P: Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001, 94: 153–156. 10.1002/ijc.1440CrossRefPubMed
3.
go back to reference Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin 2005, 55: 74–108. 10.3322/canjclin.55.2.74CrossRefPubMed Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin 2005, 55: 74–108. 10.3322/canjclin.55.2.74CrossRefPubMed
5.
go back to reference Schlesinger S, Aleksandrova K, Pischon T, Fedirko V, Jenab M, Trepo E, Boffetta P, Dahm CC, Overvad K, Tjonneland A, Halkjær J, Fagherazzi G, Boutron-Ruault MC, Carbonnel F, Kaaks R, Lukanova A, Boeing H, Trichopoulou A, Bamia C, Lagiou P, Palli D, Grioni S, Panico S, Tumino R, Vineis P, Bueno-de-Mesquita HB, van den Berg S, Peeters PH, Braaten T, Weiderpass E, et al.: Abdominal obesity, weight gain during adulthood and risk of liver and biliary tract cancer in a European cohort. Int J Cancer 2013, 132: 645–657. 10.1002/ijc.27645CrossRefPubMed Schlesinger S, Aleksandrova K, Pischon T, Fedirko V, Jenab M, Trepo E, Boffetta P, Dahm CC, Overvad K, Tjonneland A, Halkjær J, Fagherazzi G, Boutron-Ruault MC, Carbonnel F, Kaaks R, Lukanova A, Boeing H, Trichopoulou A, Bamia C, Lagiou P, Palli D, Grioni S, Panico S, Tumino R, Vineis P, Bueno-de-Mesquita HB, van den Berg S, Peeters PH, Braaten T, Weiderpass E, et al.: Abdominal obesity, weight gain during adulthood and risk of liver and biliary tract cancer in a European cohort. Int J Cancer 2013, 132: 645–657. 10.1002/ijc.27645CrossRefPubMed
6.
go back to reference Thelander L, Graslund A, Thelander M: Continual presence of oxygen and iron required for mammalian ribonucleotide reduction: possible regulation mechanism. Biochem Biophys Res Commun 1983, 110: 859–865. 10.1016/0006-291X(83)91040-9CrossRefPubMed Thelander L, Graslund A, Thelander M: Continual presence of oxygen and iron required for mammalian ribonucleotide reduction: possible regulation mechanism. Biochem Biophys Res Commun 1983, 110: 859–865. 10.1016/0006-291X(83)91040-9CrossRefPubMed
8.
go back to reference Siegers CP, Bumann D, Baretton G, Younes M: Dietary iron enhances the tumor rate in dimethylhydrazine-induced colon carcinogenesis in mice. Cancer Lett 1988, 41: 251–256. 10.1016/0304-3835(88)90285-6CrossRefPubMed Siegers CP, Bumann D, Baretton G, Younes M: Dietary iron enhances the tumor rate in dimethylhydrazine-induced colon carcinogenesis in mice. Cancer Lett 1988, 41: 251–256. 10.1016/0304-3835(88)90285-6CrossRefPubMed
9.
go back to reference Smith AG, Francis JE, Carthew P: Iron as a synergist for hepatocellular carcinoma induced by polychlorinated biphenyls in Ah-responsive C57BL/10ScSn mice. Carcinogenesis 1990, 11: 437–444. 10.1093/carcin/11.3.437CrossRefPubMed Smith AG, Francis JE, Carthew P: Iron as a synergist for hepatocellular carcinoma induced by polychlorinated biphenyls in Ah-responsive C57BL/10ScSn mice. Carcinogenesis 1990, 11: 437–444. 10.1093/carcin/11.3.437CrossRefPubMed
10.
go back to reference Hann HW, Stahlhut MW, Blumberg BS: Iron nutrition and tumor growth: decreased tumor growth in iron-deficient mice. Cancer Res 1988, 48: 4168–4170.PubMed Hann HW, Stahlhut MW, Blumberg BS: Iron nutrition and tumor growth: decreased tumor growth in iron-deficient mice. Cancer Res 1988, 48: 4168–4170.PubMed
11.
