Uveal melanoma (UM) is the major intraocular malignancy in adults, of which the molecular biology is still unknown. Therefore, this study was designed to determine the aqueous concentrations of angiogenic, inflammatory, and chemotactic cytokines in eyes with UM.Aqueous humor samples were collected from 38 patients with UM and <em>22</em> patients undergoing cataract surgery. Interleukin 6, 8 (IL-6, IL-8, respectively), interferon-inducible protein-10 (IP-10), placental <em>growth</em> <em>factor</em>1 (PIGF1), regulated on activation, normal T Cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 (MCP-1), nerve <em>growth</em> <em>factor</em>-beta (NGF-β), epidermal <em>growth</em> <em>factor</em> (EGF), basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (bFGF), and vascular endothelia <em>growth</em> <em>factor</em> A (VEGF-A) were assessed by multiplex bead assay.In the study group, significantly higher concentrations of IL-6 (P = .006), IL-8 (P = .018), IP-10 (P = .004), RANTES (P = .008), MCP-1 (P = .02), NGF-β (P = .013), EGF (P < .001), PIGF1 (P = .01), bFGF (P = .016), and VEGF (P = .017) were measured, when compared with the control group.Several angiogenic, inflammatory, and chemotactic cytokines are highly expressed in the aqueous humor of the UM eyes, which provides new insights into the pathophysiology of UM and could be potential targets for treatment.

Curative gastrectomy and adjuvant chemotherapy using S-1 is a standard treatment for stage II/III gastric cancer in Japan. The purpose of the present study was to evaluate the prognostic relevance of <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor (FGFR)2 expression in patients with stage II/III gastric cancer that underwent postoperative adjuvant chemotherapy with S-1. Formalin-fixed paraffin-embedded surgical specimens were retrospectively examined in 167 patients with stage II/III gastric cancer that underwent curative gastrectomy followed by adjuvant S1 chemotherapy. FGFR2 expression was measured using immunohistochemistry (IHC) staining. The IHC results for FGFR2 were as follows: Grade 1+, 32; grade 2+, 80; grade 3+, 55 patients. The FGFR2 expression level was not significantly associated with relapse-free or overall survival rates. However, in the diffuse type, the FGFR2 expression level tended to be negatively correlated with relapse-free survival. In particular, the proportion of patients who recurred >5 years following surgery was significantly larger in the FGFR2 grade 3+ group than in the grade 1+, 2+ group (4/<em>22</em> vs. 1/35; P=0.047). The recurrent sites of long-term failure were mostly peritoneum among the diffuse type. To the best of our knowledge, the present study indicated for the first time that FGFR2 could predict long-term failure of adjuvant S-1 chemotherapy in curative advanced gastric cancer. There was no interaction between FGFR2 expression and patient survival outcomes in stage II/III gastric cancer. Patients with FGFR2 3+ in stage II/III gastric cancer should carefully be followed-up for >5 years after surgery.

BACKGROUND

Fibroblast growth factor 19 (FGF19) is a gut-derived hormone that regulates the expression of CYP7A1, the rate-limiting enzyme in bile acid (BA) synthesis pathway. Dysregulation of the FGF19-CYP7A1 (gut-liver) axis is associated with cholestatic liver disease. Infants, especially preterm infants and those with intestinal failure are at high risk for developing cholestatic liver disease. The activity of the gut-liver axis has not been characterized in this population. Our objective was to assess relationships between circulating FGF19 concentrations and CYP7A1 activity in neonates.

METHODS

Plasma samples were obtained longitudinally from term and preterm infants (22-41-week gestation) hospitalized in a neonatal intensive care unit. Infants with congenital and acquired gastrointestinal disorders were excluded. Plasma levels of 7α-hydroxy-4-cholesten-3-one (C4), a marker of CYP7A1 activity, were quantified using HPLC-MS/MS. Plasma FGF19 concentrations were quantified by ELISA. Data were analyzed using linear regression models and structural equation modeling.

RESULTS

One hundred eighty-one plasma samples were analyzed from 62 infants. C4 concentrations were undetectable prior to 30 weeks' gestation and, thereafter, increased with advancing gestational age and with volume of enteral feeds. They did not correlate with serum FGF19 concentrations, which decreased with advancing gestational age and volume of enteral feeds.

CONCLUSIONS

The activity of CYP7A1, the rate-limiting BA synthetic enzyme in adults, is developmentally regulated and undetectable in newborns less than 30 weeks' gestation. FGF19 concentrations do not correlate with CYP7A1 activity, suggesting that the gut-liver axis is not functional in infants. High FGF19 concentrations at birth in infants less than 37 weeks' gestation is a novel finding, and its source and role in preterm infants warrants further investigation.

BACKGROUND

The intestinal hormone, fibroblast growth factor 19 (FGF19), is a major regulator of CYP7A1, the rate limiting enzyme in bile acid (BA) synthesis. Recently, dysregulation of the gut-liver (FGF19-CYP7A1) axis has been implicated in adult cholestatic liver disease, and animal studies have shown that exogenous FGF19 protects against liver injury. Given the therapeutic potential related to this signaling pathway, we sought to characterize the association between CYP7A1 and FGF19 in term and preterm infants. We conducted a prospective, observational study that measured in vivo CYP7A1 activity and FGF19 concentrations in 62 term and preterm infants (n = 181 samples). We found that CYP7A1 activity is developmentally regulated; its activity is undetectable prior to 30 weeks' gestation and increases with advancing gestational age and volume of enteral feeds. Contrary to expectation, we demonstrated that FGF19 is expressed at birth in preterm infants and decreases over time, even as enteral feeds increase. Using structural equation modeling, we were able to show that CYP7A1 activity does not correlate with FGF19 concentrations. Our results suggest that the gut-liver axis is not upregulated in preterm and term infants and that neonates with cholestatic liver disease will unlikely benefit from supplemental FGF19. We also report novel findings of elevated FGF19 concentrations in preterm infants at birth and speculate that there may be an extra-intestinal source of FGF19 that is developmentally expressed in these infants.

The inflammatory microenvironment affects breast cancer progression. Proteins that govern the inflammatory response are secreted into the extracellular space, but this compartment still needs to be characterized in human breast tissues in vivo. Dense breast tissue is a major risk <em>factor</em> for breast cancer by yet unknown mechanisms and no non-toxic prevention for these patients exists. Here, we used the minimal invasive technique of microdialysis for sampling of extracellular proteins in live tissues in situ in breast cancers of women before surgery and in healthy women having dense or non-dense breast tissue on mammography. Proteins were profiled using a proximity extension assay. Out of the 32 proteins assessed, 26 exhibited similar profiles in breast cancers and dense breast tissues; CCL-4, -7, -8, -11, -15, -16, -<em>22</em>, -23, and -25, CXCL-5, -8, -9, -16 as well as sIL-6R, IL-18, vascular endothelial <em>growth</em> <em>factor</em>, TGF-α, <em>fibroblast</em> <em>growth</em> <em>factor</em> 19, matrix metalloproteinase (MMP)-1, -2, -3, and urokinase-type plasminogen activator were all increased, whereas CCL-3, CX3CL1, hepatocyte <em>growth</em> <em>factor</em>, and MMP-9 were unaltered in the two tissues. CCL-19 and -24, CXCL-1 and -10, and IL-6 were increased in dense breast tissue only, whereas IL-18BP was increased in breast cancer only. Our results provide novel insights in the inflammatory microenvironment in human breast cancer in situ and define potential novel therapeutic targets. Additionally, we show previously unrecognized similarities of the pro-inflammatory microenvironment in dense breast tissue and breast cancer in vivo suggesting that anti-inflammatory breast cancer prevention trials for women with dense breast tissue may be feasible.

The <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF) family consists of <em>22</em> evolutionarily and structurally related proteins (FGF1 to FGF23; with FGF15 being the rodent ortholog of human FGF19). Based on their mechanism of action, FGFs can be categorized into intracrine, autocrine/paracrine and endocrine subgroups. Both autocrine/paracrine and endocrine FGFs are secreted from their cells of origin and exert their effects on target cells by binding to and activating specific single-pass transmembrane tyrosine kinase receptors (FGFRs). Moreover, FGF binding to FGFRs requires specific co<em>factor</em>s, namely heparin/heparan sulfate proteoglycans or Klothos for autocrine/paracrine and endocrine FGF signaling, respectively. FGFs are vital for embryonic development and mediate a broad spectrum of biological functions, ranging from cellular excitability to angiogenesis and tissue regeneration. Over the past decade certain FGFs (e.g. FGF1, FGF10, FGF15/FGF19 and FGF21) have been further recognized as regulators of energy homeostasis, metabolism and adipogenesis, constituting novel therapeutic targets for obesity and obesity-related cardiometabolic disease. Until recently, translational research has been mainly focused on FGF21, due to the pleiotropic, beneficial metabolic actions and the relatively benign safety profile of its engineered variants. However, increasing evidence regarding the role of additional FGFs in the regulation of metabolic homeostasis and recent developments regarding novel, engineered FGF variants have revitalized the research interest into the therapeutic potential of certain additional FGFs (e.g. FGF1 and FGF15/FGF19). This review presents a brief overview of the FGF family, describing the mode of action of the different FGFs subgroups, and focuses on FGF1 and FGF15/FGF19, which appear to also represent promising new targets for the treatment of obesity and type 2 diabetes.

OBJECTIVE

Chemotherapy resistance is a problem in the treatment of advanced retinoblastoma (RB). Since basic fibroblast growth factor (bFGF) is a survival factor for neural precursor cells, bFGF was evaluated as a growth and chemoresistance factor in RB.

METHODS

bFGF expression was analyzed in the LH-betaTag transgenic mouse model of RB and human RB cell lines by immunofluorescence, RT-PCR, and Western blot. Proliferation and apoptosis (TUNEL) assays were performed.

RESULTS

bFGF levels significantly increased during tumorigenesis in transgenic RB, as a function of tumor status (P = 0.005). PCR and confocal microscopy confirmed that the human cell lines and primary tumors expressed bFGF. bFGF was localized to vascular and tumor cells and rarely to glial cells. Exogenous 18-kDa bFGF induced proliferation in two RB cell lines (WERI and Y79). Western blot analysis demonstrated 34-, 22-, and 18-kDa isoforms in transgenic RB and both cell lines. In TUNEL assays, chemoresistance to carboplatin-induced apoptosis was observed in the Y79 line, which expressed a higher ratio of high (34 kDa)- to low-molecular-weight bFGF isoforms, compared with the WERI line. Similar to other bFGF tumor studies, exogenous low-molecular-weight (18 kDa) bFGF (1 ng) significantly enhanced carboplatin-induced apoptosis in the more chemosensitive WERI, but not the chemoresistant Y79 line.

CONCLUSIONS

RB tumors produce significant amounts of bFGF, and the differential production and response to isoforms of bFGF may have implications for invasive tumor growth and chemoresistance.

