Analysis and definition of restoration strategies with H-BIM applications. The case study of Vittorio Giorgini's “Casa Esagono” in Baratti, Italy

This contribution is focused on the “Casa Esagono” realized in 1957 by Vittorio Giorgini in Baratti (LI), Italy. The research objective is to lay the foundations for a restoration plan of this experimental wooden architecture, which is now in precarious conditions due to its location near the sea, and whose constructive features, has always raised great questions about the technical feasibility of a full restoration. The paper describes the workflow for the implementation of the H-BIM model, aimed to organise all the data deriving from the historical and on-site research, and the restoration programme. The historical analysis about the house and the architect was the basis for the geometric survey and the analysis of building materials. All building components were subjected to visual analysis aimed to identify deterioration forms. The proposed conservation approach aims to maintain as much of the original elements as possible, while increasing their durability. H-BIM revealed to be the ideal tool to manage the entire restoration process, whose ultimate goal is to celebrate Giorgini’s work, to exploit the potential of the house as a cultural attraction

Severe Reduction in Number and Function of Peripheral T Cells Does Not Afford Protection toward Emphysema and Bronchial Remodeling Induced in Mice by Cigarette Smoke

8openThe protein Lck (p56(Lck)) is a Src family tyrosine kinase expressed at all stages of thymocyte development and is required for maturation of T cells. The targeted disruption of Lck gene in mice results in severe block in thymocyte maturation with substantial reduction in the development of CD4(+)CD8(+) thymocytes, severe reduction of peripheral T cells, and disruption of T-cell receptor signaling with defective function of T-cell responses. To investigate the role of T lymphocyte in the development of cigarette smoke-induced pulmonary changes, Lck(-/-) mice and corresponding congenic wild-type mice were chronically exposed to cigarette smoke, and their lungs were analyzed by biochemical, immunologic, and morphometric methods. Smoking mice from both genotypes showed disseminated foci of emphysema and large areas of goblet cell metaplasia in bronchial and bronchiolar epithelium. Morphometric evaluation of lung changes and lung elastin determination confirmed that mice from both genotypes showed the same degree of emphysematous lesions. Thus, cigarette smoke exposure in the presence of severe reduction in number and function of peripheral T cells does not influence the development of pulmonary changes induced by cigarette smoke. The data obtained suggest that innate immunity is a leading actor in the early development of pulmonary changes in smoking mice and that the adaptive immune response may play a role at later stages.openDe Cunto, Giovanna; Lunghi, Benedetta; Bartalesi, Barbara; Cavarra, Eleonora; Fineschi, Silvia; Ulivieri, Cristina; Lungarella, Giuseppe; Lucattelli, MonicaDE CUNTO, Giovanna; Lunghi, Benedetta; Bartalesi, Barbara; Cavarra, Eleonora; Fineschi, Silvia; Ulivieri, Cristina; Lungarella, Giuseppe; Lucattelli, Monic

Ligation of human Fc receptor like-2 (FCRL2) by monoclonal antibodies downregulates B cell receptor mediated signaling

B cell antigen receptor (BCR) signaling and its regulation through negative and positive regulators are critical for balancing B cell response and function. Human Fc receptor like-2 (FCRL2), a member of the newly identified FCRL family, could influence B cell signaling due to possession of both immunoreceptor tyrosine-based activation and inhibitory motifs (ITAM and ITIM). Since the natural ligand of FCRL2 has not been identified yet, we generated FCRL2-specific monoclonal antibodies (mAbs) and employed them to investigate the influence of FCRL2 stimulation on BCR signaling in a FCRL2-expressing B cell line. Two anti-FCRL2 mAb-producing hybridoma clones (5A7-E7 and 3D8-G8) were selected. None of the mAbs displayed any cross-reactivity with the other members of the FCRL family including recombinant FCRL1, 3, 4 and 5, as tested by FACS and ELISA techniques. Engagement of the FCRL2 by these mAbs resulted in significant inhibition of BCR signaling mediators such as calcium mobilization and phosphorylation of the MAP kinases Erk, p38 and Jnk MAP. These findings indicate that the FCRL2 ITIM motifs are functional and the anti-FCRL2 mAbs may mimic the natural ligand of FCRL2 by induction of inhibitory signals in B cells.Food and Drug Administration of the Ministry of Health, Treatment and Medical Education of Iran (grant number S87P/3/414). MS was also supported by EFIS-IL fellowship grant.Accepte

p66Shc deficiency in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape

The Shc family adaptor p66Shc acts as a negative regulator of proliferative and survival signals triggered by the B Cell Receptor and, by enhancing the production of reactive oxygen species, promotes oxidative stress-dependent apoptosis. Additionally, p66Shc controls the expression and function of chemokine receptors that regulate lymphocyte traffic. Chronic lymphocytic leukemia cells have a p66Shc expression defect which contributes to their extended survival and correlates with poor prognosis. We have analyzed the impact of p66Shc ablation on disease severity and progression in the mouse model of chronic lymphocytic leukemia Eμ-TCL1. We show that Eμ-TCL1/p66Shc-/- mice develop an aggressive disease that has an earlier onset, a higher incidence and leads to earlier death compared to Eμ-TCL1 mice. Eμ-TCL1/p66Shc-/- mice display substantial leukemic cell accumulation in both nodal and extranodal sites. The target organ selectivity correlates with an upregulation of chemokine receptors whose ligands are expressed therein. This also applies to chronic lymphocytic leukemia cells, where chemokine receptor expression and extent of organ infiltration were found to inversely correlate with their p66Shc expression levels. p66Shc expression declined with disease progression in Eμ-TCL1 mice and could be restored by treatment with the Bruton tyrosine kinase inhibitor Ibrutinib. Our results highlight p66Shc deficiency as an important factor in chronic lymphocytic leukemia progression and severity and underscore p66Shc expression as a relevant therapeutic target

Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents

Microtubule-targeting agents (MTAs) are a class of clinically successful anti-cancer drugs. The emergence of multidrug resistance to MTAs imposes the need for developing new MTAs endowed with diverse mechanistic properties. Benzoxazepines were recently identified as a novel class of MTAs. These anticancer agents were thoroughly characterized for their antitumor activity, although, their exact mechanism of action remained elusive. Combining chemical, biochemical, cellular, bioinformatics and structural efforts we developed improved pyrrolonaphthoxazepines antitumor agents and their mode of action at the molecular level was elucidated. Compound 6j, one of the most potent analogues, was confirmed by X-ray as a colchicine-site MTA. A comprehensive structural investigation was performed for a complete elucidation of the structure-activity relationships. Selected pyrrolonaphthoxazepines were evaluated for their effects on cell cycle, apoptosis and differentiation in a variety of cancer cells, including multidrug resistant cell lines. Our results define compound 6j as a potentially useful optimized hit for the development of effective compounds for treating drug-resistant tumors.This work was supported in part by a grant from the Swiss National Science Foundation (31003A_166608; to M.O.S), grant BFU2016-75319-R (AEI/FEDER, EU) from Ministerio de Economia y Competitividad, Blueprint 282510, AIRC-17217. The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature - from natural products chemistry to drug discovery” (to M.O.S. and J.F.D.) and the COST Action EPICHEMBIO CM-1406 (to L.A. and G.C.). This work has also received partial funding from the European Union’s Horizon 2020 (EU) research and innovation programme under the Marie Sklodowska-Curie grant agreement No 721906. Finally, this work was partially funded by MIUR-PRIN project n. 2015Y3C5KP (to L.M.)

Systemic inflammatory status predict the outcome of k-RAS WT metastatic colorectal cancer patients receiving the thymidylate synthase poly-epitope-peptide anticancer vaccine

TSPP is an anticancer poly-epitope peptide vaccine to thymidylate synthase, recently investigated in the multi-arm phase Ib TSPP/VAC1 trial. TSPP vaccination induced immune-biological effects and showed antitumor activity in metastatic colorectal cancer (mCRC) patients and other malignancies. Progression-free and overall survival of 41 mCRC patients enrolled in the study correlated with baseline levels of CEA, immune-inflammatory markers (neutrophil/lymphocyte ratio, CRP, ESR, LDH, ENA), IL-4 and with post-treatment change in p-ANCA and CD56dimCD16brightNKs (p < 0.04). A subset of 19 patients with activating k-ras mutations showed a different immune-inflammatory response to TSPP as compared to patients with k-ras/wt and a worse outcome in term of PFS (p = 0.048). In patients with k-ras/mut, inflammatory markers lost their predictive value and their survival directly correlated with the baseline levels of IL17/A over the median value (p = 0.01). These results provide strong hints for the design of further clinical trials aimed to test TSPP vaccination in mCRC patients

Fifth European Dirofilaria and Angiostrongylus Days (FiEDAD) 2016

Peer reviewe

The BCR signalosome: where cell fate is decided

B cell antigen receptor (BCR) engagement results in the assembly of a multimolecular complex at the cytosolic side of the plasma membrane, known as signalosome. Here we briefly review the current knowledge on the molecules which participate in the BCR signalosome and on the response modulators which control the final signal output by enhancing or dampening BCR signaling

The potential of peroxisome proliferator-activated receptor gamma (PPARgamma) ligands in the treatment of hematological malignancies

PPAR␣ has emerged as a key regulator of cell growth and survival, whose activity is modulated by a number of synthetic and natural ligands. Here we shall review the activities of PPAR␣ ligands in the control of immune cell prolifera- tion, differentiation and apoptosis and their potential therapeutic applications to hematological malignancies

Statins: From cholesterol-lowering drugs to novel immunomodulators for the treatment of Th17-mediated autoimmune diseases

Statins, a class of drugs that act as inhibitors of cholesterol biosynthesis and protein isoprenylation, have been proposed as immunomodulatory agents due to their potent effects both on T lymphocytes and on antigen presenting cells. Unfortunately to date the benefits of statin therapy have not been unequivocally established due to contrasting results obtained in the setting of several autoimmune diseases. A major hurdle is our limited mechanistic understanding of the pleiotropic mechanisms underlying statin-mediated immunomodulation. Accumulating evidence has highlighted two CD4+ T cell subsets, the Th17 and Treg cells, as important disease-related targets of statins. Here we shall review recent findings on the activity of statins on Th17 and Treg differentiation and effector function. Statin-based therapies of multiple sclerosis, a Th17 cell-mediated autoimmune disease, and of Systemic Lupus Erithematosus, characterized by a Th17/Treg imbalance, will be also discussed, based on animal models and clinical trials