Vaccination with endosomal unknown epitopes produces therapeutic response in rheumatoid arthritis patients and modulates adjuvant arthritis of rats

BACKGROUND: Our previous results showed that intrasynovial Rifamycin SV caused the lysis of synoviocites and freed the autoantigens which in turn stimulated the immunoregulatory rather than autoreactive T cell response in rheumatoid patients. Here, we hypothesize that disruption in vitro of peripheral blood mononuclear cells, by freeze/thawing or by lytic action of Rifamycin SV, would induce the release of endosomal pathogenic autoantigens from APCs present in the circulation, which could then be isolated from degrading enzymes by ultrafiltration. METHODS: The preparation of the ultrafiltrates are based on the rupture of PBMCs (5 7 10(6) cells/mL) by the addition of Rifamycin SV in culture (250 \u3bcg/mL), which causes the lysis of 90 % of the cells in 3 h, or by three cycles of freeze/thawing of the PBMC, from -80 \ub0C to room temperature. The lysate and the fragmented cells were then centrifuged and ultrafiltered by passage through a filtration device with a cut-off of 10 kDa. Also the synovial fluid was subjected to ultrafiltration. RESULTS AND CONCLUSIONS: At clinical monitoring of the 30th day, 22/58 (38 %) patients subcutaneously treated with the autologous ultrafiltrate prepared by the freeze/thawing of PBMCs reached an ACR20. Comparable results were obtained with the other two ultrafiltrates. Cell cultures The addition of ultrafiltrates to rheumatoid PBMCs cultures led to the upregulation of a marker for T-regulatory cells, and downregulation of a cell proliferation marker; changes that together have the meaning of a global immunomodulatory response and that only a specific antigen (ultrafiltrate UF-f/t) might induce in the rheumatoid patient, probably by activating pre-existing protective network. Experimental arthritis All the ultrafiltrates except that prepared by Rifamycin SV were able to modulate the adjuvant arthritis in rats. In particular, longlasting synovial fluid induced a significant reduction of the severity of subsequent arthritis (p < 0.01) while SF from recent RA effusion (5-10 days after a previous complete extraction) and knee osteoarthrosis were ineffective. It is reasonable to assume there are at least two unknown endosomal immunoactive epitopes; one developing its immunotherapeutic property in RA, and the other, related to the molecule of HSP60, reduces the severity of oncoming arthritis. Both epitopes are present in humans, have a molecular weight of 6410 kDa and do not appear to be bystander antigens. Please see Additional file 1 for the abstract in Italian

A MOC-based neutron kinetics model for noise analysis

A 2-D noise model is implemented in the deterministic reactor code APOLLO3® to simulate a periodic oscillation of a structural component. The Two/Three Dimensional Transport (TDT) solver, using the Method of Characteristics, is adopted for the calculation of the case studies, constituted by a moving detector and control-rod bundle. The periodic movement is built by properly linking the geometries corresponding to the temporal positions. The calculation is entirely performed in the real time domain, without resorting to the traditional frequency approach. A specifically defined dynamic eigenvalue is used to renormalize in average the reactivity over a period. The algorithm is accelerated by the DPN synthetic method. For each cell of the domain, the time values of fission rates are analysed to determine the noise extent. Moreover we propose a systematic approach to the definition of the macroscopic cross sections to be used in dynamical calculations starting from library data. As an aside of our work we have found that even in static calculation this approach can produce significant changes

Field emission from single and few-layer graphene flakes

We report the observation and characterization of field emission current from individual single- and few-layer graphene flakes laid on a flat SiO2/Si substrate. Measurements were performed in a scanning electron microscope chamber equipped with nanoprobes, used as electrodes to realize local measurements of the field emission current. We achieved field emission currents up to 1 {\mu}A from the flat part of graphene flakes at applied fields of few hundred V/{\mu}m. We found that emission process is stable over a period of several hours and that it is well described by a Fowler-Nordheim model for currents over 5 orders of magnitude

