Citations

Abstract Purpose: Gastric adenocarcinoma is the third most common cause of cancer mortality worldwide. Accurate and affordable noninvasive detection methods have potential value for screening and surveillance. Herein, we identify novel methylated DNA markers (MDM) for gastric adenocarcinoma, validate their discrimination for gastric adenocarcinoma in tissues from geographically separate cohorts, explore marker acquisition through the oncogenic cascade, and describe distributions of candidate MDMs in plasma from gastric adenocarcinoma cases and normal controls. Experimental Design: Following discovery by unbiased whole-methylome sequencing, candidate MDMs were validated by blinded methylation-specific PCR in archival case–control tissues from U.S. and South Korean patients. Top MDMs were then assayed by an analytically sensitive method (quantitative real-time allele-specific target and signal amplification) in a blinded pilot study on archival plasma from gastric adenocarcinoma cases and normal controls. Results: Whole-methylome discovery yielded novel and highly discriminant candidate MDMs. In tissue, a panel of candidate MDMs detected gastric adenocarcinoma in 92% to 100% of U.S. and South Korean cohorts at 100% specificity. Levels of most MDMs increased progressively from normal mucosa through metaplasia, adenoma, and gastric adenocarcinoma with variation in points of greatest marker acquisition. In plasma, a 3-marker panel (ELMO1, ZNF569, C13orf18) detected 86% (95% CI, 71–95) of gastric adenocarcinomas at 95% specificity. Conclusions: Novel MDMs appear to accurately discriminate gastric adenocarcinoma from normal controls in both tissue and plasma. The point of aberrant methylation during oncogenesis varies by MDM, which may have relevance to marker selection in clinical applications. Further exploration of these MDMs for gastric adenocarcinoma screening and surveillance is warranted. Clin Cancer Res; 24(22); 5724–34. ©2018 AACR.

Abstract Female sex/gender is an undercharacterized variable in studies related to lung development and disease. Notwithstanding, many aspects of lung and sleep biology and pathobiology are impacted by female sex and female reproductive transitions. These may manifest as differential gene expression or peculiar organ development. Some conditions are more prevalent in women, such as asthma and insomnia, or, in the case of lymphangioleiomyomatosis, are seen almost exclusively in women. In other diseases, presentation differs, such as the higher frequency of exacerbations experienced by women with chronic obstructive pulmonary disease or greater cardiac morbidity among women with sleep-disordered breathing. Recent advances in -omics and behavioral science provide an opportunity to specifically address sex-based differences and explore research needs and opportunities that will elucidate biochemical pathways, thus enabling more targeted/personalized therapies. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the NIH Office of Research on Women’s Health and the Office of Rare Diseases Research, convened a workshop of investigators in Bethesda, Maryland on September 18 and 19, 2017. At the workshop, the participants reviewed the current understanding of the biological, behavioral, and clinical implications of female sex and gender on lung and sleep health and disease, and formulated recommendations that address research gaps, with a view to achieving better health outcomes through more precise management of female patients with nonneoplastic lung disease. This report summarizes those discussions.

AbstractIntroductionSince the introduction of wearable head‐up displays, there has been much interest in the surgical community adapting this technology into routine surgical practice.MethodsWe used the keywords augmented reality OR wearable device OR head‐up display AND surgery using PubMed, EBSCO, IEEE and SCOPUS databases. After exclusions, 74 published articles that evaluated the utility of wearable head‐up displays in surgical settings were included in our review.ResultsAcross all studies, the most common use of head‐up displays was in cases of live streaming from surgical microscopes, navigation, monitoring of vital signs, and display of preoperative images. The most commonly used head‐up display was Google Glass. Head‐up displays enhanced surgeons' operating experience; common disadvantages include limited battery life, display size and discomfort.ConclusionsDue to ergonomic issues with dual‐screen devices, augmented reality devices with the capacity to overlay images onto the surgical field will be key features of next‐generation surgical head‐up displays.

PurposeThe task‐based assessment of image quality using model observers is increasingly used for the assessment of different imaging modalities. However, the performance computation of model observers needs standardization as well as a well‐established trust in its implementation methodology and uncertainty estimation. The purpose of this work was to determine the degree of equivalence of the channelized Hotelling observer performance and uncertainty estimation using an intercomparison exercise.Materials and MethodsImage samples to estimate model observer performance for detection tasks were generated from two‐dimensional CT image slices of a uniform water phantom. A common set of images was sent to participating laboratories to perform and document the following tasks: (a) estimate the detectability index of a well‐defined CHO and its uncertainty in three conditions involving different sized targets all at the same dose, and (b) apply this CHO to an image set where ground truth was unknown to participants (lower image dose). In addition, and on an optional basis, we asked the participating laboratories to (c) estimate the performance of real human observers from a psychophysical experiment of their choice. Each of the 13 participating laboratories was confidentially assigned a participant number and image sets could be downloaded through a secure server. Results were distributed with each participant recognizable by its number and then each laboratory was able to modify their results with justification as model observer calculation are not yet a routine and potentially error prone.ResultsDetectability index increased with signal size for all participants and was very consistent for 6 mm sized target while showing higher variability for 8 and 10 mm sized target. There was one order of magnitude between the lowest and the largest uncertainty estimation.ConclusionsThis intercomparison helped define the state of the art of model observer performance computation and with thirteen participants, reflects openness and trust within the medical imaging community. The performance of a CHO with explicitly defined channels and a relatively large number of test images was consistently estimated by all participants. In contrast, the paper demonstrates that there is no agreement on estimating the variance of detectability in the training and testing setting.

