Competition between evaporation and fragmentation in nuclear reactions at 15-20 AMeV beam energy

The reactions 32S+58,64Ni are studied at 14.5 AMeV. From this energy on, fragmentation begins to be a dominant process, although evaporation and fission are still present. After a selection of the collision mechanism, we show that important even-odd effects are present in the isotopic fragment distributions when the excitation energy is small. The staggering effect appears to be a universal feature of fragment production, slightly enhanced when the emission source is neutron poor. A closer look at the behavior of isotopic chains reveals that odd-even effects cannot be explained by pairing effects in the nuclear mass alone, but depend in a more complex way on the de-excitation chain.

Valorisation of organic waste: new developments from proton nuclear magnetic resonance characterization

The last half-century has seen a continuing population and consumption growth, increasing the competition for land, water and energy. The solution can be found in the new sustainability theories, such as the industrial symbiosis and the zero waste objective. Reducing, reusing and recycling are challenges that the whole world have to consider. This is especially important for organic waste, whose reusing gives interesting results in terms of energy release. Before reusing, organic waste needs a deeper characterization. The non-destructive and non-invasive features of both Nuclear Magnetic Resonance (NMR) relaxometry and imaging (MRI) make them optimal candidates to reach such characterization. In this research, NMR techniques demonstrated to be innovative technologies, but an important work on the hardware and software of the NMR LAGIRN laboratory was initially done, creating new experimental procedures to analyse organic waste samples. The first results came from soil-organic matter interactions. Remediated soils properties were described in function of the organic carbon content, proving the importance of limiting the addition of further organic matter to not inhibit soil processes as nutrients transport. Moreover NMR relaxation times and the signal amplitude of a compost sample, over time, showed that the organic matter degradation of compost is a complex process that involves a number of degradation kinetics, as a function of the mix of waste. Local degradation processes were studied with enhanced quantitative relaxation technique that combines NMR and MRI. The development of this research has finally led to the study of waste before it becomes waste. Since a lot of food is lost when it is still edible, new NMR experiments studied the efficiency of conservation and valorisation processes: apple dehydration, meat preservation and bio-oils production. All these results proved the readiness of NMR for quality controls on a huge kind of organic residues and waste.

Azacitidine and Lenalidomide Combination Therapy in Myelodysplastic Syndromes: Topography and Translational Relevance of Nuclear Phospholipase C β - dependent Signalling

Nuclear inositide signalling pathways, and particularly those regulated by PI-PLCβ1, are associated with cell proliferation and differentiation. Myelodysplastic syndromes (MDS) are a heterogeneous spectrum of chronic myeloid hemopathies with associated symptomatic cytopenias and substantial potential for evolution to acute myeloid leukemia (AML). MDS patients are currently treated with two main approaches, epigenetic (Azacitidine) and immunomodulatory (Lenalidomide: above all in cell clones bearing a deletion of the long arm of the chromosome 5 [del(5q)]). As Azacitidine and Lenalidomide alone can show adverse effects or patients can be refractory, an experimental current approach is the combination of the two drugs. Clinically, this combination therapy is promising, while its molecular effect has to be clarified. Stemming from these data, in this study the effect of an Azacitidine-Lenalidomide combination therapy was studied, in both MDS patients and hematopoietic cell lines. The specific aims of this study were to evaluate the effect of Azacitidine and Lenalidomide MDS therapy on: cell cycle regulation, hematopoietic differentiation, gene mutation and miR expression. Lenalidomide alone, via PI-PLCβ1/PKC pathway, was able to induce a selective G0/G1 arrest of the cell cycle in del(5q) cells, slowing down their rate proliferation and favouring erythropoiesis activation. In addition, although the mutation profile at baseline was not entirely capable of predicting the clinical effect of Azacitidine and Lenalidomide therapy, the presence of specific point mutations affecting three inositide genes (PI3KCD, AKT3, PLCG2) was correlated to and anticipated a negative clinical outcome. Moreover, the differential miR expression was detectable even from the 4th cycle of therapy in responder patients, as compared to non-responders. In MDS, this is the first evidence that the molecular mutation profiling of inositide genes or a specific mini-cluster of differentially expressed miRs, targeting inositide signaling molecules, can be associated with the clinical response, thus possibly predicting the effect of the therapy.

