Publications by authors named "Yunxia Cao"

175 Publications

Analysis of copy number variations of WNT4 gene in a Chinese population with Müllerian anomalies.

Orphanet J Rare Dis 2021 Jun 7;16(1):258. Epub 2021 Jun 7.

Graduate School of Peking Union Medical College, Beijing, China.

Background: To investigate the genetic contribution of copy number variations (CNVs) in Wingless-type MMTV integration site family, member 4 (WNT4), in a Chinese population with Müllerian anomalies (MA), copy number analysis of WNT4 by Multiplex ligation-dependent probe amplification (MLPA) was performed on 248 female patients. Some studies have shown that heterozygous missense mutation of WNT4 can lead to MA. However, few studies on the relationship between WNT4 CNVs and MA have been performed.

Results: Among the 248 Chinese women affected by MA in this study, heterozygous deletion of WNT4 was detected in a single patient.

Conclusions: MLPA identified one heterozygous deletion in WNT4 in a single female patient among 248 Chinese women affected by MA. This study firstly reports CNVs of WNT4 in a large sample of MA patients from the Chinese population, which suggests that CNVs of WNT4 cannot be excluded in the occurrence of MA. This provides a genetic basis for precise treatment in the future.
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http://dx.doi.org/10.1186/s13023-021-01888-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183036PMC
June 2021

Establishment of an induced pluripotent stem cell line from a patient with primary ciliary dyskinesia carrying biallelic mutations in CCNO.

Stem Cell Res 2021 May 29;53:102372. Epub 2021 Apr 29.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, Anhui, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, No 81 Meishan Road, Hefei 230032, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei 230032, Anhui, China. Electronic address:

Primary ciliary dyskinesia (PCD) is an autosomal recessive hereditary disorder affecting motile cilia structure and function, which leads to respiratory diseases and infertility. Here, an induced pluripotent stem cell (iPSC) line of PCD was generated from peripheral blood mononuclear cells of a female patient carrying biallelic mutations in Cyclin O (CCNO) gene. Reprogramming was performed with the non-integrated episomal vectors. The obtained transgene-free iPSCs had normal karyotypes, expressed pluripotency genes, and differentiated into three germ layers. This iPSC line could be a useful guide for studying the pathogenic mechanism, establishing a disease model of PCD, and screening potential therapeutic targets.
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http://dx.doi.org/10.1016/j.scr.2021.102372DOI Listing
May 2021

Identification of Serotonin as a Predictive Marker for Breast Cancer Patients.

Int J Gen Med 2021 19;14:1939-1948. Epub 2021 May 19.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People's Republic of China.

Purpose: Cumulative evidence has demonstrated that breast cancer was the most commonly diagnosed cancer in women. Despite growing evidence for a link between serotonin and tumorigenesis, research on the expression of serotoninergic systems in the human breast cancer cell and tissue has only rarely been reported.

Methods: First, immunofluorescence staining, ELISA and Western blotting were used to detect serotonin and melatoninergic systems in various breast cancer cell types. Then, serotonin expression was evaluated in the cultures of TPBC cell line BT-474 and TNBC cell line MDA-MB-231 using immunofluorescence assay. To further explore the diagnostic role of serotonin in breast cancer, serotonin expression was conducted in the TPBC and TNBC tumor sections by immunostaining analysis.

Results: Our results suggested that both human breast cancer cells and human breast epithelial cell line could synthesize serotonin and melatonin. Unlike melatonin, serotonin levels varied significantly between human breast cancer and breast epithelial cell line (<0.01). In addition, serotonin N-acetyltransferase (NAT) and acetylserotonin methyltransferase (ASMT), the key enzymes in the pathway of melatonin synthesis from serotonin, were also detectable. In agreement with these findings of human breast cancer cell and human breast epithelial cell line, serotonin expression was also much higher in triple-negative (PR-, ER-, HER-2) breast cancer (TNBC) and triple-positive breast cancer (TPBC) compared to para-carcinoma tissues (PCTs).

Conclusion: Here, we provided evidence that the human breast cancer cell (MCF-7, Bcap-37) and human breast epithelial cell (MCF-10A) could synthesize intrinsic serotonin and melatonin, and serotonin expression was higher in the breast cancer tissue compared with PCT. The findings suggested that serotonin might be used as a predictive marker for breast cancer patients.
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http://dx.doi.org/10.2147/IJGM.S310591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144847PMC
May 2021

Melatonin ameliorates ovarian dysfunction by regulating autophagy in PCOS via the PI3K-Akt pathway.

Reproduction 2021 Jun 7;162(1):73-82. Epub 2021 Jun 7.

Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

Emerging evidence has demonstrated that melatonin (MT) plays a crucial role in regulating mammalian reproductive functions. It has been reported that MT has a protective effect on polycystic ovary syndrome (PCOS). However, the protective mechanisms of MT remain poorly understood. This study aims to explore the effect of MT on ovarian function in PCOS and to elucidate the relevant molecular mechanisms in vivo and in vitro. We first analysed MT expression levels in the follicular fluid of PCOS patients. A significant reduction in MT expression levels was noted in PCOS patients. Intriguingly, reduced MT levels correlated with serum testosterone and inflammatory cytokine levels in follicular fluid. Moreover, we confirmed the protective function of MT through regulating autophagy in a DHEA-induced PCOS rat model. Autophagy was activated in the ovarian tissue of the PCOS rat model, whereas additional MT inhibited autophagy by increasing PI3K--Akt pathway expression. In addition, serum-free testosterone, inflammatory and apoptosis indexes were reduced after MT supplementation. Furthermore, we also found that MT suppressed autophagy and apoptosis by activating the PI3K-Akt pathway in the DHEA-exposed human granulosa cell line KGN. Our study showed that MT ameliorated ovarian dysfunction by regulating autophagy in DHEA-induced PCOS via the PI3K-Akt pathway, revealing a potential therapeutic drug target for PCOS.
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http://dx.doi.org/10.1530/REP-20-0643DOI Listing
June 2021

The Association Between Second-hand Smoke Exposure and Psychiatric Distress Among Naturally Pregnant Women and Pregnant Women After Assisted Reproductive Technology Treatment: a Birth Cohort Study.

Reprod Sci 2021 May 12. Epub 2021 May 12.

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.

