WNT-DEPENDENT REGENERATIVE FUNCTION IS INDUCED IN LEUKEMIA-INITIATING AC133BRIGHT CELLS

The Cancer Stem Cell model supported the notion that leukemia was initiated and maintained in vivo by a small fraction of leukemia-initiating cells (LICs). Previous studies have suggested the involvement of Wnt signaling pathway in Acute Myeloid Leukemia (AML) by the ability to sustain the development of LICs. A novel hematopoietic stem and progenitor cell marker, monoclonal antibody AC133, recognizes the CD34bright CD38- subset of human acute myeloid leukemia cells, suggesting that it may be an early marker for the LICs. During the first part of my phD program we previously evaluated the ability of leukemic AC133+ fraction, to perform engraftment following to xenotransplantation in immunodeficient mouse model Rag2-/-\u3b3c-/-. The results showed that the surface marker AC133 is able to enrich for the cell fraction that contains the LICs. In consideration of our previously reported data, derived from the expression profiling analysis performed in normal (n=10) and leukemic (n=33) human long-term reconstituting AC133+ cells, we revealed that the ligand-dependent Wnt signaling is induced in AML through a diffuse expression and release of WNT10B, a hematopoietic stem cells regenerative-associated molecule. In situ detection performed on bone marrow biopsies of AML patients, showed the activation of the Wnt pathway, through the concomitant presence of the ligand WNT10B and of the active dephosphorylated \u3b2-catenin form, suggesting an autocrine / paracrine-type ligand-dependent activation mechanism. In consideration of the link between hematopoietic regeneration and developmental signaling, we transplanted primary AC133+ AML A46 cells into developing zebrafish. This biosensor model revealed the formation of ectopic structures by activation of dorsal organizer markers that act downstream of the Wnt pathway. These results suggested that the misappropriating Wnt associated functions can promote pathological stem cell-like regeneration responsiveness. The analyses performed in situ retained information on the cellular localization, enabling determination of the activity status of individual cells and allowing the tumor environment view. Taking this issue into consideration, during the second part of my phD program, I set up the application of a new in situ method for localized detection and genotyping of individual transcripts directly in cells and tissues. The mRNA in situ detection technique is based on padlock probes ligation and target priming rolling circle amplification allowing the single nucleotide resolution in heterogenous tissues. The mRNA in situ detection performed on bone marrow biopsies derived from AML patients, showed a diffuse localization pattern of WNT10B molecule in the tissue. Conversely, only the AC133bright cell population shows the Wnt signaling activation signature represented by the cytoplasmatic accumulation and nuclear translocation of the active form of \u3b2-catenin. In spite of this, we previously evidenced that the regenerative function of WNT signaling pathway is defined by the up-regulation of WNT10B, WNT10A, WNT2B and WNT6 loci, we identified the WNT10B as a major locus associated with the regenerative function and over-expressed by all AML patients. By the molecular evaluation of the WNT10B transcript, we isolated an aberrant splicing variant (WNT10BIVS1), that identify Non Core-Binding Factor Leukemia (NCBFL) class and whose potential role is discussed. Moreover, we demonstrate that the function of "leukemia stem cell", present in the cell population enriched for the marker AC133bright, is strictly related to regenerative function associated with WNT signaling, defining the key role of WNT10B ligand as a specific molecular marker for leuchemogenesis. This thesis defines the new suitable approaches to characterize the leukemia-initiating cells (LICs) and suggest the role of WNT10B as a new suitable target for AML

Adaptive dilation analysis for wavelet coding with EMDC

The Embedded Morphological Dilation Coding (EMDC) algorithm, recently proposed by the author of this work, implements a direct coding of the wavelet coefficients significance map that is based on the action of a new kind of multiresolution binary (bit-plane) morphological operator. EMDC actually includes the most part of existing morphological wavelet codecs, it produces a fully progressive bitstream with low complexity and has demonstrated competitive coding performances. A peculiar feature of EMDC is the adaptive and the extended connectivity nature of the morphological analysis of the subband coefficients. In this paper we give a detailed description of this feature and quantify the related performance improvements. We conclude that the considered pattern analysis and coding technique allow an increased reduction of the data redundancy and fills the gap between existing morphological dilation techniques and state-of-the-art wavelet coders

