#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Drosophila Myc restores immune homeostasis of Imd pathway via activating miR-277 to inhibit imd/Tab2


Autoři: Ruimin Li aff001;  Hongjian Zhou aff001;  Chaolong Jia aff001;  Ping Jin aff001;  Fei Ma aff001
Působiště autorů: Laboratory for Comparative Genomics and Bioinformatics & Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China aff001
Vyšlo v časopise: Drosophila Myc restores immune homeostasis of Imd pathway via activating miR-277 to inhibit imd/Tab2. PLoS Genet 16(8): e32767. doi:10.1371/journal.pgen.1008989
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008989

Souhrn

Drosophila Myc (dMyc), as a broad-spectrum transcription factor, can regulate the expression of a large number of genes to control diverse cellular processes, such as cell cycle progression, cell growth, proliferation and apoptosis. However, it remains largely unknown about whether dMyc can be involved in Drosophila innate immune response. Here, we have identified dMyc to be a negative regulator of Drosophila Imd pathway via the loss- and gain-of-function screening. We demonstrate that dMyc inhibits Drosophila Imd immune response via directly activating miR-277 transcription, which further inhibit the expression of imd and Tab2-Ra/b. Importantly, dMyc can improve the survival of flies upon infection, suggesting inhibiting Drosophila Imd pathway by dMyc is vital to restore immune homeostasis that is essential for survival. Taken together, our study not only reports a new dMyc-miR-277-imd/Tab2 axis involved in the negative regulation of Drosophila Imd pathway, and provides a new insight into the complex regulatory mechanism of Drosophila innate immune homeostasis maintenance.

Klíčová slova:

Drosophila melanogaster – Escherichia coli infections – Homeostasis – Immune response – Luciferase – MicroRNAs – Regulator genes – Transcriptional control


Zdroje

1. Riera Romo M, Perez-Martinez D, Castillo Ferrer C. Innate immunity in vertebrates: an overview. Immunology. 2016;148(2):125–39. doi: 10.1111/imm.12597 26878338; PubMed Central PMCID: PMC4863567.

2. Hoffmann JA. Innate immunity of insects. Curr Opin Immunol. 1995;7(1):4–10. doi: 10.1016/0952-7915(95)80022-0 7772280.

3. Hultmark D. Immune reactions in Drosophila and other insects: a model for innate immunity. Trends in genetics: TIG. 1993;9(5):178–83. doi: 10.1016/0168-9525(93)90165-e 8337755.

4. Hoffmann JA, Kafatos FC, Janeway CA, Ezekowitz RA. Phylogenetic perspectives in innate immunity. Science. 1999;284(5418):1313–8. doi: 10.1126/science.284.5418.1313 10334979.

5. Khush RS, Leulier F, Lemaitre B. Drosophila immunity: two paths to NF-kappaB. Trends Immunol. 2001;22(5):260–4. doi: 10.1016/s1471-4906(01)01887-7 11323284.

6. Myllymaki H, Valanne S, Ramet M. The Drosophila imd signaling pathway. J Immunol. 2014;192(8):3455–62. doi: 10.4049/jimmunol.1303309 24706930.

7. Chen CZ, Schaffert S, Fragoso R, Loh C. Regulation of immune responses and tolerance: the microRNA perspective. Immunol Rev. 2013;253(1):112–28. doi: 10.1111/imr.12060 23550642; PubMed Central PMCID: PMC3684622.

8. Xiong XP, Kurthkoti K, Chang KY, Li JL, Ren X, Ni JQ, et al. miR-34 Modulates Innate Immunity and Ecdysone Signaling in Drosophila. PLoS Pathog. 2016;12(11):e1006034. doi: 10.1371/journal.ppat.1006034 27893816; PubMed Central PMCID: PMC5125713.

9. Martin M, Hiroyasu A, Guzman RM, Roberts SA, Goodman AG. Analysis of Drosophila STING Reveals an Evolutionarily Conserved Antimicrobial Function. Cell reports. 2018;23(12):3537–50 e6. doi: 10.1016/j.celrep.2018.05.029 29924997; PubMed Central PMCID: PMC6114933.

