Hepatic lipogenesis is normally tightly regulated but is aberrantly elevated in obesity. <em>Fibroblast</em> <em>Growth</em> <em>Factor</em>-15/<em>19</em> (mouse FGF15, human FGF<em>19</em>) are bile acid-induced late fed-state gut hormones that decrease hepatic lipid levels by unclear mechanisms. We show that FGF15/<em>19</em> and FGF15/<em>19</em>-activated Small Heterodimer Partner (SHP/NR0B2) have a role in transcriptional repression of lipogenesis. Comparative genomic analyses reveal that most of the SHP cistrome, including lipogenic genes repressed by FGF<em>19</em>, have overlapping CpG islands. FGF<em>19</em> treatment or SHP overexpression in mice inhibits lipogenesis in a DNA methyltransferase-3a (DNMT3A)-dependent manner. FGF<em>19</em>-mediated activation of SHP via phosphorylation recruits DNMT3A to lipogenic genes, leading to epigenetic repression via DNA methylation. In non-alcoholic fatty liver disease (NAFLD) patients and obese mice, occupancy of SHP and DNMT3A and DNA methylation at lipogenic genes are low, with elevated gene expression. In conclusion, FGF15/<em>19</em> represses hepatic lipogenesis by activating SHP and DNMT3A physiologically, which is likely dysregulated in NAFLD.

Farnesoid X receptor (FXR) is a master regulator of bile acid homeostasis through transcriptional regulation of genes involved in bile acid synthesis and cellular membrane transport. Impairment of bile acid efflux due to cholangiopathies results in chronic cholestasis leading to abnormal elevation of intrahepatic and systemic bile acid levels. Obeticholic acid (OCA) is a potent and selective FXR agonist that is 100-fold more potent than the endogenous ligand chenodeoxycholic acid (CDCA). The effects of OCA on genes involved in bile acid homeostasis were investigated using sandwich-cultured human hepatocytes. Gene expression was determined by measuring mRNA levels. OCA dose-dependently increased <em>fibroblast</em> <em>growth</em> <em>factor</em>-<em>19</em> (FGF-<em>19</em>) and small heterodimer partner (SHP) which, in turn, suppress mRNA levels of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme for de novo synthesis of bile acids. Consistent with CYP7A1 suppression, total bile acid content was decreased by OCA (1 μmol/L) to 42.7 ± 20.5% relative to control. In addition to suppressing de novo bile acids synthesis, OCA significantly increased the mRNA levels of transporters involved in bile acid homeostasis. The bile salt excretory pump (BSEP), a canalicular efflux transporter, increased by 6.4 ± 0.8-fold, and the basolateral efflux heterodimer transporters, organic solute transporter α (OSTα ) and OSTβ increased by 6.4 ± 0.2-fold and 42.9 ± 7.9-fold, respectively. The upregulation of BSEP and OSTα and OSTβ, by OCA reduced the intracellular concentrations of d8 -TCA, a model bile acid, to 39.6 ± 8.9% relative to control. These data demonstrate that OCA does suppress bile acid synthesis and reduce hepatocellular bile acid levels, supporting the use of OCA to treat bile acid-induced toxicity observed in cholestatic diseases.

BACKGROUND

The bile acid-activated nuclear receptor Farnesoid X Receptor (FXR) is critical in maintaining intestinal barrier integrity and preventing bacterial overgrowth. Patients with Crohn's colitis (CC) exhibit reduced ileal FXR target gene expression. FXR agonists have been shown to ameliorate inflammation in murine colitis models. We here explore the feasibility of pharmacological FXR activation in CC.

METHODS

Nine patients with quiescent CC and 12 disease controls were treated with the FXR ligand chenodeoxycholic acid (CDCA; 15 mg/kg/day) for 8 days. Ileal FXR activation was assessed in the fasting state during 6 hrs after the first CDCA dose and on day 8, by quantification of serum levels of <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF) <em>19</em>. Since FGF<em>19</em> induces gallbladder (GB) refilling in murine models, we also determined concurrent GB volumes by ultrasound. On day 8 ileal and cecal biopsies were obtained and FXR target gene expression was determined.

RESULTS

At baseline, FGF<em>19</em> levels were not different between CC and disease controls. After the first CDCA dose, there were progressive increases of FGF<em>19</em> levels and GB volumes during the next 6 hours in CC patients and disease controls (FGF<em>19</em>: 576 resp. 537% of basal; GB volumes: <em>19</em>0 resp. 178% of basal) without differences between both groups, and a further increase at day 8. In comparison with a separate untreated control group, CDCA affected FXR target gene expression in both CC and disease controls, without differences between both groups.

