Zastosowanie etanerceptu u kobiet z niepowodzeniami rozrodu

Objective: The aim of the study was to evaluate the effect of etanercept immunotherapy on peripheral natural killer (NK) cell activity in women with a history of recurrent miscarriage (RM) or failed in vitro fertilization (IVF). Materials and methods: Thirty nonpregnant women with reproductive failure and increased peripheral NK-cell number and/or activity before conception were studied. Women with reproductive failure received 4 doses (25 mg) of etanercept twice weekly before conception. Peripheral NK-cell activity before and after etanercept therapy in RM women was measured using flow cytometry. In addition, the peripheral blood NK-cell surface antigens- CD16- and CD56 and peripheral blood regulatory T cell (T reg) antigens- CD4- and CD25 were studied using flow cytometry, before treatment and 2 weeks after the last etanercept dose. Results: NK-cell activity was significantly decreased after etanercept therapy in the study women (P0.05). Conclusion: Etanercept therapy might be effective treatment for women with increased NK-cell activity. Regulation of immune system activity may underlie the possible effect of such therapy.Cel pracy: Celem pracy była ocena wpływu etanerceptu na aktywność komórek NK krwi obwodowej u kobiet z poronieniami nawykowymi (RM) lub wielokrotnymi niepowodzeniami zapłodnienia pozaustrojowego (IVF). Materiał i metody: Badaniem objęto 30 kobiet z niepowodzeniami rozrodu i zwiększoną liczbą i/lub aktywnością komórek NK krwi obwodowej. Chore otrzymały 4 dawki (25mg) etanerceptu dwa razy w tygodniu przed planowaną ciążą. Aktywność komórek NK zbadano przed i po podaniu leku metodą cytometrii przepływowej. Dodatkowo oceniono ekspresję markerów powierzchniowych komórek NK CD16- i CD56 oraz limfocytów T regulatorowych (T reg) CD4- i CD25 metodą cytometrii przepływowej przed leczeniem oraz 2 tygodnie po ostatniej dawce leku. Wyniki: Aktywność komórek NK była znamiennie zmniejszona po podaniu etanerceptu w grupie badanych chorych (P0,05). Wnioski: Etanercept może być efektywną opcją terapeutyczną u kobiet ze zwiększoną ekspresją komórek NK. Regulacja aktywności układu immunologicznego może leżeć u podstaw skuteczności tej eksperymentalnej terapii

