Molecular mechanism of PUVA-induced apoptosis in mouse epidermal cells

A combination of psoralens and ultraviolet-A radiation referred to as PUVA, is widely used in the treatment of psoriasis. PUVA therapy is highly effective in killing hyperproliferative cells, but its mechanism of action has not been fully elucidated. Psoralen binds to DNA, and upon photoactivation by UVA, it forms monofunctional adducts and interstrand cross-links. PUVA treatment has been shown to be mutagenic and to produce tumors in animals. In addition, epidemiological studies have reported a 10 to 15 percent increased risk of developing squamous cell carcinoma in individuals treated chronically with PUVA. However, it remains a treatment for skin disorders such as psoriasis because its benefits outweigh its risks. The widespread use of PUVA therapy and its associated cancer risk requires us to understand the molecular mechanisms by which PUVA induces cell death. Immortalized JB6 mouse epidermal cells, p53−/− mice, and Fas Ligand−/− (gld) mice were used to investigate the molecular mechanism by which PUVA kills cells. Treatment of JB6 cells with 10 μg/ml 8-methoxypsoralen followed by irradiation with 20 kJ/m2 UVA resulted in cell death. The cells exhibited morphological and biochemical characteristics of apoptosis such as chromatin condensation, DNA ladder formation, and TUNEL-positivity. PUVA treatment stabilized and phosphorylated p53 leading to its activation, as measured by nuclear localization and induction of p21Waf/Cip1, a transcriptional target of p53. Subsequent in vivo studies revealed that there was statistically significantly less apoptosis in p53 −/− mice than in p53+/+ mice at 72 hours after PUVA. In addition, immunohistochemical analysis revealed more Fas and FasL expression in p53+/+ mice than in p53−/− mice, suggesting that p53 is required to transcriptionally activate Fas, which in turn causes the cells to undergo apoptosis. Studies with gld mice confirmed a role for Fas/FasL interactions in PUVA-induced apoptosis. There was statistically significantly less apoptosis in gld mice compared with wild-type mice 24, 48, and 72 hours after PUVA. These results demonstrate that PUVA-induced apoptosis in mouse epidermal cells requires p53 and Fas/FasL interactions. These findings may be important for designing effective treatments for diseases such as psoriasis without increasing the patient's risk for skin cancer. ^

A comparison of worker risk of injury while working on fully automated side loaders and other residential collection trucks at a large solid waste collection company

The study aim was to determine whether using automated side loader (ASL) trucks in higher proportions compared to other types of trucks for residential waste collection results in lower injury rates (from all causes). The primary hypothesis was that the risk of injury to workers was lower for those who work with ASL trucks than for workers who work with other types of trucks used in residential waste collection. To test this hypothesis, data were collected from one of the nation’s largest companies in the solid waste management industry. Different local operating units (i.e. facilities) in the company used different types of trucks to varying degrees, which created a special opportunity to examine refuse collection injuries and illnesses and the risk reduction potential of ASL trucks.^ The study design was ecological and analyzed end-of-year data provided by the company for calendar year 2007. During 2007, there were a total of 345 facilities which provided residential services. Each facility represented one observation.^ The dependent variable – injury and illness rate, was defined as a facility’s total case incidence rate (TCIR) recorded in accordance with federal OSHA requirements for the year 2007. The TCIR is the rate of total recordable injury and illness cases per 100 full-time workers. The independent variable, percent of ASL trucks, was calculated by dividing the number of ASL trucks by the total number of residential trucks at each facility.^ Multiple linear regression models were estimated for the impact of the percent of ASL trucks on TCIR per facility. Adjusted analyses included three covariates: median number of hours worked per week for residential workers; median number of months of work experience for residential workers; and median age of residential workers. All analyses were performed with the statistical software, Stata IC (version 11.0).^ The analyses included three approaches to classifying exposure, percent of ASL trucks. The first approach included two levels of exposure: (1) 0% and (2) >0 - <100%. The second approach included three levels of exposure: (1) 0%, (2) ≥ 1 - < 100%, and (3) 100%. The third approach included six levels of exposure to improve detection of a dose-response relationship: (1) 0%, (2) 1 to <25%, (3) 25 to <50%, (4) 50 to <75%, (5) 75 to <100%, and (6) 100%. None of the relationships between injury and illness rate and percent ASL trucks exposure levels was statistically significant (i.e., p<0.05), even after adjustment for all three covariates.^ In summary, the present study shows that there is some risk reduction impact of ASL trucks but not statistically significant. The covariates demonstrated a varied yet more modest impact on the injury and illness rate but again, none of the relationships between injury and illness rate and the covariates were statistically significant (i.e., p<0.05). However, as an ecological study, the present study also has the limitations inherent in such designs and warrants replication in an individual level cohort design. Any stronger conclusions are not suggested.^