CONCLUSIONS

Pharmacological activation of FXR is feasible in patients with CC. These data provide a rationale to explore the anti-inflammatory properties of pharmacological activation of FXR in these patients.

BACKGROUND

TrialRegister.nl NTR2009.

Although several studies have linked PM_2.5 (particulate matter with a diameter less than 2.5 μm) to ocular surface diseases such as keratitis and conjunctivitis, very few studies have previously addressed its effect on the retina. Therefore, the aim of this study was to evaluate the effect of PM_2.5 on epithelial-mesenchymal transition (EMT), a process involved in disorders of the retinal pigment epithelial (RPE) on APRE-<em>19</em> cells. PM_2.5 changed the phenotype of RPE cells from epithelial to <em>fibroblast</em>-like mesenchymal, and increased cell migration. Exposure to PM_2.5 markedly increased the expression of mesenchymal markers, but reduced the levels of epithelial markers. Moreover, PM_2.5 promoted the phosphorylation of MAPKs and the expression of transforming <em>growth</em> <em>factor</em>-β (TGF-β)-mediated nuclear transcriptional <em>factors</em>. However, these PM_2.5-mediated changes were completely reversed by LY2109761, a small molecule inhibitor of the TGF-β receptor type I/II kinases, and N-acetyl-L-cysteine (NAC), a reactive oxygen species (ROS) scavenger. Interestingly, NAC, but not LY2109761, effectively restored the PM_2.5-induced mitochondrial defects, including increased ROS, decreased mitochondrial activity, and mitochondrial membrane potential disruption. Collectively, our findings indicate that the TGF-β/Smad/ERK/p38 MAPK signaling pathway is activated downstream of cellular ROS during PM_2.5-induced EMT. The present study provides the first evidence that EMT of RPE may be one of the mechanisms of PM_2.5-induced retinal dysfunction.

<b>Background:</b> Recent evidence indicates that host-gut microbiota crosstalk has nonnegligible effects on host skeletal muscle, yet gut microbiota-regulating mechanisms remain obscure.<b>Methods:</b> C57BL/6 mice were treated with a cocktail of antibiotics (Abx) to depress gut microbiota for 4 weeks. The profiles of gut microbiota and microbial bile acids were measured by 16S rRNA sequencing and ultra-performance liquid chromatography (UPLC), respectively. We performed qPCR, western blot and ELISA assays in different tissue samples to evaluate FXR-FGF15/<em>19</em> signaling.<b>Results:</b> Abx treatment induced skeletal muscle atrophy in mice. These effects were associated with microbial dysbiosis and aberrant bile acid (BA) metabolism in intestine. Ileal farnesoid X receptor (FXR)-<em>fibroblast</em> <em>growth</em> <em>factor</em> 15 (FGF15) signaling was inhibited in response to microbial BA disturbance. Mechanistically, circulating FGF15 was decreased, which downregulated skeletal muscle protein synthesis through the extracellular-signal-regulated protein kinase 1/2 (ERK1/2) signaling pathway. Treating Abx mice with FGF<em>19</em> (human FGF15 ortholog) partly reversed skeletal muscle loss.<b>Conclusions:</b> These findings indicate that the BA-FXR-FGF15/<em>19</em> axis acts as a regulator of gut microbiota to mediate host skeletal muscle.

<strong class="sub-title"> Keywords: </strong> FGF15/<em>19</em>; FXR; Gut microbiota; bile acid; skeletal muscle.

UNASSIGNED

Retinopathy of prematurity (ROP) is a vision-threatening disease associated with abnormal retinal vascular development. Proteins from the insulin-like growth factor pathway are related to ROP. However, there is a paucity of research on the role of other proteins in ROP. The aim of this study was to identify plasma proteins related to clinically significant ROP.

UNASSIGNED

We measured 1121 plasma proteins in the early neonatal period in infants at risk for ROP using an aptamer-based proteomic technology. The primary aim of the study was to compare plasma protein concentrations in infants who did (n = 12) and did not (n = 23) subsequently develop clinically significant ROP using logistic regression. As a secondary aim, we examined patterns in the proteins across categories of clinically significant, low-grade, and no ROP groups.

UNASSIGNED

Lower levels of 16 proteins were associated with an increased risk of clinically significant ROP. In this group, superoxide dismutase (Mn), mitochondrial (MnSOD), and chordin-like protein 1 (CRDL1) were highly ranked. Other proteins in this group included: C-C motif chemokine 14 (HCC-1), prolactin, insulin-like <em>growth</em> <em>factor</em>-binding protein 7 (IGFBP-7), and eotaxin. Higher levels of 12 proteins were associated with a higher risk for ROP. <em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF-<em>19</em>) was the top-ranked protein target followed by hepatocyte <em>growth</em> <em>factor</em>-like protein (MSP), luteinizing hormone (LH), cystatin M, plasminogen, and proprotein convertase subtilisin/kexin type 9 (PCSK9). We also noted different patterns in the trend of concentrations of proteins across the clinically significant, low-grade, and no ROP groups.

