Fibroblast growth factors (FGFs) participate in embryonic development, in maintenance of tissue homeostasis in the adult, and in various diseases. FGF-binding proteins (FGFBP) are secreted proteins that chaperone FGFs stored in the extracellular matrix to their receptor, and can thus modulate FGF signaling. FGFBP1 (alias BP1, FGF-BP1, or HBp17) expression is required for embryonic survival, can modulate FGF-dependent vascular permeability in embryos, and is an angiogenic switch in human cancers. To determine the function of BP1 in vivo, we generated tetracycline-regulated conditional BP1 transgenic mice. BP1-expressing adult mice are viable, fertile, and phenotypically indistinguishable from their littermates. Induction of BP1 expression increased mouse primary fibroblast motility in vitro, increased angiogenic sprouting into subcutaneous matrigel plugs in animals and accelerated the healing of excisional skin wounds. FGF-receptor kinase inhibitors blocked these effects. Healing skin wounds showed increased macrophage invasion as well as cell proliferation after BP1 expression. Also, BP1 expression increased angiogenesis during the healing of skin wounds as well as after ischemic injury to hindlimb skeletal muscles. We conclude that BP1 can enhance FGF effects that are required for the healing and repair of injured tissues in adult animals. The family of fibroblast growth factors (FGFs) encompasses 18 distinct FGF receptor ligands, with a wide expression range and a significant role in angiogenesis, tumor progression, wound healing, and embryonic development.1-4 Many members of the FGF family, such as FGF1 and FGF2, are immobilized in the extracellular matrix (ECM) bound to heparan sulfate proteoglycans (HSPGs) and released from this storage site by proteases and heparanases. 4 -6 The involvement of carrier proteins that shuttle FGFs from their storage site to their receptors represents an alternative mode of regulation of FGF release from the ECM. 1,7 FGF-binding protein 1 (BP1, FGFBP1, FGF-BP1, or HBp17), 8 the best characterized of the three known secreted FGFBPs, 9 is an extracellular chaperone that binds FGF1, 2, 7, 10, and 22 in a reversible, noncovalent manner. 8,10 -12 Binding of the C-terminus of the BP1 protein is sufficient for its interaction with FGF2.13 After binding to BP1, the biochemical and biological activities of FGF are positively modulated.14 Several findings from different laboratories indicate that BP1 can contribute to embryonic development, 15 angiogenesis, tumor growth, and malignant progression, 11,12,14 -20 as well as the maintenance and reinnervation of the neuromuscular junction. 21 We reported earlier that expression of BP1 in SW13 cells induces FGF2 release from the cells, FGF-dependent colony formation in soft agar, and the growth of highly vascularized tumors in nude mice.11 In contrast, depletion of endogenous BP1 from ME180 cells was observed to reduce the release of ECM bound FGF2 into the cell supernatants and to increase FGF2 immobilized on the cell surface.16 Consisten...

