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Wang LJ, Lei CL, Wang TA, Lin ZF, Feng SJ, Wei T, Li YQ, Shen MR, Li Y, Liao LF. Prognostic value of the preoperative systemic immune-inflammation nutritional index in patients with gastric cancer. World J Clin Oncol 2025; 16:102294. [DOI: 10.5306/wjco.v16.i4.102294] [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: 10/14/2024] [Revised: 12/04/2024] [Accepted: 01/21/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related deaths in China. Many patients with GC frequently experience symptoms related to the disease, including anorexia, nausea, vomiting, and other discomforts, and often suffer from malnutrition, which in turn negatively affects perioperative safety, prognosis, and the effectiveness of adjuvant therapeutic measures. Consequently, some nutritional indicators such as nutritional risk index (NRI), prognostic nutritional index (PNI), and systemic immune-inflammatory-nutritional index (SIINI) can be used as predictors of the prognosis of GC patients.
AIM To examine the prognostic significance of PNI, NRI, and SIINI in postoperative patients with GC.
METHODS A retrospective analysis was conducted on the clinical data of patients with GC who underwent surgical treatment at the Guangxi Medical University Cancer Hospital between January 2010 and December 2018. The area under the receiver operating characteristic (ROC) curve was assessed using ROC curve analysis, and the optimal cutoff values for NRI, PNI, and SIINI were identified using the You-Review-HTMLden index. Survival analysis was performed using the Kaplan-Meier method. In addition, univariate and multivariate analyses were conducted using the Cox proportional hazards regression model.
RESULTS This study included a total of 803 patients. ROC curves were used to evaluate the prognostic ability of NRI, PNI, and SIINI. The results revealed that SIINI had superior predictive accuracy. Survival analysis indicated that patients with GC in the low SIINI group had a significantly better survival rate than those in the high SIINI group (P < 0.05). Univariate analysis identified NRI [hazard ratio (HR) = 0.68, 95% confidence interval (CI): 0.52-0.89, P = 0.05], PNI (HR = 0.60, 95%CI: 0.46-0.79, P < 0.001), and SIINI (HR = 2.10, 95%CI: 1.64-2.69, P < 0.001) as prognostic risk factors for patients with GC. However, multifactorial analysis indicated that SIINI was an independent risk factor for the prognosis of patients with GC (HR = 1.65, 95%CI: 1.26-2.16, P < 0.001).
CONCLUSION Analysis of clinical retrospective data revealed that SIINI is a valuable indicator for predicting the prognosis of patients with GC. Compared with NRI and PNI, SIINI may offer greater application for prognostic assessment.
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Affiliation(s)
- Li-Jing Wang
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Cai-Lu Lei
- School of Pharmaceutical Science, Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Ting-An Wang
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zhi-Feng Lin
- School of Pharmaceutical Science, Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Shi-Jie Feng
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Tao Wei
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yan-Qin Li
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Meng-Ru Shen
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yan Li
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Liu-Feng Liao
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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Liu X, Zhang W, Wang H, Yang W. Identification of CKAP2 as a Potential Target for Prevention of Gastric Cancer Progression: A Multi-Omics Study. Int J Mol Sci 2025; 26:1557. [PMID: 40004022 PMCID: PMC11855583 DOI: 10.3390/ijms26041557] [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: 01/04/2025] [Revised: 02/10/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Gastric cancer (GC) ranks as one of the most prevalent malignant tumors globally. The subtle manifestation of its early-stage symptoms often results in many GC patients being diagnosed at a late or advanced stage, thereby posing significant obstacles to the effectiveness of chemotherapy treatments. Therefore, identifying early biomarkers for GC is crucial. In recent years, an increasing number of studies have highlighted the pivotal role that aging plays in the progression of cancer. Among the various proteins involved, Cytoskeleton-associated protein 2 (CKAP2) emerges as a crucial player in controlling cell proliferation, regulating mitosis and cell division, and exerting a significant influence on the aging process. We employed a bioinformatics approach to assess the causal association between aging-related genes and GC and explore the potential significance of CKAP2 in GC by analyzing data sourced from various repositories, including Genotype Tissue Expression (GTEx), GWAS Catalog, The Database of Cell Senescence Genes (CellAge), The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Human Protein Atlas (HPA), and the Comparative Toxicology Genome Database (CTD). Our research summarized the causal relationship between CKAP2 expression and the development risk of GC, differential expression in GC, the relationship with the prognosis of GC, genetic correlation, functional analysis, and immune cell infiltration, and explored the interaction of CKAP2 and chemical substances. The findings revealed that an elevation in CKAP2 expression correlated with a reduced likelihood of developing GC. There was a significant difference in the expression of CKAP2 between GC and normal patients. Specifically, there was higher expression in GC compared to normal patients. In addition, CKAP2 has been proven to have diagnostic value in GC, and elevated levels of CKAP2 expression are indicative of a more favorable prognosis. Immune infiltration analysis revealed the relationship between CKAP2 and tumor immune microenvironment, while the Comparative Toxicology Genome Database (CTD) identified a small molecule compound that may target CKAP2. In summary, through comprehensive multivariate analyses, we identified and validated the potential role that CKAP2 may play in GC. Therefore, CKAP2 shows potential as an indicator for both the diagnosis and prognosis of GC, making it worthy of further clinical investigation.
