Publications by authors named "Jiabin Cai"

25 Publications

  • Page 1 of 1

An integrative analysis of genome-wide 5-hydroxymethylcytosines in circulating cell-free DNA detects noninvasive diagnostic markers for gliomas.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab049. Epub 2021 Apr 16.

State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, and The Collaborative Innovation Centre for Brain Science, Fudan University, Shanghai, China.

Background: Gliomas, especially the high-grade glioblastomas (GBM), are highly aggressive tumors in the central nervous system (CNS) with dismal clinical outcomes. Effective biomarkers, which are not currently available, may improve clinical outcomes through early detection. We sought to develop a noninvasive diagnostic approach for gliomas based on 5-hydroxymethylcytosines (5hmC) in circulating cell-free DNA (cfDNA).

Methods: We obtained genome-wide 5hmC profiles using the 5hmC-Seal technique in cfDNA samples from 111 prospectively enrolled patients with gliomas and 111 age-, gender-matched healthy individuals, which were split into a training set and a validation set. Integrated models comprised 5hmC levels summarized for gene bodies, long noncoding RNAs (lncRNAs), -regulatory elements, and repetitive elements were developed using the elastic net regularization under a case-control design.

Results: The integrated 5hmC-based models differentiated healthy individuals from gliomas (area under the curve [AUC] = 84%; 95% confidence interval [CI], 74-93%), GBM patients (AUC = 84%; 95% CI, 74-94%), WHO II-III glioma patients (AUC = 86%; 95% CI, 76-96%), regardless of (encoding isocitrate dehydrogenase) mutation status or other glioma-related pathological features such as TERT, TP53 in the validation set. Furthermore, the 5hmC biomarkers in cfDNA showed the potential as an independent indicator from mutation status and worked in synergy with mutation to distinguish GBM from WHO II-III gliomas. Exploration of the 5hmC biomarkers for gliomas revealed relevance to glioma biology.

Conclusions: The 5hmC-Seal in cfDNA offers the promise as a noninvasive approach for effective detection of gliomas in a screening program.
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http://dx.doi.org/10.1093/noajnl/vdab049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209591PMC
April 2021

A novel WT1 gene mutation in a chinese girl with denys-drash syndrome.

J Clin Lab Anal 2021 May 4;35(5):e23769. Epub 2021 May 4.

Department of Surgical Oncology, Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, China.

Objective: Denys-Drash syndrome (DDS) is defined by the triad of Wilms tumor, nephrotic syndrome, and/or ambiguous genitalia. Genetic testing may help identify new gene mutation sites and play an important role in clinical decision-making.

Methods: We present a patient with an XY karyotype and female appearance, nephropathy, and Wilms tumor in the right kidney. Genomic DNA was extracted from peripheral blood cells according to standard protocols. "Next-generation" sequencing (NGS) was performed to identify novel variants. The variant was analyzed with Mutation Taster, and its function was explored by a cell growth inhibition assay.

Results: We found the first case of Denys-Drash syndrome with the uncommon missense mutation (c.1420C>T, p.His474 Tyr) in the WT1 gene. In silico analysis, the variant was predicted "disease-causing" by Mutation Taster. The mutated variant showed a weaker effect in inhibiting tumor cells than wild-type WT1.

Conclusions: The uncommon missense mutation (c.1420C>T, p.His474 Tyr) in the WT1 gene may be a crucial marker in DDS.
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http://dx.doi.org/10.1002/jcla.23769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128316PMC
May 2021

Using deep learning to predict microvascular invasion in hepatocellular carcinoma based on dynamic contrast-enhanced MRI combined with clinical parameters.

J Cancer Res Clin Oncol 2021 Apr 10. Epub 2021 Apr 10.

Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.

Purpose: Microvascular invasion (MVI) is a critical determinant of the early recurrence and poor prognosis of patients with hepatocellular carcinoma (HCC). Prediction of MVI status is clinically significant for the decision of treatment strategies and the assessment of patient's prognosis. A deep learning (DL) model was developed to predict the MVI status and grade in HCC patients based on preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and clinical parameters.

Methods: HCC patients with pathologically confirmed MVI status from January to December 2016 were enrolled and preoperative DCE-MRI of these patients were collected in this study. Then they were randomly divided into the training and testing cohorts. A DL model with eight conventional neural network (CNN) branches for eight MRI sequences was built to predict the presence of MVI, and further combined with clinical parameters for better prediction.