10. Foley E O'Farrell PH. Functional dissection of an innate immune response by a genome-wide RNAi screen. PLoS Biol. 2004;2(8):E203. doi: 10.1371/journal.pbio.0020203 15221030; PubMed Central PMCID: PMC434151.

11. Valanne S, Kleino A, Myllymaki H, Vuoristo J, Ramet M. Iap2 is required for a sustained response in the Drosophila Imd pathway. Developmental and comparative immunology. 2007;31(10):991–1001. doi: 10.1016/j.dci.2007.01.004 17343912.

12. Leulier F, Lhocine N, Lemaitre B, Meier P. The Drosophila inhibitor of apoptosis protein DIAP2 functions in innate immunity and is essential to resist gram-negative bacterial infection. Mol Cell Biol. 2006;26(21):7821–31. doi: 10.1128/MCB.00548-06 16894030; PubMed Central PMCID: PMC1636742.

13. Lamiable O, Meignin C, Imler JL. WntD and Diedel: Two immunomodulatory cytokines in Drosophila immunity. Fly (Austin). 2016;10(4):187–94. doi: 10.1080/19336934.2016.1202387 27314646; PubMed Central PMCID: PMC5036923.

14. Persson C, Oldenvi S, Steiner H. Peptidoglycan recognition protein LF: a negative regulator of Drosophila immunity. Insect Biochem Mol Biol. 2007;37(12):1309–16. doi: 10.1016/j.ibmb.2007.08.003 17967349.

15. Maillet F, Bischoff V, Vignal C, Hoffmann J, Royet J. The Drosophila peptidoglycan recognition protein PGRP-LF blocks PGRP-LC and IMD/JNK pathway activation. Cell host & microbe. 2008;3(5):293–303. doi: 10.1016/j.chom.2008.04.002 18474356.

16. Basbous N, Coste F, Leone P, Vincentelli R, Royet J, Kellenberger C, et al. The Drosophila peptidoglycan-recognition protein LF interacts with peptidoglycan-recognition protein LC to downregulate the Imd pathway. EMBO Rep. 2011;12(4):327–33. doi: 10.1038/embor.2011.19 21372849; PubMed Central PMCID: PMC3077246.

17. Kleino A, Myllymaki H, Kallio J, Vanha-aho LM, Oksanen K, Ulvila J, et al. Pirk is a negative regulator of the Drosophila Imd pathway. J Immunol. 2008;180(8):5413–22. doi: 10.4049/jimmunol.180.8.5413 18390723.

18. Thevenon D, Engel E, Avet-Rochex A, Gottar M, Bergeret E, Tricoire H, et al. The Drosophila ubiquitin-specific protease dUSP36/Scny targets IMD to prevent constitutive immune signaling. Cell host & microbe. 2009;6(4):309–20. doi: 10.1016/j.chom.2009.09.007 19837371.

19. Tsichritzis T, Gaentzsch PC, Kosmidis S, Brown AE, Skoulakis EM, Ligoxygakis P, et al. A Drosophila ortholog of the human cylindromatosis tumor suppressor gene regulates triglyceride content and antibacterial defense. Development. 2007;134(14):2605–14. doi: 10.1242/dev.02859 17553907.

20. Guntermann S, Primrose DA, Foley E. Dnr1-dependent regulation of the Drosophila immune deficiency signaling pathway. Developmental and comparative immunology. 2009;33(1):127–34. doi: 10.1016/j.dci.2008.07.021 18775745.

21. Aparicio R, Neyen C, Lemaitre B, Busturia A. dRYBP contributes to the negative regulation of the Drosophila Imd pathway. PLoS One. 2013;8(4):e62052. doi: 10.1371/journal.pone.0062052 23596533; PubMed Central PMCID: PMC3626645.

22. Kim M, Lee JH, Lee SY, Kim E, Chung J. Caspar, a suppressor of antibacterial immunity in Drosophila. Proc Natl Acad Sci U S A. 2006;103(44):16358–63. doi: 10.1073/pnas.0603238103 17050695; PubMed Central PMCID: PMC1637587.

