Dynamic interactions within the host-associated microbiota cause tumor formation in the basal metazoan Hydra

Autoři: Kai Rathje aff001;  Benedikt Mortzfeld aff001;  Marc P. Hoeppner aff003;  Jan Taubenheim aff001;  Thomas C. G. Bosch aff001;  Alexander Klimovich aff001
Působiště autorů: Zoological Institute, Kiel University, Kiel, Germany aff001;  Department of Biology, University of Massachusetts Dartmouth, Dartmouth, Massachusetts, United States of America aff002;  Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany aff003;  Institute for Zoology and Organismic Interactions, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany aff004
Vyšlo v časopise: Dynamic interactions within the host-associated microbiota cause tumor formation in the basal metazoan Hydra. PLoS Pathog 16(3): e1008375. doi:10.1371/journal.ppat.1008375
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008375


The extent to which disturbances in the resident microbiota can compromise an animal’s health is poorly understood. Hydra is one of the evolutionary oldest animals with naturally occurring tumors. Here, we found a causal relationship between an environmental spirochete (Turneriella spec.) and tumorigenesis in Hydra. Unexpectedly, virulence of this pathogen requires the presence of Pseudomonas spec., a member of Hydra´s beneficial microbiome indicating that dynamic interactions between a resident bacterium and a pathogen cause tumor formation. The observation points to the crucial role of commensal bacteria in maintaining tissue homeostasis and adds support to the view that microbial community interactions are essential for disease. These findings in an organism that shares deep evolutionary connections with all animals have implications for our understanding of cancer.

Klíčová slova:

Bacteria – Carcinogenesis – Genome analysis – Hydra – Microbiome – Pathogen motility – Pseudomonas – Spirochetes


1. Domazet-Lošo T, Klimovich A, Anokhin B, Anton-Erxleben F, Hamm MJ, Lange C, et al. Naturally occurring tumours in the basal metazoan Hydra. Nat Commun. 2014;5: 4222. doi: 10.1038/ncomms5222 24957317

2. Athena Aktipis C, Boddy AM, Jansen G, Hibner U, Hochberg ME, Maley CC, et al. Cancer across the tree of life: Cooperation and cheating in multicellularity. Philos Trans R Soc B Biol Sci. 2015; doi: 10.1098/rstb.2014.0219 26056363

3. Domazet-Loso T, Tautz D. Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa. BMC Biol. 2010;8: 66. doi: 10.1186/1741-7007-8-66 20492640

4. McFall-Ngai M, Hadfield MG, Bosch TCG, Carey H V, Domazet-Lošo T, Douglas AE, et al. Animals in a bacterial world, a new imperative for the life sciences. Proc Natl Acad Sci. National Acad Sciences; 2013;110: 3229–3236. doi: 10.1073/pnas.1218525110 23391737

5. Gilbert SF, Sapp J, Tauber AI. A Symbiotic View of Life: We Have Never Been Individuals. Q Rev Biol. 2012; doi: 10.1086/668166 23397797

6. Frank SA. Models of Symbiosis. Am Nat. 1997; doi: 10.1086/286051 18811314

7. Manfredo Vieira S, Hiltensperger M, Kumar V, Zegarra-Ruiz D, Dehner C, Khan N, et al. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science. 2018; doi: 10.1126/science.aar7201 29590047

8. Backert S, Blaser MJ. The role of CagA in the gastric biology of helicobacter pylori. Cancer Res. 2016;76: 4028–4031. doi: 10.1158/0008-5472.CAN-16-1680 27655809

9. Zechner EL. Inflammatory disease caused by intestinal pathobionts. Curr Opin Microbiol. Elsevier Ltd; 2017;35: 64–69. doi: 10.1016/j.mib.2017.01.011 28189956

10. Blaser MJ, Perez-Perez GI, Kleanthous H, Cover TL, Peek RM, Chyou PH, et al. Infection with Helicobacter pylori Strains Possessing cagA Is Associated with an Increased Risk of Developing Adenocarcinoma of the Stomach1. Cancer Res. 1995;55: 2111–2115. 7743510

