Browsing by Issue Date, starting with "2019-10-26"
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- Nanotoxicology research at INSA – do NMs contribute for genotoxic effects that may lead to cancer?Publication . Louro, Henriqueta; Ventura, Célia; Silva, Maria JoãoThe technology based on manufactured nanomaterials (NMs) has been pointed as key enabling technology, due to its potential to improve many products and processes, namely in agriculture, food and feed industry. Many of such products, already available, have NMs, such as nano-encapsulates, silver, titanium dioxide nanomaterials (TiO2) or synthetic amorphous silica (SAS) and many others are being developed, such as nanocellulose and nanoformulations of pesticides. One major concern for public health is that NMs may produce adverse outcomes such as genotoxic effects that are associated with increased risk of cancer. Although NMs have been extensively investigated in recent years, the studies have generated contradictory results, possibly due to differences in the physicochemical properties of the NMs studied and to other variables in the tested systems. Furthermore, the NMs properties have been recognized as being context-dependent, i.e. can be affected by the surrounding matrix. These secondary features may be potentially more relevant for determining the toxicological outcome. In particular, processes like intake or digestion may modify the NMs characteristics leading to unexpected toxicity in human cells. Under the scope of two nationally funded projects (PTDC/SAU-PUB/29481/2017 – INGESTnano and PTDC/SAU-PUB/32587/2017- ToxApp4NanoCELFI), the research developed at INSA, focused on the nanogenotoxicology assessment of titanium dioxide nanomaterials and nanocelluloses will be presented.
- Genetic alterations of ALK in high-risk neuroblastoma patients. A SIOPEN studyPublication . Bellini, Angela; Bernard, Virginie; Ambros, Inge; F. Ambros, Peter; de Preter, Katleen; Combaret, Valérie; Beiske, Klaus; Jeison, Marta; Marques, Barbara; Morini, Martina; Mazzocco, Katia; Defferrari, Raffaella; Betts, David; Martinsson, Tommy; Mühlethaler-Mottet, Annick; Noguera, Rosa; Font de Mora, Jaime; Vicha, Ales; Ladenstein, Ruth; Valteau-Couanet, Dominique; Rossing, Caroline Maria; Bown, Nick; Tweddle, Deborah; Avigad, Smadar; Lapouble, Eve; Chicard, Mathieu; Leprovost, Nada; Clement, Nathalie; Baulande, Sylvain; Pierron, Gaelle; Irene, Jimenez; Jaydutt, Bhalshankar; Delattre, Olivier; Michon, Jean; Schleiermacher, GudrunBackground: In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through genomic amplification or activating point mutations. We studied ALK genetic alterations in high-risk NB patients to determine their frequency and prognostic impact. Methods: Diagnostic NB samples from 1039 patients enrolled in the SIOPEN-HR-NBL1 trial were studied to determine the ALK amplification status (copy number analysis; n=337), the ALK mutational profile (Sanger and/or NGS including deep sequencing, n=203) or both (n=499). The sensitivity of ALK mutated/ALK amplified or ALK wildtype NB cell lines ((CLB-GA (R1275Q), CLB-GE (F1174V; ALK-A), SKNBE-2C (ALK wt)) to simultaneous or consecutive combinations of ALK TKIs (crizotinib/lorlatinib) and/or chemotherapy (Etoposide and Doxorubicin) was then tested. Results: Genomic ALK amplifications were detected in 4.4% of cases (37/836); all but 2 showed MYCN amplification. ALK mutations were detected at a clonal level (>20% mutated allele fraction, MAF) in 9.8% of cases (69/702) (F1174 n=25, R1275 n=32, both F1174 and R1275 n=1, F1245 n=6, others n=5) and at a subclonal level (MAF 0.5-20%) in 3.7% of patients (22/586) (F1174 n=11, R1275 n=6, both F1174 and R1275 or F1174 and F1245 n=3, other n=2). A significantly poorer OS and EFS was observed in cases with clonal ALK mutations, versus all others (3-years OS 47% +/-6.4% versus 65% +/-2%, logrank, p< 0.0001) and in those with ALK amplifications, versus all others (3-years OS 31% +/-8.5% versus 66% +/- 1.9%; logrank, p<0.0001). A Cox proportional hazards procedure (450 patients with complete clinical/biological datasets) retained stage 4 disease (as opposed to non-stage 4) and ALK amplification as factors with a higher hazard of relapse/progression (hazard 2.3 and 2.2, respectively), whereas ALK mutation, MYCN amplification and age>18 months were not retained. The consecutive treatment of Doxorubicin followed by Lorlatinib had a synergistic effect in ALK mutated/amplified NB cell lines. Conclusion: Genetic alterations of ALK (clonal mutations, amplifications) in high-risk NB patients are associated with poorer survival. Further preclinical data are required to determine optimal treatment modalities for integration of TKI in upfront treatment strategies of HR NB patients with ALK alterations.