23. Kallio J, Leinonen A, Ulvila J, Valanne S, Ezekowitz RA, Ramet M. Functional analysis of immune response genes in Drosophila identifies JNK pathway as a regulator of antimicrobial peptide gene expression in S2 cells. Microbes and infection. 2005;7(5–6):811–9. doi: 10.1016/j.micinf.2005.03.014 15890554.

24. Choi IK, Hyun S. Conserved microRNA miR-8 in fat body regulates innate immune homeostasis in Drosophila. Developmental and comparative immunology. 2012;37(1):50–4. doi: 10.1016/j.dci.2011.12.008 22210547.

25. Garbuzov A, Tatar M. Hormonal regulation of Drosophila microRNA let-7 and miR-125 that target innate immunity. Fly (Austin). 2010;4(4):306–11. doi: 10.4161/fly.4.4.13008 20798594; PubMed Central PMCID: PMC3174482.

26. Li S, Shen L, Sun L, Xu J, Jin P, Chen L, et al. Small RNA-Seq analysis reveals microRNA-regulation of the Imd pathway during Escherichia coli infection in Drosophila. Developmental and comparative immunology. 2017;70:80–7. doi: 10.1016/j.dci.2017.01.008 28069431.

27. Meyer N, Penn LZ. Reflecting on 25 years with MYC. Nature reviews Cancer. 2008;8(12):976–90. doi: 10.1038/nrc2231 19029958.

28. Bretones G, Delgado MD, Leon J. Myc and cell cycle control. Biochim Biophys Acta. 2015;1849(5):506–16. doi: 10.1016/j.bbagrm.2014.03.013 24704206.

29. Garcia-Gutierrez L, Delgado MD, Leon J. MYC Oncogene Contributions to Release of Cell Cycle Brakes. Genes (Basel). 2019;10(3). doi: 10.3390/genes10030244 30909496; PubMed Central PMCID: PMC6470592.

30. Cavalheiro GR, Matos-Rodrigues GE, Gomes AL, Rodrigues PM, Martins RA. c-Myc regulates cell proliferation during lens development. PLoS One. 2014;9(2):e87182. doi: 10.1371/journal.pone.0087182 24503550; PubMed Central PMCID: PMC3913586.

31. McMahon SB. MYC and the control of apoptosis. Cold Spring Harb Perspect Med. 2014;4(7):a014407. doi: 10.1101/cshperspect.a014407 24985130; PubMed Central PMCID: PMC4066641.

32. Lutz W, Leon J, Eilers M. Contributions of Myc to tumorigenesis. Biochim Biophys Acta. 2002;1602(1):61–71. doi: 10.1016/s0304-419x(02)00036-7 11960695.

33. Gordan JD, Thompson CB, Simon MC. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer cell. 2007;12(2):108–13. doi: 10.1016/j.ccr.2007.07.006 17692803; PubMed Central PMCID: PMC3215289.

34. Gallant P. Myc/Max/Mad in invertebrates: the evolution of the Max network. Curr Top Microbiol Immunol. 2006;302:235–53. doi: 10.1007/3-540-32952-8_9 16620031.

35. Grewal SS, Li L, Orian A, Eisenman RN, Edgar BA. Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development. Nat Cell Biol. 2005;7(3):295–302. doi: 10.1038/ncb1223 15723055.

36. Prober DA, Edgar BA. Ras1 promotes cellular growth in the Drosophila wing. Cell. 2000;100(4):435–46. doi: 10.1016/s0092-8674(00)80679-0 10693760.

37. Secombe J, Li L, Carlos L, Eisenman RN. The Trithorax group protein Lid is a trimethyl histone H3K4 demethylase required for dMyc-induced cell growth. Genes Dev. 2007;21(5):537–51. doi: 10.1101/gad.1523007 17311883; PubMed Central PMCID: PMC1820896.

38. Benassayag C, Montero L, Colombie N, Gallant P, Cribbs D, Morello D. Human c-Myc isoforms differentially regulate cell growth and apoptosis in Drosophila melanogaster. Mol Cell Biol. 2005;25(22):9897–909. doi: 10.1128/MCB.25.22.9897-9909.2005 16260605; PubMed Central PMCID: PMC1280252.

