論文 - 小野 政徳

The Long-Term Outcome of Children Conceived Through Assisted Reproductive Technology

Ono M., Kuji N., Ueno K., Kojima J., Nishi H.

Reproductive Sciences 31 （ 3 ） 583 - 590 2024年03月

ISSN  19337191

　概要を見る

Abstract: Assisted reproductive technology (ART) led to the birth of 60,381 infants in 2020 in Japan. This number is set to increase as the future interest in ART is anticipated to rise. Couples receiving ART are monitoring the outcomes of these treatments to see whether any differences exist between babies conceived naturally and those conceived via ART. This study investigated the relationship between the long-term outcome of children born from ART with a focus on physical and psychomotor developments. A large volume of data concerning each relationship with ART was collected from various observational studies. Several findings indicate that, over time, the physical characteristics of babies born by ART, and those born naturally are comparable. However, some reports indicate that, until they reach school age, there may be a small difference in growth. ART and naturally conceived children do not vary in academic achievement or attention deficit hyperactivity disorder. Taken together, it is difficult to conclude with certainty that ART is the source of these differences since they may arise from the child’s genetic factors or their environment.

• Access to Document (DOI)

BMAL1 positively correlates with genes regulating steroidogenesis in human luteinized granulosa cells

Kawamura T., Dai Y., Ono M., Kikuchi T., Yamanaka A., Ueno K., Kojima J., Fujiwara T., Daikoku T., Maida Y., Ando H., Fujiwara H., Kuji N., Nishi H.

Reproduction 167 （ 2 ）  2024年02月

ISSN  14701626

　概要を見る

In brief: In this study, we examined the relationship between BMAL1 expression and the genes regulating steroid biosynthesis in human luteinized granulosa cells. BMAL1 function is crucial for steroid production and proper ovarian function, highlighting the importance of circadian clock regulation in female reproductive health. Human luteinized granulosa cells were collected to analyze circadian clock gene expression and its effect on the genes regulating steroid biosynthesis. We used siRNA to knock down the expression of BMAL1 in KGN cells. We measured the expression levels of genes regulating steroid biosynthesis and circadian clock RT-qPCR. We demonstrated that BMAL1 expression positively correlates with genes regulating steroid biosynthesis (CYP11A1, CYP19A1, STAR, and ESR2). The knockdown of BMAL1 in KGN cells revealed a significant decrease in steroid synthase expression. In contrast, when BMAL1 was overexpressed in KGN and HGL5 cells, we observed a significant increase in the expression of steroid synthases, such as CYP11A1 and CYP19A1. These results indicated that BMAL1 positively controls 17β-estradiol (E2) secretion in granulosa cells. We also demonstrated that dexamethasone synchronization in KGN cells enhanced the rhythmic alterations in circadian clock genes. Our study suggests that BMAL1 plays a critical role in steroid biosynthesis in human luteinized granulosa cells, thereby emphasizing the importance of BMAL1 in the regulation of reproductive physiology.

• Access to Document (DOI)

Assisted reproductive technology in Japan: A summary report for 2022 by the Ethics Committee of the Japan Society of Obstetrics and Gynecology

Katagiri Y., Jwa S.C., Kuwahara A., Iwasa T., Ono M., Kato K., Kishi H., Kuwabara Y., Taniguchi F., Harada M., Iwase A., Sugino N.

Reproductive Medicine and Biology 23 （ 1 ） e12620 2024年01月

ISSN  14455781

　概要を見る

Purpose: This descriptive analysis evaluated the 2022 assisted reproductive technology (ART) data collected by the Japan Society of Obstetrics and Gynecology registry. Methods and Results: In 2022 (cutoff date 30 November 2023), 634 of 635 registered ART facilities participated; 602 implemented ART treatment, with 543 630 registered cycles and 77 206 neonates (9.1% and 10.6% increases from the previous year). For fresh cycles, freeze-all in vitro fertilization and intracytoplasmic sperm injection cycles increased, resulting in 2183 and 2822 neonates, respectively. In total, 275 296 cycles resulted in oocyte retrieval, with 158 247 (57.5%) freeze-all cycles. Total single embryo transfer (ET) and singleton pregnancy rates were 82.4% and 97.2%, respectively. The singleton live birth rate was 97.4%. The number of frozen–thawed ET (FET) cycles was 264 412, with 98 348 pregnancies and 72 201 neonates. The single ET rate was 85.3%. The rate of singleton pregnancies was 96.9%; that of singleton live births was 96.9%. Per registered cycle, women had a mean age of 37.6 (standard deviation: 4.8) years; 210 322 cycles (38.7%) were conducted for women aged ≥40 years. Conclusions: Significant growth in ART cycles and outcomes reflects the impact of recent expanded insurance coverage.

