Vnitr Lek 2017, 63(2):114-123 | DOI: 10.36290/vnl.2017.023

Functional impact of hERG: from physiological role to target of anticancer therapy

Júlia Šatková, Markéta Bébarová*
Fyziologický ústav LF MU, Brno

The human ether-à-go-go related gene (hERG; officially designated as KCNH2) encodes the structure of protein forming α-subunit of voltage-gated ion channel which conducts the rapid component of delayed rectifier K+ current (IKr). This current plays an important role namely in the cardiac repolarization. Mutations in hERG result in inherited arrhythmogenic syndromes characterized by a lenghtening or shortening of QT interval on the electrocardiogram and by an increased occurrence of life-threatening arrhythmias. This review also introduces hERG channels as a part of regulatory mechanisms of the smooth muscle contractility, neuronal activity, release of several hormones, and of proliferation and apoptosis of cancer cells. There are also mentioned some of the diseases arising from hERG channel dysfunction, and some possibilities of use of hERG gene/channel as a diagnostic marker and potential therapeutic target in various diseases, namely in cancer.

Keywords: cancer; epilepsy; hERG; KCNH2; K+ channel; LQTS; membrane potential; muscle contraction; proliferation; schizophrenia

Received: November 29, 2016; Accepted: February 2, 2017; Published: February 1, 2017  Show citation

ACS AIP APA ASA Harvard Chicago Chicago Notes IEEE ISO690 MLA NLM Turabian Vancouver
Šatková J, Bébarová M. Functional impact of hERG: from physiological role to target of anticancer therapy. Vnitr Lek. 2017;63(2):114-123. doi: 10.36290/vnl.2017.023.
Share...
Download citation
  • BibTeX (.bib)
  • Bookends (.ris)
  • EasyBib (.ris)
  • EndNote (.enw)
  • EndNote 8 (.xml)
  • ISI WoS (.isi)
  • Medlars (.medlars)
  • Mendeley (.ris)
  • MODS (.xml)
  • Papers (.ris)
  • RefWorks (.txt)
  • RefManager (.ris)
  • RIS (.ris)
  • MS Word (.xml)
  • Zotero (.ris)
    • Open full article

