Репозиторий Университета

© 2019 The field of cartilage tissue engineering has been evolved in the last decade and a myriad of scaffolding biomaterials and bioactive agents have been proposed. Controlled release of growth factors encapsulated in the polymeric nanomaterials has been of interest notably for the repair of damaged articular cartilage. Here, we proposed an on-chip hydrodynamic flow focusing microfluidic approach for synthesis of alginate nanogels loaded with the transforming growth factor beta 3 (TGF-β3) through an ionic gelation method in order to achieve precise release profile of these bioactive agents during chondrogenic differentiation of mesenchymal stem cells (MSCs). Alginate nanogels with adjustable sizes were synthesized by fine-tuning the flow rate ratio (FRR) in the microfluidic device consisting of cross-junction microchannels. The result of present study showed that the proposed approach can be a promising tool to synthesize bioactive -loaded polymeric nanogels for applications in drug delivery and tissue engineering.

© 2019 The field of cartilage tissue engineering has been evolved in the last decade and a myriad of scaffolding biomaterials and bioactive agents have been proposed. Controlled release of growth factors encapsulated in the polymeric nanomaterials has been of interest notably for the repair of damaged articular cartilage. Here, we proposed an on-chip hydrodynamic flow focusing microfluidic approach for synthesis of alginate nanogels loaded with the transforming growth factor beta 3 (TGF-β3) through an ionic gelation method in order to achieve precise release profile of these bioactive agents during chondrogenic differentiation of mesenchymal stem cells (MSCs). Alginate nanogels with adjustable sizes were synthesized by fine-tuning the flow rate ratio (FRR) in the microfluidic device consisting of cross-junction microchannels. The result of present study showed that the proposed approach can be a promising tool to synthesize bioactive -loaded polymeric nanogels for applications in drug delivery and tissue engineering.

© 2019 The field of cartilage tissue engineering has been evolved in the last decade and a myriad of scaffolding biomaterials and bioactive agents have been proposed. Controlled release of growth factors encapsulated in the polymeric nanomaterials has been of interest notably for the repair of damaged articular cartilage. Here, we proposed an on-chip hydrodynamic flow focusing microfluidic approach for synthesis of alginate nanogels loaded with the transforming growth factor beta 3 (TGF-β3) through an ionic gelation method in order to achieve precise release profile of these bioactive agents during chondrogenic differentiation of mesenchymal stem cells (MSCs). Alginate nanogels with adjustable sizes were synthesized by fine-tuning the flow rate ratio (FRR) in the microfluidic device consisting of cross-junction microchannels. The result of present study showed that the proposed approach can be a promising tool to synthesize bioactive -loaded polymeric nanogels for applications in drug delivery and tissue engineering.

© 2019 The field of cartilage tissue engineering has been evolved in the last decade and a myriad of scaffolding biomaterials and bioactive agents have been proposed. Controlled release of growth factors encapsulated in the polymeric nanomaterials has been of interest notably for the repair of damaged articular cartilage. Here, we proposed an on-chip hydrodynamic flow focusing microfluidic approach for synthesis of alginate nanogels loaded with the transforming growth factor beta 3 (TGF-β3) through an ionic gelation method in order to achieve precise release profile of these bioactive agents during chondrogenic differentiation of mesenchymal stem cells (MSCs). Alginate nanogels with adjustable sizes were synthesized by fine-tuning the flow rate ratio (FRR) in the microfluidic device consisting of cross-junction microchannels. The result of present study showed that the proposed approach can be a promising tool to synthesize bioactive -loaded polymeric nanogels for applications in drug delivery and tissue engineering.

© 2019 The field of cartilage tissue engineering has been evolved in the last decade and a myriad of scaffolding biomaterials and bioactive agents have been proposed. Controlled release of growth factors encapsulated in the polymeric nanomaterials has been of interest notably for the repair of damaged articular cartilage. Here, we proposed an on-chip hydrodynamic flow focusing microfluidic approach for synthesis of alginate nanogels loaded with the transforming growth factor beta 3 (TGF-β3) through an ionic gelation method in order to achieve precise release profile of these bioactive agents during chondrogenic differentiation of mesenchymal stem cells (MSCs). Alginate nanogels with adjustable sizes were synthesized by fine-tuning the flow rate ratio (FRR) in the microfluidic device consisting of cross-junction microchannels. The result of present study showed that the proposed approach can be a promising tool to synthesize bioactive -loaded polymeric nanogels for applications in drug delivery and tissue engineering.

