Genome-Wide Diet-Gene Interaction Analyses for Risk of Colorectal Cancer

Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention. © 2014

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Morphology of the Small-Animal Lung Using Magnetic Resonance Microscopy

Small-animal imaging with magnetic resonance microscopy (MRM) has become an important tool in biomedical research. When MRM is used to image perfusion-fixed and “stained” whole mouse specimens, cardiopulmonary morphology can be visualized, nondestructively, in exquisite detail in all three dimensions. This capability can be a valuable tool for morphologic phenotyping of different mouse strains commonly used in genomics research. When these imaging techniques are combined with specialized methods for biological motion control and animal support, the lungs of the live, small animal can be imaged. Although in vivo imaging may not achieve the high resolution possible with a fixed specimen, dynamic functional studies and survival studies that follow the progression of pulmonary change related to disease or environmental exposure are possible. By combining conventional proton imaging with gas imaging, using hyperpolarized 3He, it is possible to image the tissue and gas compartments of the lung. This capability is illustrated in studies on an emphysema model in rats and on radiation damage of the lung. With further improvements in imaging and animal handling technology, we will be able to image faster and at higher resolutions, making MRM an even more valuable research tool

4-D Micro-CT of the Mouse Heart

Purpose: Demonstrate noninvasive imaging methods for in vivo characterization of cardiac structure and function in mice using a micro-CT system that provides high photon fluence rate and integrated motion control. Materials and Methods: Simultaneous cardiac- and respiratory-gated micro-CT was performed in C57BL/6 mice during constant intravenous infusion of a conventional iodinated contrast agent (Isovue-370), and after a single intravenous injection of a blood pool contrast agent (Fenestra VC). Multiple phases of the cardiac cycle were reconstructed with contrast to noise and spatial resolution sufficient for quantitative assessment of cardiac function. Results: Contrast enhancement with Isovue-370 increased over time with a maximum of ~500 HU (aorta) and 900 HU (kidney cortex). Fenestra VC provided more constant enhancement over 3 hr, with maximum enhancement of ~620 HU (aorta) and ~90 HU (kidney cortex). The maximum enhancement difference between blood and myocardium in the heart was ~250 HU for Isovue-370 and ~500 HU for Fenestra VC. In mice with Fenestra VC, volumetric measurements of the left ventricle were performed and cardiac function was estimated by ejection fraction, stroke volume, and cardiac output. Conclusion: Image quality with Fenestra VC was sufficient for morphological and functional studies required for a standardized method of cardiac phenotyping of the mouse

RESEARCH ARTICLE Molecular Imaging. Vol. 4, No.2,April-June 2005, pp.110 –116 110 4-D Micro-CT of the Mouse Heart

Purpose: Demonstrate noninvasive imaging methods for in vivo characterization of cardiac structure and function in mice using a micro-CT system that provides high photon fluence rate and integrated motion control. Materials and Methods: Simultaneous cardiac- and respiratory-gated micro-CT was performed in C57BL/6 mice during constant intravenous infusion of a conventional iodinated contrast agent (Isovue-370), and after a single intravenous injection of a blood pool contrast agent (Fenestra VC). Multiple phases of the cardiac cycle were reconstructed with contrast to noise and spatial resolution sufficient for quantitative assessment of cardiac function. Results: Contrast enhancement with Isovue-370 increased over time with a maximum of 500 HU (aorta) and 900 HU (kidney cortex). Fenestra VC provided more constant enhancement over 3 hr, with maximum enhancement of 620 HU (aorta) and 90 HU (kidney cortex). The maximum enhancement difference between blood and myocardium in the heart was 250 HU for Isovue-370 and 500 HU for Fenestra VC. In mice with Fenestra VC, volumetric measurements of the left ventricle were performed and cardiac function was estimated by ejection fraction, stroke volume, and cardiac output. Conclusion: Image quality with Fenestra VC was sufficient for morphological and functional studies required for a standardized method of cardiac phenotyping of the mouse. Mol Imaging (2005) 4, 1–7. Keywords: Micro-CT, resolution, mouse, phenotyping, cardiac imaging

Pulmonary perfusion and xenon gas exchange in rats: MR imaging with intravenous injection of hyperpolarized 129Xe.

PURPOSE: To develop and demonstrate a method for regional evaluation of pulmonary perfusion and gas exchange based on intravenous injection of hyperpolarized xenon 129 ((129)Xe) and subsequent magnetic resonance (MR) imaging of the gas-phase (129)Xe emerging in the alveolar airspaces. MATERIALS AND METHODS: Five Fischer 344 rats that weighed 200-425 g were prepared for imaging according to an institutional animal care and use committee-approved protocol. Rats were ventilated, and a 3-F catheter was placed in the jugular (n = 1) or a 24-gauge catheter in the tail (n = 4) vein. Imaging and spectroscopy of gas-phase (129)Xe were performed after injecting 5 mL of half-normal saline saturated with (129)Xe hyperpolarized to 12%. Corresponding ventilation images were obtained during conventional inhalation delivery of hyperpolarized (129)Xe. RESULTS: Injections of (129)Xe-saturated saline were well tolerated and produced a strong gas-phase (129)Xe signal in the airspaces that resulted from (129)Xe transport through the pulmonary circulation and diffusion across the blood-gas barrier. After a single injection, the emerging (129)Xe gas could be detected separately from (129)Xe remaining in the blood and was imaged with an in-plane resolution of 1 x 1 mm and a signal-to-noise ratio of 25. Images in one rat revealed a matched ventilation-perfusion deficit, while images in another rat showed that xenon gas exchange was temporarily impaired after saline overload, with recovery of function 1 hour later. CONCLUSION: MR imaging of gas-phase (129)Xe emerging in the pulmonary airspaces after intravenous injection has the potential to become a sensitive and minimally invasive new tool for regional evaluation of pulmonary perfusion and gas exchange. SUPPLEMENTAL MATERIAL: http://radiology.rsnajnls.org/cgi/content/full/2513081550/DC1