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OBJECTIVES: With SARS-CoV-2 evolving, disease severity and presentation have changed due to changes in mechanisms of entry and effector site as well as due to effects of vaccination- and/or infection-acquired immunity. We re-assessed fetal lung pathology in pregnancies with uncomplicated SARS-CoV-2 infections during the late, omicron-dominated pandemic phase to inform disease understanding and pregnancy consultation. METHODS: In this case-control study, fetal lung volumes were assessed by fetal MRI in 24 pregnancies affected by mild maternal SARS-CoV-2 infection during the omicron-dominated pandemic phase with prevailing immunity through vaccination and/or prior SARS-CoV-2 infection. RESULTS: Fetal lung volumes (normalized to estimated fetal weight) in 24 pregnancies (GA 33.3 ± 3.8, 12 female fetuses) following mild, uncomplicated SARS-CoV-2 infection did not differ significantly from both, published reference values (96.3% ± 22.5% of 50th percentile reference values, p = 0.43), or fetal lung volumes of a site-specific, non-COVID control group (n = 15, 94.2% ± 18.5%, p = 0.76). Placental assessment revealed no group differences in thrombotic changes or placental heterogeneity (p > 0.05, respectively), and fetal lung volume did not correlate with placental heterogeneity when adjusting for gestational age at scan (p > 0.05). CONCLUSION: Assessment of fetal lung volume by MRI revealed unaffected lung growth in pregnancies affected by uncomplicated SARS-CoV-2 infection in the omicron-dominated pandemic phase in the presence of prevailing hybrid immunity. This finding contrasts sharply with the observed reduction in fetal lung volume following maternal alpha-variant infection in the pre-vaccination era and might reflect tropism- as well as immunity-related effects. KEY POINTS: Question: Is fetal lung development affected by mild maternal SARS-CoV-2 infection during the omicron-dominated phase of the pandemic? FINDINGS: Fetal lung volume in 24 affected pregnancies did not differ significantly from published reference values or fetal lung volumes in 15 site-specific, non-COVID-affected control pregnancies. CLINICAL RELEVANCE: Preserved fetal lung volume following mild maternal SARS-CoV-2 infection during the omicron-dominated phase contrasts with previous findings of reduced volume in unvaccinated pregnancies during the alpha-dominated pandemic phase. These observations might reflect tropism- as well as immunity-related effects.
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PURPOSE: After living with the COVID-19 pandemic for more than 2 years, the impact of lockdown measures on preterm birth rates is inconsistent according to data from different countries. In this study, rates of preterm-born infants during the time of COVID-19-related lockdowns were analyzed in a tertiary perinatal center at Munich University, Germany. METHODS: We analyzed the number of preterm births, infants, and stillbirths before 37 weeks of gestation during the German COVID-19 lockdown period compared to the same time periods in the years 2018 and 2019 combined. Additionally, we expanded the analysis to Pre- and Post-Lockdown Periods in 2020 compared to the respective control periods in the years 2018 and 2019. RESULTS: Our database shows a reduction in the rate of preterm infants during the COVID-19 lockdown period (18.6%) compared to the combined control periods in 2018 and 2019 (23.2%, p = 0.027). This was mainly based on a reduced rate of preterm multiples during the lockdown period (12.8% vs. 28.9%, p = 0.003) followed by a reversed effect showing a threefold rise in multiple births after the lockdown. In singletons, the rate of preterm births was not reduced during the lockdown. The rate of stillbirths was not affected by the lockdown measures as compared to the control period (0.9% vs. 0.7%, p = 0.750). CONCLUSION: During the COVID-19 pandemic lockdown period, we found a reduced rate of preterm-born infants compared to a combined control period in the years 2018 and 2019 in our large tertiary University Center in Germany. Due to the predominant reduction in preterm multiples, we postulate that less physical activity might have led to the protective effect by lockdown measures.
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COVID-19 , Nascimento Prematuro , Gravidez , Lactente , Feminino , Recém-Nascido , Humanos , Recém-Nascido Prematuro , Nascimento Prematuro/epidemiologia , COVID-19/epidemiologia , COVID-19/prevenção & controle , Pandemias/prevenção & controle , Universidades , Controle de Doenças Transmissíveis , Natimorto/epidemiologiaRESUMO
Endometrial cancer (EC) is a common gynecological cancer worldwide. Treatment has been improved in recent years; however, in advanced stages, therapeutic options are still limited. The expression of galectins is increased in several tumor types and that they are involved in important cell processes. Large studies on endometrial cancer are still pending; Specimens of 225 patients with EC were immunohistochemically stained with antibodies for Gal-8 and Gal-9. Expression was correlated with histopathological variables. The cytosolic expression of both galectins is associated with grading and survival. Cytosolic Galectin-8 expression is a positive prognostic factor for overall survival (OS) and progression-free survival (PFS), while nuclear Gal-8 expression correlates only to OS. The cytosolic presence of Galectin-9 is correlated with a better prognosis regarding OS. Our results suggest that expression of both galectins is associated with OS and PFS in EC. Further studies are needed to understand the underlying molecular mechanisms.
