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Novel mutation c.1210-3C>G in with a poly-T tract of 5T affects mRNA splicing in a Chinese patient

《医学前沿（英文）》 2022年 第16卷 第1期   页码 150-155 doi: 10.1007/s11684-021-0846-5

摘要： Cystic fibrosis (CF) is a rare autosomal recessive disease with only one pathogenic gene cystic fibrosis transmembrane conductance regulator (CFTR). To identify the potential pathogenic mutations in a Chinese patient with CF, we conducted Sanger sequencing on the genomic DNA of the patient and his parents and detected all 27 coding exons of CFTR and their flanking intronic regions. The patient is a compound heterozygote of c.2909G>A, p.Gly970Asp in exon 18 and c.1210-3C>G in cis with a poly-T of 5T (T5) sequence, 3 bp upstream in intron 9. The splicing effect of c.1210-3C>G was verified via minigene assay in vitro, indicating that wild-type plasmid containing c.1210-3C together with T7 sequence produced a normal transcript and partial exon 10-skipping-transcript, whereas mutant plasmid containing c.1210-3G in cis with T5 sequence caused almost all mRNA to skip exon 10. Overall, c.1210-3C>G, the newly identified pathogenic mutation in our patient, in combination with T5 sequence in cis, affects the CFTR gene splicing and produces nearly no normal transcript in vitro. Moreover, this patient carries a p.Gly970Asp mutation, thus confirming the high-frequency of this mutation in Chinese patients with CF.

关键词： cystic fibrosis     CFTR     splicing mutation     minigene    

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Mutation profiling of 16 candidate genes in

Yang Zhang, Fang Wang, Xue Chen, Wenjing Liu, Jiancheng Fang, Mingyu Wang, Wen Teng, Panxiang Cao, Hongxing Liu

《医学前沿（英文）》 2019年 第13卷 第2期   页码 229-237 doi: 10.1007/s11684-018-0616-1

摘要： This retrospective analysis aimed to investigate the mutation profile of 16 common mutated genes in acute myeloid leukemia (AML) patients. A total of 259 patients who were diagnosed of AML were enrolled in this study. Mutation profiling of 16 candidate genes were performed in bone marrow samples by using Sanger sequencing. We identified at least 1 mutation in 199 of the 259 samples (76.8%), and 2 or more mutations in 31.7% of samples. was the most common mutated gene (16.2%, 42/259), followed by (15.1%, 39/259), (14.7%, 38/259), and (13.5%, 35/259). Concurrence was observed in 97.1% of the mutated cases and in 29.6% of the double mutated cases. Distinct patterns of co-occurrence were observed for different hotspot mutations within the gene: mutations were associated with and/or mutations, whereas mutations co-occurred with mutations only. Concurrence was also observed in 86.6% of epigenetic regulation genes, most of which co-occurred with mutations. The results showed certain rules in the mutation profiling and concurrence of AML patients, which was related to the function classification of genes. Defining the mutation spectrum and mutation pattern of AML will contribute to the comprehensive assessment of patients and identification of new therapeutic targets.

关键词： leukemia     myeloid     acute     gene     mutation    

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Distinct gene expression pattern of mutations coordinated by target repression and promoter hypermethylation in acute myeloid leukemia

