Analysis of T and NK cell subsets in Sicilian population from young to supercentenarian: the role of age and gender

Ageing dramatically affects number and function of both innate and adaptive arms of immune system, particularly T cell subsets, contributing to reduced vaccination efficacy, decreased resistance to infections and increased prevalence of cancer in the older people. In the present paper, we analysed the age-related changes in the absolute number of lymphocytes in 214 Sicilian subjects, and in the percentages of T and NK cells in a sub-cohort of donors. We compared these results with the immunophenotype of the oldest living Italian supercentenarian (111 years old). The results were also sorted by gender. The correlation between number/percentage of cells and age in all individuals and, separately, in males and females, was examined using a simple linear regression analysis. We did not record the increase in the rate of inversion of the CD4/CD8 ratio frequently reported as associated with ageing in literature. Our observation was the direct consequence of a flat average trend of CD4+ and CD8+ T cell percentages in ageing donors, even when gender differences were included. Our results also suggest that CD4+ and CD8+ subsets are not affected equally by age comparing females with males, and we speculated that gender may affect the response to CMV infection. The supercentenarian showed a unique immunophenotypic signature as regards the relative percentages of her T cell subsets, with CD4+ and CD8+ T cell percentages and CD4+ na\uefve T cell values in line with those recorded for the octogenarian subjects. This suggests that the supercentenarian has a na\uefve "younger" T cell profile comparable to that of a >80 year old female

A Phase 1 trial of human telomerase reverse transcriptase (hTERT) vaccination combined with therapeutic strategies to control immune-suppressor mechanisms

The presence of inhibitory immune cells and difficulty in generating activated effector T-cells remain obstacles to development of effective cancer vaccines. We designed a vaccine regimen combining human telomerase reverse transcriptase (hTERT) peptides with concomitant therapies targeting regulatory T-cells (Tregs) and cyclooxygenase-2 (COX2)-mediated immunosuppression. This Phase 1 trial combined an hTERT-derived 7-peptide library, selected to ensure presentation by both HLA class-I and class-II in 90% of patients, with oral low-dose cyclophosphamide (to modulate Tregs) and the COX2 inhibitor celecoxib. Adjuvants were Montanide and topical TLR-7 agonist, to optimise antigen presentation. The primary objective was determination of the safety and tolerability of this combination therapy, with anti-cancer activity, immune response and detection of antigen-specific T-cells as additional endpoints. Twenty-nine patients with advanced solid tumours were treated. All were multiply-pretreated, and the majority had either colorectal or prostate cancer. The most common adverse events were injection-site reactions, fatigue and nausea. Median progression-free survival was 9 weeks, with no complete or partial responses, but 24% remained progression-free for ≥6 months. Immunophenotyping showed post-vaccination expansion of CD4+ and CD8+ T-cells with effector phenotypes. The in vitro re-challenge of T-cells with hTERT peptides, TCR sequencing, and TCR similarity index analysis demonstrated the expansion following vaccination of oligoclonal T-cells with specificity for hTERT. However, a population of exhausted PD-1 + cytotoxic T-cells was also expanded in vaccinated patients. This vaccine combination regimen was safe and associated with antigen-specific immunological responses. Clinical activity could be improved in future by combination with anti-PD1 checkpoint inhibition to address the emergence of an exhausted T-cell population

A simplified method for collapse capacity assessment of moment-resisting frame and shear wall structural systems

A simplified methodology for predicting the median and dispersion of collapse capacity of moment-resisting frame and shear wall structural systems subjected to seismic excitations is proposed. The method is based on nonlinear static (pushover) analysis. Simple mathematical models denoted as "generic structures" are utilized to model moment-resisting frames and shear walls. After examining a wide range of structural parameters of the generic structures, a comprehensive database of collapse fragilities and pushover curves (using ASCE 7-05 lateral load pattern) are generated. Based on the obtained pushover curves, closed-form equations for estimation of median and dispersion of building collapse fragility curves are developed using multivariate regression analysis. Comparing the estimates of the median collapse capacity calculated from the closed-form equations with the actual collapse capacities determined from nonlinear response-history analysis indicates that the simplified methodology is reliable. The effectiveness of this methodology for predicting the median collapse capacity of frame and wall structures is further demonstrated with two case studies of structural systems designed based on current seismic provisions. © 2010 Elsevier Ltd

