The San Diego 2007 wildfires and Medi-Cal emergency department presentations, inpatient hospitalizations, and outpatient visits: An observational study of smoke exposure periods and a bidirectional case-crossover analysis.

BACKGROUND: The frequency and intensity of wildfires is anticipated to increase as climate change creates longer, warmer, and drier seasons. Particulate matter (PM) from wildfire smoke has been linked to adverse respiratory and possibly cardiovascular outcomes. Children, older adults, and persons with underlying respiratory and cardiovascular conditions are thought to be particularly vulnerable. This study examines the healthcare utilization of Medi-Cal recipients during the fall 2007 San Diego wildfires, which exposed millions of persons to wildfire smoke. METHODS AND FINDINGS: Respiratory and cardiovascular International Classification of Diseases (ICD)-9 codes were identified from Medi-Cal fee-for-service claims for emergency department presentations, inpatient hospitalizations, and outpatient visits. For a respiratory index and a cardiovascular index of key diagnoses and individual diagnoses, we calculated rate ratios (RRs) for the study population and different age groups for 3 consecutive 5-day exposure periods (P1 [October 22-26], P2 [October 27-31], and P3 [November 1-5]) versus pre-fire comparison periods matched on day of week (5-day periods starting 3, 4, 5, 6, 8, and 9 weeks before each exposed period). We used a bidirectional symmetric case-crossover design to examine emergency department presentations with any respiratory diagnosis and asthma specifically, with exposure based on modeled wildfire-derived fine inhalable particles that are 2.5 micrometers and smaller (PM2.5). We used conditional logistic regression to estimate odds ratios (ORs), adjusting for temperature and relative humidity, to assess same-day and moving averages. We also evaluated the United States Environmental Protection Agency (EPA)'s Air Quality Index (AQI) with this conditional logistic regression method. We identified 21,353 inpatient hospitalizations, 25,922 emergency department presentations, and 297,698 outpatient visits between August 16 and December 15, 2007. During P1, total emergency department presentations were no different than the reference periods (1,071 versus 1,062.2; RR 1.01; 95% confidence interval [CI] 0.95-1.08), those for respiratory diagnoses increased by 34% (288 versus 215.3; RR 1.34; 95% CI 1.18-1.52), and those for asthma increased by 112% (58 versus 27.3; RR 2.12; 95% CI 1.57-2.86). Some visit types continued to be elevated in later time frames, e.g., a 72% increase in outpatient visits for acute bronchitis in P2. Among children aged 0-4, emergency department presentations for respiratory diagnoses increased by 70% in P1, and very young children (0-1) experienced a 243% increase for asthma diagnoses. Associated with a 10 µg/m3 increase in PM2.5 (72-hour moving average), we found 1.08 (95% CI 1.04-1.13) times greater odds of an emergency department presentation for asthma. The AQI level "unhealthy for sensitive groups" was associated with significantly elevated odds of an emergency department presentation for respiratory conditions the day following exposure, compared to the AQI level "good" (OR 1.73; 95% CI 1.18-2.53). Study limitations include the use of patient home address to estimate exposures and demographic differences between Medi-Cal beneficiaries and the general population. CONCLUSIONS: Respiratory diagnoses, especially asthma, were elevated during the wildfires in the vulnerable population of Medi-Cal beneficiaries. Wildfire-related healthcare utilization appeared to persist beyond the initial high-exposure period. Increased adverse health events were apparent even at mildly degraded AQI levels. Significant increases in health events, especially for respiratory conditions and among young children, are expected based on projected climate scenarios of wildfire frequency in California and globally.

The direct p53 target gene, FLJ11259/DRAM, is a member of a novel family of transmembrane proteins.

