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Background: To preserve the benefit of atrial sensing without the implantation of an additional lead, a single-lead ICD system with a floating atrial dipole (DX ICD) has been developed. The purpose of this nationwide survey was to provide an overview of the current key influences of device selection focusing on DX ICD and to test the applicability of a previously published decision-making flowchart of ICD-type selection., Methods: An online questionnaire was sent to all implanting centers in Hungary. Eleven centers reported data from 361 DX ICD and 10 CRT-DX systems implantations between February 2021 and May 2023., Results: The most important influencing clinical factors indicated by the participating doctors were elevated risk of atrial fibrillation (AF)/stroke (56%), risk of sinus/supraventricular tachycardias (SVT) (42%), and a potential need for CRT upgrade in the future (36%). The DX ICD was considered in the majority of cases instead of the VVI system (87%), and only in a small proportion instead of a DDD ICD (13%). 60% of the patients with DX ICDs were also included into remote monitoring-based follow-up. In 83% of the cases, good (>2 mV) or excellent (>5) atrial signal amplitude was recorded within 6 weeks after the implantation., Conclusion: In the current national survey, the most important influencing factors indicated by the implanters for selecting a DX ICD were the elevated risk of stroke or sinus/SVT and a potential need for CRT upgrade in the future. These findings support the use of a previously published decision-making flowchart., (© 2024 The Author(s). Pacing and Clinical Electrophysiology published by Wiley Periodicals LLC.)

Although many studies have investigated the clinical aspect of early-onset preeclampsia, our knowledge about the immunological consequences of improper placenta development is scarce. The maternal immunotolerance against the fetus is greatly influenced by the Th1 predominance developed by the mother's immune system. Thirty-two early-onset preeclamptic and fifty-one healthy pregnant women with appropriately matched gestational age were involved in our study. Mononuclear cells were separated from peripheral venous blood and the frequency of CD8⁺, CD4⁺, double positive (DP), and double negative (DN) NKT cell subpopulations was determined using multicolor flow cytometry. Following the characterization, the expression levels of different immune checkpoint receptors and ligands were also defined. Soluble CD226 levels were quantified by ELISA. Novel and significant differences were revealed among the ratios of the investigated NKT subsets and in the expression patterns of PD-1, LAG-3, TIGIT and CD226 receptors. Further differences were determined in the expression of CD112, PD-1, LAG-3 and CD226 MFI values between the early-onset preeclamptic and the healthy pregnant groups. Our results suggest that the investigated NKT subpopulations act differently in the altered immune condition characteristic of early-onset preeclampsia and indicate that the different subsets may contribute to the compensation or maintenance of Th1 predominance.

Background: The importance of immune checkpoint molecules is well known in tumor and transplantation immunology; however, much less information is available regarding human pregnancy. Despite the significant amount of information about the TIGIT and CD226 immune checkpoint receptors in immune therapies, very little research has been conducted to study the possible role of these surface molecules and their ligands (CD112 and CD155) during the three trimesters of pregnancy. Methods : From peripheral blood, immune cell subpopulations were studied, and the surface expression of immune checkpoint molecules was analyzed by flow cytometry. Soluble immune checkpoint molecule levels were measured by ELISA. Results : Notable changes were observed regarding the percentage of monocyte subpopulation and the expression of CD226 receptor by CD4 + T and NKT cells. Elevated granzyme B content by the intermediate and non-classical monocytes was assessed as pregnancy proceeded. Furthermore, we revealed an important relationship between the CD226 surface expression by NKT cells and the serum CD226 level in the third trimester of pregnancy. Conclusions : Our results confirm the importance of immune checkpoint molecules in immunoregulation during pregnancy. CD226 seems to be a significant regulator, especially in the case of CD4 + T and NKT cells, contributing to the maternal immune tolerance in the late phase of pregnancy.

The neuroprotective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) have been shown in numerous in vitro and in vivo models of Parkinson's disease (PD) supporting the theory that PACAP could have an important role in the pathomechanism of the disorder affecting mostly older patients. Earlier studies found changes in PACAP levels in neurological disorders; therefore, the aim of our study was to examine PACAP in plasma samples of PD patients. Peptide levels were measured with ELISA and correlated with clinical parameters, age, stage of the disorder based on the Hoehn and Yahr (HY) scale, subtype of the disease, treatment, and specific scores measuring motor and non-motor symptoms, such as movement disorder society-unified Parkinson's disease rating scale (MDS-UPDRS), Epworth sleepiness scale (ESS), Parkinson's disease sleep scale (PDSS-2), and Beck depression inventory (BDI). Our results showed significantly decreased PACAP levels in PD patients without deep brain stimulation (DBS) therapy and in akinetic-rigid subtype; additionally we also observed a further decrease in the HY stage 3 and 4. Elevated PACAP levels were found in patients with DBS. There were no significant correlations between PACAP level with MDS-UPDRS, type of pharmacological treatment, PDSS-2 sleepiness, or depression (BDI) scales, but we found increased PACAP level in patients with more severe sleepiness problems based on the ESS scale. Based on these results, we suggest that following the alterations of PACAP with other frequently used clinical biomarkers in PD patients might improve strategic planning of further therapeutic interventions and help to provide a clearer prognosis regarding the future perspective of the disease., (© 2022. The Author(s).)

