Aging impairs the conduciveness of the lesioned hippocampus for robust survival of neurons derived from homotopic fetal cell grafts (Zaman and Shetty, Neuroscience 109:537-553, 2002), suggesting a need for graft augmentation in fetal graft-mediated therapeutic strategies for the lesioned aging hippocampus. We hypothesize that pretreatment and grafting of donor hippocampal CA3 cells with <em>fibroblast</em> <em>growth</em> <em>factor</em>-2 (FGF-2) considerably enhances graft neuronal integration into the lesioned CA3 region of the aging hippocampus. We employed the optical fractionator cell counting method and quantified the number of surviving cells and neurons derived from 5'-bromodoxyuridine-labeled embryonic day <em>19</em> CA3 cell grafts pre-treated and transplanted with FGF-2 into the lesioned CA3 region of the middle-aged and aged rat hippocampus at 4 days post-lesion. In both middle-aged and aged hippocampus, pre-treatment and transplantation of CA3 cell grafts with FGF-2 resulted in a robust yield of surviving cells (72-80% of injected cells) and neurons (62-69% of injected cells) from grafts. The overall yield was dramatically greater than the yield observed earlier from standard (untreated) fetal CA3 cell grafts into the lesioned aging hippocampus but was highly comparable to that observed for standard fetal CA3 cell grafts into the lesioned young hippocampus (Zaman and Shetty, Neuroscience 109:537-553, 2002). Thus, a robust neuronal integration from fetal CA3 cell grafts can be achieved into the lesioned CA3 region of the aging hippocampus with a simple pre-treatment and grafting of donor fetal CA3 cells with FGF-2. These results have implications toward the development of suitable cell grafting strategies for repair of the lesioned aging hippocampus in neurodegenerative diseases, particularly the temporal lobe epilepsy, stroke, and Alzheimer's disease.

Silent corticotroph adenomas (SCAs) represent a distinct subset of clinically non-functioning pituitary adenomas. There are two variants of SCA; type I are densely granulated basophilic tumors and type II are sparsely granulated and chromophobic tumors. SCAs are known to be aggressive than the more common non-functioning gonadotroph adenomas (NFGAs). Cell-matrix interactions play an important role in the pathogenesis of pituitary adenomas. In this study, we compared <em>19</em> SCAs and 50 NFGAs with known <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor-4 (FGFR4) status using semi-quantitative immunohistochemistry to localize β1-integrin, osteopontin, and matrix metalloproteinase-1 (MMP-1) as cytoplasmic, membranous, or mixed cytoplasmic-membranous staining to achieve scores of 1-4. Staining for β1-integrin was significantly higher in SCAs (100 %, score 3.3) than in NFGAs (96 %; score 2.6) (p = 0.0482); there was no statistical difference within subgroups of SCA (type II score 3.4; type I score 2.8) (p = 0.2663). Osteopontin immunoreactivity was also higher in SCAs (100 %, score 3.7) than in NFGAs (42 %, score 0.8) (p = 0.0001); there was no statistical difference within subgroups of SCA (type II score 3.6; type I score 3.9) (p = 0.2787). In contrast, MMP-1 immunoreactivity was lower in SCAs (89 %; score 2.5) than in NFGAs (98 %; score 3.6) (p = 0.0005); there was no statistical difference within subgroups of SCA (type II score 2.7; type I score 2.0) (p = 0.30704). The MMP-1 results correlated with FGFR4 expression (NFGA 96 %, type II SCA 71 %, type I SCA 40 %). Our data indicate that the biological aggressivity of SCAs compared with NFGA may be due to high osteopontin expression; in contrast, high MMP-1 is characteristic of NFGAs that also express more FGFR4. Further investigations are warranted to clarify the underlying regulatory mechanisms of these markers. The high osteopontin or FGFR4/MMP-1 expression levels in SCAs and NFGAs, respectively, indicate the potential for therapeutic strategies targeting osteopontin or FGFR4/MMP-1 for inoperable tumors of these types.

OBJECTIVE

That heparin binding epidermal growth factor-like growth factor (HB-EGF) heals chronic tympanic membrane (TM) perforations at higher rates than fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF) in an animal model.

BACKGROUND

A nonsurgical treatment for chronic TM perforation would benefit those unable to access surgery or those unable to have surgery, as well as reducing the cost of tympanoplasty. Growth factor (GF) treatments have been reported in the literature with variable success with the lack of a suitable animal providing a major obstacle.

METHODS

The GFs were tested in a validated mouse model of chronic TM perforation. A bioabsorbable hydrogel polymer was used to deliver the GF at a steady concentration as it dissolved over 4 weeks. A control (polymer only, n = 18) was compared to polymer loaded with HB-EGF (5 μg/ml, n = 18), FGF2 (100 μg/ml, n = 19), and EGF (250 μg/ml, n = 19). Perforations were inspected at 4 weeks.