The tumor suppressor p53 regulates diverse biological processes primarily via activation of downstream target genes. Even though many p53 target genes have been described, the precise mechanisms of p53 biological actions are uncertain. In previous work we identified by microarray analysis a candidate p53 target gene, FLJ11259/DRAM. In this report we have identified three uncharacterized human proteins with sequence homology to FLJ11259, suggesting that FLJ11259 is a member of a novel family of proteins with six transmembrane domains. Several lines of investigation confirm FLJ11259 is a direct p53 target gene. p53 siRNA prevented cisplatin-mediated up-regulation of FLJ11259 in NT2/D1 cells. Likewise in HCT116 p53+/+ cells and MCF10A cells, FLJ11259 is induced by cisplatin treatment but to a much lesser extent in isogenic p53-suppressed cells. A functional p53 response element was identified 22.3 kb upstream of the first coding exon of FLJ11259 and is shown to be active in reporter assays. In addition, chromatin immunoprecipitation assays indicate that p53 binds directly to this element in vivo and that binding is enhanced following cisplatin treatment. Confocal microscopy showed that an FLJ-GFP fusion protein localizes mainly in a punctate pattern in the cytoplasm. Overexpression studies in Cos-7, Saos2, and NT2/D1 cells suggest that FLJ11259 is associated with increased clonal survival. In summary, we have identified FLJ11259/DRAM as a p53-inducible member of a novel family of transmembrane proteins. FLJ11259/DRAM may be an important modulator of p53 responses in diverse tumor types.

ΔNp63α-mediated activation of bone morphogenetic protein signaling governs stem cell activity and plasticity in normal and malignant mammary epithelial cells.

Genetic analysis of TP63 indicates that ΔNp63 isoforms are required for preservation of regenerative stasis within diverse epithelial tissues. In squamous carcinomas, TP63 is commonly amplified, and ΔNp63α confers a potent survival advantage. Genome-wide occupancy studies show that ΔNp63 promotes bidirectional target gene regulation by binding more than 5,000 sites throughout the genome; however, the subset of targets mediating discreet activities of TP63 remains unclear. We report that ΔNp63α activates bone morphogenic proteins (BMP) signaling by inducing the expression of BMP7. Immunohistochemical analysis indicates that hyperactivation of BMP signaling is common in human breast cancers, most notably in the basal molecular subtype, as well as in several mouse models of breast cancer. Suppression of BMP signaling in vitro with LDN193189, a small-molecule inhibitor of BMP type I receptor kinases, represses clonogenicity and diminishes the cancer stem cell-enriched ALDH1(+) population. Importantly, LDN193189 blocks reconstitution of mixed ALDH1(+)/ALDH1(-) cultures indicating that BMP signaling may govern aspects of cellular plasticity within tumor hierarchies. These results show that BMP signaling enables reversion of committed populations to a stem-like state, potentially supporting progression and maintenance of tumorigenesis. Treatment of a mouse model of breast cancer with LDN193189 caused reduced expression of markers associated with epithelial-to-mesenchymal transition (EMT). Furthermore, in vivo limiting dilution analysis assays revealed that LDN193189 treatment suppressed tumor-initiating capacity and increased tumor latency. These studies support a model in which ΔNp63α-mediated activation of BMP signaling governs epithelial cell plasticity, EMT, and tumorigenicity during breast cancer initiation and progression.

Phosphorylation of ΔNp63α via a novel TGFß/ALK5 signaling mechanism mediates the anti-clonogenic effects of TGFß.

Genetic analysis of TP63 implicates ΔNp63 isoforms in preservation of replicative capacity and cellular lifespan within adult stem cells. ΔNp63α is also an oncogene and survival factor that mediates therapeutic resistance in squamous carcinomas. These diverse activities are the result of genetic and functional interactions between TP63 and an array of morphogenic and morphostatic signals that govern tissue and tumor stasis, mitotic polarity, and cell fate; however the cellular signals that account for specific functions of TP63 are incompletely understood. To address this we sought to identify signaling pathways that regulate expression, stability or activity of ΔNp63α. An siRNA-based screen of the human kinome identified the Type 1 TGFß receptor, ALK5, as the kinase required for phosphorylation of ΔNp63α at Serine 66/68 (S66/68). This activity is TGFß-dependent and sensitive to either ALK5-directed siRNA or the ALK5 kinase inhibitor A83-01. Mechanistic studies support a model in which ALK5 is proteolytically cleaved at the internal juxtamembrane region resulting in the translocation of the C-terminal ALK5-intracellular kinase domain (ALK5(IKD)). In this study, we demonstrate that ALK5-mediated phosphorylation of ΔNp63α is required for the anti-clonogenic effects of TGFΒ and ectopic expression of ALK5(IKD) mimics these effects. Finally, we present evidence that ultraviolet irradiation-mediated phosphorylation of ΔNp63α is sensitive to ALK5 inhibitors. These findings identify a non-canonical TGFß-signaling pathway that mediates the anti-clonogenic effects of TGFß and the effects of cellular stress via ΔNp63α phosphorylation.