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Objective To determine the efficacy of fibroblast growth factor-2 (FGF-2) in treating chronic nonhealing tympanic membrane (TM) perforations. Method Double-blinded, randomized placebo controlled phase 2 clinical trial for patients with chronic TM perforations of more than 3 months duration with a cross-over arm. Patients received either FGF-2 or placebo (sterile water) saturated gelatin sponge in the perforation after rimming the perforation under topical anesthesia. The perforation was then covered with Tisseel fibrin glue. The primary endpoint was complete closure of the TM perforation. Secondary end points included change in hearing and partial TM closure rates. The TM was examined every 3 weeks with otoendoscopy for closure. The treatment was repeated if there was incomplete closure every 3 weeks up to a total of three treatments per arm. Results Seventy four patients were recruited for the study. Fifty seven met eligibility criteria and fifty four completed the study. Ten of 14 perforations closed completely in the placebo group (71.4%) and 23 of 40 perforations closed completely in the FGF-2 treatment group (57.5%), P value = .36. Pure tone averages and word recognition scores were not statistically significantly different between study groups post-treatment. After initial complete closure, re-perforation occurred in seven FGF-2 treated patients and two placebo patients making the effective final closure rate 40% for FGF and 57% for placebo, respectively. Conclusion No statistically significant difference in tympanic membrane perforation closure rate was found between the FGF-2 and placebo groups. There were no differences in hearing outcomes between the groups. Level of evidence 1b.

Objectives: In addition to its use as a volume filler, fat grafting may have a potential role in wound healing based on the concentration of growth factors in the lipoaspirate. In this study, we compare the quantitative and qualitative concentration of the various growth factors and adipokines using the Shippert or the Coleman techniques to prepare the lipoaspirate. Methods: We measured leptin, adiponectin and the growth factors, i.e., acidic fibroblast growth factor (aFGF), basic FGF (bFGF), keratinocyte growth factor (KGF), bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) by ELISA in solid and liquid fractions obtained with both techniques in human fat obtained with Coleman technique and Shippert technique. Results: All of these peptides, except BMP-2, were detected in relevant quantities in the solid fraction. The Coleman but not the Shippert technique resulted in statistically higher adiponectin concentrations in the solid tissue fraction. The other four growth factors occurred in significantly higher concentrations in the solid fractions compared to the liquid fractions, independent of the processing technique. Conclusion: In summary, we demonstrated that KGF, aFGF, bFGF and VEGF, as well as leptin and adiponectin, are contained in fat suspensions obtained by liposuction and in the supernatant. Only the concentration of adiponectin was in the range reported to contribute to wound healing.

This study aimed to investigate whether intra-tracheal administration of basic fibroblast growth factor (b-FGF) promotes the growth of tracheal cartilage. Trachea of 4-week old mice were intubated and 2.5 μg b-FGF administered (Group 4) for periods from 1 to 5 days. Cervical tracheal outer diameter and tracheal ring length were compared in Group 1 (no intervention), Group 2 (tracheal intubation), Group 3 (intra-tracheal administration of distilled water) and Group 4, at 8 weeks of age. Outer diameter and tracheal ring length in Group 4 were also compared with that in Group 1 at 12 and 16 weeks of age. At 8 weeks of age, tracheal ring length with b-FGF administration for more than 4 days in Group 4 was significantly increased over that following 1-day administration. At 8 weeks of age, mean outer diameter and the mean tracheal ring length in Group 4 were significantly greater than in the other groups. Mean outer diameter and mean tracheal ring length were significantly greater in Group 4 than in Group 1 at 12 and 16 weeks of age. This study has shown that intra-tracheal administration of b-FGF enlarges the tracheal lumen.

In this study, we serologically and pathologically examined the clinical significance of fibroblast growth factor (FGF) expression in patients with colorectal cancer. Serum basic FGF (bFGF) levels in 92 surgical colorectal cancer patients and 31 controls were measured, and the relationship between those levels and clinicopathological factors were examined. Immunohistochemical study was also conducted on specimens from 51 cancer patients, and the association between bFGF staining and serum levels were investigated. An examination of clinicopathological factors revealed significant differences in bFGF levels between stage 0-IIIb and stage IV cancers (P = 0.013). Lymphatic invasion was one factor that differed significantly. Patients with a tumor 30 mm or smaller had a bFGF level of 7.65 ± 1.11 pg/ml while patients with a tumor 31 mm or larger had a bFGF level of 8.53 ± 3.22 pg/ml; significant differences in these bFGF levels were noted (P < 0.05). Patients with a tumor that had no lymphatic invasion (ly0) had a bFGF level of 7.25 ± 0.66 pg/ml, those with a tumor that had minimal lymphatic invasion (ly1) had a bFGF level of 7.99 ± 1.68 pg/ml, and those with a tumor that had moderate lymphatic invasion (ly2) had a bFGF level of 9.17 ± 4.23 pg/ml. bFGF levels differed significantly for tumors with no/minimal lymphatic invasion (ly0-ly1) and those with moderate lymphatic invasion (ly2) (P < 0.0001). Serological examination of bFGF levels during the proliferation of colorectal cancer revealed that moderate lymphatic invasion can be readily distinguished.

