Publications by authors named "Jiahai Shi"

93 Publications

Analgesic effect of intercostal nerve block given preventively or at the end of operation in video-assisted thoracic surgery: a randomized clinical trial.

Braz J Anesthesiol 2021 Jul 26. Epub 2021 Jul 26.

Affiliated Hospital of Nantong University, Department of Cardiothoracic Surgery, Nantong, China; Affiliated Hospital of Nantong University, Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, Nantong, China. Electronic address:

Objective: To compare the analgesic effect of intercostal nerve block (INB) with ropivacaine when given preventively or at the end of the operation in patients undergoing video-assisted thoracic surgery (VATS).

Methods: A total of 50 patients undergoing VATS were randomly divided into two groups. The patients in the preventive analgesia group (PR group) were given INB with ropivacaine before the intrathoracic manipulation combined with patient-controlled analgesia (PCA). The patients in the post-procedural block group (PO group) were administered INB with ropivacaine at the end of the operation combined with PCA. To evaluate the analgesic effect, postoperative pain was assessed with the visual analogue scale (VAS) at rest and Prince Henry Pain Scale (PHPS) scale at 6, 12, 24, 48, and 72 hours after surgery.

Results: At 6 h and 12 h post-surgery, the VAS at rest and PHPS scores in the PR group were significantly lower than those in the PO group. There were no significant differences in pain scores between two groups at 24, 48, and 72 hours post-surgery.

Conclusion: In patients undergoing VATS, preventive INB with ropivacaine provided a significantly better analgesic effect in the early postoperative period (at least through 12 h post-surgery) than did INB given at the end of surgery.
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http://dx.doi.org/10.1016/j.bjane.2021.07.010DOI Listing
July 2021

Extrachromosomal circular DNA: a new potential role in cancer progression.

J Transl Med 2021 06 10;19(1):257. Epub 2021 Jun 10.

Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, and Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, No. 20, Xisi Road, Nantong, 226001, Jiangsu, China.

Extrachromosomal circular DNA (eccDNA) is considered a circular DNA molecule that exists widely in nature and is independent of conventional chromosomes. eccDNA can be divided into small polydispersed circular DNA (spcDNA), telomeric circles (t-circles), microDNA, and extrachromosomal DNA (ecDNA) according to its size and sequence. Multiple studies have shown that eccDNA is the product of genomic instability, has rich and important biological functions, and is involved in the occurrence of many diseases, including cancer. In this review, we focus on the discovery history, formation process, characteristics, and physiological functions of eccDNAs; the potential functions of various eccDNAs in human cancer; and the research methods employed to study eccDNA.
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http://dx.doi.org/10.1186/s12967-021-02927-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194206PMC
June 2021

Self-adaptive and efficient propulsion of Ray sperms at different viscosities enabled by heterogeneous dual helixes.

Proc Natl Acad Sci U S A 2021 Jun;118(23)

Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China;

We disclose a peculiar rotational propulsion mechanism of Ray sperms enabled by its unusual heterogeneous dual helixes with a rigid spiral head and a soft tail, named Heterogeneous Dual Helixes (HDH) model for short. Different from the conventional beating propulsion of sperm, the propulsion of Ray sperms is from both the rotational motion of the soft helical tail and the rigid spiral head. Such heterogeneous dual helical propulsion style provides the Ray sperm with high adaptability in viscous solutions along with advantages in linearity, straightness, and bidirectional motion. This HDH model is further corroborated by a miniature swimming robot actuated via a rigid spiral head and a soft tail, which demonstrates similar superiorities over conventional ones in terms of adaptability and efficiency under the same power input. Such findings expand our knowledge on microorganisms' motion, motivate further studies on natural fertilization, and inspire engineering designs.
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http://dx.doi.org/10.1073/pnas.2024329118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201849PMC
June 2021

Plasmonic-doped melanin-mimic for CXCR4-targeted NIR-II photoacoustic computed tomography-guided photothermal ablation of orthotopic hepatocellular carcinoma.

Acta Biomater 2021 Jul 31;129:245-257. Epub 2021 May 31.

Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China; Institute of Digital Intelligence of Zhujiang Hospital of Southern Medical University, Guangzhou, 510280, China; Guangdong Provincial Clinical and Engineering Technology Center of Digital Medicine, Guangzhou, 510280, China. Electronic address:

Effective and noninvasive diagnosis and prompt treatment of early-stage hepatocellular carcinoma (HCC) are urgently needed to reduce its mortality rate. Herein, the integration of high-resolution diagnostic second near-infrared (NIR-II) photoacoustic computed tomography (PACT) and imaging-guided targeted photothermal ablation of orthotopic small HCC (SHCC) is presented for the first time, which was enabled by a plasmonic platinum (Pt)-doped polydopamine melanin-mimic nanoagent. As designed, an antibody-modified nanoagent (designated [email protected]) with a plasmonic blackbody-like NIR absorption and superior photothermal conversion efficiency (71.3%) selectively targeted and killed CXCR4-overexpressing HCC (HepG2) cells, which was validated in in vitro experiments. The targeted accumulation properties of [email protected] in vivo were previously recognized by demonstrating effective NIR-II PA imaging and photothermal ablation in a subcutaneous HCC mouse model. Subsequently, with real-time quantitative guidance by PACT for the accurate diagnosis of intraabdominal SHCC (approximately 4 mm depth), the effective and noninvasive photothermal ablation of SHCCs was successfully demonstrated in an orthotopic tumor-bearing mouse model without damaging adjacent liver tissues. These results show a great potential of NIR-II PACT-guided noninvasive photothermal therapy as an innovative phototheranostic approach and expand the biomedical applications of melanin-mimic materials. STATEMENT OF SIGNIFICANCE: In this paper, we report the first diagnostic NIR-II photoacoustic computed tomography (PACT)-guided noninvasive photothermal ablation of small hepatocellular carcinoma (SHCC) located in deep tissues in orthotopic tumor-bearing mice; this process is empowered by a polydopamine-based melanin-mimic tumor-targeting nanoagent doped with plasmonic platinum that provides superior NIR-II (1064 nm) absorption and photothermal conversion efficiency of 71.3%. Following surface modification with anti-CXCR4 antibodies, the nanoagent (namely [email protected]) can selectively target CXCR4-overexpressed HepG2 carcinoma cells and tumor lesions, and serve as the theranostic agent for both NIR-II PACT-based diagnosis of orthotopic SHCC (diameter less than 5 mm) and efficient NIR-II PTT in vivo. This study may also extend the potential of melanin-derived blackbody materials for optical-biomedical and water distillation applications.
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http://dx.doi.org/10.1016/j.actbio.2021.05.034DOI Listing
July 2021

Covalent conjugation of extracellular vesicles with peptides and nanobodies for targeted therapeutic delivery.