Galectins are one of the critical players in the tumor microenvironment-tumor crosstalk and the regulation of local immunity. Galectin-9 has been in the limelight in tumor immunology. Galectin-9 possesses its multiplex biological functions both extracellularly and intracellularly, plays a pivotal role in the modulation of adaptive and innate immunity, and induces immune tolerance. NK-92MI cell lines against different malignancies were extensively studied, and recently published trials used genetically chimeric antigen receptor-transfected NK-92MI cells in tumor immunotherapy. Besides the intensive research in tumor immunotherapy, limited information is available on their immune-checkpoint expression and the impact of checkpoint ligands on their effector functions. To uncover the therapeutic potential of modulating Galectin-9-related immunological pathways in NK-cell-based therapy, we investigated the dose-dependent effect of soluble Galectin-9 on the TIM-3 checkpoint receptor and NKG2D, CD69, FasL, and perforin expression of NK-92MI cells. We also examined how their cytotoxicity and cytokine production was altered after Gal-9 treatment and in the presence of different serum supplements using flow cytometric analysis. Our study provides evidence that the Galectin-9/TIM-3 pathway plays an important role in the regulation of NK cell function, and about the modulatory role of Galectin-9 on the cytotoxicity and cytokine production of NK-92MI cells in the presence of different serum supplements. We hope that our results will aid the development of novel NK-cell-based strategies that target Galectin-9/TIM-3 checkpoint in tumors resistant to T-cell-based immunotherapy.

Acute myocardial infarction (MI) is one of the most common causes of death worldwide. Pituitary adenylate cyclase activating polypeptide (PACAP) is a cardioprotective neuropeptide expressing its receptors in the cardiovascular system. The aim of our study was to examine tissue PACAP-38 in a translational porcine MI model and plasma PACAP-38 levels in patients with ST-segment elevation myocardial infarction (STEMI). Significantly lower PACAP-38 levels were detected in the non-ischemic region of the left ventricle (LV) in MI heart compared to the ischemic region of MI-LV and also to the Sham-operated LV in porcine MI model. In STEMI patients, plasma PACAP-38 level was significantly higher before percutaneous coronary intervention (PCI) compared to controls, and decreased after PCI. Significant negative correlation was found between plasma PACAP-38 and troponin levels. Furthermore, a significant effect was revealed between plasma PACAP-38, hypertension and HbA1c levels. This was the first study showing significant changes in cardiac tissue PACAP levels in a porcine MI model and plasma PACAP levels in STEMI patients. These results suggest that PACAP, due to its cardioprotective effects, may play a regulatory role in MI and could be a potential biomarker or drug target in MI.

Endometriosis is a gynecological condition that is associated with chronic pelvic inflammation, pain, and infertility. Although substantial evidence supports that immunological alterations contribute to its pathogenesis and we previously posed a pivotal role of Galectin-9 (Gal-9) in this disorder, the involvement of the TIM-3/Gal-9 pathway in the development of endometriosis-associated immunological abnormalities is not yet known. In the present study, multicolor flow cytometry was used to compare the immunophenotype and cell surface expression of TIM-3 and Gal-9 molecules on peripheral blood (PB) and peritoneal fluid (PF) lymphocytes of women with and without endometriosis. We found an altered distribution of different lymphocyte subpopulations, a markedly decreased TIM-3 labeling on all T and NK subsets and a significantly increased Gal-9 positivity on peripheral CD4+ T and Treg cells of the affected cohort. Furthermore, a significantly increased TIM-3 expression on CD4+T-cells and elevated Gal-9 labeling on all T and NK subsets was also revealed in the PF of the examined patients. In conclusion, our results suggest a persistent activation and disturbed TIM-3/Gal-9-dependent regulatory function in endometriosis, which may be involved in the impaired immune surveillance mechanisms, promotes the survival of ectopic lesions, and aids the evolution of reproductive failures in endometriosis.

