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Sex chromosome disorders severely compromise gametogenesis in both males and females. In oogenesis, the presence of an additional Y chromosome or the loss of an X chromosome disturbs the robust production of oocytes1-5. Here we efficiently converted the XY chromosome set to XX without an additional Y chromosome in mouse pluripotent stem (PS) cells. In addition, this chromosomal alteration successfully eradicated trisomy 16, a model of Down's syndrome, in PS cells. Artificially produced euploid XX PS cells differentiated into mature oocytes in culture with similar efficiency to native XX PS cells. Using this method, we differentiated induced pluripotent stem cells from the tail of a sexually mature male mouse into fully potent oocytes, which gave rise to offspring after fertilization. This study provides insights that could ameliorate infertility caused by sex chromosome or autosomal disorders, and opens the possibility of bipaternal reproduction.
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Engenharia Genética , Técnicas In Vitro , Oócitos , Cromossomo X , Animais , Feminino , Masculino , Camundongos , Oócitos/metabolismo , Oócitos/fisiologia , Cromossomo X/genética , Cromossomo Y/genética , Células-Tronco Pluripotentes/metabolismo , Síndrome de Down/genética , Síndrome de Down/terapia , Fertilização , Infertilidade/terapia , Homossexualidade Masculina , Transtornos dos Cromossomos Sexuais/complicações , Transtornos dos Cromossomos Sexuais/genética , Transtornos dos Cromossomos Sexuais/terapia , Engenharia Genética/métodosRESUMO
Meiosis is a key step during germ cell differentiation, accompanied by the activation of thousands of genes through germline-specific chromatin reorganization. The chromatin remodeling mechanisms underpinning early meiotic stages remain poorly understood. Here we focus on the function of one of the major autism genes, CHD8, in spermatogenesis, based on the epidemiological association between autism and low fertility rates. Specific ablation of Chd8 in germ cells results in gradual depletion of undifferentiated spermatogonia and the failure of meiotic double-strand break (DSB) formation, leading to meiotic prophase I arrest and cell death. Transcriptional analyses demonstrate that CHD8 is required for extensive activation of spermatogenic genes in spermatogonia, necessary for spermatogonial proliferation and meiosis. CHD8 directly binds and regulates genes crucial for meiosis, including H3K4me3 histone methyltransferase genes, meiotic cohesin genes, HORMA domain-containing genes, synaptonemal complex genes, and DNA damage response genes. We infer that CHD8 contributes to meiotic DSB formation and subsequent meiotic progression through combined regulation of these meiosis-related genes. Our study uncovers an essential role of CHD8 in the proliferation of undifferentiated spermatogonia and the successful progression of meiotic prophase I.
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Meiose , Espermatogônias , Masculino , Proliferação de Células/genética , Cromatina/genética , Cromatina/metabolismo , Meiose/genética , Espermatogênese/genética , Animais , CamundongosRESUMO
BHLHE40 is a basic helix-loop-helix transcription factor that is involved in multiple cell activities including differentiation, cell cycle, and epithelial-to-mesenchymal transition. While there is growing evidence to support the functions of BHLHE40 in energy metabolism, little is known about the mechanism. In this study, we found that BHLHE40 expression was downregulated in cases of endometrial cancer of higher grade and advanced disease. Knockdown of BHLHE40 in endometrial cancer cells resulted in suppressed oxygen consumption and enhanced extracellular acidification. Suppressed pyruvate dehydrogenase (PDH) activity and enhanced lactated dehydrogenase (LDH) activity were observed in the knockdown cells. Knockdown of BHLHE40 also led to dephosphorylation of AMPKα Thr172 and enhanced phosphorylation of pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) Ser293 and lactate dehydrogenase A (LDHA) Tyr10. These results suggested that BHLHE40 modulates PDH and LDH activity by regulating the phosphorylation status of PDHA1 and LDHA. We found that BHLHE40 enhanced AMPKα phosphorylation by directly suppressing the transcription of an AMPKα-specific phosphatase, PPM1F. Our immunohistochemical study showed that the expression of BHLHE40, PPM1F, and phosphorylated AMPKα correlated with the prognosis of endometrial cancer patients. Because AMPK is a central regulator of energy metabolism in cancer cells, targeting the BHLHE40âPPM1FâAMPK axis may represent a strategy to control cancer development.
