IEO European Institute of Oncology

Milano, Italy

IEO European Institute of Oncology

Milano, Italy
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Oliveri S.,University of Milan | Oliveri S.,IEO European Institute of Oncology | Pravettoni G.,University of Milan | Pravettoni G.,IEO European Institute of Oncology
Journal of Risk Research | Year: 2017

The prevailing scientific approach to genetic risk information centres around communication of risk in terms of numerical probabilities. However, it is well known that individuals have difficulties in understanding and making sense of this information in their own lives. There is, accordingly, a need to investigate whether any methodologies in psychological research may shed light on how individuals perceive genetic risk information within their specific contexts of family history, personal relationships, lifestyles and future plans. To explore whether hermeneutic phenomenology and methodology may offer a deeper understanding of an individual’s perception of having a hereditary predisposition, we conducted a literature search. We found that Interpretative Phenomenological Analysis may be a fruitful approach to an individual’s lived experiential world. The studies analysed showed how individuals interpret information about genetic risk in the light of their own beliefs about the multiple causes of illness, patterns of heredity and observable risk factors in their families. People’s understanding of their experience is derived from an intricate interconnectedness with others that arises in the context of a world shaped in equal measure by language and culture, on the one hand, and bodies and objects on the other. © 2017 Informa UK Limited, trading as Taylor & Francis Group

Maddaluno L.,FIRC Institute of Molecular Oncology | Rudini N.,FIRC Institute of Molecular Oncology | Cuttano R.,FIRC Institute of Molecular Oncology | Bravi L.,FIRC Institute of Molecular Oncology | And 17 more authors.
Nature | Year: 2013

Cerebral cavernous malformation (CCM) is a vascular dysplasia, mainly localized within the brain and affecting up to 0.5% of the human population. CCM lesions are formed by enlarged and irregular blood vessels that often result in cerebral haemorrhages. CCM is caused by loss-of-function mutations in one of three genes, namely CCM1 (also known as KRIT1), CCM2 (OSM) and CCM3 (PDCD10), and occurs in both sporadic and familial forms. Recent studies have investigated the cause of vascular dysplasia and fragility in CCM, but the in vivo functions of this ternary complex remain unclear. Postnatal deletion of any of the three Ccm genes in mouse endothelium results in a severe phenotype, characterized by multiple brain vascular malformations that are markedly similar to human CCM lesions. Endothelial-to-mesenchymal transition (EndMT) has been described in different pathologies, and it is defined as the acquisition of mesenchymal-and stem-cell-like characteristics by the endothelium. Here we show that endothelial-specific disruption of the Ccm1 gene in mice induces EndMT, which contributes to the development of vascular malformations. EndMT in CCM1-ablated endothelial cells is mediated by the upregulation of endogenous BMP6 that, in turn, activates the transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signalling pathway. Inhibitors of the TGF-β and BMP pathway prevent EndMT both in vitro and in vivo and reduce the number and size of vascular lesions in CCM1-deficient mice. Thus, increased TGF-β and BMP signalling, and the consequent EndMT of CCM1-null endothelial cells, are crucial events in the onset and progression of CCM disease. These studies offer novel therapeutic opportunities for this severe, and so far incurable, pathology. © 2013 Macmillan Publishers Limited. All rights reserved.

Sanchini V.,IEO European Institute of Oncology | Sanchini V.,University of Milan | Reni M.,San Raffaele Scientific Institute | Calori G.,San Raffaele Scientific Institute | And 2 more authors.
Journal of Medical Ethics | Year: 2014

We explored the comprehension of the informed consent in 77 cancer patients previously enrolled in randomised phase II or phase III clinical trials, between March and July 2011, at the San Raffaele Scientific Institute in Milano. We asked participants to complete an ad hoc questionnaire and analysed their answers. Sixty-two per cent of the patients understood the purpose and nature of the trial they were participating in; 44% understood the study procedures and 40% correctly listed at least one of the major risks or complications related to their participation in the trial. We identified three factors associated with comprehension of the informed consent: age, education and type of tumour/investigator team. We suggest several possible improvements of how to obtain informed consent that will increase patient awareness, as well as the validity and effectiveness of the clinical trials.

