Lymphocyte Subsets and Inflammatory Cytokines of Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Almost all multiple myeloma (MM) cases have been demonstrated to be linked to earlier monoclonal gammopathy of undetermined significance (MGUS). Nevertheless, there are no identified characteristics in the diagnosis of MGUS that have been helpful in differentiating subjects whose cancer may progress to a malignant situation. Regarding malignancy, the role of lymphocyte subsets and cytokines at the beginning of neoplastic diseases is now incontestable. In this review, we have concentrated our attention on the equilibrium between the diverse lymphocyte subsets and the cytokine system and summarized the current state of knowledge, providing an overview of the condition of the entire system in MGUS and MM. In an age where the therapy of neoplastic monoclonal gammopathies largely relies on drugs capable of acting on the immune system (immunomodulants, immunological checkpoint inhibitors, CAR-T), detailed knowledge of the the differences existing in benign and neoplastic forms of gammopathy is the main foundation for the adequate and optimal use of new drugs

7-Keto-Cholesterol and Cholestan-3beta, 5alpha, 6beta-Triol Induce Eryptosis through Distinct Pathways Leading to NADPH Oxidase and Nitric Oxide Synthase Activation

BACKGROUND/AIMS: We showed that patho-physiological concentrations of either 7-keto-cholesterol (7-KC), or cholestane-3beta, 5alpha, 6beta-triol (TRIOL) caused the eryptotic death of human red blood cells (RBC), strictly dependent on the early production of reactive oxygen species (ROS). The goal of the current study was to assess the contribution of the erythrocyte ROS-generating enzymes, NADPH oxidase (RBC-NOX), nitric oxide synthase (RBC-NOS) and xanthine oxido-reductase (XOR) to the oxysterol-dependent eryptosis and pertinent activation pathways. METHODS: Phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, reactive oxygen/nitrogen species (RONS) and nitric oxide formation from 2',7'-dichloro-dihydrofluorescein (DCF-DA) and 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM DA) -dependent fluorescence, respectively; Akt1, phospho-NOS3 Ser1177, and PKCζ from Western blot analysis. The activity of individual 7-KC (7 μM) and TRIOL (2, μM) on ROS-generating enzymes and relevant activation pathways was assayed in the presence of Diphenylene iodonium chloride (DPI), N-nitro-L-arginine methyl ester (L-NAME), allopurinol, NSC23766 and LY294002, inhibitors in this order of RBC-NOX, RBC-NOS, XOR and upstream regulatory proteins Rac GTPase and phosphoinositide3 Kinase (PI3K); hemoglobin oxidation from spectrophotometric analysis. RESULTS: RBC-NOX was the target of 7-KC, through a signaling including Rac GTPase and PKCζ, whereas TRIOL caused activation of RBC-NOS according to the pathway PI3K/Akt, with the concurrent activity of a Rac-GTPase. In concomitance with the TRIOL-induced .NO production, formation of methemoglobin with global loss of heme were observed, ascribable to nitrosative stress. XOR, activated after modification of the redox environment by either RBC-NOX or RBC-NOS activity, concurred to the overall oxidative/nitrosative stress by either oxysterols. When 7-KC and TRIOL were combined, they acted independently and their effect on ROS/RONS production and PS exposure appeared the result of the effects of the oxysterols on RBC-NOX and RBC-NOS. CONCLUSION: Eryptosis of human RBCs may be caused by either 7-KC or TRIOL by oxidative/nitrosative stress through distinct signaling cascades activating RBC-NOX and RBC-NOS, respectively, with the complementary activity of XOR; when combined, the oxysterols act independently and both concur to the final eryptotic effect

The role of initial entanglement and nonGaussianity in the decoherence of photon number entangled states evolving in a noisy channel

We address the degradation of continuous variable (CV) entanglement in a noisy channel focusing on the set of photon-number entangled states. We exploit several separability criteria and compare the resulting separation times with the value of non-Gaussianity at any time, thus showing that in the low-temperature regime: i) non-Gaussianity is a bound for the relative entropy of entanglement and ii) Simon' criterion provides a reliable estimate of the separation time also for nonGaussian states. We provide several evidences supporting the conjecture that Gaussian entanglement is the most robust against noise, i.e. it survives longer than nonGaussian one, and that this may be a general feature for CV systems in Markovian channels.Comment: revised version, title and figures change