• Access to Document (DOI)

Reproductive outcomes of embryo cryopreservation and transfer at the start-up phase of fertility preservation in Japan

Takae S., Harada M., Nakamura K., Furuyama S., Ono M., Osuga Y., Suzuki N.

Reproductive Medicine and Biology 23 （ 1 ）  2024年01月

ISSN  14455781

　概要を見る

Purpose: To verify the effectiveness of embryo transfer (ET) using cryopreserved embryo as fertility preservation (FP). Methods: This study was a questionnaire survey. The total number of embryo cryopreservation (EC) was investigated between 2014 and 2020. And for patients who underwent ET among study period, details of EC, outcome of ET, number of live births, and mortality were investigated. Results: Of the 150 facilities, 114 responded (76.0%). A total of 1420 EC were performed during the study period; and ET was performed for 417 patients. Breast cancer was the most common primary disease. A total of 199 live births (including prospective) were obtained by ET; 1.7 EC and 2.2 ET were performed per patient, and live birth rate was 21.4% per ET (28.1% on 35–37-year-old patients). The number of EC and ET increased with age. The final birth rate, including pregnancies other than FP, was 51.8%. Ovarian stimulation with aromatase inhibitors was commonly used, although with no effect on live birth rates. Random start stimulation was also common, experienced by 36.3% of breast cancer patients. Conclusion: Reproductive outcomes of ETs following EC as FP are acceptable. This research project was registered in the University Hospital Medical Information Network (UMIN000043664).

• Access to Document (DOI)

Retrospective comparative study of robot-assisted surgery, laparoscopic surgery, and laparotomy for endometrial cancer in patients with a low risk of recurrence

Hayashi S., Yamanaka Z., Kojima J., Ono M., Sasaki T., Yamamoto A., Ono M., Futagami M., Nishi H.

Journal of Obstetrics and Gynaecology Research 50 （ 1 ） 103 - 112 2024年01月

ISSN  13418076

　概要を見る

Aim: Minimally invasive surgeries for endometrial cancer are increasing worldwide. In Japan, some articles have examined surgical outcomes, but only a few have addressed oncological outcomes. This study aims to compare robot surgery, laparoscopic surgery, and laparotomy in terms of surgical and oncological outcomes within a low-risk group for endometrial cancer recurrence. Methods: This study included patients with endometrial cancer deemed to be at low risk of recurrence and who underwent surgery between January 2011 and December 2020. We studied 99 patients who underwent robot surgery, 85 patients who underwent laparotomy, and 77 patients who underwent laparoscopic surgery. Surgical and oncological outcomes were compared retrospectively for these groups of patients. Results: The median follow-up period was 47, 61, and 60 months in the laparotomy, laparoscopy, and robotic groups, respectively. The three groups had similar perioperative and pathological data. No significant differences in overall survival and disease-free survival were observed among the groups. Univariate and multivariate analyses conducted on the overall study population for disease-free survival and overall survival showed that the surgical approach did not have any influence. Minimally invasive surgery groups had longer operating times compared to the laparotomy group, but they had significantly less blood loss. The number of resected pelvic lymph nodes was similar, and the complication rate was not significant. Conclusions: Robot-assisted surgery and laparoscopic surgery were found to be less invasive and showed similar oncologic outcomes compared to laparotomy surgery for endometrial cancer in patients with a low risk of recurrence.

• Access to Document (DOI)

Miscarriage-Related Acute Kidney Injury: A Case Report

Kojima J., Ono M., Tasaki K., Nagai T., Nagao T., Rinno S., Kanno Y., Yoshida R., Suzuki T., Kuji N., Nishi H.

