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"Dai, Xin"
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Curing hemophilia A by NHEJ-mediated ectopic F8 insertion in the mouse
Background
Hemophilia A, a bleeding disorder resulting from
F8
mutations, can only be cured by gene therapy. A promising strategy is CRISPR-Cas9-mediated precise insertion of
F8
in hepatocytes at highly expressed gene loci, such as albumin (
Alb
). Unfortunately, the precise in vivo integration efficiency of a long insert is very low (~ 0.1%).
Results
We report that the use of a double-cut donor leads to a 10- to 20-fold increase in liver editing efficiency, thereby completely reconstituting serum F8 activity in a mouse model of hemophilia A after hydrodynamic injection of Cas9-sgAlb and B domain-deleted (BDD) F8 donor plasmids. We find that the integration of a double-cut donor at the
Alb
locus in mouse liver is mainly through non-homologous end joining (NHEJ)-mediated knock-in. We then target
BDDF8
to multiple sites on introns 11 and 13 and find that NHEJ-mediated insertion of
BDDF8
restores hemostasis. Finally, using 3 AAV8 vectors to deliver genome editing components, including Cas9, sgRNA, and
BDDF8
donor, we observe the same therapeutic effects. A follow-up of 100 mice over 1 year shows no adverse effects.
Conclusions
These findings lay the foundation for curing hemophilia A by NHEJ knock-in of
BDDF8
at
Alb
introns after AAV-mediated delivery of editing components.
Journal Article
A tough nitric oxide-eluting hydrogel coating suppresses neointimal hyperplasia on vascular stent
Vascular stent is viewed as one of the greatest advancements in interventional cardiology. However, current approved stents suffer from in-stent restenosis associated with neointimal hyperplasia or stent thrombosis. Herein, we develop a nitric oxide-eluting (NOE) hydrogel coating for vascular stents inspired by the biological functions of nitric oxide for cardiovascular system. Our NOE hydrogel is mechanically tough and could selectively facilitate the adhesion of endothelial cells. Besides, it is non-thrombotic and capable of inhibiting smooth muscle cells. Transcriptome analysis unravels the NOE hydrogel could modulate the inflammatory response and induce the relaxation of smooth muscle cells. In vivo study further demonstrates vascular stents coated with it promote rapid restoration of native endothelium, and persistently suppress inflammation and neointimal hyperplasia in both leporine and swine models. We expect such NOE hydrogel will open an avenue to the surface engineering of vascular implants for better clinical outcomes.
Neointimal hyperplasia and stent thrombosis remain issues with vascular stents. Here, the authors report on the development of a nitric oxide releasing hydrogel which allows for endothelialisation of the stent surface and prevents smooth muscle cell growth reducing hyperplasia and thrombosis in in vivo models.
Journal Article
IGF2BP2 Drives Cell Cycle Progression in Triple‐Negative Breast Cancer by Recruiting EIF4A1 to Promote the m6A‐Modified CDK6 Translation Initiation Process
IGF2BP2 is a new identified N6‐methyladenosine (m6A) reader and associated with poor prognosis in many tumors. However, its role and related mechanism in breast cancer, especially in triple‐negative breast cancer (TNBC), remains unclear. In this study, it is found that IGF2BP2 is highly expressed in TNBC due to the lower methylation level in its promoter region. Functional and mechanical studies displayed that IGF2BP2 could promote TNBC proliferation and the G1/S phase transition of the cell cycle via directly regulating CDK6 in an m6A‐dependent manner. Surprising, the regulation of protein levels of CDK6 by IGF2BP2 is related to the changes in translation rate during translation initiation, rather than mRNA stability. Moreover, EIF4A1 is found to be recruited by IGF2BP2 to promote the translation output of CDK6, providing new evidence for a regulatory role of IGF2BP2 between m6A methylation and translation. Downregulation of IGF2BP2 in TNBC cell could enhance the sensitivity to abemaciclib, a CDK4/6 inhibitor. To sum up, our study revealed IGF2BP2 could facilitate the translation output of CDK6 via recruiting EIF4A1 and also provided a potential therapeutic target for the diagnosis and treatment of TNBC, as well as a new strategy for broadening the drug indications for CDK4/6 inhibitors.
Journal Article
Circular RNA circSATB2 promotes progression of non-small cell lung cancer cells
Background
Lung cancer has high morbidity and mortality worldwide with non-small cell lung cancer (NSCLC) accounting for 85% of the cases. Therapies for lung cancer have relatively poor outcomes and further improvements are required. Circular RNAs have been reported to participate in the occurrence and progression of cancer. Information on the functions and mechanism of circRNAs in lung cancer is limited and needs more exploration.
Methods
We detected expression of genes and proteins by qPCR and western blot. Function of circSATB2 was investigated using RNA interference and overexpression assays. Location of circSATB2 was assessed by fluorescence in situ hybridization (FISH). Interaction of circSATB2, miR-326 and
FSCN1
was confirmed by dual-luciferase reporter assay.
Results
Data from the investigation showed that circSATB2 was highly expressed in NSCLC cells and tissues. circSATB2 positively regulated fascin homolog 1, actin-bundling protein 1 (FSCN1) expression via miR-326 in lung cancer cells. Furthermore, circSATB2 can be transferred by exosomes and promote the proliferation, migration and invasion of NSCLC cells, as well as induce abnormal proliferation in normal human bronchial epithelial cells. Also, circSATB2 was highly expressed in serumal exosomes from lung cancer patients with high sensitivity and specificity for clinical detection and was related to lung cancer metastasis.
