Myeloma bone disease: Pathophysiology and management.

Multiple myeloma bone disease is marked by severe dysfunction of both bone formation and resorption and serves as a model for understanding the regulation of osteoblasts (OBL) and osteoclasts (OCL) in cancer. Myeloma bone lesions are purely osteolytic and are associated with severe and debilitating bone pain, pathologic fractures, hypercalcemia, and spinal cord compression, as well as increased mortality. Interactions within the bone marrow microenvironment in myeloma are responsible for the abnormal bone remodeling in myeloma bone disease. Myeloma cells drive bone destruction that increases tumor growth, directly stimulates the OCL formation, and induces cells in the marrow microenvironment to produce factors that drive OCL formation and suppress OBL formation. Factors produced by marrow stromal cells and OCL promote tumor growth through direct action on myeloma cells and by increasing angiogenesis. Current therapies targeting MMBD focus on preventing osteoclastic bone destruction; however regulators of OBL inhibition in MMBD have also been identified, and targeted agents with a potential anabolic effect in MMBD are under investigation. This review will discuss the mechanisms responsible for MMBD and therapeutic approaches currently in use and in development for the management of MMBD

The Mid-Infrared Spectra of Normal Galaxies

The mid-infrared spectra (2.5 to 5 and 5.7 to 11.6 mu) obtained by ISO-PHOT reveal the interstellar medium emission from galaxies powered by star formation to be strongly dominated by the aromatic features at 6.2, 7.7, 8.6 and 11.3 mu. Additional emission appears in-between the features, and an underlying continuum is clearly evident at 3-5 mu. This continuum would contribute about a third of the luminosity in the 3 to 13 mu range. The features together carry 5 to 30% of the 40-to-120 mu `FIR' luminosity. The relative fluxes in individual features depend very weakly on galaxy parameters such as the far-infrared colors, direct evidence that the emitting particles are not in thermal equilibrium. The dip at 10 mu is unlikely to result from silicate absorption, since its shape is invariant among galaxies. The continuum component has a f_nu \~ nu^{0.65} shape between 3 and 5 mu and carries 1 to 4% of the FIR luminosity; its extrapolation to longer wavelengths falls well below the spectrum in the 6 to 12 mu range. This continuum component is almost certainly of non-stellar origin, and is probably due to fluctuating grains without aromatic features. The spectra reported here typify the integrated emission from the interstellar medium of the majority of star-forming galaxies, and could thus be used to obtain redshifts of highly extincted galaxies up to z=3 with SIRTF.Comment: 10 pages, 2 figures, uses AAS LaTeX; to appear in the Astrophysical Journal Letter

Calibration of the distance scale from galactic Cepheids: I Calibration based on the GFG sample

New estimates of the distances of 36 nearby galaxies are presented based on accurate distances of galactic Cepheids obtained by Gieren, Fouque and Gomez (1998) from the geometrical Barnes-Evans method. The concept of 'sosie' is applied to extend the distance determination to extragalactic Cepheids without assuming the linearity of the PL relation. Doing so, the distance moduli are obtained in a straightforward way. The correction for extinction is made using two photometric bands (V and I) according to the principles introduced by Freedman and Madore (1990). Finally, the statistical bias due to the incompleteness of the sample is corrected according to the precepts introduced by Teerikorpi (1987) without introducing any free parameters (except the distance modulus itself in an iterative scheme). The final distance moduli depend on the adopted extinction ratio {R_V}/{R_I} and on the limiting apparent magnitude of the sample. A comparison with the distance moduli recently published by the Hubble Space Telescope Key Project (HSTKP) team reveals a fair agreement when the same ratio {R_V}/{R_I} is used but shows a small discrepancy at large distance. In order to bypass the uncertainty due to the metallicity effect it is suggested to consider only galaxies having nearly the same metallicity as the calibrating Cepheids (i.e. Solar metallicity). The internal uncertainty of the distances is about 0.1 magnitude but the total uncertainty may reach 0.3 magnitude.Comment: 12 pages, 4 figures, access to a database of extragalactic Cepheids. Astronomy & Astrophysics (in press) 200

EZH2 or HDAC1 Inhibition Reverses Multiple Myeloma-Induced Epigenetic Suppression of Osteoblast Differentiation

