Ovarian Epithelium Research Articles

Impact of proper surgical treatment on the survival of patients with epithelial ovary cancer

RESUMO Objetivo: avaliar a qualidade do tratamento cirúrgico de pacientes com câncer de ovário e o impacto do tratamento oncológico cirúrgico adequado na sobrevida livre de doença e sobrevida global de pacientes com câncer de ovário epitelial avançado. Métodos: Trata-se de um estudo observacional, retrospectivo, de análise quantitativo, com coleta de dados em prontuários de uma amostra de conveniência temporal de pacientes com diagnóstico de câncer de ovário internadas em uma Unidade de Oncologia de Alta Complexidade (UNACON), em Belo Horizonte, no período de 2014 a 2020. Resultados: foram avaliadas 91 pacientes diagnosticadas com câncer de ovário, sendo o tipo histopatológico epitelial o mais frequente (85%). Desse total, 68 pacientes (74,7%) apresentavam câncer de ovário em estágio avançado. O tratamento cirúrgico adequado foi realizado em 30,9% das pacientes com câncer de ovário epitelial avançado e o tipo de cirurgia realizada foi estatisticamente significativo para a sobrevida global. Essa baixa proporção de tratamento cirúrgico oncológico adequado não esteve relacionada à especialidade cirúrgica ou competência do cirurgião, mas principalmente à doença avançada relacionada ao fluxo de pacientes na UNACON. Não foi possível confirmar se a doença em estágio avançado estava relacionada à biologia tumoral ou à perda de tempo do diagnóstico para a cirurgia oncológica. Conclusão: A sobrevida global de pacientes com câncer de ovário epitelial em estágio avançado é diretamente influenciada pelo tratamento cirúrgico adequado. Porém, o percentual de câncer de ovário avançado recebendo tratamento cirúrgico adequado foi muito inferior aos índices relatados na literatura. Para melhorar esses resultados, acreditamos que os cirurgiões devem continuar acompanhando as pacientes durante a quimioterapia neoadjuvante para apontar um melhor momento para a cirurgia, e os oncologistas clínicos devem considerar melhor a cirurgia oncológica adequada como um dos pilares do tratamento do câncer de ovário e se envolver mais na facilitação das cirurgias.

FBXO22 Promotes Growth and Metastasis and Inhibits Autophagy in Epithelial Ovarian Cancers via the MAPK/ERK Pathway.

E3 ubiquitin ligase F-box only protein 22 (FBXO22), which targets the key regulators of cellular activities for ubiquitylation and degradation, plays an important role in tumorigenesis and metastasis. However, the function of FBXO22 in epithelial ovarian cancers has not been reported. This study aims to explore the biological function of FBXO22 in epithelial ovarian cancers progression and metastasis and its specific regulation mechanism. Immunohistochemistry analysis of tissue microarray was performed to evaluate the expression of FBXO22 in epithelial ovarian cancers patients. The proliferative ability of epithelial ovarian cancers cells was examined by the CCK8. The metastasis ability was detected by the wound healing assay, migration and invasion assays. Western blot was used to verify the relationship between FBXO22 expression and mitogen-activated protein kinase related proteins. Autophagic flux was detected by electron microscopy, mRFP-GFP-LC3 adenovirus, lysosomal tracker and western blot. For in vivo experiments, the effect of FBXO22 on epithelial ovarian cancers resistance was observed in a xenograft tumor model and a metastatic mice model. We found that FBXO22 expression was significantly increased in epithelial ovarian cancers tissues and was closely correlated with clinical pathological factors. As a result, we found that FBXO22 promoted the growth and metastasis, as well as inhibited the autophagy flux. In addition, we identified that FBXO22 performed these functions via the MAPK/ERK pathway. Our results first reported the function of FBXO22 in epithelial ovarian cancer and the correlation between FBXO22 and autophagy, suggesting FBXO22 as a novel target of epithelial ovarian cancers assessment and treatment.

Tubal histopathological abnormalities in BRCA1/2 mutation carriers undergoing prophylactic salpingo-oophorectomy: a case–control study

ObjectiveTo describe tubal histopathological abnormalities in women with germline BRCA1/2 mutations and in controls.MethodsConsecutive women with BRCA1/2 mutations undergoing bilateral salpingo-oophorectomy between 2010 and 2020 in two centers (San Gerardo...

