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- Zhang, Xueli, 1991-
(författare)
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Biomarkers for Diagnosis, Therapy and Prognosis in Colorectal Cancer : a study from databases, machine learning predictions to laboratory confirmations
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. Early diagnosis and better therapy response have been believed to be associated with better prognosis. CRC biomarkers are considered as precise indicators for the early diagnosis and better therapy response. It is, therefore, of importance to find out, analyze and evaluate the CRC biomarkers to further provide the more precis evidence for predicting novel potential biomarkers and eventually to improve early diagnosis, personalized therapy and prognosis for CRC.In this study, we started with creating and establishing a CRC biomarker database. (CBD: http://sysbio.suda.edu.cn/CBD/index.html) In the CBD database, there were 870 reported CRC biomarkers collected from the published articles in PubMed. In this version of the CBD, CRC biomarker data was carefully collected, sorted, displayed, and analyzed. The major applications of the CBD are to provide 1) the records of CRC biomarkers (DNA, RNA, protein and others) concerning diagnosis, treatment and prognosis; 2) the basic and clinical research information concerning the CRC biomarkers; 3) the primary results for bioinformatics and biostatics analysis of the CRC biomarkers; 4) downloading/uploading the biomedicine information for CRC biomarkers.Based on our CBD and other public databases, we further analyzed the presented CRC biomarkers (DNAs, RNAs, proteins) and predicted novel potential multiple biomarkers (the combination of single biomarkers) with biological networks and pathways analysis for diagnosis, therapy response and prognosis in CRC. We found several hub biomarkers and key pathways for the diagnosis, treatment and prognosis in CRC. Receiver operating characteristic (ROC) test and survival analysis by microarray data revealed that multiple biomarkers could be better biomarkers than the single biomarkers for the diagnosis and prognosis of CRC.There are 62 diagnosis biomarkers for colon cancer in our CBD. In the previous studies, we found these present biomarkers were not enough to improve significantly the diagnosis of colon cancer. In order to find out novel biomarkers for the colon cancer diagnosis, we have performed /machine learning (ML) techniques such as support vector machine (SVM) and regression tree to predict candidate to discover diagnostic biomarkers for colon cancer. Based on the protein-protein interaction (PPI) network topology features of the identified biomarkers, we found 12 protein biomarkers which were considered as the candidate colon cancer diagnosis biomarkers. Among these protein biomarkers Chromogranin-A (CHGA) was the most powerful biomarker, which showed good performance in bioinformatics test and Immunohistochemistry(IHC). We are now expanding this study to CRC.Expression of CHGA protein in colon cancer was further verified with a novel logistic regressionbased meta-analysis, and convinced as a valuable diagnostic biomarker as compared with the typical diagnostic biomarkers, such as TP53, KRAS and MKI67.microRNAs (miRNAs/miRs) have been considered as potential biomarkers. A novel miRNA-mRNA interaction network-based model was used to predict miRNA biomarkers for CRC and found that miRNA-186-5p, miRNA-10b-5p and miRNA-30e-5p might be the novel biomarkers for CRC diagnosis. In conclusion, we have created a useful CBD database for CRC biomarkers and provided detailed information for how to use the CBD in CRC biomarker investigations. Our studies have been focusing on the biomarkers in diagnosis, therapy and prognosis. Based on our CBD and other powerful cancer associated databases, ML has been used to analyze the characteristics of the CRC biomarkers and predict novel potential CRC biomarkers. The predicted potential biomarkers were further confirmed at biomedical laboratory.
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- Zhang, Hong, 1957-
(författare)
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Alloxan Toxicity to macrophages and Insulinoma Cells
- 1995
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alloxan induces damage and death of pancreatic islet B-cells in severalexperimental animal models, thus causing insulin-dependent diabetes mellitus (IDDM or type I diabetes). This unique cytotoxicity of alloxan has been studied for more than fifty years. The mechanisms behind the cytotoxicity of alloxan have, however, never been fully understood, although an increasing number of authors now suggest formation of reactive oxygen species, targeting the plasma membrane, mitochondria and DNA. In the present study, we have investigated: (i) the production of superoxide and hydrogen peroxide during reactions between alloxan and reducing agents such as cysteine, reduced glutathione, and ascorbic acid; (ii) the cytotoxic effects of alloxan in the absence of reducing agents, on model systems of cultured macrophages and insulinoma cells; (iii) the cytotoxicity of alloxan together with the reducing agents on these cultured cells; (iv) the cytotoxicity of hydrogen peroxide, used at concentrations similar to those formed during the reactions of alloxan with reducing agents; (v) the influence of iron and the iron-chelator, desferrioxamine, on the alloxan-induced cytotoxicity; and (vi) the influence of starvation-induced autophagocytosis on the sensitivity of cells to hydrogen peroxide-induced oxidative stress. Cell viability was estimated by a delayed trypan blue dye exclusion test and plasma membrane permeability by a modified microfluorometric combined fluorescein diacetate-propidium iodide staining technique. Lysosomal membrane stability was microfluorometrically assayed by acridine orange and neutral red relocalization techniques. The intracellular amounts of iron, reduced glutathione, antioxidant enzymes, and ATP were biochemically and cytochemically studied under a variety of conditions. The results showed that: (i) superoxide artion radicals and hydrogen peroxide were produced by reactions between alloxan and several reducing agents (e.g. cysteine, reduced glutathione and ascorbic acid). Hydrogen peroxide readily diffused through cellular membranes into the lysosomes if it was not previously degraded by the cellular antioxidative defence systems. Hydroxyl radicals might be produced by intralysosornal Fenton reactions, if reactive iron was present, resulting in lysosomal membrane damage followed by a leakage of lysosomal lytic enzymes with ensuing cell degeneration and eventually cell death. (ii) If iron was adsorbed to plasma membranes, extracellularly produced superoxide anion radicals and hydrogen peroxide might cause the plasma membrane damage due to Fenton reactions. (iii) Preincubation with desferrioxamine, or the presence of catalase inhibited the cytotoxicity induced by alloxan and reducing agents. (iv) The antioxidative defence activity of insulinoma cells was low. (v) Starvation in PBS enhanced the sensitivity of both macrophages and insulinoma cells to oxidative stress induced by hydrogen peroxide mediated through increased activity of autophagocytotosis. Thus, the amount of intralysosomal reactive iron consequently resulted from the degradation of various iron-containing metallo-proteins. We conclude that the exposure of cells to alloxan together with a reducing agent created cellular oxidative stress through extracellular formation of superoxide anion radicals and hydrogen peroxide. The latter compound easily penetrated plasma and lysosomal membranes, reaching the lysosomal interior. If enough reactive iron was present within lysosomes and the hydrogen peroxide was not degraded by catalase or glutathione peroxidase before entering the acidic vacuolar apparatus hydroxyl radicals could be produced via intralysosomal Fenton reactions.The hydroxyl radicals, in turn, would attack and damage the lysosomalmembranes, causing a leakage of lysosomal enzymes to the cytosol and eventually leading to cell death. The sensitivity of cells to alloxan-induced cytotoxicity in the presence of reducing agents was therefore a function of (i) the rate of hydrogen peroxide production, (ii) the cellular antioxidative defence systems, (iii) the lysosomal amount of reactive iron, and (iv) the capacity of autophagocytosis.
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