Results: Among 601 HCC patients, 376 patients were pathologically MVI absent, and 225 patients were MVI present. To predict the presence of MVI, the DL model based only on images achieved an area under curve (AUC) of 0.915 in the testing cohort as compared to the radiomics model with an AUC of 0.731. The DL combined with clinical parameters (DLC) model yielded the best predictive performance with an AUC of 0.931. For the MVI-grade stratification, the DLC models achieved an overall accuracy of 0.793. Survival analysis demonstrated that the patients with DLC-predicted MVI status were associated with the poor overall survival (OS) and recurrence-free survival (RFS). Further investigation showed that hepatectomy with the wide resection margin contributes to better OS and RFS in the DLC-predicted MVI present patients.

Conclusion: The proposed DLC model can provide a non-invasive approach to evaluate MVI before surgery, which can help surgeons make decisions of surgical strategies and assess patient's prognosis.
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http://dx.doi.org/10.1007/s00432-021-03617-3DOI Listing
April 2021

Quantitative acetylome analysis reveals histone modifications that may predict prognosis in hepatitis B-related hepatocellular carcinoma.

Clin Transl Med 2021 03;11(3):e313

Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's Hospital, Fudan University, Shanghai, China.

Lysine acetylation (Kac) as an important posttranslational modification of histones is essential for the regulation of gene expression in hepatocellular carcinoma (HCC). However, the atlas of whole acetylated proteins in HCC tissues and the difference in protein acetylation between normal human tissues and HCC tissues are unknown. In this report, we characterized the proteome and acetyl proteome (acetylome) profile of normal, paracancerous, and HCC liver tissues in human clinical samples by quantitative proteomics techniques. We identified 6781 acetylation sites of 2582 proteins and quantified 2492 acetylation sites of 1190 proteins in normal, paracancerous, and HCC liver tissues. Among them, 15 proteins were multiacetylated with more than 10 lysine residues. The histone acetyltransferases p300 and CBP were found to be hyperacetylated in hepatitis B virus pathway. Moreover, we found that 250 Kac sites of 214 proteins were upregulated and 662 Kac sites of 451 proteins were downregulated in HCC compared with normal liver tissues. Additionally, the acetylation levels of lysine 120 in histone H2B (H2BK120ac), lysine 18 in histone H3.3 (H3.3K18ac), and lysine 77 in histone H4 (H4K77ac) were increased in HCC. Interestingly, the higher levels of H2BK120ac, H3.3K18ac, and H4K77ac were significantly associated with worse prognosis, such as poorer survival and higher recurrence in an independent clinical cohort of HCC patients. Overall, this study lays a foundation for understanding the functions of acetylation in HCC and provides potential prognostic factors for the diagnosis and therapy of HCC.
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http://dx.doi.org/10.1002/ctm2.313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939233PMC
March 2021

[3D organization profiling of human hepatocellular carcinoma cell line PLC/PRF/5 in comparison with normal human liver cell line L02 by in situ Hi-C].

Sheng Wu Gong Cheng Xue Bao 2021 Jan;37(1):331-341

Key Laboratory of Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai 201102, China.

Genetic and epigenetic alterations accumulate in the process of hepatocellular carcinogenesis, but the role of genomic spatial organization in HCC is still unknown. Here, we performed in situ Hi-C in HCC cell line PLC/PRF/5 compared with normal liver cell line L02, together with RNA-seq and ChIP-seq of SMC3/CTCF/H3K27ac. The results indicate that there were significant compartment switching, TAD shifting and loop pattern altering in PLC/PRF/5. These spatial changes are correlated with abnormal gene expression and more opening promoter regions of the HCC cell line. Thus, the 3D genome organization alterations in PLC/PRF/5 are important in epigenetic mechanisms of HCC tumorigenesis.
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http://dx.doi.org/10.13345/j.cjb.200293DOI Listing
January 2021

Renal cell carcinoma in children and adolescents: Single-center experience and literature review.

Medicine (Baltimore) 2021 Jan;100(2):e23717

Department of Surgical Oncology.