Purpose: Pneumothorax (PTX) following cardiac implantable electronic device procedures is traditionally treated with chest tube drainage (CTD). We hypothesized that, in a subset of patients, the less invasive needle aspiration (NA) may also be effective. We compared the strategy of primary NA with that of primary CTD in a single-center observational study., Methods: Of the 970 procedures with subclavian venous access between January 2016 and June 2018, 23 patients had PTX requiring intervention. Beginning with March 2017, the traditional primary CTD (9 cases) has been replaced by the "NA first" strategy (14 patients). Outcome measures were procedural success rate and duration of hospitalization evaluated both as time to event (log-rank test) and as a discrete variable (Wilcoxon-Mann-Whitney test)., Results: Needle aspiration was successful in 8/14 (57.1%) of the cases (95% CI 28.9-82.3%), whereas PTX resolved in all patients after CTD was 9/9 (100%, 95% CI 66.4-100.0%, p = 0.0481). Regarding length of hospital stay, intention to treat time to event analysis showed no difference between the two approaches (p = 0.73). Also, the median difference was not statistically significant (- 2.0 days, p = 0.17). In contrast, per protocol evaluation revealed reduced risk of prolonged hospitalization for NA patients (p = 0.0025) with a median difference of - 4.0 days (p = 0.0012). Failure of NA did not result in a meaningful delay in discharge timing as median difference was 1.5 days (p = 0.28)., Conclusions: Our data suggest that in a number of patients iatrogenic PTX may be successfully treated with NA resulting in shorter hospitalization without the risk of meaningful discharge delay in unsuccessful cases.

Purpose: The most common hospital-acquired enteral infection is caused by Clostridium difficile. Unfortunately, Clostridium difficile infections (CDI) are of high risk to recur and little is known about how to predict recurrences. Previous findings have shown that high risk for recurrence correlates with low levels of C. difficile toxin-A and -B specific antibodies suggesting the protective role of humoral immunity against bacterial virulence factors. Therefore, the aim of this study was to develop an immunoassay, which specifically measures C.difficile toxin-specific antibodies in the serum that might be correlated with the risk of recurrence., Methods: We developed a simple ELISA to measure the quantity of toxin-A and -B-specific antibodies in human serum. The assay was then used to test anti-toxin immune response in healthy controls, in patients with primary CDI and patients with CDI recurrence., Results: The developed assay is simple, reproducible and fast. When using this test in a small clinical trial our results showed a trend toward a higher antibody level in those patients with only one episode of CDI, whereas patients with recurrent CDI had less anti-toxin A or B-specific antibodies in their serum indicating inadequate C. difficile anti-toxin immunity may facilitate recurrent infections., Conclusions: It has already been observed that low antibody levels are associated with recurrent CDI (Bauer et al., 2014). The findings of our clinical trial show a similar trend. Our developed ELISA test could help to conduct further research and it might be helpful in clinical use to detect patients of high risk for CDI recurrence., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Remote monitoring is an established, guideline-recommended technology with unequivocal clinical benefits; however, its ability to improve survival is contradictory., Objective: The aim of our study was to investigate the effects of remote monitoring on mortality in an optimally treated heart failure patient population undergoing cardiac resynchronization defibrillator therapy (CRT-D) implantation in a large-volume tertiary referral center., Methods: The population of this single-center, retrospective, observational study included 231 consecutive patients receiving CRT-D devices in the Medical Centre of the Hungarian Defence Forces (Budapest, Hungary) from January 2011 to June 2016. Clinical outcomes were compared between patients on remote monitoring and conventional follow-up., Results: The mean follow-up time was 28.4 (SD 18.1) months. Patients on remote monitoring were more likely to have atrial fibrillation, received heart failure management at our dedicated heart failure outpatient clinic more often, and have a slightly lower functional capacity. Crude all-cause mortality of remote-monitored patients was significantly lower compared with patients followed conventionally (hazard ratio [HR] 0.368, 95% CI 0.186-0.727, P=.004). The survival benefit remained statistically significant after adjustment for important baseline parameters (adjusted HR 0.361, 95% CI 0.181-0.722, P=.004)., Conclusions: In this single-center, retrospective study of optimally treated heart failure patients undergoing CRT-D implantation, the use of remote monitoring systems was associated with a significantly better survival rate., (©Peter Bogyi, Mate Vamos, Zsolt Bari, Balazs Polgar, Balazs Muk, Noemi Nyolczas, Robert Gabor Kiss, Gabor Zoltan Duray. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 26.07.2019.)