RESULTS

The healing rates, as defined as 100% perforation closure, were control (5/18, 27.8%), HB-EGF (15/18, 83.3%), FGF2 (6/19, 31.6%), and EGF (3/19, 15.8%). There were no differences between FGF2 (p = 0.80) and EGF (p = 0.31) with control healing rates. HB-EGF (p = 0.000001) showed a significant difference for healing. The HB-EGF healed TMs showed layers similar to a normal TM, whereas the other groups showed a lack of epithelial migration.

CONCLUSIONS

This study confirms the advantage of HB-EGF over two other commonly used growth factors and is a promising nonsurgical treatment of chronic TM perforations.

Farnesoid X receptor (FXR) induces <em>fibroblast</em> <em>growth</em> <em>factor</em> 15 (FGF15; human ortholog FGF<em>19</em>) in the gut to potently inhibit bile acid (BA) synthesis in the liver. FXR activation in hepatic stellate cells (HSCs) reduces liver fibrosis (LF). Fgf15^-/- mice develop attenuated LF, but the underlying mechanisms for this protection are unclear. We hypothesized that FGF15/<em>19</em> functions as a profibrotic mediator or mitogen to HSCs and increased BAs in Fgf15^-/- mice leads to enhanced FXR activation in HSCs, subsequently reducing fibrogenesis. In this study, complimentary in vivo and in vitro approaches were used: (1) CCl₄ -induced LF model in wild type (WT), Fgf15^-/- , and Fgf15 transgenic (TG) mice with BA levels modulated by feeding cholestyramine- or cholic acid-containing diets; (2) analysis of primary HSCs isolated from WT and Fgf15^-/- mice; and (3) treatment of a human HSC line, LX-2, with FXR activators and/or recombinant FGF<em>19</em> protein. The results showed that Fgf15^-/- mice had lower basal collagen expression, which was increased by BA sequestration. CCl₄ induced fibrosis with similar severity in all genotypes; however, cholestyramine increased fibrosis severity only in Fgf15^-/- mice. HSCs from Fgf15^-/- mice showed increased FXR activity and reduced expression of profibrotic mediators. In LX-2 cells, FXR activation increased peroxisome proliferator-activated receptor gamma activity and reduced proliferation. FGF<em>19</em> activated both signal transducer and activator of transcription 3 and c-Jun N-terminal kinase pathways and reduced nuclear <em>factor</em> kappa-light-chain-enhancer of activated B cells signaling without increasing fibrogenic gene expression or cell proliferation. Conclusion: FGF15/<em>19</em> does not act as a direct profibrotic mediator or mitogen to HSCs in our models, and the protection against fibrosis by FGF15 deficiency may be mediated through increased BA activation of FXR in HSCs.

An excess of fecal bile acids (BAs) is thought to be one of the mechanisms for diarrhea-predominant irritable bowel syndrome (IBS-D). However, the <em>factors</em> causing excessive BA excretion remain incompletely studied. Given the importance of gut microbiota in BA metabolism, we hypothesized that gut dysbiosis might contribute to excessive BA excretion in IBS-D. By performing BA-related metabolic and metagenomic analyses in 290 IBS-D patients and 89 healthy volunteers, we found that 24.5% of IBS-D patients exhibited excessive excretion of total BAs and alteration of BA-transforming bacteria in feces. Notably, the increase in Clostridia bacteria (e.g., C. scindens) was positively associated with the levels of fecal BAs and serum 7α-hydroxy-4-cholesten-3-one (C4), but negatively correlated with serum <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) concentration. Furthermore, colonization with Clostridia-rich IBS-D fecal microbiota or C. scindens individually enhanced serum C4 and hepatic conjugated BAs but reduced ileal FGF<em>19</em> expression in mice. Inhibition of Clostridium species with vancomycin yielded opposite results. Clostridia-derived BAs suppressed the intestinal FGF<em>19</em> expression in vitro and in vivo. In conclusion, this study demonstrates that the Clostridia-rich microbiota contributes to excessive BA excretion in IBS-D patients, which provides a mechanistic hypothesis with testable clinical implications.

BACKGROUND

This phase 2 study investigated the efficacy and safety of dovitinib (TKI258), a receptor tyrosine kinase inhibitor with potent activity against fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR), in locally advanced or metastatic thyroid cancer patients.

METHODS

Patients with advanced thyroid cancer that was refractory or not appropriate for (131)I received dovitinib orally, 500mg once daily for five consecutive days, followed by a 2-day rest every week. The primary end-point was objective response rate. Secondary end-points were progression-free survival (PFS), overall survival (OS), duration of response, changes in tumour markers and safety.

RESULTS

Between January 2013 and October 2014, a total of 40 patients were enrolled. There were 23 (57.5%) papillary thyroid cancer, 12 (30%) medullary thyroid cancer and 5 (12.5%) follicular thyroid cancer patients. One patient had withdrawn consent before the administration of dovitinib. The overall response rate was 20.5% (8/39) and disease control rate was 69.1% (26/39). Median PFS was 5.4 months (95% confidence interval (CI), 2.0-8.8) and median OS was not reached with 8.4 months follow-up duration. Common treatment-related adverse events were diarrhoea (53.8%), anorexia (35.8%), vomiting (25.6%), fatigue (23%) and nausea (20.5%), most of which were grade 1 or 2. There were no grade 4 events or treatment-related deaths. Dose interruption occurred in 12 (30.7%) patients, and 19 (48.7%) patients experienced dose reduction due to adverse events.

