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Innate immune training involves myelopoiesis, dynamic gene modulation, and functional reprogramming of myeloid cells in response to secondary heterologous challenges. The present study evaluates whether systemic innate immune training can protect tissues from local injury. Systemic pretreatment of mice with β‐glucan, a trained immunity agonist, reduces the mortality rate of mice with bleomycin‐induced lung injury and fibrosis, as well as decreasing collagen deposition in the lungs. β‐Glucan pretreatment induces neutrophil accumulation in the lungs and enhances efferocytosis. Training of mice with β‐glucan results in histone modification in both alveolar macrophages (AMs) and neighboring lung epithelial cells. Training also increases the production of RvD1 and soluble mediators by AMs and efferocytes. Efferocytosis increases trained immunity in AMs by stimulating RvD1 release, thus inducing SIRT1 expression in neighboring lung epithelial cells. Elevated epithelial SIRT1 expression is associated with decreased epithelial cell apoptosis after lung injury, attenuating tissue damage. Further, neutrophil depletion dampens the effects of β‐glucan on macrophage accumulation, epigenetic modification in lung macrophages, epithelial SIRT1 expression, and injury‐mediated fibrosis in the lung. These findings provide mechanistic insights into innate immune training and clues to the potential ability of centrally trained immunity to protect peripheral organs against injury‐mediated disorders. [ABSTRACT FROM AUTHOR]

Cardiotoxicity is a serious adverse effect of an anticancer drug, doxorubicin (DOX), which can occur within a year or decades after completion of therapy. The present study was designed to address a knowledge gap concerning a lack of circulating biomarkers capable of predicting the risk of cardiotoxicity induced by DOX. Profiling of 2083 microRNAs (miRNAs) in mouse plasma revealed 81 differentially expressed miRNAs 1 week after 6, 9, 12, 18, or 24 mg/kg total cumulative DOX doses (early‐onset model) or saline (SAL). Among these, the expression of seven miRNAs was altered prior to the onset of myocardial injury at 12 mg/kg and higher cumulative doses. The expression of only miR‐34a‐5p was significantly (false discovery rate [FDR] < 0.1) elevated at all total cumulative doses compared with concurrent SAL‐treated controls and showed a statistically significant dose‐related response. The trend in plasma miR‐34a‐5p expression levels during DOX exposures also correlated with a significant dose‐related increase in cardiac expression of miR‐34a‐5p in these mice. Administration of a cardioprotective drug, dexrazoxane, to mice before DOX treatment, significantly mitigated miR‐34a‐5p expression in both plasma and heart in conjunction with attenuation of cardiac pathology. This association between plasma and heart may suggest miR‐34a‐5p as a potential early circulating marker of early‐onset DOX cardiotoxicity. In addition, higher expression of miR‐34a‐5p (FDR < 0.1) in plasma and heart compared with SAL‐treated controls 24 weeks after 24 mg/kg total cumulative DOX dose, when cardiac function was altered in our recently established delayed‐onset cardiotoxicity model, indicated its potential as an early biomarker of delayed‐onset cardiotoxicity. Traditional technologies or cardiac disease markers have low sensitivity in detecting early signs of subclinical changes in hearts of cancer patients treated with doxorubicin (DOX). The present study identified miRNA‐34a‐5p as a potential early circulating biomarker of DOX cardiotoxicity in mice 1 week after receiving 6, 9, 12, 18, or 24 mg/kg total cumulative doses. Higher expression of miR‐34a‐5p in plasma at 24 weeks after receiving 24 mg/kg total dose suggested its potential as an early biomarker of delayed‐onset cardiotoxicity. [ABSTRACT FROM AUTHOR]

