Poly(ortho ester) nanoparticles targeted for chronic intraocular diseases: ocular safety and localization after intravitreal injection

Treatment of posterior eye diseases is more challenging than the anterior segment ailments due to a series of anatomical barriers and physiological constraints confronted by drug delivery to the back of the eye. In recent years, concerted efforts in drug delivery have been made to prolong the residence time of drugs injected in the vitreous humor of the eye. Our previous studies demonstrated that poly(ortho ester) (POE) nanoparticles were biodegradable/biocompatible and were capable of long-term sustained release. The objective of the present study was to investigate the safety and localization of POE nanoparticles in New Zealand white rabbits and C57BL/6 mice after intravitreal administration for the treatment of chronic posterior ocular diseases. Two concentration levels of POE nanoparticles solution were chosen for intravitreal injection: 1.5?mg/ml and 10?mg/ml. Our results demonstrate that POE nanoparticles were distributed throughout the vitreous cavity by optical coherence tomography (OCT) examination 14 days post-intravitreal injection. Intraocular pressure was not changed from baseline. Inflammatory or adverse effects were undetectable by slit lamp biomicroscopy. Furthermore, we demonstrate that POE nanoparticles have negligible toxicity assessed at the cellular level evidenced by a lack of glia activation or apoptosis estimation after intravitreal injection. Collectively, POE nanoparticles are a novel and nontoxic as an ocular drug delivery system for the treatment of posterior ocular diseases.     

Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity

A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.     

Who should do endovascular repair of complex aortic aneurysms and how should they do them?

BackgroundCure of aneurysms which involve the aorta at the level of the visceral arteries and the thoracoabdominal segment remains a considerable surgical enterprise with a relatively high mortality and morbidity despite improvements of the surgical procedure and anesthetic technique. Fenestrated and branched endovascular stent grafts are currently available offering an attractive less invasive option especially for most frail patients. These grafts are relatively recent, technically more demanding to insert than the current stent graft for infrarenal aneurysm and besides, given the relative low frequency of the disease, they are much less used by practitioners. Thus, unconditional widespread of this sophisticated technique may not necessarily benefit patients.MethodsWe reviewed our experiences and articles regarding this concern, 1) who should perform this new technique and 2) in what kind of setting.ConclusionBased on the combined complexities of 1) patients selection, 2) proper planning and manufacturing of the graft, 3) the need for outstanding imaging and operating facilities, 4) and the required endovascular skill of physicians involved in the procedure, we feel that only highly specialized centers should be allowed to perform this complex procedure.     

Residential Greenness Alters Serum 25(OH)D Concentrations: A Longitudinal Cohort of Chinese Older Adults

ObjectivesVitamin D deficiency is prevalent among older adults. We aimed to study whether residential greenness could alter serum 25(OH)D concentrations as a possible mechanism of residential greenness's positive health effects.DesignA longitudinal cohort study.Setting and ParticipantsWe included older adults aged ≥65 years from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) with follow-up between 2012 and 2014.MethodsWe measured residential greenness by calculating annual average Normalized Difference Vegetation Index (NDVI) in a 500 m radius by using satellite images around each participant's residential address. Serum 25-hydroxyvitamin D (25(OH)D) concentration was dichotomized into 2 categories: nondeficiency (≥50 nmol/L) and deficiency (<50 nmol/L). We used the generalized estimating equation to examine the relationship between annual average NDVI and serum 25(OH)D.ResultsWe included 1336 participants in our analysis. The annual average NDVI was 0.49, and mean serum 25(OH)D was 43 nmol/L at baseline. Each 0.1-unit increase in annual average NDVI was associated with a 13% higher odds of vitamin D nondeficiency [95% confidence interval (CI): 1.01, 1.26]. The association was stronger among men [odds ratio (OR): 1.17, 95% CI: 1.02, 1.35] than women (OR: 1.08, 95% CI: 0.91, 1.29) and also stronger among those who were free of activities of daily living (ADL) disability at baseline (OR: 1.12, 95% CI: 1.00, 1.25). During the follow-up period, the participants who lived in greener areas were more likely to have an improved, rather than stable or deteriorated, vitamin D status (OR: 1.94, 95% CI: 1.51, 2.51).Conclusions and ImplicationsOur study suggests that higher levels of residential greenness are associated with higher serum 25(OH)D concentrations, which has implications for prevention of vitamin D deficiency among older adults.     