Second-hand smoke (SHS) has been shown to be associated with psychiatric distress in pregnant women spontaneously conceived (SC), but this has never been investigated in pregnant women with assisted reproductive technology (ART) treatment. This study aimed to investigate and compare the associations of SHS with psychiatric distress among SC and ART pregnant women. Participants (1467 SC and 857 ART women) were from the sub-study of Chinese National Birth Cohort (CNBC) in Anhui Province. SHS was assessed by the self-reported questionnaire. The symptoms of depression, anxiety, stress, and poor sleep quality were assessed using CES-D, SAS, CPSS, and PSQI questionnaire. Multivariable linear regression was used to determine the association between SHS and psychiatric distress in each trimester. In SC women, SHS (yes or no) was associated with depression and anxiety symptoms in the 3rd trimester (β = 0.90, 95% CI 0.07-1.73 for depression and β = 1.21, 95% CI 0.39-2.04 for anxiety) and stress symptom and poor sleep quality in both the 2nd and 3rd trimesters (β = 0.85, 95% CI 0.20-1.49 in the 2nd trimester and β = 0.69, 95% CI 0.07-1.32 in the 3rd trimester for stress, and β = 1.32, 95% CI 0.68-1.96 in the 2nd trimester and β = 1.38, 95% CI 0.64-2.11 in the 3rd trimester for poor sleep quality). By contrast, in ART women, SHS was associated with depression and stress symptoms in the 1st trimester (β = 1.97, 95% CI 0.59-3.35 for depression and β = 1.18, 95% CI 0.24-2.12 for stress) and poor sleep quality throughout the pregnancy (β = 0.64, 95% CI 0.22-1.06 in the 1st trimester, β = 0.77, 95% CI 0.35-1.18 in the 2nd trimester, and β = 0.99, 95% CI 0.50-1.48 in the 3rd trimester, respectively). Our findings indicate a universal and detrimental effect of SHS on psychiatric health among both SC and ART pregnant women. However, the SHS impact may be more substantial at the early stage of pregnancy for ART women and at later stages for SC women. This implies the importance of reducing SHS exposure during pregnancy and the necessary to be aware of the difference in the effect of SHS on psychiatric distress between SC and ART women.
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http://dx.doi.org/10.1007/s43032-021-00602-6DOI Listing
May 2021

Non-invasive preimplantation genetic testing for putative mosaic blastocysts: a pilot study.

Hum Reprod 2021 Jun;36(7):2020-2034

Department of Obstetrics and Gynecology, Reproductive Medicine Center, the First Affiliated Hospital of Anhui Medical University, Anhui, China.

Study Question: What is the potential of applying non-invasive preimplantation genetic testing (niPGT) for chromosome abnormalities in blastocysts reported with a mosaic trophectoderm (TE) biopsy?

Summary Answer: niPGT of cell-free DNA in blastocyst culture medium exhibited a good diagnostic performance in putative mosaic blastocysts.

What Is Known Already: Advances in niPGT have demonstrated the potential reliability of cell-free DNA as a resource for genetic assessment, but information on mosaic embryos is scarce because the mosaicism may interfere with niPGT. In addition, the high incidence of mosaicism reported in the context of PGT and the viability of mosaic blastocysts raise questions about whether mosaicism really exists.

Study Design, Size, Duration: The study was performed between May 2020 and July 2020. First, clinical data collected by a single-center over a 6-year period on PGT for chromosome aneuploidies (PGT-A) or chromosomal structural rearrangements (PGT-SR) were analyzed. After confirming the reliability of niPGT, 41 blastocysts classified as mosaics by trophectoderm (TE) biopsy were re-cultured. The chromosomal copy number of the blastocyst embryo (BE, the gold standard), TE re-biopsy, and corresponding cell-free DNA in the culture medium was assessed.

Participants/materials, Setting, Methods: Data on patients enrolled for PGT at a single center from 2014 to 2019 were collected and the cycles with available putative mosaic blastocysts were evaluated. To verify the diagnostic validity of niPGT, eight aneuploid blastocysts were thawed and re-cultured for 14-18 h. The concordance of the niPGT diagnosis results and the whole blastocyst testing results was analyzed. Forty-one blastocysts reported as mosaics from 22 patients were included and re-cultured for 14-18 h. The genetic material of the BE, TE re-biopsy, and corresponding cell-free DNA in the culture medium was amplified using multiple annealing and looping-based amplification cycles. The karyotype data from niPGT and TE re-biopsy were compared with that from the whole blastocyst, and the efficiency of niPGT was assessed.

Main Results And The Role Of Chance: Data on 3738 blastocysts from 785 PGT-A or PGT-SR cycles of 677 patients were collected. According to the TE biopsy report, of the 3662 (98%) successfully amplified samples, 24 (0.6%) yielded no results, 849 (23.2%) were euploid, 2245 (61.3%) were aneuploid, and 544 (14.9%) were mosaic. Sixty patients without euploid blastocysts opted for a single mosaic blastocyst transfer, and 30 (50%) of them obtained a clinical pregnancy. With the BE chromosome copy number as the gold standard, niPGT and TE re-biopsy showed reliable detection ability and diagnostic efficiency in eight putative aneuploid blastocysts. Of the 41 putative mosaic blastocysts re-cultured and re-tested, 35 (85.4%) showed euploid BE results. All but two of the blastocysts previously diagnosed with segmental chromosomal mosaic were actually euploid. In addition, all blastocysts previously classified as low degree (20-50%) mosaics were identified as euploid by BE PGT, whereas four of the six putative high degree (50-80%) mosaic blastocysts showed chromosomal abnormalities. The raw concordance rates of spent culture medium (SCM) and TE re-biopsies compared with BE were 74.4% and 82%, respectively, in terms of overall ploidy and 96.2% and 97.6%, respectively, per single chromosome when considering all degree mosaic results as true positives. However, when we set a mosaicism identification threshold of 50%, the concordance rates of SCM and TE re-biopsies compared with BE were 87.2% and 85% at the overall ploidy level and 98.8% and 98.3% at the chromosomal level, respectively. At the full ploidy level, the sensitivity and false negative rates for niPGT were 100% and 0, respectively. After adjustment of the threshold for mosaicism, the specificity of niPGT increased from 69.7% to 84.8% in terms of overall ploidy and from 96.1% to 98.9% at the chromosomal level.

