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

Constraining the string scale: from Planck to Weak and back again

String and field theory ideas have greatly influenced each other since the so called second string revolution. We review this interrelation paying particular attention to its phenomenological implications. Our guiding principle is the radical shift in the way that we think about the fundamental scale, in particular the way in which string models have been able to accommodate values from the Planck $M_\mathrm{Pl}\sim 10^{18}$ GeV down to the electroweak scale $M_{EW}\sim$ TeV.Comment: Invited review aimed at an experimental audienc

Baryon number violation, baryogenesis and defects with extra dimensions

In generic models for grand unified theories(GUT), various types of baryon number violating processes are expected when quarks and leptons propagate in the background of GUT strings. On the other hand, in models with large extra dimensions, the baryon number violation in the background of a string is not trivial because it must depend on the mechanism of the proton stabilization. In this paper we argue that cosmic strings in models with extra dimensions can enhance the baryon number violation to a phenomenologically interesting level, if the proton decay is suppressed by the mechanism of localized wavefunctions. We also make some comments on baryogenesis mediated by cosmological defects. We show at least two scenarios will be successful in this direction. One is the scenario of leptogenesis where the required lepton number conversion is mediated by cosmic strings, and the other is the baryogenesis from the decaying cosmological domain wall. Both scenarios are new and have not been discussed in the past.Comment: 20pages, latex2e, comments and references added, to appear in PR

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE