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Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 contributed to MPA/DMBA-induced breast cancer progression, accompanied by CD8+ T cell exhaustion. Female hormone screening revealed that progesterone stimulated B7-H4 expression in placental and breast cancer cells. Mechanistically, progesterone receptor (PR) bound to a newly identified -58 kb enhancer, thereby mediating B7-H4 transcription via the PR-P300-BRD4 axis. PR antagonist or BRD4 degrader potentiated immunotherapy in a murine B7-H4+ breast cancer model. Thus, our work unravels a mechanistic and biological connection of a female sex hormone (progesterone) to onco-fetal immune tolerance via B7-H4 and suggests that the PR-P300-BRD4 axis is targetable for treating B7-H4+ cancer.
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Tolerancia Inmunológica , Progesterona , Progestinas , Inhibidor 1 de la Activación de Células T con Dominio V-Set , Animales , Femenino , Inhibidor 1 de la Activación de Células T con Dominio V-Set/metabolismo , Humanos , Ratones , Embarazo , Progestinas/farmacología , Progestinas/metabolismo , Progesterona/metabolismo , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Receptores de Progesterona/metabolismo , Factores de Transcripción/metabolismo , Línea Celular Tumoral , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ratones Endogámicos C57BL , Placenta/metabolismo , Placenta/inmunologíaRESUMEN
(1) Background: There is a lack of direct evidence on whether SARS-CoV-2 affects women's sexual function through a biological-organic mechanism. Existing studies on the topic are few and have produced contradictory results. This study aims to explore the possible relationship between sex hormones and sexual function in patients who have been infected with SARS-CoV-2. Moreover, we aimed to determine whether these changes are related to the clinical course of COVID-19 and whether they are temporary or long-lasting. (2) Methods: A study was conducted on 104 women, including 64 women infected with COVID-19 and a control group of 40 healthy women, between January 2021 and August 2022. Blood samples were collected to measure prolactin and oxytocin levels, and a clinical assessment was performed 3 and 6 months later. Sexual function self-assessment was captured based on the FSFI scale. (3) Results: Our study found that patients with severe COVID-19 had better sexual satisfaction scores one month after recovery but no discernible difference after six months. High levels of serum prolactin were observed in patients with active COVID-19 but became similar to a control group after one month and remained stable over time. Higher prolactin levels were significantly associated with increased arousal and hydration. Individuals with severe COVID-19 had notably low levels of plasma oxytocin, but there was no correlation between oxytocin levels and sexual satisfaction. (4) Conclusions: The gynecologic symptoms, as well as disturbances in oxytocin and prolactin levels, might be observed in a short time after infection. However, SARS-CoV-2 infection has no lasting effect on sexual function, oxytocin, and prolactin levels among women.
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Introduction: A healthy vaginal microbiota is represented mainly by Lactobacillus spp. and plays a vital role in maintaining the functional balance in the vaginal environment. Scientists have drawn attention to possible correlations between the vaginal microbiome and gynecological neoplasms. Several recent studies have shown a potential link between the vaginal microbiome and the risk of developing cervical cancer from human papillomavirus (HPV) infection. This study aimed to compare the prevalence and abundance of various lactic acid bacteria species (LABs) in vaginal swabs from healthy controls and patients with abnormal Pap smear results. Methods: The study included 100 women (79 patients with abnormal cervical Pap smear results and 21 controls) from whom vaginal swabs were collected. Real-time quantitative PCR was used to determine seven lactic acid bacteria (LAB) species and their quantities. Results: Most patients were colonized by two Lactobacillus species, primarily Lactobacillus gasseri (93%) and L. crispatus (83%). Patient age and place of residence were associated with the diversity of LAB in the vaginal microbiota. The abundance of L. delbrueckii in the vaginal microbiota increased, whereas the abundance of L. gasseri abundance decreased, with patient age. Lactobacillus acidophilus and Limosilactobacillus fermentum were significantly more often detected in patients living in rural versus urban areas. Statistical analysis did not show any significant differences in LAB between groups of patients with various changes on smear tests. Discussion: The degree of dysplastic changes in the endothelium or the presence of a group of atypical cervical stratified epithelial cells was not associated with significant changes in the studied vaginal bacteria.
