Artificial local magnetic field inhomogeneity enhances T2 relaxivity

磁性探针作为分子影像技术中的磁共振成像（MRI）造影剂在医学诊断中发挥着重要作用。为满足实际诊断中的准确性和精确性要求，科研工作者们长期致力于发展高性能的MRI造影剂以降低高剂量的使用带来的潜在风险。该文章指出了探针聚集体中局域磁场不均匀性是影响T2弛豫效能的关键因素。该文章首次利用磁场不均匀性因素阐明了单个探针和它们聚集体的MRI造影剂之间的相互关系，将可能成为弥补探针聚集体的造影剂理论的空白，并为发展新型高效的MRI造影剂提供重要参考。 该论文共同第一作者为博士后周子健和博士生田蕊，通讯作者为陈小元教授和聂立铭博士，部分工作得到我校物理学系王瑞方教授和化学化工学院高锦豪教授的支持。【Abstract】Clustering of magnetic nanoparticles (MNPs) is perhaps the most effective, yet intriguing strategy to enhance T2 relaxivity in magnetic resonance imaging (MRI). However, the underlying mechanism is still not fully understood and the attempts to generalize the classic outersphere theory from single particles to clusters have been found to be inadequate. Here we show that clustering of MNPs enhances local field inhomogeneity due to reduced field symmetry, which can be further elevated by artificially involving iron oxide NPs with heterogeneous geometries in terms of size and shape. The r2 values of iron oxide clusters and Landau–Lifshitz–Gilbert simulations confirmed our hypothesis, indicating that solving magnetic field inhomogeneity may become a powerful way to build correlation between magnetization and T2 relaxivity of MNPs, especially magnetic clusters. This study provides a simple yet distinct mechanism to interpret T2 relaxivity of MNPs, which is crucial to the design of high-performance MRI contrast agents.This work was supported by the National Science Foundation of China (81571744 and 81601489), the National Basic Research Program of China (863 Program 2015AA020502), the Fundamental Research Funds for the Central Universities (20720170065), the Science Foundation of Fujian Province (No. 2014Y2004), and by the Intramural Research Program (IRP), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). 研究工作得到了国家自然科学基金委、国家高技术研究发展计划863项目、福建省重大研发平台项目和美国NIH Intramural Research Program的资助

Artificial local magnetic field inhomogeneity enhances T2 relaxivity

磁性探针作为分子影像技术中的磁共振成像（MRI）造影剂在医学诊断中发挥着重要作用。为满足实际诊断中的准确性和精确性要求，科研工作者们长期致力于发展高性能的MRI造影剂以降低高剂量的使用带来的潜在风险。该文章指出了探针聚集体中局域磁场不均匀性是影响T2弛豫效能的关键因素。该文章首次利用磁场不均匀性因素阐明了单个探针和它们聚集体的MRI造影剂之间的相互关系，将可能成为弥补探针聚集体的造影剂理论的空白，并为发展新型高效的MRI造影剂提供重要参考。 该论文共同第一作者为博士后周子健和博士生田蕊，通讯作者为陈小元教授和聂立铭博士，部分工作得到我校物理学系王瑞方教授和化学化工学院高锦豪教授的支持。【Abstract】Clustering of magnetic nanoparticles (MNPs) is perhaps the most effective, yet intriguing strategy to enhance T2 relaxivity in magnetic resonance imaging (MRI). However, the underlying mechanism is still not fully understood and the attempts to generalize the classic outersphere theory from single particles to clusters have been found to be inadequate. Here we show that clustering of MNPs enhances local field inhomogeneity due to reduced field symmetry, which can be further elevated by artificially involving iron oxide NPs with heterogeneous geometries in terms of size and shape. The r2 values of iron oxide clusters and Landau–Lifshitz–Gilbert simulations confirmed our hypothesis, indicating that solving magnetic field inhomogeneity may become a powerful way to build correlation between magnetization and T2 relaxivity of MNPs, especially magnetic clusters. This study provides a simple yet distinct mechanism to interpret T2 relaxivity of MNPs, which is crucial to the design of high-performance MRI contrast agents.This work was supported by the National Science Foundation of China (81571744 and 81601489), the National Basic Research Program of China (863 Program 2015AA020502), the Fundamental Research Funds for the Central Universities (20720170065), the Science Foundation of Fujian Province (No. 2014Y2004), and by the Intramural Research Program (IRP), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). 研究工作得到了国家自然科学基金委、国家高技术研究发展计划863项目、福建省重大研发平台项目和美国NIH Intramural Research Program的资助

The Subgingival Microbiome of Periodontal Pockets With Different Probing Depths in Chronic and Aggressive Periodontitis: A Pilot Study

