The purpose of the present study was to determine the accuracy and the sources of error in estimating regional myocardial blood flow and vascular volume from experimental residue functions obtained by external imaging of an intravascular indicator. For the analysis, a spatially distributed mathematical model was used that describes transport through a multiple-pathway vascular system. Reliability of the parameter estimates was tested by using sensitivity function analysis and by analyzing "pseudodata": realistic model solutions to which random noise was added. Increased uncertainty in the estimates of flow in the pseudodata was observed when flow was near maximal physiological values, when dispersion of the vascular input was more than twice the dispersion of the microvascular system for an impulse input, and when the sampling frequency was < 2 samples/s. Estimates of regional blood volume were more reliable than estimates of flow. Failure to account for normal flow heterogeneity caused systematic underestimates of flow. To illustrate the method used for estimating regional flow, magnetic resonance imaging was used to obtain myocardial residue functions after left atrial injections of polylysine-Gd-diethylenetriaminepentaacetic acid, an intravascular contrast agent, in anesthetized chronically instrumental dogs. To test the increase in dispersion of the vascular input after central venous injections, magnetic resonance imaging data obtained in human subjects were compared with left ventricular blood pool curves obtained in dogs. It is concluded that if coronary flow is in the normal range, when the vascular input is a short bolus, and the heart is imaged at least once per cardiac cycle, then regional myocardial blood flow and vascular volume may be reliably estimated by analyzing residue functions of an intravascular indicator, providing a noninvasive approach with potential clinical application.

Esophageal squamous cell carcinoma (ESCC) is a poor-prognosis cancer type with limited understanding of its molecular etiology. Using 508 ESCC genomes, we identified five novel significantly mutated genes and uncovered mutational signature clusters associated with metastasis and patients’ outcomes. Several functional assays implicated that NFE2L2 may act as a tumor suppressor in ESCC and that mutations in NFE2L2 probably impaired its tumor-suppressive function, or even conferred oncogenic activities. Additionally, we found that the NFE2L2 mutations were significantly associated with worse prognosis of ESCC. We also identified potential noncoding driver mutations including hotspot mutations in the promoter region of SLC35E2 that were correlated with worse survival. Approximately 5.9% and 15.2% of patients had high tumor mutation burden or actionable mutations, respectively, and may benefit from immunotherapy or targeted therapies. We found clinically relevant coding and noncoding genomic alterations and revealed three major subtypes that robustly predicted patients’ outcomes. Collectively, we report the largest dataset of genomic profiling of ESCC useful for developing ESCC-specific biomarkers for diagnosis and treatment.

Esophageal squamous cell carcinoma (ESCC) ranks fourth among cancer-related deaths in China due to the lack of actionable molecules. We performed whole-exome and T-cell receptor (TCR) repertoire sequencing on multi-regional tumors, normal tissues and blood samples from 39 ESCC patients. The data revealed 12.8% of ERBB4 mutations at patient level and functional study supported its oncogenic role. 18% of patients with early BRCA1 /2 variants were associated with high-level contribution of signature 3, which was validated in an independent large cohort ( n = 508). Furthermore, knockdown of BRCA1 /2 dramatically increased sensitivity to cisplatin in ESCC cells. 5% of patients harbored focal high-level amplification of CD274 that led to massive expression of PD-L1, and might be more sensitive to immune checkpoint blockade. Finally, we found a tight correlation between genomic and TCR repertoire intra-tumor heterogeneity (ITH). Collectively, we reveal high-level ITH in ESCC, identify several potential actionable targets and may provide novel insight into ESCC treatment.

This paper addresses the problems of observerbased fault reconstruction and fault-tolerant control for TakagiSugeno fuzzy descriptor systems subject to time delays and external disturbances. A novel fuzzy descriptor learning observer is constructed to achieve simultaneous reconstruction of system states and actuator faults. Sufficient conditions for existence of the proposed observer are explicitly provided. Utilizing the reconstructed fault information, a reconfigurable fuzzy faulttolerant controller based on the separation property is designed to compensate for the impact of actuator faults on system performance by stabilizing the closed-loop system. In addition, the design of the fault reconstruction observer and the fault-tolerant controller is formulated in terms of linear matrix inequalities that can be conveniently solved using convex optimization techniques. At last, simulation results on a truck trailer system are presented to verify the effectiveness of the proposed approaches.

