Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

SummaryWe report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Stress Inversion and Damage Quantification in Tight Gas Shale with Application to Hydraulic Fracturing

This thesis aims to advance the quantitative analysis of stress and failure process in tight gas shale under hydraulic fracturing by integrating stress inversion, microseismic monitoring, acoustic emission and discrete element modeling techniques. With the introduction of a modified Bott hypothesis that allows for out-of-plane slip, a stress inversion algorithm is developed accounting for tensile components of the source mechanism. Synthetic test datasets are employed to quantify the error in stress determination that arises when the conventional stress inversion based on the original Bott hypothesis is applied in the presence of non-double-couple sources. The proposed method is evaluated using microseismic data collected from Barnett Shale in the Fort Worth Basin, Texas. Results show the modified method introduces a roughly 15 degree correction as compared with the inversion results from the conventional algorithm. With the same dataset, a case study is conducted to investigate the dynamic interactions between injected fluids and hydraulic fractures through the spatial-temporal analysis of microseismicity. Two types of triggering front expansion patterns are evident. With the presence of a dominant hydraulic fracture, the radius of the triggering front expands linearly with time, and the microseismic event cloud forms a planar shape with low tensile components. On the other hand, in the case of a complex fracture network with the absence of any major hydraulic fracture, the triggering front grows non-linearly with time, which can be treated as equivalent to a diffusion model. The microseismic events exhibit more tensile components and an equidimensional event cloud. Two stages of the microseismic dataset are analyzed and the derived fracture widths and fluid-loss coefficients fall into a realistic range of general observations. Two acoustic emission (AE) laboratory experiments are carried out to examine the failure behavior of Montney shale samples under conventional triaxial compression and fluid injection. Detailed analysis for the triaxial compression test includes deformation-induced velocity anisotropy, source hypocenter determinations, source mechanism analysis, and stress inversions. For the hydraulic fracturing test, the mechanical correlation with the AE activity is analyzed. The AE locations correlate reasonably well with the spatial distribution of shear fracture and hydraulic fracture imaged by X-ray computer tomography (CT) scanning. However, the signal-to-noise ratio of the AE waveform emitted from Montney shale sample is relatively low, especially for the hydraulic fracturing test, which makes the data processing quite challenging. Distinct characteristics of the AE activity in Montney shale are identified, which are different from those in granite, a type of rock that has been more extensively investigated in the past. These differences could arise from the different stress settings, the low brittleness and stiffness of shale. Additionally, the AE test under triaxial compression is simulated using dynamic micromechanical models based on the discrete element method, in which the transversely isotropic feature of Montney shale and moment tensor calculations are considered. Calibration and verification are conducted against the results of previous laboratory experiments in terms of the anisotropic behavior. The model results indicate some of the low energy AE signals might not be captured by the experimental recording system, and it further demonstrates that the shear fracture initiation contains high tensile failure components

Characterization of damage processes in Montney siltstone under triaxial compression using acoustic emission and diagnostic imaging

Article accepted for publication by Geophysical Journal InternationalCrack nucleation and rock failure processes in a fine-grained siltstone (Montney Formation) under triaxial compression are investigated using combined diagnostic techniques, including ultrasonic-wave measurement, acoustic-emission (AE) monitoring, computed tomography (CT) scanning, and thin-section imaging. The sample displays a weak-to-moderate inherent seismic anisotropy and noticeable stress-induced anisotropy prior to failure. No AE event was detected until the applied axial stress reached 95% of the peak value. The signal-to-noise ratio is relatively low, however, and detectable AE events are more diffuse than those observed in highly brittle rocks. The AE locations correlate with a shear fracture zone imaged by CT scanning. AE moment-tensor analysis reveals that events with larger relative magnitudes are characterized by high volumetric (tensile or compressive) components, and the initiation of the failure zone is dominated by combined shear-tensile failure. Stress inversion of the AE events with high tensile components is in good agreement with the known applied stress. Microscopic imaging of thin sections from the failed sample shows that the failure zone is an en echelon structure consisting of a major fracture with branching micro and minor cracks. This failure mechanism is consistent with a shear-tensile source mechanism and is interpreted to be associated with the fine granular structure and mineral composition of Montney siltstone.Natural Sciences and Engineering Research Council (NSERC

Obstructive and Central Sleep Apnea and the Risk of Incident Atrial Fibrillation in a Community Cohort of Men and Women

Background: Previous studies have documented a high prevalence of atrial fibrillation (AF) in individuals with obstructive sleep apnea (OSA). Central sleep apnea (CSA) has been associated with AF in patients with heart failure. However, data from prospective cohorts are sparse and few studies have distinguished the associations of obstructive sleep apnea from CSA with AF in population studies. Methods and Results: We assessed the association of obstructive sleep apnea and CSA with incident AF among 2912 individuals without a history of AF in the SHHS (Sleep Heart Health Study), a prospective, community‐based study of existing (“parent”) cohort studies designed to evaluate the cardiovascular consequences of sleep disordered breathing. Incident AF was documented by 12‐lead ECG or assessed by the parent cohort. obstructive sleep apnea was defined by the obstructive apnea‐hypopnea index (OAHI). CSA was defined by a central apnea index ≥5 or the presence of Cheyne Stokes Respiration. Logistic regression was used to assess the association between sleep disordered breathing and incident AF. Over a mean of 5.3 years of follow‐up, 338 cases of incident AF were observed. CSA was a predictor of incident AF in all adjusted models and was associated with 2‐ to 3‐fold increased odds of developing AF (central apnea index ≥5 odds ratio [OR], 3.00, 1.40–6.44; Cheyne–Stokes respiration OR, 1.83, 0.95–3.54; CSA or Cheyne–Stokes respiration OR, 2.00, 1.16–3.44). In contrast, OAHI was not associated with incident AF (OAHI per 5 unit increase OR, 0.97, 0.91–1.03; OAHI 5 to <15 OR, 0.84, 0.59–1.17; OAHI 15 to <30 OR, 0.93, 0.60–1.45; OAHI ≥30 OR, 0.76, 0.42–1.36). Conclusions: In a prospective, community‐based cohort, CSA was associated with incident AF, even after adjustment for cardiovascular risk factors