© 2019 The field of cartilage tissue engineering has been evolved in the last decade and a myriad of scaffolding biomaterials and bioactive agents have been proposed. Controlled release of growth factors encapsulated in the polymeric nanomaterials has been of interest notably for the repair of damaged articular cartilage. Here, we proposed an on-chip hydrodynamic flow focusing microfluidic approach for synthesis of alginate nanogels loaded with the transforming growth factor beta 3 (TGF-β3) through an ionic gelation method in order to achieve precise release profile of these bioactive agents during chondrogenic differentiation of mesenchymal stem cells (MSCs). Alginate nanogels with adjustable sizes were synthesized by fine-tuning the flow rate ratio (FRR) in the microfluidic device consisting of cross-junction microchannels. The result of present study showed that the proposed approach can be a promising tool to synthesize bioactive -loaded polymeric nanogels for applications in drug delivery and tissue engineering.

© 2019 The field of cartilage tissue engineering has been evolved in the last decade and a myriad of scaffolding biomaterials and bioactive agents have been proposed. Controlled release of growth factors encapsulated in the polymeric nanomaterials has been of interest notably for the repair of damaged articular cartilage. Here, we proposed an on-chip hydrodynamic flow focusing microfluidic approach for synthesis of alginate nanogels loaded with the transforming growth factor beta 3 (TGF-β3) through an ionic gelation method in order to achieve precise release profile of these bioactive agents during chondrogenic differentiation of mesenchymal stem cells (MSCs). Alginate nanogels with adjustable sizes were synthesized by fine-tuning the flow rate ratio (FRR) in the microfluidic device consisting of cross-junction microchannels. The result of present study showed that the proposed approach can be a promising tool to synthesize bioactive -loaded polymeric nanogels for applications in drug delivery and tissue engineering.

© 2019 Elsevier Ltd The aim of the study was to investigate the content and distribution of fucosylated sugar residues and Lewis Y (LeY) in the endothelial glycocalyx (eGC) in placental tissue at early and late onset fetal growth restriction (FGR). Our findings demonstrated that the changes of the fucosylated glycans of type 2 (H2)/LeY in the vascular endothelium of the villi may reflect alteration of villi maturation, or adaptation to hypoxia through the change of cell proliferation potential and induction angiogenesis. Early onset FGR differs from late onset FGR by a markedly increased LeY expression, being associated with more severe pathological state.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. WWP2 is an E3 ubiquitin ligase that differentially regulates the contextual tumour suppressor/progressor TGFβ signalling pathway by alternate isoform expression. WWP2 isoforms select signal transducer Smad2/3 or inhibitor Smad7 substrates for degradation through different compositions of protein-protein interactionWWdomains. The WW4 domain-containing WWP2-C induces Smad7 turnover in vivo and positively regulates the metastatic epithelial-mesenchymal transition programme. This activity and the overexpression of these isoforms in human cancers make them candidates for therapeutic intervention. Here, we use NMR spectroscopy to solve the solution structure of the WWP2 WW4 domain and observe the binding characteristics of Smad7 substrate peptide. We also reveal that WW4 has an enhanced affinity for a Smad7 peptide phosphorylated at serine 206 adjacent to the PPxY motif. Using the same approach, we show that the WW3 domain also binds Smad7 and has significantly enhanced Smad7 binding affinity when expressed in tandem with the WW4 domain. Furthermore, and relevant to these biophysical findings, we present evidence for a novel WWP2 isoform (WWP2C-DHECT) comprising WW3-WW4 tandem domains and a truncated HECT domain that can inhibit TGFβ signalling pathway activity, providing a further layer of complexity and feedback to the WWP2 regulatory apparatus. Collectively, our data reveal a structural platform for Smad substrate selection by WWP2 isoform WW domains that may be significant in the context of WWP2 isoform switching linked to tumorigenesis.