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The electrical conductivity value of the human skull is important for biophysics research of the brain. In the present study, the human brain-to-skull conductivity ratio was estimated through in vivo experiments utilizing intra-cranial electrical stimulation in two epilepsy patients. A realistic geometry inhomogeneous head model including the implanted silastic grids was constructed with the aid of the finite element method, and used to estimate the conductivity ratio. Averaging over 49 sets of measurements, the mean value and standard deviation of the brain-to-skull conductivity ratio were found to be 18.7 and 2.1, respectively. KeywordsConductivity; Bioimpedance; Skull; BrainThe ability to localize brain activity from noninvasive electrical measurements over the scalp provides a better understanding of the mechanisms of brain functions and aids clinical diagnosis and management of various neurological disorders. Determination of the physical properties of the human head volume conductor 1,2,3 , is essential for accurate localization of brain electrical activity. A number of experimental studies have suggested the appropriateness of the piecewise homogeneous head volume conductor (PHVC) model, in which different conductivity values of each tissue type (brain, skull, scalp) are used 4,5 . The proper determination of these conductivity values plays an important role for obtaining high accuracy brain source localization. In the PHVC model, the conductivity values can be reflected in the ratio of scalp and skull conductivities relative to the conductivity of the brain. While the scalp is assumed to have the same conductivity as that of the brain, in most investigations 1,2,6,7 the skull is set to a much lower value than that of the soft tissues.The correct value for the brain-to-skull conductivity ratio is still controversial. Rush and Driscoll 8 estimated the value of 80 as an optimal effective conductivity ratio between the human skull and a permeating fluid (modeling the skin and scalp muscles) by using an electrolytic tank to measure the impedance of the human skull. Cohen and Cuffin 9 suggested the brain-to-skull conductivity ratio of 80 in a combined analysis of the electroencephalogram (EEG) and magnetoencephalogram (MEG) recordings evoked by the same stimulus. More recently, Oostendorp et al 10 suggested a different brain-to-skull conductivity ratio of 15 from their in vitro and in vivo experiments in two human subjects. Lai et al 7 used a spherical head model based cortical imaging technique to estimate the human brain-to-skull conductivity ratio a) Electronic Mail: binhe@umn.edu. NIH Public Access Author ManuscriptAppl Phys Lett. Author manuscript; available in PMC 2007 December 1. In the present study, we estimated the human brain-to-skull conductivity ratio through in vivo experiments in two pediatric epilepsy patients who underwent simultaneous scalp EEG measurements and intra-cranial electrical stimulation delivered via a pair of electrodes in the implanted sub-dural grids. The methods used ar...

The response of myocardial high-energy and inorganic phosphates (HEP and Pi, respectively) and associated changes in myocardial blood flow, lactate uptake, and O2 consumption (MVo2) rates were examined in an open-chest canine model during progressively increasing workloads achieved by catecholamine infusion. HEP and Pi levels (measured with transmurally localized 31P-nuclear magnetic resonance spectroscopy) were unaffected by moderate increases in the level of energy expenditure but were significantly altered by high workloads, especially in the subepicardium. The MVo2 and HEP data from three different protocols that utilized pharmacological augmentation of blood flow demonstrated that the maximal rate of myocardial energy production during inotropic stimulation was dictated by perfusion limitation. This limitation was more severe in the subepicardial layer at the high workloads despite equivalent or even higher increases in blood flow to this layer, reflecting a preferential enhancement of demand in the outer layer by catecholamines. In contrast, under basal conditions, existence of a marginal perfusion limitation was evident in the inner but not in the outer layer.

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