研究者詳細 - 小野政徳

論文 - 小野政徳

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Acute and chronic effects of imeglimin on peripheral circadian clocks in mice

Shi Y., Xu P., Morishige J.I., Yang Y., Iba T., Nagata N., Hosono T., Miyazaki R., Sakane N., Ono M., Fujiwara T., Fujiwara H., Ando H.

Journal of Pharmacological Sciences 160 （ 1 ） 51 - 58 2026年01月

ISSN 1347-8613

OBJECTIVE: This study aimed to investigate the acute and chronic effects of imeglimin, a novel antidiabetic agent, on peripheral circadian clocks in mice under a 12-h/12-h light/dark cycle. METHODS: Female C57BL/6J mice were administered imeglimin either as a single oral dose at Zeitgeber time (ZT) 0 or 12 (acute study) or via a 0.2 % admixture in chow for 4 weeks (chronic study). Clock gene mRNA expression in skeletal muscle and liver was analyzed by quantitative real-time PCR. RESULTS: Acute imeglimin administration at ZT 12 increased the peak mRNA expression of clock genes (Nr1d1 and Dbp in skeletal muscle; Per2 in liver), whereas dosing at ZT 0 decreased Nr1d1 and Dbp in both tissues. In the chronic study, imeglimin decreased the peak expression of Nr1d1 and Dbp in skeletal muscle, while liver rhythms remained unchanged. Nampt and Sirt1 expression was unaffected in either tissue. CONCLUSION: In this study, we demonstrated that imeglimin alters peripheral clock gene expression in healthy mice under both acute bolus administration and chronic mixed-feeding conditions. Further studies are warranted to clarify underlying mechanisms and their physiological relevance.

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Assisted Reproductive Technology in Japan: A Summary Report for 2023 by the Committee on Professional Scientific Conduct and Clinical Ethics 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 25 （ 1 ） e70008 2026年01月

ISSN 14455781

Purpose: To summarize assisted reproductive technology (ART) data for 2023 collected through the Japan Society of Obstetrics and Gynecology registry. Methods and Results: 625 out of 638 registered ART facilities took part in the study, documenting 561 664 treatment cycles and 85 048 newborns (+3.3% and +10.2% increases from 2022). The average age of women undergoing treatment was 37.3 years (standard deviation: 4.8); 205 986 cycles (36.7%) involved women aged ≥ 40 years. Among fresh cycles, oocyte retrieval was performed in 281 665 cycles, including 168 343 freeze-all cycles (59.8%). A total of 2329 pregnancies and 3375 newborns resulted from in vitro fertilization and intracytoplasmic sperm injection cycles, yielding 1772 and 2502 newborns, respectively. The overall rates for single embryo transfer (SET) and singleton delivery were 80.5% and 96.5%. Frozen–thawed embryo transfer accounted for 271 361 cycles, resulting in 109 850 pregnancies and 80 774 newborns, with a SET rate of 84.7% and a singleton delivery rate of 96.3%. Conclusions: In 2023, the second year of insurance coverage, the registry recorded the highest numbers of treatment cycles and newborns. Effective registry systems planned for 2026 will enable comprehensive evaluation of emerging trends in Japanese ART practice.

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Laeverin is Cell-Surface Target for Liquid-Phase Metastasizing Cancer Cells

Kasama H., Sakai Y., Kagami K., Iizuka T., Kanda T., Suzuki T., Kayahashi K., Ono M., Fujiwara T., Yagi S., Inaki N., Matsumoto I., Yamazaki R., Abiko K., Matsumura N., Hattori A., Daikoku T., Fujiwara H.

Advanced Science 12 （ 47 ） 2025年12月

Laeverin (LVRN) is a cell-surface immunoregulatory factor that is specifically expressed in embryo-derived extravillous trophoblast, which invades maternal spiral arteries without immune rejection during human placentation. Here, it is found that various epithelial cancer cell lines upregulated LVRN expression in association with the expression of POU5F1 after spheroid formation under floating conditions. Immunohistochemically, LVRN expression is detected in the lesions of vascular, lymphatic, and peritoneal invasion of ovarian, cervical, endometrial, breast, and lung cancers. LVRN-positive circulating tumor cells are also identified in the blood of uterine cervical and endometrial cancers, showing that LVRN expression is induced in cancer cells in the distant metastatic phase. Monomethylauristatin E-conjugated anti-LVRN antibody induced cell death in ovarian cancer-derived cell lines in the liquid phase in vitro and inhibited their peritoneal dissemination in nude mice in vivo. These findings indicate that LVRN is a unique and promising cell-surface target molecule for liquid-phase metastasizing cancer cells.

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Novel Subtype Classification of Diffuse Uterine Leiomyomatosis Based on a Nationwide Survey in Japan

Ishikawa H., Asano R., Ono M., Kitade M., Kusumi M., Tsuji S., Nakamura T., Maekawa R., Goto Y., Takada A., Koga K.

Journal of Obstetrics and Gynaecology Research 51 （ 12 ） 2025年12月

ISSN 13418076

Aim: Diffuse uterine leiomyomatosis (DUL) is characterized by numerous uterine leiomyomas within and diffusely replacing the myometrium. However, because of its rarity, the prevalence, diagnostic criteria, and standard treatment for patients with DUL who wish to preserve their fertility remain unknown. This study aimed to clarify the current status of the diagnosis of DUL in Japan. Methods: We conducted a web-based survey targeting 1080 Obstetrics and Gynecology training institutions registered with the Japanese Medical Specialty Board. We asked them whether they had treated patients with DUL over the past 10 years (2013–2022). We obtained magnetic resonance imaging (MRI) scans from institutions that reported clinical experience with DUL, and conducted a central review to determine whether each case was consistent with DUL. We also investigated whether DUL could be classified into subtypes. Results: Responses were obtained from 428 institutions, of which 128 reported clinical experience with DUL or DUL-like multiple uterine leiomyomas, totaling 653 cases. MRI scans from 408 cases were centrally reviewed by a subcommittee, and 307 cases were confirmed as DUL. Based on the imaging characteristics, DUL was classified into three subtypes: total replacement, myometrial replacement, and submucosal-dominant. Conclusions: This survey revealed that 653 cases of DUL or DUL-like multiple uterine leiomyomas were managed over a 10-year period in Japan. Based on a central review of MRI scans, DUL can be classified into three distinct subtypes. Given the differences between these subtypes, treatment approaches for patients wishing to preserve fertility may vary, highlighting the need for further investigation.

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Modified screening of MYC promotor region elements using the CRISPR library in ovarian cancer

Yamamoto A., Tanaka Y., Ishibashi S., Ikeda M., Sugita K., Ono M., Nishi H., Kurata M.

Journal of Ovarian Research 18 （ 1 ） 2025年12月

Ovarian cancer remains one of the most lethal gynecological malignancies owing to its high recurrence rate and chemotherapeutic resistance. MYC is a well-known proto-oncogene that is frequently amplified in ovarian cancer and has been implicated in drug resistance. Previously, we established a new promoter–reporter system combined with a CRISPR activation library to identify unknown MYC regulators, and M1AP was identified as a novel MYC regulator. However, considering the insufficient explanation for the absence of guide RNA (gRNA) of MYC, this present study explored methods to prevent the gRNA of MYC itself from binding. This study first modified the promoter–reporter vector to improve its quality, then conducted CRISPR screening and analyzed candidate genes as MYC promoter regulators using next-generation sequencing in OVSAHO ovarian cancer cells. Eighty-six genes had ≥ 1000 reads, and Pearson’s correlation coefficient analysis was performed on the cBioPortal of the Cancer Genomics database. Fourteen genes were identified as candidate MYC regulators with positive and significant correlations with MYC. Seven genes, including CYP4v2, ASPH, ANP32D, PCED1A, ABI1, FUZ, and HOOK2, demonstrated significantly higher luciferase activity than the control genes. Four genes, including ABI1, PCED1A, HOOK2, and CYP4v2, activated the MYC promoter, which showed over twofold higher activity than the control when overexpressed using a vector. In conclusion, four genes that activate MYC promoters were identified in an ovarian cancer cell line using the CRISPR library system with a modified promoter–reporter tool. These results will prove helpful in the development of novel treatment strategies for ovarian cancer.

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Role of Transcription Factor, LIM Homeobox 9 (LHX9) in Inflammatory Response by PGE2 and Thrombin in SERPINA1-Silencing Endometrial Stromal Cells

Kusama K., Ashihara M., Okita M., Yoshida K., Suzuki M., Suzuki K., Hosokawa R., Yoshie M., Kojima J., Mizuno Y., Ono M., Nishi H., Kajihara T., Tamura K.

Molecular Reproduction and Development 92 （ 8 ） 2025年08月

ISSN 1040452X

Endometriosis is hypothesized to result from retrograde menstruation where cell debris including endometrial stromal cells (ESCs) travel through the fallopian tubes. This chronic inflammatory disease is characterized by inflammatory and fibrotic endometrial tissue. We have previously observed reduced expression of the anti-inflammatory factor SERPINA1 in endometriosis-like lesions in a mouse model implanted with human ESCs. Additionally, pro-inflammatory factors present in peritoneal hemorrhage exacerbated inflammation in these grafts, partly through prostaglandin (PG) E2 and thrombin. However, it remains unclear whether the reduction of SERPINA1, in combination with PGE2 and thrombin, synergistically influences the expression of inflammatory factors in endometriosis lesions and the underlying mechanisms. We analyzed RNA sequencing data from ESCs treated with SERPINA1 siRNA and PGE2/thrombin, comparing them to data sets derived from ESCs subjected to either SERPINA1 knockdown or PGE2/thrombin treatment. Comparative analysis identified 49 transcripts that were upregulated under both conditions and enriched for transcription regulatory genes, including SNAI1, HDAC5, PBX1, SOX4, EPAS1, LHX9, and MAFK. Silencing SNAI1, HDAC5, SOX4, EPAS1, or LHX9 suppressed IL6, CXCL8, and IL1B expression, which had been upregulated by SERPINA1 siRNA and PGE2/thrombin. Among these genes, LHX9 expression was significantly elevated in ectopic lesions, predominantly localized to stromal and glandular epithelial cells, with more pronounced expression during the secretory phase. LHX9 levels were also increased in endometriotic lesions compared to the normal endometrium. In conclusion, reduced SERPINA1 expression in ectopic ESCs, combined with PGE2/thrombin, induces inflammatory cytokine expression linked to LHX9. Pharmacological targeting of LHX9 may present a promising therapeutic strategy for mitigating chronic inflammation in endometriotic lesions.

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Cumulative ongoing pregnancy and live birth rates after assisted reproduction among women with diminished ovarian reserve: A multi-institutional retrospective cohort study

Kobayashi M., Asada Y., Sugishita Y., Osuka S., Kitajima M., Kawamura K., Shirasawa H., Tsuzuki T., Yamada M., Huang H., Jwa S.C., Suzuki T., Kanasaki H., Kuroda K., Ono M., Katagiri Y., Noguchi H., Fukui A., Wada-Hiraike O., Masaki K., Kitahara Y., Iwase A.

