MTOR cross-talk in cancer and potential for combination therapy

The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy

Role of mTOR signaling in tumor microenvironment. An overview

The mammalian target of rapamycin (mTOR) pathway regulates major processes by integrating a variety of exogenous cues, including diverse environmental inputs in the tumor microenvironment (TME). In recent years, it has been well recognized that cancer cells co-exist and co-evolve with their TME, which is often involved in drug resistance. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both the tumor immunity and angiogenesis. The activation of mTOR signaling is associated with these pro-oncogenic cellular processes, making mTOR a promising target for new combination therapies. This review highlights the role of mTOR signaling in the characterization and the activity of the TME’s elements and their implications in cancer immunotherapy

Meson Correlation Function and Screening Mass in Thermal QCD

Analytical results for the spatial dependence of the correlation functions for all meson excitations in perturbative Quantum Chromodynamics, the lowest order, are calculated. The meson screening mass is obtained as a large distance limit of the correlation function. Our analysis leads to a better understanding of the excitations of Quark Gluon Plasma at sufficiently large temperatures and may be of relevance for future numerical calculations with fully interacting Quantum Chromodynamics.Comment: 11 page

A model for the degradation of polyimides due to oxidation

Polyimides, due to their superior mechanical behavior at high temperatures, are used in a variety of applications that include aerospace, automobile and electronic packaging industries, as matrices for composites, as adhesives etc. In this paper, we extend our previous model in [S. Karra, K. R. Rajagopal, Modeling the non-linear viscoelastic response of high temperature polyimides, Mechanics of Materials, In press, doi:10.1016/j.mechmat.2010.09.006], to include oxidative degradation of these high temperature polyimides. Appropriate forms for the Helmholtz potential and the rate of dissipation are chosen to describe the degradation. The results for a specific boundary value problem, using our model compares well with the experimental creep data for PMR-15 resin that is aged in air.Comment: 13 pages, 2 figures, submitted to Mechanics of Time-dependent Material

Electronic structure of warm dense copper studied by ultrafast x-ray absorption spectroscopy

We use time-resolved x-ray absorption spectroscopy to investigate the unoccupied electronic density of states of warm dense copper that is produced isochorically through the absorption of an ultrafast optical pulse. The temperature of the superheated electron-hole plasma, which ranges from 4000 to 10 000 K, was determined by comparing the measured x-ray absorption spectrum with a simulation. The electronic structure of warm dense copper is adequately described with the high temperature electronic density of state calculated by the density functional theory. The dynamics of the electron temperature is consistent with a two-temperature model, while a temperature-dependent electron-phonon coupling parameter is necessary

Risk factors for recurrence in patients with Clostridium difficile infection due to 027 and non-027 ribotypes

Objectives: Our objective was to evaluate factors associated with recurrence in patients with 027+ and 027– Clostridium difficile infection (CDI). Methods: Patients with CDI observed between January and December 2014 in six hospitals were consecutively included in the study. The 027 ribotype was deduced by the presence of tcdB, tcdB, cdt genes and the deletion Δ117 in tcdC (Xpert® C. difficile/Epi). Recurrence was defined as a positive laboratory test result for C. difficile more than 14 days but within 8 weeks after the initial diagnosis date with reappearance of symptoms. To identify factors associated with recurrence in 027+ and 027– CDI, a multivariate analysis was performed in each patient group. Subdistributional hazard ratios (sHRs) and 95% confidence intervals (95%CIs) were calculated. Results: Overall, 238 patients with 027+ CDI and 267 with 027– CDI were analysed. On multivariate analysis metronidazole monotherapy (sHR 2.380, 95%CI 1.549–3.60, p <0.001) and immunosuppressive treatment (sHR 3.116, 95%CI 1.906–5.090, p <0.001) were factors associated with recurrence in patients with 027+ CDI. In this patient group, metronidazole monotherapy was independently associated with recurrence in both mild/moderate (sHR 1.894, 95%CI 1.051–3.410, p 0.033) and severe CDI (sHR 2.476, 95%CI 1.281–4.790, p 0.007). Conversely, non-severe disease (sHR 3.704, 95%CI 1.437–9.524, p 0.007) and absence of chronic renal failure (sHR 16.129, 95%CI 2.155–125.000, p 0.007) were associated with recurrence in 027– CDI. Conclusions: Compared to vancomycin, metronidazole monotherapy appears less effective in curing CDI without relapse in the 027+ patient group, independently of disease severity

Results from the Milagrito experiment

The Milagro water Cherenkov detector near Los Alamos, New Mexico is the first air shower detector capable of continuously monitoring the sky at energies between 500 GeV and 20 TeV. Preliminary results of the Milagro experiment are presented. A predecessor of the Milagro detector, Milagrito, was operational from February 1997 to May 1998. Milagrito consisted of 228 8″ photomultiplier tubes (PMTs) arranged in a grid with a 2.8 meter spacing and submerged in 1–2 meters of water. During its operation, Milagrito collected in excess of 9 billion events with a median energy of about 3 TeV. The detector’s sensitivity extends below 1 TeV for showers from near zenith. The results of an all sky search for the Milagrito data for both transient and DC sources will be presented, including the Crab Nebula and active galaxies Markarian 501 and 421, which are known sources of TeV gamma-rays. Also presented will be a study of the TeV emission from gamma ray bursts (GRBs) in Milagrito’s field of view detected by the BATSE experiment on the Compton Gamma-Ray Observatory

Milagro: A TeV gamma-ray monitor of the Northern Hemisphere Sky

A new type of very high energy (\u3e a few 100 GeV) gamma-ray observatory, Milagro, has been built with a large field of view of \u3e1 steradian and nearly 24 hours/day operation. Milagrito, a prototype for Milagro, was operated from February 1997 to May 1998. During the summer of 1998, Milagrito was dismantled and Milagro was built. Both detectors use a 80 m×60 m×8 mpond of water in which a 3 m×3 m grid of photomultiplier tubes detects the Cherenkov light produced in the water by the relativistic particles in extensive air showers. Milagrito was smaller and had only one layer of photomultipliers, but allowed the technique to be tested. Milagrito observations of the Moon’s shadow and Mrk 501 are consistent with the Monte Carlo prediction of the telescopes parameters, such as effective area and angular resolution. Milagro is larger and consists of two layers of photomultiplier tubes. The bottom layer detects penetrating particles that are used to reject the background of cosmic-ray initiated showers