Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma

Bruton tyrosine kinase (Btk) has a well-defined role in B-cell development, whereas its expression in osteoclasts (OCs) further suggests a role in osteoclastogenesis. Here we investigated effects of PCI-32765, an oral and selective Btk inhibitor, on osteoclastogenesis as well as on multiple myeloma (MM) growth within the BM microenvironment. PCI-32765 blocked RANKL/M-CSF-induced phosphorylation of Btk and downstream PLC-γ2 in OCs, resulting in diminished TRAP5b (ED(50) = 17nM) and bone resorption activity. PCI-32765 also inhibited secretion of multiple cytokines and chemokines from OC and BM stromal cell cultures from both normal donors (ED(50) = 0.5nM) and MM patients. It decreased SDF-1-induced migration of MM cells, and down-regulated MIP1-α/CCL3 in MM cells. It also blocked MM cell growth and survival triggered by IL-6 or coculture with BM stromal cells or OCs in vitro. Importantly, PCI-32765 treatment significantly inhibits in vivo MM cell growth (P < .03) and MM cell-induced osteolysis of implanted human bone chips in SCID mice. Moreover, PCI-32765 prevents in vitro colony formation by stem-like cells from MM patients. Together, these results delineate functional sequelae of Btk activation mediating osteolysis and growth of MM cells, supporting evaluation of PCI-32765 as a novel therapeutic in MM.     

Polarity Independent Effects of Cerebellar tDCS on Short Term Ankle Visuomotor Learning

BackgroundTranscranial direct current stimulation (tDCS), an emerging technique of noninvasive brain stimulation, has shown to produce beneficial neural effects in consequence with improvements in motor behavior. There are not many studies examining the use of tDCS for lower limb motor control and learning. Most studies using tDCS for facilitating lower limb motor coordination have applied tDCS to the lower limb motor cortex (M1). As the cerebellum is also critically involved in movement control, it is important to dissociate the effect of tDCS on the cerebellum and M1 with respect to lower limb motor control before we begin the application of tDCS as a neuromodulatory tool.Objective/HypothesisThe purpose of this study was to determine the effects of cerebellar vs. motor cortical tDCS on short term ankle visuomotor learning in healthy individuals.MethodsEight healthy individuals practiced a skilled ankle motor tracking task while receiving either facilitatory anodal tDCS to cerebellum, inhibitory cathodal tDCS to cerebellum, facilitatory anodal tDCS to M1, inhibitory cathodal tDCS to M1 or sham stimulation. Pre- and post-measures of changes in cortical excitability of the tibialis anterior muscle and measures of tracking accuracy were assessed.ResultsAnodal cerebellar, cathodal cerebellar, and anodal M1 stimulation improved target-tracking accuracy of the ankle. This was not dependent on the observed changes in motor cortical excitability of the tibialis anterior muscle.Conclusion(s)Polarity independent effects of tDCS on cerebellum were observed. The present study shows that modulation effects of tDCS can occur because of changes in the cerebellum, a structure implicated in several forms of motor learning, providing an additional way in which tDCS can be used to improve motor coordination.     

Characterization of poly-4-hydroxybutyrate mesh for hernia repair applications

Background

Phasix mesh is a fully resorbable implant for soft tissue reconstruction made from knitted poly-4-hydroxybutyrate monofilament fibers. The objectives of this study were to characterize the in vitro and in vivo mechanical and resorption properties of Phasix mesh over time, and to assess the functional performance in a porcine model of abdominal hernia repair.

Materials and methods

We evaluated accelerated in vitro degradation of Phasix mesh in 3 mol/L HCl through 120 h incubation. We also evaluated functional performance after repair of a surgically created abdominal hernia defect in a porcine model through 72 wk. Mechanical and molecular weight (MW) properties were fully characterized in both studies over time.

Results

Phasix mesh demonstrated a significant reduction in mechanical strength and MW over 120 h in the accelerated degradation in vitro test. In vivo, the Phasix mesh repair demonstrated 80%, 65%, 58%, 37%, and 18% greater strength, compared with native abdominal wall at 8, 16, 32, and 48 wk post-implantation, respectively, and comparable repair strength at 72 wk post-implantation despite a significant reduction in mesh MW over time.

Conclusions

Both in vitro and in vivo data suggest that Phasix mesh provides a durable scaffold for mechanical reinforcement of soft tissue. Furthermore, a Phasix mesh surgical defect repair in a large animal model demonstrated successful transfer of load bearing from the mesh to the repaired abdominal wall, thereby successfully returning the mechanical properties of repaired host tissue to its native state over an extended time period.