Meng Ma

Shanghai Jiao Tong University

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Lu Si

Peking University

Zhihong Chi

Peking University Cancer Hospital

Xinan Sheng

Peking University

Chuanliang Cui

Peking University Cancer Hospital

Yan Kong

Peking University

Yanping Kuang

Shanghai Ninth People's Hospital

Huan Tang

Chinese Academy of Medical Sciences & Peking Union Medical College

Shi Yang

Shanghai Jiao Tong University

Ruhui Tian

Shanghai Jiao Tong University

Jun Guo

Hebei Medical University

Cooperative Institutions

Shanghai Jiao Tong University

Chinese Academy of Sciences

Chinese Academy of Medical Sciences & Peking Union Medical College

Shanghai Ninth People's Hospital

Peking University

Ministry of Agriculture and Rural Affairs

National Vaccine and Serum Institute

Capital Medical University

Nanjing Medical University

University of Chinese Academy of Sciences

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Data from Frequent Genetic Aberrations in the CDK4 Pathway in Acral Melanoma Indicate the Potential for CDK4/6 Inhibitors in Targeted Therapy

Yan Kong Xinan Sheng Xiaowen Wu Junya Yan Meng Ma

<div>AbstractPurpose: Effective therapies for the majority of metastatic acral melanoma patients have not been established. Thus, we investigated genetic aberrations of CDK4 pathway in acral melanoma and evaluated the efficacy of CDK4/6 inhibitors in targeted therapy of acral melanoma.Experimental Design: A total of 514 primary acral melanoma samples were examined for the copy number variations (CNV) of CDK4 pathway-related genes, including Cdk4, Ccnd1, and P16INK4a, by QuantiGenePlex DNA Assay. The sensitivity of established acral melanoma cell lines and patient-derived xenograft (PDX) containing typical CDK4 aberrations to CDK4/6 inhibitors was evaluated.Results: Among the 514 samples, 203 cases, 137 cases, and 310 cases, respectively, showed Cdk4 gain (39.5%), Ccnd1 gain (26.7%), and P16INK4a loss (60.3%). The overall frequency of acral melanomas that contain at least one aberration in Cdk4, Ccnd1, and P16INK4a was 82.7%. The median overall survival time for acral melanoma patients with concurrent Cdk4 gain with P16INK4a loss was significantly shorter than that for patients without such aberrations (P = 0.005). The pan-CDK inhibitor AT7519 and selective CDK4/6 inhibitor PD0332991 could inhibit the cell viability of acral melanoma cells and the tumor growth of PDX with Cdk4 gain plus Ccnd1 gain, Cdk4 gain plus P16INK4a loss, and Ccnd1 gain plus P16INK4a loss.Conclusions: Genetic aberration of CDK4 pathway is a frequent event in acral melanoma. Acral melanoma cell lines and PDX containing CDK4 pathway aberrations are sensitive to CDK4/6 inhibitors. Our study provides evidence for the testing of CDK4/6 inhibitors in acral melanoma patients. Clin Cancer Res; 23(22); 6946–57. ©2017 AACR.</div>

10.1158/1078-0432.c.6525299.v1

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Metabolic and Proteomic Profiles Associated with Immune Responses Induced by Different Inactivated SARS-CoV-2 Vaccine Candidates

International Journal of Molecular Sciences (2022)

Shouzhi Yu Yao He Wenheng Ji Rong Yang Yuxiu Zhao

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019, the virus has been mutating continuously, resulting in the continuous emergence of variants and creating challenges for epidemic prevention and control. Here, we immunized mice with different vaccine candidates, revealing the immune, protein, and metabolomic changes that take place in vaccines composed of different variants. We found that the prototype strain and Delta- and Omicron-variant inactivated vaccine candidates could all induce a high level of neutralizing antibodies and cellular immunity responses in mice. Next, we found that the metabolic and protein profiles were changed, showing a positive association with immune responses, and the level of the change was distinct in different inactivated vaccines, indicating that amino acid variations could affect metabolomics and proteomics. Our findings reveal differences between vaccines at the metabolomic and proteomic levels. These insights provide a novel direction for the immune evaluation of vaccines and could be used to guide novel strategies for vaccine design.

