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1
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Saputra HA, Karim MM. Fundamentals and research progression on electrochemical sensing of colorectal cancer. Mikrochim Acta 2025; 192:355. [PMID: 40369291 DOI: 10.1007/s00604-025-07207-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Accepted: 04/30/2025] [Indexed: 05/16/2025]
Abstract
Colorectal cancer (CRC) is a type of malignant disease that affects the large intestine (colon) and rectum. The CRC is among the causes of the highest mortality rates worldwide, so its rapid and sensitive early diagnosis is substantial. In the last few decades, CRC detection by electrochemical biosensors has progressed significantly due to their amenability and cost-effectiveness. Various electrochemical sensing strategies have been implemented, involving CRC biomarkers, such as protein, gene, or even CRC cells, that play a crucial role in screening tests, treatment, and prognosis. Electrochemical sensors are favored in this regard, owing to their ability to provide real-time, on-site detection with a straightforward preparation of samples. The present work provides an overview from the basic concepts to the recent research advances in electrochemical CRC biosensors for the management of patients. The review covers the importance of CRC detection, an introduction to electrochemical sensors, and cutting-edge electrochemical CRC biosensors. Further, challenges, limitations, and future research directions in developing and applying electrochemical sensing tools for CRC biomarkers are also comprehensively discussed. By consolidating the current research status, the present work aims to inspire further innovation in the development of electrochemical CRC biosensors. The insights presented here are expected to contribute to advancing more efficient, accessible diagnostic devices for CRC in the future.
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Affiliation(s)
| | - Md Mobarok Karim
- Department of Genetic Engineering and Biotechnology, Shahjalal University of Science and Technology, Sylhet, 3114, Bangladesh
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2
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Zhang HL, Zhao R, Wang D, Mohd Sapudin SN, Yahaya BH, Harun MSR, Zhang ZW, Song ZJ, Liu YT, Doblin S, Lu P. Candida albicans and colorectal cancer: A paradoxical role revealed through metabolite profiling and prognostic modeling. World J Clin Oncol 2025; 16:104182. [PMID: 40290696 PMCID: PMC12019262 DOI: 10.5306/wjco.v16.i4.104182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 01/11/2025] [Accepted: 01/23/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Emerging evidence implicates Candida albicans (C. albicans) in human oncogenesis. Notably, studies have supported its involvement in regulating outcomes in colorectal cancer (CRC). This study investigated the paradoxical role of C. albicans in CRC, aiming to determine whether it promotes or suppresses tumor development, with a focus on the mechanistic basis linked to its metabolic profile. AIM To investigate the dual role of C. albicans in the development and progression of CRC through metabolite profiling and to establish a prognostic model that integrates the microbial and metabolic interactions in CRC, providing insights into potential therapeutic strategies and clinical outcomes. METHODS A prognostic model integrating C. albicans with CRC was developed, incorporating enrichment analysis, immune infiltration profiling, survival analysis, Mendelian randomization, single-cell sequencing, and spatial transcriptomics. The effects of the C. albicans metabolite mixture on CRC cells were subsequently validated in vitro. The primary metabolite composition was characterized using liquid chromatography-mass spectrometry. RESULTS A prognostic model based on five specific mRNA markers, EHD4, LIME1, GADD45B, TIMP1, and FDFT1, was established. The C. albicans metabolite mixture significantly reduced CRC cell viability. Post-treatment analysis revealed a significant decrease in gene expression in HT29 cells, while the expression levels of TIMP1, EHD4, and GADD45B were significantly elevated in HCT116 cells. Conversely, LIME1 expression and that of other CRC cell lines showed reductions. In normal colonic epithelial cells (NCM460), GADD45B, TIMP1, and FDFT1 expression levels were significantly increased, while LIME1 and EHD4 levels were markedly reduced. Following metabolite treatment, the invasive and migratory capabilities of NCM460, HT29, and HCT116 cells were reduced. Quantitative analysis of extracellular ATP post-treatment showed a significant elevation (P < 0.01). The C. albicans metabolite mixture had no effect on reactive oxygen species accumulation in CRC cells but led to a reduction in mitochondrial membrane potential, increased intracellular lipid peroxidation, and induced apoptosis. Metabolomic profiling revealed significant alterations, with 516 metabolites upregulated and 531 downregulated. CONCLUSION This study introduced a novel prognostic model for CRC risk assessment. The findings suggested that the C. albicans metabolite mixture exerted an inhibitory effect on CRC initiation.
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Affiliation(s)
- Hao-Ling Zhang
- Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453000, Henan Province, China
- Department of Biomedical Science, Universiti Sains Malaysia, Pinang 13200, Malaysia
| | - Rui Zhao
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Di Wang
- Department of Biomedical Science, Universiti Sains Malaysia, Pinang 13200, Malaysia
| | - Siti Nurfatimah Mohd Sapudin
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Badrul Hisham Yahaya
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Mohammad Syamsul Reza Harun
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Zhong-Wen Zhang
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Zhi-Jing Song
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Yan-Ting Liu
- Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453000, Henan Province, China
| | - Sandai Doblin
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Ping Lu
- Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453000, Henan Province, China
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Khan F, Abdulla N, du Plessis TL, Karlsson K, Barrow P, Bebington B, Gu L, Kaur M. Identification and Validation of Biomarkers to Predict Early Diagnosis of Inflammatory Bowel Disease and Its Progression to Colorectal Cancer. Biochem Genet 2024:10.1007/s10528-024-10917-z. [PMID: 39325241 DOI: 10.1007/s10528-024-10917-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 09/13/2024] [Indexed: 09/27/2024]
Abstract
Inflammatory bowel disease (IBD) has become a common global health problem as prevalence continues to rise. It is often associated with increased risk of colorectal cancer (CRC) development. Limitations in current IBD biomarker-based diagnosis hinder the accuracy of early detection of CRC progression. Therefore, in this study, we proposed the use of transcription factor (TF)-based biomarkers that can potentially detect the transition of IBD to CRC. Various bioinformatic analysis and online database validations, and RT-qPCR validations were performed to identify possible diagnostic TFs. RUNX1 was identified as a promising TF that regulates 106 IBD/CRC-related genes. The incorporation of RUNX1 in combination with currently known IBD biomarkers, FEV + NFKB1 + RELA, achieved a comparable sensitivity and specificity scores of 99% and 87%, respectively, while RUNX1 in combination with known CRC markers, CEA + TIMP1 + CA724 + CA199, achieved a sensitivity and specificity score of 97% and 99%, respectively. Furthermore, a small pilot RT-qPCR-based analysis confirmed a demarcated shift in expression profiles in CA724, CEA, RUNX1 and TIMP1 in IBD patients compared to CRC patients' tissue samples. Specifically, CA724 is noticeably elevated in IBD, while the levels of CEA, RUNX1 with TIMP1 are probable genes that may be employed in discerning IBD progression to CRC. Therefore, these preliminary results once validated in large patient cohorts could potentially have a significant impact on CRC disease stratification, resulting in a more precise prediction for treatment and treatment outcomes, especially in South African patients.
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Affiliation(s)
- Farhat Khan
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Johannesburg, WITS-2050, South Africa
| | - Naaziyah Abdulla
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Johannesburg, WITS-2050, South Africa
| | - Thea-Leonie du Plessis
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Johannesburg, WITS-2050, South Africa
| | - Kay Karlsson
- Wits Donald Gordon Medical Centre, Park Town, Johannesburg, 2193, South Africa
| | - Peter Barrow
- Wits Donald Gordon Medical Centre, Park Town, Johannesburg, 2193, South Africa
| | - Brendan Bebington
- Wits Donald Gordon Medical Centre, Park Town, Johannesburg, 2193, South Africa
| | - Liang Gu
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Johannesburg, WITS-2050, South Africa
| | - Mandeep Kaur
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Johannesburg, WITS-2050, South Africa.
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4
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Cianciosi D, Forbes-Hernandez T, Armas Diaz Y, Elexpuru-Zabaleta M, Quiles JL, Battino M, Giampieri F. Manuka honey's anti-metastatic impact on colon cancer stem-like cells: unveiling its effects on epithelial-mesenchymal transition, angiogenesis and telomere length. Food Funct 2024; 15:7200-7213. [PMID: 38896046 DOI: 10.1039/d4fo00943f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Colorectal cancer often leads to metastasis, with cancer stem cells (CSCs) playing a pivotal role in this process. Two closely linked mechanisms, epithelial-mesenchymal transition and angiogenesis, contribute to metastasis and recent research has also highlighted the impact of telomere replication on this harmful tumor progression. Standard chemotherapy alone can inadvertently promote drug-resistant CSCs, posing a challenge. Combining chemotherapy with other compounds, including natural ones, shows promise in enhancing effectiveness while minimizing side effects. This study investigated the anti-metastatic potential of Manuka honey, both alone and in combination with 5-fluorouracil, using a 3D model of colonospheres enriched with CSC-like cells. In summary, it was observed that the treatment reduced migration ability by downregulating the transcription factors Slug, Snail, and Twist, which are key players in epithelial-mesenchymal transition. Additionally, Manuka honey downregulated pro-angiogenic factors and shortened CSC telomeres by downregulating c-Myc - demonstrating an effective anti-metastatic potential. This study suggests new research opportunities for studying the impact of natural compounds when combined with pharmaceuticals, with the potential to enhance effectiveness and reduce side effects.
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Affiliation(s)
- Danila Cianciosi
- Department of Clinical Sciences, Polytechnic University of Marche, Via Pietro Ranieri 65, Ancona, 60131, Italy.
| | - Tamara Forbes-Hernandez
- Department of Physiology, Institute of Nutrition and Food Technology "José Mataix Verdú", Biomedical Research Centre, University of Granada, Armilla, 18016, Spain
| | - Yasmany Armas Diaz
- Department of Clinical Sciences, Polytechnic University of Marche, Via Pietro Ranieri 65, Ancona, 60131, Italy.
| | - Maria Elexpuru-Zabaleta
- Research Group on Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Isabel Torres 21, Santander, 39011, Spain
- Joint Laboratory on Food Science, Nutrition, and Intelligent Processing of Foods, Polytechnic University of Marche, Italy, Universidad Europea del Atlántico Spain and Jiangsu University, China
| | - José L Quiles
- Department of Physiology, Institute of Nutrition and Food Technology "José Mataix Verdú", Biomedical Research Centre, University of Granada, Armilla, 18016, Spain
| | - Maurizio Battino
- Department of Clinical Sciences, Polytechnic University of Marche, Via Pietro Ranieri 65, Ancona, 60131, Italy.