Journal of Obstetrics and Gynaecology Research 51 （ 6 ） e16336 2025年06月

ISSN 13418076

Aim: To examine the cumulative ongoing pregnancy/live birth rate per patient by encompassing all embryo transfer (ET) cycles associated with a single oocyte retrieval cycle among women with diminished ovarian reserve (DOR), and to investigate whether serum anti-Müllerian hormone (AMH) levels can predict a live birth success. Methods: This multi-institutional retrospective cohort study included infertile women with DOR (AMH <1.1 ng/mL) who began their first cycle of in vitro fertilization and/or intracytoplasmic sperm injection between January and December 2021. Outcomes using the retrieved embryos were evaluated for up to four ET cycles. Results: Of 606 patients, 113 did not undergo ET. A total of 605 ET cycles were analyzed. Clinical pregnancy and ongoing pregnancy/live birth rates per ET cycle were significantly dependent on age, not AMH levels. Ongoing pregnancy/live birth rates per patient increased significantly with higher AMH levels. A significant difference in the cumulative ongoing pregnancy/live birth rate was observed depending on whether cases with no remaining embryos were included among the censored cases. Conclusion: Assisted reproductive technology (ART) outcomes per ET cycle in women with DOR were similar to those reported in the Japanese ART registry without distinguishing DOR. The greater the number of good-quality embryos that can be frozen, the higher the expected cumulative live birth rate.

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BMAL1 Regulates Collagen Production in the Myometrium and Leiomyomas

Dai Y., Ono M., Suzuki T., Hayashi S., Kojima J., Sasaki T., Fujiwara T., Daikoku T., Terakawa J., Maida Y., Ando H., Fujiwara H., Kuji N., Nishi H.

Reproductive Sciences 32 （ 4 ） 1115 - 1128 2025年04月

ISSN 19337191

Infertility and reproductive issues are commonly observed in animals with clock abnormalities. Substantial rodent data is available; however, relatively few studies have investigated the connection between fertility and clock abnormalities in humans. Therefore, this study aimed to analyze the expression of circadian clock genes and their impact on genes involved in collagen production in the human myometrium and leiomyomas (LM). The relationship between the expression of brain and muscle aryl-hydrocarbon-receptor-nuclear-translocator (Arnt)-like protein-1 (BMAL1) and the genes responsible for collagen synthesis in the human MM and LMs were investigated. Human MM and LM tissues were collected for analysis from patients who underwent hysterectomy analysis. Immunohistochemical analysis, cell culturing, immunofluorescence, small interfering RNA transfection, reverse transcription quantitative real-time polymerase chain reaction, scratch wound assays, and transwell assays were employed to gain a comprehensive understanding of the cellular and molecular processes. A correlation was found between BMAL1 expression and genes regulating collagen synthesis in primary cultures of human MM and LM cells. Moreover, the inhibition of BMAL1 differentially increased the migration and invasion of MM and LM cells. This work discloses the role of BMAL1 in collagen production in primary cultures of human MM and LM cells, offering insight into clock gene involvement in both normal and pathological uterine conditions. Furthermore, this study highlights the crucial role of BMAL1 in collagen synthesis in human MM and LM cells, underscoring the significance of BMAL1 in the regulation of reproductive physiology. These results suggest that BMAL1 might be a useful target molecule for anti-LM therapy.

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Clinical effectiveness of the subcutaneous steel wire-lifting method with gasless laparoscopic myomectomy for fibroids

Sakai Y., Sasaki T., Ono M., Hayashi S., Yamanaka Z., Ono M., Yamamoto A., Nishi H.

Asian Journal of Surgery 48 （ 1 ） 370 - 376 2025年01月

ISSN 10159584

Background/objective: Laparoscopic myomectomy (LM) is primarily conducted using the pneumoperitoneum method, with only few LMs performed using the gasless method (GLM). We aimed to assess the feasibility of GLM. Methods: This retrospective chart review was performed in a university-affiliated hospital. We included 1301 patients who underwent GLM with the subcutaneous steel wire-lifting method (GLMS) between 2008 and 2021. Results: A total of 6287 fibroids were removed (nodes per patient: 4.83 ± 4.51). Systematic reviews showed that compared with conventional LM, GLMS had longer operation time, greater number and larger size of fibroids removed, and lower intraoperative blood loss. The rates of severe perioperative complications, homologous blood transfusion, and open conversion were acceptable at 0.8 %, 0.5 %, and 0.3 %, respectively. Operation time, weight of surgical specimen, body mass index (BMI), and the maximum diameter of fibroids removed were important predictors of higher risk, including massive surgical bleeding. The prediction model of massive surgical bleeding showed a relatively good out-of-bag estimate of error rate of 8.6 %, with a high negative predictive value, albeit a low positive predictive value, making it unsuitable for real-world clinical applications. Conclusions: GLMS is an excellent procedure that combines safety, proficiency, and economic efficiency for fibroid removal, except in patients with severe obesity. Beyond the cost–benefit perspective, GLMS appears well-suited to countries with low average BMI, such as Japan, East-Asian countries, and LMICs in Africa.

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Conception After Chemotherapy for Intraplacental Choriocarcinoma: Favorable 5-Year Follow-Up of the Mother and Child

Suzuki T., Ono M., Kojima J., Imai Y., Nagai T., Suzuki A., Kuji N., Nishi H.

American Journal of Case Reports 26 2025年

Objective: Rare disease Background: Intraplacental choriocarcinoma (IC) is a rare subtype of gestational choriocarcinoma that can be associated with placental hemorrhage and metastases to the mother and fetus. Chemotherapy can be effective in cases of placental localization and may not adversely affect fertility. This report describes a 32-year-old woman who conceived 10 months after chemotherapy for IC and achieved successful term delivery of that pregnancy. Case Report: A 32-year-old woman delivered her first child by vacuum extraction due to weak labor and fetal distress. The newborn presented with severe anemia, as well as elevated alpha-fetoprotein and fetal hemoglobin levels, suggesting fetomaternal hemorrhage. Placental histopathology revealed IC. Postpartum elevation of human chorionic gonadotropin levels prompted EMA-CO (etoposide, methotrexate, actinomycin D/cyclophosphamide, vincristine) chemotherapy; 7 treatment courses were completed without side effects or metastasis. Ten months after completion of chemotherapy, the patient spontaneously conceived. She subsequently delivered a healthy boy at 38+5 weeks of gestation; placental examination did not reveal malignancy. During the 5-year follow-up period, both children developed normally, and no maternal recurrence or metastasis was observed. Conclusions: This report describes a case of postnatal diagnosis of IC via placental histopathology, followed by successful treatment and subsequent pregnancy within 1 year after chemotherapy completion. The findings highlight the importance of accurate diagnosis and appropriate management of IC; they support previous observations that chemotherapy does not preclude future successful pregnancies. Additionally, the report underscores the clinical challenges of IC, its implications for future pregnancies, and the need for long-term follow-up concerning both mother and child.

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Influence of lifestyle and the circadian clock on reproduction.

Ono M, Dai Y, Fujiwara T, Fujiwara H, Daikoku T, Ando H, Kuji N, Nishi H

Reproductive medicine and biology 24 （ 1 ） e12641 2025年

ISSN 1445-5781

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Out-of-pocket fertility preservation expenses: data from a Japanese nationwide multicenter survey

Ono M., Takai Y., Harada M., Horie A., Dai Y., Kikuchi E., Miyachi M., Yamamoto T., Fujii N., Kajiyama H., Manabe A., Yasuoka T., Katsuragi S., Mekaru K., Maezawa T., Horage Y., Kataoka S., Nakayama R., Nakajima T.E., Kimura F., Shimizu C., Sugimoto K., Takae S., Yumura Y., Nishi H., Furui T., Morishige K.I., Watanabe C., Osuga Y., Suzuki N.

International Journal of Clinical Oncology 29 （ 12 ） 1959 - 1966 2024年12月

ISSN 13419625

Background: The expenses related to fertility preservation or subsequent assisted reproductive treatments are significant for adolescents and young adult patients in Japan’s current healthcare system. With fertility preservation becoming more widespread in developed countries, it is expected that these costs will be covered by insurance or subsidies. It is critical for patients, healthcare providers, and the government to know the costs that patients will be responsible for. In Japan, the costs of fertility preservation and subsequent assisted reproductive technology are not covered by insurance, but patients can apply for subsidies from the local and central governments if certain conditions are met. Presently, the above-mentioned costs, as well as the amount paid by the patient, vary by facility. Therefore, it is essential to ensure patients’ continued access to necessary medical care despite the associated costs. Methods: In this study, questionnaires were mailed to 186 certified fertility preservation facilities in Japan to assess patients who had undergone fertility preservation or assisted reproduction. The questionnaires were sent between October 27, 2023 and March 31, 2024, with 140 of the 186 facilities responding (response rate: 75.3%). Results: Our findings show that approximately one-third of the costs was borne by the patients. Conclusion: Given these circumstances, sustainable pricing and insurance coverage are necessary for both patients and facilities.

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Exenatide administration time-dependently affects the hepatic circadian clock through glucagon-like peptide-1 receptors in the central nervous system

Xu P., Morishige J.i., Jing Z., Nagata N., Shi Y., Iba T., Daikoku T., Ono M., Maida Y., Fujiwara T., Fujiwara H., Ando H.

Biochemical Pharmacology 230 2024年12月

ISSN 00062952

Accumulating evidence indicates that disruption of the circadian clock contributes to the development of lifestyle-related diseases. We have previously shown that exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, can strongly affect the molecular clocks in the peripheral tissues. This study aimed to investigate the effects of its dosing time and the central nervous system-specific GLP-1 receptor knockdown (GLP1RKD) on the hepatic clock in mice treated with exenatide. Male C57BL/6J and GLP1RKD mice were housed under a 12-h/12-h light/dark cycle, and feeding was restricted to either the light period (L-TRF) or the first 4 h in the dark period (D-TRF). In parallel, exenatide was administered 4–5 times, once daily either at the beginning of the dark (ZT 12) or light period (ZT 0), and we assessed the mRNA expression rhythms of clock genes in the liver thereafter. Exenatide administration at ZT 12 counteracted the phase shift effect of the L-TRF on the hepatic clock of wild-type mice, whereas the dosing at ZT 0 enhanced its effect. However, exenatide did not influence the phase of the hepatic clock under D-TRF regardless of the dosing time. The effect of exenatide in wild-type mice weakened in GLP1RKD mice. These results showed that exenatide dosing time-dependently affects the hepatic circadian clock through the central GLP-1 system. Exenatide administration at the beginning of the active period (i.e., in the morning for humans) might prevent disruption of the peripheral clocks caused by irregular eating habits.

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Comparison of the Effects of Inappropriate Meal Timing-Induced and Genetic Models of Circadian Clock Disruption on Uterine mRNA Expression Profiles

Chen Y., Hosono T., Ono M., Daikoku T., Toyoda N., Nomura S., Kagami K., Orisaka S., Horike S.i., Shi Y., Xu P., Morishige J.i., Fujiwara T., Fujiwara H., Ando H.