Conclusions
circSATB2 participated in the progression of NSCLC and was differentially expressed in lung cancer tissue and serumal exosomes. circSATB2 may be potential biomarker for the diagnosis of NSCLC.
Journal Article
Helicobacter Pylori and Autoimmune Diseases: Involving Multiple Systems
The modern Gastroenterology have witnessed an essential stride since Helicobacter pylori was first found in the stomach and then its pathogenic effect was discovered. According to the researches conducted during the nearly 40 years, it has been found that this bacterium is associated with a natural history of many upper gastrointestinal diseases. Epidemiological data show an increased incidence of autoimmune disorders with or after infection with specific microorganisms. The researches have revealed that H. pylori is a potential trigger of gastric autoimmunity, and it may be associated with other autoimmune diseases, both innate and acquired. This paper reviews the current support or opposition about H. pylori as the role of potential triggers of autoimmune diseases, including inflammatory bowel disease, autoimmune thyroiditis, type 1 diabetes mellitus, autoimmune liver diseases, rheumatoid arthritis, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, as well as Sjogren’s syndrome, chronic urticaria and psoriasis, and tried to explain the possible mechanisms.
Journal Article
Comparison of Different Drying Methods on the Volatile Components of Ginger (Zingiber officinale Roscoe) by HS-GC-MS Coupled with Fast GC E-Nose
Ginger (Zingiber officinale Roscoe) is one of the most popular spices in the world, with its unique odor. Due to its health benefits, ginger is also widely used as a dietary supplement and herbal medicine. In this study, the main flavor components of gingers processed by different drying methods including hot air drying, vacuum drying, sun-drying, and vacuum-freeze drying, were identified on the basis of headspace-gas chromatography coupled with mass spectrometry (HS-GC-MS) and fast gas chromatography electronic-nose (fast GC e-nose) techniques. The results showed that the ginger dried by hot air drying exhibited high contents of volatile compounds and retained the richest odor in comparison with those dried by other methods, which indicated that hot air drying is more suitable for the production of dried ginger. Sensory description by fast GC e-nose exhibited that ginger flavor was mainly concentrated in the spicy, sweet, minty, fruity, and herbaceous odor. The relative content of the zingiberene was significantly higher in the hot air drying sample than those by other methods, suggesting that dried ginger by hot air drying can retain more unique spicy and pungent odorants. Furthermore, the results of chemometrics analyses showed that the main variance components among the samples by different drying methods were α-naginatene, (+)-cyclosativene, and sulcatone in HS-GC-MS analysis, and α-terpinen-7-al, dimethyl sulfide, and citronellal in fast GC e-nose analysis. For comparison of fresh and dried gingers, terpinolene, terpinen-4-ol, 2,4-decadienal, (E, Z)-, and linalool were considered the main variance components. This study generated a better understanding of the flavor characteristics of gingers by different drying methods and could provide a guide for drying and processing of ginger.
Journal Article
Enforcing Law and Norms for Good Citizens: One View of China’s Social Credit System Project
Despite widespread mischaracterization and misconception about its policy objective and content, China’s social credit system project at this point consists primarily of a set of new approaches to enforcing conduct norms that already exist in the country’s multi-layered legal and extralegal norm systems. This essay explains such enforcement logic inherent in the project’s application to regulating behaviour of individual citizens. It also argues that the project’s implementation of its envisioned new enforcement paradigm is foremost challenged by design difficulties.
Journal Article
Pancreatic cancer‐secreted miR‐155 implicates in the conversion from normal fibroblasts to cancer‐associated fibroblasts
Cancer‐associated fibroblasts (CAF) are a major constituent of the pancreatic cancer microenvironment and that the meaning is as intended. Pancreatic cancer cells can induce normal fibroblasts to convert into CAF and, reciprocally, CAF promote tumor invasions and proliferations. The mechanism of the conversion from normal fibroblasts (NF) to CAF remains unclear. MicroRNA are short non‐coding RNA involved in the post‐transcription gene regulation, which have been defined as an imperative controller in tumor invasions, proliferations and colony formations. Microvesicles (MV) have been proved to be an important mediator of intercellular communication and can selectively transport secreted microRNA from a donor cell into a recipient cell. In this study, we isolated primary pancreatic fibroblasts from wild type C57 mice and co‐cultured them with pancreatic cancer cell lines, BxPC‐3 and SW1990, and observed the conversion from NF to CAF, or at least CAF‐like cells. This phenomenon could also be replicated in primary fibroblasts treated with MV separated from a cancer cell media. We identified that miR‐155 was upregulated in PaC‐derived MV and we confirmed that normal fibroblasts could convert into CAF after MV containing miR‐155 had been taken up. TP53INP1 is a target of miR‐155 in fibroblasts and a downregulation of TP53INP1 protein levels could contribute to the fibroblasts' activation. These results indicated that pancreatic cancer cells might reprogram normal adjacent fibroblasts into CAF by means of secreted MV containing miR‐155. Targeting the circulating microRNA might be a potential therapy for malignant tumors. In this study, we discovered that microvesicles, containing miR‐155, might be released by pancreatic cancer cells and incorporated by co‐cultivated primary fibroblasts. TP53INP1 might be a target gene of miR‐155 in fibroblasts, which may mediate proliferation and the activation of normal fibroblasts and to manifest the characteristics of cancer‐associated fibroblasts.
Journal Article