CONCLUSIONS

Dovitinib has a modest activity with manageable toxicity in locally advanced or metastatic thyroid cancer.

The importance of cancer-associated <em>fibroblasts</em> (CAFs) in cancer biology has been recently highlighted owing to their critical roles in cancer <em>growth</em>, progression, metastasis, and therapeutic resistance. We have previously established a primary culture of breast cancer cells, which showed epithelial-mesenchymal transition and cancer stem cell-like properties. In this study, we found that the primary culture also showed CAF-like properties. For example, hypoxia inducible <em>factor</em> 1α (HIF1A) and its downstream genes, nuclear <em>factor</em>-kappa B2 (NF-κB2) and BCL2/adenovirus E1B <em>19</em> kd-interacting protein 3 (BNIP3), and many enzymes involved in glycolysis, such as GAPDH, LDH, PGAM1, and PKM2, were highly overexpressed in the primary culture. Moreover, media conditioned with the primary culture cells enhanced the <em>growth</em> of breast cancer cells. Similar to previous CAF studies, this enhancement suggested to be occurred through <em>fibroblast</em> <em>growth</em> <em>factor</em> signaling. This MCKH primary culture cell, which showed simultaneous expression of tumorigenic and CAF properties, offers a unique experimental system for studying the biology of CAFs.

We previously detected immunoreactive <em>fibroblast</em> <em>growth</em> <em>factor</em> 2 (FGF-2) in maternal and fetal circulations. Here, we determined whether the amounts of FGF-2 in term maternal serum, cord serum, and amniotic fluid were altered in pregnancies complicated by diabetes, as these are associated with a higher incidence of fetal macrosomia and increased placental size. Serum and amniotic fluid were collected at term from normal pregnancies (n = 17), women with pregestational insulin-dependent diabetes (n = 37; group A), patients with previously undiagnosed diabetes (n = 32; group B), women with gestational diabetes (n = 85; group C), and women with a milder form of glucose intolerance in pregnancy (n = 16; group D). Mean newborn weight and length, and placental weight did not significantly differ between normal and diabetic pregnancies, although the placental weight tended to be higher in the latter. However, 24% of the infants in group A and <em>19</em>% in group B had a birth weight in excess of the 90th percentile. Levels of insulin in cord serum and amniotic fluid in groups A and B were significantly elevated compared to control values. FGF-2 was extracted from serum and amniotic fluid by heparin-Sepharose affinity chromatography and subjected to Western blot analysis or quantified by specific RIA. Western blot analysis of maternal serum, cord serum, and amniotic fluid from diabetic pregnant patients revealed, in each case, a single immunoreactive FGF-2 species of 18 kilodaltons; this was absent from nonpregnancy serum. In normal term pregnancies, the mean immunoreactive FGF-2 level in cord serum was 1<em>19</em> +/- 28 pmol/L, and that in amniotic fluid was 91 +/- 35 pmol/L. Values were significantly increased (2- to 4-fold) in both cord serum and amniotic fluid for all groups of diabetic patients. The mean FGF-2 level in normal term maternal serum was 104 +/- 24 pmol/L, and this was significantly increased in diabetic patients in groups B and C. The amount of FGF-2 in maternal serum showed a positive correlation with newborn weight and length, and placental weight (P < 0.05 or better, by Spearman rank correlation), and significant positive correlations also existed between the amounts of FGF-2 in cord serum and newborn or placental weight. The results suggest that the FGF-2 levels in maternal serum, cord serum, and amniotic fluid at term are elevated in pregnancies complicated by diabetes, and that the amounts of FGF-2 in maternal serum and cord serum are correlated with fetal and placental size.

Previous research has shown that p-EGFR (particularly mutated EGFR) may activate <em>fibroblast</em> <em>growth</em> <em>factor</em>-inducible 14 (Fn14) expression in non-small cell lung cancer (NSCLC), and the JAK/STAT signaling pathway may participate in this process. Thus, in order to verify this hypothesis, correlations among the expression levels of EGFR Del <em>19</em>, Fn14 and JAK/STAT were detected and analyzed. The expression and location of these molecules were assessed using IHC, immunohistofluorescence, RT-qPCR and western blotting. The differences and correlations in the expression of these molecules and clinical pathological characteristics were statistically analyzed using Mann-Whitney U, Kruskal‑Wallis H and cross-table tests. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of EGFR Del <em>19</em> and Fn14 expression on survival. Data showed that EGFR Del <em>19</em>, Fn14 and JAK1/STAT1 expression was significantly related with differentiation, pTNM stage and lymphatic metastasis (P<0.01) and there was a marked correlation of EGFR Del <em>19</em>, Fn14 and JAK1/STAT1 expression with histological type, differentiation, pTNM stage of NSCLC (P<0.05; rs>0.3). Immunohistofluorescence showed that there was a co-localization phenomenon between EGFR Del <em>19</em> and Fn14 expression. NSCLC patients with higher EGFR Del <em>19</em>/Fn14 expression had a significantly worse prognosis than those with lower EGFR Del <em>19</em>/Fn14 expression (P=0.0155/P=0.001; log-rank test). The multivariate analysis indicated that Fn14 expression may be an independent prognostic <em>factor</em> in NSCLC with EGFR Del <em>19</em> [hazard ratio (HR), 0.326; P=0.042]. Therefore, our results indicate that EGFR Del <em>19</em> may promote Fn14 and JAK1/STAT1 expression in NSCLC and Fn14 may serve as a prognostic biomarker in NSCLC with EGFR Del <em>19</em>.

