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Huang J, Liu H, Zhao Y, Luo T, Liu J, Liu J, Pan X, Tang W. MicroRNAs Expression Patterns Predict Tumor Mutational Burden in Colorectal Cancer. Front Oncol 2021; 10:550986. [PMID: 33634010 PMCID: PMC7900489 DOI: 10.3389/fonc.2020.550986] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Accepted: 12/04/2020] [Indexed: 01/10/2023] Open
Abstract
Background Tumor mutational burden (TMB) could be a measure of response to immune checkpoint inhibitors therapy for patients with colorectal cancer (CRC). MicroRNAs (miRNAs) participate in anticancer immune responses. In the present study, we determined miRNA expression patterns in patients with CRC and built a signature that predicts TMB. Methods Next generation sequencing (NGS) on formalin-fixed paraffin-embedded samples from CRC patients was performed to measure TMB levels. We used datasets from The Cancer Genome Atlas to compare miRNA expression patterns in samples with high and low TMB from patients with CRC. We created an miRNA-based signature index using the selection operator (LASSO) and least absolute shrinkage method from the training set. We used an independent test set as internal validation. We used real-time polymerase chain reaction (RT-PCR) to validate the miRNA-based signature classifier. Results Twenty-seven samples from CRC patients underwent NGS to determine the TMB level. We identified four miRNA candidates in the training set for predicting TMB (N = 311). We used the test set (N = 204) for internal validation. The four-miRNA-based signature classifier was an accurate predictor of TMB, with accuracy 0.963 in the training set. In the test set, it was 0.902; and it was 0.946 in the total set. The classifier was superior to microsatellite instability (MSI) for predicting TMB in TCGA dataset. In the validation cohort, MSI status more positively correlated with TMB levels than did the classifier. Validation from RT-qPCR showed good target discrimination of the classifier for TMB prediction. Conclusion To our knowledge, this is the first miRNA-based signature classifier validated using high quality clinical data to accurately predict TMB level in patients with CRC.
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Affiliation(s)
- Jiahao Huang
- Department of Gastrointestinal Surgery, Affiliated Tumor Hospital, Guangxi Medical University, Nanning, China.,Department of Colorectal and Anal Surgery, The First Affiliated Hospital, Guangxi Medical University, Nanning, China.,Guangxi Clinical Research Center for Colorectal Cancer, Nanning, China
| | - Haizhou Liu
- Department of Research, Affiliated Tumor Hospital, Guangxi Medical University, Nanning, China
| | - Yang Zhao
- Department of Radiology, Affiliated Tumor Hospital, Guangxi Medical University, Nanning, China
| | - Tao Luo
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital, Guangxi Medical University, Nanning, China
| | - Jungang Liu
- Department of Gastrointestinal Surgery, Affiliated Tumor Hospital, Guangxi Medical University, Nanning, China.,Guangxi Clinical Research Center for Colorectal Cancer, Nanning, China
| | - Junjie Liu
- Department of Ultrasound, Affiliated Tumor Hospital, Guangxi Medical University, Nanning, China
| | - Xiaoyan Pan
- Department of Comprehensive Internal Medicine, Affiliated Tumor Hospital, Guangxi Medical University, Nanning, China
| | - Weizhong Tang
- Department of Gastrointestinal Surgery, Affiliated Tumor Hospital, Guangxi Medical University, Nanning, China.,Guangxi Clinical Research Center for Colorectal Cancer, Nanning, China
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Yang Y, Alderman C, Sehlaoui A, Xiao Y, Wang W. MicroRNAs as Immunotherapy Targets for Treating Gastroenterological Cancers. Can J Gastroenterol Hepatol 2018; 2018:9740357. [PMID: 30046565 PMCID: PMC6038585 DOI: 10.1155/2018/9740357] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 05/02/2018] [Indexed: 01/17/2023] Open
Abstract
Gastroenterological cancers are the most common cancers categorized by systems and are estimated to comprise 18.4% of all cancers in the United States in 2017. Gastroenterological cancers are estimated to contribute 26.2% of cancer-related death in 2017. Gastroenterological cancers are characterized by late diagnosis, metastasis, high recurrence, and being refractory to current therapies. Since the current targeted therapies provide limited benefit to the overall response and survival, there is an urgent need for developing novel therapeutic strategy to improve the outcome of gastroenterological cancers. Immunotherapy has been developed and underwent clinical trials, but displayed limited therapeutic benefit. Since aberrant expressions of miRNAs are found in gastroenterological cancers and miRNAs have been shown to regulate antitumor immunity, the combination therapy combining the traditional antibody-based immunotherapy and novel miRNA-based immunotherapy is promising for achieving clinical success. This review summarizes the current knowledge about the miRNAs and long noncoding RNAs that exhibit immunoregulatory roles in gastroenterological cancers and precancerous diseases of digestive system, as well as the miRNA-based clinical trials for gastroenterological cancers. This review also analyzes the ongoing challenge of identifying appropriate therapy candidates for complex and dynamic tumor microenvironment, ensuring efficient and targeted delivery to specific cancer tissues, and developing strategy for avoiding off-target effect.