Increasingly, nations are engaging in smart city development projects. Smart city development aims to build urban areas with a wholesome quality of life with modern infrastructure capabilities (e.g., economic opportunities, cultural richness, and demographic-geographical balance), technological benefits (e.g., healthcare, education, government) and sustainability goals (e.g., clean, green, safe, and secure environments). This requires huge investments of resources and participation of diverse stakeholders, whose goals are often ambiguous and conflicting. It is not unusual that many of these projects are delayed because of a lack of consensus, which further adds unnecessary social costs and a waste of time and efforts. In this sense, determining strategic priorities for smart city development is crucial for achieving a set of integrative purposes in terms of resource allocation and social benefits goals. This paper aims to determine strategic priorities by examining multiple cases of smart city projects in Korea, Europe, and the U.S. A hierarchical strategic framework, which shows the vision, core values and strategic goals, is developed and proposed from the case studies. Lessons and practical implications are discussed for future study. [ABSTRACT FROM AUTHOR]

Subclinical cardiotoxicity at low total cumulative doxorubicin (DOX) doses can manifest into cardiomyopathy in long‐term cancer survivors. However, the underlying mechanisms are poorly understood. In male B6C3F1 mice, assessment of cardiac function by echocardiography was performed at 1, 4, 10, 17, and 24 weeks after exposure to 6, 9, 12, and 24 mg/kg total cumulative DOX doses or saline (SAL) to monitor development of delayed‐onset cardiotoxicity. The 6‐ or 9‐mg/kg total cumulative doses resulted in a significant time‐dependent decline in systolic function (left ventricular ejection fraction (LVEF) and fractional shortening (FS)) during the 24‐week recovery although there was not a significant alteration in % LVEF or % FS at any specific time point during the recovery. A significant decline in systolic function was elicited by the cardiotoxic cumulative DOX dose (24 mg/kg) during the 4‐ to 24‐week period after treatment compared to SAL‐treated counterparts. At 24 weeks after DOX treatment, a significant dose‐related decrease in the expression of genes and proteins involved in sarcoplasmic reticulum (SR) calcium homeostasis (Ryr2 and Serca2) was associated with a dose‐related increase in the transcript level of Casp12 (SR‐specific apoptosis) in hearts. These mice also showed enhanced apoptotic activity in hearts indicated by a significant dose‐related elevation in the number of apoptotic cardiomyocytes compared to SAL‐treated counterparts. These findings collectively suggest that a steady decline in SR calcium handling and apoptosis might be involved in the development of subclinical cardiotoxicity that can evolve into irreversible cardiomyopathy later in life. Subclinical cardiotoxicity elicited by low total cumulative doxorubicin (DOX) doses can occur years after treatment in cancer patients. In male B6C3F1 mice, a progressive deterioration in heart function measured by echocardiography was evidenced by a significant time‐dependent decline in systolic function during 24 weeks after treatment with 6‐ or 9‐mg/kg total cumulative DOX doses. A significant dose‐related downregulation of Ryr2 and Serca2 and increased number of apoptotic cardiomyocytes at 24 weeks after treatment may underlie delayed‐onset subclinical cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Abstract In studies that use DNA arrays to assess changes in gene expression, it is preferable to measure the significance of treatment effects on a group of genes from a pathway or functional category such as gene ontology terms (GO terms, http://www.geneontology.org) because this facilitates the interpretation of effects and may markedly increase significance. A modified meta-analysis method to combine p-values was developed to measure the significance of an overall treatment effect on such functionally-defined groups of genes, taking into account the correlation structure among genes. For hypothesis testing that allows gene expression to change in both directions, p-values are calculated under the null distribution generated by a Monte Carlo method. As a test of this procedure, we attempted to distinguish altered pathways in microarray studies performed with Mitochips, oligonucleotide microarrays specific to mitochondrial DNA-encoded transcripts. We found that our analytic method improves the specificity of selection for altered pathways, due to incorporation of the inter-gene correlation structure in each pathway. It is thus a practical method to measure treatment effects on GO groups. In many actual applications, microarray experiments measure treatment effects under complicated design structures and with small sample sizes. For such applications to real data of limited statistical power, and also in computer simulations, we demonstrate that our method gives reasonable test results.