Abstract Purpose: Homozygous deletions play important roles in carcinogenesis. The genome-wide screening for homozygously deleted genes in many different cancer types with a large number of patient specimens representing the tumor heterogeneity has not been done. Experimental Design: We performed integrative analyses of the copy-number profiles of 10,759 patients across 31 cancer types from The Cancer Genome Atlas project. Results: We found that the type-I interferon, α-, and β-defensin genes were homozygously deleted in 19 cancer types with high frequencies (7%–31%, median = 12%; interquartile range = 10%–16.5%). Patients with homozygous deletion of interferons exhibited significantly shortened overall or disease-free survival time in a number of cancer types, whereas patients with homozygous deletion of defensins did not significantly associate with worse overall or disease-free survival. Gene expression analyses suggested that homozygous deletion of interferon and defensin genes could activate genes involved in oncogenic and cell-cycle pathways but repress other genes involved in immune response pathways, suggesting their roles in promoting tumorigenesis and helping cancer cells evade immune surveillance. Further analysis of the whole exomes of 109 patients with melanoma demonstrated that the homozygous deletion of interferon (P = 0.0029, OR = 11.8) and defensin (P = 0.06, OR = 2.79) genes are significantly associated with resistance to anti-CTLA4 immunotherapy. Conclusions: Our analysis reveals that the homozygous deletion of interferon and defensin genes is prevalent in human cancers, and importantly this feature can be used as a novel prognostic biomarker for immunotherapy resistance. Clin Cancer Res; 24(14); 3299–308. ©2018 AACR.

New Findings What is the central question of this study? Will discontinued stimulation of isolated cardiomyocytes (asystole) during hypothermia mitigate hypothermia–rewarming‐induced cytosolic Ca2+ overload? What is the main finding and its importance? Mimicking asystole or hypothermic cardiac arrest by discontinued stimulation of cardiomyocytes during hypothermia resulted in normal contractile function after rewarming. This result suggests that asystole during severe hypothermia provides protection from hypothermia–rewarming‐induced contractile dysfunction in cardiomyocytes. AbstractAfter exposure of spontaneously beating hearts or electrically stimulated isolated cardiomyocytes to hypothermia–rewarming (H/R), cardiac dysfunction or alteration in excitation–contraction coupling, respectively, is a consequence. In contrast, hypothermic cardiac arrest, as routinely applied during cardiac surgery, will not impose any hazard to cardiac function after rewarming. We hypothesize that by maintaining asystole during H/R, cardiomyocytes will avoid Ca2+ overload attributable to the transient stimulation‐evoked elevation of [Ca2+]i and thus, H/R‐induced elevation of phosphorylated cardiac troponin I and reduced Ca2+ sensitivity after rewarming. To test this hypothesis, the aim of the study was to determine whether discontinued electrical stimulation (to imitate hypothermic cardiac arrest) versus stimulation during 3 h of H/R prevents disruption of excitation–contraction coupling in our established cardiomyocyte H/R model. Cytosolic Ca2+ and the contractile response (sarcomere length shortening) were measured using an IonOptix system, and the dynamic assessment of Ca2+ sensitivity of contraction was conducted using a phase‐loop plot. Cardiomyocytes were divided into three groups. Group 1 (time‐matched control) was continuously stimulated at 0.5 Hz for 3 h at 35°C. Group 2 was continuously stimulated during H/R at 0.5 Hz, whereas in group 3 stimulation was discontinued during H/R and thus the cells remained quiescent until the resumption of stimulation after rewarming. The results demonstrate that discontinued stimulation of cardiomyocytes during H/R, imitating hypothermic cardiac arrest during cardiac surgery, provides protection against H/R‐induced disruption of excitation–contraction coupling. We suggest that protective effects are caused by preventing the protein kinase A‐induced elevation of phosphorylated cardiac troponin I, which is a key mechanism to reduce myofilament Ca2+ sensitivity of contraction.

Evidence is provided that the fibroproliferative actions of TGF‐β are dependent on a metabolic adaptation that sustains pathologic growth. Specifically, profibrotic TGF‐β signaling is shown to require fatty acid synthase (FASN), an essential anabolic enzyme responsible for the de novo synthesis of fatty acids. With the use of pharmacologic and genetic approaches, we show that TGF‐β‐stimulated FASN expression is independent of Smad2/ 3 and is mediated via mammalian target of rapamycin complex 1. In the absence of FASN activity or protein, TGF‐β ‐driven fibrogenic processes are reduced with no apparent toxicity. Furthermore, as increased FASN expression was also observed to correlate with the degree of lung fibrosis in bleomycin‐treated mice, inhibition of FASN was examined in a murine‐treatment model of pulmonary fibrosis. Remarkably, inhibition of FASN not only decreased expression of profibrotic targets, but lung function was also stabilized/improved, as assessed by peripheral blood oxygenation.—Jung, M.‐Y., Kang, J.‐H., Hernandez, D. M., Yin, X., Andrianifahanana, M., Wang, Y., Gonzalez‐Guerrico, A., Limper, A. H., Lupu, R., Leof, E. B. Fatty acid synthase is required for profibrotic TGF‐β signaling. FASEB J. 32, 3803–3815 (2018). www.fasebj.org