Inhibition of protein arginine methyltransferase 6 activates interferon signaling and induces the apoptosis of endometrial cancer cells via histone modification.

Histone modification, a major epigenetic mechanism regulating gene expression through chromatin remodeling, introduces dynamic changes in chromatin architecture. Protein arginine methyltransferase 6 (PRMT6) is overexpressed in various types of cancer, including prostate, lung and endometrial cancer (EC). Epigenome regulates the expression of endogenous retrovirus (ERV), which activates interferon signaling related to cancer. The antitumor effects of PRMT6 inhibition and the role of PRMT6 in EC were investigated, using epigenome multi­omics analysis, including an assay for chromatin immunoprecipitation sequencing (ChIP­seq) and RNA sequencing (RNA­seq). The expression of PRMT6 in EC was analyzed using reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and immunohistochemistry (IHC). The prognostic impact of PRMT6 expression was evaluated using IHC. The effects of PRMT6­knockdown (KD) were investigated using cell viability and apoptosis assays, as well as its effects on the epigenome, using ChIP­seq of H3K27ac antibodies and RNA­seq. Finally, the downstream targets identified by multi­omics analysis were evaluated. PRMT6 was overexpressed in EC and associated with a poor prognosis. PRMT6­KD induced histone hypomethylation, while suppressing cell growth and apoptosis. ChIP­seq revealed that PRMT6 regulated genomic regions related to interferons and apoptosis through histone modifications. The RNA­seq data demonstrated altered interferon­related pathways and increased expression of tumor suppressor genes, including NK6 homeobox 1 and phosphoinositide­3­kinase regulatory subunit 1, following PRMT6­KD. RT­qPCR revealed that eight ERV genes which activated interferon signaling were upregulated by PRMT6­KD. The data of the present study suggested that PRMT6 inhibition induced apoptosis through interferon signaling activated by ERV. PRMT6 regulated tumor suppressor genes and may be a novel therapeutic target, to the best of our knowledge, in EC.

Altered release of thrombomodulin and HMGB1 in the placenta complicated with preeclampsia.

INTRODUCTION: Preeclampsia (PE) is a severe pregnancy complication due to placental dysfunction. Thrombomodulin (TM), a glycoprotein expressed on the trophoblast cell membrane, plays an organ-protective role in the placenta by regulating coagulation and inflammation. TM-mediated regulation of High Mobility Group Box1(HMGB1) is an essential mechanism that contributes to placental homeostasis and prevents pregnancy complications in mice. Here, we aimed to clarify the role of placental TM and HMGB1 in the pathophysiology of human PE. METHODS AND RESULTS: In this study, maternal blood serum and placental tissue were obtained from 72 PE patients and 110 normal controls. Soluble TM(sTM) and HMGB1 levels in the maternal serum were assessed. The placental TM and HMGB1 expression levels were evaluated using immunohistochemistry and qPCR. Serum sTM and HMGB1 levels gradually increased with gestational age in normal pregnancies; however, both circulating sTM and HMGB1 levels were significantly higher in the PE group. Serum HMGB1/sTM ratio was elevated in PE patients compared to that in normal controls, which correlated positively with the clinical severity of PE. The immunohistochemistry analysis revealed the loss of TM and the increase in extranuclear HMGB1. TM mRNA expression was diminished in PE placentas, which negatively correlated with soluble fms-like tyrosine kinase-1 (sFlt-1) expression. DISCUSSION: The increase in circulating sTM and HMGB1 could be attributed to the enhanced placental TM shedding in PE patients. The molecular events mediated by the imbalance in the placental TM and HMGB1 levels could be an underlying feature of PE; maternal serum HMGB1/sTM ratio could reflect this status.

Increased risk of placenta previa and preterm birth in pregnant women with endometriosis/adenomyosis: A propensity-score matching analysis of a nationwide perinatal database in Japan.