Probabilistic analytical benchmarking of source-based and site-based ground motion simulation models

Scarcity of the recorded ground motions and their unavailability to meet specified design scenarios have led to an increased use of the simulated ground motions in performance-based earthquake engineering. This paper offers a benchmark study aimed at validating various ground motion simulation models for engineering practice. The ground motion simulation models used in this study cover both sitebased and source-based techniques aimed to benchmark their performance using response of single- and multi- degree-of-freedom (SDOF and MDOF) systems to seismic excitation. Source-based ground motion simulation predicts time series using models that explicitly incorporate the physics of the earthquake source and the resulting propagation of seismic wavesSouthern California Earthquake Center (SCEC) broadband simulations used in this study represent source-based ground motion simulation technique. Site-based ground motion simulation techniques, on the other hand, use statistical approaches without necessarily solving the mathematical notions that describe the physics of source dynamics and wave propagation to generate ground motion time series. Ground motions simulated from three historic events (Northridge, Loma Prieta, and Landers) are used and applied to a set of SDOF (non-deteriorating), and MDOF (Box-Girder Seat-type bridge) models and their responses are compared with what is observed using recorded ground motions. Evaluation of the efficiency and sufficiency of the synthetic ground motions show that they are in general a good representation of recorded ground motions. Ground motions obtained via the source-based simulation approach provide a more accurate estimation of RotD50 spectral acceleration (S_a) while site-based simulations provide a better representation of Arias Intensities (I_0). Issues related to variability in response of structures using recorded and simulated ground motion sets are presented

Probabilistic analytical benchmarking of source-based and site-based ground motion simulation models

Scarcity of the recorded ground motions and their unavailability to meet specified design scenarios have led to an increased use of the simulated ground motions in performance-based earthquake engineering. This paper offers a benchmark study aimed at validating various ground motion simulation models for engineering practice. The ground motion simulation models used in this study cover both sitebased and source-based techniques aimed to benchmark their performance using response of single- and multi- degree-of-freedom (SDOF and MDOF) systems to seismic excitation. Source-based ground motion simulation predicts time series using models that explicitly incorporate the physics of the earthquake source and the resulting propagation of seismic wavesSouthern California Earthquake Center (SCEC) broadband simulations used in this study represent source-based ground motion simulation technique. Site-based ground motion simulation techniques, on the other hand, use statistical approaches without necessarily solving the mathematical notions that describe the physics of source dynamics and wave propagation to generate ground motion time series. Ground motions simulated from three historic events (Northridge, Loma Prieta, and Landers) are used and applied to a set of SDOF (non-deteriorating), and MDOF (Box-Girder Seat-type bridge) models and their responses are compared with what is observed using recorded ground motions. Evaluation of the efficiency and sufficiency of the synthetic ground motions show that they are in general a good representation of recorded ground motions. Ground motions obtained via the source-based simulation approach provide a more accurate estimation of RotD50 spectral acceleration (S_a) while site-based simulations provide a better representation of Arias Intensities (I_0). Issues related to variability in response of structures using recorded and simulated ground motion sets are presented

BASIC CONCEPTS AND PERFORMANCE MEASURES IN PREDICTION OF COLLAPSE OF BUILDINGS UNDER EARTHQUAKE GROUND MOTIONS

This paper summarizes collapse performance measures and the probabilistic basis for their development to assist in understanding of collapse behaviour of buildings and implementation of performance objectives in design and evaluation of buildings for collapse safety. Collapse in this context is defi ned as the loss of lateral load-resisting capability of a building's structural system caused by ground shaking. Estimation of collapse performance requires the relation between a ground motion intensity measure (IM) and the probability of collapse, denoted as collapse fragility curve, and the relation between the same ground motion IM and the seismic hazard for the building, denoted as seismic hazard curve. Two methods for estimating the collapse fragility curve of a building are discussed: the EDP-based approach and the IM-based approach. In both approaches, collapse is associated with a scalar ground motion IM and is obtained by utilizing Incremental Dynamic Analysis. The collapse performance criteria presented in this paper are compared with the collapse performance criteria recommended in the SAC/ Federal Emergency Management Agency guidelines. An eight-storey moment-resisting frame case study is used to compare the estimates of collapse performance of various approaches discussed in this paper. Copyright © 2010 John Wiley & Sons, Ltd