Journal of Nutrition 154 （ 12 ） 3718 - 3725 2024年12月

ISSN 00223166

Background: Accumulating evidence reveals that inappropriate meal timing contributes to the development of lifestyle-related diseases. An underlying mechanism is thought to be the disruption of the intracellular circadian clock in various tissues based on observations in both systemic and tissue-specific clock gene-deficient mice. However, whether the effects of conditional clock gene knockout are comparable to those of inappropriate meal timing remains unclear. Objectives: This study aimed to compare the effects of a recently developed 28-h feeding cycle model with those of a core clock gene Bmal1 uterine conditional knockout (Bmal1 cKO) model on uterine mRNA expression profiles. Methods: The models were generated by subjecting C57BL/6J mice to an 8-h/20-h feeding/fasting cycle for 2 wk and crossing Bmal1-floxed mice with PR-Cre mice. Microarray analyses were conducted using uterine samples obtained at the beginning of the dark and light periods. Results: The analyses identified 516 and 346, significantly 4-fold and 2-fold, up- or downregulated genes in the 28-h feeding cycle and Bmal1 cKO groups, respectively, compared with each control group. Among these genes, only 7 (1.4%) and 63 (18.2%) were significantly up- or downregulated in the other model. Moreover, most (n = 44, 62.9%) of these genes were oppositely regulated. These findings were confirmed by gene set enrichment analyses. Conclusions: This study reveals that a 28-h feeding cycle and Bmal1 cKO differently affect gene expression profiles and highlights the need for considering this difference to assess the pathophysiology of diseases associated with inappropriate meal timing.

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Androgen-responsive FOXP4 is a target for endometrial carcinoma

Kayahashi K., Hasan M., Khatun A., Kohno S., Terakawa J., Horike S.I., Toyoda N., Matsuoka A., Iizuka T., Obata T., Ono M., Mizumoto Y., Takahashi C., Fujiwara H., Daikoku T.

Communications Biology 7 （ 1 ） 2024年12月

Although low estrogen is considered to suppress uterine endometrial carcinoma, the most cases occur in the postmenopausal stage. After menopause, the production of androgen level also declines. Therefore, to resolve the above enigma, we hypothesize that the postmenopausal decline of androgen is a trigger of its progression. In the present study, to validate this hypothesis, we examine the pathological roles of androgen/AR by analyzing clinical data, culturing endometrioid cancer cell lines, and using murine models. Clinical data show that androgen receptor (AR) expression and serum dihydrotestosterone (DHT) are associated with lower disease-free survival (DFS). DHT suppresses malignant behaviors in AR-transfected human endometrial cancer cells (ECC). In ovariectomized Ptenff/PRcre/+ mice, DHT decreases the proliferation of spontaneously developed murine ECC. In AR-transfected human ECC and Ptenff/PRcre/+ mice, DHT suppresses FOXP4 expression. FOXP4-overexpressed human ECC increases, while FOXP4-knocked-down ECC shows decreased malignant behaviors. DHT/AR-mediated ECC suppression is restored by FOXP4 overexpression. The high FOXP4 expression is significantly correlated with low postoperative DFS. These findings indicate that the androgen/AR system suppresses the malignant activity of endometrial carcinoma and that downstream FOXP4 is another target molecule. These findings will also impact developments in clinical approaches to elderly health.

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Impact of daily breakfast intake on the outcomes of assisted reproductive technology procedures

Ono M., Hayashizaki Y., Orihara S., Kitamizu M., Hamada C., Yamaguchi M., Kikuchi T., Kawamura T., Yamanaka A., Ueno K., Kojima J., Fujiwara T., Daikoku T., Maida Y., Ando H., Fujiwara H., Oshima K., Kuji N., Nishi H.

Nutrition 127 2024年11月

ISSN 08999007

Objective: To assess the relationship between meal consumption frequency and assisted reproductive technology (ART) outcomes among female patients with infertility. Research Methods & Procedures: This cohort study was conducted from February 2022 to January 2024 at Tokyo Medical University Hospital. Overall, 101 female patients with infertility issues and without a history of stroke, heart disease, cancer, or type 1 or type 2 diabetes were enrolled in this study. The factors extracted from the questionnaire included demographic information, meal consumption frequency before ART and at 20 years of age, smoking status, and alcohol consumption status. Data on other factors, including age, body mass index, anti-Müllerian hormone level, and parity history, were collected from medical records. The assessed clinical outcomes included number of transplanted embryos, clinical pregnancies, ongoing pregnancies, live births, and miscarriages. Results: After adjusting for potential confounding factors, including age, smoking status, alcohol consumption status, body mass index, anti-Müllerian hormone level, and parity history, a multivariate analysis of ART outcomes was performed. Patients were categorized into groups based on the frequency of weekly consumption of breakfast, lunch, and dinner. Patients who consumed breakfast 6–7 times a week were significantly more likely to have higher rates of live birth and lower rates of miscarriage in pregnancies conceived through ART. Conclusions: Consumption of breakfast 6–7 times a week before ART was associated with increased success rates following ART. This highlights the potential importance of regular breakfast consumption for optimizing ART outcomes.

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A case of Herlyn–Werner–Wunderlich syndrome with exacerbation of hematometra after adnexectomy

Hayashi S., Ono M., Sagisaka M., Mimura T., Kojima J., Ono M., Sasaki T., Yamamoto A., Nishi H.

Asian Journal of Endoscopic Surgery 17 （ 4 ） 2024年10月

ISSN 17585902

A 27-year-old nulliparous woman presented with a feeling of fullness in the lower abdomen and abdominal pain. A left ovarian tumor, uterus didelphys, left renal agenesis, and left vaginal atresia were observed on imaging. The ovarian tumor was presumed to have caused the abdominal pain, and an abdominal left adnexectomy was performed. After 3 months, she reported severe lower abdominal pain during menstruation. Transvaginal ultrasonography revealed uterine enlargement. After 17 days, the patient presented with abdominal pain and fever. She was diagnosed with peritonitis due to infection and left uterine hematometra. Because she did not improve with antibiotic treatment, left laparoscopic hysterectomy was performed. Subsequently, she did not experience the lower abdominal pain. Appropriate diagnosis and treatment based on the morphology of the reproductive tract and symptoms must be considered in patients with Herlyn–Werner–Wunderlich syndrome. Treatment must permit the outflow of menstrual blood.

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Diagnosis of abnormal uterine bleeding based on the FIGO classification: A systematic review and expert opinions

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

Journal of Obstetrics and Gynaecology Research 50 （ 10 ） 1785 - 1794 2024年10月

ISSN 13418076

Aim: To present evidence- and consensus-based recommendations for the diagnosis abnormal uterine bleeding. Methods: A literature search for the diagnosis of abnormal uterine bleeding was systematically conducted in PubMed from its inception to May 2024 to identify meta-analyses, reviews, randomized controlled trials, and clinical trials, followed by an additional systematic search using keywords. Based on this evidence, an expert panel developed background, clinical, and future research questions. Results: Based on a systematic search and the collected evidence, we developed five background questions, three clinical questions, and one future research question, with recommendations and/or statements. Evidence and recommendations are provided for clinical questions. Additionally, we developed a flowchart for diagnosis showing the steps of the examinations to be performed. Conclusion: The flowchart and nine recommendations/statements specify an efficient diagnostic procedure to differentiate abnormal causative diseases of uterine bleeding optimized for actual Japanese situations.

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A nationwide survey of diagnostic procedures for abnormal uterine bleeding in Japan

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

Journal of Obstetrics and Gynaecology Research 50 （ 9 ） 1675 - 1680 2024年09月

ISSN 13418076

Aim: To clarify the diagnostic process of the causative disease of abnormal uterine bleeding (AUB) in Japan according to the International Federation of Gynecology and Obstetrics AUB diagnostic system. Methods: Patients diagnosed with AUB were included in a nationwide survey of AUB conducted during any 2-week period between December 2019 and January 2020. The second survey included information on patient background, AUB symptoms, examinations for diagnosing AUB, the order in which they were performed, and the causative diseases of AUB. Results: Correspondence analysis showed an association between hormonal testing, hysterosalpingography, and magnetic resonance imaging (MRI) in patients with amenorrhea, and heavy menstrual bleeding was strongly correlated with various examinations, such as coagulation tests, pelvic MRI, and endometrial cytology or biopsy. The results also indicated that each AUB causative disease can be diagnosed based on a specific examination profile. Conclusion: We clarified the process of diagnosing the causative disease of AUB in our country and determined that it was mainly diagnosed by imaging and pathological examination in cases of structural disease. The high rate of AUB-E and the low rate of AUB-C are possibly associated with specific examination trends in Japan. The results of this study will be useful for the development of a standard protocol for AUB diagnosis in our country.

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Survey on the implementation status and reproductive outcomes of oocyte and ovarian tissue cryopreservation in Japan: Historical comparison with nationwide surveys

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

Journal of Obstetrics and Gynaecology Research 50 （ 4 ） 709 - 718 2024年04月

ISSN 13418076

Purpose: To clarify the reproductive outcomes of fertility preservation (FP) treatment. Methods: We conducted a mailed-in questionnaire survey at institutions certified by the Japan Society of Obstetrics and Gynecology to investigate the number of oocyte cryopreservations (OC) and ovarian tissue cryopreservations (OTC) performed from December 2016 to the end of 2020. And, we conducted a detailed investigation of cases in which frozen specimens were used during the investigation period, and made historical comparisons with previous nationwide studies. Results: Responses were received from 114 out of 150 facilities (response rate: 76.0%) for OC and 43 out of 51 for OTC (response rate: 84.3%). Breast cancer was the most common disease among patients whose FP specimens were used. During the study period, 1237 OCs and 198 OTCs were performed. In addition, 57 cycles of embryo transfer (ET) using cryopreserved oocytes and 12 cases of ovarian tissue transplantation (OTT) were performed. The mean age of patients who underwent ET using cryopreserved oocytes was 34.8 (±5.8) years, with a median age of 36 years. The pregnancy rate per ET using cryopreserved oocytes was 26.3% and the live birth rate (LBR) was 17.5%. Further, the LBR per patient was 43.3%, and the pregnancy rate following OTTs was 33.3%. Also, controlled ovarian stimulation using the random start method or the combination of aromatase inhibitors had no effect on pregnancy outcome. Conclusion: Implementation of both OCs and OTCs have markedly increased over time in Japan, with comparable reproductive outcomes as other reports.

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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

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.

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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

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.

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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

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.

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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

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).

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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

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.

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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

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.

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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

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.

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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

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.

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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

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.

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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

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.

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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

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).

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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

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.

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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

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.

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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

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.

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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

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.

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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

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.

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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

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.

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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

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.

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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

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 7th 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.

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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

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.

