#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Murine models for familial pancreatic cancer: Histopathology, latency and drug sensitivity among cancers of Palb2, Brca1 and Brca2 mutant mouse strains


Autoři: Dongju Park aff001;  Reena Shakya aff002;  Christopher Koivisto aff001;  Jason R. Pitarresi aff001;  Matthias Szabolcs aff003;  Raleigh Kladney aff001;  Ashley Hadjis aff001;  Thomas A. Mace aff004;  Thomas Ludwig aff001
Působiště autorů: Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America aff001;  The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America aff002;  Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America aff003;  Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America aff004
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0226714

Souhrn

Alterations of the PALB2 tumor suppressor gene have been identified in familial breast, ovarian and pancreatic cancer cases. PALB2 cooperates with BRCA1/2 proteins through physical interaction in initiation of homologous recombination, in maintenance of genome integrity following DNA double-strand breaks. To determine if the role of PALB2 as a linker between BRCA1 and BRCA2 is critical for BRCA1/2-mediated tumor suppression, we generated Palb2 mouse pancreatic cancer models and compared tumor latencies, phenotypes and drug responses with previously generated Brca1/2 pancreatic cancer models. For development of Palb2 pancreatic cancer, we crossed conditional Palb2 null mouse with mice carrying the KrasG12D; p53R270H; Pdx1-Cre (KPC) constructs, and these animals were observed for pancreatic tumor development. Individual deletion of Palb2, Brca1 or Brca2 genes in pancreas per se using Pdx1-Cre was insufficient to cause tumors, but it reduced pancreata size. Concurrent expression of mutant KrasG12D and p53R270H, with tumor suppressor inactivated strains in Palb2-KPC, Brca1-KPC or Brca2-KPC, accelerated pancreatic ductal adenocarcinoma (PDAC) development. Moreover, most Brca1-KPC and some Palb2-KPC animals developed mucinous cystic neoplasms with PDAC, while Brca2-KPC and KPC animals did not. 26% of Palb2-KPC mice developed MCNs in pancreata, which resemble closely the Brca1 deficient tumors. However, the remaining 74% of Palb2-KPC animals developed PDACs without any cysts like Brca2 deficient tumors. In addition, the number of ADM lesions and immune cells infiltrations (CD3+ and F/480+) were significantly increased in Brca1-KPC tumors, but not in Brca2-KPC tumors. Interestingly, the level of ADM lesions and infiltration of CD3+ or F/480+ cells in Palb2-KPC tumors were intermediate between Brca1-KPC and Brca2-KPC tumors. As expected, disruption of Palb2 and Brca1/2 sensitized tumor cells to DNA damaging agents in vitro and in vivo. Altogether, Palb2-KPC PDAC exhibited features observed in both Brca1-KPC and Brca2-KPC tumors, which could be due to its role, as a linker between Brca1 and Brca2.

Klíčová slova:

Alleles – Cancer treatment – DNA damage – Genetic causes of cancer – Mouse models – Pancreatic cancer – Tumor suppressor genes


Zdroje

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019. Epub 2019/01/08. doi: 10.3322/caac.21551 30620402.

2. Petersen GM. Familial pancreatic cancer. Semin Oncol. 2016;43(5):548–53. Epub 2016/09/22. doi: 10.1053/j.seminoncol.2016.09.002 27899186; PubMed Central PMCID: PMC5234085.

3. Zhen DB, Rabe KG, Gallinger S, Syngal S, Schwartz AG, Goggins MG, et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med. 2015;17(7):569–77. Epub 2014/11/20. doi: 10.1038/gim.2014.153 25356972; PubMed Central PMCID: PMC4439391.

4. Hofstatter EW, Domchek SM, Miron A, Garber J, Wang M, Componeschi K, et al. PALB2 mutations in familial breast and pancreatic cancer. Fam Cancer. 2011;10(2):225–31. doi: 10.1007/s10689-011-9426-1 21365267; PubMed Central PMCID: PMC3836668.

