~p l f 5~"~, a protein tyrosine kinase (PTK) co-localized with integrtns in focal adhesion plaques, is known to transduce signals invoked in the regulation of cell adhesion and motility as well as the anchorage-independent growth of transformed cells. We investigated whether pp I 25F*K could be part of a signalling pathway that contributes to the progression of human prostate carcinoma (PCa). Up-regulation of pp I 25F*K expression, its activation by phosphoryiation on tyrosine and its association with paxillin and p 5 W were preferentially observed in PCa tissues from patients with metastases, whereas normal and hyperplastic prostates and localized PCa tissues showed undetectable or low levels of both FAK mRNA and protein and an absence of pp12SFAK signalling complexes. The increase in expression and activation of pp I 25FAK in metastatic PCa tissues was also corroborated by our findings in human PCa cell lines. Indeed, higher levels of ~p l 2 5~~and FAK mRNA were observed in highly tumorigenic PC-3 cells as was the presence of activated p~1 2 5 "~, as opposed to an inactive form in LNCaP cells, which have a lower tumorigenic ability. In addition, ~~1 2 5~~ formed signalling complexes with both paxillin and p5Wk in PC-3 cells as in metastatic PCa tissues. Together, our results show that an increase in FAK mRNA and protein, as well as pp 125FM activation and association with signalling proteins, correlates with progression and invasion in human PCa tissues and cells.8 1996 Wiley-Liss, Inc.The processes of tumour formation, invasion and metastasis represent complex genetic and epigenetic events that lead to cell transformation, with subsequent changes in adhesive properties that allow the transformed cells to migrate, gain access to the circulation and form metastatic colonies (Liottaet al., 1991). It is likely that some changes in adhesion occur at focal adhesion plaques which are cell/extracellular matrix (ECM) contact points containing integrin receptors, cytoskeletal components and intracellular signalling proteins such as focal adhesion kinase ( p~1 2 5~"~) , a non-receptor protein tyrosine kinase (PTK) (Clark and Brugge, 1995; Schaller et al., 1992). Evidence from several laboratories has shown that cell adhesion to the ECM through the integrin receptors leads to an increase in the tyrosine phosphorylation of pp12FAK and a subsequent stimulation of its activity (Juliano and Haskill, 1993). Phosphorylation of ~~1 2 . 5~~ is also increased in Rous sarcoma virus-transformed cells, as a result of the expression of ~p 6 0 ' ' -~~~ oncogene product, which is also a PTK (Guan and Shalloway, 1992). These changes lead to the disassembly of actin filaments and focal adhesions and, consequently, to a decrease in cell adhesion and an increase in anchorageindependent growth.As part of the integrin signalling pathway, ~~1 2 5~"~ has also been shown to be associated with various intracellular proteins in fibroblasts and transformed cells . Among them, paxillin, a cytoskeletal phosphotyrosine (pY)-containing protein invol...

To determine if organic anions contribute to the diarrhea of inflammatory bowel disease, we measured osmolality, electrolytes, short-chain fatty acids, lactic acid, and some Krebs cycle anions in 24-hr fecal collections from 18 patients with chronic ulcerative colitis, 20 with Crohn's disease of the colon, and 16 normals. Mean lactic acid concentration was significantly elevated in ulcerative and Crohn's colitis, but values correlated with fecal weight only in the former syndrome. In ulcerative colitis, concentrations of each short-chain fatty acid, especially butyrate, were decreased compared with those from normals or Crohn's disease. Lactate and short-chain fatty acids accounted for nearly half the variability in fecal weight in ulcerative colitis. Crohn's patients had elevated mean fecal water osmolality and osmotic gap not observed in ulcerative colitis. Increased lactic acid and/or deficient short-chain fatty acids may modulate the diarrhea of ulcerative colitis. This mechanism seems less important in Crohn's colitis where an additional osmotic component may be significant.

T h e n e w e ng l a n d j o u r na l o f m e dic i n e n engl j med 356;23 www.nejm.org june 7, 2007 * All models were adjusted for the stratification variable of nephrotic status. ACE denotes angiotensin-converting enzyme, ARB angiotensin II-receptor blocker, and SAA serum amyloid A protein. † Underlying disease was categorized as rheumatoid arthritis, familial Mediterranean fever, or other. ‡ Mean arterial blood pressure values were calculated from systolic and diastolic blood pressure measurements.

Postsurgical adjuvant therapy with autologous DNP-modified vaccine appears to produce survival rates that are markedly higher than have been reported with surgery alone. Moreover, this approach has some intriguing immunobiologic features that might provide insights into the human tumor-host relationship.

Biliary glycoprotein (BGP) isoantigens are derived by alternative splicing from a single gene and are the human homologs of rat C-CAM and the mouse Bgp species. These glycoproteins represent a family of cell-adhesion molecules. The mouse Bgp isoforms also act as receptors for the hepatitis viral capsid-protein. BGP is a member of the carcinoembryonic antigen (CEA) gene family, which belongs to the immunoglobulin supergene family, yet it displays restricted expression patterns and unique functions. Since the loss or reduced expression of BGP is associated with human colorectal carcinomas, the elements in its upstream regulatory region were analyzed. A cluster of transcriptional initiation sites and the minimal promoter, located within 150 bp upstream of the major transcriptional start site, were active in human colon carcinoma and hepatoma cells. Unlike the CEA gene, BGP gene transcription was not modulated by a silencer region; repetitive elements in the BGP upstream region were not involved in activation or repression. Footprinting experiments identified two cis-acting elements and mobility-shift assays demonstrated that these elements bound several transcription factors, among them, USF, HNF-4 and an AP-2-like factor. In cotransfection experiments, both the USF and HNF-4 transcription factors transactivate the RGP gene promoter and compete for the same regulatory element. The Spl transcription factor, shown to be involved in CEA gene transcriptional regulation, does not bind to the BGP gene promoter. We, therefore, propose that the relative distributions and interactions of these transcription factors mediate distinct transcriptional regulation of the BGP gene in colon and liver; this regulation could be distorted during the oncogenic process.