Publications by authors named "Takeshi Nagamatsu"

109 Publications

Spontaneous labor curve based on a retrospective multi-center study in Japan.

J Obstet Gynaecol Res 2021 Oct 7. Epub 2021 Oct 7.

Department of Obstetrics and Gynecology, Mie University School of Medicine, Mie, Japan.

Aim: In Japan, the criteria of the latent and active phases of the first stage of labor have not been decided. The Japan Society of Obstetrics and Gynecology (JSOG) Perinatal Committee conducted a study to construct a spontaneous labor curve in order to determine the point of onset of the active phase.

Methods: The participants were women who had spontaneous deliveries at four health facilities in Japan between September 1, 2011, and September 31, 2019. Spontaneous delivery was defined as the spontaneous onset of labor at term (37 weeks, 0 days to 41 weeks, 6 days) with vaginal delivery of a mature fetus in a cephalic position without uterotonic agents or epidural analgesia. The time points for each "cm" of dilation were collected starting from the time of full dilation retrogradely. The relationship between time since labor onset and cervical dilation was expressed as a curve using a smoothing B-spline.

Results: A total of 4215 primiparous and 5266 multiparous women were included in this study. The spontaneous labor curve showed that in both primiparous and multiparous women, labor progress was slow until 5 cm cervical dilation, accelerating between 5 and 6 cm dilation, and steadily progressed after 6 cm dilation.

Conclusion: We propose that the active phase of the first stage of labor be defined as starting at 5 cm dilation of the cervix, and that it be divided into an acceleration phase (5-6 cm dilation) and a maximal phase (>6 cm dilation).
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http://dx.doi.org/10.1111/jog.15053DOI Listing
October 2021

Elevated placental histone H3K4 methylation via upregulated histone methyltransferases SETD1A and SMYD3 in preeclampsia and its possible involvement in hypoxia-induced pathophysiological process.

Placenta 2021 Sep 12;115:60-69. Epub 2021 Sep 12.

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Introduction: Disturbance in placental epigenetic regulation contributes to the pathogenesis of preeclampsia (PE). Although aberrant placental DNA methylation status in PE has been thoroughly studied, the role of histone modifications, including histone methylation, in PE remains unclear. Moreover, no study has ever reported the association between PE and placental histone methylation status by focusing on histone methyltransferases. The present study aimed to investigate the possible involvement of placental epigenetic regulation by histone methylation via histone methyltransferases in the pathophysiology of PE.

Methods: Placental mRNA expression of histone methyltransferases was examined using quantitative RT-PCR. Protein expression of histone methyltransferases and histone methylation status in placentas and trophoblast cell lines were assessed by immunoblotting and immunohistochemistry.

Results: Expression profile of histone methyltransferases in the placentas using quantitative RT-PCR revealed that the mRNA expression levels of histone 3 lysine 4 (H3K4) methyltransferases, SETD1A and SMYD3, were significantly increased in placentas from PE patients. Immunoblotting and immunohistochemistry revealed that not only protein expression levels of SETD1A and SMYD3, but also H3K4 methylation status was increased in the trophoblasts from PE placentas. In vitro studies using HTR-8/SV-neo and BeWo cells showed that hypoxia induced the expression levels of SETD1A and SMYD3, and subsequently enhanced H3K4 methylation. Furthermore, the overexpression of SETD1A and SMYD3 in HTR-8/SV-neo cells enhanced H3K4 methylation in response to hypoxia.

Discussion: Our study results suggest that placental epigenetic alteration by enhanced histone H3K4 methylation through upregulated SETD1A and SMYD3 might play a role in the pathophysiological process of PE associated with hypoxia.
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http://dx.doi.org/10.1016/j.placenta.2021.09.009DOI Listing
September 2021

Evaluation of the clinical performance of noninvasive prenatal testing at a Japanese laboratory.

J Obstet Gynaecol Res 2021 Oct 5;47(10):3437-3446. Epub 2021 Aug 5.

Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, Japan.

Aim: We aimed to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of noninvasive prenatal testing (NIPT) in high-risk pregnant women.

Methods: Pregnant women who underwent GeneTech NIPT, the most commonly used NIPT in Japan, between January 2015 and March 2019, at Japan NIPT Consortium medical sites were recruited for this study. The exclusion criteria were as follows: pregnant women with missing survey items, multiple pregnancy/vanishing twins, chromosomal abnormalities in the fetus other than the NIPT target disease, and nonreportable NIPT results. Sensitivity and specificity were calculated from the obtained data, and maternal age-specific PPV and NPV were estimated.

Results: Of the 45 504 cases, 44 263 cases fulfilling the study criteria were included. The mean maternal age and gestational weeks at the time of procedure were 38.5 years and 13.1 weeks, respectively. Sensitivities were 99.78% (95% confidence interval [95% CI]: 98.78-99.96), 99.12% (95% CI: 96.83-99.76), and 100% (95% CI: 88.30-100) for trisomies 21, 18, and 13, respectively. Specificities were more than 99.9% for trisomies 21, 18, and 13, respectively. Maternal age-specific PPVs were more than 93%, 77%, and 43% at the age of 35 years for trisomies 21, 18, and 13, respectively.

Conclusion: The GeneTech NIPT data showed high sensitivity and specificity in the detection of fetal trisomies 21, 18, and 13 in high-risk pregnant women, and maternal age-specific PPVs were obtained. These results could provide more accurate and improved information regarding NIPT for genetic counseling in Japan.
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http://dx.doi.org/10.1111/jog.14954DOI Listing
October 2021

Effects of prophylactic vaginal progesterone administration on mild cervical shortening (TROPICAL study): a multicenter, double-blind, randomized trial.

J Matern Fetal Neonatal Med 2021 Jun 28:1-7. Epub 2021 Jun 28.

Japanese Organization of Prevention of Preterm Delivery (JOPP), Tokyo, Japan.

