Nicotinamide inhibits melanoma in vitro and in vivo

Background: Even though new therapies are available against melanoma, novel approaches are needed to overcome resistance and high-toxicity issues. In the present study the anti-melanoma activity of Nicotinamide (NAM), the amide form of Niacin, was assessed in vitro and in vivo. Methods: Human (A375, SK-MEL-28) and mouse (B16-F10) melanoma cell lines were used for in vitro investigations. Viability, cell-death, cell-cycle distribution, apoptosis, Nicotinamide Adenine Dinucleotide+ (NAD+), Adenosine Triphosphate (ATP), and Reactive Oxygen Species (ROS) levels were measured after NAM treatment. NAM anti-SIRT2 activity was tested in vitro; SIRT2 expression level was investigated by in silico transcriptomic analyses. Melanoma growth in vivo was measured in thirty-five C57BL/6 mice injected subcutaneously with B16-F10 melanoma cells and treated intraperitoneally with NAM. Interferon (IFN)-γ-secreting murine cells were counted with ELISPOT assay. Cytokine/chemokine plasmatic levels were measured by xMAP technology. Niacin receptors expression in human melanoma samples was also investigated by in silico transcriptomic analyses. Results: NAM reduced up to 90% melanoma cell number and induced: I) accumulation in G1-phase (40% increase), ii) reduction in S- A nd G2-phase (about 50% decrease), iii) a 10-fold increase of cell-death and 2.5-fold increase of apoptosis in sub-G1 phase, iv) a significant increase of NAD+, ATP, and ROS levels, v) a strong inhibition of SIRT2 activity in vitro. NAM significantly delayed tumor growth in vivo (p ≤ 0.0005) and improved survival of melanoma-bearing mice (p ≤ 0.0001). About 3-fold increase (p ≤ 0.05) of Interferon-gamma (IFN-γ) producing cells was observed in NAM treated mice. The plasmatic expression levels of 6 cytokines (namely: Interleukin 5 (IL-5), Eotaxin, Interleukin 12 (p40) (IL12(p40)), Interleukin 3 (IL-3), Interleukin 10 (IL-10) and Regulated on Activation Normal T Expressed and Secreted (RANTES) were significantly changed in the blood of NAM treated mice, suggesting a key role of the immune response. The observed inhibitory effect of NAM on SIRT2 enzymatic activity confirmed previous evidence; we show here that SIRT2 expression is significantly increased in melanoma and inversely related to melanoma-patients survival. Finally, we show for the first time that the expression levels of Niacin receptors HCAR2 and HCAR3 is almost abolished in human melanoma samples. Conclusion: NAM shows a relevant anti-melanoma activity in vitro and in vivo and is a suitable candidate for further clinical investigations

Dental pulp stem cells bioadhesivity: evaluation on mineral-trioxide-aggregate.

Stem cells are undifferentiated cells that have the capacity to self-renew. They have been discovered in many adult tissues, including teeth. Dental Pulp Mesenchymal Stem Cells (DP-MSCs) are involved in dental repair by activation of growth factors, released after caries and have the ability to regenerate a dentin-pulp-like complex. The molecular/cellular research gives the possibility to grow new tissues and biological structures for clinical applications, providing cells for therapies including cell transplantation and tissue engineering. In this study DP-MSCs were derived from dental pulp of 10 donors. To evaluate material toxicity, after in vitro isolation, the cells were seeded on mineral trioxide aggregate (MTA). Initial light microscopy investigation of cells revealed no signs of cell death due to toxicity or infection, on the contrary the scaffolds supplied an excellent support for cell structures, the cells proliferated and adhered to substrate. Similar observation was seen in scanning electron microscopy, in particular the cells had proliferated and spread, covering a considerable part of the surface of the biomaterials investigated, with an elaborate form of attachment, in fact, the cells formed a continuous layer on the upper surface of the MTA. In conclusion, the aim of this study is to demonstrate that DP-MSCs combined with MTA could be a potential source for regenerative medicine, encouraging further study to evaluate the new-dentin formation

The linearity response of the Planck-LFI flight model receivers

In this paper we discuss the linearity response of the Planck-LFI receivers, with particular reference to signal compression measured on the 30 and 44 GHz channels. In the article we discuss the various sources of compression and present a model that accurately describes data measured during tests performed with individual radiomeric chains. After discussing test results we present the best parameter set representing the receiver response and discuss the impact of non linearity on in-flight calibration, which is shown to be negligible.Comment: this paper is part of the Prelaunch status LFI papers published on JINST: http://www.iop.org/EJ/journal/-page=extra.proc5/jinst; This is an author-created, un-copyedited version of an article accepted for publication in JINST. IOP Publishing Ltd is not responsible for any errors or omissions in this version of the manuscript or any version derived from it. The definitive publisher authenticated version is available online at 10.1088/1748-0221/4/12/T12011