<b>Background:</b> Up to fifty percent of the adult human sinoatrial node (SAN), is composed of dense connective tissue. Cardiac diseases including heart failure (HF) may further increase fibrosis within the SAN pacemaker complex, leading to impaired automaticity and conduction of electrical activity to the atria. However, unlike the role of cardiac <em>fibroblasts</em> in pathological fibrotic remodeling and tissue repair, nothing is known about <em>fibroblasts</em> that maintain the inherently fibrotic SAN environment. <b>Methods:</b> Intact SAN pacemaker complex was dissected from cardioplegically arrested explanted non-failing (non-HF, n=<em>22</em>; 48.7±3.1y.o,) and HF human hearts (n=16; 54.9±2.6y.o.). Connective tissue content was quantified from Masson's trichrome stained head-center and center-tail SAN sections. Expression of extracellular matrix (ECM) proteins, including Collagens 1, 3A1, cartilage intermediate layer protein 1 (CILP1) and periostin, <em>fibroblast</em> and myo<em>fibroblast</em> numbers were quantified by in situ and in vitro immunolabeling. <em>Fibroblasts</em> from the central intramural SAN pacemaker compartment (~10x5x2 mm³) and right atria (RA) were isolated, cultured, passaged once, and treated ±transforming <em>growth</em> <em>factor</em> beta-1 (TGFβ1) and subjected to comprehensive high-throughput next-generation sequencing of whole transcriptome, microRNA and proteomic analyses. <b>Results:</b> Intranodal fibrotic content was significantly higher in SAN pacemaker complex from HF vs non-HF hearts (57.7±2.6% vs 44.0±1.2% <i>p</i><0.0001). Proliferating phosphorylated histone3⁺/vimentin⁺/CD31^- <em>fibroblasts</em> were higher in HF SAN. Vimentin⁺/alpha smooth muscle actin⁺/CD31^- myo<em>fibroblasts</em> along with increased interstitial periostin expression were found only in HF SAN. RNA sequencing and proteomic analyses identified unique differences in mRNA, long non-coding RNA, microRNA and proteomic profiles between non-HF and HF SAN and RA <em>fibroblasts</em>, and TGFβ1-induced myo<em>fibroblasts</em>. Specifically, proteins and signaling pathways associated with ECM flexibility, stiffness, focal adhesion and metabolism were altered in HF SAN <em>fibroblasts</em> compared to non-HF SAN. <b>Conclusions:</b> This study revealed increased SAN-specific fibrosis with presence of myo<em>fibroblasts</em>, CILP1 and periostin-positive interstitial fibrosis only in HF vs non-HF human hearts. Comprehensive proteo-transcriptomic profiles of SAN <em>fibroblasts</em> identified upregulation of genes and proteins promoting stiffer SAN ECM in HF hearts. <em>Fibroblast</em>-specific profiles generated by our proteo-transcriptomic analyses of the human SAN, provide a comprehensive framework for future studies to investigate the role of SAN-specific fibrosis in cardiac rhythm regulation and arrhythmias.

Keywords: extracellular matrix; myofibroblast; proteomics; whole transcriptome.

<p><div><b>Background & Aims</b></div>Metabolism supports cell proliferation and <em>growth</em>. Surprisingly, the tumor suppressor <i>miR-<em>22</em></i> is induced by metabolic stimulators like bile acids. Thus, this study examines whether <i>miR-<em>22</em></i> could be a metabolic silencer.</p><p><div><b>Methods</b></div>The relationship between <i>miR-<em>22</em></i> and the expression of <em>fibroblast</em> <em>growth</em> <em>factor</em> 21 (FGF21) and its receptor FGFR1 was studied in cells and fatty livers obtained from patients and mouse models. We evaluated the effect of an <i>miR-<em>22</em></i> inhibitor alone and in combination with obeticholic acid (OCA) for the treatment of steatosis.</p><p><div><b>Results</b></div>The levels of <i>miR-<em>22</em></i> were inversely correlated with those of <i>FGF21</i>, <i>FGFR1,</i> and <i>PGC1α</i> in human and mouse fatty livers, suggesting that hepatic <i>miR-<em>22</em></i> acts as a metabolic silencer. Indeed, <i>miR-<em>22</em></i> reduced <i>FGFR1</i> by direct targeting and decreased <i>FGF21</i> by reducing the recruitment of PPARα and PGC1α to their binding motifs. In contrast, an <i>miR-<em>22</em></i> inhibitor increases hepatic FGF21 and FGFR1, leading to AMPK and ERK1/2 activation, which was effective in treating alcoholic steatosis in mouse models. The farnesoid x receptor-agonist OCA induced FGF21 and FGFR1, as well as their inhibitor <i>miR-<em>22</em></i>. An <i>miR-<em>22</em></i> inhibitor and OCA were effective in treating diet-induced steatosis, both alone and in combination. The combined treatment was the most effective at improving insulin sensitivity, releasing glucagon-like peptide 1, and reducing hepatic triglyceride in obese mice.</p><p><div><b>Conclusion</b></div>The simultaneous induction of <i>miR-<em>22</em></i>, FGF21 and FGFR1 by metabolic stimulators may maintain FGF21 homeostasis and restrict ERK1/2 activation. Reducing <i>miR-<em>22</em></i> enhances hepatic FGF21 and activates AMPK, which could be a novel approach to treat steatosis and insulin resistance.</p><p><div><b>Lay summary</b></div>This study examines the metabolic role of a tumor suppressor, <i>miR-<em>22</em></i>, that can be induced by metabolic stimulators such as bile acids. Our novel data revealed that the metabolic silencing effect of <i>miR-<em>22</em></i> occurs as a result of reductions in metabolic stimulators, which likely contribute to the development of fatty liver. Consistent with this finding, an <i>miR-<em>22</em></i> inhibitor effectively reversed both alcohol- and diet-induced fatty liver; <i>miR-<em>22</em></i> inhibition is a promising therapeutic option which could be used in combination with obeticholic acid.</p>