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Affiliation(s)
- Xueyi Liu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China; (X.L.); (W.Z.)
- Science Island Branch, Graduate School of University of Science and Technology of China, Hefei 230031, China
| | - Wenyu Zhang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China; (X.L.); (W.Z.)
| | - Hui Wang
- Laboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, Kunming 650500, China;
| | - Wulin Yang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China; (X.L.); (W.Z.)
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3
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Liu F, Hu N, Jiang K, Liu H, Wang M, Hu Y, Zhang T, Wu HH, Yang H, Weng H, Dong P, Giffen C, Zhu B, Lee MP, Abnet CC, Taylor PR, Liu Y, Liu Y, Goldstein AM. Mutational signatures in 175 Chinese gastric cancer patients. BMC Cancer 2024; 24:1208. [PMID: 39350044 PMCID: PMC11440915 DOI: 10.1186/s12885-024-12968-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 09/19/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Gastric cancer (GC), a molecularly heterogeneous disease, is the third leading cause of cancer death worldwide. The majority of GC cases worldwide occur in East Asia, predominantly China. Mutational Signature Framework offers an elegant approach to identify mutational processes present in tumors. METHODS To identify mutational signature patterns, we conducted whole exome sequencing (WES) analysis in Chinese patients with GC. Mutect2 and MutsigCV were used to identify significantly mutated genes in 175 Chinese GC cases using paired tumor-normal tissues. We investigated mutational signatures using Catalogue of Somatic Mutations in Cancer (COSMIC) Version 2 (V2) and Version 3 (V3). RESULTS We identified 104 mutated genes with P < 0.01. Seven genes (OR6B1, B2M, ELF3, RHOA, RPL22, TP53, ARIDIA) had q < 0.0001, including six previously associated with GC. Mutational signatures (COSMIC-V3) observed include 14 single base substitutions (SBS), one doublet base substitution (DBS) Signature A, and one InDel (ID2). The most frequent SBS signatures (SBS05, SBS01, SBS15, SBS20, SBS40) were also observed in 254 White GC cases from The Cancer Genome Atlas (TCGA) Project. However, SBS01 and SBS20 showed significant differences between Whites vs. All Asians (19.3% vs. 11.3% for SBS 1 (P = 0.012) and 11.4% vs. 5.9% for SBS20 (P = 0.025), respectively). Using COSMIC V2, signatures 6, 15, and 1 were the most frequent in Chinese GC cases. Further, most Chinese GC cases carried multiple signatures. CONCLUSIONS This effort represents the most detailed mutational signatures analysis of GC cases from China to date. Results hold promise for new insights in understanding risk and prognosis factors in GC.
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Affiliation(s)
- Fatao Liu
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, P. R. China
- Department of General Surgery, Xinhua Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200092, P. R. China
| | - Nan Hu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Kewei Jiang
- Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, 100044, P. R. China
| | - Huaitian Liu
- Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Mingyi Wang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Ying Hu
- Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Tongwu Zhang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Ho-Hsiang Wu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Howard Yang
- Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Hao Weng
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, P. R. China
- Department of General Surgery, Xinhua Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200092, P. R. China
| | - Ping Dong
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, P. R. China
- Department of General Surgery, Xinhua Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200092, P. R. China
| | - Carol Giffen
- Information Management Services, Inc, Silver Spring, Bethesda, MD, 20904, USA
| | - Bin Zhu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Maxwell P Lee
- Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Christian C Abnet
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Philip R Taylor
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Yun Liu
- Department of Oncology, Fudan University Pudong Medical Center, Shanghai, P. R. China.
| | - Yingbin Liu
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, P. R. China.