Limitations, Reasons For Caution: The primary limitation of this study is the small sample size, which decreases the strength of our conclusions. If possible, identifying the clinical outcome of niPGT on reassessed mosaic blastocysts would be further progress in this field.

Wider Implications Of The Findings: This study is the first to explore the practicability of niPGT in diagnostic reassessment of putative mosaicism. The present study provides a novel opportunity for patients with only mosaic blastocysts and no euploid blastocysts, regardless of the technical or biological basis of mosaicism. Employing niPGT after 14-18 h of re-culturing might be a superior option for the best use of blastocysts because of its minimally invasive nature.

Study Funding/competing Interest(s): This work was supported by grants from National Key Technology Research and Development Program of China (No. 2017YFC1002004), the Central Guiding the Science and Technology Development of the Local (2018080802D0081) and College Natural Science Project of Anhui Province (KJ2019A0287). There are no competing interests to declare.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deab080DOI Listing
June 2021

A homozygous missense mutation in TBPL2 is associated with oocyte maturation arrest and degeneration.

Clin Genet 2021 May 9. Epub 2021 May 9.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.

The genetic causes in most of patients with oocyte maturation arrest remain largely unknown. In this study, we identified a homozygous missense mutation (c.895T>C; p.C299R) in TBPL2 (TATA box binding protein like 2) in two infertile sisters with oocyte maturation arrest and degeneration from a consanguineous family by whole-exome sequencing. The TBPL2 mutation is rare and pathogenic, and impaired the transcription initiation function of the protein. Our results showed that TBPL2 mutation might be associated with female infertility due to oocyte maturation arrest and degeneration.
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http://dx.doi.org/10.1111/cge.13993DOI Listing
May 2021

Maternal heterozygous mutation in CHEK1 leads to mitotic arrest in human zygotes.

Protein Cell 2021 May 4. Epub 2021 May 4.

School of Medicine, Tsinghua University, Beijing, 100084, China.

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http://dx.doi.org/10.1007/s13238-021-00844-9DOI Listing
May 2021

Upregulated HMGB1 levels in maternal-fetal interface of patients with unexplained recurrent spontaneous abortion from different sources.

J Matern Fetal Neonatal Med 2021 May 4:1-8. Epub 2021 May 4.

Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

Objective: To investigate the expression and sources of high mobility group box 1 (HMGB1) protein in the maternal-fetal interface of patients with unexplained recurrent spontaneous abortion (URSA), and further to verify the role of HMGB1 in the etiology of URSA.

Methods: 55 women at early pregnancy with URSA and 55 women undergoing selective termination of normal early pregnancy as control were included. The abortion tissues including villi and decidua were collected. The expression of HMGB1, CD45, CK7, and vimentin in abortion tissues was detected, and the localization and sources of HMGB1 were analyzed.

Results: Infiltrating immune cells and expression of HMGB1 were significantly increased in villi and decidua in URSA group compared with those in the control group. In the URSA group, HMGB1 was colocalized with the CD45-labeled immune cells, and it was more obvious in decidua than in villi; in addition, HMGB1 was colocalized with the vimentin-labeled decidual stromal cells, but not with the CK7- labeled villous epithelial cells.

Conclusion: High expression of HMGB1 in the maternal-fetal interface in URSA patients was actively secreted by the infiltrating immune cells, and decidual stromal cells may passively release HMGB1 during necrosis.
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http://dx.doi.org/10.1080/14767058.2021.1918084DOI Listing
May 2021

Melatonin alleviates deoxynivalenol-induced apoptosis of human granulosa cells by reducing mutually accentuated FOXO1 and ER stress.

Biol Reprod 2021 Apr 28. Epub 2021 Apr 28.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.

Deoxynivalenol (DON) is one of the most prevalent Fusarium mycotoxins which cause detrimental effects on human and animal reproductive systems by inducing oxidative stress. Increasing evidence has suggested the potential roles of melatonin in protecting granulosa cells from oxidative injury, but the underlying mechanisms remain largely elusive. Here, we demonstrated that suppression of FOXO1 and endoplasmic reticulum (ER) stress was engaged in melatonin-mediated protection against oxidative damage in human granulosa cells upon DON exposure in vitro. DON induced excess reactive oxygen species (ROS) accumulation, cells viability loss, reduced estradiol-17β and progesterone production in human granulosa cells, whereas melatonin ameliorated these phenotypes. Next, we found that the protective effect of melatonin against apoptosis was via reducing ER stress because inhibition of ER stress displayed similar protective effects during DON treatment. Moreover, melatonin provided no additional protection when ER stress was inhibited. We further found that FOXO1 is a pivotal downstream effector of melatonin and ER stress in regulating DON-induced apoptosis in human granulosa cells. Blocking of FOXO1 reduced DON-induced cells death and FOXO1 activation could be suppressed by melatonin or ER stress inhibitor. However, melatonin failed to further restore cells viability in the presence of FOXO1 inhibitor. Collectively, our results reveal a new mechanism of melatonin in protecting against DON-induced apoptosis and dysfunction by suppressing ER stress and FOXO1 in human granulosa cells.
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http://dx.doi.org/10.1093/biolre/ioab084DOI Listing
April 2021

Circular RNAs: Novel potential regulators in embryogenesis, female infertility, and pregnancy-related diseases.

J Cell Physiol 2021 Apr 20. Epub 2021 Apr 20.

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.

Circular RNAs (circRNAs) are endogenous noncoding RNAs with unique cyclic structures. Although they were previously considered as nonfunctional transcription byproducts, numerous studies have demonstrated that circRNAs regulate gene transcription and expression via different mechanisms. Reproductive health influences the quality of life and affects offspring propagation in women. CircRNAs have been found to modify pregnancy-related diseases, gynecologic cancers, polycystic ovary syndrome, aging, gamete, and embryo development. It's promising for circRNAs to be the novel diagnostic and therapeutic targets for multiple reproductive diseases. With the widespread application of assisted reproduction technology (ART), it has been revealed that circRNA identification contributes to estimating the quality of gametes and embryos, reflecting the success rate of ART. CRISPR-Cas9 gene editing technology has enabled the discovery of new roles of circRNAs. So far, the roles of circRNAs in the reproductive system remain poorly defined. In this review, we describe the classification and functions of circRNAs in embryogenesis and the female reproductive system diseases, revealing potential roles of circRNAs physiologically and pathologically. In so-doing, we provide ideas for developing circRNA-based therapeutic treatment and clinical application of various female reproductive system diseases.
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http://dx.doi.org/10.1002/jcp.30376DOI Listing
April 2021

Impaired myeloid-derived suppressor cells are associated with recurrent implantation failure: A case-control study.