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Neoplasias do Endométrio , Galectinas , Humanos , Galectinas/metabolismo , Galectinas/genética , Feminino , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/mortalidade , Pessoa de Meia-Idade , Idoso , Prognóstico , Biomarcadores Tumorais/metabolismo , Adulto , Idoso de 80 Anos ou mais , Imuno-HistoquímicaRESUMO
Galectins are known to play an important role in immunoregulatory processes and autoimmune diseases. Galectin-10 is a cytoplasmic protein of human eosinophils and is involved in various eosinophilic diseases. Since increased galectin expression is already detected in the placentas of mothers with gestational diabetes mellitus (GDM), this study focuses on the specific role of galectin-10 and hints at consequences for the diagnosis and therapeutic options of GDM. It is hypothesized that the difference in galectin-10 expression will raise the pathophysiological understanding of gestational diabetes. The study population consists of 80 women: 40 healthy mothers and 40 women suffering from gestational diabetes mellitus. The expression of galectin-10 was analyzed in the syncytiotrophoblast (SCT) and the decidua of the placenta via immunohistochemistry and immunofluorescence double staining. The immunoreactivity score (IRS) was used for evaluation. The results in this study were significant for an overexpression of galectin-10 in GDM placentas compared with the control group. The syncytiotrophoblast showed overexpression in the nucleus and the cytoplasm, whereas expression of galectin-10 in the decidua was significant in the cytoplasm only. This study identified the expression changes in galectin-10 in placental tissue between healthy and GDM mothers and intensified the understanding of gestational diabetes. Assuming that gestational diabetes mellitus is involved in inflammatory processes, galectin-10 might play a role in the development and maintenance of GDM. Further investigation is required to strengthen these findings.
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INTRODUCTION: To determine whether a pelvis is wide enough for spontaneous delivery has long been the subject of obstetric research. A number of variables have been proposed as predictors, all with limited accuracy. In this study, we use a novel three-dimensional (3D) method to measure the female pelvis and assess which pelvic features influence birth mode. We compare the 3D pelvic morphology of women who delivered vaginally, women who had cesarean sections, and nulliparous women. The aim of this study is to identify differences in pelvic morphology between these groups. MATERIAL AND METHODS: This observational study included women aged 50 years and older who underwent a CT scan of the pelvis for any medical indication. We recorded biometric data including height, weight, and age, and obtained the obstetric history. The bony pelvis was extracted from the CT scans and reconstructed in three dimensions. By placing 274 landmarks on each surface model, the pelvises were measured in detail. The pelvic inlet was measured using 32 landmarks. The trial was registered at the German Clinical Trials Register DRKS (DRKS00017690). RESULTS: For this study, 206 women were screened. Exclusion criteria were foreign material in the bony pelvis, unknown birth mode, and exclusively preterm births. Women who had both a vaginal birth and a cesarean section were excluded from the group comparison. We compared the pelvises of 177 women between three groups divided by obstetric history: vaginal births only (n = 118), cesarean sections only (n = 21), and nulliparous women (n = 38). The inlet area was significantly smaller in the cesarean section group (mean = 126.3 cm2 ) compared with the vaginal birth group (mean = 134.9 cm2 , p = 0.002). The nulliparous women were used as a control group: there was no statistically significant difference in pelvic inlet area between the nulliparous and vaginal birth groups. CONCLUSIONS: By placing 274 landmarks on a pelvis reconstructed in 3D, a very precise measurement of the morphology of the pelvis is possible. We identified a significant difference in pelvic inlet area between women with vaginal delivery and those with cesarean section. A unique feature of this study is the method of measurement of the bony pelvis that goes beyond linear distance measurements as used in previous pelvimetric studies.
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Baías , Cesárea , Recém-Nascido , Feminino , Gravidez , Humanos , Pessoa de Meia-Idade , Idoso , Parto , Pelve/diagnóstico por imagem , Parto Obstétrico/métodos , Pelvimetria/métodosRESUMO
PURPOSE: Endometriosis is known to be an underestimated disease. Lately the awareness of the disease seems to have improved. Aim of this analysis is to provide an overview of the development of treatment of patients diagnosed with endometriosis. This includes a special scope on implications of the COVID-19 pandemic since in multiple settings postponed treatments resulting in negative impact on prognosis were reported. MATERIALS AND METHODS: We analysed the development of numbers of patients treated for endometriosis in an academic centre within a 7-year period, 01/2015-12/2021, performing a systematic analysis of ICD-10-Codes from our computer system used in clinical routine. RESULTS: Treatment numbers increased over the past 7 years, i.e., 239 treated cases in 2015 vs. 679 in 2021. Following restrictions for outpatient evaluation and surgical capacity at our centre, during COVID-19 pandemic the numbers of treated patients were reduced, especially in the first lockdown period (03/22/2020-05/05/2020 vs. same period in 2019: outpatient clinic (9 vs. 36; p < 0.001), patients surgically treated (27 vs. 52; p < 0,001)). The comparison of 2020 to 2019 showed a reduction in April 2020 of - 37% in outpatient department and up to - 90% for surgically treated patients. Comparing to 2019, we found a reduction of surgical interventions in 2020 by - 9% and an increase by 83% in 2021. CONCLUSIONS: Raising numbers of patients treated for endometriosis point to a new awareness for the disease. After the decline during the lockdown period numbers raised again, leading to a delay, but not an omission of treatment. A certified endometriosis centre with established and well-organized structures is required to improve not only treatment results but also quality of life of those affected.