- Research Group on Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Isabel Torres 21, Santander, 39011, Spain
- Joint Laboratory on Food Science, Nutrition, and Intelligent Processing of Foods, Polytechnic University of Marche, Italy, Universidad Europea del Atlántico Spain and Jiangsu University, China
- International Joint Research Laboratory of Intelligent Agriculture and Agri-Products Processing, Jiangsu University, Zhenjiang, 212013, China
| | - Francesca Giampieri
- Department of Clinical Sciences, Polytechnic University of Marche, Via Pietro Ranieri 65, Ancona, 60131, Italy.
- Research Group on Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Isabel Torres 21, Santander, 39011, Spain
- Joint Laboratory on Food Science, Nutrition, and Intelligent Processing of Foods, Polytechnic University of Marche, Italy, Universidad Europea del Atlántico Spain and Jiangsu University, China
- International Joint Research Laboratory of Intelligent Agriculture and Agri-Products Processing, Jiangsu University, Zhenjiang, 212013, China
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5
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Magowan D, Abdulshafea M, Thompson D, Rajamoorthy SI, Owen R, Harris D, Prosser S. Blood-based biomarkers and novel technologies for the diagnosis of colorectal cancer and adenomas: a narrative review. Biomark Med 2024; 18:493-506. [PMID: 38900496 DOI: 10.1080/17520363.2024.2345583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Accepted: 03/12/2024] [Indexed: 06/21/2024] Open
Abstract
Aim: Blood-based biomarkers have shown promise for diagnosing colorectal cancer (CRC) and adenomas (CRA). This review summarizes recent studies in this area. Methods: A literature search was undertaken for 01/01/2017-01/03/2023. Criteria included CRC, CRA, liquid-biopsy, blood-based tests and diagnosis. Results: 12,378 studies were reduced to 178 for data extraction. Sixty focused on proteomics, 53 on RNA species, 30 on cfDNA methylation, seven on antigens and autoantibodies and 28 on novel techniques. 169 case control and nine cohort studies. Number of participants ranged 100-54,297, mean age 58.26. CRC sensitivity and specificity ranged 9.10-100% and 20.40-100%, respectively. CRA sensitivity and specificity ranged 8.00-95.70% and 4.00-97.00%, respectively. Conclusion: Sensitive and specific blood-based tests exist for CRC and CRA. However, studies demonstrate heterogenous techniques and reporting quality. Further work should concentrate on validation and meta-analyzes.
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Affiliation(s)
- Drew Magowan
- Swansea University, Singleton Park, SA2 8PP, Swansea, UK
- Swansea Bay University Health Board, Department of General Surgery, Morriston Hospital, SA6 6NL, Swansea, UK
| | - Mansour Abdulshafea
- Swansea Bay University Health Board, Department of General Surgery, Morriston Hospital, SA6 6NL, Swansea, UK
| | - Dominic Thompson
- Swansea Bay University Health Board, Department of General Surgery, Morriston Hospital, SA6 6NL, Swansea, UK
| | - Shri-Ishvarya Rajamoorthy
- Swansea Bay University Health Board, Department of General Surgery, Morriston Hospital, SA6 6NL, Swansea, UK
| | - Rhiannon Owen
- Swansea University, Singleton Park, SA2 8PP, Swansea, UK
| | - Dean Harris
- Swansea University, Singleton Park, SA2 8PP, Swansea, UK
- Swansea Bay University Health Board, Department of General Surgery, Morriston Hospital, SA6 6NL, Swansea, UK
| | - Susan Prosser
- Swansea Bay University Health Board, Department of General Surgery, Morriston Hospital, SA6 6NL, Swansea, UK
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6
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Singh A, Ashok A, Pandey S, Lin Q. Editorial: Recent developments in clinical biomarkers for cancer prognosis, prediction, treatment, and their clinical utility. Front Genet 2024; 15:1437556. [PMID: 38903750 PMCID: PMC11187332 DOI: 10.3389/fgene.2024.1437556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 05/29/2024] [Indexed: 06/22/2024] Open
Affiliation(s)
- Akansha Singh
- Department of Radiation Oncology, Medical School, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | | | - Sanjay Pandey
- Department of Radiation Oncology, Albert Einstein College of Medicine, New York, NY, United States
| | - Qing Lin
- Department of Anesthesiology and Critical Care Medicine, School of Medicine, Johns Hopkins Medicine, Baltimore, MD, United States
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7
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Coates-Park S, Rich JA, Stetler-Stevenson WG, Peeney D. The TIMP protein family: diverse roles in pathophysiology. Am J Physiol Cell Physiol 2024; 326:C917-C934. [PMID: 38284123 PMCID: PMC11193487 DOI: 10.1152/ajpcell.00699.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 01/23/2024] [Accepted: 01/23/2024] [Indexed: 01/30/2024]
Abstract
The tissue inhibitors of matrix metalloproteinases (TIMPs) are a family of four matrisome proteins classically defined by their roles as the primary endogenous inhibitors of metalloproteinases (MPs). Their functions however are not limited to MP inhibition, with each family member harboring numerous MP-independent biological functions that play key roles in processes such as inflammation and apoptosis. Because of these multifaceted functions, TIMPs have been cited in diverse pathophysiological contexts. Herein, we provide a comprehensive overview of the MP-dependent and -independent roles of TIMPs across a range of pathological conditions. The potential therapeutic and biomarker applications of TIMPs in these disease contexts are also considered, highlighting the biomedical promise of this complex and often misunderstood protein family.
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Affiliation(s)
- Sasha Coates-Park
- Extracellular Matrix Pathology Section, Laboratory of Pathology, National Cancer Institute, National Institute of Health, Bethesda, Maryland, United States
| | - Joshua A Rich
- Extracellular Matrix Pathology Section, Laboratory of Pathology, National Cancer Institute, National Institute of Health, Bethesda, Maryland, United States
| | - William G Stetler-Stevenson
- Extracellular Matrix Pathology Section, Laboratory of Pathology, National Cancer Institute, National Institute of Health, Bethesda, Maryland, United States
| | - David Peeney
- Extracellular Matrix Pathology Section, Laboratory of Pathology, National Cancer Institute, National Institute of Health, Bethesda, Maryland, United States
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8
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Bagheri R, Ghorbian M, Ghorbian S. Tumor circulating biomarkers in colorectal cancer. Cancer Treat Res Commun 2023; 38:100787. [PMID: 38194840 DOI: 10.1016/j.ctarc.2023.100787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/11/2023] [Accepted: 12/21/2023] [Indexed: 01/11/2024]
Abstract
CRC is a major global health concern and is responsible for a significant number of cancer-related deaths each year. The successful treatment of CRC becomes more difficult when it goes undetected until it has advanced to a later stage. Diagnostic biomarkers can play a critical role in the early detection of CRC, which leads to improved patient outcomes and increased survival rates. It is important to develop reliable biomarkers for the early detection of CRC to enable timely diagnosis and treatment. To date, CRC detection methods such as endoscopy, blood, and stool tests are imperfect and often only identify cases in the later stages of the disease. To overcome these limitations, researchers are turning to molecular biomarkers as a promising avenue for improving CRC detection. Diagnostic information can be provided more reliably through a noninvasive approach using biomarkers such as mRNA, circulating cell-free DNA, micro-RNA, long non-coding RNA, and proteins. These biomarkers can be found in blood, tissue, feces, and volatile organic compounds. The identification of molecular biomarkers with high sensitivity and specificity for early detection of CRC that are safe, cost-effective, and easily measurable remains a significant challenge for researchers. In this article, we will explore the latest advancements in blood-based diagnostic biomarkers for CRC and their potential impact on improving patient survival rates.
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Affiliation(s)
- Raana Bagheri
- Department of Molecular Genetics, Ahar Branch, Islamic Azad University, Ahar, Iran
| | - Mohsen Ghorbian
- Department of Computer Engineering, Qom Branch, Islamic Azad University, Qom, Iran
| | - Saeid Ghorbian
- Department of Molecular Genetics, Ahar Branch, Islamic Azad University, Ahar, Iran.
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9
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Bi L, Ai C, Zhang H, Chen Z, Deng Y, Xiong J, Lv Z. Prognostic characteristics of T-cell mediated cell killing-related genes in lung adenocarcinoma. Autoimmunity 2023; 56:2250097. [PMID: 37624966 DOI: 10.1080/08916934.2023.2250097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 06/19/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023]
Abstract
Constituted by various heterogeneous cells, the tumor microenvironment (TME) is capable of promoting tumor proliferation, invasion, and metastasis through extensive crosstalk. The pivotal factor influencing the survival time of patients and their response to immunotherapy lies in the intratumoral immune environment. We obtained 112 differential genes related to T cell-mediated tumor killing in LUAD by employing bioinformatics analysis on the basis of the TCGA and TISIDB databases. Then the 6-gene prognostic risk score model (CA9, OIP5, TIMP1, SEC11C, FURIN, and TLR10) was constructed by conducting univariate LASSO as well as multivariate Cox regression analyses. The median risk score was taken as the threshold to classify the samples into two groups. Survival analysis revealed that the low-risk group exhibited a more favorable prognosis. Subsequently, the Cox regression analysis combined with clinical information (age, gender, and pathological stage) and the risk score of LUAD patients demonstrated the potential of this model as an independent prognostic factor. The nomogram established based on clinical information and a risk score in combination with the calibration curve indicated that this model had good predictive ability. Notable enrichment of the differential genes from the high- and low-risk groups was discovered in immune-associated processes or pathways, as shown by the GO and KEGG enrichment analyses. The combined use of single-sample gene enrichment analysis (ssGSEA) and immunophenoscore (IPS) demonstrated heightened immune infiltration and IPS scores in the low-risk group, indicating that immunotherapy was likely to show good efficacy in patients from this group. To sum up, the prognostic model of LUAD constructed based on T-cell-mediated cell killing-related genes was not only capable of screening the prognosis of LUAD patients but was also used for screening those LUAD patients with high sensitivity to immunotherapy. Our study offered novel insights into the clinical treatment and prognostic prediction of LUAD patients.