    References

    1. Curran ME, Splawski I, Timothy KW et al. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995; 80(5): 795-803. Go to original source... Go to PubMed...
    2. Sanguinetti MC, Jiang CG, Curran ME et al. A mechanistic link between an inherited and an acquired cardiac arrhythmia - HERG encodes the IKr potassium channel. Cell 1995; 81(2): 299-307. Go to original source... Go to PubMed...
    3. Vandenberg JI, Perry MD, Perrin MJ et al. hERG K+ channels: structure, function, and clinical significance. Physiol Rev 2012; 92(3): 1393-1478. Go to original source... Go to PubMed...
    4. Larsen AP. Role of ERG1 isoforms in modulation of ERG1 channel trafficking and function. Pflugers Arch - Eur J Physiol 2010; 460(5): 803-812. Dostupné z DOI: <http://dx.doi.org/10.1007/s00424-010-0855-8>. Go to original source... Go to PubMed...
    5. Babcock JJ, Li M. hERG channel function: beyond long QT. Acta Pharmacol Sin 2013; 34(3): 329-335. Dostupné z DOI: <http://dx.doi.org/10.1038/aps.2013.6>. Go to original source... Go to PubMed...
    6. Shimizu W, Moss AJ, Wilde AAM et al. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol 2009; 54(22): 2052-2062. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jacc.2009.08.028>. Go to original source... Go to PubMed...
    7. Cabral JHM, Lee A, Cohen SL et al. Crystal structure and functional analysis of the hERG potassium channel N terminus: a eukaryotic PAS domain. Cell 1998; 95(5): 649-655. Go to original source... Go to PubMed...
    8. Warmke JW, Ganetzky B. A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci USA 1994; 91(8): 3438-3442. Go to original source... Go to PubMed...
    9. Barros F, Domínguez P, de la Peña P. Cytoplasmic domains and voltage-dependent potassium channel gating. Front Pharmacol 2012; 3: 49. Dostupné z DOI: <http://dx.doi.org/10.3389/fphar.2012.00049>. Go to original source... Go to PubMed...
    10. Spector PS, Curran ME, Zou AR et al. Fast inactivation causes rectification of the IKr channel. J Gen Physiol 1996; 107(5): 611-619. Go to original source... Go to PubMed...
    11. Sacco T, Bruno A, Wanke E et al. Functional roles of an ERG current isolated in cerebellar Purkinje neurons. J Neurophysiol 2003; 90(3): 1817-1828. Go to original source... Go to PubMed...
    12. Farrelly AM, Ro S, Callaghan BP et al. Expression and function of KCNH2 (HERG) in the human jejunum. Am J Physiol Gastr L 2003; 284(6): G883-G895. Go to original source... Go to PubMed...
    13. Hardy AB, Fox JEM, Giglou PR et al. Characterization of Erg K+ channels in α- and β-cells of mouse and human islets. J Biol Chem 2009; 284(44): 30441-30452. Dostupné z DOI: <http://dx.doi.org/10.1074/jbc.M109.040659>. Go to original source... Go to PubMed...
    14. Hrabcová D, Pásek M, Šimurda J et al. Effect of i on concentration changes in the limited extracellular spaces on sarcolemmal ion transport and Ca2+ turnover in a model of human ventricular cardiomyocyte. Int J Mol Sci 2013; 14(12): 24271-24292. Dostupné z DOI: <http://dx.doi.org/10.3390/ijms141224271>. Go to original source... Go to PubMed...
    15. Roden DM. Taking the "idio" out of "idiosyncratic": predicting torsades de pointes. Pacing Clin Electrophysiol 1998; 21(5): 1029-1034. Go to original source... Go to PubMed...
    16. Chartrand E, Arnold AA, Gravel A et al. Potential role of the membrane in hERG channel functioning and drug-induced long QT syndrome. BBA Biomembranes 2010; 1798(9): 1651-1662. Dostupné z DOI: <http://dx.doi.org/10.1016/j.bbamem.2010.05.019>. Go to original source... Go to PubMed...
    17. Brugada R, Hong K, Dumaine R et al. Sudden death associated with short QT syndrome linked to mutations in hERG. Circulation 2004; 109(1): 30-35. Go to original source... Go to PubMed...
    18. Napolitano C, Priori SG, Schwartz PJ et al. Genetic testing in the long QT syndrome. Development and validation of an efficient approach to genotyping in clinical practice. Jama 2005; 294(23): 2975-2980. Go to original source... Go to PubMed...