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COVID-19 , Endometriose , Feminino , Humanos , Endometriose/epidemiologia , Endometriose/cirurgia , COVID-19/epidemiologia , Qualidade de Vida , Pandemias , Controle de Doenças TransmissíveisRESUMO
PURPOSE: There are different studies worldwide, which have shown a higher risk of mental disorders due to the COVID-19 pandemic. One aim of this study was to identify influencing factors of the psychological burden related to the COVID-19 pandemic and the impact on the development of postpartum depression. Further, the role of individual stress and coping strategies was analyzed in this context. MATERIALS AND METHODS: Between March and October 2020, 131 women in obstetric care at the LMU Clinic Munich completed a questionnaire at consecutive stages during their perinatal period. The times set for the questionnaire were before birth, 1 month, 2 months, and 6 months after birth. The questionnaire was designed to evaluate the psychological burden related to the COVID-19 pandemic. For this a modified version of the Stress and coping inventory (SCI) and the Edinburgh Postnatal Depression Scale (EPDS) was used. RESULTS: We could show that the psychological burden related to the COVID-19 pandemic influenced the EPDS score 1, 2 and 6 months after birth. In addition, the prenatal stress and individual coping strategies affected the EPDS and the burden related to the COVID-19 pandemic before and after birth significantly. CONCLUSION: An association of the psychological burden related to the COVID-19 pandemic with the risk of developing postpartum depressive symptoms could be shown in this study. In this context, the separation of the partner and the family was recognized as an important factor. Furthermore, the SCI was identified as an effective screening instrument for identifying mothers with an increased risk of postpartum depression. Hereby allowing primary prevention by early intervention or secondary prevention by early diagnosis.
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COVID-19 , Depressão Pós-Parto , Gravidez , Feminino , Humanos , Depressão Pós-Parto/diagnóstico , COVID-19/complicações , COVID-19/epidemiologia , Depressão/epidemiologia , Pandemias , Período Pós-Parto/psicologia , Adaptação Psicológica , Estresse Psicológico/complicaçõesRESUMO
Past studies have confirmed that aberrant activation of the Wnt/ß-catenin signaling is associated with tumorigenesis and metastasis in breast cancer, while the role of platelet-activating factor acetylhydrolase (PLA2G7/PAF-AH) in this signaling pathway remains unclear. In this study, we analyze the functional impact of PAF-AH on BRCA1 mutant breast cancer and explore its relationship to the Wnt signaling pathway. By performing immunohistochemistry, PAF-AH expression and ß-catenin expression were examined in both BRCA1 WT and BRCA1 mutant breast cancer specimens. The BRCA1 mutant breast cancer cell line HCC1937 was used for in vitro experiments to assess the impact of PAF-AH on cellular functions. The intracellular distribution of ß-catenin depending on PLA2G7/PAF-AH expression was investigated by immunocytochemistry. Significantly higher nuclear expression levels of PAF-AH were found in BRCA1 mutant tissue specimens than in BRCA1 WT samples. Cell viability, proliferation, and the motility rate of HCC1937 were significantly enhanced after PLA2G7 silencing, which indicated a protective role of PAF-AH in breast cancer. Nuclear PAF-AH expressed correlatedly with membranous ß-catenin. PLA2G7 silencing provoked the ß-catenin translocation from the membrane to the nucleus and activated Wnt signaling downstream genes. Our data showed a protective effect of high PAF-AH expression in BRCA1 mutant breast cancer. PAF-AH may achieve its protective effect by negatively regulating the Wnt pathway. In conclusion, our research sheds new light on the regulatory pathways in BRCA1 mutant breast cancer.
