Publications

Discoidin domain receptor 2 (DDR2) is an unusual receptor tyrosine kinase in that its ligand is fibrillar collagen rather than a growth factor-like peptide. We examined signal transduction pathways of DDR2. Here we show that DDR2 is also unusual in that it requires Src activity to be maximally tyrosine-phosphorylated, and that Src activity also promotes association of DDR2 with Shc. The interaction with Shc involves a portion of Shc not previously implicated in interaction with receptor tyrosine kinases. These results identify Src kinase and the adaptor protein Shc as key signaling intermediates in DDR2 signal transduction. Furthermore, Src is required for DDR2-mediated transactivation of the matrix metalloproteinase-2 promoter. The data support a model in which Src and the DDR2 receptor cooperate in a regulated fashion to direct the phosphorylation of both the receptor and its targets.

Abstract Advances in our understanding of the mechanisms involved in immune activation and immune tolerance have laid the foundation for the development of new strategies for treating autoimmune diseases. In particular, the dissection of the two-signal process of T-cell activation has identified distinct targets that may provide a means of blocking pathological autoimmune responses without causing sustained blockade of protective immune responses. These strategies have shown great promise in animal models for autoimmune diseases, and they are currently the focus of clinical investigation in several autoimmune diseases of humans.

BACKGROUND

Indirect evidence and modeling analyses suggest that colonoscopy may be the most cost-effective way to screen the average-risk population for colorectal neoplasia. However, the success and safety of primary colonoscopic screening has not been prospectively evaluated in a multicenter trial.

METHODS

Asymptomatic subjects age 50 to 75 years who had not undergone examination of the colon within 10 years were recruited from the general medicine clinics of 13 Department of Veterans Affairs Medical Centers. Eligible patients underwent colonoscopy by study coinvestigators, at which time all polyps were measured, photographed, and removed. Patients were contacted at 24 hours and 1 week to track procedure-related complications.

RESULTS

Primary screening colonoscopy was performed in a cohort of 3196 asymptomatic subjects. A "good" preparation was reported in 81% of patients, and colonoscopy to the cecum was successful in 97.2% of cases. Mean insertion time to the cecum and total procedure times were 10.5 (8.7) and 30.6 (19.1) minutes, respectively. No preprocedural patient characteristics were identified that were predictive of an incomplete procedure. At least one polyp was resected in 1672 patients. There was no perforation and no death attributed to colonoscopy. Major morbidity considered to be definitely related to colonoscopy occurred in 9 of 3196 procedures (0.3%): lower GI bleeding requiring intervention (6), myocardial infarction and/or cerebrovascular accident (2), and thrombophlebitis (1). In subjects undergoing only diagnostic procedures, the major complication rate was 0.1%.

CONCLUSIONS

Screening colonoscopy can be performed in multiple centers with a high degree of success and safety in large numbers of asymptomatic, average-risk men.

CONTEXT

Raloxifene, a selective estrogen receptor modulator, improves cardiovascular risk factors, but its effect on cardiovascular events is unknown.

OBJECTIVE

To determine the effect of raloxifene on cardiovascular events in osteoporotic postmenopausal women.

DESIGN

Secondary analysis of data from the Multiple Outcomes of Raloxifene Evaluation trial, a randomized, double-blind, placebo-controlled trial conducted between November 1994 and September 1999.

SETTING

Outpatient and community settings at 180 sites in 25 countries.

PARTICIPANTS

A total of 7705 osteoporotic postmenopausal women (mean age, 67 years).

INTERVENTION

Patients were randomly assigned to receive raloxifene, 60 mg/d (n = 2557), or 120 mg/d (n = 2572), or placebo (n = 2576) for 4 years.

MAIN OUTCOME MEASURES

Cardiovascular events, including coronary events (myocardial infarction, unstable angina, or coronary ischemia) and cerebrovascular events (stroke or transient ischemic attack), collected as safety end points and subsequently adjudicated by a cardiologist blinded to therapy. Cardiovascular risk at study entry was determined by the presence of multiple cardiovascular risk factors or prior coronary events or revascularization procedure.

RESULTS

In the overall cohort, there were no significant differences between treatment groups in the number of combined coronary and cerebrovascular events: 96 (3.7%) with placebo, 82 (3.2%) with 60 mg/d of raloxifene, and 94 (3.7%) with 120 mg/d of raloxifene. Relative risks (RRs) were 0.86 (95% confidence interval [CI], 0.64-1.15) and 0.98 (95% CI, 0.74-1.30) for 60 mg/d and 120 mg/d of raloxifene, respectively. Similar results were obtained when coronary and cerebrovascular events were analyzed separately. Among the subset of 1035 women with increased cardiovascular risk at baseline, those assigned to raloxifene had a significantly lower risk of cardiovascular events compared with placebo (RR, 0.60; 95% CI, 0.38-0.95 for both raloxifene groups). The number of cardiovascular events during the first year was not significantly different across groups in the overall cohort (P =.94), or among women at increased cardiovascular risk (P =.86) or with evidence of established coronary heart disease (P =.60).

CONCLUSIONS

Raloxifene therapy for 4 years did not significantly affect the risk of cardiovascular events in the overall cohort but did significantly reduce the risk of cardiovascular events in the subset of women with increased cardiovascular risk. There was no evidence that raloxifene caused an early increase in risk of cardiovascular events. Before raloxifene is used for prevention of cardiovascular events, these findings require confirmation in trials with evaluation of cardiovascular outcomes as the primary objective.

Transport of lung liquid is essential for both normal pulmonary physiologic processes and for resolution of pathologic processes. The large internal surface area of the lung is lined by alveolar epithelial type I (TI) and type II (TII) cells; TI cells line >95% of this surface, TII cells <5%. Fluid transport is regulated by ion transport, with water movement following passively. Current concepts are that TII cells are the main sites of ion transport in the lung. TI cells have been thought to provide only passive barrier, rather than active, functions. Because TI cells line most of the internal surface area of the lung, we hypothesized that TI cells could be important in the regulation of lung liquid homeostasis. We measured both Na(+) and K(+) (Rb(+)) transport in TI cells isolated from adult rat lungs and compared the results to those of concomitant experiments with isolated TII cells. TI cells take up Na(+) in an amiloride-inhibitable fashion, suggesting the presence of Na(+) channels; TI cell Na(+) uptake, per microgram of protein, is approximately 2.5 times that of TII cells. Rb(+) uptake in TI cells was approximately 3 times that in TII cells and was inhibited by 10(-4) M ouabain, the latter observation suggesting that TI cells exhibit Na(+)-, K(+)-ATPase activity. By immunocytochemical methods, TI cells contain all three subunits (alpha, beta, and gamma) of the epithelial sodium channel ENaC and two subunits of Na(+)-, K(+)-ATPase. By Western blot analysis, TI cells contain approximately 3 times the amount of alphaENaC/microg protein of TII cells. Taken together, these studies demonstrate that TI cells not only contain molecular machinery necessary for active ion transport, but also transport ions. These results modify some basic concepts about lung liquid transport, suggesting that TI cells may contribute significantly in maintaining alveolar fluid balance and in resolving airspace edema.