DNA Methylation-Independent Reversion of Gemcitabine Resistance by Hydralazine in Cervical Cancer Cells

BACKGROUND: Down regulation of genes coding for nucleoside transporters and drug metabolism responsible for uptake and metabolic activation of the nucleoside gemcitabine is related with acquired tumor resistance against this agent. Hydralazine has been shown to reverse doxorubicin resistance in a model of breast cancer. Here we wanted to investigate whether epigenetic mechanisms are responsible for acquiring resistance to gemcitabine and if hydralazine could restore gemcitabine sensitivity in cervical cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: The cervical cancer cell line CaLo cell line was cultured in the presence of increasing concentrations of gemcitabine. Down-regulation of hENT1 & dCK genes was observed in the resistant cells (CaLoGR) which was not associated with promoter methylation. Treatment with hydralazine reversed gemcitabine resistance and led to hENT1 and dCK gene reactivation in a DNA promoter methylation-independent manner. No changes in HDAC total activity nor in H3 and H4 acetylation at these promoters were observed. ChIP analysis showed H3K9m2 at hENT1 and dCK gene promoters which correlated with hyper-expression of G9A histone methyltransferase at RNA and protein level in the resistant cells. Hydralazine inhibited G9A methyltransferase activity in vitro and depletion of the G9A gene by iRNA restored gemcitabine sensitivity. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that acquired gemcitabine resistance is associated with DNA promoter methylation-independent hENT1 and dCK gene down-regulation and hyper-expression of G9A methyltransferase. Hydralazine reverts gemcitabine resistance in cervical cancer cells via inhibition of G9A histone methyltransferase

RPC upgrade project for CMS Phase II

The Muon Upgrade Phase II of the Compact Muon Solenoid (CMS) aims to guarantee the optimal conditions of the present system and extend the eta coverage to ensure a reliable system for the High Luminosity Large Hadron Collider (HL-LHC) period. The Resistive Plate Chambers (RPCs) system will upgrade the off-detector electronics (called link system) of the chambers currently installed chambers and place improved RPCs (iRPCs) to cover the high pseudo-rapidity region, a challenging region for muon reconstruction in terms of background and momentum resolution. In order to find the best option for the iRPCs, an R&D program for new detectors was performed and real size prototypes have been tested in the Gamma Irradiation Facility (GIF++) at CERN. The results indicated that the technology suitable for the high background conditions is based on High Pressure Laminate (HPL) double-gap RPC. The RPC Upgrade Phase II program is planned to be ready after the Long Shutdown 3 (LS3)

High voltage calibration method for the CMS RPC detector

The Resistive Plate Chambers (RPC) are used for muon triggers in the CMS experiment. To calibrate the high voltage working-points (WP) and identify degraded detectors due to radiation or chemical damage, a high voltage scan has been performed using 2017 data from pp collisions at a center-of-mass energy of 13 TeV. In this paper, we present the calibration method and the latest results obtained for the 2017 data. A comparison with all scans taken since 2011 is considered to investigate the stability of the detector performance in time

RPC radiation background simulations for the high luminosity phase in the CMS experiment

The high luminosity expected from the HL-LHC will be a challenge for the CMS detector. The increased rate of particles coming from the collisions and the radioactivity induced in the detector material could cause significant damage and result in a progressive degradation of its performance. Simulation studies are very useful in these scenarios as they allow one to study the radiation environment and the impact on detector performance. Results are presented for CMS RPC stations considering the operating conditions expected at the HL-LHC

The CMS RPC detector performance and stability during LHC RUN-2

The CMS experiment, located at the Large Hadron Collider (LHC) in CERN, has a redundant muon system composed by three different gaseous detector technologies: Cathode Strip Chambers (in the forward regions), Drift Tubes (in the central region), and Resistive Plate Chambers (both its central and forward regions). All three are used for muon reconstruction and triggering. The CMS RPC system confers robustness and redundancy to the muon trigger. The RPC system operation in the challenging background and pileup conditions of the LHC environment is presented. The RPC system provides information to all muon track finders and thus contributing to both muon trigger and reconstruction. The summary of the detector performance results obtained with proton-proton collision at root s = 13 TeV during 2016 and 2017 data taking have been presented. The stability of the system is presented in terms of efficiency and cluster size vs time and increasing instantaneous luminosity. Data-driven predictions about the expected performance during High Luminosity LHC (HL-LHC) stage have been reported

CMSRPC efficiency measurement using the tag-and-probe method

We measure the efficiency of CMS Resistive Plate Chamber (RPC) detectors in proton-proton collisions at the centre-of-mass energy of 13 TeV using the tag-and-probe method. A muon from a Z(0) boson decay is selected as a probe of efficiency measurement, reconstructed using the CMS inner tracker and the rest of CMS muon systems. The overall efficiency of CMS RPC chambers during the 2016-2017 collision runs is measured to be more than 96% for the nominal RPC chambers

