Comparison of the TaqMan and LightCycler systems in pharmacogenetic testing: evaluation of the CYP2C9*2/*3 polymorphisms.

Background: Pharmacogenetic testing for drugmetabolizing enzymes is not yet widely used in clinical practice. Methods: In an attempt to facilitate the application of this procedure, we have compared two real-time PCRbased methods, the TaqMan_ and the LightCycler_ for the pharmacogenetic evaluation of CYP2C9*2/*3 polymorphisms. Results and Conclusion: Both procedures are suitable for pharmacogenetic studies. The TaqMan procedure was less expensive in terms of cost per sample, but the TaqMan apparatus is more expensive than the LightCycler apparatus

Isolation of gravitational waves from displacement noise and utility of a time-delay device

Interferometers with kilometer-scale arms have been built for gravitational-wave detections on the ground; ones with much longer arms are being planned for space-based detection. One fundamental motivation for long baseline interferometry is from displacement noise. In general, the longer the arm length L, the larger the motion the gravitational-wave induces on the test masses, until L becomes comparable to the gravitational wavelength. Recently, schemes have been invented, in which displacement noises can be evaded by employing differences between the influence of test-mass motions and that of gravitational waves on light propagation. However, in these schemes, such differences only becomes significant when L approaches the gravitational wavelength, and shot-noise limited sensitivity becomes worse than that of conventional configurations by a factor of at least (f L/c)^(-2), for f<c/L. Such a factor, although can be overcome theoretically by employing high optical powers, makes these schemes quite impractical. In this paper, we explore the use of time delay in displacement-noise-free interferometers, which can improve their shot-noise-limited sensitivity at low frequencies, to a factor of (f L/c)^(-1) of the shot-noise-limited sensitivity of conventional configurations.Comment: 10 pages, 12 figures, a proceeding for the Spanish Relativity Meeting ERE 200

Nonclassical Light in Interferometric Measurements

It is shown that the even and odd coherent light and other nonclassical states of light like superposition of coherent states with different phases may replace the squeezed light in interferometric gravitational wave detector to increase its sensitivity. (Contribution to the Second Workshop on Harmonic Oscillator, Cocoyoc, Mexico, March 1994)Comment: 8 pages,LATEX,preprint of Naples University, INFN-NA-IV-94/30,DSF-T-94/3

Okadaic acid-Parthenolide combination at subtoxic doses induces potent synergistic apoptotic effects in human retinoblastoma Y79 cells by upregulating PTEN.

Retinoblastoma is the most common intraocular malignancy afflicting children. The incidence is higher in developing countries, where treatment is limited and long-term survival rates are low. Vincristine, etoposide, and carboplatin -the agents commonly used in the treatment of retinoblastoma- determine side effects causing significant morbidity to pediatric patients and significantly limiting dosing. Thus, identifying new drugs and molecular targets to facilitate the development of novel therapeutics, and finding natural drug combinations to kill cancer cells by synergistically acting at subtoxic doses, may be a good goal. Here, we investigated the effects of two natural compounds, okadaic acid (OKA) and parthenolide (PN), in human retinoblastoma Y79 cells. We showed that OKA/PN combination at subtoxic doses induces potent synergistic apoptotic effects accompanied by decrease in p-Akt, increase in the stabilized p53 forms and potent decrease in pS166\u2013Mdm2. We also showed the key involvement of PTEN which, after OKA/PN treatment, potently increased before p53, suggesting that p53 activation was under PTEN action. PTEN-knockdown increased p-Akt/ pS166Mdm2 over basal levels and significantly lowered p53, while OKA/PN treatment failed both to lower p-Akt and pS166\u2013Mdm2 and to increase p53 below/over their basal levels respectively. OKA/PN treatment potently increased ROS levels while decreased those of GSH. Reducing cellular GSH by butathionine-sulfoximine treatment significantly anticipated the cytotoxic effect exerted by OKA/PN. The effects of OKA/PN treatment on both GSH content and cell viability were less pronounced in PTEN silenced cells than in control cells. Our study reports for the first time both a synergistic apoptotic action between OKA and PN and the involvement of PTEN as key player in the apoptotic mechanism in human retinoblastoma Y79 cells. The results provide strong suggestion for combined inhibition of the PTEN/Akt/Mdm2/p53 pathway

In human retinoblastoma Y79 cells okadaic acid\u2013parthenolide co-treatment induces synergistic apoptotic effects, with PTEN as a key player.