AIM: We aimed to investigate the associations of endometriosis and adenomyosis with pregnancy complications by using a large-scale Japanese database. METHODS: We retrospectively analyzed 145 590 singleton pregnancies from the Japan Perinatal Registry Network Database. Pregnant women registered as having endometriosis or adenomyosis were designated as the case group (EA), whereas the control group (non-EA) was selected using propensity-score matching adjusted for variables such as age, parity, BMI, smoking history, and the use of assisted reproductive technology. The main outcomes included placental malposition, preterm birth, and hypertensive disorders of pregnancy (HDP). RESULTS: In total, 1203 patients from both the EA and non-EA groups were matched and evaluated. The EA group showed significantly higher rates of placenta previa (odds ratio [OR], 3.01; 95% confidence interval [CI], 1.84-4.92), low-lying placenta (OR, 2.02; 95% CI, 1.06-3.86), and preterm birth (OR, 1.44; 95% CI, 1.13-1.84) than the non-EA group. However, no significant difference was observed in the incidence of HDP (OR, 1.22; 95% CI, 0.90-1.66). CONCLUSION: The use of propensity-score matching to analyze a nationwide perinatal database in Japan clarified that EA was associated with increased pregnancy complications, specifically placental malposition, including placenta previa and low-lying placenta, and preterm birth, but not with HDP.

Clinical characteristics and outcomes of women with adenomyosis pain during pregnancy: a retrospective study.

OBJECTIVES: Adenomyosis is associated with unfavorable perinatal outcomes, and recent case reports show that some women with adenomyosis experience pain at the adenomyosis lesion during pregnancy and have detrimental perinatal outcomes. This study aimed to clarify the clinical characteristics of this pain and perinatal outcomes associated with this phenomenon. METHODS: This was a single-center retrospective analysis of pregnant women with adenomyosis. The incidence of pain onset at adenomyosis lesions, defined as persistent pain at the adenomyosis site with administration of analgesics for pain relief, and its association with perinatal outcomes were analyzed. RESULTS: Among 91 singleton pregnancies with adenomyosis, 12 pregnancies (13.2 %) presented with pain. One pregnancy resulted in second-trimester miscarriage, and 5 of the 11 pregnancies (45 %) developed preeclampsia, which resulted in preterm delivery, and 3 of the 12 pregnancies (25 %) achieved term delivery. The incidence of preeclampsia and preterm delivery was higher in those who experienced pain than in those without (45 % [5/11] vs. 15 % [11/74]; p<0.05, and 73 % [8/11] vs. 34 % [25/74]; p<0.05, respectively). Among women with pain, the maximum C-reactive protein level was significantly higher in women who developed preeclampsia than in those who did not (5.45 vs. 0.12 mg/dL, p<0.05). CONCLUSIONS: Our study revealed that adenomyosis can cause pain in over one of eight pregnancies with adenomyosis, which may be associated with the increased incidence of preeclampsia resulting in preterm delivery. Women with pain, especially those with high C-reactive protein levels, may be at high risk for future development of preeclampsia and consequent preterm delivery.

A Case of Ruptured Exophytic Uterine Artery Pseudoaneurysm without Specific Risk Factors That Manifested Seven Days after Vaginal Delivery.

A uterine artery pseudoaneurysm (UAP) is a life-threatening complication during pregnancy and postpartum. Early diagnosis of exophytic UAP rupture is difficult due to the absence of vaginal bleeding. This study reports the case of a 31-year-old postpartum woman who presented with abdominal pain and fever seven days after vaginal delivery, without symptoms of maternal shock. Ultrasonography revealed a ruptured exophytic UAP with hemoperitoneum, which was confirmed using computed tomography. Interventional radiology confirmed that the site of the pseudoaneurysm was at the level of the uterine artery bifurcation, and embolization was performed immediately after diagnosis using a coil and n-butyl-2-cyanoacrylate. The patient's symptoms were relieved, and she was discharged 12 days after the embolization. At eight months postpartum, the UAP was not visible on transvaginal ultrasonography. Exophytic UAP can occur even in the absence of specific risk factors such as cesarean section or endometriosis, and the UAP may not necessarily rupture immediately after delivery. Obstetricians must remain aware of the possibility of exophytic UAP rupture manifesting as abdominal pain with postpartum fever, rather than as unstable vital signs. This is the first report of an exophytic UAP that occurred at the level of the uterine artery bifurcation. Identification of the sites where exophytic UAP can occur can aid in the early diagnosis of the condition.

Differences in the incidence of obstetric complications depending on the extent and location of adenomyosis lesions.