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Proteínas Quinases Ativadas por AMP , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Neoplasias do Endométrio , Metabolismo Energético , Fosfoproteínas Fosfatases , Feminino , Humanos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/fisiopatologia , Metabolismo Energético/genética , Oxirredutases/genética , Oxirredutases/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Consumo de Oxigênio/genética , Regulação Neoplásica da Expressão Gênica/genética , Fosforilação/genéticaRESUMO
AIMS: p16 is a sensitive surrogate marker for transcriptionally active high-risk human papillomavirus (HR-HPV) infection in endocervical adenocarcinoma (ECA); however, its specificity is not perfect. METHODS AND RESULTS: We examined p16 and Rb expressions by immunohistochemistry (IHC) and the transcriptionally active HR-HPV infection by mRNA in-situ hybridisation (ISH) with histological review in 108 ECA cases. Thirteen adenocarcinomas of endometrial or equivocal origin (six endometrioid and seven serous carcinomas) were compared as the control group. HR-HPV was detected in 83 of 108 ECA cases (77%), including five HPV-associated adenocarcinomas in situ and 78 invasive HPV-associated adenocarcinomas. All 83 HPV-positive cases showed consistent morphology, p16 positivity and partial loss pattern of Rb. Among the 25 cases of HPV-independent adenocarcinoma, four (16%) were positive for p16, and of these four cases, three of 14 (21%) were gastric type adenocarcinomas and one of 10 (10%) was a clear cell type adenocarcinoma. All 25 HPV-independent adenocarcinomas showed preserved expression of Rb irrespective of the p16 status. Similarly, all 13 cases of the control group were negative for HR-HPV with preserved expression of Rb, even though six of 13 (46%) cases were positive for p16. Compared with p16 alone, the combination of p16 overexpression and Rb partial loss pattern showed equally excellent sensitivity (each 100%) and improved specificity (100 versus 73.6%) and positive predictive values (100 versus 89.2%) in the ECA and control groups. Furthermore, HR-HPV infection correlated with better prognosis among invasive ECAs. CONCLUSIONS: The results suggest that the combined use of p16 and Rb IHC could be a reliable method to predict HR-HPV infection in primary ECAs and mimics. This finding may contribute to prognostic prediction and therapeutic strategy.
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Adenocarcinoma , Biomarcadores Tumorais , Inibidor p16 de Quinase Dependente de Ciclina , Imuno-Histoquímica , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Humanos , Feminino , Infecções por Papillomavirus/complicações , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/diagnóstico , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Adenocarcinoma/virologia , Adenocarcinoma/patologia , Adenocarcinoma/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Pessoa de Meia-Idade , Adulto , Idoso , Proteína do Retinoblastoma/metabolismo , Hibridização In Situ , Papillomaviridae/genéticaRESUMO
BACKGROUND: We previously identified Il17RB, a member of the IL17 superfamily, as a candidate marker gene for endometrial aging. While IL17RB has been linked to inflammation and malignancies in several organ systems, its function in the endometrium has not been investigated and is thus poorly understood. In the present study, we performed a functional analysis of this receptor with the aim of determining the effects of its age-associated overexpression on the uterine environment. METHODS: We analyzed IL17RB-related signaling pathways and downstream gene expression in an immortalized human endometrial glandular epithelial cell line ("hEM") forced to express the receptor via lentiviral transduction ("IL17RB-hEM"). We also prepared endometrial organoids from human endometrial tissue sourced from hysterectomy patients ("patient-derived EOs") and exposed them to cytokines that are upregulated by IL17RB expression to investigate changes in organoid-forming capacity and senescence markers. We analyzed RNA-seq data (GEO accession number GSE132886) from our previous study to identify the signaling pathways associated with altered IL17RB expression. We also analyzed the effects of the JNK pathway on organoid-forming capacity. RESULTS: Stimulation with interleukin 17B enhanced the NF-κB pathway in IL17RB-hEM, resulting in significantly elevated expression of the genes encoding the senescence associated secretory phenotype (SASP) factors IL6, IL8, and IL1ß. Of these cytokines, IL1ß inhibited endometrial organoid growth. Bioinformatics analysis showed that the JNK signaling pathway was associated with age-related variation in IL17RB expression. When IL17RB-positive cells were cultured in the presence of IL17B, their organoid-forming capacity was slightly but non-significantly lower than in unexposed IL17RB-positive cells, but when IL17B was paired with a JNK inhibitor (SP600125), it was restored to control levels. Further, IL1ß exposure significantly reduced organoid-forming capacity and increased p21 expression in endometrial organoids relative to non-exposure (control), but when IL1ß was paired with SP600125, both indicators were restored to levels comparable to the control condition. CONCLUSIONS: We have revealed an association between IL17RB, whose expression increases in the endometrial glandular epithelium with advancing age, and cellular senescence. Using human endometrial organoids as in vitro model, we found that IL1ß inhibits cell proliferation and leads to endometrial senescence via the JNK pathway.
