Burn injury is a <em>growing</em> medical problem associated with public health, and few effective agents are available for treatment of this disease. In the present study, a burn injury rat model was developed and the accelerated effect of <i>Aloe vera</i> fermentation on burn injury healing was evaluated. Our results indicated that <i>Aloe vera</i> fermentation could markedly reduce the DPPH (56.12%), O^2·- (93.5%), ^·OH (76.12%), Fe²⁺ chelation (82%), and oxygen-reduction activity (0.28 <i>μ</i>g/ml) and significantly inhibited the <em>growth</em> of pathogens <i>S. typhimurium</i> ATCC 13311 (inhibition zone diameter: 14 mm), <i>S. enteritidis</i> ATCC13076 (IZD: 13 mm), <i>S. flexneri</i> ATCC 12022 (IZD: 18 mm), <i>E. coli</i> 44102 (IZD: 10 mm), <i>L. monocytogenes</i> ATCC <em>19</em>111 (IZD: 18 mm), <i>S. dysenteriae</i> 301 (IZD: 20 mm), <i>S. aureus</i> COWAN1 (IZD: <em>19</em> mm), and <i>P. acnes</i> ATCC 11827 (IZD: 25 mm) <i>in vitro</i>. The <i>in vivo</i> results indicated that <i>Aloe vera</i> fermentation produced more eosinophils and <em>fibroblasts</em> and less vessel proliferation compared with the model group on the 14^th day, which had greatly accelerated burn injury healing via shedding of the scab and promoting hair <em>growth</em>. ELISA results indicated that <i>Aloe vera</i> fermentation had significantly reduced the production of proinflammatory <em>factors</em> TNF-<i>α</i> and IL-1<i>β</i> (<i>p</i> < 0.05) and greatly enhanced the yield of anti-inflammatory <em>factor</em> IL-4 in animal serum (<i>p</i> < 0.05). In addition, the high-throughput sequencing results indicated that <i>Aloe vera</i> fermentation obviously increased the percentage of Firmicutes (65.86% vs. 49.76%), while reducing the number of Bacteroidetes (27.60% vs. 45.15%) compared with the M group at the phylum level. At the genus level, <i>Aloe vera</i> fermentation increased the probiotic bacteria <i>Lactobacillus</i> (3.13% vs. 2.09%) and reduced the pathogens <i>Prevotella</i> (10.60% vs.18.24%) and <i>Blautia</i> (2.91% vs. 16.41%) compared with the M group. Therefore, we concluded that the use of <i>Aloe vera</i> fermentation significantly accelerates burn injury healing via reduction of the severity of inflammation and through modification of gut microbiota.

Cancer-associated <em>fibroblasts</em> (CAFs) constitute a major compartment of the tumor microenvironment. In the present study, we investigated the role for CAFs in breast cancer progression and underlying molecular mechanisms. Human breast cancer MDA-MB-231 cells treated with the CAF-conditioned media manifested a more proliferative phenotype, as evidenced by enhanced messenger RNA (mRNA) expression of Cyclin D1, c-Myc, and proliferating cell nuclear antigen. Analysis of data from The Cancer Genome Atlas revealed that <em>fibroblast</em> <em>growth</em> <em>factor</em>-2 (FGF2) expression was well correlated with the presence of CAFs. We noticed that the mRNA level of FGF2 in CAFs was higher than that in normal <em>fibroblasts</em>. FGF2 exerts its biological effects through interaction with FGF receptor 1 (FGFR1). In the breast cancer tissue array, 42% estrogen receptor-negative patients coexpressed FGF2 and FGFR1, whereas only <em>19</em>% estrogen receptor-positive patients exhibited coexpression. CAF-stimulated MDA-MB-231 cell migration and invasiveness were abolished when FGF2-neutralizing antibody was added to the conditioned media of CAFs. In a xenograft mouse model, coinjection of MDA-MB-231 cells with activated <em>fibroblasts</em> expressing FGF2 dramatically enhanced tumor <em>growth</em>, and this was abrogated by silencing of FGFR1 in cancer cells. In addition, treatment of MDA-MB-231 cells with FGF2 enhanced expression of Cyclin D1, a key molecule involved in cell cycle progression. FGF2-induced cell migration and upregulation of Cyclin D1 were abolished by siRNA-mediated FGFR1 silencing. Taken together, the above findings suggest that CAFs promote <em>growth</em>, migration and invasion of MDA-MB-231 cells via the paracrine FGF2-FGFR1 loop in the breast tumor microenvironment.

