Citations

Abstract Ovarian cancer is a clinically and molecularly heterogeneous disease. The driving forces behind this variability are unknown. Here, we report wide variation in the expression of the DNA cytosine deaminase APOBEC3B, with elevated expression in the majority of ovarian cancer cell lines (three SDs above the mean of normal ovarian surface epithelial cells) and high-grade primary ovarian cancers. APOBEC3B is active in the nucleus of several ovarian cancer cell lines and elicits a biochemical preference for deamination of cytosines in 5′-TC dinucleotides. Importantly, examination of whole-genome sequence from 16 ovarian cancers reveals that APOBEC3B expression correlates with total mutation load as well as elevated levels of transversion mutations. In particular, high APOBEC3B expression correlates with C-to-A and C-to-G transversion mutations within 5′-TC dinucleotide motifs in early-stage high-grade serous ovarian cancer genomes, suggesting that APOBEC3B-catalyzed genomic uracil lesions are further processed by downstream DNA "repair" enzymes including error-prone translesion polymerases. These data identify a potential role for APOBEC3B in serous ovarian cancer genomic instability. Cancer Res; 73(24); 7222–31. ©2013 AACR.

Background and Purpose— The prognostic significance of subarachnoid extension of intracerebral hemorrhage was determined in the INTEnsive blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT2) study. Methods— INTERACT2 was an open randomized controlled trial of early intensive compared with guideline-recommended blood pressure lowering in patients with elevated systolic blood pressure within 6 hours of intracerebral hemorrhage. Independent predictors of death or major disability (scores 3–6 on the modified Rankin Scale) at 90 days were analyzed in logistic regression models. Results— Of 2582 participants, 192 (7%) had subarachnoid extension, which was associated with larger hematoma volumes ( P <0.0001) and higher National Institute of Health Stroke Scale score ( P <0.0001). Subarachnoid extension predicted death or major disability at 90 days (71% versus 53%; unadjusted odds ratio, 2.25; 95% confidence interval, 1.63–3.10; P <0.0001). The association remained significant after adjusting for age, region, lipid-lowering therapy, systolic blood pressure, glucose, location of hematoma, intraventricular extension, and randomized treatment (odds ratio, 2.17; 95% confidence interval, 1.50–3.14; P <0.0001), but not after further adjustment for baseline hematoma volume ( P =0.62). Conclusions— Subarachnoid extension of intracerebral hemorrhage is associated with poor prognosis, which is determined by a larger volume of the underlying intraparenchymal hematoma. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00716079.

Arterial wall stiffness can be associated with various diseases. The stiffness of an artery can be assessed by measurement of the pulse wave velocity (PWV). PWV is directly related to the Youngs modulus by the well-known Moens–Korteweg equation. Usually, PWV is estimated using the foot-to-foot method. However, the foot of the pressure wave is not very clear due to reflected waves. Also, the pressure wave is normally at a low frequency, hence, the time resolution is low. PWV is an average indicator of artery stiffness between the two measuring points, therefore it is not easy to identify local stiffness. We propose producing a very short pulse wave in the arterial wall using ultrasound radiation force and measuring its propagation speed along the artery by laser. The temporal resolution of this method is in the range of microseconds, which allows PWV to be measured accurately over a few millimeters. Experiments were carried out on a silicone tube in gelatin. PWV was measured by two scanning methods: (1) fixed source and scanning detector, (2) scanning source and fixed detector. Results: PWV was measured at 2 mm/40 μs by both methods. The Doppler technique was also tested which is potentially suitable for clinical applications.

Vibro-acoustography is a new noncontact imaging method based on the radiation force of ultrasound. We extend this technique for imaging of arterial vessels based on vibration resonance. The arterial vessel is excited remotely by ultrasound at a resonant frequency, at which the vibration of the vessel as well as its transmission to the body surface are large enough to be measured. By scanning the ultrasound beam across the vessel plane and measuring the vibration at one single point on the body or vessel surface, an image of the interior artery can be mapped. Theory is developed that predicts the measured velocity is proportional to the value of the mode shape at resonance. Experimental studies were carried out on a silicone tube embedded in a cylindrical gel phantom of large radius, which simulates a large artery and the surrounding body. The fundamental frequency was measured at which the ultrasound transducer scanned across the tube plane with velocity measurement at one single point on the tube or on the phantom by laser. The images obtained show clearly the interior tube and the modal shape of the tube. The present technique offers a new imaging method for arterial vessels.