J Reprod Immunol 2021 06 29;145:103316. Epub 2021 Mar 29.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei 230032, Anhui, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, No 81 Meishan Road, Hefei 230032, Anhui, China; Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, No 81 Meishan Road, Hefei 230032, Anhui, China. Electronic address:

Background: Studies have reported that myeloid-derived suppressor cells (MDSCs) contribute to maintain pregnancy. The aim of this case-control study was to test whether there is a dysregulation of peripheral MDSCs in recurrent implantation failure (RIF).

Methods: 26 RIF patients and 30 controls were recruited. Flow cytometry was applied to characterize polymorphonuclear (PMN)-MDSCs, monocytic-MDSCs (M-MDSCs), effector T cells (Teffs) and regulatory T cells (Tregs) in blood. ELISA was used to define MDSCs correlative cytokines and chemokines in serum from all patients.

Results: Compared with controls, RIF patients showed significant reductions of blood PMN-MDSCs, M-MDSCs, Tregs and NO production by PMN-MDSCs, whereas the expression of ζ chain on CD4T cell receptor (TCR) and CD8TCR displayed a remarkable upregulation in RIF patients. Moreover, RIF patients presented a lower concentration of serum chemokine (C-C motif) ligand (CCL) 5 and transforming growth factor (TGF)-β than those from controls. Furthermore, the level of TCR ζ chain on CD4 and CD8 Teffs was negatively correlated not only with the percentage of PMN-MDSCs, but also with the amount of NO produced by PMN-MDSCs. The frequency of PMN-MDSCs had positive correlations with the concentration of CCL5 and TGF-β.

Conclusions: This study indicated that the dysregulation of MDSCs might impair maternal-fetal immune balance thus resulting in RIF.
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http://dx.doi.org/10.1016/j.jri.2021.103316DOI Listing
June 2021

Sperm DNA integrity status is associated with DNA methylation signatures of imprinted genes and non-imprinted genes.

J Assist Reprod Genet 2021 Mar 30. Epub 2021 Mar 30.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China.

Purpose: To evaluate the association between the DNA methylation of specific genes and sperm DNA integrity status in human sperm samples.

Methods: A total of 166 semen samples were evaluated (86 controls and 80 cases with impaired sperm DNA integrity). We detected the methylation status of 257 CpG sites among two imprinted genes (H19 and SNRPN) and four non-imprinted genes related to male infertility (MTHFR, GSTM1, DAZL, and CREM) by using a targeted next-generation sequencing method.

Results: Differential methylation was found in 43 CpG sites of the promoters of the six candidate genes. H19, SNRPN, MTHFR, DAZL, GSTM1, and CREM contained 22, 12, 1, 4, 0, and 4 differentially methylated CpG sites (P<0.05), respectively. The imprinting genes were associated with relatively higher rates of differentially methylated CpG sites (28.21% in H19 and 41.38% in SNRPN) than the non-imprinting genes. One CpG site in H19 remained significant after performing strict Bonferroni correction.

Conclusion: In this study, we found that different site-specific DNA methylation signatures were correlated with sperm DNA integrity status. Further studies are needed to investigate the specific mechanisms leading to the epigenetic modifications.
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http://dx.doi.org/10.1007/s10815-021-02157-6DOI Listing
March 2021

Novel bi-allelic variants in DNAH2 cause severe asthenoteratozoospermia with multiple morphological abnormalities of the flagella.

Reprod Biomed Online 2021 May 22;42(5):963-972. Epub 2021 Jan 22.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei 230032, China. Electronic address:

Research Question: Multiple morphological abnormalities of the flagella (MMAF) is characterized by excessive immotile spermatozoa with severe flagellar abnormalities in the ejaculate. Previous studies have reported a heterogeneous genetic profile associated with MMAF. What other genetic variants might explain the cause of MMAF?

Design: Whole-exome sequencing was conducted in a cohort of 90 Chinese patients with MMAF. The pathogenicity of identified mutations was assessed through electron microscopy and immunofluorescent examinations.

Results: Three unrelated men with bi-allelic DNAH2 variants were identified. Sanger sequencing verified that the six novel variants originated from every parent. All these variants were located at the conserved domains of DNAH2 and predicted to be deleterious by bioinformatic tools. Haematoxylin and eosin staining and scanning electron microscopy revealed that spermatozoa harbouring DNAH2 variants displayed severely aberrant morphology mainly with absent and short flagella (≥78%). Moreover, transmission electron microscopy revealed the obvious absence of a central pair of microtubules and inner dynein arms in the spermatozoa with mutated DNAH2. Immunofluorescence data further validated these findings, showing reduced DNAH2 protein expression in the spermatozoa with DNAH2 variants, compared with normal spermatozoa. Intracytoplasmic sperm injection using spermatozoa from the three men with mutated DNAH2 resulted in blastocyst formation in all cases. Embryo transfer was carried out in two couples, both resulting in clinical pregnancy.

Conclusions: These experimental and clinical data suggest that bi-allelic DNAH2 variants might induce MMAF-associated asthenoteratozoospermia, which can be overcome through intracytoplasmic sperm injection. These findings contribute to the knowledge of the genetic landscape of asthenoteratozoospermia and clinical counselling of male infertility.
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http://dx.doi.org/10.1016/j.rbmo.2021.01.011DOI Listing
May 2021

No significant long-term complications from inadvertent exposure to gonadotropin-releasing hormone agonist during early pregnancy in mothers and offspring: a retrospective analysis.

Reprod Biol Endocrinol 2021 Mar 20;19(1):46. Epub 2021 Mar 20.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei, 230022, China.

Background: Administration of gonadotropin-releasing hormone agonist (GnRH-a) in the luteal phase is commonly used for pituitary suppression during in vitro fertilisation (IVF). There is an ineluctable risk of inadvertent exposure of spontaneous pregnancy to GnRH-a. However, little is known about the pregnancy complications and repregnancy outcomes of the affected women and the neurodevelopmental outcomes of the GnRH-a-exposed children.