Keywords: breast cancer; cancer-associated fibroblasts; fibroblast growth factor 2; fibroblast growth factor receptor 1; tumor microenvironment.

<AbstractText>We review current evidence regarding changes in bile acid (BA) metabolism, transport, and signaling after bariatric surgery and how these might bolster fat mass loss and energy expenditure to promote improvements in type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD).</AbstractText><AbstractText>The two most common bariatric techniques, Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), increase the size and alter the composition of the circulating BA pool that may then impact energy metabolism through altered activities of BA targets in the many tissues perfused by systemic blood. Recent reports in human patients indicate that gene expression of the major BA target, the farnesoid X receptor (FXR), is increased in the liver but decreased in the small intestine after RYGB. In contrast, intestinal expression of the transmembrane G protein-coupled BA receptor (TGR5) is upregulated after surgery. Despite these apparent conflicting changes in receptor transcription, changes in BAs after both RYGB and VSG are associated with elevated postprandial systemic levels of <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (from FXR activation) and glucagon-like peptide 1 (from TGR5 activation). These signaling activities are presumed to support fat mass loss and related metabolic benefits of bariatric surgery, and this supposition is in agreement with findings from rodent models of RYGB and VSG. However, inter-species differences in BA physiology limit direct translation and mechanistic understanding of how changes in individual BA species contribute to post-operative improvements of T2D and NAFLD in humans. Thus, details of all these changes and their influences on BAs' biological actions are still under scrutiny. Changes in BA physiology and receptor activities after RYGB and VSG likely support weight loss and promote sustained metabolic improvements.</AbstractText>

OBJECTIVE

NGM282 is an analog of <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>), a potent inhibitor of bile acid (BA) synthesis in animals and humans. In phase 2 trials in type 2 diabetes and primary biliary cholangitis, NGM282 was associated with dose-related abdominal cramping and diarrhea. We aimed to examine effects of NGM282 on colonic transit, stool frequency and consistency, hepatic BA synthesis (fasting serum C4), fecal fat, and BA in functional constipation (FC).

METHODS

Two-dose NGM282 (1 and 6 mg, subcutaneously daily), parallel-group, randomized, placebo-controlled, 14-day study in patients with FC (Rome III criteria) and baseline colonic transit 24 h geometric center (GC) <3.0. We explored treatment interaction with SNPs in genes KLB, FGFR4, and TGR5 (GPBAR1).

METHODS

overall ANCOVA at α = 0.025 (baseline as covariate where available), with three pairwise comparisons among the three groups (α = 0.008).

RESULTS

Overall, NGM282 altered bowel function (number of bowel movements, looser stool form, and increased ease of passage) and significantly accelerated gastric and colonic transit. Dose-related effects were seen with GC 24 h, but not with gastric emptying (GE) and GC 48 h. There were no differences in fecal fat or weight, but there was reduced fecal total BA excretion with NGM282. The most common adverse events were increased appetite (n = 0 with placebo, 2 with 1 mg, 9 with 6 mg), injection site reaction (n = 2 placebo, 4 with 1 mg, 8 with 6 mg), and diarrhea (n = 1 with 1 mg and 4 with 6 mg NGM282). There was treatment interaction with KLB SNP, with greater increase in colonic transit in participants with the minor A allele (p = 0.056).