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1-Alquil-2-acetilglicerofosfocolina Esterase , Proteína BRCA1 , Neoplasias da Mama , Via de Sinalização Wnt , Feminino , Humanos , 1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Proteína BRCA1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Células MCF-7RESUMO
BACKGROUND: Gestational diabetes mellitus is one of the most frequent pregnancy complications with a global prevalence of 13.4% in 2021. Pregnant women with COVID-19 and gestational diabetes mellitus are 3.3 times more likely to be admitted to an intensive care unit than women without gestational diabetes mellitus. Data on the association of gestational diabetes mellitus with maternal and neonatal pregnancy outcomes in pregnant women with SARS-CoV-2 infection are lacking. OBJECTIVE: This study aimed to investigate whether gestational diabetes mellitus is an independent risk factor for adverse maternal and fetal and neonatal outcomes in pregnant women with COVID-19. STUDY DESIGN: The COVID-19-Related Obstetric and Neonatal Outcome Study is a registry-based multicentric prospective observational study from Germany and Linz, Austria. Pregnant women with clinically confirmed COVID-19 were enrolled between April 3, 2020, and August 24, 2021, at any stage of pregnancy. Obstetricians and neonatologists of 115 hospitals actively provided data to the COVID-19-Related Obstetric and Neonatal Outcome Study. For collecting data, a cloud-based electronic data platform was developed. Women and neonates were observed until hospital discharge. Information on demographic characteristics, comorbidities, medical history, COVID-19-associated symptoms and treatments, pregnancy, and birth outcomes were entered by the local sites. Information on the periconceptional body mass index was collected. A primary combined maternal endpoint was defined as (1) admission to an intensive care unit (including maternal mortality), (2) viral pneumonia, and/or (3) oxygen supplementation. A primary combined fetal and neonatal endpoint was defined as (1) stillbirth at ≥24 0/7 weeks of gestation, (2) neonatal death ≤7 days after delivery, and/or (3) transfer to a neonatal intensive care unit. Multivariable logistic regression analysis was performed to evaluate the modulating effect of gestational diabetes mellitus on the defined endpoints. RESULTS: Of the 1490 women with COVID-19 (mean age, 31.0±5.2 years; 40.7% nulliparous), 140 (9.4%) were diagnosed with gestational diabetes mellitus; of these, 42.9% were treated with insulin. Overall, gestational diabetes mellitus was not associated with an adverse maternal outcome (odds ratio, 1.50; 95% confidence interval, 0.88-2.57). However, in women who were overweight or obese, gestational diabetes mellitus was independently associated with the primary maternal outcome (adjusted odds ratio, 2.69; 95% confidence interval, 1.43-5.07). Women who were overweight or obese with gestational diabetes mellitus requiring insulin treatment were found to have an increased risk of a severe course of COVID-19 (adjusted odds ratio, 3.05; 95% confidence interval, 1.38-6.73). Adverse maternal outcomes were more common when COVID-19 was diagnosed with or shortly after gestational diabetes mellitus diagnosis than COVID-19 diagnosis before gestational diabetes mellitus diagnosis (19.6% vs 5.6%; P<.05). Maternal gestational diabetes mellitus and maternal preconception body mass index of ≥25 kg/m2 increased the risk of adverse fetal and neonatal outcomes (adjusted odds ratio, 1.83; 95% confidence interval, 1.05-3.18). Furthermore, overweight and obesity (irrespective of gestational diabetes mellitus status) were influential factors for the maternal (adjusted odds ratio, 1.87; 95% confidence interval, 1.26-2.75) and neonatal (adjusted odds ratio, 1.81; 95% confidence interval, 1.32-2.48) primary endpoints compared with underweight or normal weight. CONCLUSION: Gestational diabetes mellitus, combined with periconceptional overweight or obesity, was independently associated with a severe maternal course of COVID-19, especially when the mother required insulin and COVID-19 was diagnosed with or after gestational diabetes mellitus diagnosis. These combined factors exhibited a moderate effect on neonatal outcomes. Women with gestational diabetes mellitus and a body mass index of ≥25 kg/m2 were a particularly vulnerable group in the case of COVID-19.
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COVID-19 , Diabetes Gestacional , Insulinas , Adulto , COVID-19/epidemiologia , COVID-19/terapia , Teste para COVID-19 , Diabetes Gestacional/epidemiologia , Feminino , Humanos , Recém-Nascido , Obesidade/epidemiologia , Avaliação de Resultados em Cuidados de Saúde , Sobrepeso , Gravidez , Resultado da Gravidez , SARS-CoV-2RESUMO
PURPOSE: Galectins are carbohydrate-binding proteins with multiple effects on cell biology. Research shows that they play an important role in tumor development and progression. Therefore, in this study, the presence of Galectin-8 and -9 (Gal), both already known as prognostic factors in other tumor entities, were investigated in cervical cancer. Our aim was to examine the association of Gal-8 and -9 expression with histopathological markers and survival of the patients. METHODS: Gal-8 and -9 expression was investigated in 250 cervical cancer samples by immunohistochemistry. The staining was evaluated using the immunoreactive score (IRS). The results were correlated to clinical and pathological data. The correlation of Gal-8 and -9 expression with overall and relapse-free survival was analyzed. RESULTS: Expression of Gal-8 was associated with negative N-status and lower FIGO status. Detection of Gal-9 was connected to negative N-status and lower grading regarding all specimens. A correlation of Gal-9 with lower FIGO status was detected for squamous cell carcinoma (SCC) only. Expression of Gal-8 was associated with relapse-free survival of SCC patients in a positive manner. Gal-9 expression was associated with better overall survival. CONCLUSION: Our results suggest that expression of both galectins is inversely associated with tumor stage and progression. Gal-8 expression is associated with relapse-free survival of patients with SCC, while presence of Gal-9 in cervical cancer is associated with a better prognosis in regard of overall survival.