Modeling Notch-Induced Tumor Cell Survival in the Drosophila Ovary Identifies Cellular and Transcriptional Response to Nuclear NICD Accumulation.

Notch is a conserved developmental signaling pathway that is dysregulated in many cancer types, most often through constitutive activation. Tumor cells with nuclear accumulation of the active Notch receptor, NICD, generally exhibit enhanced survival while patients experience poorer outcomes. To understand the impact of NICD accumulation during tumorigenesis, we developed a tumor model using the Drosophila ovarian follicular epithelium. Using this system we demonstrated that NICD accumulation contributed to larger tumor growth, reduced apoptosis, increased nuclear size, and fewer incidents of DNA damage without altering ploidy. Using bulk RNA sequencing we identified key genes involved in both a pre- and post- tumor response to NICD accumulation. Among these are genes involved in regulating double-strand break repair, chromosome organization, metabolism, like raptor, which we experimentally validated contributes to early Notch-induced tumor growth. Finally, using single-cell RNA sequencing we identified follicle cell-specific targets in NICD-overexpressing cells which contribute to DNA repair and negative regulation of apoptosis. This valuable tumor model for nuclear NICD accumulation in adult Drosophila follicle cells has allowed us to better understand the specific contribution of nuclear NICD accumulation to cell survival in tumorigenesis and tumor progression.

O-066 The naughty genes and 3D structure of the endometrium

Abstract The naughty genes and 3D structure of the endometrium Takayuki Enomoto, Manako Ymaguchi, Kazuaki Suda, Kosuke Yoshihara Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. The human endometrium is a highly regenerative tissue and involved in menstruation and implantation of the fertilized egg, giving it a central role in women’s reproductive health. However, the regenerative nature of the endometrial glands can lead to the development and progression of “endometrium-related diseases” such as adenomyosis, endometriosis, endometriosis-associated ovarian cancer, endometrial hyperplasia, and endometrial cancer. To clarify the pathogenesis of endometrium-related diseases and develop effective preventative measures and therapeutic strategies, comprehensive understanding of molecular biological linkage between endometrium and endometrium-related diseases was crucially important. To this end, we focused on genomic alterations of endometrial epithelium which is considered the origin of endometriosis, and sequenced 107 ovarian endometriotic and 82 normal uterine endometrial epithelium samples isolated by laser-microdissection. Intriguingly, several genes recurrently mutated in endometriosis-associated ovarian cancers were frequently mutated in both endometriotic epithelium and normal uterine endometrial glands. In particular, PIK3CA mutation was detected in 41% of endometrial epithelium subjects but none of them had shared PIK3CA mutations across multiple regions collected from the same individuals. Mutation allele frequencies of somatic mutations in uterine endometrial epithelium samples were also significantly lower than those in ovarian endometriotic epithelium samples, suggesting the heterogeneous genomic compositions in uterine endometrium. To interpret this genomic heterogeneity in uterine endometrium, we focused on endometrial gland, the minimum functional unit of uterine endometrium, and conducted 109 single endometrial glands sequencing. As a result, we unveiled that each gland carried distinct somatic mutations in cancer-associated genes, such as PIK3CA, KRAS, and PTEN, with high mutant allele frequencies, suggesting the monoclonality of each gland. The presence of cancer-associated gene mutations in histologically normal endometrial glands provides important clues regarding the pathogenesis of endometrium-related diseases. However, our previous study could not determine the spread of endometrial gland harboring cancer-associated gene mutation because there is a limitation to two-dimensional assessment of the whole shapes of endometrial gland due to its complicatedly winding morphology. Therefore, we tackled with three-dimensional (3D) assessment of human endometrium. To construct a large picture of endometrial gland structure, we performed tissue-clearing-based 3D imaging of full-thickness human uterine endometrial tissue with the use of light-sheet fluorescence microscopy. Our 3D immunohistochemistry discovered some new and unique 3D morphologies of endometrial glands, including plexus network of glands or occluded glands. Notably, computational analysis of 3D layer clarified that the plexus structure of the glands was mainly located in the stratum basalis and expanded along muscular layer horizontally, similar to the so-called “rhizome of grass”. Although previous studies have shown the 3D structure of murine endometrial glands, the bottom of these glands forms a crypt but not a rhizome. This can potentially be explained by the existence of menstruation, which is the crucial difference between the human and murine endometrium. The rhizome structure of endometrial gland in the human endometrium will have a functional advantage over the crypt in terms of the conservation of progenitor/stem cells and regeneration. In addition, some endometrial glands shared the plexus and rose toward the luminal epithelium, suggesting that these glands were the same origin. The rhizome of the endometrium may be a crucial element for understanding the expansion of endometrial glands harboring cancer-associated gene mutations. Integrated analysis of the naughty gene alterations and the 3D structure in human endometrium will lead to a better understanding of the human endometrium in various fields, including histology, pathology, pathophysiology, reproduction, and oncology.

