Pregnancy-associated Protein Research Articles

The pregnancy-associated protein glycodelin as a potential sex-specific target for resistance to immunotherapy in non-small cell lung cancer

Lung cancer has been shown to be targetable by novel immunotherapies which reactivate the immune system and enable tumor cell killing. However, treatment failure and resistance to these therapies is common. Consideration of sex as a factor influencing therapy resistance is still rare. We hypothesize that the success of the treatment is impaired by the presence of the immunosuppressive pregnancy-associated glycoprotein glycodelin that is expressed in patients with non-small-cell lung cancer (NSCLC). We demonstrate that the glycan pattern of NSCLC-derived glycodelin detected by a lectin-based enrichment assay highly resembles amniotic fluid-derived glycodelin A, which is known to have immunosuppressive properties. NSCLC-derived glycodelin interacts with immune cells in vitro and regulates the expression of genes associated with inflammatory and tumor microenvironment pathways. In tumor microarray samples of patients, high glycodelin staining in tumor areas results in an impaired overall survival of female patients. Moreover, glycodelin colocalizes to tumor infiltrating CD8+ T cells and pro-tumorigenic M2 macrophages. High serum concentrations of glycodelin prior to immunotherapy are associated with a poor progression-free survival (p < 0.001) of female patients receiving PD-(L)1 inhibitors. In summary, our findings suggest that glycodelin not only is a promising immunological biomarker for early identification of female patients that do not benefit from the costly immunotherapy, but also represents a promising immunotherapeutic target in NSCLC to improve therapeutic options in lung cancer.

Biochemical markers for prediction of the first half pregnancy losses: a review.

26% of all pregnancies end in miscarriage, and up to 10% of clinically diagnosed pregnancies, and recurrent pregnancy loss is 5% among couples of childbearing ages. Although there are several known causes of pregnancy loss in the first half, including recurrent pregnancy loss, including parental chromosomal abnormalities, uterine malformations, endocrinological disorders, and immunological abnormalities, about half of the cases of pregnancy loss in its first half remain unexplained. The review includes observational controlled studies (case-control or cohort, longitudinal studies, reviews, meta-analyses), which include the study of biochemical factors for predicting pregnancy losses in the first half, in singlet pregnancy. The Newcastle-Ottawa Scale (NOS) was used to assess the research quality. Finally, 27 studies were included in the review, which has 134904 examined patients. The results of the review include estimates of β-human chorionic gonadotropin, progesterone, pregnancy-associated protein - A, angiogenic vascular factors, estradiol, α-fetoprotein, homocysteine and CA-125 as a predictors or markers of the first half pregnancy losses. It may be concluded that to date, research data indicate the unavailability of any reliable biochemical marker for predicting pregnancy losses in its first half and require either a combination of them or comparison with clinical evidence. A fairly new model shall be considered for the assessment of α-fetoprotein in vaginal blood, which may have great prospects in predicting spontaneous miscarriages.

Clinical Application of Multi-Index Combined Risk Assessment in Early Pregnancy for Screening of Preeclampsia.

Objective To explore the predictive value of single-index screening or multi-index combined screening for preeclampsia. Methods From January 1, 2019, to December 31, 2021, pregnant women with a singleton pregnancy who had been regularly checked in each center since the first trimester (between 11 and 14 weeks of gestation) were retrieved from multiple participating centers. The risk calculation software LifeCycle 7.0 was used to calculate the risk values before 32 weeks, 34 weeks, and 37 weeks of gestation, and through a receiver operating characteristic (ROC) curve analysis, the predictive values of pregnancy-associated protein A (PAPP-A), the placental growth factor (PLGF), the mean arterial pressure (MAP), the uterine artery pulsatility index (UTPI), or a combined multi-index were calculated for preeclampsia. Results Finally, 22 pregnant women developed preeclampsia, and the area under the ROC curve of the PAPP-A + PLGF + MAP + UTPI combined screening program was greater than that of other screening programs before 37 weeks of gestation (AUC = 0.975, 0.946, or 0.840 for <32 weeks, <34 weeks, or <37 weeks, respectively). At 32 weeks, the Youden index was at its maximum. Conclusion PAPP-A + PLGF + MAP + UTPI combined screening is the optimal screening mode for preeclampsia screening before 37 weeks of gestation, and the combined prediction using multiple indicators in early pregnancy is more suitable for predicting the risk of early-onset preeclampsia.