J Extracell Vesicles 2021 Feb 16;10(4):e12057. Epub 2021 Feb 16.

Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore Singapore.

Natural extracellular vesicles (EVs) are ideal drug carriers due to their remarkable biocompatibility. Their delivery specificity can be achieved by the conjugation of targeting ligands. However, existing methods to engineer target-specific EVs are tedious or inefficient, having to compromise between harsh chemical treatments and transient interactions. Here, we describe a novel method for the covalent conjugation of EVs with high copy numbers of targeting moieties using protein ligases. Conjugation of EVs with either an epidermal growth factor receptor (EGFR)-targeting peptide or anti-EGFR nanobody facilitates their accumulation in EGFR-positive cancer cells, both and . Systemic delivery of paclitaxel by EGFR-targeting EVs at a low dose significantly increases drug efficacy in a xenografted mouse model of EGFR-positive lung cancer. The method is also applicable to the conjugation of EVs with peptides and nanobodies targeting other receptors, such as HER2 and SIRP alpha, and the conjugated EVs can deliver RNA in addition to small molecules, supporting the versatile application of EVs in cancer therapies. This simple, yet efficient and versatile method for the stable surface modification of EVs bypasses the need for genetic and chemical modifications, thus facilitating safe and specific delivery of therapeutic payloads to target cells.
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http://dx.doi.org/10.1002/jev2.12057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886705PMC
February 2021

Molecular and Immune Characteristics for Lung Adenocarcinoma Patients With ERLIN2 Overexpression.

Front Immunol 2020 7;11:568440. Epub 2020 Dec 7.

Departments of Cardio-Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, China.

Background: Endoplasmic reticulum lipid raft-associated protein 2 (ERLIN2) is protein contained in the membrane of the endoplasmic reticulum. In lung adenocarcinoma (LUAD), the molecular function of ERLIN2 and the correlation between ERLIN2 and tumor-infiltrating immune cells have been unclear. The aim of our study was to determine the role of ERLIN2 in LUAD development to provide a better understanding of the molecular pathogenesis of this disease and identify new therapeutic targets for its treatment.

Methods: Immunohistochemistry, Western blotting, and real-time quantitative polymerase chain reaction were used to detect protein and mRNA levels of ERLIN2 in LUAD and adjacent normal tissues. Using the A549, H1299 cell line, ERLIN2-short hairpin RNA was applied to silence ERLIN2 to determine its role in LUAD cell proliferation and invasion. Based on mRNA expression of ERLIN2 from the Cancer Genome Atlas (TCGA) database, we identified ERLIN2-related protein-coding genes and analyzed the Kyoto Encyclopedia of Genes and Genomes pathway to explore its potential biological functions and determined the correlation between ERLIN2 and tumor-infiltrating immune cells.

Results: ERLIN2 was abnormally expressed in a variety of tumor tissues and is highly expressed in LUAD. This overexpression was associated with histological grade (P = 0.044), TNM stage (P = 0.01), and lymph node metastasis (P = 0.038). Patient overall survival was poorer with ERLIN2 overexpression. Downregulation of ERLIN2 inhibited LUAD cell proliferation and invasion in vitro. Based on mRNA expression of ERLIN2 from the TCGA database, 13 ERLIN2-related genes and 10 pathways were identified and showed a correlation between ERLIN2 and naive B cells and neutrophils.

Conclusion: ERLIN2 could serve as a potential diagnostic and prognostic biomarker for LUAD and has demonstrated to be correlated with immune infiltrates, which suggests that it may represent a new therapeutic target for LUAD.
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http://dx.doi.org/10.3389/fimmu.2020.568440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793841PMC
May 2021

The White-Spotted Bamboo Shark Genome Reveals Chromosome Rearrangements and Fast-Evolving Immune Genes of Cartilaginous Fish.

iScience 2020 Nov 2;23(11):101754. Epub 2020 Nov 2.

Department of Biological Sciences, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia.

Chondrichthyan (cartilaginous fish) occupies a key phylogenetic position and is important for investigating evolutionary processes of vertebrates. However, limited whole genomes impede our in-depth knowledge of important issues such as chromosome evolution and immunity. Here, we report the chromosome-level genome of white-spotted bamboo shark. Combing it with other shark genomes, we reconstructed 16 ancestral chromosomes of bamboo shark and illustrate a dynamic chromosome rearrangement process. We found that genes on 13 fast-evolving chromosomes can be enriched in immune-related pathways. And two chromosomes contain important genes that can be used to develop single-chain antibodies, which were shown to have high affinity to human disease markers by using enzyme-linked immunosorbent assay. We also found three bone formation-related genes were lost due to chromosome rearrangements. Our study highlights the importance of chromosome rearrangements, providing resources for understanding of cartilaginous fish diversification and potential application of single-chain antibodies.
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http://dx.doi.org/10.1016/j.isci.2020.101754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677710PMC
November 2020

Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects.

Am J Hum Genet 2020 12 23;107(6):1170-1177. Epub 2020 Nov 23.

Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address:

KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820620PMC
December 2020

Correlation between prognostic indicator AHNAK2 and immune infiltrates in lung adenocarcinoma.

Int Immunopharmacol 2021 Jan 7;90:107134. Epub 2020 Nov 7.