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Affiliation(s)
- Lei Bi
- Department of Cardiothoracic Surgery, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Cheng Ai
- Department of Cardiothoracic Surgery, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Zhang
- Department of Cardiothoracic Surgery, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Zhengyu Chen
- Department of Cardiothoracic Surgery, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Yiping Deng
- Department of Cardiothoracic Surgery, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Xiong
- Department of Cardiothoracic Surgery, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Zhongzhu Lv
- Department of Cardiothoracic Surgery, Bishan Hospital of Chongqing Medical University, Chongqing, China
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10
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Islam MS, Gopalan V, Lam AK, Shiddiky MJA. Current advances in detecting genetic and epigenetic biomarkers of colorectal cancer. Biosens Bioelectron 2023; 239:115611. [PMID: 37619478 DOI: 10.1016/j.bios.2023.115611] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/26/2023]
Abstract
Colorectal carcinoma (CRC) is the third most common cancer in terms of diagnosis and the second in terms of mortality. Recent studies have shown that various proteins, extracellular vesicles (i.e., exosomes), specific genetic variants, gene transcripts, cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and altered epigenetic patterns, can be used to detect, and assess the prognosis of CRC. Over the last decade, a plethora of conventional methodologies (e.g., polymerase chain reaction [PCR], direct sequencing, enzyme-linked immunosorbent assay [ELISA], microarray, in situ hybridization) as well as advanced analytical methodologies (e.g., microfluidics, electrochemical biosensors, surface-enhanced Raman spectroscopy [SERS]) have been developed for analyzing genetic and epigenetic biomarkers using both optical and non-optical tools. Despite these methodologies, no gold standard detection method has yet been implemented that can analyze CRC with high specificity and sensitivity in an inexpensive, simple, and time-efficient manner. Moreover, until now, no study has critically reviewed the advantages and limitations of these methodologies. Here, an overview of the most used genetic and epigenetic biomarkers for CRC and their detection methods are discussed. Furthermore, a summary of the major biological, technical, and clinical challenges and advantages/limitations of existing techniques is also presented.
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Affiliation(s)
- Md Sajedul Islam
- Cancer Molecular Pathology, School of Medicine & Dentistry, Griffith University, Gold Coast Campus, Southport, QLD, 4222, Australia; Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, 4222, Australia
| | - Vinod Gopalan
- Cancer Molecular Pathology, School of Medicine & Dentistry, Griffith University, Gold Coast Campus, Southport, QLD, 4222, Australia; Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, 4222, Australia.
| | - Alfred K Lam
- Cancer Molecular Pathology, School of Medicine & Dentistry, Griffith University, Gold Coast Campus, Southport, QLD, 4222, Australia; Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, 4222, Australia; Pathology Queensland, Gold Coast University Hospital, Southport, QLD, 4215, Australia
| | - Muhammad J A Shiddiky
- Rural Health Research Institute, Charles Sturt University, Orange, NSW, 2800, Australia.
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11
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Krishnamoorthy A, Arasaradnam R. Colorectal cancer diagnostic biomarkers: Beyond faecal haemoglobin. Best Pract Res Clin Gastroenterol 2023; 66:101870. [PMID: 37852713 DOI: 10.1016/j.bpg.2023.101870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 09/16/2023] [Indexed: 10/20/2023]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide, and the second commonest cause of cancer deaths worldwide. One of the most important prognostic factors, and thus a potential target for improving cancer care, is the stage of cancer at diagnosis. Earlier stage diagnosis is associated with better prognosis and longer survival times after treatment. At the same time, the use of targeted therapies and immunotherapy is improving CRC outcomes. Diagnostic biomarkers are key to both early detection and prediction of treatment responses. Currently faecal immunochemical testing for haemoglobin is perhaps the most widespread CRC diagnostic biomarker. However other biomarkers are approved for clinical use and others are in the validation stage of research prior to clinical use. This review focuses on these the evidence behind these biomarkers, their current and potential future use.
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Affiliation(s)
- A Krishnamoorthy
- Warwick Medical School, Gibbet Hill Campus, University of Warwick, Coventry, CV4 7AL, UK.
| | - R Arasaradnam
- Warwick Medical School, Gibbet Hill Campus, University of Warwick, Coventry, CV4 7AL, UK
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12
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Zhang H, Zhang Z. Genetic Variants Associated with Acne Vulgaris. Int J Gen Med 2023; 16:3843-3856. [PMID: 37662507 PMCID: PMC10473401 DOI: 10.2147/ijgm.s421835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 08/11/2023] [Indexed: 09/05/2023] Open
Abstract
Acne vulgaris (AV) ranks among the common chronic inflammatory disorders that impact the sebaceous components of hair follicles. Acne vulgaris is characterised by cardinal manifestations such as the presence of pimples, nodules, pustules, and cysts, which have the potential to lead to the development of acne scarring and pigmentation. The phenomenon is influenced by polygenic inheritance or can be ascribed to the interplay between multiple genes and environmental factors. In recent years, some researchers have found that some genes (such as IL, TNF, RETN, CYP family, MMPs and TIMPs genes et al) are associated with acne vulgaris and may affect the progression and prognosis of the disease. The number of reviews addressing acne-associated genetic variants, however, is limited. In that case, we have compiled a list of prevalent genes associated with acne in recent times. This helps us understand acne's genetic basis and lets us step in early for people prone to severe acne, lowering the chance of acne scars.
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Affiliation(s)
- Huan Zhang
- Department of Dermatology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, People’s Republic of China
| | - Zhengzhong Zhang
- Department of Dermatology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, People’s Republic of China
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Zhu H, Li Q, Huang Q, Yang H, Zheng J, Xie R, Han D, Wei Q. RIG-I contributes to keratinocyte proliferation and wound repair by inducing TIMP-1 expression through NF-κB signaling pathway. J Cell Physiol 2023; 238:1876-1890. [PMID: 37269543 DOI: 10.1002/jcp.31049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 05/06/2023] [Accepted: 05/10/2023] [Indexed: 06/05/2023]
Abstract
Epithelial keratinocyte proliferation is an essential element of wound repair, and chronic wound conditions, such as diabetic foot, are characterized by aberrant re-epithelialization. In this study, we examined the functional role of retinoic acid inducible-gene I (RIG-I), a key regulator of epidermal keratinocyte proliferation, in promoting TIMP-1 expression. We found that RIG-I is overexpressed in keratinocytes of skin injury and underexpressed in skin wound sites of diabetic foot and streptozotocin-induced diabetic mice. Moreover, mice lacking RIG-I developed an aggravated phenotype when subjected to skin injury. Mechanistically, RIG-I promoted keratinocyte proliferation and wound repair by inducing TIMP-1 via the NF-κB signaling pathway. Indeed, recombinant TIMP-1 directly accelerated HaCaT cell proliferation in vitro and promoted wound healing in Ddx58-/- and diabetic mice in vivo. In summary, we demonstrated that RIG-I is a crucial factor that mediates epidermal keratinocyte proliferation and may be a potential biomarker for skin injury severity, thus making it an attractive locally therapeutic target for the treatment of chronic wounds such as diabetic foot.
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Affiliation(s)
- Huiyuan Zhu
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qianyu Li
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qiongyi Huang
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Huiqiong Yang
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jiayi Zheng
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ruting Xie
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Dongyan Han
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qing Wei
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
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Zhao Y, Lin X, Zeng W, Qin X, Miao B, Gao S, Liu J, Li Z. Berberine inhibits the progression of renal cell carcinoma cells by regulating reactive oxygen species generation and inducing DNA damage. Mol Biol Rep 2023:10.1007/s11033-023-08381-w. [PMID: 37217616 DOI: 10.1007/s11033-023-08381-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 03/09/2023] [Indexed: 05/24/2023]
Abstract
BACKGROUND Berberine is a natural isoquinoline alkaloid that has been shown to have antitumor properties in a growing number of studies. However, its role in renal cell carcinoma remains unclear. This study investigates berberine's effect and mechanism in renal cell carcinoma. METHODS The methyl-tetrazolium, colony formation, and lactate dehydrogenase assay were used to detect proliferation and cytotoxicity, respectively. Flow cytometry, caspase-Glo 3/7 assay, and adenosine triphosphate assay were used to detect apoptosis and the adenosine triphosphate levels. Wound healing and transwell assay were used to examine the migration ability of renal cell carcinoma cells. Besides, the level of reactive oxygen species (ROS) was explored using a DCFH-DA-based kit. Additionally, western blot and Immunofluorescence assay was taken to determine the levels of relative proteins. RESULTS In vitro, our findings indicated that the proliferation and migration of renal cell carcinoma cells treated with berberine in various concentrations were inhibited, while the level of ROS and apoptosis rate were increased. Furthermore, The results of western blot showed that the expression of Bax, Bad, Bak, Cyto c, Clv-Caspase 3, Clv-Caspase 9, E-cadherin, TIMP-1and γH2AX were up-regulated, while Bcl-2, N-cadherin, Vimentin, Snail, Rad51 and PCNA were down-regulated after treating with berberine with various concentration. CONCLUSION The result of this study revealed that berberine inhibits renal cell carcinoma progression via regulating ROS generation and inducing DNA break.
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Affiliation(s)
- Yuwan Zhao
- Department of Urology, Affiliated Hospital of Guangdong Medical University, 57 Renmin Street South, 524001, Zhanjiang, Guangdong, China
| | - Xinghua Lin
- Department of Urology, Affiliated Hospital of Guangdong Medical University, 57 Renmin Street South, 524001, Zhanjiang, Guangdong, China
| | - Wenfeng Zeng
- Department of Urology, Affiliated Hospital of Guangdong Medical University, 57 Renmin Street South, 524001, Zhanjiang, Guangdong, China
| | - Xingzhang Qin
- Department of Urology, Affiliated Hospital of Guangdong Medical University, 57 Renmin Street South, 524001, Zhanjiang, Guangdong, China
| | - Bailiang Miao
- Department of Urology, Affiliated Hospital of Guangdong Medical University, 57 Renmin Street South, 524001, Zhanjiang, Guangdong, China
| | - Sheng Gao
- Department of Urology, Affiliated Hospital of Guangdong Medical University, 57 Renmin Street South, 524001, Zhanjiang, Guangdong, China
| | - Jianjun Liu
- Department of Urology, Affiliated Hospital of Guangdong Medical University, 57 Renmin Street South, 524001, Zhanjiang, Guangdong, China.
- Laboratory of Urology, Affiliated Hospital of Guangdong Medical University, 57 Renmin Street South, 524001, Zhanjiang, Guangdong, China.
| | - Zhuo Li
- Department of Urology, Affiliated Hospital of Guangdong Medical University, 57 Renmin Street South, 524001, Zhanjiang, Guangdong, China.
- Laboratory of Urology, Affiliated Hospital of Guangdong Medical University, 57 Renmin Street South, 524001, Zhanjiang, Guangdong, China.
