Purging e alte dosi di chemioterapia con reinfusione di cellule staminali autologhe in linfomi non Hodgkin follicolari resistenti/refrattari

In the era of monoclonal antibodies the role of autologous stem cell transplantation (ASCT) in the management of follicular lymphoma (FL) is still debated. To evaluate the safety and efficacy of myeloablative therapy with rescue of purged or unpurged harvests in FL pts. At our institution form 1997 to 2007 28 pts with refractory/resistant FL were eligible for ASCT. Before high dose therapy they received 2-3 cycles of CHOP-like regimen (ACOD), followed by Cyclophosphamide 4g/mq to mobilize the stem cells (SC). After SC collection the pts underwent 3 cycles of subcutaneous Cladribine at a daily dose of 0,14-0,10 mg/Kg for Day 1-5 every 3-4 weeks. The conditioning regimen was based on Mitoxantrone 60mg/mq + Melphalan 180 mg/mq, followed by SC re-infusion 24-hours later and G-CSF starting 24 hours after re-infusion. In 19 pts the SC underwent purging: in 10 harvests the CD34+ were selected by immunomagnetic beads, while in the other 9 pts, only Rituximab was used as “purging in vivo” agent. The remaining 9 pts received unpurged SC. Before ASCT 11 pts were in complete response (CR), 9 in partial response (PR) and 2 in stable disease. Two pts were not eligible for ASCT because of progressive disease (PD). The remaining 25 pts were eligible for ASCT. The engraftment was at a median of 11 days for leucocytes and 14 days for platelets (>20.000/mmc), with a delay of one day in the pts, who received purged SC. Grade 3-4 mucositis was described in 8 pts. During aplasia a 48% infection rate was reported, without differences between pts with purged or unpurged SC. One patient in CR presented myelodysplastic syndrome at 18 months from ASCT. After ASCT 22 pts were in CR, 2 in PR and one patient were not valuable, because died before response assessment. Nine pts in CR showed PD at a median time of 14 months from ASCT. With a median follow up of 5 years (range 2 months -10 years), 22 pts are alive and 11 (44%) in CR. Ten pts died, 5 for progressive disease and 5 for treatment-related causes; in particular 7 of them received in-vitro purged SC. Conclusions: Our chemotherapy regimen, which included the purine analogue Cladribine in the induction phase, seems safe and feasible. The high rate of CR reported and the sustained freedom from progression up to now, makes such modality of treatment a valid option principally in relapsing FL patients. In our experience, the addition of a monoclonal antibody as part of treatment confirms its role “in vivo purging” without observing an increased incidence of infection.

Collective effects for the LHC injectors: non-ultrarelativistic approaches

The upgrade of the CERN accelerator complex has been planned in order to further increase the LHC performances in exploring new physics frontiers. One of the main limitations to the upgrade is represented by the collective instabilities. These are intensity dependent phenomena triggered by electromagnetic fields excited by the interaction of the beam with its surrounding. These fields are represented via wake fields in time domain or impedances in frequency domain. Impedances are usually studied assuming ultrarelativistic bunches while we mainly explored low and medium energy regimes in the LHC injector chain. In a non-ultrarelativistic framework we carried out a complete study of the impedance structure of the PSB which accelerates proton bunches up to 1.4 GeV. We measured the imaginary part of the impedance which creates betatron tune shift. We introduced a parabolic bunch model which together with dedicated measurements allowed us to point to the resistive wall impedance as the source of one of the main PSB instability. These results are particularly useful for the design of efficient transverse instability dampers. We developed a macroparticle code to study the effect of the space charge on intensity dependent instabilities. Carrying out the analysis of the bunch modes we proved that the damping effects caused by the space charge, which has been modelled with semi-analytical method and using symplectic high order schemes, can increase the bunch intensity threshold. Numerical libraries have been also developed in order to study, via numerical simulations of the bunches, the impedance of the whole CERN accelerator complex. On a different note, the experiment CNGS at CERN, requires high-intensity beams. We calculated the interpolating Hamiltonian of the beam for highly non-linear lattices. These calculations provide the ground for theoretical and numerical studies aiming to improve the CNGS beam extraction from the PS to the SPS.