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The standard treatment of ovarian cancer (OC) patients, including debulking surgery and first-line chemotherapy, is unsatisfactory because of recurrent episodes in the majority (~70%) of patients with advanced OC. Clinical trials have shown only a modest (10-15%) response of OC individuals to treatment based on immune checkpoint inhibitors (ICIs). The resistance of OC to therapy is caused by various factors, including OC heterogeneity, low density of tumor-infiltrating lymphocytes (TILs), non-cellular and cellular interactions in the tumor microenvironment (TME), as well as a network of microRNA regulating immune checkpoint pathways. Moreover, ICIs are the most efficient in tumors that are marked by high microsatellite instability and high tumor mutation burden, which is rare among OC patients. The great challenge in ICI implementation is connected with distinguishing hyper-, pseudo-, and real progression of the disease. The understanding of the immunological, molecular, and genetic mechanisms of OC resistance is crucial to selecting the group of OC individuals in whom personalized treatment would be beneficial. In this review, we summarize current knowledge about the selected factors inducing OC resistance and discuss the future directions of ICI-based immunotherapy development for OC patients.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias Ováricas , Humanos , Femenino , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Linfocitos Infiltrantes de Tumor , Inmunoterapia , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Microambiente TumoralRESUMEN
According to recent data, changes in the vaginal microbiota could affect the risk of gynaecological cancers. Women suffering from endometrial cancer present significant changes in cervicovaginal microbiota composition. The objective of our study was to characterize the cervicovaginal microbiota of women undergoing hysterectomy due to benign disease, atypical hyperplasia, and endometrial cancer; The study included 96 patients, who undergone surgical treatment due to benign uterine disease, precancerous endometrial lesion, and endometrial cancer. Quantitative and qualitative real-time PCR analysis of DNA isolated from vaginal fornix and endocervical canal samples was performed to detect the 19 most commonly identified microorganisms, including different Lactobacillus spp., Atopobium, Bifidobacterium, Chlamydia, and Gardnerella; At least one of the tested microorganisms was identified in 88.5% of vaginal and 83.3% of cervical samples. Lactobacillus iners was significantly more frequent in patients with benign condition, whereas Dialister pneumosintes and Mobiluncus curtisii was more frequent in cancer patients; Mobiluncus curtisi and Dialister pneumosintes, which were identified as significantly more common in endometrial cancer vaginal samples, may be considered as potential endometrial cancer co-factors which promote/stimulate carcinogenesis. However, the exact mechanism of such activity remains unexplained and requires further investigations.
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Neoplasias Endometriales , Microbiota , Enfermedades Uterinas , Humanos , Femenino , Cuello del Útero/microbiología , Vagina/microbiología , Neoplasias Endometriales/genética , Microbiota/genética , ARN Ribosómico 16S/genéticaRESUMEN
Background: Ovarian cancer (OC) is the most lethal malignancy of the female reproductive tract. Consequently, a better understanding of the malignant features in OC is pertinent. Mortalin (mtHsp70/GRP75/PBP74/HSPA9/HSPA9B) promotes cancer development, progression, metastasis, and recurrence. Yet, there is no parallel evaluation and clinical relevance of mortalin in the peripheral and local tumor ecosystem in OC patients. Methods: A cohort of 92 pretreatment women was recruited, including 50 OC patients, 14 patients with benign ovarian tumors, and 28 healthy women. Blood plasma and ascites fluid-soluble mortalin concentrations were measured by ELISA. Mortalin protein levels in tissues and OC cells were analyzed using proteomic datasets. The gene expression profile of mortalin in ovarian tissues was evaluated through the analysis of RNAseq data. Kaplan-Meier analysis was used to demonstrate the prognostic relevance of mortalin. Results: First, we found upregulation of local mortalin in two different ecosystems, i.e., ascites and tumor tissues in human OC compared to control groups. Second, abundance expression of local tumor mortalin is associated with cancer-driven signaling pathways and worse clinical outcome. Third, high mortalin level in tumor tissues, but not in the blood plasma or ascites fluid, predicts worse patient prognosis. Conclusions: Our findings demonstrate a previously unknown mortalin profile in peripheral and local tumor ecosystem and its clinical relevance in OC. These novel findings may serve clinicians and investigators in the development of biomarker-based targeted therapeutics and immunotherapies.