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Carcinoma de Células Escamosas , Neoplasias do Colo do Útero , Carcinoma de Células Escamosas/patologia , Feminino , Galectinas , Humanos , Imuno-Histoquímica , Recidiva Local de Neoplasia , Prognóstico , Neoplasias do Colo do Útero/patologiaRESUMO
PURPOSE: The tumour's ability to metastasize is the major cause for fatal outcomes in cancer diseases. In breast cancer, aberrant E-Cadherin expression has been linked to invasiveness and poor prognosis. METHOD: We assessed expression of E-Cadherin by immunohistochemistry in primary tumour tissue from 125 female breast cancer patients. Staining intensities were analysed using the immunoreactive score (IRS). We investigated E-Cadherin expression and its associations with clinicopathological parameters (age, tumour size, lymph node status, grade, hormone receptors, Her2 Status) as well as with recurrence and survival. RESULTS: Increased, rather than aberrant E-Cadherin expression was found and was associated with poor outcome (p = 0.046). Our data show an association between elevated E-Cadherin in primary tumour tissue and an unfavourable negative prognosis in patients. CONCLUSION: This association was somehow unexpected as loss of E-Cadherin has long been regarded as a prerequisite for development of invasiveness and metastases. Our findings support the notion that E-Cadherin promotes, rather than suppresses, development of metastasis and invasiveness.
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Neoplasias da Mama , Caderinas , Antígenos CD/metabolismo , Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Caderinas/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , PrognósticoRESUMO
OBJECTIVE: Ovarian cancer is the most lethal gynecologic cancer. Resveratrol (RSV) is known to alter metabolism in cancer. It affects the nuclear retinoid-X-receptor (RXR), which implies a modulating effect of RXR to gynaecologic cancers. Furthermore, RSV targets Sirtuin1 (Sirt1), a histone deacetylase. STUDY DESIGN: 123 tissue samples of patients with serous or mucinous ovarian cancer were examined for expression of Sirt1 and RXR. Ovarian cell lines were treated with RSV and consequences on viability and apoptosis were evaluated. The influence of RSV to Sirt1 and RXR expression was analyzed by western blotting RESULTS: A correlation of nuclear Sirt1 and RXRα expression could be detected (p = 0.006). Co-expression of nuclear RXRα and cytoplasmic (p = 0.026) or nuclear (p = 0.041) Sirt1 was associated with significantly increased overall survival in advanced tumour stages. Viability was decreased in all cell lines after stimulation with resveratrol, while cell apoptosis was increased. RSV treatment led to significant lower Sirt1 expression in A2780 cells (p = 0.025) and significant increased RXR expression in cisA2780 cells (p = 0.012) CONCLUSION: In order to use RSV as medical target, studies could be developed to improve the understanding of drug resistance mechanisms and consequently improve treatment outcome.
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Neoplasias Ovarianas , Resveratrol , Receptor X Retinoide alfa , Sirtuína 1 , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Prognóstico , Resveratrol/farmacologia , Receptor X Retinoide alfa/genética , Sirtuína 1/genéticaRESUMO
(1) Background: Placental immune cells are playing a very important role in a successful placentation and the prevention of pregnancy complications. Macrophages dominate in number and relevance in the maternal and the fetal part of the placenta. The evidence on the polarization state of fetal and maternal macrophages involved in both, healthy and pregnancy-associated diseases, is limited. There is no representative isolation method for the direct comparison of maternal and fetal macrophages so far. (2) Material and Methods: For the isolation of decidual macrophages and Hofbauer cells from term placenta, fresh tissue was mechanically dissected and digested with trypsin and collagenase A. Afterwards cell enrichment was increased by a Percoll gradient. CD68 is represented as pan-macrophage marker, the surface markers CD80 and CD163 were further investigated. (3) Results: The established method revealed a high cell yield and purity of the isolated macrophages and enabled the comparison between decidual macrophages and Hofbauer cells. No significant difference was observed in the percentage of single CD163+ cells in the distinct macrophage populations, by using FACS and immunofluorescence staining. A slight increase of CD80+ cells could be found in the decidual macrophages. Considering the percentage of CD80+CD163- and CD80-CD163+ cells we could not find differences. Interestingly we found an increased number of double positive cells (CD80+CD163+) in the decidual macrophage population in comparison to Hofbauer cells. (4) Conclusion: In this study we demonstrate that our established isolation method enables the investigation of decidual macrophages and Hofbauer cells in the placenta. It represents a promising method for direct cell comparison, enzyme independently, and unaffected by magnetic beads, to understand the functional subsets of placental macrophages and to identify therapeutic targets of pregnancy associated diseases.
