Alterations in osteoclast function and phenotype induced by different inhibitors of bone resorption - implications for osteoclast quality

<p>Abstract</p> <p>Background</p> <p>Normal osteoclasts resorb bone by secretion of acid and proteases. Recent studies of patients with loss of function mutations affecting either of these processes have indicated a divergence in osteoclastic phenotypes. These difference in osteoclast phenotypes may directly or indirectly have secondary effects on bone remodeling, a process which is of importance for the pathogenesis of both osteoporosis and osteoarthritis. We treated human osteoclasts with different inhibitors and characterized their resulting function.</p> <p>Methods</p> <p>Human CD14 + monocytes were differentiated into mature osteoclasts using RANKL and M-CSF. The osteoclasts were cultured on bone in the presence or absence of various inhibitors: Inhibitors of acidification (bafilomycin A1, diphyllin, ethoxyzolamide), inhibitors of proteolysis (E64, GM6001), or a bisphosphonate (ibandronate). Osteoclast numbers and bone resorption were monitored by measurements of TRACP activity, the release of calcium, CTX-I and ICTP, as well as by counting resorption pits.</p> <p>Results</p> <p>All inhibitors of acidification were equally potent with respect to inhibition of both organic and inorganic resorption. In contrast, inhibition of proteolysis by E64 potently reduced organic resorption, but only modestly suppressed inorganic resorption. GM6001 alone did not greatly affect bone resorption. However, when GM6001 and E64 were combined, a complete abrogation of organic bone resorption was observed, without a great effect on inorganic resorption. Ibandronate abrogated both organic and inorganic resorption at all concentrations tested [0.3-100 μM], however, this treatment dramatically reduced TRACP activity.</p> <p>Conclusions</p> <p>We present evidence highlighting important differences with respect to osteoclast function, when comparing the different types of osteoclast inhibitors. Each class of osteoclast inhibitors will lead to different alterations in osteoclast quality, which secondarily may lead to different bone qualities.</p

X-ray emission from the Sombrero galaxy: discrete sources

We present a study of discrete X-ray sources in and around the bulge-dominated, massive Sa galaxy, Sombrero (M104), based on new and archival Chandra observations with a total exposure of ~200 ks. With a detection limit of L_X = 1E37 erg/s and a field of view covering a galactocentric radius of ~30 kpc (11.5 arcminute), 383 sources are detected. Cross-correlation with Spitler et al.'s catalogue of Sombrero globular clusters (GCs) identified from HST/ACS observations reveals 41 X-rays sources in GCs, presumably low-mass X-ray binaries (LMXBs). We quantify the differential luminosity functions (LFs) for both the detected GC and field LMXBs, whose power-low indices (~1.1 for the GC-LF and ~1.6 for field-LF) are consistent with previous studies for elliptical galaxies. With precise sky positions of the GCs without a detected X-ray source, we further quantify, through a fluctuation analysis, the GC LF at fainter luminosities down to 1E35 erg/s. The derived index rules out a faint-end slope flatter than 1.1 at a 2 sigma significance, contrary to recent findings in several elliptical galaxies and the bulge of M31. On the other hand, the 2-6 keV unresolved emission places a tight constraint on the field LF, implying a flattened index of ~1.0 below 1E37 erg/s. We also detect 101 sources in the halo of Sombrero. The presence of these sources cannot be interpreted as galactic LMXBs whose spatial distribution empirically follows the starlight. Their number is also higher than the expected number of cosmic AGNs (52+/-11 [1 sigma]) whose surface density is constrained by deep X-ray surveys. We suggest that either the cosmic X-ray background is unusually high in the direction of Sombrero, or a distinct population of X-ray sources is present in the halo of Sombrero.Comment: 11 figures, 5 tables, ApJ in pres