go back to reference Hann HW, Stahlhut MW, Menduke H: Iron enhances tumor growth. Observation on spontaneous mammary tumors in mice. Cancer 1991, 68: 2407–2410. 10.1002/1097-0142(19911201)68:11<2407::AID-CNCR2820681113>3.0.CO;2-NCrossRefPubMed Hann HW, Stahlhut MW, Menduke H: Iron enhances tumor growth. Observation on spontaneous mammary tumors in mice. Cancer 1991, 68: 2407–2410. 10.1002/1097-0142(19911201)68:11<2407::AID-CNCR2820681113>3.0.CO;2-NCrossRefPubMed
12.
go back to reference Maffettone C, Chen G, Drozdov I, Ouzounis C, Pantopoulos K: Tumorigenic properties of iron regulatory protein 2 (IRP2) mediated by its specific 73-amino acids insert. PLoS One 2010, 5: e10163. 10.1371/journal.pone.0010163PubMedCentralCrossRefPubMed Maffettone C, Chen G, Drozdov I, Ouzounis C, Pantopoulos K: Tumorigenic properties of iron regulatory protein 2 (IRP2) mediated by its specific 73-amino acids insert. PLoS One 2010, 5: e10163. 10.1371/journal.pone.0010163PubMedCentralCrossRefPubMed
13.
go back to reference Chen G, Fillebeen C, Wang J, Pantopoulos K: Overexpression of iron regulatory protein 1 suppresses growth of tumor xenografts. Carcinogenesis 2007, 28: 785–791.PubMedCentralCrossRefPubMed Chen G, Fillebeen C, Wang J, Pantopoulos K: Overexpression of iron regulatory protein 1 suppresses growth of tumor xenografts. Carcinogenesis 2007, 28: 785–791.PubMedCentralCrossRefPubMed
14.
go back to reference Kovacevic Z, Kalinowski DS, Lovejoy DB, Quach P, Wong J, Richardson DR: Iron chelators: development of novel compounds with high and selective anti-tumour activity. Curr Drug Deliv 2010. PMID:20507267 Kovacevic Z, Kalinowski DS, Lovejoy DB, Quach P, Wong J, Richardson DR: Iron chelators: development of novel compounds with high and selective anti-tumour activity. Curr Drug Deliv 2010. PMID:20507267
15.
go back to reference Buss JL, Greene BT, Turner J, Torti FM, Torti SV: Iron chelators in cancer chemotherapy. Curr Top Med Chem 2004, 4: 1623–1635. 10.2174/1568026043387269CrossRefPubMed Buss JL, Greene BT, Turner J, Torti FM, Torti SV: Iron chelators in cancer chemotherapy. Curr Top Med Chem 2004, 4: 1623–1635. 10.2174/1568026043387269CrossRefPubMed
16.
go back to reference Whitnall M, Howard J, Ponka P, Richardson DR: A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc Natl Acad Sci U S A 2006, 103: 14901–14906. 10.1073/pnas.0604979103PubMedCentralCrossRefPubMed Whitnall M, Howard J, Ponka P, Richardson DR: A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc Natl Acad Sci U S A 2006, 103: 14901–14906. 10.1073/pnas.0604979103PubMedCentralCrossRefPubMed
17.
go back to reference Green DA, Antholine WE, Wong SJ, Richardson DR, Chitambar CR: Inhibition of malignant cell growth by 311, a novel iron chelator of the pyridoxal isonicotinoyl hydrazone class: effect on the R2 subunit of ribonucleotide reductase. Clin Cancer Res 2001, 7: 3574–3579.PubMed Green DA, Antholine WE, Wong SJ, Richardson DR, Chitambar CR: Inhibition of malignant cell growth by 311, a novel iron chelator of the pyridoxal isonicotinoyl hydrazone class: effect on the R2 subunit of ribonucleotide reductase. Clin Cancer Res 2001, 7: 3574–3579.PubMed
18.