International Medical Case Reports Journal 17   295 - 300 2024年

　概要を見る

Background: Pregnancy-related acute kidney injury (Pr-AKI) is associated with significant maternal and fetal morbidity and mortality, with a three-to four-fold increase in perinatal mortality. Pr-AKI can arise from various obstetric complications, such as hyperemesis gravidarum, septic abortion, hypertensive disorders of pregnancy, pyelonephritis, and antiphospholipid antibody syndrome. Therefore, early diagnosis and appropriate intervention, including the identification of the underlying etiology, are important to effectively manage Pr-AKI. Therefore, we report a case of Pr-AKI after early miscarriage in a patient without hyperemesis gravidarum or septic abortion whose renal function gradually improved postoperatively for miscarriage. Case Presentation: A 34-year-old primigravid woman was referred to us for perinatal management at 6 weeks of gestation. Unfortunately, she was diagnosed with miscarriage 1 week later. The patient had no history of hyperemesis gravidarum or septic abortion; however, she developed oliguria, and her serum creatinine and blood urea nitrogen levels were abnormally increased. Consequently, she underwent a renal biopsy to evaluate renal dysfunction, which indicated tubulointerstitial damage. The patient also underwent manual vacuum aspiration for a miscarriage. Postoperatively, her urine output increased, and her renal function improved. She was determined to have experienced Pr-AKI due to her miscarriage. Conclusion: Our patient had Pr-AKI after a miscarriage in the absence of other causes. This case report highlights the presence of unknown causes of Pr-AKI, warranting further research for the development of preventive interventions.

• Access to Document (DOI)

Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus

Sasaki T., Suzuki S., Ono M., Yamamoto A., Bingo M., Yamanaka G., Kuroda M., Inagaki N., Nishi H.

Frontiers in Medicine 11 2024年

　概要を見る

The nuclear receptor subfamily 5 group A member 1 (NR5A1) gene encodes NR5A1, also known as steroidogenic factor 1, a crucial transcriptional factor regulating adrenal and gonadal development and function. Although pathogenic variants in NR5A1 are known to cause a spectrum of disorders of sex development (DSD), individuals with 46,XY DSD with fully female internal and external genitalia are relatively rare. Herein, we present the case of a patient with 46,XY complete gonadal dysgenesis (CGD) who had a non-communicating rudimentary uterus due to a c.132_134del (p.Asn44del) heterozygous in-frame-deletion in NR5A1 that was diagnosed while treating a pelvic mass in which gynecological malignancy could not be disregarded. Unlike two previous cases with the p.Asn44del variant, this case presented with CGD, a severe DSD phenotype, and we found that the oligogenic inheritance of DSD-causative genes such as SRY, DHX37, SLC26A8, and CFTR may have affected the severity of the clinical phenotype.

• Access to Document (DOI)

Imeglimin profoundly affects the circadian clock in mouse embryonic fibroblasts

Miura K., Morishige J.i., Abe J., Xu P., Shi Y., Jing Z., Nagata N., Miyazaki R., Sakane N., Mieda M., Ono M., Maida Y., Fujiwara T., Fujiwara H., Ando H.

Journal of Pharmacological Sciences 153 （ 4 ） 215 - 220 2023年12月

ISSN  13478613

　概要を見る

Objective: Imeglimin is a novel antidiabetic drug structurally related to metformin. Metformin has been shown to modulate the circadian clock in rat fibroblasts. Accordingly, in the present study, we aimed to determine whether imeglimin can impact the circadian oscillator in mouse embryonic fibroblasts (MEFs). Methods: MEFs carrying a Bmal1-Emerald luciferase (Bmal1-ELuc) reporter were exposed to imeglimin (0.1 or 1 mM), metformin (0.1 or 1 mM), a nicotinamide phosphoribosyltransferase inhibitor FK866, and/or vehicle. Subsequently, Bmal1-ELuc expression and clock gene mRNA expression levels were measured at 10-min intervals for 55 h and 4-h intervals for 32 h, respectively. Results: Imeglimin significantly prolonged the period (from 26.3 to 30.0 h at 0.1 mM) and dose-dependently increased the amplitude (9.6-fold at 1 mM) of the Bmal1-ELuc expression rhythm; however, metformin exhibited minimal effects on these parameters. Moreover, imeglimin notably impacted the rhythmic mRNA expression of clock genes (Bmal1, Per1, and Cry1). The concurrent addition of FK866 partly inhibited the effects of imeglimin on both Bmal1-ELuc expression and clock gene mRNA expression. Conclusion: Collectively, these results reveal that imeglimin profoundly affects the circadian clock in MEFs. Further studies are needed to evaluate whether imeglimin treatment could exert similar effects in vivo.

• Access to Document (DOI)

Laeverin/aminopeptidase Q induces indoleamine 2,3-dioxygenase-1 in human monocytes

Suzuki T., Iizuka T., Kagami K., Matsumoto T., Yamazaki R., Daikoku T., Horie A., Ono M., Hattori A., Fujiwara H.