UNASSIGNED

We discovered plasma proteins with novel associations with clinically significant ROP (MnSOD, CRDL1, PCSK9), proteins with links to established ROP signaling pathways (IGFBP-7), and proteins such as MnSOD that may be a target for future therapeutic interventions.

Discovery of the specific bile acid receptors farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in enteroendocrine L cells has prompted research focusing on the impact of bile acids on glucagon-like peptide-1 (GLP-1) secretion and glucose metabolism. The aim of the present study was to assess the GLP-1 secretory and gluco-metabolic effects of endogenously released bile, with and without concomitant administration of the bile acid-sequestering resin, sevelamer, in patients with type 2 diabetes.

We performed a randomized, placebo-controlled, double-blinded cross-over study including 15 metformin-treated patients with type 2 diabetes. During 4 experimental study days, either sevelamer 3200 mg or placebo in combination with intravenous infusion of cholecystokinin (CCK) (0.4 pmol sulfated CCK-8/kg/min) or saline was administered in randomized order. The primary endpoint was plasma GLP-1 excursions as measured by incremental area under the curve. Secondary endpoints included plasma responses of glucose, triglycerides, insulin, CCK, <em>fibroblast</em> <em>growth</em> <em>factor</em>-<em>19</em> and 7α-hydroxy-4-cholesten-3-one (C4). In addition, gallbladder dynamics, gastric emptying, resting energy expenditure, appetite and ad libitum food intake were assessed.

CCK-mediated gallbladder emptying was demonstrated to elicit a significant induction of GLP-1 secretion compared to saline, whereas concomitant single-dose administration of the bile acid sequestrant sevelamer was shown to eliminate the acute bile acid-induced increase in plasma GLP-1 excursions.

Single-dose administration of sevelamer eliminated bile acid-mediated GLP-1 secretion in patients with type 2 diabetes, which could be explained by reduced bile acid stimulation of the basolaterally localized TGR5 on enteroendocrine L cells.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) is a gut-derived peptide hormone that is produced following activation of Farnesoid X Receptor (FXR). FGF<em>19</em> is secreted and signals to the liver, where it contributes to the homeostasis of bile acid (BA), lipid and carbohydrate metabolism. FGF<em>19</em> is a promising therapeutic target for the metabolic syndrome and cholestatic diseases, but enthusiasm for its use has been tempered by FGF<em>19</em>-mediated induction of proliferation and hepatocellular carcinoma. To inform future rational design of FGF<em>19</em>-variants, we have conducted temporal quantitative proteomic and gene expression analyses to identify FGF<em>19</em>-targets related to metabolism and proliferation. Mice were fasted for 16 hours, and injected with human FGF<em>19</em> (1 mg/kg body weight) or vehicle. Liver protein extracts (containing "light" lysine) were mixed 1:1 with a spike-in protein extract from 13C6-lysine metabolically labelled mouse liver (containing "heavy" lysine) and analysed by LC-MS/MS. Our analyses provide a resource of FGF<em>19</em> target proteins in the liver. 189 proteins were upregulated (≥ 1.5 folds) and 73 proteins were downregulated (≤ -1.5 folds) by FGF<em>19</em>. FGF<em>19</em> treatment decreased the expression of proteins involved in fatty acid (FA) synthesis, i.e., Fabp5, Scd1, and Acsl3 and increased the expression of Acox1, involved in FA oxidation. As expected, FGF<em>19</em> increased the expression of proteins known to drive proliferation (i.e., Tgfbi, Vcam1, Anxa2 and Hdlbp). Importantly, many of the FGF<em>19</em> targets (i.e., Pdk4, Apoa4, Fas and Stat3) have a dual function in both metabolism and cell proliferation. Therefore, our findings challenge the development of FGF<em>19</em>-variants that fully uncouple metabolic benefit from mitogenic potential.