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15
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El-Shenawy AA, Elsayed MMA, Atwa GMK, Abourehab MAS, Mohamed MS, Ghoneim MM, Mahmoud RA, Sabry SA, Anwar W, El-Sherbiny M, Hassan YA, Belal A, Ramadan AEH. Anti-Tumor Activity of Orally Administered Gefitinib-Loaded Nanosized Cubosomes against Colon Cancer. Pharmaceutics 2023; 15:pharmaceutics15020680. [PMID: 36840004 PMCID: PMC9960579 DOI: 10.3390/pharmaceutics15020680] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/14/2023] [Accepted: 02/14/2023] [Indexed: 02/19/2023] Open
Abstract
Gefitinib (GFT) is a tyrosine kinase inhibitor drug used as a first-line treatment for patients with advanced or metastatic non-small cell lung, colon, and breast cancer. GFT exhibits low solubility and hence low oral bioavailability, which restricts its clinical application. One of the most important trends in overcoming such problems is the use of a vesicular system. Cubosomes are considered one of the most important vesicular systems used to improve solubility and oral bioavailability. In this study, GFT cubosomal nanoparticles (GFT-CNPs) were prepared by the emulsification method. The selected formulation variables were analyzed and optimized by full factorial design and response surface methodology. Drug entrapment efficiency (EE%), transmission electron microscopy, particle size, polydispersity index, in vitro release and its kinetics, and the effect of storage studies were estimated. The chosen GFT-CNPs were subjected to further investigations as gene expression levels of tissue inhibitors of metalloproteinases-1 (TIMP-1) and matrix metalloproteinases-7 (MMP-7), colon biomarkers, and histopathological examination of colon tissues. The prepared GFT-CNPs were semi-cubic in shape, with high EE%, smaller vesicle size, and higher zeta potential values. The in vivo data showed a significant decrease in the serum level of embryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and gene expression level of TIMP-1 and MMP-7. Histopathological examination showed enhancement in cancer tissue and highly decreased focal infiltration in the lamina propria after treatment with GFT-CNPs.
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Affiliation(s)
- Ahmed A. El-Shenawy
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Mahmoud M. A. Elsayed
- Department of Pharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt
- Correspondence: ; Tel.: +20-122-766-0470
| | - Gamal M. K. Atwa
- Department of Biochemistry, Faculty of Pharmacy, Port Said University, Port Said 42515, Egypt
| | - Mohammed A. S. Abourehab
- Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Mohamed S. Mohamed
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Mohammed M. Ghoneim
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
| | - Reda A. Mahmoud
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Shereen A. Sabry
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| | - Walid Anwar
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Al-Azhar University, Cairo 11751, Egypt
| | - Mohamed El-Sherbiny
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, Riyadh 11597, Saudi Arabia
- Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Yasser A. Hassan
- Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 35712, Egypt
| | - Amany Belal
- Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
- Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Abd El hakim Ramadan
- Department of Pharmaceutics, Faculty of Pharmacy, Port Said University, Port Said 42515, Egypt
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16
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Petersen MM, Kleif J, Jørgensen LN, Hendel JW, Seidelin JB, Madsen MR, Vilandt J, Brandsborg S, Rasmussen JS, Andersen LM, Khalid A, Ferm L, Gawel SH, Martens F, Andersen B, Rasmussen M, Davis GJ, Christensen IJ, Therkildsen C. Optimizing Screening for Colorectal Cancer: An Algorithm Combining Fecal Immunochemical Test, Blood-Based Cancer-Associated Proteins and Demographics to Reduce Colonoscopy Burden. Clin Colorectal Cancer 2023; 22:199-210. [PMID: 36878807 DOI: 10.1016/j.clcc.2023.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/17/2023]
Abstract
BACKGROUND Fecal Immunochemical Test (FIT) is widely used in population-based screening for colorectal cancer (CRC). This had led to major challenges regarding colonoscopy capacity. Methods to maintain high sensitivity without compromising the colonoscopy capacity are needed. This study investigates an algorithm that combines FIT result, blood-based biomarkers associated with CRC, and individual demographics, to triage subjects sent for colonoscopy among a FIT positive (FIT+) screening population and thereby reduce the colonoscopy burden. MATERIALS AND METHODS From the Danish National Colorectal Cancer Screening Program, 4048 FIT+ (≥100 ng/mL Hemoglobin) subjects were included and analyzed for a panel of 9 cancer-associated biomarkers using the ARCHITECT i2000. Two algorithms were developed: 1) a predefined algorithm based on clinically available biomarkers: FIT, age, CEA, hsCRP and Ferritin; and 2) an exploratory algorithm adding additional biomarkers: TIMP-1, Pepsinogen-2, HE4, CyFra21-1, Galectin-3, B2M and sex to the predefined algorithm. The diagnostic performances for discriminating subjects with or without CRC in the 2 models were benchmarked against the FIT alone using logistic regression modeling. RESULTS The discrimination of CRC showed an area under the curve (AUC) of 73.7 (70.5-76.9) for the predefined model, 75.3 (72.1-78.4) for the exploratory model, and 68.9 (65.5-72.2) for FIT alone. Both models performed significantly better (P < .001) than the FIT model. The models were benchmarked vs. FIT at cutoffs of 100, 200, 300, 400, and 500 ng/mL Hemoglobin using corresponding numbers of true positives and false positives. All performance metrics were improved at all cutoffs. CONCLUSION A screening algorithm including a combination of FIT result, blood-based biomarkers and demographics outperforms FIT in discriminating subjects with or without CRC in a screening population with FIT results above 100 ng/mL Hemoglobin.
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Affiliation(s)
- Mathias M Petersen
- Gastro Unit, Hvidovre Hospital, Hvidovre, Denmark; Institute for Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
| | - Jakob Kleif
- Gastro Unit, Hvidovre Hospital, Hvidovre, Denmark; Institute for Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Department of Surgery, Nordsjællands Hospital, Hillerød, Denmark
| | - Lars N Jørgensen
- Institute for Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Digestive Disease Center, Bispebjerg Hospital, Copenhagen, Denmark
| | - Jakob W Hendel
- Gastro Unit, Section for Gastroenterology, Herlev Hospital, Herlev, Denmark
| | - Jakob B Seidelin
- Gastro Unit, Section for Gastroenterology, Herlev Hospital, Herlev, Denmark
| | | | - Jesper Vilandt
- Department of Surgery, Nordsjællands Hospital, Hillerød, Denmark
| | | | | | - Lars M Andersen
- Department of Public Health Programmes and University Research Clinic for Cancer Screening, Randers Regional Hospital, Randers, Denmark
| | - Ali Khalid
- Department of Surgery, Viborg Hospital, Viborg, Denmark
| | - Linnea Ferm
- Gastro Unit, Hvidovre Hospital, Hvidovre, Denmark
| | - Susan H Gawel
- Abbott Laboratories, Abbott Diagnostics Division, Abbott Park, IL
| | - Frans Martens
- Endocrine Laboratory, Department of Clinical Chemistry, Amsterdam UMC, AMC & VUMC, Amsterdam, The Netherlands
| | - Berit Andersen
- Department of Public Health Programmes and University Research Clinic for Cancer Screening, Randers Regional Hospital, Randers, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Morten Rasmussen
- Institute for Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Gerard J Davis
- Abbott Laboratories, Abbott Diagnostics Division, Abbott Park, IL
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17
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Multiplexed, single-molecule, epigenetic analysis of plasma-isolated nucleosomes for cancer diagnostics. Nat Biotechnol 2023; 41:212-221. [PMID: 36076083 DOI: 10.1038/s41587-022-01447-3] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 07/25/2022] [Indexed: 11/08/2022]
Abstract
The analysis of cell-free DNA (cfDNA) in plasma provides information on pathological processes in the body. Blood cfDNA is in the form of nucleosomes, which maintain their tissue- and cancer-specific epigenetic state. We developed a single-molecule multiparametric assay to comprehensively profile the epigenetics of plasma-isolated nucleosomes (EPINUC), DNA methylation and cancer-specific protein biomarkers. Our system allows for high-resolution detection of six active and repressive histone modifications and their ratios and combinatorial patterns on millions of individual nucleosomes by single-molecule imaging. In addition, our system provides sensitive and quantitative data on plasma proteins, including detection of non-secreted tumor-specific proteins, such as mutant p53. EPINUC analysis of a cohort of 63 colorectal cancer, 10 pancreatic cancer and 33 healthy plasma samples detected cancer with high accuracy and sensitivity, even at early stages. Finally, combining EPINUC with direct single-molecule DNA sequencing revealed the tissue of origin of colorectal, pancreatic, lung and breast tumors. EPINUC provides multilayered information of potential clinical relevance from limited (<1 ml) liquid biopsy material.
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18
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Lee JE, Lee E. The Probiotic Effects of the Saccharomyces cerevisiae 28-7 Strain Isolated from Nuruk in a DSS-Induced Colitis Mouse Model. J Microbiol Biotechnol 2022; 32:877-884. [PMID: 35791078 PMCID: PMC9628919 DOI: 10.4014/jmb.2206.06035] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 06/21/2022] [Accepted: 06/27/2022] [Indexed: 12/15/2022]
Abstract
Probiotics are microorganisms that can benefit host health when ingested in a live state, and lactic acid bacteria are the most common type. Among fungi, Saccharomyces boulardii (SB) is the only strain known to have a probiotic function with beneficial effects on colitis; however, information on other probiotic yeast strains is limited. Therefore, this study aimed to discover yeast strains expressing intestinal anti-inflammatory activities by exhibiting probiotic properties in dextran sodium sulfate (DSS)-induced colitis mice model. Nuruk (Korean traditional fermentation starter) containing various microbial strains was used as a source for yeast strains, and S. cerevisiae 28-7 (SC28-7) strain was selected with in vitro and in vivo characteristics to enable survival in the intestines. After 14 days of pretreatment with the yeast strains, DSS was co-administered for six days to induce colitis in mice. The results revealed that the disease activity index score was lowered by SC28-7 treatment compared to the DSS group, and the colon length and weight/length ratio were recovered in a pattern similar to that of the normal group. SC28-7 administration significantly reduced the secretion of pro-inflammatory cytokines in the serum and modified the mRNA expression of inflammatory cytokines (interleukin-1β, transforming growth factor-β, and interferon-γ) and proteins involved in gut barrier functions (mucin 2, mucin 3, zonula occludens-1, and occludin) in colon tissues. These results indicate that SC28-7 attenuates DSS-induced colon damage and inflammation, supporting its future use as a probiotic yeast for treating and preventing intestinal inflammatory diseases such as inflammatory bowel disease.