CONCLUSIONS

NGM282 significantly impacts GE and colonic transit, consistent with the observed clinical symptoms. The specific mechanism of prokinetic activity requires further research.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) and FGF21 are members of a subfamily of the FGFs called endocrine FGFs. FGF<em>19</em> regulates the bile acid synthetic pathway. FGF<em>19</em> expression is induced by farnesoid X receptor (FXR), a nuclear hormone receptor activated by bile acids in the small intestine. FGF21 plays an important role in lipolysis that occurs in white adipose tissue. FGF21 expression is stimulated by the nuclear fatty acid receptor peroxisome proliferator-activated receptor α (PPARα) in the liver. FGF<em>19</em> and FGF21 were recently identified as targets of activating transcription <em>factor</em> 4 (ATF4), which is activated in response to endoplasmic reticulum (ER) stress. ATF4 is also activated by oxidative stress and amino acid deprivation. In this study, we investigated FGF<em>19</em> and FGF21 expression in response to oxidative stress and amino acid deprivation. We found that FGF<em>19</em> mRNA is induced by oxidative stress inducers in Caco-2 cells, which are derived from the human intestinal epithelium, and rat intestinal epithelial IEC6 cells. In contrast, ileal FGF15 expression, the rodent ortholog of human FGF<em>19</em>, is not increased by oxidative stress. No notable changes in expression of FGF15/<em>19</em> took place under amino acid deprivation either in vitro or in vivo. In contrast, FGF21 expression is induced by oxidative stress and amino acid deprivation both in vitro and in vivo. These results indicate distinctive patterns of regulation of FGF<em>19</em> expression by ER stress, and FGF21 expression by ER stress, oxidative stress, and amino acid deprivation through ATF4 activation.

OBJECTIVE

<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) and 21 (FGF21) have been linked to obesity and type 2 diabetes in adults. We assessed the circulating concentrations of these <em>factors</em> in human neonates and infants, and their association with the endocrine-metabolic changes associated to prenatal <em>growth</em> restraint.

METHODS

Circulating FGF<em>19</em> and FGF21, selected hormones (insulin, insulin-like <em>growth</em> <em>factor</em> I and high- molecular-weight (HMW) adiponectin) and body composition (absorptiometry) were assessed longitudinally in 44 infants born appropriate- (AGA) or small-for-gestational-age (SGA). Measurements were performed at 0, 4 and 12 months in AGA infants; at 0 and 4 months in SGA infants; and cross-sectionally in 11 first-week AGA newborns.

RESULTS

Circulating FGF<em>19</em> and FGF21 surged >10-fold in early infancy from infra- to supra-adult concentrations, the FGF<em>19</em> surge appearing slower and more pronounced than the FGF21 surge. Whereas the FGF21 surge was of similar magnitude in AGA and SGA infants, FGF<em>19</em> induction was significantly reduced in SGA infants. In AGA and SGA infants, cord-blood FGF21 and serum FGF<em>19</em> at 4 months showed a positive correlation with HMW adiponectin (r=0.49, P=0.013; r=0.43, P=0.0<em>19</em>, respectively).

CONCLUSIONS

Our results suggest that these early FGF<em>19</em> and FGF21 surges are of a physiological relevance that warrants further delineation and that may extend beyond infancy.

BACKGROUND

<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) is a gut-derived hormone that regulates the expression of CYP7A1, the rate-limiting enzyme in bile acid (BA) synthesis pathway. Dysregulation of the FGF<em>19</em>-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 FGF<em>19</em> 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 FGF<em>19</em> 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 FGF<em>19</em> 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. FGF<em>19</em> concentrations do not correlate with CYP7A1 activity, suggesting that the gut-liver axis is not functional in infants. High FGF<em>19</em> 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 <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>), is a major regulator of CYP7A1, the rate limiting enzyme in bile acid (BA) synthesis. Recently, dysregulation of the gut-liver (FGF<em>19</em>-CYP7A1) axis has been implicated in adult cholestatic liver disease, and animal studies have shown that exogenous FGF<em>19</em> protects against liver injury. Given the therapeutic potential related to this signaling pathway, we sought to characterize the association between CYP7A1 and FGF<em>19</em> in term and preterm infants. We conducted a prospective, observational study that measured in vivo CYP7A1 activity and FGF<em>19</em> 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 FGF<em>19</em> 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 FGF<em>19</em> 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 FGF<em>19</em>. We also report novel findings of elevated FGF<em>19</em> concentrations in preterm infants at birth and speculate that there may be an extra-intestinal source of FGF<em>19</em> that is developmentally expressed in these infants.

OBJECTIVE

To apply regenerative treatment for tympanic membrane (TM) perforation to patients with severe calcification of the TM, cholesteatomas, or tumors localized to the tympanic cavity.

METHODS

Controlled clinical pilot study.