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Ecosistema , Neoplasias Ováricas , Humanos , Femenino , Ascitis , Relevancia Clínica , ProteómicaRESUMEN
Endometrial cancer is the most common female genital tract malignancy in developed countries that occurs predominantly in postmenopausal women. The primary objective of our research was to investigate whether menopause status together with selected conventional prognostic indicators may contribute to overall (all-cause) survival in endometrial cancer patients. For this purpose, we applied the Cox proportional hazards regression model. Patients in advanced FIGO stage showed a relatively poor survival rate. The time since last menstruation and postoperative FSH concentration were identified as unfavorable prognostic factors in our model. Additionally, age at diagnosis, BMI value, adjuvant treatment (brachytherapy), and parity showed no impact on survival. To our knowledge, this is the first study to report a prognostic model for endometrial cancer including exact time from last menstruation as one of the prognostic variables. Due to the fact that there are no stratifying systems to reliably predict survival in patients with endometrial cancer, there is a strong need to revise and update existing models using complementary prognostic indicators. Collection of precise data on various risk factors may contribute to increased accuracy of artificial intelligence algorithms in order to personalize cancer care in the near future.
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Cancer is a disease that induces many local and systemic changes in immunity. The difficult nature of ovarian cancer stems from the lack of characteristic symptoms that contributes to a delayed diagnosis and treatment. Despite the enormous progress in immunotherapy, its efficacy remains limited. The heterogeneity of tumors, lack of diagnostic biomarkers, and complex immune landscape are the main challenges in the treatment of ovarian cancer. Integrative approaches that combine the tumor microenvironment - local immunity - together with periphery - systemic immunity - are urgently needed to improve the understanding of the disease and the efficacy of treatment. In fact, multiparametric analyses are poised to improve our understanding of ovarian tumor immunology. We outline an integrative approach including local and systemic immunity in ovarian cancer. Understanding the nature of both localized and systemic immune responses will be crucial to boosting the efficacy of immunotherapies in ovarian cancer patients.
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Inmunoterapia , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario , Neoplasias Ováricas/terapia , Factores Inmunológicos , Microambiente TumoralRESUMEN
Several hundred million people are infected with genital genotypes of the human papillomavirus (HPV) annually in the world. The infections transmitted mainly through sexual routes are usually asymptomatic, but can lead to the development of cervical, vulvar, vaginal, anal, penile cancers, some head and neck cancers and genital warts (condylomas). The fraction HPV-related cancers range from nearly 100% in the case of cervical cancer to several/over a dozen percent in the case of other cancers and diseases. There are no effective drugs against HPV, but prophylactic HPV vaccines are available free of charge in immunization programmes in many countries around the world. In Poland, HPV vaccinations have so far been executed out on the pocket or in free-of-charge, local-governmental prevention programs, but the vaccination coverage of the target population does not exceed 10%. From November 2021, one of the vaccines is available with a 50% reimbursement, work is underway to reimburse the next ones, and the National Oncology Strategy assumes the implementation of the HPV immunization programmes and vaccination of 60% of the teen population by 2028. Three prophylactic HPV vaccines are registered. All of them are safe and their effectiveness in the prevention of diseases caused by vaccine genotypes reaches almost 100%, provided that full post-vaccination immunity is obtained before the contact with the virus. Girls aged 11-13 are the priority target cohort for HPV vaccination in Poland. The implementation of routine, free-of-charge HPV immunization in the Preventive Immunization Program (PIP) for all adolescents should be pursued. Persons over the age of 13 may also benefit from HPV vaccination and should be vaccinated according to product specifications. In addition to free access under the PIP, the key element for the success of the implementation of HPV vaccinations in Poland will be the education of medical personnel and parents of adolescents to be vaccinated.