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National survey of abnormal uterine bleeding according to the FIGO classification in Japan

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

Journal of Obstetrics and Gynaecology Research 49 （ 1 ） 321 - 330 2023年01月

ISSN 13418076

Aim: To investigate the status of abnormal uterine bleeding (AUB) in Japan using the International Federation of Gynecology and Obstetrics (FIGO) classification (AUB system 1 and 2; PALM-COEIN) and to clarify the relationship between AUB symptoms and the diseases causing AUB. Methods: In a nationwide study, we enrolled first-time patients who visited target facilities during two consecutive weeks from December 1, 2019 to January 31, 2020. The FIGO classification was used to investigate patients with symptoms and causative diseases of AUB. Based on the proportion of patients in the nationwide study, 373 cases were included in the detailed survey. Survey items included symptoms of AUB according to AUB system 1, examination details, and causative diseases according to the PALM-COEIN classification. Results: Within the study period, we encountered 61 740 first-time patients, of which 8081 (13.1%) were diagnosed with AUB. Among them, 39.9% had abnormal menstrual cycles and 56.9% had abnormal menstrual bleeding. In the survey, PALM had the highest percentage of AUB-L and COEIN had the highest percentage of AUB-O. Correspondence analysis showed that COEIN was strongly associated with abnormal menstrual cycles and PALM with abnormal menstrual bleeding. Conclusion: We conducted the first nationwide survey of AUB in Japan. The FIGO classification was a useful tool for the diagnosis of AUB, with a strong correlation between symptoms of AUB by AUB system 1 and the causative disease of AUB by PALM-COEIN. Conversely, a high percentage of AUB-N and AUB-E suggests that AUB system 1 and PALM-COEIN are ambiguous as diagnostic tools.

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The Circadian Clock, Nutritional Signals and Reproduction: A Close Relationship

Ono M., Ando H., Daikoku T., Fujiwara T., Mieda M., Mizumoto Y., Iizuka T., Kagami K., Hosono T., Nomura S., Toyoda N., Sekizuka-Kagami N., Maida Y., Kuji N., Nishi H., Fujiwara H.

International Journal of Molecular Sciences 24 （ 2 ） 2023年01月

ISSN 16616596

The circadian rhythm, which is necessary for reproduction, is controlled by clock genes. In the mouse uterus, the oscillation of the circadian clock gene has been observed. The transcription of the core clock gene period (Per) and cryptochrome (Cry) is activated by the heterodimer of the transcription factor circadian locomotor output cycles kaput (Clock) and brain and muscle Arnt-like protein-1 (Bmal1). By binding to E-box sequences in the promoters of Per1/2 and Cry1/2 genes, the CLOCK-BMAL1 heterodimer promotes the transcription of these genes. Per1/2 and Cry1/2 form a complex with the Clock/Bmal1 heterodimer and inactivate its transcriptional activities. Endometrial BMAL1 expression levels are lower in human recurrent-miscarriage sufferers. Additionally, it was shown that the presence of BMAL1-depleted decidual cells prevents trophoblast invasion, highlighting the importance of the endometrial clock throughout pregnancy. It is widely known that hormone synthesis is disturbed and sterility develops in Bmal1-deficient mice. Recently, we discovered that animals with uterus-specific Bmal1 loss also had poor placental development, and these mice also had intrauterine fetal death. Furthermore, it was shown that time-restricted feeding controlled the uterine clock’s circadian rhythm. The uterine clock system may be a possibility for pregnancy complications, according to these results. We summarize the most recent research on the close connection between the circadian clock and reproduction in this review.

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Sirtuin 1 is a potential therapeutic candidate gene for fetal growth restriction via insulin-like 4

Kojima J., Dai Y., Suzuki T., Ono M., Nishi H.

Journal of Maternal Fetal and Neonatal Medicine 36 （ 2 ） 2023年

ISSN 14767058

Objective: Insufficient placental development causes various obstetric complications, including fetal growth restriction (FGR). The Sirtuin 1 (SIRT1) and insulin-like 4 (INSL4) protein-coding genes have been demonstrated to play an important role in placental development. However, no treatment for FGR is available due to placental dysfunction. Therefore, this study aimed to examine the potential of the SIRT1–INSL4 axis as a treatment candidate for FGR caused by insufficient placental development. Methods: Twenty patients were enrolled, including 10 with FGR and 10 full-term controls. FGR and control placental samples were collected. Quantitative real-time polymerase chain reaction, immunohistochemical analysis, and western blotting were used to analyze INSL4 and SIRT1 expression. An in-vitro loss-of-function approach with the human choriocarcinoma cell line BeWo was applied for functional analyses of SIRT1 in placental development. BeWo cells were differentiated into syncytiotrophoblasts by silencing SIRT1 using small interfering RNA. SIRT1 activator was added during differentiation of SIRT1-knockdown BeWo cells into syncytiotrophoblasts. Results: The FGR samples had lower INSL4 and SIRT1 mRNA and protein expression levels than the control samples. Immunohistochemistry showed that both SIRT1 and INSL4 were expressed mainly in syncytiotrophoblasts. In-vitro analyses showed that SIRT1 knockdown decreased INSL4 expression; however, SIRT1 activator restored SIRT1 expression in SIRT1-silenced BeWo cells. Conclusions: SIRT1 and INSL4 are downregulated in the placenta of FGR, and INSL4 is regulated by SIRT1. These findings indicate that the SIRT1–INSL4 axis may be a potential therapeutic target for FGR.

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FOXP4 inhibits squamous differentiation of atypical cells in cervical intraepithelial neoplasia via an ELF3-dependent pathway

Matsumoto T., Iizuka T., Nakamura M., Suzuki T., Yamamoto M., Ono M., Kagami K., Kasama H., Wakae K., Muramatsu M., Horike S.i., Kyo S., Yamamoto Y., Mizumoto Y., Daikoku T., Fujiwara H.

Cancer Science 113 （ 10 ） 3376 - 3389 2022年10月

ISSN 13479032

Although the human papillomavirus (HPV) vaccine is effective for preventing cervical cancers, this vaccine does not eliminate pre-existing infections, and alternative strategies have been warranted. Here, we report that FOXP4 is a new target molecule for differentiation therapy of cervical intraepithelial neoplasia (CIN). An immunohistochemical study showed that FOXP4 was expressed in columnar epithelial, reserve, and immature squamous cells, but not in mature squamous cells of the normal uterine cervix. In contrast with normal mature squamous cells, FOXP4 was expressed in atypical squamous cells in CIN and squamous cell carcinoma lesions. The FOXP4-positive areas significantly increased according to the CIN stages from CIN1 to CIN3. In monolayer cultures, downregulation of FOXP4 attenuated proliferation and induced squamous differentiation in CIN1-derived HPV 16-positive W12 cells via an ELF3-dependent pathway. In organotypic raft cultures, FOXP4-downregulated W12 cells showed mature squamous phenotypes of CIN lesions. In human keratinocyte-derived HaCaT cells, FOXP4 downregulation also induced squamous differentiation via an ELF3-dependent pathway. These findings suggest that downregulation of FOXP4 inhibits cell proliferation and promotes the differentiation of atypical cells in CIN lesions. Based on these results, we propose that FOXP4 is a novel target molecule for nonsurgical CIN treatment that inhibits CIN progression by inducing squamous differentiation.

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Toll-like receptor signaling pathway triggered by inhibition of serpin A1 stimulates production of inflammatory cytokines by endometrial stromal cells

Kusama K., Satoyoshi A., Azumi M., Yoshie M., Kojima J., Mizuno Y., Ono M., Nishi H., Kajihara T., Tamura K.

Frontiers in Endocrinology 13 2022年08月

Endometriosis is characterized by the presence of inflamed and fibrotic endometrial tissue outside the uterine cavity. Previously, we found decreased SERPINA1 (alpha-1 antitrypsin) expression in endometriosis-like lesions in a mouse model of endometriosis, suggesting that it exacerbated inflammation in these lesions. However, the molecular mechanism(s) by which SERPINA1 affects expression of inflammatory factors and development of endometriotic lesions have not been fully characterized. To investigate the role of intracellular SERPINA1 in endometrial stromal cells (ESCs), we performed RNA sequence analysis using RNA extracted from ESCs in which SERPINA1 was knocked down. The analysis identified several toll-like receptor (TLR)-related factors as being upregulated. Silencing of SERPINA1 increased expression of TLR3 and TLR4 in ESCs, as well as several TLR signaling pathway components, including MYD88, IRAK1/4, interleukin (IL)-1β, and interferon (IFN)-β. TLR3 or TLR4 agonists increased expression of inflammatory factors in SERPINA1-knockdown ESCs, whereas TLR3 or TLR4 inhibitors decreased expression. In addition, treatment with recombinant IL-1β or IFN-β increased expression of MYD88 and inflammatory factors in ESCs. Immunohistochemical analysis of endometriotic tissues showed that TLR3, TLR4, and MYD88 were localized in endometriosis lesions. Taken together, the data suggest that reduced expression of SERPINA1 induces expression of inflammatory factors by ESCs, which in turn are associated with TLR3/4, IL-1β, and IFN-β signaling. Regulation of intracellular SERPINA1 levels in ESCs may be a strategy to inhibit inflammatory responses in endometriotic lesions.

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Sustained effect of habitual feeding time on daily rhythm of core body temperature in mice

Ando H., Nagata N., Hosono T., Hasan N., Morishige J.I., Daikoku T., Maida Y., Ono M., Fujiwara T., Fujiwara H.

Frontiers in Nutrition 9 2022年08月

Background and aim: Circadian clocks in most peripheral tissues are entrained mainly by feeding. Therefore, this study aimed to investigate whether the daily rhythm of core body temperature (CBT), including the effect of diet-induced thermogenesis, varies according to habitual feeding time. Methods: Wild-type and uncoupling protein 1 (UCP1) knockout mice were fed only during the first 4 h (Breakfast group) or the last 4 h of the dark period (Dinner group) for 17 days. On day 18, both groups were fed twice for 2 h, at the same starting times. Locomotor activity and CBT were measured continuously during the experiment. Results: On day 18, CBT increased at the beginning of each feeding period, regardless of the group and strain. However, the CBT increase induced by the first meal decreased sharply in the Breakfast group and mildly in the Dinner group; the opposite was observed after the second meal. In UCP1 knockout, but not wild-type, mice, the total amount of CBT was significantly lower in the Dinner group than in the Breakfast group. These effects were mostly independent of the locomotor activity and food intake. Conclusion: These results reveal that the effect of habitual feeding time on the daily rhythm of CBT is sustained at least until the following day. These effects may be mediated by both UCP1-dependent and -independent mechanisms.

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A mediator complex subunit 12 gain-of-function mutation induces partial leiomyoma cell properties in human uterine smooth muscle cells

Takao T., Ono M., Yoshimasa Y., Masuda H., Maruyama T.