Iscience 26 （ 9 ）  2023年09月

　概要を見る

Human extravillous trophoblast (EVT) invades the maternal endometrium and reconstructs uterine spiral arteries cooperatively with maternal immune cells. Although EVT has allogeneic paternal antigens, the maternal immune system does not reject it. Here, we found that laeverin (LVRN), an EVT-specific cell surface peptidase, interacts with monocytes to produce indoleamine 2,3-dioxygenase-1 (IDO1). LVRN-transfected Swan71 cells, a cytotrophoblast-derived cell line, and increased IDO1 expression in PBMC under cell-to-cell interacting conditions. Soluble recombinant LVRN (r-LVRN) interacted with CD14-positive monocytes and induced their IDO1 expression without the intervention of other immune cell populations. LVRN-induced IDO1 production was promoted in PMA-activated monocyte-like THP-1 cells. Furthermore, r-LVRN decreased the tryptophan level and increased the kynurenine/tryptophan ratio in the culture media of the PMA-treated THP-1 cells. These findings suggest that LVRN is one of the key molecules that mediate the interaction between EVT and monocytes/macrophages and creates an immunosuppressive environment at the maternal-fetal interface in the uterus.

• Access to Document (DOI)

Effect of a web-based fertility preservation training program for medical professionals in Japan

Ono M., Harada M., Horie A., Dai Y., Horiguchi I., Kikuchi E., Kimura F., Koizumi T., Komeya M., Mizunuma N., Oseto K., Ota K., Shimizu C., Sugimoto K., Takae S., Takeuchi E., Nishi H., Yumura Y., Furui T., Takai Y., Morishige K.I., Watanabe C., Osuga Y., Suzuki N.

International Journal of Clinical Oncology 28 （ 9 ） 1112 - 1120 2023年09月

ISSN  13419625

　概要を見る

Background: Our web-based training program called “Educating Medical Professionals about Reproductive Issues in Cancer Healthcare” aims to help healthcare professionals communicate promptly with patients and survivors who are adolescents and young adults, with information pertinent to reproductive health issues such as the risk of infertility and fertility preservation. Methods: The study participants were professional healthcare providers, including physicians, nurses, pharmacists, social workers, midwives, psychologists, laboratory technicians, genetic counselors, and dieticians. Pre- and post- and 3-month follow-up tests consisting of 41 questions were administered to measure changes in knowledge and confidence. The participants also received a follow-up survey that covered confidence, communication techniques, and practice habits. A total of 820 healthcare providers participated in this program. Results: The mean total score from the pre-test to the post-test grew significantly (p < 0.01), and participants’ self-confidence increased. In addition, there was a change in the behavior of healthcare providers, who began asking about patients’ marital status and parity. Conclusion: Our web-based fertility preservation training program improved knowledge and self-confidence regarding fertility preservation issues among healthcare providers caring for adolescents and young adult cancer patients and survivors.

• Access to Document (DOI)

Multicenter, 2-dose single-group controlled trial of tacrolimus for the severe infertility patients

Hisano M., Nakagawa K., Ono M., Yoshino O., Saito T., Hirota Y., Inoue E., Kikuchi K., Nakamura H., Yamaguchi K.

Medicine United States 102 （ 32 ） E34317 2023年08月

ISSN  00257974

　概要を見る

Introduction: Infertility is estimated to affect 8% to 12% of reproductive-aged couples worldwide. While approximately 85% of infertile couples have an identified cause, the remaining 15% suffer physically and emotionally from unexplained intractable infertility. In recent years, maternal-to-fetal immunological abnormalities have attracted attention as mechanisms that differ from the conventional factors contributing to infertility and pregnancy loss. A T-helper 2 (Th2)-dominant immune state has been proposed as a maternal immune alteration to eliminate rejection and induce tolerance to a semi-allogeneic fetus. An imbalance in Th1 responses would not induce adequate maternal immune tolerance to the fetus or early embryos. Tacrolimus, widely used as an immunosuppressant agent in solid organ transplant recipients, is expected to suppress maternal rejection and promote tolerance to early embryos after assisted reproductive technology by modulating the immunological environment of the preimplantation endometrium. We planned an exploratory clinical trial to determine the efficacy, safety, and dosage of tacrolimus in women with intractable infertility. Methods and analysis: This is a multicenter, 2-dose, single-group controlled trial in infertile women who failed to achieve a chemical pregnancy despite multiple in vitro fertilization (IVF) and embryo transfer (ET) treatment cycles. The following 2 key selection criteria were set: no underlying factors of infertility despite appropriate evaluation and presence of Th1-dominant immune state, defined as a Th1/Th2 cell ratio ≥ 10.3 in the peripheral blood. A total of 26 eligible participants are randomly assigned (in a 2:1 ratio) to receive immunosuppressive therapy with oral tacrolimus at a daily dose of 2 mg or 4 mg. Tacrolimus is administered for 16 days starting from 2 days before ET. The primary endpoint is the presence of clinical pregnancy 3 weeks after IVF/ET treatment, and the secondary endpoint is the presence of biochemical pregnancy 2 weeks after IVF/ET treatment. Safety evaluation and biomarker discovery for tacrolimus treatment in infertile women will be conducted simultaneously. Trial registration number: Japan Registry of Clinical Trials (jRCT; jRCTs031220235).

