Ultrasonic Pulse Wave Imaging for in vivo Assessment of Vascular Wall Dynamics and Characterization of Arterial Pathologies

Arterial diseases such as hypertension, carotid stenosis, and abdominal aortic aneurysm (AAA) may progress silently without symptoms and contribute to acute cardiovascular events such as heart attack, stroke, and aneurysm rupture, which are consistently among the leading causes of death worldwide. The arterial pulse wave, regarded as one of the fundamental vital signs of clinical medicine, originates from the heart and propagates throughout the arterial tree as a pressure, flow velocity, and wall displacement wave, giving rise to the natural pulsation of the arteries. The dynamic properties of the pulse wave are intimately related to the physical state of the cardiovascular system. Thus, the assessment of the arterial wall dynamics driven by the pulse wave may provide valuable insights into vascular mechanical properties for the early detection and characterization of arterial pathologies. The focus of this dissertation was to develop and clinically implement Pulse Wave Imaging (PWI), an ultrasound elasticity imaging-based method for the visualization and spatio-temporal mapping of the pulse wave propagation at any accessible arterial location. Motion estimation algorithms based on cross-correlation of the ultrasound radio-frequency (RF) signals were used to track the arterial walls and capture the pulse wave-induced displacements over the cardiac cycle. PWI facilitates the image-guided measurement of clinically relevant pulse wave features such as propagation speed (pulse wave velocity, or PWV), uniformity, and morphology as well as derivation of the pulse pressure waveform. A parametric study investigating the performance of PWI in two canine aortas ex vivo and 10 normal, healthy human arteries in vivo established the optimal image acquisition and signal processing parameters for reliable measurement of the PWV and wave propagation uniformity. Using this framework, three separate clinical feasibility studies were conducted in patients diagnosed with hypertension, AAA, and carotid stenosis. In a pilot study comparing hypertensive and aneurysmal abdominal aortas with normal controls, the AAA group exhibited significantly higher PWV and lower wave propagation uniformity. A “teetering” motion upon pulse wave arrival was detected in the smaller aneurysms ( 5.5 cm in diameter). While no significant difference in PWV or propagation uniformity was observed between normal and hypertensive aortas, qualitative differences in the pulse wave morphology along the imaged aortic segment may be an indicator of increased wave reflection caused by elevated blood pressure and/or arterial stiffness. Pulse Wave Ultrasound Manometry (PWUM) was introduced as an extension of the PWI method for the derivation of the pulse pressure (PP) waveform in large central arteries. A feasibility study in 5 normotensive, 9 pre-hypertensive, and 5 hypertensive subjects indicated that a significantly higher PP in the hypertensive group was detected in the abdominal aorta by PWUM but not in the peripheral arteries by alternative devices (i.e. a radial applanation tonometer and the brachial sphygmomanometer cuff). A relatively strong positive correlation between aortic PP and both radial and brachial PP was observed in the hypertensive group but not in the normal and pre-hypertensive groups, confirming the notion that PP variation throughout the arterial tree may not be uniform in relatively compliant arteries. The application of PWI in 10 stenotic carotid arteries identified phenomenon such as wave convergence, elevated PWV, and decreased cumulative displacement around and/or within regions of atherosclerotic plaque. Intra-plaque mapping of the PWV and cumulative strain demonstrated the potential to quantitatively differentiate stable (i.e. calcified) and vulnerable (i.e. lipid) plaque components. The lack of correlation between quantitative measurements (PWV, modulus, displacement, and strain) and expected plaque stiffness illuminates to need to consider several physiological and imaging-related factors such as turbulent flow, wave reflection, imaging location, and the applicability of established theoretical models in vivo. PWI presents a highly translational method for visualization of the arterial pulse wave and the image-guided measurement of several clinically relevant pulse wave features. The aforementioned findings collectively demonstrated the potential of PWI to detect, diagnose, and characterize vascular disease based on qualitative and quantitative information about arterial wall dynamics under pathological conditions

A strong mitigation scenario maintains climate neutrality of northern peatlands

Northern peatlands store 300–600 Pg C, of which approximately half are underlain by permafrost. Climate warming and, in some regions, soil drying from enhanced evaporation are progressively threatening this large carbon stock. Here, we assess future CO2 and CH4 fluxes from northern peatlands using five land surface models that explicitly include representation of peatland processes. Under Representative Concentration Pathways (RCP) 2.6, northern peatlands are projected to remain a net sink of CO2 and climate neutral for the next three centuries. A shift to a net CO2 source and a substantial increase in CH4 emissions are projected under RCP8.5, which could exacerbate global warming by 0.21°C (range, 0.09–0.49°C) by the year 2300. The true warming impact of peatlands might be higher owing to processes not simulated by the models and direct anthropogenic disturbance. Our study highlights the importance of understanding how future warming might trigger high carbon losses from northern peatlands

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that -80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAFPeer reviewe

Sex differences in oncogenic mutational processes

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.Peer reviewe

Sex differences in oncogenic mutational processes

Funder: Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology); doi: https://doi.org/10.13039/501100002790Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Canada Foundation for Innovation (Fondation canadienne pour l'innovation); doi: https://doi.org/10.13039/501100000196Funder: Terry Fox Research Institute (Institut de Recherche Terry Fox); doi: https://doi.org/10.13039/501100004376Abstract: Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts