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The cause of the middle Miocene Badenian salinity crisis in the Central Paratethys is addressed by examining the palaeotemperature evolution of Badenian waters before and after the deposition of evaporites. Selected foraminifer taxa (Globigerinoides spp., Globigerina bulloides, and Uvigerina) characterizing, respectively, the near-surface, intermediate, and bottom layers of the water column, were studied in two boreholes of SW Poland. The δ18O and δ13C values for these taxa show distinct differences which can be explained by the temperature difference between surface and bottom waters during deposition. These values also show temporal changes corresponding to the water temperature evolution in the Badenian basin. Different and quickly changing environmental conditions have been inferred from changes in foraminifer assemblages. They explain why biostratigraphic subdivisions based on well-recognized assemblages are the most accurate approach for determining the biostratigraphy of middle Miocene deposits in the Central Paratethys. The results of isotopic studies indicate that evaporites occur in a part of the Badenian section that was characterized by the lowest temperatures in the studied sections. [ABSTRACT FROM AUTHOR]

Background & Aims: The offspring of patients with premature coronary artery disease (P-CAD) are at higher risk for cardiovascular disease, compared with subjects without a family history (FH) of P-CAD. The increased risk for cardiovascular disease in subjects with FH of early-onset CAD results from unfavorable genetic variants as well as social, behavioral and environmental factors, which are more prevalent in this group. Previous studies have shown that specific sex hormone levels may be associated with the risk of cardiovascular disease. The aim of this study was to compare wide range of biochemical marker levels including i.e. the levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone, estradiol, testosterone and sex-hormone binding globulin (SHBG) between young healthy male adults with and without FH of P-CAD., Methods: The study group consisted of young healthy Polish male adults enrolled in a MAGNETIC case-control study, who were recruited between July 2015 and October 2017. The inclusion criteria were as follows: male sex, age ≥18 and ≤35 years old, FH of P-CAD (cases) or no P-CAD in first-degree relatives (controls). The comparison of continuous and categorical variables was performed using the Student's t-test or the U-Mann-Whitney test, and Fisher's exact test, respectively. The correlations between FSH, LH, testosterone, progesterone, SHBG and other laboratory parameters were assessed using the Spearman rank correlation test. Both univariable and multivariable logistic regression analyses were performed to assess the association between analyzed variables and FH of P-CAD., Results: A total of 411 subjects (223 cases and 188 controls) were included in the study. There was a higher prevalence of major cardiovascular risk factors in subjects with FH of P-CAD (smoking, higher total and LDL cholesterol levels, higher body mass index and lower HDL cholesterol level). Moreover, the offspring of patients with P-CAD had lower SHBG level, and higher LH and progesterone levels in the crude comparison, compared with individuals without FH of P-CAD. After adjustment for confounding variables, progesterone and LH were determined to be independently associated with FH of P-CAD., Conclusion: Progesterone and LH levels are significantly associated with FH of P-CAD, independent of traditional risk factors for CAD., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Obesity is often accompanied by low-grade inflammation. In recent years a few blood-based inflammatory markers - neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and monocyte-to-high-density lipoprotein ratio (MHR) - have been identified. They have been proven to correlate well with established inflammatory markers such as hsCRP and have a prognostic value among others in patients with coronary artery disease, heart failure, and malignancies. The aim of the study was to find markers associated with obesity in young heathy adults., Material and Methods: The study group included 321 young healthy adults aged 18-35 years (210 males and 111 females). Partial least squares regression analysis was used to find variables associated with body mass index (BMI), except MHR. Analysed variables included complete blood count, lipid profile, sex hormone levels, acute-phase protein levels, and blood-based inflammatory markers., Results: Variables with the strongest association with BMI in the group of men were HDL% and apolipoprotein B, and in the group of women, HDL, HDL%, triglycerides, and MHR. Novel inflammatory markers were not associated with BMI. We found significant (p < 0.001) correlations between novel biomarkers (NLR, dNLR) and hsCRP and fibrinogen levels in the group of subjects with obesity., Conclusions: Blood-based inflammatory markers significantly correlate with hsCRP and fibrinogen in young healthy adults with obesity, which may reflect the subclinical inflammation in this group of individuals.

