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      Prognostic model of patients with liver cancer based on tumor stem cell content and immune process

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          Abstract

          Globally, liver hepatocellular carcinoma (LIHC) has a high mortality and recurrence rate, leading to poor prognosis. The recurrence of LIHC is closely related to two aspects: degree of immune infiltration and content of tumor stem cells. Hence, this study aimed to used RNA-seq and clinical data of LIHC from The Cancer Genome Atlas, Estimation of Stromal and Immune cells in Malignant Tumours, mRNA stemness index score, and weighted gene correlation network analysis methods to find genes significantly linked to the aforementioned two aspects. Key genes and clinical factors were used as input. Lasso regression and multivariate Cox regression were conducted to build an effective prognostic model for patients with liver cancer. Finally, four key genes ( KLHL30, PLN, LYVE1, and TIMD4) and four clinical factors (Asian, age, grade, and bilirubin) were included in the prognostic model, namely Immunity and Cancer-stem-cell Related Prognosis (ICRP) score. The ICRP score achieved a great performance in test set. The area under the curve value of the ICRP score in test set for 1, 3, and 5 years was 0.708, 0.723, and 0.765, respectively, which was better than that of other prognostic prediction methods for LIHC. The C-index evaluation method also reached the same conclusion.

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          Most cited references28

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          The meaning and use of the area under a receiver operating characteristic (ROC) curve.

          A representation and interpretation of the area under a receiver operating characteristic (ROC) curve obtained by the "rating" method, or by mathematical predictions based on patient characteristics, is presented. It is shown that in such a setting the area represents the probability that a randomly chosen diseased subject is (correctly) rated or ranked with greater suspicion than a randomly chosen non-diseased subject. Moreover, this probability of a correct ranking is the same quantity that is estimated by the already well-studied nonparametric Wilcoxon statistic. These two relationships are exploited to (a) provide rapid closed-form expressions for the approximate magnitude of the sampling variability, i.e., standard error that one uses to accompany the area under a smoothed ROC curve, (b) guide in determining the size of the sample required to provide a sufficiently reliable estimate of this area, and (c) determine how large sample sizes should be to ensure that one can statistically detect differences in the accuracy of diagnostic techniques.
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            Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation

            Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation.
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              Deviations of the immune cell landscape between healthy liver and hepatocellular carcinoma

              Tumor-infiltrating immune cells are highly relevant for prognosis and identification of immunotherapy targets in hepatocellular carcinoma (HCC). The recently developed CIBERSORT method allows immune cell profiling by deconvolution of gene expression microarray data. By applying CIBERSORT, we assessed the relative proportions of immune cells in 41 healthy human livers, 305 HCC samples and 82 HCC adjacent tissues. The obtained immune cell profiles provided enumeration and activation status of 22 immune cell subtypes. Mast cells were evaluated by immunohistochemistry in ten HCC patients. Activated mast cells, monocytes and plasma cells were decreased in HCC, while resting mast cells, total and naïve B cells, CD4+ memory resting and CD8+ T cells were increased when compared to healthy livers. Previously described S1, S2 and S3 molecular HCC subclasses demonstrated increased M1-polarized macrophages in the S3 subclass with good prognosis. Strong total immune cell infiltration into HCC correlated with total B cells, memory B cells, T follicular helper cells and M1 macrophages, whereas weak infiltration was linked to resting NK cells, neutrophils and resting mast cells. Immunohistochemical analysis of patient samples confirmed the reduced frequency of mast cells in human HCC tumor tissue as compared to tumor adjacent tissue. Our data demonstrate that deconvolution of gene expression data by CIBERSORT provides valuable information about immune cell composition of HCC patients.
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                Author and article information

                Journal
                Aging (Albany NY)
                Aging
                Aging (Albany NY)
                Impact Journals
                1945-4589
                31 August 2020
                27 August 2020
                : 12
                : 16
                : 16555-16578
                Affiliations
                [1 ]Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
                [2 ]Peking University International Cancer Institute and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
                Author notes
                [*]

                Equal contribution

                Correspondence to: Zhengwei Xie; email: xiezhengwei@hsc.pku.edu.cn
                Correspondence to: Zhuo Huang; email: huangz@hsc.pku.edu.cn
                Article
                103832 103832
                10.18632/aging.103832
                7485734
                32852285
                0d24768d-ce4f-4f60-a396-f80833fac63b
                Copyright © 2020 Kong et al.

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

                History
                : 03 April 2020
                : 14 July 2020
                Categories
                Research Paper

                Cell biology
                bioinformatics,immunity,liver cancer,prognosis,tumor stem cells
                Cell biology
                bioinformatics, immunity, liver cancer, prognosis, tumor stem cells

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