11. Cover TL, Blaser MJ. Helicobacter pylori in Health and Disease. Gastroenterology. 2009; doi: 10.1053/j.gastro.2009.01.073 19457415

12. Dejea CM, Fathi P, Craig JM, Boleij A, Taddese R, Geis AL, et al. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science. 2018;359: 592–597. doi: 10.1126/science.aah3648 29420293

13. Guerrini MM, Vogelzang A, Fagarasan S. A Hen in the Wolf Den: A Pathobiont Tale. Immunity. Elsevier Inc.; 2018;48: 628–631. doi: 10.1016/j.immuni.2018.04.003 29669247

14. Rosshart SP, Vassallo BG, Angeletti D, Hutchinson DS, Morgan AP, Takeda K, et al. Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease Resistance. Cell. 2017; doi: 10.1016/j.cell.2017.09.016 29056339

15. Franzenburg S, Walter J, Künzel S, Wang J, Baines JF, Bosch TCG, et al. Distinct antimicrobial peptide expression determines host species-specific bacterial associations. Proc Natl Acad Sci. National Acad Sciences; 2013;110: E3730–E3738. doi: 10.1073/pnas.1304960110 24003149

16. Hemmrich G, Khalturin K, Boehm A-M, Puchert M, Anton-Erxleben F, Wittlieb J, et al. Molecular signatures of the three stem cell lineages in hydra and the emergence of stem cell function at the base of multicellularity. Mol Biol Evol. 2012;29: 3267–80. doi: 10.1093/molbev/mss134 22595987

17. Mortzfeld BM, Taubenheim J, Fraune S, Klimovich A V, Bosch TCG. Stem Cell Transcription Factor FoxO Controls Microbiome Resilience in Hydra. Frontiers in Microbiology. 2018. p. 629. Available: https://www.frontiersin.org/article/10.3389/fmicb.2018.00629

18. Fraune S, Anton-Erxleben F, Augustin R, Franzenburg S, Knop M, Schröder K, et al. Bacteria–bacteria interactions within the microbiota of the ancestral metazoan Hydra contribute to fungal resistance. ISME J. Nature Publishing Group; 2014;9: 1543. Available: http://dx.doi.org/10.1038/ismej.2014.239

19. Fraune S, Bosch TCG. Long-term maintenance of species-specific bacterial microbiota in the basal metazoan Hydra; Proc Natl Acad Sci. 2007;104: 13146 LP– 13151. Available: http://www.pnas.org/content/104/32/13146.abstract

20. Fraune S, Abe Y, Bosch TCG. Disturbing epithelial homeostasis in the metazoan Hydra leads to drastic changes in associated microbiota. Environ Microbiol. 2009;11: 2361–2369. doi: 10.1111/j.1462-2920.2009.01963.x 19508335

21. Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, et al. Metagenomic biomarker discovery and explanation. Genome Biol. BioMed Central Ltd; 2011;12: R60. doi: 10.1186/gb-2011-12-6-r60 21702898

22. Stackebrandt E, Chertkov O, Lapidus A, Nolan M, Lucas S, Hammon N, et al. Genome sequence of the free-living aerobic spirochete Turneriella parva type strain (HT), and emendation of the species Turneriella parva. Stand Genomic Sci. 2013;8: 228–238. doi: 10.4056/sigs.3617113 23991255

23. Livshits A, Shani-Zerbib L, Maroudas-Sacks Y, Braun E, Keren K. Structural Inheritance of the Actin Cytoskeletal Organization Determines the Body Axis in Regenerating Hydra. Cell Rep. ElsevierCompany.; 2017;18: 1410–1421. doi: 10.1016/j.celrep.2017.01.036 28178519

24. Fraune S, Augustin R, Anton-Erxleben F, Wittlieb J, Gelhaus C, Klimovich VB, et al. In an early branching metazoan, bacterial colonization of the embryo is controlled by maternal antimicrobial peptides. Proc Natl Acad Sci. 2010;107: 18067–18072. doi: 10.1073/pnas.1008573107 20921390