Methods: Retrospective analysis was used to determine obstetric and repregnancy outcomes after natural conception in 114 women who naturally conceived while receiving GnRH-a during their early pregnancy over the past 17 years. The GnRH-a-exposed children were evaluated to determine their neonatal characteristics and long-term neurodevelopmental outcomes. The outcomes were compared to those of relevant age-matched control groups.

Results: Sixty-five women had 66 live births. The neonatal health outcomes and the incidence of maternal complications were similar in the GnRH-a-exposed and control groups. Thirty-one GnRH-a-exposed children, aged 2-8 years, were available for investigation of neurodevelopment. Except for one case of autism spectrum disorder, the full-scale intelligence quotient score was within the normal range and similar to that of the control group. Most mothers with successful pregnancies and about one-third of the women who had spontaneous abortions were subsequently able to conceive naturally again. IVF is recommended for repregnancy in women who have experienced ectopic pregnancies.

Conclusions: Accidental exposure to GnRH-a in early pregnancy might be safe. Reproductive treatment suggestions for repregnancy should be made with consideration of the outcomes of the previously GnRH-a-exposed spontaneous pregnancy.
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http://dx.doi.org/10.1186/s12958-021-00732-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980339PMC
March 2021

Comprehensive assessment of a clinic's experience of preimplantation genetic testing by a cumulative rate.

Taiwan J Obstet Gynecol 2021 Mar;60(2):225-231

Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China. Electronic address:

Objective: This study aimed to investigate the outcomes of patients who had preimplantation genetic testing for chromosomal structural rearrangement (PGT-SR) or for aneuploidy screening (PGT-A) with different indications.

Methods: This was a retrospective study at a single center. Pregnancy outcomes of all couples who had PGT from 2014 to 2018 were retrospectively analyzed, and the cumulative pregnancy rates (CPR) and the cumulative live birth/ongoing pregnancy rate (CLB/OPR) per patient with at least one transfer cycle were calculated.

Results: A total of 313 PGT-SR cycles of 255 patients, 22 PGT-sexing cycles of 20 patients, and 190 PGT-A cycles of 168 patients were performed during the period. In PGT-SR, the overall CPR and the CLB/OPR were 68.04% and 59.79%, respectively. In PGT-A, the CPR and CLB/OPR were 67.52% and 58.12%, respectively. We also found that the CPR (93.75%) and CLB/OPR (87.50%) were highest in patients for PGT-sexing with a diagnosis of Y chromosomal microdeletion. In addition, we discovered a significant trend that aneuploidy rate significantly increased with maternal age (p = 0.000) in PGT-A population. No significant difference was found in the mosaicism rate or clinical outcomes among the age groups. Similarly, the significance was absent in the PGT-SR population.

Conclusion: We reviewed the CPR and CLB/OPR for different indications since the 24-chromosome technique has been applied in the clinical setting for 4 years in our center. We hope that our results will provide some pointed guidance and a new perspective on outcomes for PGT in certain patients and clinicians.
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http://dx.doi.org/10.1016/j.tjog.2020.11.034DOI Listing
March 2021

Differences in the Gut Microbiome of Women With and Without Hypoactive Sexual Desire Disorder: Case Control Study.

J Med Internet Res 2021 02 25;23(2):e25342. Epub 2021 Feb 25.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

Background: The gut microbiome is receiving considerable attention as a potentially modifiable risk factor and therapeutic target for numerous mental and neurological diseases.

Objective: This study aimed to explore and assess the difference in the composition of gut microbes and fecal metabolites between women with hypoactive sexual desire disorder (HSDD) and healthy controls.

Methods: We employed an online recruitment method to enroll "hard-to-reach" HSDD populations. After a stringent diagnostic and exclusion process based on DSM-IV criteria, fecal samples collected from 24 women with HSDD and 22 age-matched, healthy controls underwent microbiome analysis using 16S ribosomal RNA gene sequencing and metabolome analysis using untargeted liquid chromatography-mass spectrometry.

Results: We found a decreased abundance of Ruminococcaceae and increased abundance of Bifidobacterium and Lactobacillus among women with HSDD. Fecal samples from women with HSDD showed significantly altered metabolic signatures compared with healthy controls. The abundance of Bifidobacterium, Lactobacillus, and several fecal metabolites correlated negatively with the sexual desire score, while the number of Ruminococcaceae correlated positively with the sexual desire score in all subjects.

Conclusions: Our analysis of fecal samples from women with HSDD and healthy controls identified significantly different gut microbes and metabolic signatures. These preliminary findings could be useful for developing strategies to adjust the level of human sexual desire by modifying gut microbiota.

Trial Registration: Chinese Clinical Trial Registry ChiCTR1800020321; http://www.chictr.org.cn/showproj.aspx?proj=34267.
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http://dx.doi.org/10.2196/25342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952237PMC
February 2021

Novel variants in DNAH9 lead to nonsyndromic severe asthenozoospermia.

Reprod Biol Endocrinol 2021 Feb 20;19(1):27. Epub 2021 Feb 20.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China.

Background: Asthenozoospermia is one of the most common causes of male infertility, and its genetic etiology is poorly understood. DNAH9 is a core component of outer dynein arms in cilia and flagellum. It was reported that variants of DNAH9 (OMIM: 603330) might cause primary ciliary dyskinesia (PCD). However, variants in DNAH9 lead to nonsyndromic severe asthenozoospermia have yet to be reported.

Methods: Whole exome sequencing (WES) was performed for two individuals with nonsyndromic severe asthenozoospermia from two non-consanguineous families, and Sanger sequencing was performed to verify the identified variants and parental origins. Sperm routine analysis, sperm vitality rate and sperm morphology analysis were performed according the WHO guidelines 2010 (5th edition). Transmission electron microscopy (TEM, TECNAI-10, 80 kV, Philips, Holland) was used to observe ultrastructures of sperm tail. Quantitative realtime-PCR and immunofluorescence staining were performed to detect the expression of DNAH9-mRNA and location of DNAH9-protein. Furthermore, assisted reproductive procedures were applied.

