412 research outputs found
Pasteurella multocida toxin- induced osteoclastogenesis requires mTOR activation
Background: Pasteurella multocida toxin (PMT) is a potent inducer of osteoclast formation. Pigs suffering from an infection with toxigenic Pasteurella multocida strains develop atrophic rhinitis characterised by a loss of turbinate bones and conchae. However, on the molecular level the process of bone loss remains largely uncharacterised. Results: Recently it was found that PMT activates the serine/threonine kinase mammalian target of rapamycin (mTOR) in fibroblasts. Using RAW264.7 macrophages, we investigated the role of the mTOR complex 1 (mTORC1) in PMT-mediated osteoclast formation. PMT induces the differentiation of RAW264.7 macrophages into multinucleated, tartrate resistant acid phosphatase (TRAP) positive osteoclasts that are capable to resorb bone. In the presence of the mTORC1 inhibitor rapamycin, PMT was significantly less able to induce the formation of TRAP-positive osteoclasts. Accordingly, the resulting resorption of bone was strongly reduced. A major target of mTOR is the 70Â kDa ribosomal protein S6 kinase 1 (p70 S6K1). Activated p70 S6K1 decreases the expression of programmed cell death protein 4 (PDCD4), a negative transcriptional regulator of osteoclastogenesis, at the protein and gene level. Ultimately this results in the activation of c-Jun, a component of the activator protein 1 (AP-1) complex, which is a major transcription factor for the induction of osteoclast-specific genes. We now demonstrate that c-Jun and its downstream target, the osteoclast-specific bone degrading protease cathepsin K, are upregulated upon PMT treatment in an mTOR-dependent manner. Conclusions: Activation of mTOR signalling plays a central role in the formation of osteoclasts through the bacterial toxin PMT. On the molecular level, PMT-induced activation of mTOR leads to down regulation of PDCD4, a known repressor of AP-1 complex, culminating in the activation of c-Jun, an essential transcription factor for triggering osteoclastogenesis
Caspase-8-mediated PAR-4 cleavage is required for TNFα-induced apoptosis
The tumor suppressor protein prostate apoptosis response-4 (PAR-4) is silenced in a subset of human cancers and its down-regulation serves as a mechanism for cancer cell survival following chemotherapy. PAR-4 re-expression selectively causes apoptosis in cancer cells but how its pro-apoptotic functions are controlled and executed precisely is currently unknown. We demonstrate here that UV-induced apoptosis results in a rapid caspase-dependent PAR-4 cleavage at EEPD131¯G, a sequence that was preferentially recognized by caspase-8. To investigate the effect on cell growth for this cleavage event we established stable cell lines that express wild-type-PAR-4 or the caspase cleavage resistant mutant PAR-4 D131G under the control of a doxycycline-inducible promoter. Induction of the wild-type protein but not the mutant interfered with cell proliferation, predominantly through induction of apoptosis. We further demonstrate that TNFα-induced apoptosis leads to caspase-8-dependent PAR-4-cleavage followed by nuclear accumulation of the C-terminal PAR-4 (132-340) fragment, which then induces apoptosis. Taken together, our results indicate that the mechanism by which PAR-4 orchestrates the apoptotic process requires cleavage by caspase-8
Medicinal chemistry advances in targeting class I histone deacetylases
Histone deacetylases (HDACs) are a class of zinc (Zn)-dependent metalloenzymes that are responsible for epigenetic modifications. HDACs are largely associated with histone proteins that regulate gene expression at the DNA level. This tight regulation is controlled by acetylation [via histone acetyl transferases (HATs)] and deacetylation (via HDACs) of histone and non-histone proteins that alter the coiling state of DNA, thus impacting gene expression as a downstream effect. For the last two decades, HDACs have been studied extensively and indicated in a range of diseases where HDAC dysregulation has been strongly correlated with disease emergence and progressionâmost prominently, cancer, neurodegenerative diseases, HIV, and inflammatory diseases. The involvement of HDACs as regulators in these biochemical pathways established them as an attractive therapeutic target. This review summarizes the drug development efforts exerted to create HDAC inhibitors (HDACis), specifically class I HDACs, with a focus on the medicinal chemistry, structural design, and pharmacology aspects of these inhibitors
Analytical expressions for stopping-power ratios relevant for accurate dosimetry in particle therapy
In particle therapy, knowledge of the stopping-power ratios (STPRs) of the
ion beam for air and water is necessary for accurate ionization chamber
dosimetry. Earlier work has investigated the STPRs for pristine carbon ion
beams, but here we expand the calculations to a range of ions (1 <= z <= 18) as
well as spread out Bragg peaks (SOBPs) and provide a theoretical in-depth study
with a special focus on the parameter regime relevant for particle therapy. The
Monte Carlo transport code SHIELD-HIT is used to calculate complete
particle-fluence spectra which are required for determining STPRs according to
the recommendations of the International Atomic Energy Agency (IAEA).
