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  • 1
    Online Resource
    Online Resource
    Karyopherin α deficiency contributes to human preimplantation embryo arrest
    American Society for Clinical Investigation ; 2023
    In:  Journal of Clinical Investigation Vol. 133, No. 2 ( 2023-1-17)
    Details
    In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 133, No. 2 ( 2023-1-17)
    Type of Medium: Online Resource
    ISSN: 1558-8238
    URL: Article
    URL: Article
    DOI: 10.1172/JCI159951
    DOI: 10.1172/JCI159951DS1
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2023
    detail.hit.zdb_id: 2018375-6
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  • 2
    Online Resource
    Online Resource
    FBXO43 variants in patients with female infertility characterized by early embryonic arrest
    Oxford University Press (OUP) ; 2021
    In:  Human Reproduction Vol. 36, No. 8 ( 2021-07-19), p. 2392-2402
    Details
    In: Human Reproduction, Oxford University Press (OUP), Vol. 36, No. 8 ( 2021-07-19), p. 2392-2402
    Abstract: Can any new genetic factors responsible for early embryonic arrest in infertile patients be identified, together with the mechanism of pathogenic variants? SUMMARY ANSWER We identified three homozygous variants in the F-box protein 43 gene (FBXO43) in infertile patients and studies on the effects of the variants in HEK293T cells and mouse oocytes provided evidence for a causal relation between FBXO43 and female infertility. WHAT IS KNOWN ALREADY FBXO43, an inhibitor of the anaphase-promoting complex/cyclosome, mediates Metaphase II arrest as a component of the cytostatic factor in oocytes. Both male and female Fbxo43 knockout mice are viable but sterile. FBXO43, therefore, appears to be an essential component of the mammalian cell-cycle machinery that regulates both male and female meiosis. Until now, only one article has reported a homozygous FBXO43 variant associated with teratozoospermia, but the causal relationship was not established with functional evidence. STUDY DESIGN, SIZE, DURATION Whole-exome sequencing (WES) and homozygosity mapping were performed in 24 probands from consanguineous families who suffered from early embryonic arrest, and two different homozygous variants in FBXO43 were identified in two independent families. WES data from a further 950 infertile women with early embryonic arrest were screened for homozygous and compound heterozygous variants in FBXO43, and a third individual with an additional homozygous variant in FBXO43 was identified. The infertile patients presenting with early embryonic arrest were recruited from August 2016 to May 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS The women diagnosed with primary infertility were recruited from the reproduction centers of local hospitals. Genomic DNA samples from the affected individuals, their family members, and healthy controls were extracted from peripheral blood. The FBXO43 variants were identified using WES, homozygosity mapping, in silico analysis, and variant screening. All of the variants were confirmed by Sanger sequencing, and the effects of the variants were investigated in human embryonic kidney (HEK) 293T cells by western blotting and in mouse oocytes by complementary RNA injection. MAIN RESULTS AND THE ROLE OF CHANCE We identified three homozygous variants in FBXO43 (NM_001029860.4)—namely, c.1490_1497dup (p.(Glu500Serfs*2)), c.1747C & gt;T (p.(Gln583*)), and c.154delG (p.(Asp52Thrfs*30))—in three independent families. All of the homozygous variants reduced the protein level of FBXO43 and reduced the level of its downstream target Cyclin B1 in HEK293T cells. In addition, the variants reduced the ability of exogenous human FBXO43 to rescue the parthenogenetic activation phenotype in Fbxo43 knockdown mouse oocytes. LIMITATIONS, REASONS FOR CAUTION Owing to the lack of in vivo data from the oocytes of patients, the exact molecular mechanism remains unknown and should be further investigated using knock out or knock in mice. WIDER IMPLICATIONS OF THE FINDINGS Our study has identified three pathogenic variants in FBXO43 that are involved in human early embryonic arrest. These findings contribute to our understanding of the role of FBXO43 in human early embryonic development and provide a new genetic marker for female infertility. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Key Research and Development Program of China (2018YFC1003800, 2017YFC1001500, and 2016YFC1000600), the National Natural Science Foundation of China (81725006, 81822019, 81771581, 81971450, 81971382, and 82001552), the project supported by the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), the Project of the Shanghai Municipal Science and Technology Commission (19JC1411001), the Natural Science Foundation of Shanghai (19ZR1444500), the Shuguang Program of the Shanghai Education Development Foundation and the Shanghai Municipal Education Commission (18SG03), the Foundation of the Shanghai Health and Family Planning Commission (20154Y0162), the Capacity Building Planning Program for Shanghai Women and Children’s Health Service, and the collaborative innovation center project construction for Shanghai Women and Children’s Health. None of the authors have any competing interests. TRIAL REGISTRATION NUMBER N/A
    Type of Medium: Online Resource
    ISSN: 0268-1161 , 1460-2350
    URL: Article
    DOI: 10.1093/humrep/deab131
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1484864-8
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  • 3
    Online Resource
    Online Resource
    ALK actionable mutations (muts) within cancer types and their responses to crizotinib (CZ).