METHODS

General hospitals.

METHODS

Forty-five patients (age: 8-85; M = <em>19</em>, F = 26) were selected from patients with or without TM perforation for the regenerative treatment. Twenty-five patients had cholesteatomas, 3 had tumors, and 17 had severe TM calcification. Patients were classified into three groups based on TM perforation size: less than 1/3 of the TM as Grade I (n = 5), 1/3 to 2/3 as Grade II (n = <em>19</em>), and over 2/3 as Grade III (n = 21). Twenty patients who underwent standard tympanoplasty type I were selected as historical controls.

METHODS

Materials for the TM repair included gelatin sponge with basic fibroblast growth factor and fibrin glue. After lesions were removed through the TM perforation, gelatin sponge immersed in basic fibroblast growth factor was placed over the perforation. Fibrin glue was then dripped onto the sponge. Treatment efficacy was evaluated 6 months posttreatment.

RESULTS

Complete closure of the TM perforation was achieved in 91% (n = 41/45) of the patients in this regenerative treatment. Improvement in average hearing levels and air-bone gap were much better with this treatment than in the historical control group.

CONCLUSIONS

This new regenerative therapy is useful not only for patients with simple TM perforations but also for those with cholesteatomas, tumors, or severe calcification without requiring conventional surgical procedures. This regenerative therapy is an easy, safe, cost-effective, and minimally-invasive treatment.

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, -22, -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> <em>19</em>, 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-<em>19</em> 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.

Breast cancer remains the second leading cause of cancer-related death in women despite stratification based on standard hormonal receptor (HR) and HER2 testing. Additional prognostic markers are needed to improve breast cancer treatment. Chromothripsis, a catastrophic genome rearrangement, has been described recently in various cancer genomes and affects cancer progression and prognosis. However, little is known about chromothripsis in breast cancer. To identify novel prognostic biomarkers in breast cancer, we used molecular inversion probe (MIP) microarray to explore genome-wide copy number aberrations (CNA) and breast cancer-related gene alterations in DNA extracted from formalin-fixed paraffin-embedded tissue. We examined 42 primary breast cancers with known HR and HER2 status assessed via immunohistochemistry and FISH and analyzed MIP microarray results for correlation with standard tests and survival outcomes. Global genome-wide CNA ranged from 0.2% to 65.7%. Chromothripsis-like patterns were observed in 23/38 (61%) cases and were more prevalent in cases with ≥10% CNA (20/26, 77%) than in cases with <10% CNA (3/12, 25%; p<0.01). Most frequently involved chromosomal segment was 17q12-q21, the HER2 locus. Chromothripsis-like patterns involving 17q12 were observed in 8/<em>19</em> (42%) of HER2-amplified tumors but not in any of the tumors without HER2 amplification (0/<em>19</em>; p<0.01). HER2 amplification detected by MIP microarray was 95% concordant with conventional testing (39/41). Interestingly, 21% of patients (9/42) had <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor 1 (FGFR1)amplification and had a 460% higher risk for mortality than those without FGFR1 amplification (p<0.01). In summary, MIP microarray provided a robust assessment of genomic CNA of breast cancer.

<AbstractText>Bile acids in plasma are elevated after bariatric surgery and may contribute to metabolic improvements, but underlying changes in bile flow are poorly understood. We assessed bilio-enteric flow of bile and plasma bile concentrations in individuals with Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery compared with matched non-surgical controls (CON).</AbstractText><p><div><b>SUBJECTS/METHODS</b></div>Fifteen RYGB, 10 SG and 15 CON underwent ⁹⁹Tc-mebrofenin cholescintigraphy combined with intake of a high-fat ¹¹¹In-DTPA-labelled meal and frequent blood sampling. A ⁷⁵Se-HCAT test was used to assess bile acid retention.</p><AbstractText>After RYGB, gallbladder filling was decreased (p = 0.045 versus CON), basal flow of bile into the small intestine increased (p = 0.005), bile acid retention augmented (p = 0.021) and basal bile acid plasma concentrations elevated (p = 0.009). During the meal, foods passed unimpeded through the gastric pouch resulting in almost instant postprandial mixing of bile and foods, but the postprandial rise in plasma bile acids was brief and associated with decreased overall release of <em>fibroblast</em> <em>growth</em> <em>factor</em>-<em>19</em> (FGF-<em>19</em>) compared with CON (p = 0.033). After SG, bile flow and retention were largely unaltered (p > 0.05 versus CON), but gastric emptying was accelerated (p < 0.001) causing earlier mixture of bile and foods also in this group. Neither basal nor postprandial bile acid concentrations differed between SG and CON.</AbstractText><AbstractText>Bilio-enteric bile flow is markedly altered after RYGB resulting in changes in plasma concentrations of bile acids and FGF-<em>19</em>, whereas bile flow and plasma concentrations are largely unaltered after SG.</AbstractText>

