Current Advances in γδ T Cell-Based Tumor Immunotherapy

γδ T cells are a minor population (~5%) of CD3 T cells in the peripheral blood, but abound in other anatomic sites such as the intestine or the skin. There are two major subsets of γδ T cells: those that express Vd1 gene, paired with different Vγ elements, abound in the intestine and the skin, and recognize the major histocompatibility complex (MHC) class I-related molecules such as MHC class I-related molecule A, MHC class I-related molecule B, and UL16-binding protein expressed on many stressed and tumor cells. Conversely, γδ T cells expressing the Vδ2 gene paired with the Vγ9 chain are the predominant (50-90%) γδ T cell population in the peripheral blood and recognize phosphoantigens (PAgs) derived from the mevalonate pathway of mammalian cells, which is highly active upon infection or tumor transformation. Aminobisphosphonates (n-BPs), which inhibit farnesyl pyrophosphate synthase, a downstream enzyme of the mevalonate pathway, cause accumulation of upstream PAgs and therefore promote γδ T cell activation. γδ T cells have distinctive features that justify their utilization in antitumor immunotherapy: they do not require MHC restriction and are less dependent that aà T cells on co-stimulatory signals, produce cytokines with known antitumor effects as interferon-? and tumor necrosis factor-a and display cytotoxic and antitumor activities in vitro and in mouse models in vivo. Thus, there is interest in the potential application of γδ T cells in tumor immunotherapy, and several small-sized clinical trials have been conducted of γδ T cell-based immunotherapy in different types of cancer after the application of PAgs or n-BPs plus interleukin-2 in vivo or after adoptive transfer of ex vivo-expanded γδ T cells, particularly the Vγ9Vδ2 subset. Results from clinical trials testing the efficacy of any of these two strategies have shown that γδ T cell-based therapy is safe, but long-term clinical results to date are inconsistent. In this review, we will discuss the major achievements and pitfalls of the γδ T cell-based immunotherapy of cancer

Current Advances in γδ T Cell-Based Tumor Immunotherapy

γδ T cells are a minor population (~5%) of CD3 T cells in the peripheral blood, but abound in other anatomic sites such as the intestine or the skin. There are two major subsets of γδ T cells: those that express Vδ1 gene, paired with different Vγ elements, abound in the intestine and the skin, and recognize the major histocompatibility complex (MHC) class I-related molecules such as MHC class I-related molecule A, MHC class I-related molecule B, and UL16-binding protein expressed on many stressed and tumor cells. Conversely, γδ T cells expressing the Vδ2 gene paired with the Vγ9 chain are the predominant (50–90%) γδ T cell population in the peripheral blood and recognize phosphoantigens (PAgs) derived from the mevalonate pathway of mammalian cells, which is highly active upon infection or tumor transformation. Aminobisphosphonates (n-BPs), which inhibit farnesyl pyrophosphate synthase, a downstream enzyme of the mevalonate pathway, cause accumulation of upstream PAgs and therefore promote γδ T cell activation. γδ T cells have distinctive features that justify their utilization in antitumor immunotherapy: they do not require MHC restriction and are less dependent that αβ T cells on co-stimulatory signals, produce cytokines with known antitumor effects as interferon-γ and tumor necrosis factor-α and display cytotoxic and antitumor activities in vitro and in mouse models in vivo. Thus, there is interest in the potential application of γδ T cells in tumor immunotherapy, and several small-sized clinical trials have been conducted of γδ T cell-based immunotherapy in different types of cancer after the application of PAgs or n-BPs plus interleukin-2 in vivo or after adoptive transfer of ex vivo-expanded γδ T cells, particularly the Vγ9Vδ2 subset. Results from clinical trials testing the efficacy of any of these two strategies have shown that γδ T cell-based therapy is safe, but long-term clinical results to date are inconsistent. In this review, we will discuss the major achievements and pitfalls of the γδ T cell-based immunotherapy of cancer

Simple homogenized plate model for out-of-plane loaded masonry taking into account material and geometrical non linearity

The buckling behavior of slender unreinforced masonry (URM) walls subjected to axial compression and out-of-plane lateral loads is investigated through a simplified “homogenized” procedure. After a preliminary analysis performed on a unit cell meshed by means of elastic FEs and non-linear interfaces, macroscopic moment-curvature diagrams so obtained are implemented at a structural level, discretizing masonry by means of rigid triangular elements and non-linear interfaces. The non-linear incremental response of the structure is accounted for a specific quadratic programming routine where second order effects are suitably considered adding a further term, quadratic in the nodal displacement, within the total energy of the discretized system. As validation of the approach proposed, the buckling behavior of some existing experimental pre-compressed four-point bending tests is reproduced; furthermore square panels in two-way bending, exhibiting the classical Rondelet’s mechanisms, are also studied. The results obtained are compared with those provided by commercial FE programs and with specifically derived analytical results