EP16.01-019 The Role of the Pregnancy Associated Protein Glycodelin and Its Influence on the Immune System in Non-small-Cell Lung Cancer

Lung cancer is the leading cause of cancer related death worldwide and the challenge of developing effective therapies especially for advanced stages remains. Novel approaches in immuno-oncology showed a favorable response in lung cancer patients, making this an interesting and promising field for future research. Glycodelin is an immunomodulatory lipocalin in reproduction and pregnancy maintenance. Interestingly, high expression levels were also observed in different cancer types, e.g. in non-small-cell lung cancer.

Predicting Hypertensive Disease in the First Trimester of Pregnancy: Risk Models and Analysis of Serum D-dimer Levels Combined with Plasma Pregnancy-Associated Protein A, Free β-Subunit of Human Chorionic Gonadotropin, and Fetal Nuchal Translucency.

We aimed to investigate the predictive ability of serum levels of D-dimer (DD) in the first trimester for the occurrence of hypertensive disorders of pregnancy (HDP). In this retrospective, case-cohort study, we measured the levels of DD, plasma pregnancy-associated protein A (PAPP-A), and free β-subunit of human chorionic gonadotropin (free β-hCG) and analyzed fetal nuchal translucency (NT) in 150 healthy gravidas, 126 cases of gestational hypertension (GH), 53 cases of preeclampsia (PE), and 41 cases with severe preeclampsia (SPE). Likelihood ratio models and risk models were built using single markers (DD, PAPP-A, free β-hCG, and NT) and combinations of those markers. Analyses showed that the levels of DD multiple of the median (MoM) in the GH, PE, and SPE groups were all significantly higher than those in the control group, with significant differences between groups (χ2 = 70.325, P < 0.001). The area under curve (AUCs) for DD in the GH, PE, and SPE groups was 0.699, 0.784, and 0.893, respectively; the positive likelihood ratio (+LR) was 1.534, 1.804, and 2.941, respectively; and the negative likelihood ratio (-LR) was 0.022, 0.081, and 0, respectively. When the cut-off values of DD for the GH, PE, and SPE groups were 0.725, 0.815, and 0.945 MoM, respectively, the corresponding sensitivities were 0.992, 0.962, and 1.000, respectively. As gestational hypertension progressed, the levels of DD tended to increase gradually. The maternal serum level of DD in the first trimester had correlative and diagnostic value for HDP. The sensitivity and specificity of maternal serum levels of DD level in the first trimester for different types of HDP were significantly different; the best sensitivity and specificity were detected in the SPE group. First trimester DD level, combined with other biochemical markers, may improve our ability to diagnose HDP.

P69.01 The Role of the Pregnancy Associated Protein Glycodelin and Its Influence on the Immune System in Non-Small-Cell Lung Cancer

Lung cancer is the leading cause of cancer related death worldwide and the challenge of developing effective therapies especially for advanced stages remains. Novel approaches concentrating on immunotherapies showed a favorable response in lung cancer patients, making this an interesting and promising field for future research. Glycodelin is an immunosuppressive glycoprotein in reproduction and pregnancy maintenance. Interestingly, high expression levels were also observed in different cancer types, e.g. in non-small-cell lung cancer. To investigate whether glycodelin has similar immunomodulatory characteristics in NSCLC, 22 lectins were used to compare the glycosylation pattern of glycodelin secreted by NSCLC tumor cells to immunosuppressive glycodelin A isolated from amniotic fluid. Furthermore, tumor cell line supernatant containing high amounts of glycodelin was used to treat different immune cell lines. Binding assays were performed and possible effects of the treatment have been evaluated using microarray gene expression analyses. To investigate its influence on the efficiency of immunotherapy, glycodelin was measured in the serum of inoperable immunotherapy-treated NSCLC patients (n = 139) and progression-free survival analysis was performed. We were able to show that the glycosylation of glycodelin from NSCLC is highly similar to glycodelin A and especially shares functional sialylation which is crucial for immune system regulation. In addition, we could validate that glycodelin binds to immune cells. The evaluation of microarray gene expression assays shall give hints for immune escape mechanisms induced by glycodelin. In patients, high serum concentrations of glycodelin were associated with a decreased progression-free survival (p = 0.048) of patients receiving an anti-PD-1-/ PD-L1 therapy. In conclusion, we demonstrate that glycodelin is a protein with a high potential of being a novel target in immuno-oncology especially for NSCLC patients.