Transposable elements: structure and dynamic of the autonomous retrotransposon R2 in Arthropoda with non-canonical reproduction

Eukaryotic ribosomal DNA constitutes a multi gene family organized in a cluster called nucleolar organizer region (NOR); this region is composed usually by hundreds to thousands of tandemly repeated units. Ribosomal genes, being repeated sequences, evolve following the typical pattern of concerted evolution. The autonomous retroelement R2 inserts in the ribosomal gene 28S, leading to defective 28S rDNA genes. R2 element, being a retrotransposon, performs its activity in the genome multiplying its copy number through a “copy and paste” mechanism called target primed reverse transcription. It consists in the retrotranscription of the element’s mRNA into DNA, then the DNA is integrated in the target site. Since the retrotranscription can be interrupted, but the integration will be carried out anyway, truncated copies of the element will also be present in the genome. The study of these truncated variants is a tool to examine the activity of the element. R2 phylogeny appears, in general, not consistent with that of its hosts, except some cases (e.g. Drosophila spp. and Reticulitermes spp.); moreover R2 is absent in some species (Fugu rubripes, human, mouse, etc.), while other species have more R2 lineages in their genome (the turtle Mauremys reevesii, the Japanese beetle Popilia japonica, etc). R2 elements here presented are isolated in 4 species of notostracan branchiopods and in two species of stick insects, whose reproductive strategies range from strict gonochorism to unisexuality. From sequencing data emerges that in Triops cancriformis (Spanish gonochoric population), in Lepidurus arcticus (two putatively unisexual populations from Iceland) and in Bacillus rossius (gonochoric population from Capalbio) the R2 elements are complete and encode functional proteins, reflecting the general features of this family of transposable elements. On the other hand, R2 from Italian and Austrian populations of T. cancriformis (respectively unisexual and hermaphroditic), Lepidurus lubbocki (two elements within the same Italian population, gonochoric but with unfunctional males) and Bacillus grandii grandii (gonochoric population from Ponte Manghisi) have sequences that encode incomplete or non-functional proteins in which it is possible to recognize only part of the characteristic domains. In Lepidurus couesii (Italian gonochoric populations) different elements were found as in L. lubbocki, and the sequencing is still in progress. Two hypothesis are given to explain the inconsistency of R2/host phylogeny: vertical inheritance of the element followed by extinction/diversification or horizontal transmission. My data support previous study that state the vertical transmission as the most likely explanation; nevertheless horizontal transfer events can’t be excluded. I also studied the element’s activity in Spanish populations of T. cancriformis, in L. lubbocki, in L. arcticus and in gonochoric and parthenogenetic populations of B. rossius. In gonochoric populations of T. cancriformis and B. rossius I found that each individual has its own private set of truncated variants. The situation is the opposite for the remaining hermaphroditic/parthenogenetic species and populations, all individuals sharing – in the so far analyzed samples - the majority of variants. This situation is very interesting, because it isn’t concordant with the Muller’s ratchet theory that hypothesizes the parthenogenetic populations being either devoided of transposable elements or TEs overloaded. My data suggest a possible epigenetic mechanism that can block the retrotransposon activity, and in this way deleterious mutations don’t accumulate.

Le Coliti Microscopiche nei soggetti con diarrea non ematica: uno studio prospettico

Introduzione: le Coliti Microscopiche, altrimenti note come Colite Collagena e Colite Linfocitica, sono disordini infiammatori cronici del colon che causano diarrea e colpiscono più frequentemente donne in età avanzata e soggetti in terapia farmacologica. Negli ultimi anni la loro incidenza sembra aumentata in diversi paesi occidentali ma la prevalenza in Italia è ancora incerta. Scopo: il presente studio prospettico e multicentrico è stato disegnato per valutare la prevalenza delle CM in pazienti sottoposti a colonscopia per diarrea cronica non ematica. Pazienti e metodi: dal Maggio 2010 al Settembre 2010 sono stati arruolati consecutivamente tutti i soggetti adulti afferenti in due strutture dell’area metropolitana milanese per eseguire una pancolonscopia. Nei soggetti con diarrea cronica non ematica sono state eseguite biopsie multiple nel colon ascendente, sigma e retto nonché in presenza di lesioni macroscopiche. Risultati: delle 8008 colonscopie esaminate 265 sono state eseguite per diarrea cronica; tra queste, 8 presentavano informazioni incomplete, 52 riscontri endoscopici consistenti con altri disordini intestinali (i.e. IBD, tumori, diverticoliti). 205 colonscopie sono risultate sostanzialmente negative, 175 dotate di adeguato campionamento microscopico (M:F=70:105; età mediana 61 anni). L’analisi istologica ha permesso di documentare 38 nuovi casi di CM (M:F=14:24; età mediana 67.5 anni): 27 CC (M:F=10:17; età mediana 69 anni) e 11 CL (M:F=4:7; età mediana 66 anni). In altri 25 casi sono state osservate alterazioni microscopiche prive dei sufficienti requisiti per la diagnosi di CM. Conclusioni: nel presente studio l’analisi microscopica del colon ha identificato la presenza di CM nel 21,7% dei soggetti con diarrea cronica non ematica ed indagine pancolonscopica negativa. Lo studio microscopico del colon è pertanto un passo diagnostico fondamentale per il corretto inquadramento diagnostico delle diarree croniche, specialmente dopo i 60 anni di età. Ampi studi prospettici e multicentrici dovranno chiarire ruolo e peso dei fattori di rischio associati a questi disordini.

