Braunellis2824
In this study, the effect of ligand binding position on the polymeric nanoparticles (NPs) is based on poly(lactic-co-glycolic acid) (PLGA) with two different polymer chain length at the atomistic level was presented. We explored the conjugation of riboflavin (RF) ligand from the end of the ribityl chain (N-10) to the polymer strands as well as from the amine group on the isoalloxazine head (N-3). The energy interactions for all samples revealed that the NPs containing ligands from N-10 positions have higher total attraction energies and lower stability in comparison with their peers conjugated from N-3. As NPs containing RF conjugated from N-3 exhibit the lower energy level with 20% and 10% of RF-containing composition for lower and higher. The introduction of RF from the N-10 position in any composition has increased the energy level of nanocarriers. The results of Gibb's free energy confirm the interatomic interaction energies trend where the lowest Gibbs free energy level for N-3 NPs occurs at 20 and 10% of RF-containing polymer content for PLGA10- and PLGA11- based NPs. Furthermore, with N-10 samples based on both polymers, non-targeted models form the stablest particles in each category. These findings are further confirmed with molecular docking analysis which revealed affinity energy of RF toward polymer chain from N-3 and N-10 are -981.57 kJ/mole and -298.23 kJ/mole, respectively. This in-silico study paves the new way for molecular engineering of the bio-responsive PLGA-PEG-RF micelles and can be used to nanoscale tunning of smart carriers used in cancer treatment. Communicated by Ramaswamy H. Sarma.The conformational features of drugs are important with respect to their biological activity. In this report, we confirmed the solid-state conformation of 1-(4'-azido-2'-deoxy-2'-fluoro-β-d-arabinofuranosyl) cytosine using single-crystal X-ray crystallography and the conformations of three 2'-deoxy-2'-fluoro-4'-substituted nucleosides in solution using Altona-Haasnoot's equations and Nuclear Overhauser effect spectroscopy (NOESY). GSK 3 inhibitor Furthermore, we compared the preferred solid-state and solution conformation of these nucleosides with thermodynamics cycles to obtain more evidence of their conformations. The results showed 1-(4'-azido-2'-deoxy-2'-fluoro-β-d-arabinofuranosyl) cytosine was south type conformation (C-3'-exo) in solid-state and three 4'-substituted nucleosides were north type conformations (C-3'-endo) in solution. The north type conformations in solution indicated these compounds were steady to acidic and enzymatic N-glycolysis.Oxidative stress plays a critical role in nanotoxicity. Various types of nanoparticles are known to induce oxidative stress by generating intracellular reactive oxygen species (ROS). Cellular uptake of nanoparticles and intracellular metal ion release are important factors for intracellular ROS generation. Besides, ROS generation can result from interactions of nanoparticles and cells that lead to mitochondrial dysfunction. In vivo, nanoparticles induce the secretion of cytokines, which, in turn, induce secondary oxidative stress via generation of ROS and free radicals. However, not all nanoparticles induce oxidative stress. Intracellular ROS generation by nanoparticles depends on their physical and chemical properties, such as the crystalline phase, adsorption ability, and solubility. Even if the particle size is nanoscale (1-100 nm), physically and chemically inactive particles do not induce oxidative stress. Thus, the particle size is not a direct influencing factor in nanoparticle-induced oxidative stress.Introduction Cardiac stimulation evolved from life-saving devices to prevent asystole to the treatment of heart rhythm disorders and heart failure, capable of remote patient and disease-progression monitoring. Cardiac stimulation nowadays aims to correct the electrophysiologic roots of mechanical inefficiency in different structural heart diseases.Areas covered Clinical experience, as per available literature, has led to awareness of the concealed risks of customary cardiac pacing, that can inadvertently cause atrio-ventricular and inter/intra-ventricular dyssynchrony. New pacing modalities have emerged, leading to a new concept of what truly represents 'physiologic pacing' beyond maintenance of atrio-ventricular coupling. In this article we will analyze the emerging evidence in favor of the available strategies to achieve an individualized physiologic setting in bradycardia pacing, and the hints of future developments.Expert opinion 'physiologic stimulation' technologies should evolve to enable an effective and widespread adoption. In one way new guiding catheters and the adoption of electrophysiologic guidance and non-fluoroscopic lead implantation are needed to make His-Purkinje pacing successful and effective at long term in a shorter procedure time; in the other way leadless stimulation needs to upgrade to a superior physiologic setting to mimic customary DDD pacing and possibly His-Purkinje pacing.
To clarify factors affecting 5-year survival rates and relapse rates after spontaneous regression (SR) of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA).
This retrospective longitudinal study comprised 232 patients with RA diagnosed with LPDs between January 2000 and March 2017 at eight hospitals in Japan. The Kaplan-Meier method was used to analyze survival and the Cox proportional hazard model was applied to identify predictive factors.