Progestin significantly inhibits carcinogenesis in the mogp-TAg mouse model of fallopian tube cancer

<h3>Objectives:</h3> Recent studies suggest the fallopian tube epithelium (FTE) harbors the precursor for high grade ovarian cancer (HGSC), creating opportunities for targeting the FTE for ovarian cancer prevention. Preclinical evidence supports progestins as ovarian cancer preventives, but the effect of progestins on the FTE has not been well characterized. <i>in vitro</i> and primate models suggest that progestins clear genetically damaged cells in the ovarian epithelium and endometrium by activating molecular pathway such as apoptosis. The mogp-TAg transgenic mouse develops neoplastic lesions such as p53 signatures and serous tubal intraepithelial carcinoma (STIC) in the fallopian tube (FT) in a similar manner to that described in human fallopian and ovarian cancers. In this study, we investigated the inhibitory effects of the progestin-Depo-medroxyprogesterone acetate (DMPA) on FT carcinogenesis in the mogp-TAg mouse. <h3>Methods:</h3> Mogp-TAg mice (10 per group) at 5 weeks of age were injected with vehicle or the progestin Depo-medroxyprogesterone acetate-DMPA (1mg/mouse). The mice were euthanized at 8 and 12 weeks of age and the reproductive tract was removed. H&E stained sections were used to histologically and pathologically characterize the FTs following treatment. In addition, immunohistochemistry and immunofluorescence were used to characterize lesions and the cell death pathway. <h3>Results:</h3> There was an increase in the number of FT epithelial and stromal p53 positive cells from 5 to 12 weeks of age in the vehicle treated mice. Histologically, the FT of the vehicle treated mice developed adenocarcinoma and/or epithelial/smooth muscle hyperplasia at 8 and 12 weeks of age. Compared to the vehicle-treated mice, the FT of the DMPA treated mice were significantly smaller at 8 weeks (p<0.005) and 12 weeks (p<0.0005) of age. In addition, there was normal distribution of ciliated cells, less nuclear pleomorphism and epithelial tufting, and a significantly lower proliferative index (Ki67) (p=0.001) in 8 week DMPA treated mice compared to vehicle. Accumulation of p53 in the FT was significantly reduced in DMPA(p<0.000005) treated mice at 8 weeks compared to vehicle. There was significantly more cleaved caspase-3 in the FT of the DMPA-treated group compared to the vehicle group. <h3>Conclusions:</h3> DMPA treatments significantly reduced the tumor burden and aberrant p53 expression in the FT of mice compared to vehicle treated animals. Our data support the hypothesis that progestins have a cytocidal effect, clearing genetically damaged cells from the fallopian tube potentially via apoptosis. These data provide evidence supporting the hypothesis that progestin may be used for prevention of ovarian cancer.

Long-Term Risk of Ovarian Cancer and Borderline Tumors After Assisted Reproductive Technology

(Abstracted from J Natl Cancer Inst 2021;113:699–709) Despite inconclusive evidence, concerns that assisted reproductive technology may be associated with increased risk of ovarian cancer remain. Significant increases in gonadotropin levels and disruption of ovarian epithelium have been proposed as mechanisms to explain this potential association.

Reference Module-Based Analysis of Ovarian Cancer Transcriptome Identifies Important Modules and Potential Drugs.