It is now clear that angiogenesis and angiogenesis <em>factors</em> are important in the pathogenesis of haematological malignancies. High pretreatment levels of serum basic <em>fibroblast</em> <em>growth</em> <em>factor</em> have been shown to be associated with poor prognosis in patients with non-Hodgkin's lymphoma. The aim of this study was to evaluate whether non-Hodgkin's lymphoma cells express basic <em>fibroblast</em> <em>growth</em> <em>factor</em> and/or its receptor (<em>fibroblast</em> <em>growth</em> <em>factor</em> receptor-1) and whether basic <em>fibroblast</em> <em>growth</em> <em>factor</em> expression correlates with basic <em>fibroblast</em> <em>growth</em> <em>factor</em> serum levels, intratumoral microvessel density, and patient outcome. We measured basic <em>fibroblast</em> <em>growth</em> <em>factor</em> by enzyme-linked immunosorbent assay in sera taken from 58 patients with non-Hodgkin's lymphoma before treatment and in <em>19</em> of them also after treatment. Pathological specimens at diagnosis were evaluated by immunohistochemistry staining using polyoclonal antibody against <em>factor</em>-VIII-related antigen, basic <em>fibroblast</em> <em>growth</em> <em>factor</em> and <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor-1 to determine the expression of the microvessel count and basic <em>fibroblast</em> <em>growth</em> <em>factor</em> and <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor-1. The lymphoma specimens demonstrated positive staining for basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (in 23%) and <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor-1 (in 58.5%). The patients who expressed basic <em>fibroblast</em> <em>growth</em> <em>factor</em> had a significantly worse progression-free and overall survival than those who did not (P=0.003 and P=0.03 respectively), while patients expressing <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor-1 were less likely to achieve complete remission than those lacking the receptor (33% vs 65%, P=0.047). There was no correlation of basic <em>fibroblast</em> <em>growth</em> <em>factor</em> staining with either serum basic <em>fibroblast</em> <em>growth</em> <em>factor</em> levels or microvessel count. Basic <em>fibroblast</em> <em>growth</em> <em>factor</em> serum levels did not change significantly after treatment These results suggest that non-Hodgkin's lymphoma specimens express basic <em>fibroblast</em> <em>growth</em> <em>factor</em> and its receptor (<em>fibroblast</em> <em>growth</em> <em>factor</em> receptor-1) and this expression is associated with poor patient outcome.

OBJECTIVE

Bile acid (BA) synthesis in the liver is regulated by <em>Fibroblast</em> <em>Growth</em> <em>Factor</em> <em>19</em> (FGF<em>19</em>) secreted from the ileum as an enterohepatic feedback mechanism. Although FGF<em>19</em> mRNA is absent in normal liver, FGF<em>19</em> gene expression was reported to increase in response to both extrahepatic and intrahepatic cholestasis. The impact of upregulated FGF<em>19</em> expression on BA synthesis is unclear and the overall role of circulating FGF<em>19</em> and BA synthesis under cholestatic conditions needs to be further investigated.

METHODS

BA synthesis was directly quantified by measuring serum concentrations of 7alpha-hydroxycholest-4-en-3-one (C4), along with serum FGF<em>19</em> and other parameters, in 44 patients with primary biliary cirrhosis (PBC) and 10 healthy subjects.

RESULTS

Serum C4 were substantially lower, while those of FGF<em>19</em> were higher, in cirrhotic PBC patients, as compared to those of either healthy or non-cirrhotic PBC patients. Analyses of the relationships between circulating FGF<em>19</em>, BA synthesis and cholestasis revealed that circulating FGF<em>19</em> was strongly correlated with BA synthesis (r = -0.735, p<0.0001) and the severity of cholestasis (r = 0.590, p<0.001). Moreover, BA synthesis was found to be strongly correlated with the degree of cholestasis (r = 0.522, p = 0.0005).

CONCLUSIONS

These findings demonstrate that the regulation of BA synthesis in response to cholestasis is primarily controlled by circulating FGF<em>19</em> and that under cholestatic conditions, the FGF<em>19</em>-BA synthesis feedback mechanism remains intact. Administering FGF<em>19</em>, or suitable mimetic, as a pharmacological intervention to increase circulating levels of FGF<em>19</em> and suppress BA synthesis by inhibiting CYP7A1 gene expression is likely to provide therapeutic benefits for many PBC patients.