Abstract: Renal cell carcinoma (RCC) is infrequent in the pediatric population. In addition, till date, only a few reports have summarized the characteristics of pediatric RCC and differences between pediatric and adult RCC. Therefore, the current study aimed to investigate the clinical characteristics of RCC in children and adolescents, and identify the differences between children and adolescent patients and adult patients through literature retrieval.The data of 13 pediatric patients diagnosed with RCC at the Children's Hospital of Zhejiang University School of Medicine between 2005 and 2019 were retrospectively analyzed.Three patients were aged <5 years, 2 were aged 6 to 10 years, and 8 were aged 11 to 18 years. Among the 13 patients, common clinical manifestations included abdominal pain in 5 patients, gross hematuria in 4, and an abdominal mass in 1, while the other 3 patients were incidentally detected after an abdominal contusion. The pathological types were microphthalmia family translocation RCC in 9 patients, clear-cell RCC in 2, papillary RCC in 1, and unclassified in 1. All the children underwent radical nephrectomy, including 2 patients with advanced disease who underwent preoperative transcatheter arterial chemoembolization. The mean follow-up time was 58.6 months. Two patients died after 4 and 17 months of follow-up, respectively.In conclusion, microphthalmia family translocation renal cell carcinoma is the predominant type of pediatric RCC associated with advanced tumor stage. The early diagnosis and treatment of pediatric patients is important for improving prognosis. Nevertheless, future studies are urgently needed to determine the treatment for pediatric advanced RCC to increase the survival rate.
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http://dx.doi.org/10.1097/MD.0000000000023717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808530PMC
January 2021

Ribosome 18S mA Methyltransferase METTL5 Promotes Translation Initiation and Breast Cancer Cell Growth.

Cell Rep 2020 12;33(12):108544

Shanghai Key Laboratory of Medical Epigenetics, State International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address:

N6 methylation at adenosine 1832 (mA1832) of mammalian 18S rRNA, occupying a critical position within the decoding center, is modified by a conserved methyltransferase, METTL5. Here, we find that METTL5 shows strong substrate preference toward the 18S A1832 motif but not the other reported mA motifs. Comparison with a yeast ribosome structural model unmodified at this site indicates that the modification may facilitate mRNA binding by inducing conformation changes in the mammalian ribosomal decoding center. METTL5 promotes p70-S6K activation and proper translation initiation, and the loss of METTL5 significantly reduces the abundance of polysome. METTL5 expression is elevated in breast cancer patient samples and is required for growth of several breast cancer cell lines. We further find that Caenorhabditis elegans lacking the homolog metl-5 develop phenotypes known to be associated with impaired translation. Altogether, our findings uncover critical and conserved roles of METTL5 in the regulation of translation.
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http://dx.doi.org/10.1016/j.celrep.2020.108544DOI Listing
December 2020

TET2 promotes anti-tumor immunity by governing G-MDSCs and CD8 T-cell numbers.

EMBO Rep 2020 10 14;21(10):e49425. Epub 2020 Sep 14.

Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

The host immune response is a fundamental mechanism for attenuating cancer progression. Here we report a role for the DNA demethylase and tumor suppressor TET2 in host anti-tumor immunity. Deletion of Tet2 in mice elevates IL-6 levels upon tumor challenge. Elevated IL-6 stimulates immunosuppressive granulocytic myeloid-derived suppressor cells (G-MDSCs), which in turn reduce CD8 T cells upon tumor challenge. Consequently, systematic knockout of Tet2 in mice leads to accelerated syngeneic tumor growth, which is constrained by anti-PD-1 blockade. Removal of G-MDSCs by the anti-mouse Ly6g antibodies restores CD8 T-cell numbers in Tet2 mice and reboots their anti-tumor activity. Importantly, anti-IL-6 antibody treatment blocks the expansion of G-MDSCs and inhibits syngeneic tumor growth. Collectively, these findings reveal a TET2-mediated IL-6/G-MDSCs/CD8 T-cell immune response cascade that safeguards host adaptive anti-tumor immunity, offering a cell non-autonomous mechanism of TET2 for tumor suppression.
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http://dx.doi.org/10.15252/embr.201949425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534639PMC
October 2020

Prevention and control strategies in the diagnosis and treatment of solid tumors in children during the COVID-19 pandemic.

Pediatr Hematol Oncol 2020 Oct 12;37(7):620-629. Epub 2020 Jun 12.

Division of Surgical Oncology, Department of Pediatric Surgery, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Since the emergence of patients with COVID-19 in December 2019, the virus has rapidly spread worldwide. Children with malignant tumors are more prone to be infected and develop severe infections. Prevention and control of the pandemic and ensuring the progress of the cancer diagnosis and treatment is a significant problem in the current scenario. This article proposes a scientific management system for patients with solid tumors to guarantee emergency surgery, rationally arrange limited-term surgery, appropriately defer elective surgery, and guarantee regular chemotherapy, while protecting children from SARS-CoV-2 infection and ensuring the continuity of comprehensive diagnosis and treatment.
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http://dx.doi.org/10.1080/08880018.2020.1767740DOI Listing
October 2020

Preparation and Properties of Cyanobacteria-Based Carbon Quantum Dots/Polyvinyl Alcohol/ Nanocellulose Composite.

