Extending the release cycle of growth factors to match the cycle of bone remodeling is difficult. When using concentrated growth factors (CGFs), the release of growth factors is excessively rapid. In ...the present study, CGF samples were prepared by centrifugation. CGF samples were then lyophilized and grinded into a powder, which was termed freeze‑dried CGF. The freeze‑dried CGF samples were mixed with chitosan‑alginate composite hydrogels, and the mixture was lyophilized. The result was a chitosan‑alginate composite CGF membrane, which was called sustained‑release CGF. This study investigated whether freeze‑dried CGF in a chitosan‑alginate composite gel can release CGF steadily to achieve effective osteogenesis. The proliferation and osteogenic expression of MC3T3‑E1 cells induced by the supernatants from incubation with freeze‑dried CGF and sustained‑release CGF were evaluated. The concentrations of the growth factors, transforming growth factor β1 (TGF‑β1), insulin‑like growth factor‑1 (IGF‑1), platelet‑derived growth factor‑AB (PDGF‑AB) and vascular endothelial growth factor (VEGF), in these two experimental groups at different times were determined by ELISA kits. The freeze‑dried CGF showed better osteogenic performance than the sustained‑release CGF in the early stages. At later stages, the sustained‑release CGF had significant advantages over freeze‑dried CGF in terms of promoting osteogenic mineralization. By characterizing the biologic properties of the CGF in the two different forms in vitro, we obtained a better understanding of their clinical effects.
The sites of targeted therapy are limited and need to be expanded. The FGF‐FGFR signalling plays pivotal roles in the oncogenic process, and FGF/FGFR inhibitors are a promising method to treat ...FGFR‐altered tumours. The VEGF‐VEGFR signalling is the most crucial pathway to induce angiogenesis, and inhibiting this cascade has already got success in treating tumours. While both their efficacy and antitumour spectrum are limited, combining FGF/FGFR inhibitors with VEGF/VEGFR inhibitors are an excellent way to optimize the curative effect and expand the antitumour range because their combination can target both tumour cells and the tumour microenvironment. In addition, biomarkers need to be developed to predict the efficacy, and combination with immune checkpoint inhibitors is a promising direction in the future. The article will discuss the FGF‐FGFR signalling pathway, the VEGF‐VEGFR signalling pathway, the rationale of combining these two signalling pathways and recent small‐molecule FGFR/VEGFR inhibitors based on clinical trials.
Targeted therapies interfering with oncogenic driver alterations have achieved remarkable success in limited types of cancer with certain driver gene alterations (Nat Rev Clin Oncol, 2017; Lancet Oncol, 2018; Jama, 2019; Lancet, 2017). Novel therapeutics targeting other cancer driver alterations are urgently needed to be developed to improve the life quantity of the patients and prolong their life span. The FGF‐FGFR signalling plays pivotal roles in both the physiological and oncogenic processes (Nat Rev Clin Oncol, 2019), but FGFRs are constitutively active in malignant cells because of the upregulation of FGF and FGFR genetic alterations (Nat Rev Clin Oncol, 2019). Targeting FGF‐FGFR signalling is a promising method to treat FGFR‐altered tumours (New Engl J Med, 2019; Lancet Oncol, 2020), but patients receive limited effects by targeting only the FGF‐FGFR pathway in most clinical practice (Nat Rev Cancer, 2017; Eur J Med Chem, 2020). VEGF‐VEGFR signalling pathway also attracts our attention. The growth of tumours relies on blood supply and VEGFs are proved to be the most important angiogenic factors (Nat Rev Drug Discov, 2016). Accordingly, inhibition of the VEGF‐VEGFR signalling pathway is believed to suppress tumour development (New Engl J Med, 1971). Here we propose the simultaneous inhibition of the FGF‐FGFR pathway and VEGF‐VEGFR pathway. In terms of mechanism, the combination can target tumour cells and tumour microenvironment at the same time (Clin Cancer Res, 2019). FGFR/VEGFR inhibitors have better effects and broaden the indications in clinical use (Nat Commun, 2020; JAMA Oncol, 2018; The Lancet Oncology, 2020).
