PTH1R-CaSR Cross Talk: New Treatment Options for Breast Cancer Osteolytic Bone Metastases.

Metastatic breast cancer (BrCa) is currently incurable despite great improvements in treatment of primary BrCa. The incidence of skeletal metastases in advanced BrCa occurs up to 70%. Recent findings have established that the distribution of BrCa metastases to the skeleton is not a random process but due to the favorable microenvironment for tumor invasion and growth. The complex interplay among BrCa cells, stromal/osteoblastic cells, and osteoclasts in the osseous microenvironment creates a bone-tumor vicious cycle (a feed-forward loop) that results in excessive bone destruction and progressive tumor growth. Both the type 1 PTH receptor (PTH1R) and extracellular calcium-sensing receptor (CaSR) participate in the vicious cycle and influence the skeletal metastatic niche. Thus, this review focuses on how the PTH1R and CaSR signaling pathways interact and contribute to the pathogenesis of BrCa bone metastases. The effects of intermittent PTH and allosteric modulators of CaSR for the use of bone-anabolic agents and prevention of BrCa bone metastases constitute a proof of principle for therapeutic consideration. Understanding the interplay between PTH1R and CaSR signaling in the development of BrCa bone metastases could lead to a novel therapeutic approach to control both osteolysis and tumor burden in the bone

THE THIOL REDOX SYSTEM IN OXLDL-INDUCED MACROPHAGE INJURY

Macrophage death is likely to contribute to the transformation of fatty streaks into advanced atherosclerotic lesions. Previous work in the laboratory showed that OxLDL promotes cell death in human macrophages by a mechanism involving intracellular peroxide formation. Here we show that glutathione depletion induced by OxLDL occurs independent of peroxyl radical formation. Our data suggest that the depletion of glutathione is the fundamental defect that renders macrophages susceptible to OxLDL-induced cell injury, but alone is not sufficient to kill macrophages. We indicate that increased protein-Sglutathionylation is involved in OxLDL-induced macrophage death. A potentiation of OxLDL toxicity was observed in macrophages transfected with siRNA directed against either glutathione reductase or glutaredoxin. Our data suggests that OxLDL-induced cell injury in human macrophage is mediated by the depletion of GSH, a decreased in the GSH/GSSG ratio and peroxyl radical formation. All three signals are required for OxLDL-induced macrophage death. Our results also show that the glutathione reductase/glutaredoxin system protects macrophages from OxLDL-induced cell death

Ixazomib enhances parathyroid hormone-induced β-catenin/T-cell factor signaling by dissociating β-catenin from the parathyroid hormone receptor.

The anabolic action of PTH in bone is mostly mediated by cAMP/PKA and Wnt-independent activation of β-catenin/T-cell factor (TCF) signaling. β-Catenin switches the PTH receptor (PTHR) signaling from cAMP/PKA to PLC/PKC activation by binding to the PTHR. Ixazomib (Izb) was recently approved as the first orally administered proteasome inhibitor for the treatment of multiple myeloma; it acts in part by inhibition of pathological bone destruction. Proteasome inhibitors were reported to stabilize β-catenin by the ubiquitin-proteasome pathway. However, how Izb affects PTHR activation to regulate β-catenin/TCF signaling is poorly understood. In the present study, using CRISPR/Cas9 genome-editing technology, we show that Izb reverses β-catenin-mediated PTHR signaling switch and enhances PTH-induced cAMP generation and cAMP response element-luciferase activity in osteoblasts. Izb increases active forms of β-catenin and promotes β-catenin translocation, thereby dissociating β-catenin from the PTHR at the plasma membrane. Furthermore, Izb facilitates PTH-stimulated GSK3β phosphorylation and β-catenin phosphorylation. Thus Izb enhances PTH stimulation of β-catenin/TCF signaling via cAMP-dependent activation, and this effect is due to its separating β-catenin from the PTHR. These findings provide evidence that Izb may be used to improve the therapeutic efficacy of PTH for the treatment of osteoporosis and other resorptive bone diseases

A Location-Sentiment-Aware Recommender System for Both Home-Town and Out-of-Town Users

Spatial item recommendation has become an important means to help people discover interesting locations, especially when people pay a visit to unfamiliar regions. Some current researches are focusing on modelling individual and collective geographical preferences for spatial item recommendation based on users' check-in records, but they fail to explore the phenomenon of user interest drift across geographical regions, i.e., users would show different interests when they travel to different regions. Besides, they ignore the influence of public comments for subsequent users' check-in behaviors. Specifically, it is intuitive that users would refuse to check in to a spatial item whose historical reviews seem negative overall, even though it might fit their interests. Therefore, it is necessary to recommend the right item to the right user at the right location. In this paper, we propose a latent probabilistic generative model called LSARS to mimic the decision-making process of users' check-in activities both in home-town and out-of-town scenarios by adapting to user interest drift and crowd sentiments, which can learn location-aware and sentiment-aware individual interests from the contents of spatial items and user reviews. Due to the sparsity of user activities in out-of-town regions, LSARS is further designed to incorporate the public preferences learned from local users' check-in behaviors. Finally, we deploy LSARS into two practical application scenes: spatial item recommendation and target user discovery. Extensive experiments on two large-scale location-based social networks (LBSNs) datasets show that LSARS achieves better performance than existing state-of-the-art methods.Comment: Accepted by KDD 201

New Nonlinear Systems Admitting Virasoro-Type Symmetry Algebra and Group-Invariant Solutions

With the aid of symbolic computation by Maple, we extend the application of Virasoro-type symmetry prolongation method to coupled systems with two-component nonlinear equations. New nonlinear systems admitting infinitely dimensional centerless Virasoro-type symmetry algebra are constructed. Taking one of them as an example, we present some group-invariant solutions to one of the new model systems