Publications by authors named "Satoru Takeda"

238 Publications

Up-regulation of cytosolic prostaglandin E synthase in fetal-membrane and amniotic prostaglandin E2 accumulation in labor.

PLoS One 2021 23;16(4):e0250638. Epub 2021 Apr 23.

Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan.

Prostaglandin E2 (PGE2) is known to have important roles in labor, but the detailed mechanism underlying the spontaneous human labor remains unknown. Here, we examined the involvement of prostaglandin biosynthetic enzymes and transporter in the accumulation of PGE2 in amniotic fluid in human labor. PGE2 and its metabolites were abundant in amniotic fluid in deliveries at term in labor (TLB), but not at term not in labor (TNL). In fetal-membrane Transwell assays, levels of PGE2 production in both maternal and fetal compartments were significantly higher in the TLB group than the TNL group. In fetal-membrane, the mRNA level of PTGES3, which encodes cytosolic prostaglandin E synthase (cPGES), was significantly higher in TLB than in TNL, but the mRNA levels of the other PGE2-synthase genes were not affected by labor. Moreover, the mRNA level of PTGS2, which encodes cyclooxygenase-2 (COX-2) in the amnion was significantly higher in TLB than in TNL. Western blot analyses revealed that the levels of COX-1 and COX-2 were comparable between the two groups, however, the level of cPGES was relatively higher in TLB than in TNL. COXs, cPGES, and prostaglandin transporter (SLCO2A1) proteins were all expressed in both chorionic trophoblasts and amniotic epithelium. These findings suggest that COXs, cPGES and SLCO2A1 contribute to PGE2 production from fetal-membrane in labor.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250638PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064594PMC
April 2021

Dietary Magnesium Insufficiency Induces Salt-Sensitive Hypertension in Mice Associated With Reduced Kidney Catechol-O-Methyl Transferase Activity.

Hypertension 2021 Jul 12;78(1):138-150. Epub 2021 Apr 12.

Faculty of Medicine, Internal Medicine I, Shimane University, Izumo, Japan (A.K., K.K.).

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16377DOI Listing
July 2021

Transcriptomic analysis of hormone-sensitive patient-derived endometrial cancer spheroid culture defines Efp as a proliferation modulator.

Biochem Biophys Res Commun 2021 Apr 26;548:204-210. Epub 2021 Feb 26.

Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, 350-1241, Japan; Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, 173-0015, Japan. Electronic address:

Estrogen-responsive endometrial cancer (EC) is prevalent in uterine cancer. Its precise molecular mechanisms remain to be elucidated partly because of limited availability of estrogen-sensitive EC models recapitulating clinical pathophysiology. We previously established EC patient-derived cancer cell (EC-PDC) spheroid culture with high expression of estrogen receptor α (ERα). Using this EC-PDC, we study the transcriptional regulation and function of estrogen-responsive finger protein (Efp), a prototypic tripartite motif (TRIM) protein that modulates protein degradation and RNA processing. Intense estrogen-dependent EFP mRNA induction and high ERα occupancy to EFP estrogen responsive element (ERE) were observed in EC-PDC. Luciferase reporter gene assay showed that the ERE facilitates EFP transcriptional activity estrogen-dependently. siRNA-mediated Efp silencing in EC-PDC resulted in suppressed spheroid proliferation and altered gene expression profile, featuring downregulation of genes related to cell cycle (e.g., CDK6) and inflammation/immune responses (e.g., IL10RA, IL26, and IL6ST) while unaffected expression of cancer stemness-related markers. Taken together, EC-PDC spheroid culture is a powerful EC tool that enables to dissect Efp-mediated ERα signaling pathways as an estrogen-sensitive EC model. This study provides an insight into alternative EC therapeutic strategies targeting ERα-Efp axis.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.066DOI Listing
April 2021

YBX2 and cancer testis antigen 45 contribute to stemness, chemoresistance and a high degree of malignancy in human endometrial cancer.

Sci Rep 2021 Feb 18;11(1):4220. Epub 2021 Feb 18.

Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Y-box binding protein 2 (YBX2) has been associated with the properties of both germ cells and cancer cells. We hypothesized that YBX2 might contribute to the characteristics of cancer stem cells (CSCs). In this study, we clarified the function of YBX2 in endometrial cancer stem cells. We established a human YBX2-expressing Ishikawa (IK) cell line (IK-YBX2 cells). We analyzed gene expression associated with stemness and isolated SP cells from IK-YBX2 cells. The SP population of IK-YBX2 cells, the expression of ALDH1 and serial sphere-forming capacity were associated with levels of YBX2 expression. IK-YBX2 cells were resistant to anti-cancer drugs. In gene expression analysis, a gene for cancer testis antigen, CT45, was generally overexpressed in IK-YBX2 cells. YBX2-mediated CT45 expression was associated with increased levels of self-renewal capacity and paclitaxel resistance. The level of CT45 expression was enhanced in high-grade and/or advanced stages of human endometrial cancer tissues. We conclude that expression of YBX2 is essential for the stem cell-like phenotype. CT45 contributes to stemness associated with YBX2 and might be related to the progression of endometrial cancer.
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http://dx.doi.org/10.1038/s41598-021-83200-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893073PMC
February 2021

Predictors of resignation and sick leave after cancer diagnosis among Japanese breast cancer survivors: a cross-sectional study.

BMC Public Health 2021 01 14;21(1):138. Epub 2021 Jan 14.

Department of Hygiene, Public Health, and Preventive Medicine, Showa University, Tokyo, Japan.

Background: In Japan, 55.5% of breast cancer survivors (BCSs) are of working age, so various perspectives regarding return to work (RTW) after cancer diagnosis need to be considered. Therefore, this study aimed to clarify the risk factors for resignation and taking sick leave (SL) among BCSs in continued employment at the time of diagnosis.