    19. Splawski I, Shen JX, Timothy KW et al. Spectrum of mutations in long QT syndrome genes KVLQT1, hERG, SCN5A, KCNE1 and KCNE2. Circulation 2000; 102(10): 1178-1185. Go to original source... Go to PubMed...
    20. Moss AJ, Schwartz PJ, Crampton RS et al. The long QT syndrome: prospective longitudinal study of 328 families. Circulation 1991; 84(3): 1136-1144. Go to original source... Go to PubMed...
    21. Schwartz PJ, Priori SG, Spazzolini C et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001; 103(1): 89-95. Go to original source... Go to PubMed...
    22. Liu GX, Choi BR, Ziv O et al. Differential conditions for early after-depolarizations and triggered activity in cardiomyocytes derived from transgenic LQT1 and LQT2 rabbits. J Physiol 2012; 590(5): 1171-1180. Dostupné z DOI: <http://dx.doi.org/10.1113/jphysiol.2011.218164>. Go to original source... Go to PubMed...
    23. Meyer JS, Mehdirad A, Salem BI et al. Sudden arrhythmia death syndrome: importance of the long QT syndrome. Am Fam Physician 2003; 68(3): 483-488. Erratum in Am Fam Physician. 2004; 69(10): 2324. Go to PubMed...
    24. Kujaník Š. Regresné rovnice pre interval QT a QTc elektrokardiogramu. Vnitř Lék 2005; 51(11): 1277-1288.
    25. Goldenberg I, Moss AJ, Zareba W. QT interval: How to measure it and what is "normal". J Cardiovasc Electr 2006; 17(3): 333-336. Go to original source... Go to PubMed...
    26. Moss AJ, Zareba W, Benhorin J et al. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation 1995; 92(10): 2929-2934. Go to original source... Go to PubMed...
    27. Schwartz PJ, Priori SG, Cerrone M et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation 2004; 109(15): 1826-1833. Go to original source... Go to PubMed...
    28. Zareba W, Moss AJ, Daubert JP et al. Implantable cardioverter defibrillator in high-risk long QT syndrome patients. J Cardiovasc Electr 2003; 14(4): 337-341. Go to original source... Go to PubMed...
    29. Rajamani S, Eckhardt LL, Valdivia CR et al. Drug-induced long QT syndrome: hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine. Br J Pharmacol 2006; 149(5): 481-489. Go to original source... Go to PubMed...
    30. Šišáková M, Toman O, Floriánová A et al. Prodloužení QT intervalu jako důsledek kumulace rizikových faktorů - kazuistika. Vnitř Lék 2006; 52(3): 271-273. Go to PubMed...
    31. Gussak I, Brugada P, Brugada J et al. Idiopathic short QT interval: a new clinical syndrome? Cardiology 2000; 94(2): 99-102. Go to original source... Go to PubMed...
    32. Giustetto C, Di Monte F, Wolpert C et al. Short QT syndrome: clinical findings and diagnostic-therapeutic implications. Eur Heart J 2006; 27(20): 2440-2447. Go to original source... Go to PubMed...
    33. Sun Y, Quan XQ, Fromme S et al. A novel mutation in the KCNH2 gene associated with short QT syndrome. J Mol Cell Cardiol 2011; 50(3): 433-441. Dostupné z DOI: <http://dx.doi.org/10.1016/j.yjmcc.2010.11.017>. Go to original source... Go to PubMed...
    34. Hirdes W, Napp N, Wulfsen I et al. Erg K+ currents modulate excitability in mouse mitral/tufted neurons. Pflugers Arch 2009; 459(1): 55-70. Dostupné z DOI: <http://dx.doi.org/10.1007/s00424-009-0709-4>. Go to original source... Go to PubMed...
    35. Nie LP, Gratton MA, Mu KJ et al. Expression and functional phenotype of mouse ERG K+ channels in the inner ear: potential role in K+ regulation in the inner ear. J Neurosci 2005; 25(38): 8671-8679. Go to original source... Go to PubMed...
    36. Chiesa N, Rosati B, Arcangeli A et al. A novel role for hERG K+ channels: spike-frequency adaptation. J Physiol 1997; 501(Pt 2): 313-318. Go to original source... Go to PubMed...
    37. Krauser DG, Segal AZ, Kligfield P. Severe ataxia caused by amiodarone. Am J Cardiol 2005; 96(10): 1463-1464. Go to original source... Go to PubMed...
    38. Hindle JV, Ibrahim A, Ramaraj R. Ataxia caused by amiodarone in older people. Age Ageing 2008; 37(3): 347-348. Go to original source... Go to PubMed...
    39. Huffaker SJ, Chen J, Nicodemus KK et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nat Med 2009; 15(9): 509-518. Dostupné z DOI: <http://dx.doi.org/10.1038/nm.1962>. Go to original source... Go to PubMed...