OBJECTIVES: Although adenomyosis is reportedly associated with adverse pregnancy outcomes, clinical factors related to the high risk of obstetric complications are unclear. This study aimed to elucidate the characteristics of adenomyosis lesions associated with the increased incidence of obstetric complications based on imaging findings. METHODS: This was a retrospective, observational cohort study conducted in a tertiary perinatal care center. Eighty-eight singleton pregnant women with adenomyosis were included in the study. Based on magnetic resonance imaging or ultrasonography before and/or during pregnancy, patients were classified according to three types of image characteristics: the extent of adenomyosis lesion (focal type or diffuse type), location of the lesion (extrinsic type, intrinsic type, or indeterminate type), the positional relationship between the lesion and the placenta (placenta distant from adenomyosis or placenta over adenomyosis), and the incidence of obstetric complications were examined. RESULTS: Patients with diffuse type adenomyosis are significantly more likely to have spontaneous second-trimester miscarriage (diffuse type vs. focal type: 16.7 vs. 0%, p < .01), preterm premature rupture of membranes (19.4 vs. 1.9%, p < .01), and preeclampsia (25.0 vs. 7.7%, p = .02), as compared to those with focal type adenomyosis. In a comparison of the three location types, the incidence of placental malposition was higher in patients with the extrinsic type adenomyosis (extrinsic type vs. intrinsic type vs. indeterminate type: 20.0 vs. 6.7 vs. 2.3%, p = .03). Comparisons between the types of the placenta over or distant from adenomyosis lesion displayed no significant differences in the frequencies of obstetric complications. CONCLUSIONS: We demonstrated that the frequency of obstetric complications related to adenomyosis varies depending on the extent and location of the lesion; patients with diffuse type adenomyosis have an increased risk of spontaneous second-trimester miscarriage, preterm premature rupture of membranes, and preeclampsia, while patients with extrinsic type adenomyosis have an increased risk of placental malposition. Imaging evaluation of adenomyosis prior to conception or early in pregnancy may be useful for the obstetrical risk assessment among patients with adenomyosis.

Upregulation of autotaxin by oxidative stress via Nrf2 activation: A novel insight into the compensation mechanism in preeclamptic placenta.

The response of autotaxin (ATX)-lysophosphatidic acid (LPA) signaling system to placental oxidative stress (OS) and its significance to preeclampsia were investigated. For this purpose, oxidative stress index (OSI) and ATX levels were measured in the serum of pregnant women with preeclampsia. The expression levels of ATX and LPA receptors were assessed in trophoblast cells under high OS and glucose deprivation/re-oxygenation (OGD/R) conditions, with particular emphasis on the antioxidative nuclear factor erythroid 2-related factor 2 (NRF2) pathway. The influence of ATX-LPA signaling on cell migration was also evaluated using the wound healing assay. ATX concentrations and OSI in the serum were found to be elevated in preeclamptic women. The serum ATX levels were also positively correlated with OSI. Trophoblast cells responded to OS by increasing ATX mRNA expression concomitantly with intranuclear translocation of Nrf2, whereas inhibition of Nrf2 activation reverted this effect. The ATX-LPA signaling pathway facilitated trophoblast cell motility after Nrf2 activation. In conclusion, OS accumulation in preeclamptic placenta may activate the ATX-LPA system in trophoblasts via the Nrf2 pathway to sustain trophoblast functionality.

The sFlt-1/PlGF Ratio Trend Is Useful in Predicting Preeclampsia Severity in Hyperreactio Luteinalis Complicated with Preeclampsia.

Hyperreactio luteinalis (HL) is a rare condition that presents as bilateral ovarian enlargement during pregnancy. Typically, it is thought to be caused by increased production of human chorionic gonadotropin (hCG) associated with gestational trophoblastic diseases or multiple pregnancies. The prognosis is relatively good, with many cases resulting in term birth. However, some obstetric complications, such as preeclampsia (PE) and preterm births, have been reported. We present a serious case of HL with subsequent PE that resulted in preterm delivery at 31 weeks of gestation. The soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio was very high at the onset of PE at 24 weeks of gestation, followed by a modest decline, which then increased in proportion to the exacerbation of symptoms. Since HL cases have also been reported to be associated with PE, repeated measurement of the sFlt-1/PlGF ratio proved useful for better pregnancy management.

Possible risks and benefits of adenomyomectomy on pregnancy outcomes: a retrospective analysis.