Vaccine efficacy

10.3390/ijms231810644

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Effect of paternal body mass index on neonatal outcomes of singletons after frozen−thawed embryo transfer cycles: analysis of 7,908 singleton newborns

Fertility and Sterility (2020)

Meng Ma Wei Zhang Jie Zhang Liang Zhou Yanping Kuang

Singleton

10.1016/j.fertnstert.2020.02.100

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Citations (12)

Identification of a functional polymorphism within the 3′-untranslated region of denticleless E3 ubiquitin protein ligase homolog associated with survival in acral melanoma

European Journal of Cancer (2019)

Lu Yang Jie Dai Meng Ma Lili Mao Lu Si

SNP

10.1016/j.ejca.2019.06.006

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Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications

Genome Medicine (2017)

Shuyu D. Li Meng Ma Hui Li Aneta Waluszko Tatyana Sidorenko

Next-generation sequencing (NGS) of cancer gene panels are widely applied to enable personalized cancer therapy and to identify novel oncogenic mutations.We performed targeted NGS on 932 clinical cases of non-small-cell lung cancers (NSCLCs) using the Ion AmpliSeq™ Cancer Hotspot panel v2 assay.Actionable mutations were identified in 65% of the cases with available targeted therapeutic options, including 26% of the patients with mutations in National Comprehensive Cancer Network (NCCN) guideline genes. Most notably, we discovered JAK2 p.V617F somatic mutation, a hallmark of myeloproliferative neoplasms, in 1% (9/932) of the NSCLCs. Analysis of cancer cell line pharmacogenomic data showed that a high level of JAK2 expression in a panel of NSCLC cell lines is correlated with increased sensitivity to a selective JAK2 inhibitor. Further analysis of TCGA genomic data revealed JAK2 gain or loss due to genetic alterations in NSCLC clinical samples are associated with significantly elevated or reduced PD-L1 expression, suggesting that the activating JAK2 p.V617F mutation could confer sensitivity to both JAK inhibitors and anti-PD1 immunotherapy. We also detected JAK3 germline activating mutations in 6.7% (62/932) of the patients who may benefit from anti-PD1 treatment, in light of recent findings that JAK3 mutations upregulate PD-L1 expression.Taken together, this study demonstrated the clinical utility of targeted NGS with a focused hotspot cancer gene panel in NSCLCs and identified activating mutations in JAK2 and JAK3 with clinical implications inferred through integrative analysis of cancer genetic, genomic, and pharmacogenomic data. The potential of JAK2 and JAK3 mutations as response markers for the targeted therapy against JAK kinases or anti-PD1 immunotherapy warrants further investigation.

Pharmacogenomics

Targeted Therapy

10.1186/s13073-017-0478-1

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Analyzing treatment patterns and time to the next treatment in chronic lymphocytic leukemia real-world data using automated temporal phenotyping.

Journal of Clinical Oncology (2021)