Results: By WES and Sanger sequencing, compound heterozygous DNAH9 (NM_001372.4) variants were identified in the two individuals with nonsyndromic severe asthenozoospermia (F1 II-1: c.302dupT, p.Leu101fs*47 / c.6956A > G, p.Asp2319Gly; F2 II-1: c.6294 T > A, p.Phe2098Leu / c.10571 T > A, p.Leu3524Gln). Progressive rates less than 1% with normal sperm morphology rates and normal vitality rates were found in both of the two subjects. No respiratory phenotypes, situs inversus or other malformations were found by detailed medical history, physical examination and lung CT scans etc. Moreover, the expression of DNAH9-mRNA was significantly decreased in sperm from F1 II-1. And expression of DNAH9 is lower in sperm tail by immunofluorescence staining in F1 II-1 compared with normal control. Notably, by intracytoplasmic sperm injection (ICSI), F1 II-1 and his partner successfully achieved clinical pregnancy.

Conclusions: We identified DNAH9 as a novel pathogenic gene for nonsyndromic severe asthenospermia, and ICSI can contribute to favorable pregnancy outcomes for these patients.
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http://dx.doi.org/10.1186/s12958-021-00709-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896388PMC
February 2021

Spontaneous unscarred uterine rupture in a twin pregnancy complicated by adenomyosis: A case report.

Medicine (Baltimore) 2021 Jan;100(3):e24048

Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University.

Introduction: Uterine rupture during pregnancy is a serious obstetric complication accompanied by a high incidence of maternal morbidity and mortality, and the presence of uterine scars is the main risk factor. In the present case, uterine rupture occurred in an unscarred uterus in a nonlaboring primigravida woman with adenomyosis and twin pregnancy in the third trimester.

Patient Concerns: In this case, the patient suspected to have a history of endometriosis have got twin pregnancies following intracytoplasmic sperm injection, and complained of recurrent lower abdominal pain from 16 weeks to 29 weeks of gestation.

Diagnosis: After exploratory laparotomy, the patient was diagnosed with uterine rupture and adenomyosis.

Interventions: The patient was first administered expectant treatment such as antibiotics, tocolytics, and fluid replacement therapy. Symptoms then appeared repeatedly and worsened, followed by eventual peritoneal irritation, and exploratory laparotomy was performed.

Outcomes: Two live female fetuses were extracted by cesarean section, and the uterine laceration was repaired. The mother recovered without any postoperative complications, and the babies were discharged after receiving one month of prematurity care without any postnatal complications.

Conclusion: Adenomyosis and the conception of twins may lead to uterine rupture. For pregnant women with a history of adenomyosis with multiple gestations, close monitoring for signs of uterine rupture is necessary. Single-embryo transfer and multifetal pregnancy reduction should be recommended for infertile patients with adenomyosis.
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http://dx.doi.org/10.1097/MD.0000000000024048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837926PMC
January 2021

A novel homozygous missense mutation of PMFBP1 causes acephalic spermatozoa syndrome.

J Assist Reprod Genet 2021 Apr 23;38(4):949-955. Epub 2021 Jan 23.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.

Purpose: To identify the pathogenic mutation in PMFBP1 leading to acephalic spermatozoa syndrome.

Methods: Sanger sequencing was used to screen for mutations in the known pathogenic genes SUN5 and PMFBP1 in a patient with acephalic spermatozoa syndrome. Western blotting and immunofluorescence were used to detect the expression and localization of PMFBP1 in sperm. At the same time, a PMFBP1 mutant was constructed, and the expression level of PMFBP1 protein was further verified by in vitro experiments.

Results: We identified a novel homozygous PMFBP1 missense mutation, c.301A>C (p.T101P), in an infertile male from a consanguineous family. Our results showed that the expression of PMFBP1 mutant protein was decreased obviously in sperm of the patient.

Conclusion: Our results showed that the novel homozygous missense mutation of PMFBP1 may be a cause of acephalic spermatozoa syndrome, which provided a basis for genetic counseling for the patient.
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http://dx.doi.org/10.1007/s10815-021-02075-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079480PMC
April 2021

Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility.

Am J Hum Genet 2021 02 19;108(2):309-323. Epub 2021 Jan 19.

Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China. Electronic address:

Asthenoteratozoospermia characterized by multiple morphological abnormalities of the flagella (MMAF) has been identified as a sub-type of male infertility. Recent progress has identified several MMAF-associated genes with an autosomal recessive inheritance in human affected individuals, but the etiology in approximately 40% of affected individuals remains unknown. Here, we conducted whole-exome sequencing (WES) and identified hemizygous missense variants in the X-linked CFAP47 in three unrelated Chinese individuals with MMAF. These three CFAP47 variants were absent in human control population genome databases and were predicted to be deleterious by multiple bioinformatic tools. CFAP47 encodes a cilia- and flagella-associated protein that is highly expressed in testis. Immunoblotting and immunofluorescence assays revealed obviously reduced levels of CFAP47 in spermatozoa from all three men harboring deleterious missense variants of CFAP47. Furthermore, WES data from an additional cohort of severe asthenoteratozoospermic men originating from Australia permitted the identification of a hemizygous Xp21.1 deletion removing the entire CFAP47 gene. All men harboring hemizygous CFAP47 variants displayed typical MMAF phenotypes. We also generated a Cfap47-mutated mouse model, the adult males of which were sterile and presented with reduced sperm motility and abnormal flagellar morphology and movement. However, fertility could be rescued by the use of intra-cytoplasmic sperm injections (ICSIs). Altogether, our experimental observations in humans and mice demonstrate that hemizygous mutations in CFAP47 can induce X-linked MMAF and asthenoteratozoospermia, for which good ICSI prognosis is suggested. These findings will provide important guidance for genetic counseling and assisted reproduction treatments.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895902PMC
February 2021

A novel homozygous mutation in the meiotic gene leading to male infertility due to non-obstructive azoospermia.

Am J Transl Res 2020 15;12(12):8185-8191. Epub 2020 Dec 15.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University No 218 Jixi Road, Hefei 230022, Anhui, China.