Search for three-jet resonances in pp Collisions at √s=7 TeV

This article is published Open Access at sciencedirect.com. It is distributed under the terms of the Creative Commons Attribution License 3.0.-- et al.Results are reported from a search for the production of three-jet resonances in pp collisions at a center-of-mass energy √s=7  TeV. The study uses the data sample collected by the CMS experiment at the LHC in 2011, corresponding to an integrated luminosity of 5.0fb -1. Events with high jet multiplicity and a large scalar sum of jet transverse momenta are analyzed for the presence of resonances in the three-jet invariant mass spectrum. No evidence for a narrow resonance is found in the data, and limits are set on the cross section for gluino pair production in an R-parity-violating supersymmetry model, for gluino masses greater than 280 GeV. Assuming a branching fraction for gluino decay into three jets of 100%, gluino masses below 460 GeV are excluded at 95% confidence level. These results significantly extend the range of previous limits. © 2012 CERN.European Commission; Federal Ministry of Science, Research and Economy (Austria); ); Agency for Innovation by Science and Technology (Belgium); Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brasil); Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro; Fundação de Amparo à Pesquisa do Estado de São Paulo; Ministry of Science and Technology of the People's Republic of China; National Natural Science Foundation of China; Colciencias (Colombia); Ministry of Science, Education and Sports of the Republic of Croatia; Research Promotion Foundation (Cyprus); Centre National de la Recherche Scientifique (France); Bundesministerium für Bildung und Forschung (Deutschland); Deutsche Forschungsgemeinschaft; General Secretariat of Research and Technology (Greece); Helsinki Institute of Physics; National Office for Research and Technology (Hungary); Institute for Research in Fundamental Sciences (Iran); Science Foundation Ireland; Istituto Nazionale di Fisica Nucleare (Italia); Compagnia di San Paolo (Italia); National Research Foundation of Korea; Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (México); Consejo Nacional de Ciencia y Tecnología (México); Secretaría de Educación Pública (México); Universidad Autónoma de San Luis Potosí; Ministry of Science and Innovation (New Zealand); Pakistan Atomic Energy Commission; National Science Center (Poland); Fundação para a Ciência e a Tecnologia (Portugal); Joint Institute for Nuclear Research (Russia); Russian Foundation for Basic Research; Ministry of Education, Science and Technological Development (Serbia); Ministerio de Ciencia e Innovación (España); Swiss National Science Foundation.Peer Reviewe

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Search for dijet resonances in 7 TeV pp collisions at CMS

This is the Pre-print version of the Article. The official published version of the paper can be accessed from the link below - Copyright @ 2010 APSA search for narrow resonances in the dijet mass spectrum is performed using data corresponding to an integrated luminosity of 2.9  pb-1 collected by the CMS experiment at the Large Hadron Collider. Upper limits at the 95% confidence level are presented on the product of the resonance cross section, branching fraction into dijets, and acceptance, separately for decays into quark-quark, quark-gluon, or gluon-gluon pairs. The data exclude new particles predicted in the following models at the 95% confidence level: string resonances, with mass less than 2.50 TeV, excited quarks, with mass less than 1.58 TeV, and axigluons, colorons, and E6 diquarks, in specific mass intervals. This extends previously published limits on these models.This work is supported by FMSR (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, and FAPESP (Brazil); MES (Bulgaria); CERN; CAS, MoST, and NSFC (China); COLCIENCIAS (Colombia); MSES (Croatia); RPF (Cyprus); Academy of Sciences and NICPB (Estonia); Academy of Finland, ME, and HIP (Finland); CEA and CNRS/IN2P3 (France); BMBF, DFG, and HGF (Germany); GSRT (Greece); OTKA and NKTH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); NRF and WCU (Korea); LAS (Lithuania); CINVESTAV, CONACYT, SEP, and UASLP-FAI (Mexico); PAEC (Pakistan); SCSR (Poland); FCT (Portugal); JINR (Armenia, Belarus, Georgia, Ukraine, Uzbekistan); MST and MAE (Russia); MSTD (Serbia); MICINN and CPAN (Spain); Swiss Funding Agencies (Switzerland); NSC (Taipei); TUBITAK and TAEK (Turkey); STFC (United Kingdom); DOE and NSF (USA)

Indications of suppression of excited Υ states in Pb-Pb collisions at √sNN = 2.76TeV

This is the pre-print version of the Published Article which can be accessed from the link below.A comparison of the relative yields of Υ resonances in the μ+μ- decay channel in Pb-Pb and pp collisions at a center-of-mass energy per nucleon pair of 2.76 TeV is performed with data collected with the CMS detector at the LHC. Using muons of transverse momentum above 4  GeV/c and pseudorapidity below 2.4, the double ratio of the Υ(2S) and Υ(3S) excited states to the Υ(1S) ground state in Pb-Pb and pp collisions, [Υ(2S+3S)/Υ(1S)]Pb-Pb/[Υ(2S+3S)/Υ(1S)]pp, is found to be 0.31-0.15+0.19(stat)±0.03(syst). The probability to obtain the measured value, or lower, if the true double ratio is unity, is calculated to be less than 1%

