An early myeloma bone disease model in skeletally mature mice as a platform for biomaterial characterization of the extracellular matrix

Multiple myeloma (MM) bone disease is characterized by osteolytic bone tissue destruction resulting in bone pain, fractures, vertebral collapse, and spinal cord compression in patients. Upon initial diagnosis of MM, almost 80% of patients suffer from bone disease. Earlier diagnosis and intervention in MM bone disease would potentially improve treatment outcome and patient survival. New preclinical models are needed for developing novel diagnostic markers of bone structural changes as early as possible in the disease course. Here, we report a proof-of-concept, syngeneic, intrafemoral MOPC315.BM MM murine model in skeletally mature BALB/c mice for detection and characterization of very early changes in the extracellular matrix (ECM) of MM-injected animals. Bioluminescence imaging (BLI) in vivo confirmed myeloma engraftment in 100% of the animals with high osteoclast activity within 21 days after tumor cell inoculation. Early signs of aggressive bone turnover were observed on the outer bone surfaces by high-resolution microcomputed tomography (microCT). Synchrotron phase contrast-enhanced microcomputer tomography (PCE-CT) revealed very local microarchitecture differences highlighting numerous active sites of erosion and new bone at the micrometer scale. Correlative backscattered electron imaging (BSE) and confocal laser scanning microscopy allowed direct comparison of mineralized and nonmineralized matrix changes in the cortical bone. The osteocyte lacunar-canalicular network (OLCN) architecture was disorganized, and irregular-shaped osteocyte lacunae were observed in MM-injected bones after 21 days. Our model provides a potential platform to further evaluate pathological MM bone lesion development at the micro- and ultrastructural levels. These promising results make it possible to combine material science and pharmacological investigations that may improve early detection and treatment of MM bone disease

Modal and Polarization Qubits in Ti:LiNbO3_3 Photonic Circuits for a Universal Quantum Logic Gate

Lithium niobate photonic circuits have the salutary property of permitting the generation, transmission, and processing of photons to be accommodated on a single chip. Compact photonic circuits such as these, with multiple components integrated on a single chip, are crucial for efficiently implementing quantum information processing schemes. We present a set of basic transformations that are useful for manipulating modal qubits in Ti:LiNbO$_3$ photonic quantum circuits. These include the mode analyzer, a device that separates the even and odd components of a state into two separate spatial paths; the mode rotator, which rotates the state by an angle in mode space; and modal Pauli spin operators that effect related operations. We also describe the design of a deterministic, two-qubit, single-photon, CNOT gate, a key element in certain sets of universal quantum logic gates. It is implemented as a Ti:LiNbO$_3$ photonic quantum circuit in which the polarization and mode number of a single photon serve as the control and target qubits, respectively. It is shown that the effects of dispersion in the CNOT circuit can be mitigated by augmenting it with an additional path. The performance of all of these components are confirmed by numerical simulations. The implementation of these transformations relies on selective and controllable power coupling among single- and two-mode waveguides, as well as the polarization sensitivity of the Pockels coefficients in LiNbO$_3$

Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model

Despite evidence that deregulated Notch signalling is a master regulator of multiple myeloma (MM) pathogenesis, its contribution to myeloma bone disease remains to be resolved. Notch promotes survival of human MM cells and triggers human osteoclast activity in vitro. Here, we show that inhibition of Notch through the γ-secretase inhibitor XII (GSI XII) induces apoptosis of murine MOPC315.BM myeloma cells with high Notch activity. GSI XII impairs murine osteoclast differentiation of receptor activator of NF-κB ligand (RANKL)-stimulated RAW264.7 cells in vitro. In the murine MOPC315.BM myeloma model GSI XII has potent anti-MM activity and reduces osteolytic lesions as evidenced by diminished myeloma-specific monoclonal immunoglobulin (Ig)-A serum levels and quantitative assessment of bone structure changes via high-resolution microcomputed tomography scans. Thus, we suggest that Notch inhibition through GSI XII controls myeloma bone disease mainly by targeting Notch in MM cells and possibly in osteoclasts in their microenvironment. We conclude that Notch inhibition is a valid therapeutic strategy in MM

Centrality dependence of charged-particle pseudorapidity distributions from d+Au collisions at sqrt(s_{NN})=200 GeV

Charged-particle pseudorapidity densities are presented for the d+Au reaction at sqrt{s_{NN}}=200 GeV with -4.2 <= eta <= 4.2$. The results, from the BRAHMS experiment at RHIC, are shown for minimum-bias events and 0-30%, 30-60%, and 60-80% centrality classes. Models incorporating both soft physics and hard, perturbative QCD-based scattering physics agree well with the experimental results. The data do not support predictions based on strong-coupling, semi-classical QCD. In the deuteron-fragmentation region the central 200 GeV data show behavior similar to full-overlap d+Au results at sqrt{s_{NN}}=19.4 GeV.Comment: 4 pages, 3figures; expanded discussion of uncertainties; added 60-80% centrality range; added additional discussion on centrality selection bia

