Humanitas University

Rozzano, Italy

Humanitas University

Rozzano, Italy
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Ferrante G.,Humanitas Clinical and Research Center | Condorelli G.,Humanitas Clinical and Research Center | Condorelli G.,Humanitas University | Pagnotta P.,Humanitas Clinical and Research Center | Reimers B.,Humanitas Clinical and Research Center
Circulation: Cardiovascular Interventions | Year: 2017

Background - The benefits and harms of dual antiplatelet therapy (DAPT) continuation beyond 1 year after drug-eluting stent implantation as compared with 1-year DAPT remain controversial. Methods and Results - We searched for randomized trials that compared longer than 1-year DAPT versus 1-year DAPT after drug-eluting stenting. A meta-analysis was performed by using standard frequentist and random-effects Bayesian approaches. Four trials comprising 17 650 participants were included. Compared with 1-year DAPT, extended DAPT did not affect all-cause mortality (odds ratio [OR], 1.11; 95% confidence interval [CI], 0.79-1.5; P=0.53) or cardiovascular mortality (OR, 1.03; 95% CI, 0.72-1.46; P=0.88). Extended DAPT was associated with a reduction in the risk of myocardial infarction (OR, 0.56; 95% CI, 0.43-0.73; P<0.001), nonsignificant reductions of stent thrombosis (OR, 0.46; 95% CI, 0.16-1.27; P=0.13), similar risk of stroke (OR, 0.91; 95% CI, 0.65-1.26; P=0.56), and an increased risk of major bleeding (OR, 1.49; 95% CI, 1.06-2.11; P=0.02). By using Bayesian meta-analysis, we found moderate evidence of a reduction of myocardial infarction (OR, 0.62; 95% credible intervals, 0.39-1.05) and weak evidence of an increase in major bleeding (OR, 1.66; 95% credible intervals, 0.89-3.09) associated with extended DAPT. Conclusions - In this meta-analysis, extended DAPT beyond 1 year prevented myocardial infarctions and increased major bleedings, but the strength of evidence for these effects was not strong. DAPT continuation beyond 1 year showed no effects on mortality. © 2017 American Heart Association, Inc.


Grant
Agency: European Commission | Branch: H2020 | Program: IA | Phase: ICT-28-2015 | Award Amount: 4.60M | Year: 2016

Multispectral Optoacoustic Tomography (MSOT) brings a revolution to bio-optical imaging. Being insensitive to photon scattering, MSOT dramatically improves upon conventional bio-optic barriers by enabling (1) three-dimensional high-resolution optical imaging deep inside tissues (several millimetres to centimetres), by (2) high-scalability, ranging from optical-resolution microscopy to acoustic-resolution optical mesoscopy and macroscopy and by (3) novel label-free anatomical, physiological and molecular contrast at the tissue and single-cell-level, based on spectrally-resolved optical absorption. MSOT, originally supported by an ERC Advanced Award (2008) (TUM: Prof. Ntziachristos), is already commercialized by iThera Medical for macroscopy with systems sold around the world for small animal imaging. In parallel, ERC MSOT funding developed a mesoscopic implementation, termed raster-scan optoacoustic mesoscopy (RSOM), which has demonstrated innovative imaging capacity at 1-5mm depths. Driven by leading dermatologists (TUM: Prof. Biedermann; SUR: Prof. Costanzo) and market leader SMEs in optoacoustic and ultrasound technology (iThera, Rayfos, Sonaxis), INNODERM will design and prototype a handheld, portable, scalable, label-free RSOM device for point-of care dermatology applications, based on recommendations developed under an ERC proof of concept grant (2013) on MSOT. INNODERM brings together key photonic & ultrasound technologies and will validate the technical and economic viability of RSOM in dermatology suites for fast diagnosis and skin disease monitoring. RSOM can go beyond the abilities of current optical or optoacoustic devices and offer a paradigm shift in dermatology imaging, substantiating successful business cases.


Grant
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: SC1-PM-01-2016 | Award Amount: 16.02M | Year: 2017

The SYSCID consortium aims to develop a systems medicine approach for disease prediction in CID. We will focus on three major CID indications with distinct characteristics, yet a large overlap of their molecular risk map: inflammatory bowel disease, systemic lupus erythematodes and rheumatoid arthritis. We have joined 15 partners from major cohorts and initiatives in Europe (e.g.IHEC, ICGC, TwinsUK and Meta-HIT) to investigate human data sets on three major levels of resolution: whole blood signatures, signatures from purified immune cell types (with a focus on CD14 and CD4/CD8) and selected single cell level analyses. Principle data layers will comprise SNP variome, methylome, transcriptome and gut microbiome. SYSCID employs a dedicated data management infrastructure, strong algorithmic development groups (including an SME for exploitation of innovative software tools for data deconvolution) and will validate results in independent retrospective and prospective clinical cohorts. Using this setup we will focus on three fundamental aims : (i) the identification of shared and unique core disease signatures which are associated with the disease state and independent of temporal variation, (ii) the generation of predictive models of disease outcome- builds on previous work that pathways/biomarkers for disease outcome are distinct from initial disease risk and may be shared across diseases to guide therapy decisions on an individual patient basis, (iii) reprogramming disease - will identify and target temporally stable epigenetic alterations in macrophages and lymphocytes in epigenome editing approaches as biological validation and potential novel therapeutic tool. Thus, SYSCID will foster the development of solid biomarkers and models as stratification in future long-term systems medicine clinical trials but also investigate new causative therapies by editing the epigenome code in specific immune cells, e.g. to alleviate macrophage polarization defects.