A Proof-Of-Principle Study of Epigenetic Therapy Added to Neoadjuvant Doxorubicin Cyclophosphamide for Locally Advanced Breast Cancer

BACKGROUND: Aberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs) is at present undergoing clinical testing in cancer therapy. As epigenetic alterations are common to breast cancer, in this proof-of-concept study demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, were added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy. METHODOLOGY: This was a single-arm interventional trial on breast cancer patients (ClinicalTrials.gov Identifier: NCT00395655). After signing informed consent, patients were typed for acetylator phenotype and then treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day –7 until chemotherapy ended, the latter consisting of four cycles of doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate. MAIN FINDINGS: 16 patients were included and received treatment as planned. All were evaluated for clinical response and toxicity and 15 for pathological response. Treatment was well-tolerated. The most common toxicity was drowsiness grades 1–2. Five (31%) patients had clinical CR and eight (50%) PR for an ORR of 81%. No patient progressed. One of 15 operated patients (6.6%) had pathological CR and 70% had residual disease <3 cm. There was a statistically significant decrease in global 5(m)C content and HDAC activity. Hydralazine and magnesium valproate up- and down-regulated at least 3-fold, 1,091 and 89 genes, respectively. CONCLUSIONS: Hydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well-tolerated, and appears to increase the efficacy of chemotherapy. A randomized phase III study is ongoing to support the efficacy of so-called epigenetic or transcriptional cancer therapy

Search for resonances in the mass spectrum of muon pairs produced in association with b quark jets in proton-proton collisions at root 8 and 13 TeV

A search for resonances in the mass range 12-70 GeV produced in association with a b quark jet and a second jet, and decaying to a muon pair, is reported. The analysis is based on data from proton-proton collisions at center-of-mass energies of 8 and 13 TeV, collected with the CMS detector at the LHC and corresponding to integrated luminosities of 19.7 and 35.9 fb(-1), respectively. The search is carried out in two mutually exclusive event categories. Events in the first category are required to have a b quark jet in the central region (|| 2.4) and at least one jet in the forward region (|| > 2.4). Events in the second category are required to have two jets in the central region, at least one of which is identified as a b quark jet, no jets in the forward region, and low missing transverse momentum. An excess of events above the background near a dimuon mass of 28 GeV is observed in the 8 TeV data, corresponding to local significances of 4.2 and 2.9 standard deviations for the first and second event categories, respectively. A similar analysis conducted with the 13 TeV data results in a mild excess over the background in the first event category corresponding to a local significance of 2.0 standard deviations, while the second category results in a 1.4 standard deviation deficit. The fiducial cross section measurements and 95% confidence level upper limits on those for a resonance consistent with the 8 TeV excess are provided at both collision energies

Search for supersymmetry in proton-proton collisions at 13 TeV using identified top quarks

A search for supersymmetry is presented based on proton-proton collision events containing identified hadronically decaying top quarks, no leptons, and an imbalance p(T)(miss) in transverse momentum. The data were collected with the CMS detector at the CERN LHC at a center-of-mass energy of 13 TeV, and correspond to an integrated luminosity of 35.9 fb(-1). Search regions are defined in terms of the multiplicity of bottom quark jet and top quark candidates, the p(T)(miss) , the scalar sum of jet transverse momenta, and themT2 mass variable. No statistically significant excess of events is observed relative to the expectation from the standard model. Lower limits on the masses of supersymmetric particles are determined at 95% confidence level in the context of simplified models with top quark production. For a model with direct top squark pair production followed by the decay of each top squark to a top quark and a neutralino, top squark masses up to 1020 GeVand neutralino masses up to 430 GeVare excluded. For amodel with pair production of gluinos followed by the decay of each gluino to a top quark-antiquark pair and a neutralino, gluino masses up to 2040 GeVand neutralino masses up to 1150 GeVare excluded. These limits extend previous results.Peer reviewe

Pseudorapidity distributions of charged hadrons in proton-lead collisions at root s(NN)=5:02 and 8.16 TeV

The pseudorapidity distributions of charged hadrons in proton-lead collisions at nucleon-nucleon center-of-mass energies root s(NN) = 5.02 and 8.16 TeV are presented. The measurements are based on data samples collected by the CMS experiment at the LHC. The number of primary charged hadrons produced in non-single-diffractive proton-lead collisions is determined in the pseudorapidity range vertical bar eta(lab)vertical bar vertical bar(vertical bar eta cm vertical bar) <0.5 are 17.1 +/- 0.01 (stat) +/- 0.59 (syst) and 20.10 +/- 0.01 (stat) +/- 0.5(syst) at root s(NN) = 5.02 and 8.16 TeV, respectively. The particle densities per participant nucleon are compared to similar measurements in proton-proton, proton-nucleus, and nucleus-nucleus collisions.Peer reviewe