Department of Pathology, Affiliated Hospital of Nantong University and Medical School of Nantong University, Nantong 226001, Jiangsu, China. Electronic address:

Background: Lung adenocarcinoma (LUAD) is among the most aggressive malignant tumors in humans. Although AHNAK nucleoprotein 2 (AHNAK2) is considered a new oncogene, the function of the AHNAK2 in LUAD remains unknown.

Methods: Oncomine, Tumor Immune Estimation Resource (TIMER), and Human Protein Atlas databases were used to investigate AHNAK2 expression in LUAD. Gene Expression Profiling Interactive Analysis and Kaplan-Meier plotter databases were employed to elucidate the relationship between AHNAK2 and survival time. Data of The Cancer Genome Atlas were downloaded to analyze the correlation between AHNAK2 and clinicopathological parameters. We then immunohistochemically stained tissue chips to further confirm the correlation and conducted Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction network analyses to explore the possible functional mechanism of AHNAK2. Finally, we investigated the relationship between AHNAK2 and tumor infiltrating immune cells (TIICs).

Results: AHNAK2 gene was significantly overexpressed in LUAD tumor tissues and an independent prognostic indicator of LUAD patients. The expression of AHNAK2 was related to disease stage, differentiation, tumor size and lymph node metastasis. We found AHNAK2 expression was mainly positively correlated with cell adhesion-related pathways and negatively correlated with oxidative phosphorylation and amino acid metabolism. AHNAK2 expression was also negatively correlated with activated B cell, activated CD8 + T cell, and immature B cell infiltrates and positively correlated with central memory CD4 + T cell, tumor-associated macrophage, M1 macrophage, and M2 macrophage infiltrates.

Conclusion: Our findings provide strong evidence of AHNAK2 expression as a prognostic indicator related to TIICs in LUAD.
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http://dx.doi.org/10.1016/j.intimp.2020.107134DOI Listing
January 2021

De novo variants in MPP5 cause global developmental delay and behavioral changes.

Hum Mol Genet 2020 12;29(20):3388-3401

Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA.

Membrane Protein Palmitoylated 5 (MPP5) is a highly conserved apical complex protein essential for cell polarity, fate and survival. Defects in cell polarity are associated with neurologic disorders including autism and microcephaly. MPP5 is essential for neurogenesis in animal models, but human variants leading to neurologic impairment have not been described. We identified three patients with heterozygous MPP5 de novo variants (DNV) and global developmental delay (GDD) and compared their phenotypes and magnetic resonance imaging (MRI) to ascertain how MPP5 DNV leads to GDD. All three patients with MPP5 DNV experienced GDD with language delay/regression and behavioral changes. MRI ranged from normal to decreased gyral folding and microcephaly. The effects of MPP5 depletion on the developing brain were assessed by creating a heterozygous conditional knock out (het CKO) murine model with central nervous system (CNS)-specific Nestin-Cre drivers. In the het CKO model, Mpp5 depletion led to microcephaly, decreased cerebellar volume and cortical thickness. Het CKO mice had decreased ependymal cells and Mpp5 at the apical surface of cortical ventricular zone compared with wild type. Het CKO mice also failed to maintain progenitor pools essential for neurogenesis. The proportion of cortical cells undergoing apoptotic cell death increased, suggesting that cell death reduces progenitor population and neuron number. Het CKO mice also showed behavioral changes, similar to our patients. To our knowledge, this is the first report to show that variants in MPP5 are associated with GDD, behavioral abnormalities and language regression/delay. Murine modeling shows that neurogenesis is likely altered in these individuals, with cell death and skewed cellular composition playing significant roles.
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http://dx.doi.org/10.1093/hmg/ddaa224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906781PMC
December 2020

Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis.

Am J Med Genet A 2021 01 9;185(1):203-207. Epub 2020 Oct 9.

Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Inherited optic neuropathies (IONs) are neurodegenerative disorders characterized by optic atrophy with or without extraocular manifestations. Optic atrophy-10 (OPA10) is an autosomal recessive ION recently reported to be caused by mutations in RTN4IP1, which encodes reticulon 4 interacting protein 1 (RTN4IP1), a mitochondrial ubiquinol oxydo-reductase. Here we report novel compound heterozygous mutations in RTN4IP1 in a male proband with developmental delay, epilepsy, optic atrophy, ataxia, and choreoathetosis. Workup was notable for transiently elevated lactate and lactate-to-pyruvate ratio, brain magnetic resonance imaging with optic atrophy and T2 signal abnormalities, and a nondiagnostic initial genetic workup, including chromosomal microarray and mitochondrial panel testing. Exome sequencing identified a paternally inherited missense variant (c.263T>G, p.Val88Gly) predicted to be deleterious and a maternally inherited deletion encompassing RTN4IP1. To our knowledge, this is the first report of a non-single nucleotide pathogenic variant associated with OPA10. This case highlights the expanding phenotypic spectrum of OPA10, the association between "syndromic" cases and severe RTN4IP1 mutations, and the importance of nonbiased genetic testing, such as ES, to analyze multiple genes and variants types, in patients suspected of having genetic disease.
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http://dx.doi.org/10.1002/ajmg.a.61910DOI Listing
January 2021

A robust signature associated with patient prognosis and tumor immune microenvironment based on immune-related genes in lung squamous cell carcinoma.

Int Immunopharmacol 2020 Nov 7;88:106856. Epub 2020 Aug 7.

Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, and Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China; Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China. Electronic address:

Background: Lung squamous cell carcinoma (LUSC) is one common type of lung cancer. Immune-related genes (IRGs) are closely associated with cancer prognosis. This study aims to screen the key genes associated with LUSC and establish an immune-related prognostic model.

Methods: Based on the Cancer Genome Atlas (TCGA) database, we screened the differentially expressed genes (DEGs) between LUSC and normal samples. Intersecting the DEGs with the immune-related genes (IRGs), we obtained the differentially expressed IRGs (DEIRGs). Univariate as well as multivariate Cox regression analyses were performed to identify the survival-associated IRGs and establish an immune-related prognostic model. The relationship between the prognostic model and tumor-infiltrating immune cells was analyzed by TIMER and CIBERSORT.