Methods: A web-based retrospective cross-sectional survey was conducted on BCSs using data from a 2018 Japanese national research project (Endo-Han) commissioned by the Ministry of Health, Labour and Welfare of Japan. The subjects were women aged 18-69 years who had been diagnosed with breast cancer for the first time at least 1 year previously. The risk factors for resignation and taking SL after breast cancer diagnosis, including age at diagnosis, education level, cancer stage, surgery, chemotherapy, radiotherapy, employment status, and occupational type, were then analyzed using a logistic regression model.

Results: In total, 40 (14.9%) of 269 BCSs quit their jobs at least 1 year after being diagnosed with breast cancer. The results of the multivariable analysis indicated that lower education level (odds ratio [OR]: 3.802; 95% confidence interval [CI]: 1.233-11.729), taking SL (OR: 2.514; 95%CI: 1.202-5.261), and younger age at diagnosis (OR: 0.470; 95%CI: 0.221-0.998) were predictors of resignation. Of 229 patients who continued working, SL was taken by 72 (31.4%). In addition, undergoing surgery was found to be a predictor of taking SL (OR: 8.311; 95%CI: 1.007-68.621).

Conclusions: In total, 40 (14.9%) of 269 BCSs quit their jobs at least 1 year after being diagnosed with breast cancer. The results of this study indicated that younger age, lower education level, and taking SL were predictors of resignation after breast cancer diagnosis.
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http://dx.doi.org/10.1186/s12889-021-10168-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809813PMC
January 2021

Analysis of severe psychological stressors in women during fertility treatment: Japan-Female Employment and Mental health in Assisted reproductive technology (J-FEMA) study.

Arch Gynecol Obstet 2021 Jul 1;304(1):253-261. Epub 2021 Jan 1.

Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan.

Purpose: To identify risk factors for severe psychological stress in women undergoing fertility treatment.

Methods: This cross-sectional, multi-center study was conducted from August to December 2018. We recruited 1672 subjects who completed an anonymous, self-reported questionnaire regarding fertility treatment, conditions at work and home, and psychological stress using K6 score, which estimates psychological distress during the previous 30 days. We further focused our analysis on 1335 subjects who were working when starting fertility treatment.

Results: Of 1672 women, mean K6 score (range 0-24) was 4.8 ± 4.4, including 103 women (6.2%) with K6 score ≥ 13 (high K6), and classified as probable severe psychological distress. Multivariate logistic regression analysis showed that high K6 was strongly associated with low annual family income of ≤ USD55,700 (JPY6 million) (odds ratio [OR] 1.89, 95% confidence interval [CI] 1.04-3.42), infertility duration of ≥ 2 years (OR 1.87, 95% CI 1.08-3.25), and no experience of childbirth (OR 2.04, 95% CI 1.05-3.97). Focusing on 1335 working women, 266 (19.9%) experienced resignation from work. High K6 was strongly associated with low family income (OR 2.83, 95% CI 1.52-5.28), cessation of professional duties (OR 2.08, 95% CI 1.05-4.14), infertility-related harassment in the workplace (OR 2.07, 95% CI 1.08-3.98), and perceived difficulties to continue working during fertility treatment (OR 2.94, 95% CI 1.15-7.50).

Conclusion: Severe psychological stressors in women during fertility treatment included low family income, long infertility duration, childlessness, infertility-related harassment, and perceived difficulty in working conditions or cessation from work. Establishment of mental health care support systems is urgently required in this population.
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http://dx.doi.org/10.1007/s00404-020-05923-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775729PMC
July 2021

A Model of Germinal Matrix Hemorrhage in Preterm Rat Pups.

Front Cell Neurosci 2020 3;14:535320. Epub 2020 Dec 3.

Department of Obstetrics and Gynecology, Centre of Perinatal Medicine, Health, Institute of Clinical Sciences, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.

Germinal matrix hemorrhage (GMH) is a serious complication in extremely preterm infants associated with neurological deficits and mortality. The purpose of the present study was to develop and characterize a grade III and IV GMH model in postnatal day 5 (P5) rats, the equivalent of preterm human brain maturation. P5 Wistar rats were exposed to unilateral GMH through intracranial injection into the striatum close to the germinal matrix with 0.1, 0.2, or 0.3 U of collagenase VII. During 10 days following GMH induction, motor functions and body weight were assessed and brain tissue collected at P16. Animals were tested for anxiety, motor coordination and motor asymmetry on P22-26 and P36-40. Using immunohistochemical staining and neuropathological scoring we found that a collagenase dose of 0.3 U induced GMH. Neuropathological assessment revealed that the brain injury in the collagenase group was characterized by dilation of the ipsilateral ventricle combined with mild to severe cellular necrosis as well as mild to moderate atrophy at the levels of striatum and subcortical white matter, and to a lesser extent, hippocampus and cortex. Within 0.5 h post-collagenase injection there was clear bleeding at the site of injury, with progressive increase in iron and infiltration of neutrophils in the first 24 h, together with focal microglia activation. By P16, blood was no longer observed, although significant gray and white matter brain infarction persisted. Astrogliosis was also detected at this time-point. Animals exposed to GMH performed worse than controls in the negative geotaxis test and also opened their eyes with latency compared to control animals. At P40, GMH rats spent more time in the center of open field box and moved at higher speed compared to the controls, and continued to show ipsilateral injury in striatum and subcortical white matter. We have established a P5 rat model of collagenase-induced GMH for the study of preterm brain injury. Our results show that P5 rat pups exposed to GMH develop moderate brain injury affecting both gray and white matter associated with delayed eye opening and abnormal motor functions. These animals develop hyperactivity and show reduced anxiety in the juvenile stage.
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http://dx.doi.org/10.3389/fncel.2020.535320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744792PMC
December 2020

Structure of the miniature type V-F CRISPR-Cas effector enzyme.

