Riflessioni sotto l'albero di jacaranda

  1. Per chi avesse la curiosità di conoscere le ragioni della scelta del titolo, rimandiamo all’estratto del video dell’intervista 

  2. L'intervista è stata condotta il 5/6/2015 assieme ad Andrea Mameli all'hotel Panorama di Cagliari, che ringraziamo per l'ospitalità. Un grazie sincero va anche a Saverio Gaeta e agli organizzatori del festival Leggendo Metropolitano che hanno reso possibile questo incontro 

  3. A. Ciechanover, Early work on the ubiquitin proteasome system, an interview with Aaron Ciechanover, Cell Death and Differentiation, 12, 1167–1177, 2005 

  4. Il bortezomib come terapia per il mieloma multiplo è stato approvato dalla FDA nel 2003 per uso con i pazienti refrattari, nel 2005 come trattamento di seconda linea, nel 2008 come terapia iniziale 

  5. per una review sintetica sull’argomento si veda ad esempio Naidoo J, Page DB, and Wolchok JD, Immune modulation for cancer therapy, BJC, 111, 12:2214-2219, 201 

  6. Gerlinger M, Rowan AJ, Horswell S, Larkin J et al, Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing, NEJM, 366, 10:883-892, 2012 

  7. In particolare per i tumori solidi. Si veda il Technical corner 

  8. Vogelstein B, Kinzler KW, Cancer genes and the pathways they control, Nature Medicine, 10, 8:789-799, 2004 

  9. oltre a personalized, predictive, preventive, e participatory: è la “P4 medicine”, espressione molto popolare coniata dal Leroy Hood nel 2005 

  10. Protein degradation is a fundamental task for eukaryotes. Inside cells, proteins homeostasis results from the opposite actions of synthesis and degradation. Proteins typical half-lives vary widely, from minutes to several days: differential rates of protein degradation is a basis of cell regulation. Regulatory molecules, such as transcription factors, are rapidly degraded, as their rapid turnover allows prompt changes to external stimuli. Degradation of other proteins in response to specific signals is another well-known mechanism for regulating the intracellular enzyme activity. Another necessary task is the destruction of faulty or damaged proteins, in order to eliminate the consequences of errors made during protein synthesis. In eukaryotes two major pathways are involved in protein degradation: the ubiquitin-proteasome system and the lysosomal proteolysis. See, for instance, Cooper GM, The Cell: A Molecular Approach. 2nd edition, Sunderland (MA) Sinauer Associates, 2000. 

  11. Ciechanover A, Elias S, Heller H, Ferber S, and Hershko A, Characterization of the heat-stable polypeptide of the ATP-dependent proteolytic system from reticulocytes, J. Biol. Chem., 255, 16:7525-7528, 1980 

  12. Wilkinson KD, Urban MK, and Haas AL, Ubiquitin is the ATP-dependent proteolysis factor I of rabbit reticulocytes, J. Biol. Chem., 255, 16:7529-7532, 1980 

  13. Hershko A, and Ciechanover A, The ubiquitin system, Annu. Rev. Biochem., 67:425–79, 1998 

  14. See Nath D and Shadan S, The ubiquitin system, Nature Insight, 458, 7237:421-467, 2009, and references therein 

  15. See Table 1 in Micel LN, Tentler JJ, Smith PG, and Eckhardt SG, Role of Ubiquitin Ligases and the Proteasome in Oncogenesis: Novel Targets for Anticancer Therapies, J Clin Oncol, 31, 9:1231-1238, 2013 

  16. For a detailed analysis of molecular mechanisms of bortezomib see Cvek B, and Dvorak Z, The ubiquitin-proteasome system (UPS) and the mechanism of action of bortezomib, Curr Pharm Des, 17:1483-99, 2011 

  17. Roughly speaking, the ratio of the dose of drug that causes adverse effects divided by the dose that leads to the desired pharmacological effect 

  18. Dick LR, and Fleming PE, Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy, Drug Discovery Today, 15, 5/6:243-249, 2010 

  19. Ruschak AM, Slassi M, Kay LE, and Schimmer AD, Novel Proteasome Inhibitors to Overcome Bortezomib Resistance, JNCI J Natl Cancer Inst, 103, 13:1007-1017, 2011 

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