Results: A total of 229 DEIRGs were screened, and 14 IRGs associated with survival were identified using univariate Cox analysis. Among the 14 IRGs, six genes were selected out using Lasso and multivariate Cox analyses, and they were used to build the prognostic model. Further analysis indicated that overall survival (OS) of high-risk groups was lower than that of low-risk groups. High risk score was independently related to worse OS. Moreover, the risk score was positively correlated with several immune infiltration cells. Finally, the efficacy of the prognostic model was validated by another independent cohort GSE73403.

Conclusion: The DEIRGs described in the study may have the potential to be the prognostic molecular markers for LUSC. In addition, the risk score model could predict the OS and provides more information for the immunotherapy of patients with LUSC.
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http://dx.doi.org/10.1016/j.intimp.2020.106856DOI Listing
November 2020

LncRNA Sox2ot modulates the progression of thoracic aortic aneurysm by regulating miR-330-5p/Myh11.

Biosci Rep 2020 07;40(7)

Department of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Hankou 430030, Hubei, China.

Thoracic aortic aneurysm (TAA) has been causing the death of elder people. Myosin heavy chain 11 (Myh11) has been reported associated with aortic aneurysm, but there is no specific study on its function on TAA. Here we aimed to explore the function of Myh11 on mouse aortic smooth muscle cells (SMCs) for studying the inner mechanism of TAA. H2O2 treatment was implemented on mouse aortic SMCs for detecting cell apoptosis. Meanwhile, functional assays were conducted to verify the function of Myh11 on mouse aortic SMCs. Also, pull-down assay, RIP assay were implemented to identify the potential RNAs for study. Quantitative real-time polymerase chain reaction (qRT-PCR) and luciferase reporter assay were implemented to identify the expression and binding relationships of RNAs. Myh11 expression was increased by treatment of H2O2. Myh11 could decrease proliferation and enhance apoptosis of mouse aortic SMCs. At the same time, mmu-miR-330-5p could bind to Myh11 and Sox2ot, forming a competing endogenous RNA (ceRNA) pathway to regulate the proliferation and apoptosis of mouse aortic SMCs. Moreover, both Sox2ot and Myh11 were proved to be up-regulated whereas miR-330-5p down-regulated in Fbn1C1039G/+ mice, the in vivo model of TAA. In a word, long noncoding RNA (lncRNA) Sox2ot modulates the progression of TAA by regulating miR-330-5p/Myh11 axis.
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http://dx.doi.org/10.1042/BSR20194040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364482PMC
July 2020

High expression of interleukin-enhancer binding factor 3 predicts poor prognosis in patients with lung adenocarcinoma.

Oncol Lett 2020 Mar 22;19(3):2141-2152. Epub 2020 Jan 22.

Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China.

Interleukin-enhancer binding factor 3 (ILF3) is a double-stranded RNA-binding protein that has been reported to contribute to the occurrence and progression of various malignant tumors. The aim of the present study was to evaluate the prognostic value of ILF3 and to apply this knowledge to avoid excessive medical treatment in patients with lung adenocarcinoma (LUAD). ILF3 expression in a discovery set consisting of tumor and peri-tumor tissue microarrays was analyzed using immunohistochemical methods. The mRNA level of ILF3 was subsequently analyzed in a validation set downloaded from The Cancer Genome Atlas. The Kaplan-Meier method, univariate and multivariate Cox analyses, decision curve analysis and nomogram models were used to evaluate the prognostic value of ILF3. ILF3 expression was upregulated in tumor tissues compared with peri-tumor tissues and was negatively associated with the overall survival time of patients with LUAD in the discovery and validation sets. Moreover, ILF3 expression was used for risk stratification in patients with tumor-node-metastasis stages II-IV and poor-to-moderate tumor differentiation. ILF3 expression was identified as an independent predictor of adverse prognosis for patients with LUAD in the discovery and validation sets. Finally, nomogram models for the 3- and 5 year survival time of patients with LUAD revealed that ILF3 expression may be used to improve the predictive accuracy of the prognosis and to avoid excessive medical treatment for certain patients with the disease. Overall, the data obtained in the current study revealed that high ILF3 expression was associated with poor prognosis, and demonstrated that ILF3, as a potential independent risk factor, may improve the hierarchical postoperative management of patients with LUAD.
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http://dx.doi.org/10.3892/ol.2020.11330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039148PMC
March 2020

Exosomes derived from mmu_circ_0000250-modified adipose-derived mesenchymal stem cells promote wound healing in diabetic mice by inducing miR-128-3p/SIRT1-mediated autophagy.

Am J Physiol Cell Physiol 2020 05 11;318(5):C848-C856. Epub 2020 Mar 11.

Department of Interventional Radiology, Affiliated Hospital of Nantong University, Nantong, People's Republic of China.

More and more evidence advises that circular RNAs (circRNAs) function critically in regulating different disease microenvironments. Our previous study found that autotransplantation of adipose-derived mesenchymal stem cells (ADSCs) promotes diabetes wound healing. Exosomes derived in ADSCs play an important regulatory role. This study aimed to characterize if mmu_circ_0000250 played a role in ADSC-exosome-mediated full-thickness skin wound repair in diabetic rats. Endothelial progenitor cells (EPCs) were selected to study the therapeutic mechanism of exosomes in high-glucose (HG)-induced cell damage and dysfunction. Analysis and luciferase reporter assay were utilized to explore the interaction among mmu_circ_0000250, miRNA (miR)-128-3p, and sirtuin (SIRT)1. The diabetic rats were used to confirm the therapeutic effect of mmu_circ_0000250 against exosome-mediated wound healing. Exosomes containing a high concentration of mmu_circ_0000250 had a greater therapeutic effect on restoration of the function of EPCs by promotion autophagy activation under HG conditions. Expression of mmu_circ_0000250 promoted SIRT1 expression by miR-128-3p adsorption, which was confirmed via luciferase reporter assay and bioinformatics analysis. In vivo, exosomes containing a high concentration of mmu_circ_0000250 had a more therapeutic effect on wound healing when compared with wild-type exosomes from ADSCs. Immunohistochemistry and immunofluorescence detection showed that mmu_circ_0000250 increased angiopoiesis with exosome treatment in wound skin and suppressed apoptosis by autophagy activation. In conclusion, we verified that mmu_circ_0000250 enhanced the therapeutic effect of ADSC-exosomes to promote wound healing in diabetes by absorption of miR-128-3p and upregulation of SIRT1. Therefore, these findings advocate targeting the mmu_circ_0000250/miR-128-3p/SIRT1 axis as a candidate therapeutic option for diabetic ulcers.
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http://dx.doi.org/10.1152/ajpcell.00041.2020DOI Listing
May 2020

A phenotypically severe, biochemically "silent" case of HIBCH deficiency in a newborn diagnosed by rapid whole exome sequencing and enzymatic testing.