Investigating serum and tissue expression identified a cytokine/chemokine signature as a highly effective melanoma marker

The identification of reliable and quantitative melanoma biomarkers may help an early diagnosis and may directly affect melanoma mortality and morbidity. The aim of the present study was to identify effective biomarkers by investigating the expression of 27 cytokines/chemokines in melanoma compared to healthy controls, both in serum and in tissue samples. Serum samples were from 232 patients recruited at the IDI-IRCCS hospital. Expression was quantified by xMAP technology, on 27 cytokines/chemokines, compared to the control sera. RNA expression data of the same 27 molecules were obtained from 511 melanoma-and healthy-tissue samples, from the GENT2 database. Statistical analysis involved a 3-step approach: analysis of the single-molecules by Mann–Whitney analysis; analysis of paired-molecules by Pearson correlation; and profile analysis by the machine learning algorithm Support Vector Machine (SVM). Single-molecule analysis of serum expression identified IL-1b, IL-6, IP-10, PDGF-BB, and RANTES differently expressed in melanoma (p < 0.05). Expression of IL-8, GM-CSF, MCP-1, and TNF-α was found to be significantly correlated with Breslow thickness. Eotaxin and MCP-1 were found differentially expressed in male vs. female patients. Tissue expression analysis identified very effective marker/predictor genes, namely, IL-1Ra, IL-7, MIP-1a, and MIP-1b, with individual AUC values of 0.88, 0.86, 0.93, 0.87, respectively. SVM analysis of the tissue expression data identified the combination of these four molecules as the most effective signature to discriminate melanoma patients (AUC = 0.98). Validation, using the GEPIA2 database on an additional 1019 independent samples, fully confirmed these observations. The present study demonstrates, for the first time, that the IL-1Ra, IL-7, MIP-1a, and MIP-1b gene signature discriminates melanoma from control tissues with extremely high efficacy. We therefore propose this 4-molecule combination as an effective melanoma marker

Design, development and verification of the 30 and 44 GHz front-end modules for the Planck Low Frequency Instrument

We give a description of the design, construction and testing of the 30 and 44 GHz Front End Modules (FEMs) for the Low Frequency Instrument (LFI) of the Planck mission to be launched in 2009. The scientific requirements of the mission determine the performance parameters to be met by the FEMs, including their linear polarization characteristics. The FEM design is that of a differential pseudo-correlation radiometer in which the signal from the sky is compared with a 4-K blackbody load. The Low Noise Amplifier (LNA) at the heart of the FEM is based on indium phosphide High Electron Mobility Transistors (HEMTs). The radiometer incorporates a novel phase-switch design which gives excellent amplitude and phase match across the band. The noise temperature requirements are met within the measurement errors at the two frequencies. For the most sensitive LNAs, the noise temperature at the band centre is 3 and 5 times the quantum limit at 30 and 44 GHz respectively. For some of the FEMs, the noise temperature is still falling as the ambient temperature is reduced to 20 K. Stability tests of the FEMs, including a measurement of the 1/f knee frequency, also meet mission requirements. The 30 and 44 GHz FEMs have met or bettered the mission requirements in all critical aspects. The most sensitive LNAs have reached new limits of noise temperature for HEMTs at their band centres. The FEMs have well-defined linear polarization characteristcs.Comment: 39 pages, 33 figures (33 EPS files), 12 tables. Planck LFI technical papers published by JINST: http://www.iop.org/EJ/journal/-page=extra.proc5/1748-022

Advanced modelling of the Planck-LFI radiometers

The Low Frequency Instrument (LFI) is a radiometer array covering the 30-70 GHz spectral range on-board the ESA Planck satellite, launched on May 14th, 2009 to observe the cosmic microwave background (CMB) with unprecedented precision. In this paper we describe the development and validation of a software model of the LFI pseudo-correlation receivers which enables to reproduce and predict all the main system parameters of interest as measured at each of the 44 LFI detectors. These include system total gain, noise temperature, band-pass response, non-linear response. The LFI Advanced RF Model (LARFM) has been constructed by using commercial software tools and data of each radiometer component as measured at single unit level. The LARFM has been successfully used to reproduce the LFI behavior observed during the LFI ground-test campaign. The model is an essential element in the database of LFI data processing center and will be available for any detailed study of radiometer behaviour during the survey.Comment: 21 pages, 15 figures, this paper is part of the Prelaunch status LFI papers published on JINST: http://www.iop.org/EJ/journal/-page=extra.proc5/jins