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic and multifunctional neuropeptide having neurotrophic, neuroprotective, and general cytoprotective actions in a variety of tissues based on its anti-apoptotic, anti-inflammatory, and antioxidant effects. Several studies have demonstrated its cardioprotective effects in vitro and in various animal models. However, few data are available on the presence of PACAP in human cardiac tissues and its role in the pathomechanism and progression of different cardiac disorders, particularly heart failure. Earlier, our research group has shown PAC1 receptor immunoreactivity in human heart tissue samples and we have found significantly elevated PACAP27- and PACAP38-like immunoreactivity in ischemic cardiac samples compared to valvular abnormalities with radioimmunoassay. In the last few years, numerous studies examined the presence and the changes of PACAP levels in different human tissue samples and biological fluids to show alterations in different physiological and pathological conditions. Therefore, the aim of the present study was to measure the alterations of blood PACAP levels in chronic heart failure caused by primary dilated cardiomyopathy or ischemic cardiomyopathy and to examine the possible relationship between serum levels of PACAP, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and systolic left ventricular function, the most reliable biomarkers of heart failure. In the group of mild heart failure patients, a significant strong negative correlation was detected. Furthermore, in moderate heart failure, we found a significant moderate negative correlation between PACAP and NT-proBNP levels only in ischemic subgroup. Positive correlation was found between serum PACAP level and ejection fraction only in patients with heart failure due to ischemic cardiomyopathy but not in patients with primary dilated cardiomyopathy. In summary, remarkable differences were observed between the ischemic and non-ischemic heart failure suggesting that PACAP might play an important role in the pathomechanism and progression of ischemic heart failure and it might be a potential biomarker of cardiac diseases in the future.

The abortifacient Mifepristone (RU486) has proven to be a safe, effective, acceptable option for millions of women seeking abortion during the first and second trimester of pregnancy although its precise mechanism of action is not well understood. The main objective of this study was to investigate the impact of low dose Mifepristone administration on placental Galectin-9 (Gal-9) expression, as well as its effect on the cell surface expression of Gal-9, TIM-3 and CD107a molecules by different T and NK cell subsets. A model of Mifepristone-induced immunological changes was established in syngeneic pregnant BALB/c mice. RU486-induced alteration in placental Gal-9 expression was determined by immunohistochemistry. For immunophenotypic analysis, mid-pregnancy decidual lymphocytes and peripheral mononuclear cells were obtained from Mifepristone treated and control mice at the 14.5 day of gestation. TIM-3 and Gal-9 expression by peripheral and decidual immune cells were examined by flow cytometry. Our results revealed a dramatically decreased intracellular Gal-9 expression in the spongiotrophoblast layer of the haemochorial placenta in Mifepristone treated pregnant mice. Although low dose RU486 treatment did not cause considerable change in the phenotypic distribution of decidual and peripheral immune cells, it altered the Gal-9 and TIM-3 expression by different NK and T cell subsets. In addition, the treatment significantly decreased the CD107a expression by decidual TIM-3+ NK cells, but increased its expression by decidual NKT cell compared to the peripheral counterparts. These findings suggest that low dose Mifepristone administration might induce immune alterations in both progesterone dependent and independent way.