Polymers (Basel) 2020 May 17;12(5). Epub 2020 May 17.

College of Materials Science and Engineering, Nanjing Forestry University, Nanjing 210037, China.

Blue luminescent carbon quantum dots (CQDs) were prepared from cyanobacteria by a hydrothermal method. The PL quantum yields of the obtained CQDs was 5.30%. Cyanobacteria-based carbon quantum dots/polyvinyl alcohol/nanocellulose composite films were prepared, which could emit bright blue under UV light. FTIR characterization showed that the composite films had hydroxyl groups on the surface and no new groups were formed after combining the three materials. The photoluminescence (PL) spectra revealed that the emission of the prepared CQDs was excitation dependent. Studies on the water resistance performance and light barrier properties of the composite films showed that they possessed higher water resistance properties and better UV/infrared light barrier properties. Therefore, we report the cyanobacteria-based carbon quantum dots/polyvinyl alcohol/nanocellulose composite films have the potential to be applied in flexible packaging materials, anti-fake materials, UV/infrared light barrier materials and so on.
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http://dx.doi.org/10.3390/polym12051143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285183PMC
May 2020

Effects of impregnation combined heat treatment on the pyrolysis behavior of poplar wood.

PLoS One 2020 17;15(3):e0229907. Epub 2020 Mar 17.

Department of Wood Science, Nanjing Forestry University, Nanjing, Jiangsu, China.

To investigate the effects of urea-formaldehyde (UF) resin impregnation combined heat treatment (IMPG-HT) on the pyrolysis behavior of poplar wood, the chemical composition, pyrolysis characteristics, pyrolysis kinetics, and gaseous products released during pyrolysis of untreated (control), IMPG-HT, IMPG and HT woods were analyzed. The results demonstrate that IMPG-HT changes pyrolysis behavior of poplar wood significantly. Unlike the control and HT samples, the thermogravimetric / derivative thermogravimetric (TG/DTG) curves of IMPG wood shift toward lower temperature, and the shoulder on DTG curves weaken or even disappear. The maximum mass loss rate of IMPG-HT samples decreases, and carbon residual yield increases to 23% or more and activation energy (E) increases sharply after conversion rate (α) reaching 0.80. HT improves the thermal stability of IMPG wood, which is represented by the increase of decomposition temperature (Td) and DTG peak temperature (Tpeak) and the higher E value of IMPG-HT wood. For the pyrolysis gaseous products, IMPG-HT wood produces nitrogen-containing gases (HNCO and NH3) due to the presence of UF resin, but the amounts of these gases are less than that produced by IMPG wood because the heat treatment had removed part of N elements.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229907PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077805PMC
June 2020

Enamel-inspired materials design achieving balance of high stiffness and large energy dissipation.

J Mech Behav Biomed Mater 2020 03 9;103:103587. Epub 2019 Dec 9.

Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200050, China.

Owing to the unique non-self-similar hierarchical microstructure, enamel achieves the balance of high stiffness and toughness, and in turn provides important ideas for the bio-inspired materials design. In this study, a multiscale numerical study has been conducted to investigate whether the property of high stiffness and large energy dissipation could be duplicated in engineering materials through certain material design principles. Motivated by the structure of enamel, the bio-inspired materials consisting of hard and soft phases were considered, and the designing parameters including the cross-sectional shape, volume fraction, and inclination angle of the reinforcement, and other three parameters related to the waviness of the reinforcement were taken into account. It was found that by employing the non-self-similar hierarchical structure, the designed composites exhibited the balance between stiffness and toughness, which has not been achieved in many engineering materials yet. Furthermore, the influences of the aforementioned designing parameters on the mechanical performance of the composites have been elucidated. The findings of this study have provided a guideline for designing bio-inspired composites achieving the balance between stiffness and toughness.
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http://dx.doi.org/10.1016/j.jmbbm.2019.103587DOI Listing
March 2020

Preparation and Performance of Radiata-Pine-Derived Polyvinyl Alcohol/Carbon Quantum Dots Fluorescent Films.

Materials (Basel) 2019 Dec 21;13(1). Epub 2019 Dec 21.

College of Materials Science and Engineering, Nanjing Forestry University, Nanjing 210037, China.

