Sviluppo di un Calorimetro Acromatico per Protoni in ambito medico

iMPACT, innovative Medical Proton Achromatic Calorimeter and Tracker, is a University of Padua and INFN project, funded by the European Research Council. The project aim is to design, develop and prototype an extremely fast and accurate proton Computed Tomography Scanner, with the ultimate goal of enabling the realization of a clinically viable proton Computed Tomography (pCT) system. Proton Computed Tomography is an extremely promising technique able to reconstruct density maps of the human body with minimal dose release and high accuracy on tissue density, a particularly critical feature in cancer Hadron-Therapy treatment planning. Hadron-Therapy is a leading edge technique where protons or heavy-ions, instead of X-rays, are used to target and destroy a tumor within the human body. By exploiting the peculiar energy deposition distribution of hadrons, it is in fact possible to confine within a volume of few mm3 most of the energy released, hence sparing the healthy tissues surrounding the tumor. However, despite all its beneficial aspects, Hadron-Therapy is not yet widespread as other more established procedures, such as X-ray therapy. In particular, imaging techniques based on X-ray Computed Tomography (X-ray CT), currently used to produce body density maps, cannot provide information accurate enough to exploit the intrinsic accuracy of the hadron treatment. It is in fact necessary to possess very accurate knowledge of the density of the tissues crossed by the proton before reaching the tumor in order to precisely aim its energy release with millimeter precision. The idea standing behind the development of a pCT scanner is that using the same energy loss behavior for both the imaging process and the treatment would improve the performance of the latter, the physical interaction being the same. Currently, several pCT scanner prototypes are being developed around the world; pCT scanner technology however is still far from being applicable in a clinical environment, mainly due to the slow acquisition rates. The iMPACT project therefore plans to develop a pCT scanner able to overcome such limitation, leading the way towards sound and medical-grade apparatuses. This thesis begins by displaying both limitations and advantages of the Hadron Therapy technique; the pCT state-of-the-art is then reviewed, highlighting positive features as well as constraints that limit its applicability. The current state of development of the the iMPACT scanner, which embeds a tracker system and a calorimeter, is illustrated and discussed, focusing on the study of data collected with proton beams for the qualification of the iMPACT calorimeter and the development of future prototypes. The analysis therefore demonstrates that the hybrid energy-range calorimeter being designed for the iMPACT project has the necessary features to be an effective component to realize a fast and accurate proton Tomography scanner.ope

Misidentification and Other Preanalytical Errors

Misidentification and Other Preanalytical Errors The largest number of laboratory errors occur in the preanalytical phase and are mainly due to educational and organizational reasons. The experience of our institution, as well as the results of an Italian interlaboratory effort to detect and reduce errors/risk of errors in laboratory medicine will be illustrated

ERK1 and ERK2 mitogen-activated protein kinases affect Ras-dependent cell signaling differentially

BACKGROUND: The mitogen-activated protein (MAP) kinases p44(ERK1 )and p42(ERK2 )are crucial components of the regulatory machinery underlying normal and malignant cell proliferation. A currently accepted model maintains that ERK1 and ERK2 are regulated similarly and contribute to intracellular signaling by phosphorylating a largely common subset of substrates, both in the cytosol and in the nucleus. RESULTS: Here, we show that ablation of ERK1 in mouse embryo fibroblasts and NIH 3T3 cells by gene targeting and RNA interference results in an enhancement of ERK2-dependent signaling and in a significant growth advantage. By contrast, knockdown of ERK2 almost completely abolishes normal and Ras-dependent cell proliferation. Ectopic expression of ERK1 but not of ERK2 in NIH 3T3 cells inhibits oncogenic Ras-mediated proliferation and colony formation. These phenotypes are independent of the kinase activity of ERK1, as expression of a catalytically inactive form of ERK1 is equally effective. Finally, ectopic expression of ERK1 but not ERK2 is sufficient to attenuate Ras-dependent tumor formation in nude mice. CONCLUSION: These results reveal an unexpected interplay between ERK1 and ERK2 in transducing Ras-dependent cell signaling and proliferation. Whereas ERK2 seems to have a positive role in controlling normal and Ras-dependent cell proliferation, ERK1 probably affects the overall signaling output of the cell by antagonizing ERK2 activity

