Genetic Deletion of Sost or Pharmacological Inhibition of Sclerostin Prevent Multiple Myeloma-induced Bone Disease without Affecting Tumor Growth

Multiple myeloma (MM) causes lytic bone lesions due to increased bone resorption and concomitant marked suppression of bone formation. Sclerostin (Scl) levels, an osteocyte-derived inhibitor of Wnt/β-catenin signaling, are elevated in MM patient sera and are increased in osteocytes in MM-bearing mice. We show here that genetic deletion of Sost, the gene encoding Scl, prevented MM-induced bone disease in an immune-deficient mouse model of early MM, and that administration of anti-Scl antibody (Scl-Ab) increased bone mass and decreases osteolysis in immune-competent mice with established MM. Sost/Scl inhibition increased osteoblast numbers, stimulated new bone formation and decreased osteoclast number in MM-colonized bone. Further, Sost/Scl inhibition did not affect tumor growth in vivo or anti-myeloma drug efficacy in vitro. These results identify the osteocyte as a major contributor to the deleterious effects of MM in bone and osteocyte-derived Scl as a promising target for the treatment of established MM-induced bone disease. Further, Scl did not interfere with efficacy of chemotherapy for MM suggesting that combined treatment with anti-myeloma drugs and Scl-Ab should effectively control MM growth and bone disease, providing new avenues to effectively control MM and bone disease in patients with active MM

Microfinance and entrepreneurship:An introduction

As microfinance gains increasing attention and application as a financing mechanism for entrepreneurs at the base of the economic pyramid, this Special Issue of International Small Business Journal aims to enhance scholarly understanding of how microfinance fosters entrepreneurial activity. Microfinance brings a range of financial services, including microcredit loans, savings, and insurance, within the reach of millions of poor households not served by traditional banks. This introduction summarizes the articles in this Special Issue of International Small Business Journal on ‘Microfinance’, which address a range of topics in this important domain of research and practice

Bidirectional Notch signaling and osteocyte-derived factors in the bone marrow microenvironment promote tumor cell proliferation and bone destruction in multiple myeloma

In multiple myeloma, an overabundance of monoclonal plasma cells in the bone marrow induces localized osteolytic lesions that rarely heal due to increased bone resorption and suppressed bone formation. Matrix-embedded osteocytes comprise more than 95% of bone cells and are major regulators of osteoclast and osteoblast activity, but their contribution to multiple myeloma growth and bone disease is unknown. Here, we report that osteocytes in a mouse model of human MM physically interact with multiple myeloma cells in vivo, undergo caspase-3-dependent apoptosis, and express higher RANKL (TNFSF11) and sclerostin levels than osteocytes in control mice. Mechanistic studies revealed that osteocyte apoptosis was initiated by multiple myeloma cell-mediated activation of Notch signaling and was further amplified by multiple myeloma cell-secreted TNF. The induction of apoptosis increased osteocytic Rankl expression, the osteocytic Rankl/Opg (TNFRSF11B) ratio, and the ability of osteocytes to attract osteoclast precursors to induce local bone resorption. Furthermore, osteocytes in contact with multiple myeloma cells expressed high levels of Sost/sclerostin, leading to a reduction in Wnt signaling and subsequent inhibition of osteoblast differentiation. Importantly, direct contact between osteocytes and multiple myeloma cells reciprocally activated Notch signaling and increased Notch receptor expression, particularly Notch3 and 4, stimulating multiple myeloma cell growth. These studies reveal a previously unknown role for bidirectional Notch signaling that enhances MM growth and bone disease, suggesting that targeting osteocyte-multiple myeloma cell interactions through specific Notch receptor blockade may represent a promising treatment strategy in multiple myeloma

First Observation of the decay KL -> pi0 e e gamma

We report on the first observation of the decay KL -> pi0 ee gamma by the KTeV E799 experiment at Fermilab. Based upon a sample of 48 events with an estimated background of 3.6 +/- 1.1 events, we measure the KL -> pi0 ee gamma branching ratio to be (2.34 +/- 0.35 +/- 0.13)x10^{-8}. Our data agree with recent O(p^6) calculations in chiral perturbation theory that include contributions from vector meson exchange through the parameter a_V. A fit was made to the KL -> pi0 ee gamma data for a_V with the result -0.67 +/- 0.21 +/- 0.12, which is consistent with previous results from KTeV.Comment: Submitted to Physical Review Letters, 5 pages, 5 figure

