Stage-Specific Immune Dysregulation in Multiple Sclerosis

A large body of data indicates that multiple sclerosis (MS) is an autoimmune disease which is initiated by CD4+ T-helper 1 (Th1) and Th17 cells that are reactive against proteins in the myelin sheath. MS typically begins with a relapsing-remitting course, punctuated by clinical exacerbations associated with the development of focal inflammatory lesions in central nervous system white matter, followed by a secondary progressive (SP) phase, characterized by a gradual accumulation of neurological disability associated with widespread microglial activation and axonal loss. The molecular and cellular basis for this transition is unclear, and the role of inflammation during the SP stage is a subject of active debate. As of now, no immunological biomarkers have been identified in MS that are predictive of the clinical course or therapeutic responsiveness to disease-modifying agents, or that correlate with new lesion development, cumulative lesion load, or degree of disability. The discovery of such biomarkers would greatly facilitate clinical management and provide power for smaller and shorter clinical trials. In this article, we discuss the literature on immunological biomarkers in MS with a focus on stage-specific differences and similarities.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140109/1/jir.2014.0025.pd

Long-term treatment with high-dose of sildenafil in a thalassemic patient with pulmonary hypertension

We report a case of a 37-years-old man, affected by thalassemia major, hypogonadotropic hypogonadism, chronic HCV-hepatitis, diabetes mellitus, severe osteoporosis, prior septic pulmonary embolism and pulmonary artery hypertension was performed a long-term treatment with highdose of sildenafil (120 mg/die) with reduction of pulmonary arterial systolic pressure and of the dyspnea

Thiazolidin-4-one formation. Mechanistic and synthetic aspects of the reaction of imines and mercaptoacetic acid under microwave and conventional heating

Microwave irradiation of a mixture of benzylidene-anilines and mercaptoacetic acid in benzene gives 1,3-thiazolidin-4- ones in very high yield (65–90%), whereas the same reaction performed through using the conventional method, at refluxtemperature, requires a much longer time and gives a much lower yield (25–69%). This difference seems to be due to someintermediates and by-products formed during the conventional reaction. On the basis of 1H NMR studies, two differentmechanisms, acting in benzene and in DMF, respectively, have been hypothesized for the thiazolidin-4-one system formation

Reaction between quinone and thiazolidine. A study on the formation mechanism of new antiproliferative quinolindiones

Reaction between quinolinquinone and thiazolidine in basic medium was investigated. 2-Arylthiazolidine-4-carboxylic acid ethyl esters undergo two different cleavages in basic medium, yielding the 1-aryl-2-azadiene and a thiolic species. In the presence of quinolinquinone, the isomeric 1-aryl-3-ethoxycarbonyl-pyridoisoquinolin-5,10-diones and 3-amino-3-ethoxycarbonyl-dihydrothienoquinolin- 4,9-diones are formed by a hetero-Diels–Alder reaction and 1,4-Michael addition reaction, respectively. A mechanism for the formation of the reaction products is presented

Tumor infiltration by chemokine receptor 7 (CCR7)+ T-lymphocytes is a favorable prognostic factor in metastatic colorectal cancer

The immune interactions occurring within the tumor microenvironment have a critical role in determining the outcome of colorectal cancer patients. We carried-out an immunohistochemical analysis of tumor infiltrating T-lymphocytes expressing chemokine receptor 7 (CCR7) in a series of colorectal cancer patients enrolled in a prospective clinical trial. We demonstrated that a high tumor infiltration score of this lymphocyte subset is predictive of longer progression free survival and overall survival. © 2012 Landes Bioscience

Finite size corrections to random Boolean networks

Since their introduction, Boolean networks have been traditionally studied in view of their rich dynamical behavior under different update protocols and for their qualitative analogy with cell regulatory networks. More recently, tools borrowed from statistical physics of disordered systems and from computer science have provided a more complete characterization of their equilibrium behavior. However, the largest part of the results have been obtained in the thermodynamic limit, which is often far from being reached when dealing with realistic instances of the problem. The numerical analysis presented here aims at comparing - for a specific family of models - the outcomes given by the heuristic belief propagation algorithm with those given by exhaustive enumeration. In the second part of the paper some analytical considerations on the validity of the annealed approximation are discussed.Comment: Minor correction

Computational core and fixed-point organisation in Boolean networks

In this paper, we analyse large random Boolean networks in terms of a constraint satisfaction problem. We first develop an algorithmic scheme which allows to prune simple logical cascades and under-determined variables, returning thereby the computational core of the network. Second we apply the cavity method to analyse number and organisation of fixed points. We find in particular a phase transition between an easy and a complex regulatory phase, the latter one being characterised by the existence of an exponential number of macroscopically separated fixed-point clusters. The different techniques developed are reinterpreted as algorithms for the analysis of single Boolean networks, and they are applied to analysis and in silico experiments on the gene-regulatory networks of baker's yeast (saccaromices cerevisiae) and the segment-polarity genes of the fruit-fly drosophila melanogaster.Comment: 29 pages, 18 figures, version accepted for publication in JSTA