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Affiliation(s)
- Jang Eun Lee
- Reserch Group of Traditional Food, Korea Food Research Institute, Wanju-gun, Jeollabuk-do 55365, Republic of Korea,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon 34113, Republic of Korea
| | - Eunjung Lee
- Reserch Group of Traditional Food, Korea Food Research Institute, Wanju-gun, Jeollabuk-do 55365, Republic of Korea,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon 34113, Republic of Korea,Corresponding author Phone: +82-63-219-9413 E-mail:
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19
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Liu L, Yang S, Lin K, Yu X, Meng J, Ma C, Wu Z, Hao Y, Chen N, Ge Q, Gao W, Wang X, Lam EWF, Zhang L, Li F, Jin B, Jin D. Sp1 induced gene TIMP1 is related to immune cell infiltration in glioblastoma. Sci Rep 2022; 12:11181. [PMID: 35778451 PMCID: PMC9249770 DOI: 10.1038/s41598-022-14751-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 06/13/2022] [Indexed: 11/29/2022] Open
Abstract
Tumor immune microenvironment exerts a profound effect on the population of infiltrating immune cells. Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) is frequently overexpressed in a variety of cells, particularly during inflammation and tissue injury. However, its function in cancer and immunity remains enigmatic. In this study, we find that TIMP1 is substantially up-regulated during tumorigenesis through analyzing cancer bioinformatics databases, which is further confirmed by IHC tissue microarrays of clinical samples. The TIMP1 level is significantly increased in lymphocytes infiltrating the tumors and correlated with cancer progression, particularly in GBM. Notably, we find that the transcriptional factor Sp1 binds to the promoter of TIMP1 and triggers its expression in GBM. Together, our findings suggest that the Sp1-TIMP1 axis can be a potent biomarker for evaluating immune cell infiltration at the tumor sites and therefore, the malignant progression of GBM.
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Affiliation(s)
- Lu Liu
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Shuyao Yang
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Kefeng Lin
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Xiaoman Yu
- Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou, 510623, Guangdong, People's Republic of China
| | - Jiaqi Meng
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Chao Ma
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Zheng Wu
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Yuchao Hao
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Ning Chen
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Qi Ge
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Wenli Gao
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Xiang Wang
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Eric W-F Lam
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Lin Zhang
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Fangcheng Li
- Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou, 510623, Guangdong, People's Republic of China.
| | - Bilian Jin
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China.
| | - Di Jin
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China.
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Fonghem P, Pisitkun T, Rattanapinyopituk K, Sirivisoot S, Rungsipipat A. Investigation of proteomic profiles in canine lymphoma using tandem mass tag-based quantitative proteomics approach. Vet World 2022; 15:1333-1340. [PMID: 35765478 PMCID: PMC9210836 DOI: 10.14202/vetworld.2022.1333-1340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 04/18/2022] [Indexed: 11/16/2022] Open
Abstract
Background and Aim: Specific tumor biomarkers are useful for the early diagnosis of cancer or can predict the recurrence of neoplastic disease in humans and animals. Lymphoma in dogs could be classified into B-, T-, and NK-cell origins. T-cell lymphoma has the worst prognosis with a shorter survival time and disease-free interval. This study aimed to identify the differential serum protein expressions of canine B- and T-cell lymphomas compared with healthy dogs using a tandem mass tag (TMT)-based quantitative proteomics. Materials and Methods: Serum samples were collected from 20 untreated canine lymphomas (14 B-cells and 6 T-cells) and four healthy control dogs. Sera peptides from each sample were processed for TMT 10-plex tagging and analyzed using liquid chromatography-mass spectrometry (MS). Differential proteome profiling was then compared between lymphoma and control. Results: We discovered 20 elevated and 14 decreased serum proteins in the lymphoma group relative to the healthy group. Six candidate increased proteins in canine lymphomas were beta-actin cytoplasmic 1 (ACTB, p=0.04), haptoglobin (p=0.002), beta-2 microglobulin (aaaaaaaa2M, p=0.007), beta-2 glycoprotein 1 (APOH, p=0.03), metalloproteinase inhibitor 1 (TIMP-1, p=0.03), and CD44 antigen (p=0.02). When compared between B- and T-cell lymphomas, B-cell phenotypes had upregulated immunoglobulin (Ig) heavy chain V region GOM (p=0.02), clusterin (p=0.01), apolipoprotein C1 (APOC1, p=0.05), and plasminogen (p=0.02). Conclusion: These findings were investigated quantitative serum proteomes between B- and T-cell lymphomas using TMT-based MS. ACTB, aaaaaaaa2M, APOH, TIMP-1, CD44 antigen, Ig heavy chain V region GOM, and APOC1 are novel candidate proteins and might serve as a lymphoma biomarker in dogs. However, evaluation with an increased sample size is needed to confirm their diagnostic and prognostic ability.
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Affiliation(s)
- Piyanoot Fonghem
- Center of Excellence for Companion Animal Cancer, Department of Veterinary Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | - Trairak Pisitkun
- Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Kasem Rattanapinyopituk
- Center of Excellence for Companion Animal Cancer, Department of Veterinary Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | - Sirintra Sirivisoot
- Center of Excellence for Companion Animal Cancer, Department of Veterinary Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | - Anudep Rungsipipat
- Center of Excellence for Companion Animal Cancer, Department of Veterinary Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
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21
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Shyamala N, Kongettira CL, Puranam K, Kupsal K, Kummari R, Padala C, Hanumanth SR. In silico identification of single nucleotide variations at CpG sites regulating CpG island existence and size. Sci Rep 2022; 12:3574. [PMID: 35246549 PMCID: PMC8897451 DOI: 10.1038/s41598-022-05198-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 01/03/2022] [Indexed: 12/20/2022] Open
Abstract
Genetic and epigenetic modifications of genes involved in the key regulatory pathways play a significant role in the pathophysiology and progression of multifactorial diseases. The present study is an attempt to identify single nucleotide variations (SNVs) at CpG sites of promoters of ACAT1, APOB, APOE, CYBA, FAS, FLT1, KSR2, LDLR, MMP9, PCSK9, PHOX2A, REST, SH2B3, SORT1 and TIMP1 genes influencing CpG island (CGI) existence and size associated with the pathophysiology of Diabetes mellitus, Coronary artery disease and Cancers. Promoter sequences located between -2000 to + 2000 bp were retrieved from the EPDnew database and predicted the CpG island using MethPrimer. Further, SNVs at CpG sites were accessed from NCBI, Ensembl while transcription factor (TF) binding sites were accessed using AliBaba2.1. CGI existence and size were determined for each SNV at CpG site with respect to wild type and variant allele by MethPrimer. A total of 200 SNVs at CpG sites were analyzed from the promoters of ACAT1, APOB, APOE, CYBA, FAS, FLT1, KSR2, LDLR, MMP9, PCSK9, PHOX2A, REST, SH2B3, SORT1 and TIMP1 genes. Of these, only 17 (8.5%) SNVs were found to influence the loss of CGI while 70 (35%) SNVs were found to reduce the size of CGI. It has also been found that 59% (10) of CGI abolishing SNVs are showing differences in binding of TFs. The findings of the study suggest that the candidate SNVs at CpG sites regulating CGI existence and size might influence the DNA methylation status and expression of genes involved in molecular pathways associated with several diseases. The insights of the present study may pave the way for new experimental studies to undertake challenges in DNA methylation, gene expression and protein assays.
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Affiliation(s)
- Nivas Shyamala
- Department of Genetics and Biotechnology, University College of Science, Osmania University, Hyderabad, 500007, Telangana State, India
| | - Chaitra Lava Kongettira
- Department of Genetics and Biotechnology, University College of Science, Osmania University, Hyderabad, 500007, Telangana State, India
| | - Kaushik Puranam
- Department of Genetics and Biotechnology, University College of Science, Osmania University, Hyderabad, 500007, Telangana State, India
| | - Keerthi Kupsal
- Department of Genetics and Biotechnology, University College of Science, Osmania University, Hyderabad, 500007, Telangana State, India
| | - Ramanjaneyulu Kummari
- Department of Genetics and Biotechnology, University College of Science, Osmania University, Hyderabad, 500007, Telangana State, India
| | - Chiranjeevi Padala
- Department of Genetics and Biotechnology, University College of Science, Osmania University, Hyderabad, 500007, Telangana State, India
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, Telangana State, India
| | - Surekha Rani Hanumanth
- Department of Genetics and Biotechnology, University College of Science, Osmania University, Hyderabad, 500007, Telangana State, India.
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22
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Huang Z, Yang M. Molecular Network of Colorectal Cancer and Current Therapeutic Options. Front Oncol 2022; 12:852927. [PMID: 35463300 PMCID: PMC9018988 DOI: 10.3389/fonc.2022.852927] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/11/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC), a leading cause of cancer-related mortalities globally, results from the accumulation of multiple genetic and epigenetic alterations in the normal colonic and rectum epithelium, leading to the progression from colorectal adenomas to invasive carcinomas. Almost half of CRC patients will develop metastases in the course of the disease and most patients with metastatic CRC are incurable. Particularly, the 5-year survival rate of patients with stage 4 CRC at diagnosis is less than 10%. Although genetic understanding of these CRC tumors and paired metastases has led to major advances in elucidating early driver genes responsible for carcinogenesis and metastasis, the pathophysiological contribution of transcriptional and epigenetic aberrations in this malignancy which influence many central signaling pathways have attracted attention recently. Therefore, treatments that could affect several different molecular pathways may have pivotal implications for their efficacy. In this review, we summarize our current knowledge on the molecular network of CRC, including cellular signaling pathways, CRC microenvironment modulation, epigenetic changes, and CRC biomarkers for diagnosis and predictive/prognostic use. We also provide an overview of opportunities for the treatment and prevention strategies in this field.
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Affiliation(s)
- Zhe Huang
- The Department of 11 General Surgery, Minimally Invasive Colorectal Hernia Unit, Shengjing Hospital of China Medical University, Shenyang, China
| | - Mingli Yang
- The Department of 3Oncology, Gastrointestinal Cancer Unit, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Mingli Yang,
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23
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Kassid AA, Abdul-Rasheed OF, AlKhalidy NM. The Evaluation of Methylated Septin 9 in Blood Plasma and Tissue Biopsies for the Early Detection for Asymptomatic Colon Cancer. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.7156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
The purpose of this study was to assess the utility of the SEPT9 genetic marker in the early detection of colon cancer patients. A case-control study was conducted on forty newly diagnosed colon cancer patients. The study was done between March 2019 and January 2020, patients from the Gastroenterology and Liver Education Hospital, Al-imamain Al-Kadhimain Medical City, and Baghdad Teaching Hospital were recruited. Colon cancer patients' mean age ± standard deviation was 54.4 ± 10.79 years while the age ± standard deviation of the mean of the control group was 55.1±8.54 years. For septin9 tissue methylation of the controls was done on the non-malignant tissues of the same patients.