Background: Despite the important roles of vascular smooth muscle cells and endothelial cells in atherosclerotic lesion formation, data regarding the associations of functional polymorphisms in the genes encoding growth factors with the severity of coronary artery disease (CAD) are lacking. The aim of the present study is to analyze the relationships between functional polymorphisms in genes encoding basic fibroblast growth factor (bFGF, FGF2), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), platelet derived growth factor-B (PDGFB), transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor A (VEGF-A) and the severity of coronary atherosclerosis in patients with stable CAD undergoing their first coronary angiography., Methods: In total, 319 patients with stable CAD who underwent their first coronary angiography at the Silesian Centre for Heart Diseases in Zabrze, Poland were included in the analysis. CAD burden was assessed using the Gensini score. The TaqMan method was used for genotyping of selected functional polymorphisms in the FGF2, PDGFB, TGFB1, IGF1 and VEGFA genes, while rs4444903 in the EGF gene was genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The associations between the selected polymorphisms and the Gensini were calculated both for the whole cohort and for a subgroup of patients without previous myocardial infarction (MI)., Results: There were no differences in the distribution of the Gensini score between the genotypes of the analyzed polymorphisms in FGF2, EGF, IGF1, PDFGB, and TGFB1 in the whole cohort and in the subgroup of patients without previous MI. The Gensini score for VEGFA rs699947 single-nucleotide polymorphism (SNP) in patients without previous myocardial infarction, after correction for multiple testing, was highest in patients with the A/A genotype, lower in heterozygotes and lowest in patients with the C/C genotype, (p value for trend = 0.013, false discovery rate (FDR) = 0.02). After adjustment for clinical variables, and correction for multiple comparisons the association between the VEGFA genotype and Gensini score remained only nominally significant (p = 0.04, FDR = 0.19) under the dominant genetic model in patients without previous MI., Conclusions: We were unable to find strong association between analyzed polymorphisms in growth factors and the severity of coronary artery disease, although there was a trend toward association between rs699947 and the severity of CAD in patients without previous MI.

Purpose: The renin-angiotensin-aldosterone system may influence in-stent restenosis (ISR) via angiotensin II, which stimulates the production of growth factors for smooth muscle cells. The aim of this work is to assess the influence of the rs1799752 polymorphism of the angiotensin-converting enzyme (ACE) gene and the rs699 polymorphism of the angiotensinogen (AGT) gene on the ISR in Polish patients with stable coronary artery disease (SCAD) who underwent stent implantation., Material/methods: Two hundred and sixty-five patients with SCAD were included in the study. All patients underwent stent implantation upon admission to the hospital and had subsequent coronary angiography performed. The patients were divided into two groups - those with significant ISR (n=53) and those without ISR (n=212). The ACE polymorphism was assessed using the classical PCR method and the AGT polymorphism was determined using the TaqMan method for SNP genotyping., Results: No difference in the frequency of angiographically significant ISR occurrence associated with the different ACE and AGT gene polymorphisms was observed. In a multivariable analysis, after correction for clinical variables, the relationship between the ACE and AGT genotypes within the scope of the analyzed polymorphisms and the process of restenosis was not found using a dominant, recessive and log-additive model. Late lumen loss was also independent of the genotypes of the polymorphisms before and after correction with angiographic variables., Conclusions: The rs1799752 polymorphism and the rs699 polymorphism had no relationship with the occurrence of angiographically significant ISR and late lumen loss in a group of Polish patients who underwent metal stent implantation., (Copyright © 2016 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Background: Neointima forming after stent implantation consists of vascular smooth muscle cells (VSMCs) in 90%. Growth factors TGF-β1, PDGFB, EGF, bFGF and VEGF-A play an important role in VSMC proliferation and migration to the tunica intima after arterial wall injury. The aim of this paper was an analysis of functional polymorphisms in genes encoding TGF-β1, PDGFB, EGF, bFGF and VEGF-A in relation to in-stent restenosis (ISR)., Materials and Methods: 265 patients with a stable coronary artery disease (SCAD) hospitalized in our center in the years 2007-2011 were included in the study. All patients underwent stent implantation at admission to the hospital and had another coronary angiography performed due to recurrence of the ailments or a positive result of the test assessing the coronary flow reserve. Angiographically significant ISR was defined as stenosis >50% in the stented coronary artery segment. The patients were divided into two groups-with angiographically significant ISR (n = 53) and without significant ISR (n = 212). Additionally, the assessment of late lumen loss (LLL) in vessel was performed. EGF rs4444903 polymorphism was genotyped using the PCR-RFLP method whilst rs1800470 (TGFB1), rs2285094 (PDGFB) rs308395 (bFGF) and rs699947 (VEGF-A) were determined using the TaqMan method., Results: Angiographically significant ISR was significantly less frequently observed in the group of patients with the A/A genotype of rs1800470 polymorphism (TGFB1) versus patients with A/G and G/G genotypes. In the multivariable analysis, LLL was significantly lower in patients with the A/A genotype of rs1800470 (TGFB1) versus those with the A/G and G/G genotypes and higher in patients with the A/A genotype of the VEGF-A polymorphism versus the A/C and C/C genotypes. The C/C genotype of rs2285094 (PDGFB) was associated with greater LLL compared to C/T heterozygotes and T/T homozygotes., Conclusions: The polymorphisms rs1800470, rs2285094 and rs6999447 of the TGFB1, PDGFB and VEGF-A genes, respectively, are associated with LLL in patients with SCAD treated by PCI with a metal stent implantation.