BACKGROUND: Adenomyosis is associated with unfavorable perinatal outcomes; however, the effect of an adenomyomectomy on pregnancy outcomes remains unclear. Pregnancy following an adenomyomectomy has been reported to be associated with a high risk for uterine rupture; however, the actual incidence remains unknown. OBJECTIVE: This study aimed to evaluate the effect of an adenomyomectomy on pregnancy outcomes by retrospectively comparing the pregnancy outcomes of women who underwent an adenomyomectomy with those of women with adenomyosis. STUDY DESIGN: This was a single-center retrospective study in which the pregnancy outcomes of women who underwent an adenomyomectomy and for whom complete resection of the affected tissue under laparotomy was achieved were compared with those of women with adenomyosis. The following pregnancy outcomes were examined: second-trimester miscarriage, preterm prelabor rupture of membranes, preterm delivery, spontaneous preterm delivery, preeclampsia, rate of cesarean delivery, blood loss during cesarean delivery, incidence of placenta accreta spectrum, neonatal body weight, and small for gestational age infants. RESULTS: A total of 18 pregnant women who underwent an adenomyomectomy and 105 pregnant women with adenomyosis were included in this study. All women who underwent an adenomyomectomy delivered via cesarean delivery, and among them, 1 had a uterine rupture at 30 weeks of gestation. Although there was no significant difference between pregnant women who underwent an adenomyomectomy and those with adenomyosis in the incidence of second-trimester miscarriage (0% [0/18] vs 7.6% [8/105], respectively; P=.22), preterm delivery (50% [9/18] vs 32% [34/105], respectively; P=.15), and spontaneous preterm delivery (6% [1/18] vs 15% [16/105], respectively; P=.26), a significant decrease in preterm prelabor rupture of membrane (0% [0/18] vs 12% [13/105], respectively; P<.05), preeclampsia (0% [0/18] vs 12% [13/105], respectively; P<.05), and small for gestational infants (0% [0/18] vs 15% [16/105], respectively; P<.05), as well as a significant increase in the incidence of placenta accreta spectrum (50% [9/18] vs 0% [0/105], respectively; P<.01) and blood loss during cesarean delivery (1748 mL vs 1330 mL, respectively; P<.05) were observed. CONCLUSION: Uterine rupture following an adenomyomectomy may occur because of the high incidence of placenta accreta spectrum. However, an adenomyomectomy may reduce adverse pregnancy outcomes associated with adenomyosis, such as preterm prelabor rupture of membranes, preeclampsia, and small for gestational age infants. An adenomyomectomy may be a viable option for women among whom the procedure is inevitable before conception.

Efficacy of prompt administration of cryoprecipitate in severe postpartum hemorrhage of preeclampsia patients.

AIM: Cryoprecipitate (CRYO) is a concentrated preparation of coagulation factors formulated from fresh frozen plasma (FFP), which can replenish coagulation factors rapidly. Preeclampsia (PE) is frequently associated with postpartum hemorrhage (PPH), and the rapid replenishment of coagulation factors is vital in the management. We conducted a retrospective cohort study to determine the efficacy of administering CRYO irrespective of fibrinogen levels in patients with PE who experienced severe PPH. METHODS: Patients with PPH accompanied by PE and those who required red blood cell (RBC) transfusion were included. Cases were divided into two groups: those treated with CRYO (N = 16) and those not treated with CRYO (N = 10). The total transfusion volume, blood loss before and after transfusion initiation, duration of hospitalization, presence of pulmonary edema, and performance of either interventional radiology or hysterectomy were compared. RESULTS: The median fibrinogen levels before transfusion were 2.24 and 2.34 g/L in the CRYO group and the not using group, respectively. Although blood loss before transfusion was comparable between the two groups, blood loss after transfusion was significantly less in the CRYO group (median: 520 vs. 2352 mL, p = 0.015), as well as the total blood loss (median: 2285 vs. 3825 mL, p = 0.005) and total transfusion volume (median: RBC 6 vs. 16 U, p = 0.01, FFP 10 vs. 20 U, p = 0.017). CONCLUSION: Prompt replenishment of coagulation factors using CRYO to patients with PE who experience severe PPH could decrease further bleeding.

A successful management of refractory immune thrombocytopenic purpura with Eltrombopag during pregnancy complicated with superimposed preeclampsia.