Ovarian cancer (OVC) is often diagnosed at the advanced stage resulting in a poor overall outcome for the patient. The disease mechanisms, prognosis, and treatment require imperative elucidation. A rank-based module-centric framework was proposed to analyze the key modules related to the development, prognosis, and treatment of OVC. The ovarian cancer cell line microarray dataset GSE43765 from the Gene Expression Omnibus database was used to construct the reference modules by weighted gene correlation network analysis. Twenty-three reference modules were tested for stability and functionally annotated. Furthermore, to demonstrate the utility of reference modules, two more OVC datasets were collected, and their gene expression profiles were projected to the reference modules to generate a module-level expression. An epithelial-mesenchymal transition module was activated in OVC compared to the normal epithelium, and a pluripotency module was activated in ovarian cancer stroma compared to ovarian cancer epithelium. Seven differentially expressed modules were identified in OVC compared to the normal ovarian epithelium, with five up-regulated, and two down-regulated. One module was identified to be predictive of patient overall survival. Four modules were enriched with SNP signals. Based on differentially expressed modules and hub genes, five candidate drugs were screened. The hub genes of those modules merit further investigation. We firstly propose the reference module-based analysis of OVC. The utility of the analysis framework can be extended to transcriptome data of other kinds of diseases.

Dynamic transcriptome analysis and Methoprene-tolerant gene knockdown reveal that juvenile hormone regulates oogenesis and vitellogenin synthesis in Propylea Japonica

Propylea japonica has been regarded as one of the most remarkable natural enemies against aphid in China. However, the mechanism of juvenile hormone (JH) regulation of reproduction in P. japonica is still unclear. In this study, we investigated the JH titers of P. japonica and the development of the ovaries. We selected the six different developmental stages of ladybeetle females for transcriptome sequencing. We identified 583 genes involved in insect reproduction regulation, including 107 insect hormone synthesis signaling pathway-related genes and 476 nutrition-sensing signaling pathway-related genes. Transcriptome analysis indicated that a large number JH synthesis- and metabolism-related enzyme genes and some potential nutrient signal sensing- and transduction-related genes were significantly differentially expressed during P. japonica development. We investigated the effects of Met gene silencing on the reproduction of female adults and found that the ovarian maturation, vitellogenesis, and follicular epithelium development in the dsMet treatment group were significantly inhibited.

Neoadjuvant and adjuvant systemic therapy for newly diagnosed stage II- IV epithelial ovary, fallopian tube, or primary peritoneal carcinoma: A systematic review.

To systematically review neoadjuvant and adjuvant therapy options for women with newly diagnosed stage II-IV ovarian cancer. Phase III trials were searched using MEDLINE, EMBASE, and Cochrane Library. Maintenance therapies were excluded. Thirty-three trials were included. For women with high-risk profiles that would contraindicate upfront cytoreductive surgery, neoadjuvant chemotherapy can be an option. In the post-surgical adjuvant setting, the three-weekly regimen consisting of paclitaxel and carboplatin remains the standard of care. Docetaxel may be offered to those who are unable to tolerate paclitaxel. Intraperitoneal cisplatin and paclitaxel increased OS for stage III optimally debulked women (GOG 172). The intraperitoneal regimens in GOG 252 offered no survival benefit and some harms in terms of toxicity and quality of life. There is no evidence to support adding a third agent to the standard carboplatin and paclitaxel. Results of the iPocc study will clarify the role of intraperitoneal chemotherapy.

Correlation between HPV infection and ovarian epithelial cancer diagnosed by Dynamic Contrast-enhanced magnetic resonance imaging information technology under exponential distribution mathematical model

This research aims to analyze the correlation between human papillomavirus (HPV) infection and ovarian epithelial cancer based on exponential distribution mathematical model, so as to provide an experimental basis for the early diagnosis of ovarian epithelial cancer by magnetic resonance imaging (MRI) in the future. In this study, 124 patients with ovarian epithelial cancer tissues pathologically confirmed in our hospital from March 31, 2017 to February 20, 2019 were selected as the experimental group, and 64 patients with normal ovarian tissues were selected as the control group, and the positive rate of HPV infection was detected by the computer cell test (CCT) system. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was constructed and adopted to analyze the scanning images. The correlation between HPV infection and pathological type, clinical stage, tissue differentiation degree, and CA125 in serum was studied by exponential distribution mathematical model. The results showed that the positive rate of HPV infection in the ovarian tissues of the experimental group was significantly higher than that of the control group (P < 0.05). Highly differentiated patients accounted for 25.97%, moderately differentiated patients accounted for 43.81%, and lowly differentiated patients accounted for 30.22%. Patients with clinical stage I-II accounted for 24.72%, patients with stage III accounted for 49.11%, and patients with stage IV accounted for 26.17%. HPV infection was significantly correlated with clinical stage III and moderate tissue differentiation by MRI of patients (P < 0.05), and extremely significantly correlated with clinical stage IV and low tissue differentiation by MRI (P < 0.001). The above findings show that the information technology of dynamic contrast-enhanced magnetic resonance imaging can clearly display the lesion metastasis of ovarian epithelial cancer patients with high soft tissue resolution.