VEGF Over-Expression by Engineered BMSC Accelerates Functional Perfusion, Improving Tissue Density and In-Growth in Clinical-Size Osteogenic Grafts

The first choice for reconstruction of clinical-size bone defects consists of autologous bone flaps, which often lack the required mechanical strength and cause significant donor-site morbidity. We have previously developed biological substitutes in a rabbit model by combining bone tissue engineering and flap pre-fabrication. However, spontaneous vascularization was insufficient to ensure progenitor survival in the core of the constructs. Here, we hypothesized that increased angiogenic stimulation within constructs by exogenous VEGF can significantly accelerate early vascularization and tissue in-growth. Bone marrow stromal cells from NZW rabbits (rBMSC) were transduced with a retroviral vector to express rabbit VEGF linked to a truncated version of rabbit CD4 as a cell-surface marker. Autologous cells were seeded in clinical-size 5.5 cm; 3; HA scaffolds wrapped in a panniculus carnosus flap to provide an ample vascular supply, and implanted ectopically. Constructs seeded with VEGF-expressing rBMSC showed significantly increased progenitor survivival, depth of tissue ingrowth and amount of mineralized tissue. Contrast-enhanced MRI after 1 week; in vivo; showed significantly improved tissue perfusion in the inner layer of the grafts compared to controls. Interestingly, grafts containing VEGF-expressing rBMSC displayed a hierarchically organized functional vascular tree, composed of dense capillary networks in the inner layers connected to large-caliber feeding vessels entering the constructs at the periphery. These data constitute proof of principle that providing sustained VEGF signaling, independently of cells experiencing hypoxia, is effective to drive rapid vascularization and increase early perfusion in clinical-size osteogenic grafts, leading to improved tissue formation deeper in the constructs

High Pt Hadron Spectra at High Rapidity

We report the measurement of charged hadron production at different pseudo-rapidity values in deuteron+gold as well as proton+proton collisions at $sqrt{s_{NN}}$ = 200GeV at RHIC. The nuclear modification factors $R_{dAu}$ and $R_{cp}$ are used to investigate new behaviors in the deuteron+gold system as function of rapidity and the centrality of the collisions respectively.Comment: Nine pages 4 figures to be published in the QM2004 Proceedings, typos corrected and one reference adde

Nuclear Stopping in Au+Au Collisions at sqrt(sNN) = 200 GeV

Transverse momentum spectra and rapidity densities, dN/dy, of protons, anti-protons, and net--protons (p-pbar) from central (0-5%) Au+Au collisions at sqrt(sNN) = 200 GeV were measured with the BRAHMS experiment within the rapidity range 0 < y < 3. The proton and anti-proton dN/dy decrease from mid-rapidity to y=3. The net-proton yield is roughly constant for y<1 at dN/dy~7, and increases to dN/dy~12 at y~3. The data show that collisions at this energy exhibit a high degree of transparency and that the linear scaling of rapidity loss with rapidity observed at lower energies is broken. The energy loss per participant nucleon is estimated to be 73 +- 6 GeV.Comment: 5 pages, 4 figure

Evolution of the nuclear modification factors with rapidity and centrality in d+Au collisions at $\sqrt{s_{NN}} = 200 GeV

We report on a study of the transverse momentum dependence of nuclear modification factors $R_{dAu}$ for charged hadrons produced in deuteron + gold collisions at $\sqrt{s_{NN}}= 200$GeV, as a function of collision centrality and of the pseudorapidity ($\eta = 0,1,2.2,3.2$) of the produced hadrons. We find significant and systematic decrease of $R_{dAu}$ with increasing rapidity. The midrapidity enhancement and the forward rapidity suppression are more pronounced in central collisions relative to peripheral collisions. These results are relevant to the study of the possible onset of gluon saturation at RHIC energies.Comment: Four pages, four figures. Published in PRL. Figures 1 and 2 have been updated, and several changes made to the tex

Charged particle densities from Au+Au collisions at sqrt{s_{NN}}=130 GeV

We present charged particle densities as a function of pseudorapidity and collision centrality for the 197Au+197Au reaction at sqrt{s_{NN}}=130 GeV. An integral charged particle multiplicity of 3860+/-300 is found for the 5% most central events within the pseudorapidity range -4.7 <= eta <= 4.7. At mid-rapidity an enhancement in the particle yields per participant nucleon pair is observed for central events. Near to the beam rapidity, a scaling of the particle yields consistent with the ``limiting fragmentation'' picture is observed. Our results are compared to other recent experimental and theoretical discussions of charged particle densities in ultra-relativistic heavy-ion collisions.Comment: 14 pages, 4 figures; to be published in Phys. Lett.