Vaginal progesterone reduces the preterm birth frequency among high-risk women with a cervical length ≤25 mm at midtrimester. However, the strategy may promote no substantial reduction in overall preterm birth rates, because such high-risk women are only approximately 2% of all pregnant women, which restrict the number of participants. Our purpose was to determine whether prophylactic vaginal progesterone administration can preserve cervical length and reduce preterm birth rates among women with mild cervical shortening.This multicenter, parallel-arm, double-blind, randomized, placebo-controlled trial involved vaginal progesterone administration (200 mg daily from 16 to 33 weeks of gestation) among asymptomatic women with a singleton pregnancy and a sonographic cervical length of 25 to <30 mm between 16 and 23 weeks of gestation. The primary and secondary endpoints were cervical shortening rates at 34 weeks of gestation and preterm birth rates, respectively. The trial was registered at the University Hospital Medical Information Network (UMIN000013518) in Japan.Between April 2014 and March 2018, 119 women were randomly assigned to the progesterone group ( = 59) and the placebo group ( = 60). No significant differences in the frequency of women with a cervical length ≥20 mm at 34 weeks of gestation were observed between both groups. All preterm births occurred after 34 weeks of gestation, except for one patient in the placebo group. The progesterone group had a lower rate of preterm birth before 37 weeks than the placebo group (3.4% vs. 15.0%, respectively;  < .05).Despite having no effect on preserving cervical length, prophylactic vaginal progesterone administration reduced preterm birth frequency among women with mild cervical shortening. Our results are suggesting that women with mild cervical shortening are at risk for late preterm birth and the need for expanding progesterone treatment indications to include not only high-risk but also low-risk populations.
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http://dx.doi.org/10.1080/14767058.2021.1940935DOI Listing
June 2021

Thrombomodulin promotes placental function by up-regulating placental growth factor via inhibition of high-mobility-group box 1 and hypoxia-inducible factor 1α.

Placenta 2021 08 11;111:1-9. Epub 2021 Jun 11.

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Introduction: Pregnancy is a state of maternal systemic stress due to inflammation and hypoxic reactions originating from the utero-placental unit. Maternal tolerance to these stresses is a key for successful outcomes. Thrombomodulin (TM), a glycoprotein expressed on cell surface, regulates local inflammatory pathways by inhibiting proinflammatory factor, High-mobility-group box1(HMGB1). Although TM is highly expressed on placental trophoblast cells, biological activities of TM during pregnancy remains unclear. Here, we hypothesized that TM may contribute to the maternal stress coping mechanisms.

Methods: By administering recombinant-TM (rTM) to the pregnant mice, we investigated the influence of TM functions on the placenta and fetal growth. We further examined its effect on trophoblast cells, focusing on HMGB1-regulated inflammatory signalings and hypoxia-inducible factor 1α (HIF1α)-dependent regulation of placental angiogenic factors.

Results: Administration of rTM increased fetal weight and fetal/placental-weight ratios, which implies the improvement of placental function. These features were accompanied by maternal serum HMGB1 reduction and suppressed placental proinflammatory cytokine, IL-6 and TNF-α, expressions. In addition, rTM reduced HIF1α protein accumulation and enhanced placental growth factor (PlGF) expression in the placenta, that explains the improvement of maternal features.

Discussion: Our study revealed the supportive effect of TM on the placental function in mice. By inhibiting HMGB1, rTM suppresses proinflammatory cytokines, downregulates HIF1α and induces PlFG expression in the placental tissue. Our results have elucidated the novel aspects of TM; the regulation of placental inflammatory cytokines and angiogenic factors, during pregnancy. These findings may reveal potential therapeutic opportunities for the management of maternal complications.
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http://dx.doi.org/10.1016/j.placenta.2021.06.002DOI Listing
August 2021

A Fetus with Imperforate Anus Developing Pulmonary Hypoplasia Triggered by Transient Urethral Obstruction.

Case Rep Obstet Gynecol 2021 13;2021:9950578. Epub 2021 May 13.

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

Pulmonary hypoplasia is a rare entity in a fetus with imperforate anus. The fetus was diagnosed with high-type imperforate anus with rectourethral fistula based on the dilated fetal bowel and the presence of bowel calcification at 19 weeks of gestation. As gestation advanced, fetal ultrasonography demonstrated development of pulmonary hypoplasia, progressive bowel dilation, and persistent oligohydramnios from 28 weeks of gestation despite a fluid-filled bladder without hydroureter or hydronephrosis. To prevent further worsening of pulmonary hypoplasia caused by thoracic compression due to bowel dilation and oligohydramnios, a male neonate was delivered by cesarean section at 32 weeks of gestation. The neonate showed respiratory failure requiring full respiratory support. Although a catheter did not pass through the urethra into the bladder at birth, cystourethrography revealed the patency of fistula and stenosed lower urinary tract. Prenatal and postnatal findings strongly suggested that the meconium in the colon might have passed into the urethra in the penis, resulting in the physical blockage of urine outflow to the amniotic space which leads urine flow from the bladder to the colon through the fistula, which resulted in subsequent oligohydramnios and bowel dilation. To the best of our knowledge, this is the first case report of a fetus with imperforate anus developing pulmonary hypoplasia possibly due to urethral obstruction.
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http://dx.doi.org/10.1155/2021/9950578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137300PMC
May 2021

A Placebo-Controlled, Double-Blind Randomized (Phase IIB) Trial of Oral Administration with HPV16 E7-Expressing , GLBL101c, for the Treatment of Cervical Intraepithelial Neoplasia Grade 2 (CIN2).

Vaccines (Basel) 2021 Apr 1;9(4). Epub 2021 Apr 1.

Department of Obstetrics and Gynecology, Nihon University School of Medicine, 30-1 Oyaguchi-kamimachi, Itabashi-ku, Tokyo 173-8610, Japan.

Cervical intraepithelial neoplasia (CIN), a precursor lesion to cervical cancer, is caused by high-risk human papillomavirus (HPV); high-grade CIN lesions (CIN2-3) are precancerous and require treatment. No globally approved therapy is available for CIN2-3 treatment. This study is a placebo-controlled randomized clinical trial of GLBL101c treatment for CIN2 in 40 patients with HPV16-positive CIN2 who were 1:1 randomized to receive GLBL101c (1 g/daily) or placebo for 5 days at 1, 2, 4, and 8 weeks. No differences were noted between the GLBL101c and placebo groups for patient background and adverse events. Moreover, no statistically significant difference was noted between the two groups at the primary endpoint, pathological regression after 16 weeks of the first oral dose; however, only in the GLBL101c group, two patients had complete regression (CR; regression to normal within 16 weeks). IFNγ production was significantly correlated with the number of spots identified by the interferon gamma enzyme-linked immunospot (IFNγ-ELISPOT) assay using cervical lymphocytes (CxLs) or peripheral blood mononuclear cells. In the two cases of CR, E7-specific Th1 immune responses were observed at week 16. Therefore, we concluded as a novel -based vaccine with stronger immunogenicity than GLBL101c should be developed.
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http://dx.doi.org/10.3390/vaccines9040329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066592PMC
April 2021

Short-term prediction of preeclampsia using the sFlt-1/PlGF ratio: a subanalysis of pregnant Japanese women from the PROGNOSIS Asia study.