PubMed | Genextra, National Health Research Institute, IEO European Institute of Oncology, University of Pavia and 2 more.
Type: | Journal: European journal of medicinal chemistry | Year: 2015

The pure enantiomers of the N-(2-, 3-, and 4-(2-aminocyclopropyl)phenyl)benzamides hydrochlorides 11a-j were prepared and tested against LSD1 and MAO enzymes. The evaluation of the regioisomers 11a-j highlighted a net increase of the anti-LSD1 potency by shifting the benzamide moiety from ortho to meta and mainly to para position of tranylcypromine phenyl ring, independently from their trans or cis stereochemistry. In particular, the para-substituted 11a,b (trans) and 11g,h (cis) compounds displayed LSD1 and MAO-A inhibition at low nanomolar levels, while were less potent against MAO-B. The meta analogs 11c,d (trans) and 11i,j (cis) were in general less potent, but more efficient against MAO-A than against LSD1. In cellular assays, all the para and meta enantiomers were able to inhibit LSD1 by inducing Gfi-1b and ITGAM gene expression, with 11b,c and 11g-i giving the highest effects. Moreover, 11b and 11g,h strongly inhibited the clonogenic potential of murine promyelocytic blasts.

Ferrucci P.F.,IEO European Institute of Oncology | Tosti G.,IEO European Institute of Oncology | di Pietro A.,IEO European Institute of Oncology | Passoni C.,IEO European Institute of Oncology | And 5 more authors.
Current Topics in Medicinal Chemistry | Year: 2012

Immunogenicity of tumour cells, immunomodulation and direct targeting of signalling pathways are promising avenues and matter of dated and innovative research in melanoma. Unfortunately, tumour cells are considered to be antigenic, but not immunogenic, either due to presentation of weakly recognized antigens or to the inability of the immune system to recognize them. However, spontaneous complete remission can be rarely observed in patients affected by melanoma, which are mainly attributed to the immune response against the tumour. Also, an elevated frequency of spontaneous humoral immune responses against tumour antigens was occasionally found in patients. These data confirm the existence of an interaction of the immune system with the tumour which can be used as a promising pathway for intervention and incorporates all portions of the immune system. The cancer immunotherapy approach is based on artificial activation of the immune system against the tumour and groups several types of treatments including immunization/vaccination but also modulation of immunity by cytokines or antibodies. Immunization approaches could either be based on undefined tumour antigens (e.g. whole tumour cells, tumour cell lysates, or tumour-antigen enriched fractions) or aimed at eliciting T-cell responses against specific tumour antigens. Novel and contemporary antigen-targeted therapy strategies, mainly directed to Cancer Testis and Heat Shock Proteins, leading to a possible active immunization against melanoma through Tcell specific activation, are discussed in this review. © 2012 Bentham Science Publishers.

Molinaro V.,University of Pavia | Pensotti V.,Genomics Unit | Marabelli M.,University of Pavia | Feroce I.,IEO European Institute of Oncology | And 7 more authors.
Genes Chromosomes and Cancer | Year: 2014

Germline inactivation of the E-cadherin gene (CDH1) is associated with hereditary diffuse gastric cancer (HDGC), a rare autosomal dominant syndrome predisposing to both diffuse gastric cancer (DGC) and lobular breast cancer (LBC). We searched for CDH1 germline defects in 32 HDGC Italian probands selected according to international consensus criteria and in 5 selected relatives. We used a series of molecular methods, including: DNA sequencing, multiplex ligation-dependent probe amplification, single-nucleotide primer extension, bisulfite sequencing, reverse-transcription PCR, and bioinformatics tools. We identified pathogenic mutations in 6 out of 32 probands (19%): one truncating and two missense mutations, one large deletion, one allelic expression imbalance and one splicing defect. Three out of six CDH1 constitutive alterations were novel. Our data support the need for a multimethod approach for CDH1 genetic testing, demonstrating that both DNA and RNA analyses are required to increase the detection rate of pathogenic mutations, thus reducing the number of patients without a clear molecular diagnosis. On the whole, our results indicate that not only DGC patients, but also subjects with personal or family history of LBC might benefit from CDH1 genetic testing. Moreover, our findings support the notion that prophylactic gastrectomy should be offered to asymptomatic CDH1 mutation carriers; indeed, while endoscopic analysis with histological examination of random gastric biopsies can miss cancer foci, gastrectomy performed in these subjects always revealed foci of cancer cells. © 2014 Wiley Periodicals, Inc.

PubMed | Paul Strickland Scanner Center, IEO European Institute of Oncology and King's College
Type: Editorial | Journal: European urology | Year: 2015

MRI directed prostate biopsy will change the cancer risk profiles of diagnosed patients, towards those requiring radical treatments. Increased costs can be balanced by improvements in the efficiency of the patient pathway. Effective communication of imaging findings and improved urological understanding of imaging limitations will improve the quality of care for prostate cancer patients.