• Access to Document (DOI)

Current Status and Issues of the Japan Oncofertility Registry

Shigematsu K., Shimizu C., Furui T., Kataoka S., Kawai K., Kishida T., Kuwahara A., Maeda N., Makino A., Mizunuma N., Morishige K.I., Nakajima T.E., Ota K., Ono M., Shiga N., Tada Y., Takae S., Tamura N., Watanabe C., Yumura Y., Suzuki N., Takai Y.

Journal of Adolescent and Young Adult Oncology 12 （ 4 ） 584 - 591 2023年08月

ISSN  21565333

　概要を見る

Purpose: Fertility preservation (FP) is becoming increasingly common among child, adolescent, and young-adult (CAYA) patients with cancer. However, Japan has long lacked definite estimates of utilization rates for FP services among CAYA patients with cancer, and little is known about disease/FP outcomes among users. Therefore, the Japan Society for Fertility Preservation (JSFP) launched the Japan Oncofertility Registry (JOFR) in 2018 and started the online registration of information regarding primary disease, FP, and data on prognosis and pregnancy outcomes. This study reports the analytical results of FP data registered in the JOFR as of 2021. Methods: Data about patients’ primary disease(s), treatment courses, cancer and pregnancy outcomes, and specific procedures were extracted from the JOFR and analyzed. Results: In 2021, 1244 patients received counseling or treatment related to FP (540 males, 704 females). While the numbers of males in each age group were approximately equal, most females were aged between 31 and 40 years. In total, 490 male and 540 female patients underwent FP procedures. Leukemia, testicular cancer, and malignant lymphoma accounted for the majority of male cases seeking treatment, whereas breast cancer was the primary disease in two-thirds of the females. Since 1999, 395 patients have accumulatively experienced subsequent pregnancy. Conclusions: As of January 2022, >7000 cases from >100 fertility facilities have been registered in the JOFR. In the future, maintaining JOFR to disseminate information on cancer prognoses, pregnancy rates, and other oncofertility outcomes is expected to drive further expansion of oncofertility services in Japan.

• Access to Document (DOI)

Desynchronization between Food Intake and Light Stimulations Induces Uterine Clock Quiescence in Female Mice

Nomura S., Hosono T., Ono M., Daikoku T., Michihiro M., Kagami K., Iizuka T., Chen Y., Shi Y., Morishige J.i., Fujiwara T., Fujiwara H., Ando H.

Journal of Nutrition 153 （ 8 ） 2283 - 2290 2023年08月

ISSN  00223166

　概要を見る

Background: Dysmenorrhea is associated with breakfast skipping in young women, suggesting that fasting in the early active phase disrupts uterine functions. Objectives: To investigate the possible involvement of the uterine clock system in fasting-induced uterine dysfunction, we examined core clock gene expressions in the uterus using a 28-h interval-fed mouse model. Methods: Young female mice (8 wk of age) were divided into 3 groups: group I (ad libitum feeding), group II (time-restricted feeding, initial 4 h of the active period every day), and group III (time-restricted feeding for 8 h with a 28-h cycle). Groups II and III have the same fasting interval of 20 h. After analyzing feeding and wheel running behaviors during 2 wk of dietary restriction, mice were sacrificed at 4-h intervals, and the expression profiles of clock genes in the uterus and liver were examined by qPCR. Results: The mice in group I took food mainly during the dark phase and those in group II during the initial 4 h of the dark phase, whereas those in group III delayed feeding time by 4 h per cycle. In all groups, spontaneous wheel running was observed during the dark phase. There was no difference in the quantity of feeding and the amount of running exercise among the 3 groups during the second week. The mRNA expressions of peripheral clock genes, Bmal1, Clock, Per1, Per2, Cry1, Nr1d1, and Dbp and a clock-controlled gene, Fabp1, in the uterus showed rhythmic oscillations with normal sequential expression cascade in groups I and II, whereas their expressions decreased and circadian cycles disappeared in group III. In contrast, liver core clock genes in group III showed clear circadian cycles. Conclusions: Fluctuations in the timing of the first food intake impair the uterine clock oscillator system to reduce clock gene expressions and abolish their circadian rhythms.

