Myeloproliferative neoplasms (MPNs) are bone marrow diseases characterized by excess clonal hematopoiesis resulting in elevated peripheral blood counts. Subtypes include polycythemia vera (PV), ...essential thrombocythemia (ET), and primary myelofibrosis (PMF). They share clinical features (e.g., splenomegaly, thrombotic complications, risk of leukemic transformation), and a common molecular basis: the dysregulation of the JAK-STAT pathway, which confers a hypersensitivity of hematopoietic stem cells (HSC) to the action of growth factors and cytokines, and, as a result, an overproduction of blood cells. Genetic analysis of patients with MPNs revealed that >95% of patients with PV and about 50% of patients with ET or PMF carry an activating point mutation in the JAK2 gene (JAK2-V617F). Despite clinical evidence indicating a higher susceptibility of MPN patients to develop thrombotic disease, the underlying pathogenetic mechanisms are not fully understood. It appears that thrombosis is the result of a severe inflammatory response associated to remarkable oxidative stress in the presence of endothelial dysfunction and a procoagulant environment. Hypercoagulability is a consequence of disrupted hemostasis and fibrinolysis due to damage of the endothelium and defective fibrinolysis. Evidence suggests that overproduction of ROS and a deprived antioxidant system play a major role in the pathogenesis of MPN, as well as in the resistance to tyrosine-kinase inhibitor therapy. Moreover, systemic inflammation is thought to be the main trigger of thrombosis and seems to be mainly mediated by pro-inflammatory cytokines along with endothelial cell dysfunction. Recent studies have provided evidence that fibrinogen plays a multifaceted role in inflammatory responses and autoimmunity. The ability of fibrinogen to participate in the inflammatory response depends on its specific interaction with integrins, the leukocyte cell surface adhesion receptors expressed on neutrophils, monocytes, macrophages, and several subsets of lymphocytes. In MPN patients, endothelial cell dysfunction, increased reactive oxygen species (ROS) production, and proinflammatory cytokines have been reported, together with impaired fibrinolysis. We also investigated the potential role of oxidative stress and inflammation in the promotion of thrombosis. In order to study the mechanisms of inflammation-induced thrombosis in MPN patients, the aim of the present study was to investigate the role of oxidation-induced structural and functional fibrinogen modifications in MPN patients. The eventual counteracting effects of ruxolitinib, a first-in-class JAK inhibitor, were also assessed. 40 MPN patients and 40 age- and sex-matched healthy control subjects were included in the study. We measured specific oxidative stress markers andtheir modifications in plasma, and functional and structural parameters in purified fibrinogen fractions. Marked signs of oxidative stress in plasma (P<0.01 versus controls) and, correspondingly, an increased extent of fibrinogen oxidation (P<0.01 versus controls) were observed in patients. Furthermore, fibrinogen fractions purified from MPN patients exhibited significantly reduced clotting ability and decreased susceptibility to plasmin-induced lysis (P<0.01 versus controls). Alterations in fibrinogen secondary structure, as suggested by circular dichroism spectroscopy, and in fibrin clot architecture were also identified. Importantly, clot structure obtained by stimulated emission depletion (STED) super-resolution microscopy indicated modifications in fiber diameter and clot porosity in MPN patients (P<0.01 versus controls). In patient samples, fibrinogen clot analysis and oxidative-dependent changes reveal novel structural and functional fibrinogen modifications which may favor thrombotic complications in MPNs. In patients receiving ruxolitinib, a significant improvement in redox status was observed, accompanied by a significant improvement in fibrinogen structural and functional features, suggesting a potential impactof ruxolitinib on cardiovascular prevention in MPNs.
Nous prendrons en considération la redéfinition de l’Idée kantienne de Dieu impliquée par la spéculation de Quentin Meillassoux et nous verrons que celle-ci a été élaborée dans le cadre de ...l’ouverture du possible au virtuel. Nous confronterons ainsi ce détournement avec celui proposé par Gilles Deleuze, lui aussi redéfinissant le rôle du Dieu de la Dialectique transcendantale dans l’ouverture du possible au virtuel. Le point de départ des deux stratégies est la négation des limites imposées a priori au possible, dont Dieu est traditionnellement considéré comme le garant. Toutefois, comme nous le verrons, même dans la négation de l’ordre divin il reste encore de la place, dans les deux systèmes, pour une fonction divine.