Autoantibodies in patients with psoriasis on anti-TNFalpha therapy

Introduction: Anti-TNF-alfa therapy has been effective in the treatment of patients with refractory psoriasis and psoriasic arthritis. However, the risk of developing autoantibodies in these patients undergoing this therapy is not clear. Objective: To evaluate the induction of specific autoantibodies after anti-TNFα therapy in patients with psoriasis and psoriasic arthritis and, to evaluate the influence of the use of methotrexate on the values of autoantibodies developed during this therapy. Patients and methods: Serum samples from 120 patients, obtained before(baseline) the introduction of anti-TNF-alpha therapy and approximately each 3-6 months during the therapy.O f these 120 patients, 113 were found negative for autoantibodies before starting anti -TNFalpha therapy, 7 were found positive for ANA. The analysis included detection of antinuclear antibodies (ANA) and anti-dsDNA antibodies (indirect immunofluorescence on Hep-2 cells and Crithidia luciliae, respectively); anti extractable nuclear antigens antibodies( ENA)(ELISA). RESULTS: Infliximab is associated with the highest occurrence rate of ANA, anti-dsDNA, ENA with approximately 69,2%, 11,5%, 7,6% of patients treated testing positive. In comparison, only 20%, 6,6%, 2,2% of patients treated with Adalimumab, and 19%, 2,3%, 2,3% of patients treated with Etanercept were positive for ANA, Anti-dsDNA, ENA respectively. As regard the seven patients who were positive at baseline, six of them (85.7%) in addition to being remained positive during the therapy they have also increased the autoantibodies ’s titers. Conclusion: our study have shown that Infliximab is associated with the highest rate of autoantibodies. The concomitant treatment with methotrexate did not modify the titers of autoantibodies developed during the therapy anti-TNFalph. The incidence of ANA, anti-dsDNA antibodies did not correlate with development of Lupus-like syndromes. The difference in the frequency of autoantibodies between psoriasis and psoriatic arthritis was not statistically significant (p = 0.867).

Aging of nuclear power plant cables: in search of non-destructive diagnostic quantities

The safety systems of nuclear power plants rely on low-voltage power, instrumentation and control cables. Inside the containment area, cables operate in harsh environments, characterized by relatively high temperature and gamma-irradiation. As these cables are related to fundamental safety systems, they must be able to withstand unexpected accident conditions and, therefore, their condition assessment is of utmost importance as plants age and lifetime extensions are required. Nowadays, the integrity and functionality of these cables are monitored mainly through destructive test which requires specific laboratory. The investigation of electrical aging markers which can provide information about the state of the cable by non-destructive testing methods would improve significantly the present diagnostic techniques. This work has been made within the framework of the ADVANCE (Aging Diagnostic and Prognostics of Low-Voltage I\&C Cables) project, a FP7 European program. This Ph.D. thesis aims at studying the impact of aging on cable electrical parameters, in order to understand the evolution of the electrical properties associated with cable degradation. The identification of suitable aging markers requires the comparison of the electrical property variation with the physical/chemical degradation mechanisms of polymers for different insulating materials and compositions. The feasibility of non-destructive electrical condition monitoring techniques as potential substitutes for destructive methods will be finally discussed studying the correlation between electrical and mechanical properties. In this work, the electrical properties of cable insulators are monitored and characterized mainly by dielectric spectroscopy, polarization/depolarization current analysis and space charge distribution. Among these techniques, dielectric spectroscopy showed the most promising results; by means of dielectric spectroscopy it is possible to identify the frequency range where the properties are more sensitive to aging. In particular, the imaginary part of permittivity at high frequency, which is related to oxidation, has been identified as the most suitable aging marker based on electrical quantities.

Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy (NFLE).

Nocturnal Frontal Lobe Epilepsy (NFLE) is characterized by onset during infancy or childhood with persistence in adulthood, family history of similar nocturnal episodes simulating non-REM parasomnias (sleep terrors or sleepwalking), general absence of morphological substrates, often by normal interictal electroencephalographical recordings (EEGs) during wakefulness. A family history of epilepsy may be present with Mendelian autosomal dominant inheritance has been described in some families. Recent studies indicate the involvement of neuronal nicotinic acetylcholine receptors (nAChRs) in the molecular mechanisms of NFLE. Mutations in the genes encoding for the α4 (CHRNA4) and ß2 (CHRNB2) subunits of the nAChR induce changes in the biophysical properties of nAChR, resulting generally in a “gain of function”. Preclinical studies report that activation of a nuclear receptor called type peroxisome proliferator-activated receptor (PPAR-α) by endogenous molecules or by medications (e.g. fenofibrate) reduces the activity of the nAChR and, therefore, may decrease the frequency of seizures. Thus, we hypothesize that negative modulation of nAChRs might represent a therapeutic strategy to be explored for pharmacological treatment of this form of epilepsy, which only partially responds to conventional antiepileptic drugs. In fact, carbamazepine, the current medication for NFLE, abolishes the seizures only in one third of the patients. The aim of the project is: 1)_to verify the clinical efficacy of adjunctive therapy with fenofibrate in pharmacoresistant NFLE and ADNFLE patients; focousing on the analysis of the polysomnographic action of the PPAR- agonist (fenofibrate). 2)_to demonstrate the subtended mechanism of efficacy by means of electrophysiological and behavioral experiments in an animal model of the disease: particularly, transgenic mice carrying the mutation in the nAChR 4 subunit (Chrna4S252F) homologous to that found in the humans. Given that a PPAR-α agonist, FENOFIBRATE, already clinically utilized for lipid metabolism disorders, provides a promising therapeutic avenue in the treatment of NFLE\ADNFLE.