Abstract
Context
Collagens are the most abundant proteins in the human body. In a growth plate, collagen types II, IX, X, and XI are present. Defects in collagen genes cause heterogeneous syndromic ...disorders frequently associated with short stature. Less is known about oligosymptomatic collagenopathies.
Objective
This work aims to evaluate the frequency of collagenopathies in familial short stature (FSS) children and to describe their phenotype, including growth hormone (GH) treatment response.
Methods
Eighty-seven FSS children (pretreatment height ≤ –2 SD both in the patient and his or her shorter parent) treated with GH were included in the study. Next-generation sequencing was performed to search for variants in the COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, and COL11A2 genes. The results were evaluated using American College of Medical Genetics and Genomics guidelines. The GH treatment response of affected children was retrospectively evaluated.
Results
A likely pathogenic variant in the collagen gene was found in 10 of 87 (11.5%) children. Detailed examination described mild asymmetry with shorter limbs and mild bone dysplasia signs in 2 of 10 and 4 of 10 affected children, respectively. Their growth velocity improved from a median of 5.3 cm/year to 8.7 cm/year after 1 year of treatment. Their height improved from a median of –3.1 SD to –2.6 SD and to –2.2 SD after 1 and 3 years of therapy, respectively. The final height reached by 4 of 10 children differed by –0.67 to +1.0 SD and –0.45 to +0.5 SD compared to their pretreatment height and their affected untreated parent’s height, respectively.
Conclusion
Oligosymptomatic collagenopathies are a frequent cause of FSS. The short-term response to GH treatment is promising.
Tissue engineering is a rapidly developing field with many potential clinical applications in tissue and organ regeneration. The development of a mature and stable vasculature within these engineered ...tissues (ET) remains a significant obstacle. Currently, several growth factors (GFs) have been identified to play key roles within in vivo angiogenesis, including vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), FGF and angiopoietins. In this article we attempt to build on in vivo principles to review the single, dual and multiple GF release systems and their effects on promoting angiogenesis. We conclude that multiple GF release systems offer superior results compared to single and dual systems with more stable, mature and larger vessels produced. However, with more complex release systems this raises other problems such as increased cost and significant GF–GF interactions. Upstream regulators and pericyte-coated scaffolds could provide viable alternative to circumnavigate these issues.
Puzzles of economic growth Balcerowicz, Leszek; Rzonca, Andrzej
2015., 2014, 12-3-2014, 2015
eBook, Book
Odprti dostop
Looking at the economic growth of seemingly similar countries one can find striking differences. Why has Australia gotten so much ahead of New Zealand, in spite of the latter being held up as a ...paragon of free market reform? How is it possible that Austria, with its persistently oversized state enterprise sector, has managed to (nearly) catch up with Switzerland? How can we account for the differences in economic growth between Estonia and Slovenia, and which of these two countries has been more successful at systemic transformation? Why is Mexico so much poorer than Spain, despite having been wealthier all the way into the 1960s? Why has Venezuela, which in 1950 had a per capita income higher than that of Norway and remains a major exporter of oil, slipped behind Chile? Why is Costa Rica lagging behind Puerto Rico, even though in the 1970s the U.S. territory's fast development slowed to a crawl and is now far below other comparable island economies? Why has 'communist' China outstripped 'capitalist' India? Why has Pakistan's growth lagged behind that of Indonesia, even though the latter suffered one of the deepest crises in world economic history in the years 1997-98? Why, even before the 2010 earthquake, the Dominican Republic has been visited by several dozen times more tourists than Haiti, despite being situated on the same island? This book strives to answer these (and many other) questions. They are all part of a broader question that we wish to address: how do differences in economic growth arise?