Objective- IGF-1 (insulin-like <em>growth</em> <em>factor</em> 1) is a major autocrine/paracrine <em>growth</em> <em>factor</em>, which promotes cell proliferation, migration, and survival. We have shown previously that IGF-1 reduced atherosclerosis and promoted features of stable atherosclerotic plaque in Apoe-/- mice-an animal model of atherosclerosis. The aim of this study was to assess effects of smooth muscle cell (SMC) IGF-1 signaling on the atherosclerotic plaque. Approach and Results- We generated Apoe-/- mice with IGF1R (IGF-1 receptor) deficiency in SMC and <em>fibroblasts</em> (SM<em>22</em>α [smooth muscle protein <em>22</em> α]-CreKI/IGF1R-flox mice). IGF1R was decreased in the aorta and adventitia of SM<em>22</em>α-CreKI/IGF1R-flox mice and also in aortic SMC, embryonic, skin, and lung <em>fibroblasts</em> isolated from SM<em>22</em>α-CreKI/IGF1R-flox mice. IGF1R deficiency downregulated collagen mRNA-binding protein LARP6 (La ribonucleoprotein domain family, member 6) and vascular collagen, and mice exhibited <em>growth</em> retardation. The high-fat diet-fed SM<em>22</em>α-CreKI/IGF1R-flox mice had increased atherosclerotic burden and inflammatory responses. α-SMA (α-smooth muscle actin)-positive plaque cells had reduced proliferation and elevated apoptosis. SMC/<em>fibroblast</em>-targeted decline in IGF-1 signaling decreased atherosclerotic plaque SMC, markedly depleted collagen, reduced plaque fibrous cap, and increased plaque necrotic cores. Aortic SMC isolated from SM<em>22</em>α-CreKI/IGF1R-flox mice had decreased cell proliferation, migration, increased sensitivity to apoptosis, and these effects were associated with disruption of IGF-1-induced Akt signaling. Conclusions- IGF-1 signaling in SMC and in <em>fibroblast</em> is a critical determinant of normal vascular wall development and atheroprotection.

<b>Introduction</b>. Several biomaterials are used in periodontal tissue engineering in order to obtain a three-dimensional scaffold, which could enhance the oral bone regeneration. These novel biomaterials, when placed in the affected area, activate a cascade of events, inducing regenerative cellular responses, and replacing the missing tissue. Natural and synthetic polymers can be used alone or in combination with other biomaterials, <em>growth</em> <em>factors</em>, and stem cells. Natural-based polymer chitosan is widely used in periodontal tissue engineering. It presents biodegradability, biocompatibility, and biological renewability properties. It is bacteriostatic and nontoxic and has hemostatic and mucoadhesive capacity. The aim of this systematic review is to obtain an updated overview of the utilization and effectiveness of chitosan-based scaffold (CS-bs) in the alveolar bone regeneration process. <b>Materials and Methods</b>. During database searching (using PubMed, Cochrane Library, and CINAHL), 72 items were found. The title, abstract, and full text of each study were carefully analyzed and only <em>22</em> articles were selected. Thirteen articles were excluded based on their title, five after reading the abstract, twenty-six after reading the full text, and six were not considered because of their publication date (prior to 2010). Quality assessment and data extraction were performed in the twelve included randomized controlled trials. Data concerning cell proliferation and viability (CPV), mineralization level (M), and alkaline phosphatase activity (ALPA) were recorded from each article <b>Results</b><i>.</i> All the included trials tested CS-bs that were combined with other biomaterials (such as hydroxyapatite, alginate, polylactic-co-glycolic acid, polycaprolactone), <em>growth</em> <em>factors</em> (basic <em>fibroblast</em> <em>growth</em> <em>factor</em>, bone morphogenetic protein) and/or stem cells (periodontal ligament stem cells, human jaw bone marrow-derived mesenchymal stem cells). Values about the proliferation of cementoblasts (CB) and periodontal ligament cells (PDLCs), the activity of alkaline phosphatase, and the mineralization level determined by pure chitosan scaffolds resulted in lower than those caused by chitosan-based scaffolds combined with other molecules and biomaterials. <b>Conclusions</b>. A higher periodontal regenerative potential was recorded in the case of CS-based scaffolds combined with other polymeric biomaterials and bioceramics (bio compared to those provided by CS alone. Furthermore, literature demonstrated that the addition of <em>growth</em> <em>factors</em> and stem cells to CS-based scaffolds might improve the biological properties of chitosan.

<AbstractText>Clinical application of platelet-rich-plasma (PRP) has been accelerated to investigate early recovery from various musculoskeletal conditions. It involves the promotion of tissue damage repair through the action of multiple <em>growth</em> <em>factors</em> at physiological concentrations. The composition of PRP differs based on many <em>factors</em>, which may include age and gender. Therefore, we analyzed correlations between age, gender, and platelet counts in PRP with <em>growth</em> <em>factors</em> in Japanese subjects.</AbstractText><p><div><b>METHOD</b></div>Peripheral blood was drawn from 39 healthy volunteers between 20 and 49 years of age (age, mean ± standard deviation = 33 ± 8.7 years; gender ratio, male:female = 19:20; BMI, mean ± standard deviation = <em>22</em> ± 4.0) and prepared through centrifugation (volume, 6 mL per sample). After being activated with CaCl₂, the supernatant was stored. The mean platelet count in PRP was 41.4 ± 12.2 × 10⁴/μL. PRP concentration rate (i.e., PRP/peripheral platelet counts) was 1.8 ± 0.4 times. <em>Growth</em> <em>factor</em> levels (platelet-derived <em>growth</em> <em>factor</em>-BB, transforming <em>growth</em> <em>factor</em>-β1, vascular endothelial <em>growth</em> <em>factor</em>, epidermal <em>growth</em> <em>factor</em>, <em>fibroblast</em> <em>growth</em> <em>factor</em>, insulin-like <em>growth</em> <em>factor</em>-1, and hepatocyte <em>growth</em> <em>factor</em>) were measured using enzyme-linked immunosorbent assay (ELISA), and correlations with age, gender, and PRP platelet counts were statistically analyzed by calculating Spearman's rank correlation coefficients (r).</p><AbstractText>Age was negatively correlated with platelet-derived <em>growth</em> <em>factor</em>-BB and insulin-like <em>growth</em> <em>factor</em>-1 (r = - 0.32, - 0.39), and gender had no influence on <em>growth</em> <em>factors</em>. Platelet counts in PRP positively correlated with platelet-derived <em>growth</em> <em>factor</em>-BB, transforming <em>growth</em> <em>factor</em>-β1, epidermal <em>growth</em> <em>factor</em>, and hepatocyte <em>growth</em> <em>factor</em> (r = 0.39, 0.75, 0.71, and 0.48, respectively).</AbstractText><AbstractText>This clinical study shows a significant variation of PRP among individual patients and that this variation is influenced by the age and the platelet counts of the subjects. Our data demonstrate that patient characteristics account for the differences in PRP physiological activity.</AbstractText>

