FGF-23, a novel member of the FGF family, is the product of the gene mutated in autosomal dominant hypophosphatemic rickets (ADHR). FGF-23 has been proposed as a circulating factor causing renal phosphate wasting not only in ADHR (as a result of inadequate degradation), but also in tumor-induced osteomalacia (as a result of excess synthesis by tumor cells). Renal phosphate wasting occurs in approximately 50% of patients with McCune-Albright syndrome (MAS) and fibrous dysplasia of bone (FD), which result from postzygotic mutations of the GNAS1 gene. We found that FGF-23 is produced by normal and FD osteoprogenitors and bone-forming cells in vivo and in vitro. In situ hybridization analysis of FGF-23 mRNA expression identified "fibrous" cells, osteogenic cells, and cells associated with microvascular walls as specific cellular sources of FGF-23 in FD. Serum levels of FGF-23 were increased in FD/MAS patients compared with normal age-matched controls and significantly higher in FD/MAS patients with renal phosphate wasting compared with those without, and correlated with disease burden bone turnover markers commonly used to assess disease activity. Production of FGF-23 by FD tissue may play an important role in the renal phosphate-wasting syndrome associated with FD/MAS

Purpose: Each year in the United States, ϳ 30,000 people die from pancreatic cancer. Fewer than 5% of patients survive >5 years after diagnosis, because most patients present with advanced disease. Early diagnosis may improve the prognosis of patients with pancreatic cancer.Experimental Design: In an attempt to improve on current approaches to the serological diagnosis of pancreatic cancer, we analyzed serum samples from patients with and without pancreatic cancer using surface-enhanced laser desorption and ionization (SELDI) protein chip mass spectrometry. Using a case-control study design, serum samples from 60 patients with resectable pancreatic adenocarcinoma were compared with samples from 60 age-and sex-matched patients with nonmalignant pancreatic diseases, as well as 60 age-and sex-matched healthy controls. To increase the number of proteins potentially identifiable, serum was fractionated using anion exchange and profiled on two ProteinChip surfaces (metal affinity capture and weak cation exchange).Results: We determined a minimum set of protein peaks able to discriminate between patient groups and used the unified maximum separability algorithm to compare the performance of the individual marker panels alone or in conjunction with CA19 -9. Among the peaks identified by SELDI profiling that had the ability to distinguish between patient groups, the 2 most discriminating protein peaks could differentiate patients with pancreatic cancer from healthy controls with a sensitivity of 78% and specificity of 97%. These 2 markers performed significantly better than the current standard serum marker, CA19 -9 (P < 0.05).The diagnostic accuracy of the 2 markers was improved by using them in combination with CA 19 -9. Similarly, a combination of 3 SELDI markers and CA19 -9 was superior to CA19 -9 alone in distinguishing individuals with pancreatic cancer from the combined pancreatic disease controls and healthy subject groups (P ‫؍‬ 0.078). SELDI markers were also better than CA19 -9 in distinguishing patients with pancreatic cancer from those with pancreatitis.Conclusion: SELDI profiling of serum can be used to accurately differentiate patients with pancreatic cancer from those with other pancreatic diseases and from healthy controls.

Purpose: Members of the small integrin binding ligand N-linked glycoprotein (SIBLING) gene family have the capacity to bind and modulate the activity of matrix metalloproteinases (MMPs). The expression levels of five SIBLING gene family members [bone sialoprotein (BSP), osteopontin (OPN), dentin matrix protein 1 (DMP1), matrix extracellular phosphoglycoprotein (MEPE), and dentin sialophosphoprotein (DSPP)] and certain MMPs were determined using a commercial cancer array.Experimental Design: Cancer profiling arrays containing normalized cDNA from both tumor and corresponding normal tissues from 241 individual patients were used to screen for SIBLING and MMP expression in nine distinct cancer types.Results: Significantly elevated expression levels were observed for BSP in cancer of the breast, colon, stomach, rectum, thyroid, and kidney; OPN in cancer of the breast, uterus, colon, ovary, lung, rectum, and thyroid; DMP1 in cancer of the breast, uterus, colon, and lung; and dentin sialophosphoprotein in breast and lung cancer. The degree of correlation between a SIBLING and its partner MMP was found to be significant within a given cancer type (e.g., BSP and MMP-2 in colon cancer, OPN and MMP-3 in ovarian cancer; DMP1 and MMP-9 in lung cancer). The expression levels of SIBLINGs were distinct within subtypes of cancer (e.g., breast ductal tumors compared with lobular tumors). In general, SIBLING expression increased with cancer stage for breast, colon, lung, and rectal cancer.Conclusions: These results suggest SIBLINGs as potential markers of early disease progression in a number of different cancer types, some of which currently lack vigorous clinical markers.

A novel 131 ␣-linked glucose disaccharide with sulfate at C-2 of one of the glucose moieties, 1-(2-O-sulfo-␣-D-glucopyranosyl)-␣-D-glycopyranose, was found to be the major organic solute accumulated by a Natronococcus sp. and several Natronobacterium species. The concentration of this novel disaccharide, termed sulfotrehalose, increased with increasing concentrations of external NaCl, behavior consistent with its identity as an osmolyte. A variety of noncharged disaccharides (trehalose, sucrose, cellobiose, and maltose) were added to the growth medium to see if they could suppress synthesis and accumulation of sulfotrehalose. Sucrose was the most effective in suppressing biosynthesis and accumulation of sulfotrehalose, with levels as low as 0.1 mM being able to significantly replace the novel charged osmolyte. Other common osmolytes (glycine betaine, glutamate, and proline) were not accumulated or used for osmotic balance in place of the sulfotrehalose by the halophilic archaeons.