Kyeryoung Lee Zongzhi Liu Meng Ma Yun Mai Christopher Gilman

e19512 Background: Targeted therapy is an important treatment for chronic lymphocytic leukemia (CLL). However, optimal strategies for deploying small molecule inhibitors or antibody therapies in the real world are not well understood, largely due to a lack of outcomes data. We implemented a novel temporal phenotyping algorithm pipeline to derive lines of therapy (LOT) and disease progression in CLL patients. Here, the CLL treatment pattern and time to the next treatment (TTNT) were analyzed in real-world data (RWD) using patient electronic health records. Methods: We identified a CLL cohort with LOT from the Mount Sinai Data Warehouse (2003-2020). Each LOT consisted of either a single agent or combinations defined by NCCN CLL guidelines. We developed a natural language processing (NLP)-based temporal phenotyping approach to automatically identify the number of lines and therapeutic regimens. The sequence of treatment and time interval for each patient were derived from the systematic treatment data. Time to event analysis and multivariate (i.e., age, gender, race, other treatment patterns) Cox proportional hazard (CoxPH) models were used to analyze the patterns and predictors of TTNT. Results: Four hundred eleven CLL patients received 1 to 7 LOTs. Ibrutinib was the predominant 1 st LOT (40.8% of patients) followed by anti-CD20-based antibody therapies and chemotherapy in 30.6 and 19.2% of patients, respectively, followed by Acalabrutinib, Venetoclax, and Idelalisib in 3.4, 2.7, and 0.7% of patients, respectively (Table 1). The 2 nd to 5 th LOT showed the same or similar trends. We next analyzed the TTNT in the 1 st line of each therapeutic class. Acalabrutinib resulted in a longer median TTNT than Ibrutinib. Both Acalabrutinib and Ibrutinib showed longer TTNT compared to Venetoclax (median TTNTs were 742 and 598 vs. 373 days: HR = 0.23, p=0.015 and HR = 0.48, p=0.03, respectively). In addition, patients with age equal to or older than 65 showed longer TNNT (HR=0.16, p=0.016). Conclusions: Our result shows the potential of RWD usage in clinical decision making as real-world evidence reported here is consistent with results derived from clinical trial data. Linking this study to genetic data and other covariates affecting treatment outcomes may provide additional insights into the optimal sequences of the targeted therapies in CLL. Table 1: Therapeutic class and patient numbers (%) in each line.[Table: see text]

Venetoclax

Idelalisib

Real world data

10.1200/jco.2021.39.15_suppl.e19512

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Citations (1)

Comparison of a progestin-primed ovarian stimulation protocol with a flexible GnRH antagonist protocol in patients with polycystic ovary syndrome who are participating in an IVF programme: study protocol for a randomised controlled trial

BMJ Open (2020)

Ningling Wang Qianqian Zhu Meng Ma Liang Zhou Yu Tao

Introduction Women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF) protocols are typically characterised by an increased number of oocytes retrieved. The oocytes are often of poor quality, leading to lower pregnancy rates, higher miscarriage rates and an increased risk of developing ovarian hyperstimulation syndrome (OHSS). Since our previous preliminary study showed that a novel progestin-primed ovarian stimulation (PPOS) protocol blocked the luteinising hormone (LH) surge during IVF and achieved a higher pregnancy rate with a lower incidence of OHSS, we designed a prospective randomised controlled trial to compare the efficacy and safety of this PPOS protocol with the flexible gonadotropin-releasing hormone (GnRH) antagonist protocol in patients with PCOS who are undergoing IVF procedures. Methods and analysis Patients with PCOS will be randomised to one of two controlled ovarian stimulation regimens—GnRH antagonist or PPOS—using a computer-generated random number. A freeze-all strategy using embryo vitrification techniques and frozen embryo transfer will be performed in both groups. The primary outcome is the live-birth rate per transfer. Secondary outcomes include the incidence of premature LH surges, the duration and total dose of human menopausal gonadotropin stimulation, the number of oocytes retrieved, the incidence of moderate or severe OHSS, the number of embryos available for transfer, implantation rates, clinical pregnancy rates, pregnancy loss rates, ectopic pregnancy rates, pregnancy and neonatal complications, and congenital anomalies. The necessary sample size for this trial was estimated as 392 participants, with 196 participants in each group. Intention-to-treat analysis was used in processing our experimental data. Ethics and dissemination This study was approved by the Institutional Review Board of the hospital (2016-133-T82). The trial will be conducted according to the principles of the World Medical Association’s Declaration of Helsinki and in accordance with Good Clinical Practice standards. The findings of this trial will be published in a peer-reviewed journal. Trial registration number ChiCTRIPR16009580.

Ovarian hyperstimulation syndrome

Live birth

10.1136/bmjopen-2020-038153

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Whole genome and RNA sequencing reveal the distinct genomic landscape of acral melanoma.