Pulmonary fibrosis (PF) is a progressive and irreversible lung disease, characterized by poor prognosis with limited treatment options. Mesenchymal stem cells (MSCs) are multi-potent cells having the ability to self-renew and differentiate into multiple tissues, thus considered a novel treatment option. The present study aimed to investigate the possible antifibrotic effect of undifferentiated adipose tissue-derived mesenchymal stem cell (AD-MSC) therapy on PF experimentally induced in rats using amiodarone (AMD). AMD (30 mg/kg) was given orally, once daily for 12 consecutive weeks to induce lung fibrosis. Following the confirmation of lung damage with histopathological examination, AD-MSCs (2 × 10⁶ and 4 × 10⁶ undifferentiated MSCs) were injected once intravenously, followed by 2 months for treatment. AMD induced focal <em>fibroblast</em>ic cells proliferation in the peribronchiolar tissue, as well as in between the collapsed emphysematous alveoli. Also, AMD significantly increased serum and lung homogenate <em>fibroblast</em> <em>growth</em> <em>factor</em>-7 (FGF7), Clara cell protein-16 (CC16), and cytokeratin -<em>19</em> (CK<em>19</em>) levels, as well as the expression of both iNOS and NFкB in the lung alveoli. Moreover, AMD caused excessive collagen deposition and increased alpha smooth muscle actin (α-SMA) expression. All findings significantly regressed on stem cell therapy in both doses, with superior effect of the high dose, providing evidence that adipose tissue-derived MSCs could be a promising approach for the treatment of PF. Graphical Abstract.

Abnormal activation of the <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>)/<em>fibroblast</em> <em>growth</em> <em>factor</em> receptor 4 (FGFR4) signaling pathway has been shown to drive the proliferation of a significant portion of hepatocellular carcinoma (HCC). Resistance and toxicity are serious drawbacks that have been observed upon use of the current first- and second-line treatment options for HCC, therefore warranting the investigation of alternative therapeutic approaches. We report the development and biological characterization of a covalent inhibitor that is highly potent and exquisitely specific to FGFR4. The crystal structure of this inhibitor in complex with FGFR4 was solved, confirming its covalent binding and revealing its binding mode. We also describe the first clickable probe for FGFR4 that can be used to directly measure target engagement in cells. Our compound exhibited great antitumor activity in HCC cell lines and tumor xenograft models. These results provide evidence of a promising therapeutic lead for the treatment of a subset of HCC patients.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> (FGF)<em>19</em>, an endocrine hormone produced in the gut, acts in the liver to control bile acid synthesis. NGM282, an engineered FGF<em>19</em> analog, is currently in clinical development for treating nonalcoholic steatohepatitis. However, the molecular mechanisms that integrate FGF<em>19</em> with cholesterol metabolic pathways are incompletely understood. Here, we report that FGF<em>19</em> and NGM282 promote HDL biogenesis and cholesterol efflux from the liver by selectively modulating LXR signaling while ameliorating hepatic steatosis. We further identify ABCA1 and FGF receptor 4 as mediators of this effect, and that administration of a HMG-CoA reductase inhibitor or a blocking antibody against proprotein convertase subtilisin/kexin type 9 abolished FGF<em>19</em>-associated elevations in total cholesterol, HDL cholesterol (HDL-C), and LDL cholesterol in <i>db/db</i> mice. Moreover, we show that a constitutively active MEK1, but not a constitutively active STAT3, mimics the effect of FGF<em>19</em> and NGM282 on cholesterol change. In dyslipidemic <i>Apoe</i>^-/- mice fed a Western diet, treatment with NGM282 dramatically reduced atherosclerotic lesion area in aortas. Administration of NGM282 to healthy volunteers for 7 days resulted in a 26% increase in HDL-C levels compared with placebo. These findings outline a previously unrecognized role for FGF<em>19</em> in the homeostatic control of cholesterol and may have direct impact on the clinical development of FGF<em>19</em> analogs.