Retinoblastoma is the most common intraocular malignancy of childhood. In developing countries, treatment is limited, long-term survival rates are low and current chemotherapy causes significant morbidity to pediatric patients and significantly limits dosing. Therefore there is an urgent need to identify new therapeutic strategies to improve the clinical outcome of patients with retinoblastoma. here, we investigated the effects of two natural compounds okadaic acid (OKa) and parthenolide (PN) on human retinoblastoma Y79 cells. For the first time we showed that OKa/PN combination at subtoxic doses induces potent synergistic apoptotic effects accompanied by lowering in p-akt levels, increasing in the stabilized forms of p53 and potent decrease in ps166-Mdm2. We also showed the key involvement of PTeN which, after OKa/PN treatment, potently increased before p53, thus suggesting that p53 activation was under PTeN action. Moreover, after PTEN-knockdown p-akt/ ps166Mdm2 increased over basal levels and p53 significantly lowered, while OKa/PN treatment failed both to lower p-akt and ps166-Mdm2 and to increase p53 below/over their basal levels respectively. OKa/PN treatment potently increased ROs levels whereas decreased those of Gsh. Reducing cellular Gsh by l-butathionine-[s,R]-sulfoximine treatment significantly anticipated the cytotoxic effect exerted by OKa/ PN. Furthermore, the effects of OKa/PN treatment on both Gsh content and cell viability were less pronounced in PTeN silenced cells than in control cells. The results provide strong suggestion for combining a treatment approach that targets the PTeN/akt/Mdm2/p53 pathway

Performance of the diamond active target prototype for the PADME experiment at the DAΦ\PhiNE BTF

The PADME experiment at the DA$\Phi$NE Beam-Test Facility (BTF) is designed to search for the gauge boson of a new $\rm U(1)$ interaction in the process e$^+$e$^-\rightarrow\gamma$+$\rm A'$, using the intense positron beam hitting a light target. The $\rm A'$, usually referred as dark photon, is assumed to decay into invisible particles of a secluded sector and it can be observed by searching for an anomalous peak in the spectrum of the missing mass measured in events with a single photon in the final state. The measurement requires the determination of the 4-momentum of the recoil photon, performed by a homogeneous, highly segmented BGO crystals calorimeter. A significant improvement of the missing mass resolution is possible using an active target capable to determine the average position of the positron bunch with a resolution of less than 1 mm. This report presents the performance of a real size $\rm (2x2 cm^2)$ PADME active target made of a thin (50 $\mu$m) diamond sensor, with graphitic strips produced via laser irradiation on both sides. The measurements are based on data collected in a beam test at the BTF in November 2015.Comment: 7 pages, 10 figure

Parthenolide generates reactive oxygen species and autophagy in MDA-MB231 cells. A soluble parthenolide analogue inhibits tumour growth and metastasis in a xenograft model of breast cancer.

Triple-negative breast cancers (TNBCs) are clinically aggressive forms associated with a poor prognosis. We evaluated the cytotoxic effect exerted on triple-negative MDA-MB231 breast cancer cells both by parthenolide and its soluble analogue dimethylamino parthenolide (DMAPT) and explored the underlying molecular mechanism. The drugs induced a dose- and timedependent decrement in cell viability, which was not prevented by the caspase inhibitor z-VAD-fmk. In particular in the first hours of treatment (1–3 h), parthenolide and DMAPT strongly stimulated reactive oxygen species (ROS) generation. The drugs induced production of superoxide anion by activating NADPH oxidase. ROS generation caused depletion of thiol groups and glutathione, activation of c-Jun N-terminal kinase (JNK) and downregulation of nuclear factor kB (NF-kB). During this first phase, parthenolide and DMAPT also stimulated autophagic process, as suggested by the enhanced expression of beclin-1, the conversion of microtubule-associated protein light chain 3-I (LC3-I) to LC3-II and the increase in the number of cells positive to monodansylcadaverine. Finally, the drugs increased RIP-1 expression. This effect was accompanied by a decrement of pro-caspase 8, while its cleaved form was not detected and the expression of c-FLIPS markedly increased. Prolonging the treatment (5–20 h) ROS generation favoured dissipation of mitochondrial membrane potential and the appearance of necrotic events, as suggested by the increased number of cells positive to propidium iodide staining. The administration of DMAPT in nude mice bearing xenografts of MDA-MB231 cells resulted in a significant inhibition of tumour growth, an increment of animal survival and a marked reduction of the lung area invaded by metastasis. Immunohistochemistry data revealed that treatment with DMAPT reduced the levels of NF-kB, metalloproteinase-2 and -9 and vascular endothelial growth factor, while induced upregulation of phosphorylated JNK. Taken together, our data suggest a possible use of parthenolide for the treatment of TNBCs

