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Hypertensive disorders of pregnancy (HDP) significantly increase the risk of developing hypertension and cardiovascular disease (CVD) later in life and are a major cause of maternal mortality. However, little is known about the nationwide, long-term, all-inclusive status of HDP. To estimate the incidence of HDP from 2011 to 2019 in Hokkaido, Japan, with a focus on age groups. Using National Database (NDB) insurance medical data, a retrospective analysis was conducted. Due to the absence of direct pregnancy data, birth numbers were used as a surrogate for the number of pregnant women to calculate the incidence of HDP. The average incidence rate of HDP over 9 years was 6.37%. The incidence rate was lowest among women aged 25-29 years, at 5.58% (95% confidence interval [CI]: 5.43-5.73), and increased with age, peaking at 10.58% (95% CI: 10.10-11.09) among women over 40 years. Notably, the incidence rate for women under 20 years of age was 6.70% (95% CI: 5.97-7.51), which was higher than that for women in their 20s. A mean annual increase of 0.25% in age-adjusted incidence was observed during this period, which was statistically significant (R² =  0.87, p <  0.01). This study reveals that the risk of developing HDP is associated with both older childbearing and younger pregnancies and follows a J-curve, suggesting that factors other than maternal aging also contribute to the increased incidence of HDP and that further research on risk factors for HDP, which is on the rise worldwide, is urgently needed.

Structural analysis of small supernumerary marker chromosomes (sSMCs) has revealed that many have complex structures. Structural analysis of sSMCs by whole genome sequencing using short-read sequencers is challenging however because most present with a low level of mosaicism and consist of a small region of the involved chromosome. In this present study, we applied adaptive sampling using nanopore long-read sequencing technology to enrich the target region and thereby attempted to determine the structure of two sSMCs with complex structural rearrangements previously revealed by cytogenetic microarray. In adaptive sampling, simple specification of the target region in the FASTA file enables to identify whether or not the sequencing DNA is included in the target, thus promoting efficient long-read sequencing. To evaluate the target enrichment efficiency, we performed conventional pair-end short-read sequencing in parallel. Sequencing with adaptive sampling achieved a target enrichment at about a 11.0- to 11.5-fold higher coverage rate than conventional pair-end sequencing. This enabled us to quickly identify all breakpoint junctions and determine the exact sSMC structure as a ring chromosome. In addition to the microhomology and microinsertion at the junctions, we identified inverted repeat structure in both sSMCs, suggesting the common generation mechanism involving replication impairment. Adaptive sampling is thus an easy and beneficial method of determining the structures of complex chromosomal rearrangements.

Inositol plays a crucial role in follicular development by regulating insulin signaling and ovarian function. However, its precise mechanism of action remains unclear. This study investigated the effects of myo-inositol (MI) and D-chiro-inositol (DCI) on the development of murine ovarian follicles in vitro. Follicles treated with DCI exhibited larger diameters than controls on Day 6 (275.20 ± 12.54 μm; p = 0.037) and Day 8 (277.47 ± 11.47 μm; p = 0.048), indicating a modest, marginally significant effect that was not maintained by Day 10. The rate of follicular antrum formation was significantly higher in the DCI-treated group on Day 6 (p < 0.05); however, no significant differences were observed on Days 8 and 10. In contrast, MI treatment did not affect follicular survival, diameter, or antrum formation compared with controls. Estradiol concentrations and the expression levels of follicle-stimulating hormone receptor and aromatase genes did not differ significantly among groups. Together, these data provide in vitro evidence that DCI can facilitate the transition from the secondary (preantral) to the early antral stage under these culture conditions. Given the small experimental sample size, the use of healthy murine follicles cultured under a high FSH concentration, and the absence of a PCOS-like ovarian milieu, these findings should be interpreted cautiously and cannot be directly generalized to infertility treatment in women with PCOS. Future studies using PCOS animal models and human follicle systems are needed to clarify translational relevance of these findings.

