764 research outputs found
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
Mutant p53 gain of function can be at the root of dedifferentiation of human osteosarcoma MG63 cells into 3AB-OS cancer stem cells.
Osteosarcoma is a highly metastatic tumor affecting adolescents, for which there is no second-line chemotherapy. As suggested for most tumors, its capability to overgrow is probably driven by cancer stem cells (CSCs), and finding new targets to kill CSCs may be critical for improving patient survival. TP53 is the most frequently mutated tumor suppressor gene in cancers and mutant p53 protein (mutp53) can acquire gain of function (GOF) strongly contributing to malignancy. Studies thus far have not shown p53-GOF in osteosarcoma. Here, we investigated TP53 gene status/role in 3AB-OS cells-a highly aggressive CSC line previously selected from human osteosarcoma MG63 cells-to evaluate its involvement in promoting proliferation, invasiveness, resistance to apoptosis and stemness. By RT-PCR, methylation-specific PCR, fluorescent in situ hybridization, DNA sequence, western blot and immunofluorescence analyses, we have shown that-in comparison with parental MG63 cells where TP53 gene is hypermethylated, rearranged and in single copy-in 3AB-OS cells, TP53 is unmethylated, rearranged and in multiple copies, and mutp53 (p53-R248W/P72R) is post-translationally modified and with nuclear localization. p53-R248W/P72R-knockdown by short-interfering RNA reduced the growth and replication rate of 3AB-OS cells, markedly increasing cell cycle inhibitor levels and sensitized 3AB-OS cells to TRAIL-induced apoptosis by DR5 up-regulation; moreover, it strongly decreased the levels of stemness and invasiveness genes. We have also found that the ectopic expression of p53-R248W/P72R in MG63 cells promoted cancer stem-like features, as high proliferation rate, sphere formation, clonogenic growth, high migration and invasive ability; furthermore, it strongly increased the levels of stemness proteins. Overall, the findings suggest the involvement of p53-R248W/P72R at the origin of the aberrant characters of the 3AB-OS cells with the hypothesis that its GOF can be at the root of the dedifferentiation of MG63 cells into CSCs
A telerehabilitation approach to chronic facial paralysis in the COVID-19 pandemic scenario: what role for electromyography assessment?
There is a lack of data on patient and diagnostic factors for prognostication of complete recovery in patients with peripheral facial palsy. Thus, the aim of this study was to evaluate the role of a telerehabilitave enhancement through the description of a case report with the use of short-wave diathermy and neuromuscular electrical stimulation combined to facial proprioceptive neuromuscular facilitation (PNF) rehabilitation in unrecovered facial palsy, in a COVID-19 pandemic scenario describing a paradigmatic telerehabilitation report. A 43-year-old woman underwent a facial rehabilitation plan consisting of a synergistic treatment with facial PNF rehabilitation, short-wave diathermy, and neuromuscular electrical stimulation (12 sessions lasting 45 min, three sessions/week for 4 weeks). Concerning the surface electromyography evaluation of frontal and orbicularis oris muscles, the calculated ratio between amplitude of the palsy side and normal side showed an improvement in terms of movement symmetry. At the end of the outpatient treatment, a daily telere-habilitation protocol with video and teleconsultation was provided, showing a further improvement in the functioning of a woman suffering from unresolved facial paralysis. Therefore, an adequate telerehabilitation follow-up seems to play a fundamental role in the management of patients with facial palsy
Virgo calibration and reconstruction of the gravitational wave strain during VSR1
Virgo is a kilometer-length interferometer for gravitational waves detection
located near Pisa. Its first science run, VSR1, occured from May to October
2007. The aims of the calibration are to measure the detector sensitivity and
to reconstruct the time series of the gravitational wave strain h(t). The
absolute length calibration is based on an original non-linear reconstruction
of the differential arm length variations in free swinging Michelson
configurations. It uses the laser wavelength as length standard. This method is
used to calibrate the frequency dependent response of the Virgo mirror
actuators and derive the detector in-loop response and sensitivity within ~5%.
The principle of the strain reconstruction is highlighted and the h(t)
systematic errors are estimated. A photon calibrator is used to check the sign
of h(t). The reconstructed h(t) during VSR1 is valid from 10 Hz up to 10 kHz
with systematic errors estimated to 6% in amplitude. The phase error is
estimated to be 70 mrad below 1.9 kHz and 6 micro-seconds above.Comment: 8 pages, 8 figures, proceedings of Amaldi 8 conference, to be
published in Journal of Physics Conference Series (JPCS). Second release:
correct typo
Calibration and sensitivity of the Virgo detector during its second science run
The Virgo detector is a kilometer-length interferometer for gravitational
wave detection located near Pisa (Italy). During its second science run (VSR2)
in 2009, six months of data were accumulated with a sensitivity close to its
design. In this paper, the methods used to determine the parameters for
sensitivity estimation and gravitational wave reconstruction are described. The
main quantities to be calibrated are the frequency response of the mirror
actuation and the sensing of the output power. Focus is also put on their
absolute timing. The monitoring of the calibration data as well as the
parameter estimation with independent techniques are discussed to provide an
estimation of the calibration uncertainties. Finally, the estimation of the
Virgo sensitivity in the frequency-domain is described and typical
sensitivities measured during VSR2 are shown.Comment: 30 pages, 23 figures, 1 table. Published in Classical and Quantum
Gravity (CQG), Corrigendum include
Reconstruction of the gravitational wave signal during the Virgo science runs and independent validation with a photon calibrator
The Virgo detector is a kilometer-scale interferometer for gravitational wave
detection located near Pisa (Italy). About 13 months of data were accumulated
during four science runs (VSR1, VSR2, VSR3 and VSR4) between May 2007 and
September 2011, with increasing sensitivity.