Hypertens Res 2021 07 17;44(7):813-821. Epub 2021 Mar 17.

Roche Diagnostics International Ltd, Rotkreuz, Switzerland.

Two prospective multicenter studies demonstrated that a soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio cutoff of ≤38 can rule out preeclampsia within 1 week with a negative predictive value (NPV) of 99.3% (PROGNOSIS) and 98.6% (PROGNOSIS Asia). We report a subanalysis of the Japanese cohort from the PROGNOSIS Asia study. Pregnant women with suspected preeclampsia between gestational weeks 18 + 0 days and 36 + 6 days were enrolled at eight Japanese sites. Primary objectives: Assess the performance of the Elecsys sFlt-1/PlGF ratio cutoff ≤38 to rule out preeclampsia within 1 week and of the cutoff >38 to rule in preeclampsia within 4 weeks. Key secondary objectives: Prediction of maternal and fetal adverse outcomes (MAOs/FAOs) and their relationship with duration of pregnancy. Of 192 women enrolled, 180 (93.8%)/175 (91.1%) were evaluable for primary/combined endpoint analyses. Overall preeclampsia prevalence was 13.3%. A sFlt-1/PlGF ratio of ≤38 provided an NPV of 100% (95% confidence interval [CI], 97.5-100) for ruling out preeclampsia within 1 week, and a ratio of >38 provided a positive predictive value of 32.4% (95% CI, 18.0-49.8) for ruling in preeclampsia within 4 weeks. The area under the curve for the prediction of preeclampsia/maternal/fetal adverse outcomes within 1 week was 94.2% (95% CI, 89.3-97.8). After adjusting for gestational age and final preeclampsia status, Cox regression indicated a 2.8-fold greater risk of imminent delivery for women with a sFlt-1/PlGF ratio >38 versus ≤38. This subanalysis of Japanese women with suspicion of preeclampsia showed high predictive value for a Elecsys sFlt-1/PlGF ratio cutoff of 38 for short-term prediction of preeclampsia.
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http://dx.doi.org/10.1038/s41440-021-00629-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255209PMC
July 2021

Assessment of the choroidal structure in pregnant women in the first trimester.

Sci Rep 2021 Feb 25;11(1):4629. Epub 2021 Feb 25.

Department of Ophthalmology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

We investigated the anatomical differences in the choroidal structure between pregnant women in the first trimester of pregnancy and age-matched healthy nonpregnant women using enhanced depth imaging optical coherence tomography (EDI-OCT) and choroidal binarization analysis. The main parameters measured in the two study groups, namely, pregnant women in the first trimester and healthy nonpregnant women, were choroidal thickness and the choroidal luminal area. Binarization of the EDI-OCT images from each patient was performed, and the choroidal vascularity index (CVI) was calculated. The correlations between the baseline characteristics of the subjects and the CVI were investigated using linear mixed model analysis. As a result, there was no statistically significant difference in the mean age, best-corrected visual acuity, axial length, central retinal thickness, subfoveal choroidal thickness, systolic blood pressure (BP), or diastolic BP between the two study groups. Conversely, a significant difference was observed in the CVI (P = 0.012) between the two groups. The multivariate analysis identified a significant correlation between the CVI and the systolic BP (P = 0.0044, linear mixed test). Taken together, a larger choroidal luminal area was associated with a higher systolic BP, especially in the first trimester of pregnancy. Our findings may provide further insight into the choroidal changes that occur during pregnancy.
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http://dx.doi.org/10.1038/s41598-021-84204-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907119PMC
February 2021

Identification of epigenetic memory candidates associated with gestational age at birth through analysis of methylome and transcriptional data.

Sci Rep 2021 02 9;11(1):3381. Epub 2021 Feb 9.

Department of Pediatrics, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Preterm birth is known to be associated with chronic disease risk in adulthood whereby epigenetic memory may play a mechanistic role in disease susceptibility. Gestational age (GA) is the most important prognostic factor for preterm infants, and numerous DNA methylation alterations associated with GA have been revealed by epigenome-wide association studies. However, in human preterm infants, whether the methylation changes relate to transcription in the fetal state and persist after birth remains to be elucidated. Here, we identified 461 transcripts associated with GA (range 23-41 weeks) and 2093 candidate CpG sites for GA-involved epigenetic memory through analysis of methylome (110 cord blood and 47 postnatal blood) and transcriptional data (55 cord blood). Moreover, we discovered the trends of chromatin state, such as polycomb-binding, among these candidate sites. Fifty-four memory candidate sites showed correlation between methylation and transcription, and the representative corresponding gene was UCN, which encodes urocortin.
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http://dx.doi.org/10.1038/s41598-021-83016-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873311PMC
February 2021

Postpartum Stanford type B aortic dissection in a woman with Loeys-Dietz syndrome who underwent a prophylactic aortic root replacement before conception: A case report.

Taiwan J Obstet Gynecol 2021 Jan;60(1):145-147

Departments of Obstetrics & Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.

Objective: Loeys-Dietz syndrome (LDS) is associated with a higher risk of aortic dissections (ADs) during pregnancy and postpartum. However, there is limited evidence about the perinatal management of LDS patients who have undergone prophylactic aortic root replacements (ARRs) before conception.

Case Report: We present the case of a 28-year-old nulliparous pregnant woman with LDS with a pathogenic variant within exon 5 of TGFBR2 (c.1379G > T, p.[Arg460Leu]), who underwent an ARR at 20 years of age. Cardiac echocardiography did not show any significant changes in the aorta during pregnancy, and her blood pressure remained normal. She had a cesarean section at 37 weeks of gestation. She developed an acute Stanford type B AD extending from the aortic arch to the infrarenal aorta 8 days postpartum and underwent a total arch replacement.