Studio sulla perfusione di fegato e milza in animali non convenzionali mediante ecografia e tomografia computerizzata (TC) con mezzo di contrasto

Il presente studio rappresenta la prima applicazione della tecnica CEUS in alcune delle più diffuse specie non convenzionali, nonché la prima nei rettili. In particolare è stata investigata la perfusione di fegato e milza in 10 conigli, 10 furetti e il fegato in 8 iguane. Per quanto riguarda i mammiferi, la tecnica è risultata di facile attuazione e i risultati ottenuti erano equiparabili a quelli documentati per i piccoli animali. Maggiore variabilità si è messa in evidenza a livello splenico in entrambe le specie e nel coniglio rispetto al furetto. Nelle iguane è stata necessaria una modifica del protocollo a seguito dei tempi più lunghi delle fasi di wash in e di wash out. Le curve ottenute erano caratterizzate da picchi più bassi e TTP più lunghi, con wash out incompleto anche dopo 10 minuti di indagine. Nelle iguane l’indagine del fegato è stata approfondita grazie all’esecuzione di TC dinamiche con MDC, studio pioneristico per quanto riguarda la medicina dei rettili. L’esecuzione è avvenuta senza problemi in anestesia generale. Diffusione del MDC e conseguenti variazione di HU a livello aortico e epatico sono state considerate contemporaneamente, con costruzione di curve HU-tempo piuttosto ripetibili, entrambe caratterizzate da un wash in rapido, un picco, particolarmente alto a livello aortico, e da una fase di wash out più lento, anche qui incompleto dopo i 600 secondi di indagine. Una certa variabilità è stata notata in tre individui, risultato attendibile conseguentemente alla forte dipendenza da fattori intriseci ed estrinseci del metabolismo e della funzionalità epatica dei rettili. L’intero protocollo è stato applicato in un furetto e due iguane patologiche, al fine di evidenziare le potenzialità cliniche delle tecniche. Sebbene il numero esiguo di casi non permetta di trarre conclusioni a questo riguardo, l’ultimo capitolo della tesi vuole essere uno spunto per studi futuri.

Non-Linear Analysis and Design of Synchronous Bearingless Multiphase Permanent Magnet Machines and Drives

A two-dimensional model to analyze the distribution of magnetic fields in the airgap of a PM electrical machines is studied. A numerical algorithm for non-linear magnetic analysis of multiphase surface-mounted PM machines with semi-closed slots is developed, based on the equivalent magnetic circuit method. By using a modular structure geometry, whose the basic element can be duplicated, it allows to design whatever typology of windings distribution. In comparison to a FEA, permits a reduction in computing time and to directly changing the values of the parameters in a user interface, without re-designing the model. Output torque and radial forces acting on the moving part of the machine can be calculated. In addition, an analytical model for radial forces calculation in multiphase bearingless Surface-Mounted Permanent Magnet Synchronous Motors (SPMSM) is presented. It allows to predict amplitude and direction of the force, depending on the values of torque current, of levitation current and of rotor position. It is based on the space vectors method, letting the analysis of the machine also during transients. The calculations are conducted by developing the analytical functions in Fourier series, taking all the possible interactions between stator and rotor mmf harmonic components into account and allowing to analyze the effects of electrical and geometrical quantities of the machine, being parametrized. The model is implemented in the design of a control system for bearingless machines, as an accurate electromagnetic model integrated in a three-dimensional mechanical model, where one end of the motor shaft is constrained to simulate the presence of a mechanical bearing, while the other is free, only supported by the radial forces developed in the interactions between magnetic fields, to realize a bearingless system with three degrees of freedom. The complete model represents the design of the experimental system to be realized in the laboratory.

Non-thermal emission in High Frequency Peaked blazars towards the Square Kilometer Array era

In this thesis work we will explore and discuss the properties of the gamma-ray sources included in the first Fermi-LAT catalog of sources above 10 GeV (1FHL), by considering both blazars and the non negligible fraction of still unassociated gamma-ray sources (UGS, 13%). We perform a statistical analysis of a complete sample of hard gamma-ray sources, included in the 1FHL catalog, mostly composed of HSP blazars, and we present new VLBI observations of the faintest members of the sample. The new VLBI data, complemented by an extensive search of the archives for brighter sources, are essential to gather a sample as large as possible for the assessment of the significance of the correlation between radio and very high energy (E>100 GeV) emission bands. After the characterization of the statistical properties of HSP blazars and UGS, we use a complementary approach, by focusing on an intensive multi-frequency observing VLBI and gamma-ray campaign carried out for one of the most remarkable and closest HSP blazar Markarian 421.

