Italian National Cancer Institute

Milan, Italy

Italian National Cancer Institute

Milan, Italy

The European Institute of Oncology is a non-profit comprehensive cancer centre located in Milan, Italy that is active in three areas:ClinicResearchTrainingThe European Institute of Oncology works on the prevention, diagnosis and treatment of cancer by developing clinical and scientific research coupled with organisation and management. Wikipedia.

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Smale S.T.,University of California at Los Angeles | Tarakhovsky A.,Rockefeller University | Natoli G.,Italian National Cancer Institute
Annual Review of Immunology | Year: 2014

A fundamental property of cells of the innate immune system is their ability to elicit a transcriptional response to a microbial stimulus or danger signal with a high degree of cell type and stimulus specificity. The selective response activates effector pathways to control the insult and plays a central role in regulating adaptive immunity through the differential regulation of cytokine genes. Selectivity is dictated by signaling pathways and their transcription factor targets. However, a growing body of evidence supports models in which different subsets of genes exhibit distinct chromatin features that play active roles in shaping the response. Chromatin also participates in innate memory mechanisms that can promote tolerance to a stimulus or prime cells for a more robust response. These findings have generated interest in the capacity to modulate chromatin regulators with small-molecule compounds for the treatment of diseases associated with innate or adaptive immunity. © 2014 by Annual Reviews. All rights reserved.

Rocco G.,Italian National Cancer Institute
Journal of Thoracic and Cardiovascular Surgery | Year: 2012

One-port (uniportal) video-assisted thoracic surgery (VATS) consists of approaching an intrathoracic target lesion through a sagittal, craniocaudal plane through 1 single-port incision. The use of articulating instruments inserted parallel to the videothoracoscope enables the surgeon to mimic inside the chest the maneuvers that are usually performed during open surgery. Through this VATS approach, several thoracic conditions can be addressed, including lung cancer in selected patients. Unlike conventional, 3-port VATS, the uniportal VATS technique enables the surgeon to bring the operative fulcrum inside the chest when the target lunge lesion is approached through a sagittal plan, thanks to articulating instruments. Uniportal wedge VATS resections of peripheral nodules can help in solving diagnostic dilemmas, be of therapeutic benefit, and provide tissue for biomolecular studies. Copyright © 2012 by The American Association for Thoracic Surgery.

Rescigno M.,Italian National Cancer Institute
Trends in Immunology | Year: 2011

In the intestine, multiple interactions occur with the external world. Thus, the intestinal mucosal barrier has to tolerate millions of microorganisms that commonly inhabit the gut, degrade and absorb food, and establish tolerance or immunity, depending on the nature of the encountered antigens. Recent findings have highlighted that intestinal epithelial cells are not simply a barrier, but also are crucial for integrating these external and internal signals and for coordinating the ensuing immune response. Here, I review these findings and show how epithelial cells harmonize information that comes from inflammatory and non-inflammatory components of the microbiota to preserve intestinal homeostasis. If dysregulated, this immunomodulatory function of epithelial cells might contribute to the development of intestinal inflammation. © 2011 Elsevier Ltd.

Rescigno M.,Italian National Cancer Institute
Cellular Microbiology | Year: 2014

Summary: The microbiota colonizes every surface exposed to the external world and in the gut, it plays important roles in physiological functions such as the maturation of the immune system, the degradation of complex food macromolecules and also behaviour. As such, the immune system has developed tools to cohabit with the microbiota, but also to keep it under control. When this control is lost, dysbiosis, i.e. deregulation in bacterial communities, can occur and this can lead to inflammatory disorders, including inflammatory bowel disease, obesity, diabetes and autism. For these reasons, the analysis of the microbiota, its interactions with the host and its composition in disease, have been intensively investigated in the last few years. In this review, we summarize the major findings in the interaction of the microbiota with the host immune system. © 2014 John Wiley & Sons Ltd.

Rescigno M.,Italian National Cancer Institute
Immunological Reviews | Year: 2014

Intestinal epithelial cells are fundamental to maintain barrier integrity and to participate in food degradation and absorption, but they can also decipher signals coming from the outside world and 'educate' the immune system accordingly. In particular, they interact with dendritic cells (DCs) and other intraepithelial immune cells to drive tolerogenic responses under steady state, but they can also release immune mediators to recruit inflammatory cells and to elicit immunity to infectious agents. When these interactions are deregulated, immune disorders can develop. In this review, we discuss some important features of epithelial cells and DCs and their fruitful interactions. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Natoli G.,Italian National Cancer Institute
Immunity | Year: 2010

Cell differentiation entails early lineage choices leading to the activation, and the subsequent maintenance, of the gene expression program characteristic of each cell type. Alternative lineage choices involve the activation of different regulatory and coding regions of the genome, a process instructed by lineage-determining transcription factors, and at least in part mediated by the deposition of chromatin marks that modify functionality and accessibility of the underlying genome. According to classic epigenetics, subsequent maintenance of chromatin marks across mitoses and in spite of environmental perturbations occurs largely through autonomous and unsupervised mechanisms. However, paradigmatic genetic and biochemical studies in immune system and hematopoietic cells strongly point to the concept that both induction and maintenance of the differentiated state require constant supervision by lineage-determining transcription factors, which may act to globally organize the genome in both the one- and the three-dimensional space. © 2010 Elsevier Inc.