Mol Cell 2021 02 16;81(3):558-570.e3. Epub 2020 Dec 16.

Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address:

RNA-guided DNA endonucleases derived from CRISPR-Cas adaptive immune systems are widely used as powerful genome-engineering tools. Among the diverse CRISPR-Cas nucleases, the type V-F Cas12f (also known as Cas14) proteins are exceptionally compact and associate with a guide RNA to cleave single- and double-stranded DNA targets. Here, we report the cryo-electron microscopy structure of Cas12f1 (also known as Cas14a) in complex with a guide RNA and its target DNA. Unexpectedly, the structure revealed that two Cas12f1 molecules assemble with the single guide RNA to recognize the double-stranded DNA target. Each Cas12f1 protomer adopts a different conformation and plays distinct roles in nucleic acid recognition and DNA cleavage, thereby explaining how the miniature Cas12f1 enzyme achieves RNA-guided DNA cleavage as an "asymmetric homodimer." Our findings augment the mechanistic understanding of diverse CRISPR-Cas nucleases and provide a framework for the development of compact genome-engineering tools critical for therapeutic genome editing.
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http://dx.doi.org/10.1016/j.molcel.2020.11.035DOI Listing
February 2021

Risk factors for resignation from work after starting infertility treatment among Japanese women: Japan-Female Employment and Mental health in Assisted reproductive technology (J-FEMA) study.

Occup Environ Med 2020 Dec 3. Epub 2020 Dec 3.

Department of Public Health, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan

Objective: To elucidate the risk factors associated with resignation from work of Japanese women undergoing infertility treatment.

Methods: A total of 1727 female patients who attended a private fertility clinic in Japan participated in the Japan-Female Employment and Mental health in Assisted reproductive technology study. Questions related to demographic, clinical and socioeconomic characteristics were employed in the questionnaire. Out of the 1727 patients, 1075 patients who were working at the time of initiating infertility treatment and felt infertility treatment incompatible with work were included in the analysis. Risk factors for resignation were assessed by using multivariable logistic regression models.

Results: Among 1075 working women who started infertility treatment, 179 (16.7%) subsequently resigned. Multivariable-adjusted ORs for resignation in those with lower educational background and infertility for ≥2 years were 1.58 (95% CI: 1.07 to 2.34) and 1.82 (95% CI: 1.15 to 2.89), respectively. The OR for resignation in non-permanent workers undergoing infertility treatment was 2.65 (95% CI: 1.61 to 4.37). While experiencing harassment in the workplace approached significance, lack of support from the company was significantly associated with resignation after starting infertility treatment, with ORs of 1.71 (95% CI: 0.98 to 2.99) and 1.91 (95% CI: 1.28 to 2.86), respectively.

Conclusion: One-sixth of women resigned after starting infertility treatments. It was found that factors related to education, infertility duration and work environment were significantly associated with resignation. Reducing the physical and psychological burden endured by women, for example, by increasing employer-provided support, is vitally important in balancing infertility treatment with maintenance of work life.
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http://dx.doi.org/10.1136/oemed-2020-106745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142458PMC
December 2020

Depth structure analysis by surface scanning in near-field microscopes.

Opt Lett 2020 Nov;45(22):6302-6305

High-resolution imaging of the surfaces of samples can be performed using near-field optical microscopes by scanning a small light spot; however, structures located deep beneath cannot be observed because the light spot spreads in three directions. In this study, we propose an observation technique for near-field optical microscopes that can obtain depth information within the resolution of the diffraction limit of light by analyzing interference patterns formed with divergent incident light and scattered light from a sample. We analyze depth structures by evaluating correlation coefficients between observed interference patterns and calculated reference patterns. Our technique can observe both high-resolution surface images and the diffraction-limited three-dimensional structure by scanning a near-field light source on a single plane.
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http://dx.doi.org/10.1364/OL.402490DOI Listing
November 2020

A Retrospective Multicenter Study on the Usefulness of 50 g Glucose Challenge Test in Gestational Diabetes Mellitus Screening.

JMA J 2020 Apr 6;3(2):125-130. Epub 2020 Apr 6.

Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan.

Introduction: To clarify the usefulness of glucose challenge test (GCT), the rate of gestational diabetes mellitus (GDM) detection and perinatal outcomes were compared between the groups of random blood glucose level (RBG) and 50 g GCT in this study.

Methods: The first survey was conducted at 255 institutions registered by the Kanto Society of Obstetrics and Gynecology and clinical training institutions in the Kanto Area, followed by a second survey. The included women were broadly classified into the RBG and GCT groups, according to the mid-trimester blood glucose screening method, and the perinatal outcomes of the two groups were retrospectively compared. The primary outcomes were the proportion of infants weighing 3,500 g or more and birth weight ≥90-percentile infants.

Results: The rate of GDM diagnosis was significantly higher in the GCT group (7.6%) than that in the RBG group (4.8%). However, no significant differences were observed in perinatal outcomes, i.e., the proportion of infants weighing 3,500 g or more or birth weight ≥90 percentile.

Conclusions: GCT is not superior for predicting infants weighing 3,500 g or more and birth weight ≥90 percentile, as compared with RBG.
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http://dx.doi.org/10.31662/jmaj.2019-0072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590393PMC
April 2020

Whole exome sequencing of fetal structural anomalies detected by ultrasonography.