• Access to Document (DOI)

Spheroid formation induces chemokine production in trophoblast-derived Swan71 cells

Kanda T., Kagami K., Iizuka T., Kasama H., Matsumoto T., Sakai Y., Suzuki T., Yamamoto M., Matsuoka A., Yamazaki R., Hattori A., Horie A., Daikoku T., Ono M., Fujiwara H.

American Journal of Reproductive Immunology 90 （ 2 ）  2023年08月

ISSN  10467408

　概要を見る

Problem: In the cell column of anchoring villi, the cytotrophoblast differentiates into extravillous trophoblast (EVT) and invades the endometrium in contact with maternal immune cells. Recently, chemokines were proposed to regulate the decidual immune response. To investigate the roles of chemokines around the anchoring villi, we examined the expression profiles of chemokines in the first-trimester trophoblast-derived Swan71 cells using a three-dimensional culture model. Method of Study: The gene expressions in the spheroid-formed Swan71 cells were examined by microarray and qPCR analyses. The protein expressions were examined by immunochemical staining. The chemoattractant effects of spheroid-formed Swan71 cells were examined by migration assay using monocyte-derived THP-1 cells. Results: The expressions of an EVT marker, laeverin, and matrix metalloproteases, MMP2 and MMP9, were increased in the spheroid-cultured Swan71 cells. Microarray and qPCR analysis revealed that mRNA expressions of various chemokines, CCL2, CCL7, CCL20, CXCL1, CXCL2, CXCL5, CXCL6, CXCL8, and CXCL10, in the spheroid-cultured Swan71 cells were up-regulated as compared with those in the monolayer-cultured Swan71 cells. These expressions were significantly suppressed by hypoxia. Migration assay showed that culture media derived from the spheroid-formed Swan71 cells promoted THP-1 cell migration. Conclusion: This study indicated that chemokine expressions in Swan71 cells increase under a spheroid-forming culture and the culture media have chemoattractant effects. Since three-dimensional cell assembling in the spheroid resembles the structure of the cell column, this study also suggests that chemokines play important roles in the interaction between EVT and immune cells in their early differentiation stage.

• Access to Document (DOI)

Text mining in a literature review of abnormal uterine bleeding according to the FIGO classification

Ono M., Hiraike O., Kitahara Y., Maekawa R., Ota I., Yoshino O., Takai Y., Iwase A.

Journal of Obstetrics and Gynaecology Research 49 （ 7 ） 1827 - 1837 2023年07月

ISSN  13418076

　概要を見る

Aim: Abnormal uterine bleeding, as proposed in 2007, is defined as unexpected uterine bleeding in women of reproductive age; the cause of the bleeding is categorized using the PALM-COEIN system. Identifying the diagnostic and treatment modalities for each cause might be intriguing. To summarize the options for abnormal uterine bleeding assessment, we employed text-mining analysis for each of its causes. Methods: We analyzed abstracts based on PALM-COEIN from PubMed and Web of Science in March 2022. The literature was divided into categories; topics about the disorders were retrieved, and covalent network analysis was conducted to find information for evaluating abnormal uterine bleeding. Results: Diagnostic approaches for PALM included histological and image analysis, including computerized tomography, magnetic resonance imaging, sonography, and hysteroscopy. The therapeutic approaches varied according to the cause. Diagnostic approaches for COEIN were mostly medical history interviews and blood sampling, and the therapeutic approaches for COEIN were ablation, hysteroscopy, and hormonal treatment. The PALM-COEIN classification co-occurrence search revealed each cause's diagnostic procedures, symptoms, and treatment procedures. Conclusion: Our text-mining methodology revealed comprehensive insights, important study themes, and clinical trends for abnormal uterine bleeding. A tailored approach to medical realities is required for treating abnormal uterine bleeding properly.

• Access to Document (DOI)

Androgen promotes squamous differentiation of atypical cells in cervical intraepithelial neoplasia via an ELF3-dependent pathway

Matsumoto T., Suzuki T., Nakamura M., Yamamoto M., Iizuka T., Ono M., Kagami K., Kasama H., Kanda T., Sakai Y., Iwadare J., Matsuoka A., Kayahashi K., Wakae K., Muramatsu M., Kyo S., Yamamoto Y., Mizumoto Y., Daikoku T., Fujiwara H.