Periodontitis is a kind of infectious disease initiated by colonization of subgingival periodontal pathogens, which cause destruction of tooth-supporting tissues, and is a predominant threat to oral health as the most common cause of loss of teeth. The aim of this pilot study was to characterize the subgingival bacterial biodiversity of periodontal pockets with different probing depths in patients with different forms of periodontitis. Twenty-one subgingival plaque samples were collected from three patients with chronic periodontitis (ChP), three patients with aggressive periodontitis (AgP) and three periodontally healthy subjects (PH). Each patient with periodontitis was sampled at three sites, at different probing depths (PDs, one each at 4 mm, 5–6 mm, and ≥ 7 mm). Using 16S rRNA gene high-throughput sequencing and bioinformatic analysis, we found that subgingival communities in health and periodontitis samples largely differed. Meanwhile, Acholeplasma, Fretibacterium, Porphyromonas, Peptococcus, Treponema_2, Defluviitaleaceae_UCG_011, Filifactor, and Mycoplasma increased with the deepening of the pockets in ChP, whilst only Corynebacterium was negatively associated with PD. In AgP, Corynebacterium and Klebsiella were positively associated with PD, while Serratia, Pseudoramibacter, Defluviitaleaceae_UCG_011, and Desulfobulbus were negatively associated with PD. And among these two groups, Corynebacterium shifted differently. Moreover, in subgingival plaque, the unweighted UniFrac distances between samples from pockets with different PD in the same patients were significantly lower than those from pockets within the same PD category from different patients. This study demonstrated the shift of the subgingival microbiome in individual teeth sites during disease development. Within the limitation of the relative small sample size, this pilot study shed new light on the dynamic relationship between the extent of periodontal destruction and the subgingival microbiome

Danshen-Honghua Ameliorates Stress-Induced Menopausal Depression in Rats

Objective. Previously, we have shown that Danshen-Honghua (DSHH) for cognitive deficits after ischemia induced impairments of the hippocampus. Here, we investigate the effects of DSHH on stress-induced depression in menopausal rats. Methods. A rat model with menopausal depression was established with bilateral ovariectomies in female SD rats followed by chronic mild stress treatment for 21 days. 40 rats were randomly divided into the sham surgery group (sham surgery and no stress treatment), surgery group (surgery with no stress treatment), surgery/stress group (surgery and stress treatment), fluoxetine group (2.4 mg·kg−1, with surgery and stress treatment), and DSHH group (35 g·kg−1, with surgery and stress treatment). The rats in the last two groups were treated with stresses together with intragastric drug administration for three weeks after the surgery. Then open-field locomotor scores and sucrose intake were tested for behavior changes. Also, the levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT), and cortisone were determined by high-performance liquid chromatography (HPLC). Serum estradiol (E2), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were determined by radioimmunoassay. Results. The results of open-field locomotor scores, sucrose intake in both the fluoxetine group and DSHH group, were significantly higher than those of the surgery/stress group (P<0.01). Serum LH, FSH, and cortisone levels in both the DSHH group and fluoxetine group were significantly lower than those in the surgery/stress group (P<0.01). Serum E2 levels in these groups were slightly increased in these medicine groups (P<0.01). The monoamine levels in the DSHH group were much higher than those in the surgery/stress group (P<0.01). Conclusion. DSHH can ameliorate stress-induced depressed syndromes in the surgery/stressed rats via regulating LH and FSH levels as well as monoamine levels

Enhanced antitumor efficacy of an oncolytic herpes simplex virus expressing an endostatin-angiostatin fusion gene in human glioblastoma stem cell xenografts.

Viruses have demonstrated strong potential for the therapeutic targeting of glioblastoma stem cells (GSCs). In this study, the use of a herpes simplex virus carrying endostatin-angiostatin (VAE) as a novel therapeutic targeting strategy for glioblastoma-derived cancer stem cells was investigated. We isolated six stable GSC-enriched cultures from 36 human glioblastoma specimens and selected one of the stable GSCs lines for establishing GSC-carrying orthotopic nude mouse models. The following results were obtained: (a) VAE rapidly proliferated in GSCs and expressed endo-angio in vitro and in vivo 48 h and 10 d after infection, respectively; (b) compared with the control gliomas treated with rHSV or Endostar, the subcutaneous gliomas derived from the GSCs showed a significant reduction in microvessel density after VAE treatment; (c) compared with the control, a significant improvement was observed in the length of the survival of mice with intracranial and subcutaneous gliomas treated with VAE; (d) MRI analysis showed that the tumor volumes of the intracranial gliomas generated by GSCs remarkably decreased after 10 d of VAE treatment compared with the controls. In conclusion, VAE demonstrated oncolytic therapeutic efficacy in animal models of human GSCs and expressed an endostatin-angiostatin fusion gene, which enhanced antitumor efficacy most likely by restricting tumor microvasculature development