Metabolic syndrome as a factor influencing the course of pregnancy

Background. According to the WHO guidelines, the criteria for metabolic syndrome (MS) include obesity (body mass index (BMI) &gt;30 kg/m2), abdominal obesity (ratio of waist circumference and hips circumference &gt;0.85 for females), blood pressure &gt;160/90 mm Hg, triglyceride level &gt;1.7 mmol/l, impaired glucose tolerance, microalbuminuria &gt;20 μg/min.&#x0D; Objective. To assess the impact of MS on pregnancy.&#x0D; Materials and methods. Analysis of literature data on this issue and our own study involving 38 obese women. Pregnant women in the study were tested for pregnancy-associated protein A (PAPP-A), placental growth factor (PIGF), arginine, and leptin. They were also prescribed a comprehensive preventive treatment (from 12 weeks of pregnancy – 150 mg of aspirin 1 g per day, from 16 weeks – L-arginine solution (Tivortin aspartate, “Yuria-Pharm”) 5 ml (1 g) 4 times per day for 2 months). The control group consisted of 30 healthy pregnant women, the comparison group – of 30 obese pregnant women who did not receive L-arginine.&#x0D; Results and discussion. The pathological consequences of the mother’s MS for the foetus are mediated by the insulin resistance, hyperglycemia, and vascular damage. The negative effects include birth injuries, caesarean section, childhood obesity, and cardiovascular disease. Eclampsia and preeclampsia (PE), which increase the risk of perinatal mortality, are also the important problems of modern obstetrics. The presence of obesity in pregnant women increases the likelihood of PE by 2-3 times. Pre-pregnancy BMI increase by 5-7 kg/m2 also doubles the risk. In addition to PE, obesity also increases the risk of gestational hypertension, premature birth, foetal growth retardation syndrome, macrosomia, gestational diabetes mellitus, sudden foetal death. Endothelial dysfunction (ED) is one of the main pathogenetic links of obstetric complications, primarily PE. Thus, hypertension in PE is a consequence of impaired endothelial control of vascular tone, proteinuria and oedema – of increased vascular permeability, coagulopathy – of overexpression of procoagulants. In obesity, the likelihood of PE increases as chronic inflammation and ED are induced. PE development is also mediated by the increase in the leptin concentration. Nitric oxide donors, namely L-arginine, should be prescribed to correct ED and prevent PE. According to the results of our own study, obese women in the first trimester had significantly higher leptin levels and significantly lower PIGF levels, which is a prerequisite for PE and other gestational complications. In the main group, compared to the comparison group, there was a lower frequency of early moderate PE (5 % vs. 8 %), early severe PE (1 % vs. 5 %), moderate PE after 34 weeks of pregnancy (8 % vs. 12 %), and severe PE after 34 weeks of pregnancy (1 % vs. 4 %).&#x0D; Conclusions. 1. Obesity significantly increases the risk of PE and other gestational complications. 2. The main mechanisms of adverse effects of obesity are chronic inflammation and ED. 3. The use of complex prophylaxis with aspirin and L-arginine for 2 months almost 5 times reduced the degree of severe early PE.