In this study, the low-cost processing residue of Radiata pine (Pinus radiata D. Don) was used as the lone carbon source for synthesis of CQDs (Carbon quantum dots) with a QY (The quantum yield of the CQDs) of 1.60%. The CQDs were obtained by the hydrothermal method, and +a PVA-based biofilm was prepared by the fluidized drying method. The effects of CQDs and CNF (cellulose nanofibers) content on the morphology, optical, mechanical, water-resistance, and wettability properties of the PVA/CQDs and PVA/CNF/CQDs films are discussed. The results revealed that, when the excitation wavelength was increased from 340 to 390 nm, the emission peak became slightly red-shifted, which was induced by the condensation between CQDs and PVA. The PVA composite films showed an increase in fluorescence intensity with the addition of the CNF and CQDs to polymers. The chemical structure of prepared films was determined by the FTIR spectroscopy, and no new chemical bonds were formed. In addition, the UV transmittance was inversely proportional to the change of CQDs content, which indicated that CQDs improved the UV barrier properties of the films. Furthermore, embedding CQDs Nano-materials and CNF into the PVA matrix improved the mechanical behavior of the Nano-composite. Tensile modulus and strength at break increased significantly with increasing the concentration of CQDs Nano-materials inside the Nano-composite, which was due to the increased in the density of crosslinking behavior. With the increase of CQDs content (>1 mL), the water absorption and surface contact angle of the prepared films decreased gradually, and the water-resistance and surface wettability of the films were improved. Therefore, PVA/CNF/CQDs bio-nanocomposite films could be used to prepare anti-counterfeiting, high-transparency, and ultraviolet-resistant composites, which have potential applications in ecological packaging materials.
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http://dx.doi.org/10.3390/ma13010067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981502PMC
December 2019

Reply to 'Are the 5-hydroxymethylcytosine-based wd-scores really superior over α-fetoprotein for the early diagnosis of hepatocellular carcinoma?'

Gut 2020 10 23;69(10):1903-1904. Epub 2019 Dec 23.

Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China

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http://dx.doi.org/10.1136/gutjnl-2019-320298DOI Listing
October 2020

Ewing-like sarcoma/undifferentiated round cell sarcoma in an infant with APC and MSH6 variation: A case report.

Medicine (Baltimore) 2019 Nov;98(45):e17872

Pathology & Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA.

Rationale: Ewing-like sarcoma (ELS)/undifferentiated round cell sarcoma (URCS) is a rare type of soft tissue sarcomas (STS), especially in infants, with poor prognosis. It is a so-called "small round cell" sarcoma, and has many features of Ewing sarcoma, but lacks rearrangements in EWSR1. The diagnosis and treatment of this kind of STS remains challenging. BCOR genetic abnormalities have been found in some Ewing-like sarcomas.

Patient Concerns: This report presents an ELS case of a female infant, who was 2 months old when initially diagnosed, with the clinical stage of IIIA (G2T2N0M0). Histologic findings revealed an undifferentiated neoplasm composed of small round tumor cells with round, open chromatic nuclei, and scant cytoplasm in a sheet growth pattern. Fluorescence in situ hybridization (FISH) analysis showed absence of EWSR1 and ETV6 gene rearrangement. Molecular genetic testing found no established variants of clinical significance but variants of unknown significance in APC, KMT2D, and MSH6 were detected. Immunostaining revealed that the tumor cells were positive for TLE1 and BCOR, and negative for cytokeratin (AE1/AE3), Desmin, CD45, S100, CD31, HMB45, and SATB2. INI-1 was retained.

Diagnosis: Ewing-like sarcoma (ELS)/undifferentiated round cell sarcoma (URCS) INTERVENTIONS:: After initial diagnosis, the patient received 4 cycles of combination chemotherapy for 2 months. Radical amputation of left upper extremity was performed 3 months after diagnosis. Postoperative chemotherapy was continued for 6 cycles.

Outcomes: The patient died of intracranial metastasis with hemorrhage in 13 months after initial diagnosis, 5 months after the last cycle of chemotherapy.

Lessons: ELS in infancy is extremely rare and has a poorer prognosis than Ewing sarcoma or infantile fibrosarcoma. APC and MSH6 variation might be related with the disease progression and predict a poorer prognosis. This rare case promotes better understanding of the disease and suggests a promising role for the combination chemotherapy regimen in treating infantile ELS. Importantly, it brings to light the possibility of intracranial metastasis, which requires proactive screening for timely detection.
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http://dx.doi.org/10.1097/MD.0000000000017872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855612PMC
November 2019

Landscape and Regulation of mA and mAm Methylome across Human and Mouse Tissues.

