Structure and function of small airways in health and disease.

During the last two decades, great strides have been made in our understanding of the functional aspects of airflow in the periphery of the lung. It seems that the small airways are the important site of obstruction in a variety of chronic respiratory disorders associated with airflow obstruction. This review deals with the anatomic and functional aspects of small airways in normal and diseased lungs. In particular, the basis of obstruction or narrowing that is not dependent on intrinsic airway lesion is reviewed. The variety of pathologic changes in small airways observed in these diseases are outlined along with physiologic tests that are currently used to detect dysfunction at a stage long before they produce symptoms or alter standard tests of lung function.     

Residential exposure to magnetic fields: an empirical examination of alternative measurement strategies

OBJECTIVES: To investigate the impact of measuring a single home then imputing information from another home among subjects who lived in two homes in a subset of the National Cancer Institute/Children's Cancer Group (NCI/CCG) investigation of residential exposure to magnetic fields and risk of childhood leukaemia. METHODS: Each subject's summary time weighted average (TWA) exposure was derived from measurements of two homes, weighted by the fraction of the reference period lived in the residence. The three cost efficient field work strategies examined were measuring: (a) the longer lived in home; (b) the currently lived in home; and (c) the former lived in home. Two different methods were used for imputing the missing values: (a) control mean imputation, (b) status specific mean imputation. The subject's summary exposure to magnetic fields estimated with each approach was compared with the subject's TWA calculated from measurements in both homes. The association between estimated exposure to magnetic fields and the risk of leukaemia under different approaches was examined with unconditional logistic regression analysis. RESULTS: The Pearson correlation coefficient between the two measurements within subjects was 0.31 (p < 10(-4), indicating a lack of independence of measurements. Differences were found between mean exposures in current and former homes of cases, and between longer and shorter lived in homes of controls. All methods with measurements from one of the homes in conjunction with imputation of measurements for the second home led to marked attenuation of risk estimates at the highest exposure category, particularly when measurements from current homes were used and those from former homes were imputed. CONCLUSION: Results argue against attempting to estimate lifetime magnetic field exposure from imputed values derived from current residences to fill in gaps caused by unmeasured residences previously lived in.     

Liposomal muramyl tripeptide (CGP 19835A lipid) therapy for resectable melanoma in patients who were at high risk for relapse: an update

Liposome-encapsulated muramyl tripeptide-phosphatidyl ethanolamine (L-MTP-PE) was used in a pilot study for resectable melanoma patients who were at high risk for relapse. We entered 18 evaluable patients. The patient group included: (a) patients with stage III disease and clinically measurable regional metastases at presentation as confirmed by needle biopsy and (b) patients with stage IV disease presenting with measurable and resectable distant metastases confirmed by needle biopsy and limited to lungs, lymph nodes and subcutaneous tissues. L-MTP-PE was given for 4 weeks prior to surgical resection and for an additional 20 weeks postoperatively. Disease-free intervals were then determined based on the date of surgery. A preliminary report published in 1993 indicated an average disease-free interval of 18 months (range 8-33 months). This article presents an updated report on the long-term, disease-free survival status of these patients and shows that of the 18 evaluable patients, 4 remain free of disease for more than 5 years after surgical resection and therapy. The period of survival for these patients ranged from 69 months to more than 91 months (average 80.5 months). Although this was only a pilot study, we believe that the duration of survival indicates that L-MTP-PE may produce significant biologic activity in patients with melanoma, resulting in long-term benefits in terms of tumor eradication.     

Interleukin-12 enhances the sensitivity of human osteosarcoma cells to 4-hydroperoxycyclophosphamide by a mechanism involving the Fas/Fas-ligand pathway.