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Senescência Celular , Endométrio , Receptores de Interleucina-17 , Transdução de Sinais , Humanos , Feminino , Endométrio/metabolismo , Endométrio/citologia , Receptores de Interleucina-17/metabolismo , Receptores de Interleucina-17/genética , Senescência Celular/genética , Organoides/metabolismo , Linhagem CelularRESUMO
The administration of immune checkpoint inhibitors (ICIs) is increasing in endometrial cancer, especially in the mismatch repair (MMR)-deficient group. To prevent unnecessary immune-related adverse events, ICIs need to be administered to more appropriate patients. The tumor immune microenvironment has been reported to be a predictive marker of the efficacy of ICI therapies. This study evaluated CD8, FoxP3, CD68, PD-L1, and ß-catenin expression in endometrial endometrioid carcinoma, grade 1 (G1) with DNA mismatch repair protein loss (MMR loss), and their association with clinicopathological features. We retrospectively analyzed tumor samples from 107 patients with endometrial endometrioid carcinoma, G1 (MMR-deficient group: n=67; MMR-proficient group: n=40). Overall, 47 cases of MLH1/PMS2 loss and 20 cases of MSH2/MSH6 loss were observed. The patients with low intraepithelial CD8 expression significantly more frequently exhibited deep myometrial invasion, and the elderly group (≥60 y) significantly more frequently showed low stromal CD8 expression. In addition, FoxP3-positive cell count and FoxP3/CD8+ ratio were significantly correlated with the International Federation of Obstetrics and Gynecology 2023 stage and lymph node metastasis. In the Kaplan-Meier analysis, the patients with low intraepithelial or stromal CD8 expression had shorter progression-free survival (PFS) than those with high intraepithelial or stromal CD8 expression, albeit not significantly. We clarified that the tumor immune microenvironment had an impact on clinicopathological features within the group with MMR loss, which is the main target for ICIs, limited to endometrioid carcinoma, G1. Further studies are needed, including on patients administered ICIs.
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BACKGROUND: The influence of the coronavirus disease 2019 (COVID-19) pandemic on the number of newly diagnosed gynecological cancers has not been extensively investigated in Japan. This study determined the impact of COVID-19 on the incidence of gynecological cancer. METHODS: Using the Japanese Society of Obstetricians and Gynecologic Oncology registry database, the distribution of the number of patients based on clinical staging or tumor-node-metastasis classifications before and during the COVID-19 pandemic was analyzed to compare the trends. The clinical staging classification of cervical cancer in Japan was based on the International Federation of Gynecology and Obstetrics (FIGO) 2008 from 2018 to 2020 and on the FIGO 2018 from 2021. Since FIGO-2018 classified N1 cases as stage IIIC, we focused on T classification without referencing the clinical staging (FIGO staging) of patients with cervical cancer in 2021. RESULTS: The number of patients with endometrial cancer and malignant ovarian tumors of all clinical stages increased uniformly yearly, while that of those with stage III cervical cancer rapidly increased in 2021 owing to the adoption of the revised classification. On comparing cases of cervical cancer in 2020 and 2021, we found that T1 cases decreased and T2 and T3 cases increased in 2021 compared to those in 2020 (p = 0.006). Cervical intraepithelial neoplasia/adenocarcinoma in situ incidence decreased in 2020 compared to that in 2019 but increased again in 2021. The number of patients with cervical cancer decreased in most prefectures in 2020. CONCLUSION: The incidence of locally advanced cervical cancer increased during the COVID-19 pandemic.