The relationships between pregnancy-associated protein A levels, placental localization and fetal birth weight

Aim. This study was designed to determine the relationship between pregnancy-associated protein A (PAPP-A), placenta localization and fetal birth weight (FBW).Materials and methods. First trimester PAPP-A levels, second trimester placental localization and birth weights of 1145 infants were obtained through a retrospective review of the patient follow up charts in Koru Hospital. Serum PAPP-A levels were recorded as the multiple of median (MоM) values, the FBW values of infants were recorded in grams, and the placental localization was recorded under seven different pre-defined categories: 1. placenta anterior; 2. placenta posterior; 3. placenta fundal; 4. placenta fundal-anterior; 5. placenta fundal-posterior; 6. placenta lateral-right; 7. placenta lateral-left. The data were analyzed using the Statistical Package for Social Sciences (SPSS) program (SPSS Inc., Chicago, IL, USA).Results.There was no significant difference between the FBW and PAPP-A levels. The comparison of seven placental localizations shows that the anterior and posterior localizations have an impact on FBW of the infants.Conclusion. The FBW was highest in the cases where the placenta was located in the corpus uteri. We believe this finding is consistent with the fact that the corpus uteri receives the largest blood supply.

FGF10 enhances yak oocyte fertilization competence and subsequent blastocyst quality and regulates the levels of CD9, CD81, DNMT1, and DNMT3B.

The fusion of sperm and oocytes determines the fertilization competence and subsequent development of embryos, which, in turn, can be affected by various proteins and DNA methylation. However, several factors in this whole regulation process remain unknown, especially in yaks. Here, we report that fibroblast growth factor 10 (FGF10) is an important growth factor that can enhance the maturation rate of yak oocytes and the motility of frozen spermatozoa. Subsequent blastocyst quality was also improved by increasing the total cell number and level of pregnancy-associated protein in blastocysts. These effects were significantly high in the group that received the 5 ng/ml FGF10 treatment, during both in vitro maturation (IVM) and capacitation. Our data show that the effects of FGF10 were dose-dependent at vital steps of embryogenesis in vitro. Furthermore, quantitative polymerase chain reaction, western blot analysis, and immunofluorescence demonstrated that the levels of CD9, CD81, DNMT1, and DNMT3B in both mature cumulus-oocyte complexes and capacitated sperms were regulated by FGF10, which was also highly expressed in the group treated with 5 ng/ml FGF10 during both IVM and capacitation. From our present study, we concluded that FGF10 promotes yak oocyte fertilization competence and subsequent blastocyst quality, and could also regulate CD9, CD81, DNMT1, and DNMT3B to optimize sperm-oocyte interactions and DNA methylation during fertilization.

Diagnosis of Late Embryonic Mortality in Dairy Cows by Measuring Pregnancy-Associated Glycoprotein and Pregnancy-Specific Protein B Levels

Diagnosis of Late Embryonic Mortality in Dairy Cows by Measuring Pregnancy-Associated Glycoprotein and Pregnancy-Specific Protein B Levels

Genetically Engineering a Sheep Model of Hypophosphatasia

Hypophosphatasia (HPP) is a rare inherited disorder that affects the development of bones and teeth. The disease is caused by mutations in the tissue‐nonspecific alkaline phosphatase (TNSALP) gene (ALPL) and accompanied by a highly variable clinical presentation. Although HPP patient studies have advanced our understanding of HPP, as well as documented disease severity, the rarity of the disease combined with a lack of sufficient animal models has significantly delayed mechanistic understanding and therapeutic development. Similar to other human disease models, current HPP models have been engineered virtually exclusively in rodents – specifically mice harboring null or loss‐of‐function mutations. Although useful for modeling some features of HPP, these murine models do not faithfully represent the broad spectrum of human HPP clinical bone, muscle and tooth (odonto‐HPP) phenotypes. However, in sheep both Haversian bone remodeling and tooth development are analogous to humans with sheep TNSALP amino acid sequence sharing 89% identity with human. Thus, our objective was to generate a sheep model of HPP and we posit that ALPL mutation‐specific replacements in the sheep genome using CRISPR/Cas9 will produce a model that accurately phenocopies the bone and tooth pathophysiology of HPP. To genetically engineer a sheep model of HPP, a total of 52 in vitro genetically manipulated embryos were generated targeting the Exon 10 c.1077G&gt;A mutation using CRISPR/Cas9. Three embryos were implanted per recipient ewe and implantations were performed in a total of 17 recipient ewes. Nine ewe pregnancies were confirmed by the measurement of Pregnancy‐Associated Protein on post‐implantation day 35 and further validated by ultrasound. From 9 live newborn lambs, four were heterozygous for our specific point mutation (4/6), one compound heterozygous (1/6) and one homozygous (1/6) for a total mutation efficiency rate of 66.6% (6/9). Similar to HPP patients with the same mutation, mutant sheep have variable clinical expression accompanied with decreased bone formation and mineralization in tails observed by DXA as well as significantly and appropriately decreased serum alkaline phosphatase activity. Additionally, an apparent “shell tooth” phenotype is observed in mutant lambs, further suggesting a mutant exon 10 genotype/phenotype that more completely recapitulates human skeletal and odonto‐HPP.Support or Funding Information1. William Townsend Porter Pre‐doctoral Fellowship2. TAMU/Texas Heart Institute Center for Cell and Organ Biotechnology Innovation Kitchen GrantThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Influence of Weight of Pregnant Women on First Trimester Biochemical Markers Values