The Discovery Potential of a Super B Factory

The Proceedings of the 2003 SLAC Workshops on flavor physics with a high luminosity asymmetric e+e- collider. The sensitivity of flavor physics to physics beyond the Standard Model is addressed in detail, in the context of the improvement of experimental measurements and theoretical calculations.Comment: 476 pages. Printed copies may be obtained by request to [email protected] . arXiv admin note: v2 appears to be identical to v

Measurements of the rare decay K_{L} -> e^{+} e^{-} e^{+} e^{-}

We observe 441 K_{L} -> e^{+} e^{-} e^{+} e^{-} candidate events with a background of 4.2 events and measure B(K_{L} -> e^{+} e^{-} e^{+} e^{-}) = (3.72 \pm 0.18(stat) \pm 0.23(syst)) \times 10^{-8} in the KTeV/E799II experiment at Fermilab. Using the distribution of the angle between the planes of the e^{+} e^{-} pairs, we measure the CP parameters beta_{CP} = -0.23 \pm 0.09(stat) \pm 0.02(syst) and gamma_{CP} = -0.09 \pm 0.09(stat) \pm 0.02(syst). We also present the first detailed study of the e^{+} e^{-} invariant mass spectrum in this decay mode.Comment: 14 pages, 4 figure

Measurement of the branching ratio of pi^0 -> e^+e^- using K_L -> 3 pi^0 decays in flight

The branching ratio of the rare decay pi^0 -> e^+e^- has been measured in E799-II, a rare kaon decay experiment using the KTeV detector at Fermilab. The pi^0's were produced in fully-reconstructed K_L -> 3 pi^0 decays in flight. We observed 275 candidate pi^0 -> e^+e^- events, with an expected background of 21.4 +- 6.2 events which includes the contribution from Dalitz decays. We measured BR(pi^0 -> e^+e^-, x>0.95) = (6.09 +- 0.40 +- 0.24) times 10^{-8}, where the first error is statistical and the second systematic. This result is the first significant observation of the excess rate for this decay above the unitarity lower bound.Comment: New version shortened to PRL length limit. 5 pages, 4 figures. Published in Phys. Rev. Let

Light Gluino Search for Decays Containing pi+pi- or pi0 from a Neutral Hadron Beam at Fermilab

We report on two null searches, one for the spontaneous appearance of $\pi^+\pi^-$ pairs, another for a single $\pi^0$, consistent with the decay of a long-lived neutral particle into hadrons and an unseen neutral particle. For the lowest level gluon-gluino bound state, known as the $R^0$, we exclude the decays $R^0\to \pi^+\pi^-\tilde{\gamma}$ and $R^0\to \pi^0\tilde{\gamma}$ for the masses of $R^0$ and $\tilde{\gamma}$ in the theoretically allowed range. In the most interesting $R^0$ mass range, $\leq 3 GeV/c^2$, we exclude $R^0$ lifetimes from $3\times 10^{-10}$ seconds to as high as $10^{-3}$ seconds, assuming perturbative QCD production for the $R^0$.Comment: 15 pages, 7 figure

A New Measurement of the Radiative Ke3 Branching Ratio and Photon Spectrum

We present a preliminary report on a new measurement of the radiative neutral Ke3 branching ratio and the first study of the photon spectrum in this decay. We find BR(Ke3g, E*_g>30 GeV, Th*_eg>20 deg)/BR(Ke3) = 0.911+-0.009(stat)+0.021-0.010(syst)%. Our measurement of the spectrum is consistent with inner bremsstrahlung only as the source of photons at the 2 sigma level.Comment: 5 pages, 4 figures, proceedings paper from Meson 2000, Cracow, Poland, May 200

A Measurement of the Branching Ratio of KL→e+e−γγK_L \to e^+e^-\gamma\gamma

We report on a study of the decay $K_L \to e^+e^-\gamma\gamma$ carried out as a part of the KTeV/E799 experiment at Fermilab. The 1997 data yielded a sample of 1543 events, including an expected background of $56 \pm 8$ events. An effective form factor was determined from the observed distribution of the $e^+e^-$ invariant mass. Using this form factor in the calculation of the detector acceptance, the branching ratio was measured to be ${\mathcal B}(K_L \to e^+ e^- \gamma \gamma, E^*_\gamma > 5 {MeV}) = (5.84 \pm 0.15 {\rm ~(stat)} \pm 0.32 {\rm ~(sys)})\times 10^{-7}$.Comment: 5 pages, 4 figure