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Frontiers in Immunology 2022Tissue-resident macrophages (TRMs) are highly heterogeneous and have a complex and important role in tissue support, homeostasis, and function. The heterogeneity,...
INTRODUCTION
Tissue-resident macrophages (TRMs) are highly heterogeneous and have a complex and important role in tissue support, homeostasis, and function. The heterogeneity, maintenance, and function of TRMs, as one of the major immune cells in the ovary, are not well understood.
METHODS
Application of flow cytometry, Parabiosis, Fate mapping, Macrophage depletion, etc.
RESULTS
Here, we described two distinct macrophage subsets, F4/80CD11b and F4/80CD11b, with different phenotypic characteristics in the ovary of mice. The F4/80CD11b population contained a distinct CD206 subgroup and highly expressed CD81, while the F4/80CD11b subset showed higher expression of CCR2 and TLR2. Notably, Ly6c macrophages were present almost exclusively in the F4/80CD11b subpopulation. Combining in vivo fate mapping and parabiotic mouse models, we characterized the longevity and replenishment of the two macrophage populations. We found that both the F4/80CD11b and F4/80CD11b subsets were ovary-resident. Importantly, the F4/80CD11b macrophages acted as a self-maintaining and long-lived population with a modest monocyte contribution at a steady state, and the F4/80CD11b subpopulation had a relatively short lifespan with a greater contribution from monocytes. After macrophage ablation, disturbance of estradiol secretion and ovarian hemorrhage due to damaged vascular integrity was observed in mice.
DISCUSSION
Our data provide critical insights into ovarian macrophage heterogeneity and highlight the strategic role of TRMs in ovarian homeostasis and physiology.
Topics: Female; Mice; Animals; Ovary; Macrophages; Monocytes; Disease Models, Animal
PubMed: 36605192
DOI: 10.3389/fimmu.2022.1007711 -
Reproductive Biology and Endocrinology... Jun 2023It has been hypothesized that the origin of early-onset endometriosis could be from endometrial mesenchymal stem cells (eMSCs) in neonatal uterine blood (NUB). There is...
BACKGROUND
It has been hypothesized that the origin of early-onset endometriosis could be from endometrial mesenchymal stem cells (eMSCs) in neonatal uterine blood (NUB). There is no information on the possible mechanistic basis linking an association between NUB/neonatal endometrium and development of early-onset endometriosis. In this study we performed a series of experiments to clarify the mechanistic link between NUB and/or neonatal endometrium and development of early-onset endometriosis.
METHODS
We retrospectively collected postmortem neonatal endometria (n = 15) and prospectively collected NUB (n = 18) of female babies for the analysis of different biological markers including eMSCs. Immunohistochemical analysis of neonatal endometria was performed to examine the expression patterns of ovarian steroid receptors (ER/PGR), decidualization (prolactin, IGFBP1), pre-decidualization (Glycodelin A, α-SMA), proliferation (Ki-67 index), vascularity (CD31 + cells), immunocompetent CD68+, CD45+, CD56 + cells and some putative markers of eMSCs. Cell transfer method and immunocytochemistry were used to investigate the eMSCs and/or endometrial cells in NUB.
RESULTS
Immunohistochemical analysis of postmortem neonatal endometria revealed variable staining response to ER/PGR, decidual markers, and substantial proliferative and angiogenic activity. A moderate to strong immunoexpression of Glycodelin-A was found in both neonatal and adult endometria. The tissue infiltration of CD56+, CD45 + and CD68 + immunocompetent cells was significantly low in neonatal endometria than that in adult endometria (p = 0.0003, p < 0.0001, p = 0.034, respectively). No eMSCs or even endometrial cells were detected in NUB. However, a variable expression of some phenotypes of eMSCs (CD90/CD105) was found in neonatal endometria.