Am J Med Genet A 2020 04 5;182(4):780-784. Epub 2020 Feb 5.

Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

3-Hydroxyisobutyryl-CoA dehydrogenase (HIBCH) deficiency is a rare error in valine catabolism associated with a Leigh syndrome-like phenotype, mitochondrial dysfunction, and increased C4-OH. We report the most severe case to date in a full-term female who presented with poor feeding and nystagmus on day of life (DOL) 1. Although initial neuroimaging findings were concerning for metabolic disease, further metabolic testing was nondiagnostic and she was discharged on DOL 18. She was readmitted on DOL 22 after severe apneic episodes requiring intubation, with EEG demonstrating multifocal seizures and MRI/MRS demonstrating worsening findings. Care was withdrawn DOL 27 and she expired. Rapid whole exome sequencing (WES) demonstrated compound heterozygous variants in HIBCH with a paternal pathogenic variant (c.852delA, p.L284FfsX10) and a maternal likely pathogenic variant (c.488G>T, p.C163F). Fibroblast enzymatic testing demonstrated marked reduction in HIBCH levels. This case demonstrates the importance of rapid WES and follow-up functional testing in establishing a diagnosis when metabolic disease is suspected but lacks an expected biochemical signature.
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http://dx.doi.org/10.1002/ajmg.a.61498DOI Listing
April 2020

Wdr26 regulates nuclear condensation in developing erythroblasts.

Blood 2020 01;135(3):208-219

MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.

Mammalian red blood cells lack nuclei. The molecular mechanisms underlying erythroblast nuclear condensation and enucleation, however, remain poorly understood. Here we show that Wdr26, a gene upregulated during terminal erythropoiesis, plays an essential role in regulating nuclear condensation in differentiating erythroblasts. Loss of Wdr26 induces anemia in zebrafish and enucleation defects in mouse erythroblasts because of impaired erythroblast nuclear condensation. As part of the glucose-induced degradation-deficient ubiquitin ligase complex, Wdr26 regulates the ubiquitination and degradation of nuclear proteins, including lamin B. Failure of lamin B degradation blocks nuclear opening formation leading to impaired clearance of nuclear proteins and delayed nuclear condensation. Collectively, our study reveals an unprecedented role of an E3 ubiquitin ligase in regulating nuclear condensation and enucleation during terminal erythropoiesis. Our results provide mechanistic insights into nuclear protein homeostasis and vertebrate red blood cell development.
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http://dx.doi.org/10.1182/blood.2019002165DOI Listing
January 2020

Rationally engineered Cas9 nucleases with high genome-wide specificity.

Proc Natl Acad Sci U S A 2019 10 30;116(42):20969-20976. Epub 2019 Sep 30.

Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China;

RNA-guided CRISPR-Cas9 proteins have been widely used for genome editing, but their off-target activities limit broad application. The minimal Cas9 ortholog from (SaCas9) is commonly used for in vivo genome editing; however, no variant conferring high genome-wide specificity is available. Here, we report rationally engineered SaCas9 variants with highly specific genome-wide activity in human cells without compromising on-target efficiency. One engineered variant, referred to as SaCas9-HF, dramatically improved genome-wide targeting accuracy based on the genome-wide unbiased identification of double-stranded breaks enabled by sequencing (GUIDE-seq) method and targeted deep sequencing analyses. Among 15 tested human endogenous sites with the canonical NNGRRT protospacer adjacent motif (PAM), SaCas9-HF rendered no detectable off-target activities at 9 sites, minimal off-target activities at 6 sites, and comparable on-target efficiencies to those of wild-type SaCas9. Furthermore, among 4 known promiscuous targeting sites, SaCas9-HF profoundly reduced off-target activities compared with wild type. When delivered by an adeno-associated virus vector, SaCas9-HF also showed reduced off-target effects when targeting in a human retinal pigmented epithelium cell line compared with wild type. Then, we further altered a previously described variant named KKH-SaCas9 that has a wider PAM recognition range. Similarly, the resulting KKH-HF remarkably reduced off-target activities and increased on- to off-target editing ratios. Our finding provides an alternative to wild-type SaCas9 for genome editing applications requiring exceptional genome-wide precision.
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http://dx.doi.org/10.1073/pnas.1906843116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800346PMC
October 2019

CtBP1 interacts with SOX2 to promote the growth, migration and invasion of lung adenocarcinoma.

Oncol Rep 2019 Jul 2;42(1):67-78. Epub 2019 May 2.

Department of Cardio‑Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China.