39. Montero L, Muller N, Gallant P. Induction of apoptosis by Drosophila Myc. Genesis. 2008;46(2):104–11. doi: 10.1002/dvg.20373 18257071.

40. Moreno E, Basler K. dMyc transforms cells into super-competitors. Cell. 2004;117(1):117–29. doi: 10.1016/s0092-8674(04)00262-4 15066287.

41. de la Cova C, Abril M, Bellosta P, Gallant P, Johnston LA. Drosophila myc regulates organ size by inducing cell competition. Cell. 2004;117(1):107–16. doi: 10.1016/s0092-8674(04)00214-4 15066286.

42. Purvis IJ, Avilala J, Guda MR, Venkataraman S, Vibhakar R, Tsung AJ, et al. Role of MYC-miR-29-B7-H3 in Medulloblastoma Growth and Angiogenesis. Journal of clinical medicine. 2019;8(8). doi: 10.3390/jcm8081158 31382461; PubMed Central PMCID: PMC6723910.

43. Li H, Liu J, Cao W, Xiao X, Liang L, Liu-Smith F, et al. C-myc/miR-150/EPG5 axis mediated dysfunction of autophagy promotes development of non-small cell lung cancer. Theranostics. 2019;9(18):5134–48. doi: 10.7150/thno.34887 31410206; PubMed Central PMCID: PMC6691579.

44. Su R, Gong JN, Chen MT, Song L, Shen C, Zhang XH, et al. c-Myc suppresses miR-451 dash, verticalYWTAZ/AKT axis via recruiting HDAC3 in acute myeloid leukemia. Oncotarget. 2016;7(47):77430–43. doi: 10.18632/oncotarget.12679 27764807; PubMed Central PMCID: PMC5363596.

45. Yu X, Hu Y, Wu Y, Fang C, Lai J, Chen S, et al. The c-Myc-regulated miR-17-92 cluster mediates ATRA-induced APL cell differentiation. Asia-Pacific journal of clinical oncology. 2019;15(6):364–70. doi: 10.1111/ajco.13225 31264378.

46. Aakko S, Straume AH, Birkeland EE, Chen P, Qiao X, Lonning PE, et al. MYC-Induced miR-203b-3p and miR-203a-3p Control Bcl-xL Expression and Paclitaxel Sensitivity in Tumor Cells. Translational oncology. 2019;12(1):170–9. doi: 10.1016/j.tranon.2018.10.001 30359947; PubMed Central PMCID: PMC6199766.

47. Luo H, Chen Z, Wang S, Zhang R, Qiu W, Zhao L, et al. c-Myc-miR-29c-REV3L signalling pathway drives the acquisition of temozolomide resistance in glioblastoma. Brain: a journal of neurology. 2015;138(Pt 12):3654–72. doi: 10.1093/brain/awv287 26450587.

48. Psathas JN, Doonan PJ, Raman P, Freedman BD, Minn AJ, Thomas-Tikhonenko A. The Myc-miR-17-92 axis amplifies B-cell receptor signaling via inhibition of ITIM proteins: a novel lymphomagenic feed-forward loop. Blood. 2013;122(26):4220–9. doi: 10.1182/blood-2012-12-473090 24169826; PubMed Central PMCID: PMC3868926.

49. Qian J, Zhang Z, Liang J, Ge Q, Duan X, Ma F, et al. The full-length transcripts and promoter analysis of intergenic microRNAs in Drosophila melanogaster. Genomics. 2011;97(5):294–303. doi: 10.1016/j.ygeno.2011.02.004 21333734.

50. Kleino A, Valanne S, Ulvila J, Kallio J, Myllymaki H, Enwald H, et al. Inhibitor of apoptosis 2 and TAK1-binding protein are components of the Drosophila Imd pathway. The EMBO journal. 2005;24(19):3423–34. doi: 10.1038/sj.emboj.7600807 16163390; PubMed Central PMCID: PMC1276168.

51. Goto A, Matsushita K, Gesellchen V, El Chamy L, Kuttenkeuler D, Takeuchi O, et al. Akirins are highly conserved nuclear proteins required for NF-kappaB-dependent gene expression in Drosophila and mice. Nat Immunol. 2008;9(1):97–104. doi: 10.1038/ni1543 18066067; PubMed Central PMCID: PMC2680477.