The <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF) family comprises a number of polypeptides which share a common homology core region. FGF-23, produced by osteoblasts and osteocytes, belongs to the FGF-<em>19</em> subfamily and serves as the main phosphatonine. Two forms of circulating FGF-23 are detectable in serum: full-length FGF-23--intact FGF-23 (iFGF-23), which is biologically active, and the inactive C-terminal FGF-23 (cFGF-23). FGF-23 with a coreceptor (Klotho protein) inhibits renal phosphate reabsorption and synthesis of calcitriol by reducing 1alpha-hydroxylase (CYP27B1) activity, reducing vitamin D-dependent phosphate intestinal absorption. High phosphorus intake, 1,25-dihydroxyvitamin D3 and PTH are the main stimuli for FGF-23 secretion. Impaired FGF-23 metabolism is involved in phosphate disturbances manifesting as rickets or osteomalacia or increased tissue calcinosis. FGF-23 may be also produced by some tumors leading to hypophosphatemia. Both cFGF-23 and iFGF-23 concentrations start to increase with mild impairment of the glomerular filtration rate in stage 2 or 3 of chronic kidney disease (CKD) as a consequence of the increased FGF-23 production. It seems that enhanced FGF-23 secretion may constitute a protective mechanism against enhanced phosphate accumulation in the early stages of CKD. However, it may lead to calcitriol deficiency and escalation of secondary hyperparathyroidism. Increased FGF-23 level is supposed to be an independent <em>factor</em> increasing mortality of CKD patients. There is ambiguous data if FGF-23 only reflects disturbances in calcium-phosphate metabolism or if it exerts a detrimental effect itself by diminishing calcitriol synthesis, inducing cell proliferation or acting through low-affinity, Klotho-independent receptors in the heart and endothelium. So far, little evidence supports direct FGF-23 toxicity.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> (FGF) has been reported to increase the volume of callus in a fracture model of rats. There are, however, no reports of successful repair of segmental bony defects by application of an FGF solution. In this study, the effects of basic FGF on the repair of segmental bony defects in the rabbit femur were examined. Minipellet, a new drug delivery system using atelocollagen, was employed to ensure effective delivery of FGF. Segmental bony defects (10 mm in length) were created in the right femurs of <em>19</em> rabbits. In pilot studies, no defects of this size healed spontaneously within 6 weeks. Bones were stabilized with miniexternal fixators. Minipellets containing basic FGF were implanted between fragments so as to bridge the two fragments. The healing processes were monitored radiographically and studied histologically. In rabbits in which FGF was added to the defect site at doses of 1.4 microgram or higher, approximately 90% of the defects were filled with new bone and cartilage within 6 weeks after minipellet implantation. In rabbits receiving placebo minipellets, however, approximately 15% of the defects were filled by callus within 6 weeks. Furthermore, this callus did not change into mature bone. An injection of 2 microgram of FGF solution to bony defects had no effect on the repair of segmental bony defects. These findings suggest that FGF plays a role in the production of adequate volumes of callus particularly in the initial stages of fracture healing and that sustained local release enables FGF to be effective at a low dose. In summary, large segmental bony defects healed after insertion of low-dose FGF minipellets. An adequate dose of FGF and an appropriate delivery system are required for successful healing of large bony defects. These findings imply the potential value of FGF minipellets in clinical practice.

Obesity-induced fat ectopic deposition results in mitochondrial dysfunction and oxidative stress in skeletal muscle, which could impair the quality and function of the skeletal muscle. Human <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) acts as a vital metabolic regulator of bile acid synthesis and metabolic homeostasis. Recent studies have shown that FGF<em>19</em> regulates skeletal muscle mass through the enlargement of muscle fiber size and protects muscles from atrophy. However, the role of FGF<em>19</em> in regulating mitochondrial function and the antioxidant response in skeletal muscle remains unknown. Therefore, we investigated the effect of FGF<em>19</em> on palmitic acid (PA)-induced mitochondrial dysfunction and oxidative stress in C2C12 cells. In this study, we found that FGF<em>19</em> can increase the mRNA and protein expression levels of mitochondrial biogenesis regulators (PGC-1α, Nrf-1, and TFAM) and antioxidant response regulators (Nrf-2 and HO-1), alleviating PA-induced mitochondrial dysfunction and oxidative stress. However, the regulatory effect of FGF<em>19</em> was blocked by Compound C, an AMP-activated protein kinase (AMPK) inhibitor, and siRNA knockdown of PGC-1a. Taken together, these findings indicate that FGF<em>19</em> might promote mitochondrial biogenesis and antioxidant response via the AMPK/PGC-1α pathway, attenuating the effect of PA on mitochondrial dysfunction and oxidative stress; therefore, FGF<em>19</em> might be a potential therapeutic target for the effects of obesity on skeletal muscle.

