Understanding paclitaxel/pluronic F127 nanocrystals prepared by the stabilization of nanocrystal (SNC) method

The objectives of this study were to understand the structure and stability of paclitaxel nanocrystals, as well as the biodistribution of nanocrystals after intravenous injection in mice. The nanocrystal size increased after 2 h 37 oC incubation due to thermal induced aggregation. The addition of more F127 surfactant further destabilized nanocrystals and led to a larger size increase concurrent with micelle formation. PTX/F127 nanocrystals (1/5 w/w) had little size increase upon dilution, indicating tight monomer surfactant absorption. Nanocrystals of more F127 surfactant (1/20, 1/30 w/w) increased much in size upon dilution, suggesting low-affinity surfactant absorption with micelle formation in solution. The re-nanonization after 37 oC incubation effectively inhibited crystal growth after 37 oC incubation again by disturbing the preferred crystal growth pattern of PTX. The biodistribution of nanocrystals revealed that the majority of nanocrystals were quickly taken up by reticuloendothelial system and went to the liver 1 h post injection

Understanding the structure and stability of paclitaxel nanocrystals

Previously, PTX/Pluronic F127 nanocrystals were prepared in our laboratory using the Stabilization of Nanocrystals (SNC) method. For PTX nanocrystals, dosages could be increased to yield improved antitumor activity over Taxol® without incidence of acute toxicity. The objectives of this current study are to further understand the structure and stability of PTX nanocrystals. More Pluronic F127 surfactant was added in the formulation to attempt to further stabilize the nanocrystals against thermal induced aggregation. However, this resulted in formation of micelles that worsened the stability of nanocrystals. The F127 desorption experiment suggested different surfactant adsorption affinity to nanocrystal surface below and above the CMC. Below the CMC monomers bound to nanocrystal surface with high affinity, but above the CMC low affinity surfactant aggregates readily left the surface upon dilution. At higher temperature the tendency of F127 micellization is enhanced due to drastically lower CMC. Consequently, at 37 °C there was F127 desorption even for nanocrystals prepared with low amounts of F127 (1/5 w/w PTX/F127). To improve the stability of nanocrystals, re-nanonization by Incubation-Sonication procedure was used to disrupt the preferred crystal growth pattern of PTX. Furthermore, we have demonstrated that a higher heating temperature (45 °C vs. 37 °C) used in the Incubation-Sonication procedure was able to provide even better nanocrystal stability for long periods of incubation time

Drug development progress in duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe, progressive, and incurable X-linked disorder caused by mutations in the dystrophin gene. Patients with DMD have an absence of functional dystrophin protein, which results in chronic damage of muscle fibers during contraction, thus leading to deterioration of muscle quality and loss of muscle mass over time. Although there is currently no cure for DMD, improvements in treatment care and management could delay disease progression and improve quality of life, thereby prolonging life expectancy for these patients. Furthermore, active research efforts are ongoing to develop therapeutic strategies that target dystrophin deficiency, such as gene replacement therapies, exon skipping, and readthrough therapy, as well as strategies that target secondary pathology of DMD, such as novel anti-inflammatory compounds, myostatin inhibitors, and cardioprotective compounds. Furthermore, longitudinal modeling approaches have been used to characterize the progression of MRI and functional endpoints for predictive purposes to inform Go/No Go decisions in drug development. This review showcases approved drugs or drug candidates along their development paths and also provides information on primary endpoints and enrollment size of Ph2/3 and Ph3 trials in the DMD space

Interaction Effects of Life Events and Hair Cortisol on Perceived Stress, Anxiety, and Depressive Symptoms Among Chinese Adolescents: Testing the Differential Susceptibility and Diathesis-Stress Models

The differential susceptibility model and the diathesis-stress model on the interaction effect between the individuals’ traits and environmental factors will be conducive to understand in depth whether the psychophysiological traits are the risk factors of child development. However, there is no study focusing on the activity of the hypothalamic-pituitary-adrenal (HPA) axis. We examined whether the HPA activity serves as a physiological marker of the differential susceptibility model or the diathesis-stress model by exploring the interactive effect of life events and hair cortisol on perceived stress, anxiety, and depressive symptoms among Chinese adolescents. The participants were 324 students in senior high school. They reported their psychological states with questionnaires in their first semester after a 3-month adaptation period; 2 weeks later, they provided 1-cm hair segments closest to the scalp. We measured hair cortisol concentration as a biomarker of HPA activity using high-performance liquid chromatography–tandem mass spectrometry. There was a significant interaction effect of academic events and hair cortisol on adolescents’ perceived stress, anxiety, and depression symptoms. We also observed a significant interaction between interpersonal events and hair cortisol on adolescents’ anxiety symptoms. Looking at the region of significance, proportion of interaction index, and proportion affected index, we found that adolescents with higher cortisol levels had a tendency to experience higher perceived stress and anxiety symptoms when they had high academic events scores, but lower perceived stress and anxiety symptoms when they had lower academic events scores. By contrast, adolescents with higher cortisol levels had a greater risk of experiencing high depressive symptoms only when they had higher academic events scores. Adolescents with higher cortisol levels also tended to have lower anxiety symptoms when they had higher interpersonal events scores, but greater anxiety symptoms when they had lower interpersonal events scores. These results suggested that HPA activity might serve as a biomarker of the differential susceptibility model for perceived stress and anxiety symptoms, while for depressive symptoms, it might serve as a marker of the diathesis-stress model