Abstract Background In studies that use DNA arrays to assess changes in gene expression, our goal is to evaluate the statistical significance of treatments on sets of genes. Genes can be grouped by a molecular function, a biological process, or a cellular component, e.g., gene ontology (GO) terms. The meaning of an affected GO group is often clearer than interpretations arising from a list of the statistically significant genes. Results Computer simulations demonstrated that correlations among genes invalidate many statistical methods that are commonly used to assign significance to GO terms. Ignoring these correlations overstates the statistical significance. Meta-analysis methods for combining p-values were modified to adjust for correlation. One of these methods is elaborated in the context of a comparison between two treatments. The form of the correlation adjustment depends upon the alternative hypothesis. Conclusion Reliable corrections for the effect of correlations among genes on the significance level of a GO term can be constructed for an alternative hypothesis where all transcripts in the GO term increase (decrease) in response to treatment. For general alternatives, which allow some transcripts to increase and others to decrease, the bias of naïve significance calculations can be greatly decreased although not eliminated.

In this paper, we propose a method for compositing a synthetic mammogram (SM) from digital breast tomosynthesis (DBT) slice images. The method consists of four parts. The first part is image reconstruction of DBT from the acquired projection data by use of backprojection-filtration (BPF) algorithm with a low-frequency boosting scheme and a high-density object reduction technique embedded. Also, a few expectation-maximization (EM) iterations have been additively implemented on top of the BPF algorithm to prepare a separate volume image. The second is generating three kinds of intermediate SMs. A forward projection image and a linear structure weighted forward projection image were computed. A maximum intensity projection of the BPF reconstructed volume image was also generated. The third part is integrating three intermediate SMs. The last is the post-processing of the SM. We scanned two physical phantoms in a prototype DBT scanner, and we have evaluated the performance of the proposed method. We also performed a clinical data study by use of 30 patient data who went through both DBT and digital mammography (DM) scans. Three experienced radiologists have read the SMs generated by several component techniques and also read the DM of each patient, and evaluated the generated SMs. The experimental phantom study and the clinical reader study consistently demonstrated the usefulness of the proposed method. [ABSTRACT FROM AUTHOR]

Uncontrolled activation of transforming growth factor (TGF)-β results in a wide range of pathologic conditions. Therapeutic interventions to regulate TGF-β signaling during fibrosis have been developed but the effectiveness is still limited. Here, we show that developmental endothelial locus-1 (Del-1) ameliorates fibrosis in mice by inhibiting αv integrin-mediated activation of TGF-β. Del-1 bound to αvβ6 integrin, an important activator of TGF-β, and inhibited the binding of αvβ6 integrin to the latency-associated peptide (LAP), thereby suppressing αv integrin-mediated activation of TGF-β. Lack of Del-1 increased colocalization of αv integrin and LAP in the lungs, which was reversed by Del-1 supplementation. The crucial role of Del-1 in regulating TGF-β activity was recapitulated in a mouse model of fibrosis using an adenovirus expressing inactive TGF-β1. Del-1 supplementation improved the pathological characteristics of the mice and reduced mortality. Thus, we propose that Del-1 is a negative regulator of TGF-β activation and a potential anti-fibrotic factor. [ABSTRACT FROM AUTHOR]