Rescigno M.,Italian National Cancer Institute
Advances in Immunology | Year: 2010

Dendritic cells (DCs) are specialized antigen-presenting cells that orchestrate innate and adaptive immune responses. The intestinal mucosa contains numerous DCs that are highly specialized in function. Mucosal DCs display a unique response to toll-like receptor ligands, are capable of driving immunoglobulin isotype switching to IgA, can imprint gut-homing receptors on T and B cells, and drive either T regulatory or Th17 cells depending on the analyzed subtype. These functions are partly cell autonomous and partly conferred by the local microenvironment. In this review, we will summarize the different DC subtypes present in the intestine and in the gut-associated lymphoid tissue (GALT), the unique characteristics of these subtypes, and how the local microenvironment can shape DC function. © 2010 Elsevier Inc.

Santoro F.,Italian National Cancer Institute
Blood | Year: 2013

Aberrant recruitment of histone deacetylases (HDACs) by the oncogenic fusion protein PML-RAR is involved in the pathogenesis of acute promyelocytic leukemia (APL). PML-RAR, however, is not sufficient to induce disease in mice but requires additional oncogenic lesions during the preleukemic phase. Here, we show that knock-down of Hdac1 and Hdac2 dramatically accelerates leukemogenesis in transgenic preleukemic mice. These events are not restricted to APL because lymphomagenesis driven by deletion of p53 or, to a lesser extent, by c-myc overexpression, was also accelerated by Hdac1 knock-down. In the preleukemic phase of APL, Hdac1 counteracts the activity of PML-RAR in (1) blocking differentiation; (2) impairing genomic stability; and (3) increasing self-renewal in hematopoietic progenitors, as all of these events are affected by the reduction in Hdac1 levels. This led to an expansion of a subpopulation of PML-RAR-expressing cells that is the major source of leukemic stem cells in the full leukemic stage. Remarkably, short-term treatment of preleukemic mice with an HDAC inhibitor accelerated leukemogenesis. In contrast, knock-down of Hdac1 in APL mice led to enhanced survival duration of the leukemic animals. Thus, Hdac1 has a dual role in tumorigenesis: oncosuppressive in the early stages, and oncogenic in established tumor cells.

Natoli G.,Italian National Cancer Institute
Immunological Reviews | Year: 2012

Release of nuclear factor κΒ (NF-κB) dimers from the inhibitors of NF-κΒ (IκBs) and their subsequent nuclear translocation are only the initial events leading to the induction of NF-κB-regulated genes. Once in the nucleus, NF-κB dimers must gain access to their cognate sites in target genes. While some sites are found in a constitutively accessible state, many others are associated with nucleosomal histones in a manner that prevents NF-κB binding. Binding to such sites requires specific chromatin remodeling events driven by functionally cooperating transcription factors. Ten years of research on the complex interplay between chromatin and NF-κB led to some major successes, most notably the identification of the specific sequence features or trans-acting factors controlling the state of accessibility of κB sites, as well as the dissection of the mechanisms and players involved in the opening of occluded sites. Moreover, attempts at identifying mechanism-based compounds that inhibit the activation of selected subsets of NF-κB-dependent genes acting on chromatin-regulated transitions are starting to give initial promising results in preclinical tests. © 2012 John Wiley & Sons A/S.

Sormani M.P.,University of Genoa | Bruzzi P.,Italian National Cancer Institute
The Lancet Neurology | Year: 2013

Background: A meta-analysis of randomised trials in relapsing-remitting multiple sclerosis published in 2009 showed a quantitative relation between the treatment effects detected on MRI lesions and clinical relapses. We aimed to validate that relation using data from a large and independent set of clinical trials in multiple sclerosis. Methods: We searched Medline for clinical trials that assessed disease-modifying drugs for relapsing-remitting multiple sclerosis published from Sept 1, 2008, to Oct 31, 2012. We extracted data for the treatment effects on MRI lesions and on relapses from each trial, and the correlation of log transformed relative measures of these treatment effects was assessed with a weighted linear regression analysis. The R2 value was estimated to quantify the strength of the correlation, and we used an interaction test to test for a difference in slope from the previously estimated equation. We also ran several sensitivity analyses. Findings: We identified 31 eligible trials, which provided data for 18 901 patients with relapsing-remitting multiple sclerosis. The regression equation derived using data from these studies showed a relation between the concurrent treatment effects on MRI lesions and relapses (slope = 0·52; R2 = 0·71), much the same as was previously estimated (pinteraction = 0·45). Analysis of trials that tested the same drugs in phase 2 and phase 3 studies showed that the effects on MRI lesions over short follow-up periods (6-9 months) can also predict the effects on relapses over longer follow-up periods (12-24 months), with reported effects on relapses that were within the 95% prediction intervals in eight of nine trials. Interpretation: Our findings indicate that the effect of a treatment on relapses can be accurately predicted by the effect of that therapy on MRI lesions, implying that the use of MRI markers as primary endpoints in future clinical trials of treatments for multiple sclerosis can be considered, in specific situations, such as in trials testing generics or biosimilars of drugs with a well known mechanism of action or in paediatric trials testing drugs already approved for adults. Funding: None. © 2013 Elsevier Ltd.

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