25. Liu TT, Chang JT. Number of Tentacles in Hydra vulgaris as a Genetic Character. Nature. 1946;157: 728. doi: 10.1038/157728b0

26. Khalturin K, Anton-Erxleben F, Sassmann S, Wittlieb J, Hemmrich G, Bosch TCG. A novel gene family controls species-specific morphological traits in Hydra. PLoS Biol. Public Library of Science; 2008;6: e278. doi: 10.1371/journal.pbio.0060278 19018660

27. Mortzfeld BM, Taubenheim J, Klimovich A V, Fraune S, Rosenstiel P, Bosch TCG. Temperature and insulin signaling regulate body size in Hydra by the Wnt and TGF-beta pathways. Nat Commun. 2019;10: 3257. doi: 10.1038/s41467-019-11136-6 31332174

28. Haiko J, Westerlund-Wikström B. The role of the bacterial flagellum in adhesion and virulence. Biology. 2013. doi: 10.3390/biology2041242 24833223

29. Josenhans C, Suerbaum S. The role of motility as a virulence factor in bacteria. Int J Med Microbiol. 2002; doi: 10.1078/1438-4221-00173 12008914

30. Duan Q, Zhou M, Zhu L, Zhu G. Flagella and bacterial pathogenicity. J Basic Microbiol. 2013; doi: 10.1002/jobm.201100335 22359233

31. Garcia M, Morello E, Garnier J, Barrault C, Garnier M, Burucoa C, et al. Pseudomonas aeruginosa flagellum is critical for invasion, cutaneous persistence and induction of inflammatory response of skin epidermis. Virulence. Taylor & Francis; 2018;9: 1163–1175. doi: 10.1080/21505594.2018.1480830 30070169

32. Kao CY, Sheu BS, Wu JJ. Helicobacter pylori infection: An overview of bacterial virulence factors and pathogenesis. Biomed J. Elsevier Ltd; 2016;39: 14–23. doi: 10.1016/j.bj.2015.06.002 27105595

33. Craig L, Pique ME, Tainer JA. Type IV pilus structure and bacterial pathogenicity. Nature Reviews Microbiology. 2004. doi: 10.1038/nrmicro885 15100690

34. Pizarro-Cerdá J, Cossart P. Bacterial adhesion and entry into host cells. Cell. 2006. doi: 10.1016/j.cell.2006.02.012 16497583

35. Green ER, Mecsas J. Bacterial Secretion Systems: An Overview. Microbiol Spectr. 2016; doi: 10.1128/microbiolspec.vmbf-0012-2015 26999395

36. Lee VT, Schneewind O. Protein secretion and the pathogenesis of bacterial infections. Genes and Development. 2001. doi: 10.1101/gad.896801 11459823

37. Costa TRD, Felisberto-Rodrigues C, Meir A, Prevost MS, Redzej A, Trokter M, et al. Secretion systems in Gram-negative bacteria: Structural and mechanistic insights. Nature Reviews Microbiology. 2015. doi: 10.1038/nrmicro3456 25978706

38. Lewis VG, Ween MP, McDevitt CA. The role of ATP-binding cassette transporters in bacterial pathogenicity. Protoplasma. 2012. doi: 10.1007/s00709-011-0360-8 22246051

39. Tanaka KJ, Song S, Mason K, Pinkett HW. Selective substrate uptake: The role of ATP-binding cassette (ABC) importers in pathogenesis. Biochimica et Biophysica Acta—Biomembranes. 2018. doi: 10.1016/j.bbamem.2017.08.011 28847505

40. Garmory HS, Titball RW. ATP-binding cassette transporters are targets for the development of antibacterial vaccines and therapies. Infection and Immunity. 2004. doi: 10.1128/IAI.72.12.6757–6763.2004