© 2019 The authors. Estrogens may affect bone growth locally or systemically via the known estrogen receptors ESR1, ESR2 and G protein-coupled estrogen receptor 1 (GPER1). Mouse and human growth plate chondrocytes have been demonstrated to express GPER1 and ablation of this receptor increased bone length in mice. Therefore, GPER1 is an attractive target for therapeutic modulation of bone growth, which has never been explored. To investigate the effects of activated GPER1 on the growth plate, we locally exposed mouse metatarsal bones to different concentrations of the selective GPER1 agonist G1 for 14 days ex vivo. The results showed that none of the concentrations of G1 had any direct effect on metatarsal bone growth when compared to control. To evaluate if GPER1 stimulation may systemically modulate bone growth, ovariectomized C57BL/6 mice were treated with G1 or β-estradiol (E2). Similarly, G1 did not influence tibia and femur growth in treated mice. As expected, E2 treatment suppressed bone growth in vivo. We conclude that ligand stimulation of GPER1 does not influence bone growth in mice.

© 2019 Walter de Gruyter GmbH, Berlin/Boston. Altered cardiac geometry affects a proportion of fetuses with growth restriction (FGR). The aim of this study was to explore the hemodynamic factors associated with cardiac remodeling in late FGR. This was a prospective study of singleton pregnancies complicated by late-onset FGR undergoing assessment of left (LV) and right (RV) ventricular sphericity-index (SI). The study population was divided in two groups according to the presence of cardiac remodelling, defined as LVSI <5th centile. The following outcomes were explored: Gestational age at birth, birthweight, caesarean section (CS) for fetal distress, umbilical artery (UA) pH and neonatal admission to special care unit. The differences between the 2 groups in UA pulsatility index (PI), middle cerebral artery (MCA) PI, uterine artery PI, cerebroplacental ratio (CPR) and umbilical vein (UV) flow corrected for fetal abdominal circumference (UVBF/AC) were tested. In total, 212 pregnancies with late FGR were enrolled in the study. An abnormal LV SI was detected in 119 fetuses (56.1%). Late FGR fetuses with cardiac remodeling had a lower birthweight (2390 g vs. 2490; P = 0.04) and umbilical artery pH (7.21 vs. 7.24; P = 0.04) and were more likely to have emergency CS (42.8% vs. 26.9%; P = 0.023) and admission to special care unit (13.4% vs. 4.3%; P = 0.03) compared to those with normal LVSI. No difference in either UA PI (p = 0.904), MCA PI (P = 0.575), CPR (P = 0.607) and mean uterine artery PI (P = 0.756) were present between fetuses with or without an abnormal LV SI. Conversely, UVBF/AC z-score was lower (-1.84 vs.-0.99; P ≤ 0.001) in fetuses with cardiac remodeling and correlated with LV (P ≤ 0.01) and RV SI (P ≤ 0.02). Fetal cardiac remodelling occurs in a significant proportion of pregnancies complicated by late FGR and is affected by a high burden of short-term perinatal compromise. The occurrence of LV SI is independent from fetal arterial Dopplers while it is positively associated with umbilical vein blood flow.

© 2019 John Wiley  &  Sons Ltd Background: Human milk (HM) transforming growth factor beta (TGF-β) is critical for inflammation regulation and oral tolerance promotion. Previous reports suggested that variations in HM TGF-β levels are associated with allergic outcomes. Objective: We undertook a systematic review (PROSPERO 2017 CRD42017069920) to reassess the evidence on the relationships between HM TGF-β and allergic outcomes in children. Methods: Electronic bibliographic databases (MEDLINE, EMBASE and Cochrane Library) were systematically searched. Two independent reviewers screened reference lists, extracted the data and assessed risk of bias using the National Institute for Clinical Excellence methodological checklist. Results: A total of 21 studies were identified. Sixteen studies assessed relationships between HM TGF-β and risk of eczema; 14, allergic sensitization; nine, wheezing/asthma; six, food allergy; three, allergic rhinitis/conjunctivitis. Five cohorts (5/18, 28%) reported a protective effect of TGF-β1, while 3 (3/10, 30%) suggested increased risk of allergic outcomes development and 1 (1/10, 10%), a protective effect of TGF-β2 on eczema. Meta-analysis was not possible due to significant heterogeneity in methodology, age of outcome assessment and differing statistical approaches. 71% (15/21) of studies carried a high risk of bias. Conclusion and clinical relevance: In contrast with previous findings, we did not find strong evidence of associations between HM TGF-β and allergic outcomes. Differences in studies' methodology and outcomes do not allow unconditional rejection or acceptance of the hypothesis that HM TGF-β influences the risk of allergy development. Future studies on diverse populations employing standardized methods, accurate phenotyping of outcomes and evaluation of the effect of TGF-β in combination with other HM immune markers, microbiome and oligosaccharides are required.

