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Rozzano, Italy

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

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. Source

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

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. Source

Bonavita O.,Humanitas Clinical and Research Center | Bonavita O.,University of Milan | Massara M.,Humanitas Clinical and Research Center | Massara M.,University of Milan | And 2 more authors.
Cytokine and Growth Factor Reviews

The role of neutrophils in cancer and metastasis is still debated and controversial since they have been shown to be endowed with both pro- and antitumor functions. These contradictory results seem to be now explained by recent discoveries of tumor-associated neutrophils plasticity and multiple neutrophil subsets.Chemokines and chemokine receptors are known to tightly regulate the release of neutrophils from the bone marrow, their passage into circulation and transmigration into the tissues as well as tumor infiltration. It is emerging that chemokine receptors are differentially expressed by neutrophil subsets and they affect not only their recruitment but also their effector functions.Here we are resuming human and murine data suggesting that therapeutic modulation of neutrophil activity through the targeting of specific chemokines or chemokine receptors can improve their anti-tumoral properties. © 2016 Elsevier Ltd. Source

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

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. Source

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

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. Source

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