Genetic susceptibility, cigarette smoking, and wood dust exposure in lung cancer: Case control analyses

This case control study was conducted to assess the association between lung cancer risk, mutagen sensitivity (a marker of cancer susceptibility), and a putative lung carcinogen, wood dust exposure. There were 165 cases (98 African-Americans, 67 Mexican-Americans) with newly diagnosed, previously untreated lung cancer, and 239 controls, frequency-matched on age, sex, and ethnicity.^ Mutagen sensitivity ($\ge$1 break/cell) was associated with a statistically significant elevated risk for lung cancer (odds ratio (OR) = 4.1, 95% confidence limits (CL) = 2.3,7.2). Wood dust exposure was also a significant predictor of risk (OR = 2.8, 95% CL = 1.2,6.6) after controlling for smoking and mutagen sensitivity. When stratified by ethnicity, wood dust exposure was a significant risk factor for African-Americans (OR = 4.0, 95% CL = 1.4,11.5), but not for Mexican-Americans (OR = 1.5, 95% CL = 0.3,7.1). Stratified analysis suggested a greater than multiplicative interaction between wood dust exposure and both mutagen sensitivity and smoking.^ The cases had significantly more breaks on chromosomes 4 and 5 than the controls did with ORs of 4.9 (95% CL = 2.0, 11.7) and 3.9 (95% CL = 1.6, 9.3), respectively. Breaks at 4p14, 4q27, 4q31, 5q21-22, 5q31, and 5q33 were significantly more common in lung cancer patients than in controls. Lung cancer risk had a dose-response relationship with breaks on chromosomes 4 and 5. Cigarette smoking had a strong interaction with breaks on chromosomes 2, 4, and 5.^ In a molecular cytogenetic study, using chromosome painting and G-banding, we showed that: (1) the proportion of chromosome 5 abnormalities surviving as chromosome-type aberrations remained significantly higher in cells of lung cancer cases (14%) than in controls (5%) (P $<$ 0.001). However, no significant differences were detected in chromosome 4 abnormalities between cases and controls; (2) the proportion of chromosome 5q13-22 abnormalities was 5.3% in the cases and 0.7% in the controls (P $<$ 0.001). 5q13-22 regions represented 40% of all abnormalities on chromosome 5 in the cases and only 14% in the controls.^ This study suggests that mutagen sensitivity, wood dust exposure, and cigarette smoking were independent risk factors for lung cancer, and the susceptibility of particular chromosome loci to mutagenic damage may be a genetic marker for specific types of lung cancer. ^

Exploration of genetic susceptibility to pancreatic cancer: A GWAS approach

Pancreatic cancer is the 4th most common cause for cancer death in the United States, accompanied by less than 5% five-year survival rate based on current treatments, particularly because it is usually detected at a late stage. Identifying a high-risk population to launch an effective preventive strategy and intervention to control this highly lethal disease is desperately needed. The genetic etiology of pancreatic cancer has not been well profiled. We hypothesized that unidentified genetic variants by previous genome-wide association study (GWAS) for pancreatic cancer, due to stringent statistical threshold or missing interaction analysis, may be unveiled using alternative approaches. To achieve this aim, we explored genetic susceptibility to pancreatic cancer in terms of marginal associations of pathway and genes, as well as their interactions with risk factors. We conducted pathway- and gene-based analysis using GWAS data from 3141 pancreatic cancer patients and 3367 controls with European ancestry. Using the gene set ridge regression in association studies (GRASS) method, we analyzed 197 pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Using the logistic kernel machine (LKM) test, we analyzed 17906 genes defined by University of California Santa Cruz (UCSC) database. Using the likelihood ratio test (LRT) in a logistic regression model, we analyzed 177 pathways and 17906 genes for interactions with risk factors in 2028 pancreatic cancer patients and 2109 controls with European ancestry. After adjusting for multiple comparisons, six pathways were marginally associated with risk of pancreatic cancer ( P < 0.00025): Fc epsilon RI signaling, maturity onset diabetes of the young, neuroactive ligand-receptor interaction, long-term depression (Ps < 0.0002), and the olfactory transduction and vascular smooth muscle contraction pathways (P = 0.0002; Nine genes were marginally associated with pancreatic cancer risk (P < 2.62 × 10−5), including five reported genes (ABO, HNF1A, CLPTM1L, SHH and MYC), as well as four novel genes (OR13C4, OR 13C3, KCNA6 and HNF4 G); three pathways significantly interacted with risk factors on modifying the risk of pancreatic cancer (P < 2.82 × 10−4): chemokine signaling pathway with obesity ( P < 1.43 × 10−4), calcium signaling pathway (P < 2.27 × 10−4) and MAPK signaling pathway with diabetes (P < 2.77 × 10−4). However, none of the 17906 genes tested for interactions survived the multiple comparisons corrections. In summary, our current GWAS study unveiled unidentified genetic susceptibility to pancreatic cancer using alternative methods. These novel findings provide new perspectives on genetic susceptibility to and molecular mechanisms of pancreatic cancer, once confirmed, will shed promising light on the prevention and treatment of this disease. ^

