Understanding the mechanisms underlying carcinogenesis provides insights that are necessary for the development of therapeutic strategies to prevent cancer. Chemoprevention, the use of drugs or natural substances to inhibit carcinogenesis, is a rapidly evolving aspect of cancer research. Evidence is presented that cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) are potential pharmacologic targets to prevent cancer. In this paper, we review key data implicating a causal relationship between COX-2, EGFR, and carcinogenesis and possible mechanisms of action. We discuss evidence of crosstalk between COX-2 and EGFR in order to strengthen the rationale for combination chemoprevention, and review plans for a clinical trial that will evaluate the concept of combination chemoprevention targeting COX-2 and EGFR.

Prostaglandin E2 (PGE2) can stimulate tumor progression by modulating several proneoplastic pathways, including proliferation, angiogenesis, cell migration, invasion, and apoptosis. Although steady-state tissue levels of PGE2 stem from relative rates of biosynthesis and breakdown, most reports examining PGE2 have focused solely on the cyclooxygenase-dependent formation of this bioactive lipid. Enzymatic degradation of PGE2 involves the NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). The present study examined a range of normal tissues in the human and mouse and found high levels of 15-PGDH in the large intestine. By contrast, the expression of 15-PGDH is decreased in several colorectal carcinoma cell lines and in other human malignancies such as breast and lung carcinomas. Consistent with these findings, we observe diminished 15-Pgdh expression in ApcMin+/- mouse adenomas. Enzymatic activity of 15-PGDH correlates with expression levels and the genetic disruption of 15-Pgdh completely blocks production of the urinary PGE2 metabolite. Finally, 15-PGDH expression and activity are significantly down-regulated in human colorectal carcinomas relative to matched normal tissue. In summary, these results suggest a novel tumor suppressive role for 15-PGDH due to loss of expression during colorectal tumor progression.

We investigated health effects associated with fine particulate matter during a long-lived, large wildfire complex in northern California in the summer of 2008. We estimated exposure to PM2.5 for each day using an exposure prediction model created through data-adaptive machine learning methods from a large set of spatiotemporal data sets. We then used Poisson generalized estimating equations to calculate the effect of exposure to 24-hour average PM2.5 on cardiovascular and respiratory hospitalizations and ED visits. We further assessed effect modification by sex, age, and area-level socioeconomic status (SES). We observed a linear increase in risk for asthma hospitalizations (RR=1.07, 95% CI=(1.05, 1.10) per 5µg/m(3) increase) and asthma ED visits (RR=1.06, 95% CI=(1.05, 1.07) per 5µg/m(3) increase) with increasing PM2.5 during the wildfires. ED visits for chronic obstructive pulmonary disease (COPD) were associated with PM2.5 during the fires (RR=1.02 (95% CI=(1.01, 1.04) per 5µg/m(3) increase) and this effect was significantly different from that found before the fires but not after. We did not find consistent effects of wildfire smoke on other health outcomes. The effect of PM2.5 during the wildfire period was more pronounced in women compared to men and in adults, ages 20-64, compared to children and adults 65 or older. We also found some effect modification by area-level median income for respiratory ED visits during the wildfires, with the highest effects observed in the ZIP codes with the lowest median income. Using a novel spatiotemporal exposure model, we found some evidence of differential susceptibility to exposure to wildfire smoke.

Significant increases in asthma morbidity and mortality in the United States have occurred since the 1970s, particularly among African-Americans. Exposure to various environmental factors, including air pollutants and allergens, has been suggested as a partial explanation of these trends. To examine relations between several air pollutants and asthma exacerbation in African-Americans, we recruited a panel of 138 children in central Los Angeles. We recorded daily data on respiratory symptoms and medication use for 13 weeks and examined these data in conjunction with data on ozone (O3) nitrogen dioxide (NO2), particulate matter (PM10 and PM2.5), meteorological variables, pollens, and molds. Using generalized estimating equations, we found associations between respiratory symptom occurrence and several environmental factors. For example, new episodes of cough were associated with exposure to PM10 (OR = 1.25; 95% CI = 1.12-1.39; interquartile range [IQR] = 17 microg/m3, 24-hour average), PM2.5 (OR = 1.10; 95% CI = 1.03-1.18; IQR = 30 microg/m3, 12-hour average), NO2, and the molds Cladosporium and Alternaria, but not with exposure to O3 or pollen. The factors PM10 and O3 were associated with the use of extra asthma medication. For this population several bioaerosols and air pollutants had effects that may be clinically significant.

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