Pancreatic metastases are rare,with a reported incidence varying from 1.6%to 11%in autopsy studies of patients with advanced malignancy.In clinical series,the frequency of pancreatic metastases ...ranges from 2%to 5%of all pancreatic malignant tumors.However,the pancreas is an elective site for metastases from carcinoma of the kidney and this peculiarity has been reported by several studies.The epidemiology,clinical presentation,and treatment of pancreatic metastases from renal cell carcinoma are known from singleinstitution case reports and literature reviews.Thereis currently very limited experience with the surgical resection of isolated pancreatic metastasis,and the role of surgery in the management of these patients has not been clearly defined.In fact,for many years pancreatic resections were associated with high rates of morbidity and mortality,and metastatic disease to the pancreas was considered to be a terminal-stage condition.More recently,a significant reduction in the operative risk following major pancreatic surgery has been demonstrated,thus extending the indication for these operations to patients with metastatic disease.
Increased angiogenesis and vascular endothelial growth factor (VEGF) levels contribute to higher metastasis and mortality in uveal melanoma (UM), an aggressive malignancy of the eye in adults. ...(±)-MRJF22, a prodrug of the sigma (σ) ligand haloperidol metabolite II conjugated with the histone deacetylase (HDAC) inhibitor valproic acid, has previously demonstrated a promising antiangiogenic activity. Herein, the asymmetric synthesis of (R)-(+)-MRJF22 and (S)-(−)-MRJF22 was performed to investigate their contribution to (±)-MRJF22 antiangiogenic effects in human retinal endothelial cells (HREC) and to assess their therapeutic potential in primary human uveal melanoma (UM) 92-1 cell line. While both enantiomers displayed almost identical capabilities to reduce cell viability than the racemic mixture, (S)-(−)-MRJF22 exhibited the highest antimigratory effects in endothelial and tumor cells. Given the fundamental contribution of cell motility to cancer progression, (S)-(−)-MRJF22 may represent a promising candidate for novel antimetastatic therapy in patients with UM.
Nous prendrons en considération la redéfinition de l’Idée kantienne de Dieu impliquée par la spéculation de Quentin Meillassoux et nous verrons que celle-ci a été élaborée dans le cadre de ...l’ouverture du possible au virtuel. Nous confronterons ainsi ce détournement avec celui proposé par Gilles Deleuze, lui aussi redéfinissant le rôle du Dieu de la Dialectique transcendantale dans l’ouverture du possible au virtuel. Le point de départ des deux stratégies est la négation des limites imposées a priori au possible, dont Dieu est traditionnellement considéré comme le garant. Toutefois, comme nous le verrons, même dans la négation de l’ordre divin il reste encore de la place, dans les deux systèmes, pour une fonction divine.
This paper deals with Quentin Meillassoux’s reformulation of the notion of God as a consequence of his speculative access to the absolute contingency of everything. We will compare this move with Gilles Deleuze’s overturning of the role of Kantian God. Both, Meillassoux’s and Deleuze’s strategies aim at subverting the necessary order of the world as ruled by God – a world where nothing absolutely new can happen. Accordingly, the two philosophers’ different notions of the virtual can be seen as rational alternatives to the divine order of the world, so to justify the emergence of the unpredictable, of something that did not existed before as a possible. However, as we will see, both these dissimilar speculations, while subverting the divine order, cannot avoid to include a principle playing at least one of God’s traditional roles.
EPR/alanine dosimetry for two therapeutic proton beams Marrale, Maurizio; Carlino, Antonio; Gallo, Salvatore ...
