Inhibition of cathepsin K (CatK) is a potential new treatment for osteoporosis. In two double‐blind, randomized, placebo‐controlled phase I studies, postmenopausal female subjects received odanacatib ...(ODN), an orally active, potent, and selective CatK inhibitor, once weekly for 3 weeks or once daily for 21 days. Bone turnover biomarkers, safety monitoring, and plasma ODN concentrations were assessed. These studies showed ODN to be well tolerated. Pharmacokinetic (PK) analysis revealed a long half‐life (t1/2; 66–93 h) consistent with once‐weekly dosing. Pronounced reductions in C‐terminal telopeptide of type I collagen (~62%) and N‐terminal telopeptide of type I collagen normalized to creatinine (NTx/Cr) (~62%) at trough (C168 h) were seen following weekly administration. Robust reductions in CTx (up to 81%) and NTx/Cr (up to 81%) were seen following daily administration. ODN exhibits robust and sustained suppression of bone resorption biomarkers (CTx and NTx/Cr) at weekly doses ≥25 mg and daily doses ≥2.5 mg.
Clinical Pharmacology & Therapeutics (2009); 86, 2, 175–182 doi:10.1038/clpt.2009.60
ABSTRACT
This work explores the detailed chemistry of the Milky Way bulge using the HERMES spectrograph on the Anglo-Australian Telescope. Here, we present the abundance ratios of 13 elements for 832 ...red giant branch and clump stars along the minor bulge axis at latitudes b = −10○, − 7.5○, and −5○. Our results show that none of the abundance ratios vary significantly with latitude. We also observe disc-like Na/Fe abundance ratios, which indicate that the bulge does not contain helium-enhanced populations as observed in some globular clusters. Helium enhancement is therefore not the likely explanation for the double red-clump observed in the bulge. We confirm that bulge stars mostly follow abundance trends observed in the disc. However, this similarity is not confirmed across all elements and metallicity regimes. The more metal-poor bulge population at Fe/H ≲ − 0.8 is enhanced in the elements associated with core collapse supernovae (SNeII). In addition, the La/Eu abundance ratio suggests higher r-process contribution, and likely higher star formation in the bulge compared to the disc. This highlights the complex evolution in the bulge, which should be investigated further, both in terms of modelling; and with additional observations of the inner Galaxy.
Summary
This post hoc analysis and modeling study examined the mechanism of action of odanacatib using a statistical model to explain sCTx response in ODN-treated patients as a function of other ...bone-turnover biomarkers that, with other observed biomarker changes, showed that odanacatib persistently inhibited osteoclastic bone removal activity without preventing osteoclastogenesis.
Introduction
Odanacatib (ODN) is an oral selective cathepsin K (CatK) inhibitor, previously in development for osteoporosis treatment. A post hoc analysis examined ODN’s mechanism of action on bone-turnover biomarkers.
Methods
A subset of patients who completed 60 months’ treatment in the Long-Term Odanacatib Fracture Trial (LOFT; NCT00529373) (
N
= 112 57 ODN, 55 placebo) were evaluated. Serum (s) and urine (u) samples were assayed at baseline and months 6–60 for 10 known bone-remodeling biomarkers: sCTx, uαα- and uββCTx/Cr, uNTx/Cr, sNTx, uDPD/Cr, sICTP, sTRAP5b, sPINP, and sBSAP. Because the CrossLaps® CTx assay identifies the CTx peptide as well as larger molecular weight CTx-containing peptides, including ICTP, a best-fit model was developed to explain the transient sCTx reduction in ODN-treated patients.
Results
ODN persistently reduced the bone-resorption markers sNTx, uNTx/Cr, uαα- and uββCTx/Cr, and uDPD/Cr, and gradually increased the target-engagement marker sICTP and osteoclast number (sTRAP5b), versus placebo from baseline to month 60. sCTx was transiently reduced with ODN within 12 months, returning to baseline by month 48. Modeling suggested that sCTx changes in the ODN group were primarily due to increased accumulation of larger CTx species, including sICTP. The bone-formation markers sPINP and sBSAP showed partial reductions, versus placebo, in the first 6 months but approached baseline by months 48–60.
Conclusion
Observed changes in bone-turnover biomarkers support the persistent efficacy of ODN in direct inhibition of osteoclastic bone-resorption activity, without inhibition of osteoclastogenesis. Long-term evaluation also underscores the unique mechanism of ODN on osteoclastic collagen processing and subsequently osteoblastic bone formation.
Trial registration
NCT00529373.