Eltrombopag, a thrombopoietin receptor agonist, is approved for treating patients with immune thrombocytopenic purpura (ITP) refractory to corticosteroids and intravenous immunoglobulin (IVIg) therapy. We report a 32-years-old nulliparous Japanese woman with ITP and chronic hypertension who developed pulmonary edema due to superimposed preeclampsia at 27 weeks of gestation. She received therapy with corticosteroids, IVIg and Eltrombopag, but her platelet level was fluctuating and was difficult to achieve a well sustained response. A transient leukocytosis was noted but resolved by Eltrombopag dose reduction. Her pregnancy was complicated with preeclampsia with severe features required a prompt delivery. Although recent evidence supports the safety and efficacy of Eltrombopag use during pregnancy, unreported risks may underlie its use during pregnancy.

Evolution of a surgical system using deep learning in minimally invasive surgery (Review).

Recently, artificial intelligence (AI) has been applied in various fields due to the development of new learning methods, such as deep learning, and the marked progress in computational processing speed. AI is also being applied in the medical field for medical image recognition and omics analysis of genomes and other data. Recently, AI applications for videos of minimally invasive surgeries have also advanced, and studies on such applications are increasing. In the present review, studies that focused on the following topics were selected: i) Organ and anatomy identification, ii) instrument identification, iii) procedure and surgical phase recognition, iv) surgery-time prediction, v) identification of an appropriate incision line, and vi) surgical education. The development of autonomous surgical robots is also progressing, with the Smart Tissue Autonomous Robot (STAR) and RAVEN systems being the most reported developments. STAR, in particular, is currently being used in laparoscopic imaging to recognize the surgical site from laparoscopic images and is in the process of establishing an automated suturing system, albeit in animal experiments. The present review examined the possibility of fully autonomous surgical robots in the future.

[Optimal safety management procedures for medications with potent teratogenic properties: a prospective intervention cluster randomized non-inferiority comparative study].

Using the "periodic confirmation sheet" employed in the safety management procedure of thalidomide drugs, we looked at whether patients' knowledge of compliance with the procedure varies depending on the length of the gap between confirmations. In 31 centers, 215 participants were male patients and female patients who might be pregnant participants. Subjects have treated a group of patients who used periodic confirmation slips at the standard confirmation interval and a group of patients who increase the confirmation interval to 4 or 6 months, the % of respondents that correctly answered each of all six questions in questions 1-6 on the second comprehension questionnaire, excluding question 7 to confirm behavior change, was 87.0%. Comparing the percentage of correct answers to all questions the first time and the second time, no pregnancy cases were observed and there was no decline in the percentage of accurate responses after the second attempt for either group. One cannot judge changes in behavior. The mixed-effect model also additionally demonstrated non-inferiority in the patient group with the extended confirmation interval (a difference of -6.7% in the proportion of correct answers on the comprehension test (95%CI: -20.3-7.0%)), thus it appears that going forward, both male patients and female patients of potential pregnancy should complete the periodic confirmation form once every 4 or 6 months.

Changes in fetal presentation in the preterm period and the prediction of non-cephalic delivery.

OBJECTIVE: Since fetal presentation is an essential factor for planning mode of delivery, the estimation of fetal presentation at delivery is important in prenatal management. This study aimed to clarify the transition of fetal presentation during pregnancy and to propose practical strategy to predict final fetal presentation. METHODS: During the period of 2 years, fetal presentations were analyzed using ultrasonography during the prenatal visits at and after 22 weeks of gestation in a single facility. The relationship between the transition of fetal presentation and final presentation at delivery was analyzed. Further, a prediction model was developed to predict the final fetal presentation at birth. RESULTS: Among 1737 singleton pregnancies with full-term delivery, non-cephalic delivery occurred in 76 pregnancies (4.4%). Non-cephalic presentation in later half of the gestational period was associated with low incidence of spontaneous cephalic version. Furthermore, we found that in 46% of women with a final non-cephalic delivery, the non-cephalic presentation continued during whole of the observational period without spontaneous cephalic version. Based on the analyzed data of this cohort, we show that in a group of women with non-cephalic presentation at 35/36 weeks, the best predictability for spontaneous cephalic version depended on whether the cephalic presentation was observed at least once at and after 30 weeks of gestation. CONCLUSION: Our findings suggest that information on the changes in fetal presentation during gestation contributes to the prediction of the fetal presentation at delivery and planning mode of delivery.

The head direction to the angle of progression ratio: a quantitative parameter for intrapartum evaluation of cephalic malposition.