J Hum Genet 2021 May 3;66(5):499-507. Epub 2020 Nov 3.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

The objective of this study was to evaluate the efficacy of whole exome sequencing (WES) for the genetic diagnosis of cases presenting with fetal structural anomalies detected by ultrasonography. WES was performed on 19 cases with prenatal structural anomalies. Genomic DNA was extracted from umbilical cords or umbilical blood obtained shortly after birth. WES data were analyzed on prenatal phenotypes alone, and the data were re-analyzed after information regarding the postnatal phenotype was obtained. Based solely on the fetal phenotype, pathogenic, or likely pathogenic, single nucleotide variants were identified in 5 of 19 (26.3%) cases. Moreover, we detected trisomy 21 in two cases by WES-based copy number variation analysis. The overall diagnostic rate was 36.8% (7/19). They were all compatible with respective fetal structural anomalies. By referring to postnatal phenotype information, another candidate variant was identified by a postnatal clinical feature that was not detected in prenatal screening. As detailed phenotyping is desirable for better diagnostic rates in WES analysis, we should be aware that fetal phenotype is a useful, but sometimes limited source of information for comprehensive genetic analysis. It is important to amass more data of genotype-phenotype correlations, especially to appropriately assess the validity of WES in prenatal settings.
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http://dx.doi.org/10.1038/s10038-020-00869-8DOI Listing
May 2021

Downregulation of 5-hydroxymethylcytosine is associated with the progression of cervical intraepithelial neoplasia.

PLoS One 2020 3;15(11):e0241482. Epub 2020 Nov 3.

Department of Obstetrics and Gynecology, School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Around the world, cervical cancer is one of the most common neoplastic diseases among women, and the prognosis of patients in an advanced stage remains poor. To reduce the mortality rate of cervical cancer, early diagnosis and treatment are essential. DNA methylation is an important aspect of gene regulation, and aberrant DNA methylation contributes to carcinogenesis and cancer progression in various cancers. Although 5-methylcytosine (5mC) has been analyzed intensively, the function of 5-hydroxymethylcytosine (5hmC) has not been clarified. The purpose of our study was to identify the molecular biomarkers for early diagnosis of cervical tumors due to epigenetic alterations. To assess the clinical relevance of DNA methylation, we used immunohistochemistry (IHC) to characterize the level of 5hmC in 102 archived human cervical intraepithelial neoplasia (CIN) samples and cervical cancer specimens. The level of 5hmC was significantly decreased between CIN2 and CIN3. The progression of cervical tumors is caused by a reduction of TP53 and RB1 because of HPV infection. We observed that Tp53 and Rb1 were knocked down in mouse embryonic fibroblasts (MEF), a model of normal cells. The level of 5hmC was reduced in Tp53-knockdown cells, and the expression levels of DNA methyltransferase 1 (DNMT1) and ten-eleven translocation methylcytosine dioxygenase 1 (TET1) were induced. In contrast, there was no significant change in Rb1-knockdown cells. Mechanistically, we focused on apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) 3B (A3B) as a cause of 5hmC reduction after TP53 knockdown. In the human cell line HHUA with a wild-type TP53 gene, A3B was induced in TP53-knockdown cells, and A3B knockdown recovered 5hmC levels in TP53-knockdown cells. These data indicate that TP53 suppression leads to 5hmC reduction in part through A3B induction. Moreover, IHC showed that expression levels of A3B in CIN3 were significantly higher than those in both normal epithelium and in CIN2. In conclusion, 5hmC levels are decreased between CIN2 and CIN3 through the TP53-A3B pathway. Since A3B could impair genome stability, 5hmC loss might increase the chances of accumulating mutations and of progressing from CIN3 to cervical cancer. Thus, these epigenetic changes could predict whether CINs are progressing to cancer or disappearing.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241482PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608920PMC
December 2020

Nonsense variants of result in distinct congenital anomalies.

Hum Genome Var 2020 18;7:26. Epub 2020 Sep 18.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Herein, we report two female cases with novel nonsense mutations of at Xq25, encoding stromal antigen 2, a component of the cohesion complex. Exome analysis identified c.3097 C>T, p.(Arg1033*) in Case 1 (a fetus with multiple congenital anomalies) and c.2229 G>A, p.(Trp743*) in Case 2 (a 7-year-old girl with white matter hypoplasia and cleft palate). X inactivation was highly skewed in both cases.
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http://dx.doi.org/10.1038/s41439-020-00114-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501222PMC
September 2020

Weekend and off-hour effects on the incidence of cerebral palsy: contribution of consolidated perinatal care.

Environ Health Prev Med 2020 Sep 10;25(1):52. Epub 2020 Sep 10.

Department of the Japan Obstetric Compensation System for Cerebral Palsy, Japan Council for Quality Health Care, Tokyo, Japan.

Objective: This study estimated the effects of weekend and off-hour childbirth and the size of perinatal medical care center on the incidence of cerebral palsy.

Methods: The cases were all children with severe cerebral palsy born in Japan from 2009 to 2012 whose data were stored at the Japan Obstetric Compensation System for Cerebral Palsy database, a nationally representative database. The inclusion criteria were the following: neonates born between January 2009 and December 2012 who had a birth weight of at least 2000 g and gestational age of at least 33 weeks and who had severe disability resulting from cerebral palsy independent of congenital causes or factors during the neonatal period or thereafter. Study participants were restricted to singletons and controls without report of death, scheduled cesarean section, or ambulance transportation. The controls were newborns, randomly selected by year and type of delivery (normal spontaneous delivery without cesarean section and emergency cesarean section) using a 1:10 case to control ratio sampled from the nationwide Japan Society of Obstetrics and Gynecology database.

Results: A total of 90 cerebral palsy cases and 900 controls having normal spontaneous delivery without cesarean section were selected, as were 92 cerebral palsy cases and 920 controls with emergent cesarean section. A significantly higher risk for cerebral palsy was found among cases that underwent emergent cesarean section on weekends (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.06-2.81) and during the night shift (OR 2.29, 95% CI 1.30-4.02). No significant risk was found among normal spontaneous deliveries on weekends (OR 1.63, 95% CI 0.97-2.73) or during the quasi-night shift (OR 1.26, 95% CI 0.70-2.27). Regional perinatal care centers showed significantly higher risk for cerebral palsy in both emergent cesarean section (OR 2.35, 95% CI 1.47-3.77) and normal spontaneous delivery (OR 2.92, 95% CI 1.76-4.84).