Cancer Medicine 12 （ 9 ） 10816 - 10828 2023年05月

　概要を見る

Background: Since the human papillomavirus vaccines do not eliminate preexisting infections, nonsurgical alternative approaches to cervical intraepithelial neoplasia (CIN) have been required. We previously reported that FOXP4 (forkhead box transcription factor P4) promoted proliferation and inhibited squamous differentiation of CIN1-derived W12 cells. Since it was reported that FOXP expressions were regulated by the androgen/androgen receptor (AR) complex and AR was expressed on the CIN lesions, in this study we examined the effects of androgen on CIN progression. Methods: Since AR expression was negative in W12 cells and HaCaT cells, a human male skin-derived keratinocyte cell line, we transfected AR to these cell lines and investigated the effects of dihydrotestosterone (DHT) on their proliferation and squamous differentiation. We also examined the immunohistochemical expression of AR in CIN lesions. Results: DHT reduced the intranuclear expression of FOXP4, attenuating cell proliferation and promoting squamous differentiation in AR-transfected W12 cells. Si-RNA treatments showed that DHT induced the expression of squamous differentiation-related genes in AR-transfected W12 cells via an ELF3-dependent pathway. DHT also reduced FOXP4 expression in AR-transfected HaCaT cells. An immunohistochemical study showed that AR was expressed in the basal to parabasal layers of the normal cervical epithelium. In CIN1 and 2 lesions, AR was detected in atypical squamous cells, whereas AR expression had almost disappeared in the CIN3 lesion and was not detected in SCC, suggesting that androgens do not act to promote squamous differentiation in the late stages of CIN. Conclusion: Androgen is a novel factor that regulates squamous differentiation in the early stage of CIN, providing a new strategy for nonsurgical and hormone-induced differentiation therapy against CIN1 and CIN2.

• Access to Document (DOI)

Hypoxia-induced paclitaxel resistance in cervical cancer modulated by miR-100 targeting of USP15

Nishi H., Ono M., Ohno S., Yamanaka Z., Sasaki T., Ohyashiki K., Ohyashiki J.H., Kuroda M.

Gynecologic Oncology Reports 45 2023年02月

　概要を見る

Objective: Hypoxia, which occurs during the development of cervical cancer, confers chemotherapy resistance. MicroRNA expression is regulated by hypoxia and is associated with the onset and progression of certain types of cancer. MicroRNA-100 (miR-100) is a microRNA, associated with nasopharyngeal and oral squamous cell carcinomas, whose expression is decreased in cervical cancer. This study aims to ascertain the effect of hypoxia on expression levels of both miR-100 and its target genes, as well as exploring the sensitivity to paclitaxel under hypoxic conditions. Methods: We investigated the effect of hypoxia on miR-100 expression. We also explored the regulators of paclitaxel response under hypoxic conditions of cervical cancer. Results: Using RT-qPCR, we found that expression of miR-100 in cervical cancer cell lines SiHa and HeLa is significantly higher under hypoxic conditions (1% O<inf>2</inf>). We also confirmed that human ubiquitin-specific protease 15 (USP15) is the one of the target proteins of miR-100. Hypoxia and overexpression of miR-100 both reduced the activity of the luciferase reporter containing the 3′-untranslated region of USP15, which contains the miR-100 binding site. Furthermore, a western blot analysis showed that hypoxia suppresses the expression of the USP15 protein, while RT-qPCR showed hypoxia-induced downregulation of USP15 mRNA levels. We also discovered that overexpression of miR-100 induces paclitaxel resistance, thereby reducing the drug's therapeutic effect on cell death. Conclusions: Our results are consistent with the hypothesis that cervical cancer cells overexpress miR-100 in response to hypoxia and that miR-100 is a facilitator of USP15 downregulation and inactivation.

• Access to Document (DOI)

Pivotal Role of Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) in Uterine Leiomyoma

Suzuki T., Dai Y., Ono M., Kojima J., Sasaki T., Fujiwara H., Kuji N., Nishi H.

Biomolecules 13 （ 2 ）  2023年02月

　概要を見る

Uterine leiomyomas are smooth-muscle tumors originating in the myometrium and are the most common pelvic tumors in women of reproductive age. Symptomatic tumors may result in abnormal uterine bleeding, bladder dysfunction, pelvic discomfort, and reproductive issues, such as infertility and miscarriage. There are currently few non-invasive treatments for leiomyoma, but there are no practical early intervention or preventive methods. In this study, human uterine leiomyoma and myometrial tissues were used to detect the protein and mRNA expression levels of UCHL1. To explore the effects of UCHL1 knockdown and inhibition in leiomyoma and myometrial cells, we determined the mRNA expressions of COL1A1 and COL3A1. Collagen gel contraction and wound-healing assays were performed on myometrial and leiomyoma cells. We found that UCHL1 expression was considerably higher in uterine leiomyomas than in the myometrium. COL1A1 and COL3A1 expression levels were downregulated after inhibition of UCHL1 in human leiomyoma cells. Furthermore, the elimination of UCHL1 significantly decreased the migration and contractility of leiomyoma cells. In conclusion, these results indicate that UCHL1 is involved in the growth of leiomyoma in humans. For the treatment of uterine leiomyoma, targeting UCHL1 activity may be a unique and possible therapeutic strategy.