52. Myllymaki H, Ramet M. Transcription factor zfh1 downregulates Drosophila Imd pathway. Developmental and comparative immunology. 2013;39(3):188–97. doi: 10.1016/j.dci.2012.10.007 23178405.

53. Gnanaprakasam JN, Wang R. MYC in Regulating Immunity: Metabolism and Beyond. Genes (Basel). 2017;8(3). doi: 10.3390/genes8030088 28245597; PubMed Central PMCID: PMC5368692.

54. Hirano M, Das S, Guo P, Cooper MD. The evolution of adaptive immunity in vertebrates. Advances in immunology. 2011;109:125–57. doi: 10.1016/B978-0-12-387664-5.00004-2 21569914.

55. Gallant P. Myc function in Drosophila. Cold Spring Harb Perspect Med. 2013;3(10):a014324. doi: 10.1101/cshperspect.a014324 24086064; PubMed Central PMCID: PMC3784813.

56. Bellosta P, Gallant P. Myc Function in Drosophila. Genes & cancer. 2010;1(6):542–6. doi: 10.1177/1947601910377490 21072325; PubMed Central PMCID: PMC2976539.

57. Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W, et al. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell. 2012;151(1):68–79. doi: 10.1016/j.cell.2012.08.033 23021216; PubMed Central PMCID: PMC3471363.

58. Lin CY, Loven J, Rahl PB, Paranal RM, Burge CB, Bradner JE, et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell. 2012;151(1):56–67. doi: 10.1016/j.cell.2012.08.026 23021215; PubMed Central PMCID: PMC3462372.

59. Zhuang ZH, Sun L, Kong L, Hu JH, Yu MC, Reinach P, et al. Drosophila TAB2 is required for the immune activation of JNK and NF-kappaB. Cellular signalling. 2006;18(7):964–70. doi: 10.1016/j.cellsig.2005.08.020 16311020.

60. Esslinger SM, Schwalb B, Helfer S, Michalik KM, Witte H, Maier KC, et al. Drosophila miR-277 controls branched-chain amino acid catabolism and affects lifespan. RNA biology. 2013;10(6):1042–56. doi: 10.4161/rna.24810 23669073; PubMed Central PMCID: PMC3904584.

61. Jones CI, Grima DP, Waldron JA, Jones S, Parker HN, Newbury SF. The 5'-3' exoribonuclease Pacman (Xrn1) regulates expression of the heat shock protein Hsp67Bc and the microRNA miR-277-3p in Drosophila wing imaginal discs. RNA biology. 2013;10(8):1345–55. doi: 10.4161/rna.25354 23792537; PubMed Central PMCID: PMC3817156.

62. Tan H, Poidevin M, Li H, Chen D, Jin P. MicroRNA-277 modulates the neurodegeneration caused by Fragile X premutation rCGG repeats. PLoS Genet. 2012;8(5):e1002681. doi: 10.1371/journal.pgen.1002681 22570635; PubMed Central PMCID: PMC3343002.

63. Winer A, Bodor JN, Borghaei H. Identifying and managing the adverse effects of immune checkpoint blockade. Journal of thoracic disease. 2018;10(Suppl 3):S480–S9. doi: 10.21037/jtd.2018.01.111 29593893; PubMed Central PMCID: PMC5861268.

64. Arefin B, Kunc M, Krautz R, Theopold U. The Immune Phenotype of Three Drosophila Leukemia Models. G3. 2017;7(7):2139–49. doi: 10.1534/g3.117.039487 28476910; PubMed Central PMCID: PMC5499123.

65. He X, Yu J, Wang M, Cheng Y, Han Y, Yang S, et al. Bap180/Baf180 is required to maintain homeostasis of intestinal innate immune response in Drosophila and mice. Nature microbiology. 2017;2:17056. doi: 10.1038/nmicrobiol.2017.56 28418397.