Cyclophosphamide (CY) and its derivative ifosfamide are alkylating agents used to treat osteosarcoma (OS). The purpose of these studies was to determine whether alkylating agents affect the expression of Fas ligand (FasL) and whether interleukin 12 enhances the sensitivity of human OS cells to alkylating agents. 4-Hydroperoxycyclophosphamide (4-HC), the preactivated CY compound, and 4-hydroperoxydidechlorocloclophosphamide (4-HDC), its nonalkylating analogue, human OS LM6 cells, and a clone of cells derived by transfection with the interleukin 12 gene (LM6-#6) were used for these studies. Incubation of LM6 and LM6-#6 with 10 micro M 4-HC increased the expression of FasL mRNA (2.5- and 3.0-fold, respectively). By contrast, 4-HDC, Adriamycin (ADR), cisplatin (CDP), and methotrexate (MTX) had no effect on FasL mRNA expression. Increased FasL expression after treatment with 4-HC was also demonstrated by immunohistochemistry and flow cytometry. Drug-induced FasL was functional and mediated cell death. We examined the effect of FasL up-regulation by 4-HC on LM6 and LM6-#6 cells. Flow cytometry showed that LM6-#6 cells expressed 2.2-fold more Fas than LM6 cells. Cytotoxicity of 4-HC, 4-HDC, ADR, CDP, and MTX on LM6, LM6-neo, and LM6-#6 were quantified. Colony-forming assay revealed an IC(50) of 2.10 micro M for 4-HC in LM6-neo cells compared with 0.41 micro M in LM6-#6 cells. The IC(50) for 4-HDC, ADR, CDP, and MTX were not significantly different between the two cell lines. We concluded that the increased expression of Fas enhanced LM6-#6 sensitivity to 4-HC. These data indicate that Fas/FasL may be involved in the cytotoxic pathway of CY. Combining biological agents with chemotherapeutic agents that have complementary Fas/FasL pathway actions may offer new therapeutic alternatives.     

Increased Fas expression reduces the metastatic potential of human osteosarcoma cells.

PURPOSE: The process of metastasis requires the single tumor cell that seeds the metastatic clone to complete a complex series of steps. Identifying factors responsible for these steps is essential in developing and improving targeted therapy for metastasis. Resistance to receptor-mediated cell death, such as the Fas/Fas ligand pathway, is one mechanism commonly exploited by metastatic cell populations. EXPERIMENTAL DESIGN AND RESULTS: LM7, a subline of the SAOS human osteosarcoma cell line with low Fas expression, was selected for its high metastatic potential in an experimental nude mouse model. When transfected with the full-length Fas gene (LM7-Fas), these cells expressed higher levels of Fas than the parental LM7 cells or LM7-neo control-transfected cells. These cells were also more sensitive to Fas-induced cell death than controls. When injected intravenously into nude mice, the LM7-Fas cell line produced a significantly lower incidence of tumor nodules than control cell lines. Lung weight and tumor nodule size were also decreased in those mice injected with LM7-Fas. Levels of Fas were quantified in osteosarcoma lung nodules from 17 patients. Eight samples were Fas negative, whereas the remaining 9 were only weakly positive compared with normal human liver (positive control). CONCLUSIONS: Our results demonstrate that altering Fas expression can impact the metastatic potential of osteosarcoma cells. We conclude that the increase of Fas on the surface of the LM7 osteosarcoma cells increased their sensitivity to Fas-induced cell death in the microenvironment of the lung, where Fas ligand is constitutively expressed. Thus, loss of Fas expression is one mechanism by which osteosarcoma cells may evade host resistance mechanisms in the lung, increasing metastatic potential. Fas may therefore be a new therapeutic target for osteosarcoma.     

Are children living near high-voltage power lines at increased risk of acute lymphoblastic leukemia?

In the National Cancer Institute/Children's Cancer Group case-control study of childhood acute lymphoblastic leukemia (1989-1993), living in a home with a high-voltage wire code was not associated with disease risk. To further investigate risk near power lines, the authors analyzed distance to transmission and three-phase primary distribution lines within 40 m of homes and created an exposure index of distance and strength of multiple power lines (408 case-control pairs). Neither distance nor exposure index was related to risk of childhood acute lymphoblastic leukemia, although both were associated with in-home magnetic field measurements. Residence near high-voltage lines did not increase risk.     

Vascular modulation through exercise improves chemotherapy efficacy in Ewing sarcoma

Recent studies in mouse models of cancer have shown that exercise improves tumor vascular function, thereby improving chemotherapy delivery and efficacy. However, the mechanisms underlying this improvement remain unclear and the effect of exercise on Ewing sarcoma (ES), a pediatric bone and soft tissue cancer, is unknown. The effect of exercise on tumor vascular hyperpermeability, which inversely correlates with drug delivery to the tumor, has also not been evaluated. We hypothesized that exercise improves chemotherapy efficacy by enhancing its delivery through improving tumor vascular permeability. We treated ES‐bearing mice with doxorubicin with or without moderate treadmill exercise. Exercise did not significantly alter ES tumor vessel morphology. However, compared to control mice, tumors of exercised mice had significantly reduced hyperpermeability, significantly decreased hypoxia, and higher doxorubicin penetration. Compared to doxorubicin alone, doxorubicin plus exercise inhibited tumor growth more efficiently. We evaluated endothelial cell sphingosine‐1‐phosphate receptors 1 and 2 (S1PR1 and S1PR2) as potential mediators of the improved vascular permeability and increased function afforded by exercise. Relative to tumors from control mice, vessels in tumors from exercised mice had increased S1PR1 and decreased S1PR2 expression. Our results support a model in which exercise remodels ES vasculature to reduce vessel hyperpermeability, potentially via modulation of S1PR1 and S1PR2, thereby improving doxorubicin delivery and inhibiting tumor growth more than doxorubicin alone does. Our data suggest moderate aerobic exercise should be tested in clinical trials as a potentially useful adjuvant to standard chemotherapy for patients with ES.     

Pharmacology of human spontaneous monocyte-mediated cytotoxicity

The effect of various antiinflammatory agents on the spontaneous cytotoxicity of human mononuclear cells in vitro was assessed. Acetylsalicylic acid (ASA) and hydrocortisone enhanced spontaneous monocyte-mediated cytotoxicity compared to control values. This enhancement could not be mediated through inhibition of prostaglandin biosynthesis since indomethacin had no effect on cytotoxic function and since the direct addition of PGE₂ to the cell cultures did not inhibit the expression of cytotoxicity. Likewise, salicylic acid (SA), which has no effect on prostaglandin biosynthesis, also enhanced monocyte cytotoxicity. Stimulation of monocyte-mediated cytotoxicity resulting in more efficient antigen removal and thus decreasing antigen persistence may be an additional mechanism by which ASA, SA, and hydrocortisone modulate the destructive inflammatory response in rheumatoid arthritis.     

Adenovirus-E1A gene therapy enhances the in vivo sensitivity of Ewing's sarcoma to VP-16

This study determined the effect of Ad-E1A gene therapy in vivo. TC71 cells (2 x 10(6)) injected subcutaneously into nude mice resulted in tumor development (1-3 mm) 6 days later. Animals were then treated with Ad-E1A or Ad-beta-gal (5 x 10(9) plaque-forming units) by intratumoral injection twice weekly for 2 weeks. Animals received 8 mg/kg VP-16 given by intraperitoneal injection daily for 5 days following the first week of treatment with Ad-E1A or Ad-beta-gal. Control animals received no therapy or VP-16 only after tumor cells were injected. When tumors exceeded 2 x 2 cm, the mice were sacrificed and the tumors underwent histologic and immunohistochemical analysis. Tumors from mice treated with Ad-E1A plus VP-16 were 9.6-fold smaller than those treated with VP-16 alone and 6.3-fold smaller than those treated with Ad-E1A alone. HER2/neu p185 protein expression decreased in all tumors that received Ad-E1A therapy. TUNEL fluorescence staining revealed more apoptosis in the tumors from animals treated with Ad-E1A plus VP-16 than in those from animals treated with Ad-E1A alone, Ad-beta-gal plus VP-16, or VP-16 alone. These data demonstrated that Ad-E1A gene therapy down-regulated HER2/neu expression, increased tumor cell apoptosis induced by VP-16, and enhanced tumor cell sensitivity to VP-16. Ad-E1A may have potential in the treatment of relapsed drug-resistant Ewing's sarcoma.