Conclusion: This case report suggests that patients with LDS after prophylactic ARRs still possess a risk for Stanford type B ADs.
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http://dx.doi.org/10.1016/j.tjog.2020.10.005DOI Listing
January 2021

Recombinant Thrombomodulin Attenuates Preeclamptic Symptoms by Inhibiting High-Mobility Group Box 1 in Mice.

Endocrinology 2021 04;162(4)

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Preeclampsia (PE) is a common gestational complication that involves systemic endothelial dysfunction and inflammatory responses primarily due to placental damage. Recombinant thrombomodulin (rTM), a novel anticoagulant clinically used for disseminated intravascular coagulation, is reported to have a unique anti-inflammatory endothelial repair function by inhibiting proinflammatory mediator high-mobility group box 1 (HMGB1). Despite the severe patient outcomes, there are currently no effective therapeutic options to treat PE. Here, we verified the efficacy of rTM as a novel therapeutic agent for PE using a murine model and human trophoblast cells. We revealed the therapeutic potential of rTM in an angiotensin II(Ang II)-induced PE mouse model. Injection of rTM significantly attenuated clinical features of PE, such as hypertension, proteinuria, fetal growth restriction, and impaired placental vasculature. Elevation of maternal soluble fms-like tyrosine kinase-1 (sFlt-1), a well-accepted causal factor of PE that induces systemic endothelial dysfunction, was suppressed in response to rTM treatment. Supporting these findings, our in vitro experiments revealed that rTM reduces Ang II-triggered overproduction of sFlt-1 in human trophoblast cells. Moreover, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), well-known key inflammatory mediators in PE pathogenesis, were diminished by rTM. SiRNA knockdown experiments further determined that these processes were directly mediated by HMGB1. Our studies demonstrate that rTM exerts its clinical effect as HMBG1 inhibitor and ameliorates placental dysfunction, which is central to PE pathogenesis. Our findings suggest that rTM could be a promising therapeutic that significantly improve the outcomes of PE patients.
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http://dx.doi.org/10.1210/endocr/bqaa248DOI Listing
April 2021

T-cell receptor repertoire of cytomegalovirus-specific cytotoxic T-cells after allogeneic stem cell transplantation.

Sci Rep 2020 12 17;10(1):22218. Epub 2020 Dec 17.

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan.

Cytomegalovirus (CMV) infection is a major complication during allogeneic stem cell transplantation (allo-SCT). However, mechanisms of adaptive immunity that drive this remain unclear. To define early immunological responses to CMV after transplantation, we using next-generation sequencing to examine the repertoire of T-cell receptors in CD8/CMV pp65 tetramer cells (CMV-CTLs) in peripheral blood samples obtained from 16 allo-SCT recipients with HLA-A*24:02 at the time of CMV reactivation. In most patients, TCR beta repertoire of CMV-CTLs was highly skewed (median Inverse Simpson's index: 1.595) and, 15 of 16 patients shared at least one TCR-beta clonotype with ≥ 2 patients. The shared TCRs were dominant in 12 patients and, two clonotypes were shared by about half of the patients. Similarity analysis showed that CDR3 sequences of shared TCRs were more similar than unshared TCRs. TCR beta repertoires of CMV-CTLs in 12 patients were also analyzed after 2-4 weeks to characterize the short-term dynamics of TCR repertoires. In ten patients, we observed persistence of prevailing clones. In the other two patients, TCR repertoires became more diverse, major clones declined, and new private clones subsequently emerged. These results provided the substantive clue to understand the immunological behavior against CMV reactivation after allo-SCT.
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http://dx.doi.org/10.1038/s41598-020-79363-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747720PMC
December 2020

Secretory leukocyte protease inhibitor and progranulin as possible regulators of cervical remodeling in pregnancy.

J Reprod Immunol 2021 02 1;143:103241. Epub 2020 Nov 1.

Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Japan.

Secretory leukocyte protease inhibitor (SLPI) and progranulin (PGRN) are secretory proteins with an anti-inflammatory property. Their involvement in cervical remodeling in pregnant uterus is not yet elucidated. Thus, this study aimed to explore the significance of SLPI and PGRN in the maintenance of pregnancy by investigating the factors associated with their expression levels at the cervix. Concentrations of SLPI and PGRN proteins were measured in cervical mucus samples collected from asymptomatic pregnant women at 24-26 weeks of gestation (n = 166). The concentrations of those molecules were analyzed with clinical parameters related to risk for preterm delivery (PD). In pregnant mice, we evaluated the effect of lipopolysaccharide-induced inflammation and progesterone effect modulation on cervical mRNA expression of SLPI and PGRN. The cervical PGRN level was significantly lower in women with short cervix (<35 mm) and with a history of threatened PD. In women with short cervix, cervical SLPI concentrations were positively correlated with inflammatory cytokines, interleukin-6 (R = 0.75) and interleukin-8 (R = 0.71). In pregnant mice, cervical mRNA expressions of PGRN and SLPI were increased in response to progesterone supplementation and were suppressed by a progesterone antagonist, mifepristone. Lipopolysaccharide-induced inflammation caused remarkable upregulation in cervical SLPI mRNA level but not in PGRN. Progesterone and local inflammation are the factors controlling expression levels of PGRN and SLPI at the cervix. The observed relationship of PGRN and SLPI levels in the cervical mucus with PD-related clinical parameters supports that those anti-inflammatory molecules possibly play a significant role in appropriate regulation of cervical remodeling.
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http://dx.doi.org/10.1016/j.jri.2020.103241DOI Listing
February 2021

Efficacy and safety of controlled-release dinoprostone vaginal delivery system (PROPESS) in Japanese pregnant women requiring cervical ripening: Results from a multicenter, randomized, double-blind, placebo-controlled phase III study.

J Obstet Gynaecol Res 2021 Jan 22;47(1):216-225. Epub 2020 Oct 22.

Ferring Pharmaceuticals Co. Ltd., Minato-ku, Tokyo, Japan.

Aim: To evaluate the efficacy and safety of dinoprostone vaginal insert (PROPESS) in pregnant post-term Japanese women requiring cervical ripening.