Field emission properties of as-grown multiwalled carbon nanotube films

Multiwalled carbon nanotubes have been produced by ethylene catalytic chemical vapor deposition and used to fabricate thick and dense freestanding films ("buckypapers") by membrane filtering. Field emission properties of buckypapers have been locally studied by means of high vacuum atomic force microscopy with a standard metallic cantilever used as anode to collect electrons emitted from the sample. Buckypapers showed an interesting linear dependence in the Fowler-Nordheim plots demonstrating their suitability as emitters. By precisely tuning the tip-sample distance in the submicron region we found out that the field enhancement factor is not affected by distance variations up to 2um. Finally, the study of current stability showed that the field emission current with intensity of about 3,3*10-5A remains remarkably stable (within 5% fluctuations) for several hours.Comment: 18 pages, 5 figure

Biomarkers changes after neoadjuvant chemotherapy in breast cancer: A seven-year single institution experience

The adoption of neoadjuvant chemotherapy (NACT) for breast cancer (BC) is increasing. The need to repeat the biomarkers on a residual tumor after NACT is still a matter of debate. We verified estrogen receptors (ER), progesterone receptors (PR), Ki67 and human epidermal growth factor receptor 2 (HER2) status changes impact in a retrospective monocentric series of 265 BCs undergoing NACT. All biomarkers changed with an overall tendency toward a reduced expression. Changes in PR and Ki67 were statistically significant (p = 0.001). Ki67 changed in 114/265 (43.0%) cases, PR in 44/265 (16.6%), ER in 31/265 (11.7%) and HER2 in 26/265 (9.8%). Overall, intrinsic subtype changed in 72/265 (27.2%) cases after NACT, and 10/265 (3.8%) cases switched to a different adjuvant therapy accordingly. Luminal subtypes changed most frequently (66/175; 31.7%) but with less impact on therapy (5/175; 2.8%). Only 3 of 58 triple-negative BCs (5.2%) changed their intrinsic subtype, but all of them switched treatment. No correlation was found between intrinsic subtype changes and clinicopathological features. To conclude, biomarkers changes with prognostic implications occurred in all BC intrinsic subtypes, albeit they impacted therapy mostly in HER2 negative and/or hormone receptors negative BCs. Biomarkers retesting after NACT is important to improve both tailored adjuvant therapies and prognostication of patients

Further progress/developments, on surface/bulk treated Constantan wires, for anomalous heat generation by H2/D2 interaction

In the framework of those studies aimed to analyze anomalous effects (thermal and/or nuclear) due to the interaction among some specific materials (pure and/or alloys) and H2 (or D2), we focused, since 2011, on a specific alloy called Constantan (Cu55-Ni44-Mn1). We selected such material using our own considerations and intuitions and because, according to a scientific paper [1], it has the largest energy value for dissociation of H2 to 2H, i.e. about 3eV. Among others B. Ahern suggested that Ni-Cu-H can be used for heat generation. We improved the preparation procedure of such wire from simple thermal treatments (up to May 2012 [2])to more sophisticated ones, with more tight control of the multilayered (400-700) surface structures. Some of the results were presented at ICCF17, Aug. 2012 [3]. After [3], several groups asked to make their own experiments using such kind of wires ([phi]=200[mu]m, l=100cm) to cross-check (and possibly improve) our results. Some of such Researchers (group of M. Fleischmann Memorial Project; U. Mastromatteo) made public their (positive) results since Dec. 14, 2012 at Ministry of Aeronautics in Rome, Italy. In short, using an (home-made) apparatus integrated with an acquisition system (type PXi) by National Instruments, we made, since September 2012, not mentioning qualitative reconfirmation of previous results, further and unexpected progress and discoveries: a) We developed a new kind of procedure of measurement (about anomalous excess heat) under dynamic vacuum, to avoid the effect of different thermal conductivity, inside the gas cell, due to type of gas and pressure variation: the wire didn't lose, macroscopically, H even at T=600[degrees]C. b) We developed a new, very simple, type of surface coating (2 layers) that is nano-diamandoidslike; c) We observed, at least 2 times, the phenomenon of water splitting due to catalytic effect of surface treated Constantan. Such phenomenon is larger in comparison with what expected just by thermal splitting (wires temperature of about 300-500[degrees]C); d) We observed a very large variation (about a factor 100) of Resistive Thermal Coefficient (RTC) of the wire used (400 layers) as the amount of H (related to the macroscopic value of resistive ratio R/Ro, normalize to empty wire Ro) increased. As example, with "treated" virgin wire (w/o H2) the RTC was about 5*10-6 and increased to6*10-4 when the R/Ro reduced to 0.68; temperature range 20-300[degrees]C. The RTC is larger with D in respect to H. Experiments are in progress also at 77K. e) Overall results are affected by previous operating conditions