Values of first trimester biochemical markers (PAPP-A and free b-hCG) concentration are included in aneuploidies risk evaluation algorithm. Since both markers are produced by the fetus and placenta their concentration depends on the volume in which they are dissolved, respectively the weight of the pregnant women. Our study aimed to analyze the influence of maternal weight on first trimester biochemical markers concentration and the ability of the risk calculation software to correct this influence. Pregnancy-associated protein A (PAPP-A) and free � chorionic gonadotropin hormone (free � hCG) first trimester sera concentration respectively weight were measured in 1629 pregnant women. First trimester PAPP-A and free beta hCG concentrations inverse correlate with weight of pregnant women rho=-0.33, p[0.0001, respectively rho=-0.18, p[0.0001. Weight of pregnant women inversely correlates with multiple of median (MoM) values of first trimester markers too: rho=-0.38, p[0.0001 (PAPP-A), respectively rho=-0.17, p[0.0001 (free-b-hCG). The software counterbalances the influence of weight on biochemical markers values. PAPP-A corrected MoM (MoMc) values don�t inversely correlate with the weight (rho=-0.03, p=0.12), whereas free � hCG MoMc values showed an extremely weak inverse correlation (rho=-0.08, p=0.0008). The software counterbalances the influence of weight on PAPP-A values, whereas an extremely weak but insignificant inverse correlation between weight and free-beta hCG values persists after correction.

128 Evidence that Pregnancy-Associated Serum Protein A (PAPP-A) Plays Role on Bovine In Vitro Embryo Production

The aim of present work was to assess the effects of pregnancy-associated serum protein A (PAPP-A) during oocyte in vitro maturation (IVM) on meiosis progression, DNA fragmentation, IGF-1 free bioavailability, as well as effects on embryo yield and transcriptional profile of matured cumulus–oocyte complexes (COC). First, the COC from a local abattoir were submitted to IVM for 24 h with TCM-199 serum-free medium supplemented with PAPP-A (100 ng mL−1: P100 group) or not (control group). The matured oocytes were submitted to evaluation of DNA fragmentation (TUNEL assay) and meiosis progression (Hoechst 33342; n = 5 replicates; 20 COC/replicate per group), and maturation medium was collected to measure levels of free IGF-1. Then, the oocytes were separated from their respective cumulus cells and followed for the transcriptional profile of 96 genes (3 reference genes; ACTH, GAPDH, PPIA) by RT-qPCR using Taqman® assays in the HD-Biomark System® (Fluidigm Corp., South San Francisco, CA, USA). Further, the matured oocytes were submitted to in vitro fertilization followed by in vitro culture for 7 days. On Days 3 and 7, the cleavage and blastocyst (BL) rates were verified. On Day 7, BL (3 BL/pool; control: n = 4 pools; P100: n = 5 pools) were collected to analyse the transcriptional pattern of 96 genes (4 reference genes; ACTH, GAPDH, PPIA, and SDHA) as described above for COC. The DNA fragmentation, meiosis progression, cleavage, and BL rates were calculated as percentages and transformed to arcsine. The mRNA abundance of target genes was normalized by geometric mean of reference genes and data were transformed to fold change. The free IGF-I concentration also was transformed to fold change. All data were tested by ANOVA and means were compared with t-test or Wilcoxon tests using JMP software (SAS Institute Inc., Cary, NC, USA). Differences were considered significant when P ≤ 0.05. The addition of PAPP-A increased free IGF-I concentration 1.27-fold in IVM medium. There were no alterations in the percentage of oocytes in metaphase II or oocyte DNA fragmentation. In cumulus cells, the genes BCL2, GPX1, RPLP0, and RPS25 (anti-apoptotic and anti-oxidative stress) was higher in the P100 group, whereas DICER, GREM1, GUCY1B3, and FOXO3 (cell proliferation, cumulus expansion, cGMP regulator, and apoptotic initiator, respectively) were higher in the control group. In oocytes, the mRNA relative abundance of ACACA, BCL2, H1FOO, TXNRD1, and VCAN (related with fatty acid synthesis, anti-apoptotic effect, chromatin regulation, oxidative stress processes, and cell proliferation, respectively) was higher in the P100 group. There was no difference in cleavage rate or embryo yield. The mRNA abundance of genes related to cellular stress (ATF4, GPX4, and HIF1A) and lipid metabolism (FASN and SREBF1) was lower in embryos of the P100 group. On the other hand, genes involved in cellular proliferation/differentiation (MAPK1) and pluripotency (POU5F1) were up-regulated in embryos of the P100 group. In conclusion, the addition of PAPP-A during the IVM increased free IGF-I and modulates the gene expression in COC and blastocysts, which could modify oocyte competence and embryo development.