F and S Science 3 （ 3 ） 288 - 298 2022年08月

Objective: To clarify whether a mediator complex subunit 12 (MED12) gain-of-function mutation induces leiomyoma cell properties in human uterine smooth muscle cells (USMCs). Design: Experimental study. Setting: Academic research laboratory. Patient(s): Women undergoing hysterectomy for leiomyoma. Intervention(s): CRISPR/Cas9-mediated genome editing to introduce an MED12 gain-of-function mutation (G44D) into human USMCs. Main Outcome Measure(s): Cell proliferation, collagen production, and in vivo tumorigenicity of USMCs with vs. without the MED12 mutation. Result(s): Uterine smooth muscle cells isolated from the uterine myometrium of a 44-year-old patient were subjected to lentiviral vector-mediated gene transduction of the fluorescent protein Venus, followed by long-term passage. Uterine smooth muscle cells with a normal female karyotype, high cell proliferative activity, and Venus expression, but without stem/progenitor cell populations, were obtained and designated as USMC44. Using CRISPR/Cas9-mediated genome editing, mtUSMC44 (MED12, 131G>A, p.G44D) and mock USMC44 without MED12 mutation (wtUSMC44) were established from USMC44. wtUSMC44 and mtUSMC44 showed similar cell proliferation activity, even in the presence of estradiol and progesterone (EP) together with transforming growth factor-beta 3 (TGFB3). In addition, wtUSMC44 and mtUSMC44 generated similar tiny smooth muscle-like tissue constructs when xenotransplanted beneath the kidney capsule in immunodeficient mice treated with EP alone or TGFB3. In contrast, mtUSMC44 produced more collagen type I than wtUSMC in vitro, and this production was likely enhanced by EP and TGFB3. Conclusion(s): The results suggest that the MED12 gain-of-function mutation is involved in collagen production. Although approximately 70% of leiomyomas have MED12 mutations, additional factors and/or events other than MED12 and/or myometrial stem/progenitor cells may be required for fully inducing leiomyoma cell properties, including transformation, in USMCs.

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Human Chorionic Villous Differentiation and Placental Development

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

International Journal of Molecular Sciences 23 （ 14 ） 2022年07月

ISSN 16616596

In humans, the placenta provides the only fetomaternal connection and is essential for establishing a pregnancy as well as fetal well-being. Additionally, it allows maternal physiological adaptation and embryonic immunological acceptance, support, and nutrition. The placenta is derived from extra-embryonic tissues that develop rapidly and dynamically in the first weeks of pregnancy. It is primarily composed of trophoblasts that differentiate into villi, stromal cells, macrophages, and fetal endothelial cells (FEC). Placental differentiation may be closely related to perinatal diseases, including fetal growth retardation (FGR) and hypertensive disorders of pregnancy (HDP), and miscarriage. There are limited findings regarding human chorionic villous differentiation and placental development because conducting in vivo studies is extremely difficult. Placental tissue varies widely among species. Thus, experimental animal findings are difficult to apply to humans. Early villous differentiation is difficult to study due to the small tissue size; however, a detailed analysis can potentially elucidate perinatal disease causes or help develop novel therapies. Artificial induction of early villous differentiation using human embryonic stem (ES) cells/induced pluripotent stem (iPS) cells was attempted, producing normally differentiated villi that can be used for interventional/invasive research. Here, we summarized and correlated early villous differentiation findings and discussed clinical diseases.

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Uterine Deletion of Bmal1 Impairs Placental Vascularization and Induces Intrauterine Fetal Death in Mice

Ono M., Toyoda N., Kagami K., Hosono T., Matsumoto T., Horike S.I., Yamazaki R., Nakamura M., Mizumoto Y., Fujiwara T., Ando H., Fujiwara H., Daikoku T.

International Journal of Molecular Sciences 23 （ 14 ） 2022年07月

ISSN 16616596

Recently, it was demonstrated that the expression of BMAL1 was decreased in the endometrium of women suffering from recurrent spontaneous abortion. To investigate the pathological roles of uterine clock genes during pregnancy, we produced conditional deletion of uterine Bmal1 (cKO) mice and found that cKO mice could receive embryo implantation but not sustain pregnancy. Gene ontology analysis of microarray suggested that uterine NK (uNK) cell function was suppressed in cKO mice. Histological examination revealed the poor formation of maternal vascular spaces in the placenta. In contrast to WT mice, uNK cells in the spongiotrophoblast layer, where maternal uNK cells are directly in contact with fetal trophoblast, hardly expressed an immunosuppressive NK marker, CD161, in cKO mice. By progesterone supplementation, pregnancy could be sustained until the end of pregnancy in some cKO mice. Although this treatment did not improve the structural abnormalities of the placenta, it recruited CD161-positive NK cells into the spongiotrophoblast layer in cKO mice. These findings indicate that the uterine clock system may be critical for pregnancy maintenance after embryo implantation.

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Case-based survey: The impact of breast-cancer treatment on fertility in Japan

Yamazaki R., Ono M., Sugie T., Inokuchi M., Ishikawa S., Horage Y., Kojima Y., Iwasa T., Hara T., Nagata Y., Kato K., Michikura Y., Kuramoto T., Uchida S., Horie A., Fujiwara H., Matsuzaki T.

Journal of Obstetrics and Gynaecology Research 48 （ 3 ） 553 - 562 2022年03月

ISSN 13418076

Aim: To assess the impact of breast-cancer treatment on fertility. Methods: We conducted a retrospective, case-based survey of treatments administered for infertility and pregnancy outcomes after patients underwent treatment for breast cancer. Surveys were distributed to breast oncology facilities and reproductive endocrinology and infertility (REI) facilities. Results: As high as 60% of the pregnancies in women under the age of 35 years occurred spontaneously. Additionally, the fertility rates decreased as age increased (under 35 years of age: 40%, 35–39 years of age: 21%, 40–44 years of age: 10%, respectively). In women who became pregnant after treatment for breast cancer, conception was achieved within 1 to 3 years after beginning to try for pregnancy. Conclusions: After treatment for breast cancer, women can expect spontaneous pregnancy, especially if they are under 35 years of age. It is important for patients 35 years of age and older to commence assisted reproductive technology in a timely manner when pursuing fertility after treatment for breast cancer.

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The GPI-anchored protein CD109 protects hematopoietic progenitor cells from undergoing erythroid differentiation induced by TGF-β

Tanabe M., Hosokawa K., Nguyen M.A.T., Nakagawa N., Maruyama K., Tsuji N., Urushihara R., Espinoza L., Elbadry M.I., Mohiuddin M., Katagiri T., Ono M., Fujiwara H., Chonabayashi K., Yoshida Y., Yamazaki H., Hirao A., Nakao S.

Leukemia 36 （ 3 ） 847 - 855 2022年03月

ISSN 08876924

Although a glycosylphosphatidylinositol-anchored protein (GPI-AP) CD109 serves as a TGF-β co-receptor and inhibits TGF-β signaling in keratinocytes, the role of CD109 on hematopoietic stem progenitor cells (HSPCs) remains unknown. We studied the effect of CD109 knockout (KO) or knockdown (KD) on TF-1, a myeloid leukemia cell line that expresses CD109, and primary human HSPCs. CD109-KO or KD TF-1 cells underwent erythroid differentiation in the presence of TGF-β. CD109 was more abundantly expressed in hematopoietic stem cells (HSCs) than in multipotent progenitors and HSPCs of human bone marrow (BM) and cord blood but was not detected in mouse HSCs. Erythroid differentiation was induced by TGF-β to a greater extent in CD109-KD cord blood or iPS cell-derived megakaryocyte–erythrocyte progenitor cells (MEPs) than in wild-type MEPs. When we analyzed the phenotype of peripheral blood MEPs of patients with paroxysmal nocturnal hemoglobinuria who had both GPI(+) and GPI(−) CD34+ cells, the CD36 expression was more evident in CD109− MEPs than CD109+ MEPs. In summary, CD109 suppresses TGF-β signaling in HSPCs, and the lack of CD109 may increase the sensitivity of PIGA-mutated HSPCs to TGF-β, thus leading to the preferential commitment of erythroid progenitor cells to mature red blood cells in immune-mediated BM failure.

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Indications for fertility preservation not included in the 2017 Japan Society of Clinical Oncology Guideline for Fertility Preservation in Pediatric, Adolescent, and Young Adult Patients treated with gonadal toxicity, including benign diseases

Ono M., Matsumoto K., Boku N., Fujii N., Tsuchida Y., Furui T., Harada M., Kanda Y., Kawai A., Miyachi M., Murashima A., Nakayama R., Nishiyama H., Shimizu C., Sugiyama K., Takai Y., Fujio K., Morishige K.I., Osuga Y., Suzuki N.

International Journal of Clinical Oncology 27 （ 2 ） 301 - 309 2022年02月

ISSN 13419625

In recent years, local governments in Japan have established a public financial support system for fertility preservation in pediatric, adolescent, and young adult cancer patients. Fertility preservation has become popular for patients with cancers included in the gonadal toxicity risk classification of the 2017 edition of the Guideline for Fertility Preservation in Children, Adolescents and Young Adult Cancer Patients from the Japan Society of Clinical Oncology. However, patients with cancer and non-cancer diseases that are not included in the Guideline’s gonadal toxicity risk classification also often receive treatment that may affect fertility, but they are often denied the opportunity of fertility preservation because no public financial support is available for diseases not listed in the Guideline. The national research project proposes including these diseases in the indications and treatment for fertility preservation. Therefore, we cooperated with the Japan Society for Fertility Preservation and the Ministry of Health, Labour and Welfare research group to solicit opinions from experts in each therapeutic area and reviewed the literature and overseas guidelines. This paper summarizes the findings of the project. We believe that it will be an important source of information for clinicians treating patients who need fertility preservation but note that the appropriateness of fertility preservation for the disorders listed in this report needs to be continuously reviewed as medical care advances.

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Assisted reproductive technology in Japan: A summary report for 2019 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 21 （ 1 ） 2022年01月

ISSN 14455781

Purpose: The Japan Society of Obstetrics and Gynecology records online annual cycle-based information for assisted reproductive technology (ART). This report presents the characteristics and treatment outcomes of ART cycles registered during 2019. Methods: The Japanese ART registry includes cycle-specific information from 619 participating facilities, including treatment and pregnancy outcomes. Descriptive analyses were conducted for cycles registered during 2019. Results: In 2019, 458 101 treatment cycles and 60 598 neonates were reported, both of which increased from 2018. The number of fresh cycles, including in vitro fertilization and intracytoplasmic sperm injection, decreased, while frozen-thawed embryo transfer (ET) cycles increased. The mean maternal age was 37.9 years (standard deviation ± 4.7). Of 239 348 oocyte retrievals, 123 690 (51.7%) involved freeze-all-embryos cycles; fresh ET was performed in 41 831 cycles (a decreasing trend since 2015). In 2019, there were 211 597 frozen-thawed ET cycles, resulting in 74 882 pregnancies and 54 168 neonates born. Single ET was performed in 82.6% of fresh transfers and 85.1% of frozen-thawed cycles, with singleton live birth rates of 97.3% for both. Conclusions: The number of fresh cycles decreased but frozen cycles increased in 2019. Single ET was performed in >80% of cases, and the proportion of babies born from frozen-thawed ET increased.