Search for supersymmetry in events with b jets and missing transverse momentum at the LHC

A search for supersymmetry is presented using a sample of events with b jets and missing transverse momentum. The search uses a data sample of proton-proton collisions at a centre-of-mass energy of 7TeV, corresponding to an integrated luminosity of 35 pb(-1), collected with the CMS detector. A total of 0.33(-0.33)(+0.43) (stat.) +/- 0.13 (syst.) events is predicted, using control samples in the data, to arise from standard model processes, and one event is observed in the data. Upper limits are set at the 95% confidence level on the cross sections of benchmark supersymmetric models

Measurement of the inclusive jet cross section in pp collisions at √s = 7TeV

This is the pre-print version of the Published Article which can be accessed from the link below.The inclusive jet cross section is measured in pp collisions with a center-of-mass energy of 7 TeV at the Large Hadron Collider using the CMS experiment. The data sample corresponds to an integrated luminosity of 34  pb-1. The measurement is made for jet transverse momenta in the range 18–1100 GeV and for absolute values of rapidity less than 3. The measured cross section extends to the highest values of jet pT ever observed and, within the experimental and theoretical uncertainties, is generally in agreement with next-to-leading-order perturbative QCD predictions

Search for same-sign top-quark pair production at root s=7 TeV and limits on flavour changing neutral currents in the top sector

An inclusive search for same-sign top-quark pair production in pp collisions at root s = 7 TeV is performed using a data sample recorded with the CMS detector in 2010, corresponding to an integrated luminosity of 35 pb(-1). This analysis is motivated by recent studies of p (p) over bar -> t (t) over bar reporting mass-dependent forward-backward asymmetries larger than expected from the standard model. These asymmetries could be due to Flavor Changing Neutral Currents (FCNC) in the top sector induced by t -channel exchange of a massive neutral vector boson (Z'). Models with such a Z' also predict enhancement of same-sign top-pair production in pp or pp collisions. Limits are set as a function of the Z' mass and its couplings to u and t quarks. These limits disfavour the FCNC interpretation of the Tevatron results

Search for supersymmetry in pp collisions at 7 TeV in events with jets and missing transverse energy

This is the Pre-print version of the Article. The official published version of the paper can be accessed from the link below - Copyright @ 2011 ElsevierA search for supersymmetry with R-parity conservation in proton-proton collisions at a centre-of-mass energy of 7 TeV is presented. The data correspond to an integrated luminosity of 35 inverse picobarns collected by the CMS experiment at the LHC. The search is performed in events with jets and significant missing transverse energy, characteristic of the decays of heavy, pair-produced squarks and gluinos. The primary background, from standard model multijet production, is reduced by several orders of magnitude to a negligible level by the application of a set of robust kinematic requirements. With this selection, the data are consistent with the standard model backgrounds, namely t t-bar, W + jet and Z + jet production, which are estimated from data control samples. Limits are set on the parameters of the constrained minimal supersymmetric extension of the standard model. These limits extend those set previously by experiments at the Tevatron and LEP colliders.This work is supported by FMSR (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, and FAPESP (Brazil); MES (Bulgaria); CERN; CAS, MoST, and NSFC (China); COLCIENCIAS (Colombia); MSES (Croatia); RPF (Cyprus); Academy of Sciences and NICPB (Estonia); Academy of Finland, ME, and HIP (Finland); CEA and CNRS/IN2P3 (France); BMBF, DFG, and HGF (Germany); GSRT (Greece); OTKA and NKTH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); NRF and WCU (Korea); LAS (Lithuania); CINVESTAV, CONACYT, SEP, and UASLP-FAI (Mexico); PAEC (Pakistan); SCSR (Poland); FCT (Portugal); JINR (Armenia, Belarus, Georgia, Ukraine, Uzbekistan); MST and MAE (Russia); MSTD (Serbia); MICINN and CPAN (Spain); Swiss Funding Agencies (Switzerland); NSC (Taipei); TUBITAK and TAEK (Turkey); STFC (United Kingdom); DOE and NSF (USA)