Objective: To investigate the usefulness of soluble galectin-9 (Gal-9) in the noninvasive laboratory diagnosis of endometriosis and various gynecologic disorders., Design: Prospective case-control study., Setting: University medical centers., Patient(s): A total of 135 women of reproductive age were involved in the study, 77 endometriosis patients, 28 gynecologic controls, and 30 healthy women., Intervention(s): Diagnostic laparoscopy and collection of tissue biopsies, peritoneal cells, and native peripheral blood from different case groups of gynecology patients and healthy women., Main Outcome Measure(s): The expression of mRNA and serum concentration of Gal-9., Result(s): Semiquantitative reverse transcription-polymerase chain reaction analysis and serum soluble Gal-9 ELISA were performed on three different cohorts of patients: those with endometriosis, those with benign gynecologic disorders, and healthy controls. Differences in the Gal-9 concentrations between the investigated groups and the stability of Gal-9 in the serum and diagnostic characteristics of Gal-9 ELISA were determined by statistical evaluation and receiver operating characteristic (ROC) curve analysis. Significantly elevated Gal-9 levels were found in both minimal-mild (I-II) and moderate-severe (III-IV) stages of endometriosis in comparison with healthy controls. At a cutoff of 132 pg/mL, ROC analysis revealed an excellent diagnostic value of Gal-9 ELISA in endometriosis (area under the curve = 0.973) with a sensitivity of 94% and specificity of 93.75%, indicating better diagnostic potential than that of other endometriosis biomarkers. Furthermore, various pelvic pain or infertility-associated benign gynecologic conditions were also associated with increased serum Gal-9 levels., Conclusion(s): Our results suggest that Gal-9 could be a promising noninvasive biomarker of endometriosis and a predictor of various infertility or pelvic pain-related gynecologic disorders., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The aim of the study was to compare urine and serum concentrations of PIBF at 24-28 gestational weeks in women with preterm birth, with those of women who delivered at term and to evaluate the impact of PIBF on the outcome of pregnancy. Case-control study was performed in period from 1.6.2010-31.7.2013. Biological samples (urine and serum) were collected from 126 pregnant women. All biological samples were obtained at 24-28 gestation weeks. We measured PIBF concentration and compared women who delivered preterm and those who delivered at term. Thirteen of 126 pregnant women (10.3%) who were included in the study delivered preterm. Among women that actually delivered preterm, median concentrations of PIBF were significantly lower (12.3ng/ml; 101.3ng/ml) than in women who delivered at term (77.0ng/ml; 412.7ng/ml). The serum and urine 24-28 gestational weeks PIBF in those who delivered preterm were generally low from 24 to 37 gestational weeks, while the serum and urine PIBF concentration reached a peak in those delivering between 37-38 gestational weeks, even significantly different from those delivering at 39 to 40 and after 40 gestational weeks. Preterm birth may be predictable at 24-28 gestational week by lower than normal pregnancy PIBF values and measurement of PIBF concentration in biological fluids at that time may be of importance in clinical practice., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The objective of this study was to analyze the maternal serum concentration of progesterone-induced blocking factor (PIBF) with regard to the prediction and the interval between sampling and the onset of preterm birth. A prospective study was conducted on a sample of 37 women with threatened pre-term birth and 41 healthy pregnant women between the 24th and 28th gestational weeks. Out of 37 patients with threatened preterm birth 11 delivered pre-term and three groups of patients were formed: the preterm delivery group, patients with threatened preterm delivery, and healthy pregnant women. In samples that were taken within 5 days before labor started (6/11, 54.5%), PIBF concentrations were significantly lower than in those obtained more than 5 days before labor (5/11, 45.5%; the mean interval between sampling and the onset of labor was 4.1 ± 1.8 days). Multiple regression analysis of the individual contributions of each observed parameter for preterm delivery demonstrated the significant contribution of a lack of PIBF to preterm birth (p = 0.002). Receiver operating characteristics (ROC) analysis was performed to evaluate the diagnostic accuracy of PIBF for the prediction of preterm birth of women with symptoms of pre-term delivery. The PIBF demonstrated an excellent diagnostic value in the prediction of preterm birth with an area under the ROC curve (AUC) of 0.956 (95% CI = 0.884-0.989; p < 0.0001). Our data suggest that pregnancy termination can be predicted by lower than normal pregnancy PIBF values within 5 days before labor and can contribute to the diagnosis of preterm birth., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Problem: The T-cell immunoglobulin and mucin domain (TIM) family is a relatively newly described group of molecules with a conserved structure and important immunological functions. Identification of Galectin-9 as a ligand for TIM-3 has established the Galectin-9/TIM-3 pathway as an important negative regulator of Th1 immunity and tolerance induction. Data about the TIM-3/Gal-9 pathway in the pathogenesis of human diseases is emerging, but their possible role during human pregnancy is not precisely known. The aim of our study was to investigate the number, phenotype and functional activity of TIM-3+ peripheral blood mononuclear cells during healthy human pregnancy., Methods of Study: 57 healthy pregnant women [first trimester (n = 16); second trimester (n = 19); third trimester (n = 22)] and 30 non-pregnant controls were enrolled in the study. We measured the surface expression of TIM-3 by cytotoxic T cells, NK cells and NK cell subsets as well as Galectin-9 expression by regulatory T cells by flow cytometry. We analyzed the cytokine production and cytotoxicity of TIM3+ and TIM3- CD8 T and NK cells obtained from non-pregnant and healthy pregnant women at different stages of pregnancy by flow cytometry. Serum Galectin-9 levels were measured by ELISA., Results: Our results show that the numbers of peripheral NK and cytotoxic T cells and their TIM-3 expression do not change between the first, second and third trimesters of pregnancy. Compared to non-pregnant individuals, regulatory T cells show higher level of Galectin-9 expression as pregnancy proceeds, which is in line with the level of Galectin-9 in the patients sera. Cytotoxic T cells, NK cells and NK cell subsets expressing TIM-3 molecule show altered cytokine production and cytotoxicity during pregnancy compared to non-pregnant individuals., Conclusion: Our results indicate that Galectin-9 expressing regulatory T cells, TIM-3+ cytotoxic T cells and NK cells could play an important role in the maintenance of healthy pregnancy.