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COVID-19 , Neoplasias do Colo do Útero , Feminino , Humanos , Estudos de Coortes , Estadiamento de Neoplasias , Neoplasias do Colo do Útero/patologia , Japão/epidemiologia , Pandemias , COVID-19/epidemiologia , COVID-19/patologiaRESUMO
A 25-year-old female Carney complex patient with a PRKAR1A mutation who had undergone surgery to remove teratomas visited our dermatology department. She was suspected of having a malignant melanoma in a teratoma. On clinical examination, a black nodule was found within the cyst. On histopathological examination, the black lesion was composed of heavily pigmented round cells with vesicular nuclei and single prominent nucleoli. Additionally, there were large cells with irregularly shaped nuclei. Upon immunohistochemical examination, the large, irregularly shaped cells were positively stained with Melan A, HMB45, S-100 protein, SOX10, CD10 (focally), and BRAFV600E , but negatively stained with PRAME. Based on the histopathological features, we diagnosed the patient with pigmented epithelioid melanocytoma (PEM) in a teratoma of a Carney complex patient. This is the first case of PEM developing from a teratoma. Since PEM lesions may spread to regional lymph nodes, careful follow-up is necessary.
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Complexo de Carney , Melanoma , Neoplasias Cutâneas , Teratoma , Feminino , Humanos , Adulto , Complexo de Carney/diagnóstico , Neoplasias Cutâneas/patologia , Mutação , Teratoma/diagnóstico , Antígenos de NeoplasiasRESUMO
AIM: The aim of this study was to determine the level of awareness of sexual reproductive health and rights (SRHR) among the members of the Japan Society of Obstetrics and Gynecology (JSOG) and identify what the JSOG should do to address SRHR issues. METHODS: A survey questionnaire on JSOG members' awareness of SRHR and what the JSOG should address regarding SRHR was administered in 2019 and 2023. Changes in awareness and the issues that should be addressed from the first to the second survey were evaluated. RESULTS: Seven hundred twelve members responded to the first survey and 506 to the second. Response rates were 4.2% and 2.9%, respectively. There was a significant increase in the number of respondents in the second survey who were aware of sexual reproductive health (SRH) and Sustainable Development Goals (SDGs) compared with the first survey (SRH: 72.6%-86.4%; SDGs: 33.8%-86.4%). Most respondents agreed that SRHR should be promoted. In the first survey, cervical cancer was the most important issue, followed by women's right to self-determination and family planning/contraception. In the second survey, women's right to self-determination was the most important issue. Several free responses highlighted the importance of comprehensive sexuality education as a significant concern for SRHR. CONCLUSION: Between 2019 and 2023, the level of awareness of SRHR among JSOG members increased. The identification of SRHR issues that should be addressed by the JSOG was confirmed. The JSOG and individual obstetricians and gynecologists are responsible for being involved in achieving SRHR.
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The emergence of the placenta is a revolutionary event in the evolution of therian mammals, to which some LTR retroelement-derived genes, such as PEG10, RTL1, and syncytin, are known to contribute. However, therian genomes contain many more LTR retroelement-derived genes that may also have contributed to placental evolution. We conducted large-scale evolutionary genomic and transcriptomic analyses to comprehensively search for LTR retroelement-derived genes whose origination coincided with therian placental emergence and that became consistently expressed in therian placentae. We identified NYNRIN as another Ty3/Gypsy LTR retroelement-derived gene likely to contribute to placental emergence in the therian stem lineage. NYNRIN knockdown inhibited the invasion of HTR8/SVneo invasive-type trophoblasts, whereas the knockdown of its nonretroelement-derived homolog KHNYN did not. Functional enrichment analyses suggested that NYNRIN modulates trophoblast invasion by regulating epithelial-mesenchymal transition and extracellular matrix remodeling and that the ubiquitin-proteasome system is responsible for the functional differences between NYNRIN and KHNYN. These findings extend our knowledge of the roles of LTR retroelement-derived genes in the evolution of therian mammals.
