The ubiquitin–proteasome system as a molecular target in solid tumors: an update on bortezomib

The ubiquitin–proteasome system has become a promising molecular target in cancer therapy due to its critical role in cellular protein degradation, interaction with cell cycle and apoptosis regulation, and unique mechanism of action. Bortezomib (PS-341) is a potent and specific reversible proteasome inhibitor, which has shown strong in vitro antitumor activity as single agent and in combination with other cytotoxic drugs in a broad spectrum of hematological and solid malignancies. In preclinical studies, bortezomib induced apoptosis of malignant cells through the inhibition of NF-|B and stabilization of pro-apoptotic proteins. Bortezomib also promotes chemo- and radiosensitization of malignant cells in vitro and inhibits tumor growth in murine xenograft models. The proteasome has been established as a relevant target in hematologic malignancies and bortezomib has been approved for the treatment of multiple myeloma. This review summarizes recent data from clinical trials in solid tumors

Position and velocity space diffusion of test particles in stochastic electromagnetic fields

The two--dimensional diffusive dynamics of test particles in a random electromagnetic field is studied. The synthetic electromagnetic fluctuations are generated through randomly placed magnetised ``clouds'' oscillating with a frequency $\omega$. We investigate the mean square displacements of particles in both position and velocity spaces. As $\omega$ increases the particles undergo standard (Brownian--like) motion, anomalous diffusion and ballistic motion in position space. Although in general the diffusion properties in velocity space are not trivially related to those in position space, we find that energization is present only when particles display anomalous diffusion in position space. The anomalous character of the diffusion is only in the non--standard values of the scaling exponents while the process is Gaussian.Comment: 10 pages, 4 figure

Study of PVI-based diagnostics for 1D time-series in space plasma

Context. In the last few decades, increasing evidence has been found in both numerical studies and high-resolution in situ data that magnetic turbulence spontaneously generates coherent structures over a broad range of scales. Those structures play a key role in energy conversion because they are sites where magnetic energy is locally dissipated in plasma heating and particle energization. How much turbulent energy is dissipated via processes such as magnetic reconnection of thin coherent structures, namely current sheets, remains an open question. Aims. We aim to develop semi-automated methods for detecting reconnection sites over multiple spatial scales. This is indeed pivotal in advancing our knowledge of plasma dissipation mechanisms and for future applications to space data. Methods. By means of hybrid-Vlasov-Maxwell 2D-3V simulations, we combine three methods based on the partial variance of increments measured at a broad range of spatial scales and on the current density, which together, and in a synergistic way, provide indications as to the presence of sites of magnetic reconnection. We adopt the virtual satellite method, which in upcoming works will allow us to easily extend this analysis to in situ time-series. Results. We show how combining standard threshold analysis to a 2D scalogram based on magnetic field increments represents an efficient diagnostic for recognizing reconnecting structure in 1D spatial- and time-series. This analysis can serve as input to automated machine-learning algorithms

Teaching business ethics: Plato was right

Ethical lapses in major corporations continue to draw public attention to the specter of corporate misconduct. This paper presents a pedagogical approach that is designed to enhance student understanding and appreciation of the challenges that business leaders face when confronted with the conflict between the profit-maximizing demands of capitalism and the ethical expectations of society. This is an approach that fully acknowledges the seductive nature of unethical conduct in search of corporate rewards. This paper presents a method which can be applied both in undergraduate and graduate coursework, facilitates the examination of two corruption cases (Enron and WorldCom), and highlights short-term gain versus the eventual long-term pain of unethical behavior

a smart nanofibrous material for adsorbing and detecting elemental mercury in air

Abstract. The combination of the affinity of gold for mercury and nanosized frameworks has allowed for the design and fabrication of novel kinds of sensors with promising sensing features for environmental applications. Specifically, conductive sensors based on composite nanofibrous electrospun layers of titania easily decorated with gold nanoparticles were developed to obtain nanostructured hybrid materials capable of entrapping and revealing gaseous elemental mercury (GEM) traces from the environment. The electrical properties of the resulting chemosensors were measured. A few minutes of air sampling were sufficient to detect the concentration of mercury in the air, ranging between 20 and 100 ppb, without using traps or gas carriers (LOD: 1.5 ppb). Longer measurements allowed the sensor to detect lower concentrations of GEM. The resulting chemosensors are expected to be low cost and very stable (due to the peculiar structure), requiring low power, low maintenance, and simple equipment

The 26 year-long X-ray light curve and the X-ray spectrum of the BL Lac Object 1E 1207.9+3945 in its brightest state

We studied the temporal and spectral evolution of the synchrotron emission from the high energy peaked BL Lac object 1E 1207.9+3945. Two recent observations have been performed by the XMM-Newton and Swift satellites; we carried out X-ray spectral analysis for both of them, and photometry in optical-ultraviolet filters for the Swift one. Combining the results thus obtained with archival data we built the long-term X-ray light curve, spanning a time interval of 26 years, and the Spectral Energy Distribution (SED) of this source. The light curve shows a large flux increasing, about a factor of six, in a time interval of a few years. After reaching its maximum in coincidence with the XMM-Newton pointing in December 2000 the flux decreased in later years, as revealed by Swift. The very good statistics available in the 0.5-10 keV XMM-Newton X-ray spectrum points out a highly significant deviation from a single power law. A log-parabolic model with a best fit curvature parameter of 0.25 and a peak energy at ~1 keV describes well the spectral shape of the synchrotron emission. The simultaneous fit of Swift UVOT and XRT data provides a milder curvature (b~0.1) and a peak at higher energies (~15 keV), suggesting a different state of source activity. In both cases UVOT data support the scenario of a single synchrotron emission component extending from the optical/UV to the X-ray band. New X-ray observations are important to monitor the temporal and spectral evolution of the source; new generation gamma-ray telescopes like AGILE and GLAST could for the first time detect its inverse Compton emission.Comment: 7 pages, 6 figures, accepted for publication in A&

Log-parabolic spectra and particle acceleration in blazars - II: The BeppoSAX wide band X-ray spectra of Mkn 501

We present the results of a spectral and temporal study of the complete set of BeppoSAX NFI (11) and WFC (71) observations of the BL Lac object Mkn 501. The WFC 2-28 keV data, reported here for the first time, were collected over a period of about five years, from September 1996 to October 2001. These observations, although not evenly distributed, show that Mkn 501, after going through a very active phase from spring 1997 to early 1999, remained in a low brightness state until late 2001. The data from the LECS, MECS and PDS instruments, covering the wide energy interval 0.1-150 keV, have been used to study in detail the spectral variability of the source. We show that the X-ray energy distribution of Mkn 501 is well described by a log-parabolic law in all luminosity states. This model allowed us to obtain good estimates of the SED synchrotron peak energy and of its associated power. The strong spectral variability observed, consisting of strictly correlated changes between the synchrotron peak energy and bolometric flux, suggests that the main physical changes are not only due to variations of the maximum Lorentz factor of the emitting particles but that other quantities must be varying as well. During the 1997 flare the high energy part of the spectrum of Mkn 501 shows evidence of an excess above the best fit log-parabolic law suggesting the existence of a second emission component that may be responsible for most of the observed variability.Comment: Accepted for publication in Astronomy & Astrophysics (11 pages, 7 figures