5. Lynch HT, Deters CA, Snyder CL, Lynch JF, Villeneuve P, Silberstein J, et al. BRCA1 and pancreatic cancer: pedigree findings and their causal relationships. Cancer Genet Cytogenet. 2005;158(2):119–25. doi: 10.1016/j.cancergencyto.2004.01.032 15796958.

6. Breast Cancer Linkage C. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 1999;91(15):1310–6. doi: 10.1093/jnci/91.15.1310 10433620.

7. Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324(5924):217. doi: 10.1126/science.1171202 19264984; PubMed Central PMCID: PMC2684332.

8. Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531(7592):47–52. Epub 2016/02/26. doi: 10.1038/nature16965 26909576.

9. Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378(6559):789–92. doi: 10.1038/378789a0 8524414.

10. Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994;265(5181):2088–90. doi: 10.1126/science.8091231 8091231.

11. Schutte M, da Costa LT, Hahn SA, Moskaluk C, Hoque AT, Rozenblum E, et al. Identification by representational difference analysis of a homozygous deletion in pancreatic carcinoma that lies within the BRCA2 region. Proc Natl Acad Sci U S A. 1995;92(13):5950–4. doi: 10.1073/pnas.92.13.5950 7597059; PubMed Central PMCID: PMC41619.

12. Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res. 1996;56(23):5360–4. 8968085.

13. Ozcelik H, Schmocker B, Di Nicola N, Shi XH, Langer B, Moore M, et al. Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet. 1997;16(1):17–8. doi: 10.1038/ng0597-17 9140390.

14. Hahn SA, Greenhalf B, Ellis I, Sina-Frey M, Rieder H, Korte B, et al. BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst. 2003;95(3):214–21. doi: 10.1093/jnci/95.3.214 12569143.

15. Feldmann G, Karikari C, dal Molin M, Duringer S, Volkmann P, Bartsch DK, et al. Inactivation of Brca2 cooperates with Trp53(R172H) to induce invasive pancreatic ductal adenocarcinomas in mice: a mouse model of familial pancreatic cancer. Cancer Biol Ther. 2011;11(11):959–68. Epub 2011/04/02. doi: 10.4161/cbt.11.11.15534 21455033; PubMed Central PMCID: PMC3127047.

16. Rowley M, Ohashi A, Mondal G, Mills L, Yang L, Zhang L, et al. Inactivation of Brca2 promotes Trp53-associated but inhibits KrasG12D-dependent pancreatic cancer development in mice. Gastroenterology. 2011;140(4):1303–13.e1-3. Epub 2011/01/05. doi: 10.1053/j.gastro.2010.12.039 21199651; PubMed Central PMCID: PMC3066280.

17. Skoulidis F, Cassidy LD, Pisupati V, Jonasson JG, Bjarnason H, Eyfjord JE, et al. Germline Brca2 heterozygosity promotes Kras(G12D) -driven carcinogenesis in a murine model of familial pancreatic cancer. Cancer Cell. 2010;18(5):499–509. Epub 2010/11/09. doi: 10.1016/j.ccr.2010.10.015 21056012.

18. Thompson D, Easton DF, Breast Cancer Linkage C. Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002;94(18):1358–65. doi: 10.1093/jnci/94.18.1358 12237281.

19. Gieldon L, Wagner J, Rump A. A frameshift mutation in BRCA1 leads to hereditary breast and ovarian cancer in one part of a family and to familial pancreatic cancer in another. Breast Cancer Res Treat. 2018;167(1):305–7. Epub 2017/09/12. doi: 10.1007/s10549-017-4500-5 28900739.

20. Shakya R, Reid LJ, Reczek CR, Cole F, Egli D, Lin CS, et al. BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science. 2011;334(6055):525–8. Epub 2011/10/29. doi: 10.1126/science.1209909 22034435; PubMed Central PMCID: PMC3904783.

21. Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006;22(6):719–29. doi: 10.1016/j.molcel.2006.05.022 16793542.

22. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321(5897):1801–6. doi: 10.1126/science.1164368 18772397; PubMed Central PMCID: PMC2848990.