γδ T Cells and Tumor Microenvironment: From Immunosurveillance to Tumor Evasion

γδ T cells possess cytotoxic antitumor activity mediated by production of proinflammatory cytokines, direct cytotoxic activity, and regulation of the biological functions of other cell types. Hence, these features have prompted the development of therapeutic strategies in which γδ T cells agonists or ex vivo-expanded γδ T cells are administered to tumor patients. Several studies have shown that γδ T cells are an important component of tumor-infiltrating lymphocytes in patients affected by different types of cancer and a recent analysis of ~18,000 transcriptomes from 39 human tumors identified tumor-infiltrating γδ T cells as the most significant favorable cancer-wide prognostic signature. However, the complex and intricate interactions between tumor cells, tumor microenvironment (TME), and tumor-infiltrating immune cells results in a balance between tumor-promoting and tumor-controlling effects, and γδ T cells functions are often diverted or impaired by immunosuppressive signals originating from the TME. This review focuses on the dangerous liason between γδ T cells and tumoral microenvironment and raises the possibility that strategies capable to reduce the immunosuppressive environment and increase the cytotoxic ability of γδ T cells may be the key factor to improve their utilization in tumor immunotherapy

Seismic Behavior of the San Pietro di Coppito Church Bell Tower in L'Aquila, Italy

In the present paper, a non-linear numerical study on the 13th century masonry bell tower of the church of San Pietro di Coppito is described. The aim is to have an insight into the causes at the base of the partial collapse suffered by the structure during the L'Aquila earthquake in 2009. To this aim, two different numerical analyses have been performed namely non-linear static (pushover) and limit analysis. In both cases, the same full 3D detailed FE model of the structure is adopted, changing the seismic load direction and assuming different distributions of the equivalent static horizontal load. When dealing with the FEM incremental analysis, a commercial code is utilized assuming for masonry a smeared crack isotropic model. For limit analysis, a non-commercial full 3D code developed by the authors is utilized. It provides limit good estimates of limit loads and failure mechanisms, to compare with standard FEM results. From numerical re-sults, the role played by the actual geometry and by the masonry mechanical characteristics of the tower is envisaged, as well as a detailed comparison of failure mechanisms provided by the incremental FEM and limit analysis is provided. In all cases, the numerical analysis has given a valuable picture of damage mechanisms which can be compared with actual damage patterns so providing useful hints for the introduction of structural monitoring

Single-cell RNA sequencing unveils the shared and the distinct cytotoxic hallmarks of human TCRVδ1 and TCRVδ2 γδ T lymphocytes

gamma delta T lymphocytes represent similar to 1% of human peripheral blood mononuclear cells and even more cells in most tissues of vertebrates. Although they have important anticancer functions, most current single-cell RNA sequencing (scRNA-seq) studies do not identify gamma delta T lymphocytes because their transcriptomes at the single-cell level are unknown. Here we show that high-resolution clustering of large scRNA-seq datasets and a combination of gene signatures allow the specific detection of human gamma delta T lymphocytes and identification of their T cell receptor (TCR)V delta 1 and TCRV delta 2 subsets in large datasets from complex cell mixtures. In t-distributed stochastic neighbor embedding plots from blood and tumor samples, the few gamma delta T lymphocytes appear collectively embedded between cytotoxic CD8 T and NK cells. Their TCRV delta 1 and TCRV delta 2 subsets form close yet distinct subclusters, respectively neighboring NK and CD8 T cells because of expression of shared and distinct cytotoxic maturation genes. Similar pseudotime maturation trajectories of TCRV delta 1 and TCRV delta 2 gamma delta T lymphocytes were discovered, unveiling in both subsets an unattended pool of terminally differentiated effector memory cells with preserved proliferative capacity, a finding confirmed by in vitro proliferation assays. Overall, the single-cell transcriptomes of thousands of individual gamma delta T lymphocytes from different CMV+ and CMV- donors reflect cytotoxic maturation stages driven by the immunological history of donors. This landmark study establishes the rationale for identification, subtyping, and deep characterization of human gamma delta T lymphocytes in further scRNA-seq studies of complex tissues in physiological and disease conditions

Cardiac rehabilitation in very old patients: data from the Italian Survey onCardiac Rehabilitation-2008 (ISYDE-2008)--official report of the ItalianAssociation for Cardiovascular Prevention, Rehabilitation, and Epidemiology

BACKGROUND: Using data from the Italian SurveY on carDiac rEhabilitation-2008 (ISYDE-2008), this study provides insight into the level of implementation of cardiac rehabilitation (CR) in very old cardiac patients. METHODS: Data from 165 CR units were collected online from January 28 to February 10, 2008. RESULTS: The study cohort consisted of 2,281 patients (66.9 ± 11.8 years): 1,714 (62.4 ± 9.6 years, 78% male) aged<75 years and 567 aged ≥ 75 years (80.8 ± 4.5 years, 59% male). Compared with adults, a higher percentage of older patients were referred to CR programs after cardiac surgery or acute heart failure and showed more acute phase complications and comorbidity. Older patients were less likely discharged to home, more likely transferred to nursing homes, or discharged with social networks activation. Older patients had higher death rate during CR programs (odds ratio = 4.6; 95% confidence interval = 1.6-12.9; p = .004). CONCLUSION: The ISYDE-2008 survey provided a detailed snapshot of CR in very old cardiac patients