Yuki Yamada

Mechanism of pain generation for endometriosis-associated pelvic pain.

PurposeEndometriosis-associated pelvic pain appears due to persistent nociceptive stimulation, but the precise mechanisms remain poorly understood.MethodsA search was conducted to screen and select articles from PubMed.Main resultsNeurotrophins (NTs), a family of neuronal growth factors, are overexpressed in endometriosis and encompass NGF, BDNF and NT-3 and NT-4/5. NT receptors, TrkA and p75NTR, and NT receptor-interacting proteins, MAGE and NDN, were also expressed. NTs and their receptors play a role in the development and maintenance of neural tissues in non-neuronal cell types such as endometriosis. Nerve fibers contain unmyelinated sensory C, myelinated sensory Adelta and adrenergic nerve fibers that innervate abnormal cell growths. An increased release of proinflammatory cytokines from endometriotic lesions is responsible for the excessive sensory innervation and development of chronic pelvic pain.ConclusionsThe preponderance of the inflammatory milieu and subsequent hyperinnervation might be involved in the pathophysiology of pain generation in women with endometriosis.

Fetal programming theory: Implication for the understanding of endometriosis

Comparison of the transcriptomes and proteomes of the decidualization-specific genes that express high vs low levels of the eutopic and ectopic endometrium of women with endometriosis compared with controls, could be useful in understanding the pathogenesis of endometriosis. Genome-wide comparison between decidual tissue and non-decidual tissue identified many genes significantly modulated in the process of decidualization. Comparison of eutopic endometrium and endometriotic sites also revealed up- and down-regulated genes. A combined analysis of the experimental data showed specific genes up-regulated both at the endometriotic site and in the decidualization process, representing a broad diversity of molecular functions, including cell cycle regulation, angiogenesis and adhesion molecules. In contrast, down-regulated genes identified in endometriosis among genes overexpressed in decidualization encode Müllerian embryogenesis, which includes transcription factors, hormonal regulation and cytokine expression. The mechanism responsible for insufficient decidualization in endometriosis may be mediated through down-regulation of the Müllerian embryogenesis-related genes. In conclusion, a range of decidualization resistance has been associated with endometriosis. Future study will identify the putative mechanisms relating epigenetic changes of decidualization susceptibility genes in early life to the risk of developing endometriosis in adulthood.

Role of Oxidative Stress in Epigenetic Modification in Endometriosis

Aberrant DNA methylation and histone modification are associated with an increased risk of reproductive disorders such as endometriosis. However, a cause–effect relationship between epigenetic mechanisms and endometriosis development has not been fully determined. This review provides current information based on oxidative stress in epigenetic modification in endometriosis. This article reviews the English-language literature on epigenetics, DNA methylation, histone modification, and oxidative stress associated with endometriosis in an effort to identify epigenetic modification that causes a predisposition to endometriosis. Oxidative stress, secondary to the influx of hemoglobin, heme, and iron during retrograde menstruation, is involved in the expression of CpG demethylases, ten–eleven translocation, and jumonji (JMJ). Ten–eleven translocation and JMJ recognize a wide range of endogenous DNA methyltransferases (DNMTs). The increased expression levels of DNMTs may be involved in the subsequent downregulation of the decidualization-related genes. This review supports the hypothesis that there are at least 2 distinct phases of epigenetic modification in endometriosis: the initial wave of iron-induced oxidative stress would be followed by the second big wave of epigenetic modulation of endometriosis susceptibility genes. We summarize the recent advances in our understanding of the underlying epigenetic mechanisms focusing on oxidative stress in endometriosis.

Bacteremia secondary to Alloscardovia omnicolens urinary tract infection.

A 70-year-old woman was admitted to our hospital with malaise, bilateral leg edema, and oliguria. She had a history of advanced uterine cancer. Bilateral double-J catheters were inserted because growth of intra-abdominal metastases led to bilateral ureteral stricture and hydronephrosis. Two days later, she suddenly developed high fever. Thin gram-positive bacilli of moderate length were detected in the anaerobic blood culture bottles. We performed 16S ribosomal RNA analysis of the isolate and it showed 100% match with Alloscardovia omnicolens DSM 21503(T). She was successfully treated with cefmetazole in addition to percutaneous nephrostomy.

Skin–mucous membrane disorder and therapeutic effect of pegylated liposomal doxorubicin in recurrent ovarian cancer

Hand–foot syndrome (HFS) induced by chemotherapy and molecule‐targeting drugs is correlated with treatment efficacy. We conducted a retrospective analysis to evaluate the relationship between HFS and efficacy of pegylated liposomal doxorubicin (PLD) for recurrent ovarian cancer.

Sequential molecular changes and dynamic oxidative stress in high-grade serous ovarian carcinogenesis

Abstract The mechanism of high-grade serous ovarian cancer (HGSC) development remains elusive. This review outlines recent advances in the understanding of sequential molecular changes associated with the development of HGSC, as well as describes oxidative stress-induced genomic instability and carcinogenesis. This article reviews the English language literature between 2005 and 2017. Clinicopathological features analysis provides a sequential progression of fallopian tubal epithelium to precursor lesions to type 2 HGSC. HGSC may develop over a long time after incessant ovulation and repeated retrograde menstruation via stepwise accumulation of genetic alterations, including PAX2, ALDH1A1, STMN1, EZH2 and CCNE1, which confer positive selection of cells with growth advantages through acquiring driver mutations such as BRCA1/2, p53 or PTEN/PIK3CA. Haemoglobin and iron-induced oxidative stress leads to the emergence of genetic alterations in fallopian tubal epithelium via increased DNA damage and impaired DNA repair. Serous tubal intraepithelial carcinoma (STIC), the likely precursor of HGSC, may be susceptible to DNA double-strand breaks, exhibit DNA replication stress and increase genomic instability. The induction of genomic instability is considered to be a driving mechanism of reactive oxygen species (ROS)-induced carcinogenesis. HGSC exemplifies the view of stepwise cancer development. We describe how genetic alterations emerge during HGSC carcinogenesis related to oxidative stress.

A case of phosphoglyceride crystal deposition disease in the pelvic soft tissues recurring after initial surgery.

Phosphoglyceride crystal deposition disease (PGDD) is a rare disease entity that is characterized by phosphoglyceride crystal deposition that stimulates the formation of masses in soft tissue scars or bones. We report a case of PGDD in the pelvic soft tissues that recurred after initial surgical treatment. A 50-year-old woman was referred to our hospital for the evaluation of pelvic masses that were observed on an abdominal ultrasound. Magnetic resonance imaging (MRI) revealed masses in the pelvic region, with the largest being 10 cm in diameter. The masses were diagnosed as ovarian malignant tumors, and an exploratory laparotomy was performed. Operative findings revealed them to be foreign body granulomas, and the patient was diagnosed with PGDD. The patient had a history of cesarean delivery at the age of 24 years. PGDD is extremely rare, but it should be considered in the differential diagnosis of abdominal masses in patients with a history of abdominal surgery.

Genes Downregulated in Endometriosis Are Located Near the Known Imprinting Genes

There is now accumulating evidence that endometriosis is a disease associated with an epigenetic disorder. Genomic imprinting is an epigenetic phenomenon known to regulate DNA methylation of either maternal or paternal alleles. We hypothesize that hypermethylated endometriosis-associated genes may be enriched at imprinted gene loci. We sought to determine whether downregulated genes associated with endometriosis susceptibility are associated with chromosomal location of the known paternally and maternally expressed imprinting genes. Gene information has been gathered from National Center for Biotechnology Information database geneimprint.com. Several researchers have identified specific loci with strong DNA methylation in eutopic endometrium and ectopic lesion with endometriosis. Of the 29 hypermethylated genes in endometriosis, 19 genes were located near 45 known imprinted foci. There may be an association of the genomic location between genes specifically downregulated in endometriosis and epigenetically imprinted genes.

The HNF-1β―USP28―Claspin pathway upregulates DNA damage-induced Chk1 activation in ovarian clear cell carcinoma

Transcription factor hepatocyte nuclear factor 1-beta (HNF-1β) enhances checkpoint kinase 1 (Chk1) activation and promotes G2/M cell cycle progression in ovarian clear cell carcinoma (CCC) following exposure to diverse genotoxic agents including bleomycin. However, the underlying mechanism leading to checkpoint activation of HNF-1β still remains largely unknown. To clarify the effects of HNF-1β on cell cycle checkpoints, human CCC cell lines were transfected with siRNAs targeting HNF-1β, Claspin, USP28, or a control vector. Ubiquitination and stabilization of Claspin protein by HNF-1β was assessed by immunoprecipitation. Loss-of-function studies using RNAi-mediated gene silencing indicated that HNF-1β facilitated the Claspin expression after treatment with a genotoxic agent bleomycin, resulting in accumulation of phosphorylated Chk1 (p-Chk1) and promotion of survival in CCC cell lines. This study showed for the first time that USP28, a de-ubiquitinase crucial for Claspin expression, is one target gene of HNF-1β. Knockdown of endogenous USP28 suppressed the Claspin expression and p-Chk1 activation and cell viability. Our findings identify a novel pathway of the HNF-1β―USP28―Claspin―Chk1 axis in checkpoint signal amplification in response to DNA damage. Targeting this pathway may represent a putative, novel, anticancer strategy in ovarian CCC.

Comparison of redox parameters in ovarian endometrioma and its malignant transformation

The present study aimed to evaluate the levels of oxidative stress and antioxidant markers in benign endometrioma (OE) and its malignant transformation [endometriosis-associated ovarian cancer (EAOC)] by measuring 8-hydroxy-2-deoxyguanosine (8-OHdG), heme oxygenase-1 (HO-1) and total antioxidant capacity (TAC/Heme-iron) alterations associated with disease progression. Cyst fluid samples from 44 patients with OE and 14 patients with EAOC were studied using an enzyme-linked immunosorbent assay. A χ2 test, t-test and Pearson correlation test were performed using SPSS version 22.0. The cut-off point, sensitivity and specificity of each marker for EAOC diagnosis were evaluated by receiver operating characteristic curve analysis. Cyst fluid 8-OHdG and HO-1 levels in the EAOC group were significantly decreased compared with the OE subjects (P=0.013 and P<0.001, respectively). The levels of TAC/Heme-iron in patients with EAOC were significantly higher compared with those in the OE subjects (P<0.001). The present study demonstrated a positive correlation between 8-OHdG and HO-1 levels (P=0.012). HO-1 exhibited the highest discriminant value for EAOC (Area Under the Curve=0.901). The optimal cut-off point of HO-1 for the diagnosis of EAOC was 2.314 ng/ml, with a sensitivity and specifity of 95.2 and 85.7%, respectively. The present study revealed a clear separation between the overall redox state in OE and EAOC. It was concluded that characteristic alterations in important factors in redox may be helpful for understanding the pathogenesis of the malignant transformation of endometriosis.