Esophageal cancer (EC) is one of the most common malignancies with high incidence and mortality. Tumor-associated macrophages (TAMs) in the tumor microenvironment have been linked to the accelerated tumor progression. MicroRNAs (miR) are 19-25 nucleotide-long, noncoding RNA molecules, functioning as modulators of gene expression, and mediate a variety of biological functions, including tumor <em>growth</em>. In the present study, the effects and molecular mechanism of miR-155 in TAMs isolated from EC were explored. The expression of miR-155 and <em>fibroblast</em> <em>growth</em> <em>factor</em>-2 (FGF2) in EC tissues and cell lines were analyzed using reverse transcription-quantitative PCR (qRT-PCR) and western blot assays. TAMs were also transfected with the described constructs. Following, the culture medium from TAMs was collected for further analysis. The released FGF2, and inflammatory cytokines were quantified using ELISA. The cell viability, migrated and invaded levels were calculated through Cell Counting kit-8 (CCK8), and transwell analysis. Moreover, human umbilical vein endothelial cells (HUVEC) vasculature formation was determined using matrigel angiogenesis analysis. The results indicated that miR-155 expression was decreased in EC tissues and cell lines, while FGF2 expression was increased in comparison to those in the normal control group. Moreover, miR-155 mimics transfection up-regulated tumor necrosis <em>factor</em> α (TNF-α), interleukin (IL)-12 and inducible nitric oxide synthase (iNOS), while down-regulated IL-10, Arginase-1 (Arg-1) and IL-<em>22</em> levels in the culture medium from TAMs. And enhancing miR-155 expression in TAMs suppressed the cell viability, migration and invasion of ECA109 cells and reduced the angiogenesis. Nevertheless, over-expressing FGF2 abolished the role of miR-155 in cancer cell survival, migration, invasion as well as angiogenesis. Our findings indicated that miR-155-regulated FGF2 expression from TAMs suppressed EC cell proliferation, migration, invasion and inhibited vasculature formation. Thus, miR-155-modulated FGF2 might be a potential therapeutic target to prevent EC progression.

In an attempt to reconstruct the 6-hydroxydopamine lesioned nigrostriatal system of the adult rat we have combined homotopic grafting of embryonic ventral mesencephalon suspensions with the implantation of long oblique "bridge" grafts of <em>fibroblast</em> <em>growth</em> <em>factor</em>-4-transfected RN-<em>22</em> schwannoma cells stretching from the site of the neuronal grafts to the striatum. At seven weeks after receiving both grafts, animals were killed and processed for immunohistochemistry against tyrosine hydroxylase. Tyrosine hydroxylase-immunoreactive axons were seen to extend from the nigral grafts, along the bridge graft to the striatum where terminal arborizations could be seen. The retrograde tracer Fluoro-gold was injected intrastriatally in some of the experimental animals and was taken up by grafted neurons confirming their projection to the striatum. In parallel to the anatomical reconstruction of the system, a decrease in amphetamine-induced rotation was demonstrated in those animals receiving both grafts which had received>> 98% complete lesions. This decrease was greatest in those animals with the most tyrosine hydroxylase-immunoreactive axons in their bridge grafts. The presence of the bridge graft also led to an increase in neuronal graft survival with twice as many tyrosine hydroxylase-immunoreactive neurons being found in the grafts of those animals that had received both grafts compared to those that had received a neuronal graft but no bridge graft.

Both nerve <em>growth</em> <em>factor</em> (NGF) and basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (bFGF) have been proposed for the treatment of Alzheimer's disease. This study describes a comparative, dose-response analysis of recombinant human (rh)NGF and rhbFGF in a rat unilateral fimbria-fornix model of acute cholinergic neuronal degeneration. Doses for rhNGF were 0.6, 6, 60, 600 and 1,800 ng/rat/day and for rhbFGF were 600, 1,800, 3,000 and 6,000 ng/rat/day, delivered for 4 weeks. The number of surviving septal cholinergic neurons was evaluated using ChAT immunohistochemistry. In control animals, the number of ChAT-positive neurons remaining on the lesioned side was between <em>22</em> and 18% compared to the non-lesioned side. Infusion with either neurotrophic <em>factor</em> increased the number of ChAT-positive neurons on the lesioned side in a dose-dependent manner. The maximal response to rhbFGF peaked at 3,000 ng/rat/day with a cell savings of 47%. However, there was evidence of neuropathological changes associated with rhbFGF. In contrast, rhNGF produced a maximal response with an infusion of 600 ng rhNGF/rat/day and a cell savings of 70% and no evidence of neuropathology, indicating that rhNGF was better tolerated and more efficacious than rhbFGF.