《医学前沿（英文）》 2022年 第16卷 第4期   页码 627-636 doi: 10.1007/s11684-020-0815-4

摘要： Runt-related transcription factor 1 (RUNX1) is an essential regulator of normal hematopoiesis. Its dysfunction, caused by either fusions or mutations, is frequently reported in acute myeloid leukemia (AML). However, RUNX1 mutations have been largely under-explored compared with RUNX1 fusions mainly due to their elusive genetic characteristics. Here, based on 1741 patients with AML, we report a unique expression pattern associated with RUNX1 mutations in AML. This expression pattern was coordinated by target repression and promoter hypermethylation. We first reanalyzed a joint AML cohort that consisted of three public cohorts and found that RUNX1 mutations were mainly distributed in the Runt domain and almost mutually exclusive with NPM1 mutations. Then, based on RNA-seq data from The Cancer Genome Atlas AML cohort, we developed a 300-gene signature that significantly distinguished the patients with RUNX1 mutations from those with other AML subtypes. Furthermore, we explored the mechanisms underlying this signature from the transcriptional and epigenetic levels. Using chromatin immunoprecipitation sequencing data, we found that RUNX1 target genes tended to be repressed in patients with RUNX1 mutations. Through the integration of DNA methylation array data, we illustrated that hypermethylation on the promoter regions of RUNX1-regulated genes also contributed to dysregulation in RUNX1-mutated AML. This study revealed the distinct gene expression pattern of RUNX1 mutations and the underlying mechanisms in AML development.

关键词： RUNX1     gene mutation     acute myeloid leukemia     transcriptional repression     DNA methylation    

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背包问题的混合粒子群优化算法

高尚,杨静宇

《中国工程科学》 2006年 第8卷 第11期   页码 94-98

摘要：

经典的粒子群是一个有效的寻找连续函数极值的方法，结合遗传算法的思想提出的混合粒子群算法来解决背包问题，经过比较测试，6种混合粒子群算法的效果都比较好，特别交叉策略A和变异策略C的混合粒子群算法是最好的且简单有效的算法，并成功地运用在投资问题中。对于目前还没有好的解法的组合优化问题，很容易地修改此算法就可解决。

关键词： 粒子群算法     背包问题     遗传算法     变异    

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Dynein axonemal heavy chain 10 deficiency causes primary ciliary dyskinesia in humans and mice

《医学前沿（英文）》   页码 957-971 doi: 10.1007/s11684-023-0988-8

摘要： Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 (DNAH10) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C > T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10-knockin mice harboring missense variants and Dnah10-knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. To the best of our knowledge, this study is the first to report DNAH10 deficiency related to PCD in human and mouse models, which suggests that DNAH10 recessive mutation is causative of PCD.

关键词： DNAH10     mice     motile cilia     mutation     primary ciliary dyskinesia    

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Antithrombin deficiency and decreased protein C activity in a young man with venous thromboembolism: a case report

null

《医学前沿（英文）》 2018年 第12卷 第3期   页码 319-323 doi: 10.1007/s11684-017-0553-4

摘要：

Antithrombin and protein C are two crucial members in the anticoagulant system and play important roles in hemostasis. Mutations in and lead to deficiency or dysfunction of the two proteins, which could result in venous thromboembolism (VTE). Here, we report a Chinese 22-year-old young man who developed recurrent and serious VTE in cerebral veins, visceral veins, and deep veins of the lower extremity. Laboratory tests and direct sequencing of and were conducted for the patient and his family members. Coagulation tests revealed that the patient presented type I antithrombin deficiency combined with decreased protein C activity resulting from a small insertion mutation c.848_849insGATGT in and a short deletion variant c.572_574delAGA in . This combination of the two mutations was absent in 400 healthy subjects each from southern and northern China. Then, we summarized all the mutations of the and gene reported in the Chinese Han population. This study demonstrates that the combination of antithrombin deficiency and decreased protein C activity can result in severe VTE and that the coexistence of different genetic factors may increase the risk of VTE.

关键词： antithrombin deficiency     protein C activity     mutation     variant     venous thromboembolism     anticoagulants    

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Decitabine induces -mediated immune responses in p53-mutated triple-negative breast cancer: a clinical and translational study

《医学前沿（英文）》 doi: 10.1007/s11684-023-1016-8

摘要： p53 is mutated in half of cancer cases. However, no p53-targeting drugs have been approved. Here, we reposition decitabine for triple-negative breast cancer (TNBC), a subtype with frequent p53 mutations and extremely poor prognosis. In a retrospective study on tissue microarrays with 132 TNBC cases, DNMT1 overexpression was associated with p53 mutations (P = 0.037) and poor overall survival (OS) (P = 0.010). In a prospective DEciTabinE and Carboplatin in TNBC (DETECT) trial (NCT03295552), decitabine with carboplatin produced an objective response rate (ORR) of 42% in 12 patients with stage IV TNBC. Among the 9 trialed patients with available TP53 sequencing results, the 6 patients with p53 mutations had higher ORR (3/6 vs. 0/3) and better OS (16.0 vs. 4.0 months) than the patients with wild-type p53. In a mechanistic study, isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53. In the DETECT trial, decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line (upregulation by 16-fold) and the most responsive patient with TNBC. Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.