Hereditary breast and ovarian cancer syndrome (HBOC) resulting from pathogenic variants of BRCA1 or BRCA2 is the most common and well-documented hereditary tumor. Although founder variants have been identified in population-based surveys in various countries, the types of variants are not uniform across races and regions. Recently, the Tohoku Medical Megabank Organization (ToMMo) released whole-genome sequence data including approximately 54,000 individuals from the general population of the Tohoku area in Japan. We analyzed these data and comprehensively identified the prevalence of BRCA1/2 pathogenic and truncating variants. We believe that an accurate understanding of the unique distribution and characteristics of pathogenic BRCA1/2 variants in Japan through this analysis will enable better surveillance and intervention for HBOC patients, not only in Japan but also worldwide.

Mutations in the choline acetyltransferase ( CHAT ) gene cause congenital myasthenic syndrome (CMS). Episodic apnea is frequently observed in patients with CMS due to CHAT mutations (CMS-CHAT), and muscle hypotonia at birth or in early infancy is also common. We report two siblings with compound heterozygous mutations in the CHAT gene: c.1231G > A (missense) and c.752 + 2 T > C (splice site). To confirm the splice site mutation induces a splicing variant, we performed a minigene assay and demonstrated that the splice site mutation, c.752 + 2 T > C, results in complete exon skipping. AlphaFold2 analysis predicted that the skipped exon constitutes an α helix, a highly conserved core structural element of ChAT. These structural alterations in ChAT may underlie the clinical phenotype associated with these mutations.

Constitutional complex chromosomal rearrangements (CCRs) are rare cytogenetic aberrations arising in the germline via an unknown mechanism. Here we analyzed the breakpoint junctions of microscopically three-way or more complex translocations using comprehensive genomic and epigenomic analyses. All of these translocation junctions showed submicroscopic genomic complexity reminiscent of chromothripsis. The breakpoints were clustered within small genomic domains with junctions showing microhomology or microinsertions. Notably, all of the de novo cases were of paternal origin. The breakpoint distributions corresponded specifically to the ATAC-seq (assay for transposase-accessible chromatin with sequencing) read data peak of mature sperm and not to other chromatin markers or tissues. We propose that DNA breaks in CCRs may develop in an accessible region of densely packaged chromatin during post-meiotic spermiogenesis.

Early diagnosis is essential for the safer perinatal management of placenta accreta spectrum (PAS). We used transcriptome analysis to investigate diagnostic maternal serum biomarkers and the mechanisms of PAS development. We analyzed eight formalin-fixed paraffin-embedded placental specimens from two placenta increta and three placenta percreta cases who underwent cesarean hysterectomy at Sapporo Medical University Hospital between 2013 and 2019. Invaded placental regions were isolated from the uterine myometrium and RNA was extracted. The transcriptome difference between normal placenta and PAS was analyzed by microarray analysis. The PAS group showed markedly decreased expression of placenta-specific genes such as LGALS13 and the pregnancy-specific beta-1-glycoprotein (PSG) family. Term enrichment analysis revealed changes in genes related to cellular protein catabolic process, female pregnancy, autophagy, and metabolism of lipids. From the highly dysregulated genes in the PAS group, we investigated the expression of PSG family members, which are secreted into the intervillous space and can be detected in maternal serum from the early stage of pregnancy. The gene expression level of PSG6 in particular was progressively decreased from placenta increta to percreta. The PSG family, especially PSG6, is a potential biomarker for PAS diagnosis.