Role of nuclear redox control, intra-population heterogeneity and oxygen tension in human amniotic fluid stem cells aging

Amniotic fluid stem cells (hAFSC) are emerging as a potential therapeutic approach for various disorders. The low number of available hAFSC requires their ex vivo expansion prior to clinical use, however, during their in vitro culture, hAFSC quickly reach replicative senescence. The principal aim of this study was to investigate the aging process occurring during in vitro expansion of hAFSC, focusing on the redox control that has been reported to be affected in premature and physiological aging. My results show that a strong heterogeneity is present among samples that reflects their different behaviour in culture. I identified three proteins, namely Nox4, prelamin A and PML, which expression increases during hAFSC aging process and could be used as new biomarkers to screen the samples. Furthermore, I found that Nox4 degradation is regulated by sumoylation via proteasome and involves interactions with PML bodies and prelamin A. Since various studies revealed that donor-dependent differences could be explained by cell-to-cell variation within each patient, I studied in deep this phenomenon. I showed that the heterogeneity among samples is also accompanied by a strong intra-population heterogeneity. Separation of hAFSC subpopulations from the same donor, using Celector® technology, showed that an enrichment in the last eluted fraction could improve hAFSC application in regenerative medicine. One of the other problems is that nowadays hAFSC are expanded under atmospheric O2 concentration, which is higher than the O2 tension in their natural niches. This higher O2 concentration might cause environmental stress to the in vitro cultured hAFSCs and accelerate their aging process. Here, I showed that prolonged low oxygen tension exposure preserves different hAFSC stemness properties. In conclusion, my study pointed different approaches to improve in vitro hAFSC expansion and manipulation with the purpose to land at stem cell therapy.

Female melanoma: the role of ovarian stimulation and antioestrogens cancer therapy A retrospective study with immunohistochemical oestrogen receptors alpha and beta analysis.

Cutaneous melanoma (CM) represents the third most common cancer in Italian women under 49 years old. In the last decades, many molecular studies confirmed that sex hormones have a part in melanogenesis and melanoma genesis. However, many controversies are present regarding the role of exogenous oestrogens intake and endogenous hormonal status in female melanoma. Our study's primary objective is to investigate the features of melanoma in women of fertile age and women in postmenopausal age. The secondary aim is to evaluate the expression of ERα and ERβ by immunohistochemical analysis in women who underwent ovarian stimulation for medically assisted procreation and in women in cancer therapy for breast cancer (BC) comparing to two control groups. The tertiary objective is to correlate ERα and ERβ with the Breslow thickness and other relevant histopathological, clinical and dermoscopic characteristics Results A total of 998 women were included in the study. Women in fertile age are significantly more prone to have CM on the trunk. Conversely, postmenopausal females are more likely to develop CM on acral locations. Breslow thickness and ulceration were statistically significant among postmenopausal women (P-value <0,001). In the group for women with a history of breast cancer (BC), we observed a significantly higher CM percentage with “non-brisk” TILs. Upon immunohistochemical analysis, most cases with inhibitor aromatase therapy displayed a strong cytoplasmatic ERα positivity. Upon the Pearson correlation analysis, no association was shown between nuclear ERβ and Breslow thickness. The meaning of cytoplasmatic ERα in melanoma is still debated. It could suggest a potentially significant role of oestrogen non-genomic pathway in these patients, or it can be a mechanism of ERs modulation in response to aromatase inhibitor therapy. Our work tried to enlighten some of the existing shadows on the role of ERs and hormonal factors in CM.

Molecular changes induced by a centrally-induced state of synthetic torpor in multiple organs:a new strategy for radioprotection.

Torpor is a successful survival strategy displayed by several mammalian species to cope with harsh environmental conditions. A complex interplay of ambient, genetic and circadian stimuli acts centrally to induce a severe suppression of metabolic rate, usually followed by an apparently undefended reduction of body temperature. Some animals, such as marmots, are able to maintain this physiological state for months (hibernation), during which torpor bouts are periodically interrupted by short interbouts of normothermia (arousals). Interestingly, torpor adaptations have been shown to be associated with a large resistance towards stressors, such as radiation: indeed, if irradiated during torpor, hibernators can tolerate higher doses of radiation, showing an increased survival rate. New insights for radiotherapy and long-term space exploration could arise from the induction of torpor in non-hibernators, like humans. The present research project is centered on synthetic torpor (ST), a hypometabolic/hypothermic condition induced in a non-hibernator, the rat, through the pharmacological inhibition of the Raphe Pallidus, a key brainstem area controlling thermogenic effectors. By exploiting this procedure, this thesis aimed at: i) providing a multiorgan description of the functional cellular adaptations to ST; ii) exploring the possibility, and the underpinning molecular mechanisms, of enhanced radioresistance induced by ST. To achieve these aims, transcriptional and histological analysis have been performed in multiple organs of synthetic torpid rats and normothermic rats, either exposed or not exposed to 3 Gy total body of X-rays. The results showed that: i) similarly to natural torpor, ST induction leads to the activation of survival and stress resistance responses, which allow the organs to successfully adapt to the new homeostasis; ii) ST provides tissue protection against radiation damage, probably mainly through the cellular adaptations constitutively induced by ST, even though the triggering of specific responses when the animal is irradiated during hypothermia might play a role.