Non-obstructive azoospermia (NOA) is the most severe form of male infertility. Although some causes have been established, including genetic causes, the etiology in most cases remains idiopathic. Mutations in (OMIM: 602105), an important gene involved in meiosis, may be related to female infertility due to primary ovarian insufficiency (POI) and male NOA. Here, we report a novel homozygous stop-gain mutation of associated with NOA. Whole exome sequencing (WES) and bioinformatic analysis were performed in a patient with NOA from a consanguineous family (F1 II-1). A rare homozygous stop-gain mutation (c.1552C>T:p.Q518X) was observed in the patient, and his parents were heterozygous carriers, as verified by Sanger sequencing. Testicular biopsy and hematoxylin and eosin staining of testicular tissue suggested meiotic arrest (MA), and no sperm were observed. was detected in other 50 separate cases with same pathological results of MA using the same procedures, but only one heterozygous mutation was observed. Subsequent real-time quantitative polymerase chain reaction and immunohistochemistry were performed to examine mRNA expression levels and the localization of the MSH4 protein in the testicular tissue. Furthermore, the expression of MSH4 mRNA was significantly decreased compared with normal control. MSH4 protein was highly expressed in spermatocytes in the seminiferous tubules of the normal control, while no obvious expression was observed in F1 II-1. In this present study, was identified as a candidate gene of male infertility causing NOA. A novel mutation of MSH4 (c.1552C>T:p.Q518X) is associated with the MA phenotype during spermatogenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791528PMC
December 2020

Novel compound heterozygous variants in dynein axonemal heavy chain 17 cause asthenoteratospermia with sperm flagellar defects.

J Genet Genomics 2020 11 9;47(11):713-717. Epub 2020 Oct 9.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, 230032, China; Ministry of Education Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Hefei, 230032, China; Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, 230032, China. Electronic address:

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http://dx.doi.org/10.1016/j.jgg.2020.07.004DOI Listing
November 2020

Polymorphisms and haplotype of mitochondrial DNA D-loop region are associated with polycystic ovary syndrome in a Chinese population.

Mitochondrion 2021 03 30;57:173-181. Epub 2020 Dec 30.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei 230032, Anhui, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, No 81 Meishan Road, Hefei 230032, Anhui, China. Electronic address:

Polymorphisms in mitochondrial DNA (mtDNA) have been linked to a range of diseases. Here we investigate the relationship between mtDNA D-loop region polymorphisms, mtDNA haplotype and polycystic ovary syndrome (PCOS), as well as the correlation of D-loop variants and clinical characteristics of PCOS, in a Chinese population. The mtDNA D-loop of whole blood samples from 421 PCOS patients and 409 controls underwent next generation sequencing. The variants G207A (P<0.05), 16036GGins (P<0.05) and 16049Gins (P<0.001) were associated with decreased risk of PCOS. No variants were associated with PCOS, and within the PCOS group, no statistical significance was found between D-loop polymorphisms and clinical characteristics. Patient haplotype was identified from D-loop single nucleotide polymorphisms and analysis suggested that haplotype A15 (P adjusted <0.01) was significantly associated with decreased risk of PCOS. In conclusion, mtDNA D-loop alterations and haplotype appear to confer resistance to PCOS in Chinese women.
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http://dx.doi.org/10.1016/j.mito.2020.12.006DOI Listing
March 2021

Melatonin improves the effect of cryopreservation on human oocytes by suppressing oxidative stress and maintaining the permeability of the oolemma.

J Pineal Res 2021 Mar 12;70(2):e12707. Epub 2020 Dec 12.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Anhui, China.

Cryopreservation causes cryoinjury to oocytes and impairs their developmental competence. Melatonin (MLT) can improve the effect of cryopreservation in animal oocytes. However, no such studies on human oocytes have been reported. In this study, collected in vitro-matured human oocytes were randomly divided into the following groups: fresh group, MLT-treated cryopreservation (MC) group, and no-MLT-treated cryopreservation (NC) group. After vitrification and warming, viable oocytes from these three groups were assessed for their mitochondrial function, ultrastructure, permeability of oolemma, early apoptosis, developmental competence, and cryotolerance-related gene expression. First, fluorescence staining results revealed that oocytes from the 10  M subgroup showed the lowest intracellular reactive oxygen species and Ca levels and highest mitochondrial membrane potential among the MC subgroups (10 , 10 , 10 , and 10  M). In subsequent experiments, oocytes from the 10  M-MC group were observed to maintain the normal ultrastructural features and the permeability of the oolemma. Compared with those of the oocytes in the NC group, the early apoptosis rate significantly decreased (P < .01), whereas both the high-quality cleavage embryo and blastocyst rates significantly increased (both P < .05) in the oocytes of the 10  M-MC group. Finally, single-cell RNA sequencing and immunofluorescence results revealed that aquaporin (AQP) 1/2/11 gene expression and AQP1 protein expression were upregulated in the MC group. Therefore, these results suggest that MLT can improve the effect of cryopreservation on human oocytes by suppressing oxidative stress and maintaining the permeability of the oolemma.
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http://dx.doi.org/10.1111/jpi.12707DOI Listing
March 2021

The combined action of monocytic myeloid-derived suppressor cells and mucosal-associated invariant T cells promotes the progression of cervical cancer.

Int J Cancer 2021 Mar 4;148(6):1499-1507. Epub 2020 Dec 4.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.

One of the most common promoters of the initiation and growth of the tumor is an immune disturbance. Numerous immune cells and inflammatory factors play a role in the tumor-immune microenvironment. However, few studies have investigated the correlation between these immunological events and clinical consequences in cervical cancer. We measured the levels of numerous inflammatory mediators and frequencies of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and mucosal-associated invariant T (MAIT) cells in peripheral blood (PB) of cervical cancer patients. Cervical cancer patients showed elevated production of interleukin (IL)-18 and plasma C-C chemokine ligand (CCL) 3/5. Meanwhile, an accumulation of C-C chemokine receptor 5 (CCR5) monocytic (Mo)-MDSCs and Tregs was observed. The cervical cancer group displayed increased frequencies of CD8 , CD4 and highly activated CD38 CD8 MAIT cells, and reduction of double-negative (DN) and PD1(CD279 ) DN MAIT cells. Importantly, it was demonstrated that MAIT cells were positively related to Mo-MDSCs. Furthermore, an elevated concentration of PD1(CD279 ) DN MAIT cells was significantly related to increased progression-free survival of patients with cervical cancer. In conclusion, our study suggests that the combined action of Mo-MDSCs and MAIT cells might be associated with the progression of cervical cancer, and the frequency of DN MAIT cells in the peripheral blood mononuclear cells was associated with the survival benefit of patients.
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http://dx.doi.org/10.1002/ijc.33411DOI Listing
March 2021

ASMT Regulates Tumor Metastasis Through the Circadian Clock System in Triple-Negative Breast Cancer.