UNASSIGNED

Bile acid homeostasis is essential and imbalance may lead to liver damage and liver failure. The bile acid induced intestinal <em>factor</em> <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) has been identified as a key protein for mediating negative feedback inhibition of bile acid synthesis. The aim of the study was to define FGF<em>19</em> and bile acid concentrations in portal and systemic blood in the fasted and postprandial state. We also addressed the question if physiological portal levels of FGF<em>19</em> can be extrapolated from the concentration in systemic blood.

UNASSIGNED

Portal and systemic blood was collected from 75 fasted patients undergoing liver surgery and from three organ donors before and after enteral nutrition. Serum concentration of FGF<em>19</em> was determined with ELISA and bile acid concentration with gas chromatography-mass spectrometry.

UNASSIGNED

Concentration of bile acids was twice as high in portal compared to systemic blood in the fasted group and 3-5 times higher in the postprandial group. FGF<em>19</em> increased after enteral nutrition but did not differ between portal and systemic blood, in either group. In addition, a strong, positive correlation between bile acids and FGF<em>19</em> was found.

UNASSIGNED

Our results confirm that bile acids drive the postprandial increase of circulating FGF<em>19</em> but a hepatic clearance of FGF<em>19</em> is unlikely. We conclude that systemic concentrations of FGF<em>19</em> reflect portal concentrations of FGF<em>19</em>.

The poor prognosis of patients with hepatocellular carcinoma (HCC) is mainly attributed to its high rate of metastasis and recurrence. However, the molecular mechanisms underlying HCC metastasis need to be elucidated. The SRY-related HMG box (SOX) family proteins, which are a group of highly conserved transcription <em>factors</em>, play important roles in cancer initiation and progression. Here, we report a novel role of SOX18, a member of the SOX family, in promoting HCC invasion and metastasis. The elevated expression of SOX18 was positively correlated with poor tumor differentiation, higher TNM stage, and poor prognosis. The overexpression of SOX18 promoted HCC metastasis by upregulating metastasis-related genes, including <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor 4 (FGFR4) and fms-related tyrosine kinase 4 (FLT4). Knockdown of both FGFR4 and FLT4 significantly decreased SOX18-mediated HCC invasion and metastasis, while the stable overexpression of FGFR4 and FLT4 reversed the decrease in cell invasion and metastasis that was induced by the inhibition of SOX18. <em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>), which is the ligand of FGFR4, upregulated SOX18 expression. A mechanistic investigation indicated that the upregulation of SOX18 that was mediated by the FGF<em>19</em>-FGFR4 pathway relied on the p-FRS2/p-GSK3β/β-catenin pathway. SOX18 knockdown significantly reduced FGF<em>19</em>-enhanced HCC invasion and metastasis. Furthermore, BLU9931, a specific FGFR4 inhibitor, significantly reduced the SOX18-mediated HCC invasion and metastasis. In human HCC tissues, SOX18 expression was positively correlated with FGF<em>19</em>, FGFR4 and FLT4 expression, and patients that coexpressed FGF<em>19</em>/SOX18, SOX18/FGFR4, or SOX18/FLT4 had the worst prognosis. CONCLUSION: We defined a FGF<em>19</em>-SOX18-FGFR4 positive feedback loop that played a pivotal role in HCC metastasis, and targeting this pathway may be a promising therapeutic option for the clinical management of HCC.

Currently there are very few pharmacological options available to treat acute liver injury. Because its natural exposure to noxious stimuli the liver has developed a strong endogenous hepatoprotective capacity. Indeed, experimental evidence exposed a variety of endogenous hepatic and systemic responses naturally activated to protect the hepatic parenchyma and to foster liver regeneration, therefore preserving individual's survival. The fibroblast growth factor (FGF) family encompasses a range of polypeptides with important effects on cellular differentiation, growth survival and metabolic regulation in adult organisms. Among these FGFs, FGF19 and FGF21 are endocrine hormones that profoundly influence systemic metabolism but also exert important hepatoprotective activities. In this review, we revisit the biology of these factors and highlight their potential application for the clinical management of acute liver injury.