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Placenta , Retroelementos , Animais , Feminino , Genoma , Mamíferos/genética , Gravidez , Retroelementos/genética , TrofoblastosRESUMO
Indocyanine green (ICG) with near-infrared (NIR) fluorescence imaging is used for lymphatic mapping. However, binding of ICG to blood proteins like serum albumin can shorten its retention time in sentinel lymph nodes (SLNs). Here, we investigated the efficacy and safety of a new fluorescence tracer comprising phytate and liposome (LP)-encapsulated ICG. Coadministration of phytate with LP containing phosphatidic acid promotes chelation mediated by Ca2+ in bodily fluids to enhance SLN retention. Uniformly sized LPs (100 nm) encapsulating ICG under conditions that minimized fluorescence self-quenching during storage were produced. We analyzed the behavior of the new tracer (ICG-phytate-LP) and control tracers (ICG and ICG-LP) in the lymphatic flow of mice in terms of lymph node retention time. We also tested lymphatic flow and safety in pigs that have a more human-like lymphatic system. LPs encapsulating stabilized ICG were successfully prepared. Mixing LP with phytate in the presence of Ca2+ increased both the particle size and negative surface charge. In mice, ICG-phytate-LP had the best lymph node retention, with a fluorescence intensity ratio that increased over 6 h and then decreased slowly over the next 24 h. In pigs, administration of ICG and ICG-phytate-LP resulted in no death or weight loss. There were no obvious differences between blood test results for the ICG and ICG-phytate-LP groups, and the overall safety was good. ICG-phytate-LP may be a useful new tracer for gynecological cancers that require time for lymph node identification due to a retroperitoneal approach.
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Linfonodo Sentinela , Neoplasias do Colo do Útero , Feminino , Camundongos , Humanos , Suínos , Animais , Linfonodo Sentinela/diagnóstico por imagem , Linfonodo Sentinela/patologia , Biópsia de Linfonodo Sentinela/métodos , Neoplasias do Colo do Útero/patologia , Ácido Fítico , Lipopolissacarídeos , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Verde de IndocianinaRESUMO
BACKGROUND: Tracking gestational weight gain (GWG) during pregnancy makes it possible to optimize pregnancy outcomes, and GWG growth curves are well suitable for this purpose. The GWG guidelines for Japanese were revised in 2021. However, currently, there are no GWG growth curves to guide women on how to gain weight to meet these guidelines. METHODS: Using data on 96,631 live births from the Japan Environment and Children's Study (JECS), we created descriptive GWG percentile curves estimating the trajectory of GWG required to meet the GWG guidelines stratified by pre-pregnancy body mass index (BMI). For both analyses, Bayesian mixed models with restricted cubic splines adjusted for maternal characteristics were used. RESULTS: GWG curves substantially differed by pre-pregnancy BMI and were higher among multiparas and those with lower maternal age and with no previous disease. We estimated that underweight, normal weight, overweight, and obese women who gain 8.4 to 11.1 kg, 6.4 to 9.1 kg, 3.8 to 6.5 kg, and <1.9 kg at 30 weeks of gestation are on the trajectory to reach the new guidelines at 40 weeks of gestation. CONCLUSION: We provide GWG percentiles curves for Japanese women, as well as GWG trajectory curves to meet the new GWG recommendations. These results may help pregnant women monitor weight during pregnancy.
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Ganho de Peso na Gestação , Feminino , Humanos , Gravidez , Teorema de Bayes , Índice de Massa Corporal , População do Leste Asiático , Gráficos de Crescimento , Japão , Estudos Longitudinais , Sobrepeso , Resultado da Gravidez , Fatores de Risco , Aumento de Peso , Valores de ReferênciaRESUMO
A set of sex chromosomes is required for gametogenesis in both males and females, as represented by sex chromosome disorders causing agametic phenotypes. Although studies using model animals have investigated the functional requirement of sex chromosomes, involvement of these chromosomes in gametogenesis remains elusive. Here, we elicit a germ cell-intrinsic effect of sex chromosomes on oogenesis, using a novel culture system in which oocytes were induced from embryonic stem cells (ESCs) harboring XX, XO or XY. In the culture system, oogenesis using XO and XY ESCs was severely disturbed, with XY ESCs being more strongly affected. The culture system revealed multiple defects in the oogenesis of XO and XY ESCs, such as delayed meiotic entry and progression, and mispairing of the homologous chromosomes. Interestingly, Eif2s3y, a Y-linked gene that promotes proliferation of spermatogonia, had an inhibitory effect on oogenesis. This led us to the concept that male and female gametogenesis appear to be in mutual conflict at an early stage. This study provides a deeper understanding of oogenesis under a sex-reversal condition.