Front Oncol 2020 21;10:537247. Epub 2020 Oct 21.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

Objective: Triple-negative (PR, ER, HER-2) breast cancer (TNBC) is regarded as more aggressive and more likely to recur after medical care. Emerging evidence has demonstrated that the circadian clock system regulates cell-signaling pathways critical to cancer cell proliferation, survival and metastasis, meaning that it could be a good candidate for TNBC treatment. As such, the aim of the current study was to examine the molecular mechanism by which the circadian clock system contributes to cancer progression in TNBC.

Methods: Cancer cells and primary breast cancer tissues were immunostained for the measurement of circadian clock proteins (CLOCK, BMAL1 and PER1) and acetylserotonin methyltransferase (ASMT). The association between ASMT and clock proteins was assessed using siRNA and Western blot. Transwell assays were used to detect cancer cell migration and invasion while MTT assays were utilized to evaluate cell proliferation.

Results: Circadian clock proteins (CLOCK, BMAL1, and PER1) and ASMT expression were higher in TNBC and triple positive breast cancer (TPBC) compared with para-carcinoma tissues (PCTs). Intriguingly, there was an obvious correlation between circadian clock proteins and ASMT expression in both TPBC and TNBC. Similarly, circadian clock proteins and ASMT were expressed to a greater extent in BT-474 (triple-positive) cells than in MDA-MB-231 (triple-negative) cells. The inhibition of ASMT reduced circadian clock protein levels in both breast cancer cell lines. Further analysis showed that the expression levels of ASMT and circadian clock proteins did not correlate with clinical parameters such as age, tumor size, histologic grade and CK5/6, but increased significantly with lymphatic invasion in TNBC. In agreement with this finding, knockdown of ASMT significantly leads to reductions in migration and invasion in MDA-MB-231 cells. However, over-expression of CLOCK reversed the decreases seen in ASMT inhibited cells.

Conclusion: Our study suggests that ASMT regulates the circadian clock system in breast cancer and inhibition of ASMT reduces the invasiveness of triple-negative breast cancer cells by downregulating clock protein in a certain extent, indicating the potential value of ASMT as a drug target for TNBC treatment.
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http://dx.doi.org/10.3389/fonc.2020.537247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609885PMC
October 2020

Association between exposure to airborne particulate matter less than 2.5 μm and human fecundity in China.

Environ Int 2021 01 7;146:106231. Epub 2020 Nov 7.

Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China; National Clinical Research Center for Obstetrics and Gynecology, Beijing 100191, China; Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing 100191, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing 100191, China. Electronic address:

Background: Whether exposure to airborne particulate matter less than 2.5 μm (PM) could impact human fecundity is unclear. We aimed to evaluate the potential impact of PM exposure on time to pregnancy (TTP) and the prevalence of infertility in the general Chinese population.

Method: We collected reproductive information, sociodemographic characteristics, and lifestyle data of 10,211 couples at risk of pregnancy from a large-scale community-based fertility survey in China. Then, we estimated each participant's 1-year, 3-year, and 5-year average PM exposure levels based on remote sensing information. After adjusting for demographic, lifestyle, and environmental co-variables, discrete-time Cox regression models were used to estimate the fecundability odds ratio (FOR) per 10 μg/m change of PM. We also estimated the odds ratio (OR) of infertility per 10 μg/m change of PM, using logistic regression models.

Findings: Among the 10,211 couples, 6,875 (67%) had conceived spontaneously, with a median TTP of 5 months (interquartile range: 2-10 months). The median PM exposure was 56.8 μg/m, with a wide range of 9.2-93.5 μg/m. In Cox regression models, each increase of 10 μg/m in the 1-year average PM exposure was associated with a significant decrease in fecundity by 11% (FOR: 0.89; 95% confidence interval [CI]: 0.86-0.92). In logistic regression models, it was also associated with an 20% increased likelihood of infertility (OR: 1.20; 95% CI: 1.13-1.27).

Conclusion: PM exposure was associated with reduced human fecundity, presented by a longer TTP and higher odds of infertility, which might explain the increased infertility rates in areas with heavy PM pollution.
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http://dx.doi.org/10.1016/j.envint.2020.106231DOI Listing
January 2021

The predictive value of pre-delivery laboratory test results for the severity of placental abruption and pregnancy outcome.

Placenta 2021 01 8;103:220-225. Epub 2020 Oct 8.

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Hefei, Anhui, China. Electronic address:

Introduction: To analyze the relationship between placental abruption severity and maternal pregnancy outcome and to explore the predictive value of pre-delivery laboratory test results for the severity of placental abruption.

Methods: The clinical datas of 126 patients with placental abruption diagnosed and treated in our hospital over the past 4 years were retrospectively analyzed. The severity of placental abruption was divided into degrees I to III. The pre-delivery laboratory results of all patients and data on maternal and fetal delivery outcomes were collected.

Results: The analysis of maternal outcomes showed that the volumes of antepartum, intrapartum and postpartum hemorrhage and the rates of utero-placental apoplexy, uterine compression sutures and vascular embolization significantly increased with increasing placental abruption severity. Fetal delivery data revealed that 1- and 5-min Apgar scores decreased significantly with increasing placental abruption severity. Pre-delivery laboratory findings suggest that the white blood cell count, hemoglobin, hematocrit, platelet count, albumin, aspartate aminotransferase (AST), creatinine, prothrombin time (PT), prothrombin activity, prothrombin time - international standardization ratio (INR), D-dimer, fibrinogen (FIB), and fibrin degradation products (FDP) changed significantly with increasing placental abruption severity. Further analysis by Spearman and Pearson correlation found that the pre-delivery volume of antepartum hemorrhage, D-dimer, FDP and other indicators were correlated with placental abruption severity.

Conclusions: The harm of placental abruption to pregnant women and neonates increases with increasing abruption severity. Some laboratory test results can be predictors of placental abruption degree.
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http://dx.doi.org/10.1016/j.placenta.2020.10.006DOI Listing
January 2021