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e14739-e14739
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e14739-e14739
    Abstract: e14739 Background: CZ was recommended by NCCN for ALK-rearranged metastasis NSCLC as first-line therapy. Knowledge on the occurrence of ALK actionable muts within cancer types and the responses of ALK fusion types to CZ could better guide the treatment of ALK-rearranged pts. Methods: 772 ALK-mutated pts (with any ALK muts) detected by tissue/ctDNA NGS in our institution from Oct. 2016 to Oct. 2018 were included. ALK + (with any ALK actionable muts) and EGFR - (with no EGFR actionable muts) pts treated with CZ at any line were included for survival analysis. Progress-free survival (PFS) was estimated using Kaplan-Meier method and compared using log-rank test. Results: 339 ALK + pts were analyzed, including 331 lung cancer (LC: 265 NSCLC; 1 SCLC; 65 Unknown histology), 3 brain cancer (BC), 1 colon cancer (CC), 3 cancer of unknown primary (CUP), and 1 with no clinical information. The most common ALK mut was fusion (331/339), including 315 EML4-ALK, 5 KIF5B-ALK, 4 STRN-ALK, 1 ACSL3-ALK, 1 CLIP4-ALK, 1 DCTN1-ALK, 1 HIP1-ALK, 1 SRBD1-ALK, 1 TFG-ALK, and 1 ZFP161-ALK. Fusion position was known for 308 EML4-ALK, including 132 V1, 108 V3, 32 V2, 19 V5’, and 17 other variants (Vx). Except for 2 V1 with CUP, 1 KIF5B-ALK with CUP, 1 Vx with CC, and 1 EML4-ALK (no variant information) with BC, all the other fusions occurred in LC. ALK F1174L was detected only in 2 pts, both of whom had BC, specifically neuroblastoma. CZ was given to 76 ALK + EGFR - pts (mPFS: 9 mo, 95% CI: 8 – 13), including 70 EML4-ALK and 6 non- EML4-ALK (mPFS: 10 vs. 9 mo, p = 0.7). Though non-significant, V1 (n = 32) on average had a longer mPFS than V3 (n = 28) (12 vs. 8 mo, p = 0.3), which may partially be explained by the younger age at diagnosis of V1 than V3 (48 vs. 53, p = 0.005). 1 TFG-ALK, 1 CLIP4-ALK, 1 DCTN1-ALK, 1 HIPI-ALK, 1 ZFP161-ALK, and 1 KIF5B-ALK achieved a PFS of 3, 4, 8, 9, 13, and 19 mo on CZ, respectively. 1 SCLC (V3) received CZ at first-line progressed after 6 mo. Conclusions: Though majority of the ALK actionable muts were commonly found in LC, some alterations may occur more often in other cancer types, such as F1174L in neuroblastoma. Some fusion types (e.g. TFG-ALK) may benefit less from CZ than others (e.g. KIF5B-ALK). Limited by relative small sample size, these results merit further validation and investigation.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.e14739
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    Bi‐allelic pathogenic variants in PABPC1L cause oocyte maturation arrest and female infertility
    EMBO ; 2023
    In:  EMBO Molecular Medicine Vol. 15, No. 6 ( 2023-06-07)
    Details
    In: EMBO Molecular Medicine, EMBO, Vol. 15, No. 6 ( 2023-06-07)
    Abstract: image Seven rare variants in PABPC1L were identified in five infertile females mainly characterized by oocyte maturation arrest followed recessive inheritance pattern. In vitro and in vivo functional studies confirmed the destructive effects and pathogenicity of PABPC1L variants. In vitro , truncating variants resulted in truncated proteins, reduced protein abundance, and altered cytoplasmic localization. Missense variants impaired the ability of RNA‐binding and mRNA translational activation of PABPC1L protein. In vivo , three strains of Pabpc1l KI mice corresponding to patient‐derived variants showed early embryonic arrest and female infertility. Mos‐MAPK pathway was abnormally activated in KI zygotes and the phenotype of KI mice was mimicked by injecting MOS mRNA into the zygotes.