This study concluded that the percentage of Septin 9 (SEPT9) in the tissue of patients with colon cancer (CC) was the highest value, which is more significant than that of the serum of CC patients. Both of these groups were significantly higher than the percentage of SEPT9 methylation of control tissue and serum.
Non-significant differences were obtained in the levels of CEA and CA19-9 between CC patients and controls.
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24
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Mohammed SMA, Sabry HH, Ameen SG, Salem RM. MMP-1 (519 A/G) and TIMP-1 (372 T/C) genes polymorphism in an Egyptian sample of Acne vulgaris patients. J Cosmet Dermatol 2021; 21:1705-1711. [PMID: 34214240 DOI: 10.1111/jocd.14316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 06/08/2021] [Accepted: 06/28/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Different Matrix metalloproteinases (MMPs) family members may be implicated in acne vulgaris development. However, there are no published data about the role of MMP-1 and TIMP-1 gene polymorphisms in acne vulgaris development. AIMS To evaluate the association between MMP-1 (519 A/G) and TIMP-1 (372 T/C) gene polymorphisms and the risk of developing acne vulgaris among a sample of Egyptian acne patients. PATIENTS/METHODS This case-control study included 100 acne vulgaris patients and 120 apparently healthy control subjects. Acne severity was assessed according to Global Acne Grading System (GAGS). MMP-1 (519 A/G) and TIMP-1 (372 T/C) gene polymorphisms were investigated using RFLP-PCR technique. RESULTS The MMP-1 (519 A/G) AG and GG genotypes and G allele increase the risk of acne vulgaris~2-3 folds. In female patients, TIMP-1 (372 C/T) TT genotype and T allele showed significantly higher frequency in cases compared with the control group (p = 0.004, 0.001 respectively) with a higher risk to develop acne. On the other hand, in male patients, there was insignificant difference between the frequency of alleles in patients and control subjects. TIMP-1 (372C/T) TT genotype has been shown to be significantly detected in the studied female patients associated with the positive family history of the disease, and it increases the risk of back affection, severe acne grade development, and the liability to postacne scar formation. CONCLUSION MMP-1 (519 A/G) and TIMP-1 (372 T/C) gene polymorphisms may be related to acne vulgaris development.
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Affiliation(s)
| | - Hanan Hassan Sabry
- Dermatology and Andrology Department, Faculty of Medicine, Benha University, Benha, Egypt
| | - Seham Gouda Ameen
- Clinical and Chemical Pathology Department, Faculty of Medicine, Benha University, Benha, Egypt
| | - Rehab Mohammed Salem
- Dermatology and Andrology Department, Faculty of Medicine, Benha University, Benha, Egypt
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25
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Mazouji O, Ouhajjou A, Incitti R, Mansour H. Updates on Clinical Use of Liquid Biopsy in Colorectal Cancer Screening, Diagnosis, Follow-Up, and Treatment Guidance. Front Cell Dev Biol 2021; 9:660924. [PMID: 34150757 PMCID: PMC8213391 DOI: 10.3389/fcell.2021.660924] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, being the third most diagnosed in the world and the second deadliest. Solid biopsy provides an essential guide for the clinical management of patients with colorectal cancer; however, this method presents several limitations, in particular invasiveness, and cannot be used repeatedly. Recently, clinical research directed toward the use of liquid biopsy, as an alternative tool to solid biopsy, showed significant promise in several CRC clinical applications, as (1) detect CRC patients at early stage, (2) make treatment decision, (3) monitor treatment response, (4) predict relapses and metastases, (5) unravel tumor heterogeneity, and (6) detect minimal residual disease. The purpose of this short review is to describe the concept, the characteristics, the genetic components, and the technologies used in liquid biopsy in the context of the management of colorectal cancer, and finally we reviewed gene alterations, recently described in the literature, as promising potential biomarkers that may be specifically used in liquid biopsy tests.
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Affiliation(s)
- Omayma Mazouji
- GES-LCM2E, FPN, Mohamed First University, Oujda, Morocco
| | | | - Roberto Incitti
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Hicham Mansour
- GES-LCM2E, FPN, Mohamed First University, Oujda, Morocco
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26
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Cao Z, Zhao K, Jose I, Hoogenraad NJ, Osellame LD. Biomarkers for Cancer Cachexia: A Mini Review. Int J Mol Sci 2021; 22:4501. [PMID: 33925872 PMCID: PMC8123431 DOI: 10.3390/ijms22094501] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/14/2021] [Accepted: 04/23/2021] [Indexed: 01/08/2023] Open
Abstract
Cancer cachexia is a common condition in many cancer patients, particularly those with advanced disease. Cancer cachexia patients are generally less tolerant to chemotherapies and radiotherapies, largely limiting their treatment options. While the search for treatments of this condition are ongoing, standards for the efficacy of treatments have yet to be developed. Current diagnostic criteria for cancer cachexia are primarily based on loss of body mass and muscle function. However, these criteria are rather limiting, and in time, when weight loss is noticeable, it may be too late for treatment. Consequently, biomarkers for cancer cachexia would be valuable adjuncts to current diagnostic criteria, and for assessing potential treatments. Using high throughput methods such as "omics approaches", a plethora of potential biomarkers have been identified. This article reviews and summarizes current studies of biomarkers for cancer cachexia.
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Affiliation(s)
- Zhipeng Cao
- Department of Biochemistry and Genetics, La Trobe University, Bundoora, VIC 3086, Australia; (K.Z.); (I.J.); (N.J.H.)
| | - Kening Zhao
- Department of Biochemistry and Genetics, La Trobe University, Bundoora, VIC 3086, Australia; (K.Z.); (I.J.); (N.J.H.)
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Irvin Jose
- Department of Biochemistry and Genetics, La Trobe University, Bundoora, VIC 3086, Australia; (K.Z.); (I.J.); (N.J.H.)
| | - Nick J. Hoogenraad
- Department of Biochemistry and Genetics, La Trobe University, Bundoora, VIC 3086, Australia; (K.Z.); (I.J.); (N.J.H.)
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
| | - Laura D. Osellame
- Department of Biochemistry and Genetics, La Trobe University, Bundoora, VIC 3086, Australia; (K.Z.); (I.J.); (N.J.H.)
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
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27
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Dalal N, Jalandra R, Sharma M, Prakash H, Makharia GK, Solanki PR, Singh R, Kumar A. Omics technologies for improved diagnosis and treatment of colorectal cancer: Technical advancement and major perspectives. Biomed Pharmacother 2020; 131:110648. [PMID: 33152902 DOI: 10.1016/j.biopha.2020.110648] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/09/2020] [Accepted: 08/16/2020] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) ranks third among the most commonly occurring cancers worldwide, and it causes half a million deaths annually. Alongside mechanistic study for CRC detection and treatment by conventional techniques, new technologies have been developed to study CRC. These technologies include genomics, transcriptomics, proteomics, and metabolomics which elucidate DNA markers, RNA transcripts, protein and, metabolites produced inside the colon and rectum part of the gut. All these approaches form the omics arena, which presents a remarkable opportunity for the discovery of novel prognostic, diagnostic and therapeutic biomarkers and also delineate the underlying mechanism of CRC causation, which may further help in devising treatment strategies. This review also mentions the latest developments in metagenomics and culturomics as emerging evidence suggests that metagenomics of gut microbiota has profound implications in the causation, prognosis, and treatment of CRC. A majority of bacteria cannot be studied as they remain unculturable, so culturomics has also been strengthened to develop culture conditions suitable for the growth of unculturable bacteria and identify unknown bacteria. The overall purpose of this review is to succinctly evaluate the application of omics technologies in colorectal cancer research for improving the diagnosis and treatment strategies.
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Affiliation(s)
- Nishu Dalal
- Gene Regulation Laboratory, National Institute of Immunology, New Delhi 110067, India; Department of Environmental Science, Satyawati College, Delhi University, Delhi 110052, India
| | - Rekha Jalandra
- Gene Regulation Laboratory, National Institute of Immunology, New Delhi 110067, India; Department of Zoology, Maharshi Dayanand University, Rohtak 124001, India
| | - Minakshi Sharma
- Department of Zoology, Maharshi Dayanand University, Rohtak 124001, India
| | - Hridayesh Prakash
- Amity Institute of Virology and Immunology, Amity University, Sector 125, Noida 201313, Uttar Pradesh, India
| | - Govind K Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Pratima R Solanki
- Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi 110067, India
| | - Rajeev Singh
- Department of Environmental Science, Satyawati College, Delhi University, Delhi 110052, India.
| | - Anil Kumar
- Gene Regulation Laboratory, National Institute of Immunology, New Delhi 110067, India.
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28
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Scheurlen KM, Billeter AT, O'Brien SJ, Galandiuk S. Metabolic dysfunction and early-onset colorectal cancer - how macrophages build the bridge. Cancer Med 2020; 9:6679-6693. [PMID: 33624450 PMCID: PMC7520341 DOI: 10.1002/cam4.3315] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 06/26/2020] [Indexed: 12/12/2022] Open
Abstract
Background The incidence of colorectal cancer (CRC) among patients <50 years of age has increased dramatically over the last decades. At the same time, the growing proportion of obese children and adolescents and the increasing proportion of young and obese patients with CRC suggests an association between metabolic dysfunction and carcinogenesis. Tumor‐associated macrophages (TAMs) are able to orchestrate tumor promoting and suppressing mechanisms in CRC. The aim of this review was to discuss the different roles of TAMs in CRC and their phenotype‐specific metabolic pathways to identify potential new targets for CRC treatment. Methods A literature search was performed using PubMed, Cochrane and Embase to identify studies on TAMs and their metabolism in CRC. The following search terms were used in various combinations: (obesity OR adiposity OR obese) AND (macrophage OR polarization OR macrophage metabolism) AND ((colon cancer*) OR (colon carcinoma) OR (colonic tumor*) OR (colonic neoplasm[MeSH]) OR (rectal cancer*) OR (rectal carcinoma) OR (rectal tumor*) OR (rectal neoplasm[MeSH]) OR (colorectal cancer*) OR (colorectal carcinoma) OR (colorectal tumor*) OR (colorectal neoplasm[MeSH])). Studies including data on the phenotype and metabolism of TAMs in CRC were analyzed. Results Evidence for the prognostic utility of macrophage markers in CRC is currently evolving, with a particular role of stage‐dependent cellular metabolism profiles of TAMs. Itaconate is one of the metabolites produced by proinflammatory subtypes of TAMs and it is known to have tumor promoting effects. Metabolic pathways that are involved in macrophage activation and reprogramming play a role in a chronic inflammatory setting, consequently affecting the onset and development of CRC. Conclusions Tumor‐promoting metabolites, such as itaconate, are directly regulating these mechanisms, thereby triggering carcinogenesis. Metabolic reprogramming in TAMs can build a bridge between metabolic dysfunction and the onset and progression of CRC through inflammatory pathways, particularly in younger patients with early‐onset CRC.