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Placenta , Receptores de Superfície Celular , Antígenos CD , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígeno B7-1/metabolismo , Moléculas de Adesão Celular/metabolismo , Feminino , Humanos , Macrófagos/metabolismo , Placenta/metabolismo , Gravidez , Receptores de Superfície Celular/metabolismoRESUMO
There are several open questions to be answered regarding the pathophysiology of the development of preeclampsia (PE). Numerous factors are involved in its genesis, such as defective placentation, vascular impairment, and an altered immune response. The activation of the adaptive and innate immune system represents an immunologic, particularity during PE. Proinflammatory cytokines are predominantly produced, whereas immune regulatory and immune suppressive factors are diminished in PE. In the present study, we focused on the recruitment of regulatory T cells (Tregs) which are key players in processes mediating immune tolerance. To identify Tregs in the decidua, an immunohistochemical staining of FoxP3 of 32 PE and 34 control placentas was performed. A clearly reduced number of FoxP3-positive cells in the decidua of preeclamptic women could be shown in our analysis (p = 0.036). Furthermore, CCL22, a well-known Treg chemoattractant, was immunohistochemically evaluated. Interestingly, CCL22 expression was increased at the maternal-fetal interface in PE-affected pregnancies (psyncytiotrophoblast = 0.035, pdecidua = 0.004). Therefore, the hypothesis that Tregs undergo apoptosis at the materno-fetal interface during PE was generated, and verified by FoxP3/TUNEL (TdT-mediated dUTP-biotin nick end labeling) staining. Galectin-2 (Gal-2), a member of the family of carbohydrate-binding proteins, which is known to be downregulated during PE, seems to play a pivotal role in T cell apoptosis. By performing a cell culture experiment with isolated Tregs, we could identify Gal-2 as a factor that seems to prevent the apoptosis of Tregs. Our findings point to a cascade of apoptosis of Tregs at the materno-fetal interface during PE. Gal-2 might be a potential therapeutic target in PE to regulate immune tolerance.
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Decídua/imunologia , Regulação para Baixo , Galectina 2/metabolismo , Pré-Eclâmpsia/metabolismo , Linfócitos T Reguladores/citologia , Adolescente , Adulto , Apoptose , Estudos de Casos e Controles , Células Cultivadas , Quimiocina CCL22/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Idade Materna , Gravidez , Linfócitos T Reguladores/metabolismo , Regulação para Cima , Adulto JovemRESUMO
BACKGROUND: An abundance of tumor-associated macrophages has been shown to be an independent prognostic factor for a poor prognosis of human breast cancer (BC). Adipose tissue accounts for the largest proportion of the breast and has also been identified as an independent indicator of poor survival in BC. This study aims to elucidate if the influence of adipose tissue in BC might be mediated by macrophages. The roles of macrophages in the breast tumor-stroma (breast tumor stroma macrophages, BTSM) and macrophages in the surrounding adipose tissue (breast adipose tissue macrophages, BATM) were explored separately. METHODS: Two hundred ninety-eight BC tissue samples were analyzed immunohistochemically. The number of macrophages was detected by CD68+ staining. The quantity of BATMs and BTSMs was correlated to clinical and pathological parameters as well as to disease-free survival (DFS) and overall survival (OS). RESULTS: The amounts of BATMs and BTSMs strongly correlated with each other (r = 0.5, p = 2.98E-15). The quantity of BTSMs, but not of BATMs, was significantly associated with the BC molecular subtype (p = 0.000011), and all triple-negative BC tumors contained high amounts of BTSMs. BATMs were negatively associated with DFS (p = 0.0332). Both BATMs (p = 0.000401) and BTSMs (p = 0.021) were negatively associated with OS in the Kaplan-Meier analysis, but only BATMs remained an independent factor in the multivariate Cox-regression analysis (HR = 4.464, p = 0.004). Combining prostaglandin E2 receptor 3 (EP3)-expression and the quantity of BATMs, a subgroup with an extremely poor prognosis could be identified (median OS 2.31 years in the "high BATMs/low EP3" subgroup compared to 11.42 years in the most favorable "low BATMs/high EP3" subgroup, p = 0.000002). CONCLUSION: Our findings suggest that BTSMs and BATMs seem to be involved differently in BC. Breast adipose tissue might contribute to the aggressiveness of BC via BATMs, which were independently associated with BC survival. BATMs' role and occurrence might be functionally dependent on EP3, as a combination of both factors was strongly associated with survival. Targeting BATMs-eventually in combination with targeting the EP3-pathway-might be promising for future therapies.
