324,079 research outputs found
Cutaneous Melanoma Classification: The Importance of High-Throughput Genomic Technologies
No full textCutaneous melanoma is an aggressive tumor responsible for 90% of mortality related to skin cancer. In the recent years, the discovery of driving mutations in melanoma has led to better treatment approaches. The last decade has seen a genomic revolution in the field of cancer. Such genomic revolution has led to the production of an unprecedented mole of data. High-throughput genomic technologies have facilitated the genomic, transcriptomic and epigenomic profiling of several cancers, including melanoma. Nevertheless, there are a number of newer genomic technologies that have not yet been employed in large studies. In this article we describe the current classification of cutaneous melanoma, we review the current knowledge of the main genetic alterations of cutaneous melanoma and their related impact on targeted therapies, and we describe the most recent high-throughput genomic technologies, highlighting their advantages and disadvantages. We hope that the current review will also help scientists to identify the most suitable technology to address melanoma-related relevant questions. The translation of this knowledge and all actual advancements into the clinical practice will be helpful in better defining the different molecular subsets of melanoma patients and provide new tools to address relevant questions on disease management. Genomic technologies might indeed allow to better predict the biological - and, subsequently, clinical - behavior for each subset of melanoma patients as well as to even identify all molecular changes in tumor cell populations during disease evolution toward a real achievement of a personalized medicine
Substitution of arginine 120 in human D-amino acid oxidase favors FAD-binding and nuclear mistargeting
No full textThe peroxisomal enzyme human D-amino acid oxidase (hDAAO) is attracting attention owing to its role in degrading D-serine, the main co-agonist of N-methyl D-aspartate receptors in brain, and its involvement in brain functions and diseases. Here, we focused on arginine 120, a residue located at the protein interface, 20 Å from the assumed second ligand-binding site, showing a different orientation of the side chain in the hDAAO-benzoate complex, and corresponding to Ser119 in rat DAAO, which is part of a putative nuclear translocation signal (NTS). By substituting Arg120 in hDAAO with a glutamate (to mimic the active NTS) or a leucine (to eliminate the positive charge) the protein conformation, thermal stability, and kinetic properties are slightly altered, while the dimeric structure and the ligand-binding properties are unchanged. The most relevant alteration in Arg120 variants is the strongest interaction with FAD. Nevertheless, the activity assayed at low D-serine and FAD concentrations (resembling physiological conditions) was quite similar for wild-type and Arg120 hDAAO variants. These results resemble the ones obtained substituting another residue located at the interface region (i.e., the W209R variant), indicating that substitutions at the monomer-monomer interface mainly affects the FAD binding in hDAAO. Indeed, U87 glioblastoma cells transiently transfected for hDAAO variants show that substitution of Arg120 favors mistargeting: the increase in cytosolic localization observed for the variants promotes nuclear targeting, especially for the R120E hDAAO, without affecting cell viability. Notably, mistargeting to the nucleus is an innate process as it is apparent for the wild-type hDAAO, too: whether such a process is related to specific pathologic processes is still unknown
Regulation mechanisms of human D-amino acid oxidase
No full textThe human peroxisomal FAD-dependent enzyme D-amino acid oxidase (hDAAO, EC 1.4.3.3) plays a key role in important physiological processes by catalyzing the stereospecific degradation of several D-amino acids (D-AAs). A number of studies demonstrated that a dysregulation in processes regulating D-AAs concentration is related to the mechanism(s) predisposing to several pathologies. The important role played by hDAAO in modulating D-AAs levels increased the interest for this flavoenzyme: while structural and biochemical properties have been extensively investigated, several aspects in the modulation of its functionality remain elusive. Furthermore, it has been recently suggested that DAAO could be mistargeted to the nucleus or secreted in the (mouse) intestinal lumen, where it could select the composition of gut microbiota by generating H2O2.