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Células Germinativas/metabolismo , Oócitos/metabolismo , Cromossomo X , Cromossomo Y , Animais , Diferenciação Celular/fisiologia , Células-Tronco Embrionárias/metabolismo , Feminino , Células Germinativas/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Endogâmicos , Oócitos/citologia , Oócitos/ultraestrutura , OogêneseRESUMO
As 2 years have passed since the outbreak of coronavirus disease 2019 (COVID-19), we had an examination of the measures taken at the perinatal medical and child centers during this period at 42 National University Hospital. The first questionnaire survey was conducted during March 17-25, 2022 and the second questionnaire survey was conducted during April 4-30, 2022. For the treatment of pregnant women with COVID-19, a public health center-coordinated triage system had been created and implemented in each region and prefecture. The issues related to the hospital management of pregnant women with COVID-19 include the hindrances to the normal functioning of the center, the limited number of hospital beds and medical care systems as the beds were dedicated to patients with COVID-19, and the problems associated with the mode of delivery. There were no set rules regarding the management of mothers and babies at delivery and thereafter. Initially, cesarean delivery was allowed in almost all cases to reduce the risk of exposure to medical staff. Furthermore, many institutions did not permit expressed breast milk feeding and direct breastfeeding during the quarantine period. The COVID-19 pandemic has been created a shortage of healthcare delivery systems. It is expected that the emergence of new infectious diseases and pandemics will cause the same pressure on systems providing healthcare in the future.
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COVID-19 , Complicações Infecciosas na Gravidez , Feminino , Humanos , Gravidez , Hospitais , Pandemias , Complicações Infecciosas na Gravidez/terapia , Gestantes , SARS-CoV-2 , Recém-NascidoRESUMO
OBJECTIVE: To analyze the effects of in-person attendance at an academic conference held during the Covid-19 pandemic on the health of the attendees, as assessed based on symptoms such as fever and cough attributed to infection with the Covid-19 virus. METHODS: A questionnaire was used to survey the members of the Japan Society of Obstetrics and Gynecology (JSOG) about their health during the period from August 7 to August 12, 2022, after the 74th Annual Congress of the JSOG, which was held August 5 to 7. RESULTS: Our survey yielded responses from 3054 members (1566 of whom had attended the congress in person and 1488 of whom had not attended in person); 102 (6.5%) of the in-person attendees and 93 (6.2%) of the people who did not attend in person reported problems with their health. No statistically significant difference was found between these two groups (p = 0.766). In a univariate analysis of factors affecting the presence of health problems, attendees with age ≥60 years had significantly fewer health problems than attendees who were in their 20s (odds ratio: 0.366 [0.167-0.802; p = 0.0120]). In a multivariate analysis, attendees who had received four vaccine shots had significantly fewer health problems than attendees who had received three shots (odds ratio: 0.397 [0.229-0.690, p = 0.0010]). CONCLUSION: Congress attendees who took precautions at the congress to avoid being infected and who had a high vaccination rate did not develop significantly more health problems associated with in-person attendance at the congress.
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COVID-19 , Feminino , Humanos , Pessoa de Meia-Idade , Gravidez , Razão de Chances , Pandemias , SARS-CoV-2 , Inquéritos e Questionários , Congressos como AssuntoRESUMO
INTRODUCTION: The prognostic significance of lymphovascular space invasion (LVSI) in stage IA endometrial cancer remains unclear. The aim of this study was to evaluate the clinical significance of LVSI in stage IA endometrial cancer. METHODS: Clinical data of patients with stage IA endometrial cancer who underwent initial surgery at our institution between January 2008 and December 2018 were reviewed retrospectively. Information of patients, surgery, and characteristics of cancer were obtained from medical records and pathological reports. RESULTS: Two hundred ninety-seven patients were enrolled in this study. With a median follow-up of 60 months, 15 patients experienced recurrence (5.1%) and 4 patients died of endometrial cancer (1.3%). The recurrence and mortality rates did not differ significantly between the LVSI-positive and -negative groups (p = 0.07 and p = 0.41, respectively). Recurrence-free survival and endometrial cancer-specific survival also did not differ significantly between these groups (p = 0.11 and p = 0.49, respectively). The 5-year endometrial cancer-specific survival rates for tumors with and without LVSI were 97.0% and 98.9%, respectively. Among patients with low-grade tumors, recurrence-free survival and endometrial cancer-specific survival did not differ significantly between patients with tumors with and without LVSI (p = 0.92 and p = 0.72, respectively). The 5-year endometrial cancer-specific survival rates for low-grade tumors with and without LVSI were 100% and 99.3%, respectively. CONCLUSION: LVSI was not a prognostic factor of not only stage IA endometrial cancer but also stage IA low-grade cancer.