Introduction We have designed an engineered graft fabricated from a biodegradable scaffold using chondrocytes and applied this construct to augment repair of tracheal stenosis. This study investigated the feasibility of using such tissue-engineered airways with autologous chondrocytes in a rabbit model. Material and Methods Chondrocytes were isolated and expanded from the auricular cartilage of New Zealand white rabbits, then seeded onto composite 3-layer scaffolds consisting of a collagen sheet, a polyglycolic acid mesh, and a copolymer (l-lactide/ ɛ -caprolactone) coarse mesh. The engineered grafts were implanted into a 0.5 × 0.8-cm defect created in the midventral portion of the cervical trachea. Gelatin sponges that slowly released basic fibroblast growth factor (b-FGF) were then placed on the constructs, which were retrieved 1 or 3 months after implantation. Results The biodegradable scaffold seeded with chondrocytes could maintain airway structure up to 3 months after implantation. Tracheal epithelial regeneration occurred in the internal lumen of this composite scaffold. Three months after implantation, staining of the sections showed cartilage accumulation in the engineered tracheal wall. Conclusion This composite biodegradable scaffold may be useful for developing engineered trachea. A gelatin sponge slowly releasing b-FGF might enhance chondrogenesis.

Background The search for biomarkers of pulmonary tuberculosis (PTB) disease, infection, treatment progress among others is especially due to lack of suitable tests for diagnosis or differentiation of active PTB disease and mere latent TB infection. The existing methods have, among others, poor sensitivity, long turnaround time, high cost and the need for skilled personnel and infrastructure. Therefore, this study analysed 27 analytes (previously identified as promising) in TB research for their trend during TB treatment among PTB disease suspects in Mulago Hospital in Kampala, Uganda. Methods This study used plasma samples from 76 TB suspects enrolled as part of a bigger longitudinal African-European TB Consortium (AETBC) study funded by the EDCTP within Kampala, Uganda. 71% were males, average age was 32±10, 14% were HIV-infected. PTB was confirmed by MGIT (mycobacteria growth indicator tube) and speciated for MTB complex. Subjects were followed at month 2 and 6 of treatment. The 27 analytes: (IL-1b,1ra, 2, 4, 5, 6, 7, 8, 9, 10,12p70,13,15,17A, eotaxin, Basic FGF,G-CSF, GM-CSF, IFNg,IP10, MCP-1, MIP-1a,b, PDGF-BB, RANTES, TNF-a, VEGF) were analysed using Luminex. Of the TB suspects, 38 had confirmed MTB by MGIT. The 38 TB suspects, used as controls, had X-ray results ranging from normal to consistent with TB. Results Levels of 14 of the analytes most notably MIP-1a, b, IP-10, RANTES, IL-8, IL-12p70, IL-17A and VEGF significantly reduced throughout treatment. Notably, levels of IFNg, IL-12p70, 4,6,IP10, and VEGF significantly reduced by month of treatment. Combinations of IP10, RANTES, MIP-1b and VEGF also showed promising abilities in identifying treatment success with an interesting trend appearing in suspects with non-TB chest infections and with HIV−TB co-infection. Conclusions The above markers have promising abilities for PTB diagnosis and identification of possible relapse or treatment failures.

Loss of the stromal TGF- signaling in the prostate has been shown to initiate prostate cancer (PCa), promote PCa progression, and facilitate the development of mixed osteoblastic/osteolytic bone lesions. However, the effects on bone lesions are found to be transient. We thus focused on delineating the context-dependent role of TGF- signaling in the bone microenvironment effects on PCa bone lesions. Using genetic engineered mouse models, TGF- signaling is cell-specifically knockout (KO) in the prostate fibroblasts and osteoblasts in the bone by Colcre/Tgfbr2 KO, or in the myeloid lineage cells, including osteoclasts in the bone by LysMcre/Tgfbr2 KO. Compared the PCa-induced bone lesions in the KO mice tibiae to the lesions in the Flox mice, we found that PC3-induced osteolytic bone lesions were significantly increased by Colcre/Tgfbr2 KO,but were significantly decreased by LysMcre/Tgfbr2 KO. Our findings suggested that osteoblastic TGF- signaling inhibits PCa bone lesions development, but myeloid TGF- signaling promotes PCa bone lesion development. We further found that basic FGF mediated the effect of increased PC3 bone lesions in Colcre/Tgfbr2 KO mice.