Abstract Odanacatib (ODN) is a selective, potent and reversible inhibitor of cathepsin K (CatK) that inhibits bone loss in postmenopausal osteoporosis. Evidence from osteoclast (OC) formation from ...bone marrow of CatK−/− mice or human OC progenitors treated with ODN, demonstrated that CatK inhibition has no effect on osteoclastogenesis or survival of OCs. Although having no impact on OC activation, ODN reduces resorption activity as measured by CTx release (IC50 = 9.4 nM) or resorption area (IC50 = 6.5 nM). While untreated cells generate deep trail-like resorption lacunae, treated OCs form small discrete shallow pits. ODN leads to significant accumulation of intracellular vesicles intensely stained for CatK and TRAP. CatK (+) vesicles localize toward the basolateral and functional secretory membranes of the polarized OC and TRAP(+) vesicles evenly distribute in the cytoplasm, suggesting that ODN disrupts multiple vesicular trafficking pathways. Intracellular levels of both precursor and mature TRAP were increased by 2-fold and the pre-pro and mature CatK by 6- and 2-fold in ODN-treated OCs compared to untreated controls. ODN treated OC accumulates labeled degraded bone matrix proteins in CatK containing vesicles. In summary, ODN treatment inhibits bone resorption by blocking degradation of demineralized collagen in the resorption lacunae, and retarding transcytosis for further processing of degraded proteins.
The GALAH survey: scientific motivation De Silva, G. M.; Freeman, K. C.; Bland-Hawthorn, J. ...
Monthly notices of the Royal Astronomical Society,
05/2015, Letnik:
449, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The Galactic Archaeology with HERMES (GALAH) survey is a large high-resolution spectroscopic survey using the newly commissioned High Efficiency and Resolution Multi-Element Spectrograph (HERMES) on ...the Anglo-Australian Telescope. The HERMES spectrograph provides high-resolution (R ∼ 28 000) spectra in four passbands for 392 stars simultaneously over a 2 deg field of view. The goal of the survey is to unravel the formation and evolutionary history of the Milky Way, using fossil remnants of ancient star formation events which have been disrupted and are now dispersed throughout the Galaxy. Chemical tagging seeks to identify such dispersed remnants solely from their common and unique chemical signatures; these groups are unidentifiable from their spatial, photometric or kinematic properties. To carry out chemical tagging, the GALAH survey will acquire spectra for a million stars down to V ∼ 14. The HERMES spectra of FGK stars contain absorption lines from 29 elements including light proton-capture elements, α-elements, odd-Z elements, iron-peak elements and n-capture elements from the light and heavy s-process and the r-process. This paper describes the motivation and planned execution of the GALAH survey, and presents some results on the first-light performance of HERMES.
The Galactic Archaeology with HERMES (GALAH) survey is a massive observational project to trace the Milky Way's history of star formation, chemical enrichment, stellar migration and minor mergers. ...Using high-resolution (R ... 28 000) spectra, taken with the High Efficiency and Resolution Multi-Element Spectrograph (HERMES) instrument at the Anglo-Australian Telescope, GALAH will determine stellar parameters and abundances of up to 29 elements for up to one million stars. Selecting targets from a colour-unbiased catalogue built from 2MASS, APASS and UCAC4 data, we expect to observe dwarfs at 0.3-3 kpc and giants at 1-10 kpc. This enables a thorough local chemical inventory of the Galactic thin and thick discs, and also captures smaller samples of the bulge and halo. In this paper, we present the plan, process and progress as of early 2016 for GALAH survey observations. In our first two years of survey observing we have accumulated the largest high-quality spectroscopic data set at this resolution, over 200 000 stars. We also present the first public GALAH data catalogue: stellar parameters (Teff, log(g), Fe/H, a/Fe), radial velocity, distance modulus and reddening for 10 680 observations of 9860 Tycho-2 stars, 7894 of which are included in the first Gaia data release. (ProQuest: ... denotes formulae/symbols omitted.)
Older age is associated with deteriorating health, including escalating risk of diseases such as cancer, and a diminished ability to repair following injury. This rise in age-related ...diseases/co-morbidities is associated with changes to immune function, including in myeloid cells, and is related to immunosenescence. Immunosenescence reflects age-related changes associated with immune dysfunction and is accompanied by low-grade chronic inflammation or inflammageing. This is characterised by increased levels of circulating pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1β and IL-6. However, in healthy ageing, there is a concomitant age-related escalation in anti-inflammatory cytokines such as transforming growth factor-β1 (TGF-β1) and IL-10, which may overcompensate to regulate the pro-inflammatory state. Key inflammatory cells, macrophages, play a role in cancer development and injury repair in young hosts, and we propose that their role in ageing in these scenarios may be more profound. Imbalanced pro- and anti-inflammatory factors during ageing may also have a significant influence on macrophage function and further impact the severity of age-related diseases in which macrophages are known to play a key role. In this brief review we summarise studies describing changes to inflammatory function of macrophages (from various tissues and across sexes) during healthy ageing. We also describe age-related diseases/co-morbidities where macrophages are known to play a key role, focussed on injury repair processes and cancer, plus comment briefly on strategies to correct for these age-related changes.