    Type of Medium: Online Resource
    ISSN: 1757-4676 , 1757-4684
    URL: Article
    DOI: 10.15252/emmm.202217177
    Language: English
    Publisher: EMBO
    Publication Date: 2023
    detail.hit.zdb_id: 2485479-7
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  • 5
    Online Resource
    Online Resource
    Protective Effects of Chinese Traditional Medicine Buyang Huanwu Decoction on Myocardial Injury
    Hindawi Limited ; 2011
    In:  Evidence-Based Complementary and Alternative Medicine Vol. 2011 ( 2011), p. 1-7
    Details
    In: Evidence-Based Complementary and Alternative Medicine, Hindawi Limited, Vol. 2011 ( 2011), p. 1-7
    Abstract: Many clinical studies have reported that Buyang Huanwu Decoction (BYHWD) has a protective effect on ischemic heart disease (IHD). In the present study, the protective effect of BYHWD on myocardial ischemia was investigated. Different doses of BYHWD and Compound Danshen Dropping Pills (CDDP) were lavaged to rats, respectively, isoproterenol (ISO) was intraperitoneally injected in to all animals to induce myocardial ischemia except the control group. Electrocardiogram (ECG) of each animal was recorded; activities of lactate dehydrogenase (LDH), creatine kinase (CK) and aspartate aminotransferase (AST) in serum were detected. As the results of ECG showed, pre-treatment with BYHWD inhibited ischemic myocardial injury, and the activities of LDH, CK and AST were lower than those in the myocardial ischemia model group, which suggests that BYHWD rescues the myocardium from ischemia status. To research the potential mechanism, the level of nitric oxide (NO), nitric oxide syntheses (NOS) and inducible nitric oxide syntheses (iNOS), the expression of iNOS and ligand of cluster of differentiation 40 (CD40L) were detected. The results revealed that BYHWD significantly decreased the level of NO, NOS and iNOS in serum. Moreover, BYHWD decreased the expression of iNOS and CD40L in myocardial tissues. These results indicate that the protective effect of BYHWD on myocardial ischemia and mechanism are associated with inhibition of iNOS and CD40L expression.
    Type of Medium: Online Resource
    ISSN: 1741-427X , 1741-4288
    URL: Article
    DOI: 10.1093/ecam/nep013
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2011
    detail.hit.zdb_id: 2148302-4
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  • 6
    Online Resource
    Online Resource
    Participation of lipid transport and fatty acid metabolism in valproate sodium-induced hepatotoxicity in HepG2 cells
    Elsevier BV ; 2010
    In:  Toxicology in Vitro Vol. 24, No. 4 ( 2010-6), p. 1086-1091
    Details
    In: Toxicology in Vitro, Elsevier BV, Vol. 24, No. 4 ( 2010-6), p. 1086-1091
    Type of Medium: Online Resource
    ISSN: 0887-2333
    URL: Article
    DOI: 10.1016/j.tiv.2010.03.014
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2010
    detail.hit.zdb_id: 1501079-X
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  • 7
    Online Resource
    Online Resource
    Homozygous mutations in REC114 cause female infertility characterised by multiple pronuclei formation and early embryonic arrest
    BMJ ; 2020
    In:  Journal of Medical Genetics Vol. 57, No. 3 ( 2020-03), p. 187-194
    Details
    In: Journal of Medical Genetics, BMJ, Vol. 57, No. 3 ( 2020-03), p. 187-194
    Abstract: Abnormal pronuclear formation during fertilisation and subsequent early embryonic arrest results in female infertility. In recent years, with the prevalence of assisted reproductive technology, a few genes have been identified that are involved in female infertility caused by abnormalities in oocyte development, fertilisation and embryonic development. However, the genetic factors responsible for multiple pronuclei formation during fertilisation and early embryonic arrest remain largely unknown. Objective We aim to identify genetic factors responsible for multiple pronuclei formation during fertilisation or early embryonic arrest. Methods Whole-exome sequencing was performed in a cohort of 580 patients with abnormal fertilisation and early embryonic arrest. Effects of mutations were investigated in HEK293T cells by western blotting and immunoprecipitation, as well as minigene assay. Results We identified a novel homozygous missense mutation (c.397T 〉 G, p.C133G) and a novel homozygous donor splice-site mutation (c.546+5G 〉 A) in the meiotic gene REC114 . REC114 is involved in the formation of double strand breaks (DSBs), which initiate homologous chromosome recombination. We demonstrated that the splice-site mutation affected the normal alternative splicing of REC114 , while the missense mutation reduced the protein level of REC114 in vitro and resulted in the loss of its function to protect its partner protein MEI4 from degradation. Conclusions Our study has identified mutations in REC114 responsible for human multiple pronuclei formation and early embryonic arrest, and these findings expand our knowledge of genetic factors that are responsible for normal human female meiosis and fertility.
