Periodic myometrial contraction is one of the important uterine functions to achieve embryo implantation and parturition. Although it is well-known that the mammalian myometrium is composed of ...longitudinal (outer) and circular (inner) layers, the precise mechanisms that coordinate both muscular contractions to produce peristaltic movements remain unclear. Recently, by treatment with our modified Clear Unobstructed Brain Imaging Cocktails and Computational analysis (CUBIC) tissue-clearing method, we obtained well-contrasted three-dimensional images of the transparent murine ovary using enhanced green fluorescent protein (EGFP) transgenic mice and light-sheet microscopy. Consequently, to investigate accurate anatomical connections between outer and inner myometrial fibers, we observed whole structures of the myometrium using a transparent murine uterus. By this method, we identified a novel muscle layer, a middle layer of the myometrium, which anatomically connects the conventional outer longitudinal and inner circular muscles. This new layer was visualized as a mesh-like structure and this structure was observed throughout the whole uterus from proximal to distal sites. In this area, CD31-positive vessels were abundantly localized around the mesh-like muscle fibers. In addition, CD34-positive uterine telocytes and tubulin β-3-positive nerve fibers were closely located in this middle layer. These findings indicate the presence of a novel mesh-like stratum that connects longitudinal and circular muscle layers, and suggest its coordinating role in myometrial contractions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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.
Downregulation of FOXP4 inhibits cell proliferation and promotes differentiation of atypical cells in CIN lesions. We propose that FOXP4 is a novel target molecule for non‐surgical CIN treatment that inhibits CIN progression by inducing squamous differentiation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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 (
) and cryptochrome (
) is activated by the heterodimer of the transcription factor circadian locomotor output cycles kaput (
) and brain and muscle Arnt-like protein-1 (
). By binding to E-box sequences in the promoters of
and
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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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
Endoscopic surgery for infrarenal para-aortic lymphadenectomy has been widely accepted. Two major approaches, “transperitoneal” and “extraperitoneal”, are generally used; however, they ...have several disadvantages. A “transperitoneal” approach to the left para-aortic region is usually indirect, often performed after wide extension of the right para-aortic region. An “extraperitoneal” approach is unsuitable when a peritoneal tear exists after a prior surgical procedure such as hysterectomy. Here, we propose a modified transperitoneal technique, “Left dome formation (LDF),” which directly provides a surgical field for left infrarenal para-aortic lymphadenectomy even after hysterectomy.
Methods
The LDF procedure comprised three processes: (1) setting, (2) dissection of inframesenteric lymph nodes (step 1), and (3) dissection of infrarenal lymph nodes (step 2). Setting: two trocars were added 4 cm bilateral to the low-mid abdominal trocar that was used in prior hysterectomy. Step 1: The posterior layer of the renal fascia along with the left ureter and left ovarian vessel were separated from the left common iliac artery and iliopsoas. Left inframesentric nodes were removed from the surgical field. Step 2: The left ureter was isolated from the posterior renal fascia, and the dome was expanded cranially to the left renal vein, with the ovarian vein always visualizable at the dome ceiling. Left infrarenal nodes were removed.
Results
We applied LDF to ten endometrial cancer patients, recommended for additional dissection of para-aortic nodes based on intraoperative evaluation using the laparoscopically removed uterus. The operative time and number of removed lymph nodes in Step 1 and Step 2 were 28.8 (20–49) min and 5.3 (2–10) and 54.6 (52–70) min and 6.5 (1–11), respectively. Blood loss was below 50 ml. No serious organ injury occurred during procedures.
Conclusion
Since the left ureter is always observable, LDF procedure facilitates effective surgery to overcome the anatomical complexity of the left para-aortic region and is potentially useful for sentinel node sampling.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Recently, we demonstrated the three-dimensional (3D) localization of murine trophoblast giant cells in the pregnant uterus using a modified Clear Unobstructed Brain Imaging Cocktails and ...Computational analysis (CUBIC) tissue-clearing method and hybrid construct consisting of the cytomegalovirus enhancer fused to the chicken beta-actin promoter (CAG) conjugated enhanced green fluorescent protein (EGFP) transgenic mice. In this study, we applied this method to obtain a transparent whole-image of the ovary and observed the 3D localization of individual oocytes in the developing follicles.
Ovarian samples were obtained from EGFP transgenic mice and subjected to nuclear staining with propidium iodide (PI) and CUBIC treatment. The detection of double fluorescence signals (green and red) and subsequent reconstruction of 3D images of the whole ovary were performed by light-sheet microscopy and computer programs, respectively.
The ovary became transparent using the CUBIC method and each nucleus of the follicle component cells was uniformly fluoro-stained by PI perfusion. In contrast, EGFP signals were strong in oocytes, whereas those of surrounding granulosa cells were faint. These signal differences in EGFP expression among oocytes, granulosa cells, and theca-interstitial cells produce well-contrasted images of the growing follicles, providing clear information of the 3D localization of individual oocytes.