Problem: Progesterone induced blocking factor (PIBF) is required for successful pregnancy. Alternative splicing produces PIBF isoforms with different functions. The full-length (90 kDa) PIBF is involved in cell cycle regulation, whereas smaller secreted forms act as cytokines. We aim to examine the PIBF exon pattern and protein isoform profile in normal and failed murine pregnancies., Method of Study: Pregnant Balb/c mice were killed on gestation days 12-14 or 17-19. Normal and resorbed fetuses, placentae, and uterine tissue were used for RNA and protein analysis with RT-PCR and Western blot, respectively., Results: Late pregnancy and resorption were associated with lower expression of the N-terminal exons, together with significantly reduced production of the full-length protein., Conclusion: Reduced production of the full-length PIBF protein might result in disturbed cell cycle regulation and dysregulated trophoblast invasion, while the absence of PIBF isoforms containing exon 2-4 coded sequences might lead to the loss of local immunosuppression., (© 2013 John Wiley & Sons Ltd.)

Invasiveness is a common feature of trophoblast and tumors; however, while tumor invasion is uncontrolled, trophoblast invasion is strictly regulated. Both trophoblast and tumor cells express high levels of the immunomodulatory progesterone-induced blocking factor (PIBF), therefore, we aimed to test the possibility that PIBF might be involved in invasion. To this aim, we used PIBF-silenced or PIBF-treated trophoblast (HTR8/Svneo, and primary trophoblast) and tumor (HT-1080, A549, HCT116, PC3) cell lines. Silencing of PIBF increased invasiveness as well as MMP-2,-9 secretion of HTR8/SVneo, and decreased those of HT-1080 cells. PIBF induced immediate STAT6 activation in both cell lines. Silencing of IL-4Rα abrogated all the above effects of PIBF, suggesting that invasion-related signaling by PIBF is initiated through the IL-4Rα/PIBF-receptor complex. In HTR-8/SVneo, PIBF induced fast, but transient Akt and ERK phosphorylation, whereas in tumor cells, PIBF triggered sustained Akt, ERK, and late STAT3 activation. The late signaling events might be due to indirect action of PIBF. PIBF induced the expression of EGF and HB-EGF in HT-1080 cells. The STAT3-activating effect of PIBF was reduced in HB-EGF-deficient HT-1080 cells, suggesting that PIBF-induced HB-EGF contributes to late STAT3 activation. PIBF binds to the promoters of IL-6, EGF, and HB-EGF; however, the protein profile of the protein/DNA complex is different in the two cell lines. We conclude that in tumor cells, PIBF induces proteins, which activate invasion signaling, while-based on our previous data-PIBF might control trophoblast invasion by suppressing proinvasive genes.

Objective: Recently, 14-3-3 zeta protein was identified as a potential serum biomarker of epithelial ovarian cancer (EOC). The goal of this study was to investigate the clinical potential of 14-3-3 zeta protein for monitoring EOC progression compared with CA-125 and HE4., Design: Prospective follow-up study., Setting: University of Pecs Medical Center Department of Obstetrics and Gynecology/Oncology (Pecs, Hungary)., Population: Thirteen EOC patients with advanced stage (FIGO IIb-IIIc) epithelial ovarian cancer that underwent radical surgery and received six consecutive cycles of first line chemotherapy (paclitaxel, carboplatin) in 21-day intervals., Methods: Pre- and post-chemotherapy computed tomography (CT) scans were performed. Serum levels of CA-125, HE4, and 14-3-3 zeta protein were detected by enzyme-linked immunosorbent assay (ELISA) and quantitative electrochemiluminescence assay (ECLIA)., Main Outcome Measures: Serum levels of CA-125, HE4, and 14-3-3 zeta protein, as well as lesion size according to pre- and post-chemotherapy CT scans., Results: Serum levels of CA-125 and HE4 were found to significantly decrease following chemotherapy, and this was consistent with the decrease in lesion size detected post-chemotherapy. In contrast, 14-3-3 zeta protein levels did not significantly differ in healthy postmenopausal patients versus EOC patients., Conclusions: Determination of CA-125 and HE4 serum levels for the determination of the risk of ovarian malignancy algorithm (ROMA) represents a useful tool for the prediction of chemotherapy efficacy for EOC patients. However, levels of 14-3-3 zeta protein were not found to vary significantly as a consequence of treatment. Therefore we question if 14-3-3 zeta protein is a reliable biomarker, which correlates with the clinical behavior of EOC.