A gene expression inflammatory signature specifically predicts multiple myeloma evolution and patients survival

Multiple myeloma (MM) is closely dependent on cross-talk between malignant plasma cells and cellular components of the inflammatory/immunosuppressive bone marrow milieu, which promotes disease progression, drug resistance, neo-angiogenesis, bone destruction and immune-impairment. We investigated the relevance of inflammatory genes in predicting disease evolution and patient survival. A bioinformatics study by Ingenuity Pathway Analysis on gene expression profiling dataset of monoclonal gammopathy of undetermined significance, smoldering and symptomatic-MM, identified inflammatory and cytokine/chemokine pathways as the most progressively affected during disease evolution. We then selected 20 candidate genes involved in B-cell inflammation and we investigated their role in predicting clinical outcome, through univariate and multivariate analyses (log-rank test, logistic regression and Cox-regression model). We defined an 8-genes signature (IL8, IL10, IL17A, CCL3, CCL5, VEGFA, EBI3 and NOS2) identifying each condition (MGUS/smoldering/symptomatic-MM) with 84% accuracy. Moreover, six genes (IFNG, IL2, LTA, CCL2, VEGFA, CCL3) were found independently correlated with patients' survival. Patients whose MM cells expressed high levels of Th1 cytokines (IFNG/LTA/IL2/CCL2) and low levels of CCL3 and VEGFA, experienced the longest survival. On these six genes, we built a prognostic risk score that was validated in three additional independent datasets. In this study, we provide proof-of-concept that inflammation has a critical role in MM patient progression and survival. The inflammatory-gene prognostic signature validated in different datasets clearly indicates novel opportunities for personalized anti-MM treatment

A two-component mantle source feeding Mt. Etna magmatism; insights from the geochemistry of primitive magmas.

The major elements, trace elements and Sr and Nd isotopes of selected Etnean primitive rocks (b15 ky BP) were studied in order to characterize their mantle source. The noble-gas geochemistry of fluid inclusions in minerals fromthe same lavaswas also investigated. Themajor element compositions ofwhole rocks and minerals showed that these products are among the most primitive atMt. Etna, comprising 6.3–17.5 wt.% MgO. The variable LREE (Light Rare Earth Elements) enrichment relative to MORB (Mid-Ocean Ridge Basalt) (Lan/Ybn = 11–26), togetherwith the patterns of certain trace-element ratios (i.e., Ce/Yb versus Zr/Nb and Th/Y versus La/Yb), can be attributed to varying degrees of melting of a common mantle source. Numerical simulations performed with the MELTS program allowed the melting percentages associated with each product to be estimated. This led us to recalculate the hypothetical parental trace-element content of the Etneanmantle source, whichwas common to all of the investigated rocks. The characteristics of the Sr, Nd and He isotopes confirmed the primitive nature of the rocks,with themost-depleted and primitive lava being that ofMt. Spagnolo (SPA; 143Nd/144Nd = 0.512908 87Sr/ 86Sr = 0.703317–0.703325 and 3He/4He = 7.6 Ra), and highlighted the similarity of the mantle sources feeding the volcanic activity of Mt. Etna and the Hyblean Plateau (a region to the south of Mt. Etna and characterized by oldermagmatismthan Mt. Etna). The coupling of noble gases and trace elements suggests an origin for the investigated Etnean lavas from melting of a Hyblean-like mantle, consisting of a two-component source where a peridotitic matrix is veined by 10% pyroxenite. A variable degree of mantle contamination by crustal-like fluids, probably related to subduction, is proposed to explain the higher Sr-isotope and lowerNd-isotope values in some rocks (143Nd/144Nd up to 0.512865 and 87Sr/86Sr up to 0.703707). This process probably occurred in the source prior tomagma generation, refertilizing some portions of themantle. Accordingly, the estimated degree of melting responsible for each magma appears to be related to its 87Sr/86Sr enrichment. In contrast, the decoupling between 3He/4He and 87Sr/86Sr ratios requires the occurrence in the crustal reservoirs of further processes capable of shifting the He isotope ratio towards slightly more radiogenic values, such as magma aging or a contribution of shallow fluid. Therefore, different residence times in the Etnean reservoir and/or various rates of magma ascent could be key parameters for preserving the original He isotope marker of the Etnean mantle source. © 2013 Published by Elsevier