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. Colostrum is produced in the first days postpartum. It is a known source of immune mediators for a newborn within the first week of life. Although it is still unclear if colostrum composition varies between populations, recent data suggest differences. Hepatocyte growth factor (HGF); transforming growth factor-β (TGF-β) 1, 2, and 3; and immunoglobulin A (IgA) are key immunological components of colostrum that stimulate neonatal gastrointestinal and immune system development. We aimed to investigate the differences in the concentration between immune markers in the colostrum of mothers living in Burundi and Italy, and to identify the factors associated with differences. In this cross-sectional birth cohort study, a total of 99 colostrum samples from Burundian (n = 23) and Italian (n = 76) women were collected at 0 to 6 days postpartum. A clinical chemistry analyser was used for IgA quantification and electro-chemiluminescence, for HGF and TGFβ1-3 assessment. A univariate analysis and multivariate linear regression model were used for statistical testing. The concentrations of TGF-β2 (p = 0.01) and IgA (p < 0.01) were significantly higher in the colostrum from the women residing in Burundi than in Italy, both in a univariate analysis and upon the adjustment for confounding factors. A similar trend is seen for HGF, reaching statistical significance upon a multivariate analysis. We found a moderate to strong positive correlation between the TGF-β isoforms and IgA concentration in both countries (p < 0.01), with stronger concentration in the colostrum from Burundi. The results of this study are in support of previous data, suggesting that concentration of the immune active molecules is higher in the human milk of women residing in developing countries. However, with a small sample size, caution must be applied, as the findings require further confirmation. Future work should also be focused on other factors (e.g., lipid and microbial composition), as well as the investigation into colostrum and between populations comparison, adjusting for potential confounders.

© 2018, Pleiades Publishing, Ltd. Fibroblast growth factor (FGF) plays an important role in human embryogenesis, angiogenesis, cell proliferation, and differentiation. Carcinogenesis is accompanied by aberrant constitutive activation of FGF receptors (FGFRs) resulting from missense mutation in the FGFR1-4 genes, generation of chimeric oncogenes, FGFR1-4 gene amplification, alternative splicing shift toward formation of mesenchymal FGFR isoforms, and FGFR overexpression. Altogether, these alterations contribute to auto-and paracrine stimulation of cancer cells and neoangiogenesis. Certain missense mutations are found at a high rate in urinary bladder cancer and can be used for non-invasive cancer recurrence diagnostics by analyzing urine cell pellet DNA. Chimeric FGFR1/3 and amplified FGFR1/2 genes can predict cell response to the targeted therapy in various oncological diseases. In recent years, high-throughput sequencing has been used to analyze exomes of virtually all human tumors, which allowed to construct phylogenetic trees of clonal cancer evolution with special emphasis on driver mutations in FGFR1-4 genes. At present, FGFR blockers, such as multi-kinase inhibitors, specific FGFR inhibitors, and FGF ligand traps are being tested in clinical trials. In this review, we discuss current data on the functioning of the FGFR family proteins in both normal and cancer cells, mutations in the FGFR1-4 genes, and mechanisms underlying their oncogenic potential, which might be interesting to a broad range of scientists searching for specific tumor markers and targeted anti-cancer drugs.