The Effect of Chemical Compounds from Cigarettes Smoke on First Trimester Biochemical Markers

Previous studies showed that certain behavioral and physical parameters influence the concentration of first trimester biochemical markers. The scope of the present article was to study the relationship between smoking and first trimester screening biochemical markers and the capability of the software to counterbalance this influence. Concentrations of pregnancy-associated protein A (PAPP-A) and free b chorionic gonadotropin hormone (free b hCG) were measured in sera of 1554 first trimester pregnant women, 1349 of which were non-smokers and 205 were smokers. First trimester PAPP-A values are lower in smoking compared to non-smoking pregnant women (0.94�0.04 vs. 1.09�0.02, p=0.0004), since smoking seems not to influence free b hCG concentration (1.11�0.07 vs. 1.03�0.02, ns). The software used by us corrected successfully the effect of chemical compounds from cigarette smoke on PAPP-A values.

P2.01-059 Regulation of Glycodelin Expression - An Immunomodulatory and Pregnancy Associated Protein in NSCLC

Glycodelin (gene name: progesterone-associated endometrial protein, PAEP) is a protein initially described as an immune system modulator during the establishment of pregnancy. Former studies determined an atypical expression and secretion of glycodelin in non-small cell lung cancer (NSCLC), the most common type of lung cancer. To date, there is not much known about the signaling pathway which regulates PAEP/glycodelin expression in cancer. However, initial experiments already revealed an inducing effect of epidermal growth factor (EGF), heparin-binding epidermal growth factor-like growth factor (HB-EGF), lysophosphatidic acid (LPA) and Phorbol 12-myristate 13 acetate (PMA) on PAEP/glycodelin expression in two NSCLC cell lines (H1975 and 2106T). In this study, we analyzed an extended number of possible regulatory candidates to acquire a more detailed view on the regulatory pathway of PAEP/glycodelin in NSCLC. A lung adenocarcinoma (H1975) and a lung squamous cell carcinoma cell line (2106T) were transfected with siRNA targeting nuclear factor κB1 (NFκB1) or treated with human chorionic gonadotropin (hCG), transforming growth factor-β (TGF-β) 1, -2, -3, protein kinase C (PKC) activator bryostatin 1 and PKC inhibitor GF109203x, respectively. Additionally, combined treatments with GF109203x and TGF-β 1,-2, EGF or HB-EGF were performed. PAEP expression in the manipulated cells was determined by quantitative polymerase chain reaction (qPCR), while glycodelin expression or secretion was detected by western blot analysis. NFκB1 siRNA transfection resulted in decreased PAEP and glycodelin amounts (H1975 and 2106T), whereas hCG (H1975 and 2106T) and TGF-β 1, -2, -3 (2106T) treatment led to higher levels. In bryostatin treated cells (H1975 and 2106T), PAEP/glycodelin expression was upregulated. The contradictory effect could be demonstrated for cells treated with the PKC inhibitor GF109203x alone and in combination with TGF-β 1,-2, EGF or HB-EGF (H1975 and 2106T). This study revealed that there are different regulation mechanisms of PAEP/glycodelin induction in NSCLC. Especially, PKC seems to be involved as a key molecule. The investigated candidates which play a crucial role in driving this signaling pathway are all known to promote the development of cancer. Elucidating the regulatory pathway of the immune system modulating protein glycodelin might reveal a potential strategy to weaken the immune system defense of lung tumors.