41. Guerrero-Mandujano A, Hernández-Cortez C, Ibarra JA, Castro-Escarpulli G. The outer membrane vesicles: Secretion system type zero. Traffic. John Wiley & Sons, Ltd (10.1111); 2017;18: 425–432. doi: 10.1111/tra.12488 28421662

42. Macdonald IA, Kuehn MJ. Stress-induced outer membrane vesicle production by Pseudomonas aeruginosa. J Bacteriol. 2013/04/26. American Society for Microbiology; 2013;195: 2971–2981. doi: 10.1128/JB.02267-12 23625841

43. Schwechheimer C, Kuehn MJ. Outer-membrane vesicles from Gram-negative bacteria: biogenesis and functions. Nat Rev Microbiol. 2015;13: 605–619. doi: 10.1038/nrmicro3525 26373371

44. Tahara H, Takabe K, Sasaki Y, Kasuga K, Kawamoto A, Koizumi N, et al. The mechanism of two-phase motility in the spirochete Leptospira: Swimming and crawling. Sci Adv. 2018;4: eaar7975. doi: 10.1126/sciadv.aar7975 29854948

45. Burrows LL. Pseudomonas aeruginosa Twitching Motility: Type IV Pili in Action. Annu Rev Microbiol. Annual Reviews; 2012;66: 493–520. doi: 10.1146/annurev-micro-092611-150055 22746331

46. Levett PN, Morey RE, Galloway R, Steigerwalt AG, Ellis WA. Reclassification of Leptospira parva Hovind-Hougen et al. 1982 as Turneriella parva gen. nov., comb. nov. Int J Syst Evol Microbiol. 2005; doi: 10.1099/ijs.0.63088–0

47. Wynwood SJ, Graham GC, Weier SL, Collet TA, McKay DB, Craig SB. Leptospirosis from water sources. Pathog Glob Health. 2014; doi: 10.1179/2047773214Y.0000000156 25348115

48. Bergeron AC, Seman BG, Hammond JH, Archambault LS, Hogan DA, Wheeler RT. Candida albicans and Pseudomonas aeruginosa interact to enhance virulence of mucosal infection in transparent zebrafish. Infect Immun. 2017; doi: 10.1128/IAI.00475-17 28847848

49. Trejo-Hernández A, Andrade-Domínguez A, Hernández M, Encarnación S. Interspecies competition triggers virulence and mutability in Candida albicans-Pseudomonas aeruginosa mixed biofilms. ISME J. 2014; doi: 10.1038/ismej.2014.53 24739628

50. Buret AG, Motta J-P, Allain T, Ferraz J, Wallace JL. Pathobiont release from dysbiotic gut microbiota biofilms in intestinal inflammatory diseases: a role for iron? J Biomed Sci. BioMed Central; 2019;26: 1. doi: 10.1186/s12929-018-0495-4 30602371

51. Richard JF. Bacterial toxins modifying the actin cytoskeleton. Int Microbiol. 1999;2: 185–194. 10943412

52. Cowell BA, Evans DJ, Fleiszig SMJ. Actin cytoskeleton disruption by ExoY and its effects on Pseudomonas aeruginosa invasion. FEMS Microbiol Lett. 2005;250: 71–76. doi: 10.1016/j.femsle.2005.06.044 16039071

53. Aktories K, Lang AE, Schwan C, Mannherz HG. Actin as target for modification by bacterial protein toxins. FEBS J. 2011;278: 4526–4543. doi: 10.1111/j.1742-4658.2011.08113.x 21466657

54. Baldassarre M, Ayala I, Beznoussenko G, Giacchetti G, Machesky LM, Luini A, et al. Actin dynamics at sites of extracellular matrix degradation. Eur J Cell Biol. 2006; doi: 10.1016/j.ejcb.2006.08.003 17010475

55. Alfano M, Canducci F, Nebuloni M, Clementi M, Montorsi F, Salonia A. The interplay of extracellular matrix and microbiome in urothelial bladder cancer. Nat Rev Urol. Nature Publishing Group; 2016;13: 77–90. doi: 10.1038/nrurol.2015.292 26666363