Conclusion: Labor on weekends, during the night shift, and at regional perinatal medical care centers was associated with significantly elevated risk for cerebral palsy in emergency cesarean section.
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http://dx.doi.org/10.1186/s12199-020-00889-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488476PMC
September 2020

Risk factors for cerebral palsy in neonates due to placental abruption.

J Obstet Gynaecol Res 2021 Jan 3;47(1):159-166. Epub 2020 Sep 3.

Department of the Japan Obstetric Compensation System for Cerebral Palsy in Public Interest Incorporated Foundation, Japan Council for Quality Health Care, Tokyo, Japan.

Aim: This study aimed to identify risk factors for the onset of cerebral palsy (CP) in neonates due to placental abruption and investigate their characteristics.

Methods: A retrospective case-control study was conducted using a nationwide registry from Japan. The study population included pregnant women (n = 122) who delivered an infant with CP between 2009 and 2015, where placental abruption was identified as the single cause of CP. The control group consisted of pregnant women with placental abruption, who delivered an infant without CP and were managed from 2013 to 2014. They were randomly identified from the prenatal database of the Japan Society of Obstetrics and Gynecology (JSOG-DB; n = 1214). Risk factors were investigated using multivariate analysis.

Results: Alcohol consumption (3.38, 2.01-5.68) (odds ratio, 95% confidence interval), smoking during pregnancy (3.50, 1.32-9.25), number of deliveries (1.28, 1.05-1.56), polyhydramnios (5.60, 1.37-22.6), oral administration of ritodrine hydrochloride (2.09, 1.22-3.57) and hypertensive disorders in pregnancy (2.25, 1.27-4.07) were significant risk factors. In contrast, intravenous administration of oxytocin (odds ratio, 95% confidence interval: 0.22, 0.09-0.58) and magnesium sulfate (0.122, 0.02-0.89) attenuated risk.

Conclusion: Alcohol consumption, smoking during pregnancy, number of deliveries, polyhydramnios, oral administration of ritodrine hydrochloride and hypertensive disorders in pregnancy were identified as risk factors for CP following placental abruption. Regarding alcohol consumption and smoking during pregnancy, the results suggest the importance of educational activities targeting pregnant women to increase their awareness of placental abruption.
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http://dx.doi.org/10.1111/jog.14447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818445PMC
January 2021

Respiratory Distress Syndrome in Infants Delivered via Cesarean from Mothers with Preterm Premature Rupture of Membranes: A Propensity Score Analysis.

J Pregnancy 2020 31;2020:5658327. Epub 2020 Jul 31.

Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan.

Objective: This study aimed to clarify the effects of cesarean delivery on neonatal respiratory morbidity when women had preterm premature rupture of membranes.

Methods: This retrospective study included women with preterm premature rupture of membranes who delivered from 23 weeks to 33 weeks of gestation between January 2009 and December 2014. Neonatal outcomes were compared between infants delivered by cesarean section and those delivered vaginally. The primary outcome was respiratory distress syndrome (RDS). Neonatal intubation and mechanical ventilation periods were secondary outcomes. Propensity score matching was used to compare outcomes between cesarean and vaginal delivery cases.

Results: There were 101 cesarean deliveries and 89 vaginal deliveries. A comparison of the presence or absence of neonatal complications based on the delivery type indicated a higher occurrence of RDS with cesarean deliveries ( = 0.025). The intubation and mechanical ventilation periods were not significantly longer in neonates delivered via cesarean section.

Conclusions: Cesarean delivery is a risk factor for neonatal RDS in women with preterm premature rupture of membranes. Trials identifying long-term neonatal prognoses are needed to further develop optimal management strategies in such cases.
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http://dx.doi.org/10.1155/2020/5658327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415122PMC
September 2020

Cesarean Section for Placenta Previa and Placenta Previa Accreta Spectrum.

Surg J (N Y) 2020 Jul 9;6(Suppl 2):S110-S121. Epub 2020 Mar 9.

Department of Obstetrics and Gynecology, Faculty of Medicine, Juntendo University, Tokyo, Japan.

According to the increase in the rate of cesarean section and the increase of high-aged pregnancy, we seem to more often encounter cases with placenta previa and placenta previa accrete spectrum. There are concerns about these cases, such as difficulty in controlling bleeding from the separation surface of placenta previa, the need for hysterectomy as a life-saving procedure, systemic management and hemostasis during massive hemorrhage, and treatment of disseminated intravascular coagulation (DIC). These cases are most frequently associated with cesarean hysterectomy.
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http://dx.doi.org/10.1055/s-0039-3402036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396465PMC
July 2020

Clinical Tips of Cesarean Section in Case of Breech, Transverse Presentation, and Incarcerated Uterus.

Surg J (N Y) 2020 Jul 18;6(Suppl 2):S81-S91. Epub 2020 Mar 18.

Department of Obstetrics and Gynecology, Faculty of Medicine, Juntendo University, Tokyo, Japan.