Deposition of thin films by a non-equilibrium atmospheric pressure Plasma Jet: a poly-diagnostic study

The use of atmospheric pressure plasmas for thin film deposition on thermo-sensitive materials is currently one of the main challenges of the plasma scientific community. Despite the growing interest in this field, the existing knowledge gap between gas-phase reaction mechanisms and thin film properties is still one of the most important barriers to overcome for a complete understanding of the process. In this work, thin films surface characterization techniques, combined with passive and active gas-phase diagnostic methods, were used to provide a comprehensive study of the Ar/TEOS deposition process assisted by an atmospheric pressure plasma jet. SiO2-based thin films exhibiting a well-defined chemistry, a good morphological structure and high uniformity were studied in detail by FTIR, XPS, AFM and SEM analysis. Furthermore, non-intrusive spectroscopy techniques (OES, filter imaging) and laser spectroscopic methods (Rayleigh scattering, LIF and TALIF) were employed to shed light on the complexity of gas-phase mechanisms involved in the deposition process and discuss the influence of TEOS admixture on gas temperature, electron density and spatial-temporal behaviours of active species. The poly-diagnostic approach proposed in this work opens interesting perspectives both in terms of process control and optimization of thin film performances.

Seismic vulnerability of buildings and non-structural elements: insights from the 2011 Lorca earthquake

This PhD dissertation presents a profound study of the vulnerability of buildings and non-structural elements stemming from the investigation of the Mw 5.2 Lorca 2011 earthquake; which constitutes one of the most significant earthquakes in Spain. It left nine fatalities due to falling debris from reinforced concrete buildings, 394 injured and material damage valued at 800 million euros. Within this framework, the most relevant initiatives concerning the vulnerability of buildings and the exposure of Lorca are studied. This work revealed two lines of research: the elaboration of a rational method to determine the adequacy of a specific fragility curve for the particular seismic risk study of a region; and the relevance of researching the seismic performance of non-structural elements. As a consequence, firstly, a method to assess and select fragility curves for seismic risk studies from the catalogue of those available in the literature is elaborated and calibrated by means of a case study. The said methodology is based on a multidimensional index and provides a ranking that classifies the curves in terms of adequacy. Its results for the case of Lorca led to the elaboration of new fragility curves for unreinforced masonry buildings. Moreover, a simplified method to account for the unpredictable directionality of the seism in the creation of fragility curves is contributed. Secondly, the characterisation of the seismic capacity and demand of the non-structural elements that caused most of the human losses is studied. Concerning the capacity, an analytical approach derived from theoretical considerations to characterise the complete out-of-plane seismic response curve of unreinforced masonry cantilever walls is provided; as well as a simplified and more practical trilinear version of it. Concerning the demand, several methods for characterising the Floor Response Spectra of reinforced concrete buildings are tested through case studies.

NB-IoT via non terrestrial networks

Massive Internet of Things is expected to play a crucial role in Beyond 5G (B5G) wireless communication systems, offering seamless connectivity among heterogeneous devices without human intervention. However, the exponential proliferation of smart devices and IoT networks, relying solely on terrestrial networks, may not fully meet the demanding IoT requirements in terms of bandwidth and connectivity, especially in areas where terrestrial infrastructures are not economically viable. To unleash the full potential of 5G and B5G networks and enable seamless connectivity everywhere, the 3GPP envisions the integration of Non-Terrestrial Networks (NTNs) into the terrestrial ones starting from Release 17. However, this integration process requires modifications to the 5G standard to ensure reliable communications despite typical satellite channel impairments. In this framework, this thesis aims at proposing techniques at the Physical and Medium Access Control layers that require minimal adaptations in the current NB-IoT standard via NTN. Thus, firstly the satellite impairments are evaluated and, then, a detailed link budget analysis is provided. Following, analyses at the link and the system levels are conducted. In the former case, a novel algorithm leveraging time-frequency analysis is proposed to detect orthogonal preambles and estimate the signals’ arrival time. Besides, the effects of collisions on the detection probability and Bit Error Rate are investigated and Non-Orthogonal Multiple Access approaches are proposed in the random access and data phases. The system analysis evaluates the performance of random access in case of congestion. Various access parameters are tested in different satellite scenarios, and the performance is measured in terms of access probability and time required to complete the procedure. Finally, a heuristic algorithm is proposed to jointly design the access and data phases, determining the number of satellite passages, the Random Access Periodicity, and the number of uplink repetitions that maximize the system's spectral efficiency.