56. Ho BT, Dong TG, Mekalanos JJ. A view to a kill: The bacterial type VI secretion system. Cell Host and Microbe. 2014. doi: 10.1016/j.chom.2013.11.008 24332978

57. Bosch TCG, Miller DJ. The Hydra Holobiont: A Tale of Several Symbiotic Lineages —The Holobiont Imperative: Perspectives from Early Emerging Animals. In: Bosch TCG, Miller DJ, editors. Vienna: Springer Vienna; 2016. pp. 79–97. doi: 10.1007/978-3-7091-1896-2_7

58. Garrett WS. Cancer and the microbiota. Science. 2015;348: 80–86. doi: 10.1126/science.aaa4972 25838377

59. Fulbright LE, Ellermann M, Arthur JC. The microbiome and the hallmarks of cancer. PLoS Pathog. 2017;13: 1–6. doi: 10.1371/journal.ppat.1006480 28934351

60. Blaser MJ, Atherton JC. Helicobacter pylori persistence: biology and disease. J Clin Invest. 2004;113: 321–333. doi: 10.1172/JCI20925 14755326

61. Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014. doi: 10.1016/j.cell.2014.03.011 24679531

62. Phelps D, Brinkman NE, Keely SP, Anneken EM, Catron TR, Betancourt D, et al. Microbial colonization is required for normal neurobehavioral development in zebrafish. Sci Rep. 2017; doi: 10.1038/s41598-017-10517-5 28894128

63. Willing BP, Russell SL, Finlay BB. Shifting the balance: Antibiotic effects on host-microbiota mutualism. Nature Reviews Microbiology. 2011. doi: 10.1038/nrmicro2536 21358670

64. Langdon A, Crook N, Dantas G. The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation. Genome Medicine. 2016. doi: 10.1186/s13073-016-0294-z 27074706

65. Lenhoff HM, Brown RD. Mass culture of hydra: an improved method and its application to other aquatic invertebrates. Lab Anim. 1970;4: 139–154. doi: 10.1258/002367770781036463 5527814

66. Weisburg WG, Barns SM, Pelletier DA, Lane DJ. 16S Ribosomal DNA Amplification for Phylogenetic Study. J Bacteriol. 1991;173: 697–703. doi: 10.1128/jb.173.2.697-703.1991 1987160

67. Sarras MP, Madden ME, Zhang X, Gunwar S, Huff JK, Hudson BG. Extracellular matrix (mesoglea) of Hydra vulgaris. I. Isolation and characterization. Dev Biol. 1991;148: 481–494. doi: 10.1016/0012-1606(91)90266-6 1743396

68. Hovind-Hougen K, Ellis WA, Birch-Andersen A. Leptospira parva sp.npv.: some morphological and biological characters. Zentralblatt Fur Bakteriol Mikrobiol Und Hyg—1—Abt—Orig A, Medizinische Mikrobiol Infekt Und Parasitol. 1981; doi: 10.1016/S0174-3031(81)80126-6

69. Haas BJ, Gevers D, Earl AM, Feldgarden M, Ward D V, Giannoukos G, et al. Chimeric 16{S} r{RNA} Sequence Formation and Detection in {S}anger and 454-Pyrosequenced {PCR} Amplicons. Genome Res. 2011;21: 494–504. doi: 10.1101/gr.112730.110 21212162

70. Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. Nature Publishing Group; 2010;7: 335. doi: 10.1038/nmeth.f.303 20383131

71. Edgar RC. Search and clustering orders of magnitude faster than BLAST. Bioinformatics. 2010;26: 2460–2461. doi: 10.1093/bioinformatics/btq461 20709691

72. DeSantis TZ, Hugenholtz P, Larsen N, Rojas M, Brodie EL, Keller K, et al. Greengenes, a chimera-checked 16S rRNA gene database and workbench compatible with ARB. Appl Environ Microbiol. 2006;72: 5069–5072. doi: 10.1128/AEM.03006-05 16820507

73. Faith JJ, Guruge JL, Charbonneau M, Subramanian S, Seedorf H, Goodman AL, et al. The long-term stability of the human gut microbiota. Science. 2013;341. doi: 10.1126/science.1237439 23828941

74. Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing Author (s): Yoav Benjamini and Yosef Hochberg Source: Journal of the Royal Statistical Society. Series B (Methodological), Vol. 57, No. 1 Published by: J R Stat Soc. 1995;57: 289–300.

75. Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: New perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017; doi: 10.1093/nar/gkw1092 27899662

76. Chen L, Zheng D, Liu B, Yang J, Jin Q. VFDB 2016: Hierarchical and refined dataset for big data analysis—10 years on. Nucleic Acids Res. 2016; doi: 10.1093/nar/gkv1239 26578559

77. Medema MH, Blin K, Cimermancic P, De Jager V, Zakrzewski P, Fischbach MA, et al. AntiSMASH: Rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nucleic Acids Res. 2011; doi: 10.1093/nar/gkr466 21672958

78. Zhou Y, Liang Y, Lynch KH, Dennis JJ, Wishart DS. PHAST: A Fast Phage Search Tool. Nucleic Acids Res. 2011; doi: 10.1093/nar/gkr485 21672955

79. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. Oxford University Press; 2014;30: 2114–2120. doi: 10.1093/bioinformatics/btu170 24695404

80. Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. Nature Publishing Group; 2012;9: 357.

81. Team RC. R: A language and environment for statistical computing. Vienna, Austria; 2013;

82. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. BioMed Central; 2014;15: 550.

83. Klimovich A, Rehm A, Wittlieb J, Herbst E-M, Benavente R, Bosch TCG. Non-senescent Hydra tolerates severe disturbances in the nuclear lamina. Aging (Albany NY). Impact Journals, LLC; 2018;10: 951.

84. Anzai Y, Kim H, Park J-Y, Wakabayashi H, Oyaizu H. Phylogenetic affiliation of the pseudomonads based on 16S rRNA sequence. Int J Syst Evol Microbiol. Microbiology Society; 2000;50: 1563–1589. doi: 10.1099/00207713-50-4-1563 10939664

85. Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG. The CLUSTAL X windows interface: Flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res. 1997;25: 4876–4882. doi: 10.1093/nar/25.24.4876 9396791

86. Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. MEGA6: molecular evolutionary genetics analysis version 6.0. Mol Biol Evol. Oxford University Press; 2013;30: 2725–2729. doi: 10.1093/molbev/mst197 24132122

87. Holstein TW, Hess MW, Salvenmoser W. Preparation techniques for transmission electron microscopy of hydra. Methods in Cell Biology. Elsevier Inc.; 2010. doi: 10.1016/S0091-679X(10)96013–5

88. Klimovich A, Rehm A, Wittlieb J, Herbst E-M, Benavente R, Bosch TCG. Non-senescent Hydra tolerates severe disturbances in the nuclear lamina. Aging (Albany NY). 2018;10. doi: 10.18632/aging.101440 29754147

89. Siebert S, Anton-Erxleben F, Bosch TCG. Cell type complexity in the basal metazoan Hydra is maintained by both stem cell based mechanisms and transdifferentiation. Dev Biol. 2008;313: 13–24. doi: 10.1016/j.ydbio.2007.09.007 18029279

Článek vyšel v časopise

PLOS Pathogens

2020 Číslo 3
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Hypertenze a hypercholesterolémie – synergický efekt léčby
nový kurz
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Úloha kombinovaných preparátů v léčbě arteriální hypertenze
Autoři: prof. MUDr. Martin Haluzík, DrSc.

Autoři: MUDr. Ladislav Korábek, CSc., MBA

Terapie roztroušené sklerózy v kostce
Autoři: MUDr. Dominika Šťastná, Ph.D.

Všechny kurzy
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se