- Department of General Surgery, Xinhua Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200092, P. R. China.
| | - Alisa M Goldstein
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.
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Mamun TI, Younus S, Rahman MH. Gastric cancer-Epidemiology, modifiable and non-modifiable risk factors, challenges and opportunities: An updated review. Cancer Treat Res Commun 2024; 41:100845. [PMID: 39357127 DOI: 10.1016/j.ctarc.2024.100845] [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: 05/29/2024] [Revised: 08/27/2024] [Accepted: 09/20/2024] [Indexed: 10/04/2024]
Abstract
Gastric cancer represents a significant global health challenge due to its high mortality and incidence rates, particularly in Eastern Asia, Eastern Europe, and South America. This comprehensive review synthesizes the latest epidemiological data and explores both modifiable and non-modifiable risk factors associated with gastric cancer, aiming to delineate the multifactorial etiology of this disease. Modifiable risk factors include Helicobacter pylori infection, obesity, dietary habits, smoking and alcohol consumption, whereas nonmodifiable factors comprise genetic predispositions, age, family history and male gender. The interplay of these factors significantly impacts the risk and progression of gastric cancer, suggesting potential preventive strategies. The challenges in treating gastric cancer are considerable, largely because of the late-stage diagnosis and the heterogeneity of the disease, which complicate effective treatment regimens. Current treatment strategies involve a combination of surgery, chemotherapy, radiotherapy, and targeted therapies. The FLOT regimen (5-FU, Leucovorin, Oxaliplatin and Docetaxel) is now a standard for resectable cases in Europe and the US, showing superior survival and response rates over ECF and ECX regimens. For HER2-positive gastric cancer, trastuzumab combined with chemotherapy improves overall survival, as demonstrated by the ToGA trial. Additionally, immune checkpoint inhibitors like pembrolizumab and nivolumab offer promising results. However, the five-year survival rate remains low, underscoring the urgency for improved therapeutic approaches. Recent advancements in molecular biology and cancer genomics have begun to pave the way for personalized medicine in gastric cancer care, focusing on molecular targeted therapies and immunotherapy. This review also highlights the critical need for better screening methods that could facilitate early detection and treatment, potentially improving the prognosis. By integrating epidemiological insights with new therapeutic strategies, this article aims to thoroughly understand of gastric cancer's dynamics and outline a framework for future research and clinical management, advocating for a multidisciplinary approach to tackle this formidable disease.
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Affiliation(s)
- Tajul Islam Mamun
- Department of Epidemiology and Public Health, Sylhet Agricultural University, Sylhet 3100, Bangladesh.
| | - Sabrina Younus
- Department of Pharmacy, University of Chittagong, Chattogram 4331, Bangladesh
| | - Md Hashibur Rahman
- Department of Physiology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh
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Wang Y, Lei X, Shan F, Li S, Jia Y, Miao R, Xue K, Li Z, Ji J, Li Z. Long-term outcomes of laparoscopic versus open total gastrectomy in patients with advanced gastric cancer after neoadjuvant chemotherapy: a retrospective cohort study. BMC Cancer 2024; 24:1074. [PMID: 39215275 PMCID: PMC11365285 DOI: 10.1186/s12885-024-12669-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 07/22/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND This study was conducted to investigate the long-term outcomes of laparoscopic total gastrectomy (LTG) versus open total gastrectomy (OTG) in patients with advanced gastric cancer (AGC) after neoadjuvant chemotherapy (NACT). METHODS Patients with AGC who received NACT before surgery were enrolled in either the LTG or OTG group. Propensity score matching (PSM) (1:2) was performed between the two groups based on the propensity score using a 0.15 calliper width. Three-year overall survival (OS) and disease-free survival (DFS) were compared between these two groups before and after PSM. OS and DFS rates were calculated by the Kaplan‒Meier method, and any differences in survival were evaluated with a log-rank test. Univariate and multivariate Cox proportional hazards analyses were used to estimate the simultaneous effects of prognostic factors on survival and the hazard ratio (HR) between LTG and OTG patients. RESULTS A total of 144 patients completed the follow-up, with 24 patients in the LTG group and 120 patients in the OTG group. After a mean follow-up of 64.40 months, there were no significant differences in the 3-year OS or DFS rates between the two groups before (P = 0.453 and P = 0.362, respectively) or after PSM (P = 0.972 and P = 0.884, respectively). Multivariate Cox proportional hazards analysis indicated that ypN stage was an independent risk factor for worse OS (P = 0.013). CONCLUSIONS This study showed that LTG with D2 lymphadenectomy performed by an experienced surgical team resulted in comparable 3-year OS and DFS compared with OTG in patients with AGC after NACT. TRIAL REGISTRATION This study is not registered.