关键词： p53 mutation     triple-negative breast cancer     decitabine     DNMT1     IRF7     innate immune response    

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Dual faces of SH2-containing protein-tyrosine phosphatase

null

《医学前沿（英文）》 2012年 第6卷 第3期   页码 275-279 doi: 10.1007/s11684-012-0216-4

摘要：

PTPN11, which encodes tyrosine phosphatase Shp2, is a critical gene mediating cellular responses to hormones and cytokines. Against original prediction as tumor suppressor for tyrosine phosphatases, PTPN11 was first identified as a proto-oncogene because activating mutations of this gene are associated with leukemogenesis. However, most recent experimental data suggest PTPN11/Shp2 acting as a tumor suppressor in hepatocarcinogenesis. This review focuses on the tumor-promoting or suppressing roles of the gene PTPN11/Shp2 in different cell types.

关键词： PTPN11/Shp2     leukemia     hepatocellular carcinoma     mutation    

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AML1-ETO driven acute leukemia: insights into pathogenesis and potential therapeutic approaches

null

《医学前沿（英文）》 2012年 第6卷 第3期   页码 248-262 doi: 10.1007/s11684-012-0206-6

摘要：

The AML1-ETO fusion transcription factor is generated by the t(8;21) translocation, which is present in approximately 4%–12% of adult and 12%–30% of pediatric acute myeloid leukemia (AML) patients. Both human and mouse models of AML have demonstrated that AML1-ETO is insufficient for leukemogenesis in the absence of secondary events. In this review, we discuss the pathogenetic insights that have been gained from identifying the various events that can cooperate with AML1-ETO to induce AML in vivo. We also discuss potential therapeutic strategies for t(8;21) positive AML that involve targeting the fusion protein itself, the proteins that bind to it, or the genes that it regulates. Recently published studies suggest that a targeted therapy for t(8;21) positive AML is feasible and may be coming sometime soon.

关键词： AML1-ETO     mouse model     leukemia     t(8     21)     pathway hits     mutation     hematopoiesis     Kasumi-1     CD34+    

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662 A/G gene variation in human tumor necrosis factor receptor superfamily, member 9 (TNFRSF9)

QU Yanchun, YANG Ze, SUN Liang, JI Linong

《医学前沿（英文）》 2008年 第2卷 第3期   页码 283-285 doi: 10.1007/s11684-008-0053-7

摘要： The aim of this paper is to report a new coding variance of the gene, a candidate for autoimmune diseases. We found the variation in two families with type 2 diabetes mellitus by D-HPLC mutation screening method and confirmed our results by direct sequencing and PCR-RFLP. Although without changing the amino acid coding, the variance may have an effect on codon usage and play a role in disease development, such as type 2 diabetes mellitus. However, we cannot define the role of this variance because the frequency of the minor allele is low in the Chinese population and no homozygote of the variance was found. More research in multiple populations will be necessary to define the role of this variance.

关键词： D-HPLC mutation     development     autoimmune     PCR-RFLP     candidate    

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Monitoring checkpoint inhibitors: predictive biomarkers in immunotherapy

Min Zhang, Jingwen Yang, Wenjing Hua, Zhong Li, Zenghui Xu, Qijun Qian

《医学前沿（英文）》 2019年 第13卷 第1期   页码 32-44 doi: 10.1007/s11684-018-0678-0

摘要：

Immunotherapy has become the fourth cancer therapy after surgery, chemotherapy, and radiotherapy. In particular, immune checkpoint inhibitors are proved to be unprecedentedly in increasing the overall survival rates of patients with refractory cancers, such as advanced melanoma, non-small cell lung cancer, and renal cell carcinoma. However, inhibitor therapies are only effective in a small proportion of patients with problems, such as side effects and high costs. Therefore, doctors urgently need reliable predictive biomarkers for checkpoint inhibitor therapies to choose the optimal therapies. Here, we review the biomarkers that can serve as potential predictors of the outcomes of immune checkpoint inhibitor treatment, including tumor-specific profiles and tumor microenvironment evaluation and other factors.