23. Borecka M, Zemankova P, Vocka M, Soucek P, Soukupova J, Kleiblova P, et al. Mutation analysis of the PALB2 gene in unselected pancreatic cancer patients in the Czech Republic. Cancer Genet. 2016;209(5):199–204. Epub 2016/04/24. doi: 10.1016/j.cancergen.2016.03.003 27106063.

24. Zhang F, Ma J, Wu J, Ye L, Cai H, Xia B, et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol. 2009;19(6):524–9. doi: 10.1016/j.cub.2009.02.018 19268590; PubMed Central PMCID: PMC2750839.

25. Sawyer SL, Tian L, Kähkönen M, Schwartzentruber J, Kircher M, Majewski J, et al. Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. Cancer Discov. 2015;5(2):135–42. Epub 2014/12/03. doi: 10.1158/2159-8290.CD-14-1156 25472942; PubMed Central PMCID: PMC4320660.

26. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002;297(5581):606–9. Epub 2002/06/13. doi: 10.1126/science.1073834 12065746.

27. Reid S, Schindler D, Hanenberg H, Barker K, Hanks S, Kalb R, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007;39(2):162–4. doi: 10.1038/ng1947 17200671.

28. Mathew CG. Fanconi anaemia genes and susceptibility to cancer. Oncogene. 2006;25(43):5875–84. doi: 10.1038/sj.onc.1209878 16998502.

29. Shakya R, Szabolcs M, McCarthy E, Ospina E, Basso K, Nandula S, et al. The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression. Proc Natl Acad Sci U S A. 2008;105(19):7040–5. doi: 10.1073/pnas.0711032105 18443292; PubMed Central PMCID: PMC2365565.

30. Ludwig T, Fisher P, Murty V, Efstratiadis A. Development of mammary adenocarcinomas by tissue-specific knockout of Brca2 in mice. Oncogene. 2001;20(30):3937–48. doi: 10.1038/sj.onc.1204512 11494122.

31. Huo Y, Cai H, Teplova I, Bowman-Colin C, Chen G, Price S, et al. Autophagy opposes p53-mediated tumor barrier to facilitate tumorigenesis in a model of PALB2-associated hereditary breast cancer. Cancer Discov. 2013;3(8):894–907. doi: 10.1158/2159-8290.CD-13-0011 23650262; PubMed Central PMCID: PMC3740014.

32. Sizemore GM, Balakrishnan S, Thies KA, Hammer AM, Sizemore ST, Trimboli AJ, et al. Stromal PTEN determines mammary epithelial response to radiotherapy. Nat Commun. 2018;9(1):2783. Epub 2018/07/17. doi: 10.1038/s41467-018-05266-6 30018330; PubMed Central PMCID: PMC6050339.

33. Rantakari P, Nikkilä J, Jokela H, Ola R, Pylkäs K, Lagerbohm H, et al. Inactivation of Palb2 gene leads to mesoderm differentiation defect and early embryonic lethality in mice. Hum Mol Genet. 2010;19(15):3021–9. Epub 2010/05/18. doi: 10.1093/hmg/ddq207 20484223.

34. Sharan SK, Morimatsu M, Albrecht U, Lim DS, Regel E, Dinh C, et al. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature. 1997;386(6627):804–10. doi: 10.1038/386804a0 9126738.

35. Gowen LC, Johnson BL, Latour AM, Sulik KK, Koller BH. Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nat Genet. 1996;12(2):191–4. doi: 10.1038/ng0296-191 8563759.

36. Jørgensen MC, Ahnfelt-Rønne J, Hald J, Madsen OD, Serup P, Hecksher-Sørensen J. An illustrated review of early pancreas development in the mouse. Endocr Rev. 2007;28(6):685–705. Epub 2007/09/19. doi: 10.1210/er.2007-0016 17881611.

37. Hakem R, de la Pompa JL, Sirard C, Mo R, Woo M, Hakem A, et al. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell. 1996;85(7):1009–23. Epub 1996/06/28. doi: 10.1016/s0092-8674(00)81302-1 8674108.