Methods: This randomized, double-blind, placebo-controlled study included 114 pregnant Japanese women at term (41 weeks of gestation) requiring cervical ripening (baseline Bishop score (BS) ≤ 4). The primary end-point was the proportion of subjects with successful cervical ripening defined as BS ≥ 7 or vaginal delivery in 12 h. The secondary end-points were changes in BS, proportion of women with vaginal delivery, proportion of women receiving mechanical cervical ripening procedure and use of oxytocic drugs.

Results: PROPESS administration for a maximum of 12 h showed significantly higher successful cervical ripening rate (47.4% vs 14.3%, respectively; treatment contrast [TC]: 33.1%; P = 0.0002). The median time from administration to vaginal delivery was significantly shorter in the PROPESS group than in the placebo group (26.18 h vs 33.02 h; OR 2.51; 95% CI [1.60-3.92]; P < 0.0001). In the PROPESS group, the dosage of uterotonic drugs, such as oxytocin, decreased, and the number of patients who used these drugs also decreased.

Conclusion: PROPESS administration for a maximum of 12 h was an effective and well-tolerated treatment for pregnant Japanese women post-term requiring cervical ripening.
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http://dx.doi.org/10.1111/jog.14472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820955PMC
January 2021

Use of Cap Analysis Gene Expression to detect human papillomavirus promoter activity patterns at different disease stages.

Sci Rep 2020 10 22;10(1):17991. Epub 2020 Oct 22.

Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Transcription of human papillomavirus (HPV) genes proceeds unidirectionally from multiple promoters. Direct profiling of transcription start sites (TSSs) by Cap Analysis Gene Expression (CAGE) is a powerful strategy for examining individual HPV promoter activity. The objective of this study was to evaluate alterations of viral promoter activity during infection using CAGE technology. We used CAGE-based sequencing of 46 primary cervical samples, and quantitatively evaluated TSS patterns in the HPV transcriptome at a single-nucleotide resolution. TSS patterns were classified into two types: early promoter-dominant type (Type A) and late promoter-dominant type (Type B). The Type B pattern was more frequently found in CIN1 and CIN2 lesions than in CIN3 and cancer samples. We detected transcriptomes from multiple HPV types in five samples. Interestingly, in each sample, the TSS patterns of both HPV types were the same. The viral gene expression pattern was determined by the differentiation status of the epithelial cells, regardless of HPV type. We performed unbiased analyses of TSSs across the HPV genome in clinical samples. Visualising TSS pattern dynamics, including TSS shifts, provides new insights into how HPV infection status relates to disease state.
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http://dx.doi.org/10.1038/s41598-020-75133-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582169PMC
October 2020

Polyhydramnios is associated with postnatal dysphagia determining short-term prognosis of the newborn with 22q11.2 deletion syndrome - A case series analysis.

Taiwan J Obstet Gynecol 2020 Sep;59(5):744-747

Department of Obstetrics and Gynecology, Faculty of Medicine, Japan.

Objective: We experienced a case of 22q11.2 deletion syndrome (22qDS), with severe polyhydramnios, and dysphagia, which prompted us to review prognosis in neonates with 22qDS, with a focus on dysphagia.

Case Report: A patient was referred to our hospital at 35 gestational weeks because of polyhydramnios. After amniotic fluid reduction, labor was induced at 38 weeks. The neonate had serious dysphagia, and 22qDS was diagnosed postnatally by fluorescent in situ hybridization analysis. This prompted a retrospective analysis of 9 cases with 22qDS experienced in our facility. Three out of these nine cases showed polyhydramnios, and had severe dysphagia postnatally. In total, 4 cases had dysphagia, while mortality was observed in 2 of these 4 cases. Additionally, 5 cases without dysphagia had normal development and no major complications.

Conclusion: Polyhydramnios associated with postnatal dysphagia might be a risk factor related to short-term prognostic outcomes in newborns with 22qDS.
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http://dx.doi.org/10.1016/j.tjog.2020.07.021DOI Listing
September 2020

Abdominal compartment syndrome complicated by preeclampsia and partial HELLP syndrome in a 45-year-old woman: A case report.

Clin Case Rep 2020 Jul 28;8(7):1251-1254. Epub 2020 Apr 28.

Department of Obstetrics and Gynecology Faculty of Medicine The University of Tokyo Tokyo Japan.

HELLP syndrome is sometimes followed by massive bleeding, leading to DIC. In cases of intra-abdominal compartment syndrome due to massive intra-abdominal bleeding after cesarean section, if preeclampsia and partial HELLP syndrome persist, hematoma removal helps in the recovery from preeclampsia and partial HELLP syndrome.
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http://dx.doi.org/10.1002/ccr3.2904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364097PMC
July 2020

The β -Glycoprotein I/HLA-DR Complex As a Major Autoantibody Target in Obstetric Antiphospholipid Syndrome.

Arthritis Rheumatol 2020 11 30;72(11):1882-1891. Epub 2020 Sep 30.

Kobe University Graduate School of Medicine, Kobe, Japan.

Objective: The clinical manifestations of antiphospholipid syndrome (APS) include vascular thrombosis and pregnancy morbidity as well as recurrent pregnancy loss (RPL). However, in more than half of patients with RPL, the cause is never determined. Recently, β -glycoprotein I (β GPI) complexed with HLA class II molecules (β GPI/HLA-DR) was found to be a major autoantibody target in APS. The present study was undertaken to assess the serum levels of autoantibodies against the β GPI/HLA II complex as a potential risk factor for RPL in women.

Methods: Serum levels of antiphospholipid antibodies (aPLs), including IgG/IgM anticardiolipin antibodies, IgG/IgM anti-β GPI antibodies, and lupus anticoagulant as well as anti-β GPI/HLA-DR antibodies, were measured in 227 women with RPL. In this prospective, multicenter, cross-sectional study, women with RPL and their partners underwent HLA-DR immunotyping and analysis to identify potential causes and risk factors associated with RPL. The normal range for anti-β GPI/HLA-DR antibody levels was determined using serum samples obtained from a control population of female subjects (208 women of childbearing potential).

Results: Of the 227 women with RPL, aPL antibodies were detected in 19.8%, and 52 (22.9%) tested positive for anti-β GPI/HLA-DR antibodies. Among the 227 women, 121 (53.3%) had no risk factors for RPL, and among these women with unexplained RPL, 24 (19.8%) were positive for anti-β GPI/HLA-DR antibodies. Of the 112 women who had clinical symptoms of APS but did not have levels of aPLs that met the diagnostic criteria for APS, 21 (18.8%) were positive for anti-β GPI/HLA-DR antibodies.