Does Outcome/Survival of Patients With Myelodysplastic Syndromes Should Be Predicted by Reduced Levels of ADAMTS-13? Results From a Pilot Study

IntroductionVon Willebrand factor (vWF) cleaving protease ADAMTS-13 has a key role for maintaining normal size of vWF. A deficiency or dysfunction of vWF cleaving protease is associated with ultra large vWF multimers and thrombotic microangiopathy. Patients with cancers have reduced levels of vWF cleaving protease. In this pilot study, we have evaluated whether or not deficiencies of ADAMTS-13 were present in myelodysplastic syndromes (MDS). Moreover, we assessed if a reduction in basal levels of ADAMTS-13 may play a role in the prognosis of MDS.Patients and MethodsWe measured and compared the levels of vWF cleaving protease ADAMTS-13 in 100 patients with MDS and 35 healthy controls. Patients were divided into 2 groups according to the International Prognostic Scoring System: group I consisting of 44 patients with low-risk MDS and group II of 56 patients with high-risk MDS. Patients with high-risk and low-risk MDS presented significantly lower levels of ADAMTS-13 than controls (P < .001 and P = .0177, respectively). High-risk patients had significantly lower levels of ADAMTS-13 when compared with the low-risk group (P < .001).ResultsWe found that reduced levels of ADAMTS-13 have a relationship with overall survival (P < .001). Statistical analysis showed that ADAMTS-13 correlates with cytogenetics (P < .001) and a tendency of slight correlation with platelet count and basal levels of ADAMTS-13 (R, 0.35; P value, 0.001). Moreover, we found that levels of ADAMTS-13 have correlation with response to treatment (P < .001).ConclusionsADAMTS-13 in MDS might represent a surrogate marker of prognosis, response to therapy, or disease progression. Further studies are needed.     

热疗对肿瘤免疫微环境中免疫细胞及免疫相关细胞因子的影响

随着对肿瘤热疗和肿瘤免疫微环境(TIME)的深入研究,近年来热疗对TIME的作用越来越受到学者们的重视。本文就目前国内外研究进展,对热疗与TIME中几类主要免疫细胞和免疫相关细胞因子的影响及作用机制作一综述。全面而透彻的了解热疗对TIME的调控作用,有助于为肿瘤治疗提供新的思路和方法。     

Evaluation of mutagenic,recombinogenic and carcinogenic potential of (+)-usnic acid in somatic cells of Drosophila melanogaster

The main of this study was to evaluate the mutagenic and carcinogenic potential of (+) – usnic acid (UA), using Somatic Mutation and Recombination Test (SMART) and the test for detecting epithelial tumor clones (wts) in Drosophila melanogaster. Larvae from 72 ± 4 h from Drosophila were fed with UA (5.0, 10.0 or 20.0 mM); urethane (10.0 mM) (positive control); and solvent (Milli-Q water, 1% Tween-80 and 3% ethanol) (negative control). ST cross produced increase in total mutant spots in the individuals treated with 5.0, 10.0 or 20.0 mM of UA. HB cross produced spot frequencies in the concentration of 5.0 mM that were higher than the frequency for the same concentration in the ST cross. In the highest concentrations the result was negative, which means that the difference observed can be attributed, in part, to the high levels of P450, suggesting that increasing the metabolic capacity maximized the toxic effect of these doses. In the evaluation of carcinogenesis using the wts test, the results obtained for the same concentrations of UA show a positive result for the presence of tumors when compared to the negative control. We conclude that UA has recombinogenic, mutagenic and carcinogenic effects on somatic cells in D. melanogaster.