    40. Hashimoto R, Ohi K, Yasuda Y et al. The KCNH2 gene is associated with neurocognition and the risk of schizophrenia. World J Biol Psychiatry 2013; 14(2): 114-120. Dostupné z DOI: <http://dx.doi.org/10.3109/15622975.2011.604350>. Go to original source... Go to PubMed...
    41. Apud JA., Zhang F, Decot H et al. Genetic variation in KCNH2 associated with expression in the brain of a unique hERG isoform modulates treatment response in patients with schizophrenia. Am J Psychiatry 2012; 169(7): 725-734. Dostupné z DOI: <http://dx.doi.org/10.1176/appi.ajp.2012.11081214>. Go to original source... Go to PubMed...
    42. Partemi S, Cestele S, Pezzella M et al. Loss-of-function KCNH2 mutation in a family with long QT syndrome, epilepsy, and sudden death. Epilepsia 2013; 54(8): 112-116. Dostupné z DOI: <http://dx.doi.org/10.1111/epi.12259>. Go to original source... Go to PubMed...
    43. Zamorano-Leon JJ, Yanez R, Jaime G et al. KCNH2 gene mutation: a potential link between epilepsy and long QT-2 syndrome. J Neurogenet 2012; 26(3-4): 382-386. Dostupné z DOI: <http://dx.doi.org/10.3109/01677063.2012.674993>. Go to original source... Go to PubMed...
    44. Emmi A, Wenzel HJ, Schwartzkroin PA et al. Do glia have heart? Expression and functional role for ether-a-go-go currents in hippocampal astrocytes. J Neurosci 2000; 20(10): 3915-3925. Go to original source... Go to PubMed...
    45. Parr E, Pozo MJ, Horowitz B et al. ERG K+ channels modulate the electrical and contractile activities of gallbladder smooth muscle. Am J Physiol Gastrointest Liver Physiol 2003; 284(3): G392-G398. Go to original source... Go to PubMed...
    46. Greenwood IA, Yeung SY, Tribe RM et al. Loss of functional K+ channels encoded by ether-a-go-go-related genes in mouse myometrium prior to labour onset. J Physiol 2009; 587(Pt 10): 2313-2326. Dostupné z DOI: <http://dx.doi.org/10.1113/jphysiol.2009.171272>. Go to original source... Go to PubMed...
    47. Mewe M, Wulfsen I, Schuster AME et al. Erg K+ channels modulate contractile activity in the bovine epididymal duct. Am J Physiol Regul Integr Comp Physiol 2008; 294(3): R895-R904. Dostupné z DOI: <http://dx.doi.org/10.1152/ajpregu.00521.2007>. Go to original source... Go to PubMed...
    48. Parkington HC, Stevenson J, Tonta MA et al. Diminished hERG K+ channel activity facilitates strong human labour contractions but is dysregulated in obese women. Nat Commun 2014; 5: 4108. Dostupné z DOI: <http://dx.doi.org/10.1038/ncomms5108>. Go to original source... Go to PubMed...
    49. Jiang M, Zhang M, Tang DG et al. KCNE2 protein is expressed in ventricles of different species, and changes in its expression contribute to electrical remodeling in diseased hearts. Circulation 2004; 109(14): 1783-1788. Go to original source... Go to PubMed...
    50. Crociani O, Cherubini A, Piccini E et al. erg gene(s) expression during development of the nervous and muscular system of quail embryos. Mech Dev 2000; 95(1-2): 239-243. Go to original source... Go to PubMed...
    51. Muehlbauer E, Bazwinsky I, Wolgast S et al. Circadian changes of ether-a-go-go-related-gene (Erg) potassium channel transcripts in the rat pancreas and β-cell. Cell Mol Life Sci 2007; 64(6): 768-780. Go to original source... Go to PubMed...
    52. Rosati B, Marchetti P, Crociani O et al. Glucose- and arginine-induced insulin secretion by human pancreatic β-cells: the role of HERG K+ channels in firing and release. FASEB J 2000; 14(15): 2601-2610. Go to original source... Go to PubMed...
    53. Bauer CK, Schafer R, Schiemann D et al. A functional role of the ERG-like inward-rectifying K+ current in prolactin secretion from rat lactotrophs. Mol Cell Endocrinol 1999; 148(1-2): 37-45. Go to original source... Go to PubMed...
    54. Hirdes W, Dinu C, Bauer CK et al. Gonadotropin-releasing hormone inhibits ether-a-go-go-related gene K+ currents in mouse gonadotropes. Endocrinology 2010; 151(3): 1079-1088. Dostupné z DOI: <http://dx.doi.org/10.1210/en.2009-0718>. Go to original source... Go to PubMed...