Optimization of Planck/LFI on--board data handling

To asses stability against 1/f noise, the Low Frequency Instrument (LFI) onboard the Planck mission will acquire data at a rate much higher than the data rate allowed by its telemetry bandwith of 35.5 kbps. The data are processed by an onboard pipeline, followed onground by a reversing step. This paper illustrates the LFI scientific onboard processing to fit the allowed datarate. This is a lossy process tuned by using a set of 5 parameters Naver, r1, r2, q, O for each of the 44 LFI detectors. The paper quantifies the level of distortion introduced by the onboard processing, EpsilonQ, as a function of these parameters. It describes the method of optimizing the onboard processing chain. The tuning procedure is based on a optimization algorithm applied to unprocessed and uncompressed raw data provided either by simulations, prelaunch tests or data taken from LFI operating in diagnostic mode. All the needed optimization steps are performed by an automated tool, OCA2, which ends with optimized parameters and produces a set of statistical indicators, among them the compression rate Cr and EpsilonQ. For Planck/LFI the requirements are Cr = 2.4 and EpsilonQ <= 10% of the rms of the instrumental white noise. To speedup the process an analytical model is developed that is able to extract most of the relevant information on EpsilonQ and Cr as a function of the signal statistics and the processing parameters. This model will be of interest for the instrument data analysis. The method was applied during ground tests when the instrument was operating in conditions representative of flight. Optimized parameters were obtained and the performance has been verified, the required data rate of 35.5 Kbps has been achieved while keeping EpsilonQ at a level of 3.8% of white noise rms well within the requirements.Comment: 51 pages, 13 fig.s, 3 tables, pdflatex, needs JINST.csl, graphicx, txfonts, rotating; Issue 1.0 10 nov 2009; Sub. to JINST 23Jun09, Accepted 10Nov09, Pub.: 29Dec09; This is a preprint, not the final versio

Off-line radiometric analysis of Planck/LFI data

The Planck Low Frequency Instrument (LFI) is an array of 22 pseudo-correlation radiometers on-board the Planck satellite to measure temperature and polarization anisotropies in the Cosmic Microwave Background (CMB) in three frequency bands (30, 44 and 70 GHz). To calibrate and verify the performances of the LFI, a software suite named LIFE has been developed. Its aims are to provide a common platform to use for analyzing the results of the tests performed on the single components of the instrument (RCAs, Radiometric Chain Assemblies) and on the integrated Radiometric Array Assembly (RAA). Moreover, its analysis tools are designed to be used during the flight as well to produce periodic reports on the status of the instrument. The LIFE suite has been developed using a multi-layered, cross-platform approach. It implements a number of analysis modules written in RSI IDL, each accessing the data through a portable and heavily optimized library of functions written in C and C++. One of the most important features of LIFE is its ability to run the same data analysis codes both using ground test data and real flight data as input. The LIFE software suite has been successfully used during the RCA/RAA tests and the Planck Integrated System Tests. Moreover, the software has also passed the verification for its in-flight use during the System Operations Verification Tests, held in October 2008.Comment: Planck LFI technical papers published by JINST: http://www.iop.org/EJ/journal/-page=extra.proc5/1748-022

Synchronous Optical and Radio Polarization Variability in the Blazar OJ287

We explore the variability and cross-frequency correlation of the flux density and polarization of the blazar OJ287, using imaging at 43 GHz with the Very Long Baseline Array, as well as optical and near-infrared polarimetry. The polarization and flux density in both the optical waveband and the 43 GHz compact core increased by a small amount in late 2005, and increased significantly along with the near-IR polarization and flux density over the course of 10 days in early 2006. Furthermore, the values of the electric vector position angle (EVPA) at the three wavebands are similar. At 43 GHz, the EVPA of the blazar core is perpendicular to the flow of the jet, while the EVPAs of emerging superluminal knots are aligned parallel to the jet axis. The core polarization is that expected if shear aligns the magnetic field at the boundary between flows of disparate velocities within the jet. Using variations in flux density, percentage polarization, and EVPA, we model the inner jet as a spine-sheath system. The model jet contains a turbulent spine of half-width 1.2 degrees and maximum Lorentz factor of 16.5, a turbulent sheath with Lorentz factor of 5, and a boundary region of sheared field between the spine and sheath. Transverse shocks propagating along the fast, turbulent spine can explain the superluminal knots. The observed flux density and polarization variations are then compatible with changes in the direction of the inner jet caused by a temporary change in the position of the core if the spine contains wiggles owing to an instability. In addition, we can explain a stable offset of optical and near-IR percentage polarization by a steepening of spectral index with frequency, as supported by the data.Comment: 34 pages, 12 figures; To be published in Astrophysical Journal, accepted 03/200