Insulin-like growth factors 1 and 2 (IGF1 and IGF2) and their binding proteins (IGFBPs) are expressed in the placenta and known to regulate fetal growth. DNA methylation is an epigenetic mechanism ...which involves addition of methyl group to a cytosine base in the DNA forming a methylated cytosine-phosphate-guanine (CpG) dinucleotide which is known to silence gene expression. This silences gene expression, potentially altering the expression of IGFs and their binding proteins. This study investigates the relationship between DNA methylation of components of the IGF axis in the placenta and disorders in fetal growth. Placental samples were obtained from cord insertions immediately after delivery from appropriate, small (defined as birthweight <10th percentile for the gestation SGA) and macrosomic (defined as birthweight > the 90th percentile for the gestation LGA) neonates. Placental DNA methylation, mRNA expression and protein levels of components of the IGF axis were determined by pyrosequencing, rtPCR and Western blotting.
In the placenta from small for gestational age (SGA) neonates (n = 16), mRNA and protein levels of IGF1 were lower and of IGFBPs (1, 2, 3, 4 and 7) were higher (p < 0.05) compared to appropriately grown neonates (n = 37). In contrast, in the placenta from large for gestational age (LGA) neonates (n = 20), mRNA and protein levels of IGF1 was not different and those of IGFBPs (1, 2, 3 and 4) were lower (p < 0.05) compared to appropriately grown neonates. Compared to appropriately grown neonates, CpG methylation of the promoter regions of IGF1 was higher in SGA neonates. The CpG methylation of the promoter regions of IGFBP1, IGFBP2, IGFBP3, IGFBP4 and IGFBP7 was lower in the placenta from SGA neonates as compared to appropriately grown neonates, but was unchanged in the placenta from LGA neonates.
Our results suggest that changes in CpG methylation contribute to the changes in gene expression of components of the IGF axis in fetal growth disorders. Differential methylation of the IGF1 gene and its binding proteins is likely to play a role in the pathogenesis of SGA neonates.
FGFR signaling is deregulated in many human cancers, and FGFR is considered a valid target in FGFR-deregulated tumors. Here, we examine the preclinical profile of futibatinib (TAS-120; ...1-(3S)-4-amino-3-(3,5-dimethoxyphenyl)ethynyl-1H-pyrazolo3, 4-d pyrimidin-1-yl-1-pyrrolidinyl-2-propen-1-one), a structurally novel, irreversible FGFR1-4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1-4 with IC
values of 1.4 to 3.7 nmol/L. Futibatinib covalently bound the FGFR kinase domain, inhibiting FGFR phosphorylation and, in turn, downstream signaling in FGFR-deregulated tumor cell lines. Futibatinib exhibited potent, selective growth inhibition of several tumor cell lines (gastric, lung, multiple myeloma, bladder, endometrial, and breast) harboring various
genomic aberrations. Oral administration of futibatinib led to significant dose-dependent tumor reduction in various FGFR-driven human tumor xenograft models, and tumor reduction was associated with sustained FGFR inhibition, which was proportional to the administered dose. The frequency of appearance of drug-resistant clones was lower with futibatinib than a reversible ATP-competitive FGFR inhibitor, and futibatinib inhibited several drug-resistant FGFR2 mutants, including the FGFR2 V565I/L gatekeeper mutants, with greater potency than any reversible FGFR inhibitors tested (IC
, 1.3-50.6 nmol/L). These results indicate that futibatinib is a novel orally available, potent, selective, and irreversible inhibitor of FGFR1-4 with a broad spectrum of antitumor activity in cell lines and xenograft models. These findings provide a strong rationale for testing futibatinib in patients with tumors oncogenically driven by FGFR genomic aberrations, with phase I to III trials ongoing. SIGNIFICANCE: Preclinical characterization of futibatinib, an irreversible FGFR1-4 inhibitor, demonstrates selective and potent antitumor activity against FGFR-deregulated cancer cell lines and xenograft models, supporting clinical evaluation in patients with FGFR-driven tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/22/4986/F1.large.jpg.