Pigs are increasingly important animals for modeling human pediatric nutrition and gastroenterology and complementing mechanistic studies in rodents. The comparative advantages in size and physiology of the neonatal pig have led to new translational and clinically relevant models of important diseases of the gastrointestinal tract and liver in premature infants. Studies in pigs have established the essential roles of prematurity, microbial colonization, and enteral nutrition in the pathogenesis of necrotizing enterocolitis. Studies in neonatal pigs have demonstrated the intestinal trophic effects of akey gut hormone, glucagon-like peptide 2 (GLP-2), and its role in the intestinal adaptation process and efficacy in the treatment of short bowel syndrome. Further, pigs have been instrumental in elucidating the physiology of parenteral nutrition-associated liver disease and the means by which phytosterols, <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em>, and a new generation of lipid emulsions may modify disease. The premature pig will continue to be a valuable model in the development of optimal infant diets (donor human milk, colostrum), specific milk bioactives (arginine, <em>growth</em> <em>factors</em>), gut microbiota modifiers (pre-, pro-, and antibiotics), pharmaceutical drugs (GLP-2 analogs, FXR agonists), and novel diagnostic tools (near-infrared spectroscopy) to prevent and treat these pediatric diseases.

The interest on the role of angiogenesis in the pathogenesis and progression of human interstitial lung diseases is <em>growing</em>, with conventional sprouting (SA) and non-sprouting intussusceptive angiogenesis (IA) being differently represented in specific pulmonary injury patterns. The role of viruses as key regulators of angiogenesis is known for several years. A significantly enhanced amount of new vessel <em>growth</em>, through a mechanism of IA, has been reported in lungs of patients who died from Covid-<em>19</em>; among the angiogenesis-related genes, <em>fibroblast</em> <em>growth</em> <em>factor</em> 2 (FGF2) was found to be upregulated. These findings are intriguing. FGF2 plays a role in some viral infections: the upregulation is involved in the MERS-CoV-induced strong apoptotic response crucial for its highly lytic replication cycle in lung cells, whereas FGF2 is protective against the acute lung injury induced by H1N1 influenza virus, improving the lung wet-to-dry weight ratio. FGF2 plays a role also in regulating IA, acting on pericytes (crucial for the formation of intraluminal pillars), and endothelium, and FGF2-induced angiogenesis may be promoted by inflammation and hypoxia. IA is a faster and probably more efficient process than SA, able to modulate vascular remodeling through pruning of redundant or inefficient blood vessels. We can speculate that IA might have the function of restoring a functional vascular plexus consequently to extensive endothelialitis and alveolar capillary micro-thrombosis observed in Covid-<em>19</em>. Anti-Vascular endothelial <em>growth</em> <em>factor</em> (anti-VEGF) strategies are currently investigated for treatment of severe and critically ill Covid-<em>19</em> patients, but also FGF2, and its expression and/or signaling, might represent a promising target.

<strong class="sub-title"> Keywords: </strong> Angiogenesis; Covid-<em>19</em>; FGF2; Intussusceptive; VEGF; Virus.

The ability to enhance muscle size and function is important for overall health. In this study, skeletal myofiber vascular endothelial <em>growth</em> <em>factor</em> (VEGF) was hypothesized to regulate hypertrophy, capillarity, and contractile function in response to functional overload (FO). Adult myofiber-specific VEGF gene-ablated mice (skmVEGF(-/-)) and wild-type (WT) littermates underwent plantaris FO or sham surgery (SHAM). Mass, morphology, in vivo function, IGF-1, basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (bFGF), hepatocyte <em>growth</em> <em>factor</em> (HGF), and Akt were measured at 7, 14, and 30 days. FO resulted in hypertrophy in both genotypes, but fiber sizes were 13% and 23% smaller after 14 and 30 days, respectively, and mass 15% less after 30 days in skmVEGF(-/-) than WT. FO increased isometric force after 30 days in WT and decreased in skmVEGF(-/-) after 7 and 14 days. FO also resulted in a reduction in specific force and this differed between genotypes at 14 days. Fatigue resistance improved only in 14-day WT mice. Capillary density was decreased by FO in both genotypes. However, capillary-to-fiber ratios were <em>19</em>% and 15% lower in skmVEGF(-/-) than WT at the 14- and 30-day time points, respectively. IGF-1 was increased by FO at all time points and was 45% and 40% greater in skmVEGF(-/-) than WT after 7 and 14 days, respectively. bFGF, HGF, total Akt, and phospho-Akt, independent of VEGF expression, and VEGF levels in WT were increased after 7 days of FO. These findings suggest VEGF-dependent capillary maintenance supports muscle <em>growth</em> and function in overloaded muscle and is not rescued by compensatory IGF-1 expression.

Background: Since 2015, mechanical thrombectomy has been the standard treatment for emergent large vessel occlusion ischemic stroke.

Objective: To investigate, using the previously published Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) protocol (clinicaltrials.gov NCT03153683), how the protein expression of a patient's intracranial blood during ischemic stroke compares with the protein expression of their systemic arterial blood in order to better understand and treat stroke.

Methods: Plasma samples from 25 subjects underwent proteomic analysis, where intracranial protein expression was compared with systemic protein levels. Data including sex, comorbidities, infarct volume, and infarct time were included for each subject.

