TGFβ inhibition stimulates collagen maturation to enhance bone repair and fracture resistance in a murine myeloma model

Multiple myeloma is a plasma cell malignancy that causes debilitating bone disease and fractures, in which TGFβ plays a central role. Current treatments do not repair existing damage and fractures remain a common occurrence. We developed a novel low tumour phase murine model mimicking the plateau phase in patients, as we hypothesized this would be an ideal time to treat with a bone anabolic. Using in vivo microCT we show substantial and rapid bone lesion repair (and prevention) driven by SD‐208 (TGFβ receptor I kinase inhibitor) and chemotherapy (bortezomib and lenalidomide) in mice with human U266‐GFP‐luc myeloma. We discovered that lesion repair occurred via an intramembranous fracture repair‐like mechanism and that SD‐208 enhanced collagen matrix maturation to significantly improve fracture resistance. Lesion healing was associated with VEGFA expression in woven bone, reduced osteocyte‐derived PTHrP, increased osteoblasts, decreased osteoclasts and lower serum TRACP‐5b. SD‐208 also completely prevented bone lesion development mice with aggressive JJN3 tumors, and was more effective than an anti‐TGFβ neutralizing antibody (1D11). We also discovered that SD‐208 promoted osteoblastic differentiation (and overcame the TGFβ‐induced block in osteoblastogenesis) in myeloma patient bone marrow stromal cells in vitro, comparable to normal donors. The improved bone quality and fracture‐resistance with SD‐208 provides incentive for clinical translation to improve myeloma patient quality of life by reducing fracture risk and fatality

A TNF Variant that Associates with Susceptibility to Musculoskeletal Disease Modulates Thyroid Hormone Receptor Binding to Control Promoter Activation

Tumor necrosis factor (TNF) is a powerful pro-inflammatory cytokine and immuno-regulatory molecule, and modulates susceptibility to musculoskeletal diseases. Several meta-analyses and replicated association studies have implicated the minor ‘A’ variant within the TNF promoter single nucleotide polymorphism (SNP) rs361525 (-238A/G) as a risk allele in joint related disorders, including psoriatic and juvenile idiopathic arthritis, and osteolysis after joint arthroplasty. Here we characterized the effect of this variant on TNF promoter function. A transcriptional reporter, encoding the -238A variant of the TNF promoter, resulted in 2.2 to 2.8 times greater transcriptional activation versus the ‘G’ variant in murine macrophages when stimulated with pro-inflammatory stimuli. Bioinformatic analysis predicted a putative binding site for thyroid hormone receptor (TR) for the -238A but not the -238G allele. Overexpression of TR-α induced promoter expression 1.8-fold in the presence of the ‘A’ allele only. TR-α expression both potentiated and sensitized the -238A response to LPS or a titanium particulate stimulus, whilst siRNA knockdown of either THRA or THRB impaired transcriptional activation for the -238A variant only. This effect was independent of receptor-ligand binding of triiodothyronine. Immunohistochemical analysis of osteolysis interface membranes from patients undergoing revision surgery confirmed expression of TR-α within osteoclast nuclei at the resorption surface. The ‘A’ allele at rs361525 confers increased transcriptional activation of the TNF promoter and influences susceptibility to several arthritic conditions. This effect is modulated, at least in part, by binding of TR, which both sensitizes and potentiates transcriptional activation of the ‘A’ variant independent of its endogenous ligand

New Particles Working Group Report of the Snowmass 2013 Community Summer Study

This report summarizes the work of the Energy Frontier New Physics working group of the 2013 Community Summer Study (Snowmass)

Search for the K(L) --> PI0 PI0 E+ E- Decay in the KTeV Experiment

The recent discovery of a large CP violating asymmetry in K(L) --> PI+ PI- E+ E- mode has prompted us to seach for the associated K(L) --> PI0 PI0 E+ E- decay mode in the KTeV-E799 experiment at Fermilab. In 2.7E+11 K(L) decays, one candidate event has been observed with an expected background of 0.3 event, resulting in an upper limit for the K(L) --> PI0 PI0 E+ E- branching ratio of 6.6E-09 at the 90% confidence level.Comment: To be published in Phys. Rev. Let

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

Jet Substructure at the Tevatron and LHC: New results, new tools, new benchmarks

In this report we review recent theoretical progress and the latest experimental results in jet substructure from the Tevatron and the LHC. We review the status of and outlook for calculation and simulation tools for studying jet substructure. Following up on the report of the Boost 2010 workshop, we present a new set of benchmark comparisons of substructure techniques, focusing on the set of variables and grooming methods that are collectively known as "top taggers". To facilitate further exploration, we have attempted to collect, harmonise, and publish software implementations of these techniques.Comment: 53 pages, 17 figures. L. Asquith, S. Rappoccio, C. K. Vermilion, editors; v2: minor edits from journal revision

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

Radiative Decay Width Measurements of Neutral Kaon Excitations Using the Primakoff Effect

We produce a sample consisting of 147 candidate events, with minimal backgrounds, of the mixed axial vector pair K1(1270)-K1(1400) by exciting Kl's in the Coulomb field of lead and report the first measurements of the radiative widths Gamma_r(K1(1400)) = 280.8+-23.2(stat)+-40.4(syst) keV and Gamma_r(K1(1270)) = 73.2+- 6.1(stat)+-28.3(syst) keV. We also place 90% CL upper limits Gamma_r(K*(1410)) < 52.9 keV for the vector state and Gamma_r(K2*(1430)) < 5.4 keV for the tensor state. These measurements allow for significant tests of quark-model predictions of radiative widths for the low-lying vector mesons.Comment: PRL-size article, 4 figure