Noninvasive methods for liver disease diagnoses offer great advantages over biopsy, but they cannot be utilized in all cases. Therefore, specific indicators for chronic liver disease management are ...necessary. The aim was to assess the production of insulin-like growth factor-binding proteins (IGFBPs) 1–7 and their correlation with the different stages of fibrosis in chronic hepatitis C (CHC). A prospective, cross-sectional, multicenter study was conducted. CHC patients were categorized by FibroTest® and/or FibroScan®. Serum concentrations of IGFBPs 1–7 were determined through multiple suspension arrangement array technology. Significant differences were validated by the Kruskal–Wallis and Mann–Whitney
U
tests. Logistic regression models were performed to assess the association between the IGFBPs and fibrosis stages. The association was determined utilizing odds ratios (ORs), and receiver operating characteristic (ROC) curves were constructed to distinguish the IGFBPs in relation to the diagnosis of fibrosis. IGFBP-1 and IGFBP-7 concentrations were higher in CHC than in the healthy individuals, whereas IGFBP-3, IGFBP-5, and IGFBP-6 were downregulated in the patients. An apparent increase of all the IGFBPs was found at fibrosis stage F4, but with different regulations. IGFBP-2, -4, -6, and -7 had the best OR, showing the relation to fibrosis progression. The ROC curves showed that IGFBP-7 was the only protein that distinguished F1 from F3 and F2 from F3. IGFBPs participate in liver fibrosis progression and could be employed as circulating novel protein panels for diagnosis and as possible therapeutic targets in liver fibrosis progression.
Angiogenesis, the growth of new blood vessels, involves specification of endothelial cells to tip cells and stalk cells, which is controlled by Notch signalling, whereas vascular endothelial growth ...factor receptor (VEGFR)-2 and VEGFR-3 have been implicated in angiogenic sprouting. Surprisingly, we found that endothelial deletion of Vegfr3, but not VEGFR-3-blocking antibodies, postnatally led to excessive angiogenic sprouting and branching, and decreased the level of Notch signalling, indicating that VEGFR-3 possesses passive and active signalling modalities. Furthermore, macrophages expressing the VEGFR-3 and VEGFR-2 ligand VEGF-C localized to vessel branch points, and Vegfc heterozygous mice exhibited inefficient angiogenesis characterized by decreased vascular branching. FoxC2 is a known regulator of Notch ligand and target gene expression, and Foxc2(+/-);Vegfr3(+/-) compound heterozygosity recapitulated homozygous loss of Vegfr3. These results indicate that macrophage-derived VEGF-C activates VEGFR-3 in tip cells to reinforce Notch signalling, which contributes to the phenotypic conversion of endothelial cells at fusion points of vessel sprouts.
Pharmacological inhibition of VEGF-A has proven to be effective in inhibiting angiogenesis and vascular leak associated with cancers and various eye diseases. However, little information is currently ...available on the binding kinetics and relative biological activity of various VEGF inhibitors. Therefore, we have evaluated the binding kinetics of two anti-VEGF antibodies, ranibizumab and bevacizumab, and VEGF Trap (also known as aflibercept), a novel type of soluble decoy receptor, with substantially higher affinity than conventional soluble VEGF receptors. VEGF Trap bound to all isoforms of human VEGF-A tested with subpicomolar affinity. Ranibizumab and bevacizumab also bound human VEGF-A, but with markedly lower affinity. The association rate for VEGF Trap binding to VEGF-A was orders of magnitude faster than that measured for bevacizumab and ranibizumab. Similarly, in cell-based bioassays, VEGF Trap inhibited the activation of VEGFR1 and VEGFR2, as well as VEGF-A induced calcium mobilization and migration in human endothelial cells more potently than ranibizumab or bevacizumab. Only VEGF Trap bound human PlGF and VEGF-B, and inhibited VEGFR1 activation and HUVEC migration induced by PlGF. These data differentiate VEGF Trap from ranibizumab and bevacizumab in terms of its markedly higher affinity for VEGF-A, as well as its ability to bind VEGF-B and PlGF.
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