• Access to Document (DOI)

Two oxytocin analogs, N-(p-fluorobenzyl) glycine and N-(3-hydroxypropyl) glycine, induce uterine contractions ex vivo in ways that differ from that of oxytocin

Cherepanov S.M., Yuhi T., Iizuka T., Hosono T., Ono M., Fujiwara H., Yokoyama S., Shuto S., Higashida H.

Plos One 18 （ 2 February ）  2023年02月

　概要を見る

Contraction of the uterus is critical for parturient processes. Insufficient uterine tone, resulting in atony, can potentiate postpartum hemorrhage; thus, it is a major risk factor and is the main cause of maternity-related deaths worldwide. Oxytocin (OT) is recommended for use in combination with other uterotonics for cases of refractory uterine atony. However, as the effect of OT dose on uterine contraction and control of blood loss during cesarean delivery for labor arrest are highly associated with side effects, small amounts of uterotonics may be used to elicit rapid and superior uterine contraction. We have previously synthesized OT analogs 2 and 5, prolines at the 7^th positions of which were replaced with N-(p-fluorobenzyl) glycine [thus, compound 2 is now called fluorobenzyl (FBOT)] or N-(3-hydroxypropyl) glycine [compound 5 is now called hydroxypropyl (HPOT)], which exhibited highly potent binding affinities for human OT receptors in vitro. In this study, we measured the ex vivo effects of FBOT and HPOT on contractions of uteri isolated from human cesarean delivery samples and virgin female mice. We evaluated the potency and efficacy of the analogs on uterine contraction, additivity with OT, and the ability to overcome the effects of atosiban, an OT antagonist. In human samples, the potency rank judged by the calculated EC<inf>50</inf> (pM) was as follows: HPOT (189) > FBOT (556) > OT (5,340) > carbetocin (12,090). The calculated Emax was 86% for FBOT and 75% for HPOT (100%). Recovery from atosiban inhibition after HPOT treatment was as potent as that after OT treatment. HPOT showed additivity with OT. FBOT (56 pM) was found to be the strongest agonist in virgin mouse uterus. HPOT and FBOT demonstrated high potency and partial agonist efficacy in the human uterus. These results suggested that HPOT and FBOT are highly uterotonic for the human uterus and performed better than OT, indicating that they may prevent postpartum hemorrhage.

• Access to Document (DOI)

Assisted reproductive technology in Japan: A summary report for 2020 by the ethics Committee of the Japan Society of obstetrics and gynecology

Katagiri Y., Jwa S.C., Kuwahara A., Iwasa T., Ono M., Kato K., Kishi H., Kuwabara Y., Harada M., Hamatani T., Osuga Y.

Reproductive Medicine and Biology 22 （ 1 ）  2023年01月

ISSN  14455781

　概要を見る

Purpose: Since 1986, the Japan Society of Obstetrics and Gynecology assisted reproductive technology (ART) registry system has collected data on national ART use and outcomes trends in Japan. Herein, we describe the characteristics and outcomes of ART cycles registered during 2020 and compare the results with those from 2019. Methods and Results: In 2020, 621 ART facilities participated in the registration. The total number of registered cycles was 449 900, and there were 60 381 live births, which decreased from the previous year (1.79% and 0.36% decrease, respectively). The number of freeze-all in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles increased in 2020, and the number of neonates born was 2282 for IVF-embryo transfer (ET) cycles and 2596 for ICSI cycles, which had decreased from the previous year. Frozen–thawed ET (FET) cycles had slightly increased from 2019 (0.04%). In 2020, 215 285 FET cycles were conducted, resulting in 76 196 pregnancies and 55 503 neonates. Single ET was performed in 81.6% of fresh transfers and 85.1% of frozen–thawed cycles, respectively, resulting in over 97% singleton pregnancies/livebirths rates. Conclusion: Despite the COVID-19 pandemic during 2020, the overall number of ART cycles and neonates born demonstrated only a slight decrease in 2020 compared with 2019.

• Access to Document (DOI)