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Affiliation(s)
- Yixin Yang
- College of Natural, Applied and Health Sciences, Kean University, 100 Morris Avenue, Union, NJ 07083, USA
| | - Christopher Alderman
- School of Medicine, University of Colorado, 13001 E 17th Pl, Aurora, CO 80045, USA
| | - Ayoub Sehlaoui
- Department of Biological Sciences, Emporia State University, 1 Kellogg Circle, Emporia, KS 66801, USA
| | - Yuan Xiao
- Department of Biological Sciences, Emporia State University, 1 Kellogg Circle, Emporia, KS 66801, USA
| | - Wei Wang
- Department of Thoracic Surgery III, Cancer Hospital of China Medical University, No. 44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning 110042, China
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Masuda T, Hayashi N, Kuroda Y, Ito S, Eguchi H, Mimori K. MicroRNAs as Biomarkers in Colorectal Cancer. Cancers (Basel) 2017; 9:cancers9090124. [PMID: 28902152 PMCID: PMC5615339 DOI: 10.3390/cancers9090124] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 09/01/2017] [Accepted: 09/10/2017] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRs) are small RNAs that repress mRNA translation, resulting in the degradation of mRNAs and regulation of the expression levels of various genes. Recent studies have shown that aberrant miR expression has a functional role in the initiation and progression of various malignancies, including colorectal cancer (CRC), which is one of the leading causes of cancer-related death worldwide. miRs have also been shown to have applications as diagnostic, prognostic, and predictive biomarkers because of their high tissue specificity, stability, and altered expression in tumor development. In this report, we examined the role of miRs as biomarkers in CRC through a review of meta-analyses and large-scale analyses having strong statistical confidence in the study outcomes. We also discuss current issues in the clinical application of these miRs.
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Affiliation(s)
- Takaaki Masuda
- Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan.
| | - Naoki Hayashi
- Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan.
| | - Yosuke Kuroda
- Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan.
| | - Shuhei Ito
- Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan.
| | - Hidetoshi Eguchi
- Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan.
| | - Koshi Mimori
- Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan.
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Mirzaei N, Poursina F, Moghim S, Rashidi N, Ghasemian Safaei H. The study of H. pylori putative candidate factors for single- and multi-component vaccine development. Crit Rev Microbiol 2017; 43:631-650. [PMID: 28581361 DOI: 10.1080/1040841x.2017.1291578] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Helicobacter pylori has grown to colonize inside the stomach of nearly half of the world's population, turning into the most prevalent infections in the universe. Medical care failures noticeably confirm the need for a vaccine to hinder or deal with H. pylori. This review is planned to discuss the most known factors as a vaccine candidate, including single (AhpC, BG, CagA, KatA, Fla, Hsp, HWC, Lpp, LPS, NAP, OMP, OMV, SOD, Tpx, Urease, VacA) and multi-component vaccines. Many promising results in the field of single and multivalent vaccine can be seen, but there is no satisfactory outcome and neither a prophylactic nor a therapeutic vaccine to treat or eradicate the infection in human has been acquired. Hence, selecting suitable antigen is an important factor as an appropriate adjuvant. Taken all together, the development of efficient anti-H. pylori vaccines relies on the fully understanding of the interactions between H. pylori and its host immune system. Therefore, more work should be done on epitope mapping, analysis of molecular structure, and determination of the antigen determinant region as well due to design a vaccine, preferably a multi-component vaccine to elicit specific CD4 T-cell responses that are required for H. pylori vaccine efficacy.