Journal of Clinical Oncology (2017)

Yan Kong Zhihong Chi Lu Si Xinan Sheng Chuanliang Cui

9589 Background: Acral melanoma is a common subtype of melanoma in Asians with extremely poor prognosis, and therapy strategy has not been clearly established for acral melanoma. The aim of this study is to perform genomic and RNA profiling of acral melanoma to obtain the comprehensive genomic view of this subtype of melanoma. Methods: Genomic DNA was extracted with Qiagen DNeasy Blood or Tissue Kit . DNA libraries were prepared using a CancerPROTM-P88 BOX library Prep kit and sequencing was performed using the Illumina HiSeq X10. RNA was isolated with Qiagen RNeasy mini-spin column. cDNA was synthesized from total RNA using the SuperScript III first-strand synthesis system . RNA libraries were prepared using the NEBNext Ultra II Directional RNA Library Prep Kit and sequencing was performed using the Illumina HiSeq X10. Results: To obtain a comprehensive genomic and functional genomic view of acral melanoma, we sequenced the genomes of 14 acral melanoma and transcriptomes of 11 of these melanoma samples. We found a new mutation in the V28 codon of BRAF in three patients. Furthermore, we identified recurrent non-synonymous single nucleotide variants in previously described oncogene NRAS, as well as in genes encoding keratin associated proteins (KRTAP4-7, KRTAP4-5) and mucin (MUC2, MUC21). Notably, a recurrent noncoding hotspot mutation was discovered in 4 of 11 cases. By analyzing the RNA sequencing data, we found significant divergence on transcriptome between patients with or without ulcer. In total, we identified 201 genes were significantly up-regulated and 386 genes significantly down-regulated in acral melanoma patients with ulcer. Differentially expressed genes were enriched in pathways associated with cancers, melanogenesis, cell death signaling, skin diseases, etc. Conclusions: Our study reveals potentially different driver mutations and distinct transcriptome in acral melanoma patients compared with cutaneous melanoma patients and sheds lights to the further personalized medicine for acral melanoma patients.

genomic DNA

10.1200/jco.2017.35.15_suppl.9589

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Novel deoxyvasicinone and tetrahydro-beta-carboline hybrids as inhibitors of acetylcholinesterase and amyloid beta aggregation

Bioorganic & Medicinal Chemistry Letters (2020)

Hongtao Du Xinyu Jiang Meng Ma Huili Xu Shuang Liu

Amyloid beta

IC50

Amyloid (mycology)

BETA (programming language)

10.1016/j.bmcl.2020.127659

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Citations (13)

Construction linkage maps and identification of quantitative trait loci associated with important agronomic traits in purple-fleshed sweetpotato

ACTA AGRONOMICA SINICA (2021)

Meng Ma Hui Yan Runfei Gao Meng Kou Wei Tang

Ideal agronomic traits are the important objectives in sweetpotato breeding, but the breeding methods are still lacking. We constructed linkage maps using a mapping population of 274 individuals derived from a cross between the female parent Xuzishu 8 (a purple-fleshed cultivar with many branches, medium vine, and high yield) and the male parent Meiguohong (a white-fleshed cultivar with few branches, long vine, and medium yield) by simple sequence repeats (SSR) markers in this study. The female parent map contained 24 linkage groups, and covered 1325.8 cM with an average marker interval of 9.2 cM. The male parent map contained 21 linkage groups, and covered 1088.6 cM with an average marker interval of 8.2 cM. The maps could increase the density of existing genetic maps. Using the composite interval mapping, we analyzed five important agronomic traits, including branch number, vine diameter, longest vine length, petiole length, and internode length in sweetpotato, thus identified one QTL related to branch number explaining the phenotypic variance of 53.2%, one QTL related to internode diameter explaining the phenotypic variance of 16.7%, two QTLs related to longest vine length explaining the phenotypic variance of 9.5% and 13.7%, two QTLs related to petiole length explaining the phenotypic variance of 8.8% and 11.3%, and five QTLs related to internode length explaining the phenotypic variance of 9.6%–28.1%. The QTLs can be used to develop molecular markers and assist the screening of plants with ideal agronomic traits at early seedling stage, thus improved the efficiency of field selection.

Petiole (insect anatomy)

Linkage (software)

Vine

Genetic linkage

Trait

Phenotypic trait

10.3724/sp.j.1006.2021.04271

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Citations (1)