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      Prognostic Assessment of Oxidative Stress-Related Genes in Colorectal Cancer and New Insights into Tumor Immunity

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          Abstract

          Oxidative stress is crucial to the biology of tumors. Oxidative stress' potential predictive significance in colorectal cancer (CRC) has not been studied; nevertheless here, we developed a forecasting model based on oxidative stress to forecast the result of CRC survival and enhance clinical judgment. The training set was chosen from the transcriptomes of 177 CRC patients in GSE17536. For validation, 65 samples of colon cancer from GSE29621 were utilized. For the purpose of choosing prognostic genes, the expression of oxidative stress-related genes (OXEGs) was found. Prognostic risk models were built using multivariate Cox regression analysis, univariate Cox regression analysis, and LASSO regression analysis. The outcomes of the western blot and transcriptome sequencing tests were finally confirmed. ATF4, CARS2, CRP, GPX1, IL1B, MAPK8, MRPL44, MTFMT, NOS1, OSGIN2, SOD2, AARS2, and FOXO3 were among the 14 OXEGs used to build prognostic characteristics. Patients with CRC were categorized into low-risk and high-risk groups according on their median risk scores. Cox regression analysis using single and multiple variables revealed that OXEG-related signals were independent risk factors for CRC. Additionally, the validation outcomes from western blotting and transcriptome sequencing demonstrated that OXEGs were differently expressed. Using 14 OXEGs, our work creates a predictive signature that may be applied to the creation of new prognostic models and the identification of possible medication candidates for the treatment of CRC.

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          Colorectal cancer statistics, 2020

          Colorectal cancer (CRC) is the second most common cause of cancer death in the United States. Every 3 years, the American Cancer Society provides an update of CRC occurrence based on incidence data (available through 2016) from population-based cancer registries and mortality data (through 2017) from the National Center for Health Statistics. In 2020, approximately 147,950 individuals will be diagnosed with CRC and 53,200 will die from the disease, including 17,930 cases and 3,640 deaths in individuals aged younger than 50 years. The incidence rate during 2012 through 2016 ranged from 30 (per 100,000 persons) in Asian/Pacific Islanders to 45.7 in blacks and 89 in Alaska Natives. Rapid declines in incidence among screening-aged individuals during the 2000s continued during 2011 through 2016 in those aged 65 years and older (by 3.3% annually) but reversed in those aged 50 to 64 years, among whom rates increased by 1% annually. Among individuals aged younger than 50 years, the incidence rate increased by approximately 2% annually for tumors in the proximal and distal colon, as well as the rectum, driven by trends in non-Hispanic whites. CRC death rates during 2008 through 2017 declined by 3% annually in individuals aged 65 years and older and by 0.6% annually in individuals aged 50 to 64 years while increasing by 1.3% annually in those aged younger than 50 years. Mortality declines among individuals aged 50 years and older were steepest among blacks, who also had the only decreasing trend among those aged younger than 50 years, and excluded American Indians/Alaska Natives, among whom rates remained stable. Progress against CRC can be accelerated by increasing access to guideline-recommended screening and high-quality treatment, particularly among Alaska Natives, and elucidating causes for rising incidence in young and middle-aged adults.
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            Reactive oxygen species (ROS) as pleiotropic physiological signalling agents