关键词： immune checkpoint     companion diagnosis     PD-L1     tumor mutation burden     immune score    

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Analysis of the genomic landscape of primary central nervous system lymphoma using whole-genome sequencing in Chinese patients

《医学前沿（英文）》   页码 889-906 doi: 10.1007/s11684-023-0994-x

摘要： Primary central nervous system lymphoma (PCNSL) is an uncommon non-Hodgkin’s lymphoma with poor prognosis. This study aimed to depict the genetic landscape of Chinese PCNSLs. Whole-genome sequencing was performed on 68 newly diagnosed Chinese PCNSL samples, whose genomic characteristics and clinicopathologic features were also analyzed. Structural variations were identified in all patients with a mean of 349, which did not significantly influence prognosis. Copy loss occurred in all samples, while gains were detected in 77.9% of the samples. The high level of copy number variations was significantly associated with poor progression-free survival (PFS) and overall survival (OS). A total of 263 genes mutated in coding regions were identified, including 6 newly discovered genes (ROBO2, KMT2C, CXCR4, MYOM2, BCLAF1, and NRXN3) detected in ≥ 10% of the cases. CD79B mutation was significantly associated with lower PFS, TMSB4X mutation and high expression of TMSB4X protein was associated with lower OS. A prognostic risk scoring system was also established for PCNSL, which included Karnofsky performance status and six mutated genes (BRD4, EBF1, BTG1, CCND3, STAG2, and TMSB4X). Collectively, this study comprehensively reveals the genomic landscape of newly diagnosed Chinese PCNSLs, thereby enriching the present understanding of the genetic mechanisms of PCNSL.

关键词： primary central nervous system lymphoma     whole-genome sequencing     TMSB4X     copy number variation     gene mutation    

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关于核农学创新的几点思考

王志东,高美须

《中国工程科学》 2008年 第10卷 第1期   页码 86-90

摘要：

文章简要介绍了我国核农学在诱变育种、核素示踪技术应用、食品辐照和辐射不育技术防治害虫等方面的研究成果和目前存在的主要问题，以及解决问题途径的思考与建议。文章认为我国的核农学正处在能否继续深入发展的关键时期，迫切需要通过加强学术创新和机制创新来提升我国核农学的发展速度与研究水平。文章强调我国核农学开展学术创新的重点应该是加强基础研究与应用基础研究，而支撑这个创新的关键点在于管理机制的创新。

关键词： 核农学     诱变育种     核素示踪技术应用     食品辐照     昆虫不育     学术创新     机制创新    

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一种基于变异算子与淘汰重组机制的改进GWO及其应用 Article

Xiao-qing ZHANG, Zheng-feng MING

《信息与电子工程前沿（英文）》 2017年 第18卷 第11期   页码 1705-1719 doi: 10.1631/FITEE.1601555

摘要： 标准苍狼优化算法（grey wolf optimizer, GWO）因其简单易用的特性受到广泛关注。由于存在搜索结构不完善、易陷入局部最优等问题，其应用范围受到了限制。本文提出了一种基于变异算子和淘汰重组机制的苍狼优化算法（eliminating-reconstructing GWO, MR-GWO）。对GWO的分析表明，GWO仅以三个领导层苍狼为核心进行搜索，且仅通过调整参数a来平衡算法的探索和开发性能，意味着苍狼群在一定程度上失去了多样性。因此，本文对优秀的搜索狼引入变异算子，对性能较差的搜索狼采用淘汰重组机制，不仅有效地扩展了算法的随机搜索面，同时加快了算法收敛速度。为了验证改进后算法的有效性，通过13个标准连续函数全局优化实验及RBF（radial basis function）网络逼近试验将MR-GWO算法与其它算法进行了比较，试验结果表明MR-GWO算法具有较强的竞争力。