Anaplastic lymphoma kinase (ALK) is a transmembrane tyrosine kinase receptor that has an increased expression in various tumors and areas of active angiogenesis. In pancreatic tissues of mice with endogenously expressed mutant KrasG12D under embryonic acinar promoter p48, we detected ALK expression in pre maligant pancreatic intra-epithelial neoplastic ducts (PanIN) as well as malignant adenocarcinoma (PDAC). We have developed an antagonistic mouse monoclonal IgG antibody to the ALK receptor (anti-ALK IgG). To determine the antibody's binding efficacy, we used a quantum dot labeled anti-ALK IgG for the fluorescent visualization of pancreatic allografts in nude mice. Intravenously injected Qdot labeled anti-ALK IgG concentrated in allograft areas more than a Qdot labeled control antibody. In a prospective treatment study, we treated KrasG12D mice to determine the antibody's efficacy at preventing the progression from early to late PanIN and ultimately PDAC. Mice of three different age cohorts were treated with the antibody inta-peritoneal for six weeks. Upon completion of antibody treatment, the pancreata of mice were histologically examined for the appearance of early PanIN, late PanIN, or PDAC. Anti-ALK IgG treatment was most effective at preventing the progression of late PanIN to PDAC, with 8.3% of antibody treated mice harboring PDAC compared to 33.3% of saline treated control mice. Metastasis was also prevented in mice treated with antibody. Anti-ALK IgG treatment did not prevent the progression of early or late PanINs better than control treatment. Preliminary experiments have determined a change in microRNA expression in the pancreatic tissues of mice treated with antibody compared to controls and during different stages of pancreatic cancer progression. Expression of miR-375 decreased approximately 100 fold in PanIN and PDAC tissues compared to control tissues, but this decrease was not seen in PanIN tissues of mice treated with anti-ALK IgG. Reports have shown miR-375's role in pancreas development and the regulation of glucose homeostasis, and that its expression decreased in certain cancers. These data suggest miR-375 is necessary for normal physiological pancreatic activity and has a possible tumor suppressive role, and that anti-ALK IgG can help maintain this function. MiR- 22, 141, 148a, 148b, and 301a also had similar expression patterns in PanIN tissues and controls when pancreata were from mice treated with antibody. Another group of microRNAs, including miR- 10, 16, 21, 100, 155, and 199 showed little change in expression in antibody or control treated mice. These changes in microRNA expression suggest a response to antibody treatment at the genetic level, which may provide further insights into the functional mechanism of anti-ALK IgG's efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 721.

Purpose In South Korea, investigations into Turner syndrome (TS) prevalence and TS-associated cancer and mortality are lacking. Accurate data were estimated from the National Health Insurance Service (NHIS) and the Rare Diseases Registry (RDR) records. Materials and Methods Data on patients with TS who were registered in the RDR between 2007 and 2017 were collected. To estimate TS-associated cancer and mortality risk, the data were compared with data of 1:3 age-matched controls. Results In 2017, 2054 patients with TS were identified from a total population of 26186952 South Korean women; therefore, the prevalence was 7.84 per 100000 persons. TS prevalence across 10-year interval age groups were 11.82, 23.17, 18.37, 10.49, 4.09, and 0.38 for age under 10 years, teenagers, 20s, 30s, 40s, and older than 50, respectively (per 100000 persons). The cancer risk in patients with TS was higher than that of age-matched controls over 5.3 person-years [hazard ratio (HR)=1.82, 95% confidence interval (CI) 1.01–3.27, p =0.045]. Among different types of cancer, thyroid cancer risk in patients with TS was significantly higher than that of age-matched controls (HR=2.78, 95% CI 1.06–7.26, p =0.037). We also observed that TS-associated all-cause mortality risk was higher than that of age-matched controls (HR=3.36, 95% CI 1.59–7.10, p =0.002). Conclusion National prevalence of TS was suggested, and an increased risk of TS-associated thyroid cancer and mortality were observed in this study.

Background: Autoimmune thyroid disease (AITD) manifests with a female predominance, and much attention has been directed towards the integral membrane protein 2 A (ITM2A) gene located on the X chromosome. Methods: In a study of 166 pediatric patients with autoimmune thyroid disease (AITD), the ITM2A rs1751094 single-nucleotide polymorphism (SNP) was genotyped. The sample comprised 143 females and 23 males, with 67 patients diagnosed with Hashimoto chronic thyroiditis (HD) and 99 with Graves' disease (GD). In the 99 GD patients, 49 (49.5%) exhibited thyroidassociated ophthalmopathy (TAO). Among the 85 GD patients, 70.6% (60/85) were considered intractable GD. The results were compared to those from 198 healthy Korean individuals, including 97 females and 101 males. Results:The frequency of the rs1751094 C allele and CC/AC genotype were higher in AITD, GD and HD patients compared to controls, while the frequency of the A allele and AA genotype were lower. The results were more pronounced in female AITD and GD patients compared to male patients. The association was also found in intractable GD and TAO patients. Target SNP fits Hardy-Weinberg equilibrium. Conclusions: These findings indicate that the ITM2A gene polymorphism on the X chromosome may contribute to the immunological basis of femalepredominant AITD in Korean children.