Limits on the high redshift growth of massive black holes

We place firm upper limits on the global accretion history of massive black holes at z>5 from the recently measured unresolved fraction of the cosmic X-ray background. The maximum allowed unresolved intensity observed at 1.5 keV implies a maximum accreted-mass density onto massive black holes of rho_acc < 1.4E4 M_sun Mpc^{-3} for z>5. Considering the contribution of lower-z AGNs, the value reduces to rho_acc < 0.66E4 M_sun Mpc^{-3}. The tension between the need for the efficient and rapid accretion required by the observation of massive black holes already in place at z>7 and the strict upper limit on the accreted mass derived from the X-ray background may indicate that black holes are rare in high redshift galaxies, or that accretion is efficient only for black holes hosted by rare galaxies.Comment: 5 pages, 1 figure, published in A&A Letter

Critical behavior of 3D SU(2) gauge theory at finite temperature: exact results from universality

We show that universality arguments, namely the Svetitsky-Yaffe conjecture, allow one to obtain exact results on the critical behavior of 3D SU(2) gauge theory at the finite temperature deconfinement transition,through a mapping into the 2D Ising model. In particular, we consider the finite-size scaling behavior of the plaquette operator, which can be mapped into the energy operator of the 2D Ising model. We obtain exact predictions for the dependence of the plaquette expectation value on the size and shape of the lattice and we compare them to Monte Carlo results, finding complete agreement. We discuss the application of this method to the computation of more general correlators of the plaquette operator at criticality, and its relevance to the study of the color flux tube structure.Comment: 10 pages, LaTeX file + 3 eps figure

Earth-Moon Lagrangian points as a testbed for general relativity and effective field theories of gravity

We first analyse the restricted four-body problem consisting of the Earth, the Moon and the Sun as the primaries and a spacecraft as the planetoid. This scheme allows us to take into account the solar perturbation in the description of the motion of a spacecraft in the vicinity of the stable Earth-Moon libration points L4 and L5 both in the classical regime and in the context of effective field theories of gravity. A vehicle initially placed at L4 or L5 will not remain near the respective points. In particular, in the classical case the vehicle moves on a trajectory about the libration points for at least 700 days before escaping away. We show that this is true also if the modified long-distance Newtonian potential of effective gravity is employed. We also evaluate the impulse required to cancel out the perturbing force due to the Sun in order to force the spacecraft to stay precisely at L4 or L5. It turns out that this value is slightly modified with respect to the corresponding Newtonian one. In the second part of the paper, we first evaluate the location of all Lagrangian points in the Earth-Moon system within the framework of general relativity. For the points L4 and L5, the corrections of coordinates are of order a few millimeters and describe a tiny departure from the equilateral triangle. After that, we set up a scheme where the theory which is quantum corrected has as its classical counterpart the Einstein theory, instead of the Newtonian one. In other words, we deal with a theory involving quantum corrections to Einstein gravity, rather than to Newtonian gravity. By virtue of the effective-gravity correction to the long-distance form of the potential among two point masses, all terms involving the ratio between the gravitational radius of the primary and its separation from the planetoid get modified. Within this framework, for the Lagrangian points of stable equilibrium, we find quantum corrections of order two millimeters, whereas for Lagrangian points of unstable equilibrium we find quantum corrections below a millimeter. In the latter case, for the point L1, general relativity corrects Newtonian theory by 7.61 meters, comparable, as an order of magnitude, with the lunar geodesic precession of about 3 meters per orbit. The latter is a cumulative effect accurately measured at the centimeter level through the lunar laser ranging positioning technique. Thus, it is possible to study a new laser ranging test of general relativity to measure the 7.61-meter correction to the L1 Lagrangian point, an observable never used before in the Sun-Earth-Moon system. Performing such an experiment requires controlling the propulsion to precisely reach L1, an instrumental accuracy comparable to the measurement of the lunar geodesic precession, understanding systematic effects resulting from thermal radiation and multi-body gravitational perturbations. This will then be the basis to consider a second-generation experiment to study deviations of effective field theories of gravity from general relativity in the Sun-Earth-Moon system