    55. Bianchi L, Wible B, Arcangeli A et al. herg encodes a K+ current highly conserved in tumors of different histogenesis: a selective advantage for cancer cells? Cancer Res 1998; 58(4): 815-822.
    56. Crociani O, Guasti L, Balzi M et al. Cell cycle-dependent expression of HERG1 and HERG1B isoforms in tumor cells. J Biol Chem 2003; 278(5): 2947-2955. Go to original source... Go to PubMed...
    57. Yang M, Brackenbury WJ. Membrane potential and cancer progression. Front Physiol 2013; 4: 185. Dostupné z DOI: <http://dx.doi.org/10.3389/fphys.2013.00185>. Go to original source... Go to PubMed...
    58. Rao VR, Perez-Neut M, Kaja S et al. Voltage-gated ion channels in cancer cell proliferation. Cancers 2015; 7(2): 849-875. Dostupné z DOI: <http://dx.doi.org/10.3390/cancers7020813>. Go to original source... Go to PubMed...
    59. Jehle J, Schweizer PA, Katus HA et al. Novel roles for hERG K+ channels in cell proliferation and apoptosis. Cell Death Dis 2011; 2: e193. Dostupné z DOI: <http://dx.doi.org/10.1038/cddis.2011.77>. Go to original source... Go to PubMed...
    60. Smith GAM, Tsui HW, Newell EW et al. Functional up-regulation of HERG K+ channels in neoplastic hematopoietic cells. J Biol Chem 2002; 277(21): 18528-18534. Go to original source... Go to PubMed...
    61. Pillozzi S, Brizzi MF, Balzi M et al. HERG potassium channels are constitutively expressed in primary human acute myeloid leukemias and regulate cell proliferation of normal and leukemic hemopoietic progenitors. Leukemia 2002; 16(9): 1791-1798. Go to original source... Go to PubMed...
    62. Larsen AP, Olesen SP, Grunnet M et al. Characterization of hERG1a and hERG1b potassium channels: a possible role for hERG1b in the IKr current. Pflugers Arch 2008; 456(6): 1137-1148. Dostupné z DOI: <http://dx.doi.org/10.1007/s00424-008-0476-7>. Go to original source... Go to PubMed...
    63. Staudacher I, Jehle J, Staudacher K et al. Herg K+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells. PLoS One. 2014; 9(2): e88164. Dostupné z DOI: <http://dx.doi.org/10.1371/journal.pone.0088164>. Go to original source... Go to PubMed...
    64. Cherubini A, Hofmann G, Pillozzi S et al. Human ether-a-go-go-related gene 1 channels are physically linked to β1 integrins and modulate adhesion-dependent signaling. Mol Biol Cell 2005; 16(6): 2972-2983. Go to original source... Go to PubMed...
    65. Cherubini A, Taddei GL, Crociani O et al. HERG potassium channels are more frequently expressed in human endometrial cancer as compared to non-cancerous endometrium. Br J Cancer 2000; 83(12): 1722-1729. Go to original source... Go to PubMed...
    66. Dolderer JH, Schuldes H, Bockhorn H et al. HERG1 gene expression as a specific tumor marker in colorectal tissues. Eur J Surg Oncol 2010; 36(1): 72-77. Dostupné z DOI: <http://dx.doi.org/10.1016/j.ejso.2009.05.009>. Go to original source... Go to PubMed...
    67. Lastraioli E, Guasti L, Crociani O et al. herg1 gene and HERG1 protein are overexpressed in colorectal cancers and regulate cell invasion of tumor cells. Cancer Res 2004; 64(2): 606-611. Go to original source... Go to PubMed...
    68. Shao XD, Wu KC, Guo XZ et al. Expression and significance of hERG protein in gastric cancer. Cancer Biol Ther 2008; 7(1): 45-50. Go to original source... Go to PubMed...
    69. Afrasiabi E, Hietamaki M, Viitanen T et al. Expression and significance of hERG (KCNH2) potassium channels in the regulation of MDA-MB-435S melanoma cell proliferation and migration. Cell Signal 2010; 22(1): 57-64. Dostupné z DOI: <http://dx.doi.org/10.1016/j.cellsig.2009.09.010>. Go to original source... Go to PubMed...
    70. D'Amico M, Biagiotti T, Fontana L et al. A HERG current sustains a cardiac-type action potential in neuroblastoma S cells. Biochem Biophys Res Commun 2003; 302(1): 101-108. Go to original source... Go to PubMed...
    71. Masi A, Becchetti A, Restano-Cassulini R et al. hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines. Br J Cancer 2005; 93(7): 781-792. Go to original source... Go to PubMed...