INTRODUCTION. Orthodontic teeth movement is accompanied by remodeling of alveolar bone, including the interradicular septum and periodontal ligaments (PDL). Periodontal signaling molecules have important functions during tooth movement and they are active in the bone remodeling process. Patients involved in orthodontic treatment belong to different age groups: therefore age must be considered as a contributing <em>factor</em> compromising the remodeling potential of periodontal tissues. The aim of the current study was to investigate the specific expression of signaling molecules in the PDL of interradicular septum in patients from different groups of age. MATERIALS AND METHODS. The study group included 25 patients to whom extractions of teeth was recommended as a part of further orthodontic treatment. 25 patients (10 males and 15 females) were divided into three groups as follows: 1) 12-14 years old; 2) 15-<em>22</em> years old; and 3) 23 years old or older. The routine histological method was followed and samples were stained with hematoxyline-eosine. According to literature data in current immunohistochemical study were included and examined expression of NGFR (nerve <em>growth</em> <em>factor</em> receptor), TGF-β (transforming <em>growth</em> <em>factor</em> β), bFGF (basic <em>fibroblast</em> <em>growth</em> <em>factor</em>), FGFR1 (<em>fibroblast</em> <em>growth</em> <em>factor</em> receptor), IL-1 (interleukin 1), IL-6 (interleukin 6), IL-8 (interleukin 8), MMP-1 (matrix metalloproteinase 1), MMP-2 (matrix metalloproteinase 2), MMP-8 (matrix metalloproteinase 8), MMP-9 (matrix metalloproteinase 9), MMP-13 (matrix metalloproteinase 13) in PDL of interradicular septum. The distribution of these <em>factors</em> was evaluated semi quantitatively. RESULTS. Expression levels of FGFR1, bFGF, MMP 8 and 9, and IL-6 in PDL of interradicular septum structure were determined in all samples. Decreases in the mean values of signaling <em>factors</em> relevant to age were statistically significant in bFGF. CONCLUSIONS. Analyzed data suggest that bFGF, FGFR, IL-6, MMP 8 and 9 were determined as signaling <em>factors</em> in PDL of interradicular septum. Mean expression level decrease with age of FGFR1, IL-6, MMP-8, MMP-9 was non- statistically significant. The mean expression level of bFGF decreased with age, and this decrease was statistically significant. In younger patients, signal molecule expression is higher because of increased PDL metabolic activity. Increased PDL metabolic activity is a reason for higher expression of signal molecule in younger patients. Activity of remodeling process of periodontal tissue decreases with the aging and expression of signaling molecule decreases in adults.

UNASSIGNED

Higher circulating fibroblast growth factor 23 (FGF23) concentrations are associated with cardiovascular disease events linked to heart failure, but associations of FGF23 with coronary heart disease (CHD) have been less consistent.

UNASSIGNED

To determine the association of plasma FGF23 concentrations with incident CHD and whether this association differs by race, sex, or chronic kidney disease status.

UNASSIGNED

We examined the association of FGF23 concentrations with incident CHD risk within the Reasons for Geographic and Racial Differences in Stroke study, a prospective cohort of black and white adults 45 years and older enrolled between January 2003 and October 2007 with follow-up through December 31, 2011. Using a case-cohort design, we measured FGF23 concentrations in 829 participants who developed incident CHD and in 812 participants randomly selected from the Reasons for Geographic and Racial Differences in Stroke study cohort (cohort random sample). To account for the stratified sampling design, the cohort random sample was weighted back to the original cohort overall (n = 22 127). Cox proportional hazards models were used to examine the association of FGF23 concentration with incident CHD, adjusting for CHD risk factors and kidney function. In prespecified analyses, we examined whether race, sex, or chronic kidney disease modified the association of FGF23 concentration with incident CHD.

UNASSIGNED

Plasma C-terminal FGF23 concentrations.

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Investigator-adjudicated incident CHD events.

UNASSIGNED

Of the 22 127 participants in the weighted cohort random sample, 13 059 (58.9%) were female and 9435 (42.6%) were black, and the mean age was 64.3 (95% CI, 63.7-64.9) years. Greater age, lower estimated glomerular filtration rate, higher urine albumin to creatinine ratio, and female sex were associated with higher FGF23 concentration at baseline. In multivariable models adjusted for established CHD risk factors and kidney function, higher FGF23 concentrations were associated with greater risk of CHD (hazard ratio [HR] comparing fourth with first quartile, 2.15; 95% CI, 1.35-3.42). The magnitude and strength of these associations differed by sex. However, these differences were no longer observed when adjusting for hormone therapy in women (men: HR comparing fourth with first quartile, 2.40; 95% CI, 1.30-4.42; women: HR comparing fourth with first quartile, 2.34; 95% CI, 1.04-5.27) or when using sex-specific FGF23 quartiles (men: HR comparing fourth with first quartile, 2.65; 95% CI, 1.43-4.90; women: HR comparing fourth with first quartile, 2.26; 95% CI, 1.02-5.03).

UNASSIGNED

Higher FGF23 concentrations were associated with greater risk of CHD. Heterogeneity in the association by sex may be caused by differences in the distribution of plasma FGF23 concentrations or the use of hormone therapy in men vs women.