ABSTRACT
To better understand the origin and evolution of the Milky Way bulge, we have conducted a survey of bulge red giant branch and clump stars using the High Efficiency and Resolution ...Multi-Element Spectrograph on the Anglo–Australian Telescope. We targeted ARGOS survey stars with predetermined bulge memberships, covering the full metallicity distribution function. The spectra have signal-to-noise ratios comparable to, and were analysed using the same methods as the GALAH survey. In this work, we present the survey design, stellar parameters, distribution of metallicity, and alpha-element abundances along the minor bulge axis at latitudes b = −10°, − 7.5°, and −5°. Our analysis of ARGOS stars indicates that the centroids of ARGOS metallicity components should be located ≈0.09 dex closer together. The vertical distribution of α-element abundances is consistent with the varying contributions of the different metallicity components. Closer to the plane, alpha abundance ratios are lower as the metal-rich population dominates. At higher latitudes, the alpha abundance ratios increase as the number of metal-poor stars increases. However, we find that the trend of alpha-enrichment with respect to metallicity is independent of latitude. Comparison of our results with those of GALAH DR2 revealed that for Fe/H ≈ −0.8, the bulge shares the same abundance trend as the high-α disc population. However, the metal-poor bulge population (Fe/H ≲ −0.8) show enhanced alpha abundance ratios compared to the disc/halo. These observations point to fairly rapid chemical evolution in the bulge, and that the metal-poor bulge population does not share the same similarity with the disc as the more metal-rich populations.
Abstract The cathepsin K (CatK) inhibitor odanacatib (ODN) is currently being developed for the treatment of osteoporosis. In clinical trials, efficacy and resolution of effect of ODN treatment on ...bone turnover biomarkers and accrued bone mass have been demonstrated. Here, we examine the effects of continuing treatment and discontinuation of ODN versus alendronate (ALN) on osteoclast (OC) function. First, accessibility and reversible engagement of active CatK in intracellular vesicles and resorption lacunae of actively resorbing OCs were demonstrated by the selective and reversible CatK inhibitors, BODIPY-L-226 (IC50 = 39 nM) and L-873,724 (IC50 = 0.5 nM). Next, mature human OCs on bone slices were treated with vehicle, ODN, or ALN for 2 days, followed by either continuing with the same treatment, or replacement of the inhibitors by vehicle for additional times as specified per experimental conditions. Maintaining OCs on ODN or ALN significantly reduced CTx-I release compared to vehicle controls. However, only the treatment of OCs with ODN resulted in the formation of small shallow discrete resorption pits, retention of intracellular vesicles enriched with CatK and other lysosomal enzymes, increase in 1-CTP release and number of TRAP(+) OCs. Upon discontinuation of ODN treatment, OCs rapidly resumed bone resorption activity, as demonstrated by a return of OC functional markers (CTx-I, 1-CTP), cell number and size, morphology and number of resorption pits, and vesicular secretion of CatK toward the respective vehicle levels. As expected, discontinuation of ALN did not reverse the treatment-related inhibition of OC activity in the time frame of the experiment. In summary, this study demonstrated rapid kinetics of inhibition and reversibility of the effects of ODN on OC bone resorption, that differentiated the cellular mechanism of CatK inhibition from that of the bisphosphate antiresorptive ALN.
Wood mechanical properties of Acacia crassicarpa were assessed at the age of ten years old in a progeny test at Cam Lo, Quang Tri Province, central Vietnam. A total of 208 trees from 52 ...open-pollinated families were selected for study. Height and diameter at breast height were measured for all selected trees and spiral grain was also measured at breast height on the standing trees using a Chalmers device, which measures the grain angle of the surface wood. Basic density and shrinkage were measured on one 12-mm bark-to-bark increment cores taken at breast height from each sampled tree. Microfibril angle was measured on fiber prepared from the core samples using polarized light microscopy. Genetic parameters of the wood and growth traits were estimated using individual-tree linear mixed models. High coefficients of additive genetic variation (CVₐ, 17-34%) and high heritabilities (h² = 0.61-0.82) for all wood traits indicated that there is potential to improve basic density, wood shrinkage, grain angle and microfibril angle in the species in central Vietnam. The genetic correlation between DBH and shrinkage was positive and thus unfavourable, whereas correlations between DBH and both spiral grain and microfibril angle were negative and favourable. The Chalmers device appeared to be a reliable indirect method for investigating genetic variation in spiral grain in A. crassicarpa. Index selection, based on genetic parameters and economic weighting dependent on breeding objectives is suggested for development of seed orchards to deliver genetic gain for A. crassicarpa in central Vietnam.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, FFLJ, IZUM, KILJ, NMLJ, NUK, ODKLJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
PDF