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Tecido Adiposo/patologia , Neoplasias da Mama/mortalidade , Macrófagos Associados a Tumor/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptores de Prostaglandina E Subtipo EP3/metabolismo , Taxa de SobrevidaRESUMO
OBJECTIVES: While research on doctor-patient interaction has often focused on the decision-making abilities of physicians, it rarely centers around the question of how patients choose their respective practitioners. Research on fundamental decision processes is of high importance and understanding the factors that influence people's choices in real-life decision-making would potentially provide patients, and physicians alike, with the means to provide better resources to achieve greater satisfaction from visits to a medical practitioner. METHODS: At our tertiary referral center, patients were given the opportunity to voluntarily participate in our survey. We collected questionnaires from 1,002 patients during their visit from November 2018 to February 2020. Statistical analysis was performed using SPSS V26.0 software (SPSS Statistics, Version 26.0.; IBM, Armonk, NY, USA). Results are reported as percentages for categorial variables. RESULTS: Our patient cohort consisted of a higher percentage of men than of women (82 vs. 18%) with significantly more men having a university-based education (44 vs. 31%; p = 0.001). Women were more likely to have statutory health insurance than men (85 vs. 74%; p = 0.013). Men significantly preferred to be treated by a doctor of the same sex (24 vs. 8%; p < 0.001), which significantly increased with age. Overall, more women than men trusted a referral by their primary care physician (75 vs. 66%, p = 0.017), while preference of a higher academic degree in the attending urologist was significantly correlated with the patients' education. CONCLUSIONS: Information on a specialist, such as professional qualifications and academic accomplishments, is easily accessible to patients with or without access to the Internet. However, recommendations and referrals, in addition to consistent care by the same treating physician, seem to be of high importance to all patients, regardless of gender or age.
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Comportamento de Escolha , Conhecimentos, Atitudes e Prática em Saúde , Preferência do Paciente , Encaminhamento e Consulta , Urologistas , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Educação de Pós-Graduação em Medicina , Escolaridade , Feminino , Pesquisa sobre Serviços de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Inquéritos e Questionários , Urologistas/educação , Adulto JovemRESUMO
The aim of this study was to analyze the expression of peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor α (RxRα), a binding heterodimer playing a pivotal role in the successful trophoblast invasion, in the placental tissue of preeclamptic patients. Furthermore, we aimed to characterize a possible interaction between PPARγ and H3K4me3 (trimethylated lysine 4 of the histone H3), respectively H3K9ac (acetylated lysine 9 of the histone H3), to illuminate the role of histone modifications in a defective trophoblast invasion in preeclampsia (PE). Therefore, the expression of PPARγ and RxRα was analyzed in 26 PE and 25 control placentas by immunohistochemical peroxidase staining, as well as the co-expression with H3K4me3 and H3K9ac by double immunofluorescence staining. Further, the effect of a specific PPARγ-agonist (Ciglitazone) and PPARγ-antagonist (T0070907) on the histone modifications H3K9ac and H3K4me3 was analyzed in vitro. In PE placentas, we found a reduced expression of PPARγ and RxRα and a reduced co-expression with H3K4me3 and H3K9ac in the extravillous trophoblast (EVT). Furthermore, with the PPARγ-antagonist treated human villous trophoblast (HVT) cells and primary isolated EVT cells showed higher levels of the histone modification proteins whereas treatment with the PPARγ-agonist reduced respective histone modifications. Our results show that the stimulation of PPARγ-activity leads to a reduction of H3K4me3 and H3K9ac in trophoblast cells, but paradoxically decreases the nuclear PPARγ expression. As the importance of PPARγ, being involved in a successful trophoblast invasion has already been investigated, our results reveal a pathophysiologic connection between PPARγ and the epigenetic modulation via H3K4me3 and H3K9ac in PE.
Assuntos
Epigênese Genética , Histonas/genética , PPAR gama/genética , Pré-Eclâmpsia/genética , Receptor X Retinoide alfa/genética , Trofoblastos/metabolismo , Adulto , Benzamidas/farmacologia , Estudos de Casos e Controles , Feminino , Histonas/metabolismo , Humanos , Metilação/efeitos dos fármacos , PPAR gama/agonistas , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismo , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/patologia , Gravidez , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Piridinas/farmacologia , Receptor X Retinoide alfa/metabolismo , Transdução de Sinais , Tiazolidinedionas/farmacologia , Trofoblastos/efeitos dos fármacos , Trofoblastos/patologiaRESUMO
Sialic acid-binding immunoglobulin-like lectins (Siglecs) are involved in various immune cell-mediated diseases. Their role in cancer is poorly investigated, and research focusses on Siglec-expression on immune cells interacting with tumor cells. This study evaluates the role of Siglec-8 in breast cancer (BC). Siglec-8 expression was analyzed immunohistochemically on 235 primary BC cases and was correlated with clinical and pathological parameters and outcome. Cell culture experiments were performed with various BC cell lines. Siglec-8 was expressed in 215 BC cases and expression was lowest in triple-negative BC. It correlated with estrogen receptor-status, grading and the prognostic factors galectin (Gal)-7 and tumor-associated mucin-1 (TA-MUC1). However, Gal-7 and TA-MUC1 were only prognosticators for clinical outcome in the cohort expressing high (Immunoreactivity score IRS > 3) Siglec-8 levels but not in the low-expressing cohort. Siglec-8 knockdown led to a significantly reduced Gal-7 expression in MCF7 cells. All BC cell lines expressed low Siglec-8-levels, that could be elevated in MCF7 by Peroxisome proliferator-activated receptor (PPARγ)-stimulation. This study demonstrates that Siglec-8 is expressed in BC cells and correlates with known clinical and prognostic parameters. It is probably associated with Gal-7 and TA-MUC1 and might be regulated via PPARγ. Further analyses focusing on functional associations will clarify Siglec-8's eligibility as a possible therapeutic target.