Background Although many cervical cytology diagnostic support systems have been developed, it is challenging to classify overlapping cell clusters with a variety of patterns in the same way that humans do. In this study, we developed a fast and accurate system for the detection and classification of atypical cell clusters by using a two‐step algorithm based on two different deep learning algorithms. Methods We created 919 cell images from liquid‐based cervical cytological samples collected at Sapporo Medical University and annotated them based on the Bethesda system as a dataset for machine learning. Most of the images captured overlapping and crowded cells, and images were oversampled by digital processing. The detection system consists of two steps: (1) detection of atypical cells using You Only Look Once v4 (YOLOv4) and (2) classification of the detected cells using ResNeSt. A label smoothing algorithm was used for the dataset in the second classification step. This method annotates multiple correct classes from a single cell image with a smooth probability distribution. Results The first step, cell detection by YOLOv4, was able to detect all atypical cells above ASC‐US without any observed false negatives. The detected cell images were then analyzed in the second step, cell classification by the ResNeSt algorithm, which exhibited average accuracy and F‐measure values of 90.5% and 70.5%, respectively. The oversampling of the training image and label smoothing algorithm contributed to the improvement of the system's accuracy. Conclusion This system combines two deep learning algorithms to enable accurate detection and classification of cell clusters based on the Bethesda system, which has been difficult to achieve in the past. We will conduct further research and development of this system as a platform for augmented reality microscopes for cytological diagnosis. Through two different types of CNNs, we were able to exclusively detect and determine atypical cell clusters with high sensitivity. The deep learning approach was also extremely useful for cervical Pap Smears with diverse images.

Background/Aim: Clear cell carcinoma is a prevalent histological type of ovarian cancer in East Asia, particularly in Japan, known for its resistance to chemotherapeutic agents and poor prognosis. ARID1A gene mutations, commonly found in ovarian clear cell carcinoma (OCCC), contribute to its pathogenesis. Recent data revealed that the ARID1A mutation is related to better outcomes of cancer immunotherapy. Thus, this study aimed to investigate the immunotherapy treatment susceptibility of OCCC bearing ARID1A mutations. Materials and Methods: Expression of ARID1A was analyzed using western blotting in ovarian cancer cell lines. OCCC cell lines JHOC-9 and RMG-V were engineered to overexpress NY-ESO-1, HLA-A*02:01, and ARID1A. Sensitivity to chemotherapy and T cell receptor-transduced T (TCR-T) cells specific for NY-ESO-1 was assessed in ARID1A-restored cells compared to ARID1A-deficient wild-type cells. Results: JHOC-9 cells and RMG-V cells showed no expression of ARID1A protein. Overexpression of ARID1A in JHOC-9 and RMG-V cells did not impact sensitivity to gemcitabine. While ARID1A overexpression decreased sensitivity to cisplatin in RMG-V cells, it had no such effect in JHOC-9 cells. ARID1A overexpression reduced the reactivity of NY-ESO-1-specific TCR-T cells, as observed by the IFNγ ESLIPOT assay. Conclusion: Cancer immunotherapy is an effective approach to target ARID1A-deficient clear cell carcinoma of the ovary.

Intrauterine infection is one of the most important causes of maternal death. In perinatal emergency, we often miss an opportunity to obtain culture specimens. In this study, we tried to examine whether we investigated whether bacteria causing infection can be detected from a formalin-fixed paraffin-embedded (FFPE) placental specimen. We examined the placenta from a maternal invasive infection that resulted in infectious abortion at 18 weeks of gestation. The case was diagnosed by acute fever and abdominal pain, and the patient was cured after 3 weeks of intensive antimicrobial treatment. Four Streptococcus pyogenes strains were isolated from vaginal fluid and blood cultures of the patient. All of the strain types were emm 1/ST28. We amplified the V1–V2 region of 16S rRNA from an FFPE placental specimen and sequencing was performed using a next-generation sequencer (NGS). Taxonomic analysis was then performed for sequenced data. We succeeded in detecting causative pathogens from the FFPE placenta: 69.1% of the predominantly identified bacteria were S. pyogenes and other small populations of bacteria were detected. Our results revealed the utility of NGS for 16S rRNA analysis of an FFPE placenta. This method may reveal previous perinatal invasive infections of unknown origin retrospectively.