The present study intends to investigate the correlation between clinicopathologic features of non-small cell lung cancer and matrix metalloproteinase-7 (MMP-7) and basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (bFGF) and to investigate the roles of MMP-7 and bFGF in detecting the course of disease of non-small cell lung cancer. Ninety cases of paraffin-embedded tissue samples from patient with primary non-small cell lung cancer and fifty cases of lung tissue samples from normal subjects were included in the present study. Immunohistochemical S-P method was used to detect proteins MMP-7 and bFGF. (1) The positive rate of MMP-7 protein was 14 % in normal lung tissue section and 68.89 % in non-small cell lung cancer tissue section, and the difference was statistically significant (χ (2) = 38.774, P = 0.000 < 0.05). There were 43 cases (43/56) with positive expression in patients with squamous cell carcinoma and <em>22</em> cases (<em>22</em>/34) with positive expression in patients with adenocarcinoma, and the difference was not statistically significant (χ (2) = 1.539, P = 0.215>> 0.05). There were 14 cases (14/51) with positive expression in patients with moderate- and well-differentiated lung carcinoma and 36 cases (36/39) with positive expression in patients with poor-differentiated lung carcinoma, and the difference was statistically significant (χ (2) = 35.068, P = 0.000 < 0.05). There were 37 cases (37/42) with positive expression in patients with lymphatic metastasis and 26 cases (26/48) with positive expression in patients without lymphatic metastasis, and the difference was statistically significant (χ (2) = 12.279, P = 0.000 < 0.05). (2) The mean intratumoral microvessel density (iMVD) was 46.2 ± 6.77 in the field of lung cancer tissue at high magnification under MMP-7-positive condition and 30.8 ± 7.54 in the field of lung cancer tissue at high magnification under MMP-7-negative condition, and the difference was statistically significant (t = 9.641, P = 0.000 < 0.05). (3) The positive rate of bFGF was 12 % in normal tissue section and 63.3 % in non-small cell lung cancer tissue section, and the difference was statistically significant (χ (2) = 34.<em>22</em>2, P = 0.000 < 0.05). There were 41 cases (41/56) with positive expression in patients with squamous cell carcinoma and 20 cases (20/34) with positive expression in patients with adenocarcinoma, and the difference was not statistically significant (χ(2) = 2.006, P = 0.157>> 0.05). There were 29 cases (29/51) with positive expression in patients with moderate- and well-differentiated lung carcinoma and 35 cases (35/39) with positive expression in patients with poor-differentiated lung carcinoma, and the difference was statistically significant (χ (2) = 10.085, P = 0.001 < 0.05). There were 37 cases (37/42) with positive expression in patients with lymphatic metastasis and 25 cases (25/48) with positive expression in patients without lymphatic metastasis, and the difference was statistically significant (χ (2) = 13.554, P = 0.001 < 0.05). (4) The (iMVD) was 45.8 ± 7.16 in the field at high magnification under bFGF-positive condition and 31.2 ± 6.46 in the field at high magnification under bFGF-negative condition, and the difference was statistically significant (t = 9.654, P = 0.001 < 0.05). (5) A correlation was demonstrated between MMP-7 and bFGF in non-small cell lung cancer (r = 0.353, P = 0.000 < 0.05). Both MMP-7 and bFGF are participated in the progression of non-small cell lung cancer and exert a synergistic effect during physiological processes including pathogenesis, invasion, and metastasis of non-small cell lung cancer. Therefore, a combined detection of MMP-7 and bFGF for non-small cell lung cancer contributes to predict the progression and prognosis of non-small cell lung cancer, with significant clinical value.

In the current studies we investigated the timing of onset and the conditions needed for the maintenance of the upregulation of basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (bFGF) and glial fibrillary acidic protein (GFAP) in the cingulate cortex area 2 (Cg2) that occurs in postpartum animals. We have previously shown that this upregulation is present from day 4 to day 24, and is not seen late in pregnancy (days 21-<em>22</em>). In the current studies, we demonstrate that bFGF and GFAP are both upregulated in Cg2 as early as 3 h postpartum, and are maintained until at least day 24 postpartum in animals deprived of pup stimulation for 8 days prior to perfusion. bFGF and GFAP immunoreactivity returns to prepartum levels by 5-6 weeks post-weaning, and the typical postpartum increase is not further enhanced in multiparous rats. We also show that, although there are significant changes in levels of bFGF immunoreactivity across the phases of the estrous cycle, peak cycling levels remain much lower than those observed in lactating rats. Possible stimuli involved in the induction of bFGF and GFAP in Cg2, and the potential relevance of these changes to the maternal state are discussed.

OBJECTIVE

We investigated the use of graded-dose peginterferon α-2b (Peg-IFN) in patients with stage IV melanoma overexpressing basic fibroblast growth factor (FGF-2). The primary objective was suppression of plasma FGF-2 to within reference range (≤ 7.5 pg/mL).

METHODS

Plasma FGF-2 was measured at baseline (step 1), and patients with concentrations of 15 pg/mL or more were eligible for study treatment (step 2). Peg-IFN was given weekly at a starting dose of 0.5 μg/kg/wk with increment every 3 weeks based on serial FGF-2 concentrations.

RESULTS

Two hundred seven patients entered step 1; 45 (22%) overexpressed FGF-2 (median = 22 pg/dL). Twenty-nine eligible patients entered step 2 and received treatment. Patients' median age was 64 years (range, 29-84 years). Most had more than two prior therapies. FGF-2 decreased in 28 (97%) patients, with suppression to reference range in 10 (35%). Median time to FGF-2 suppression was 30 days. The best clinical responses were partial response (7%) and stable disease (17%). Median progression-free survival (PFS) and overall survival (OS) were 2.0 and 9.7 months, respectively. Patients who achieved FGF-2 suppression were more likely than those who did not to have a response or stable disease (P = 0.03). VEGF concentrations decreased in 27 patients (93%) during treatment and paralleled those of FGF-2 over time. We found no compensatory increase in VEGF among those with FGF-2 suppression.

CONCLUSIONS

Graded-dose Peg-IFN suppresses FGF-2 in patients with metastatic melanoma who overexpress FGF-2. Over one third of patients had complete suppression of plasma FGF-2, which correlated with clinical response to this therapy.

A 40-base oligodeoxynucleotide probe is described which has been prepared corresponding to the amino acid sequence 9-<em>22</em> of acidic <em>fibroblast</em> <em>growth</em> <em>factor</em>. Following electrophoretic separation of rat brain mRNA under denaturing conditions the probe hybridizes to a major polyadenylated mRNA species of approximately 4.8 kb. This mRNA is the same size as that reported for acidic <em>fibroblast</em> <em>growth</em> <em>factor</em> mRNA. The relative abundance of the hybridizing 4.8 kb mRNA species increases in rat brain 3 days after cortical lesion indicating increased expression of the gene for acidic <em>fibroblast</em> <em>growth</em> <em>factor</em>.