Inflammatory bowel disease (IBD), the precise etiology of which remains unknown, is comprised of two forms of chronic intestinal inflammation; ulcerative colitis (UC) and Crohn's disease (CD). Recent evidence increasingly suggests that IBD is the result of dysfunctional immunoregulation manifested by inappropriate production of mucosal cytokines. An abnormal microcirculatory system has also been implicated in its pathogenesis. To elucidate the mechanism of ischemic change in IBD, we assesse serum concentration levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF), and plasma level of endothelin-1 (ET-1). We also investigated the expression of VEGF, b-FGF, and transforming growth factor-beta1,2,3 (TGF-beta1,2,3) in tissue by immunostaining.Blood samples were obtained from 11 patients with UC, 11 patients with CD, and 10 patients as controls. Paraffin-embedded samples were used for an immunohistochemical study.The concentration levels (in picograms per milliliter) were as follows: for ET-1, UC: 127+/-47.0, CD: 167.3+/-35.1, and controls (asthma: 38.5+/-23.8, p0.01; diverticulitis: 40.5+/-25.6, p0.01), for b-FGF, UC: 9.2+/-1.9, CD: 9.1+/-1.5, and controls (asthma: 5.0+/-0, p0.01; diverticulitis: 5.0+/-0, p0.01), for VEGF, UC: 659.8+/-181.0, CD: 740.0+/-182.3, and controls (asthma: 193.7+/-58.7, p0.01; diverticulitis: 199.6+/-59.7, p0.01). The levels of VEGF and b-FGF were significantly higher in active IBD than those in the controls. There was a significant positive correlation among the serum levels of VEGF and b-FGF and the plasma level of ET-1; that is, elevated VEGF, b-FGF, and ET-1 levels correlated well with each other. Immunohistochemical studies showed increased venula in the submucosa and lamina propria. Overexpression of VEGF and b-FGF in endothelial cells was revealed and TGF-beta2 and TGF-beta3 were found in inflammatory cells of active IBD, but no change was observed around the vessels in the controls.It is suggested that the reciprocal reaction of these cytokines may contribute to angiogenesis in IBD b inducing intestinal ischemia through vasoconstriction.

Basic fibroblast growth factor (bFGF) is a growth factor with proangiogenetic properties. Elevated bone marrow (BM) and peripheral serum bFGF levels have been reported in patients with multiple myeloma (MM)[1][1]-[3][2]; however, the source of bFGF in patients with MM is not completely elucidated.

Angiogenic markers such as VEGF/basic FGF (bFGF) can enlarge the diagnostic biomarkers panel for pancreatic cancer. Materials & methods: Serum samples from 32 stage I–IV pancreatic cancer patients and 20 controls were analyzed for soluble VEGF/bFGF by ELISA and xMAP array. Results: VEGF/bFGF serum levels were significantly increased in patients compared with controls (p

Background The effectiveness of sustained-release basic fibroblast growth factor (bFGF) in potentiating arteriogenesis and angiogenesis was evaluated, as well as determining whether chronic oral administration of sarpogrelate, a serotonin blocker, would further increase collateral blood flow in the rabbit hindlimb following surgical induction of ischemia by femoral artery extraction. Methods and Results Two weeks after femoral artery removal, the rabbits were assigned to 1 of 4 experimental groups and treated for 4 weeks: group A, no treatment; group B, supplemented with diet containing sarpogrelate; group C, single intramuscular injection of sustained-release form of bFGF microspheres; group D: combined treatment with sustained-release bFGF and sarpogrelate. Endpoint measurements performed at 6 weeks found that the ischemic hindlimb blood flow was significantly improved in the rabbits that received sustained-release bFGF, with a further significant improvement in those with the additional administration of sarpogrelate. Angiographic assessment revealed augmented density of collateral vessels in the medial thigh region in the rabbits given the combined treatment. Conclusions The findings demonstrate that sustained-release bFGF stimulated the development of collateral vessels, and additional administration of sarpogrelate produced a further improvement in hindlimb blood flow in the rabbit hindlimb ischemia model. (Circ J 2006; 70: 1190 - 1194)

Trafermin, a form of basic fibroblast growth factor, has been used in Japan since 2001. This study investigates whether it can facilitate closure in wounds with deep soft-tissue defects and exposed bone, where surgical closure is not possible.