Background: There is no data regarding the association between the platelet-to-lymphocyte ratio (PLR) and long-term mortality in patients with stable coronary artery disease (SCAD). The aim of this study is to evaluate the utility of the pre-procedural PLR for predicting long-term, all-cause mortality in patients with SCAD undergoing percutaneous coronary intervention (PCI) and stent implantation., Methods: We analyzed a total of 2959 consecutive patients with SCAD who underwent PCI (balloon angioplasty followed by stent implantation or direct stenting) between July 2006 and December 2011 at our institution. The patients were stratified into tertiles according to their admission PLR. The association between the PLR value and the outcomes was assessed using Cox proportional regression analysis after adjusting for clinical angiographic and laboratory data., Results: During median follow-up of 1124 days, mortality was highest in patients with PLR within the 3rd tertile as compared to the 2nd and the 1st tertile (11.0% vs 8.7% vs. 9.6%, respectively, p = 0.03). PLR remained associated with mortality in multivariable analysis including clinical variables, ejection fraction and angiographic parameters HR (per 10 units increase) = 1.02 [95%CI,1.01 ÷ 1.04, p = 0.006]. After adjustment for the eGFR and hemoglobin levels, PLR was however no longer significantly associated with mortality., Conclusion: PLR has potential predictive value in patients with SCAD, which has not been reported previously, but statistical significance disappears after adjusting for estimated glomerular filtration rate (eGFR) and hemoglobin levels as a potential confounding variable.

Aim: To analyze the association between in-stent restenosis (ISR) and polymorphisms in genes coding IGF-1, IGFBP3, ITGB3 and GLUT1, which play an important role in the smooth muscle cell proliferation and extracellular matrix synthesis - the main components of neointima., Materials & Methods: We analyzed 265 patients who underwent bare metal stent implantation., Results: The differences in the occurrence of ISR between genotypes of the analyzed polymorphisms in the IGF-1, IGFBP3 and ITGB3 were not statistically significant. The T/T genotype of the rs710218 polymorphism in the GLUT1 (SLC2A1) gene was more common in the ISR group compared with non-ISR patients (81.1 vs 64.8%; p = 0.02). In a multivariable model the A/A and A/T genotype remained correlated with lower occurrence of ISR (odds ratio: 0.45; 95% CI: 0.21-0.97; p = 0.03)., Conclusion: The rs710218 polymorphism in the gene coding GLUT1 protein is a novel risk factor for ISR.