Copyright © 2018. All rights reserved. Objective: Evaluate growth in patients with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with tocilizumab (TCZ) for up to 2 years in a phase III trial. Methods: Patients with pcJIA lasting at least 6 months and inadequate response to methotrexate received open-label TCZ intravenously every 4 weeks (randomly assigned to 8 or 10 mg/kg if they weighed < 30 kg; received 8 mg/kg if they weighed ≥ 30 kg) for 16 weeks. Patients with JIA American College of Rheumatology 30 response at Week 16 were randomly assigned to TCZ or placebo for 24 weeks, with an open-label extension through Week 104. Mean ± SD height velocity (cm/yr) and World Health Organization (WHO) height SD score (SDS) were measured in patients receiving ≥ 1 dose of TCZ who did not receive growth hormone and in patients whose baseline Tanner stage was ≤ 3. Results: The study included 187 of 188 patients (99.5%) with mean WHO height SDS -0.5 ± 1.2, which was unrelated to age or disease duration (Spearman rank correlations r = 0.08 and r = -0.12, respectively). There were 123 patients at Tanner stage ≤ 3 at baseline, among whom 103 completed the study with 2 years of height SDS data. Mean height SDS increased from baseline to year 2 (+0.40, p < 0.0001). In 74 of 103 patients (72%), height SDS was greater than at baseline, and mean height velocity was 6.7 ± 2.0 cm/year. Conclusion. Among patients with pcJIA at Tanner stage ≤ 3 at baseline, 72% (74/103) had increased height SDS at the end of the study.

© 2018 The Authors There are several pitfalls associated with research based on transgenic mice. Here, we describe our interpretation and analysis of mTORC1 activation in growth plate chondrocytes and compare these to a recent publication (Yan et al., Nature Communications 2016, 7:11151). Both laboratories employed TSC1-floxed mice crossed with collagen type 2-driven Cre (Col2-Cre), but drew substantially different conclusions. It was reported that activation of mechanistic target of rapamycin complex 1 (mTORC1) via Tsc1 ablation promotes the hypertrophy of growth plate chondrocytes, whereas we observe only disorganization in the resting zone, with no effect on chondrocyte hypertrophy or proliferation. Here, we present our data and discuss the differences in comparison to the earlier phenotypic characterization of TSC1 ablation in cartilage. Importantly, we detect Col2-Cre activity in non-cartilaginous tissues (including the brain) and discuss it in relation to other studies reporting non-cartilaginous expression of collagen alpha(1) II. Altogether, we conclude that mouse phenotypes following genetic ablation using Col2-Cre should be interpreted with care. We also conclude that activation of mTORC1 by TSC1 ablation in postnatal chondrocytes with inducible Col2-Cre (Col2-CreERt) leads to disorganization of the resting zone but causes no changes in chondrocyte proliferation or differentiation.

© 2018, Pediatria Ltd.. All rights reserved. Objective of the research: to dentify risk factors for growth retardation in patients with juvenile scleroderma (JSD). The presented data show that the most unfavorable factors for growth retardation in patients with JSD are the systemic form of the disease, debut age less than 4 years. Other unfavorable factors of growth retardation developing are father's height less than 175 cm and a mother's height less than 165 cm. Analysis of the effect of glucocorticoid saverage daily dose during the year on the growth rate in patients with JSD, normalization of growth rates was noted with its decrease to 0,2 mg/kg/day or less.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. We created an anisotropic material based on collagen sponge and reactive polylactide structured by laser photopolymerization. The combination of collagen with reactive polylactide improves the resistance of the formed matrices to biodegradation in comparison with collagen sponge, while the existence of sites with different mechanical characteristics and cell affinity on the matrix provides directed cell growth during their culturing. It was shown that reinforcement of the collagen sponges 7-fold increased the mean Young’s modulus for the hybrid matrix without affecting its cytotoxicity. The developed matrix provides cell adhesion and proliferation along reinforcement lines and can be used for fabrication of tissue engineering constructs.