<strong class="sub-title"> Results: </strong> A majority of important proteins had a lower expression in intracranial blood than in systemic arterial blood. Proteins with the most significant changes in expression were: endopeptidase at -0.26 (p<0.0001), phospholipid transfer protein (PLTP) at -0.26 (p=0.0005), uromodulin (UMOD) at -0.14 (p=0.002), ficolin-2 (FCN2) at -0.46 (p=0.005), C-C motif chemokine <em>19</em> (CCL<em>19</em>) at -0.51 (p<0.0001), C-C motif chemokine 20 (CCL20) at -0.40 (p<0.0001), <em>fibroblast</em> <em>growth</em> <em>factor</em> 21 at -0.37 (p=0.0002), and C-C motif chemokine (CCL23) at -0.43 (p=0.0003).

Conclusions: Evaluation of proteomic changes in the intravascular space of a cerebral infarct in progress in human subjects suggested that changes in proteins such PLTP, fetuin-B (FETUB), and FCN2 may be involved in atherosclerotic changes, and chemokines such as CCL23 are known to play a role in the Th2 autoimmune response. These data provide a scientific springboard for identifying clinically relevant biomarkers for diagnosis/prognosis, and targets for much needed neuroprotective/neuroreparative pharmacotherapies.

Keywords: artery; stroke; thrombectomy.

Structural changes involving tissue remodelling and fibrosis are major features of many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Abnormal deposition of extracellular matrix (ECM) proteins is a key factor in the development of tissue remodelling that results in symptoms and impaired lung function in these diseases. Tissue remodelling in the lungs is complex and differs between compartments. Some pathways are common but tissue remodelling around the airways and in the parenchyma have different morphologies. Hence it is critical to evaluate both common fibrotic pathways and those that are specific to different compartments; thereby expanding the understanding of the pathogenesis of fibrosis and remodelling in the airways and parenchyma in asthma, COPD and IPF with a view to developing therapeutic strategies for each. Here we review the current understanding of remodelling features and underlying mechanisms in these major respiratory diseases. The differences and similarities of remodelling are used to highlight potential common therapeutic targets and strategies. One central pathway in remodelling processes involves transforming growth factor (TGF)-β induced fibroblast activation and myofibroblast differentiation that increases ECM production. The current treatments and clinical trials targeting remodelling are described, as well as potential future directions. These endeavours are indicative of the renewed effort and optimism for drug discovery targeting tissue remodelling and fibrosis.

Keywords: Asthma; COPD; COVID-19; Collagen; Extracellular matrix; Fibroblasts; Fibrosis; IPF; Remodelling.

<em>Fibroblast</em> <em>Growth</em> <em>Factors</em> <em>19</em> and 21 (FGF<em>19</em> and FGF21) are novel endocrine messengers that regulate multiple aspects of energy homeostasis. The magnitude and pleotropic character of their beneficial actions on many, if not all abnormalities of the metabolic syndrome in animals led to extensive exploration of their biology and coordinated efforts to design novel FGF<em>19</em>/21-based analogs for therapeutic purposes. While initial attempts to develop such medicines were primarily focused on improving hyperglycemia in type 2 diabetes patients, the robust, consistent and durable effects on lipid metabolism in human trials gradually transformed clinical emphasis for these <em>factors</em> toward their use for non-alcoholic steatohepatitis (NASH) and severe hypertriglyceridemia (SHTG). In this review, we will communicate an overview of FGF<em>19</em> and FGF21 biology and the basic mechanisms of their action, that will be followed by in-depth analysis of the recent developments with FGF21/<em>19</em>-based analogs in the clinic.

<strong class="sub-title"> Keywords: </strong> FGF<em>19</em>; FGF21; NASH; clinical trials; drug development; metabolism.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> (FGF) 15/<em>19</em> and FGF21 are two atypical members of FGF<em>19</em> subfamily that function as hormones. Exogenous FGF15/<em>19</em> and FGF21 have pharmacological effects, and endogenous FGF15/<em>19</em> and FGF21 play vital roles in the maintenance of energy homeostasis. Recent reports have expanded the effects of FGF15/<em>19</em> and FGF21 on carbohydrate and lipid metabolism. However, the regulations of FGF15/<em>19</em> and FGF21 on metabolism are different. FGF15/<em>19</em> is mainly secreted from the small intestine in response to feeding, and FGF21 is secreted from the liver in response to extended fasting and from the liver and adipose tissue in response to feeding. In this work, we reviewed the regulatory effects of FGF15/<em>19</em> and FGF21 on metabolism in the fast and fed states. This information may provide some insight into the metabolic regulation of FGF15/<em>19</em> and FGF21 in different physiological condition.