Transcriptional heterogeneity of stemness phenotypes in the ovarian epithelium

The ovarian surface epithelium (OSE) is a monolayer of epithelial cells surrounding the ovary that ruptures during each ovulation to allow release of the oocyte. This wound is quickly repaired, but mechanisms promoting repair are poorly understood. The contribution of tissue-resident stem cells in the homeostasis of several epithelial tissues is widely accepted, but their involvement in OSE is unclear. We show that traits associated with stem cells can be increased following exposure to the cytokine TGFB1, overexpression of the transcription factor Snai1, or deletion of Brca1. We find that stemness is often linked to mesenchymal-associated gene expression and higher activation of ERK signalling, but is not consistently dependent on their activation. Expression profiles of these populations are extremely context specific, suggesting that stemness may not be associated with a single, distinct population, but rather is a heterogeneous cell state that may emerge from diverse environmental cues. These findings support that the OSE may not require distinct stem cells for long-term maintenance, and may instead achieve this through transient dedifferentiation into a stem-like state.

Consolidation or maintenance systemic therapy for newly diagnosed stage II, III, or IV epithelial ovary, fallopian tube, or primary peritoneal carcinoma: A systematic review.

To systematically review the effectiveness and harm of consolidation or maintenance therapy in patients with newly diagnosed stage II-IV EOC. MEDLINE, EMBASE, PubMed, Cochrane Library, and PROSPERO databases, and four relevant conferences were systematically searched. We adhered to PRISMA guidelines, and used the GRADE approach to aggregate data. Among 12,675 citations, 28 comprising 16,310 patients were analyzed. The certainty of aggregated study evidence ranged from high to low. The existing evidence does not find overall survival benefit for consolidation therapy with chemotherapy. For maintenance therapy, comparing with placebo, olaparib, niraparib, veliparib, and bevacizumab are effective as maintenance therapy for certain patients with newly diagnosed stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal carcinoma respectively without reducing quality of life. Longer follow-up with more mature results of overall survival will better define the effect of these agents.

How Does Endometriosis Lead to Ovarian Cancer? The Molecular Mechanism of Endometriosis-Associated Ovarian Cancer Development.

Simple SummaryDriver gene mutations have been identified in not only various types of endometriosis which are considered the origin of endometriosis-associated ovarian cancer but also the normal endometrium which is considered the origin of endometriosis. We focused on genomic linkage from normal endometrium to ovarian endometriosis and endometriosis-associated ovarian cancer (EAOC) and summarized the current knowledge of the commonality and differentiation of genomic features in the uterine endometrium, endometriosis, and EAOC. In addition, we have proposed molecular mechanism of ovarian carcinogenesis from the normal endometrium via endometriosis based on genomic alterations. This review is expected to contribute to research for the prevention of endometriosis and EAOC.Numerous epidemiological and histopathological studies support the notion that clear cell and endometrioid carcinomas derive from ovarian endometriosis. Accordingly, these histologic types are referred to as “endometriosis-associated ovarian cancer” (EAOC). Although the uterine endometrium is also considered an origin of endometriosis, the molecular mechanism involved in transformation of the uterine endometrium to EAOC via ovarian endometriosis has not yet been clarified. Recent studies based on high-throughput sequencing technology have revealed that cancer-associated gene mutations frequently identified in EAOC may exist in the normal uterine endometrial epithelium and ovarian endometriotic epithelium. The continuum of genomic alterations from the uterine endometrium to endometriosis and EAOC has been described, though the significance of cancer-associated gene mutations in the uterine endometrium or endometriosis remains unclear. In this review, we summarize current knowledge regarding the molecular characteristics of the uterine endometrium, endometriosis, and EAOC and discuss the molecular mechanism of cancer development from the normal endometrium through endometriosis in an effort to prevent EAOC.