Effect of Different Harvest Maturity on the Nutritional Quality of Midknight Valencia Orange Fruit

Midknight Valencia Orange is one of the most important late maturing citrus varieties. In order to study the effect of different harvest maturity on the nutritional quality of this variety and to determine its optimal harvesting period, the quality indexes of Midknight Valencia Orange, including color difference, firmness, carotenoid, soluble sugars, organic acids, free amino acids, mineral elements, flavonoid and total phenol content were measured and a correlation analysis was performed. The result showed that different harvest maturity had significant effects on the quality of Midknight Valencia Orange. With the delay of harvesting time, the coloration process of the peel gradually changed from the stem end to the bottom end and the peel showed a bright yellow after 360 days of flowering. The contents of carotenoid, ascorbic acid, total phenol and flavonoid increased, while the content of soluble solid increased first and then decreased, and the titrable acid content decreased significantly. The main soluble sugars in Midknight Valencia Orange fruit were glucose, sucrose, fructose, talose and inositol, and the contents of glucose and sucrose showed an increasing trend during harvesting. The main organic acids were citric acid, malic acid and quinic acid, and the content of citric acid decreased during harvesting. The main free amino acids were proline, arginine and serine, which showed an increasing trend during harvesting. Based on the evaluation indexes prescribed above, 360~400 days (April~May) after flowering is the appropriate harvesting time for Midknight Valencia Orange. Besides, the correlation analysis results showed that, as the indicator often used to judge the maturity of fruit, the firmness and titratable acid content of Midknight Valencia Orange have highly correlation with the content of carotenoid, soluble sugars, organic acids, free amino acids, mineral elements, flavonoid and total phenol. The firmness, titratable acid content and TSSC/TA ratio of Midknight Valencia can be used for the determination of harvesting time, namely fruit with a firmness 1.33~1.03 kg, titratable acid content 1.77%~1.30% and 5.41~6.96 TSS/TA ratio showed a good quality. The results of this study can provide a scientific basis for the determination the suitable harvesting period of Midknight Valencia Orange

Association of a low ankle brachial index with progression to end-stage kidney disease in patients with advanced-stage diabetic kidney disease

AbstractIntroductions The effect of a low ankle-brachial index (ABI) in patients with advanced-stage diabetic kidney disease is not fully understood. This study investigates the prevalence of a low ABI in patients with advanced-stage diabetic kidney disease, which was defined as a urinary albumin-to-creatinine ratio (UACR) ≥300 mg/g and an estimated glomerular filtration rate (eGFR) between 15–60 mL/min/1.73 m2. Furthermore, the association between a low ABI and end-stage kidney disease (ESKD) was determined.Methods This single-center, retrospective, cohort study included 529 patients with advanced-stage diabetic kidney disease who were stratified into groups according to the ABI: high (>1.3), normal (0.9–1.3), and low (<0.9). The Kaplan-Meier method and Cox proportional analysis were used to examine the association between the ABI and ESKD.Results A total of 42.5% of patients with a low ABI progressed to ESKD. A low ABI was associated with a greater risk of ESKD (hazard ratio (HR): 1.073). After adjusting for traditional chronic kidney disease risk factors, a low ABI remained associated with a greater risk of ESKD (HR: 1.758; 95% confidence interval: 1.243–2.487; p = 0.001).Conclusions These results indicate that patients with a low ABI should be monitored carefully. Furthermore, preventive therapy should be considered to improve the long-term kidney survival of patients with residual kidney function

Combined influence of depression and low-grade inflammation on mortality in peritoneal dialysis patients

Abstract Background The relationship between depression and systemic inflammation as risk factors for mortality is not well understood and requires further investigation. Methods Patients undergoing continuous ambulatory peritoneal dialysis (CAPD) between July 01, 2015 to December 31, 2019, were analyzed and followed up until December 31, 2020. According to their status of depression (PHQ-9 score ≥ 5) and low-grade inflammation (hs-CRP level ≥ 3 mg/L), patients were divided into four groups (G1, without depression, nor inflammation; G2, with depression, without inflammation; G3, with inflammation, without depression; G4, with both depression and inflammation). We performed Kaplan–Meier and multivariable Cox proportional analyses of mortality for the combined influence of depression and systemic inflammation in this cohort. Results During the mean follow-up of 36.3 ± 14.8 months, 73 deaths were recorded in 358 participants. Compared with patients in group G1, patients in group G2 and G3 carried 137% {hazard ratio (HR): 2.37, 95% confidence interval (CI): 1.06—5.23, p = 0.035} and 140% (HR: 2.40, 95% CI: 1.01—5.69, p = 0.048) higher risk of mortality. Patients in group G4 (with both depression and inflammation) showed the highest risks of all-cause mortality with 276% higher mortality risk (HR: 3.76, 95% CI: 1.73—8.15, p = 0.001), respectively. Conclusion The combined of depression and inflammation is associated with all-cause mortality in peritoneal dialysis patients, suggesting a need for further study of depression and low-grade inflammation in PD patients and potential relationship between them