Mechanisms of thrombin-Induced myometrial contractions: Potential targets of progesterone

Intrauterine bleeding during pregnancy is a major risk factor for preterm birth. Thrombin, the most abundant coagulation factor in blood, is associated with uterine myometrial contraction. Here, we investigated the molecular mechanism and signaling of thrombin-induced myometrial contraction. First, histologic studies of placental abruption, as a representative intrauterine bleeding, revealed that thrombin was expressed within the infiltrating hemorrhage and that thrombin receptor (protease-activated receptor 1, PAR1) was highly expressed in myometrial cells surrounding the hemorrhage. Treatment of human myometrial cells with thrombin resulted in augmented contraction via PAR1. Thrombin-induced signaling to myosin was then mediated by activation of myosin light chain kinase- and Rho-induced phosphorylation of myosin light chain-2. In addition, thrombin increased prostaglandin-endoperoxidase synthase-2 (PTGS2 or COX2) mRNA and prostaglandin E2 and F2α synthesis in human myometrial cells. Thrombin significantly increased the mRNA level of interleukine-1β, whereas it decreased the expressions of prostaglandin EP3 and F2α receptors. Progesterone partially blocked thrombin-induced myometrial contractions, which was accompanied by suppression of the thrombin-induced increase of PTGS2 and IL1B mRNA expressions as well as suppression of PAR1 expression. Collectively, thrombin induces myometrial contractions by two mechanisms, including direct activation of myosin and indirect increases in prostaglandin synthesis. The results suggest a therapeutic potential of progesterone for preterm labor complicated by intrauterine bleeding

Impact of efforts to prevent maternal deaths due to obstetric hemorrhage on trends in epidemiology and management of severe postpartum hemorrhage in Japan: a nationwide retrospective study

BACKGROUND: The Japan Society of Obstetrics and Gynecology and the Japan Association of Obstetricians and Gynecologists have issued the guidelines and recommendations on postpartum hemorrhage since 2010 and have been conducted widespread educational activities from 2012. The aim of this study was to investigate the impact of these efforts by the Societies to prevent maternal deaths due to obstetric hemorrhage on trends in epidemiology and management of severe postpartum hemorrhage in Japan. METHODS: A national retrospective cohort study was conducted using the national database of health insurance claims for the period 2012 and 2018. The subjects were all insured women who received a blood transfusion for postpartum hemorrhage. The primary endpoints of this study were hysterectomy and maternal mortality. The etiology of hemorrhage, treatment facility, type of procedure, and blood transfusion volume were tabulated. RESULTS: Women with postpartum hemorrhage that underwent transfusion increased from 3.5 to 5.5 per 1000 deliveries between 2012 and 2018. The most common cause of postpartum hemorrhage was atonic hemorrhage. After insurance coverage in 2013, the intrauterine balloon tamponade use increased to 20.3% of postpartum hemorrhages treated with transfusion in 2018, while the proportion of hysterectomy was decreased from 7.6% (2013-2015) to 6.4% (2016-2018) (p < 0.0001). The proportion of postpartum hemorrhage in maternal deaths decreased from 21.1% (2013-2015) to 14.1% (2016-2018) per all maternal deaths cases (p = 0.14). Cases with postpartum hemorrhage managed in large referral hospitals was increased (65.9% in 2012 to 70.4% in 2018) during the study period (p < 0.0001). CONCLUSIONS: The efforts by the Societies to prevent maternal mortality due to obstetric hemorrhage resulted in a significant decrease in the frequency of hysterectomies and a downward trend in maternal mortality due to obstetric hemorrhage

The effect of celecoxib for treatment of preterm labor on fetuses during the second trimester of pregnancy: A pilot case series