The influence of antibacterial susceptibility and pharmacodynamics on the therapeutic response of infection

This prospective cohort study estimated how antibacterial resistance affected the time until clinical response. Relative rates of improvement and cure were estimated by proportional-hazards regression for 391 patients with culture-confirmed bacterial keratitis who had the ciprofloxacin minimal inhibitory concentration (MIC) measured of the principal corneal isolate and who were treated with ciprofloxacin 0.3% solution or ointment. After adjusting for age and hypopyon status and stratifying by ulcer size, clinic, and ciprofloxacin formulation, the summary rate of clinical improvement with ciprofloxacin therapy was reduced by 42% (95% confidence limits [CL], 3%, 65%) among patients whose corneal isolate's ciprofloxacin MIC exceeded 1.0 μg/mL compared to those with more sensitive isolates. The summary rate of resolution to improvement and cure was reduced by 36% (95% CL, 11%, 53%) among corneal infections having a higher ciprofloxacin MIC. Rate ratios were modified by the size of the presenting corneal ulceration; for ulcer diameters of 4 mm or less and of more than 4 mm, improvement rate ratios were 0.56 (95% CL, 0.31, 1.02) and 0.65 (95% CL, 0.23, 1.80), respectively; resolution rate ratios were 0.63 (95% CL, 0.44, 0.91) and 0.67 (95% CL, 0.32, 1.39), respectively. Sensitivity analysis showed that the summary improvement rate ratio could be maximally overestimated by 24% (95% CL, −29%, 114%) because of informative censoring or by 33% (95% CL, −21%, 126%) from loss to follow up. Based on reported corneal pharmacokinetics of topical ciprofloxacin, the probability of clinical improvement was 90% or more if the ratio of the achievable corneal ciprofloxacin concentration to the corneal isolate's ciprofloxacin MIC was above 8 or the ratio of the area under the 24-hour corneal concentration curve to the ciprofloxacin MIC was greater than 151. This study suggests that corneal infections by bacteria having a higher ciprofloxacin MIC respond more slowly to ciprofloxacin treatment than those with a lower MIC. While the rate of clinical resolution is affected by patient age and clinical severity, antimicrobial susceptibility testing of corneal cultures can indicate the relative effectiveness of antibacterial therapy. A pharmacodynamic approach to treating bacterial keratitis offers the prospect of optimal antimicrobial selection and modification. ^

Magnetic susceptibility dataset from the early Givetian to early Frasnian in the La Thure section

Recent advances in radiometric dating result in significant improvements in the geological timescale and provide better insight into the timing of various processes and evolutions within the Earth's system. However, no radiometric ages are contained within the Givetian. Consequently, the absolute ages of the Givetian Stage boundaries, as well as the stage's duration, remain poorly constrained. As an alternative, the analysis of sedimentary cycles allows for the estimation of the duration of this stage. We examined the high-resolution magnetic susceptibility signals of four Givetian outcrops in the Givet area for a possible astronomical imprint, to fully understand the rates of evolutionary and environmental change. All four sections are firmly correlated and wavelet analyses of the magnetic susceptibility signals reveal the imprint of astronomical eccentricity forcing. The highly stable 405 kyr cycles constrain the duration of the Givetian Stage at 4.35±0.45 Myr, which is in good agreement with the International Chronostratigraphic Chart (5.0 Myr). The studied sections also exhibit an imprint of obliquity, suggesting a climatic teleconnection between low and high latitudes. The corresponding microfacies curves demonstrate similar astronomical imprint, and thereby indicate that the observed 10**5 year-scale cyclicity is the result of climatic and environmental change.

XRF data, magnetic susceptibility, greyscale values and revised depths of sediments from ODP Leg 154 sites

The distinctly cyclic sediments recovered during ODP Leg 154 played an important role in constructing the astronomical time scale and associated astro(bio)chronology for the Miocene, and in deciphering ocean-climate history. The accuracy of the timescale critically depends on the reliability of the shipboard splice used for the tuning and on the tuning itself. New high-resolution colour- and magnetic susceptibility core scanning data supplemented with limited XRF-data allow improvement of the stratigraphy. The revised composite record results in an improved astronomical age model for ODP Site 926 between 5 and 14.4 Ma. The new age model is confirmed by results of complex amplitude demodulation of the precession and obliquity related cycle patterns. Different values for tidal dissipation are applied to improve the fit between the sedimentary cycle patterns and the astronomical solution. Due to the improved stratigraphy and tuning, supported by the results of amplitude demodulation, the revised time scale yields more reliable age estimates for planktic foraminiferal and calcareous nannofossil events. The results of this study highlight the importance of stratigraphy for timescale construction.