Minnelide Overcomes Oxaliplatin Resistance by Downregulating the DNA Repair Pathway in Pancreatic Cancer

INTRODUCTION: Oxaliplatin is part of pancreatic cancer therapy in FOLFIRINOX or GEMOX/XELOX regimen. DNA damage repair is one of the factors responsible for oxaliplatin resistance that eventually develops in this cancer. Triptolide/Minnelide has been shown to be effective against pancreatic cancer in preclinical trials. In this study, we evaluated the efficacy of combination of triptolide and oxaliplatin against pancreatic cancer. METHODS: Highly aggressive pancreatic cancer cells (MIA PaCa-2 and PANC-1) were treated with oxaliplatin (0-10μM), low dose triptolide (50nM) or a combination of both for 24-48h. Cell viability, apoptosis and DNA damage was evaluated by appropriate methods. Nucleotide excision repair pathway components were quantitated using qPCR and western blot. Combination of low doses of Minnelide and oxaliplatin was tested in an orthotopic murine model of pancreatic cancer. RESULTS: Proliferation of pancreatic cancer cells was markedly inhibited by combination treatment. Triptolide potentiated apoptotic cell death induced by oxaliplatin and sensitized cancer cells towards oxaliplatin induced DNA damage by suppressing oxaliplatin induced DNA damage repair pathway. Combination of low doses of Minnelide and oxaliplatin inhibited tumor progression by inducing significant apoptotic cell death in these tumors. CONCLUSIONS: Combination of low doses of Minnelide and oxaliplatin has immense potential to emerge as novel therapeutic strategy against pancreatic cancer

Determination of the top-quark pole mass and strong coupling constant from the ttbar production cross section in pp collisions at sqrt(s) = 7 TeV

The inclusive cross section for top-quark pair production measured by the CMS experiment in proton-proton collisions at a center-of-mass energy of 7 TeV is compared to the QCD prediction at next-to-next-to-leading order with various parton distribution functions to determine the top-quark pole mass, mtpole, or the strong coupling constant, alphaS. With the parton distribution function set NNPDF2.3, a pole mass of 176.7 +3.8 -3.4 GeV is obtained when constraining alphaS at the scale of the Z boson mass, mZ, to the current world average. Alternatively, by constraining mtpole to the latest average from direct mass measurements, a value of alphaS(mZ) = 0.1151 +0.0033 -0.0032 is extracted. This is the first determination of alphaS using events from top-quark production

Description and performance of track and primary-vertex reconstruction with the CMS tracker

A description is provided of the software algorithms developed for the CMS tracker both for reconstructing charged-particle trajectories in proton-proton interactions and for using the resulting tracks to estimate the positions of the LHC luminous region and individual primary-interaction vertices. Despite the very hostile environment at the LHC, the performance obtained with these algorithms is found to be excellent. For t (t) over bar events under typical 2011 pileup conditions, the average track-reconstruction efficiency for promptly-produced charged particles with transverse momenta of p(T) > 0.9GeV is 94% for pseudorapidities of vertical bar eta vertical bar < 0.9 and 85% for 0.9 < vertical bar eta vertical bar < 2.5. The inefficiency is caused mainly by hadrons that undergo nuclear interactions in the tracker material. For isolated muons, the corresponding efficiencies are essentially 100%. For isolated muons of p(T) = 100GeV emitted at vertical bar eta vertical bar < 1.4, the resolutions are approximately 2.8% in p(T), and respectively, 10 m m and 30 mu m in the transverse and longitudinal impact parameters. The position resolution achieved for reconstructed primary vertices that correspond to interesting pp collisions is 10-12 mu m in each of the three spatial dimensions. The tracking and vertexing software is fast and flexible, and easily adaptable to other functions, such as fast tracking for the trigger, or dedicated tracking for electrons that takes into account bremsstrahlung

Alignment of the CMS tracker with LHC and cosmic ray data

The central component of the CMS detector is the largest silicon tracker ever built. The precise alignment of this complex device is a formidable challenge, and only achievable with a significant extension of the technologies routinely used for tracking detectors in the past. This article describes the full-scale alignment procedure as it is used during LHC operations. Among the specific features of the method are the simultaneous determination of up to 200 000 alignment parameters with tracks, the measurement of individual sensor curvature parameters, the control of systematic misalignment effects, and the implementation of the whole procedure in a multiprocessor environment for high execution speed. Overall, the achieved statistical accuracy on the module alignment is found to be significantly better than 10 mu m