In multiple myeloma, osteolytic lesions rarely heal because of persistent suppressed osteoblast differentiation resulting in a high fracture risk. Herein, chromatin immunoprecipitation analyses reveal that multiple myeloma cells induce repressive epigenetic histone changes at the Runx2 locus that prevent osteoblast differentiation. The most pronounced multiple myeloma-induced changes were at the Runx2-P1 promoter, converting it from a poised bivalent state to a repressed state. Previously, it was observed that multiple myeloma induces the transcription repressor GFI1 in osteoblast precursors, which correlates with decreased Runx2 expression, thus prompting detailed characterization of the multiple myeloma and TNFα-dependent GFI1 response element within the Runx2-P1 promoter. Further analyses reveal that multiple myeloma-induced GFI1 binding to Runx2 in osteoblast precursors and recruitment of the histone modifiers HDAC1, LSD1, and EZH2 is required to establish and maintain Runx2 repression in osteogenic conditions. These GFI1-mediated repressive chromatin changes persist even after removal of multiple myeloma. Ectopic GFI1 is sufficient to bind to Runx2, recruit HDAC1 and EZH2, increase H3K27me3 on the gene, and prevent osteogenic induction of endogenous Runx2 expression. Gfi1 knockdown in MC4 cells blocked multiple myeloma-induced recruitment of HDAC1 and EZH2 to Runx2, acquisition of repressive chromatin architecture, and suppression of osteoblast differentiation. Importantly, inhibition of EZH2 or HDAC1 activity in pre-osteoblasts after multiple myeloma exposure in vitro or in osteoblast precursors from patients with multiple myeloma reversed the repressive chromatin architecture at Runx2 and rescued osteoblast differentiation.Implications: This study suggests that therapeutically targeting EZH2 or HDAC1 activity may reverse the profound multiple myeloma-induced osteoblast suppression and allow repair of the lytic lesions

The HST Key Project on the Extragalactic Distance Scale XXV. A Recalibration of Cepheid Distances to Type Ia Supernovae and the Value of the Hubble Constant

Cepheid-based distances to seven Type Ia supernovae (SNe)-host galaxies have been derived using the standard HST Key Project on the Extragalactic Distance Scale pipeline. For the first time, this allows for a transparent comparison of data accumulated as part of three different HST projects, the Key Project, the Sandage et al. Type Ia SNe program, and the Tanvir et al. Leo I Group study. Re-analyzing the Tanvir et al. galaxy and six Sandage et al. galaxies we find a mean (weighted) offset in true distance moduli of 0.12+/-0.07 mag -- i.e., 6% in linear distance -- in the sense of reducing the distance scale, or increasing H0. Adopting the reddening-corrected Hubble relations of Suntzeff et al. (1999), tied to a zero point based upon SNe~1990N, 1981B, 1998bu, 1989B, 1972E and 1960F and the photometric calibration of Hill et al. (1998), leads to a Hubble constant of H0=68+/-2(random)+/-5(systematic) km/s/Mpc. Adopting the Kennicutt et al. (1998) Cepheid period-luminosity-metallicity dependency decreases the inferred H0 by 4%. The H0 result from Type Ia SNe is now in good agreement, to within their respective uncertainties, with that from the Tully-Fisher and surface brightness fluctuation relations.Comment: Accepted for publication in The Astrophysical Journal. 62 pages, LaTeX, 9 Postscript figures. Also available at http://casa.colorado.edu/~bgibson/publications.htm

The HST Key Project on the Extragalactic Distance Scale XXVI. The Calibration of Population II Secondary Distance Indicators and the Value of the Hubble Constant

A Cepheid-based calibration is derived for four distance indicators that utilize stars in the old stellar populations: the tip of the red giant branch (TRGB), the planetary nebula luminosity function (PNLF), the globular cluster luminosity function (GCLF) and the surface brightness fluctuation method (SBF). The calibration is largely based on the Cepheid distances to 18 spiral galaxies within cz =1500 km/s obtained as part of the HST Key Project on the Extragalactic Distance Scale, but relies also on Cepheid distances from separate HST and ground-based efforts. The newly derived calibration of the SBF method is applied to obtain distances to four Abell clusters in the velocity range between 3800 and 5000 km/s, observed by Lauer et al. (1998) using the HST/WFPC2. Combined with cluster velocities corrected for a cosmological flow model, these distances imply a value of the Hubble constant of H0 = 69 +/- 4 (random) +/- 6 (systematic) km/s/Mpc. This result assumes that the Cepheid PL relation is independent of the metallicity of the variable stars; adopting a metallicity correction as in Kennicutt et al. (1998), would produce a (5 +/- 3)% decrease in H0. Finally, the newly derived calibration allows us to investigate systematics in the Cepheid, PNLF, SBF, GCLF and TRGB distance scales.Comment: Accepted for publication in the Astrophysical Journal. 48 pages (including 13 figures and 4 tables), plus two additional tables in landscape format. Also available at http://astro.caltech.edu/~lff/pub.htm K' SBF magnitudes have been update