38. Suzuki A, de la Pompa JL, Hakem R, Elia A, Yoshida R, Mo R, et al. Brca2 is required for embryonic cellular proliferation in the mouse. Genes Dev. 1997;11(10):1242–52. Epub 1997/05/15. doi: 10.1101/gad.11.10.1242 9171369.

39. Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT, et al. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell. 2004;119(6):847–60. doi: 10.1016/j.cell.2004.11.004 15607980.

40. de Vries A, Flores ER, Miranda B, Hsieh HM, van Oostrom CT, Sage J, et al. Targeted point mutations of p53 lead to dominant-negative inhibition of wild-type p53 function. Proc Natl Acad Sci U S A. 2002;99(5):2948–53. Epub 2002/02/26. doi: 10.1073/pnas.052713099 11867759; PubMed Central PMCID: PMC122453.

41. Morris JP, Wang SC, Hebrok M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer. 2010;10(10):683–95. Epub 2010/09/03. doi: 10.1038/nrc2899 20814421; PubMed Central PMCID: PMC4085546.

42. Yonezawa S, Higashi M, Yamada N, Goto M. Precursor lesions of pancreatic cancer. Gut Liver. 2008;2(3):137–54. Epub 2008/12/31. doi: 10.5009/gnl.2008.2.3.137 20485640; PubMed Central PMCID: PMC2871636.

43. Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4(6):437–50. doi: 10.1016/s1535-6108(03)00309-x 14706336.

44. Strobel O, Dor Y, Alsina J, Stirman A, Lauwers G, Trainor A, et al. In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia. Gastroenterology. 2007;133(6):1999–2009. Epub 2007/09/14. doi: 10.1053/j.gastro.2007.09.009 18054571; PubMed Central PMCID: PMC2254582.

45. Matthaei H, Schulick RD, Hruban RH, Maitra A. Cystic precursors to invasive pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2011;8(3):141–50. doi: 10.1038/nrgastro.2011.2 21383670; PubMed Central PMCID: PMC3236705.

46. Klimstra DS. Cystic, mucin-producing neoplasms of the pancreas: the distinguishing features of mucinous cystic neoplasms and intraductal papillary mucinous neoplasms. Semin Diagn Pathol. 2005;22(4):318–29. doi: 10.1053/j.semdp.2006.04.005 16939060.

47. Moynahan ME, Jasin M. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol. 2010;11(3):196–207. doi: 10.1038/nrm2851 20177395; PubMed Central PMCID: PMC3261768.

48. Lohse I, Borgida A, Cao P, Cheung M, Pintilie M, Bianco T, et al. BRCA1 and BRCA2 mutations sensitize to chemotherapy in patient-derived pancreatic cancer xenografts. Br J Cancer. 2015;113(3):425–32. Epub 2015/07/17. doi: 10.1038/bjc.2015.220 26180923; PubMed Central PMCID: PMC4522629.

49. Nepomuceno TC, De Gregoriis G, de Oliveira FMB, Suarez-Kurtz G, Monteiro AN, Carvalho MA. The Role of PALB2 in the DNA Damage Response and Cancer Predisposition. Int J Mol Sci. 2017;18(9). Epub 2017/09/01. doi: 10.3390/ijms18091886 28858227; PubMed Central PMCID: PMC5618535.

50. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–7. Epub 2005/04/15. doi: 10.1038/nature03443 15829966.

51. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–21. Epub 2005/04/15. doi: 10.1038/nature03445 15829967.

52. Bhattacharyya A, Ear US, Koller BH, Weichselbaum RR, Bishop DK. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J Biol Chem. 2000;275(31):23899–903. Epub 2000/06/14. doi: 10.1074/jbc.C000276200 10843985.

53. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65. Epub 2012/06/02. doi: 10.1056/NEJMoa1200694 22658128; PubMed Central PMCID: PMC3563263.

54. Torphy RJ, Zhu Y, Schulick RD. Immunotherapy for pancreatic cancer: Barriers and breakthroughs. Ann Gastroenterol Surg. 2018;2(4):274–81. Epub 2018/06/22. doi: 10.1002/ags3.12176 30003190; PubMed Central PMCID: PMC6036358.