Mol Cell 2020 01 29;77(2):426-440.e6. Epub 2019 Oct 29.

State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Department of Chemical Biology and Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China. Electronic address:

N-methyladenosine (mA), the most abundant internal mRNA modification, and N,2'-O-dimethyladenosine (mAm), found at the first-transcribed nucleotide, are two reversible epitranscriptomic marks. However, the profiles and distribution patterns of mA and mAm across human and mouse tissues are poorly characterized. Here, we report the mA and mAm methylome through profiling of 43 human and 16 mouse tissues and demonstrate strongest tissue specificity for the brain tissues. A small subset of tissue-specific mA peaks can also readily classify tissue types. The overall mA and mAm level is partially correlated with the expression level of their writers and erasers. Additionally, the mA-containing regions are enriched for SNPs. Furthermore, cross-species analysis revealed that species rather than tissue type is the primary determinant of methylation. Collectively, our study provides an in-depth resource for dissecting the landscape and regulation of the mA and mAm epitranscriptomic marks across mammalian tissues.
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http://dx.doi.org/10.1016/j.molcel.2019.09.032DOI Listing
January 2020

Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma.

Gut 2019 12 29;68(12):2195-2205. Epub 2019 Jul 29.

Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.

Objective: The lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We sought to develop a non-invasive diagnostic approach using circulating cell-free DNA (cfDNA) for the early detection of HCC.

Design: Applying the 5hmC-Seal technique, we obtained genome-wide 5-hydroxymethylcytosines (5hmC) in cfDNA samples from 2554 Chinese subjects: 1204 patients with HCC, 392 patients with chronic hepatitis B virus infection (CHB) or liver cirrhosis (LC) and 958 healthy individuals and patients with benign liver lesions. A diagnostic model for early HCC was developed through case-control analyses using the elastic net regularisation for feature selection.

Results: The 5hmC-Seal data from patients with HCC showed a genome-wide distribution enriched with liver-derived enhancer marks. We developed a 32-gene diagnostic model that accurately distinguished early HCC (stage 0/A) based on the Barcelona Clinic Liver Cancer staging system from non-HCC (validation set: area under curve (AUC)=88.4%; (95% CI 85.8% to 91.1%)), showing superior performance over α-fetoprotein (AFP). Besides detecting patients with early stage or small tumours (eg, ≤2.0 cm) from non-HCC, the 5hmC model showed high capacity for distinguishing early HCC from high risk subjects with CHB or LC history (validation set: AUC=84.6%; (95% CI 80.6% to 88.7%)), also significantly outperforming AFP. Furthermore, the 5hmC diagnostic model appeared to be independent from potential confounders (eg, smoking/alcohol intake history).

Conclusion: We have developed and validated a non-invasive approach with clinical application potential for the early detection of HCC that are still surgically resectable in high risk individuals.
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http://dx.doi.org/10.1136/gutjnl-2019-318882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872444PMC
December 2019

eIF3a mediates HIF1α-dependent glycolytic metabolism in hepatocellular carcinoma cells through translational regulation.

Am J Cancer Res 2019 5;9(5):1079-1090. Epub 2019 May 5.

Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University Shanghai 200032, China.

eIF3a is the largest subunit of eIF3 complex and is a key player in translational control. Recently eIF3a is recognized as a proto-oncogene, which is overexpressed and connected to tumorigenesis of many cancers. However, the mechanistic roles of eIF3a during the tumorigenesis remain largely elusive. Here, we report that depletion of eIF3a significantly reduced HIF1α protein level and cellular glycolysis ability. Mechanistically, we found that eIF3a regulates HIF1α protein synthesis through internal ribosomal entry site (IRES)-dependent translation. Importantly, through analyses of our own sample collection, we found that eIF3a is overexpressed in hepatocellular carcinoma (HCC) tissues, and a high level of eIF3a predicts poor prognosis of HCC patients. TCGA analyses further confirmed that eIF3a is coincident with an elevated activity of HIF1α pathway genes. Collectively, we identify eIF3a as a regulator for glycolysis through HIF1α IRES-dependent translational regulation, which may be a potential therapeutic target for HCC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556603PMC
May 2019

Publisher Correction: N-Methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation.

Nat Chem Biol 2019 05;15(5):549

Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA.

In the version of this article originally published, the references were incorrectly re-ordered during production. The hyphen in "N-methyladenosine" in the title was also superscript. The errors have been corrected in the HTML and PDF versions of the paper.
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http://dx.doi.org/10.1038/s41589-019-0233-6DOI Listing
May 2019

NMethyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation.