Prenatal and pubertal exposure to 17α-ethinylestradiol disrupts folliculogenesis and promotes morphophysiological changes in ovaries of old gerbils (Meriones unguiculatus).

17α-Ethinylestradiol is an endocrine-disrupting chemical that make up most contraceptive pills and can be found in the environment. Exposure to ethinylestradiol in different development periods may promote changes in morphophysiological parameters of reproductive and endocrine organs. Considering that the effects of low doses (15 µg/kg/day) of ethinylestradiol in ovaries from 12-month-old female gerbils (Meriones unguiculatus) were investigated. Four experimental groups used were control (without treatment), EE/PRE (treated from the 18th to the 22nd gestational day), EE/PUB (treated from the 42nd to the 49th day of life), and EE/PRE-PUB (treated in the both periods). The animals were euthanized at 12 months. Testosterone and 17β-estradiol levels were measured. The ovaries were stained with Hematoxylin and Eosin, Periodic Acid Schiff, and Gomori's Trichome. The follicles, corpus luteum, interstitial gland, lipofuscin, ovarian epithelium, and tunica albuginea were analyzed. Estradiol was higher in EE/PRE and EE/PUB groups, while testosterone was higher only in EE/PUB group. The main changes in follicle count occurred in EE/PUB and EE/PRE-PUB groups, with higher primordial follicle count and lower maturation of follicles. The corpus luteum was more evident in EE/PRE group. No differences were found in atretic follicles count. A higher area occupied by interstitial gland cells and lipofuscin deposit in these cells was noted in EE/PUB and EE/PRE-PUB groups. Higher epithelium height and thicker tunic albuginea were showed in treated groups. These results suggest that exposure to doses of EE2 in prenatal and pubertal periods of the development leads to morphological changes in senile ovaries.

High expression of ENPP1 in high-grade serous ovarian carcinoma predicts poor prognosis and as a molecular therapy target.

Recent studies have shown that the expression of ENPP1 is related to differentiation, death, dissemination and chemosensitivity of tumor cells. So far, there is no research in ovarian carcinoma. This study aimed at exploring the role of ENPP1 gene in ovarian carcinoma, the relationship with prognostic indicators and chemotherapy resistance, and investigates the possibility of molecular targeted therapy. The expression of ENPP1 in 41 normal ovarian epithelial tissues, 97 ovarian serous cystadenoma and 103 HGSOC tissues was detected by IHC. In ovarian cancer tissues and ovarian cancer cell lines, mRNA and protein expression of ENPP1 was determined by qRT-PCR and Western blot. The ENPP1 expression was knockdowned by siRNA. Cell proliferation was measured with the BrdU Cell Proliferation ELISA. Cell migration and invasion were detected by Wound-Healing, Transwell migration and Matrigel invasion assay. Caspase 3 activity was determined by the CaspACE. The expression of EMT markers such as E-cadherin, N-cadherin, and Vimentin was measured, and the expression of PCNA and MMP9 was also be detected. The results showed that the expression of ENPP1 was significantly increased in high-grade ovarian serous carcinoma, the number of strong expression was 85.4% (22.3%+63.1%) and only 1.03% (1.03%+0.0%) in serous cystadenoma, but no in normal ovarian epithelium (P< 0.05). And the stronger the expression of ENPP1, the later the FIGO stage and the poorer differentiation of cells (P = 0.001 or <0.001, respectively). However, no correlation was found between the expression of ENPP1 and chemosensitivity. ENPP1 was also highly expressed in ovarian cancer tissues and in epithelial ovarian cancer cell lines (A2780, CaoV3, OVCAR3, SKOV3 and 3ao). After down-regulation of ENPP1 expression by RNA interference, the cell proliferation, migration and invasion of ovarian cancer cell decreased significantly, the expression of apoptosis related gene caspase 3 increased significantly, while the expression of PCNA and MMP9 was significantly down regulated. In addition, EMT biological characteristics of A2780 and SKOV3 cells were also inhibited. In summary, the increased expression of ENPP1 may be related to the occurrence of HGSOC, and indicate that the disease progresses rapidly and the prognosis is poor. ENPP1 may be considered as a potential molecular therapeutic target.