UNASSIGNED

Nintedanib is an oral, triple angiokinase inhibitor of vascular endothelial growth factor/platelet-derived growth factor/fibroblast growth factor receptors. This randomized, multicenter, open-label, phase I/II study evaluated the safety, pharmacokinetics, maximum tolerated dose (MTD) in terms of dose-limiting toxicities (DLTs), and efficacy of nintedanib versus sorafenib in Asian patients with unresectable advanced hepatocellular carcinoma (HCC).

UNASSIGNED

For the phase I portion, patients were stratified into two groups according to their alanine aminotransferase/aspartate aminotransferase (ALT/AST) and Child-Pugh score at baseline. For phase I, the primary endpoint was determination of the MTD in terms of DLTs. For phase II, patients with a Child-Pugh score of 5-6, an Eastern Cooperative Oncology Group performance score ≤2, and an ALT/AST ≤2× the upper limit of normal were enrolled and randomized 2: 1 to nintedanib 200 mg twice daily (b.i.d.) (the MTD determined in phase I) or sorafenib 400 mg b.i.d. continuously in 28-day cycles until intolerable adverse events (AEs) or disease progression (PD); treatment beyond PD was allowed if clinical benefit was perceived. The primary endpoint for phase II was time to progression (TTP) by central independent review (CIR; by Response Evaluation Criteria in Solid Tumors v1.0); the secondary endpoints included overall survival (OS). All analyses were exploratory.

UNASSIGNED

The MTD was 200 mg in both groups. For phase II, 95 patients were randomized to nintedanib (n = 63) or sorafenib (n = 32). For nintedanib and sorafenib, respectively, the median CIR TTP was 2.8 vs. 3.7 months (hazard ratio [HR] = 1.21, 95% confidence interval [CI] 0.73-2.01) and the median OS 10.2 vs. 10.7 months (HR = 0.94, 95% CI 0.59-1.49). Nintedanib-treated patients had fewer grade 3 or higher AEs (56 vs. 84%), serious AEs (46 vs. 56%), and AEs leading to dose reduction (19 vs. 59%) and drug discontinuation (24 vs. 34%). AEs associated more frequently with nintedanib were vomiting and nausea, whereas those associated more frequently with sorafenib were ALT/AST increases, diarrhea, rash, and palmar-plantar erythrodysesthesia syndrome.

UNASSIGNED

Nintedanib showed numerically similar efficacy to sorafenib for CIR TTP and OS in Asian patients with advanced HCC and adequate liver function. AEs were generally manageable.

<em>Fibroblast</em> <em>growth</em> <em>factor</em>-<em>19</em> (human FGF<em>19</em>; murine FGF15) suppresses bile acid synthesis. In FGF<em>19</em> deficiency, diarrhea resulting from bile acid spillage into the colon mimics irritable bowel syndrome. To seek other consequences of FGF<em>19</em>/15 deficiency, we used Fgf15-/- and wild-type (WT) mice to assess gallbladder filling, the bile acid pool, fecal bile acid levels, and colon neoplasia. We fasted mice for six hours before assessing gallbladder size by magnetic resonance imaging (MRI). We measured bile acid levels in different compartments by enzymatic assay, and induced colon neoplasia with azoxymethane (AOM)/dextran sodium sulfate (DSS) and quantified epithelial Ki67 immunostaining and colon tumors 20 weeks later. In vivo MRI confirmed the gross finding of tubular gallbladders in FGF15-deficient compared to WT mice, but fasting gallbladder volumes overlapped. After gavage with a bile acid analogue, ex vivo MRI revealed diminished gallbladder filling in FGF15-deficient mice (P = 0.0399). In FGF15-deficient mice, the total bile acid pool was expanded 45% (P <0.05) and fecal bile acid levels were increased 2.26-fold (P <0.001). After AOM/DSS treatment, colons from FGF15-deficient mice had more epithelial cell Ki67 staining and tumors (7.33 ± 1.32 vs. 4.57 ± 0.72 tumors/mouse; P = 0.003 compared to WT mice); carcinomas were more common in FGF15-deficient mice (P = 0.01). These findings confirm FGF15, the murine homolog of FGF<em>19</em>, plays a key role in modulating gallbladder filling and bile acid homeostasis. In a well-characterized animal model of colon cancer, increased fecal bile acid levels in FGF15-deficient mice promoted epithelial proliferation and advanced neoplasia.