go back to reference Abboud S, Haile DJ: A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 2000, 275: 19906–19912. 10.1074/jbc.M000713200CrossRefPubMed Abboud S, Haile DJ: A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 2000, 275: 19906–19912. 10.1074/jbc.M000713200CrossRefPubMed
19.
go back to reference McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F, Hediger MA, Hentze MW, Simpson RJ: A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 2000, 5: 299–309. 10.1016/S1097-2765(00)80425-6CrossRefPubMed McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F, Hediger MA, Hentze MW, Simpson RJ: A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 2000, 5: 299–309. 10.1016/S1097-2765(00)80425-6CrossRefPubMed
20.
go back to reference Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, Paw BH, Drejer A, Barut B, Zapata A, Law TC, Brugnara C, Lux SE, Pinkus GS, Pinkus JL, Kingsley PD, Palis J, Fleming MD, Andrews NC, Zon LI: Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 2000, 403: 776–781. 10.1038/35001596CrossRefPubMed Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, Paw BH, Drejer A, Barut B, Zapata A, Law TC, Brugnara C, Lux SE, Pinkus GS, Pinkus JL, Kingsley PD, Palis J, Fleming MD, Andrews NC, Zon LI: Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 2000, 403: 776–781. 10.1038/35001596CrossRefPubMed
21.
go back to reference Canonne-Hergaux F, Donovan A, Delaby C, Wang HJ, Gros P: Comparative studies of duodenal and macrophage ferroportin proteins. Am J Physiol Gastrointest Liver Physiol 2006, 290: G156-G163.CrossRefPubMed Canonne-Hergaux F, Donovan A, Delaby C, Wang HJ, Gros P: Comparative studies of duodenal and macrophage ferroportin proteins. Am J Physiol Gastrointest Liver Physiol 2006, 290: G156-G163.CrossRefPubMed
22.
go back to reference Anderson GJ, Wang F: Essential but toxic: controlling the flux of iron in the body. Clin Exp Pharmacol Physiol 2012, 39: 719–724. 10.1111/j.1440-1681.2011.05661.xCrossRefPubMed Anderson GJ, Wang F: Essential but toxic: controlling the flux of iron in the body. Clin Exp Pharmacol Physiol 2012, 39: 719–724. 10.1111/j.1440-1681.2011.05661.xCrossRefPubMed
23.
go back to reference Zhang DL, Hughes RM, Ollivierre-Wilson H, Ghosh MC, Rouault TA: A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression. Cell Metab 2009, 9: 461–473. 10.1016/j.cmet.2009.03.006PubMedCentralCrossRefPubMed Zhang DL, Hughes RM, Ollivierre-Wilson H, Ghosh MC, Rouault TA: A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression. Cell Metab 2009, 9: 461–473. 10.1016/j.cmet.2009.03.006PubMedCentralCrossRefPubMed
24.
go back to reference Lymboussaki A, Pignatti E, Montosi G, Garuti C, Haile DJ, Pietrangelo A: The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression. J Hepatol 2003, 39: 710–715. 10.1016/S0168-8278(03)00408-2CrossRefPubMed Lymboussaki A, Pignatti E, Montosi G, Garuti C, Haile DJ, Pietrangelo A: The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression. J Hepatol 2003, 39: 710–715. 10.1016/S0168-8278(03)00408-2CrossRefPubMed
25.
go back to reference Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J: Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004, 306: 2090–2093. 10.1126/science.1104742CrossRefPubMed Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J: Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004, 306: 2090–2093. 10.1126/science.1104742CrossRefPubMed
26.
go back to reference Boult J, Roberts K, Brookes MJ, Hughes S, Bury JP, Cross SS, Anderson GJ, Spychal R, Iqbal T, Tselepis C: Overexpression of cellular iron import proteins is associated with malignant progression of esophageal adenocarcinoma. Clin Cancer Res 2008, 14: 379–387. 10.1158/1078-0432.CCR-07-1054CrossRefPubMed Boult J, Roberts K, Brookes MJ, Hughes S, Bury JP, Cross SS, Anderson GJ, Spychal R, Iqbal T, Tselepis C: Overexpression of cellular iron import proteins is associated with malignant progression of esophageal adenocarcinoma. Clin Cancer Res 2008, 14: 379–387. 10.1158/1078-0432.CCR-07-1054CrossRefPubMed
27.