66. Ragab A, Buechling T, Gesellchen V, Spirohn K, Boettcher AL, Boutros M. Drosophila Ras/MAPK signalling regulates innate immune responses in immune and intestinal stem cells. The EMBO journal. 2011;30(6):1123–36. doi: 10.1038/emboj.2011.4 21297578; PubMed Central PMCID: PMC3061042.

67. Greer C, Lee M, Westerhof M, Milholland B, Spokony R, Vijg J, et al. Myc-dependent genome instability and lifespan in Drosophila. PLoS One. 2013;8(9):e74641. doi: 10.1371/journal.pone.0074641 24040302; PubMed Central PMCID: PMC3765364.

68. Hofmann JW, Zhao X, De Cecco M, Peterson AL, Pagliaroli L, Manivannan J, et al. Reduced expression of MYC increases longevity and enhances healthspan. Cell. 2015;160(3):477–88. doi: 10.1016/j.cell.2014.12.016 25619689; PubMed Central PMCID: PMC4624921.

69. Ruby JG, Stark A, Johnston WK, Kellis M, Bartel DP, Lai EC. Evolution, biogenesis, expression, and target predictions of a substantially expanded set of Drosophila microRNAs. Genome research. 2007;17(12):1850–64. doi: 10.1101/gr.6597907 17989254; PubMed Central PMCID: PMC2099593.

70. Enright AJ, John B, Gaul U, Tuschl T, Sander C, Marks DS. MicroRNA targets in Drosophila. Genome Biol. 2003;5(1):R1. doi: 10.1186/gb-2003-5-1-r1 14709173; PubMed Central PMCID: PMC395733.

71. John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS. Human MicroRNA targets. PLoS Biol. 2004;2(11):e363. doi: 10.1371/journal.pbio.0020363 15502875; PubMed Central PMCID: PMC521178.

72. Messeguer X, Escudero R, Farre D, Nunez O, Martinez J, Alba MM. PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics. 2002;18(2):333–4. doi: 10.1093/bioinformatics/18.2.333 11847087.

73. Farre D, Roset R, Huerta M, Adsuara JE, Rosello L, Alba MM, et al. Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN. Nucleic acids research. 2003;31(13):3651–3. doi: 10.1093/nar/gkg605 12824386; PubMed Central PMCID: PMC169011.

74. Neyen C, Bretscher AJ, Binggeli O, Lemaitre B. Methods to study Drosophila immunity. Methods. 2014;68(1):116–28. doi: 10.1016/j.ymeth.2014.02.023 24631888.

75. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–8. doi: 10.1006/meth.2001.1262 11846609.

76. Leulier F, Parquet C, Pili-Floury S, Ryu JH, Caroff M, Lee WJ, et al. The Drosophila immune system detects bacteria through specific peptidoglycan recognition. Nat Immunol. 2003;4(5):478–84. doi: 10.1038/ni922 12692550.

77. Kim YS, Han SJ, Ryu JH, Choi KH, Hong YS, Chung YH, et al. Lipopolysaccharide-activated kinase, an essential component for the induction of the antimicrobial peptide genes in Drosophila melanogaster cells. The Journal of biological chemistry. 2000;275(3):2071–9. doi: 10.1074/jbc.275.3.2071 10636911.

78. Orian A, van Steensel B, Delrow J, Bussemaker HJ, Li L, Sawado T, et al. Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network. Genes Dev. 2003;17(9):1101–14. doi: 10.1101/gad.1066903 12695332; PubMed Central PMCID: PMC196053.


Článek vyšel v časopise

PLOS Genetics


2020 Číslo 8
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autoři: MUDr. Tomáš Ürge, PhD.

Střevní příprava před kolonoskopií
Autoři: MUDr. Klára Kmochová, Ph.D.

Závislosti moderní doby – digitální závislosti a hypnotika
Autoři: MUDr. Vladimír Kmoch

Aktuální možnosti diagnostiky a léčby AML a MDS nízkého rizika
Autoři: MUDr. Natália Podstavková

Jak diagnostikovat a efektivně léčit CHOPN v roce 2024
Autoři: doc. MUDr. Vladimír Koblížek, Ph.D.

Všechny kurzy
Přihlášení
Zapomenuté heslo

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

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#