Carboxyl‑terminal binding protein 1 (CtBP1) is overexpressed in many types of solid tumors and has been found to be functionally associated with proliferation, migration, invasion and drug resistance of cancer cells. However, its expression pattern and functions in lung adenocarcinoma remain unclear. In the present study, we observed that the expression of CtBP1 was upregulated in the lung adenocarcinoma tissues of patients with lymph node metastasis and that its overexpression was correlated with tumor differentiation, size and poor overall survival. Silencing of CtBP1 by transfection with shRNA inhibited the proliferation, migration and invasion of A459 lung adenocarcinoma cells in vitro as determined by MTT assay and Transwell assay, respectively. In vivo studies using a lung patient‑derived tumor xenograft (PDTX) mouse model implicated CtBP1 expression in lung adenocarcinoma growth, and further in vitro co‑immunoprecipitation and depletion experiments indicated that CtBP1 regulated the biological behavior of lung adenocarcinoma cells by interacting with SOX2. Patients with elevated expression of both CtBP1 and SOX2 expression had a significantly shorter overall survival rate than patients with reduced expression of these transcripts, or than patients with elevated expression of only one transcript (P<0.01 in both cases). Taken together, these findings suggest that CtBP1 plays an important role in lung adenocarcinoma and, along with SOX2, may serve as a viable prognostic marker and therapeutic target for lung adenocarcinoma.
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http://dx.doi.org/10.3892/or.2019.7142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549098PMC
July 2019

MicroRNA-214 promotes the calcification of human aortic valve interstitial cells through the acceleration of inflammatory reactions with activated MyD88/NF-κB signaling.

Clin Res Cardiol 2019 Jun 5;108(6):691-702. Epub 2018 Dec 5.

Department of Cardiology, Affiliated Hospital of Nantong University, No. 20, Xisi Road, Chongchuan District, Nantong, 226001, Jiangsu, China.

Calcific aortic valve disease (CAVD) is a complex active process involving in endothelial injury, lipid infiltration, chronic inflammation, matrix remodeling, cell differentiation, progressive bone formation, and new angiogenesis. The excess inflammatory responses induced by aortic valve interstitial cells (AVICs) are one of the common pathogeneses of this disease. Although many microRNAs (miRs) have been identified to play crucial roles in the calcification process of the aortic valve, numerous miRs are still waiting to be explored. In this study, we explored the functional role of miR-214 in the inflammatory reaction and calcification of human AVICs and its underlying molecular mechanism. Alizarin red staining was used to determine the number of calcified nodules. The protein levels of ICAM-1, IL-6, IL-8, and MCP-1 detected by enzyme-linked immunosorbent assay (ELISA) were used to assess the inflammatory reaction of AVICs; expression levels of RUNX2, Msx2, and BMP2 were used to evaluate AVICs osteoblast differentiation. Results showed that the expression levels of TLR4, MyD88, NF-κB, and miR-214 were up-regulated in the blood and aortic valve tissue samples of patients with CAVD when compared with normal individuals. Knockdown of miR-214 in AVICs inhibited the secretion of IL-6, IL-8, ICAM-1, and MCP-1, while this effect was repressed when lipopolysaccharide (LPS) was added to AVICs. LPS also enhanced the effects of miR-214 in promoting the secretion of pro-inflammatory factors. Besides, up-regulation of miR-214 promoted the protein expression of MyD88 and NF-κB but had no influence on TLR4, and miR-214 could directly combine with MyD88 protein. Up-regulation of MyD88 facilitated the secretion of pro-inflammatory factors and increased calcified nodules number and accelerated the expression of RUNX2, Msx2, and BMP2. Moreover, promotion of the expressions of pro-inflammatory factors and "osteoblast-like" cell markers induced by miR-214 overexpression was abolished when MyD88 was down-regulated in AVICs. In conclusion, this study revealed that miR-214 promoted calcification by facilitating inflammatory reaction through MyD88/NF-κB signaling pathway in AVICs.
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http://dx.doi.org/10.1007/s00392-018-1398-9DOI Listing
June 2019

Involvement of Nrf2 in myocardial ischemia and reperfusion injury.

Int J Biol Macromol 2019 Mar 20;125:496-502. Epub 2018 Nov 20.

Department of Cardiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China. Electronic address:

The morbidity rate of myocardial ischemia and reperfusion has increased in modern society, and oxidative stress plays a critical role in the pathological process. Nuclear factor E2-associated factor 2 (Nrf2) is considered a pivotal regulator for maintaining the redox balance and is involved in the initiation of the transcriptional expression of downstream antioxidant enzymes. Moreover, Nrf2 also can be regulated in various ways. Nrf2/Keap1/ARE is one of the essential signaling pathways that can attenuate myocardial infarct size and preserve cardiac function after myocardial ischemia and reperfusion injury (MIRI). Nrf2 activation provides cardioprotection via the coordinated up-regulation of antioxidant, anti-inflammatory, and autophagy mechanisms. Numerous studies have shown that ischemic preconditioning and ischemic post-conditioning have a clear protective effect on MIRI, and the potential role of the Nrf2 signaling pathway in cardioprotection may be worth discussing. This review will summarize the current knowledge on the regulation of and involvement of Nrf2 in MIRI.
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http://dx.doi.org/10.1016/j.ijbiomac.2018.11.190DOI Listing
March 2019

De novo variant of TRRAP in a patient with very early onset psychosis in the context of non-verbal learning disability and obsessive-compulsive disorder: a case report.

BMC Med Genet 2018 11 13;19(1):197. Epub 2018 Nov 13.

The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, 3 Blackfan Circle, CLSB 15031, Boston, MA, 02115, USA.

Background: TRRAP encodes a multidomain protein kinase that works as a genetic cofactor to influence DNA methylation patterns, DNA damage repair, and chromatin remodeling. TRRAP protein is vital to early neural developmental processes, and variants in this gene have been associated with schizophrenia and childhood disintegrative disorder.

Case Presentation: Here, we report on a patient with a de novo nonsynonymous TRRAP single-nucleotide variant (EST00000355540.3:c.5957G > A, p.Arg1986Gln) and early onset major depression accompanied by a psychotic episode (before age 10) that occurred in the context of longer standing nonverbal learning disability and a past history of obsessions and compulsions.

Conclusions: The de novo variant and presentation of very early onset psychosis indicate a rare Mendelian disorder inheritance model. The genotype and behavioral abnormalities of this patient are reviewed.
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http://dx.doi.org/10.1186/s12881-018-0711-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234620PMC
November 2018

FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity.

J Biol Chem 2018 12 26;293(51):19797-19811. Epub 2018 Oct 26.

the Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.

