CT-measured bone attenuation in patients with chronic obstructive pulmonary disease: Relation to clinical features and outcomes

Osteoporosis is highly prevalent in COPD patients and has been related to several clinical features. However, most studies have been in relatively small COPD cohorts. Therefore, the objectives of this study were to compare bone attenuation measured on low-dose chest computed tomography (CT) between COPD subjects, smoker and non-smoker controls, and to relate bone attenuation to clinical parameters, inflammatory biomarkers and outcomes in a large, well-characterized COPD cohort. We studied 1634 COPD subjects, 259 smoker controls and 186 non-smoker controls who participated in a large longitudinal study (ECLIPSE). We measured bone attenuation, extent of emphysema and coronary artery calcification (Agatston score) on baseline CT scans, and clinical parameters, inflammatory biomarkers and outcomes. Bone attenuation was lower in COPD subjects compared with smoker and non-smoker controls (164.9+/-49.5 HU versus 183.8+/-46.1 HU versus 212.1+/-54.4 HU, p<0.001). Bone attenuation was not significantly different between COPD subjects and smoker controls after adjustment for age, sex and pack-years of smoking(=). In the COPD subjects, bone attenuation correlated positively with FEV(1) (r=0.062, p=0.014), FEV(1) /FVC ratio (r=0.102, p<0.001), body mass index (r=0.243, p<0.001), fat free mass index (FFMI, r=0.265, p<0.001) and C-reactive protein (r=0.104, p<0.001), and correlated negatively with extent of emphysema (r=-0.090, p<0.001), Agatston score (r=-0.177, p<0.001) and interleukin-8 (r=-0.054, p=0.035). In a multiple regression model, older age, lower FFMI and higher Agatston score were associated with lower bone attenuation. Lower bone attenuation was associated with higher exacerbation (r=-0.057, p=0.022) and hospitalization (r=-0.078, p=0.002) rates, but was not associated with all-cause mortality. In conclusion, CT measured bone attenuation was lower in COPD subjects compared with non-smoker controls but not compared with smoker controls, after adjustment for age, sex and pack-years of smoking. In the COPD subjects, bone attenuation was associated with age, body composition and coronary artery calcification, but was not associated with all-cause mortality. (c) 2013 American Society for Bone and Mineral Research

Bone attenuation on routine chest CT correlates with bone mineral density on DXA in patients with COPD

Chronic obstructive pulmonary disease (COPD), although primarily a disease of the lungs, is associated with extrapulmonary effects such as muscle weakness and osteoporosis. Fractures owing to osteoporosis cause significant morbidity and mortality, particularly in patients with COPD. To prevent osteoporotic fractures, it is important to diagnose osteoporosis in an early stage and to start anti-osteoporotic therapy in at-risk patients. Because routine chest computed tomography (CT) is increasingly used to assess the extent of emphysema and airways disease in patients with COPD, we investigated whether simple attenuation measurement of the thoracic spine on routine chest CT may provide useful information on bone health in patients with COPD. Fifty-eight patients with moderate to very severe COPD were included in our study. The average attenuation of thoracic vertebrae 4, 7, and 10 on chest CT was correlated with the lowest bone mineral density (BMD) of the hip and lumbar spine (L-1 to L-4) on dual-energy X-ray absorptiometry (DXA) in patients with COPD. The inter- and intra-observer variabilities of the attenuation measurements were low as shown by Bland-Altman plots. Pearson's correlation coefficient between the average attenuation of the three thoracic vertebrae and the lowest BMD of the hip and lumbar spine was high (r = 0.827, p <0.001). A receiver-operating characteristic (ROC) analysis of the area under the curve for osteoporosis was 0.969 (p <0.001), corresponding to an attenuation threshold of 147 Hounsfield Units (HU). In conclusion, our data demonstrated that bone attenuation measured on routine chest CT correlated strongly with BMD assessed on DXA in patients with COPD. Routine chest CT may provide useful information on bone health in patients with COPD. (C) 2012 American Society for Bone and Mineral Research