Non-Gaussian quantum discord for Gaussian states

In recent years the paradigm based on entanglement as the unique measure of quantum correlations has been challenged by the rise of new correlation concepts, such as quantum discord, able to reveal quantum correlations that are present in separable states. It is in general difficult to compute quantum discord, because it involves a minimization over all possible local measurements in a bipartition. In the realm of continuous variable (CV) systems, a Gaussian version of quantum discord has been put forward upon restricting to Gaussian measurements. It is natural to ask whether non-Gaussian measurements can lead to a stronger minimization than Gaussian ones. Here we focus on two relevant classes of two-mode Gaussian states: squeezed thermal states (STS) and mixed thermal states (MTS), and allow for a range of experimentally feasible non-Gaussian measurements, comparing the results with the case of Gaussian measurements. We provide evidence that Gaussian measurements are optimal for Gaussian states.Comment: 12 pages, 9 figures (3 appendices

It\u27s Nothing Personal

Senior Project submitted to The Division of Arts of Bard College

Phenolic composition of hydrophilic extract of manna from sicilian Fraxinus angustifolia vahl and its reducing, antioxidant and anti-inflammatory activity in vitro

Manna, a very singular vegetable product derived from the spontaneous solidification of the sap of some Fraxinus species, has long been known for its mild laxative and emollient properties. In this work, a hydro-alcoholic extract of manna (HME) from Sicilian Fraxinus angustifolia Vahl was investigated using HPLC-DAD to find phenol components and using chemical and biological in vitro assays to determine its reducing, antioxidant and anti-inflammatory capacity. We identified elenolic acid, tyrosol, hydroxytyrosol, catechin, fraxetin, verbascoside, gallic acid, procyanidin-B1, and luteolin 3,7 glucoside, in order of abundance. Measurements of total antioxidant activity by Folin-Ciocalteu reaction and ferric reducing ability (FRAP), as well as of scavenger activity towards ABTS•+, DPPH•, and perferryl-myoglobin radicals, showed that the phytocomplex effectively reduced oxidants with different standard potentials. When compared with vitamin E, HME also behaved as an efficient chain-breaking antioxidant against lipoperoxyl radicals from methyl linoleate. In cellular models for oxidative stress, HME counteracted membrane lipid oxidation of human erythrocytes stimulated by tert-butyl hydroperoxide and prevented the generation of reactive oxygen species, as well as the GSH decay in IL-1β–activated intestinal normal-like cells. Moreover, in this in vitro intestinal bowel disease model, HME reduced the release of the pro-inflammatory cytokines IL-6 and IL-8. These findings may suggest that manna acts as an antioxidant and anti-inflammatory natural product in humans, beyond its well-known effects against constipation

Recurrent Varicose Veins Following Surgical Treatment: Our Experience with Five Years Follow-up

ObjectiveTo report the 5 year outcome of varicose veins surgery and to establish the factors determining recurrence.Study DesignProspective observational study.Materials and MethodsThis study reports the outcome in 1326 patients treated in a day surgery centre of an institutional referral centre. Patients were investigated clinically and by colour flow duplex scanning before operation. Treatments used included flush ligation of the sapheno-femoral junction (SFJ) and the sapheno-popliteal junction (SPJ). Incompetence of the great saphenous vein (GSV) and small saphenous vein (SSV) were managed by stripping of these veins. Perforating vein ligation and hook phlebectomy were also used. Patients were evaluated 3 weeks and 5 years following treatment by clinical examination and duplex ultrasonography.Results412 patients were excluded from the study because they failed to attend for follow-up or did not wear elastic stockings post-operatively. No residual saphenous truncal reflux was found at the initial assessment 3 weeks following surgery. After 5 years, recurrence of varicose veins occurred in 332 patients out of 1326 (25 %). Recurrences arose at the sapheno-femoral junction in 109 out of 862 patients (13%), at the sapheno-popliteal junction in 39 out of 132 patients (30%), in both saphenous regions 38 out of 107 patients (36%) and in 146 out of 225 subjects (65 %) with secondary varicose veins.ConclusionVaricose veins recurred despite technically correct surgery confirmed on post-operative duplex ultrasonography. The likelihood of recurrence increased in the presence of SSV reflux, perforating vein incompetence and post-thrombotic deep vein incompetence