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Affiliation(s)
- Katharina M Scheurlen
- Price Institute of Surgical Research, Department of Surgery, University of Louisville, Louisville, KY, USA
| | - Adrian T Billeter
- Department of General, Visceral, and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Baden-Wuerttemberg, Germany
| | - Stephen J O'Brien
- Price Institute of Surgical Research, Department of Surgery, University of Louisville, Louisville, KY, USA
| | - Susan Galandiuk
- Price Institute of Surgical Research, Department of Surgery, University of Louisville, Louisville, KY, USA
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29
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Loktionov A, Soubieres A, Bandaletova T, Francis N, Allison J, Sturt J, Mathur J, Poullis A. Biomarker measurement in non-invasively sampled colorectal mucus as a novel approach to colorectal cancer detection: screening and triage implications. Br J Cancer 2020; 123:252-260. [PMID: 32398859 PMCID: PMC7374197 DOI: 10.1038/s41416-020-0893-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 04/11/2020] [Accepted: 04/24/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Faecal tests are widely applied for colorectal cancer (CRC) screening and considered for triaging symptomatic patients with suspected CRC. However, faecal tests can be inconvenient, complex and expensive. Colorectal mucus (CM) sampled using our new patient-friendly non-invasive technique is rich in CRC biomarkers. This study aimed to evaluate diagnostic accuracy of CRC detection by measuring protein biomarkers in CM. METHODS Colorectal mucus samples were provided by 35 healthy controls, 62 CRC-free symptomatic patients and 40 CRC patients. Biomarkers were quantified by ELISA. Diagnostic performances of haemoglobin, C-reactive protein, tissue inhibitor of metalloproteinases-1, M2-pyruvate kinase, matrix metalloproteinase-9, peptidyl arginine deiminase-4, epidermal growth factor receptor, calprotectin and eosinophil-derived neurotoxin were assessed using receiver operating characteristic (ROC) curve analysis. RESULTS Colorectal mucus haemoglobin was superior compared to other biomarkers. For haemoglobin, the areas under the curve for discriminating between CRC and healthy groups ('screening') and between CRC and symptomatic patients ('triage') were 0.921 and 0.854 respectively. The sensitivity of 80.0% and specificities of 94.3% and 85.5% for the two settings respectively were obtained. CONCLUSIONS Haemoglobin quantification in CM reliably detects CRC. This patient-friendly approach presents an attractive alternative to faecal immunochemical test; however, the two methods need to be directly compared in larger studies.
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Affiliation(s)
- Alexandre Loktionov
- DiagNodus Ltd, Babraham Research Campus, Cambridge, UK.
- DiagNodus Ltd, St John's Innovation Centre, Cowley Road, Cambridge, UK.
| | - Anet Soubieres
- Department of Gastroenterology, St George's Hospital, London, UK
- Department of Gastroenterology, Charing Cross Hospital, London, UK
| | - Tatiana Bandaletova
- DiagNodus Ltd, Babraham Research Campus, Cambridge, UK
- DiagNodus Ltd, St John's Innovation Centre, Cowley Road, Cambridge, UK
| | - Nader Francis
- Department of Surgery, Yeovil District Hospital, Yeovil, UK
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Joanna Allison
- Department of Surgery, Yeovil District Hospital, Yeovil, UK
| | - Julian Sturt
- Department of Surgery, Southend University Hospital, Southend-on-Sea, UK
| | - Jai Mathur
- Department of Gastroenterology, St George's Hospital, London, UK
| | - Andrew Poullis
- Department of Gastroenterology, St George's Hospital, London, UK
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30
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Loktionov A. Biomarkers for detecting colorectal cancer non-invasively: DNA, RNA or proteins? World J Gastrointest Oncol 2020; 12:124-148. [PMID: 32104546 PMCID: PMC7031146 DOI: 10.4251/wjgo.v12.i2.124] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 10/30/2019] [Accepted: 11/29/2019] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a global problem affecting millions of people worldwide. This disease is unique because of its slow progress that makes it preventable and often curable. CRC symptoms usually emerge only at advanced stages of the disease, consequently its early detection can be achieved only through active population screening, which markedly reduces mortality due to this cancer. CRC screening tests that employ non-invasively detectable biomarkers are currently being actively developed and, in most cases, samples of either stool or blood are used. However, alternative biological substances that can be collected non-invasively (colorectal mucus, urine, saliva, exhaled air) have now emerged as new sources of diagnostic biomarkers. The main categories of currently explored CRC biomarkers are: (1) Proteins (comprising widely used haemoglobin); (2) DNA (including mutations and methylation markers); (3) RNA (in particular microRNAs); (4) Low molecular weight metabolites (comprising volatile organic compounds) detectable by metabolomic techniques; and (5) Shifts in gut microbiome composition. Numerous tests for early CRC detection employing such non-invasive biomarkers have been proposed and clinically studied. While some of these studies generated promising early results, very few of the proposed tests have been transformed into clinically validated diagnostic/screening techniques. Such DNA-based tests as Food and Drug Administration-approved multitarget stool test (marketed as Cologuard®) or blood test for methylated septin 9 (marketed as Epi proColon® 2.0 CE) show good diagnostic performance but remain too expensive and technically complex to become effective CRC screening tools. It can be concluded that, despite its deficiencies, the protein (haemoglobin) detection-based faecal immunochemical test (FIT) today presents the most cost-effective option for non-invasive CRC screening. The combination of non-invasive FIT and confirmatory invasive colonoscopy is the current strategy of choice for CRC screening. However, continuing intense research in the area promises the emergence of new superior non-invasive CRC screening tests that will allow the development of improved disease prevention strategies.
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31
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Rasmussen L, Nielsen HJ, Christensen IJ. Early Detection and Recurrence of Colorectal Adenomas by Combination of Eight Cancer-Associated Biomarkers in Plasma. Clin Exp Gastroenterol 2020; 13:273-284. [PMID: 32884322 PMCID: PMC7434628 DOI: 10.2147/ceg.s251633] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 07/27/2020] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION Plasma levels of eight combined proteins have shown value as biomarkers for detection of colorectal cancer (CRC). However, their value in identifying colorectal adenoma needs further evaluation. The aim was to evaluate the eight proteins (AFP, CA19-9, CEA, CyFra21-1, Ferritin, Galectin-3, hs-CRP and TIMP-1) in detection of high-risk adenoma (HRA) and in prediction of recurrence of adenoma. Furthermore, the discrimination between HRA and low-risk adenoma (LRA) or CRC lesions was evaluated. METHODS The study included 4698 individuals undergoing diagnostic colonoscopy. Automated ELISA platforms were used in the determination of protein levels in samples collected just before colonoscopy. RESULTS Univariably, five proteins (AFP, CEA, CyFra21-1, hs-CRP and TIMP-1), respectively, significantly discriminated individuals with HRA from individuals with non-malignant findings. Multivariably, the combination of CEA and hs-CRP improved performance; AUC= 0.63 (sensitivity=0.19 at specificity=0.90). CyFra21-1, Ferritin and TIMP-1 demonstrated significant discrimination between individuals with HRA and LRA in univariable analyses, respectively. Performance was improved in multivariable analysis; AUC=0.61 (sensitivity=0.13 at specificity=0.90). Discrimination between individuals with colorectal adenomas and healthy individuals was significant for CA19-9, CEA, hs-CRP and TIMP-1, respectively, in univariable analyses. Multivariable analysis improved performance; AUC=0.63 (sensitivity=0.17 at specificity=0.90). All proteins except AFP demonstrated significant discrimination between individuals with HRA and CRC. Combination of CEA, CyFra21-1, Ferritin, hs-CRP and TIMP-1 in multivariable analysis improved discrimination; AUC=0.78 (sensitivity=0.34 at specificity=0.90). Association between plasma levels of any of the eight proteins and recurrence of colorectal adenomas after endoscopic removal could not be demonstrated. DISCUSSION The protein panel shows a promising potential in detection of colorectal adenomas in general, but specifically of HRA. However, improvements are needed for the panel to be valuable as a screening test. Finally, plasma levels of the eight proteins were not predictive of recurrence of colorectal adenomas.
