Infrequent point mutations of ras oncogenes in gastric cancers

Adenocarcinomas of the proximal and distal stomach have significant clinical and biological differences. A study was undertaken to determine if a difference in the incidence of mutated ras oncogenes exists between proximal (gastroesophageal junction or cardia) and distal (body or antrum) gastric tumors, and to assess the overall incidence in gastric cancers from non-Asian patients. Deoxyribonucleic acid from 28 primary gastric adenocarcinomas were analyzed for point mutations in codons 12, 13, and 61 of the Ha-ras, Ki-ras, and N-ras protooncogenes using polymerase-catalyzed chain reaction methodology. Twelve tumors were located at the gastroesophageal junction or cardia, and 16 in the body or antrum. Mutated ras genes were detected in 2 of 28 tumors for an overall incidence of 7%. The mutations occurred in codon 61 of the N-ras gene in a proximal gastric cancer and in codon 12 of the Ki-ras gene in a distal gastric cancer. These data indicate that mutations in ras genes are an uncommon event in primary gastric cancers and that there is no meaningful difference in the incidence of ras mutations in proximal and distal stomach cancers.     

Mac-1 (CD11b/CD18) and the urokinase receptor (CD87) form a functional unit on monocytic cells

The leukocyte integrin Mac-1 (CD11b/CD18) and the urokinase receptor (uPAR, CD87) mediate complementary functions in myelomonocytic cells. Both receptors promote degradation of fibrin(ogen) and also confer adhesive properties on cells because Mac-1 and uPAR bind fibrin and vitronectin, respectively. Staining of lung biopsy specimens from patients with acute lung injury indicated that fibrin and vitronectin colocalize at exudative sites in which macrophages bearing these receptors accumulate. Because of the parallel roles and physical proximity of Mac-1 and uPAR, the capacity of these receptors to functionally interact was explored. Induction of Mac-1 and uPAR expression on monocytic cell lines by transforming growth factor- beta 1 and 1.25-(OH)2 vitamin D3 conferred urokinase and uPAR-dependent adhesion to vitronectin, which was further promoted by engagement of Mac-1. Vitronectin attachment promoted subsequent Mac-1-mediated fibrinogen degradation threefold to fourfold. In contrast, enhancement of uPAR occupancy by exogenous urokinase or receptor binding fragments thereof inhibited Mac-1 function. Addition of urokinase progressively inhibited Mac-1-mediated fibrinogen binding and degradation (maximal inhibition, 91% +/- 14% and 72% +/- 15%, respectively). Saturation of uPAR with urokinase also inhibited binding of the procoagulant Mac-1 ligand, Factor X. These inhibitory effects of uPAR were reproduced in fresh monocytes, cultured monocytic cells, and in Chinese hamster ovary (CHO) cells transfected with both human Mac-1 and human uPAR. These data show that the procoagulant and fibrinolytic potential of monocytic cells is co-ordinately regulated by ligand binding to both Mac-1 and uPAR and identify uPAR as a regulator of integrin function. Vitronectin- enhanced fibrin(ogen) turnover by Mac-1 may operate as a salvage pathway in the setting of urokinase and plasmin inhibitors to promote clearance of the provisional matrix and subsequent healing.     

Unrelated donor bone marrow transplantation: influence of HLA A and B incompatibility on outcome

We have studied the outcome of 211 consecutive unrelated donor (URD) bone marrow transplants (BMT) performed at the University of Minnesota (Minneapolis, MN) between May 1985 and December 1992. Ninety patients (43%) received marrow matched serologically at HLA A, B, and DR loci; 86 (41%) received marrow with a major and 32 (15%) marrow with a minor serologic mismatch at the HLA A or B locus. Multivariate analysis revealed that older age had an adverse effect on survival. In younger (age less than 18 years) recipients, survival after fully matched (A, B, and DR sub-type) or major mismatched (A or B locus), DR subtype- matched donor BMT was not significantly different (P = .4; survival: 53% v 41%, respectively, at 3 years). For adults, survival after matched donor BMT was significantly better than that with mismatched donors (P < .01; survival: 30% v 10%, respectively, at 3 years). Formal quality of life assessment by telephone interview demonstrated similar functional status in survivors of URD and related donor (RD) BMT at least 2 years post-BMT. URD BMT provides effective therapy for a variety of lethal hematopoietic diseases that rivals outcome of RD transplant in some cases. Use of URD marrow with a major mismatch at one HLA A or B locus is well tolerated in young, but not in older, recipients. These observations should be used to improve donor selection and counseling for URD BMT candidates.