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Affiliation(s)
- Nasrin Mirzaei
- a Department of Microbiology , Tonekabon Branch, Islamic Azad University , Tonekabon , Iran
| | - Farkhondeh Poursina
- b Department of Microbiology , Isfahan University of Medical Sciences , Isfahan , Iran
| | - Sharareh Moghim
- b Department of Microbiology , Isfahan University of Medical Sciences , Isfahan , Iran
| | - Niloufar Rashidi
- c Department of Laboratory Sciences , Ahvaz University of Medical Sciences , Ahvaz , Iran
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Li X, Nie J, Mei Q, Han WD. MicroRNAs: Novel immunotherapeutic targets in colorectal carcinoma. World J Gastroenterol 2016; 22:5317-5331. [PMID: 27340348 PMCID: PMC4910653 DOI: 10.3748/wjg.v22.i23.5317] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 04/23/2016] [Accepted: 05/04/2016] [Indexed: 02/06/2023] Open
Abstract
Colorectal carcinoma (CRC) is one of the most common types of cancer worldwide and the prognosis for CRC patients with recurrence or metastasis is extremely poor. Although chemotherapy and radiation therapy can improve survival, there are still numerous efforts to be performed. Immunotherapy is frequently used, either alone or in combination with other therapies, for the treatment of CRC and is a safe and feasible way to improve CRC treatment. Furthermore, the significance of the immune system in the biology of CRC has been demonstrated by retrospective assessments of immune infiltrates in resected CRC tumors. MicroRNAs (miRNAs) are short, non-coding RNAs that can regulate multiple target genes at the post-transcriptional level and play critical roles in cell proliferation, differentiation and apoptosis. MiRNAs are required for normal immune system development and function. Nevertheless, aberrant expression of miRNAs is often observed in various tumor types and leads to immune disorders or immune evasion. The immunomodulatory function of miRNAs indicates that miRNAs may ultimately be part of the portfolio of anti-cancer targets. Herein, we will review the potential roles of miRNAs in the regulation of the immune response in CRC and then move on to discuss how to utilize different miRNA targets to treat CRC. We also provide an overview of the major limitations and challenges of using miRNAs as immunotherapeutic targets.
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Vachirayonstien T, Yan B. MicroRNA-30c-1-3p is a silencer of the pregnane X receptor by targeting the 3'-untranslated region and alters the expression of its target gene cytochrome P450 3A4. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2016; 1859:1238-1244. [PMID: 27085140 DOI: 10.1016/j.bbagrm.2016.03.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Revised: 03/17/2016] [Accepted: 03/30/2016] [Indexed: 01/07/2023]
Abstract
The pregnane X receptor (PXR) is a master regulator of genes involved in drug elimination. Recently, activation of PXR has also been linked to the development of many disease conditions such as metabolic disorders and malignancies. MicroRNAs (miRs) emerge as important molecular species involved in these conditions. This study was undertaken to test a large number of miRs for their ability to regulate PXR expression. As many as 58 miRs were tested and miR-30c-1-3p was identified to suppress PXR expression. The suppression was achieved by targeting the 3'-untranslated region, 438 nucleotides from the stop codon. The suppression was detected in multiple cell lines from different organ origins. In addition, miR-30c-1-3p altered basal and induced expression of cytochrome P450 3A4 (CYP3A4), a prototypical target gene of PXR. The alteration varied depending on the time and amounts of miR-30c-1-3p. CYP3A4 is responsible for the metabolism of more than 50% medicines. The interconnection between miR-30c-1-3p and PXR signifies a role of miRs in drug-drug interactions and chemosensitivity. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.