Successful pregnancy in humans has been associated with production of IL-4 by T cells at the feto-maternal interface. Soluble HLA-G5 produced by trophoblasts potentially controls the decidual T cell cytokine profile. We studied the effect of HLA-G5 on the cytokine profile of purified human macrophages and Ag-specific T cells in vitro. We demonstrated that HLA-G5 increased production of IL-12 by purified peripheral blood macrophages. Although IL-12 production by macrophages is known to induce IFN-γ production by CD4(+) T cells, HLA-G5 increased production of IL-4 but not IFN-γ by CD4(+) T cells after Ag presentation by macrophages. We found that this apparent paradox was due to the differential expression of the ILT2 HLA-G5 receptor on activated T cells and macrophages. This receptor was upregulated in the former and downregulated in the latter after Ag presentation and activation of both cell types. This observation was confirmed in situ, where decidual macrophages and T cells are continuously exposed to HLA-G5 produced locally and activated by trophoblast alloantigens. Freshly isolated decidua basalis macrophages expressed lower levels of ILT2 than peripheral blood macrophages from the same pregnant women. They did not spontaneously produce IL-12, whereas freshly isolated decidual CD4(+) T cells expressed high levels of activation markers (CD25, HLA-DR, and CD69) as well as ILT2 and spontaneously produced IL-4 but not IFN-γ. Therefore, HLA-G5 could be responsible, at least in part, via its interaction with ILT2, for decidual T cell IL-4 production, known to be crucial for successful pregnancy.

Here we discuss CD160 an essential NK cell activating receptor that remains poorly understood. CD160 receptor exhibits a number of unique structural and functional characteristics that are not common to other killer immunoglobulin-like receptors that recognize major histocompatibility complex (MHC) class I molecules: (1) In addition to humans and mice, the cd160 gene is conserved in several other mammal species; (2) cd160 is located outside the NK gene complex and the Leukocyte Receptor Complex in humans; (3) CD160 expression is associated to the CD56(dim) CD16+ cytotoxic NK cell phenotype; (4) both human and mouse CD160 recognize MHC class Ia and Ib molecules; (5) unlike the other MHC class I-dependent activating NK receptors, CD160 is a glycosylphosphatidylinositol-anchored molecule with a single immunoglobulin-like domain, and does not bear immunoreceptor tyrosine-based activation motifs. Consequently, CD160 cannot signal by itself, requiring the recruitment of adaptor proteins. CD160 recruits phosphoinositide-3 kinase to trigger cytotoxicity and cytokine secretion; (6) specific engagement of NK CD160 receptor expressed by circulating NK cells produces proinflammatory cytokines IFN-γ, TNF-α, and, most notably, IL-6 and IL-8 as well as MIP1-β chemokine. The level of CD160-mediated IFN-γ production is always higher than the one observed after engagement of the CD16 receptor., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Problem: The role of progesterone-dependent immunomodulation in the maintenance of normal pregnancy., Methods: In vitro and in vivo data on the effect that progesterone and its mediator progesterone-induced blocking factor (PIBF) exert on the immune functions of pregnant women are reviewed, together with clinical findings., Results: Activated pregnancy lymphocytes express progesterone receptors, which enable progesterone to induce a protein called PIBF. PIBF increases Th2 type cytokine production by signaling via a novel type of IL-4 receptor and activating the Jak/STAT pathway. PIBF inhibits phosholipase A2, thus reduces prostaglandin synthesis. PIBF inhibits perforin release in human decidual lymphocytes and reduces the deleterious effect of high NK activity on murine pregnancy. PIBF production is a characteristic feature of normal human pregnancy, and its concentration is reduced in threatened pregnancies. PIBF mRNA and protein are expressed in a variety of malignant tumors. Inhibition of PIBF synthesis increases survival rates of leukemic mice., Conclusion: Progesterone-induced blocking factor is produced by pregnancy lymphocytes and also by malignant tumors. The PIBF-induced Th2-dominant immune response is favorable during pregnancy but might facilitate tumor growth by suppressing local antitumor immune responses.