关键词： 群智能；苍狼优化算法；优化；RBF（radial basis function）网络    

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Growth suppression of colorectal cancer expressing S492R EGFR by monoclonal antibody CH12

Qiongna Dong, Bizhi Shi, Min Zhou, Huiping Gao, Xiaoying Luo, Zonghai Li, Hua Jiang

《医学前沿（英文）》 2019年 第13卷 第1期   页码 83-93 doi: 10.1007/s11684-019-0682-z

摘要：

Colorectal cancer (CRC) is a common malignant tumor in the digestive tract, and 30%–85% of CRCs express epidermal growth factor receptors (EGFRs). Recently, treatments using cetuximab, also named C225, an anti-EGFR monoclonal antibody, for CRC have been demonstrated to cause an S492R mutation in EGFR. However, little is known about the biological function of S492R EGFR. Therefore, we attempted to elucidate its biological function in CRC cells and explore new treatment strategies for this mutant form. Our study indicated that EGFR and S492R EGFR accelerate the growth of CRC cells in vitro and in vivo and monoclonal antibody CH12, which specifically recognizes an EGFR tumor-specific epitope, can bind efficiently to S492R EGFR. Furthermore, mAb CH12 showed significantly stronger growth suppression activities and induced a more potent antibody-dependent cellular cytotoxicity effect on CRC cells bearing S492R EGFR than mAb C225. mAb CH12 obviously suppressed the growth of CRC xenografts with S492R EGFR mutations in vivo. Thus, mAb CH12 may be a promising therapeutic agent in treating patients with CRC bearing an S492R EGFR mutation.

关键词： S492R EGFR ectodomain mutation     colorectal cancer     mAb CH12     immunnotherapy    

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标题 作者 时间 类型 操作

Novel mutation c.1210-3C>G in with a poly-T tract of 5T affects mRNA splicing in a Chinese patient

期刊论文

Mutation profiling of 16 candidate genes in

Yang Zhang, Fang Wang, Xue Chen, Wenjing Liu, Jiancheng Fang, Mingyu Wang, Wen Teng, Panxiang Cao, Hongxing Liu

期刊论文

Distinct gene expression pattern of mutations coordinated by target repression and promoter hypermethylation in acute myeloid leukemia

期刊论文

背包问题的混合粒子群优化算法

高尚,杨静宇

期刊论文

Dynein axonemal heavy chain 10 deficiency causes primary ciliary dyskinesia in humans and mice

期刊论文

Antithrombin deficiency and decreased protein C activity in a young man with venous thromboembolism: a case report

null

期刊论文

Decitabine induces -mediated immune responses in p53-mutated triple-negative breast cancer: a clinical and translational study

期刊论文

Dual faces of SH2-containing protein-tyrosine phosphatase

null

期刊论文

AML1-ETO driven acute leukemia: insights into pathogenesis and potential therapeutic approaches

null

期刊论文

662 A/G gene variation in human tumor necrosis factor receptor superfamily, member 9 (TNFRSF9)

QU Yanchun, YANG Ze, SUN Liang, JI Linong

期刊论文

Monitoring checkpoint inhibitors: predictive biomarkers in immunotherapy

Min Zhang, Jingwen Yang, Wenjing Hua, Zhong Li, Zenghui Xu, Qijun Qian

期刊论文

Analysis of the genomic landscape of primary central nervous system lymphoma using whole-genome sequencing in Chinese patients

期刊论文

关于核农学创新的几点思考

王志东,高美须

期刊论文

一种基于变异算子与淘汰重组机制的改进GWO及其应用

Xiao-qing ZHANG, Zheng-feng MING

期刊论文

Growth suppression of colorectal cancer expressing S492R EGFR by monoclonal antibody CH12

Qiongna Dong, Bizhi Shi, Min Zhou, Huiping Gao, Xiaoying Luo, Zonghai Li, Hua Jiang

期刊论文