Multiple Fetal Nutritional Patterns Before Parturition in Viviparous Fish Sebastes schlegelii (Hilgendorf, 1880)

Sebastes schlegeliiis a commercially important fish with a special viviparous reproductive system that is cultured in near-shore seawater net cages in East Asia. In the gonadal development of the species, the gonad of males mature before those of females, which mature after mating. Mating in male/female fishes occurs in October of each year. Then, females undergoing oocyte maturation complete fertilization using stored sperm in March of the following year. The pregnancy is completed when larvae are produced in the ovary. It has been reported that embryonic nutrient supply originates entirely from the female viviparous reproductive systems. However, until now, the nutritional patterns and the processes of nutrient provision inS. schlegeliibefore parturition have not been clear. The goal of this research was to study the embryos, larvae and juveniles ofS. schlegeliiduring pregnancy. Anatomical observations, light microscopy and scanning electron microscopy were used to study the developmental characteristics of early embryos and larvae and the connecting structures between the mother and the fetus. The results showed the following: (1) Placental-like structures were found during the process of embryonic development inS. schlegelii, and these placental-like structures proliferated after fertilization. (2) The embryos ofS. schlegeliiwere encased by a saclike structure composed of blood vessels, connective tissue, and surface epithelial cells. The vessels near the embryo existed in the thecal layer. Vascularized proliferation was detected following embryonic development. (3) Starting in the gastrula stage, connections between the embryo and surrounding cells loosened, and ovarian fluid became abundant. In addition, a large number of small holes and cristae were observed on the surface of the embryo. We speculate that embryos may be able to absorb nutrients from the ovarian fluid. (4) Yolk was present throughout embryo development. (5) Two types of nutritional modes were observed, lecithotrophic and matrotrophic during embryonic development. Three forms of placental analogs may exist inS. schlegelii: (1) external epithelial absorptive surfaces; (2) trophonemata, with modifications of the ovarian epithelia for absorbing the histotroph; and (3) a follicular pseudoplacenta, with close apposition between follicle cells and embryonic absorptive epithelia.

Sperm maturation, migration, and localization before and after copulation in black rockfish (Sebastes schlegelii)

Sebastes schlegelii is a typical viviparous teleost with six months sperm storage duration from November to April. In this study, spermatozoa morphological and physiological characteristics and sperm location in the female ovary were investigated by electron microscopy, computer-assisted sperm analyzer and histologic analysis, respectively. During copulation, we observed that spermatozoa in the testis had mature structure with rod-shaped head, a short midpiece, and a long flagellum. And further verified sperm swam freely at a high speed in the ovary fluid. After copulation, we only found swimming sperm in the ovary fluid at the early storage stage (November to December) and the majority of sperm were scattered randomly in the ovary cavity and partially concentrated in the crypt between the oocyte and stalk of follicle. Thereafter, the ovarian epithelium around the oocytes proliferated rapidly and wrapping spermatozoa outside of the follicular layer and formed a lot of crypts outside of the follicular layer which served as the sperm storage site until fertilization. The present findings would be useful for further understanding the mechanism of long-term sperm storage in viviparous teleost.

Meta-analysis identifying epithelial-derived transcriptomes predicts poor clinical outcome and immune infiltrations in ovarian cancer