Towards an Understanding of the Mid-Infrared Surface Brightness of Normal Galaxies

We report a mid-infrared color and surface brightness analysis of IC 10, NGC 1313, and NGC 6946, three of the nearby galaxies studied under the Infrared Space Observatory Key Project on Normal Galaxies. Images with < 9 arcsecond (170 pc) resolution of these nearly face-on, late-type galaxies were obtained using the LW2 (6.75 mu) and LW3 (15 mu) ISOCAM filters. Though their global I_nu(6.75 mu)/I_nu(15 mu) flux ratios are similar and typical of normal galaxies, they show distinct trends of this color ratio with mid-infrared surface brightness. We find that I_nu(6.75 mu)/I_nu(15 mu) ~< 1 only occurs for regions of intense heating activity where the continuum rises at 15 micron and where PAH destruction can play an important role. The shape of the color-surface brightness trend also appears to depend, to the second-order, on the hardness of the ionizing radiation. We discuss these findings in the context of a two-component model for the phases of the interstellar medium and suggest that star formation intensity is largely responsible for the mid-infrared surface brightness and colors within normal galaxies, whereas differences in dust column density are the primary drivers of variations in the mid-infrared surface brightness between the disks of normal galaxies.Comment: 19 pages, 6 figures, uses AAS LaTeX; to appear in the November Astronomical Journa

The HST Key Project on the Extragalactic Distance Scale. XXVIII. Combining the Constraints on the Hubble Constant

Since the launch of the Hubble Space Telescope nine years ago, Cepheid distances to 25 galaxies have been determined for the purpose of calibrating secondary distance indicators. A variety of these can now be calibrated, and the accompanying papers by Sakai, Kelson, Ferrarese, and Gibson employ the full set of 25 galaxies to consider the Tully-Fisher relation, the fundamental plane of elliptical galaxies, Type Ia supernovae, and surface brightness fluctuations. When calibrated with Cepheid distances, each of these methods yields a measurement of the Hubble constant and a corresponding measurement uncertainty. We combine these measurements in this paper, together with a model of the velocity field, to yield the best available estimate of the value of H_0 within the range of these secondary distance indicators and its uncertainty. The result is H_0 = 71 +/- 6 km/sec/Mpc. The largest contributor to the uncertainty of this 67% confidence level result is the distance of the Large Magellanic Cloud, which has been assumed to be 50 +/- 3 kpc

The HST Key Project on the Extragalactic Distance Scale. XV. A Cepheid Distance to the Fornax Cluster and Its Implications

Using the Hubble Space Telescope (HST) 37 long-period Cepheid variables have been discovered in the Fornax Cluster spiral galaxy NGC 1365. The resulting V and I period-luminosity relations yield a true distance modulus of 31.35 +/- 0.07 mag, which corresponds to a distance of 18.6 +/- 0.6 Mpc. This measurement provides several routes for estimating the Hubble Constant. (1) Assuming this distance for the Fornax Cluster as a whole yields a local Hubble Constant of 70 +/-18_{random} [+/-7]_{systematic} km/s/Mpc. (2) Nine Cepheid-based distances to groups of galaxies out to and including the Fornax and Virgo clusters yield Ho = 73 (+/-16)_r [+/-7]_s km/s/Mpc. (3) Recalibrating the I-band Tully-Fisher relation using NGC 1365 and six nearby spiral galaxies, and applying it to 15 galaxy clusters out to 100 Mpc gives Ho = 76 (+/-3)_r [+/-8]_s km/s/Mpc. (4) Using a broad-based set of differential cluster distance moduli ranging from Fornax to Abell 2147 gives Ho = 72 (+/-)_r [+/-6]_s km/s/Mpc. And finally, (5) Assuming the NGC 1365 distance for the two additional Type Ia supernovae in Fornax and adding them to the SnIa calibration (correcting for light curve shape) gives Ho = 67 (+/-6)_r [+/-7]_s km/s/Mpc out to a distance in excess of 500 Mpc. All five of these Ho determinations agree to within their statistical errors. The resulting estimate of the Hubble Constant combining all these determinations is Ho = 72 (+/-5)_r [+/-12]_s km/s/Mpc.Comment: Accepted for publication in the Astrophysical Journal, Apr. 10 issue 28 pages, 3 tables, 12 figures (Correct figures and abstract