Assuntos
Antígenos CD/biossíntese , Antígenos de Diferenciação de Linfócitos B/biossíntese , Neoplasias da Mama/metabolismo , Lectinas/biossíntese , Receptores de Estrogênio/metabolismo , Adulto , Idoso , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos B/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Galectinas/biossíntese , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica/métodos , Lectinas/genética , Células MCF-7 , Pessoa de Meia-Idade , Mucina-1/biossíntese , Gradação de Tumores , PrognósticoRESUMO
Prostaglandin induced signalling is involved in different cancers. As previously described, the EP3 receptor expression decreases with increasing stage of cervical intraepithelial lesions (CIN). In addition, in cervical cancer EP3 is an independent prognosticator for overall survival and correlates with FIGO stages. Currently the role of Prostaglandin 2 receptor 2 (EP2) in CIN is unknown. The aim of this study was to analyse the expression of EP2 for potential prognostic value for patients with cervical dysplasia. EP2 expression was analysed by immunohistochemistry in 33 patient samples (CIN1-3) using the immune-reactivity scoring system (IRS). Expression levels were correlated with clinical outcome to analyse prognostic relevance in patients with CIN2. Data analysis was performed using non parametric Kruskal-Wallis and Spearman rank sum test. Cytoplasmic expression levels of EP2 correlated significantly (p < 0.001) with different grades of cervical dysplasia. Median EP2-IRS in CIN1 was 2 (n = 8), 3 in CIN2 (n = 9) and 6 in CIN3 (n = 16). Comparing regressive (n = 3, median IRS = 2) to progressive (n = 6, median IRS = 4) CIN2 cases the median IRS differed significantly (p = 0.017). Staining intensity (p = 0.009) and IRS (p = 0.005) of EP2 and EP3 correlate inversely. EP2 expression level significantly increases with higher grade of CIN and could qualify as a potential prognostic marker for the regressive or progressive course in CIN2 lesions. These findings emphasize the significant role of PGE2 signalling in CIN and could help to identify targets for future therapies.
Assuntos
Biomarcadores Tumorais/biossíntese , Receptores de Prostaglandina E Subtipo EP2/biossíntese , Displasia do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Prognóstico , Receptores de Prostaglandina E Subtipo EP2/análise , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Neoplasias do Colo do Útero/diagnóstico , Displasia do Colo do Útero/diagnósticoRESUMO
The vitamin D receptor (VDR), primarily known as a crucial mediator of calcium homeostasis and metabolism, has been shown to play a significant role in various cancer entities. Previous studies have focused on vitamin D and its receptor in gynecological cancers, noting that the receptor is upregulated in epithelial ovarian cancer (EOC). The aim of this study is to analyze the prognostic impact of VDR and its functional significance in ovarian cancer. Through immunohistochemistry, VDR staining was examined in 156 ovarian cancer samples. Evaluation of VDR staining was conducted in the nucleus and the cytoplasm using the semi-quantitative immunoreactive score, and the scores were classified into high- and low-level expressions. Expression levels were correlated with clinical and pathological parameters as well as with overall survival to assess for prognostic impact. Differences in cytoplasmic VDR expression were identified between the histological subtypes (p = 0.001). Serous, clear cell, and endometrioid subtypes showed the highest staining, while the mucinous subtype showed the lowest. Cytoplasmic VDR correlated with higher FIGO stage (p = 0.013; Cc = 0.203), positive lymph node status (p = 0.023; Cc = 0.236), high-grade serous histology (p = 0.000; Cc = 0.298) and grading from the distinct histological subtypes (p = 0.006; Cc = - 0.225). Nuclear VDR did not correlate with clinicopathological data. High cytoplasmic expression of VDR was associated with impaired overall survival (HR 2.218, 32.5 months vs. median not reached; p < 0.001) and was confirmed as a statistically independent prognostic factor in the Cox regression multivariate analysis. Additional knowledge of VDR as a biomarker and its interactions within the mitogen-activated protein kinase (MAPK) signaling pathway could potentially improve the prognosis of therapeutic approaches for specific subgroups in EOC.