Functionalized Nanoparticles for the Dispersion of Gas Hydrates in Slurry Flow.

Gas hydrates are crystals that can form in oil and gas production. Their agglomeration in flowlines may disrupt the normal production. One current strategy of hydrate management is to inject an anti-agglomerant, a type of low-dosage hydrate inhibitor that prevents hydrate agglomeration. Concerns in the use of these chemicals include their toxicity, cost, and environmental impacts. In this study, we exploited functionalized nanoparticles in place of anti-agglomerants to produce hydrate slurry, with the potential benefit of nanoparticles to be more environmentally friendly and conveniently recyclable. We coated 256 nm spherical silica nanoparticles with different hydrophobicity and evaluated their performance for the hydrate dispersion at atmospheric and high pressure. Nanoparticles with moderate hydrophobicity stabilized oil-in-water (O/W) or water-in-oil (W/O) emulsions. Direct visualization of the cyclopentane hydrate formation from the nanoparticle-stabilized emulsions revealed different morphologies of hydrate particles depending on whether the nanoparticles prevented agglomeration. We also measured the apparent viscosity of a hydrate-nanoparticle mixture using a high-pressure rheometer. Nanoparticles with moderate hydrophobicity during hydrate formation slowed the viscosification, reduced the maximum viscosity, increased the water conversion, and ultimately helped to maintain a low steady-state viscosity. Increasing nanoparticle or salt concentrations also improved the gas hydrate dispersion. Our study demonstrated the great potential of using nanoparticles in preventing agglomeration of gas hydrates under realistic pipeline flow conditions.

MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts.

The interaction between osteoclasts (OCs) and multiple myeloma (MM) cells plays a key role in the pathogenesis of MM-related osteolytic bone disease (OBD). MM cells promote OC formation and, in turn, OCs enhance MM cell proliferation. Chemokines are mediators of MM effects on bone and vice versa; in particular, CCL3 enhances OC formation and promotes MM cell migration and survival. Here, we characterize the effects of MLN3897, a novel specific antagonist of the chemokine receptor CCR1, on both OC formation and OC-MM cell interactions. MLN3897 demonstrates significant impairment of OC formation (by 40%) and function (by 70%), associated with decreased precursor cell multinucleation and down-regulation of c-fos signaling. OCs secrete high levels of CCL3, which triggers MM cell migration; conversely, MLN3897 abrogates its effects by inhibiting Akt signaling. Moreover, MM cell-to-OC adhesion was abrogated by MLN3897, thereby inhibiting MM cell survival and proliferation. Our results therefore show novel biologic sequelae of CCL3 and its inhibition in both osteoclastogenesis and MM cell growth, providing the preclinical rationale for clinical trials of MLN3897 to treat OBD in MM.

BIRB 796 enhances cytotoxicity triggered by bortezomib, heat shock protein (Hsp) 90 inhibitor, and dexamethasone via inhibition of p38 mitogen-activated protein kinase/Hsp27 pathway in multiple myeloma cell lines and inhibits paracrine tumour growth.

We have previously shown that heat shock protein (Hsp) 27 or its upstream activator p38 mitogen-activated protein kinase (MAPK) confers resistance to bortezomib and dexamethasone (Dex) in multiple myeloma (MM) cells. This study examined anti-MM activity of a novel p38 MAPK inhibitor, BIRB 796, alone and in combination with conventional and novel therapeutic agents. BIRB 796 blocked baseline and bortezomib-triggered upregulation of p38 MAPK and Hsp27 phosphorylation, thereby enhancing cytotoxicity and caspase activation. The Hsp90 inhibitor 17-allylamino-17-demethoxy-geldanamycin (17-AAG) upregulated protein expression and phosphorylation of Hsp27; conversely, BIRB 796 inhibited this phosphorylation and enhanced 17-AAG-induced cytotoxicity. Importantly, BIRB 796 inhibited Hsp27 phosphorylation induced by 17-AAG plus bortezomib, thereby enhancing cytotoxicity. In bone marrow stromal cells (BMSC), BIRB 796 inhibited phosphorylation of p38 MAPK and secretion of interleukin-6 (IL-6) and vascular endothelial growth factor triggered by either tumour necrosis factor-alpha or tumour growth factor-beta1. BIRB 796 also inhibited IL-6 secretion induced in BMSCs by adherence to MM cells, thereby inhibiting tumour cell proliferation. These studies therefore suggest that BIRB 796 overcomes drug-resistance in the BM microenvironment, providing the framework for clinical trials of a p38 MAPK inhibitor, alone and in combination with bortezomib, Hsp90 inhibitor, or Dex, to improve patient outcome in MM.