Vibro-acoustography is a new noncontact imaging method based on the radiation force of ultrasound. We extend this technique for tissue characterization of arterial tubes by vibration techniques. The arterial tube can be excited remotely by ultrasound at its resonant frequencies where the vibration and acoustic emission of the tube can be measurable. From these resonant frequencies, the material properties of the arterial tube can be found. A theory for a tube with tissue is formulated using first-order shear deformation theory to include the effects of transverse shear deformation and rotary inertia. A wave propagation approach is applied for easy handling of the boundary conditions. Experimental studies were carried out on a silicone tube embedded in a cylindrical gel phantom. A confocal transducer is used to produce the radiation force of ultrasound for exciting the tube–phantom structure. The vibration of the tube and the phantom are measured with a laser vibrometry system. The fundamental mode of a tube–phantom structure is well excited by the radiation force of ultrasound, and was measured to be 81.8 Hz, which is close to the theoretical prediction of 83.3 Hz. Both excitation and measurement are remote and noncontact, important attributes for future study of arteries.

A coupled vibration model, which takes into account the elastic arterial wall, the interior blood, and exterior tissue, is presented. The arterial wall is considered as a cylindrical elastic shell and is modeled with the thick shell theory due to the large thickness-to-radius ratios. Both the blood and the tissue are considered as ideal fluids and are modeled with acoustic wave theory. A newly developed method, the wave propagation approach, is extended for the coupled vibration of arterial walls. The theoretic model is evaluated against those available in the literature. The experiments were carried out on a silicone rubber tube in a water tank with an ultrasound stimulated system. This system uses the radiation force of ultrasound to vibrate the tube at low frequency and records the resulting response by a laser vibrometer. Both the excitation and measurement are remote and noncontact. The measured fundamental frequency is in good agreement with the theoretical prediction.

Background Neurohormonal dysregulation contributes to heart failure (HF) progression. We sought to determine the effect of cardiac resynchronisation therapy (CRT) on the nerve growth factor (NGF), a biomarker that promotes the maturation, and survival of sympathetic nerve endings, and amino-terminal propeptide of type III procollagen (PIIINP), a marker of type III collagen synthesis. Methods This prospective study enrolled 20 healthy age-matched controls and 45 consecutive patients (pts) who received CRT-D. NYHA class, distance of 6-min walk and echocardiography and plasma concentrations of NGF, PIIINP, b-type natriuretic peptide (BNP), norepinephrine (NE), epinephrine (EPI) and dopamine (DA) were measured before and 6 month after CRT. Response to CRT was defined as ≥15% reduction in left ventricular end-systolic volume index (LVESVI) at 6-month follow-up. Results The baseline BNP (557±692 vs 47±35, p<0.01) and PIIINP (8.22±3.76 vs 5.36±1.47, p<0.01) were elevated in HF compared to controls, while NGF, NE, EPI and DA levels were not different. Twenty two of 45 pts (49%) responded to CRT. The responder group demonstrated significant decrease only in BNP level (p=0.04) at 6-month follow-up, parallelling with the clinical improvements (table 1). The baseline PIIINP was lower in CRT responders than non-responders (p=0.04), and it correlated with the reduction of LVESVI (p=0.01, r=−0.50) after CRT. The further multivariate analysis showed only the plasma PIIINP level among clinic characters and all the biomarkers can predict the improvement of LVESV index (OR=8.33, P=0.01). Conclusion The low PIIINP level, which is consistent with possible less cardiac fibrosis and a more plastic ventricle at baseline, is associated with CRT responsiveness. Contrary to previous reports, the NGF levels were not reduced during HF and that there was no NGF rebound in CRT responders.

Pulse wave velocity (PWV) is widely used for estimating the stiffness of an artery. It is well known that a stiffened artery can be associated with disease and aging. Usually, PWV is measured using the foot-to-foot time-delay method. However, the foot of the pulse wave cannot be accurately determined due to reflected waves. In addition, PWV is an average indicator of artery stiffness between the two measuring points. We propose to generate a wave in the artery wall using localized ultrasound radiation force. The wave velocity can be measured accurately by the phase change versus distance over a few millimeters. A mathematical model is developed by which the real part of the complex Young’s modulus of the artery can be determined from measured wave velocities. The imaginary part of the complex modulus can be assessed by the wave amplitude decay over distance. Experiments were conducted on a pig carotid artery in gelatin. The measured wave velocity is about 3 m/s at 100 Hz and 6.5 m/s at 500 Hz. The real part of complex modulus is estimated to be 300 kPa. The present technique offers a new method for estimating the complex elastic modulus of the artery over a short length.