The gene expression profile of cumulus cells reveals altered pathways in patients with endometriosis

PURPOSE: The objective of this experimental study was to compare the global gene expression profile of CC of mature oocytes in 18 patients with severe endometriosis and CC in 18 control patients affected by a severe male factor. METHODS: For each group, the CC were pooled, RNA was extracted and a microarray performed. For validating the microarray, a quantitative real-time PCR was performed in the CC of an independent set of patients with endometriosis (n = 5) and controls (n = 7). RESULTS: 595 differentially expressed genes (320 down-regulated, 275 up-regulated, p < 0.05, fold change ≥1.5) were identified. The most significant changes were observed in genes involved in the chemokine signaling and cell-cell or cell-extracellular matrix adhesion pathways. Several genes of these pathways were down-regulated in endometriosis. Individual RT-PCR assays confirmed the microarray for ten genes. CONCLUSIONS: Several genes involved in the chemokine mediated-signaling pathway and in the functional cross-talk between CC and the oocyte are down-regulated in endometriosis CC. The impairment of these processes could explain the reduction of oocyte competence in endometriosis. This preliminary knowledge could be the starting point for a more detailed elucidation of the relationship between endometriosis and oocyte competence

The Chemokine CCL2 Mediates the Seizure-enhancing Effects of Systemic Inflammation

Epilepsy is a chronic disorder characterized by spontaneous recurrent seizures. Brain inflammation is increasingly recognized as a critical factor for seizure precipitation, but the molecular mediators of such proconvulsant effects are only partly understood. The chemokine CCL2 is one of the most elevated inflammatory mediators in patients with pharmacoresistent epilepsy, but its contribution to seizure generation remains unexplored. Here, we show, for the first time, a crucial role for CCL2 and its receptor CCR2 in seizure control. We imposed a systemic inflammatory challenge via lipopolysaccharide (LPS) administration in mice with mesial temporal lobe epilepsy. We found that LPS dramatically increased seizure frequency and upregulated the expression of many inflammatory proteins, including CCL2. To test the proconvulsant role of CCL2, we administered systemically either a CCL2 transcription inhibitor (bindarit) or a selective antagonist of the CCR2 receptor (RS102895). We found that interference with CCL2 signaling potently suppressed LPS-induced seizures. Intracerebral administration of anti-CCL2 antibodies also abrogated LPS-mediated seizure enhancement in chronically epileptic animals. Our results reveal that CCL2 is a key mediator in the molecular pathways that link peripheral inflammation with neuronal hyperexcitability

Suicidal erythrocyte death in metabolic syndrome

Eryptosis is a coordinated, programmed cell death culminating with the disposal of cells without disruption of the cell membrane and the release of endocellular oxidative and pro-inflammatory milieu. While providing a convenient form of death for erythrocytes, dysregulated eryptosis may result in a series of detrimental and harmful pathological consequences highly related to the endothelial dysfunction (ED). Metabolic syndrome (MetS) is described as a cluster of cardiometabolic factors (hyperglycemia, dyslipidemia, hypertension and obesity) that increases the risk of cardiovascular complications such as those related to diabetes and atherosclerosis. In the light of the crucial role exerted by the eryptotic process in the ED, the focus of the present review is to report and discuss the involvement of eryptosis within MetS, where vascular complications are utterly relevant. Current knowledge on the mechanisms leading to eryptosis in MetS-related conditions (hyperglycemia, dyslipidemia, hypertension and obesity) will be analyzed. Moreover, clinical evidence supporting or proposing a role for eryptosis in the ED, associated to MetS cardiovascular complications, will be discussed