Nuclear instruments & methods in physics research. Section B, Beam interactions with materials and atoms,
02/2016, Letnik:
368
Journal Article
Recenzirano
In this work the analysis of the electron paramagnetic resonance (EPR) response of alanine pellets exposed to two different clinical proton beams employed for radiotherapy is performed. One beam is ...characterized by a passive delivery technique and is dedicated to the eyes treatment (OPTIS2 beam line). Alanine pellets were irradiated with a 70MeV proton beam corresponding to 35mm range in eye tissue. We investigated how collimators with different sizes and shape used to conform the dose to the planned target volume influence the delivered dose. For this purpose we performed measurements with varying the collimator size (Output Factor) and the results were compared with those obtained with other dosimetric techniques (such as Markus chamber and diode detector). This analysis showed that the dosimeter response is independent of collimator diameter if this is larger than or equal to 10mm. The other beam is characterized by an active spot-scanning technique, the Gantry1 beam line (maximum energy 230MeV), and is used to treat deep-seated tumors. The dose linearity of alanine response in the clinical dose range was tested and the alanine dose response at selected locations in depth was measured and compared with the TPS planned dose in a quasi-clinical scenario. The alanine response was found to be linear in the dose in the clinical explored range (from 10 to 70Gy). Furthermore, a depth dose profile in a quasi-clinical scenario was measured and compared to the dose computed by the Treatment Planning System PSIPLAN. The comparison of calibrated proton alanine measurements and TPS dose shows a difference under 1% in the SOBP and a “quenching” effect up to 4% in the distal part of SOBP. The positive dosimetric characteristics of the alanine pellets confirm the feasibility to use these detectors for “in vivo” dosimetry in clinical proton beams.
•Calcium ethoxide nanosuspension proposed as a novel limestone consolidant.•Porosity data obtained with two techniques, MIP and NMRR, and then correlated.•NMRR resulted a good ND tool to evaluate the ...efficacy of a consolidation product.
Pore-space properties, such as pore-size distribution and connected porosity, are relevant factors in the evaluation of the performance of a consolidation treatment. In this study, two different techniques – Mercury Intrusion Porosimetry (MIP) and Nuclear Magnetic Resonance Relaxometry (NMRR) – were adopted to study the compatibility and the efficacy of a new consolidation product for limestones. This work aims at comparing and combining data obtained by MIP and NMRR; to confirm the relationship between the quantitative results of MIP and the qualitative ones of NMRR, a calibration which leads to correlate T2 distribution and pore size distribution has been applied. Experimental results showed that, in most cases, NMRR results agree with MIP data. Therefore, NMRR technique can be considered a powerful tool to evaluate the change in pore size distribution due to the application of a consolidating agent on stone, especially in cases when sampling should be avoided.
Familial amyloidotic polyneuropathy (FAP) is a progressive neuropathy, with onset in adulthood and high mortality. It is related to an altered transthyretin (TTR) plasma protein, mainly produced by ...the liver and responsible for amyloid deposit in the peripheral nervous system. SNPs in the
TTR
gene were associated with FAP, and the G>C substitution (NM_000371.3:c.325G>C) in the 109th codon (GAG vs CAG; NP_362.1:p.E109Q) was previously described in Sicily (Italy). Here, we report on a Sicilian family with several patients affected by FAP related to the E109Q mutation, which displayed a somatic mosaicism with the reversion to normality of the c.325G>C mutation. After exclusion of isodisomy and allele deletion, this event seems to be due to a rare, post-zygotic interallelic gene conversion with the wild-type allele serving as a donor. Further investigations will be necessary to better understand the molecular basis of this phenomenon, and could help determine if this can be induced in a targeted manner in the context of natural gene therapy to treat TTR-related FAP patients, as previously proposed for other diseases. Moreover, our results confirm the need to perform DNA-based diagnostic tests with at least a second tissue when a suspected germline mutation in a candidate gene is not identified in the first tissue.
The ability to discriminate the quality of ionizing radiation is important because the biological effects produced in tissue strongly depends on both absorbed dose and linear energy transfer (LET) of ...ionizing particles. Here we present an experimental electron spin resonance (ESR) analysis aimed at discriminating the effective LETs of various radiation beams (e.g., 19.3 MeV protons, 60Co photons and thermal neutrons). The measurement of the intensities of the continuous wave spectrometer signal channel first harmonic in-phase and the second harmonic out-of-phase components are used to distinguish the radiation quality. A computational analysis, was carried out to evaluate the dependence of the first harmonic in-phase and second harmonic out-of-phase components on microwave power, modulation amplitude and relaxation times, and highlights that these components could be used to point out differences in the relaxation times. On the basis of this numerical analysis the experimental results are discussed. The methodology described in this study has the potential to provide information on radiation quality.
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