In this paper, the method used to reconstruct, in the range 10 Hz-10 kHz, the
gravitational wave strain time series from the detector signals is
described. The standard consistency checks of the reconstruction are discussed
and used to estimate the systematic uncertainties of the signal as a
function of frequency. Finally, an independent setup, the photon calibrator, is
described and used to validate the reconstructed signal and the
associated uncertainties.
The uncertainties of the time series are estimated to be 8% in
amplitude. The uncertainty of the phase of is 50 mrad at 10 Hz with a
frequency dependence following a delay of 8 s at high frequency. A bias
lower than and depending on the sky direction of the GW is
also present.Comment: 35 pages, 16 figures. Accepted by CQ
A Cross-correlation method to search for gravitational wave bursts with AURIGA and Virgo
We present a method to search for transient GWs using a network of detectors
with different spectral and directional sensitivities: the interferometer Virgo
and the bar detector AURIGA. The data analysis method is based on the
measurements of the correlated energy in the network by means of a weighted
cross-correlation. To limit the computational load, this coherent analysis step
is performed around time-frequency coincident triggers selected by an excess
power event trigger generator tuned at low thresholds. The final selection of
GW candidates is performed by a combined cut on the correlated energy and on
the significance as measured by the event trigger generator. The method has
been tested on one day of data of AURIGA and Virgo during September 2005. The
outcomes are compared to the results of a stand-alone time-frequency
coincidence search. We discuss the advantages and the limits of this approach,
in view of a possible future joint search between AURIGA and one
interferometric detector.Comment: 11 pages, 6 figures, submitted to CQG special issue for Amaldi 7
Proceeding
Sensitivity to Gravitational Waves from Compact Binary Coalescences Achieved during LIGO's Fifth and Virgo's First Science Run
We summarize the sensitivity achieved by the LIGO and Virgo gravitational
wave detectors for compact binary coalescence (CBC) searches during LIGO's
fifth science run and Virgo's first science run. We present noise spectral
density curves for each of the four detectors that operated during these
science runs which are representative of the typical performance achieved by
the detectors for CBC searches. These spectra are intended for release to the
public as a summary of detector performance for CBC searches during these
science runs.Comment: 12 pages, 5 figure
Search for Gravitational Wave Bursts from Six Magnetars
Soft gamma repeaters (SGRs) and anomalous X-ray pulsars (AXPs) are thought to be magnetars: neutron stars powered by extreme magnetic fields. These rare objects are characterized by repeated and sometimes spectacular gamma-ray bursts. The burst mechanism might involve crustal fractures and excitation of non-radial modes which would emit gravitational waves (GWs). We present the results of a search for GW bursts from six galactic magnetars that is sensitive to neutron star f-modes, thought to be the most efficient GW emitting oscillatory modes in compact stars. One of them, SGR 0501+4516, is likely similar to 1 kpc from Earth, an order of magnitude closer than magnetars targeted in previous GW searches. A second, AXP 1E 1547.0-5408, gave a burst with an estimated isotropic energy >10(44) erg which is comparable to the giant flares. We find no evidence of GWs associated with a sample of 1279 electromagnetic triggers from six magnetars occurring between 2006 November and 2009 June, in GW data from the LIGO, Virgo, and GEO600 detectors. Our lowest model-dependent GW emission energy upper limits for band-and time-limited white noise bursts in the detector sensitive band, and for f-mode ringdowns (at 1090 Hz), are 3.0 x 10(44)d(1)(2) erg and 1.4 x 10(47)d(1)(2) erg, respectively, where d(1) = d(0501)/1 kpc and d(0501) is the distance to SGR 0501+4516. These limits on GW emission from f-modes are an order of magnitude lower than any previous, and approach the range of electromagnetic energies seen in SGR giant flares for the first time.United States National Science FoundationScience and Technology Facilities Council of the United KingdomMax-Planck-SocietyState of Niedersachsen/GermanyItalian Istituto Nazionale di Fisica NucleareFrench Centre National de la Recherche ScientifiqueAustralian Research CouncilCouncil of Scientific and Industrial Research of IndiaIstituto Nazionale di Fisica Nucleare of ItalySpanish Ministerio de Educacion y CienciaConselleria d'Economia Hisenda i Innovacio of the Govern de les Illes BalearsFoundation for Fundamental Research on Matter supported by the Netherlands Organisation for Scientific ResearchPolish Ministry of Science and Higher EducationFoundation for Polish ScienceRoyal SocietyScottish Funding CouncilScottish Universities Physics AllianceNational Aeronautics and Space Administration NNH07ZDA001-GLASTCarnegie TrustLeverhulme TrustDavid and Lucile Packard FoundationResearch CorporationAlfred P. Sloan FoundationRussian Space AgencyRFBR 09-02-00166aIPN JPL Y503559 (Odyssey), NASA NNG06GH00G, NASA NNX07AM42G, NASA NNX08AC89G (INTEGRAL), NASA NNG06GI896, NASA NNX07AJ65G, NASA NNX08AN23G (Swift), NASA NNX07AR71G (MESSENGER), NASA NNX06AI36G, NASA NNX08AB84G, NASA NNX08AZ85G (Suzaku), NASA NNX09AU03G (Fermi)Astronom
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