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Recurrent vulvovaginal candidosis (RVVC) is a chronic, difficult to treat vaginal infection, caused by Candida species, which affects women of all ages and ethnic and social background. A long-term prophylactic maintenance regimen with antifungals is often necessary. In most clinical practice guidelines, oral fluconazole is recommended as the first-line treatment. Although clinical resistance to antifungal agents remains rare, overexposure to azoles may increase the development of fluconazole-resistant C. albicans strains. In addition, non-albicans Candida species are frequently dose-dependent susceptible or resistant to fluconazole and other azoles, and their prevalence is rising. Available therapeutic options to treat such fluconazole-resistant C. albicans and low susceptibility non-albicans strains are limited. Ten experts from different European countries discussed problematic issues of current RVVC diagnosis and treatment in two audiotaped online sessions and two electronic follow-up rounds. A total of 340 statements were transcribed, summarized, and compared with published evidence. The profile of patients with RVVC, their care pathways, current therapeutic needs, and potential value of novel drugs were addressed. Correct diagnosis, right treatment choice, and patient education to obtain adherence to therapy regimens are crucial for successful RVVC treatment. As therapeutic options are limited, innovative strategies are required. Well- tolerated and effective new drugs with an optimized mechanism of action are desirable and are discussed. Research into the impact of RVVC and treatments on health-related quality of life and sex life is also needed.
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Candidiasis Vulvovaginal , Fluconazol , Antifúngicos/farmacología , Azoles/farmacología , Azoles/uso terapéutico , Candida , Candida albicans , Candidiasis Vulvovaginal/diagnóstico , Candidiasis Vulvovaginal/tratamiento farmacológico , Femenino , Fluconazol/farmacología , Fluconazol/uso terapéutico , Humanos , Pruebas de Sensibilidad Microbiana , Calidad de VidaRESUMEN
Luteinizing hormone-releasing hormone receptor (LHRHR) expression has been reported in various cancers, including endometrial neoplasms. Thus, LHRHR provides a potential point for therapeutic approach using LHRH analogs as carrier molecules for chemotherapeutic agents in this cancer population. However, clinical data did not prove any potential benefits for patients. We decided to assess LHRHR expression in patients with endometrial cancer to explain possible lack of efficacy in previous clinical reports. LHRHR expression was assessed immunohistochemically in different anatomic and histogenetic compartments of female genital tract of patients with endometrial cancer. The study sample consisted of paraffin tissue blocks obtained from patients who has undergone primary surgery owing to endometrial cancer. Strong LHRHR expression was found in endometrial cancer, fallopian tube, and concurrent atypical hyperplasia. Interestingly, LHRHR expression showed significant differences depending on the respective compartment of the ovary analyzed. Level of LHRHR expression in patients with primary advanced and unresectable disease, particularly in certain ovarian compartments may be substantially lower, which may influence the use of new targeted therapy regimens. The studies on secondary Müllerian system compartment and its hormonal receptor status may be crucial to understand mechanisms of lack of efficacy of LHRH hybrid molecules anti-cancer treatment.