Cesarean section in breech or transverse presentation involves more complicated procedures than cesarean section in cephalic presentation because the former requires additional manipulations for guiding the presenting part of the fetus, liberation of the arms, and the after-coming head delivery; therefore, those cesarean sections are likely to be more invasive. Making a rather wide uterine incision to prevent uterine injury during delivery of the fetus facilitates smooth delivery of the fetus. Furthermore, in cases of breech or transverse presentation, it is important to initially identify the presenting part of the fetus and guide it to the incision opening in the lower uterine segment, because delivering the presenting part of the fetus first is a basic rule of delivery of the fetus. Smooth delivery of the fetus by means of breech extraction can prevent excessive stress or injury to the fetus. Therefore, it is important to acquire the knowledge and skills necessary to perform these techniques, including the internal version. Smooth delivery of the fetus is also less invasive for the mother because an extension of the uterine excision or injury to arteries and veins in the uterus and parametrium can be avoided. Incarcerated uterus occurring in cases of pregnancy with intrapelvic adhesion, endometriosis, cervical myoma, or extended cervix may result in excessive uterine and cervical injury when a transverse incision of the lower uterine segment is performed without caution. These conditions may result in difficulty in fetal delivery. Therefore, it is important to identify risks in advance and to choose the incision line with great care. Countermeasures for difficult delivery of the fetus need to be mastered by all practitioners of obstetrics. If the transverse incision fails to reach the uterine cavity, an inverted T-shaped or J-shaped incision should be made. Risks of complications such as injury to the cervical canal, the vagina, the bladder or ureter, and massive hemorrhage must be kept in mind.
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http://dx.doi.org/10.1055/s-0040-1702985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396468PMC
July 2020

Maternal risk score for the prediction of fetal inflammatory response syndrome after preterm premature rupture of membranes.

J Obstet Gynaecol Res 2020 Oct 2;46(10):2019-2026. Epub 2020 Aug 2.

Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan.

Aim: Preterm premature rupture of membranes (PPROM) is common in preterm births. Fetal inflammatory response syndrome (FIRS) is present in nearly 50% of PPROM cases. We created a risk score to predict FIRS using maternal factors after PPROM.

Methods: We conducted a retrospective study of singleton pregnancies complicated by PPROM that resulted in delivery at 23-35 weeks of gestation. Antepartum maternal factors and umbilical cord blood interleukin-6 (IL-6) data were analyzed. FIRS was defined as IL-6 > 11 pg/mL.

Results: Umbilical cord blood IL-6 and maternal blood data within 24 h before parturition were available for 158 cases; 66 were diagnosed with FIRS (41.8%; median IL-6, 57.55 pg/mL). We created a risk score (FIRS score) comprising expected delivery weeks (≤30 weeks), maternal C-reactive protein (≥1.2 mg/dL), maternal white blood cell count (≥13 000/μL), corticosteroid use (none) and PROM latency period (≥3 days) from the multivariate logistic regression model predicting FIRS. Receiver operating characteristic curve analysis of the score produced the following results: area under the curve, 0.82; 95% CI, 0.76-0.89; cut-off value, 7.5; sensitivity, 89%; specificity, 63%; positive predictive value, 63% and negative predictive value, 89%. The probability of FIRS according to the categories of the FIRS score was 11% for those with a score of 0-7, 50% for a score of 8-15, and 88% for a score of 16-22.

Conclusion: The devised maternal risk score could predict FIRS and be helpful to decide the delivery timing for the cases of PPROM.
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http://dx.doi.org/10.1111/jog.14414DOI Listing
October 2020

Adoptive Immune-Cell Therapy for the Treatment of Neuroendocrine Carcinoma of the Uterine Cervix.

Anticancer Res 2020 Aug;40(8):4741-4748

Department of Obstetrics and Gynecology, Juntendo University School of Medicine, Tokyo, Japan.

Background/aim: We aimed to investigate the efficacy of immune-cell therapy in terms of the survival of patients with neuroendocrine carcinoma of the uterine cervix (NECC), which lacks standardized therapeutic approaches.

Patients And Methods: We identified 17 patients who were diagnosed as having NECC and treated with immune-cell therapy. The clinical characteristics of these patients were extracted from their records and their overall survival was measured.

Results: Of the 17 patients, two patients with early-stage NECC without recurrence and three patients with less than four treatments were excluded. The median survival times from the time of diagnosis and from the initial administration of immune-cell therapy were 49.7 and 24.4 months, respectively. The overall survival rates at 1, 2, and 5 years were 63.6%, 38.2%, and 25.5%, respectively. Long-term survival was observed in the patients with distant metastases.

Conclusion: The preliminary results of this retrospective study suggested the potential efficacy of immune-cell therapy for NECC.
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http://dx.doi.org/10.21873/anticanres.14475DOI Listing
August 2020

Pure 9p duplication syndrome with aplasia of the middle phalanges of the fifth fingers.

Eur J Med Genet 2020 Oct 18;63(10):104005. Epub 2020 Jul 18.

Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan.

9p duplication syndrome is a common congenital anomaly syndrome with specific facial features, mental and developmental retardations, and characteristic fingers. Pure 9p duplication without other chromosomal structural variations is very rare. It has recently been reported that cases with partial 9p duplication including SMARCA2 have phenotypes overlapping with Coffin-Siris syndrome (CSS). Herein, we present a family with pure 9p duplication syndrome in which phenotypes partially characteristic of CSS were identified. In one of two siblings, X-ray examination revealed hypoplasia of the distal phalanges of the fifth fingers, aplasia of the middle phalanges of the fifth fingers, and aplasia of the distal phalanges of the second to fifth toes. In pure 9p duplication together with our one affected case, 9 out of 14 cases (64.3%), excluding cases whose clinical data were unavailable, presented the absence or hypoplasia of the middle phalanges of fingers or toes. Interestingly, there are no reports on CSS with aplasia or hypoplasia of the middle phalanx. Therefore, this family might suggest that the aplasia or hypoplasia of the middle phalanges of the fifth fingers or toes is a distinct finding that can distinguish between pure 9p duplication and CSS.
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http://dx.doi.org/10.1016/j.ejmg.2020.104005DOI Listing
October 2020

Retraction Note to: Nonsense variants in STAG2 result in distinct sex-dependent phenotypes.

J Hum Genet 2020 09;65(9):811

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s10038-020-0782-2DOI Listing
September 2020

Abdominal Myomectomy for Huge Uterine Myomas with Intra-arterial Balloon Occlusion: Approach to Reduce Blood Loss.