    72. Pillozzi S, Accordi B, Rebora P et al. Differential expression of hERG1A and hERG1B genes in pediatric acute lymphoblastic leukemia identifies different prognostic subgroups. Leukemia 2014; 28(6): 1352-1355. Dostupné z DOI: <http://dx.doi.org/10.1038/leu.2014.26> Go to original source... Go to PubMed...
    73. Erdem M, Tekiner TA, Fejzullahu A et al. herg1b expression as a potential specific marker in pediatric acute myeloid leukemia patients with HERG 897K/K genotype. Pediatr Hematol Oncol 2015; 32(3): 182-192. Dostupné z DOI: <http://dx.doi.org/10.3109/08880018.2014.949941>. Go to original source... Go to PubMed...
    74. Pillozzi S, Brizzi MF, Bernabei PA et al. VEGFR-1 (FLT-1), β1 integrin, and hERG K+ channel for a macromolecular signaling complex in acute myeloid leukemia: role in cell migration and clinical outcome. Blood 2007; 110(4): 1238-1250. Go to original source... Go to PubMed...
    75. Pillozzi S, Masselli M, De Lorenzo E et al. Chemotherapy resistance in acute lymphoblastic leukemia requires hERG1 channels and is overcome by hERG1 blockers. Blood 2011; 117(3): 902-914. Dostupné z DOI: <http://dx.doi.org/10.1182/blood-2010-01-262691>. Go to original source... Go to PubMed...
    76. Lastraioli E, Lottini T, Bencini L et al. hERG1 potassium channels: novel biomarkers in human solid cancers. Biomed Res Int 2015; 2015: 896432. Dostupné z DOI: <http://dx.doi.org/10.1155/2015/896432>. Go to original source... Go to PubMed...
    77. Chen SZ, Jiang M, Zhen YS. HERG K+ channel expression-related chemosensitivity in cancer cells and its modulation by erythromycin. Cancer Chemother Pharmacol 2005; 56(2): 212-220. Go to original source... Go to PubMed...
    78. Marek J, Linhart A, Rucklová Z et al. Kardiotoxicita onkologické léčby. Vnitř Lék 2011; 57(5): 472-484. Go to PubMed...
    79. Raschi E, Ceccarini L, De Ponti F et al. hERG-related drug toxicity and models for predicting hERG liability and QT prolongation. Expert Opin Drug Metab Toxicol 2009; 5(9): 1005-1021. Dostupné z DOI: <http://dx.doi.org/10.1517/17425250903055070>. Go to original source... Go to PubMed...
    80. Ganapathi SB, Kester M, Elmslie KS. State-dependent block of HERG potassium channels by R-roscovitine: implications for cancer therapy. Am J Physiol Cell Ph 2009; 296(4): C701-C710. Dostupné z DOI: <http://dx.doi.org/10.1152/ajpcell.00633.2008>. Go to original source... Go to PubMed...
    81. Zhao H, Wei XL, Jia YS et al. Silencing of herg gene by shRNA inhibits SH-SY5Y cell growth in vitro and in vivo. Eur J Pharmacol 2008; 579(1-3): 50-57. Go to original source... Go to PubMed...
    82. Cho K, Wang X, Nie S et al. Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res 2008; 14(5): 1310-1316. Dostupné z DOI: <http://dx.doi.org/10.1158/1078-0432.CCR-07-1441>. Go to original source... Go to PubMed...

    Return to the content


    Vnitřní lékařství

    Madam, Sir,
    please be aware that the website on which you intend to enter, not the general public because it contains technical information about medicines, including advertisements relating to medicinal products. This information and communication professionals are solely under §2 of the Act n.40/1995 Coll. Is active persons authorized to prescribe or supply (hereinafter expert).
    Take note that if you are not an expert, you run the risk of danger to their health or the health of other persons, if you the obtained information improperly understood or interpreted, and especially advertising which may be part of this site, or whether you used it for self-diagnosis or medical treatment, whether in relation to each other in person or in relation to others.

    I declare:

    1. that I have met the above instruction
    2. I'm an expert within the meaning of the Act n.40/1995 Coll. the regulation of advertising, as amended, and I am aware of the risks that would be a person other than the expert input to these sites exhibited

    No
    Yes

    If your statement is not true, please be aware
    that brings the risk of danger to their health or the health of others.