Improvement of the in vitro safety profile and cytoprotective efficacy of amifostine against chemotherapy by PEGylation strategy

Amifostine, an organic thiophosphate prodrug, has been clinically utilized for selective protection of normal tissues with high expression of alkaline phosphatase from oxidative damage elicited by chemotherapy or radiotherapy. However, the patients receiving amifostine suffer from severe dose-dependent adverse effects. Strategies for improvement of the protective efficacy and toxicity profile of amifostine are urgently required. Here we constructed a PEGylated amifostine (PEG-amifostine) through conjugation of amifostine to the 4-arm PEG (5000 Da) by a mild one-step reaction. The relatively large PEG-amifostine molecules clustered into spherical nanoparticles, resulting in distinct hydrolysis properties, cell uptake profile and antioxidative activity compared with the free small molecules. PEGylation prolonged the hydrolysis time of amifostine, providing sustained transformation to its functional metabolites. PEG-amifostine could be internalized into cells and translocated to acidic organelles in a time-dependent manner. The intrinsic cytotoxicity of amifostine, which is related to the reductive reactivity of its metabolites and their ability to diffuse readily, was attenuated after PEGylation. This modification impeded the interaction between free sulfhydryls and functional biomolecules, providing PEG-amifostine with an improved safety profile in vitro. Moreover, PEG-amifostine showed higher efficiency in the elimination of reactive oxygen species and prevention of cisplatin-induced cytotoxicity compared with free amifostine. Overall, our study for the first time developed a PEGylated form of amifostine which significantly improved the efficacy and decreased the adverse effects of this antioxidant in vitro with great promise for clinical translation. In vivo study is urgently needed to confirm and redeem the cytoprotective effects of the PEG-amifostine in chemotherapy

IMonitor:a robust pipeline for TCR and BCR repertoire analysis

The advance of next generation sequencing (NGS) techniques provides an unprecedented opportunity to probe the enormous diversity of the immune repertoire by deep sequencing T-cell receptors (TCRs) and B-cell receptors (BCRs). However, an efficient and accurate analytical tool is still on demand to process the huge amount of data. We have developed a high-resolution analytical pipeline, Immune Monitor (“IMonitor”) to tackle this task. This method utilizes realignment to identify V(D)J genes and alleles after common local alignment. We compare IMonitor with other published tools by simulated and public rearranged sequences, and it demonstrates its superior performance in most aspects. Together with this, a methodology is developed to correct the PCR and sequencing errors and to minimize the PCR bias among various rearranged sequences with different V and J gene families. IMonitor provides general adaptation for sequences from all receptor chains of different species and outputs useful statistics and visualizations. In the final part of this article, we demonstrate its application on minimal residual disease detection in patients with B-cell acute lymphoblastic leukemia. In summary, this package would be of widespread usage for immune repertoire analysis

Photothermal Effect Enhanced Cascade-Targeting Strategy for Improved Pancreatic Cancer Therapy by Gold Nanoshell@Mesoporous Silica Nanorod

Pancreatic cancer, one of the leading causes of cancer-related mortality, is characterized by desmoplasia and hypovascular cancerous tissue, with a 5 year survival rate of <8%. To overcome the severe resistance of pancreatic cancer to conventional therapies, we synthesized gold nanoshell-coated rod-like mesoporous silica (GNRS) nanoparticles which integrated cascade tumor targeting (mediated by photothermal effect and molecular receptor binding) and photothermal treatment-enhanced gemcitabine chemotherapy, under mild near-infrared laser irradiation condition. GNRS significantly improved gemcitabine penetration and accumulation in tumor tissues, thus destroying the dense stroma barrier of pancreatic cancer and reinforcing chemosensitivity in mice. Our current findings strongly support the notion that further development of this integrated plasmonic photothermal strategy may represent a promising translational nanoformulation for effective treatment of pancreatic cancer with integral cascade tumor targeting strategy and enhanced drug delivery efficacy

Expression of the exogenous endo–angio fusion gene and the activity of the fusion protein in vitro and in vivo.

<p>(A) RT–PCR results indicated that a significant induction of endo–angio mRNA expression existed after VAE infection in vitro and in vivo. By contrast, only the internal standard control, GAPDH, could be detected in the r-HSV-, Endostar-, and PBS-treated groups. (B) Cell lysates and ECM were harvested 48 h after infection, and the orthotopically implanted tumors were harvested 10 d after injection, as described in the Materials and Methods section. The temporal pattern of the expression of endo–angio was investigated via western blot analysis of cell lysates and ECM for the in vitro experiments, and proteins extracted from the tumors for the in vivo experiments. Western blotting results indicated that a 58 kDa fusion protein recognized by the endostatin antibody was present in the VAE group, but not in the r-HSV group or the Endostar group. β-actin was detectable in all samples.</p