go back to reference Holmstrom P, Gafvels M, Eriksson LC, Dzikaite V, Hultcrantz R, Eggertsen G, Stal P: Expression of iron regulatory genes in a rat model of hepatocellular carcinoma. Liver Int 2006, 26: 976–985. 10.1111/j.1478-3231.2006.01316.xCrossRefPubMed Holmstrom P, Gafvels M, Eriksson LC, Dzikaite V, Hultcrantz R, Eggertsen G, Stal P: Expression of iron regulatory genes in a rat model of hepatocellular carcinoma. Liver Int 2006, 26: 976–985. 10.1111/j.1478-3231.2006.01316.xCrossRefPubMed
28.
go back to reference Pinnix ZK, Miller LD, Wang W, D’Agostino R, Kute T, Willingham MC, Hatcher H, Tesfay L, Sui G, Di X, Torti SV, Torti FM: Ferroportin and iron regulation in breast cancer progression and prognosis. Sci Transl Med 2010, 2: 43–56.CrossRef Pinnix ZK, Miller LD, Wang W, D’Agostino R, Kute T, Willingham MC, Hatcher H, Tesfay L, Sui G, Di X, Torti SV, Torti FM: Ferroportin and iron regulation in breast cancer progression and prognosis. Sci Transl Med 2010, 2: 43–56.CrossRef
29.
go back to reference Finberg KE: Unraveling mechanisms regulating systemic iron homeostasis. Hematol Am Soc Hematol Educ Program 2011, 2011: 532–537. 10.1182/asheducation-2011.1.532CrossRef Finberg KE: Unraveling mechanisms regulating systemic iron homeostasis. Hematol Am Soc Hematol Educ Program 2011, 2011: 532–537. 10.1182/asheducation-2011.1.532CrossRef
30.
go back to reference Alkhateeb AA, Han B, Connor JR: Ferritin stimulates breast cancer cells through an iron-independent mechanism and is localized within tumor-associated macrophages. Breast Cancer Res Treat 2013, 137: 733–744. 10.1007/s10549-012-2405-xCrossRefPubMed Alkhateeb AA, Han B, Connor JR: Ferritin stimulates breast cancer cells through an iron-independent mechanism and is localized within tumor-associated macrophages. Breast Cancer Res Treat 2013, 137: 733–744. 10.1007/s10549-012-2405-xCrossRefPubMed
31.
go back to reference Daniels TR, Delgado T, Helguera G, Penichet ML: The transferrin receptor part II: targeted delivery of therapeutic agents into cancer cells. Clin Immunol 2006, 121: 159–176. 10.1016/j.clim.2006.06.006CrossRefPubMed Daniels TR, Delgado T, Helguera G, Penichet ML: The transferrin receptor part II: targeted delivery of therapeutic agents into cancer cells. Clin Immunol 2006, 121: 159–176. 10.1016/j.clim.2006.06.006CrossRefPubMed
32.
go back to reference Daniels TR, Delgado T, Rodriguez JA, Helguera G, Penichet ML: The transferrin receptor part I: biology and targeting with cytotoxic antibodies for the treatment of cancer. Clin Immunol 2006, 121: 144–158. 10.1016/j.clim.2006.06.010CrossRefPubMed Daniels TR, Delgado T, Rodriguez JA, Helguera G, Penichet ML: The transferrin receptor part I: biology and targeting with cytotoxic antibodies for the treatment of cancer. Clin Immunol 2006, 121: 144–158. 10.1016/j.clim.2006.06.010CrossRefPubMed
33.