    Type of Medium: Online Resource
    ISSN: 0022-2593 , 1468-6244
    URL: Article
    DOI: 10.1136/jmedgenet-2019-106379
    RVK:
    WA 15000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 2009590-9
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Characteristics of different asthma phenotypes associated with cough: a prospective, multicenter survey in China
    Springer Science and Business Media LLC ; 2022
    In:  Respiratory Research Vol. 23, No. 1 ( 2022-09-12)
    Details
    In: Respiratory Research, Springer Science and Business Media LLC, Vol. 23, No. 1 ( 2022-09-12)
    Abstract: Asthma is a heterogeneous disease with variable symptoms, which presents with cough either as the sole or predominant symptom with or without wheezing. We compared the clinical and pathophysiological characteristics of cough predominant asthma (CPA), cough variant asthma (CVA) and classic asthma (CA) in order to determine any differential phenotypic traits. Methods In 20 clinics across China, a total of 2088 patients were finally recruited, including 327 CVA, 1041 CPA and 720 CA patients. We recorded cough and wheezing visual analogue scale, Leicester cough questionnaire (LCQ) and asthma control test scores. Fractional exhaled nitric oxide (FeNO), induced sputum cell counts, and capsaicin cough challenge were also measured and compared. Results CPA patients more frequently presented with cough as the initial symptom, and laryngeal symptoms (p  〈  0.001), had less symptoms related with rhinitis/sinusitis and gastroesophageal reflux (p  〈  0.05) than CA patients. Comorbidities including rhinitis and gastroesophageal reflux were similar, while the proportion of COPD and bronchiectasis was higher in CA patients. There were no differences in FeNO levels, sputum eosinophil and neutrophil counts, FEV1 (%pred) decreased from CVA to CPA to CA patients (p  〈  0.001). Cough sensitivity was higher in CVA and CPA compared to CA (p  〈  0.001), and was positively correlated with LCQ scores. Conclusions CVA, CPA and CA can be distinguished by the presence of laryngeal symptoms, cough sensitivity and airflow obstruction. Asthma-associated chronic cough was not associated with airway inflammation or comorbidities in our cohort. Trial registration The Chinese Clinical Trial Registration Center, ChiCTR-POC-17011646, 13 June 2017
    Type of Medium: Online Resource
    ISSN: 1465-993X
    URL: Article
    DOI: 10.1186/s12931-022-02104-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2041675-1
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  • 9
    Online Resource
    Online Resource
    Novel biallelic mutations in MEI1: expanding the phenotypic spectrum to human embryonic arrest and recurrent implantation failure
    Oxford University Press (OUP) ; 2021
    In:  Human Reproduction Vol. 36, No. 8 ( 2021-07-19), p. 2371-2381
    Details
    In: Human Reproduction, Oxford University Press (OUP), Vol. 36, No. 8 ( 2021-07-19), p. 2371-2381
    Abstract: Are any novel mutations and corresponding new phenotypes, other than recurrent hydatidiform moles, seen in patients with MEI1 mutations? SUMMARY ANSWER We identified several novel mutations in MEI1 causing new phenotypes of early embryonic arrest and recurrent implantation failure. WHAT IS KNOWN ALREADY It has been reported that biallelic mutations in MEI1, encoding meiotic double-stranded break formation protein 1, cause azoospermia in men and recurrent hydatidiform moles in women. STUDY DESIGN, SIZE, DURATION We first focused on a pedigree in which two sisters were diagnosed with recurrent hydatidiform moles in December 2018. After genetic analysis, two novel mutations in MEI1 were identified. We then expanded the mutational screening to patients with the phenotype of embryonic arrest, recurrent implantation failure, and recurrent pregnancy loss, and found another three novel MEI1 mutations in seven new patients from six families recruited from December 2018 to May 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS Nine primary infertility patients were recruited from the reproduction centers in local hospitals. Genomic DNA from the affected individuals, their family members, and healthy controls was extracted from peripheral blood. The MEI1 mutations were screened using whole-exome sequencing and were confirmed by the Sanger sequencing. In silico analysis of mutations was performed with Sorting Intolerant From Tolerant (SIFT) and Protein Variation Effect Analyzer (PROVEAN). The influence