High-Performance Embedded Morphological Wavelet Coding

Morphological analysis can be applied in wavelet domain to analyze and represent the position of significant coefficients. New operators have to be introduced which are able to exploit both the multiresolution and the filter bank peculiarities of the subband representation of visual information. In this paper an efficient morphological wavelet coder is proposed. The clustering trend of significant coefficients is captured by a new kind of multi resolution binary dilation operator. The layered and adaptive nature of this subband dilation makes it possible for the coding technique to produce an embedded bit-stream with a modest computational cost and state-of-the-art Rate-Distortion performance. Morphological wavelet coding appears promising because the localized analysis of wavelet coefficient clusters is adequate to capture intrinsic patterns of the source which can have substantial benefits for perceptual or even object-based reconstruction quality concerns. Here we test the performance of our algorithm and compare the effects of different wavelet filters. We obtain state of the art coding performance and good perceptual results both for 2D and 3D images, with a new technique that seems to be well suited for further developments

Embedded Morphological Dilation Coding for 2D and 3D Images

Current wavelet-based image coders obtain high performance thanks to the identification and the exploitation of the statistical properties of natural images in the transformed domain. Zerotree-based algorithms, as Embedded Zerotree Wavelets (EZW) and Set Partitioning In Hierarchical Trees (SPIHT), offer high Rate-Distortion (RD) coding performance and low computational complexity by exploiting statistical dependencies among insignificant coefficients on hierarchical subband structures. Another possible approach tries to predict the clusters of significant coefficients by means of some form of morphological dilation. An example of a morphology-based coder is the Significance-Linked Connected Component Analysis (SLCCA) that has shown performance which are comparable to the zerotree-based coders but is not embedded. A new embedded bit-plane coder is proposed here based on morphological dilation of significant coefficients and context based arithmetic coding. The algorithm is able to exploit both intra-band and inter-band statistical dependencies among wavelet significant coefficients. Moreover, the same approach is used both for two and three-dimensional wavelet-based image compression. Finally we the algorithms are tested on some 2D images and on a medical volume, by comparing the RD results to those obtained with the state-of-the-art wavelet-based coders

Improving SPIHT-based Compression of Volumetric Medical Data

Volumetric medical data (CT,MR) are useful tools for diagnostic investigation however their usage may be made diffcult because of the amount of data to store or because of the duration of communication over a limited capacity channel. In order to code such information sources we present a progressive three dimensional image compression algorithm based on zerotree wavelet coder with arithmetic coding. We make use of a 3D separable biorthogonal wavelet transform and we extend the zerotree SPIHT algorithm to three dimensions. Moreover we propose some improvements to the SPIHT encoder in order to obtain a better rate distortion performance without increasing the computational complexity. Finally we propose an efficient context-based adaptive arithmetic coding which eliminates high order redundancy. The results obtained on progressive coding of a test CT volume are better than those presented in recent similar works both for the mean PSNR on the whole volume and for the PSNR homogeneity between various slices

Radiation and magnetic field effects on new semiconductor power devices for HL-LHC experiments

The radiation hardness of commercial Silicon Carbide and Gallium Nitride power MOSFETs is presented in this paper, for Total Ionizing Dose effects and Single Event Effects, under gamma, neutrons, protons and heavy ions. Similar tests are discussed for commercial DC-DC converters, also tested in operation under magnetic field

The role of clinically significant antiphospholipid antibodies in systemic lupus erythematosus

