Novel Mannan-PEG-PE Modified Bioadhesive PLGA Nanoparticles for Targeted Gene Delivery

Purpose. Biodegradable polymeric nanoparticles have been used frequently as gene delivery vehicles. The aim of this study is to modify bioadhesive PLGA nanoparticles with novel synthetic mannan-PEG-PE (MN-PEG-PE) to obtain active targeted gene delivery system. Methods. Mannan-PEG-PE ligands were synthesized and modified onto the NPs/pEGFP complexes. The modification rate was optimized, and the characteristics of the vehicle were evaluated. Then, the modified vectors were intravenous delivered to rats, and in vivo targeting behavior of MN-PEG-PE modified PLGA nanoparticles/pEGFP complexes (MN-PEG-PE-NPs/pEGFP) in liver macrophages was investigated. Results. MN-PEG-PE-NPs/pEGFP displayed remarkably higher transfection efficiencies than nonmodified NPs/pEGFP both in vitro and in vivo. Conclusions. Mannan containing targeting ligands could significantly improve the transfection efficiency of the carriers. MN-PEG-PE modified vectors very useful in targeted gene delivery

High Accordance in Prognosis Prediction of Colorectal Cancer across Independent Datasets by Multi-Gene Module Expression Profiles

A considerable portion of patients with colorectal cancer have a high risk of disease recurrence after surgery. These patients can be identified by analyzing the expression profiles of signature genes in tumors. But there is no consensus on which genes should be used and the performance of specific set of signature genes varies greatly with different datasets, impeding their implementation in the routine clinical application. Instead of using individual genes, here we identified functional multi-gene modules with significant expression changes between recurrent and recurrence-free tumors, used them as the signatures for predicting colorectal cancer recurrence in multiple datasets that were collected independently and profiled on different microarray platforms. The multi-gene modules we identified have a significant enrichment of known genes and biological processes relevant to cancer development, including genes from the chemokine pathway. Most strikingly, they recruited a significant enrichment of somatic mutations found in colorectal cancer. These results confirmed the functional relevance of these modules for colorectal cancer development. Further, these functional modules from different datasets overlapped significantly. Finally, we demonstrated that, leveraging above information of these modules, our module based classifier avoided arbitrary fitting the classifier function and screening the signatures using the training data, and achieved more consistency in prognosis prediction across three independent datasets, which holds even using very small training sets of tumors

A novel defined pyroptosis-related gene signature predicts prognosis and correlates with the tumour immune microenvironment in lung adenocarcinoma

Abstract Lung adenocarcinoma (LUAD) is one of the most common causes of cancer-related death. The role of pyroptosis in LUAD remains unclear. Our study aimed to identify a prognostic signature of pyroptosis-related genes (PRGs) and explore the connection of PRGs with the tumour microenvironment in LUAD. Gene expression and clinical information were obtained from The Cancer Genome Atlas database. Consensus clustering was applied to classify LUAD patients. The least absolute shrinkage and selection operator Cox and multivariate Cox regression models were used to generate a PRG-related prognostic signature. The correlations between PRGs and tumour-infiltrating immune cells or the tumour mutational burden were analysed by Spearman’s correlation analysis. In this study, 44 PRGs significantly differed in expression between LUAD and normal tissues. Based on these genes, patients were clustered into three clusters with significantly different distributions of tumour-infiltrating immune cells and immune checkpoint regulators. A total of four PRGs (NLRP1, HMGB1, CYCS, and BAK1) were used to construct a prognostic model. Significant correlations were observed between these prognostic PRGs and immune cell infiltration or the tumour mutational burden. Predictive nomogram results showed that BAK1 could be an independent prognostic biomarker in LUAD. Additionally, the expression level of BAK1 was validated in two independent Gene Expression Omnibus cohorts. Our identified prognostic PRG signature may provide insight for future studies targeting pyroptosis and the tumour microenvironment in LUAD. Future studies are needed to verify our current findings

Clinical observations on intensive immunosuppressive therapy combined with umbilical cord blood support for the treatment of severe aplastic anemia

Abstract Objective To evaluate the efficacy of enhanced, intensive, immuno-suppressive therapy with umbilical cord blood support for severe aplastic anemia (SAA). Methods A total of 25 patients with SAA received enhanced, intensive, immuno-suppressive therapy and a cord blood transfusion. Therapy protocol: Anti-thymocyte globulin (ATG) 2.5 mg/(kg•d) × 5d; Cyclophosphamide 50 mg/(kg•d) × 2d; cyclosporin A (CsA) maintenance therapy. Result 25 patients were enrolled. 18 underwent a complete recovery, 4 made significant improvements, 1 did not respond, and 2 died. Therefore, the efficacy rate was 88%. The median follow-up time was 35 months (range 13-47 months), and the 3-year overall survival rate was 92%. Patients rapidly achieved reconstitution of hematopoiesis. The median time to neutrophil ANC > 0.5 × 109/L was 18 days (range 8-36), platelets >20 × 109/L was 34 days (range 12-123), and Hb > 100 g/L 95 dyas (range 35-173). Conclusion Enhanced, intensive, immuno-suppressive therapy with umbilical cord blood support may be an effective option for SAA therapy.</p

Mannan-Modified PLGA Nanoparticles for Targeted Gene Delivery

The studies of targeted gene delivery nanocarriers have gained increasing attention during the past decades. In this study, mannan modified DNA loaded bioadhesive PLGA nanoparticles (MAN-DNA-NPs) were investigated for targeted gene delivery to the Kupffer cells (KCs). Bioadhesive PLGA nanoparticles were prepared and subsequently bound with pEGFP. Following the coupling of the mannan-based PE-grafted ligands (MAN-PE) with the DNA-NPs, the MAN-DNA-NPs were delivered intravenously to rats. The transfection efficiency was determined from the isolated KCs and flow cytometry was applied for the quantitation of gene expression after 48 h post transfection. The size of the MAN-DNA-NPs was found to be around 190 nm and the Zeta potential was determined to be −15.46mV. The pEGFP binding capacity of MAN-DNA-NPs was (88.9±5.8)% and the in vitro release profiles of the MAN-DNA-NPs follow the Higuchi model. When compared with non-modified DNA-NPs and Lipofectamine 2000-DNA, MAN-DNA-NPs produced the highest gene expressions, especially in vivo. The in vivo data from flow cytometry analysis showed that MAN-DNA-NPs displayed a remarkably higher transfection efficiency (39%) than non-modified DNA-NPs (25%) and Lipofectamine 2000-DNA (23%) in KCs. The results illustrate that MAN-DNA-NPs have the ability to target liver KCs and could function as promising active targeting drug delivery vectors