Reversal of Bortezomib-Induced Neurotoxicity by Suvecaltamide, a Selective T-Type Ca-Channel Modulator, in Preclinical Models

This study evaluated suvecaltamide, a selective T-type calcium channel modulator, on chemotherapy-induced peripheral neurotoxicity (CIPN) and anti-cancer activity associated with bortezomib (BTZ). Rats received BTZ (0.2 mg/kg thrice weekly) for 4 weeks, then BTZ alone (n = 8) or BTZ+suvecaltamide (3, 10, or 30 mg/kg once daily; each n = 12) for 4 weeks. Nerve conduction velocity (NCV), mechanical threshold, β-tubulin polymerization, and intraepidermal nerve fiber (IENF) density were assessed. Proteasome inhibition was evaluated in peripheral blood mononuclear cells. Cytotoxicity was assessed in human multiple myeloma cell lines (MCLs) exposed to BTZ alone (IC50 concentration), BTZ+suvecaltamide (10, 30, 100, 300, or 1000 nM), suvecaltamide alone, or vehicle. Tumor volume was estimated in athymic nude mice bearing MCL xenografts receiving vehicle, BTZ alone (1 mg/kg twice weekly), or BTZ+suvecaltamide (30 mg/kg once daily) for 28 days, or no treatment (each n = 8). After 4 weeks, suvecaltamide 10 or 30 mg/kg reversed BTZ-induced reduction in NCV, and suvecaltamide 30 mg/kg reversed BTZ-induced reduction in IENF density. Proteasome inhibition and cytotoxicity were similar between BTZ alone and BTZ+suvecaltamide. BTZ alone and BTZ+suvecaltamide reduced tumor volume versus the control (day 18), and BTZ+suvecaltamide reduced tumor volume versus BTZ alone (day 28). Suvecaltamide reversed CIPN without affecting BTZ anti-cancer activity in preclinical models.

Describing the Full Pore Size Distribution of Tight Sandstone and Analyzing the Impact of Clay Type on Pore Size Distribution

Understanding the pore size distribution (PSD) of tight sandstone and the effect of clay minerals on the PSD is important for reservoir evaluation. Due to the complex shape of clay minerals, the multiscale pore size of tight sandstone, and the limitation of different experimental methods, it is hard to characterize the full PSD of tight sandstone, especially the point of connection (POC) of different derived PSD curves. In this paper, a more comprehensive technique integrated different precision methods of N2/CO2 low-pressure adsorption isotherms (N2/CO2-LPAI), mercury injection capillary pressure (MICP), nuclear magnetic resonance (NMR), and synchrotron X-ray computed tomography (XCT) to investigate the full PSD for three typical tight sandstones in China. Two different forms of PSD data presentations, differential pore volume versus diameter (dV/dR) and the log differential pore volume versus diameter (dV/dlogR), were firstly used to determine the POC. The full integrated PSD curves and scanning electron microscopy (SEM) images were carried out on the different clay-rich tight sandstones. The results show that the pores are classified into three types: intercrystalline pores (less than 0.01 μm), clay-related pores and residual intergranular pores (0.01 μm to 10 μm), and microfractures and dissolution pores (greater than 10 μm). The percentage of intercrystalline pores has a small relation on the porosity and connectivity, while there is a strong correlation among microfractures, dissolution pores, porosity, and especially connectivity. The microfractures and dissolution pores are the main connection channels, so a little change of the main connection channels will have a great effect on the permeability of the tight sandstones.