Among all patients, 1-, 2- and 5-year overall survival rates were 89.5%, 86.1%, and 78.2%, respectively. Multivariable analysis revealed four 5-year survival risk factors assessed at diagnosis age above 70 years (
= .002), deep lymphadenopathy and/or more than one extranodal lesion (
= .008), Eastern Cooperative Oncology Group/Zubrod performance status of 2-4 (
= .004), and classic Hodgkin lymphoma (CHL) histology (
= .047). Among 143 patients who achieved SR, 2- and 5-year relapse rates were 14.2% and 24.9%, respectively. CHL histology (
= .003) and serum soluble interleukin-2 receptor levels exceeding 2000 IU/L (
= .014) were associated with post-SR relapse-free survival. Blood lymphocyte counts were significantly lower at relapse than at 3-6 months prior (
< .001).
Assessment of the above risk factors and routine inspection of blood lymphocyte counts could aid in the care management of LPDs in RA.
Assessment of the above risk factors and routine inspection of blood lymphocyte counts could aid in the care management of LPDs in RA.Introduction Tricuspid valve (TV) dysfunction treatment experiences exponential growth of the interest over the last years. New techniques for percutaneous tricuspid valve treatment are either on the market or in the early stages of development.Areas covered Deficiency of uniform guideline-based recommendations leads to diverse TV dysfunction treatment options. The current review describes the development of surgical techniques for TV dysfunction in Ebstein's anomaly and transition to a variety of new technologies. Then, the focus is on the potential of percutaneous interventions to reduce the total number of open-heart surgeries in patients with congenital heart disease (CHD) after TV replacement with a bioprosthesis to improve TV function.Expert opinion TV dysfunction is usually a complex combination of anatomical cardiac features in CHD. Compared to adults with secondary TV dysfunction, CHD patients usually are younger and have experienced several open-heart surgeries at a young age. Therefore, TV dysfunction can affect long-term life expectancy and quality of life significantly. So far, surgery was the gold standard for TV dysfunction treatment. The duration of TV plasty or bioprosthesis is limited, while the risk of re-do operations increases with every procedure. Percutaneous TV implantation may reduce the total number of open-heart surgeries over a patient's life.
Glycogen phosphorylase B (PYGB), the rate-determining enzyme in glycogen degradation, plays a critical role in progression of various tumors. The present study focused on the potential molecular mechanism toward PYGB in non-small cell lung cancer (NSCLC) progression.
Expression of PYGB in NSCLC tissues and cell lines was evaluated via quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry. Cell viability, proliferation and apoptosis were investigated using 3-(4,5-Dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay, 5-bromo-2-deoxyuridine (
) and flow cytometry, respectively. Cell migration and invasion ability were detected by wound healing and transwell invasion assays, respectively. The
effect of PYGB on NSCLC tumor growth was determined via subcutaneous xenotransplanted tumor model.
PYGB was upregulated in NSCLC tissues and cell lines, suggesting a poor prognosis in NSCLC patients.
functional assays indicated that knockdown of PYGB suppressed cell viability, proliferation, migration and invasion, while promoted cell apoptosis in NSCLC. Mechanistically, we found that overexpression of PYGB could activate phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, while these effects were effectively reversed by knockdown of PYGB.
tumorigenesis and PI3K/AKT signaling pathway were also inhibited by PYGB knockdown.
Knockdown of PYGB suppressed NSCLC progression, suggesting PYGB as a novel biomarker and potential molecular therapeutic target for further investigation in NSCLC.
Knockdown of PYGB suppressed NSCLC progression, suggesting PYGB as a novel biomarker and potential molecular therapeutic target for further investigation in NSCLC.Sexual assault victimization (SAV) histories may impede, increase, or have no effect on women's risk recognition. Yet, even though risk recognition is a component of bystander intervention, the effect of SAV on bystander behaviors is understudied. For example, how different SAV histories, such as the severity of the assault and if women were revictimized since entering college, have not been examined with bystander behaviors; we intended to address this gap in the literature. Building on recent work, we also examined the potential interactive effects of alcohol consumption and SAV history in predicting bystander behaviors. College women (n = 560) completed a web-based survey on alcohol consumption, SAV experiences since entering college, and bystander behaviors in alcohol-involved settings. We found that the effect of SAV history on bystander behavior varied based on alcohol consumption. As women's alcohol consumption increased so did their self-reported engagement in bystander behaviors. For non-victims, increased alcohol consumption had a greater positive effect on their bystander behaviors than victims. However, after a certain quantity of alcohol was consumed, both victims and non-victims reported decreased bystander behavior. Finally, alcohol consumption did not interact with severity of SAV or revictimization status in predicting bystander behavior. Findings suggest alcohol consumption may be more influential on bystander behaviors for women with no history of SAV; however, consuming a greater quantity of alcohol is related to a decrease in bystander behavior-regardless of SAV history. Given these findings, more work is needed to explore when and how alcohol impedes, and potentially encourages, bystander behavior. How SAV histories relate to bystander behaviors also warrants further research.