These results indicate that this procedure is one of the effective approaches to analyze the 3D structure of follicles in the whole ovary.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Embryo implantation in the uterus is an essential process for successful pregnancy in mammals. In general, the endocrine system induces sufficient embryo receptivity in the endometrium, where ...adhesion-promoting molecules increase and adhesion-inhibitory molecules decrease. Although the precise mechanisms remain unknown, it is widely accepted that maternal-embryo communications, including embryonic signals, improve the receptive ability of the sex steroid hormone-primed endometrium. The embryo may utilize repulsive forces produced by an Eph-ephrin system for its timely attachment to and subsequent invasion through the endometrial epithelial layer. Importantly, the embryonic signals are considered to act on maternal immune cells to induce immune tolerance. They also elicit local inflammation that promotes endometrial differentiation and maternal tissue remodeling during embryo implantation and placentation. Additional clarification of the immune control mechanisms by embryonic signals, such as human chorionic gonadotropin, pre-implantation factor, zona pellucida degradation products, and laeverin, will aid in the further development of immunotherapy to minimize implantation failure in the future.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Recently, it was demonstrated that the expression of
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
(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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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
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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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Although direct adhesion of cancer cells to the mesothelial cell layer is considered to be a key step for peritoneal invasion of ovarian cancer cell masses (OCM), we recently identified a different ...strategy for the peritoneal invasion of OCM. In 6 out of 20 cases of ovarian carcinoma, extraperitoneal growth of the OCM was observed along with the neovascularization of feeding vessels, which connect the intraperitoneal host stroma and extraperitoneal lesions through the intact mesothelial cell layer. As an early step, the OCMs anchor in the extraperitoneal fibrin networks and then induce the migration of CD34‐positive and vascular endothelial growth factor A (VEGF‐A)‐positive endothelial cells, constructing extraperitoneal vascular networks around the OCM. During the extraperitoneal growth of OCM, podoplanin‐positive and α smooth muscle actin (αSMA)‐positive cancer‐associated fibroblasts (CAF) appears. In more advanced lesions, the boundary line of mesothelial cells disappears around the insertion areas of feeding vessels and then extraperitoneal and intraperitoneal stroma are integrated, enabling the OCM to invade the host stroma, being associated with CAF. In addition, tissue factors (TF) are strongly detected around these peritoneal implantation sites and their levels in ascites were higher than that in blood. These findings demonstrate the presence of neovascularization around fibrin net‐anchored OCMs on the outer side of the intact peritoneal surface, suggesting a novel strategy for peritoneal invasion of ovarian cancer and TF‐targeted intraperitoneal anti‐cancer treatment. We observed and propose a novel strategy for peritoneal implantation of ovarian cancer. The strategy includes the preinvasive growth of fibrin‐anchored cancer cells along with neovascularization on the outer side of the intact peritoneal surface.
We observed and propose a novel strategy for peritoneal implantation of ovarian cancer. The strategy include the pre‐invasive growth of fibrin‐anchored cancer cells along with neovaschlarization on the outer side of the intact pertoneal surface.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Aim
To evaluate obstetric outcomes in embryo transfer (ET) during estrogen with progestin hormone replacement therapy (HRT) cycles using assisted reproductive technology (ART).
Methods
Of the 118 ...singleton pregnancies conceived with ART and delivered between January 2015 and December 2017, we reviewed the data of 87 cases that had information on HRT at the time of ET. Data on pregnancy outcomes included the presence of small for gestational age fetuses, hypertensive disorders of pregnancy, placenta previa (including low‐lying placenta), placental abruption and placenta accreta spectrum (including placenta accreta, placenta increta and placenta percreta). We investigated the relationship between HRT cycles and adverse placental outcomes (placenta accreta spectrum, placental abruption, placenta previa, hypertensive disorders of pregnancy and small for gestational age fetuses). We then analyzed the associations that correlated with adverse placental outcomes.
Results
Patients with ET during HRT cycles were more likely to have placenta accreta spectrum. During the study period, 87 out of 118 singleton live births using ART had information on HRT (60 HRT cycles and 27 ovulation cycles). The incidence of placenta accreta spectrum was significantly higher in the HRT cycle group than in the ovulation cycle group (HRT cycle, 31.7% 19 of 60 vs ovulation cycle, 7.4% 2 of 27; P < 0.01).
Conclusion
The obstetric outcomes occurring in pregnancies involving HRT use may differ among ET cycles. ET during HRT cycles were associated with adverse obstetric outcomes due to placenta accreta spectrum. The potential interaction between HRT cycles and adverse placental events is novel and warrants further investigation.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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