Diabetes affects cardiac structure and function, where it leads to diabetic cardiomyopathy. Reactive oxygen species (ROS) produced by oxidative stress play an important role in the development of diabetic cardiomyopathy. <em>Fibroblast</em> <em>growth</em> <em>factor</em> (FGF) <em>19</em>, an enterokine, is synthesized and released into the ileum. In the present study, we revealed that FGF<em>19</em> induced an antioxidant response through stimulating the expression of nuclear erythroid <em>factor</em> 2 (NE-F2)-related <em>factor</em> 2 (Nrf2) and as well as reducing ROS production through the AMPK signaling pathway. Additionally, AMPK inhibition by the AMPK-specific inhibitor compound C decreased Nrf2 and heme oxygenase-1 (HO-1) protein expression. Taken together, these results suggested that FGF<em>19</em>, through the anti-oxidative defense system, attenuated the development of diabetic cardiomyopathy and restored cardiac function.

To study the tear cytokine and the conjunctival and oral mucosal marker profile in chronic ocular Stevens-Johnson syndrome (SJS) and their alteration following mucous membrane grafting (MMG) for lid margin keratinisation (LMK).

In a 1-year prospective study, SJS cases (n=25) and age-matched/sex-matched healthy controls (n=25) were recruited. Tear specimen (Schirmer's strip), conjunctival and oral mucosal imprints were collected from controls and SJS cases pre-MMG and post-MMG (at first follow-up, n=17). Tear cytokines were profiled using 27-bioplex array. Transforming <em>growth</em> <em>factor</em>-beta (TGF-β)-mediated extracellular matrix changes in conjunctival and oral mucosal cells were analysed by gene expression studies. 30 RESULTS: Tear cytokine profiling of chronic SJS cases at pre-MMG stage revealed significant upregulation of cytokines granulocyte-macrophage colony-stimulating <em>factor</em> (GM-CSF), interleukin (IL)-8, IL-1β, monocyte chemoattractant protein-1, IL-15, IL-2, IL-17A and basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (bFGF) with downregulation of IP-10 (interferon gamma-induced protein 10), tumour necrosis <em>factor</em>-α, interferon-γ, IL-10, vascular endothelial <em>growth</em> <em>factor</em>, regulated upon activation normal T-cell expressed and secreted (RANTES), IL-7, IL-12p70 and IL-13, with maximal increase in GM-CSF and maximal downregulation of IP-10, respectively. Of these, IL-2, IL-15, bFGF and IL-17A showed significant correlation with disease severity, pre-MMG. Conjunctival cells pre-MMG showed increase in TGF-β1, TGF-βRII, connective tissue <em>growth</em> <em>factor</em> and collagen-III gene expression by 10, 67, 173 and 184 folds, respectively, which dropped to 1.3, 11, 13.5 and <em>19</em> folds correspondingly, post-MMG. However, their expressions in oral mucosa were negligible.

A proinflammatory, profibrotic, antiapoptotic ocular surface milieu characterises chronic ocular SJS. IP-10, an antifibrotic cytokine was noted to be maximally downregulated, unlike in other forms of chronic dry eye disease. The alterations in the ocular surface are seen to reverse largely with MMG for LMK.

The liver has an extraordinary regenerative capacity rapidly triggered upon injury or resection. This response is intrinsically adjusted in its initiation and termination, a property termed the "hepatostat". Several molecules have been involved in liver regeneration, and among them bile acids may play a central role. Intrahepatic levels of bile acids rapidly increase after resection. Through the activation of farnesoid X receptor (FXR), bile acids regulate their hepatic metabolism and also promote hepatocellular proliferation. FXR is also expressed in enterocytes, where bile acids stimulate the expression of <em>fibroblast</em> <em>growth</em> <em>factor</em> 15/<em>19</em> (FGF15/<em>19</em>), which is released to the portal blood. Through the activation of FGFR4 on hepatocytes FGF15/<em>19</em> regulates bile acids synthesis and finely tunes liver regeneration as part of the "hepatostat". Here we review the experimental evidences supporting the relevance of the FXR-FGF15/<em>19</em>-FGFR4 axis in liver regeneration and discuss potential therapeutic applications of FGF15/<em>19</em> in the prevention of liver failure. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Cholestatic liver diseases are hereditary or acquired disorders with impaired hepatic excretion and enterohepatic circulation of bile acids and other cholephiles. The distinct pathological mechanisms, particularly for the acquired forms of cholestasis, are not fully revealed, but advances in the understanding of the molecular mechanisms and identification of key regulatory mechanisms of the enterohepatic circulation of bile acids have unraveled common and central mechanisms, which can be pharmacologically targeted. This overview focuses on the central roles of farnesoid X receptor, <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em>, and apical sodium-dependent bile acid transporter for the enterohepatic circulation of bile acids and their potential as new drug targets for the treatment of cholestatic liver disease.