Abstract Cardiotoxicity is a serious adverse effect of doxorubicin (DOX) treatment in cancer patients. Currently, there is a lack of sensitive biomarkers to predict the risk of DOX-induced cardiotoxicity. Using SOMAmer-based proteomic technology, 1129 proteins were profiled to identify potential early biomarkers of cardiotoxicity in plasma from male B6C3F 1 mice given a weekly intravenous dose of 3 mg/kg DOX or saline (SAL) for 2, 3, 4, 6, or 8 weeks (6, 9, 12, 18, or 24 mg/kg cumulative DOX doses, respectively). Also, a group of mice received the cardio-protectant, dexrazoxane (DXZ; 60 mg/kg; intraperitoneal) 30 min before a weekly DOX or SAL dose. Proteomic analysis in plasma collected a week after the last dose showed a significant ≥1.2-fold change in level of 18 proteins in DOX-treated mice compared to SAL-treated counterparts during 8-week exposure. Of these, neurogenic locus notch homolog protein 1 (NOTCH1), von Willebrand factor (vWF), mitochondrial glutamate carrier 2, Wnt inhibitory factor 1, legumain, and mannan-binding lectin serine protease 1 were increased in plasma at 6 mg/kg cumulative DOX dose, prior to the release of myocardial injury marker, cardiac troponin I at 12 mg/kg and higher cumulative doses. These six proteins also remained significantly elevated following myocardial injury or pathology at 24 mg/kg. Pretreatment of mice with DXZ significantly attenuated DOX-induced elevated levels of only NOTCH1 and vWF with mitigation of cardiotoxicity. This suggests NOTCH1 and vWF as candidate early biomarkers of DOX cardiotoxicity, which may help in addressing a clinically important question of identifying cancer patients at risk for cardiotoxicity. Highlights • Significant increase in plasma NOTCH1 prior to and after myocardial injury by doxorubicin in mice. • Significant increase in plasma vWF level prior to and after myocardial injury by doxorubicin in mice. • Dexrazoxane completely prevented formation of cardiac lesions in doxorubicin-treated mice. • Dexrazoxane significantly attenuated increased plasma NOTCH1 level in doxorubicin-treated mice. • Dexrazoxane significantly attenuated increased plasma vWF level in doxorubicin-treated mice. [ABSTRACT FROM AUTHOR]

To reduce the radiation dose given to patients, a tube current modulation (TCM) method has been widely used in diagnostic CT systems. However, the TCM method has not yet been applied to a kV-CBCT system on a LINAC machine. The purpose of this study is to investigate if a TCM method would be desirable in a kV-CBCT system for image-guided radiation therapy (IGRT) or not. We have developed an attenuation–based TCM method using prior knowledge from planning CT images of patients. The TCM method can provide optimized dose reductions without degrading image quality for kV-CBCT imaging. Here, we investigate whether or not our suggested TCM method is desirable to use in kV-CBCT systems to confirm and revise the exact position of a patient for IGRT. Patients go through diagnostic CT scans for RT planning; therefore, using information from prior CT images can enable estimations of the total X-ray attenuation through a patient’s body in a CBCT setting for radiation treatment. Having this planning CT image allows to use the proposed TCM method in RT. The proposed TCM method provides a minimal amount of current for each projection, as well as total current, required to reconstruct the current modulated CBCT image with an image quality similar to that of CBCT. After applying a calculated TCM current for each projection, projection images were acquired and the current modulated CBCT image was reconstructed using a FDK algorithm. To validate the proposed approach, we used a numerical XCAT phantom and a real ATOM phantom and evaluated the performance of the proposed method via visual and quantitative image quality metrics. The organ dose due to imaging radiation was calculated in both cases and compared using the GATE simulation toolkit. As shown in the quantitative evaluation, normalized noise and SSIM values of the TCM were similar to those of conventional CBCT images. In addition, the proposed TCM method yielded comparable image quality to that of conventional CBCT images for both simulations and experimental studies as organ doses were decreased. We have successfully demonstrated the feasibility and dosimetric merit of a prototypical TCM method for kV-CBCT via simulations and experimental study. The results indicate that the proposed TCM method and overall framework can be a viable option for CBCT imaging that utilizes an optimal dose reduction without degrading image quality. Thus, this method reduces the probability for side effects due to radiation exposure. [ABSTRACT FROM AUTHOR]

A single-scan dual-energy low-dose cone-beam CT (CBCT) imaging technique that exploits a multi-slit filter is proposed in this paper. The multi-slit filter installed between the x-ray source and the scanned object is reciprocated during a scan. The x-ray beams through the slits would generate relatively low-energy x-ray projection data, while the filtered beams would make high-energy projection data. An iterative image reconstruction algorithm that uses an adaptive-steepest-descent method to minimize image total-variation under the constraint of data fidelity was applied to reconstructing the image from the low-energy projection data. Since the high-energy projection data suffer from a substantially high noise level due to the beam filtration, we have developed a new algorithm that exploits the joint sparsity between the low- and high-energy CT images for image reconstruction of the high-energy CT image. The proposed image reconstruction algorithm uses a gradient magnitude image (GMI) of the low-energy CT image by regularizing the difference of GMIs of the low- and high-energy CT images to be minimized. The feasibility of the proposed technique has been demonstrated by the use of various phantoms in the experimental CBCT setup. Furthermore, based on the proposed dual-energy imaging, a material differentiation was performed and its potential utility has been shown. The proposed imaging technique produced promising results for its potential application to a low-dose single-scan dual-energy CBCT. [ABSTRACT FROM PUBLISHER]

