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      Discovery of lipid biomarkers correlated with disease progression in clear cell renal cell carcinoma using desorption electrospray ionization imaging mass spectrometry

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          Abstract

          Clear cell renal cell carcinoma (ccRCC) often results in recurrence or metastasis, and there are only a few clinically effective biomarkers for early diagnosis and personalized therapy. Metabolic changes have been widely studied using mass spectrometry (MS) of tissue lysates to identify novel biomarkers. Our objective was to identify lipid biomarkers that can predict disease progression in ccRCC by a tissue-based approach. We retrospectively investigated lipid molecules in cancerous tissues and normal renal cortex tissues obtained from patients with ccRCC ( n = 47) using desorption electrospray ionization imaging mass spectrometry (DESI-IMS). We selected eight candidate lipid biomarkers showing higher signal intensity in cancerous than in normal tissues, with a clear distinction of the tissue type based on the images. Of these candidates, low maximum intensity ratio (cancerous/normal) values of ions of oleic acid, m/z 389.2, and 391.3 significantly correlated with shorter progression-free survival compared with high maximum intensity ratio values ( P = 0.011, P = 0.022, and P < 0.001, respectively). This study identified novel lipid molecules contributing to the prediction of disease progression in ccRCC using DESI-IMS. Our findings on lipid storage may provide a new diagnostic or therapeutic strategy for targeting cancer cell metabolism.

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          An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma.

          Dysregulated metabolism is a hallmark of cancer, manifested through alterations in metabolites. We performed metabolomic profiling on 138 matched clear cell renal cell carcinoma (ccRCC)/normal tissue pairs and found that ccRCC is characterized by broad shifts in central carbon metabolism, one-carbon metabolism, and antioxidant response. Tumor progression and metastasis were associated with metabolite increases in glutathione and cysteine/methionine metabolism pathways. We develop an analytic pipeline and visualization tool (metabolograms) to bridge the gap between TCGA transcriptomic profiling and our metabolomic data, which enables us to assemble an integrated pathway-level metabolic atlas and to demonstrate discordance between transcriptome and metabolome. Lastly, expression profiling was performed on a high-glutathione cluster, which corresponds to a poor-survival subgroup in the ccRCC TCGA cohort.
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            Metabolic reprogramming in clear cell renal cell carcinoma

            Clear cell renal cell carcinoma is associated with reprogramming of metabolic pathways including glucose and fatty acid metabolism and the tricarboxylic acid cycle. Here, the authors discuss these reprogrammed pathways and the opportunities they provide for new therapies, imaging modalities and biomarkers.
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              Biostatistics Series Module 3: Comparing Groups: Numerical Variables

              Numerical data that are normally distributed can be analyzed with parametric tests, that is, tests which are based on the parameters that define a normal distribution curve. If the distribution is uncertain, the data can be plotted as a normal probability plot and visually inspected, or tested for normality using one of a number of goodness of fit tests, such as the Kolmogorov–Smirnov test. The widely used Student's t-test has three variants. The one-sample t-test is used to assess if a sample mean (as an estimate of the population mean) differs significantly from a given population mean. The means of two independent samples may be compared for a statistically significant difference by the unpaired or independent samples t-test. If the data sets are related in some way, their means may be compared by the paired or dependent samples t-test. The t-test should not be used to compare the means of more than two groups. Although it is possible to compare groups in pairs, when there are more than two groups, this will increase the probability of a Type I error. The one-way analysis of variance (ANOVA) is employed to compare the means of three or more independent data sets that are normally distributed. Multiple measurements from the same set of subjects cannot be treated as separate, unrelated data sets. Comparison of means in such a situation requires repeated measures ANOVA. It is to be noted that while a multiple group comparison test such as ANOVA can point to a significant difference, it does not identify exactly between which two groups the difference lies. To do this, multiple group comparison needs to be followed up by an appropriate post hoc test. An example is the Tukey's honestly significant difference test following ANOVA. If the assumptions for parametric tests are not met, there are nonparametric alternatives for comparing data sets. These include Mann–Whitney U-test as the nonparametric counterpart of the unpaired Student's t-test, Wilcoxon signed-rank test as the counterpart of the paired Student's t-test, Kruskal–Wallis test as the nonparametric equivalent of ANOVA and the Friedman's test as the counterpart of repeated measures ANOVA.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                1 March 2019
                1 March 2019
                : 10
                : 18
                : 1688-1703
                Affiliations
                1 Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
                2 Department of Urology, Hamamatsu University School of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
                3 International Mass Imaging Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
                4 Preeminent Medical Photonics Education and Research Center, Hamamatsu, Shizuoka, Japan
                5 Department of Anatomy, The University of Hong Kong, Hong Kong, China
                Author notes
                Correspondence to: Mitsutoshi Setou, setou@ 123456hama-med.ac.jp
                Article
                26706
                10.18632/oncotarget.26706
                6422196
                30899441
                5221378c-03a5-44d7-8af8-0d1926b034d3
                Copyright: © 2019 Tamura et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 27 October 2018
                : 9 February 2019
                Categories
                Research Paper

                Oncology & Radiotherapy
                clear cell renal cell carcinoma,desorption electrospray ionization imaging mass spectrometry,lipid,biomarker,disease progression

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