CONCLUSIONS
Based on our serial experiments we did not find any supporting evidence for the role of NUB in early-onset endometriosis. Neonatal endometria showed variable expression of ovarian steroid receptors, decidualization, and a substantial amount of proliferative and angiogenic activity. As an alternative mechanism, a significantly less tissue accumulation of immunocompetent cells in neonatal endometria may explain the survival of ER + and PGR + cells should they make entry into the pelvis and consequent development of early endometriosis with the onset of ovarian function. Future study with large sample size and application of modified technological tools is warranted to test the NUB hypothesis and to clarify their biological or clinical significance.
TRIAL REGISTRATION
not applicable.
Topics: Humans; Female; Endometriosis; Retrospective Studies; Glycodelin; Endometrium; Uterine Hemorrhage
PubMed: 37337237
DOI: 10.1186/s12958-023-01099-1 -
BMC Medical Genomics Sep 2023The most prevalent mutation in ovarian cancer is the TP53 mutation, which impacts the development and prognosis of the disease. We looked at how the TP53 mutation...
BACKGROUND
The most prevalent mutation in ovarian cancer is the TP53 mutation, which impacts the development and prognosis of the disease. We looked at how the TP53 mutation associates the immunophenotype of ovarian cancer and the prognosis of the disease.
METHODS
We investigated the state of TP53 mutations and expression profiles in culturally diverse groups and datasets and developed an immune infiltration predictive model relying on immune-associated genes differently expressed between TP53 WT and TP53 MUT ovarian cancer cases. We aimed to construct an immune infiltration predictive model (IPM) to enhance the prognosis of ovarian cancer and investigate the impact of the IPM on the immunological microenvironment.
RESULTS
TP53 mutagenesis affected the expression of seventy-seven immune response-associated genes. An IPM was implemented and evaluated on ovarian cancer patients to distinguish individuals with low- and high-IPM subgroups of poor survival. For diagnostic and therapeutic use, a nomogram is thus created. According to pathway enrichment analysis, the pathways of the human immune response and immune function abnormalities were the most associated functions and pathways with the IPM genes. Furthermore, patients in the high-risk group showed low proportions of macrophages M1, activated NK cells, CD8 T cells, and higher CTLA-4, PD-1, PD-L1, and TIM-3 than patients in the low-risk group.
CONCLUSIONS
The IPM model may identify high-risk patients and integrate other clinical parameters to predict their overall survival, suggesting it is a potential methodology for optimizing ovarian cancer prognosis.
Topics: Humans; Female; CD8-Positive T-Lymphocytes; Ovarian Neoplasms; Mutation; Killer Cells, Natural; Macrophages; Tumor Microenvironment
PubMed: 37759229
DOI: 10.1186/s12920-023-01657-x -
Frontiers in Bioscience (Elite Edition) Jan 2011Endometriosis affects an estimated 10% of women in the reproductive-age group. Here, we review current knowledge on molecular genesis of endometriosis-associated... (Review)
Review
Endometriosis affects an estimated 10% of women in the reproductive-age group. Here, we review current knowledge on molecular genesis of endometriosis-associated epithelial ovarian carcinoma (EOC). This article reviews the English language literature for biology, pathogenesis, and pathophysiological studies on endometriosis-associated EOC. Although endometriosis generally remains a benign condition, it demonstrates somatically acquired genetic alterations. Clear cell carcinoma (CCC) and endometrioid adenocarcinoma (EAC) are the most frequent types of EOC associated with endometriosis. Retrograde menstruation or ovarian hemorrhage carries highly pro-oxidant factors, such as iron, into the peritoneal cavity or ovarian endometrioma. CCC and EAC should be considered separately in studies of endometriosis-associated EOC. The repeated events of hemorrhage in endometriosis can contribute to carcinogenesis and progression via 3 major processes: 1) increasing oxidative stress promotes DNA methylation; 2) activating anti-apoptotic pathways supports tumor promotion; and 3) aberrant expression of stress signaling pathways contributes to tumor progression. This review summarizes recent advances in the understanding of epidemiology, carcinogenesis, pathogenesis, and pathophysiology of endometriosis-associated EOC; and a possible novel model is proposed.