go back to reference Galy B, Ferring-Appel D, Kaden S, Grone HJ, Hentze MW: Iron regulatory proteins are essential for intestinal function and control key iron absorption molecules in the duodenum. Cell Metab 2008, 7: 79–85. 10.1016/j.cmet.2007.10.006CrossRefPubMed Galy B, Ferring-Appel D, Kaden S, Grone HJ, Hentze MW: Iron regulatory proteins are essential for intestinal function and control key iron absorption molecules in the duodenum. Cell Metab 2008, 7: 79–85. 10.1016/j.cmet.2007.10.006CrossRefPubMed
34.
go back to reference Wu LJ, Leenders AG, Cooperman S, Meyron-Holtz E, Smith S, Land W, Tsai RY, Berger UV, Sheng ZH, Rouault TA: Expression of the iron transporter ferroportin in synaptic vesicles and the blood–brain barrier. Brain Res 2004, 1001: 108–117. 10.1016/j.brainres.2003.10.066CrossRefPubMed Wu LJ, Leenders AG, Cooperman S, Meyron-Holtz E, Smith S, Land W, Tsai RY, Berger UV, Sheng ZH, Rouault TA: Expression of the iron transporter ferroportin in synaptic vesicles and the blood–brain barrier. Brain Res 2004, 1001: 108–117. 10.1016/j.brainres.2003.10.066CrossRefPubMed
35.
go back to reference Rice AE, Mendez MJ, Hokanson CA, Rees DC, Bjorkman PJ: Investigation of the biophysical and cell biological properties of ferroportin, a multipass integral membrane protein iron exporter. J Mol Biol 2009, 386: 717–732. 10.1016/j.jmb.2008.12.063PubMedCentralCrossRefPubMed Rice AE, Mendez MJ, Hokanson CA, Rees DC, Bjorkman PJ: Investigation of the biophysical and cell biological properties of ferroportin, a multipass integral membrane protein iron exporter. J Mol Biol 2009, 386: 717–732. 10.1016/j.jmb.2008.12.063PubMedCentralCrossRefPubMed
36.
go back to reference Montosi G, Donovan A, Totaro A, Garuti C, Pignatti E, Cassanelli S, Trenor CC, Gasparini P, Andrews NC, Pietrangelo A: Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 2001, 108: 619–623. 10.1172/JCI200113468PubMedCentralCrossRefPubMed Montosi G, Donovan A, Totaro A, Garuti C, Pignatti E, Cassanelli S, Trenor CC, Gasparini P, Andrews NC, Pietrangelo A: Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 2001, 108: 619–623. 10.1172/JCI200113468PubMedCentralCrossRefPubMed
37.
go back to reference Beutler E, Barton JC, Felitti VJ, Gelbart T, West C, Lee PL, Waalen J, Vulpe C: Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans. Blood Cells Mol Dis 2003, 31: 305–309. 10.1016/S1079-9796(03)00165-7CrossRefPubMed Beutler E, Barton JC, Felitti VJ, Gelbart T, West C, Lee PL, Waalen J, Vulpe C: Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans. Blood Cells Mol Dis 2003, 31: 305–309. 10.1016/S1079-9796(03)00165-7CrossRefPubMed
38.
go back to reference Pogribny IP: Ferroportin and hepcidin: a new hope in diagnosis, prognosis, and therapy for breast cancer. Breast Cancer Res 2010, 12: 314. 10.1186/bcr2641PubMedCentralCrossRefPubMed Pogribny IP: Ferroportin and hepcidin: a new hope in diagnosis, prognosis, and therapy for breast cancer. Breast Cancer Res 2010, 12: 314. 10.1186/bcr2641PubMedCentralCrossRefPubMed
Metadata
Title
RETRACTED ARTICLE: Ferroportin in the progression and prognosis of hepatocellular carcinoma
Authors
Qin Wang
Jun Zhou
Dewu Zhong
Qunwei Wang
Jiangsheng Huang
Publication date
01-12-2013
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2013
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/2047-783X-18-59

Other articles of this Issue 1/2013

European Journal of Medical Research 1/2013 Go to the issue