Surg J (N Y) 2020 May 5;6(Suppl 1):S11-S21. Epub 2019 Aug 5.

Department of Radiology, Faculty of Medicine, Juntendo University, Tokyo, Japan.

Abdominal myomectomy for a huge myomas, especially uterine cervical myoma, is difficult because of risks, such as intraoperative bleeding or injury to adjacent organs. Therefore, understanding of the positional relationships among a huge myoma, especially cervical or intraligamental myoma, and the vascular plexuses in the right and left cardinal ligaments is important for prevention of massive bleeding during myomectomy. While sufficiently performing preoperative assessment with pelvic examination, ultrasonography, magnetic resonance imaging (MRI), etc., surgeons should always keep in mind how they can reduce the blood loss volume, while safely and surely performing resections. For a cervical myoma of the uterus and giant uterine leiomyoma that leave no intrapelvic space and prevent palpation and identification of the uterine arteries and the internal iliac arteries, surgery can be performed safely by preoperatively placing balloon catheters in the internal iliac arteries. Hemostaic strategies for myomectomy and tips of subsequent pregnancy following myomectomy are also described.
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http://dx.doi.org/10.1055/s-0039-1693041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214084PMC
May 2020

LEFTY2/endometrial bleeding-associated factor up-regulates Na+ Coupled Glucose Transporter SGLT1 expression and Glycogen Accumulation in Endometrial Cancer Cells.

PLoS One 2020 1;15(4):e0230044. Epub 2020 Apr 1.

Women's Health Research Institute, Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany.

LEFTY2 (endometrial bleeding associated factor; EBAF or LEFTYA), a cytokine released shortly before menstrual bleeding, is a negative regulator of cell proliferation and tumour growth. LEFTY2 down-regulates Na+/H+ exchanger activity with subsequent inhibition of glycolytic flux and lactate production in endometrial cancer cells. Glucose can be utilized not only for glycolysis but also for glycogen formation. Both glycolysis and glycogen formation require cellular glucose uptake which could be accomplished by the Na+ coupled glucose transporter-1 (SGLT1; SLC5A1). The present study therefore explored whether LEFTY2 modifies endometrial SGLT1 expression and activity as well as glycogen formation. Ishikawa and HEC1a cells were exposed to LEFTY2, SGLT1 and glycogen synthase (GYS1) transcript levels determined by qRT-PCR. SGLT1, GYS1 and phospho-GYS1 protein abundance was quantified by western blotting, cellular glucose uptake from 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG) uptake, and cellular glycogen content utilizing an enzymatic assay and subsequent colorimetry. As a result, a 48-hour treatment with LEFTY2 significantly increased SGLT1 and GYS1 transcript levels as well as SGLT1 and GYS1 protein abundance in both Ishikawa and HEC1a cells. 2-NBDG uptake and cellular glycogen content were upregulated significantly in Ishikawa (type 1) but not in type 2 endometrial HEC1a cells, although there was a tendency of increased 2-NBDG uptake. Further, none of the effects were seen in human benign endometrial cells (HESCs). Interestingly, in both Ishikawa and HEC1a cells, a co-treatment with TGF-β reduced SGLT1, GYS and phospho-GYS protein levels, and thus reduced glycogen levels and again HEC1a cells had no significant change. In conclusion, LEFTY2 up-regulates expression and activity of the Na+ coupled glucose transporter SGLT1 and glycogen synthase GYS1 in a cell line specific manner. We further show the treatment with LEFTY2 fosters cellular glucose uptake and glycogen formation and TGF-β can negate this effect in endometrial cancer cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230044PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112196PMC
July 2020

Biphasic changes in β-cell mass around parturition are accompanied by increased serotonin production.

Sci Rep 2020 03 18;10(1):4962. Epub 2020 Mar 18.

Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Pancreatic β-cell mass is known to be considerably altered during pregnancy and after parturition in rodents and humans. While β-cell mass increases during pregnancy and starts to return toward its original level after parturition, the cellular mechanisms by which β-cell mass during this period is regulated remains unclear. To address this issue in mice, we quantified β-cell mass and investigated the mechanisms underlying its regulation throughout the perinatal and postpartum period. The increased β-cell size and proliferation during pregnancy were significantly reduced shortly after parturition, whereas there was no evidence of β-cell reprogramming or increased apoptosis. Direct RNA sequencing of islets from pregnant and postpartum mice demonstrated dynamic changes in gene expression patterns, showing robust downregulation of cell cycle-related genes 1 day after parturition, and the reupregulation of serotonin metabolism-related genes at postpartum day 7. Serotonin synthesis was activated only in lactating females, accompanied by increased β-cell mass. Taken together, these findings demonstrate that β-cell mass is decreased shortly after parturition owing to reduced β-cell size and proliferation, and is subsequently increased, in association with lactation and serotonin biosynthesis.
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http://dx.doi.org/10.1038/s41598-020-61850-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080838PMC
March 2020

Dual-specificity phosphatase 6 plays a critical role in the maintenance of a cancer stem-like cell phenotype in human endometrial cancer.

Int J Cancer 2020 10 26;147(7):1987-1999. Epub 2020 Mar 26.

Department of Obstetrics and Gynecology, School of Medical Sciences, Kyushu University, Fukuoka, Japan.