Erythropoietin (EPO) signaling is critical to many processes essential to terminal erythropoiesis. Despite the centrality of iron metabolism to erythropoiesis, the mechanisms by which EPO regulates iron status are not well-understood. To this end, here we profiled gene expression in EPO-treated 32D pro-B cells and developing fetal liver erythroid cells to identify additional iron regulatory genes. We determined that FAM210B, a mitochondrial inner-membrane protein, is essential for hemoglobinization, proliferation, and enucleation during terminal erythroid maturation. deficiency led to defects in mitochondrial iron uptake, heme synthesis, and iron-sulfur cluster formation. These defects were corrected with a lipid-soluble, small-molecule iron transporter, hinokitiol, in -deficient murine erythroid cells and zebrafish morphants. Genetic complementation experiments revealed that FAM210B is not a mitochondrial iron transporter but is required for adequate mitochondrial iron import to sustain heme synthesis and iron-sulfur cluster formation during erythroid differentiation. FAM210B was also required for maximal ferrochelatase activity in differentiating erythroid cells. We propose that FAM210B functions as an adaptor protein that facilitates the formation of an oligomeric mitochondrial iron transport complex, required for the increase in iron acquisition for heme synthesis during terminal erythropoiesis. Collectively, our results reveal a critical mechanism by which EPO signaling regulates terminal erythropoiesis and iron metabolism.
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http://dx.doi.org/10.1074/jbc.RA118.002742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314115PMC
December 2018

Dynamics changes of CRISPR-Cas9 systems induced by high fidelity mutations.

Phys Chem Chem Phys 2018 Nov;20(43):27439-27448

School of Biological Sciences, Nanyang Technological University, Singapore.

CRISPR-Cas9, a powerful genome editing tool, has widely been applied in biological fields. Since the discovery of CRISPR-Cas9 as an adaptive immune system, it has been gradually modified to perform precise genome editing in eukaryotic cells by creating double-strand breaks. Although it is robust and efficient, the current CRISPR-Cas9 system faces a major flaw: off-target effects, which are not well understood. Several Cas9 mutants show significant improvement, with very low off-target effects; however, they also show relatively lower cleavage efficiency for on-target sequences. In this study, the dynamics of wild-type Cas9 from Streptococcus pyogenes and a high fidelity Cas9 mutant have been explored using molecular dynamics simulations. It was found that the mutations cause decreased electrostatic interactions between Cas9 and the R-loop. Consequently, the flexibility of the tDNA/sgRNA heteroduplex is decreased, which may explain the lower tolerance of mismatches in the heteroduplex region. The mutations also affect the protein dynamics and the correlation networks among Cas9 domains. In mutant Cas9, weakened communications between two catalytic domains as well as a slight opening of the conformation induced by the mutations account for the lower on-target cleavage efficiency and probably the lower off-target efficiency as well. These findings will facilitate more precise Cas9 engineering in future.
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http://dx.doi.org/10.1039/c8cp04226hDOI Listing
November 2018

Structurally- and dynamically-driven allostery of the chymotrypsin-like proteases of SARS, Dengue and Zika viruses.

Prog Biophys Mol Biol 2019 05 11;143:52-66. Epub 2018 Sep 11.

Department of Biological Sciences, Faculty of Science, National University of Singapore, Republic of Singapore. Electronic address:

Coronavirus 3C-like and Flavivirus NS2B-NS3 proteases utilize the chymotrypsin fold to harbor their catalytic machineries but also contain additional domains/co-factors. Over the past decade, we aimed to decipher how the extra domains/co-factors mediate the catalytic machineries of SARS 3C-like, Dengue and Zika NS2B-NS3 proteases by characterizing their folding, structures, dynamics and inhibition with NMR, X-ray crystallography and MD simulations, and the results revealed: 1) the chymotrypsin fold of the SARS 3C-like protease can independently fold, while, by contrast, those of Dengue and Zika proteases lack the intrinsic capacity to fold without co-factors. 2) Mutations on the extra domain of SARS 3C-like protease can transform the active catalytic machinery into the inactive collapsed state by structurally-driven allostery. 3) Amazingly, even without detectable structural changes, mutations on the extra domain are sufficient to either inactivate or enhance the catalytic machinery of SARS 3C-like protease by dynamically-driven allostery. 4) Global networks of correlated motions have been identified: for SARS 3C-like protease, N214A inactivates the catalytic machinery by decoupling the network, while STI/A and STIF/A enhance by altering the patterns of the network. The global networks of Dengue and Zika proteases are coordinated by their NS2B-cofactors. 5) Natural products were identified to allosterically inhibit Zika and Dengue proteases through binding a pocket on the back of the active site. Therefore, by introducing extra domains/cofactors, nature develops diverse strategies to regulate the catalytic machinery embedded on the chymotrypsin fold through folding, structurally- and dynamically-driven allostery, all of which might be exploited to develop antiviral drugs.
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http://dx.doi.org/10.1016/j.pbiomolbio.2018.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111307PMC
May 2019

De novo variant in KIF26B is associated with pontocerebellar hypoplasia with infantile spinal muscular atrophy.

Am J Med Genet A 2018 12 27;176(12):2623-2629. Epub 2018 Aug 27.

Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

KIF26B is a member of the kinesin superfamily with evolutionarily conserved functions in controlling aspects of embryogenesis, including the development of the nervous system, though its function is incompletely understood. We describe an infant with progressive microcephaly, pontocerebellar hypoplasia, and arthrogryposis secondary to the involvement of anterior horn cells and ventral (motor) nerves. We performed whole exome sequencing on the trio and identified a de novo KIF26B missense variant, p.Gly546Ser, in the proband. This variant alters a highly conserved amino acid residue that is part of the phosphate-binding loop motif and motor-like domain and is deemed pathogenic by several in silico methods. Functional analysis of the variant protein in cultured cells revealed a reduction in the KIF26B protein's ability to promote cell adhesion, a defect that potentially contributes to its pathogenicity. Overall, KIF26B may play a critical role in the brain development and, when mutated, cause pontocerebellar hypoplasia with arthrogryposis.
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http://dx.doi.org/10.1002/ajmg.a.40493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481602PMC
December 2018

Histone deacetylase 5 promotes the proliferation and invasion of lung cancer cells.