OBJECTIVE: Although cyclooxygenase inhibitors effectively suppress uterine contraction, constriction of the fetal ductus arteriosus (DA) and oligohydramnios are major concerns. Celecoxib, a selective cyclooxygenase 2 inhibitor, is a potential potent tocolytic agent, but there are no studies that have evaluated the beneficial or adverse effects of celecoxib use on fetuses for more than 48 hours in pregnant women. We therefore aimed to evaluate the effect of middle-long-term celecoxib administration on the fetus during the second trimester of pregnancy, particularly in terms of fetal DA and amniotic fluid volume. MATERIALS AND METHODS: We retrospectively extracted and reviewed data from patients with preterm labor who received celecoxib for tocolysis for more than 48 hours between 2016 and 2020. Celecoxib was used for tocolysis only when treatment of patients with conventional tocolytic agents was ineffective. Data on the peak systolic velocity in ductus arteriosus (PSV-DA) and the maximum vertical pocket (MVP) were collected. RESULTS: A total of 15 patients were eligible. The median gestational age at celecoxib introduction was 22.6 weeks, and the median period of administration was 9 days (range 3-40 days). The median gestational age at delivery was 27.1 weeks, and the median duration from initial celecoxib administration to delivery was 40 days. The Z scores of PSV-DA and MVP did not change significantly after celecoxib administration. During administration, PSV-DA exceeded the 95th percentile of the corresponding normal reference range in three cases, but the levels returned to normal after reduction or discontinuation of treatment. There was no oligohydramnios during the treatment. CONCLUSION: Celecoxib administration for more than 48 hours in the second trimester of pregnancy might be safe and tolerable in terms of fetal PSV-DA and amniotic fluid volume as long as careful ultrasound monitoring is performed. Celecoxib could be an alternative for preterm labor when conventional tocolysis is not effective

Placenta Accreta in a Woman with Childhood Uterine Irradiation: A Case Report and Literature Review

The pregnancies of childhood cancer survivors who have received uterine irradiation are associated with a high risk of several obstetrical complications, including placenta accreta. The present case was a 26-year-old pregnant woman with a history of myelodysplastic syndrome treated with umbilical cord blood transplantation following chemotherapy and total body irradiation at the age of 10. Despite every possible measure to prevent preterm labor, uterine contractions became uncontrollable and a female infant weighing 892 g was vaginally delivered at 27⁺⁴ weeks of gestation. Under the postpartum ultrasonographic diagnosis of placenta accreta, we selected to leave the placenta in situ. Although emergency bilateral uterine artery embolization was required, complete resorption of the residual placenta was accomplished on the 115th day postpartum. Our experience highlighted the following points. (1) The expectant management of placenta accreta arising in an irradiated uterus may not only fulfill fertility preservation, but may also reduce possible risks associated with cesarean hysterectomy. (2) Due to extreme thinning of and a poor blood supply to the myometrium, reaching an antepartum diagnosis of placenta accreta in an irradiated uterus is difficult. (3) The recurrence of placenta accreta in subsequent pregnancies needs to be considered after successful preservation of the uterus

The significance of clinical symptoms of subchorionic hematomas, “bleeding first”, to stratify the high-risk subgroup of very early preterm delivery

OBJECTIVE: To investigate the factors that stratify high-risk cases among subchorionic hematomas (SCHs) patients with persistent vaginal bleeding in early pregnancy. MATERIALS AND METHODS: A total of 56 patients who required hospitalization for SCH with vaginal bleeding in early pregnancy were classified into two groups: 1) no hematoma by ultrasonography when vaginal bleeding occurred, and then hematoma was observed by ultrasonography "bleeding to hematoma (BH group, n = 15)" and 2) no vaginal bleeding when hematoma was observed by routine ultrasonography, and then vaginal bleeding occurred later "hematoma to bleeding (HB group, n = 41)". Retrospective cohort study was performed and maternal and neonatal outcomes were evaluated. RESULTS: The duration of SCHs and/or vaginal bleeding was significantly longer in the BH group than in the HB group (mean: 60.8 days [BH group] vs. 33.3 days [HB group], p = 0.015). BH group patients delivered earlier than HB group patients significantly (mean: 27.3 weeks [BH group] vs. 35.6 weeks [HB group], p = 0.0028). The frequency of chronic abruption and oligohydramnios sequence (CAOS) was significantly higher in the BH group than in the HB group (3/15; 20.0% [BH group] vs. 0/41; 0.0% [HB group], p = 0.016). The frequency of sever fetal distress (Apgar score <4 points) was significantly higher in the BH group than in the HB group (4/15; 26.7% [BH group] vs. 0/41; 0.0% [HB group], p = 0.0037). The levels of factor XIII were relatively lower in the BH group than in the HB group (mean: 54.8% (n = 4) [BH group] vs. 76.1% (n = 7) [HB group], p = 0.077). CONCLUSION: The order of the symptoms, bleeding first, is an important feature that reflects the subsequent prolonged duration of SCHs/vaginal bleeding, resulting in very early preterm delivery. Continuous hemorrhage consumes coagulation factor XIII, which further worsen the hemostasis