Conclusion: The anti-β GPI/HLA-DR antibody is frequently associated with RPL. Detection of these autoantibodies is useful in understanding the pathogenesis of RPL. Our findings may provide potential new therapeutic strategies for addressing RPL in patients with obstetric APS.
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http://dx.doi.org/10.1002/art.41410DOI Listing
November 2020

Congenital extracardiac venous system anomaly in two siblings with normal karyotype and increased nuchal translucency thickness: a case report.

Oxf Med Case Reports 2020 Jun 13;2020(6):omaa034. Epub 2020 Jun 13.

Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Previous studies have reported that congenital heart diseases (CHDs) develop in patients with genetic and environmental predisposition. Compared to CHDs, the significance of hereditary factors in the pathogenesis of congenital venous system anomalies remains unclear. Additionally, reports describing the pathogenic relationship between venous system anomalies and increased nuchal translucency (NT) are few. We report sibling recurrence of congenital venous system anomalies. In the prenatal periods of both siblings, increased NT without aneuploidy was confirmed. In the first sibling, the absence of ductus venosus (ADV) and umbilical vein-coronary sinus anastomosis was detected using prenatal ultrasonography. In the second sibling, abnormality of the pulmonary vein was suspected prenatally, leading to a final diagnosis of infracardiac total anomalous pulmonary venous return (TAPVR). This is the first report of extracardiac venous anomaly-associated recurrence of increased NT among siblings. We conclude that a hereditary factor may be responsible for the development of ADV and TAPVR.
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http://dx.doi.org/10.1093/omcr/omaa034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293141PMC
June 2020

Pravastatin for preeclampsia: From animal to human.

J Obstet Gynaecol Res 2020 Aug 2;46(8):1255-1262. Epub 2020 Jun 2.

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

Preeclampsia is characterized by the emergence of hypertension and proteinuria after 20 weeks of pregnancy, and it threatens both maternal and fetal lives if it proceeds unabated. Despite numerous studies, thus far the only fundamental therapy for preeclampsia is termination of pregnancy, leading to preterm birth. Furthermore, preeclamptic women are reported to be at risk for cardiovascular diseases for 10 years after delivery. Therefore, preventative and therapeutic strategies for preeclampsia are required. Recently, statins have been reported to improve the regeneration of vascular endothelium, and pravastatin has attracted attention as a potential preventative or therapeutic candidate for preeclampsia. Pravastatin has been demonstrated to have preventative effects in preeclampsia model mice, and a large volume of human data from pregnant women taking statins supports the safety of these drugs. Moreover, small clinical trials have reported that pravastatin has strong preventative or therapeutic effects on preeclampsia and it has the potential to improve the prognosis of pregnant women, fetuses and neonates affected by this condition.
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http://dx.doi.org/10.1111/jog.14295DOI Listing
August 2020

Establishment and Molecular Phenotyping of Organoids from the Squamocolumnar Junction Region of the Uterine Cervix.

Cancers (Basel) 2020 Mar 15;12(3). Epub 2020 Mar 15.

Department of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.

The metaplastic epithelium of the transformation zone (TZ) including the squamocolumnar junction (SCJ) of the uterine cervix is a prime target of human papilloma virus (HPV) infection and subsequent cancer development. Due to the lack of adequate in vitro models for SCJ, however, investigations into its physiological roles and vulnerability to carcinogenesis have been limited. By using Matrigel-based three-dimensional culture techniques, we propagated organoids derived from the normal SCJ region, along with metaplastic squamous cells in the TZ. Consisting predominantly of squamous cells, organoids basically exhibited a dense structure. However, at least in some organoids, a small but discrete population of mucin-producing endocervix cells co-existed adjacent to the squamous cell population, virtually recapitulating the configuration of SCJ in a TZ background. In addition, transcriptome analysis confirmed a higher expression level of many SCJ marker genes in organoids, compared to that in the immortalized cervical cell lines of non-SCJ origin. Thus, the obtained organoids appear to mimic cervical SCJ cells and, in particular, metaplastic squamous cells from the TZ, likely providing a novel platform in which HPV-driven cervical cancer development could be investigated.
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http://dx.doi.org/10.3390/cancers12030694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140077PMC
March 2020

Differential expression of human papillomavirus 16-, 18-, 52-, and 58-derived transcripts in cervical intraepithelial neoplasia.

Virol J 2020 03 6;17(1):32. Epub 2020 Mar 6.

Department of Obstetrics and Gynecology, Nihon University School of Medicine, Tokyo, Japan.

Background: Human papillomavirus (HPV) infection is a primary cause of cervical cancer. Although epidemiologic study revealed that carcinogenic risk differs according to HPV genotypes, the expression patterns of HPV-derived transcripts and their dependence on HPV genotypes have not yet been fully elucidated.

Methods: In this study, 382 patients with abnormal cervical cytology were enrolled to assess the associations between HPV-derived transcripts and cervical intraepithelial neoplasia (CIN) grades and/or HPV genotypes. Specifically, four HPV-derived transcripts, namely, oncogenes E6 and E6*, E1^E4, and viral capsid protein L1 in four major HPV genotypes-HPV 16, 18, 52, and 58-were investigated.

Results: The detection rate of E6/E6* increased with CIN progression, whereas there was no significant change in the detection rate of E1^E4 or L1 among CIN grades. In addition, we found that L1 gene expression was HPV type-dependent. Almost all HPV 52-positive specimens, approximately 50% of HPV 58-positive specimens, around 33% of HPV 16-positive specimens, and only one HPV18-positive specimen expressed L1.

Conclusions: We demonstrated that HPV-derived transcripts are HPV genotype-dependent. Especially, expression patterns of L1 gene expression might reflect HPV genotype-dependent patterns of carcinogenesis.
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http://dx.doi.org/10.1186/s12985-020-01306-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060624PMC
March 2020

Impact of additional risk factors on the incidence of preterm delivery among pregnant women diagnosed with short cervix.

Taiwan J Obstet Gynecol 2020 Mar;59(2):195-199

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan.