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Antineoplásicos , Neoplasias Endometriales , Antineoplásicos/uso terapéutico , Neoplasias Endometriales/metabolismo , Femenino , Genitales Femeninos/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Receptores LHRH/metabolismo , Receptores LHRH/uso terapéuticoRESUMEN
The distinguishing of uterine leiomyosarcomas (ULMS) and uterine leiomyomas (ULM) before the operation and histopathological evaluation of tissue is one of the current challenges for clinicians and researchers. Recently, a few new and innovative methods have been developed. However, researchers are trying to create different scales analyzing available parameters and to combine them with imaging methods with the aim of ULMs and ULM preoperative differentiation ULMs and ULM. Moreover, it has been observed that the technology, meaning machine learning models and artificial intelligence (AI), is entering the world of medicine, including gynecology. Therefore, we can predict the diagnosis not only through symptoms, laboratory tests or imaging methods, but also, we can base it on AI. What is the best option to differentiate ULM and ULMS preoperatively? In our review, we focus on the possible methods to diagnose uterine lesions effectively, including clinical signs and symptoms, laboratory tests, imaging methods, molecular aspects, available scales, and AI. In addition, considering costs and availability, we list the most promising methods to be implemented and investigated on a larger scale.
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Quality of life is related to good health, family relations, feeling of self-esteem, and ability to cope with difficult situations. Endometriosis is a chronic condition which affects different areas of life. The lack of satisfaction in everyday life is mainly due to constant pain. The process of adjusting to a life with illness is associated with negative emotions. The aim of the article is to review the current state of knowledge concerning the impact of social and medical factors on a population of women affected by endometriosis. Women with endometriosis have an impaired quality of life compared to the general female population. Psychological consequences of endometriosis include: depression, anxiety, powerlessness, guilt, self-directed violence, and deterioration of interpersonal relations. It may contribute to lower productivity at work and less satisfying intimate life. A multi-disciplinary, evidence-based care is needed. The disease can take away the ability to be physically active, obtain an education, work continuously, and interact with friends. Social support and cognitive-behavioral therapy are extremely important for healing.
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OBJECTIVES: The presence of the endometrium outside the uterine cavity affects about 10% of women of childbearing age. Studies of the progression of endometriosis to cancer have been supported by numerous evidences of gene expression or gene defect caused by oxidative stress and inflammation. We decided to check the expression of selected factors responsible for the proliferation, as in the stages of neoplasia. MATERIAL AND METHODS: A group of 80 women with ovary localization of endometriosis was qualified for research. The control group was 90 patients with ovarian simplex or follicular cysts. The DNA isolation, immunohistochemical analysis of IGF 1, IGF-R, TSG 101, and LSF expressions with a quantitative scoring of slides and electron microscopy was performed. RESULTS: The IGF-1-immunopositive cells in the reference group were in statistically significantly higher number compared to the cells forming the foci of endometriosis (p = 0.0282). However, the number of IGF-R-immunopositive cells was comparable to the endometriosis (p = 0.1264). In the control group, the number of LSF-immunopositive cells was statistically significantly higher in comparison to endometriosis foci (p = 0.000001), but the number of TSG 101-immunositive cells was comparable to endometriosis foci (p = 0.3834). A weak negative correlation between the number of cells expressing the TSG 101 factor and the IGF-1 receptor was found in the endometriosis group (r = -0.26, p = 0.0196). The analysis of CA single nucleotide polymorphism in the DNA isolated from both groups showed a comparable incidence of MSS and MSI-L genotypes (chi2 p = 0,9160). CONCLUSIONS: How these factors affect the development of endometriosis and whether they could be helpful in the diagnosis requires further research.
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ADN , Factor I del Crecimiento Similar a la Insulina , Humanos , Femenino , Factor I del Crecimiento Similar a la Insulina/genéticaRESUMEN
Insulin resistance and hyperinsulinemia play a key role in type 1 endometrial cancer pathogenesis. Most of these cancers develop on a background of overweight or type 2 diabetes mellitus (T2DM). One of the medications widely used in the treatment of T2DM is biguanide derivative, metformin, which exerts promising anticancer properties principally through activation of adenosine monophosphate kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) pathways. Many epidemiological studies on diabetic patients show potential preventative role of metformin in endometrial cancer patients, but data regarding its therapeutic role is still limited. So far, most of attention has been paid to the concept of metformin use in fertility sparing treatment of early-stage cancer. Another investigated alternative is its application in patients with primary advanced or recurrent disease. In this review we present the latest data on clinical use of metformin in endometrial cancer patients and potential underlying mechanisms of its activity. Finally, we present some most important clinical information regarding metformin efficacy in other gynaecological malignancies, mainly breast and ovarian cancer.