There is increasing evidence to suggest that platelet-derived <em>growth</em> <em>factor</em> (PDGF), or PDGF-like molecules, play a role in fetal lung morphogenesis. The cellular sources of PDGF and its target cells within the fetal lung remain to be defined. In the present study, we investigated the developmental expression of PDGF and its cognate receptor genes in fetal rat lung <em>fibroblasts</em>. Northern analysis revealed that fetal lung <em>fibroblasts</em> express the PDGF A-chain, B-chain, and beta-receptor genes. The cells actively translated these mRNAs into protein as demonstrated by immunocytochemistry and by metabolic labeling with [35S]methionine, followed by immunoprecipitation with specific PDGF-AA and -BB antibodies. Affinity cross-linking with 125I-labeled PDGF-BB demonstrated the presence of PDGF beta-receptors on fetal lung <em>fibroblasts</em>. The development expression of the PDGF genes was examined in <em>fibroblasts</em> derived from the early canalicular (Day 19) to the early saccular stage (Day 21) of lung development (term = <em>22</em> days). PDGF A-chain gene expression was at a low but constant level during late gestation. No change in either the transcription rate or stability of the message for this gene was observed with advancing gestation. Despite these mRNA observations, PDGF-AA is the major secreted form in the medium of the <em>fibroblasts</em>. Expression of PDGF B-chain gene was greatest during the early canalicular stage (Day 19) and declined sharply thereafter. The greater expression of PDGF B-chain during the canalicular stage was due to a greater rate of transcription and a greater PDGF B-chain mRNA stability. The PDGF beta-receptor gene was expressed at a lower but constant level in these cells during late gestation. The constant level of PDGF beta-receptor mRNA could be attributed to a balanced increased synthesis of the message coupled to an increased breakdown of the transcript. These data indicate that fetal lung <em>fibroblasts</em> synthesize PDGF-AA, PDGF-BB, and PDGF beta-receptor and that they regulate the developmental expression of these PDGF genes differently.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> 2 (FGF2) is a key regulator of muscle cell proliferation and differentiation. To address how FGF2 and <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor 1 (FGFR1) gene expression influences skeletal muscle development and <em>growth</em>, pectoralis major muscle was isolated at embryonic days (ED) 14, 16, 18, 20, <em>22</em>, and 24, and at 1-, 8-, 12-, and 16-week posthatch from a turkey line (F) selected only for increased 16-week body weight and its genetic control line (RBC2). The mRNA levels of FGF2 and FGFR1 were measured by semi-quantitative reverse transcription polymerase chain reaction. Compared to the RBC2 line males, the F line males had higher FGF2 mRNA levels at ED 14 and 16, and higher FGFR1 mRNA levels at ED 18, but down-regulated FGF2 and FGFR1 gene expression at ED <em>22</em>. Although no FGF2 mRNA was detected in posthatch muscle tissue, the F line turkeys had more FGFR1 gene expression at 8-, 12-, and 16-week posthatch than the RBC2 line turkeys. During myogenic satellite cell proliferation, the F line cells had higher FGF2 and FGFR1 mRNA levels than the RBC2 line cells. The satellite cell responsiveness to FGF2 treatment was evaluated by the ability of the cells to proliferate. The male satellite cells were more responsive to FGF2 stimulation than the female cells in both lines. These results suggest that the F line turkeys have increased FGF2 signaling that may affect muscle cell proliferation and differentiation, which may also lead to an enhancement in muscle development and <em>growth</em> rate.

Sturge-Weber syndrome (SWS) consists of a capillary-venous vascular malformation of the brain, skin and eye. Urine vascular biomarkers have been demonstrated to be abnormal in other vascular anomalies and to correlate with clinical severity and progression. The current study investigated the use of urinary matrix metalloproteinase (MMP)-2, MMP-9, vascular endothelial <em>growth</em> <em>factor</em> (VEGF), and basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (bFGF) levels to non-invasively monitor the progression of SWS. Fifty-four urine samples were collected from patients seen at the Hunter Nelson Sturge-Weber Center at Kennedy Krieger Institute. Urine was analyzed for MMP-2, MMP-9, VEGF and bFGF levels and correlated with clinical outcome at the time of urine collection (n = 48) and 1 year following urine collection (n = <em>22</em>). Analysis revealed that MMP-2 (p = 0.033) and MMP-9 (p = 0.010) were significantly more likely to be present in the urine of SWS subjects compared to controls and that bFGF was significantly more likely to be present at abnormal levels (p = 0.005). MMP-2 correlated with a more severe clinical score at the time of urine collection, while both MMP-2 and MMP-9 levels correlated with greater disease severity at time of collection. bFGF levels correlated with improved clinical score 1 year after urine collection. These results suggest that MMP-2 and MMP-9 levels may be useful in assessing SWS progression, as well as indicating which patients might benefit from more aggressive treatment, while bFGF levels may be useful in judging the efficacy of neurologic treatment in SWS.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> 2 (FGF-2) is a neurotrophic <em>factor</em> that regulates many neuronal functions and survival. We have characterised FGF-2 expression immunohistochemically in the cerebellum of young (4 months) and old (<em>22</em> months) mice. About half of the population of the granule cells (GC), and all Purkinje cells (PC) expressed FGF-2 in all folia of the cerebellum at both ages. FGF-2 showed differential intracellular localization: predominantly localised to the nuclei of GC and present mainly in the cytosol of PC. There was a statistically significant (P = 0.0028) reduction in the number of FGF-2-positive GC in the cerebella of old (41.3+/-0.91%) compared to young (48.5+/-1.67%) mice, whereas no statistically significant age-dependent difference occurred in the number of FGF-2 positive PC. These results indicate a possible role of FGF-2 in cerebellar ageing.