Problem: The objective of this study was to compare serum concentrations of progesterone-induced blocking factor (PIBF), anti-inflammatory (IL-10),and pro-inflammatory (IL-6, TNFa, and IFNc) cytokines of women with threatened pre-term delivery, with those of women with normal pregnancy and to evaluate the impact of PIBF on the outcome of pregnancy., Method of Study: A prospective study was conducted on a sample of 30 women with threatened pre-term delivery (study group) and 20 healthy pregnant women (control group) between the 24th and 37th gestational weeks. Serum PIBF, anti-inflammatory (IL-10), and pro-inflammatory (IL-6, TNFa, and IFNc) cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA)., Results: Thirteen of 30 patients (43.3%) with symptoms of threatened pre-term delivery, and one of 20 patients (5%) in the control group delivered before the 37th week of gestation. Mean PIBF concentrations in serum samples of patients with threatened pre-term delivery were significantly lower than in those of healthy pregnant women (171.12 +/-162.06 ng/mL versus 272.85 +/- 114.87 ng/mL; P < 0.05).Women with symptoms of threatened pre-term delivery had significantly lower serum levels of IL-10, and higher levels of IL-6 as well as IFNc compared with healthy controls., Conclusion: Our results indicate that measuring PIBF and cytokine concentrations in serum during pregnancy is feasible and may be important for understanding immunological causes of pre-term delivery.

Progesterone-induced blocking factor (PIBF) induces Th2-dominant cytokine production. Western blotting and EMSA revealed phosphorylation as well as nuclear translocation of STAT6 and inhibition of STAT4 phosphorylation in PIBF-treated cells. The silencing of STAT6 by small interfering RNA reduced the cytokine effects. Because the activation of the STAT6 pathway depends on the ligation of IL-4R, we tested the involvement of IL-4R in PIBF-induced STAT6 activation. Although PIBF does not bind to IL-4R, the blocking of the latter with an Ab abolished PIBF-induced STAT6 activation, whereas the blocking of the IL-13R had no effect. PIBF activated suppressor of cytokine signaling-3 and inhibited IL-12-induced suppressor of cytokine signaling-1 activation. The blocking of IL-4R counteracted all the described effects, suggesting that the PIBF receptor interacts with IL-4R alpha-chain, allowing PIBF to activate the STAT6 pathway. PIBF did not phosphorylate Jak3, suggesting that the gamma-chain is not needed for PIBF signaling. Confocal microscopic analysis revealed a colocalization and at 37 degrees C a cocapping of the FITC PIBF-activated PIBF receptor and PE anti-IL-4R-labeled IL-4R. After the digestion of the cells with phosphatidylinositol-specific phospholipase C, the STAT6-activating effect of PIBF was lost, whereas that of IL-4 remained unaltered. These data suggest the existence of a novel type of IL-4R composed of the IL-4R alpha-chain and the GPI-anchored PIBF receptor.

CD160 is an Ig-like activating NK cell receptor expressed on the majority of circulating NK cells. This population corresponds to the nonproliferating, highly cytolytic, CD56dimCD16+ subset. CD160 engagement by HLA-C molecules mediates cytotoxic function. In this study, we report that upon specific activation by the physiological ligand HLA-C, or Ab cross-linking, CD160+ peripheral blood NK cells produce IFN-gamma, TNF-alpha, and IL-6. This unique CD160-mediated cytokine production differs from the one observed after CD16 engagement whose expression is also restricted to the CD56dim cytotoxic NK cell subset. As already reported for the CD160-mediated cytotoxic effector function, CD160-mediated cytokine production by peripheral blood-NK cells is negatively controlled by the killer Ig-like receptor CD158b. Thus, the CD160 receptor represents a unique triggering surface molecule expressed by cytotoxic NK cells that participates in the inflammatory response and determines the type of subsequent specific immunity.

Previous studies from our laboratory showed that the immunomodulatory effects of progesterone are mediated by a 34-kDa protein, named the progesterone-induced blocking factor (PIBF). Lymphocytes of women with threatened abortion fail to produce this factor. Via inducing a Th2 biased cytokine production and blocking of NK activity, PIBF prevents induced pregnancy loss in mice, suggesting that substitution therapy with PIBF could be useful as an alternative treatment of certain forms of recurrent spontaneous abortions. Our study was aimed at mapping the sequence and structure of PIBF coding cDNA and characterizing the encoded protein product. Screening of a human liver cDNA library revealed a 2765-bp clone with a 2271-bp open reading frame. The PIBF1 cDNA encodes a protein of 757 amino acid residues with an 89-kDa predicted molecular mass, which shows no significant amino acid sequence homology with any known protein. PIBF produced via recombinant technique is recognized by the Ab specific for the secreted lymphocyte PIBF Ab, and possesses the biological activities of the secreted lymphocyte PIBF. The full-length PIBF is associated with the nucleus, whereas secretion of shorter forms, such a 34-kDa protein is induced by activation of the cell. The 48-kDa N-terminal part of PIBF is biologically active, and the part of the molecule, responsible for modulating NK activity is encoded by exons 2-4. These data provide an initial step for exploiting the possible diagnostic and therapeutic potential of this immunomodulatory molecule.