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Diabetes Mellitus Tipo 2 , Neoplasias Endometriales , Neoplasias de los Genitales Femeninos , Metformina , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/metabolismo , Femenino , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Humanos , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéuticoRESUMEN
The latest literature demonstrates the predominant role of the programmed cell death axis (PD-1/PD-L1/PD-L2) in ovarian cancer (OC) pathogenesis. However, data concerning this issue is ambiguous. Our research aimed to evaluate the clinical importance of PD-L1/PD-L2 expression in OC environments. We evaluated the role of PD-L1/PD-L2 in OC patients (n = 53). The analysis was performed via flow cytometry on myeloid (mDCs) and plasmacytoid dendritic cells (pDCs) and monocytes/macrophages (MO/MA) in peripheral blood, peritoneal fluid (PF), and tumor tissue (TT). The data were correlated with clinicopathological characteristics and prognosis of OC patients. The concentration of soluble PD-L1 (sPD-L1) and PD-1 in the plasma and PF were determined by ELISA. We established an accumulation of PD-L1+/PD-L2+ mDCs, pDCs, and MA in the tumor microenvironment. We showed an elevated level of sPD-L1 in the PF of OC patients in comparison to plasma and healthy subjects. sPD-L1 levels in PF showed a positive relationship with Ca125 concentration. Moreover, we established an association between higher sPD-L1 levels in PF and shorter survival of OC patients. An accumulation of PD-L1+/PD-L2+ mDCs, pDCs, and MA in the TT and high sPD-L1 levels in PF could represent the hallmark of immune regulation in OC patients.
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Células Presentadoras de Antígenos/metabolismo , Células Presentadoras de Antígenos/patología , Antígeno B7-H1/metabolismo , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Líquido Ascítico/metabolismo , Líquido Ascítico/patología , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/patología , Células Dendríticas/metabolismo , Células Dendríticas/patología , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , Microambiente Tumoral/fisiología , Adulto JovenRESUMEN
Endometriosis (EMS) is a common gynecological disease characterized by the presence of endometrial tissue outside the uterus. Approximately 10% of women around the world suffer from this disease. Recent studies suggest that endometriosis has potential to transform into endometriosis-associated ovarian cancer (EAOC). Endometriosis is connected with chronic inflammation and changes in the phenotype, activity, and function of immune cells. The underlying mechanisms include quantitative and functional disturbances of neutrophils, monocytes/macrophages (MO/MA), natural killer cells (NK), and T cells. A few reports have shown that immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) may promote the progression of endometriosis. MDSCs are a heterogeneous population of immature myeloid cells (dendritic cells, granulocytes, and MO/MA precursors), which play an important role in the development of immunological diseases such as chronic inflammation and cancer. The presence of MDSCs in pathological conditions correlates with immunosuppression, angiogenesis, or release of growth factors and cytokines, which promote progression of these diseases. In this paper, we review the impact of MDSCs on different populations of immune cells, focusing on their immunosuppressive role in the immune system, which may be related with the pathogenesis and/or progression of endometriosis and its transformation into ovarian cancer.
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Endometriosis/metabolismo , Endometrio/metabolismo , Granulocitos/metabolismo , Células Supresoras de Origen Mieloide/metabolismo , Endometrio/inmunología , Femenino , Humanos , Tolerancia Inmunológica/inmunología , Células Mieloides/metabolismoRESUMEN
One of the most intriguing problems in biomedical sciences is the theory explaining cancer formation. It is known that cancer is the result of many molecular processes, the presence of oncogenic factors and the loss of apoptosis of affected cells. We currently have hypotheses based on carcinogenesis because of a single cell gene mutation, i.e. somatic mutation theory (SMT), or disorders in tissue architecture and intercellular communication called (TOFT) Tissue Organization Field Theory. An attempt to combine these separate and compatible cause and effect pathways into one unified theory of cancer transformation is the theory of chaotic adaptation. The new interpretative model is the systemic-evolution theory of cancer (SETOC) which postulates disintegration between the symbiosis of "energy" and "information" in normal cells. There are also epidemiological studies confirming that some types of cancer arise from viral infection. So, let us ask the question, can one hypothesis explain all the features of cancer?