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Affiliation(s)
- Louise Rasmussen
- Department of Surgical Gastroenterology 360, Hvidovre Hospital, University of Copenhagen, Hvidovre2650, Denmark
- Correspondence: Louise RasmussenDepartment of Surgical Gastroenterology 360, Hvidovre Hospital, University of Copenhagen, Hvidovre2650, Denmark Email
| | - Hans Jørgen Nielsen
- Department of Surgical Gastroenterology 360, Hvidovre Hospital, University of Copenhagen, Hvidovre2650, Denmark
| | - Ib Jarle Christensen
- Department of Surgical Gastroenterology 360, Hvidovre Hospital, University of Copenhagen, Hvidovre2650, Denmark
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32
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Liu X, Bing Z, Wu J, Zhang J, Zhou W, Ni M, Meng Z, Liu S, Tian J, Zhang X, Li Y, Jia S, Guo S. Integrative Gene Expression Profiling Analysis to Investigate Potential Prognostic Biomarkers for Colorectal Cancer. Med Sci Monit 2020; 26:e918906. [PMID: 31893510 PMCID: PMC6977628 DOI: 10.12659/msm.918906] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Despite noteworthy advancements in the multidisciplinary treatment of colorectal cancer (CRC) and deeper understanding in the molecular mechanisms of CRC, many of CRC patients with histologically identical tumors present different treatment response and prognosis. Thus, more evidence on novel predictive and prognostic biomarkers for CRC remains urgently needed. This study aims to identify potential prognostic biomarkers for CRC with integrative gene expression profiling analysis. MATERIAL AND METHODS Differential expression analysis of paired CRC and adjacent normal tissue samples in 6 microarray datasets was independently performed, and the 6 datasets were integrated by the robust rank aggregation method to detect consistent differentially expressed genes (DEGs). Aberrant expression patterns of these genes were further validated in RNA sequencing data. Then, gene set enrichment analysis (GSEA) was performed to investigate significantly dysregulated biological functions in CRC. Finally, univariate, LASSO and multivariate Cox regression models were built to identify key prognostic genes in CRC patients. RESULTS A total of 990 DEGs (495 downregulated and 495 upregulated genes) were acquired after integratedly analyzing the 6 microarray datasets, and 4131 DEGs (2050 downregulated and 2081 upregulated genes) were obtained from the RNA sequencing dataset. Subsequently, these DEGs were intersected and 885 consistent DEGs were finally identified, including 458 downregulated and 427 upregulated genes. Two risky prognostic genes (TIMP1 and LZTS3) and 5 protective prognostic genes (AXIN2, CXCL1, ITLN1, CPT2 and CLDN23) were identified, which were significantly associated with the prognosis of CRC. CONCLUSIONS The 7 genes that we identified would provide more evidence for further applying novel diagnostic and prognostic biomarkers in clinical practice to facilitate personalized treatment of CRC.
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Affiliation(s)
- Xinkui Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China (mainland)
| | - Zhitong Bing
- Evidence Based Medicine Center, School of Basic Medical Science, Lanzhou University, Lanzhou, Gansu, China (mainland).,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, Gansu, China (mainland).,Institute of Modern Physics of Chinese Academy of Sciences, Lanzhou, Gansu, China (mainland)
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China (mainland)
| | - Jingyuan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China (mainland)
| | - Wei Zhou
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China (mainland)
| | - Mengwei Ni
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China (mainland)
| | - Ziqi Meng
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China (mainland)
| | - Shuyu Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China (mainland)
| | - Jinhui Tian
- Evidence Based Medicine Center, School of Basic Medical Science, Lanzhou University, Lanzhou, Gansu, China (mainland).,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, Gansu, China (mainland)
| | - Xiaomeng Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China (mainland)
| | - Yingfei Li
- Center for Drug Metabolism and Pharmacokinetics (DMPK) Research of Herbal Medicines, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China (mainland)
| | - Shanshan Jia
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China (mainland)
| | - Siyu Guo
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China (mainland)
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ÜÇÜNCÜ MZ. Kolorektal Kanserlerin Tanı ve Prognostik Takibinde Eski ve Yeni Serum Biyobelirteçleri: Sistematik İnceleme ve Meta-Analiz. İSTANBUL GELIŞIM ÜNIVERSITESI SAĞLIK BILIMLERI DERGISI 2019. [DOI: 10.38079/igusabder.592956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Loktionov A, Soubieres A, Bandaletova T, Mathur J, Poullis A. Colorectal cancer detection by biomarker quantification in noninvasively collected colorectal mucus: preliminary comparison of 24 protein biomarkers. Eur J Gastroenterol Hepatol 2019; 31:1220-1227. [PMID: 31498281 DOI: 10.1097/meg.0000000000001535] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Noninvasive colorectal cancer detection and screening remain global diagnostic challenges because the existing stool tests either lack sensitivity or are complex and expensive. Moreover, colorectal cancer screening uptake is low due to stool sampling inconvenience. We have developed a simple and patient-friendly noninvasive technique for collecting highly informative colorectal mucus. In this study, we aimed to comparatively assess a range of candidate biomarkers in colorectal mucus samples for colorectal cancer detection. METHODS The study included 17 patients with colorectal cancer and 35 healthy controls, who provided noninvasively collected colorectal mucus samples. Protein biomarker quantification in these samples by enzyme-linked immunosorbent assays allowed comparing diagnostic performances of 24 candidate biomarkers that comprised haemoglobin, D-dimer, M2-pyruvate kinase, carcinoembryonic antigen, C-reactive protein, calprotectin, eosinophil-derived neurotoxin, protein S100A12, tumour necrosis factor α, clusterin, soluble cytokeratin 18, caspase-cleaved cytokeratin 18, citrullinated histone H3, peptidyl arginine deiminase 4, epidermal growth factor, epidermal growth factor receptor, matrix metalloproteinase 9, tissue inhibitor of metalloproteinase 1, periostin, vascular endothelial growth factor A, vascular endothelial growth factor receptor 1, vascular cell adhesion molecule 1, intercellular adhesion molecule 1 and mucin 2. Tested biomarkers were ranked for colorectal cancer detection efficiency using receiver operating characteristic curve analysis. RESULTS High area under the curve values between 0.943 and 0.768 were observed for haemoglobin, tissue inhibitor of metalloproteinase 1, M2-pyruvate kinase, peptidyl arginine deiminase 4, C-reactive protein, matrix metalloproteinase 9, epidermal growth factor receptor, eosinophil-derived neurotoxin and calprotectin. CONCLUSION Quantification of protein biomarkers in noninvasively collected samples of colorectal mucus certainly allows detecting colorectal cancer. Further clinical evaluation of the optimal biomarkers identified by this study is needed.
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Affiliation(s)
| | - Anet Soubieres
- Department of Gastroenterology, St George's Hospital, London, UK
| | | | - Jai Mathur
- Department of Gastroenterology, St George's Hospital, London, UK
| | - Andrew Poullis
- Department of Gastroenterology, St George's Hospital, London, UK
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Tuomisto AE, Mäkinen MJ, Väyrynen JP. Systemic inflammation in colorectal cancer: Underlying factors, effects, and prognostic significance. World J Gastroenterol 2019; 25:4383-4404. [PMID: 31496619 PMCID: PMC6710177 DOI: 10.3748/wjg.v25.i31.4383] [Citation(s) in RCA: 187] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 06/07/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Systemic inflammation is a marker of poor prognosis preoperatively present in around 20%-40% of colorectal cancer patients. The hallmarks of systemic inflammation include an increased production of proinflammatory cytokines and acute phase proteins that enter the circulation. While the low-level systemic inflammation is often clinically silent, its consequences are many and may ultimately lead to chronic cancer-associated wasting, cachexia. In this review, we discuss the pathogenesis of cancer-related systemic inflammation, explore the role of systemic inflammation in promoting cancer growth, escaping antitumor defense, and shifting metabolic pathways, and how these changes are related to less favorable outcome.
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Affiliation(s)
- Anne E Tuomisto
- Cancer and Translational Medicine Research Unit, University of Oulu, Oulu 90220, Finland
- Department of Pathology, Oulu University Hospital and Medical Research Center Oulu, Oulu 90220, Finland
| | - Markus J Mäkinen
- Cancer and Translational Medicine Research Unit, University of Oulu, Oulu 90220, Finland
- Department of Pathology, Oulu University Hospital and Medical Research Center Oulu, Oulu 90220, Finland
| | - Juha P Väyrynen
- Cancer and Translational Medicine Research Unit, University of Oulu, Oulu 90220, Finland
- Department of Pathology, Oulu University Hospital and Medical Research Center Oulu, Oulu 90220, Finland
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, United States
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TIMP-1-Mediated Chemoresistance via Induction of IL-6 in NSCLC. Cancers (Basel) 2019; 11:cancers11081184. [PMID: 31443242 PMCID: PMC6721590 DOI: 10.3390/cancers11081184] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 08/05/2019] [Accepted: 08/11/2019] [Indexed: 01/28/2023] Open
Abstract
Elevated tissue inhibitor of metalloproteinase-1 (TIMP-1) is a negative prognosticator in non-small cell lung carcinoma NSCLC patients. This study sought to identify mechanisms whereby TIMP-1 impacts anticancer therapy. Using NSCLC cells and their TIMP-1 knockdown clones, we examined the chemoresistance against two chemotherapeutic agents, Gemcitabine and Cisplatin, as identified by increased apoptosis in the knockdown clones. A bead-based cytokine screening assay identified interleukin-6 (IL-6) as a key factor in chemoresistance. Exogenous human recombinant rhTIMP-1 or rhIL-6 resulted in reduced apoptosis. IL-6 expression was closely correlated with TIMP-1 kinetics and was upregulated by the addition of exogenous TIMP-1 while TIMP-1 neutralizing antibodies delayed IL-6 elevation. IL-6 production was regulated by TIMP-1, exerting its effect via activation of downstream signal transducer and activator of transcription 3 (STAT3) signaling. Both molecules and their documented transcription factors were upregulated and activated in chemoresistant NSCLC cells, confirming the roles of TIMP-1 and IL-6 in chemoresistance. To examine the role of these genes in patients, survival data from lung adenocarcinoma (LUAD) patients was curated from the cancer genome atlas (TCGA) database. Kaplan-Meier analysis found that individuals expressing low TIMP-1 and IL-6 have a higher survival rate and that the two-gene signature was more significant than the single-gene status. We define for the first time, a regulatory relationship between TIMP-1 and IL-6 in NSCLCs, suggesting that the TIMP-1/IL6 axis may be a valuable prognostic biomarker. Therapeutic interventions directed at this dual target may improve overall prognosis while negatively affecting the development of chemoresistance in NSCLC.
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Tumor Extracellular Matrix Remodeling: New Perspectives as a Circulating Tool in the Diagnosis and Prognosis of Solid Tumors. Cells 2019; 8:cells8020081. [PMID: 30678058 PMCID: PMC6406979 DOI: 10.3390/cells8020081] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 01/18/2019] [Accepted: 01/21/2019] [Indexed: 12/12/2022] Open
Abstract
In recent years, it has become increasingly evident that cancer cells and the local microenvironment are crucial in the development and progression of tumors. One of the major components of the tumor microenvironment is the extracellular matrix (ECM), which comprises a complex mixture of components, including proteins, glycoproteins, proteoglycans, and polysaccharides. In addition to providing structural and biochemical support to tumor tissue, the ECM undergoes remodeling that alters the biochemical and mechanical properties of the tumor microenvironment and contributes to tumor progression and resistance to therapy. A novel concept has emerged, in which tumor-driven ECM remodeling affects the release of ECM components into peripheral blood, the levels of which are potential diagnostic or prognostic markers for tumors. This review discusses the most recent evidence on ECM remodeling-derived signals that are detectable in the bloodstream, as new early diagnostic and risk prediction tools for the most frequent solid cancers.
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