Objective: Additional risk factors for preterm delivery in pregnant women with cervical shortening are not fully understood; however, mid-trimester cervical shortening is accepted as a risk factor for preterm delivery. This study aimed to identify risk factors associated with subsequent preterm delivery among patients with short cervix detected after late mid-trimester.

Materials And Methods: This was a retrospective study of medical data from a single perinatal tertiary facility. We identified 134 asymptomatic women with singleton pregnancies where cervical shortening (≤25 mm) was detected during routine universal screening at 22-33 weeks. Statistical analyses were conducted to identify causal relationships between the incidence of preterm delivery and known risk factors for preterm delivery.

Results: Incidence of preterm delivery was 27.6% (37/134) and preterm premature rupture of membrane was preceded in 46.0% (17/37) of the women with preterm delivery. Using logistic regression analysis, we identified uterine contractions [aOR 4.25, 95% confidence intervals (CI):1.68-12.1] and increased C-reactive protein (CRP) and increased white blood cell (WBC) in blood test (CRP: aOR 3.45, 95% CI:1.50-9.71; WBC: aOR 1.28, 95% CI: 1.08-1.55) as risk factors which significantly increased the risk of preterm delivery among women diagnosed with short cervix. Preterm delivery occurred in 91% of women positive for both uterine contractions and CRP >0.5 mg/dl.

Conclusions: Uterine contraction and elevated CRP were additional risk factors for preterm delivery among women with short cervix. These results might be clinically useful to evaluate subsequent risk for preterm delivery in asymptomatic pregnant women presenting with short cervix in mid-pregnancy.
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http://dx.doi.org/10.1016/j.tjog.2020.01.005DOI Listing
March 2020

Real-time Monitoring of Hypoxic-Ischemic Brain Damage in Neonatal Rats Using Diffuse Light Reflectance Spectroscopy.

Reprod Sci 2020 01 1;27(1):172-181. Epub 2020 Jan 1.

Division of Biomedical Information Sciences, National Defense Medical College Research Institute, Saitama, Japan.

Obstetric management to prevent hypoxic ischemic encephalopathy (HIE) during labor is important to reduce the cerebral palsy incidence in neonates. A novel approach to monitor or predict fetal brain damage during labor is required. Diffuse reflectance spectroscopy is a noninvasive method routinely used to assess the intrinsic characteristics of tissues. This study investigated the time course of diffuse reflectance signals during an early stage of cerebral cortical damage in a neonatal rat HIE model (Vannucci's model). In the model, an HIE lesion was induced by hypoxic exposure following ligation of the left common carotid artery. Using this model, we established an experimental system to detect diffuse light reflectance signals at time points of interest. Quantitative monitoring of total hemoglobin, oxygen saturation, and scattering amplitude was conducted to examine the basis of the diffused reflectance signals. During hypoxic exposure, which induced HIE damage in the left hemisphere after ligation, the oxygen saturation level decreased, but the difference between the two hemispheres was relatively small. During this period, total hemoglobin was increased in both hemispheres, but the change in the left hemisphere was significantly greater than that in the right, which is attributable to a vigorous compensation response. During hypoxia, scattering amplitude, which reflects cellular/subcellular morphology, revealed a remarkable difference between the two hemispheres. We confirmed that scattering amplitude levels negatively correlated with the extent of edema. These findings suggest that simultaneous monitoring of the scattering amplitude, in addition to hemodynamic parameters, is useful for detecting brain tissue alterations leading to HIE.
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http://dx.doi.org/10.1007/s43032-019-00020-9DOI Listing
January 2020

Production of an anti-angiogenic factor sFLT1 is suppressed via promoter hypermethylation of FLT1 gene in choriocarcinoma cells.

BMC Cancer 2020 Feb 10;20(1):112. Epub 2020 Feb 10.

Institute of Physiology and Medicine, Jobu University, 270-1 Shin-machi, Takasaki, Gunma, 370-1393, Japan.

Background: Soluble Fms-like tyrosine kinase-1 (sFLT1) as an anti-angiogenic factor is abundantly expressed in placental trophoblasts. Choriocarcinoma, a malignant tumor derived from trophoblasts, is known to be highly angiogenic and metastatic. However, the molecular mechanism underlying angiogenesis in choriocarcinoma pathogenesis remains unclear. We aimed to investigate the mRNA expression and DNA methylation status of the FLT1 gene in human choriocarcinoma cells and trophoblast cells.

Methods: qRT-PCR, Western blotting and ELISA were conducted to evaluate the mRNA and protein expression levels of sFLT1. 5-aza-2'-deoxycytidine (5azadC) treatment and bisulfite sequencing were used to study the FLT1 gene promoter methylation. The effect of sFLT1 on choriocarcinoma growth and angiogenesis was evaluated in a xenograft mouse model.

Results: Expression of the FLT1 gene was strongly suppressed in choriocarcinoma cell lines compared with that in the primary trophoblasts. Treatment of choriocarcinoma cell lines with 5azadC, a DNA methyltransferase inhibitor, markedly increased in mRNA expression of three FLT1 splice variants and secretion of sFLT1 proteins. Bisulfite sequencing revealed that the CpG hypermethylation was observed at the FLT1 promoter region in choriocarcinoma cell lines and a human primary choriocarcinoma tissue but not in human trophoblast cells. Interestingly, in 5azadC-treated choriocarcinoma cell lines, sFLT1 mRNA expression and sFLT1 production were further elevated by hypoxic stimulation. Finally, as expected, sFLT1-expressing choriocarcinoma cells implanted into nude mice showed significantly slower tumor growth and reduced microvessel formation compared with GFP-expressing control choriocarcinoma cells.

Conclusions: Inhibition of sFLT1 production by FLT1 silencing occurs via the hypermethylation of its promoter in choriocarcinoma cells. The stable expression of sFLT1 in choriocarcinoma cells resulted in the suppression of tumor growth and tumor vascularization in vivo. We suggest that the FLT1 gene may be a cell-type-specific tumor suppressor in choriocarcinoma cells.
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http://dx.doi.org/10.1186/s12885-020-6598-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011436PMC
February 2020

ASK1 promotes uterine inflammation leading to pathological preterm birth.

Sci Rep 2020 02 5;10(1):1887. Epub 2020 Feb 5.