&lt;abstract&gt; &lt;sec&gt;&lt;title&gt;Background&lt;/title&gt;&lt;p&gt;Previous studies revealed that the epithelial component is associated with the modulation of the ovarian tumor microenvironment (TME). However, the identification of key transcriptional signatures of laser capture microdissected human ovarian cancer epithelia remains lacking.&lt;/p&gt; &lt;/sec&gt; &lt;sec&gt;&lt;title&gt;Methods&lt;/title&gt;&lt;p&gt;We identified the differentially expressed transcriptional signatures of human ovarian cancer epithelia by meta-analysis of GSE14407, GSE2765, GSE38666, GSE40595, and GSE54388. Then we investigated the enrichment of KEGG pathways that are associated with epithelia-derived transcriptomes. Finally, we investigated the correlation of key epithelia-hub genes with the survival prognosis and immune infiltrations. Finally, we investigated the genetic alterations of key prognostic hub genes and their diagnostic efficacy in ovarian cancer epithelia.&lt;/p&gt; &lt;/sec&gt; &lt;sec&gt;&lt;title&gt;Results&lt;/title&gt;&lt;p&gt;We identified 1339 differentially expressed genes (DEGs) in ovarian cancer epithelia including 541upregulated and 798 downregulated genes. We identified 21 (such as E2F4, FOXM1, TFDP1, E2F1, and SIN3A) and 11 (such as JUN, DDX4, FOSL1, NOC2L, and HMGA1) master transcriptional regulators (MTRs) that are interacted with upregulated and the downregulated genes in ovarian tumor epithelium, respectively. The STRING-based analysis identified hub genes (such as &lt;italic&gt;CDK1, CCNB1, AURKA, CDC20,&lt;/italic&gt; and &lt;italic&gt;CCNA2&lt;/italic&gt;) in ovarian cancer epithelia. The significant clusters of identified hub genes are associated with the enrichment of KEGG pathways including cell cycle, DNA replication, cytokine-cytokine receptor interaction, pathways in cancer, and focal adhesion. The upregulation of &lt;italic&gt;SCNN1A&lt;/italic&gt; and &lt;italic&gt;CDCA3&lt;/italic&gt; and the downregulation of &lt;italic&gt;SOX6&lt;/italic&gt; are correlated with a shorter survival prognosis in ovarian cancer (OV). The expression level of &lt;italic&gt;SOX6&lt;/italic&gt; is negatively correlated with immune score and positively correlated with tumor purity in OV. Moreover, &lt;italic&gt;SOX6&lt;/italic&gt; is negatively correlated with the infiltration of TILs, CD8+ T cells, CD4+ Regulatory T cells, cytolytic activity, T cell activation, pDC, neutrophils, and macrophages in OV. Also, &lt;italic&gt;SOX6&lt;/italic&gt; is negatively correlated with various immune markers including &lt;italic&gt;CD8A, PRF1, GZMA, GZMB, NKG7, CCL3,&lt;/italic&gt; and &lt;italic&gt;CCL4,&lt;/italic&gt; indicating the immune regulatory efficiency of &lt;italic&gt;SOX6&lt;/italic&gt; in the TME of OV. Furthermore, &lt;italic&gt;SCNN1A, CDCA3,&lt;/italic&gt; and &lt;italic&gt;SOX6&lt;/italic&gt; genes are genetically altered in OV and the expression levels of &lt;italic&gt;SCNN1A&lt;/italic&gt; and &lt;italic&gt;SOX6&lt;/italic&gt; genes showed diagnostic efficacy in ovarian cancer epithelia.&lt;/p&gt; &lt;/sec&gt; &lt;sec&gt;&lt;title&gt;Conclusions&lt;/title&gt;&lt;p&gt;The identified ovarian cancer epithelial-derived key transcriptional signatures are significantly correlated with survival prognosis and immune infiltrations, and may provide new insight into the diagnosis and treatment of epithelial ovarian cancer.&lt;/p&gt; &lt;/sec&gt; &lt;/abstract&gt;

PAX8, an Emerging Player in Ovarian Cancer.

Ovarian Cancer is one of the most lethal and widespread gynecological malignancies. It is the seventh leading cause of all cancer deaths worldwide. High-Grade Serous Cancer (HGSC), the most commonly occurring subtype, alone contributes to 70% of all ovarian cancer deaths. This is mainly attributed to the complete lack of symptoms during the early stages of the disease and absence of an early diagnostic marker.PAX8 is emerging as an important histological marker for most of the epithelial ovarian cancers, as it is expressed in about 90% of malignant ovarian cancers, specifically in HGSC. PAX8 is a member of the Paired-Box gene family (PAX1-9) of transcription factors whose expression is tightly controlled temporally and spatially. The PAX genes are well known for their role in embryonic development and their expression continues to persist in some adult tissues. PAX8 is required for the normal development of Müllerian duct that includes Fallopian tube, uterus, cervix, and upper part of vagina. In adults, it is expressed in the Fallopian tube and uterine epithelium and not in the ovarian epithelium. Considering the recent studies that predict the events preceding the tumorigenesis of HGSC from the Fallopian tube, PAX8 appears to have an important role in the development of ovarian cancer.In this chapter, we review some of the published findings to highlight the significance of PAX8 as an important marker and an emerging player in the pathogenesis of ovarian cancer. We also discuss regardingthe future perspectives of PAX8wherein itcould contribute to the betterment of ovarian cancer diagnosis and treatment.