Milk fat globule--epidermal growth factor--factor VIII (MFGE8)/lactadherin promotes bladder tumor development.

Milk fat globule-epidermal growth factor-factor VIII (MFGE8), also called lactadherin or SED1, is a secreted integrin-binding protein that promotes elimination of apoptotic cells by phagocytes leading to tolerogenic immune responses, and vascular endothelial growth factor (VEGF)-induced angiogenesis: two important processes for cancer development. Here, by transcriptomic analysis of 228 biopsies of bladder carcinomas, we observed overexpression of MFGE8 during tumor development, correlated with expression of genes involved in cell adhesion or migration and in immune responses, but not in VEGF-mediated angiogenesis. To test whether MFGE8 expression was instrumental in bladder tumor development, or a simple consequence of this development, we used genetic ablation in a mouse model of carcinogen-induced bladder carcinoma. We showed that Mfge8 was also upregulated in mouse carcinoma, and that in its absence, Mfge8-deficient animals developed less advanced tumors. Angiogenesis was similar in carcinogen-treated Mfge8-expressing or -deficient bladders, thus ruling out a major role of the proangiogenic function of Mfge8 for its protumoral role. By contrast, the tumor-promoting role of Mfge8 was not observed anymore in mice devoid of adaptive immune system, and human tumors overexpressing MFGE8 where invaded with macrophages and regulatory T cells, thus suggesting that MFGE8/lactadherin favors development of bladder tumors at least partly by an immune system-dependent mechanism. Our observations suggest future use of MFGE8-inhibiting molecules as therapies of bladder carcinomas, and of a limited number of other human cancers, in which our analysis of public databases also revealed overexpression of MFGE8.

Computation of recurrent minimal genomic alterations from array-CGH data.

MOTIVATION: The identification of recurrent genomic alterations can provide insight into the initiation and progression of genetic diseases, such as cancer. Array-CGH can identify chromosomal regions that have been gained or lost, with a resolution of approximately 1 mb, for the cutting-edge techniques. The extraction of discrete profiles from raw array-CGH data has been studied extensively, but subsequent steps in the analysis require flexible, efficient algorithms, particularly if the number of available profiles exceeds a few tens or the number of array probes exceeds a few thousands. RESULTS: We propose two algorithms for computing minimal and minimal constrained regions of gain and loss from discretized CGH profiles. The second of these algorithms can handle additional constraints describing relevant regions of copy number change. We have validated these algorithms on two public array-CGH datasets. AVAILABILITY: From the authors, upon request. CONTACT: celine@lri.fr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Dipyridamole thallium-201 imaging pre- and post-coronary angioplasty for assessment of regional myocardial ischemia in humans.

To examine the effect of coronary angioplasty on myocardial perfusion and to examine anatomic correlates of dipyridamole-thallium images, we performed dipyridamole thallium scanning before and after 24 angioplasty procedures in 23 patients with clinical ischemia. Dipyridamole thallium tomography was performed 1 to 4 (mean +/- S.D. 1.5 +/- 0.9) days before and 1 to 25 (6.3 +/- 6.9) days after angioplasty. Coronary angioplasty was anatomically successful (less than 50% residual stenosis) in 23 of 24 patients. Before angioplasty, 3 of 24 scans were interpreted as normal, with no change in these patients following angioplasty. Prior to angioplasty, 19 scans showed redistribution. After successful coronary angioplasty in 18 of 19, 17 showed improvement in dipyridamole thallium scanning; one did not show improvement and later required repeat coronary dilatation. In one patient with failed angioplasty, images before and after angioplasty were unchanged. Nine scans showed "fixed" defects before angioplasty, with improvement in three of nine following angioplasty. Quantitative analysis of the dipyridamole thallium scans revealed significant improvement in uptake in the myocardial regions supplied by the successfully dilated artery (involved regions), but not in the remote (uninvolved) regions. We conclude that myocardial perfusion, as judged by dipyridamole thallium scanning, almost always improves following anatomically successful coronary angioplasty. "Fixed" defects may improve following angioplasty and presumably represent ischemia with incomplete redistribution, rather than infarction.

Differential effects of milrinone and dobutamine on right ventricular preload, afterload and systolic performance in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

To compare the effects of intravenous dobutamine and milrinone on right ventricular (RV) systolic function, 14 patients with severe congestive heart failure underwent simultaneous radionuclide-hemodynamic study. Patients were randomized to receive intravenous milrinone (50 micrograms/kg bolus then 0.5 microgram/kg/min) or dobutamine (2.5 to 15 micrograms/kg/min) to achieve equal increases in cardiac output. Both drugs significantly improved cardiac performance, with identical 24% increases in mean cardiac index (p less than 0.05 vs baseline; difference not significant for milrinone vs dobutamine) and no change in heart rate. Neither drug substantially altered RV preload, as reflected by mean right atrial pressure and RV end-diastolic volume. Both drugs caused similar increases in RV ejection fraction (mean +/- standard deviation; dobutamine: 0.32 +/- 0.09 to 0.40 +/- 0.11; p less than 0.05; milrinone: 0.35 +/- 0.19 to 0.43 +/- 0.21; p less than 0.05) resulting from reductions in RV end-systolic volume. RV afterload reduction contributed substantially to drug effect on RV systolic performance in patients treated with milrinone but not those treated with dobutamine. With doses effecting equal increases in cardiac index and RV systolic performance, pulmonary artery end-systolic pressure was significantly reduced by milrinone (40 +/- 12 to 33 +/- 12 mm Hg; p less than 0.05), but not by dobutamine. Thus, in patients with congestive heart failure milrinone's effect on RV systolic function is explainable, at least in part, by RV afterload reduction, whereas RV inotropic augmentation contributed more strongly to dobutamine's effect.