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

It is widely accepted that enhanced uterine inflammation associated with microbial infection is a main causative factor for preterm birth. However, little is known about the molecular basis by which inflammation is associated with preterm birth. Here, we demonstrate that apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein 3-kinase family, facilitates inflammation-induced preterm birth and that inhibition of ASK1 activity is sufficient to suppress preterm birth. ASK1-deficient pregnant mice exhibited reduced incidence of lipopolysaccharide (LPS)-induced preterm birth. ASK1 was required for the induction of LPS-induced inflammatory responses related to preterm birth, including pro-inflammatory cytokine production in the uterus and peritoneal cavities. In addition, selective suppression of uterine ASK1 activity through a chemical genetic approach reduced the incidence of LPS-induced preterm birth. Moreover, translational studies with human choriodecidua demonstrated that ASK1 was required for LPS-induced activation of JNK and p38 and pro-inflammatory cytokine production. Our findings suggest that ASK1 activation is responsible for the induction of inflammation that leads to preterm birth and that the blockade of ASK1 signaling might be a promising therapeutic target for preventing preterm birth.
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http://dx.doi.org/10.1038/s41598-020-58653-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002619PMC
February 2020

Multistate Markov Model to Predict the Prognosis of High-Risk Human Papillomavirus-Related Cervical Lesions.

Cancers (Basel) 2020 Jan 22;12(2). Epub 2020 Jan 22.

Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Cervical intraepithelial neoplasia (CIN) has a natural history of bidirectional transition between different states. Therefore, conventional statistical models assuming a unidirectional disease progression may oversimplify CIN fate. We applied a continuous-time multistate Markov model to predict this CIN fate by addressing the probability of transitions between multiple states according to the genotypes of high-risk human papillomavirus (HPV). This retrospective cohort comprised 6022 observations in 737 patients (195 normal, 259 CIN1, and 283 CIN2 patients at the time of entry in the cohort). Patients were followed up or treated at the University of Tokyo Hospital between 2008 and 2015. Our model captured the prevalence trend satisfactory, particularly for up to two years. The estimated probabilities for 2-year transition to CIN3 or more were the highest in HPV 16-positive patients (13%, 30%, and 42% from normal, CIN1, and CIN2, respectively) compared with those in the other genotype-positive patients (3.1%-9.6%, 7.6%-16%, and 21%-32% from normal, CIN1, and CIN2, respectively). Approximately 40% of HPV 52- or 58-related CINs remained at CIN1 and CIN2. The Markov model highlights the differences in transition and progression patterns between high-risk HPV-related CINs. HPV genotype-based management may be desirable for patients with cervical lesions.
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http://dx.doi.org/10.3390/cancers12020270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072567PMC
January 2020

Reconstructed uterine length is critical for the prevention of cervical stenosis following abdominal trachelectomy in cervical cancer patients.

J Obstet Gynaecol Res 2020 Feb 20;46(2):328-336. Epub 2020 Jan 20.

Department of Obstetrics and Gynecology, Nihon University School of Medicine, Tokyo, Japan.

Aim: Although the procedure of abdominal trachelectomy has been remarkably improved, preventing subsequent cervical stenosis remains challenging. In this study, we analyzed the clinicopathological risk factors for cervical stenosis to explore the appropriate surgical procedures for the prevention of cervical stenosis following trachelectomy.

Methods: Thirty-two patients who underwent abdominal extended and radical trachelectomy were assessed retrospectively (median follow-up period = 33 months). To evaluate the risk factors, the clinicopathological factors were analyzed by univariate and multivariate analyses. The reconstructed uterine length (UtL), that is, the length between the vaginal end of the neo-cervix and the uterine fundus, was measured by transvaginal ultrasound after surgery. The cut-off value for the UtL was assessed by a receiver operating characteristic (ROC) curve analysis.

Results: Cervical stenosis of any grade was observed in 12 patients (grade 1 = 9, grade 3b = 3). Among the various clinicopathological factors, the UtL and cervical length (CL) were significantly related to cervical stenosis following trachelectomy. The multivariate analysis revealed that the UtL, but not CL, is an independent risk factor for stenosis. The ROC curve analysis revealed that stenosis was significantly more likely to occur in patients with a UtL shorter than 53 mm (area under the ROC curve = 0.902). UtL in the patients who became pregnant was longer than that in the patients who did not. No evidence of recurrent cancer was observed during the follow-up period.

Conclusion: Our proposed method may provide a functional reconstructed uterus with preserving fertility by remaining UtL more than 53 mm.
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http://dx.doi.org/10.1111/jog.14153DOI Listing
February 2020

Reciprocal upregulation of hypoxia-inducible factor-1α and persistently enhanced placental adenosine signaling contribute to the pathogenesis of preeclampsia.

FASEB J 2020 03 12;34(3):4041-4054. Epub 2020 Jan 12.

Department of Biochemistry and Molecular Biology, The University of Texas McGovern Medical School, Houston, TX, USA.

Recent evidence indicates that elevated placental adenosine signaling contributes to preeclampsia (PE). However, the molecular basis for the chronically enhanced placental adenosine signaling in PE remains unclear. Here, we report that hypoxia-inducible factor-1α (HIF-1α) is crucial for the enhancement of placental adenosine signaling. Utilizing a pharmacologic approach to reduce placental adenosine levels, we found that enhanced adenosine underlies increased placental HIF-1α in an angiotensin receptor type 1 receptor agonistic autoantibody (AT -AA)-induced mouse model of PE. Knockdown of placental HIF-1α in vivo suppressed the accumulation of adenosine and increased ecto-5'-nucleotidase (CD73) and adenosine A receptor (ADORA2B) in the placentas of PE mouse models induced by AT -AA or LIGHT, a TNF superfamily cytokine (TNFSF14). Human in vitro studies using placental villous explants demonstrated that increased HIF-1α resulting from ADORA2B activation facilitates the induction of CD73, ADORA2B, and FLT-1 expression. Overall, we demonstrated that (a) elevated placental HIF-1α by AT -AA or LIGHT upregulates CD73 and ADORA2B expression and (b) enhanced adenosine signaling through upregulated ADORA2B induces placental HIF-1α expression, which creates a positive feedback loop that promotes FLT-1 expression leading to disease development. Our results suggest that adenosine-based therapy targeting the malicious cycle of placental adenosine signaling may elicit therapeutic effects on PE.
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http://dx.doi.org/10.1096/fj.201902583RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060108PMC
March 2020
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