Nat Chem Biol 2019 01 10;15(1):88-94. Epub 2018 Dec 10.

Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA.

N-Methyladenosine (mA) RNA modification is present in messenger RNAs (mRNA), ribosomal RNAs (rRNA), and spliceosomal RNAs (snRNA) in humans. Although mRNA mA modifications have been extensively studied and shown to play critical roles in many cellular processes, the identity of mA methyltransferases for rRNAs and the function of rRNA mA modifications are unknown. Here we report a new mA methyltransferase, ZCCHC4, which primarily methylates human 28S rRNA and also interacts with a subset of mRNAs. ZCCHC4 knockout eliminates mA4220 modification in 28S rRNA, reduces global translation, and inhibits cell proliferation. We also find that ZCCHC4 protein is overexpressed in hepatocellular carcinoma tumors, and ZCCHC4 knockout significantly reduces tumor size in a xenograft mouse model. Our results highlight the functional significance of an rRNA mA modification in translation and in tumor biology.
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http://dx.doi.org/10.1038/s41589-018-0184-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463480PMC
January 2019

Bisulfite-Free, Nanoscale Analysis of 5-Hydroxymethylcytosine at Single Base Resolution.

J Am Chem Soc 2018 10 4;140(41):13190-13194. Epub 2018 Oct 4.

State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences , Peking University , Beijing 100871 , China.

High-resolution detection of genome-wide 5-hydroxymethylcytosine (5hmC) sites of small-scale samples remains challenging. Here, we present hmC-CATCH, a bisulfite-free, base-resolution method for the genome-wide detection of 5hmC. hmC-CATCH is based on selective 5hmC oxidation, chemical labeling and subsequent C-to-T transition during PCR. Requiring only nanoscale input genomic DNA samples, hmC-CATCH enabled us to detect genome-wide hydroxymethylome of human embryonic stem cells in a cost-effective manner. Further application of hmC-CATCH to cell-free DNA (cfDNA) of healthy donors and cancer patients revealed base-resolution hydroxymethylome in the human cfDNA for the first time. We anticipate that our chemical biology approach will find broad applications in hydroxymethylome analysis of limited biological and clinical samples.
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http://dx.doi.org/10.1021/jacs.8b08297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423965PMC
October 2018

Synthesis of Magnetic Wood Fiber Board and Corresponding Multi-Layer Magnetic Composite Board, with Electromagnetic Wave Absorbing Properties.

Nanomaterials (Basel) 2018 Jun 16;8(6). Epub 2018 Jun 16.

College of Materials Science and Engineering, Nanjing Forestry University, Nanjing 210037, China.

With the rapid growth in the use of wireless electronic devices, society urgently needs electromagnetic wave (EMW) absorbing material with light weight, thin thickness, wide effective absorbing band width, and strong absorption capacity. Herein, the multi-layer magnetic composite boards are fabricated by hot-pressing magnetic fiber boards and normal veneer layer-by-layer. The magnetic fibers obtained using in-situ chemical co-precipitation are used to fabricate magnetic fiber board by hot-pressing. The magnetic wave absorbing capacities of the magnetic fiber boards obtained with 72 h impregnation time exhibit strongest adsorption capacities of −51.01 dB with a thickness of 3.00 mm. It is proved that this outstanding EMW absorption property is due to the strongest dielectric loss, the optimal magnetic loss, and the dipole relaxation polarization. Meanwhile, the EMW absorbing capacities of the corresponding multi-layer composite magnetic board increases from −14.14 dB (3-layer) to −60.16 dB (7-layer). This is due to the generated multi-interfaces between magnetic fiber board and natural wood veneer in the EMW propagation direction, which significantly benefit multireflection and attenuation of the incident waves. The results obtained in this work indicate that natural wood fibers are of great potential in the fabrication of magnetic multi-layer boards treated as EMW absorbers via a low cost, green, and scalable method.
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http://dx.doi.org/10.3390/nano8060441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027180PMC
June 2018

Enhanced anti-tumor effects of doxorubicin on glioma by entrapping in polybutylcyanoacrylate nanoparticles.

Tumour Biol 2016 Feb 24;37(2):2703-8. Epub 2015 Sep 24.

Department of General Surgery, Children's Hospital Zhejiang University School of Medicine, No. 57 Zhugan Lane, Hangzhou, Zhejiang, 310003, China.