Comparing DNA Sequence Collections by Direct Comparison of Compressed Text Indexes

Cox AJ, Jakobi T, Rosone G, Schulz-Trieglaff OB. Comparing DNA Sequence Collections by Direct Comparison of Compressed Text Indexes. In: Raphael B, Tang J, eds. Algorithms in Bioinformatics. Lecture Notes in Computer Science. Vol 7534. Berlin, Heidelberg: Springer Berlin Heidelberg; 2012: 214-224

Two of a kind: transmissible Schwann cell cancers in the endangered Tasmanian devil (Sarcophilus harrisii)

Devil facial tumour disease (DFTD) comprises two genetically distinct transmissible cancers (DFT1 and DFT2) endangering the survival of the Tasmanian devil (Sarcophilus harrisii) in the wild. DFT1 first arose from a cell of the Schwann cell lineage; however, the tissue-of-origin of the recently discovered DFT2 cancer is unknown. In this study, we compared the transcriptome and proteome of DFT2 tumours to DFT1 and normal Tasmanian devil tissues to determine the tissue-of-origin of the DFT2 cancer. Our findings demonstrate that DFT2 expresses a range of Schwann cell markers and exhibits expression patterns consistent with a similar origin to the DFT1 cancer. Furthermore, DFT2 cells express genes associated with the repair response to peripheral nerve damage. These findings suggest that devils may be predisposed to transmissible cancers of Schwann cell origin. The combined effect of factors such as frequent nerve damage from biting, Schwann cell plasticity and low genetic diversity may allow these cancers to develop on rare occasions. The emergence of two independent transmissible cancers from the same tissue in the Tasmanian devil presents an unprecedented opportunity to gain insight into cancer development, evolution and immune evasion in mammalian species.Amanda L. Patchett, Tim H.H. Coorens, Jocelyn Darby, Richard Wilson, Matthew J. McKay, Karthik S. Kamath, Alan Rubin, Matthew Wakefield, Lachlan Mcintosh, Stefano Mangiola, Ruth J. Pye, Andrew S. Flies, Lynn M. Corcoran, A. Bruce Lyons, Gregory M. Woods, Elizabeth P. Murchison, Anthony T. Papenfuss, Cesar Tova

Somatic evolution and global expansion of an ancient transmissible cancer lineage

The canine transmissible venereal tumor (CTVT) is a cancer lineage that arose several millennia ago and survives by “metastasizing” between hosts through cell transfer. The somatic mutations in this cancer record its phylogeography and evolutionary history. We constructed a time-resolved phylogeny from 546 CTVT exomes and describe the lineage's worldwide expansion. Examining variation in mutational exposure, we identify a highly context-specific mutational process that operated early in the cancer's evolution but subsequently vanished, correlate ultraviolet-light mutagenesis with tumor latitude, and describe tumors with heritable hyperactivity of an endogenous mutational process. CTVT displays little evidence of ongoing positive selection, and negative selection is detectable only in essential genes. We illustrate how long-lived clonal organisms capture changing mutagenic environments, and reveal that neutral genetic drift is the dominant feature of long-term cancer evolution. © 2019 American Association for the Advancement of Science. All rights reserved

Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer

Autonomous replication and segregation of mitochondrial DNA (mtDNA) creates the potential for evolutionary conflict driven by emergence of haplotypes under positive selection for ‘selfish’ traits, such as replicative advantage. However, few cases of this phenomenon arising within natural populations have been described. Here, we survey the frequency of mtDNA horizontal transfer within the canine transmissible venereal tumour (CTVT), a contagious cancer clone that occasionally acquires mtDNA from its hosts. Remarkably, one canine mtDNA haplotype, A1d1a, has repeatedly and recently colonised CTVT cells, recurrently replacing incumbent CTVT haplotypes. An A1d1a control region polymorphism predicted to influence transcription is fixed in the products of an A1d1a recombination event and occurs somatically on other CTVT mtDNA backgrounds. We present a model whereby ‘selfish’ positive selection acting on a regulatory variant drives repeated fixation of A1d1a within CTVT cells. © 2020, The Author(s)