Structure of and Signalling Through Chimeric Antigen Receptor

AbstractChimeric antigen receptor (CAR) is a synthetic transmembrane protein expressed at the surface of immune effector cells (IECs) that are reprogrammed either in vitro or in vivo (June et al. 2018; June and Sadelain 2018). Techniques for genetic engineering of autologous or allogeneic IECs are described in the next chapter. The synthetic CAR incorporates several functional domains. The extracellular domain is composed of a single chain variable fragment (ScFV) of immunoglobulin and recognizes the "tumour" antigen. The clinical relevance of the selected tumour antigen—with a view to minimize "on-target/off-tumour" side effects—is discussed in the third chapter of this section. Bispecific and trispecific CARs are currently being evaluated in preclinical and early clinical trials (Bielamowicz et al. 2018; Shah et al. 2020). The use of an immunoglobulin domain as the ligand of the target antigen means that recognition is not restricted to HLA antigens and that CAR-T cells are universally applicable as opposed to T cell receptor (TCR) transgenic T cells that recognize antigenic peptides presented in the context of a defined major histocompatibility complex (MHC), limiting clinical applications to subsets of patients with defined HLA typing. The intracellular domain is composed of the intracellular domain of the zeta chain of the CD3 component of the TCR, which will trigger signalling when the CAR engages the targeted ligand. The transmembrane region links the two extracellular and intracellular domains through the cell membrane and plays an important role in determining the conformation and flexibility of the CAR and its ability to efficiently bind the targeted antigen/epitope. Association of only these three functional domains characterized first generation CARs, as described in the original publications (Kuwana et al. 1987; Eshhar et al. 1993). However, full activation of T cells requires the addition of one (second generation CARs) or two (third generation CARs) domains from costimulatory molecules, such as CD28, 4-1BB/CD137, or OX40/CD134, that provide the T cell costimulatory signal. Currently approved CAR-T cells are second generation CAR-T cells; as an illustration, the CAR in tisagenlecleucel contains a 4-1BB domain, while the CAR in axicabtagene ciloleucel contains a CD28 domain. The nature of the costimulatory domain influences the ability of CAR-T cells to expand or persist (limit T cell exhaustion) in vivo after infusion into the patient, although it is unclear how this translates clinically and affects disease control, occurrence of adverse events, and overall survival due to the lack of head-to-head comparison between approved products. Finally, fourth generation CAR-T cells have been developed for preclinical projects. These cells, named armoured CAR cells or T cells redirected for universal cytokine-mediated killing (TRUCKS), encode not only a CAR (usually with one costimulatory domain, such as in second generation CARs) but also a cytokine, interleukin, pro-inflammatory ligand, or chemokine that will counteract the immune suppressive microenvironment that prevails in most solid tumours (Eshhar et al. 1993; Chmielewski and Abken 2015)

414. CAR Spacers Including NGFR Domains Allow Efficient T-Cell Tracking and Mediate Superior Antitumor Effects

In conclusion, we demonstrated that the incorporation of the LNGFR marker gene directly in the CAR sequence allows for a single molecule to work as a therapeutic and as a selection/tracking gene and shows an increased efficacy/safety profile compared to the IgG1-CH2CH3 spacer

The Use of Empirical Methods for Testing Granular Materials in Analogue Modelling

The behaviour of a granular material is mainly dependent on its frictional properties, angle of internal friction, and cohesion, which, together with material density, are the key factors to be considered during the scaling procedure of analogue models. The frictional properties of a granular material are usually investigated by means of technical instruments such as a Hubbert-type apparatus and ring shear testers, which allow for investigating the response of the tested material to a wide range of applied stresses. Here we explore the possibility to determine material properties by means of different empirical methods applied to mixtures of quartz and K-feldspar sand. Empirical methods exhibit the great advantage of measuring the properties of a certain analogue material under the experimental conditions, which are strongly sensitive to the handling techniques. Finally, the results obtained from the empirical methods have been compared with ring shear tests carried out on the same materials, which show a satisfactory agreement with those determined empirically

The Suicide Gene Therapy Challenge: How to Improve a Successful Gene Therapy Approach

The transfer of a suicide gene into donor lymphocytes to control alloreactivity in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the widest clinical application of T-cell based gene transfer, as shown by more than 100 patients treated worldwide to date, several phase I–II studies completed, and a registrative phase III study, sponsored by a biotech firm, about to begin. In this mini-review, we will summarize the clinical results obtained to date, and attempt to identify the steps envisaged to optimize the suicide gene therapy approach