Interrelation between systemic inflammation markers, endothelial dysfunction and coronary heart disease clinical course after community-acquired pneumonia

Extensive research has established that community acquired pneumonia has negative impact on clinical course on coronary heart disease (CHD), but the pathogenic mechanism was not understood. Aim. To study the pro-inflammatory biomarkers and endothelial dysfunction, its interrelation with CHD clinical course in patients with community acquired pneumonia, 90 patients were recruited. Methods and results . The I (main) subcohort included 60 CHD patients with community acquired pneumonia, the II subcohort included 30 stable angina pectoris without community acquired pneumonia and 21 community acquired pneumonia patients, ІІІ clinical group – without CHD. Using immunoassay high-sensitive C-reactive protein, neopterine and pregnancy-associated protein A were assessed. Among patients with CHD and community acquired pneumonia the significant increasing of all biomarkers was observed at the beginning and after 1 month of disease. The increasing of these biomarkers was associated with was associated with poorer prognosis in CHD patients during 1 year follow-up. Conclusions. The direct correlation between high-sensitive C-reactive protein and neopterine, РАРР-А was found, which suggests the pathogenic ties between immune inflammation and endothelial dysfunction among patients with CHD and community acquired pneumonia.

Influence of medically assisted reproduction techniques on crown-rump length and biochemical markers of trisomy 21 in the first trimester of pregnancy

To determine whether there is a difference between the known gestational age in pregnancies conceived after IVF and the estimated gestational age based on the crown-rump length (CRL) measurement during the first trimester. We retrospectively (between 2007 and 2012) studied a cohort of 6,739 patients who underwent ultrasonography between 11 and 13+6weeks of amenorrhea. Hospital. Group A consisted of 6,621 patients with regular menses whose term was calculated based on the date of their last menstrual period (LMP). Group B consisted of 529 patients whose pregnancies had been achieved by IVF and in whom term was calculated based on the date of fresh or frozen ET. None. The gestational age difference was obtained by comparing the age obtained by measuring the CRL (Robinson's curve) with the gestational age calculated in accordance with LMP in group A or with ET day in group B. The gestational age difference was significantly more in group B (2.3days vs. 0.84days in group A). We found a significant difference regarding biochemical markers for trisomy 21 to the detriment of group B with a significantly reduced pregnancy-associated protein P-A multiple of median (0.78 vs. 0.92). There appears to be a small difference in CRL development between spontaneous pregnancies and pregnancies conceived by assisted reproductive technology (ART). Specific ultrasonographic curves for pregnancies conceived by ART would be more relevant and precise. The underlying pathophysiological mechanisms are not very clear and offer possibilities for future research.

Pregnancy associated plasma protein-A links pregnancy and melanoma progression by promoting cellular migration and invasion.

Melanoma is the most common cancer diagnosed in pregnant women and an aggressive course with poorer outcomes is commonly described during pregnancy or shortly after childbirth. The underlying mechanisms for this are not understood. Here, we report that melanoma migration, invasiveness and progression are promoted by Pregnancy-Associated Plasma Protein-A (PAPPA), a pregnancy-associated metalloproteinase produced by the placenta that increases the bioavailability of IGF1 by cleaving it from a circulating complex formed with IGFBP4. We show that PAPPA is widely expressed by metastatic melanoma tumors and is elevated in melanoma cells exhibiting mesenchymal, invasive and label-retaining phenotypes. Notably, inhibition of PAPPA significantly reduced invasion and migration of melanoma cells in vitro and in vivo within the embryonic chicken neural tube. PAPPA-enriched pregnancy serum treatment enhanced melanoma motility in vitro. Furthermore, we report that IGF1 can induce the phenotypic and functional effects of epithelial-to-mesenchymal transition (EMT) in melanoma cells. In this study, we establish a clear relationship between a pregnancy-associated protein PAPPA, melanoma and functional effects mediated through IGF1 that provides a plausible mechanism for accelerated melanoma progression during pregnancy. This opens the possibility of targeting the PAPPA/IGF1 axis therapeutically.