Cone-beam computed tomography (CBCT) is gaining widespread use in various medical and industrial applications but suffers from substantially larger amount of scatter than that in the conventional diagnostic CT resulting in relatively poor image quality. Various methods that can reduce and/or correct for the scatter in the CBCT have therefore been developed. Scatter correction method that uses a beam-blocker has been considered a direct measurement-based approach providing accurate scatter estimation from the data in the shadows of the beam-blocker. To the best of our knowledge, there has been no record reporting the significance of the scatter from the beam-blocker itself in such correction methods. In this paper, we identified the scatter from the beam-blocker that is detected in the object-free projection data investigated its influence on the image accuracy of CBCT reconstructed images, and developed a scatter correction scheme that takes care of this scatter as well as the scatter from the scanned object. [ABSTRACT FROM AUTHOR]

Sex is a risk factor for development of cardiotoxicity, induced by the anti-cancer drug, doxorubicin (DOX), in humans. To explore potential mechanisms underlying differential susceptibility to DOX between sexes, 8-week old male and female B6C3F 1 mice were dosed with 3 mg/kg body weight DOX or an equivalent volume of saline via tail vein once a week for 6, 7, 8, and 9 consecutive weeks, resulting in 18, 21, 24, and 27 mg/kg cumulative DOX doses, respectively. At necropsy, one week after each consecutive final dose, the extent of myocardial injury was greater in male mice compared to females as indicated by higher plasma concentrations of cardiac troponin T at all cumulative DOX doses with statistically significant differences between sexes at the 21 and 24 mg/kg cumulative doses. A greater susceptibility to DOX in male mice was further confirmed by the presence of cytoplasmic vacuolization in cardiomyocytes, with left atrium being more vulnerable to DOX cardiotoxicity. The number of TUNEL-positive cardiomyocytes was mostly higher in DOX-treated male mice compared to female counterparts, showing a statistically significant sex-related difference only in left atrium at 21 mg/kg cumulative dose. DOX-treated male mice also had an increased number of γ-H2A.X-positive (measure of DNA double-strand breaks) cardiomyocytes compared to female counterparts with a significant sex effect in the ventricle at 27 mg/kg cumulative dose and right atrium at 21 and 27 mg/kg cumulative doses. This newly established mouse model provides a means to identify biomarkers and access potential mechanisms underlying sex-related differences in DOX-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

This paper experimentally demonstrates a feasibility of moving beam-blocker-based low-dose cone-beam CT (CBCT) and exploits the beam-blocking configurations to reach an optimal one that leads to the highest contrast-to-noise ratio (CNR). Sparse-view CT takes projections at sparse view angles and provides a viable option to reducing dose. We have earlier proposed a many- view under-sampling (MVUS) technique as an alternative to sparse-view CT. Instead of switching the x-ray tube power, one can place a reciprocating multi-slit beam-blocker between the x-ray tube and the patient to partially block the x-ray beam. We used a bench-top circular cone-beam CT system with a lab-made moving beam-blocker. For image reconstruction, we used a modified total-variation minimization (TV) algorithm that masks the blocked data in the back-projection step leaving only the measured data through the slits to be used in the computation. The number of slits and the reciprocation frequency have been varied and the effects of them on the image quality were investigated. For image quality assessment, we used CNR and the detectability. We also analyzed the sampling efficiency in the context of compressive sensing: the sampling density and data incoherence in each case. We tested three sets of slits with their number of 6, 12 and 18, each at reciprocation frequencies of 10, 30, 50 and 70 Hz/rot. The optimum condition out of the tested sets was found to be using 12 slits at 30 Hz/rot. [ABSTRACT FROM AUTHOR]