Clinical studies indicate that specific cyclooxygenase-2 (Cox-2) inhibitors are less ulcerogenic than their non-selective predecessors (e.g. indomethacin). However, Cox-2 inhibitors may also interfere with ulcer healing. Re-epithelialization is a crucial factor in both gastrointestinal mucosal injury and ulcer healing. This study was aimed to compare the effects of selective Cox-2 inhibitor (NS398) versus non-selective Cox inhibitor (indomethacin) on basal and basic fibroblast growth factor (bFGF) - stimulated gastric wound re-epithelialization. In-vitro epithelial wounds were created in confluent monolayers of RGM1 rat gastric epithelial cells by a razor blade scrape. Following wounding there was a significant re-epithelialization by 24 hrs. Indomethacin (0.25 mM and 0.5 mM) significantly inhibited basal wound re-epithelialization in a dose dependent manner. In contrast, selective Cox-2 inhibitor NS398 did not inhibit the basal re-epithelialization process. Basic FGF treatment produced significant enhancement of wound re-epitheliazation at the various concentrations [10, 20, 30, 40, 50 and 70 ng/ml] studied. Both indomethacin and NS398 inhibited bFGF stimulated wound re-epithelialization, with indomethacin having a greater inhibitory effect. The extent of NS398 inhibition was limited to the bFGF-stimulated component, whereas indomethacin inhibition extended to both the bFGF-stimulated and the basal re-epithelialization components. These findings indicate that specific Cox-2 inhibitor (NS398) does not interfere with the basal re-epithelialization but significantly inhibits the bFGF - stimulated re-epithelialization, whereas indomethacin interferes with both the basal as well as the bFGF-stimulated wound re-epithelialization.

A 61-year-old Japanese woman developed pressure ulcer on her sacral and coccygeal area due to a long-term bed rest. After she received the treatment by bucladesine sodium ointment, trafermin (recombinant human basic FGF) splay and TIELLE ® (Johnson & Johnson Co) hydropolymer dressing, the ulcer gradually reduced in size and depth. How- ever, the improvement of the fissure-like ulcer decelerated when the size became around 2X2cm. Thereafter the occlusion by hydrocolloid dressing was continued for around two years with only slight effect, decreasing the size to around 1X1cm. Finally, we changed the dressing to the hydropolymer dressing TIELLE ® plus, which can absorb superfluous ooz- ing well, because maceration was found on the perilesional skin. Then, the ulcer was rapidly healed and epithelized in two weeks, suggesting that the excess secretion had delayed of wound healing.

Modern research in rheumatic diseases has led to the development of anti-cytokine therapies and some treatment specific biomarkers have been discovered. Our aim in this report is to observe the changes in a set of cytokine/chemokine pre- and post Actemra anti-cytokine therapy in naive rheumatoid arthritis (RA) patients. Thirty-four naive RA patients were selected and treated with 8 mg/kg of Actemra once every 4 weeks. Before, and 16 weeks after therapy, we used Bio-plex beads based array method to measure and analyze patients’ serum cytokine/chemokine levels: IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, 101 IL-10, IL-12 (p70), IL-13, IL-15, IL-17, basic FGF, eotaxin, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF. Clinical response according to disease activity score (DAS-28) criteria was determined at week 16 of therapy and clinical efficacy was judged as remission or non-remission (further divided into high, moderate, low) depending on patients’ DAS-28 value. Fifty percent of patients (n = 17) experienced complete remission and the remaining 17 patients were classified as non-remission even though many of them displayed some improvements. A comparison of cytokine/chemokine changes before and after therapy revealed that patients with extremely high levels of inflammatory cytokines (such as IL-1b, IL-8, IL-12p40, IFN-γ) before therapy did not go into remission even though these cytokine levels decreased after treatment. Contrary to this, these cytokines significantly decreased in patients who went into complete remission. These results demonstrate that anti-IL-6 therapy affects many kinds of cytokine/chemokine systems, and suppression of the IL-6 network may lead to clinical efficacy. Further analysis is required to reveal more detailed mechanism of anti-IL-6 therapy.

