Although obesity is known as a risk factor for several human cancers, the association of obesity with cancer recurrence and metastasis remains to be characterized. Here, B16-BL6 melanoma and Lewis lung carcinoma cells were intravenously injected into diabetic (db/db) and obese (ob/ob) mice. The number of experimental lung colonies was markedly promoted in these mice when compared with C57BL/6 mice. In contrast, tumor growth at the implanted site was comparable when cells were inoculated orthotopically. The use of B16-BL6 cells stably transfected with the luciferase gene revealed that the increased metastasis reflected a difference mainly within 6 hr after the intravenous inoculation of tumor cells. Administration of recombinant leptin in ob/ob mice abolished the increase in metastasis early on as well as the decrease in the splenic NK cell number. In addition, depletion of NK cells by an anti-asialo-GM1 antibody abrogated the enhanced metastasis in db/db mice. These results demonstrate that metastasis is markedly promoted in diabetic and obese mice mainly because of decreased NK cell function during the early phase of metastasis. ' 2006 Wiley-Liss, Inc.Key words: obesity; metastasis; NK cell; leptin Obesity has become one of the most critical problems in human health, because it can lead to more serious disorders such as cardiovascular disease, pulmonary disorders and metabolic syndrome. 1 Attention has recently been focused on the influence of obesity on carcinogenesis and the progression of cancer. A cohort study in the United States revealed that an increased body-mass index is significantly associated with higher rates of death because of cancer. 2 In addition, obesity increases the risk of cancer developing in the prostate, colorectum, breast, endometrium and elsewhere. [3][4][5][6][7] Similarly, the risk of renal cell cancer is increased in patients with diabetes mellitus, a disease closely associated with obesity. 8 These observations are well correlated with the finding that the carcinogen-induced multiplicity of premalignant colonic lesions is increased in db/db obese and diabetic mice. 9 Metastasis is the major cause of mortality in cancer patients. Maehle et al. reported that breast cancer patients with obesity had a higher risk of lymph node metastases. 10 Although evidence has accumulated of an association of cancer with obesity, the influence of obesity and diabetes on cancer metastasis remains to be investigated. In addition, the mechanisms by which obesity promotes the development and progression of cancer are still unknown. Material and methods MiceMale C57BL/6, C57BL/KsJ-db/db (db/db) and C57BL/6J-ob/ob (ob/ob) mice, 5-6 weeks old, were maintained in a specific pathogen-free barrier facility under laminar airflow conditions with a 12-hr light/dark cycle, a controlled humidity of 55% 6 5% and a temperature of 22°C 6 1°C. This study was conducted in accordance with the standards outlined in the Guidelines for the Care and Use of Laboratory Animals of the University of Toyama. Cell cultureB16-BL6 ...

A new circuit recognition and reduction method to extract subcircuit data corresponding to the critical paths, including all relevant parasitics and intemal loading, is presented. Circuit elements extracted from layout pattem data are combined together to reconstruct logic gates, and a structure of the gates are recognized by the connection between the gate terminals. The recognized circuit data is reduced by tracing signal flows and picking up the gates along the specified critical paths. The circuit elements connected between a remaining net and an eliminated net are terminated as capacitive loads, and parasitic elements are merged or eliminated when the estimated error is permissible, compared with the specified error tolerance. The error is estimated by the first-order moment of the impulse response. Results on logic macrocells and memory peripheral control circuits show that the reduced circuit sizes are 15 -50 times smaller, resulting in circuit simulation speedups of 50x -300x.

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