Modeling noise experiments performed at AKR-2 and CROCUS zero-power reactors

CORTEX is a EU H2020 project (2017-2021) devoted to the analysis of ’reactor neutron noise’ in nuclear reactors, i.e. the small fluctuations occurring around the stationary state due to external or internal disturbances in the core. One important aspect of CORTEX is the development of neutron noise simulation codes capable of modeling the spatial variations of the noise distribution in a reactor. In this paper we illustrate the validation activities concerning the comparison of the simulation results obtained by several noise simulation codes with respect to experimental data produced at the zero-power reactors AKR-2 (operated at TUD, Germany) and CROCUS (operated at EPFL, Switzerland). Both research reactors are modeled in the time and frequency domains, using transport or diffusion theory. Overall, the noise simulators managed to capture the main features of the neutron noise behavior observed in the experimental campaigns carried out in CROCUS and AKR-2, even though computational biases exist close to the region where the noise-inducing mechanical vibration was located (the so-called ”noise source”). In some of the experiments, it was possible to observe the spatial variation of the relative neutron noise, even relatively far from the noise source. This was achieved through reduced uncertainties using long measurements, the installation of numerous, robust and efficient detectors at a variety of positions in the near vicinity or inside the core, as well as new post-processing methods. For the numerical simulation tools, modeling the spatial variations of the neutron noise behavior in zero-power research reactors is an extremely challenging problem, because of the small magnitude of the noise field; and because deviations from a point-kinetics behavior are most visible in portions of the core that are especially difficult to be precisely represented by simulation codes, such as experimental channels. Nonetheless the limitations of the simulation tools reported in the paper were not an issue for the CORTEX project, as most of the computational biases are found close to the noise source

Serum klotho concentrations inversely correlate with the severity of nailfold capillaroscopic patterns in patients with systemic sclerosis

Klotho is a transmembrane and soluble glycoprotein that governs vascular integrity. Previous studies have demonstrated reduced serum klotho concentrations in patients with systemic sclerosis (SSc), and it is known that klotho deficiency can impair the healing of digital ulcers related to microvessel damage. The aim of this study was to evaluate the association between serum klotho levels and nailfold capillaroscopic abnormalities in SSc patients. We retrospectively enrolled 54 consecutive patients with SSc diagnosed on the basis of the 2013 EULAR/ACR criteria [11 with diffuse SSc; 47 females; median age 68.0 years (IQ 18); median disease duration 11.0 years (IQ 7)]. Serum klotho concentrations were determined by means of an enzyme-linked immunosorbent assay. On the basis of the 2000 classification of Cutolo et al., 14 patients had normal nailfold capillaroscopic findings, 8 had an early scleroderma pattern, 21 an active scleroderma pattern, and 11 a late scleroderma pattern. The median serum klotho concentration was 0.29 ng/mL (IQ 1). Regression analysis of variation showed an inverse correlation between serum klotho concentrations and the severity of the capillaroscopic pattern (p=0.02; t -2.2284), which was not influenced by concomitant treatment. Logistic regression did not reveal any significant association between the risk of developing digital ulcers and nailfold capillaroscopic patterns, serum klotho levels, or concomitant medications. The presence of avascular areas significantly correlated with calcinosis (p=0.006). In line with previous studies, our findings confirm that klotho plays a role in preventing microvascular damage detected with nailfold capillaroscopy

Non-Equilibrium and Quantum Coherent Phenomena in the Electromechanics of Suspended Nanowires

Strong coupling between electronic and mechanical degrees of freedom is a basic requirement for the operation of any nanoelectromechanical device. In this Review we consider such devices and in particular investigate the properties of small tunnel-junction nanostructures that contain a movable element in the form of a suspended nanowire. In these systems, electrical current and charge can be concentrated to small spatial volumes resulting in strong coupling between the mechanics and the charge transport. As a result, a variety of mesoscopic phenomena appear, which can be used for the transduction of electrical currents into mechanical operation. Here we will in particular consider nanoelectromechanical dynamics far from equilibrium and the effect of quantum coherence in both the electronic and mechanical degrees of freedom in the context of both normal and superconducting nanostructures.Comment: 20 pages, 13 figures, figures update