Daigo K.,Humanitas Clinical and Research Center | Inforzato A.,Humanitas Clinical and Research Center | Inforzato A.,University of Milan | Barajon I.,Humanitas University | And 5 more authors.
Immunological Reviews | Year: 2016

Humoral fluid phase pattern recognition molecules (PRMs) are a key component of the activation and regulation of innate immunity. Humoral PRMs are diverse. We focused on the long pentraxin PTX3 as a paradigmatic example of fluid phase PRMs. PTX3 acts as a functional ancestor of antibodies and plays a non-redundant role in resistance against selected microbes in mouse and man and in the regulation of inflammation. This molecule interacts with complement components, thus modulating complement activation. In particular, PTX3 regulates complement-driven macrophage-mediated tumor progression, acting as an extrinsic oncosuppressor in preclinical models and selected human tumors. Evidence collected over the years suggests that PTX3 is a biomarker and potential therapeutic agent in humans, and pave the way to translation of this molecule into the clinic. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd


Vigano L.,Humanitas University | Capussotti L.,Ospedale Mauriziano Umberto i | Majno P.,University of Geneva | Toso C.,University of Geneva | And 4 more authors.
British Journal of Surgery | Year: 2015

Background Patients with large numbers of colorectal liver metastases (CRLMs) are potential candidates for resection, but the benefit from surgery is unclear. Justified in selected patientsMethods Patients undergoing resection for CRLMs between 1998 and 2012 in two high-volume liver surgery centres were categorized according to the number of CRLMs: between one and seven (group 1) and eight or more (group 2). Overall (OS) and recurrence-free (RFS) survival were compared between the groups. Multivariable analysis was performed to identify adverse prognostic factors.Results A total of 849 patients were analysed: 743 in group 1 and 106 in group 2. The perioperative mortality rate (90 days) was 0·4 per cent (all group 1). Median follow-up was 37·4 months. Group 1 had higher 5-year OS (44·2 versus 20·1 per cent; P < 0·001) and RFS (28·7 versus 13·6 per cent; P < 0·001) rates. OS and RFS in group 2 were similar for patients with eight to ten, 11-15 or more than 15 metastases (48, 40 and 18 patients respectively). In group 2, multivariable analysis identified three preoperative adverse prognostic factors: extrahepatic disease (P = 0·010), no response to chemotherapy (P = 0·023) and primary rectal cancer (P = 0·039). Patients with two or more risk factors had very poor outcomes (median OS and RFS 16·9 and 2·5 months; 5-year OS zero); patients in group 2 with no risk factors had similar survival to those in group 1 (5-year OS rate 44 versus 44·2 per cent).Conclusion Liver resection is safe in selected patients with eight or more metastases, and offers reasonable 5-year survival independent of the number of metastases. However, eight or more metastases combined with at least two adverse prognostic factors is associated with very poor survival, and surgery may not be beneficial. No numerical limit © 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd. © 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.


Garlanda C.,Humanitas Clinical Research Center | Jaillon S.,Humanitas Clinical Research Center | Doni A.,Humanitas Clinical Research Center | Bottazzi B.,Humanitas Clinical Research Center | And 2 more authors.
Current Opinion in Immunology | Year: 2016

Innate immunity consists of a cellular and a humoral arm. PTX3 is a fluid patter recognition molecule (PRM) with antibody-like properties. Gene targeted mice and genetic associations in humans suggest that PTX3 plays a non-redundant role in resistance against selected pathogens ( e.g. Aspergillus fumigatus, Pseudomonas aeruginosa, uropathogenic Escherichia coli) and in the regulation of inflammation. PTX3 acts as an extrinsic oncosuppressor by taming complement elicited tumor-promoting inflammation. Recent results indicate that, by interacting with provisional matrix components, PTX3 contributes to the orchestration of tissue repair. An acidic pH sets PTX3 in a tissue repair mode, while retaining anti-microbial recognition. Based on these data and scattered information on humoral PRM and matrix components, we surmise that matrix and microbial recognition are related functions in evolution. © 2015 Elsevier Ltd.


