Mercato diritti e consumi: la tutela del consumatore nella disciplina antitrust

Lo studio “Mercato, diritti e consumi: la tutela del consumatore nella disciplina antitrust”, ricostruisce e analizza i rapporti intercorrenti tra pubbliche amministrazioni e consumatore, singolo e associato, concentrando l’attenzione sulla protezione del consumatore quale soggetto che opera nel mercato, titolare di un diritto economico, in relazione all’attività regolativa svolta dall’amministrazione nella cura dell’interesse pubblico alla tutela della concorrenza. Il lavoro è strutturato in quattro parti. Una prima parte, di carattere generale, è dedicata alla nozione di consumatore e ai diritti in capo allo stesso contemplati, nonché alle associazioni dei consumatori ed al ruolo istituzionale ad esse affidato. Nella seconda parte si concentra l’attenzione, da un lato, sulla posizione assunta dalle Regioni per quel che concerne la competenza legislativa ad esse riconosciuta nell’ambito della tutela dei consumatori e degli utenti e, dall’altro lato, sul versante degli strumenti più propriamente di diritto amministrativo, sull’attività amministrativa di controllo, vigilanza e disciplina delle attività economiche private rilevanti per i consumatori, attuata dalle autorità indipendenti e, per ciò che attiene alle loro funzioni, dalle Camere di commercio. La terza parte riferisce in ordine al quadro normativo in cui si colloca l’attività di regolazione del mercato soprattutto avendo riguardo alle recenti modifiche legislative che hanno profondamente modificato il Codice del consumo relativamente ai suddetti temi ed al ruolo svolto dall’Autorità Garante della Concorrenza e del Mercato, per poi dar conto dell’evoluzione giurisprudenziale cui si è assistito recentemente circa la rilevanza dell’interesse del consumatore nella disciplina Antitrust. Nell’ultima parte, anche alla luce delle osservazioni svolte, si affronta il fondamento giuridico – costituzionale dell’interesse del consumatore anche alla luce del nuovo assetto dei rapporti con l’Autorità Garante della Concorrenza e del Mercato e si tenta, attraverso una reinterpretazione del concetto di iniziativa economica, di ricondurlo al primo comma dell’articolo 41 della Costituzione.

Mechanism of resistance to tyrosine kinase inhibitors in philadelphia-positive acute lymphblastic leukaemia (all): from genetic alterations to impaired RNA editing

The Ph chromosome is the most frequent cytogenetic aberration associated with adult ALL and it represents the single most significant adverse prognostic marker. Despite imatinib has led to significant improvements in the treatment of patients with Ph+ ALL, in the majority of cases resistance developed quickly and disease progressed. Some mechanisms of resistance have been widely described but the full knowledge of contributing factors, driving both the disease and resistance, remains to be defined. The observation of rapid development of lymphoblastic leukemia in mice expressing altered Ikaros (Ik) isoforms represented the background of this study. Ikaros is a zinc finger transcription factor required for normal hemopoietic differentiation and proliferation, particularly in the lymphoid lineages. By means of alternative splicing, Ikaros encodes several proteins that differ in their abilities to bind to a consensus DNA-binding site. Shorter, DNA nonbinding isoforms exert a dominant negative effect, inhibiting the ability of longer heterodimer partners to bind DNA. The differential expression pattern of Ik isoforms in Ph+ ALL patients was analyzed in order to determine if molecular abnormalities involving the Ik gene could associate with resistance to imatinib and dasatinib. Bone marrow and peripheral blood samples from 46 adult patients (median age 55 yrs, 18-76) with Ph+ ALL at diagnosis and during treatment with imatinib (16 pts) or dasatinib (30 pts) were collected. We set up a fast, high-throughput method based on capillary electrophoresis technology to detect and quantify splice variants. 41% Ph+ ALL patients expressed high levels of the non DNA-binding dominant negative Ik6 isoform lacking critical N-terminal zinc-fingers which display abnormal subcellular compartmentalization pattern. Nuclear extracts from patients expressed Ik6 failed to bind DNA in mobility shift assay using a DNA probe containing an Ikaros-specific DNA binding sequence. In 59% Ph+ ALL patients there was the coexistence in the same PCR sample and at the same time of many splice variants corresponded to Ik1, Ik2, Ik4, Ik4A, Ik5A, Ik6, Ik6 and Ik8 isoforms. In these patients aberrant full-length Ikaros isoforms in Ph+ ALL characterized by a 60-bp insertion immediately downstream of exon 3 and a recurring 30-bp in-frame deletion at the end of exon 7 involving most frequently the Ik2, Ik4 isoforms were also identified. Both the insertion and deletion were due to the selection of alternative splice donor and acceptor sites. The molecular monitoring of minimal residual disease showed for the first time in vivo that the Ik6 expression strongly correlated with the BCR-ABL transcript levels suggesting that this alteration could depend on the Bcr-Abl activity. Patient-derived leukaemia cells expressed dominant-negative Ik6 at diagnosis and at the time of relapse, but never during remission. In order to mechanistically demonstrated whether in vitro the overexpression of Ik6 impairs the response to tyrosine kinase inhibitors (TKIs) and contributes to resistance, an imatinib-sensitive Ik6-negative Ph+ ALL cell line (SUP-B15) was transfected with the complete Ik6 DNA coding sequence. The expression of Ik6 strongly increased proliferation and inhibited apoptosis in TKI sensitive cells establishing a previously unknown link between specific molecular defects that involve the Ikaros gene and the resistance to TKIs in Ph+ ALL patients. Amplification and genomic sequence analysis of the exon splice junction regions showed the presence of 2 single nucleotide polymorphisms (SNPs): rs10251980 [A/G] in the exon2/3 splice junction and of rs10262731 [A/G] in the exon 7/8 splice junction in 50% and 36% of patients, respectively. A variant of the rs11329346 [-/C], in 16% of patients was also found. Other two different single nucleotide substitutions not recognized as SNP were observed. Some mutations were predicted by computational analyses (RESCUE approach) to alter cis-splicing elements. In conclusion, these findings demonstrated that the post-transcriptional regulation of alternative splicing of Ikaros gene is defective in the majority of Ph+ ALL patients treated with TKIs. The overexpression of Ik6 blocking B-cell differentiation could contribute to resistance opening a time frame, during which leukaemia cells acquire secondary transforming events that confer definitive resistance to imatinib and dasatinib.