            'Reactive oxygen species' (ROS) is an umbrella term for an array of derivatives of molecular oxygen that occur as a normal attribute of aerobic life. Elevated formation of the different ROS leads to molecular damage, denoted as 'oxidative distress'. Here we focus on ROS at physiological levels and their central role in redox signalling via different post-translational modifications, denoted as 'oxidative eustress'. Two species, hydrogen peroxide (H2O2) and the superoxide anion radical (O2·-), are key redox signalling agents generated under the control of growth factors and cytokines by more than 40 enzymes, prominently including NADPH oxidases and the mitochondrial electron transport chain. At the low physiological levels in the nanomolar range, H2O2 is the major agent signalling through specific protein targets, which engage in metabolic regulation and stress responses to support cellular adaptation to a changing environment and stress. In addition, several other reactive species are involved in redox signalling, for instance nitric oxide, hydrogen sulfide and oxidized lipids. Recent methodological advances permit the assessment of molecular interactions of specific ROS molecules with specific targets in redox signalling pathways. Accordingly, major advances have occurred in understanding the role of these oxidants in physiology and disease, including the nervous, cardiovascular and immune systems, skeletal muscle and metabolic regulation as well as ageing and cancer. In the past, unspecific elimination of ROS by use of low molecular mass antioxidant compounds was not successful in counteracting disease initiation and progression in clinical trials. However, controlling specific ROS-mediated signalling pathways by selective targeting offers a perspective for a future of more refined redox medicine. This includes enzymatic defence systems such as those controlled by the stress-response transcription factors NRF2 and nuclear factor-κB, the role of trace elements such as selenium, the use of redox drugs and the modulation of environmental factors collectively known as the exposome (for example, nutrition, lifestyle and irradiation).
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              Oxidative Stress in Cancer

              Contingent upon concentration, reactive oxygen species (ROS) influence cancer evolution in apparently contradictory ways, either initiating/stimulating tumorigenesis and supporting transformation/proliferation of cancer cells or causing cell death. To accommodate high ROS levels, tumor cells modify sulfur-based metabolism, NADPH generation, and the activity of antioxidant transcription factors. During initiation, genetic changes enable cell survival under high ROS levels by activating antioxidant transcription factors or increasing NADPH via the pentose phosphate pathway (PPP). During progression and metastasis, tumor cells adapt to oxidative stress by increasing NADPH in various ways, including activation of AMPK, the PPP, and reductive glutamine and folate metabolism.
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                Author and article information

                Contributors
                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi
                1942-0900
                1942-0994
                2022
                15 October 2022
                : 2022
                : 2518340
                Affiliations
                1Nanjing University of Chinese Medicine, Nanjing 210023, China
                2Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
                3Department of Ultrasound, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210001, China
                4Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, China
                5Department of Oncology, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing, Jiangsu 210028, China
                6School of Acupuncture and Tuina, School of Regimen and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing 210023, China
                7School of Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
                Author notes

                Academic Editor: Wenjie Shi

                Author information
                https://orcid.org/0000-0002-0931-0369
                https://orcid.org/0000-0003-0450-2000
                https://orcid.org/0000-0002-7411-4364
                https://orcid.org/0000-0002-2072-9822
                https://orcid.org/0000-0003-4086-4324
                https://orcid.org/0000-0003-0263-9150
                https://orcid.org/0000-0001-5479-318X
                https://orcid.org/0000-0002-4974-7274
                https://orcid.org/0000-0001-8203-1166
                https://orcid.org/0000-0002-5374-7162
                https://orcid.org/0000-0002-0111-6502
                https://orcid.org/0000-0001-6857-9168
                https://orcid.org/0000-0002-3334-9124
                https://orcid.org/0000-0001-7244-4290
                Article
                10.1155/2022/2518340
                9590115
                36299603
                47b0411f-7128-4af6-9fce-cbfa036df3fc
                Copyright © 2022 Zilu Chen et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 19 August 2022
                : 21 September 2022
                Funding
                Funded by: Postgraduate Research Innovation Program of Jiangsu Province
                Award ID: KYCX22_1888
                Funded by: Changzhou Science and Technology Bureau
                Award ID: CE20205039
                Funded by: Young Talent Development Plan of Changzhou Health Commission
                Award ID: CZQM2020004
                Funded by: Jiangsu Commission of Health
                Award ID: LGY2020003
                Funded by: National Natural Science Foundation of China
                Award ID: 81773947
                Categories
                Research Article

                Molecular medicine
                Molecular medicine

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