This study was to enrich prostate cancer stem cells (PrCSC) from primary prostate cancer cultures (PPrCC). Primary prostate cancer cells were amplified in keratinocyte serum-free medium with epidermal <em>growth</em> <em>factor</em> (EGF) and bovine pituitary extract (BPE), supplemented with leukemia inhibitory <em>factor</em> (LIF), stem cell <em>factor</em> (SCF) and cholera toxin. After amplification, cells were transferred into ultra-low attachment dishes with serum-free DMEM/F12 medium, supplemented with EGF, basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (bFGF), bovine serum albumin (BSA), insulin, and N2 nutrition. Expression of cell-type-specific markers was determined by RT-qPCR and immunostaining. Tumorigenicity of enriched PrCSC was determined by soft agar assay and xenograft assay in NOD/SCID mice. Biopsy samples from <em>19</em> confirmed prostate cancer patients were used for establishing PPrCC, and 18 cases (95%) succeeded. Both basal marker (CK5) and luminal markers (androgen receptor and CK8) strongly co-expressed in most of PPrCC, indicating their basal epithelial origin. After amplification under adherent culture condition in vitro, transient amplifying cells were the dominant cells. Sphere formation efficiency (SFE) of passaged PPrCC was about 0.5%, which was 27 times lower than SFE of LNCaP (13.67%) in the same condition. Compared with adherent cells from PPrCC, prostasphere from PPrCC showed up regulated stem cell markers and increased tumorigenic potential in soft-agar assay. However, spheroid cells from PPrCC prostasphere failed to initiate tumor in xenograft assay in 6 months. Thus, PPrCC can be established and amplified from prostate cancer biopsy samples. Our modified sphere culture system can enrich PrCSC from PPrCC.

BACKGROUND

Advanced hepatocellular carcinoma (HCC) is a neoplastic disease with a very bad prognosis and increasing worldwide incidence. HCCs are resistant to conventional chemotherapy and the multikinase inhibitor sorafenib is the only agent that has shown some clinical efficacy. It is therefore important to identify key molecular mechanisms driving hepatocarcinogenesis for the development of more efficacious therapies. However, HCCs are heterogeneous tumors and different molecular subclasses have been characterized. This heterogeneity may underlie the poor performance of most of the targeted therapies so far tested in HCC patients. The <em>fibroblast</em> <em>growth</em> <em>factor</em> 15/<em>19</em> (FGF15/<em>19</em>), FGF receptor 4 (FGFR4) and beta-Klotho (KLB) correceptor signaling system, a key regulator of bile acids (BA) synthesis and intermediary metabolism, is emerging as an important player in hepatocarcinogenesis. Key Messages: Aberrant signaling through the FGF15/<em>19</em>-FGFR4 pathway participates in the neoplastic behavior of HCC cells, promotes HCC development in mice and its overexpression has been characterized in a subset of HCC tumors from patients with poorer prognosis. Pharmacological interference with FGF15/<em>19</em>-FGFR4 signaling inhibits experimental hepatocarcinogenesis, and specific FGFR4 inhibitors are currently being tested in selected HCC patients with tumoral FGF<em>19</em>-FGFR4/KLB expression.

CONCLUSIONS

Interference with FGF<em>19</em>-FGFR4 signaling represents a novel strategy in HCC therapy. Selection of candidate patients based on tumoral FGF<em>19</em>-FGFR4/KLB levels as biomarkers may result in increased efficacy of FGFR4-targeted drugs. Nevertheless, attention should be paid to the potential on target toxic effects of FGFR4 inhibitors due to the key role of this signaling system in BA metabolism.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and it is the third leading cause of cancer-related deaths worldwide. Recently, aberrant signaling through 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) axis has been implicated in HCC. Here, we describe the development of FGF401, a highly potent and selective, first in class, reversible-covalent small-molecule inhibitor of the kinase activity of FGFR4. FGF401 is exquisitely selective for FGFR4 versus the other FGFR paralogues FGFR1, FGFR2, FGFR3 and all other kinases in the kinome. FGF401 has excellent drug-like properties showing a robust pharmacokinetic / pharmacodynamics / efficacy relationship, driven by a fraction of time above the phospho-FGFR4 IC90 value. FGF401 has remarkable anti-tumor activity in mice bearing HCC tumor xenografts and patient-derived xenograft models that are positive for FGF<em>19</em>, FGFR4 and KLB. FGF401 is the first FGFR4 inhibitor to enter clinical trials, and a PhI/II study is currently ongoing in HCC and other solid malignancies.

Efforts to explain the possible effects of blood transfusion on the recurrence of colorectal cancer have been based entirely on the immunosuppressive effects of blood transfusion. However, the relationship between solid tumour development and the immune system is inconclusive. We have investigated an alternative mechanism involving the potential role of <em>growth</em> <em>factors</em> in this phenomenon. Using a human <em>fibroblast</em>: [125I]deoxyuridine uptake mitogenesis assay, the relative amounts of <em>growth</em> <em>factor</em> in the plasma of stored blood were measured. There was a progressive increase in mitogenesis from day 0 (n = 6) to day 28 (n = 6; P less than 0.001, Mann-Whitney U test). The effect of <em>growth</em> <em>factors</em> on the development of liver and intraperitoneal metastases was studied in Hooded Lister rats. Following an intraportal injection of 10(5) MC28 tumour cells, the experimental group (n = 25) received 2 ml of syngeneic serum intravenously for 4 days. Likewise, colonic anastomoses were performed on omentectomized rats and the peritoneal cavity seeded with 10(3) cells. The experimental groups (n = 20) received either 2 ml serum intravenously repeatedly or 3 ml serum intraperitoneally (n = <em>19</em>). There was no significant increase in liver metastases or peritoneal disease following intravenous infusion of serum but serum delivered intraperitoneally resulted in a significant increase in tumour from 22 per cent in the controls to 89 per cent in the study group (P less than 0.01). <em>Growth</em> <em>factors</em> released from platelets following blood loss into the peritoneal cavity may be important in enhancing local recurrence of colorectal cancer.