Procesy starzenia się komórki jajowej a niepłodność

The biological state of the ovum remains the key element in normal reproduction. Age-related decrease in the number of oocytes, as well as disturbed neuroendocrine function of the ovary and lesions in the uterus, contribute to reduced fertility. Decreasing number of ovarian follicles is accompanied by reduction of their quality, including mainly abnormalities of the nucleus (dispersed chromatin, decondensation of chromosomes and abnormalities connected with the spindle apparatus). This results in failed reproduction due to abnormal gametogenesis, fertilization process, early development of the embryo and abnormal implantation. This work describes age-related biochemical mechanisms conditioning molecular changes occurring due to abnormal microenvironment of the ovary; their accumulation leads to aging and to a more rapid apoptosis of the oocyte. There are many theories explaining the causes of oocyte destruction, including abnormal vascularization, oxidative stress, imbalance of free radicals, influence of toxic compounds and genetic changes. Decreased blood perfusion in the microenvironment of a maturating ovum leads to hypoxia and thus to a chain of reactions of oxidative stress. Oxidative imbalance leads to abnormalities of cellular biomolecules. Moreover, it is suggested that glycation processes in a cell, leading to the formation of compounds called AGEs (Advanced Glycation End Products), are also responsible for aging of the cells. They contribute directly to protein damage, induce a chain of reactions of oxidative stress, and increase the inflammatory reactions. Recently, the role of mitochondria and telomeres in the aging process and loss of reproductive functions has been especially underscored. Moreover, this work stresses the prognostic value of clinically used markers evaluating the ovarian reserve. The role of Anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), estradiol, inhibin B and antral follicle count (AFC) was presented in this paper.Kluczowym elementem warunkującym prawidłowy rozród pozostaje stan biologiczny komórki jajowej. Spadek liczby oocytów związany ze starzeniem, a także zaburzenia neuroendokrynnej funkcji jajnika oraz zmiany w macicy przyczyniają się do ograniczenia płodności. Zmniejszaniu liczby pęcherzyków jajnikowych towarzyszy znaczne obniżenie ich jakości, obejmujące zwłaszcza nieprawidłowości jądra komórkowego (rozproszona chromatyna, de kondensacja chromosomów oraz zaburzenia związane z wrzecionem podziałowym). Konsekwencją tego są następnie niepowodzenia rozrodu wynikające z nieprawidłowości gametogenezy, procesu zapłodnienia, wczesnego rozwoju zarodka oraz nieprawidłowej implantacji. Praca ta opisuje związane z wiekiem mechanizmy biochemiczne warunkujące zmiany molekularne zachodzące pod wpływem nieprawidłowego mikrośrodowiska jajnika, których kumulacja prowadzi do starzenia się oraz do przyśpieszonego wejścia oocytu na drogę apoptozy. Istnieje wiele teorii wskazujących na przyczyny uszkodzenia oocytów: nieprawidłowe unaczynienie, stres oksydacyjny i zaburzenia równowagi wolnych rodników, wpływ związków toksycznych oraz zmiany na poziomie genetycznym. Zmniejszony przepływ krwi w mikrośrodowisku dojrzewającej komórki jajowej prowadzi do hipoksji, a w efekcie do rozwoju ciągu reakcji stresu oksydacyjnego. Konsekwencją zaburzenia równowagi oksydacyjnej są nieprawidłowości biomolekuł komórkowych. Ponadto sugeruje się, że zachodzące w komórkach procesy glikacji prowadzące do powstania związków nazywanych ogólnie AGEs (ang. Advanced Glycation End Products), także są odpowiedzialne za starzenie się komórek. Przyczyniają się bezpośrednio do uszkodzenia białek, indukują ciąg reakcji stresu oksydacyjnego oraz nasilają reakcje zapalne. Ostatnio szczególną uwagę zwraca się na rolę mitochondriów i telomerów w procesie starzenia i utraty funkcji reprodukcyjnych. W pracy tej podkreślono ponadto wartość prognostyczną stosowanych w praktyce klinicznej markerów oceniających rezerwę jajnikową. Przedstawiono rolę hormonu antymüllerowskiego, hormonu folikulotropowego, estradiolu, inhibiny B oraz rolę oceny liczby pęcherzyków antralnych

3D laparoscopy as a tertiary cytoreductive (TCR) surgery in infiltrating ureter recurrent epithelial ovarian cancer : case report and a mini-review of the literature

The paper describes a case of a 61-year-old woman with recurrent epithelial ovarian cancer infiltrating the ureter treated with 3D laparoscopy as a tertiary cytoreductive surgery (TCR). In addition, a mini-review of the literature concerning TCR is presented

CA 125 regression after two cycles of neoadjuvant chemiotherapy as prognostic factor in patients with advanced ovarian cancer and primary peritoneal serous cancer who underwent interval surgical cytoreduction

Abstract Objectives: The aim of our study was to assess the prognostic role of CA 125 regression during neoadjuvant chemotherapy (NAC) in patients with ovarian cancer (OC) or primary peritoneal serous carcinoma (PPSC) that underwent interval debulking surgery (IOC). Material and methods: Thirty one patients with advanced OC or PPSC (FIGO stage IIIC and IV) who underwent initial exploratory surgery, followed by NAC containing platinum analogs, have been analyzed, retrospectively. We have used a regression coefficient (RCA 125), which was calculated as following: log10 (CA 125 level measured after two cycles of NAC/ baseline CA 125) for statistical analysis. The median value of RCA 125 reached -0.788 and has been used to dichotomize. Optimal IOC has been performed in 67.74% (21/31) patients, suboptimal in 25.81% (8/31) patients and 6.45% (2/31) of patients did not undergo IOC due to the progression of the disease. Results: We have noted significant correspondence between time to progression and RCA 125 in univariate analysis, which we have also confirmed in multivariate analysis (HR 0.27; 95%CI, 0.15-0.96; p=0.0118). Similarly, we have observed significant relationship between overall survival, RCA 125 and extension IOC in univariate analysis. Multivariate analysis confirmed that RCA 125 was independent prognostic factor, HR-0.18 (95%CI, 0.07-0.56; p=0.004). In case of patients with high RCA 125, a greater rate of optimal debulking cytoreduction (p=0.0278, U=50.0) has been observed. Conclusions: RCA 125 after two courses of NAC appears to be an important prognostic factor in patients with OC or PPSC, who underwent IOC. High RCA125 during NAC seems to be a good predictive factor in order to achieve optimal IOC