Introduction Major burn injury induces an inflammatory response, which is accompanied by the release of various cytokines.This study was performed to investigate changes in levels of pro-inflammatory and anti-inflammatory cytokines following burn injury, and to investigate the relationship between levels of these cytokines and prognosis in burn patients. Methods Blood samples of 40 burn patients were collected on days 1 and 3 after burn injury, and concentrations of G-CSF, GM-CSF, INF- γ , TNF-α, IL-1β, IL-1rα, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, VEGF, Basic FGF, and Eotaxin were measured using the Bio-Plex Suspension Array System. Blood samples of 25 healthy non-burn subjects were used as controls. Clinical data including patients’ outcome (survival or death) were collected from the patients’ medical records. Statistical differences in each cytokine concentrations between control and patient groups, between day 1 and day 3, and between survival and death groups were analyzed using the Mann-Whitney’s U -test. Results Median concentrations of G-CSF, GM-CSF, IL-1β, IL-1rα, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, MCP-1, MIP-1α, MIP-1β, and VEGF were significantly increased in burn patients compared to those in non-burn controls ( P γ , IL-1β, IL-1rα, IL-2, IL-4, IL-7, IL-9, IL-10, IL-12p70, IL-13, IL-17, MIP-1α, MIP-1β, PDGF-BB, VEGF, basic FGF, and Eotaxin were significantly higher on day 1 compared to day 3, whereas G-CSF were significantly higher on day 3 compared to day 1 ( P Conclusion These findings indicate that G-CSF, GM-CSF, IL-1β, IL-1rα, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, MCP-1, MIP-1α, MIP-1β, and VEGF play important roles in inflammatory changes after burn injury and most cytokine levels are increased on day 1 compared to on day 3 after burn injury. The concentrations of various cytokines in this study measured on day 1 or day 3 after burn injury failed to predict the prognosis related to patient’s survival or death.

e21050 Background: Colorectal cancer has an important place in worldwide death from cancer causes. Angiogenesis, in which angiogenic factors such as VEGF and basic FGF have a key role, is an important factor in patient survival with respect to progression and metastatic spreading in colorectal cancer. In this study, we aimed to determine that whether serum VEGF and bFGF pre- and post-treatment serum levels are decisive in evaluating response to treatment and progression in metastatic colorectal cancer (mCRC) patients treated with FOLFIRI-bevacizumab. Methods: In 33 mCRC patients treated in our department serum VEGF and bFGF levels were monitored in the beginning of treatment and until progression during FOLFIRI-bevacizumab treatment before 4.-, 8.- and 12.-regimens. Serum levels of VEGF and bFGF were assssed using the quantitative sandwich enzyme immunoassay technique. Results: In our study serumVEGF and bFGF levels were significantly higher than the healthy controls (p

Recently, various studies for tissue engineering have been conducted successfully to explore a new era of tissue defect treatment. To this end, three essential factors were examined extensively, that is, cells to be transplanted, signaling molecules, and scaffold. Currently, undifferentiated mesenchymal stem cells (MSCs) or the differentiated forms are transplanted with the appropriate scaffolds, producing excellent tissue regeneration. In addition, it is demonstrated that various signaling molecules such as basic FGF, BDNF, BMP, and TGF-beta are available for new tissue formation. Under such background, a special issue on tissue regeneration in dentistry was designed to summarize the current status of tissue regeneration. Thus, we have invited authors to submit original research and review articles that seek the nature of tissue regeneration and the relevant factors. As the results, various interesting and scientifically significant papers have been accepted. These studies are categorized into MSCs and/or dental MSCs and the relevant factors, cellular responses to various signaling molecules and biomaterials, in vivo studies for tissue regeneration in animal models with artificially created tissue defects, and confirmation for the safety of tissue regeneration with ethical consideration.

Fibroblast growth factor has been implied as a central mediator in wound healing, including epithelialization and ingrowth of capillaries [ 1]. It was the aim of our animal study to investigate the effects of recombinant human basic FGF (rhbFGF) on wound healing in chroni­cally ischemic tissue.

9627 Background: To differentiate between malignant and nonmalignant ascites is an important clinical problem for further diagnostic and therapeutic procedures. As the majority of angiogenic factors are soluble peptides secreted by tumors, their use have been proposed as tumor markers in effusions. Three angiogenic cytokines were dosed in ascites samples - Vascular Endothelial Growth Factor (VEGF), basic Fibroblast Growth Factor (bFGF) and Transforming Growth Factor - β1 (TGF- β1) - to evaluate their ability to discriminate malignant and nonmalignant etiologies and to establish a correlation between the three growth factors in these two groups. Methods: A total of 63 (32 malignant and 31 nonmalignant) ascites samples obtained from paracentesis were used. Concentrations of VEGF, basic FGF and TGF-β1 in ascites were determined with ELISA (Quantikine, R&D Systems) following the manufacturer’s guidelines and the samples were analyzed in duplicate. Differences between the two groups were tested with nonparamet...