Oncol Rep 2018 Oct 24;40(4):2224-2232. Epub 2018 Jul 24.

Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China.

Histone deacetylase 5 (HDAC5), as a member of the class IIa family of HDACs, is frequently dysregulated in human malignancies. However, little is known regarding the specific role of HDAC5 in lung cancer. We aimed to evaluate HDAC5 expression in human lung cancer and to determine the effects of HDAC5 on lung cancer cells. First, the expression levels of both HDAC5 protein and mRNA were evaluated in lung cancer tissues and cell lines by western blot analysis and RT‑qPCR, and the results suggested that HDAC5 was significantly upregulated in human lung cancer tissues and cell lines. To address the effects of HDAC5 on the biological behavior of human lung adenocarcinoma cells, we generated human lung cancer A549 cell lines in which HDAC5 was either overexpressed or depleted. The results indicated that overexpression of HDAC5 significantly promoted the proliferation and invasion, and inhibited the apoptosis of A549 cells. On the contrary, HDAC5 knockdown largely decreased the proliferation and invasion and enhanced the apoptosis of A549 cells. Furthermore, we demonstrated that HDAC5 overexpression promoted the expression of DLL4, Six1, Notch 1 and Twist 1 in A549 cells. Downregulation of HDAC5 caused a significant inhibition of the expression of DLL4, Six1, Notch 1 and Twist 1 in A549 cells. Taken together, our data demonstrated that HDAC5 displayed a significant upregulation in lung cancer, and elevated HDAC5 might be involved in the potentiation of proliferation and invasion of lung cancer cells, as well as the inhibition of lung cancer cell apoptosis by the upregulation of DLL4, Six1, Notch 1 and Twist 1. The present study may provide an evidence for the potential application of HDAC5 inhibitors in the therapy of lung cancer.
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http://dx.doi.org/10.3892/or.2018.6591DOI Listing
October 2018

EphA2 chimeric antigen receptor-modified T cells for the immunotherapy of esophageal squamous cell carcinoma.

J Thorac Dis 2018 May;10(5):2779-2788

Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong 226001, China.

Background: It is urgent to explore an effective potential therapeutic strategy for ESCC. In recent years, cell-based cancer immunotherapy has become a potentially close for carcinoma therapy. Chimeric antigen receptor (CAR) T cell technology is a kind of adoptive cell therapy technique which has been developed rapidly. We sought to obtain EphA2.CAR-T cell and revealed the ability of EphA2.CAR-T cells to kill esophageal squamous cell carcinoma (ESCC) cells .

Methods: Firstly, the expression and location of EphA2 in ESCC tissues and cells was tested by immunohistochemistry staining and Western blot. Secondly, the second generation of EphA2.CAR was constructed via molecular biology technology, and transduced into T cells to obtain the EphA2.CAR-T cell. The transduction efficacies were assessed using flow cytometry (FCM). Thirdly, the effect of cell killing of EphA2.CAR-T cell on ESCC cells was detected by co-culture experiments. The productions of cytokines (TNF-α and IFN-γ) by EphA2.CAR-T cell after co-culture with ESCC cells were analyzed by ELISA assay.

Results: The expression of EphA2 was significantly upregulated in ESCC tissues and cells (P<0.05). EphA2 was expressed on the membrane of ESCC cells, so it could be served as tumor-associated surface antigens (TAA) of CAR for ESCC treatment. The EphA2.CAR-T cell was obtained successfully, and its' transduction efficacies was 61.4% by FCM. The ability of cell killing of EphA2.CAR-T cell was better than that of T cells (P<0.01), and demonstrated a dose-dependent cell killing. The results of ELISA assay showed that the levels of TNF-α and IFN-γ in EphA2.CAR-T cells were notably raised compared with T cells (P<0.05).

Conclusions: We firstly constructed the second generation of EphA2.CAR and established EphA2.CAR-T cells. The EphA2.CAR-T cells showed a dose-dependent cell killing of ESCC cells, and promoted the production of cytokines . These findings open a new way for treatment of ESCC by immunotherapy in the future.
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http://dx.doi.org/10.21037/jtd.2018.04.91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006048PMC
May 2018

Long non-coding RNA DANCR promotes cell proliferation, migration, invasion and resistance to apoptosis in esophageal cancer.

J Thorac Dis 2018 May;10(5):2573-2582

Laboratory Animals Center, Nantong University, Nantong 226001, China.

Background: Long non-coding RNAs (lncRNAs) have important effects on the development and progression of multiple carcinomas. Our studies aimed to investigate the expression of lncRNA DANCR in esophageal squamous cell carcinoma (ESCC) tissues and paracancerous tissues, and to explore its effect on the cell biological characteristics of ESCC ECA109 cells.

Methods: The expression of DANCR was detected by qRT-PCR in human ESCC tissues and paracancerous normal tissues in ESCC patients. Small interfering RNA (siRNA) was transfected to knock down the expression of DANCR and interference efficiency was analyzed by qRT-PCR in ECA109 cells. MTT, wound healing, Transwell, TUNEL and flow cytometry (FCM) assay was used to measure the influence of DANCR on proliferation, invasion, migration and apoptosis in ECA109 cells, respectively.

Results: The expression of DANCR in ESCC tissues and ESCC cells was significantly higher compared with that in the adjacent normal tissues (P<0.05). Furthermore, cell proliferation, migration and invasion were significantly suppressed by knock-down mediated down-regulation of DANCR expression. On the contrary, cell apoptosis was promoted by silencing of DANCR.

Conclusions: According to our research, the expression of DANCR was up-regulated in human ESCC tissues, and the important role that DANCR played in ESCC cells was similar to an oncogene. Therefore, silencing of lncRNA DANCR could have potentially beneficial effects on the prognostic and therapy for ESCC in the future.
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http://dx.doi.org/10.21037/jtd.2018.04.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006063PMC
May 2018
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