Kinetics of gene expression and bone remodelling in the clinical phase of collagen-induced arthritis.

IntroductionPathological bone changes differ considerably between inflammatory arthritic diseases and most studies have focused on bone erosion. Collagen-induced arthritis (CIA) is a model for rheumatoid arthritis, which, in addition to bone erosion, demonstrates bone formation at the time of clinical manifestations. The objective of this study was to use this model to characterise the histological and molecular changes in bone remodelling, and relate these to the clinical disease development.MethodsA histological and gene expression profiling time-course study on bone remodelling in CIA was linked to onset of clinical symptoms. Global gene expression was studied with a gene chip array system.ResultsThe main histopathological changes in bone structure and inflammation occurred during the first two weeks following the onset of clinical symptoms in the joint. Hereafter, the inflammation declined and remodelling of formed bone dominated.Global gene expression profiling showed simultaneous upregulation of genes related to bone changes and inflammation in week 0 to 2 after onset of clinical disease. Furthermore, we observed time-dependent expression of genes involved in early and late osteoblast differentiation and function, which mirrored the histopathological bone changes. The differentially expressed genes belong to the bone morphogenetic pathway (BMP) and, in addition, include the osteoblast markers integrin-binding sialoprotein (Ibsp), bone gamma-carboxyglutamate protein (Bglap1), and secreted phosphoprotein 1 (Spp1). Pregnancy-associated protein A (Pappa) and periostin (Postn), differentially expressed in the early disease phase, are proposed to participate in bone formation, and we suggest that they play a role in early bone formation in the CIA model. Comparison to human genome-wide association studies (GWAS) revealed differential expression of several genes associated with human arthritis.ConclusionsIn the CIA model, bone formation in the joint starts shortly after onset of clinical symptoms, which results in bony fusion within one to two weeks. This makes it a candidate model for investigating the relationship between inflammation and bone formation in inflammatory arthritis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0531-7) contains supplementary material, which is available to authorized users.

Correlation of plasma soluble cluster of differentiation 40 ligand, alpha fetoprotein A, and pregnancy-associated plasma protein A with carotid plaque in patients with ischemic stroke.

This study investigated the correlation of plama levels of inflammatory biomarkers [soluble cluster of differentiation 40 ligand (sCD40L), alpha fetoprotein A (fetuin-A), and pregnancy-associated protein A (PAPP-A)] with carotid plaque in patients with acute ischemic stroke. After undergoing color Doppler ultrasonography of the bilateral carotid arteries, 200 patients with acute ischemic stroke were grouped into plaque and non-plaque groups. The plaque group was further divided into stable and unstable plaque sub-groups by carotid plaque stability. Inter-group and -subgroup comparisons included demographic characteristics, current condition and medical history, and clinical laboratory and plama inflammatory biomarker data, and logistic regression explored the correlations between plama inflammatory biomarker levels and carotid plaques. Significantly higher sCD40L and fetuin-A levels were found in the plaque group than in the non-plaque group (all P < 0.05), with odds ratios (plaque vs non-plaque) of 6.372 and 4.101, respectively. Increased plama inflammatory biomarker levels were accompanied by a high risk of carotid plaque formation. Similarly, significantly higher plama sCD40L and PAPP-A levels were found in the unstable plaque subgroup than in the stable plaque subgroup (all P < 0.05), and the odds ratios (unstable vs stable) were 5.290 and 4.125, respectively. Increased plama inflammatory biomarker levels were accompanied by a high risk of carotid plaque instability. The study findings showed that plasma sCD40L, fetuin-A, and PAPP-A levels are associated with carotid plaque formation and instability. Fetuin-A and sCD40L might be predictors of carotid plaque formation, while PAPP-A and sCD40L might be predictors of carotid plaque instability.