BACKGROUND: No previous study has evaluated the transitions of intrapartum transperineal ultrasound parameters during labor progression in cephalic malposition. OBJECTIVE: We aimed to quantitate the characteristic trends of fetal head position and descent in cephalic malposition by analyzing the transitions of intrapartum transperineal ultrasound parameters and explore an indicator associated with the degree of cephalic malposition. STUDY DESIGN: We retrospectively analyzed pregnant women who delivered at term from January 2018 to December 2020 at the University of Tokyo Hospital. The fetal occipital position was classified as occiput anterior and nonocciput anterior according to the fetal occipital angle of 0° to 75° and 75° to 180°, respectively. Fetal occipital angle was defined by the midline angle and position of the ocular orbit. The differences in the trends of head direction, head-symphysis distance, and progression distance relative to the angle of progression between occiput anterior and nonocciput anterior cases were evaluated. In addition, the parameters that showed differences were analyzed to evaluate their relationship to the degree of cephalic malposition. RESULTS: A total of 502 images (occiput anterior, 319; nonocciput anterior, 183) met the inclusion criteria. The distribution of head direction values relative to the angle of progression was smaller in the nonocciput anterior group than in the occiput anterior group, whereas the head-symphysis distance and progression distance values relative to the angle of progression showed no difference in their distribution between the occiput anterior and nonocciput anterior groups. The ratio of head direction to the angle of progression was significantly smaller in the nonocciput anterior group than in the occiput anterior group (median [interquartile range], 0.03 [-0.02 to 0.10] vs 0.21 [0.12-0.28]; P<.0001). Furthermore, this ratio was negatively correlated with fetal occipital angle (Spearman correlation coefficient, -0.66). CONCLUSION: Our results indicated that the head direction to angle of progression ratio reflects the deviation in the fetal head direction toward the maternal dorsal side, and decreases in proportion to the degree of cephalic malposition. This concept of deviation in the head direction as an indicator for evaluating cephalic malposition with intrapartum transperineal ultrasound may contribute to improving labor management in the case of cephalic malposition.

Development of a deep learning method for improving diagnostic accuracy for uterine sarcoma cases.

Uterine sarcomas have very poor prognoses and are sometimes difficult to distinguish from uterine leiomyomas on preoperative examinations. Herein, we investigated whether deep neural network (DNN) models can improve the accuracy of preoperative MRI-based diagnosis in patients with uterine sarcomas. Fifteen sequences of MRI for patients (uterine sarcoma group: n = 63; uterine leiomyoma: n = 200) were used to train the models. Six radiologists (three specialists, three practitioners) interpreted the same images for validation. The most important individual sequences for diagnosis were axial T2-weighted imaging (T2WI), sagittal T2WI, and diffusion-weighted imaging. These sequences also represented the most accurate combination (accuracy: 91.3%), achieving diagnostic ability comparable to that of specialists (accuracy: 88.3%) and superior to that of practitioners (accuracy: 80.1%). Moreover, radiologists' diagnostic accuracy improved when provided with DNN results (specialists: 89.6%; practitioners: 92.3%). Our DNN models are valuable to improve diagnostic accuracy, especially in filling the gap of clinical skills between interpreters. This method can be a universal model for the use of deep learning in the diagnostic imaging of rare tumors.

The Histone Methyltransferase SETD8 Regulates the Expression of Tumor Suppressor Genes via H4K20 Methylation and the p53 Signaling Pathway in Endometrial Cancer Cells.

The histone methyltransferase SET domain-containing protein 8 (SETD8), which methylates histone H4 lysine 20 (H4K20) and non-histone proteins such as p53, plays key roles in human carcinogenesis. Our aim was to determine the involvement of SETD8 in endometrial cancer and its therapeutic potential and identify the downstream genes regulated by SETD8 via H4K20 methylation and the p53 signaling pathway. We examined the expression profile of SETD8 and evaluated whether SETD8 plays a critical role in the proliferation of endometrial cancer cells using small interfering RNAs (siRNAs). We identified the prognostically important genes regulated by SETD8 via H4K20 methylation and p53 signaling using chromatin immunoprecipitation sequencing, RNA sequencing, and machine learning. We confirmed that SETD8 expression was elevated in endometrial cancer tissues. Our in vitro results suggest that the suppression of SETD8 using siRNA or a selective inhibitor attenuated cell proliferation and promoted the apoptosis of endometrial cancer cells. In these cells, SETD8 regulates genes via H4K20 methylation and the p53 signaling pathway. We also identified the prognostically important genes related to apoptosis, such as those encoding KIAA1324 and TP73, in endometrial cancer. SETD8 is an important gene for carcinogenesis and progression of endometrial cancer via H4K20 methylation.