We examined the influence of initial graft composition on the number, type, and distribution of human progenitor cells after transplantation into the anterior subventricular zone (SVZa) of normal adult rats. The grafted populations were derived from <em>19</em>-week-old human cortical tissue grown under adherent conditions in the presence of <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF) and from a subpopulation of nestin-expressing cells, isolated using negative immunoselection methods, which exhibited properties of neural progenitors. Identical numbers of each were transplanted and the number and location of engrafted cells were compared 4 weeks later. We found a significantly greater number of presumptive neurons and astrocytes in animals that received mixed grafts compared to those enriched for progenitors. In addition, the number of human cells undergoing division was significantly greater in animals that received mixed grafts. The spatial distribution of grafted cells was not significantly different, suggesting that the patterns of cell migration were unaffected by transplant composition, whereas, a greater proportion of neurons was observed in the neurogenic areas of animals that received progenitor-enriched grafts. From a clinical perspective, our results suggest that the cellular composition of human fetal-derived transplants may be an important parameter that influences the number and pattern of differentiation of engrafted cells following transplantation in the mature CNS.

As a newly emerging metabolic regulator, accumulating evidence suggests that the circulating <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) level correlated with lipid and glucose metabolism. Several independent groups have found that FGF<em>19</em> was highly likely associated with multiple metabolic disorders. Thyroid dysfunction is believed to be associated with metabolism diseases. However, to date, few studies have investigated the role of FGF<em>19</em> in patients with thyroid dysfunctions. For this purpose, a cross-sectional study was done to estimate the role of FGF<em>19</em> in patients with different thyroid functions. Compared with the healthy control, the present study revealed that serum FGF<em>19</em> levels were significantly decreased in overt hypothyroidism patients (78.7 [52.7-121.2] vs 292.4 [210.2-426.5] pg/mL, P <0.001). FGF<em>19</em> concentration was also lower in the subclinical hypothyroidism group than it was in the healthy control group (95.8 [71.7-126.3] vs 292.4 [210.2-426.5] pg/mL, P <0.001). However, there was no significant difference in FGF<em>19</em> level between the isolated thyroid autoantibody positive group and the healthy control group (252.0 [205.9-353.5] vs 292.4 [210.2-426.5] pg/mL, P >0.05). Also, serum thyroid stimulating hormone (TSH) was an independent predictor of FGF<em>19</em>. In conclusion, thyroid insufficiency but not thyroid autoimmunity may have impacted serum FGF<em>19</em> concentrations. As the role of FGF<em>19</em> is becoming more and more important in the pathogenesis of many metabolic diseases, we proposed that the thyroid hormone level should be taken into account when the serum concentration is explained. Further studies are needed to elucidate the role of FGF<em>19</em> in the development of hypothyroidism.

BACKGROUND

To determine the role of <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF)-<em>19</em> and FGF21 and the endocrine FGFs receptor system in the metabolic alterations that manifest in HIV-1-infected patients undergoing highly active antiretroviral treatment (HAART).

METHODS

Serum FGF<em>19</em> and FGF21 levels were determined in 4 groups of individuals as follows: (1) HIV-1-infected HAART patients with lipodystrophy (n = 38); or (2) without lipodystrophy (n = 34); (3) untreated (naive) HIV-1-infected patients (n = 34); and (4) healthy controls (n = 31). Serum FGF<em>19</em> levels were correlated with anthropometric, metabolic, HIV-1 infection-related, and HAART-related parameters and with FGF21 levels. The gene expression of FGF receptor 1 and the coreceptor β-Klotho was analyzed in adipose tissue from 10 individuals from each group.

RESULTS

Serum FGF<em>19</em> levels were significantly reduced in all groups of HIV-1-infected patients, whereas FGF21 levels were increased. FGF<em>19</em> levels were negatively correlated with insulin resistance and insulin levels and positively correlated with high-density lipoprotein cholesterol. FGF<em>19</em> was inversely correlated with cumulative exposure to nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor drugs. The expression of FGF receptor 1 and coreceptor β-Klotho was reduced in adipose tissue from all groups of HIV-infected patients.

CONCLUSIONS

FGF<em>19</em> levels are reduced in HIV-1-infected patients, in contrast with FGF21 levels. Impaired expression of the corresponding receptor and coreceptor, which mediate the actions of endocrine FGFs in adipose tissue, suggests a resistance to the metabolic effects of FGF<em>19</em> and FGF21 in HIV-1-infected patients. Considering the beneficial effects of endocrine FGFs on metabolism, the observed reduction in FGF<em>19</em> levels and decreased sensitivity to endocrine FGFs in adipose tissue may contribute to metabolic alterations in HIV-1-infected patients.