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Carcinoma Endometrioide , Neoplasias do Endométrio , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
OBJECTIVE: Sentinel node biopsy alone (SNB) reduces the postoperative complications of pelvic lymphadenectomy, such as lymphedema and lymphangitis; however, the long-term prognosis after SNB is unclear. The objective of this study was to evaluate the long-term outcome and complications of patients with early-stage cervical cancer who underwent SNB for hysterectomy or trachelectomy. METHODS: We performed SNB for cervical cancer using a radioisotope method in 181 patients between 2009 and 2017. If the intraoperative sentinel lymph node evaluation was negative for metastasis, no further lymph nodes were removed. RESULTS: The median age of the patients was 34 years (range, 21-73 years). The International Federation of Gynecology and Obstetrics 2008 stage was IA1 in 6 patients, IA2 in 18, IB1 in 154, and IIA1 in 3. Of the 181 patients (44 with hysterectomy, 137 with trachelectomy), 8 did not undergo pelvic lymphadenectomy because of a false-negative intraoperative diagnosis, 20 received adjuvant therapy after surgery, and 4 (2.2%) experienced recurrence over a median follow-up period of 83.5 months (range, 25-145 months). In the four recurrent cases, recurrence occurred in the pelvis, lung, and bone in one patient each, while the remaining patient developed pelvic and para-aortic lymph node metastases. Of these four patients, one died, and the remaining three are alive without disease after multidisciplinary therapy. The 5-year progression-free and overall survival rates were 98.8% and 99.4%, respectively. Postoperative complications, such as lymphedema, were very low rate. CONCLUSIONS: SNB for early-stage cervical cancer might be safe and effective, with no increase in the recurrence and postoperative complications rate.
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Linfedema , Neoplasias do Colo do Útero , Adulto , Idoso , Feminino , Seguimentos , Humanos , Histerectomia/métodos , Excisão de Linfonodo/efeitos adversos , Linfonodos/patologia , Linfonodos/cirurgia , Linfedema/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Complicações Pós-Operatórias/patologia , Estudos Retrospectivos , Biópsia de Linfonodo Sentinela/efeitos adversos , Biópsia de Linfonodo Sentinela/métodos , Neoplasias do Colo do Útero/patologia , Adulto JovemRESUMO
The pathogenesis of hypertensive disorder of pregnancy (HDP), which affects about 10% of pregnant women, is still incompletely understood. Our previous study showed that endoplasmic reticulum (ER) stress influences high-temperature requirement A serine peptidase 1 (HTRA1) expression and trophoblast invasion. However, the involvement of ER stress in the regulation of HTRA subtype expression and pathophysiology of HDP has not been characterized in extravillous trophoblasts (EVTs). To investigate this, HTR8/SVneo EVTs cell line was treated with the ER stress inducers Thapsigargin (Thap) or Tunicamycin (Tuni). Treatment with either Thap or Tuni inhibited trophoblast invasion, reduced HTRA1 and HTRA3 expression, but did not alter HTRA2 or HTRA4 expression. Knockdown of HTRA1 or HTRA3 also inhibited trophoblast invasion. Furthermore, treatment with either ER stress inducer or HTRA1 silencing increased the ratio of soluble fms-like tyrosine kinase-1/placental growth factor (sFLT1/PlGF), which is a marker of HDP. Immunohistochemical analysis revealed that HTRA1 is localized to EVTs and the endometrial decidua in the placenta of patients with HDP. These results suggest that factors that cause ER stress could result in the inhibition of EVTs invasion via HTRA1.