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Correction to: Indications for fertility preservation not included in the 2017 Japan Society of Clinical Oncology Guideline for Fertility Preservation in Pediatric, Adolescent, and Young Adult Patients treated with gonadal toxicity, including benign diseases (International Journal of Clinical Oncology, (2022), 27, 2, (301-309), 10.1007/s10147-021-02082-9)

Ono, M., Matsumoto, K., Boku, N., Fujii, N., Tsuchida, Y., Furui, T., Harada, M., Kanda, Y., Kawai, A., Miyachi, M., Murashima, A., Nakayama, R., Nishiyama, H., Shimizu, C., Sugiyama, K., Takai, Y., Fujio, K., Morishige, K. I., Osuga, Y. and Suzuki, N.

International Journal of Clinical Oncology 27 （ 4 ） 825 - 826 2022年

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Guidelines for Reproductive Medicine in Japan

Yamada, M., Ishikawa, T., Iwasa, T., Oishi, H., Osuka, S., Oka, K., Ono, S., Ono, M., Orisaka, M., Kanasaki, H., Kawano, Y., Kawamura, K., Kishi, H., Kimura, F., Kuroda, S., Kuwahara, A., Kobayashi, H., Komiya, A., Saito, H., Sato, K., Sato, S., Shiraishi, K., Shirasawa, H., Suzuki, T., Takai, Y., Takae, S., Takahashi, T., Takiuchi, T., Tachibana, M., Tamura, I., Tamura, H., Jwa, S. C., Baba, T., Harada, M., Hirata, T., Fukui, A., Fukuda, Y., Fukuhara, S., Maruyama, T., Yumura, Y., Yoshino, O., Hirota, Y., Tsujimura, A., Kuji, N. and Osuga, Y.

Reproductive Medicine and Biology 21 （ 1 ） 2022年

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Activation-induced cytidine deaminase is a possible regulator of cross-talk between oocytes and granulosa cells through GDF-9 and SCF feedback system

Iizuka T., Wakae K., Ono M., Suzuki T., Mizumoto Y., Kitamura K., Horike S.i., Muramatsu M., Fujiwara H.

Scientific Reports 11 （ 1 ） 2021年12月

Activation-induced cytidine deaminase (AID, Aicda) is a master gene regulating class switching of immunoglobulin genes. In this study, we investigated the significance of AID expression in the ovary. Immunohistological study and RT-PCR showed that AID was expressed in murine granulosa cells and oocytes. However, using the Aicda-Cre/Rosa-tdRFP reporter mouse, its transcriptional history in oocytes was not detected, suggesting that AID mRNA in oocytes has an exogenous origin. Microarray and qPCR validation revealed that mRNA expressions of growth differentiation factor-9 (GDF-9) in oocytes and stem cell factor (SCF) in granulosa cells were significantly decreased in AID-knockout mice compared with wild-type mice. A 6-h incubation of primary granuloma cells markedly reduced AID expression, whereas it was maintained by recombinant GDF-9. In contrast, SCF expression was induced by more than threefold, whereas GDF-9 completely inhibited its increase. In the presence of GDF-9, knockdown of AID by siRNA further decreased SCF expression. However, in AID-suppressed granulosa cells and ovarian tissues of AID-knockout mice, there were no differences in the methylation of SCF and GDF-9. These findings suggest that AID is a novel candidate that regulates cross-talk between oocytes and granulosa cells through a GDF-9 and SCF feedback system, probably in a methylation-independent manner.

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Amniotic band syndrome in a monochorionic diamniotic twin pregnancy after rupture of the dividing membrane in the early second trimester: A case report

Nakashima M., Iizuka T., Kagami K., Yamazaki R., Ono M., Fujiwara H.

BMC Pregnancy and Childbirth 21 （ 1 ） 2021年12月

Background: Amniotic band syndrome is a rare phenomenon, but it can result in serious complications. We report herein our experience of amniotic band syndrome in a monochorionic diamniotic twin pregnancy where rupture of the dividing membrane occurred early in the second trimester. Case Presentation: A 29-year-old nulliparous woman was referred to us for management of her monochorionic diamniotic twin pregnancy at 10 weeks of gestation. When we were unable to identify a dividing membrane at 15 weeks of gestation using two-dimensional ultrasonography, we used three-dimensional ultrasonography to confirm its absence. Both modalities showed that the left arm of baby B was swollen and attached to a membranous structure originating from the placenta at 18 weeks of gestation. Tangled umbilical cords were noted on magnetic resonance imaging at 18 weeks of gestation. Emergency cesarean delivery was performed at 30 weeks of gestation because of the nonreassuring fetal status of baby A. The left arm of baby B had a constrictive ring with a skin defect. Both neonates had an uncomplicated postnatal course and were discharged around 2 months after delivery. Conclusions: Attention should be paid to the potential for amniotic band syndrome if rupture of the dividing membrane between twins is noted during early gestation.

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Brown adipocyte-specific knockout of Bmal1 causes mild but significant thermogenesis impairment in mice

Hasan N., Nagata N., Morishige J.i., Islam M.T., Jing Z., Harada K.i., Mieda M., Ono M., Fujiwara H., Daikoku T., Fujiwara T., Maida Y., Ota T., Shimba S., Kaneko S., Fujimura A., Ando H.

Molecular Metabolism 49 2021年07月

Objective: Impaired circadian clocks can cause obesity, but their pathophysiological role in brown adipose tissue (BAT), a major tissue regulating energy metabolism, remains unclear. To address this issue, we investigated the effects of complete disruption of the BAT clock on thermogenesis and energy expenditure. Methods: Mice with brown adipocyte-specific knockout of the core clock gene Bmal1 (BA-Bmal1 KO) were generated and analyzed. Results: The BA-Bmal1 KO mice maintained normal core body temperatures by increasing shivering and locomotor activity despite the elevated expression of thermogenic uncoupling protein 1 in BAT. BA-Bmal1 KO disrupted 24 h rhythmicity of fatty acid utilization in BAT and mildly reduced both BAT thermogenesis and whole-body energy expenditure. The impact of BA-Bmal1 KO on the development of obesity became obvious when the mice were fed a high-fat diet. Conclusions: These results reveal the importance of the BAT clock for maintaining energy homeostasis and preventing obesity.

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Time-Restricted Feeding Regulates Circadian Rhythm of Murine Uterine Clock

Hosono T., Ono M., Daikoku T., Mieda M., Nomura S., Kagami K., Iizuka T., Nakata R., Fujiwara T., Fujiwara H., Ando H.

Current Developments in Nutrition 5 （ 5 ） 2021年05月

Background: Skipping breakfast is associated with dysmenorrhea in young women. This suggests that the delay of food intake in the active phase impairs uterine functions by interfering with circadian rhythms. Objectives: To examine the relation between the delay of feeding and uterine circadian rhythms, we investigated the effects of the first meal occasion in the active phase on the uterine clock. Methods: Zeitgeber time (ZT) was defined as ZT0 (08:45) with lights on and ZT12 (20:45) with lights off. Young female mice (8 wk of age) were divided into 3 groups: group I (ad libitum consumption), group II (time-restricted feeding during ZT12-16, initial 4 h of the active period), and group III (time-restricted feeding during ZT20-24, last 4 h of the active period, a breakfast-skipping model). After 2 wk of dietary restriction, mice in each group were killed at 4-h intervals and the expression profiles of uterine clock genes, Bmal1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1), Per1 (period circadian clock 1), Per2, and Cry1 (cryptochrome 1), were examined. Results: qPCR and western blot analyses demonstrated synchronized circadian clock gene expression within the uterus. Immunohistochemical analysis confirmed that BMAL1 protein expression was synchronized among the endometrium and myometrium. In groups I and II, mRNA expression of Bmal1 was elevated after ZT12 at the start of the active phase. In contrast, Bmal1 expression was elevated just after ZT20 in group III, showing that the uterine clock rhythm had shifted 8 h backward. The changes in BMAL1 protein expression were confirmed by western blot analysis. Conclusions: This study is the first to indicate that time-restricted feeding regulates a circadian rhythm of the uterine clock that is synchronized throughout the uterine body. These findings suggest that the uterine clock system is a new candidate to explain the etiology of breakfast skipping-induced uterine dysfunction.

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Wavy floating greater omentum findings are useful for differentiating the etiology of fetal ascites

Iizuka T., Ono M., Yamazaki R., Kagami K., Mitani Y., Sakai S., Fujiwara H.

Diagnostics 11 （ 2 ） 2021年02月

The greater omentum is an apron-like peritoneal mesothelial sheet that was described by ultrasound as a floating fluid-filled viscus in ascites during the fetal period. To examine the association between the etiology of fetal ascites and ultrasound findings of the greater omentum, a retrospective study was conducted. Ultrasound findings of fetal omentum were defined as follows: (1) a cyst-like shape with a thin membrane observed as wavy in the ascites, (2) beside the stomach and below the liver, and (3) no blood flow noted on color Doppler. Eleven pregnancies had fetal ascites. A fetal greater omentum was confirmed in eight cases in which ascites were caused by non-peritonitis: fetal hydrops (n = 4), congenital cytomegalovirus infection (n = 2), idiopathic chylous ascites (n = 1), and unknown cause (n = 1). Of these eight cases, no abdominal surgical management was required in three live babies. However, a fetal greater omentum was not confirmed in all three cases of meconium peritonitis. It was suggested that the finding of the greater omentum can be an important clue for estimating the pathophysiological etiology of fetal ascites and helping with postnatal management. It should be reasonable to add the finding of the greater omentum to the detailed ultrasound examination checklist.

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A direct endoscopic approach for left-sided infrarenal para-aortic lymphadenectomy immediately after hysterectomy for endometrial cancer treatment: left dome formation (LDF)

Mizumoto, Y., Iwadare, J., Nakade, K., Obata, T., Matsumoto, T., Kagami, K., Iizuka, T., Matsuoka, A., Ono, M., Nakamura, M. and Fujiwara, H.

Surgical Endoscopy 34 （ 8 ） 3338 - 3343 2020年

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Promoting roles of embryonic signals in embryo implantation and placentation in cooperation with endocrine and immune systems

Fujiwara, H., Ono, M., Sato, Y., Imakawa, K., Iizuka, T., Kagami, K., Fujiwara, T., Horie, A., Tani, H., Hattori, A., Daikoku, T. and Araki, Y.

International Journal of Molecular Sciences 21 （ 5 ） 2020年

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Prenatal diagnosis facilitated prompt enzyme replacement therapy for prenatal benign hypophosphatasia

Ishijima, Y., Iizuka, T., Kagami, K., Masumoto, S., Nakade, K., Mitani, Y., Niida, Y., Watanabe, A., Yamazaki, R., Ono, M. and Fujiwara, H.

Journal of Obstetrics and Gynaecology 40 （ 1 ） 132 - 134 2020年

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Ovarian hyperstimulation closely associated with resumption of follicular growth after chemotherapy during tamoxifen treatment in premenopausal women with breast cancer: A multicenter retrospective cohort study

Yamazaki, R., Inokuchi, M., Ishikawa, S., Ayabe, T., Jinno, H., Iizuka, T., Ono, M., Myojo, S., Uchida, S., Matsuzaki, T., Tangoku, A., Kita, M., Sugie, T. and Fujiwara, H.