For effective therapy for glioma, it is essential for chemotherapeutics to pass the blood-brain barrier to target glioma cells with little side effects to surrounding normal cells. In this study, we prepared doxorubicin-polybutylcyanoacrylate nanoparticles (Dox-PBCA-NP) and assessed its inhibition effects on glioma both in vitro and in vivo. Dox-PBCA-NP was prepared using the emulsion polymerization method. The size and size distribution of nanoparticles were measured by Malven laser mastersizer and the morphology was observed under transmission electron microscope. Drug loading (DL) and entrapment efficiency (EE) of doxorubicin in the nanoparticles were measured by UV spectra. The proliferation of C6 glioma cells was detected by MTT assay, and cell cycle was analyzed by flow cytometry. The expression of telomerase was detected by immunocytochemical analysis. The anti-tumor efficiency of Dox-PBCA-NP was assessed in C6 glioma intracranial implant rat model. The average diameter of NP-Dox was 120 nm, DL was 10.58 %, and EE was 87.43 %. We found that the cytotoxicity of Dox-PBCA-NP was lower than Dox in vitro. In vivo, Dox-PBCA-NP could transport more Dox into tumors compared to contralateral control, and the life span was longer than Dox. Moreover, Dox-PBCA-NP had less cardiotoxicity than Dox. Taken together, our results suggest that Dox-PBCA-NP exhibits better therapeutic effects against glioma and fewer side effects and is a potential nano-scale drug delivery system for glioma chemotherapy.
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http://dx.doi.org/10.1007/s13277-015-4106-7DOI Listing
February 2016

BRD4 promotes tumor growth and epithelial-mesenchymal transition in hepatocellular carcinoma.

Int J Immunopathol Pharmacol 2015 Mar;28(1):36-44

Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, PR China Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, PR China

Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that play an important role in chromatin remodeling and transcriptional regulation. In this study, we found that BRD4, a BET family member, is significantly upregulated in hepatocellular carcinoma (HCC) tissues compared with adjacent normal tissues. Furthermore, the overexpression of BRD4 in cancer tissues was correlated with poor prognosis in HCC patients. Using shRNA-mediated knockdown of BRD4 or lentivirus-mediated overexpression of BRD4 in HCC cells, we further showed that BRD4 was involved in HCC cell growth and invasion in vitro. Forced expression of BRD4 was sufficient to induce epithelial-mesenchymal transition (EMT) phenotypes in HCC cells. Additionally, BRD4 shRNA significantly inhibited HCC cell proliferation in vivo. Collectively, our study confirmed that BRD4 expression is a valuable predictor of recurrence and survival in patients with HCC. BRD4 can be further used as a potential therapeutic target of HCC.
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http://dx.doi.org/10.1177/0394632015572070DOI Listing
March 2015

Laparoscopy-assisted orchiopexy for recurrent undescended testes in children.

J Pediatr Surg 2009 Apr;44(4):806-10

Department of Pediatric Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China.

Objective: Reoperative orchidopexy is a technical challenge to pediatric surgeons. The laparoscopy-assisted procedure is described for securing the testis in the scrotum in patients with a past history of open orchidopexy and testes in an unsatisfactory position.

Patients And Methods: Thirty-one patients with 35 abnormally positioned testes (4 bilateral) were evaluated. All patients had a past history of inguinal surgery, and ages ranged between 2.5 and 13 years (mean, 5.5 years). Previous surgical procedures included 32 orchiopexies and 3 testicular detorsion of undescended testis. If needed, inguinal dissection was performed to loose the adherence between the cord and inguinal canal. Laparoscopic orchidopexy was applied to allow the testis to remain in the scrotum without tension. Patients underwent follow-up every 3 months after the operation with physical and ultrasound examinations.

Results: Ten low inguinal testes were treated directly with open inguinal redo orchidopexy, whereas laparoscopy-assisted orchidopexy was possible in 23 (92%) of the remaining 25 reoperations. In 2 (8%) of these cases, severe scarring was present between the cord and the inguinal canal impeding the laparoscopy-assisted orchidopexy. For laparoscopy-assisted procedure, the operation time was 42 to 67 minutes (mean = 52 min). After the laparoscopy-assisted reoperations, 23 (92%) testes remain within the scrotum after a mean follow-up of 22 months (range, 6-32 months).

Conclusion: When feasible, laparoscopy-assisted orchiopexy is a simple and effective technique for securing testicles in reoperative orchiopexy procedures.
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http://dx.doi.org/10.1016/j.jpedsurg.2008.07.024DOI Listing
April 2009
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