Topics: Carcinoma; DNA Methylation; Endometriosis; Female; Genes, Wilms Tumor; Genes, ras; Hemorrhage; Hepatocyte Nuclear Factor 1; Humans; Loss of Heterozygosity; Microsatellite Repeats; Molecular Biology; Ovarian Neoplasms; Oxidative Stress; PTEN Phosphohydrolase; Receptors, Estrogen; Risk Factors; Signal Transduction; Stress, Physiological
PubMed: 21196332
DOI: 10.2741/e267 -
Journal of Ovarian Research May 2019Prognostic biomarkers are highly needed to properly manage patients with cancer and improve their clinical courses. The relationship between lymphocyte-to-monocyte ratio... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Prognostic biomarkers are highly needed to properly manage patients with cancer and improve their clinical courses. The relationship between lymphocyte-to-monocyte ratio (LMR) at diagnosis and ovarian cancer prognosis has been extensively studied, but little consensus has been reached regarding its utility as a biomarker of poor outcome. Thus, this study aimed to investigate the potential prognostic value of pretreatment LMR in such patients to shed light on this issue.
METHODS
We searched the scientific databases of MEDLINE, Embase, Cochrane Library, and WangFang for relevant studies about the inflammatory prognostic factor LMR in ovarian cancer, based on specific inclusion and exclusion criteria. The following parameters were analyzed among others: LMR values and respective cut-offs, patient's overall survival (OS) and progression-free survival (PFS), and clinicopathological features.
RESULTS
Eight studies, including 2259 patients, were eligible for inclusion in this meta-analysis. We found that low LMR was associated with both poor OS [Hazard ratio (HR): 1.92; 95% confidence interval (CI): 1.58-2.34; p < 0.001] and PFS (HR: 1.70; 95% CI: 1.54-1.88; p < 0.001). Moreover, our findings revealed that low LMR was correlated with high G2/G3 histological grade (OR: 1.67; 95% CI: 1.26-2.20; p < 0.001) and late III-IV FIGO stage tumors (OR: 3.55; 95% CI: 2.68-4.70; p < 0.001), high serum CA-125 level (OR: 2.18; 95% CI: 1.71-2.77; p < 0.001), and presence of malignant ascites (OR: 1.87; 95% CI: 1.11-3.14; p = 0.02) and lymph node metastases (OR: 1.70; 95% CI: 1.13-2.54; p = 0.01).
CONCLUSION
Pretreatment LMR is a potential prognostic marker of poor outcome in ovarian cancer patients and may thus be important in clinical care and disease control.
Topics: Biomarkers, Tumor; Female; Humans; Leukocyte Count; Lymphocytes; Monocytes; Ovarian Neoplasms; Prognosis; Progression-Free Survival; Survival Rate
PubMed: 31151469
DOI: 10.1186/s13048-019-0527-z -
International Journal of Molecular... Jun 2019Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies. Despite surgery and chemotherapy, 5-years survival rates have improved... (Review)
Review
Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies. Despite surgery and chemotherapy, 5-years survival rates have improved only modestly over the past few decades remaining at 45% for advanced stages. Therefore, novel therapies are urgently needed. The presence of tumor-infiltrating lymphocytes (TILs) in OC tumor microenvironment (TME) has already proved to be correlated with overall survival (OS), while immune evasion mechanisms are associated with poor prognosis. Although these data indicate that immunotherapy has a strong rationale in OC, single agent immune-checkpoints inhibitors (ICIs) have shown only modest results in this malignancy. In this review, we will discuss immune-targeting combination therapies and adoptive cell therapy (ACT), highlighting the challenges represented by these strategies, which aim at disrupting the stroma-tumor barrier to boost immune system against ovarian cancer.
