PADGEM (GMP140) is a component of Weibel-Palade bodies of human endothelial cells

PADGEM protein (PADGEM), also known as GMP140, is a platelet alpha- granule membrane protein that is translocated to the external membrane after platelet activation. Although the biosynthesis of this protein was originally thought to be confined to megakaryocytes, the synthesis of PADGEM in endothelial cells was recently demonstrated (McEver et al: Blood 70:1974a, 1987). We now describe the subcellular localization of this protein in endothelial cells. Immunofluorescence staining of permeabilized human umbilical vein endothelial cells with KC4, a well characterized monoclonal antibody to PADGEM, showed positively stained elongated structures similar in distribution and shape to Weibel-Palade bodies. Their identity as Weibel-Palade bodies was confirmed by double label immunofluorescence using KC4 and a polyclonal antiserum to von Willebrand factor (vWf), a protein known to be specifically stored in these organelles. All Weibel-Palade bodies were found to contain PADGEM. In contrast to strong perinuclear staining produced with anti- vWf antibodies, no significant perinuclear staining was obtained with KC4, indicating that relatively little PADGEM is present in the endoplasmic reticulum and in the Golgi apparatus. In endothelial cells treated with secretagogues that stimulate vWf release the elongated structures positive for PADGEM disappeared, further identifying these structures as Weibel-Palade bodies. This observation extends the parallels between Weibel-Palade bodies and alpha-granules and suggests a possible functional association between vWf and PADGEM.     

BUILDING THE FOUNDATION OF EXCELLENCE IN HEART FAILURE NURSING

This column contains the presidential address presented during the Third Annual Meeting of the American Association of Heart Failure Nurses on June 28, 2007, in San Diego, California, titled "Building the Foundation of Excellence in Heart Failure Nursing."     

Locoregional chemotherapy in the treatment of liver metastasis of breast carcinoma]

Locoregional chemotherapy enables specific treatment of organ metastases by using a dosage of medication that is maximally effective but only has minimal side effects on other organs. Since 1983, we have applied this procedure in patients whose liver represented the only target-organ of metastases. Between 1983 and 1990, locoregional chemotherapy was performed in 59 women suffering from liver metastases of breast cancer. The average age of our patients was 52 years. 4 patients were treated for solitary metastases that could not be resected, in 5 patients the infiltration of hepatic parenchyma with metastases accounted to 25%, in 32 patients hepatic infiltration ranged between 25% and 75% and in 18 patients it surpassed 75%. In 39% of our patients, a partial remission occurred. The mean period of survival after beginning of treatment was 149 days, whereas the longest survival time lasted 1009 days. We conclude that the locoregional chemotherapy, destined for treatment of liver-metastases of breast cancer, with a mean survival time of only five months could insufficiently satisfy our expectations. Therefore, a decision to administer such palliative therapy should be made on an individual basis. In our opinion, one indication represents solitary metastases that are not resectable, a further indication is pain due to expansion of the liver capsule because of diffuse metastases.     

Diethylnitrosamine-induced metastasizing hepatocellular carcinomas in New Zealand white rabbits

Summary The aim of this study was to produce large liver tumors reliably, and to diagnose the tumors during development. Therefore, New Zealand white rabbits were treated withN-nitrosodiethylamine orally three times per week by gavage and were examined by clinical-chemical assay at regular intervals during the average treatment period of 14 months. The total cumulative dose was 1200 mgN-nitrosodiethylamine over 14 months. After a short treatment period the initial dose of 3 mg/kg had to be reduced to 1.5 mg/kg. In all 11 treated animals (100%) liver tumors were seen at the end of the study. Four control animals did not show any neoplastic changes. Clinical parameters investigated were for an assessment of liver function, total protein, urea, creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin and neuraminic acid as well as some serum electrolytes. The in vivo diagnosis of liver tumors based on changes in these parameters proved to be relatively unreliable. The liver enzyme tests and urea concentration only yielded significant changes when the liver tumors were very large. Changes in neuraminic acid levels were the most reliable indicator for the presence of a liver tumor in this animal model. In the 11 treated animals, serum values of this marker increased towards the end of the study'by an average of 300 mg/dl. The induced tumors were mainly hepatocellular carcinomas. Only in 1 animal was a hepatocellular adenoma found. Further primary tumors diagnosed were six adenomas in the kidneys and two uterus adenomas, as well as nasal cavity tumors (two papillomas, one carcinoma, one adenoma and one adenocarcinoma). In 70% of the treated rabbits the hepatocellular carcinomas had metastasized to the lungs.