Sildenafil Citrate Downregulates PDE5A mRNA Expression in Women with Recurrent Pregnancy Loss without Altering Angiogenic Factors—A Preliminary Study

In our previous study, we showed that sildenafil citrate (SC), a selective PDE5A blocker, modulated NK cell activity in patients with recurrent pregnancy loss, which correlated with positive pregnancy outcomes. It was found that NK cells had a pivotal role in decidualization, angiogenesis, spiral artery remodeling, and the regulation of trophoblast invasion. Thus, in the current study, we determined the effects of SC on angiogenic factor expression and production, as well as idNK cell activity in the presence of nitric synthase blocker L-NMMA. Methods: NK cells (CD56+) were isolated from the peripheral blood of 15 patients and 15 fertile women on MACS columns and cultured in transformation media containing IL-15, TGF-β, and AZA—a methylation agent—for 7 days in hypoxia (94% N2, 1% O2, 5% CO2). Cultures were set up in four variants: (1) with SC, (2) without SC, (3) with NO, a synthase blocker, and (4) with SC and NO synthase blocker. NK cell activity was determined after 7 days of culturing as CD107a expression after an additional 4h of stimulation with K562 erythroleukemia cells. The expression of the PDE5A, VEGF-A, PIGF, IL-8, and RENBP genes was determined with quantitative real-time PCR (qRT-PCR) using TaqMan probes and ELISA was used to measure the concentrations of VEGF-A, PLGF, IL-8, Ang-I, Ang-II, IFN–γ proteins in culture supernatants after SC supplementation. Results: SC downregulated PDE5A expression and had no effect on other studied angiogenic factors. VEGF-A expression was increased in RPL patients compared with fertile women. Similarly, VEGF production was enhanced in RPL patients’ supernatants and SC increased the concentration of PIGF in culture supernatants. SC did not affect the expression or concentration of other studied factors, nor idNK cell activity, regardless of NO synthase blockade

Differences in the Expression of KIR, ILT Inhibitory Receptors, and VEGF Production in the Induced Decidual NK Cell Cultures of Fertile and RPL Women

Problem. Natural killer (NK) cells are the most abundant leukocyte population in the uterus. The interactions of the maternal NK expression of killer cell immunoglobulin-like receptors (KIRs) and human inhibitory receptor Ig-like transcript (ILT) with fetal HLA determine the activation of NK cells and pregnancy outcomes. Moreover, dNK cells release numerous angiogenic factors including VEGF. Our previous study showed that sildenafil citrate (SC) significantly decreased peripheral blood NK (pbNK) cell activity and improved intrauterine blood flow, which correlated with a successful pregnancy outcome. Thus, in this study, we investigated whether SC influenced the expression of KIR or ILT receptors on induced decidual NK (idNK), the apoptosis of cells, and VEGF-A production in the culture supernatants of idNK cells. Method of Study. pbNK cells from 24 healthy women and 23 women with RPL were converted to idNK cells under hypoxia, IL-15, and TGF-β conditions. The cultures were prepared with or without SC. Changes in KIR2DL1 (CD158a), NKG2A (CD159a), ILT-2 (CD85j), and ILT-4 (CD85d) expression on CD56+CD16- cells and their apoptosis were determined via flow cytometry. VEGF-A level was established in culture supernatants with the ELISA method. Results. KIR2DL1 and ILT-2 expression on idNK cells was higher in healthy women than in RPL patients. Sildenafil enhanced NKG2A expression in RPL patients. VEGF concentration was higher in fertile woman idNK cell cultures. idNK cells were more sensitive for necrosis in RPL than in fertile women. SC did not influence VEGF production or idNK cell apoptosis. Conclusions. A combination of hypoxia, IL-15, and AZA promotes the conversion of pbNK into idNK cells CD56+CD16--expressing KIR receptors and produces VEGF. Alterations in KIR2DL1 and ILT-2 expression as well as impaired VEGF production were associated with RPL. SC affects NKG2A expression on RPL idNK cells. SC had no effect on VEGF release or idNK cell apoptosis