Dissipative particle dynamics simulation of multicompartment micelle nanoreactor with channel for reactants

The structural variation of multicompartment micelles is investigated using a dissipative particle dynamics simulation method for nano-reactor application. It turns out that well-defined multicompartment micelles with channel structures can be generated through the self-assembly of triblock copolymers consisting of a hydrophilic (A), a lipophilic (B), and a fluorophobic (C) block arranged in a B–A–C sequence: The corona and core are formed by the hydrophilic A block and the fluorophilic C block, respectively while the channel between the aqueous phase and core is formed by the lipophilic B block and the core. By performing a set of simulations, it is confirmed that channel size can be controlled as a function of the block length ratios between blocks A and B. Furthermore, it is also confirmed that the reactants pass through such channels to reach the micelle core by analyzing the pair correlation functions. By monitoring the change of the number of reactants in the multicompartment micelle, it is revealed that the diffusion of reactants into the core is slowed down as the concentration gradient is decreased. This work provides mesoscopic insight for the formation of multicompartment micelles and transport of reactants for use in the design of micelles as nanoreactors.

The structural variation of multicompartment micelles is investigated using a dissipative particle dynamics simulation method for nano-reactor application.     

Incidence of major hemorrhage after aggressive image-guided liver mass biopsy in the era of individualized medicine

Purpose

To analyze a large volume of image-guided liver mass biopsies to assess for an increased incidence of major hemorrhage after aggressive liver mass sampling, and to determine if coaxial technique reduces major hemorrhage rate.

Methods

Patients who underwent image-guided liver mass biopsy over a 15-year period (December 7, 2001–September 22, 2016) were retrospectively identified. An aggressive biopsy was defined as a biopsy event in which ≥ 4 core needle passes were performed. Association of major hemorrhage after aggressive liver mass biopsy and other potential risk factors of interest were assessed using logistic regression analysis. For the subset of aggressive biopsies, Fisher’s exact test was used to compare the incidence of major hemorrhage using coaxial versus noncoaxial techniques.

Results

Aggressive biopsies constituted 11.6% of biopsy events (N =579/5011). The incidence of major hemorrhage with <4 passes was 0.4% (N =18/4432) and with ≥4 passes 1.2% (N =6/579). In univariable models, aggressive biopsy was significantly associated with major hemorrhage (OR 3.0, 95% CI 1.16–6.92, p =0.025). After adjusting for gender and platelet count, the association was not significant at the p =0.05 level (OR 2.58, 95% CI 0.927–6.24, p =0.067). The rate of major hemorrhage in the coaxial biopsy technique group was 1.4% (N =3/209) compared to 1.1% (N =4/370) in the noncoaxial biopsy technique group, which was not a significant difference (p =0.707).

Conclusions

Although aggressive image-guided liver mass biopsies had an increased incidence of major hemorrhage, the overall risk of bleeding remained low. The benefit of such biopsies will almost certainly outweigh the risk in most patients.

     

Effect of Nitric Oxide Synthase Inhibitors on Preventing Ethanol-Induced Suppression of the Hypothalamic-Pituitary-Gonadal Axis in the Male Rat

Ethanol (EtOH) suppression of the hypothalamic-pituitary-gonadal (HPG) axis results in broad reproductive malfunction. In the HPG axis, the suppressive effects of EtOH are manifested by decreased serum testosterone, reduced testicular luteinizing hormone (LH) receptor numbers, lowered serum LH and pituitary β-LH mRNA levels (in castrated animals), and impaired luteiniring hormone releasing hormone (LHRH) release from the hypothalamus. Increasing evidence has suggested that nitric oxide (NO) plays a role in regulation of the HPG axis. NO was shown to stimulate LHRH secretion from the hypothalamus and to have variable effects on LH release from the pituitary. At the gonadal level, NO is inhibitory to testosterone production. NO may directly inhibit some testicular steroidogenic enzymes. To investigate the effect of EtOH, NO, and their interaction on the male HPG axis, three NO synthase (NOS) inhibitors, N^Q-nitro- l -arginine methyl ester, N^Q-nitro- l -arginine, and 7-nitro indazole were used to study overall HPG function in the presence and absence of EtOH. Animals were given intraperitoneal injections of saline, EtOH, various NOS inhibitors, or EtOH, along with NOS inhibitors 2 hr before sacrifice. Serum testosterone and LH concentrations, pituiiry βLH mRNA levels, hypothalamic LHRH mRNA levels, and LHRH content were determined. It was found that blocking NOS by these NOS inhibitors prevented EtOH-induced suppression of testosterone and, in some cases, serum LH. However, this was not accompanied by concurrent changes with NOS blockade on LHRH mRNA, hypothalamic pro-LHRH or LHRH content or pituitary LH β mRNA levels. It appears that the protective effect of NOS blockade was largely, although not completely, due to a direct effect at the gonadal level.     

Dual targeting of the proteasome regulates survival and homing in Waldenstrom macroglobulinemia

Waldenström macroglobulinemia (WM) is an incurable low-grade B-cell lymphoma characterized by high protein turnover. We dissected the biologic role of the proteasome in WM using 2 proteasome inhibitors, NPI-0052 and bortezomib. We found that NPI-0052 inhibited proliferation and induced apoptosis in WM cells, and that the combination of NPI-0052 and bortezomib induced synergistic cytotoxicity in WM cells, leading to inhibition of nuclear translocation of p65NF-B and synergistic induction of caspases-3, -8, and -9 and PARP cleavage. These 2 agents inhibited the canonical and noncanonical NF-B pathways and acted synergistically through their differential effect on Akt activity and on chymotrypsin-like, caspaselike, and trypsinlike activities of the proteasome. We demonstrated that NPI-0052–induced cytotoxicity was completely abrogated in an Akt knockdown cell line, indicating that its major activity is mediated through the Akt pathway. Moreover, we demonstrated that NPI-0052 and bortezomib inhibited migration and adhesion in vitro and homing of WM cells in vivo, and overcame resistance induced by mesenchymal cells or by the addition of interleukin-6 in a coculture in vitro system. Theses studies enhance our understanding of the biologic role of the proteasome pathway in WM, and provide the preclinical basis for clinical trials of combinations of proteasome inhibitors in WM.