Nold-Petry C.A.,MIMR PHI Institute of Medical Research | Nold-Petry C.A.,Monash University | Lo C.Y.,MIMR PHI Institute of Medical Research | Lo C.Y.,Monash University | And 28 more authors.
Nature Immunology | Year: 2015

Interleukin 37 (IL-37) and IL-1R8 (SIGIRR or TIR8) are anti-inflammatory orphan members of the IL-1 ligand family and IL-1 receptor family, respectively. Here we demonstrate formation and function of the endogenous ligand-receptor complex IL-37-IL-1R8-IL-18Rα. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Rα impaired the anti-inflammatory activity of IL-37. Whereas mice with transgenic expression of IL-37 (IL-37tg mice) with intact IL-1R8 were protected from endotoxemia, IL-1R8-deficient IL-37tg mice were not. Proteomic and transcriptomic investigations revealed that IL-37 used IL-1R8 to harness the anti-inflammatory properties of the signaling molecules Mer, PTEN, STAT3 and p62(dok) and to inhibit the kinases Fyn and TAK1 and the transcription factor NF-κB, as well as mitogen-activated protein kinases. Furthermore, IL-37-IL-1R8 exerted a pseudo-starvational effect on the metabolic checkpoint kinase mTOR. IL-37 thus bound to IL-18Rα and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program. © 2015 Nature America, Inc. All rights reserved.


Isailovic N.,Humanitas Research Hospital | Daigo K.,IRCCS Humanitas Research Hospital | Mantovani A.,IRCCS Humanitas Research Hospital | Mantovani A.,Humanitas University | And 2 more authors.
Journal of Autoimmunity | Year: 2015

Interleukin 17 (IL-17) includes several cytokines among which IL-17A is considered as one of the major pro-inflammatory cytokine being central to the innate and adaptive immune responses. IL-17 is produced by unconventional T cells, members of innate lymphoid cells (ILCs), mast cells, as well as typical innate immune cells, such as neutrophils and macrophages located in the epithelial barriers and characterised by a rapid response to infectious agents by recruiting neutrophils as first line of defence and inducing the production of antimicrobial peptides. Th17 responses appear pivotal in chronic and acute infections by bacteria, parasites, and fungi, as well as in autoimmune and chronic inflammatory diseases, including rheumatoid arthritis, psoriasis, and psoriatic arthritis. The data discussed in this review cumulatively indicate that innate-derived IL-17 constitutes a major element in the altered immune response against self antigens or the perpetuation of inflammation, particularly at mucosal sites. New drugs targeting the IL17 pathway include brodalumab, ixekizumab, and secukinumab and their use in psoriatic disease is expected to dramatically impact our approach to this systemic condition. © 2015 Elsevier Ltd.


Bonecchi R.,Humanitas Clinical and Research Center | Bonecchi R.,Humanitas University | Graham G.J.,University of Glasgow
Frontiers in Immunology | Year: 2016

Chemokines and their receptors are key mediators of the inflammatory process regulating leukocyte extravasation and directional migrationinto inflamed and infected tissues. The control of chemokine availability within inflamed tissues is necessary to attain a resolving environment and when this fails chronic inflammation ensues. Accordingly, vertebrates have adopted a number of mechanisms for removing chemokines from inflamed sites to help precipitate resolution. Over the past 15 years, it has become apparent that essential players in this process are the members of the atypical chemokine receptor (ACKR) family. Broadly speaking, this family is expressed on stromal cell types and scavenges chemokines toeither limit their spatial availability or to remove them from in vivo sites. Here, we provide a brief review of these ACKRs and discusstheir involvement in the resolution of inflammatory responses and the therapeutic implications of our current knowledge. © 2016 Bonecchi and Graham.


Grant
Agency: European Commission | Branch: H2020 | Program: ERC-ADG | Phase: ERC-ADG-2015 | Award Amount: 2.50M | Year: 2016

Tissue responses to microbial and endogenous danger signals involve the activation of both resident and monocyte-derived macrophages, as well as the coordinated inducible expression of hundreds of inflammatory genes. Gene transcription is controlled by the information contained in thousands of genomic regulatory elements (enhancers and promoters), which is first read by transcription factors (TFs) and then integrated and relayed to the transcriptional machinery via an array of co-regulators with disparate biochemical activities and functions. The recent work of several groups, including our own, has extensively characterized how in macrophages the genomic regulatory sequences controlling inflammatory gene expression are coordinately bound and activated by myeloid lineage-determining TFs and broadly expressed stimulus-activated TFs. However, we still have a very incomplete understanding of the necessary next step in the process, namely how distinct combinations of DNA-bound TFs regulate recruitment and function of the co-regulators and machineries that control gene transcription. Here, I propose to systematically identify the complement of co-regulators that control the induction of inflammatory genes in macrophages, which will be then mechanistically and functionally characterized both in vitro and in vivo. By integrating cutting edge genomic and computational approaches with focused genetic screens and biochemical analyses, and eventually validating relevant results in mouse models, this project aims at obtaining an unprecedented level of understanding of the information flow linking genomic regulatory elements to inflammatory gene transcription.

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