<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 = <em>19</em>:20; BMI, mean ± standard deviation = 22 ± 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>

<AbstractText>To review the formation, catabolism, and the possible atherogenic properties of Lp-X.</AbstractText><AbstractText>The conversion of cholesterol to bile acids is regulated by several mechanisms including cholesterol 7 alpha hydroxylase, <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em>, and farnesoid X receptors. During cholestasis these mechanisms are altered and there is an accumulation of bile acids and cholesterol in plasma. The hypercholesterolemia observed in cholestasis is due to the presence of an anomalous lipoprotein called lipoprotein-X (Lp-X). Lp-X is a lipoprotein rich in phospholipid and free cholesterol present in plasma of patients with cholestasis and, with some variations, in patients with lecithin-cholesterol-acyl-transferase deficiency (LCAT), and after lipid infusion. Lp-X is formed from a bile lipoprotein moving to the blood vessels where it incorporates small quantities of triglycerides, apo-C and esterified cholesterol and becomes a "mature" Lp-X. The activity of the phosphatidilcholine canalicular transporter Mdr2 P-glycoprotein (homologous to the human ABCB4) is essential for LpX appearance, since its suppression abolishes Lp-X formation. However, the concentration of Lp-X in plasma is determined also by the degree of the cholestasis, the residual liver function, and the LCAT deficiency. The Lp-X catabolism seems to be mediated by the reticuloendothelial system and possibly the kidney.</AbstractText><AbstractText>Lp-X might be considered a defense mechanism against the toxic effect of free cholesterol in cholestasis. The frequency of cardiovascular events in patients affected by primary biliary cholangitis, in whom the Lp-X is present in high concentration, are not increased. Further studies could now clarify the remaining open questions on the role of Lp-X in the dyslipidemia of cholestasis.</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 <em>19</em>-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-22 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.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> receptor 4 (FGFR4) has been confirmed to be associated with the progression and prognosis of ovarian cancer, while the underlying mechanism has not been well elucidated and the clinical significance of its ligand, <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>), has not been explored. To study the clinical significance of FGF<em>19</em> in advanced‑stage serous ovarian cancer, we detected the expression of FGF<em>19</em> and FGFR4 by immunohistochemistry (IHC), evaluated the correlation between FGF<em>19</em> and clinicopathological <em>factors</em> by Chi-square (χ2) test, and analyzed the association between FGF<em>19</em>, FGFR4 and the overall survival rate using the Kaplan‑Meier method. As a result, we demonstrated that high expression of FGF<em>19</em> and FGFR4 both predicted unfavorable prognosis (P=0.033 and 0.018, respectively), whereas FGF<em>19</em>-FGFR4 double high expression was a more sensitive prognostic <em>factor</em> of advanced-stage serous ovarian cancer (P<0.001). With experiments in vitro, we demonstrated that both recombinant FGF<em>19</em> and secreted FGF<em>19</em> promoted ovarian cancer proliferation and invasion by activating FGFR4 and the subsequent AKT-MAPK signaling pathway, suggesting that FGF<em>19</em>-FGFR4 signaling may auto-activate in a paracrine or autocrine manner. In conclusion, FGF<em>19</em>-FGFR4 double high expression was a more sensitive prognostic <em>factor</em> than FGF<em>19</em> or FGFR4 alone in advanced-stage serous ovarian cancer. The FGF<em>19</em>-FGFR4 signaling pathway can promote ovarian cancer proliferation and invasion by the AKT-MAPK signaling pathway, indicating that FGF<em>19</em> could be a potential therapeutic drug target of advanced-stage serous ovarian cancer.