Assembly of independent chemical modules through oxorhenium coordination by a NS(2)+S chelation motif was applied to the synthesis of RGD (Arg-Gly-Asp) analogs. Modules were assembled through oxorhenium chelation to give a series of 18 metal complexes in good yields and satisfactory purities. Screening of these oxorhenium coordinates as antagonists of integrins αVβ3, αIIbβ3 and αVβ5 led to the identification of 3 bioactive compounds that exhibit submicromolar affinities for the 3 integrins. Preliminary studies showed that the corresponding oxotechnetium complexes are stable in mice plasma and therefore could be proposed for the molecular imaging of pathologies that overexpress integrins αVβ3 and αVβ5., (Copyright © 2011 Elsevier Inc. All rights reserved.)

A library of RGD tripeptide analogs cyclized through oxorhenium coordination by an NS2/S chelation motif was synthesized. Screening towards integrins αVβ3, αIIbβ3 and αVβ5 led to the identification of 6 oxorhenium complexes that bind to integrin αVβ3 in the submicromolar range. In vivo evaluation of five of the corresponding oxotechnetium complexes using nude mice bearing a U87MG human tumor xenograft showed a significant and specific accumulation of radioactivity inside the tumor. The best results in vivo were obtained with complexes Tc-16 and Tc-50 that displayed a higher tumor accumulation and a lower distribution in other tissues relative to a reference cyclopentapeptide tracer., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

The parallel oxorhenium-mediated assembly of 288 noncyclic RGD analogues is reported. All complexes contain a NS(2) +S chelating motif that enables the unambiguous coordination of the oxorhenium and oxotechnetium cores. In this study, "modules S" contain a variety of pending guanidinium groups whereas the "NS(2) modules" are made of a series of N-acylated amino acids. Combination of sets of "NS(2) " and "S modules" together with tetrabutylammonium tetrachlorooxorhenate gave the corresponding oxorhenium complexes in good yields and satisfactory purities. Evaluation of these metalloconstructs towards integrins α(V) β(3) , α(IIb) β(3) , and α(V) β(5) led to the identification of micromolar and submicromolar antagonists of theses integrins. These compounds exhibit interesting selectivities and promise attractive applications for the molecular imaging of integrin-dependent pathologies., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report the design of a new ligand of integrins that might be used for the molecular imaging of tumor neoangiogenesis. For this purpose, we designed a modified RGD tripeptide bearing a N-terminal N-bis(thioethyl)glycinate (NS(2)) motif and a thioethyl moiety at the C-terminus. Simultaneous coordination of an oxorhenium core by the NS(2) and thioethyl moieties led to peptide cyclization and gave the corresponding monomers 13a and b (major isomer) resulting from the syn/anti-isomerism, along with dimers' species 16a and b. Cyclometallated peptide 13b showed the most promising activity with an IC(50) of 86 nM for integrin alpha(V)beta(3) whereas it binds integrin alpha(IIb)beta(3) with an affinity lower by an order of magnitude. Labeling with [(99m)Tc]oxotechnetium gluconate led exclusively to complex 17, the equivalent of compound 13b, which displayed satisfactory stabilities in mice plasma and towards glutathione.

Evidence has emerged that repair of clustered DNA lesions may be compromised, possibly leading to the formation of double-strand breaks (DSB) and, thus, to deleterious events. The first repair event occurring at a multiply damaged site (MDS) is of major importance and will largely contribute to the hazardousness of MDS. Here, using protein extracts from wild type or hOGG1-overexpressing Chinese hamster ovary cells, we investigated the initial incision rate at base damage and the formation of repair intermediates in various complex MDS. These MDS comprise a 1 nt gap and 3-4 base damage, including 8-oxoguanine (oG) and 5-hydroxyuracil (hU). We report a hierarchy in base excision that mainly depends on the nature and the distribution of the damage. We also show that excision at both oG and hU, and consequently DSB formation, can be modulated by hOGG1 overexpression. Anyhow, for all the MDS analyzed, DSB formation is limited, due to impaired base excision. Interestingly, repair intermediates contain a short single-stranded region carrying a potentially mutagenic base damage. This in vitro study provides new insight into the processing of MDS and suggests that repair intermediates resulting from the processing of such MDS are rather mutagenic than toxic.