Background-Obesity increases the risk of cardiovascular disease, hypertension, diabetes, digestive diseases, and some cancers. Several studies have shown that excess weight or weight gain is related to pulmonary dysfunction, but this issue needs to be further clarified. Methods-The analysis was based on data of the Humboldt cohort study which was conducted in the town of Humboldt, Saskatchewan, Canada. The baseline survey in 1977 included 1202 adults, comprising 94% of all residents aged 25-59 years. Of these, 709 (59%) were followed up in 1983. Pulmonary function (forced vital capacity (FVC), forced expiratory volume in one second (FEVy) and maximal mid expiratory flow rate (MMFR)) and weight were measured in both surveys. Weight gain was determined by subtracting weight at baseline from weight at follow up. A residual analysis was used to examine the relationship between body mass index (BMI) at baseline, weight gain, and pulmonary function decline. Results-Both BMI at baseline and weight gain were significantly related to pulmonary function at follow up. The effect of weight gain during the study period, however, was more prominent. The results showed that both mean residual FVC and FEV, were highest in the group that gained <10 kg, lowest in the group that gained > 4.0 kg, and intermediate in the group that gained 1-03-9 kg in both men and women after taking age, BMI at baseline, and smoking into account. The effect of weight gain on pulmonary function was greater in men than in women. Multiple regression analysis showed that each kilogram of weight gain was associated with an excess loss of 26 ml in FVC and 23 ml in FEV, in men, and 14 ml and 9 ml respectively in women.Conclusions-Weight gain is significantly The relationship between obesity or excess weight and health and longevity has been receiving increasing attention.' 2 Numerous epidemiological studies have shown that obesity might increase the risk of cardiovascular disease, hypertension, diabetes, and cancer, as well as other diseases including arthritis, gout, kidney stones, and gallbladder disease.' A number of clinical studies3-"3 have described the effects of obesity on lung function test variables including functional residual capacity and expiratory reserve volume; however, the studies on the relationship between obesity and airways function have given inconsistent results.Body weight and weight gain as risk factors for pulmonary dysfunction have not been well documented by population based studies. In a cross sectional study of data from 3046 children and adults (seven years and over), Schoenberg et aP4 found that pulmonary function initially increased as weight increased and then decreased as weight continued to increase. They considered that the increase of pulmonary function with weight may reflect increasing muscle force, and the decrease with further weight gain may be due to obesity which limits the mobility of the thoracic cage. 14

Approximately one third of patients with advanced human epidermal growth factor receptor 2 (HER-2)/neu-positive breast cancer respond to trastuzumab monotherapy, a humanized anti-HER-2/neu antibody. However, de novo and acquired antibody resistance is one of the major limitations of trastuzumab therapy warranting the search for other therapeutic strategies. One of the most remarkable features of adenovirus (AdV)-based vaccine is its ability to induce exceptionally high and sustained frequencies of transgene product-specific CD8 þ T-cell responses. In this study, we constructed two recombinant AdVs (AdV OVA and AdV HER-2 ) expressing ovalbumin (OVA) and HER-2/neu, and assessed AdV-induced antigen-specific cellular immune responses and preventive/therapeutic antitumor immunity. We demonstrate that AdV OVA stimulates efficient OVA-specific CD8 þ cytotoxic T lymphocyte (CTL) and natural killer responses, leading to preventive long-term immunity against OVA-expressing BL6-10ova melanoma in wild-type C56BL/6 mice. We further demonstrate that AdV HER-2 stimulates HER-2/neu-specific CD8 þ CTL responses, leading to a significant reduction in breast carcinogenesis in transgenic FVBneuN mice (Po0.05), but has little therapeutic effect on pre-existing Tg1-1 tumor even at early stage (15 mm 3 ). In contrast, the anti-HER-2/neu antibody therapy is capable of completely inhibiting Tg1-1 tumor growth at early stage, but fails to eradicate well-established Tg1-1 breast tumor (100 mm 3 ). Interestingly, a combinatorial immunotherapy of anti-HER-2/neu antibody with AdV HER-2 vaccine was capable of curing 4 of 10 studied mice bearing well-established Tg1-1 breast tumors and significantly delaying in death of the remaining six tumor-bearing mice (Po0.05). Taken together, our results suggest an adjuvant effect of AdV HER-2 on anti-HER-2/neu antibody therapy for well-established breast tumor in transgenic FVBneuN mice, and this combinatorial immunotherapy of trastuzumab with AdV HER-2 vaccine may be used as a new therapeutic strategy for treatment of advanced HER-2/neu-positive breast cancer.

One of the major obstacles in human epidermal growth factor receptor (HER)-2/neu-specific trastuzumab immunotherapy of HER2/neu-positive breast cancer is the development of trastuzumab resistance, warranting the search for other therapeutic strategies. Although dendritic cell (DC) vaccines have been extensively applied in clinical trials for cancer treatment, the vaccination efficacy is still limited, mostly because DC vaccines are not sufficient to break tumor-associated antigen-specific self-immune tolerance in cancer patients. P30 (FNNFTVSFWLRVPKVSASHLE) derived from tetanus toxin is a universally potent CD4(+) T helper epitope capable of enhancing CD8(+) cytotoxic T-lymphocyte (CTL) responses. In this study, we constructed two recombinant adenoviral vectors (AdVs), AdVOVA-P30 and AdVHER2/neu-P30, expressing ovalbumin (OVA)-P30 and HER2/neu-P30. In order to enhance DC vaccine efficacy, we transfected mouse bone marrow (BM)-derived DCs with AdVOVA-P30 and AdVHER2/neu-P30 to generate engineered DCOVA-P30 and DCHER2/neu-P30 vaccines, respectively. We, then, compared CD4(+) and CD8(+) T-cell responses and antitumor immunity derived from DCOVA-P30 and DCHER2/neu-P30 vaccination in wild-type C57BL/6 and transgenic FVBneuN mice, respectively. We demonstrate that engineered DCOVA-P30 vaccine stimulates more efficient CD4(+) and CD8(+) T-cell responses than DCOVA in C57BL/6 mice. Interestingly, the increased DCOVA-P30-induced CTL responses are mainly contributed by enhanced CD4(+) T-cell-stimulated CTL proliferation. We show that DCOVA-P30 vaccine also stimulates more efficient therapeutic immunity against OVA-expressing BL6-10OVA melanoma than DCOVA in C57BL/6 mice. In addition, we demonstrate that DCHER2/neu-P30 vaccine stimulates more efficient CD4(+) and CD8(+) T-cell responses and protective immunity against HER2/neu-expressing Tg1-1 breast cancer than DCHER2/neu in transgenic FVBneuN mice with HER2/neu-specific self-immune tolerance. Therefore, the engineered DCHER2/neu-P30 vaccine may provide a new immunotherapy alternative for women with HER2/neu(+) breast cancer, especially for trastuzumab-resistant HER2/neu(+) breast cancer patients.