BMC Cancer 20 （ 1 ） 2020年

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Nationwide survey of Japanese breast oncology and reproductive endocrinology departments about the impact of breast cancer treatment on fertility

Yamazaki, R., Ono, M., Sugie, T., Inokuchi, M., Ishikawa, S., Iizuka, T., Masumoto, S., Myojo, S., Uchida, S., Horie, A. and Matsuzaki, T.

Journal of Obstetrics and Gynaecology Research 46 （ 12 ） 2488 - 2496 2020年

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Hypertensive disorders of pregnancy are associated with dysmenorrhea in early adulthood: A cohort study

Nakayama, M., Ono, M., Iizuka, T., Kagami, K., Fujiwara, T., Sekizuka-Kagami, N., Maida, Y., Obata, T., Yamazaki, R., Daikoku, T. and Fujiwara, H.

Journal of Obstetrics and Gynaecology Research 46 （ 11 ） 2292 - 2297 2020年

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Breakfast skipping in female college students is a potential and preventable predictor of gynecologic disorders at health service centers

Fujiwara, T., Ono, M., Iizuka, T., Sekizuka-Kagami, N., Maida, Y., Adachi, Y., Fujiwara, H. and Yoshikawa, H.

Diagnostics 10 （ 7 ） 2020年

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Adolescent dietary habit-induced obstetric and gynecologic disease (ADHOGD) as a new hypothesis—possible involvement of clock system

Fujiwara, T., Ono, M., Mieda, M., Yoshikawa, H., Nakata, R., Daikoku, T., Sekizuka-Kagami, N., Maida, Y., Ando, H. and Fujiwara, H.

Nutrients 12 （ 5 ） 2020年

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A novel third mesh-like myometrial layer connects the longitudinal and circular muscle fibers -A potential stratum to coordinate uterine contractions

Kagami, K., Ono, M., Iizuka, T., Matsumoto, T., Hosono, T., Sekizuka-Kagami, N., Shinmyo, Y., Kawasaki, H. and Fujiwara, H.

Scientific Reports 10 （ 1 ） 2020年

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Amniotic epithelial cells damage by oxidative stress in cases of diffuse chorioamniotic hemosiderosis

Iizuka, T., Ono, M., Masumoto, S., Mitani, Y., Yamazaki, R. and Fujiwara, H.

Journal of Obstetrics and Gynaecology Research 45 （ 10 ） 2095 - 2099 2019年

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Twin anemia-polycythemia sequence with blood chimerism in monochorionic dizygotic opposite-sex twins

Suzuki, T., Kagami, K., Mitani, Y., Yamazaki, R., Ono, M. and Fujiwara, H.

Journal of Obstetrics and Gynaecology Research 45 （ 6 ） 1201 - 1204 2019年

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Time Restriction of Food Intake during the Circadian Cycle Is a Possible Regulator of Reproductive Function in Postadolescent Female Rats

Fujiwara, T., Nakata, R., Ono, M., Mieda, M., Ando, H., Daikoku, T. and Fujiwara, H.

Current Developments in Nutrition 3 （ 4 ） 2019年

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Novel strategy of ovarian cancer implantation: Pre-invasive growth of fibrin-anchored cells with neovascularization

Matsuoka, A., Mizumoto, Y., Ono, M., Kagami, K., Obata, T., Terakawa, J., Maida, Y., Nakamura, M., Daikoku, T. and Fujiwara, H.

Cancer Science 110 （ 8 ） 2658 - 2666 2019年

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Embryo transfer associated with hormone replacement therapy cycles using assisted reproductive technology increases placenta accreta spectrum

Sakai, Y., Ono, M., Iizuka, T., Kagami, K., Masumoto, S., Nakayama, M., Nakade, K., Shitano, Y., Yamazaki, R. and Fujiwara, H.

Journal of Obstetrics and Gynaecology Research 45 （ 12 ） 2394 - 2399 2019年

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Factors regulating human extravillous trophoblast invasion: Chemokine-peptidase and CD9-integrin systems

Fujiwara, H., Matsumoto, H., Sato, Y., Horie, A., Ono, M., Nakamura, M., Mizumoto, Y., Kagami, K., Fujiwara, T., Hattori, A., Maida, Y., Daikoku, T., Imakawa, K. and Araki, Y.

Current Pharmaceutical Biotechnology 19 （ 10 ） 764 - 770 2018年

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Three-dimensional evaluation of murine ovarian follicles using a modified CUBIC tissue clearing method

Kagami, K., Shinmyo, Y., Ono, M., Kawasaki, H. and Fujiwara, H.

Reproductive Biology and Endocrinology 16 （ 1 ） 2018年

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APOBEC3G is increasingly expressed on the human uterine cervical intraepithelial neoplasia along with disease progression

Iizuka, T., Wakae, K., Nakamura, M., Kitamura, K., Ono, M., Fujiwara, H. and Muramatsu, M.

American Journal of Reproductive Immunology 78 （ 4 ） 2017年

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Three-dimensional visualization of intrauterine conceptus through the uterine wall by tissue clearing method

Kagami, K., Shinmyo, Y., Ono, M., Kawasaki, H. and Fujiwara, H.

Scientific Reports 7 （ 1 ） 2017年

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Platelet-derived microparticles and soluble factors differentially regulate human endometrial epithelial cell movement

Suginami, K., Sato, Y., Horie, A., Matsumoto, H., Tani, H., Mizumoto, Y., Ono, M., Matsuoka, A., Kyo, S., Araki, Y., Konishi, I. and Fujiwara, H.

American Journal of Reproductive Immunology 77 （ 4 ） 2017年

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Paracrine pathways in uterine leiomyoma stem cells involve insulinlike growth factor 2 and insulin receptor a

Moravek, M. B., Yin, P., Coon, J. S., Ono, M., Druschitz, S. A., Malpani, S. S., Dyson, M. T., Rademaker, A. W., Robins, J. C., Wei, J. J., Kim, J. J. and Bulun, S. E.

Journal of Clinical Endocrinology and Metabolism 102 （ 5 ） 1588 - 1595 2017年

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Giant fetal hydrometrocolpos associated with cloacal anomaly causing postnatal respiratory distress

Kanda, T., Iizuka, T., Yamazaki, R., Iwadare, J., Ono, M. and Fujiwara, H.

Journal of Obstetrics and Gynaecology Research 43 （ 11 ） 1769 - 1772 2017年

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Dual expression of immunoreactive estrogen receptor β and p53 is a potential predictor of regional lymph node metastasis and postoperative recurrence in endometrial endometrioid carcinoma

Obata, T., Nakamura, M., Mizumoto, Y., Iizuka, T., Ono, M., Terakawa, J., Daikoku, T. and Fujiwara, H.

PLoS ONE 12 （ 11 ） 2017年

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Laparoscopic repair of an indirect inguinal hernia containing a fallopian tube in an adult woman

Shirahashi, M., Ono, M., Yokoyama, N., Okamoto, N., Motomura, Y., Ikeda, T. and Yakubo, K.

Gynecology and Minimally Invasive Therapy 5 （ 2 ） 94 - 95 2016年

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Short, severe dizziness attacks in a pregnant woman with type I ARNOLD–Chiari malformation

Ono, M., Kojima, A., Shirahashi, M., Noda, S., Akiba, Y., Nishijima, S., Amagata, T., Ikeda, T., Yakubo, K. and Fukuiya, T.

Journal of Obstetrics and Gynaecology 36 （ 4 ） 430 - 431 2016年

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Polyhydramnios associated with Prader-Willi syndrome

Akiba, Y., Ono, M., Shirahashi, M., Noda, S., Nishijima, S., Amagata, T., Kusano, R., Fuke, T., Hayashida, S., Ikeda, T., Yakubo, K. and Fukuiya, T.

Journal of Obstetrics and Gynaecology 35 （ 7 ） 752 - 753 2015年

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Uterine Leiomyoma Stem Cells: Linking Progesterone to Growth

Bulun, S. E., Moravek, M. B., Yin, P., Ono, M., Coon V, J. S., Dyson, M. T., Navarro, A., Marsh, E. E., Zhao, H., Maruyama, T., Chakravarti, D., Kim, J. J. and Wei, J. J.

Seminars in Reproductive Medicine 33 （ 5 ） 357 - 365 2015年

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Two consecutive births after ovarian preservation in a Gorlin syndrome patient

Ono, M., Nishijima, S., Amagata, T., Ikeda, T., Yakubo, K., Akatsuka, S. and Fukuiya, T.

Journal of Obstetrics and Gynaecology 35 （ 1 ） 96 - 97 2015年

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Stem Cells in Myometrial Physiology

Ono, M. and Maruyama, T.

Seminars in Reproductive Medicine 33 （ 5 ） 350 - 356 2015年

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Ovarian steroids, stem cells and uterine leiomyoma: Therapeutic implications

Moravek, M. B., Yin, P., Ono, M., Coon, V. J. S., Dyson, M. T., Navarro, A., Marsh, E. E., Chakravarti, D., Julie Kim, J., Wei, J. J. and Bulun, S. E.

Human Reproduction Update 21 （ 1 ） 1 - 12 2015年

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Human uterine leiomyoma stem/progenitor cells expressing CD34 and CD49b initiate tumors in vivo

Yin, P., Ono, M., Moravek, M. B., Coon, J. S. V., Navarro, A., Monsivais, D., Dyson, M. T., Druschitz, S. A., Malpani, S. S., Serna, V. A., Qiang, W., Chakravarti, D., Julie Kim, J. and Bulun, S. E.

Journal of Clinical Endocrinology and Metabolism 100 （ 4 ） E601 - E606 2015年

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CD34 and CD49f double-positive and lineage marker-negative cells isolated from human myometrium exhibit stem cell-like properties involved in pregnancy-induced uterine remodeling

Ono, M., Kajitani, T., Uchida, H., Arase, T., Oda, H., Uchida, S., Ota, K., Nagashima, T., Masuda, H., Miyazaki, K., Asada, H., Hida, N., Mabuchi, Y., Morikawa, S., Ito, M., Bulun, S. E., Okano, H., Matsuzaki, Y., Yoshimura, Y. and Maruyama, T.

Biology of Reproduction 93 （ 2 ） 2015年

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Aberrant expression and localization of deoxyribonucleic acid methyltransferase 3B in endometriotic stromal cells

Dyson, M. T., Kakinuma, T., Pavone, M. E., Monsivais, D., Navarro, A., Malpani, S. S., Ono, M. and Bulun, S. E.

Fertility and Sterility 104 （ 4 ） 953 - 963.e2 2015年

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5-hydroxymethylcytosine promotes proliferation of human uterine leiomyoma: A biological link to a new epigenetic modification in benign tumors

Navarro, A., Yin, P., Ono, M., Monsivais, D., Moravek, M. B., Coon, J. S. V., Dyson, M. T., Wei, J. J. and Bulun, S. E.

Journal of Clinical Endocrinology and Metabolism 99 （ 11 ） E2437 - E2445 2014年

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Tissue-specific stem cells in the myometrium and tumor-initiating cells in Leiomyoma

Ono, M., Bulun, S. E. and Maruyama, T.

