Sensitization of cervix cancer cells to Adriamycin by Pentoxifylline induces an increase in apoptosis and decrease senescence

<p>Abstract</p> <p>Background</p> <p>Chemotherapeutic drugs like Adriamycin (ADR) induces apoptosis or senescence in cancer cells but these cells often develop resistance and generate responses of short duration or complete failure. The methylxantine drug Pentoxifylline (PTX) used routinely in the clinics setting for circulatory diseases has been recently described to have antitumor properties. We evaluated whether pretreatment with PTX modifies apoptosis and senescence induced by ADR in cervix cancer cells.</p> <p>Methods</p> <p>HeLa (HPV 18+), SiHa (HPV 16+) cervix cancer cells and non-tumorigenic immortalized HaCaT cells (control) were treated with PTX, ADR or PTX + ADR. The cellular toxicity of PTX and survival fraction were determinated by WST-1 and clonogenic assay respectively. Apoptosis, caspase activation and ADR efflux rate were measured by flow cytometry, senescence by microscopy. IκBα and DNA fragmentation were determinated by ELISA. Proapoptotic, antiapoptotic and senescence genes, as well as HPV-E6/E7 mRNA expression, were detected by time real RT-PCR. p53 protein levels were assayed by Western blot.</p> <p>Results</p> <p>PTX is toxic (WST-1), affects survival (clonogenic assay) and induces apoptosis in cervix cancer cells. Additionally, the combination of this drug with ADR diminished the survival fraction and significantly increased apoptosis of HeLa and SiHa cervix cancer cells. Treatments were less effective in HaCaT cells. We found caspase participation in the induction of apoptosis by PTX, ADR or its combination. Surprisingly, in spite of the antitumor activity displayed by PTX, our results indicate that methylxantine, <it>per se </it>does not induce senescence; however it inhibits senescence induced by ADR and at the same time increases apoptosis. PTX elevates IκBα levels. Such sensitization is achieved through the up-regulation of proapoptotic factors such as <it>caspase </it>and <it>bcl </it>family gene expression. PTX and PTX + ADR also decrease E6 and E7 expression in SiHa cells, but not in HeLa cells. p53 was detected only in SiHa cells treated with ADR.</p> <p>Conclusion</p> <p>PTX is a good inducer of apoptosis but does not induce senescence. Furthermore, PTX reduced the ADR-induced senescence and increased apoptosis in cervix cancer cells.</p

Milagro limits and HAWC sensitivity for the rate-density of evaporating Primordial Black Holes

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On the sensitivity of the HAWC observatory to gamma-ray bursts

We present the sensitivity of HAWC to Gamma Ray Bursts (GRBs). HAWC is a very high-energy gamma-ray observatory currently under construction in Mexico at an altitude of 4100 m. It will observe atmospheric air showers via the water Cherenkov method. HAWC will consist of 300 large water tanks instrumented with 4 photomultipliers each. HAWC has two data acquisition (DAQ) systems. The main DAQ system reads out coincident signals in the tanks and reconstructs the direction and energy of individual atmospheric showers. The scaler DAQ counts the hits in each photomultiplier tube (PMT) in the detector and searches for a statistical excess over the noise of all PMTs. We show that HAWC has a realistic opportunity to observe the high-energy power law components of GRBs that extend at least up to 30 GeV, as it has been observed by Fermi LAT. The two DAQ systems have an energy threshold that is low enough to observe events similar to GRB 090510 and GRB 090902b with the characteristics observed by Fermi LAT. HAWC will provide information about the high-energy spectra of GRBs which in turn could help to understanding about e-pair attenuation in GRB jets, extragalactic background light absorption, as well as establishing the highest energy to which GRBs accelerate particles

The Great Markarian 421 Flare of 2010 February: Multiwavelength Variability and Correlation Studies

We report on variability and correlation studies using multiwavelength observations of the blazar Mrk 421 during the month of 2010 February, when an extraordinary flare reaching a level of ∼27 Crab Units above 1 TeV was measured in very high energy (VHE) γ-rays with the Very Energetic Radiation Imaging Telescope Array System (VERITAS) observatory. This is the highest flux state for Mrk 421 ever observed in VHE γ-rays. Data are analyzed from a coordinated campaign across multiple instruments, including VHE γ-ray (VERITAS, Major Atmospheric Gamma-ray Imaging Cherenkov), high-energy γ-ray (Fermi-LAT), X-ray (Swift, Rossi X-ray Timing Experiment, MAXI), optical (including the GASP-WEBT collaboration and polarization data), and radio (Metsahovi, Owens Valley Radio Observatory, University of Michigan Radio Astronomy Observatory). Light curves are produced spanning multiple days before and after the peak of the VHE flare, including over several flare "decline" epochs. The main flare statistics allow 2 minute time bins to be constructed in both the VHE and optical bands enabling a cross-correlation analysis that shows evidence for an optical lag of ∼25-55 minutes, the first time-lagged correlation between these bands reported on such short timescales. Limits on the Doppler factor (δ ⪆ 33) and the size of the emission region (δ-1RB≲ 3.8 × 1013cm) are obtained from the fast variability observed by VERITAS during the main flare. Analysis of 10 minute binned VHE and X-ray data over the decline epochs shows an extraordinary range of behavior in the flux-flux relationship, from linear to quadratic to lack of correlation to anticorrelation. Taken together, these detailed observations of an unprecedented flare seen in Mrk 421 are difficult to explain with the classic single-zone synchrotron self-Compton model.</p

All-sky measurement of the anisotropy of cosmic rays at 10 TeV and mapping of the local interstellar magnetic field

We present the first full-sky analysis of the cosmic ray arrival direction distribution with data collected by the High-Altitude Water Cherenkov and IceCube observatories in the northern and southern hemispheres at the same median primary particle energy of 10 TeV. The combined sky map and angular power spectrum largely eliminate biases that result from partial sky coverage and present a key to probe into the propagation properties of TeV cosmic rays through our local interstellar medium and the interaction between the interstellar and heliospheric magnetic fields. From the map, we determine the horizontal dipole components of the anisotropy δ0h= 9.16×10¯⁴ and δ6h=7.25×10¯⁴(±0.04 × 10¯⁴). In addition, we infer the direction (229°.2 ± 3°.5 R.A., 11°.4 ± 3°.0 decl.) of the interstellar magnetic field from the boundary between large-scale excess and deficit regions from which we estimate the missing corresponding vertical dipole component of the large-scale anisotropy to be δN ~ 3.97 −₂⋅₀¯¹·⁰ ×10¯⁴A. U. Abeysekara, R. Alfaro, C. Alvarez, R. Arceo, J. C. Arteaga-Velázquez ... Gary C. Hill ... et al. (HAWC Collaboration and IceCube Collaboration