Three-dimensional human placenta-like bud synthesized from induced pluripotent stem cells

Placental dysfunction is related to the pathogenesis of preeclampsia and fetal growth restriction, but there is no effective treatment for it. Recently, various functional three-dimensional organs have been generated from human induced-pluripotent cells (iPSCs), and the transplantation of these iPSCs-derived organs has alleviated liver failure or diabetes mellitus in mouse models. Here we successfully generated a three-dimensional placental organ bud from human iPSCs. The iPSCs differentiated into various lineages of trophoblasts such as cytotrophoblast-like, syncytiotrophoblast-like, and extravillous trophoblast-like cells, forming organized layers in the bud. Placental buds were transplanted to the murine uterus, where 22% of the buds were successfully engrafted. These iPSC-derived placental organ buds could serve as a new model for the study of placental function and pathology

Alterations of circulating endothelial cell and endothelial progenitor cell counts around the ovulation.

Context:Circulating endothelial cells (CECs) and progenitor cells (CEPs) have been intensively studied as a promising tool for treating ischemic diseases and monitoring cancer treatments, but how the menstrual cycle affects the variation in their counts remains unclear. Objective:The aims of the study were to determine the influence of the menstrual cycle on the number of CECs and CEPs and to investigate the association of their counts with circulating hormones and angiogenesis-associated factors. Design:CEP and CEC counts by flow cytometry and the CellSearch system and circulating factor levels were measured eight times during the menstrual cycle in 18 volunteers. The menstrual cycle was divided into six phases based on hormone concentrations. Results:CEP counts peaked in the periovulatory and middle luteal phases with a drop in the early luteal phase. CEC counts showed no significant variation. There were significant correlations between the CEP counts and the serum concentrations of estradiol (E2), LH, and granulocyte colony-stimulating factor (G-CSF) (P < 0.0001, P < 0.0001, and P = 0.01, respectively). The difference in CEP counts between two adjacent phases was significantly correlated with that in E2, LH, G-CSF, and serum vascular endothelial growth factor (P < 0.0001, P < 0.0001, P = 0.02, and P = 0.006, respectively). Conclusion:CEP counts peaked in the periovulatory and middle luteal phases, with a drop in the early luteal phase, and were correlated with serum E2, LH, and G-CSF concentrations. Consideration of the variation in CEP counts would be important for the clinical application of CEPs

Evolutionary histories of breast cancer and related clones

乳がん発生の進化の歴史を解明 --ゲノム解析による発がんメカニズムの探索--. 京都大学プレスリリース. 2023-07-28.Tracking the ol' mutation trail: Unraveling the long history of breast cancer formation. 京都大学プレスリリース. 2023-08-31.Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1, 2, 3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient’s early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves

胎盤における酸化LDL受容体LOX-1の発現低下は、ABCA1の発現およびNrf2の活性化をそれぞれ低下させ、preeclampsiaに関与する

京都大学0048新制・課程博士博士(医学)甲第18125号医博第3845号新制||医||1001(附属図書館)30983京都大学大学院医学研究科医学専攻(主査)教授 横出 正之, 教授 柳田 素子, 教授 岩井 一宏学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA