Tocolytic effect of a selective FP receptor antagonist in rodent models reveals an innovative approach to the treatment of preterm labor

<p>Abstract</p> <p>Background</p> <p>Management of preterm labor by tocolysis remains an unmet medical need. Prostaglandins play a major role in regulation of uterine activity and in molecular mechanisms of human labor and parturition. There is some circumstantial evidence that prostaglandin F2α by action through the prostaglandin receptor subtype FP is effective in key events during labor uterine contraction, rupture of membranes and cervical dilation. This role of FP is briefly reviewed. In this study, we tested the hypothesis that an orally active and selective FP antagonist may arrest labor and delay parturition in animal models.</p> <p>Methods</p> <p>We examined the effects of a small molecule selective antagonist of the FP receptor (AS604872) in inhibition of spontaneous uterine contraction in pregnant rat near term. We tested AS604872 for its ability to delay preterm birth in a mouse model in which the anti-progestin agent RU486 triggered parturition.</p> <p>Results</p> <p>By oral or intravenous dosing AS604872 reduced markedly and dose-dependently the spontaneous uterine contractions in late-term pregnant rats at gestational days 19–21. In pregnant mice, AS604872 delayed the preterm birth caused by RU486 administration. The effect was dose-dependent with a significant increase in the mean delivery time of 16 and 33 hours at oral doses of 30 mg/kg and 100 mg/kg, respectively, in the case of labor triggered at gestational day 14. In both models AS604872 appeared more effective than the β-agonist ritodrine.</p> <p>Conclusion</p> <p>The tocolytic activity displayed by a selective FP receptor antagonist supports a key role for the FP receptor in the pathophysiology of premature birth and demonstrates the therapeutic potential of an FP antagonist for the treatment of preterm labor cases in which uterine hyperactivity plays a dominant role.</p

Factors associated with tocolytic hospitalizations in Taiwan: evidence from a population-based and longitudinal study from 1997 to 2004

<p>Abstract</p> <p>Background</p> <p>The use of tocolytic hospitalization in antenatal care is controversial and worthy of more research. We investigated individual, institutional, and area factors that affect the use of tocolytic hospitalizations in Taiwan where fertility has rapidly declined.</p> <p>Methods</p> <p>Longitudinal data from the 1996 to 2004 National Health Insurance Research Database in Taiwan were used to identify tocolytic hospitalizations. The probit model was used to estimate factors associated with tocolytic hospitalizations.</p> <p>Results</p> <p>The decline in fertility was significantly associated with the probability of tocolytic hospitalizations. Several physician and institutional factors-including physician's age, hospital ownership, accreditation status, bed size, and teaching status-were also significantly correlated to the dependent variables.</p> <p>Conclusions</p> <p>The provision of inpatient tocolysis is influenced not only by clinical considerations but also by physician, institutional, and area factors unrelated to clinical need. Fertility declines in Taiwan may have led obstetricians/gynecologists to provide more tocolysis to make up for their lost income. If the explanation is further validated, reimbursement policies may need to be reviewed to correct for overuse of inpatient tocolysis. The correlation could also be explained by the increasing use of artificial reproductive technologies and higher social value of newborns. In addition, the physician and institutional variations observed in the study indicate potential misuse of inpatient tocolysis that warrant further investigation.</p

Promoter methylation-associated loss of ID4 expression is a marker of tumour recurrence in human breast cancer

<p>Abstract</p> <p>Background</p> <p>Inhibitor of DNA binding/Inhibitor of differentiation 4 (<it>ID4</it>) is a critical factor for cell proliferation and differentiation in normal vertebrate development. <it>ID4</it> has regulative functions for differentiation and growth of the developing brain. The role of <it>ID1</it>, <it>ID2</it> and <it>ID3</it> are expected to be oncogenic due to their overexpression in pancreatic cancer and colorectal adenocarcinomas, respectively. Aside from these findings, loss of <it>ID3</it> expression was demonstrated in ovarian cancer. The aim of the present study was to reveal the factual role of <it>ID4</it> in carcinogenesis in more detail, since its role for the pathogenesis of human breast cancer has been discussed controversially, assigning both oncogenic and tumour suppressive functions. </p> <p>Methods</p> <p><it>ID4</it> promoter methylation, <it>ID4</it> mRNA expression and <it>ID4</it> protein expression were analysed in primary human breast cancer specimens using methylation-specific PCR (MSP) (n=170), semiquantitative realtime RT-PCR (n=46) and immunhistochemistry (n=3), respectively. In order to demonstrate a functional association of <it>ID4</it> promoter methylation with its gene silencing, we performed DNA demethylation analysis with four human breast cell lines using MSP and semiquantitative realtime RT-PCR. In addition, we performed correlations of <it>ID4</it> promoter methylation with <it>ID4</it> mRNA and <it>ID4</it> protein expression in matched samples of breast tumour and corresponding normal tissue. We carried out statistical analyses in order to find correlations between <it>ID4</it> promoter methylation and clinicopathological parameters. </p> <p>Results</p> <p>Frequent <it>ID4</it> promoter methylation was observed in primary breast cancer samples (69%, 117/170). We found a tight correlation (P<0.0001) between <it>ID4</it> promoter methylation and loss of <it>ID4</it> expression in primary breast cancer 3 specimens. Demethylating treatment with breast cancer cell lines was associated with clear ID4 mRNA re-expression. Tumours with <it>ID4</it> promoter methylation showed distinct loss of <it>ID4</it> expression on both transcription and protein level. Interestingly, <it>ID4</it> promoter methylation was a factor for unfavourable recurrence-free survival (P=0.036) and increased risk for lymph node metastasis (P=0.030). </p> <p>Conclusion</p> <p>ID4 is indeed a novel tumour suppressor gene in normal human breast tissue and is epigenetically silenced during cancer development, indicating increased risk for tumour relapse. Thus, <it>ID4</it> methylation status could serve as a prognostic biomarker in human breast cancer.</p

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Search for R-parity-violating supersymmetry in events with four or more leptons in sqrt(s) =7 TeV pp collisions with the ATLAS detector

A search for new phenomena in final states with four or more leptons (electrons or muons) is presented. The analysis is based on 4.7 fb−1 of $\sqrt{s}=7\;\mathrm{TeV}$ proton-proton collisions delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in two signal regions: one that requires moderate values of missing transverse momentum and another that requires large effective mass. The results are interpreted in a simplified model of R-parity-violating supersymmetry in which a 95% CL exclusion region is set for charged wino masses up to 540 GeV. In an R-parity-violating MSUGRA/CMSSM model, values of m 1/2 up to 820 GeV are excluded for 10 < tan β < 40

Search for high-mass resonances decaying to dilepton final states in pp collisions at s√=7 TeV with the ATLAS detector

The ATLAS detector at the Large Hadron Collider is used to search for high-mass resonances decaying to an electron-positron pair or a muon-antimuon pair. The search is sensitive to heavy neutral Z′ gauge bosons, Randall-Sundrum gravitons, Z * bosons, techni-mesons, Kaluza-Klein Z/γ bosons, and bosons predicted by Torsion models. Results are presented based on an analysis of pp collisions at a center-of-mass energy of 7 TeV corresponding to an integrated luminosity of 4.9 fb−1 in the e + e − channel and 5.0 fb−1 in the μ + μ −channel. A Z ′ boson with Standard Model-like couplings is excluded at 95 % confidence level for masses below 2.22 TeV. A Randall-Sundrum graviton with coupling k/MPl=0.1 is excluded at 95 % confidence level for masses below 2.16 TeV. Limits on the other models are also presented, including Technicolor and Minimal Z′ Models