We confirm that the STPR depends primarily on the current energy of the ions
rather than on their charge z or absolute position in the medium. However,
STPRs for different sets of stopping-power data for water and air recommended
by the International Commission on Radiation Units & Measurements (ICRU) are
compared, including also the recently revised data for water, yielding
deviations up to 2% in the plateau region. In comparison, the influence of the
secondary particle spectra on the STPR is about two orders of magnitude smaller
in the whole region up till the practical range. The gained insights enable us
to propose an analytic approximation for the STPR for both pristine and SOBPs
as a function of penetration depth, which parametrically depend only on the
initial energy and the residual range of the ion, respectively.Comment: 21 pages, 5 figures, fixed bug with figures in v
Status Of The FAIR Synchrotron Projects SIS18 And SIS100
A large fraction of the program to upgrade the existingheavy ion synchrotron SIS18 as injector for the FAIR synchrotron SIS100 has been successfully completed. With the achieved technical status, a major increase of theaccelerated number of heavy ions could be reached. Thenow available performance especially demonstrates thefeasibility of high intensity beams of medium charge stateheavy ions with a sufficient control of the dynamicvacuum and connected charge exchange loss. Two furtherupgrade measures, the installation of additional magneticalloy (MA) acceleration cavities and the exchange of themain dipole power converter, are presently beingimplemented. For the FAIR synchrotron SIS100, theprocurement of all major components with longproduction times has been started. With the delivery andtesting of several pre-series components, the phase ofoutstanding technical reserach and developments could becompleted and the readiness for series productionachieved
Mechanistic insights into p53âregulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells
Lateâstage colorectal cancer (CRC) is still a clinically challenging problem. The activity of the tumor suppressor p53 is regulated via postâtranslational modifications (PTMs). While the relevance of p53 Câterminal acetylation for transcriptional regulation is well defined, it is unknown whether this PTM controls mitochondrially mediated apoptosis directly. We used wildâtype p53 or p53ânegative human CRC cells, cells with acetylationâdefective p53, transformation assays, CRC organoids, and xenograft mouse models to assess how p53 acetylation determines cellular stress responses. The topoisomeraseâ1 inhibitor irinotecan induces acetylation of several lysine residues within p53. Inhibition of histone deacetylases (HDACs) with the class I HDAC inhibitor entinostat synergistically triggers mitochondrial damage and apoptosis in irinotecanâtreated p53âpositive CRC cells. This specifically relies on the Câterminal acetylation of p53 by CREBâbinding protein/p300 and the presence of Câterminally acetylated p53 in complex with the proapoptotic BCL2 antagonist/killer protein. This control of Câterminal acetylation by HDACs can mechanistically explain why combinations of irinotecan and entinostat represent clinically tractable agents for the therapy of p53âproficient CRC
Measurements of fiducial and differential cross sections for Higgs boson production in the diphoton decay channel at sâ=8 TeV with ATLAS
Measurements of fiducial and differential cross sections are presented for Higgs boson production in proton-proton collisions at a centre-of-mass energy of sâ=8 TeV. The analysis is performed in the H â γγ decay channel using 20.3 fbâ1 of data recorded by the ATLAS experiment at the CERN Large Hadron Collider. The signal is extracted using a fit to the diphoton invariant mass spectrum assuming that the width of the resonance is much smaller than the experimental resolution. The signal yields are corrected for the effects of detector inefficiency and resolution. The pp â H â γγ fiducial cross section is measured to be 43.2 ±9.4(stat.) ââ2.9 +â3.2 (syst.) ±1.2(lumi)fb