55. Mace TA, Shakya R, Pitarresi JR, Swanson B, McQuinn CW, Loftus S, et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut. 2018;67(2):320–32. Epub 2016/10/21. doi: 10.1136/gutjnl-2016-311585 27797936; PubMed Central PMCID: PMC5406266.

56. Domchek SM, Tang J, Stopfer J, Lilli DR, Hamel N, Tischkowitz M, et al. Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer. Cancer Discov. 2013;3(4):399–405. Epub 2012/12/26. doi: 10.1158/2159-8290.CD-12-0421 23269703; PubMed Central PMCID: PMC3625496.

57. Petrucelli N, Daly MB, Feldman GL. Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2. Genet Med. 2010;12(5):245–59. doi: 10.1097/GIM.0b013e3181d38f2f 20216074.

58. Zhang F, Fan Q, Ren K, Andreassen PR. PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2. Mol Cancer Res. 2009;7(7):1110–8. doi: 10.1158/1541-7786.MCR-09-0123 19584259.

59. Sy SM, Huen MS, Chen J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc Natl Acad Sci U S A. 2009;106(17):7155–60. doi: 10.1073/pnas.0811159106 19369211; PubMed Central PMCID: PMC2678481.

60. Gannon M, Herrera PL, Wright CV. Mosaic Cre-mediated recombination in pancreas using the pdx-1 enhancer/promoter. Genesis. 2000;26(2):143–4. doi: 10.1002/(sici)1526-968x(200002)26:2<143::aid-gene13>3.0.co;2-l 10686611.

61. Chahla E, Cheesman A, Mahon SM, Garrett RW, Bradenham BP Jr., Schwartz TL, et al. Frequency and Significance of Abnormal Pancreatic Imaging in Patients with BRCA1 and BRCA2 Genetic Mutations. Scientifica (Cairo). 2016;2016:5619358. Epub 2016/04/14. doi: 10.1155/2016/5619358 27069714; PubMed Central PMCID: PMC4812496.

62. Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev Cancer. 4. England2004. p. 814–9. doi: 10.1038/nrc1457 15510162

63. Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer. 2016;16(2):110–20. Epub 2016/01/19. doi: 10.1038/nrc.2015.21 26775620.

64. Locke I, Kote-Jarai Z, Bancroft E, Bullock S, Jugurnauth S, Osin P, et al. Loss of heterozygosity at the BRCA1 and BRCA2 loci detected in ductal lavage fluid from BRCA gene mutation carriers and controls. Cancer Epidemiol Biomarkers Prev. 2006;15(7):1399–402. doi: 10.1158/1055-9965.EPI-05-0971 16835343.

65. Hartley T, Cavallone L, Sabbaghian N, Silva-Smith R, Hamel N, Aleynikova O, et al. Mutation analysis of PALB2 in BRCA1 and BRCA2-negative breast and/or ovarian cancer families from Eastern Ontario, Canada. Hered Cancer Clin Pract. 2014;12(1):19. Epub 2014/08/28. doi: 10.1186/1897-4287-12-19 25225577; PubMed Central PMCID: PMC4163678.

66. Bouwman P, Drost R, Klijn C, Pieterse M, van der Gulden H, Song JY, et al. Loss of p53 partially rescues embryonic development of Palb2 knockout mice but does not foster haploinsufficiency of Palb2 in tumour suppression. J Pathol. 2011;224(1):10–21. doi: 10.1002/path.2861 21404276.


Článek vyšel v časopise

PLOS One


2019 Číslo 12
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

KOST
Koncepce osteologické péče pro gynekology a praktické lékaře
nový kurz
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková

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

Svět praktické medicíny 5/2023 (znalostní test z časopisu)

Imunopatologie? … a co my s tím???
Autoři: doc. MUDr. Helena Lahoda Brodská, Ph.D.

Všechny kurzy
Kurzy Podcasty Doporučená témata Časopisy
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#