Topics: Animals; Antineoplastic Agents, Immunological; Biomarkers, Tumor; Clinical Trials as Topic; Combined Modality Therapy; Female; Humans; Immunotherapy; Immunotherapy, Adoptive; Lymphocytes, Tumor-Infiltrating; Molecular Targeted Therapy; Ovarian Neoplasms; T-Lymphocyte Subsets; Tumor Microenvironment
PubMed: 31208030
DOI: 10.3390/ijms20122927 -
Journal of Ovarian Research Apr 2022To investigate the alterations of peripheral lymphocyte subpopulations in ovarian cancer patients compared to benign or borderline counterparts. The possible...
BACKGROUND
To investigate the alterations of peripheral lymphocyte subpopulations in ovarian cancer patients compared to benign or borderline counterparts. The possible clinicopathological implications were also evaluated.
METHODS
We enrolled 112 treatment-naive ovarian cancer patients, 14 borderline tumor patients and 44 benign tumor patients between 09/2016 and 01/2019. Flow cytometry was used to measure the peripheral lymphocyte subsets consisting of T cells (CD3, CD3CD4, CD3CD8 and CD8CD28), regulatory T cells (Tregs, CD4CD25CD127), natural killer cells (NK cells, CD3CD56) and B cells (CD19).
RESULTS
Most ovarian cancer patients were high-grade serous carcinoma (84.8%), followed by clear cell carcinoma (8.03%). Late-stage tumor (FIGO III + IV) accounted for 82.1%. The study showed that the proportions of peripheral lymphocyte subsets underwent apparent changes in ovarian cancer patients. We observed elevated levels of Treg cells in patients with both ovarian borderline and malignant tumor compared to those with benign tumors, which achieved statistic significance. In contrast, CD3CD8 T and CD8CD28 T cells were significantly lower in ovarian cancer patients. Interestingly, low level of B cells was correlated to clear cell carcinoma (P = 0.024), advanced tumor (P = 0.028) and platinum-resistant recurrence (P = 0.014). Regarding the changes of lymphocyte subsets after surgery, CD8CD28 T cells had a significant decreasing tendency (P = 0.007) while B cells were the opposite (P < 0.001).
CONCLUSIONS
Ovarian cancer patients have altered circulating lymphocyte profile (elevated Treg cell, depressed CD3CD8 T and CD8CD28 T cells). Low level of B cells might be related to disease aggressiveness, and it recovered after the removal of tumor, which merits further study.
Topics: CD28 Antigens; CD8-Positive T-Lymphocytes; Carcinoma, Ovarian Epithelial; Female; Flow Cytometry; Humans; Killer Cells, Natural; Lymphocyte Count; Lymphocyte Subsets; Ovarian Neoplasms
PubMed: 35410290
DOI: 10.1186/s13048-022-00977-3 -
Annals of the New York Academy of... Jun 1997Dysfunctional uterine bleeding (DUB) is a frequent gynecological problem during adolescence and the most frequent cause of urgent admission to the hospital over this... (Review)
Review
Dysfunctional uterine bleeding (DUB) is a frequent gynecological problem during adolescence and the most frequent cause of urgent admission to the hospital over this period of life. In about 95% of cases it is caused by the late maturation of the hypothalamic-pituitary-ovarian axis (HPO), leading to anovulatory cycles. These adolescents lack the E2 positive feedback on LH. Thus, the continuous production of estrogen with endometrial stimulation is the basic cause of dysfunctional uterine bleeding. The initial step in the evaluation of DUB includes detailed clinical history, followed by complete physical examination. Laboratory tests should include coagulation profile, complete blood count with platelet evaluation, and sometimes a serum pregnancy test. The treatment of DUB is related to the severity of symptomatology with the objective of stopping bleeding and preventing recurrences. Modern hormonal and other medical therapies enable physicians to treat DUB effectively, regardless of the cause. Surgical treatment, such as dilatation and curettage, is rarely indicated in the adolescent patient. The importance of continued follow-up in DUB cases should be underlined, until stabilization of ovulatory menstrual cycles.