for a Higgs boson of mass 125.4GeV decaying to two isolated photons that have transverse momentum greater than 35% and 25% of the diphoton invariant mass and each with absolute pseudorapidity less than 2.37. Four additional fiducial cross sections and two cross-section limits are presented in phase space regions that test the theoretical modelling of different Higgs boson production mechanisms, or are sensitive to physics beyond the Standard Model. Differential cross sections are also presented, as a function of variables related to the diphoton kinematics and the jet activity produced in the Higgs boson events. The observed spectra are statistically limited but broadly in line with the theoretical expectations
STAT3 regulated ARF expression suppresses prostate cancer metastasis.
Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.Lukas Kenner and Jan Pencik are supported by FWF, P26011 and the Genome Research-Austria project âInflammobiotaâ grants. Helmut Dolznig is supported by the Herzfelder Family Foundation and the Niederösterr. Forschungs-und Bildungsges.m.b.H (nfb). Richard Moriggl is supported by grant SFB-F2807 and SFB-F4707 from the Austrian Science Fund (FWF), Ali Moazzami is supported by Infrastructure for biosciences-Strategic fund, SciLifeLab and Formas, Zoran Culig is supported by FWF, P24428, Athena Chalaris and Stefan Rose-John are supported by the Deutsche Forschungsgemeinschaft (Grant SFB 877, Project A1and the Cluster of Excellence --âInflammation at Interfacesâ). Work of the Aberger lab was supported by the Austrian Science Fund FWF (Projects P25629 and W1213), the European FP7 Marie-Curie Initial Training Network HEALING and the priority program Biosciences and Health of the Paris-Lodron University of Salzburg. Valeria Poli is supported by the Italian Association for Cancer Research (AIRC, No IG13009). Richard Kennedy and Steven Walker are supported by the McClay Foundation and the Movember Centre of Excellence (PC-UK and Movember). Gerda Egger is supported by FWF, P27616. Tim Malcolm and Suzanne Turner are supported by Leukaemia and Lymphoma Research.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms873
Search for supersymmetry in events with b-quark jets and missing transverse energy in pp collisions at 7 TeV
Results are presented from a search for physics beyond the standard model
based on events with large missing transverse energy, at least three jets, and
at least one, two, or three b-quark jets. The study is performed using a sample
of proton-proton collision data collected at sqrt(s) = 7 TeV with the CMS
detector at the LHC in 2011. The integrated luminosity of the sample is 4.98
inverse femtobarns. The observed number of events is found to be consistent
with the standard model expectation, which is evaluated using control samples
in the data. The results are used to constrain cross sections for the
production of supersymmetric particles decaying to b-quark-enriched final
states in the context of simplified model spectra.Comment: Submitted to Physical Review
Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set
We report a measurement of the bottom-strange meson mixing phase \beta_s
using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays
in which the quark-flavor content of the bottom-strange meson is identified at
production. This measurement uses the full data set of proton-antiproton
collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment
at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity.
We report confidence regions in the two-dimensional space of \beta_s and the
B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2,
-1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in
agreement with the standard model expectation. Assuming the standard model
value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +-
0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +-
0.009 (syst) ps, which are consistent and competitive with determinations by
other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012
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