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Affiliation(s)
- Thaveechai Vachirayonstien
- Department of Biomedical and Pharmaceutical Sciences, Center for Integrated Drug Development, University of Rhode Island, Kingston, RI 02881, United States
| | - Bingfang Yan
- Department of Biomedical and Pharmaceutical Sciences, Center for Integrated Drug Development, University of Rhode Island, Kingston, RI 02881, United States.
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Park K, Dhupal M, Kim CS, Park YS, Kim SK. Implication of immunokine profiling for cancer staging. Med Hypotheses 2016; 88:46-8. [PMID: 26880636 DOI: 10.1016/j.mehy.2016.01.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 01/19/2016] [Indexed: 10/22/2022]
Abstract
Tumor may arise from the dysregulation of immune system, which plays pivotal roles in counteracting tumor colonization, late-stage tumors, and metastases. In the midst of the establishment of cancer in vivo, immune cells are activated to release a multitude of immunokines, such as cytokines, and chemokines. Thus, since cytokine levels in tumor bearing host would be differential among local (intratumoral lesion, peritumoral normal tissue), and systemic sample site (serum), these differences might be significantly correlated to prognosis and treatment outcome for cancer patients. Previously, despite small number of patients, we demonstrated the feasibility of this proposition via only cytokine profiling. Based on this, herein we propose that immunokine profiling would be used as a surrogate, predictive tool for cancer staging, and progression.
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Affiliation(s)
- Kawngwoo Park
- Department of Radiation Oncology, Wonju College of Medicine, Yonsei University, Wonju 26426, Republic of Korea
| | - Madhusmita Dhupal
- Department of Microbiology, Wonju College of Medicine, Yonsei University, Wonju 26426, Republic of Korea
| | - Cheol-Su Kim
- Department of Microbiology, Wonju College of Medicine, Yonsei University, Wonju 26426, Republic of Korea
| | - Yoon-Sun Park
- Department of Microbiology and Institute for Clinical and Translational Research, Catholic Kwandong University College of Medicine, Gangneung 25601, Republic of Korea
| | - Soo-Ki Kim
- Department of Microbiology, Wonju College of Medicine, Yonsei University, Wonju 26426, Republic of Korea; Institute of Genomic Cohort, Wonju College of Medicine, Yonsei University, Wonju 26426, Republic of Korea.
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Abstract
MicroRNAs (miRNAs) control physiological and fundamental processes in cellular development and differentiation by modulating the expression of their target genes. They have been found to participate in cell transformation and multiplication by functioning as oncomiRs and tumor suppressors in diverse cancers. Introduction of antisense miRNAs (antagomiRs) into primary cells such as immune cells by lipofection, viral vectors or electroporation can achieve the specific silencing of individual miRNAs. Therefore, harnessing miRNAs may lead to promising cancer therapeutics. There is emerging evidence demonstrating the involvement of miRNAs in combined cancer therapies, including chemotherapy, radiotherapy and immunotherapy combining with miRNA therapy.
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Affiliation(s)
- Hong W Yu
- Hong Kong Polytechnic University, Department of Health Technology and Informatics , Kowloon, Hong Kong , China
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Botta C, Gullà A, Correale P, Tagliaferri P, Tassone P. Myeloid-derived suppressor cells in multiple myeloma: pre-clinical research and translational opportunities. Front Oncol 2014; 4:348. [PMID: 25538892 PMCID: PMC4258997 DOI: 10.3389/fonc.2014.00348] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 11/23/2014] [Indexed: 12/31/2022] Open
Abstract
Immunosuppressive cells have been reported to play an important role in tumor-progression mainly because of their capability to promote immune-escape, angiogenesis, and metastasis. Among them, myeloid-derived suppressor cells (MDSCs) have been recently identified as immature myeloid cells, induced by tumor-associated inflammation, able to impair both innate and adaptive immunity. While murine MDSCs are usually identified by the expression of CD11b and Gr1, human MDSCs represent a more heterogeneous population characterized by the expression of CD33 and CD11b, low or no HLA-DR, and variable CD14 and CD15. In particular, the last two may alternatively identify monocyte-like or granulocyte-like MDSC subsets with different immunosuppressive properties. Recently, a substantial increase of MDSCs has been found in peripheral blood and bone marrow (BM) of multiple myeloma (MM) patients with a role in disease progression and/or drug resistance. Pre-clinical models recapitulating the complexity of the MM-related BM microenvironment (BMM) are major tools for the study of the interactions between MM cells and cells of the BMM (including MDSCs) and for the development of new agents targeting MM-associated immune-suppressive cells. This review will focus on current strategies for human MDSCs generation and investigation of their immunosuppressive function in vitro and in vivo, taking into account the relevant relationship occurring within the MM–BMM. We will then provide trends in MDSC-associated research and suggest potential application for the treatment of MM.