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Carcinogénesis , Neoplasias , Adaptación Fisiológica , Carcinogénesis/genética , Transformación Celular Neoplásica , Humanos , MutaciónRESUMEN
Altered immune mechanisms are implicated in the pathogenesis of endometriosis. CTLA-4 is a membrane receptor that favors the anergic state of lymphocytes, which may disrupt the immune system response in the endometriotic environment. In this study, we examined the expression of CTLA-4 on T and B cells by flow cytometry and its levels in blood serum and peritoneal fluid by ELISA. Levels of CTLA-4+ T cells were significantly higher in patients with more advanced endometriosis than in those with less advanced disease. Additionally, the negative correlation of CTLA-4+ T lymphocytes and the percentage of NK and NKT-like cells in women with endometriosis and infertility may indicate a different etiopathogenesis of endometriosis accompanying infertility. Our findings shed light on the potential of CTLA-4 in developing new diagnostic and therapeutic approaches in endometriosis management.
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Antígeno CTLA-4/metabolismo , Endometriosis/metabolismo , Infertilidad/metabolismo , Inflamación/metabolismo , Adulto , Antígenos CD19/metabolismo , Líquido Ascítico/metabolismo , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Antígeno CTLA-4/sangre , Estudios de Casos y Controles , Enfermedad Crónica , Endometriosis/sangre , Endometriosis/inmunología , Femenino , Humanos , Infertilidad/sangre , Infertilidad/inmunología , Inflamación/sangre , Inflamación/inmunología , Persona de Mediana Edad , Dolor Pélvico/sangre , Dolor Pélvico/complicaciones , Dolor Pélvico/inmunología , Solubilidad , Linfocitos T/inmunología , Adulto JovenRESUMEN
Introduction: mTOR inhibitors are anticancer agents affecting mTOR/AKT/PI3K pathway that is one of the most important in human cancer cells. Hyperactivation of mTOR/AKT/PI3K and overexpression of this pathway members are frequently reported in uterine sarcoma and carcinosarcoma. Present study is aimed to assess the activity of the two mTOR inhibitors (rapamycin - RAP and sapanisertib - MLN) as a single agent and combined with gemcitabine (GEM, one of substances commonly used in systemic anticancer treatment) in uterine sarcoma and carcinosarcoma in vitro models. Material and methods: SK-UT-1 and SK-UT1-B (uterine carcinosarcoma), MES-SA (leiomyosarcoma) and ESS-1 (endometrial stromal sarcoma) cell lines were used. An MTT assay was performed to examine the cytotoxicity of RAP, MLN and mixtures: RAP+MLN, RAP+GEM, MLN+GEM against these cells. The interactions between tested compounds were assessed in isobolographic analysis. Results and conclusions: Carcinosarcoma cell lines (both SK-UT-1 and SK-UT-1B) do not respond to RAP and respond relatively weakly to MLN treatment. Additive and supraadditive effects were noted for combined treatment with GEM and MLN. Endometrial stromal sarcoma cell line (ESS-1) occured to be sensitive to both RAP and MLN, but the response was stronger for MLN. Additive effect of all tested drug combinations was observed for ESS-1. Leiomyosarcoma cell line (MES-SA) was found sensitive to both mTOR inhibitors. Additive effects in combinations of GEM, RAP and MLN were observed, what makes them promising for future preclinical and clinical trials. Additivity with slight tendency towards antagonism between GEM and MLN observed in MES-SA cell line is unexpected finding and might prompt the mechanistic research aimed to explain this phenomenon.