<strong class="sub-title">Purpose:</strong> NCI-MATCH is a nationwide, histology-agnostic, signal-finding, molecular profile-driven trial for patients with refractory cancers, lymphomas, or myelomas. Patients with tumors harboring actionable aberration(s) in <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor (<i>FGFR</i>) <i>1-3</i> were treated with AZD4547, an oral FGFR1-3 inhibitor.

Methods: Patients' tumors were screened by next-generation sequencing for predefined FGFR amplification, activating mutations, or fusions. Patients were treated with AZD4547, 80 mg orally twice daily until progression of disease or drug intolerance. A response rate of 16% was considered promising.

Results: Between July 2016 and June 2017, 70 patients were assigned and 48 received protocol therapy and are eligible for analysis. Patients' tumors harbored FGFR1 or FGFR2 amplification (n = 20), FGFR2 or FGFR3 single-nucleotide variants (n = 19), or FGFR1 or FGFR3 fusions (n = 9). The most common primary tumors were breast (33.3%), urothelial (12.5%), and cervical cancer (10.4%).Grade 3 adverse events were consistent with those described in previous clinical trials. Confirmed partial responses were seen in 8% (90% CI, 3% to 18%) and were observed only in patients whose tumors harbored FGFR1-3 point mutations or fusions. Stable disease was observed in 37.5% (90% CI, 25.8% to 50.4%). The median progression-free survival (PFS) was 3.4 months, and the 6-month PFS rate was 15% (90% CI, 8% to 31%). For patients with tumors harboring FGFR fusions, the response rate was 22% (90% CI, 4.1% to 55%), and 6-month PFS rate was 56% (90% CI, 31% to 100%).

Conclusion: Preliminary signals of activity appeared to be limited to cancers harboring FGFR activating mutations and fusions, although AZD4547 did not meet the primary end point. Different FGFR somatic alterations may confer different levels of signaling potency and/or oncogene dependence.

Background Preclinical studies suggest that imatinib resistance in gastrointestinal stromal tumor (GIST) can be mediated by MAP-kinase activation via <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF) signaling. In FGF stimulated GIST cell lines, BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib, was cytotoxic and superior to imatinib therapy alone. In FGF-dependent GIST, the combination of BGJ398 and imatinib may provide a mechanism to overcome imatinib resistance. Methods This phase Ib study of BGJ398 and imatinib was performed in patients with imatinib refractory advanced GIST. A standard 3 + 3 dosing schema was utilized to determine the recommended phase II dose (RP2D). Two treatment schedules were evaluated incorporating imatinib 400 mg daily in combination with (A) BGJ398 daily 3 weeks on, 1 week off or (B) BGJ398 daily 1 week on, 3 weeks off. Results 16 patients enrolled. The median age was 54 years (range: 44-77), 81% were male, and the median number of lines of prior therapy was 4 [range: 2-6, 13 patients had ≥3 prior therapies]. 12 patients received treatment on schedule A [BGJ398 dose range: 25 - 75 mg]: 2 patients experienced dose limiting toxicities (DLT) (n = 1, myocardial infarction & grade (G)4 CPK elevation; n = 1, G3 ALT elevation) on schedule A (BGJ398 75 mg), significant hyperphosphatemia, an on-target effect, was not observed, implying the maximum tolerated dose was below the therapeutic dose. Following protocol amendment, 4 patients enrolled on schedule B [BGJ398 dose range: 75 - 100 mg]: no DLTs were observed. The most common treatment related adverse events occurring in >15% of patients included CPK elevation (50%), lipase elevation (44%), hyperphosphatemia (24%), anemia (<em>19</em>%), and peripheral edema (<em>19</em>%). Among the 12 evaluable patients, stable disease (SD) was the best response observed in 7 patients by RECIST v1.1 and 9 patients by CHOI. Stable disease ≥ 32 weeks was observed in 3 patients (25%). Median progression free survival was 12.1 weeks (95% CI 4.7-<em>19</em>.5 weeks). Conclusions Toxicity was encountered with the combination therapy of BGJ398 and imatinib. Due to withdrawal of sponsor support the study closed before the RP2D or dosing schedule of the combination therapy was identified. In heavily pre-treated patients, stable disease ≥ 32 weeks was observed in 3 of 12 evaluable patients.

BACKGROUND

NCT02257541 .