Serrano D.,IEO European Institute of Oncology | Gnagnarella P.,IEO European Institute of Oncology | Raimondi S.,IEO European Institute of Oncology | Gandini S.,IEO European Institute of Oncology
European Journal of Cancer Prevention | Year: 2016

Vitamin D plays a significant role in our health, including cancer incidence and mortality. Vitamin D receptor (VDR) single-nucleotide polymorphisms (SNPs) may affect its activity, influencing the risk of cancer. Several studies have investigated VDR SNPs, but the association with the risk of cancer is controversial. Here, we present a meta-analysis to assess the association of TaqI, ApaI, and Cdx2 SNPs with the risk of cancer. A systematic literature search was performed following a predefined protocol and using validated search strategies. This meta-analysis shows the summary odd ratio (SOR) overall, by cancer sites and by ethnicity. Up to January 2014, we identified 73 independent studies with 35 525 cases and 38 675 controls. The metaanalysis of Cdx2 gg versus GG showed a significant 12% increased risk for all cancers [SOR=1.12; 95% confidence interval (CI): 1.00-1.25]. The other SNPs analyzed did not show an overall significant association with the risk of cancer: SOR=0.98 (95% CI: 0.90-1.07) and 1.06 (95% CI: 0.95-1.19) for TaqI tt versus TT and ApaI aa versus AA, respectively. TaqI shows a significant 43% increased risk for colorectal cancer (SOR=1.43; 95% CI: 1.30-1.58 for tt vs. TT). Strong frequency variations are present among different ethnic groups. This meta-analysis showed an overall increased risk of cancer associated with Cdx2 SNP and a specific higher risk of colorectal cancer associated with the TaqI polymorphism. The VDR genotype might become more relevant when clustered in a specific haplotype, associated with other SNPs of genes involved in Vitamin D metabolism, or for specific tumors and/or patient Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

PubMed | IEO European Institute of Oncology and University of Milan
Type: Journal Article | Journal: Medical physics | Year: 2016

To evaluate the geometric and dosimetric accuracies of the CyberKnife Synchrony respiratory tracking system (RTS) and to validate a method for pretreatment patient-specific delivery quality assurance (DQA).An EasyCube phantom was mounted on the ExacTrac gating phantom, which can move along the superior-inferior (SI) axis of a patient to simulate a moving target. The authors compared dynamic and static measurements. For each case, a Gafchromic EBT3 film was positioned between two slabs of the EasyCube, while a PinPoint ionization chamber was placed in the appropriate space. There were three steps to their evaluation: (1) the field size, the penumbra, and the symmetry of six secondary collimators were measured along the two main orthogonal axes. Dynamic measurements with deliberately simulated errors were also taken. (2) The delivered dose distributions (from step 1) were compared with the planned ones, using the gamma analysis method. The local gamma passing rates were evaluated using three acceptance criteria: 3% local dose difference (LDD)/3 mm, 2%LDD/2 mm, and 3%LDD/1 mm. (3) The DQA plans for six clinical patients were irradiated in different dynamic conditions, to give a total of 19 cases. The measured and planned dose distributions were evaluated with the same gamma-index criteria used in step 2 and the measured chamber doses were compared with the planned mean doses in the sensitive volume of the chamber.(1) A very slight enlargement of the field size and of the penumbra was observed in the SI direction (on average <1 mm), in line with the overall average CyberKnife system error for tracking treatments. (2) Comparison between the planned and the correctly delivered dose distributions confirmed the dosimetric accuracy of the RTS for simple plans. The multicriteria gamma analysis was able to detect the simulated errors, proving the robustness of their method of analysis. (3) All of the DQA clinical plans passed the tests, both in static and dynamic conditions. No statistically significant differences were found between static and dynamic cases, confirming the high degree of accuracy of the Synchrony RTS.The presented methods and measurements verified the mechanical and dosimetric accuracy of the Synchrony RTS. Their method confirms the fact that the RTS, if used properly, is able to treat a moving target with great precision. By combining PinPoint ion chamber, EBT3 films, and gamma evaluation of dose distributions, their DQA method robustly validated the effectiveness of CyberKnife and Synchrony system.

PubMed | Genextra, National Health Research Institute, IEO European Institute of Oncology, University of Pavia and 2 more.
Type: Journal Article | Journal: ACS medicinal chemistry letters | Year: 2015

The pure four diastereomers (11a-d) of trans-benzyl (1-((4-(2-aminocyclopropyl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate hydrochloride 11, previously described by us as LSD1 inhibitor, were obtained by enantiospecific synthesis/chiral HPLC separation method. Tested in LSD1 and MAO assays, 11b (S,1S,2R) and 11d (R,1S,2R) were the most potent isomers against LSD1 and were less active against MAO-A and practically inactive against MAO-B. In cells, all the four diastereomers induced Gfi-1b and ITGAM gene expression in NB4 cells, accordingly with their LSD1 inhibition, and 11b and 11d inhibited the colony forming potential in murine promyelocytic blasts.

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