of the MEI1 mutations was determined by western blotting and minigene analysis in vitro. MAIN RESULTS AND THE ROLE OF CHANCE In this study, we identified five novel mutations in MEI1 in nine patients from seven independent families. Apart from recurrent hydatidiform moles, biallelic mutations in MEI1 were also associated with early embryonic arrest and recurrent implantation failure. In addition, we demonstrated that protein-truncating and missense mutations reduced the protein level of MEI1, while the splicing mutations caused abnormal alternative splicing of MEI1. LIMITATIONS, REASONS FOR CAUTION Owing to the lack of in vivo data from the oocytes of the patients, the exact molecular mechanism(s) involved in the phenotypes remains unknown and should be further investigated using knock-out or knock-in mice. WIDER IMPLICATIONS OF THE FINDINGS Our results not only reveal the important role of MEI1 in human oocyte meiosis and early embryonic development, but also extend the phenotypic and mutational spectrum of MEI1 and provide new diagnostic markers for genetic counseling of clinical patients. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Key Research and Development Program of China (2018YFC1003800, 2017YFC1001500, and 2016YFC1000600), the National Natural Science Foundation of China (81725006, 81822019, 81771581, 81971450, and 81971382), the project supported by the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), the Project of the Shanghai Municipal Science and Technology Commission (19JC1411001), the Natural Science Foundation of Shanghai (19ZR1444500), the Shuguang Program of the Shanghai Education Development Foundation and the Shanghai Municipal Education Commission (18SG03), the Shanghai Health and Family Planning Commission Foundation (20154Y0162), the Strategic Collaborative Research Program of the Ferring Institute of Reproductive Medicine, Ferring Pharmaceuticals and the Chinese Academy of Sciences (FIRMC200507) and the Chongqing Key Laboratory of Human Embryo Engineering (2020KFKT008). No competing interests are declared. TRIAL REGISTRATION NUMBER N/A.
    Type of Medium: Online Resource
    ISSN: 0268-1161 , 1460-2350
    URL: Article
    DOI: 10.1093/humrep/deab118
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1484864-8
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  • 10
    Online Resource
    Online Resource
    Post‐hospitalization rehabilitation alleviates long‐term immune repertoire alteration in COVID‐19 convalescent patients
    Wiley ; 2023
    In:  Cell Proliferation Vol. 56, No. 10 ( 2023-10)
    Details
    In: Cell Proliferation, Wiley, Vol. 56, No. 10 ( 2023-10)
    Abstract: The global pandemic of Coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is an once‐in‐a‐lifetime public health crisis. Among hundreds of millions of people who have contracted with or are being infected with COVID‐19, the question of whether COVID‐19 infection may cause long‐term health concern, even being completely recovered from the disease clinically, especially immune system damage, needs to be addressed. Here, we performed seven‐chain adaptome immune repertoire analyses on convalescent COVID‐19 patients who have been discharged from hospitals for at least 6 months. Surprisingly, we discovered lymphopenia, reduced number of unique CDR3s, and reduced diversity of the TCR/BCR immune repertoire in convalescent COVID‐19 patients. In addition, the BCR repertoire appears to be activated, which is consistent with the protective antibody titres, but serological experiments reveal significantly lower IL‐4 and IL‐7 levels in convalescent patients compared to those in healthy controls. Finally, in comparison with convalescent patients who did not receive post‐hospitalization rehabilitation, the convalescent patients who received post‐hospitalization rehabilitation had attenuated immune repertoire abnormality, almost back to the level of healthy control, despite no detectable clinic demographic difference. Overall, we report the potential long‐term immunological impairment for COVID‐19 infection, and correction of this impairment via post‐hospitalization rehabilitation may offer a new prospect for COVID‐19 recovery strategy.
    Type of Medium: Online Resource
    ISSN: 0960-7722 , 1365-2184
    URL: Issue
    URL: Article
    DOI: 10.1111/cpr.v56.10
    DOI: 10.1111/cpr.13450
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2019986-7
    SSG: 12
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