Accumulating evidence has shown that <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) plays an important role in regulating cell proliferation. Psoriasis is characterized by the hyperproliferation of keratinocytes in skin lesions. However, whether FGF<em>19</em> regulates the proliferation of keratinocytes in psoriasis remains unknown. In this study, we aimed to explore the potential relevance of FGF<em>19</em> in psoriasis. We found that FGF<em>19</em> was highly expressed in psoriatic skin from psoriasis patients, as well as keratinocytes that were stimulated with a cocktail of cytokines (M5), which is an in vitro model of psoriasis. Functional experiments demonstrated that FGF<em>19</em> overexpression promoted the <em>growth</em> and proliferation of keratinocytes, while FGF<em>19</em> knockdown showed opposite effect. Moreover, we found that FGF<em>19</em> increased the phosphorylation of glycogen synthase kinase (GSK)-3β and promoted the expression of β-catenin and the activation of T cell <em>factor</em> 4 (TCF4) transcriptional activity. Notably, blocking Wnt/β-catenin signalling by silencing β-catenin partially reversed FGF<em>19</em>-mediated promotional effects on keratinocyte proliferation. In addition, FGFR4 inhibition significantly blocked the promotional effect of FGF<em>19</em> on keratinocyte proliferation and GSK-3β/β-catenin/TCF4 signalling. Taken together, our results demonstrated that FGF<em>19</em> contributes to sustaining the high proliferative ability of keratinocytes through promoting Wnt/GSK-3β/β-catenin signalling via FGFR4, highlighting the importance of FGF<em>19</em> in the pathogenesis of psoriasis. Our study suggests that FGF<em>19</em> may serve as a novel and potential therapeutic target for psoriasis.

Parenteral nutrition (PN) has revolutionized the care of patients with intestinal failure by providing nutrition intravenously. Worldwide, PN remains a standard tool of nutrition delivery in neonatal, pediatric, and adult patients. Though the benefits are evident, patients receiving PN can suffer serious cholestasis due to lack of enteral feeding and sometimes have fatal complications from liver injury and gut atrophy, including PN-associated liver disease or intestinal failure-associated liver disease. Recent studies into gut-systemic cross talk via the bile acid-regulated farnesoid X receptor (FXR)-<em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) axis, gut microbial control of the TGR5-glucagon-like peptide (GLP) axis, sepsis, and role of prematurity of hepatobiliary receptors are greatly broadening our understanding of PN-associated injury. It has also been shown that the composition of ω-6/ω-3 polyunsaturated fatty acids given parenterally as lipid emulsions can variably drive damage to hepatocytes and cell integrity. This manuscript reviews the mechanisms for the multi<em>factor</em>ial pathogenesis of liver disease and gut injury with PN and discusses novel ameliorative strategies.

Poly-L-ornithine with an average molecular weight of 32K was reacted with beta-amanitin hydroxysuccinimide ester to form an amide-linked toxin conjugate. Loading of the polymeric chain with amanitin was high, corresponding to up to 35% of the total weight. To this amatoxin vehicle we attached a targeting molecule, human recombinant leucine-21 epidermal <em>growth</em> <em>factor</em> (hrEGFL), via a disulfide-containing linker moiety. A typical average stoichiometry of the hrEGFL labeled toxin conjugate was (L-Orn)164(beta-amanitin)<em>19</em>(COC2H4SSC2H4CO-hrEGFL)2. The affinity for EGF receptors of hrEGFL bound in this conjugate was tested by using A 431 cells. The affinity was eight times lower than that of unsubstituted hrEGFL but regarded as high enough for studying specific toxicity effects with cells bearing EGF receptors. We found that beta-amanitin in the labeled conjugate was able to inhibit the <em>growth</em> of A 431 cells at a concentration of 28 nM, 80 times lower than for native beta-amanitin and 20 times lower than for poly-L-ornithine-bound beta-amanitin without the hrEGFL label. The approximately 20-fold enhancement of cytotoxicity suggests a specific internalization of the toxin conjugate mediated by the hormone label. This idea is supported by the fact that also in another transformed <em>fibroblast</em> cell line, with an increased though smaller number of EGF receptors than A 431 cells, the corresponding enhancement of cytotoxicity was demonstrable but less pronounced (7-fold). The hormone-mediated increase in cytotoxicity of EGF labeled poly-L-ornithine-beta-amanitin conjugates, combined with their moderate toxicity in the mouse, encourages further examination of such compounds in tumor model systems in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)