Glomerular lesions are considered one of the more detrimental pathologic changes associated with chronic rejection of renal allografts. To elucidate potential pathophysiologic mechanisms associated with transplant glomerulopathy, we examined the expression of acidic <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF-1) and its high-affinity receptors (FGFR) in both relevant renal transplant controls (n=5) and tissue from patients (n=<em>19</em>) who underwent nephrectomy following graft loss secondary to chronic rejection. In situ immunohistochemical analyses demonstrated minimal staining and distribution of FGFR and FGF-1, which was localized to the mesangial matrix in glomeruli from normal human kidneys. In situ hybridization failed to detect the presence of FGF-1 mRNA in control tissue. In contrast, each stage of the developing glomerular lesion associated with chronic rejection demonstrated the exaggerated appearance of FGF-1 protein in visceral and parietal epithelial cells. Intense staining for FGF-1 protein did not correlate with the increased appearance of FGF-1 mRNA, which was restricted to circulating inflammatory cells. Glomeruli in kidneys with findings of chronic rejection also exhibited increased immunodetection of both FGFR and PCNA in mesangial and epithelial cells. Immunogold labeling of chronically rejected visceral epithelial cells revealed both cytoplasmic and nuclear/localization of FGF-1, thereby establishing mitogenic potential of the <em>growth</em> <em>factor</em>. The enhanced appearance of both biologically active FGF-1 and FGFR suggests that this polypeptide may serve as an important mediator of <em>growth</em> responses associated with glomerular lesion development during chronic rejection.

BACKGROUND

Immunological mechanisms are suspected in sensory neuropathy (SN) occurring with systemic autoimmune diseases and in some idiopathic cases, but so far there are no antibodies (Abs) identifying these neuropathies.

METHODS

In the search for such specific antibodies, serum samples were collected from 106 patients with SN of these 72 fulfilled the diagnosis criteria of sensory neuronopathy (SNN) and 211 control subjects including patients with sensorimotor neuropathies, other neurological diseases (ONDs), systemic autoimmune diseases and healthy blood donors.

RESULTS

In the first step, a protein array with 8000 human proteins allowed identification of the intracellular domain of the <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor 3 (FGFR3) as a target of Abs in 7/16 SNN and 0/30 controls. In the second step, an ELISA method was used to test the 317 patients and controls for anti-FGFR3 Abs. Abs were detected in 16/106 patients with SN and 1/211 controls (p<0.001). Among the 106 patients with SN, anti-FGFR3 Abs were found in 11/38 patients with autoimmune context, 5/46 with idiopathic neuropathy and 0/22 with neuropathy of other aetiology (p=0.006). The only control patient with anti-FGFR3 Abs had lupus and no recorded neuropathy. Sensitivity, specificity, and positive and negative predictive values of anti-FGFR3 Abs for a diagnosis of idiopathic or dysimmune SN were <em>19</em>%, 99.6%, 94.1% and 77.3%, respectively. A cell-based assay confirmed serum reactivity against the intracellular domain of FGFR3. The neuropathy in patients with anti-FGF3 Abs was non-length dependent in 87% of patients and fulfilled the criteria of probable SNN in 82%. Trigeminal nerve involvement and pain were frequent features.

CONCLUSIONS

A anti-FGFR3 Abs identify a subgroup of patients with SN in whom an underlying autoimmune disorder affecting sensory neurons in the dorsal root and trigeminal nerve ganglia is suspected.

BACKGROUND

The enterohepatic pathway involving the <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) and bile acids (BA) has been linked with the etiology and remission of type 2 diabetes (T2D) following Roux-en-Y gastric bypass (RYGB) surgery. Specifically, diabetic patients had lower FGF<em>19</em> circulating levels but postoperative FGF<em>19</em> and BA levels were higher in diabetic patients that experience remission of T2D, as compared to non-diabetic patients and diabetic patients that do not experience remission. It has been proposed that this may be due to the direct flow of digestate-free bile acids into the ileum benefiting mostly T2D patients without severe diabetes.

RESULTS

We used a human colorectal cell line (LS174T) that endogenously expresses FGF<em>19</em>, real time PCR, and Elisas for precise quantitation of FGF<em>19</em> mRNA and secreted protein levels. We report here that BA and fractions of BA stimulated FGF<em>19</em> in vitro but this effect was partially blocked when BA were pre-incubated with a lipoprotein mix which emulates digested food. In addition, we show that FGF<em>19</em> mRNA was stimulated by meal replacement drinks (Ensure, Glucerna, SlimFast), non-fat milk, and coffee which has been linked with reduced risk for developing diabetes. Pure caffeine and the 5-hour Energy drink, on the other hand, decreased FGF<em>19</em> mRNA.

CONCLUSIONS

In summary, FGF<em>19</em> expression in vitro is modifiable by popular drinks suggesting that such approaches could potentially be used for modulating FGF<em>19</em> expression in humans.