The objective is to investigate the role of clinically significant antiphospholipid antibodies (aPL) in a cohort of systemic lupus erythematosus (SLE) patients. All SLE patients followed for at least 5 years and with available aPL profile at the beginning of the follow-up in our center were studied. Clinically significant aPL were defined as: positive lupus anticoagulant test, anti-cardiolipin and/or anti- β2Glycoprotein I IgG/IgM >99th percentile on two or more occasions at least 12 weeks apart. Patients with and without clinically significant aPL were compared by univariate (Chi square or Fisher's exact test for categorical variables and Student's t or Mann-Whitney test for continuous variables) and multivariate analysis (logistic regression analysis). P values <0.05 were considered significant. Among 317 SLE patients studied, 117 (37%) had a clinically significant aPL profile at baseline. Such patients showed at univariate analysis an increased prevalence of deep venous thrombosis, pulmonary embolism, cardiac valvular disease, cognitive dysfunction and antiphospholipid syndrome (APS), but a reduced prevalence of acute cutaneous lupus and anti-extractable nuclear antigens (ENA) when compared with patients without clinically significant aPL. Multivariate analysis confirmed the association between clinically significant aPL and reduced risk of acute cutaneous lupus [p=0.003, odds ratio (OR) 0.43] and ENA positivity (p<0.001, OR 0.37), with increased risk of cardiac valvular disease (p=0.024, OR 3.1) and APS (p<0.0001, OR 51.12). Triple positivity was the most frequent profile and was significantly associated to APS (p<0.0001, OR 28.43). Our study showed that one third of SLE patients had clinically significant aPL, and that this is associated with an increased risk, especially for triple positive, of APS, and to a different clinical and serological pattern of disease even in the absence of APS

Cholesterol Serum Levels and Use of Statins in Graves' Orbitopathy: A New Starting Point for the Therapy.

Graves' Orbitopathy (GO) is the most frequent extrathyroidal manifestation of Graves' disease (GD). Its ultimate cause remains unclear, but it is commonly considered an autoimmune disorder due to self recognition of autoantigens constitutively expressed by orbital fibroblasts (OFs), and thyroid epithelial cells. High dose intravenous glucocorticoids (ivGC) are the most commonly used treatment for moderately severe and active GO. However, based on the complex pathogenesis of GO, a number of factors may have a protective and maybe a therapeutic role. The use of other medications improving the effect of GC may increase the overall effectiveness of the therapy and reduce GC doses, thereby limiting side effects. Recently, a possible protective role of 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors, the so-called statins, and perhaps of lowering cholesterol levels, has been proposed. Thus, statins have been reported to be associated with a reduced frequency of GO in GD patients and in recent cross-sectional and retrospective studies a significant correlation was found between the occurrence of GO and both total and LDL-cholesterol in patients with a GD of relatively recent onset, suggesting a role of cholesterol in the development of GO. Moreover, a correlation was found between the GO clinical activity score and total as well as LDL-cholesterol in untreated GO patients, depending on GO duration, indicating a role of cholesterol on GO activity. Therefore, statin treatment may be beneficial for GO. Here we review this subject, which offers new therapeutic perspectives for patients with GO

Highly cross-linked bifunctional magnesium porphyrin-imidazolium bromide polymer: Unveiling the key role of co-catalysts proximity for CO2 conversion into cyclic carbonates

Highly cross-linked materials containing an imidazolium salt and magnesium porphyrin, either in the absence (TSP-Mg-imi) or in the presence (7a and 7b) of multi-walled carbon nanotubes (MWCNTs), were synthesized and used as heterogeneous bifunctional catalysts for the conversion of CO2 into cyclic carbonates. The metalloporphyrin moiety acts both as a “covalent swelling agent”, generating hybrids with high surface area, and as a Lewis acid co-catalytic species. TSP-Mg-imi produced excellent conversion and TONMg values, under solvent-free conditions, even at room temperature and with low catalytic loading (0.003 mol%). In terms of conversion and TONMg, TSP-Mg-imi exhibited better catalytic performance compared to a reference homogeneous system, demonstrating that the proximity between the metal centers and the nucleophilic site results in a synergistic effect during the catalytic cycle. The results of the computational study confirmed both the cooperative function and the significance of incorporating a co-catalytic species into the system