Here, some biochemical properties of the recombinant enzyme were investigated. Moreover, we focused on mistargeting of DAAO by studying a variant lacking the N-terminal signal peptide (thus shedding light on the mechanism of microbiota selection) and two variants at position 120 (a residue belonging to a putative nuclear translocation signal): the cellular targeting of the flavoenzyme seems a way to modulate hDAAO functionality. This modulation allows hDAAO to fulfil different physiological functions, such as the control of the level of D-Ser in the brain and of other D-AAs in different tissues or the selection of microbiota in the gut
Measurement of Gamma(K-S ->pi(+)pi(-)(gamma))/Gamma(K-S ->pi(0)pi(0))
No full textWe have measured the ratio R-S(pi) = Gamma(K-S --> pi(+)pi(-)(gamma))/Gamma(K-S --> pi(0)pi(0)) with the KLOE detector at the DAPhiNE e(+)e(-) collider. This measurement is fully inclusive with respect to the pi(+)pi(-)gamma final state. The sample of over 106 two-pion decays of tagged K-S mesons allows a statistical error as low as similar to 0.1% to be obtained. The accuracy is limited by systematic uncertainties, which are estimated primarily from data. We find R-S(pi) = 2.236 +/- 0.003(stat) +/- 0.015(syst). (C) 2002 Elsevier Science B.V. All rights reserved. RI Gauzzi, Paolo/D-2615-2009; valente, paolo/A-6640-2010; ANTONELLI, ANTONELLA/C-6238-2011; Di Domenico, Antonio/G-6301-2011; De Lucia, Erika/D-2250-2011; Passalacqua, Luca/F-5127-2011; branchini, paolo/A-4857-2011; Murtas, Fabrizio/B-5729-201
Diffusive author(s), cohesive author: Analysis of S/N (1994)
No full textThis study indicates the ways in which various aspects of the author(s) are brought forth in Dumb type’s performance art, the S/N production. Previous research has suggested a non-hierarchical organization of Dumb type and the absence of a “privileged author” in Dumb type’s collaborative work, S/N. However, the results that I have investigated from member’s interviews on the creative process of S/N along with my analysis of the recorded images of S/N, indicate a different aspect of the author(s). First, S/N was created through, so to speak, the collective ideas of the members of Dumb type. Further, S/N has at least nine quotations from previous performances, installations, and printed writings, besides the work-in-progress technique. Explicating one of the “author functions” as given by Michel Foucault, each text has plural subjects of the author. However, it has been revealed from members’ interviews that Teiji Furuhashi had a decision-making role in selecting the members’ ideas within the performance. Since then, S/N has had plural subjects of creation; however, Furuhashi is one of the subjects of creation along with the “privileged author.” S/N has plural authors (diffusive authors) yet at the same time, it has a “privileged author,” Teiji Furuhashi (cohesive author)
Evaluation of Residual Kidney Function during Once-Weekly Incremental Hemodialysis
No full textBackground: The initial once-weekly administration of incremental hemodialysis to patients with residual kidney function (RKF) has recently attracted considerable interest. Methods: The aim of our study was to assess the performance of a series of different methods in measuring serum urea nitrogen and serum Cr (sCr) RKF in patients on once-weekly hemodialysis (1WHD). Evaluations were carried out by means of 24-h predialysis urine collection (Kr-24H) or 6-day inter-dialysis collection (Kr-IDI) and estimation of glomerular filtration rate based on (KrSUN + KrsCr)/2 for the purpose of identifying a simple reference calculation to be used in assessing RKF in patients on 1WHD dialysis. Ninety-five urine samples were collected from 12 1WHD patients. A solute solver urea and Cr kinetic modeling program was used to calculate residual urea and Cr clearances. Mann-Whitney U test, Pearson's correlation coefficient (R), and linear determination coefficient (R-2) were used for statistical analysis. Results: 1WHD patients displayed a mean KrSUN-IDI of 4.5 +/- 1.2 mL/min, while KrSUN-24H corresponded to 4.1 +/- 0.9 mL/min, mean KrsCr-IDI to 9.1 +/- 4.0 mL/min, and KrsCr 24H to 8.9 +/- 4.2 mL/min, with a high regression between IDI and 24-h clearances (for IDI had R-2 = 0.9149 and for 24H had R-2 = 0.9595). A good correlation was also observed between KrSUN-24H and (KrSUN + KrsCR/2) (R-2 = 0.7466, p < 0.01. Discussion: Urine collection over a 24-h predialysis period yielded similar results for both KrSUN and KrsCr compared to collection over a longer interdialytic interval (KrSUN + KrsCr)/2 could be applied to reliably assess RKF in patients on 1WHD. Conclusion: The parameters evaluated are suitable for use as a routine daily method indicating the commencement and continued use of the 1WHD Incremental Program
RaDoM: A lung dosimeter for radon progeny
No full textThis paper discusses a novel Timepix-based on-line radon dose monitor called RaDoM. The detector provides a direct estimate of the effective dose to the lung via a system of filters having the same absorption characteristics as this organ and a measurement of the PAEC (the potential alpha energy concentration). Measurements performed in a reference radon chamber and in normal environmental conditions showed that RaDoM well follows changes in the radon concentration and is accurate in both long- and short-term measurements. The paper describes the detector and associated software for data acquisition and analysis, and compares the measurement of the lung dose with the value derived from a measurement of the radon concentration
MBGEM: a stack of borated GEM detector for high efficiency thermal neutron detection
No full textA new position-sensitive thermal neutron detector based on boron-coated converters has been developed as an alternative to today’s standard 3He -based technology for application to thermal neutron scattering. The key elements of the development are the boron-coated GEM foils (Sauli in Nucl Instrum Methods Phys Res Sect A Accel Spectrom Detect Assoc Equip 386:531, 1997) that are used as a multi-layer neutron converter via the 10B (n, α) 7Li reaction together with an efficient collection of the produced secondary electrons. This paper reports the test performed on a 3 layers converter prototype coupled to a GEMPix detector (Murtas in Radiat Meas 138:106421, 2020), carried out in order to study the possibility to produce a large-scale multi-layer neutron detector capable to reach high detection efficiency with high spatial resolution and able to sustain the high neutron flux expected in the new neutron spallation source under development like the ESS
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