Topics: Adolescent; Female; Humans; Menstrual Cycle; Pregnancy; Pregnancy Complications; Uterine Hemorrhage
PubMed: 9238265
DOI: 10.1111/j.1749-6632.1997.tb52139.x -
Women's Health (London, England) Jan 2016Heavy menstrual bleeding (HMB) is a common gynecological complaint with multiple etiologies and diverse pathophysiological origins. This review discusses HMB with... (Review)
Review
Heavy menstrual bleeding (HMB) is a common gynecological complaint with multiple etiologies and diverse pathophysiological origins. This review discusses HMB with reference to the recently proposed PALM-COEIN classification system for abnormal uterine bleeding, initially describing the endometrial events in normal menstruation followed by discussion of the perturbations of normal endometrial shedding that can result in HMB. Our present understanding of the mechanisms of menstrual bleeding as well as many of the pathological aberrations of HMB is incomplete. Further research into the pathophysiology of HMB is urgently needed, as clear knowledge of the mechanisms of this disorder will provide new therapeutic targets to formulate more effective treatments.
Topics: Endometrium; Female; Humans; Menorrhagia; Quality of Life; Women's Health
PubMed: 26695831
DOI: 10.2217/whe.15.81 -
American Journal of Obstetrics and... Apr 2024This study aimed to provide procedure-specific estimates of the risk of symptomatic venous thromboembolism and major bleeding in the absence of thromboprophylaxis,... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
This study aimed to provide procedure-specific estimates of the risk of symptomatic venous thromboembolism and major bleeding in the absence of thromboprophylaxis, following gynecologic cancer surgery.
DATA SOURCES
We conducted comprehensive searches on Embase, MEDLINE, Web of Science, and Google Scholar for observational studies. We also reviewed reference lists of eligible studies and review articles. We performed separate searches for randomized trials addressing effects of thromboprophylaxis and conducted a web-based survey on thromboprophylaxis practice.
STUDY ELIGIBILITY CRITERIA
Observational studies enrolling ≥50 adult patients undergoing gynecologic cancer surgery procedures reporting absolute incidence for at least 1 of the following were included: symptomatic pulmonary embolism, symptomatic deep vein thrombosis, symptomatic venous thromboembolism, bleeding requiring reintervention (including reexploration and angioembolization), bleeding leading to transfusion, or postoperative hemoglobin <70 g/L.
METHODS
Two reviewers independently assessed eligibility, performed data extraction, and evaluated risk of bias of eligible articles. We adjusted the reported estimates for thromboprophylaxis and length of follow-up and used the median value from studies to determine cumulative incidence at 4 weeks postsurgery stratified by patient venous thromboembolism risk factors. The GRADE approach was applied to rate evidence certainty.
RESULTS
We included 188 studies (398,167 patients) reporting on 37 gynecologic cancer surgery procedures. The evidence certainty was generally low to very low. Median symptomatic venous thromboembolism risk (in the absence of prophylaxis) was <1% in 13 of 37 (35%) procedures, 1% to 2% in 11 of 37 (30%), and >2.0% in 13 of 37 (35%). The risks of venous thromboembolism varied from 0.1% in low venous thromboembolism risk patients undergoing cervical conization to 33.5% in high venous thromboembolism risk patients undergoing pelvic exenteration. Estimates of bleeding requiring reintervention varied from <0.1% to 1.3%. Median risks of bleeding requiring reintervention were <1% in 22 of 29 (76%) and 1% to 2% in 7 of 29 (24%) procedures.
CONCLUSION
Venous thromboembolism reduction with thromboprophylaxis likely outweighs the increase in bleeding requiring reintervention in many gynecologic cancer procedures (eg, open surgery for ovarian cancer and pelvic exenteration). In some procedures (eg, laparoscopic total hysterectomy without lymphadenectomy), thromboembolism and bleeding risks are similar, and decisions depend on individual risk prediction and values and preferences regarding venous thromboembolism and bleeding.
Topics: Adult; Humans; Female; Anticoagulants; Venous Thromboembolism; Postoperative Complications; Hemorrhage; Thrombosis; Neoplasms
PubMed: 37827272
DOI: 10.1016/j.ajog.2023.10.006