The prognosis of patients with high-grade or advanced-stage endometrial cancer remains poor. As cancer stem-like cells (CSCs) are thought to be associated with endometrial cancers, it is essential to investigate the molecular mechanisms that regulate endometrial CSCs. Dual-specificity phosphatase 6 (DUSP6) functions as a negative-feedback regulator of MAPK-ERK1/2 signaling, but its role in endometrial cancer remains unknown. We investigated whether DUSP6 is involved in cancer cell stemness using endometrial cancer cell lines and specimens from endometrial cancer patients. DUSP6 induced the expression of CSC-related genes including ALDH1, Nanog, SOX2 and Oct4A, increased the population of cells in the G0/G1 phase, and promoted sphere formation ability. DUSP6 knockdown resulted in reduced cell invasion and metastasis, whereas DUSP6 overexpression inhibited apoptosis under serum-free conditions. Moreover, DUSP6 decreased phosphorylated ERK1/2 and increased phosphorylated Akt levels, which potentially induces CSC features. In patients with endometrial cancers, DUSP6 expression was determined using immunohistochemistry, and based on the results, the patients were dichotomized into high- and low-DUSP6-expression groups. Progression-free survival and overall survival were significantly shorter in the high-DUSP6-expression group. These results suggest that DUSP6 has potential value as a biomarker of CSCs and as a target of therapies designed to eliminate CSCs in endometrial cancer.
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http://dx.doi.org/10.1002/ijc.32965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496376PMC
October 2020

Retrospective study of the recurrence risk of preterm birth in Japan.

J Matern Fetal Neonatal Med 2020 Feb 18:1-5. Epub 2020 Feb 18.

Department of Obstetrics and Gynecology, Juntendo University, Tokyo, Japan.

A history of preterm birth is a risk factor for preterm birth in a future pregnancy, and there are some reports of prevention methods, such as the administration of progesterone. However, the rate of recurrence of preterm birth in Japan has not been clarified, and there is no data for judging whether these preventive methods are effective. To clarify the risk of recurrence of preterm birth and preterm prelabor rupture of membranes (pPROM) in Japan. A retrospective study was conducted using the perinatal registration database of the Japan Obstetrics and Gynecology Society for the Perinatal Center from 2014 to 2016. There were 704,418 subjects, of which 190,990 were excluded those with unknown maternal information, those under the age of 20 years, those with perinatal disease related to preterm birth, and first-time mothers. Logistic model unavailable and multivariate analysis were performed. An analysis of the preterm birth history indicated the risk of preterm birth in the current pregnancy, and the odds ratio for preterm birth recurrence once, twice, and three times or more was 3.3, 6.6, and 7.8, respectively. As a secondary analysis, we analyzed whether the history of pPROM is a risk factor of recurrence of pPROM and found a significant association with an odds ratio of 3.4. Having a preterm birth history increases the risk of recurrence of preterm birth, and the risk of recurrent preterm birth increases as the number of preterm births increases. Although this report is intended for high-risk pregnancies wherein the rate of preterm birth is high, as previously reported, our data indicate that in Japan, preterm birth is a risk factor of recurrent preterm birth.
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http://dx.doi.org/10.1080/14767058.2020.1727435DOI Listing
February 2020

Novel Method of Cervicoplasty Using Autologous Peritoneum for Cervicovaginal Atresia.

Surg J (N Y) 2020 Jan 11;6(1):e28-e32. Epub 2020 Feb 11.

Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan.

Cervicovaginal atresia with a functional uterus is rare. There are no established surgical methods to treat this condition, and only a few reports have been published on surgical techniques. Furthermore, postoperative complications, such as restenosis, often require reoperation. A 19-year-old woman was pointed out cervical hypoplasia and referred to our hospital for further examination and treatment. A pelvic examination revealed that the vagina had a slight recession with a blind end. Transrectal ultrasound and pelvic magnetic resonance imaging revealed congenital vaginal agenesis and cervical hypoplasia. Elective surgery was performed after reshaping the vagina. A radical surgery was performed 10 months later after sufficient self-dilation by using Frank's technique in an outpatient setting. At first, we approached by laparoscopically to correct autologous peritoneum and to bladder detach, then the cervical canal was identified. Next, a skin biopsy punch was used several times to hollow out the cervical tissue to shape and expand the cervical canal. A catheter was then placed in the uterus and autologous peritoneum was wrapped around it and fixed to the cervical canal. The catheter was removed 6 weeks postoperatively, and the patient continued dilating her vagina until she was able to have sexual intercourse, and then stopped the self-dilation. Eight months postoperatively, the patient did not report any menstrual irregularities. It is important to make corrections to prevent restenosis of the vagina and cervical canal and prevent the symptoms from recurring. Make use of autologous peritoneum as graft onto the cervical canal is effective method for the treatment of cervicovaginal atresia.
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http://dx.doi.org/10.1055/s-0040-1701213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012647PMC
January 2020

MicroRNA-191 regulates endometrial cancer cell growth via TET1-mediated epigenetic modulation of APC.

J Biochem 2020 Jul;168(1):7-14

Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.

Endometrial cancer (EC) is a common gynecological malignancy with relatively favourable prognosis, although alternative diagnostic and therapeutic options remain to be explored for advanced disease. Recent studies enabled to apply microRNAs (miRs) to clinical cancer management as promising diagnostic and therapeutic biomarkers. We here aimed to identify proliferation-associated miRNAs and characterize their functions in EC cells. Our small RNA-sequencing analysis showed that miR-191 is abundantly expressed in HEC-1A and Ishikawa EC cells along with the high expression of miR-182, which was previously characterized as an EC proliferation-related miRNA in EC. We showed that miR-191 was upregulated in EC tissues than in adjacent normal tissues and its knockdown repressed EC cell proliferation. In silico miRNA target screening identified that ten-eleven translocation 1 (TET1) is one of the putative miR-191 targets. TET1 expression could be downregulated by miR-191 through the mRNA-miRNA interaction in the 3'-untranslated region of TET1. In line with TET1 functions as a methylcytosine dioxygenase, which removes genome-wide DNA methylation marks, decreased TET1 expression resulted in hypermethylation in the promotor region of tumour suppressor adenomatous polyposis coli. Taken together, miR-191 could function as an oncogenic miRNA in EC and serve as a prospective diagnostic and therapeutic target for advanced disease.
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http://dx.doi.org/10.1093/jb/mvaa014DOI Listing
July 2020