Assuntos
Trofoblastos , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Humanos , Feminino , Gravidez , Trofoblastos/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Estresse do Retículo Endoplasmático/genética , Temperatura , Fator de Crescimento Placentário , Placenta/química , Placenta/metabolismo , Movimento Celular/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/análise , Serina Endopeptidases/metabolismo , Serina Proteases/genética , Serina Proteases/metabolismoRESUMO
DNA double-strand breaks (DSBs) are deleterious lesions that lead to genetic mutations and cell death. Protein ubiquitination mediated by the E3 ubiquitin ligase RNF8 within the regions surrounding DSBs recruits DNA DSB response (DDR) factors and induces chromatin remodeling, which supports cell survival after DNA damage. Nevertheless, the impact of RNF8-mediated ubiquitination on DNA repair remains to be elucidated. Here, we report that depletion of the deubiquitinating enzyme OTUB2 enhances RNF8-mediated ubiquitination in an early phase of the DDR and promotes faster DSB repair but suppresses homologous recombination. The rapid ubiquitination results in accelerated accumulation of 53BP1 and RAP80 at DSBs, which in turn protects DSB ends from resection in OTUB2-depleted cells. Mechanistically, OTUB2 suppresses RNF8-mediated L3MBTL1 ubiquitination and Lys 63-linked ubiquitin chain formation in a deubiquitinating activity-dependent manner. Thus, OTUB2 fine-tunes the speed of DSB-induced ubiquitination so that the appropriate DNA repair pathway is chosen.
Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA , Tioléster Hidrolases/química , Proteínas de Transporte/metabolismo , Morte Celular , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/química , Biblioteca Gênica , Inativação Gênica , Células HeLa , Chaperonas de Histonas , Histonas/química , Recombinação Homóloga , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lisina/química , Mutação , Proteínas Nucleares/metabolismo , Plasmídeos/metabolismo , RNA Interferente Pequeno/metabolismo , Recombinação Genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53 , Ubiquitina/química , Ubiquitina-Proteína LigasesRESUMO
BACKGROUND: Women with nausea and vomiting of pregnancy (NVP) have higher birth weight infants, while those with hyperemesis gravidarum, a severe manifestation of NVP, have lower birth weight infants. We aimed to investigate the associations between maternal weight loss (a consequence of hyperemesis gravidarum), NVP, and infant birth weight. METHODS: This study was a secondary analysis of a nationwide birth cohort in Japan. Singleton pregnancies delivered at 28-41 weeks of gestation were included in the analysis. Women were categorized based on their weight change in the 1st trimester (as a proportion to their pre-pregnancy weight: > + 3%, > 0 to + 3%, > -3 to 0%, > -5 to -3%, ≤ -5%) and severity of NVP (no nausea, only nausea, vomiting but able to eat, vomiting and unable to eat). The effects of weight change and severity of NVP on infant birth weight and small for gestational age (SGA) were assessed using regression models. We further examined how these effects could be modified by maternal weight gain up to the 2nd trimester. RESULTS: Among 91,313 women, 5,196 (5.7%) lost ≥ 5% of their pre-pregnancy weight and 9,983 (10.9%) experienced vomiting and were unable to eat in the 1st trimester. Women with weight loss ≥ 5% in the 1st trimester had infants 66 (95% CI: 53, 78) g lighter and higher odds of SGA (aOR: 1.29; 95% CI: 1.14, 1.47) than women who gained > 3% during the same period. However, when adjusting for weight gain up to the 2nd trimester, women with weight loss ≥ 5% in the 1st trimester had infants 150 (95% CI: 135, 165) g heavier and lower odds of SGA (aOR: 0.39; 95% CI: 0.33, 0.46) than those who gained > 3% during the same period. In contrast, women with more severe NVP tended to have infants with larger birth weight and lower odds of SGA compared to women without NVP. These trends were strengthened when adjusting for weight gain up to the 2nd trimester. CONCLUSIONS: Our study suggests the possibility that reduced fetal growth in pregnancies with hyperemesis gravidarum may be caused by the lack of catch-up in gestational weight gain up to the 2nd trimester.