Biology of Reproduction 91 （ 6 ） 2014年

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Inhibition of canonical WNT signaling attenuates human leiomyoma cell growth

Ono, M., Yin, P., Navarro, A., Moravek, M. B., Coon V, J. S., Druschitz, S. A., Gottardi, C. J. and Bulun, S. E.

Fertility and Sterility 101 （ 5 ） 1441 - 1449.e1 2014年

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Genome-Wide DNA Methylation Analysis Predicts an Epigenetic Switch for GATA Factor Expression in Endometriosis

Dyson, M. T., Roqueiro, D., Monsivais, D., Ercan, C. M., Pavone, M. E., Brooks, D. C., Kakinuma, T., Ono, M., Jafari, N., Dai, Y. and Bulun, S. E.

PLoS Genetics 10 （ 3 ） 2014年

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Fenretinide: A novel treatment for endometrial cancer

Mittal, N., Malpani, S., Dyson, M., Ono, M., Coon, J. S., Kim, J. J., Schink, J. C., Bulun, S. E. and Pavone, M. E.

PLoS ONE 9 （ 10 ） 2014年

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Establishment of human patient-derived endometrial cancer xenografts in NOD scid gamma mice for the study of invasion and metastasis

Unno, K., Ono, M., Winder, A. D., Maniar, K. P., Paintal, A. S., Yu, Y., Wei, J. J., Lurain, J. R. and Kim, J. J.

PLoS ONE 9 （ 12 ） 2014年

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ERβ- and prostaglandin E2-regulated pathways integrate cell proliferation via Ras-like and estrogen-regulated growth inhibitor in endometriosis

Monsivais, D., Dyson, M. T., Yin, P., Coon, J. S., Navarro, A., Feng, G., Malpani, S. S., Ono, M., Ercan, C. M., Wei, J. J., Pavone, M. E., Su, E. and Bulun, S. E.

Molecular Endocrinology 28 （ 8 ） 1304 - 1315 2014年

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Ligand-Activated Peroxisome Proliferator-Activated Receptor β/δ Modulates Human Endometrial Cancer Cell Survival

Ma, J. J., Monsivais, D., Dyson, M. T., Coon, J. S., Malpani, S., Ono, M., Zhao, H., Xin, H., Pavone, M. E., Kim, J. J., Chakravarti, D. and Bulun, S. E.

Hormones and Cancer 4 （ 6 ） 358 - 370 2013年

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Somatic stem cells in the myometrium and in myomas

Maruyama, T., Ono, M. and Yoshimura, Y.

Seminars in Reproductive Medicine 31 （ 1 ） 77 - 81 2013年

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Review: Human uterine stem/progenitor cells: Implications for uterine physiology and pathology

Maruyama, T., Miyazaki, K., Masuda, H., Ono, M., Uchida, H. and Yoshimura, Y.

34 S68 - S72 2013年

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Possible involvement of nerve growth factor in dysmenorrhea and dyspareunia associated with endometriosis

Kajitani, T., Maruyama, T., Asada, H., Uchida, H., Oda, H., Uchida, S., Miyazaki, K., Arase, T., Ono, M. and Yoshimura, Y.

Endocrine Journal 60 （ 10 ） 1155 - 1164 2013年

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Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells promotes tumor growth

Ono, M., Yin, P., Navarro, A., Moravek, M. B., Coon V, J. S., Druschitz, S. A., Serna, V. A., Qiang, W., Brooks, D. C., Malpani, S. S., Ma, J., Ercan, C. M., Mittal, N., Monsivais, D., Dyson, M. T., Yemelyanov, A., Maruyama, T., Chakravarti, D., Kim, J. J., Kurita, T., Gottardi, C. J. and Bulun, S. E.

Proceedings of the National Academy of Sciences of the United States of America 110 （ 42 ） 17053 - 17058 2013年

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Role of stem cells in human uterine leiomyoma growth

Ono, M., Qiang, W., Serna, V. A., Yin, P., Coon, J. S., Navarro, A., Monsivais, D., Kakinuma, T., Dyson, M., Druschitz, S., Unno, K., Kurita, T. and Bulun, S. E.

PLoS ONE 7 （ 5 ） 2012年

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Weight gain increases human aromatase expression in mammary gland

Chen, D., Zhao, H., Coon, J. S., Ono, M., Pearson, E. K. and Bulun, S. E.

Molecular and Cellular Endocrinology 355 （ 1 ） 114 - 120 2012年

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Abdominal wall leiomyoma in a reproductive age woman without antecedent pelvic surgery

Ono, M., Inoue, Y., Yokota, M., Uehara, I., Kamijo, S., Hattori, Y., Kurahashi, T., Shimada, T. and Nakagawa, H.

European Journal of Obstetrics and Gynecology and Reproductive Biology 151 （ 2 ） 225 - 226 2010年

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Stem cell-like properties of the endometrial side population: Implication in endometrial regeneration

Masuda, H., Matsuzaki, Y., Hiratsu, E., Ono, M., Nagashima, T., Kajitani, T., Arase, T., Oda, H., Uchida, H., Asada, H., Ito, M., Yoshimura, Y., Maruyama, T. and Okano, H.

PLoS ONE 5 （ 4 ） 2010年

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OCT4 expression in human uterine myometrial stem/progenitor cells

Ono, M., Kajitani, T., Uchida, H., Arase, T., Oda, H., Nishikawa-Uchida, S., Masuda, H., Nagashima, T., Yoshimura, Y. and Maruyama, T.

Human Reproduction 25 （ 8 ） 2059 - 2067 2010年

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Human uterine stem/progenitor cells: Their possible role in uterine physiology and pathology

Maruyama, T., Masuda, H., Ono, M., Kajitani, T. and Yoshimura, Y.

Reproduction 140 （ 1 ） 11 - 22 2010年

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Fibroma of the omentum resembling an ovarian tumor in the pelvis

Ono, M., Tanaka, K., Ikezawa, N., Kobayashi, Y., Inoue, Y., Yokota, M., Matsumura, S., Uehara, I., Hattori, Y., Kurahashi, T., Shimada, T. and Nakagawa, H.

Keio Journal of Medicine 58 （ 4 ） 234 - 236 2009年

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The UDP-glucose receptor P2RY14 triggers innate mucosal immunity in the female reproductive tract by inducing IL-8

Arase, T., Uchida, H., Kajitani, T., Ono, M., Tamaki, K., Oda, H., Nishikawa, S., Kagami, M., Nagashima, T., Masuda, H., Asada, H., Yoshimura, Y. and Maruyama, T.

Journal of Immunology 182 （ 11 ） 7074 - 7084 2009年

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Activation of SRC kinase and phosphorylation of signal transducer and activator of transcription-5 are required for decidual transformation of human endometrial stromal cells

Nagashima, T., Maruyama, T., Uchida, H., Kajitani, T., Arase, T., Ono, M., Oda, H., Kagami, M., Masuda, H., Nishikawa, S., Asada, H. and Yoshimura, Y.

Endocrinology 149 （ 3 ） 1227 - 1234 2008年

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Pregnancy outcomes of reciprocal translocation carriers who have a history of repeated pregnancy loss

Ozawa, N., Maruyama, T., Nagashima, T., Ono, M., Arase, T., Ishimoto, H. and Yoshimura, Y.

Fertility and Sterility 90 （ 4 ） 1301 - 1304 2008年

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Glycodelin blocks progression to S phase and inhibits cell growth: A possible progesterone-induced regulator for endometrial epithelial cell growth

Ohta, K., Maruyama, T., Uchida, H., Ono, M., Nagashima, T., Arase, T., Kajitani, T., Oda, H., Morita, M. and Yoshimura, Y.

Molecular Human Reproduction 14 （ 1 ） 17 - 22 2008年

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Analysis of serum FSH bioactivity in a patient with an FSH-secreting pituitary microadenoma and multicystic ovaries: A case report

Kajitani, T., Liu, S., Maruyama, T., Uchida, H., Sakurai, R., Masuda, H., Nagashima, T., Ono, M., Arase, T. and Yoshimura, Y.

Human Reproduction 23 （ 2 ） 435 - 439 2008年

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Histone acetylation and subcellular localization of chromosomal protein BRD4 during mouse oocyte meiosis and mitosis

Nagashima, T., Maruyama, T., Furuya, M., Kajitani, T., Uchida, H., Masuda, H., Ono, M., Arase, T., Ozato, K. and Yoshimura, Y.

Molecular Human Reproduction 13 （ 3 ） 1 - 8 2007年

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Side population in human uterine myometrium displays phenotypic and functional characteristics of myometrial stem cells

Ono, M., Maruyama, T., Masuda, H., Kajitani, T., Nagashima, T., Arase, T., Ito, M., Ohta, K., Uchida, H., Asada, H., Yoshimura, Y., Okano, H. and Matsuzaki, Y.

Proceedings of the National Academy of Sciences of the United States of America 104 （ 47 ） 18700 - 18705 2007年

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Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/γcnull immunodeficient mice

Masuda, H., Maruyama, T., Hiratsu, E., Yamane, J., Iwanami, A., Nagashima, T., Ono, M., Miyoshi, H., Okano, H. J., Ito, M., Tamaoki, N., Nomura, T., Okano, H., Matsuzaki, Y. and Yoshimura, Y.

Proceedings of the National Academy of Sciences of the United States of America 104 （ 6 ） 1925 - 1930 2007年

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Histone deacetylase inhibitors stimulate cell migration in human endometrial adenocarcinoma cells through up-regulation of glycodelin

Uchida, H., Maruyama, T., Ono, M., Ohta, K., Kajitani, T., Masuda, H., Nagashima, T., Arase, T., Asada, H. and Yoshimura, Y.

Endocrinology 148 （ 2 ） 896 - 902 2007年

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Histone deacetylase inhibitor-induced glycodelin enhances the initial step of implantation

Uchida, H., Maruyama, T., Ohta, K., Ono, M., Arase, T., Kagami, M., Oda, H., Kajitani, T., Asada, H. and Yoshimura, Y.

Human Reproduction 22 （ 10 ） 2615 - 2622 2007年

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Human endometrial cytodifferentiation by histone deacetylase inhibitors

Uchida, H., Maruyama, T., Nagashima, T., Ono, M., Masuda, H., Arase, T., Sugiura, I., Onouchi, M., Kajitani, T., Asada, H. and Yoshimura, Y.

Human cell : official journal of Human Cell Research Society 19 （ 1 ） 38 - 42 2006年

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Uterine leiomyoma

Maruyama, T., Asada, H., Ono, M., Arase, T. and Yoshimura, Y.

Nippon rinsho. Japanese journal of clinical medicine Suppl 2 477 - 484 2006年

Histone acetylation in reproductive organs: Significance of histone deacetylase inhibitors in gene transcription

Uchida, H., Maruyama, T., Arase, T., Ono, M., Nagashima, T., Masuda, H., Asada, H. and Yoshimura, Y.

Reproductive Medicine and Biology 4 （ 2 ） 115 - 122 2005年

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