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Affiliation(s)
- Cirino Botta
- Department of Experimental and Clinical Medicine, "Magna Graecia" University and Medical Oncology Unit, T. Campanella Cancer Center, "Salvatore Venuta" University Campus , Catanzaro , Italy
| | - Annamaria Gullà
- Department of Experimental and Clinical Medicine, "Magna Graecia" University and Medical Oncology Unit, T. Campanella Cancer Center, "Salvatore Venuta" University Campus , Catanzaro , Italy
| | | | - Pierosandro Tagliaferri
- Department of Experimental and Clinical Medicine, "Magna Graecia" University and Medical Oncology Unit, T. Campanella Cancer Center, "Salvatore Venuta" University Campus , Catanzaro , Italy
| | - Pierfrancesco Tassone
- Department of Experimental and Clinical Medicine, "Magna Graecia" University and Medical Oncology Unit, T. Campanella Cancer Center, "Salvatore Venuta" University Campus , Catanzaro , Italy ; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University , Philadelphia, PA , USA
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Shang J, Yang F, Wang Y, Wang Y, Xue G, Mei Q, Wang F, Sun S. MicroRNA-23a antisense enhances 5-fluorouracil chemosensitivity through APAF-1/caspase-9 apoptotic pathway in colorectal cancer cells. J Cell Biochem 2014; 115:772-84. [PMID: 24249161 DOI: 10.1002/jcb.24721] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Accepted: 11/14/2013] [Indexed: 12/18/2022]
Abstract
Current literature provided information that alteration in microRNA expression impacted sensitivity or resistance of certain tumor types to anticancer treatment, including the possible intracellular pathways. The microRNA-23a (miR-23a)-regulated apoptosis in response to the 5-fluorouracil (5-FU)-induced mitochondria-mediated apoptotic pathway was determined in this study. The miR-23a expression in 5-FU-treated and untreated colon cancer cells and tissues was assessed using real-time PCR analysis. To determine the function of miR-23a in the regulation of 5-FU-induced apoptosis, cell-proliferation, cytotoxicity, and apoptosis analyses were performed. Dual luciferase reporter assay was used to identify the apoptosis-related target gene for miR-23a. The activity of caspases-3, -7, and -9 were also assessed in miR-23a antisense and 5-FU treated tumor cells. A xenograft tumor model was established to evaluate the biological relevance of altered miR-23a expression to the 5-FU-based chemotherapy in vivo. We found that the expression of miR-23a was increased and the level of apoptosis-activating factor-1 (APAF-1) was decreased in 5-FU-treated colon cancer cells compared to untreated cells. The activation of the caspases-3 and 7 was increased in miR-23a antisense and 5-FU-treated colon cancer cells compared to negative control. APAF-1, as a target gene of miR-23a, was identified and miR-23a antisense-induced increase in the activation of caspase-9 was observed. The overexpression of miR-23a antisense up-regulated the 5-FU induced apoptosis in colon cancer cells. However, the miR-23a knockdown did not increase the antitumor effect of 5-FU in xenograft model of colon cancer. This study shows that miR-23a antisense enhanced 5-FU-induced apoptosis in colorectal cancer cells through the APAF-1/caspase-9 apoptotic pathway.
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Affiliation(s)
- Jingli Shang
- Department of Medical Genetics, Institute of Genetics, Second Military Medical University, Shanghai, China
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