Suspicious Positive Peritoneal Cytology (Class III) in Endometrial Cancer Does Not Affect Prognosis.

Positive peritoneal cytology is a poor prognostic factor in patients with advanced endometrial cancer. Suspicious positive peritoneal cytology (class III) is commonly encountered in clinical practice. However, no standard treatment protocol exists for its management. Here, we investigated a possible relationship between suspicious positive peritoneal cytology, disease stage, risk factors, and endometrial cancer prognosis. We included patients diagnosed with endometrial cancer who underwent total hysterectomy and peritoneal cytology at the University of Tokyo Hospital between 2008 and 2022. Overall, 670 patients were included in the analyses; both demographic and clinical data of the patients were collected. The proportion of patients with lymph node metastasis was significantly different between peritoneal cytology groups, showing lymph node metastasis to be more extensive in patients with positive or suspicious positive peritoneal cytology than in patients with negative peritoneal cytology (p < 0.05). Thirty-nine patients had suspicious positive peritoneal cytology. Omental resection and biopsy were performed in 16 cases. No case of omental metastasis was found. Among patients with suspected ascites cytology, no patient experienced symptom recurrence or death. Therefore, monitoring lymph node metastasis in suspicious positive cases is essential. Moreover, a change of treatment method based on the finding of suspected positive peritoneal cytology is not necessary.

Increased production of inflammatory cytokines and activation of microglia in the fetal brain of preeclamptic mice induced by angiotensin II.

Preeclampsia (PE) is a hypertensive obstetric disorder with poor prognosis for both the mother and offspring. Infants born to mothers with PE are known to be at increased risk of developing higher brain dysfunction, such as autism. However, how maternal PE can affect the environment in the fetal brain has not been fully elucidated. Here, we examined the impact of PE on the fetal brain in a mouse model of PE induced by angiotensin II (Ang II), focusing on changes in the inflammatory condition. We confirmed that pregnant mice which were continuously administered Ang II exhibited PE phenotypes, including high blood pressure, proteinuria, and fetal growth restriction. Quantitative RT-PCR analysis demonstrated that the brain of fetuses on embryonic day 17.5 (E17.5) in the Ang II-administered pregnant mice showed increased expression of cytokines, interleukin (IL)- 6, IL-17a, tumor necrosis factor-α, interferon-γ, IL-12, IL-4, and IL-10. Immunohistochemical analysis over a wide area, from the tip of the frontal lobe to the posterior cerebral end, on E17.5 revealed that the microglia in the fetal brain of the Ang II-administered group displayed higher solidity and circularity than those of the control group, indicating that the microglia had transformed to an amoeboid morphology and were activated. Our findings suggest that maternal PE may cause altered inflammatory conditions in the fetal brain, which might be associated with the pathological mechanism connecting maternal PE and brain dysfunction in the offspring.

Postpartum degeneration of adenomyosis with diffuse cyst-like changes and localized hemorrhage detected by sequential magnetic resonance imaging.

Imaging and histological changes occurring in adenomyosis due to pregnancy are unclear. A 38-year-old nulliparous woman presented with dysmenorrhea and infertility. Pelvic magnetic resonance imaging (MRI) showed diffuse-type adenomyosis. Following pregnancy by in vitro fertilization, she was hospitalized at 23 weeks of gestation due to fetal growth restriction and subsequently diagnosed with preeclampsia. A second MRI performed due to an elevated inflammatory response at 31 weeks of gestation detected no obvious degenerative findings. An emergency cesarean section was performed at 33 weeks of gestation because of nonreassuring fetal status. On postpartum day 2, she showed uterine tenderness with a dramatically elevated inflammatory response. A third MRI showed cyst-like degenerations with hemorrhagic changes without abscess. By postpartum day 7, she was quickly relieved and discharged from the hospital. A fourth MRI at postpartum month 4 confirmed the disappearance of degenerations. This is the first report of imaging findings of early postpartum degeneration of adenomyosis.