© 2018 Media Sphera Publishing Group. All rights reserved. Aim of the study was to explore the role of the FGF-23/sKlotho/sclerostin ratio disturbance in the determining of cardiovascular risk in end stage renal disease (ESRD) patients, receiving treatment with regular hemodialysis (ÍD) or hemodiafiltration (ÍDF) online in Russia. Materials and methods. 42 patients with ESRD, at the age of 18-55 years, treated with HD or HDF on line for at least 6 months, were examined. 22 (52.3%) patients received traditional HD, the remaining 20 (47.7%) - HDF online. In all the patients, in addition to a general examination, the serum levels of FGF-23, sKlotho, sclerostine (by ELISA), their associations with cardiovascular risk factors (left ventricular hypertrophy (LVH), acute coronary syndrome (ACS), serum troponin I levels) with the numbers of techniques (ECG; Eho-CGF (with calculation of left ventricular myocardium mass index (LVMMI), as well as the relative thickness of the walls of the left ventricle (RWT); sphygmography (central (aortal) blood pressure (CBP), subendocardial blood flow (SBF) - by Sphygmocor), and the effect of regular HD and HDF on serum levels of the studied markers, were assessed. Results and discussion. An independent effect of FGF-23 on the risk of LVH, as well as on the increase of serum troponin I in the studied ESRD patients [β=3.576 p<0.01, and β=1.115, p<0.05, respectively] was found. Serum Klotho was the factor most associated with the CBP [β=-0.023; p<0.001]. The increased serum sclerostin was correlated with a lower incidence of both reduced SBF [r=0.492; p<0.05], symptoms of coronary heart disease [r=-0.449; p<0.05] and rhythm disturbances [r=-0.446; p<0.05]. In addition, in HD patients higher FGF-23 and lower Klotho and sclerostine serum levels were associated with: inadequate dialysis syndrome (Kt/V <1.1; r=0.463; p<0.05), chronic inflammation (C-reactive protein >10 mg/L; r=0.612; p<0.01), and with a decrease in serum albumin level (<35 g/l; r=0.459; p<0.05). The FGF-23/sKlotho/sclerostin ratio disturbance was more pronounced in patients treated with traditional HD then HDF online. A direct correlation (r=0.445; p<0.05) was established between FGF-23 serum levels and serum phosphorus, which was more pronounced in HD patients (r=0.545; p<0.01). Conclusion. In HD and HDF ESRD patients, higher serum FGF-23 and lower sKlotho and sclerostin levels were associated with a chronic inflammation, malnutrition, secondary hyperparathyroidism, and may considered as predictors of cardiovascular complications such as LVH, ACS, rhythm disturbances, persisting of subincreased serum troponin I.

© 2018, Media Sphera Publishing Group. All rights reserved. Objective — to investigate the growth mechanisms of large uterine leiomyoma (LULM) on the basis of a clinical morphology examination, by providing immunohistochemical (IHC) characteristics of the expression of growth factors (transforming growth factor-beta (TGFβ) and platelet-derived endothelial cell growth factor (PD-ECGF)) and markers of stemness (CD117/c-kit, Connexin 43, Nestin) and proliferation (Ki-67). Subject and methods. The investigators examined surgical specimens from 38 women diagnosed with simple uterine leiomyoma (ULM), who had been divided into two groups: 1) 21 patients with LULM (>6 cm in diameter) (a study group); 2) 17 patients with small ULM (<4 cm in diameter) (a comparison group). Each group was also divided into two age subgroups (younger (<45 years) and older (≥45 years) subgroups (1a (n=12), 1b (n=9), 2a (n=8) and 2b (n=9), respectively. Histological specimens were used to make IHC examination with antibodies against TGFβ, PD-ECGF, CD117/ckit, Connexin 43, Nestin, and Ki-67. Results. The growth mechanisms of LULM of simple histological structure were found to be associated with the larger number of growth zones in the tumors, with their enhanced cellular proliferative activity, and with the appearance of cells with signs of stemness, which is combined with the preserved subsequent maturation of tumor cells and determines the benign nature of LULM. Conclusion. There were differences in the molecular profile of LULM and small ULM, as well as LULM in perimenopausal and young women by the expression levels of Ki-67, TGFβ, PD-ECGF, CD117, and Connexin 43, which can be used for diagnosis, prediction, and development of targeted therapies.