Effective treatment of ductal carcinoma in situ with a HER-2- targeted alpha-particle emitting radionuclide in a preclinical model of human breast cancer.

The standard treatment for ductal carcinoma in situ (DCIS) of the breast is surgical resection, followed by radiation. Here, we tested localized therapy of DCIS in mice using the immunoconjugate 225Ac linked-trastuzumab delivered through the intraductal (i.duc) route. Trastuzumab targets HER-2/neu, while the alpha-emitter 225Ac (half-life, 10 days) delivers highly cytotoxic, focused doses of radiation to tumors. Systemic 225Ac, however, elicits hematologic toxicity and at high doses free 213Bi, generated by its decay, causes renal toxicity. I.duc delivery of the radioimmunoconjugate could bypass its systemic toxicity. Bioluminescent imaging showed that the therapeutic efficacy of intraductal 225Ac-trastuzumab (10-40 nCi per mammary gland; 30-120 nCi per mouse) in a DCIS model of human SUM225 cancer cells in NSG mice was significantly higher (p<0.0003) than intravenous (120 nCi per mouse) administration, with no kidney toxicity or loss of body weight. Our findings suggest that i.duc radioimmunotherapy using 225Ac-trastuzumab deserves greater attention for future clinical development as a treatment modality for early breast cancer.

Alterations in vascular gene expression in invasive breast carcinoma.

The molecular signature that defines tumor microvasculature will likely provide clues as to how vascular-dependent tumor proliferation is regulated. Using purified endothelial cells, we generated a database of gene expression changes accompanying vascular proliferation in invasive breast cancer. In contrast to normal mammary vasculature, invasive breast cancer vasculature expresses extracellular matrix and surface proteins characteristic of proliferating and migrating endothelial cells. We define and validate the up-regulated expression of VE-cadherin and osteonectin in breast tumor vasculature. In contrast to other tumor types, invasive breast cancer vasculature induced a high expression level of specific transcription factors, including SNAIL1 and HEYL, that may drive gene expression changes necessary for breast tumor neovascularization. We demonstrate the expression of HEYL in tumor endothelial cells and additionally establish the ability of HEYL to both induce proliferation and attenuate programmed cell death of primary endothelial cells in vitro. We also establish that an additional intracellular protein and previously defined metastasis-associated gene, PRL3, appears to be expressed predominately in the vasculature of invasive breast cancers and is able to enhance the migration of endothelial cells in vitro. Together, our results provide unique insights into vascular regulation in breast tumors and suggest specific roles for genes in driving tumor angiogenesis.

Blood lead level of children in the urban areas in China / 中华流行病学杂志

<p><b>OBJECTIVE</b>The purpose of this study was to investigate the blood lead level of 3 - 5 year old children living in the cities in China and to provide scientific data for making policy on environmental lead pollution for children health protection.</p><p><b>METHODS</b>Six thousand five hundred and two vein blood samples from 3 - 5 year old children in nineteen cities of nine provinces were sampled. Inductively coupled plasma-mass spectrometry (ICP-MS) were employed to determine lead level in whole blood after microwave digestion for sample preparation and questionnaire survey was also performed. Data were analyzed with multiple regression on factors which affecting blood lead levels.</p><p><b>RESULTS</b>Results showed that mean blood lead level was 88.3 micro g/L for 3 - 5 year old children living in the cities in China and mean blood lead level of boys (91.1 micro g/L) was higher than that of girls (87.3 micro g/L). Twenty-nine point nine one per cent of the children's blood lead level exceeded 100 micro g/L. The research finding showed: (1) higher blood lead levels had negative effects on children's physical growth, language ability etc. (2) behavior of parents had certain effects on children's blood lead levels. (3) blood lead levels of children were affected by unhealthy habits.</p><p><b>CONCLUSIONS</b>Problem of childhood lead poisoning in China has become more serious. During the past ten years, blood lead levels of children has been increased in China while decreasing in developed countries. Blood lead levels of children in China are higher than that of developed countries, which called for special concern by government and society.</p>