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Affiliation(s)
- Yinkui Wang
- Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Xiaokang Lei
- Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Fei Shan
- Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Shuangxi Li
- Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Yongning Jia
- Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Rulin Miao
- Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Kan Xue
- Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Zhemin Li
- Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Jiafu Ji
- Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Ziyu Li
- Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China.
- Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
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Seo JW, Lee KN, Do Han K, Park KB. Lifestyle Behaviors in Patients With Gastric Cancer: Continuous Need for Alcohol Abstinence and Muscle Strength Training Education. J Gastric Cancer 2024; 24:316-326. [PMID: 38960890 PMCID: PMC11224717 DOI: 10.5230/jgc.2024.24.e27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 06/03/2024] [Accepted: 06/10/2024] [Indexed: 07/05/2024] Open
Abstract
PURPOSE This study was performed to assess the lifestyle-related behaviors of patients with gastric cancer (GC) and to investigate the associations between the time since GC diagnosis and these behaviors. MATERIALS AND METHODS This study included 29,478 adults (including 338 patients with GC) aged ≥ 40 years who participated in the Korea National Health and Nutrition Examination Survey 2014-2021. Multiple logistic regression analysis explored the associations between the time since GC diagnosis (patients diagnosed with GC less than 5 years ago [<5 years group] and those diagnosed with GC 5 or more than years ago [≥5 years group]) and lifestyle factors. Subgroup analyses were conducted based on age and sex. RESULTS The current smoking rate was not lower in the GC group than in the healthy group, regardless of time since diagnosis. Compared to the healthy controls, monthly alcohol intake was lower in the <5 years group (odds ratio [OR], 0.450; 95% confidence interval [CI], 0.275-0.736). The ≥5 years group showed a lower rate of strength training (OR, 0.548; CI, 0.359-0.838), compared with the healthy control group. Subgroup analysis focusing on the ≥5 years group revealed a significantly lower rate of strength training, particularly in patients aged ≥65 years and male patients (OR, 0.519 and 0.553; CI, 0.302-0.890 and 0.340-0.901, respectively). CONCLUSIONS Clinicians should continue educating patients on lifestyle behavior modifications, particularly alcohol abstinence, even beyond 5 years after GC diagnosis. Education on strength training is especially important for patients ≥65 years or male patients.
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Affiliation(s)
- Ji Won Seo
- Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - Kyu Na Lee
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Korea
| | - Kyung Do Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Korea
| | - Ki Bum Park
- Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea.
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7
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Zhang X, Chen YC, Yao M, Xiong R, Liu B, Zhu X, Ao P. Potential therapeutic targets of gastric cancer explored under endogenous network modeling of clinical data. Sci Rep 2024; 14:13127. [PMID: 38849404 PMCID: PMC11161650 DOI: 10.1038/s41598-024-63812-3] [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: 01/02/2024] [Accepted: 06/03/2024] [Indexed: 06/09/2024] Open
Abstract
Improvement in the survival rate of gastric cancer, a prevalent global malignancy and the leading cause of cancer-related mortality calls for more avenues in molecular therapy. This work aims to comprehend drug resistance and explore multiple-drug combinations for enhanced therapeutic treatment. An endogenous network modeling clinic data with core gastric cancer molecules, functional modules, and pathways is constructed, which is then transformed into dynamics equations for in-silicon studies. Principal component analysis, hierarchical clustering, and K-means clustering are utilized to map the attractor domains of the stochastic model to the normal and pathological phenotypes identified from the clinical data. The analyses demonstrate gastric cancer as a cluster of stable states emerging within the stochastic dynamics and elucidate the cause of resistance to anti-VEGF monotherapy in cancer treatment as the limitation of the single pathway in preventing cancer progression. The feasibility of multiple objectives of therapy targeting specified molecules and/or pathways is explored. This study verifies the rationality of the platform of endogenous network modeling, which contributes to the development of cross-functional multi-target combinations in clinical trials.
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Affiliation(s)
- Xile Zhang
- Center for Quantitative Life Sciences and Physics Department, Shanghai University, Shanghai, 200444, China
| | - Yong-Cong Chen
- Center for Quantitative Life Sciences and Physics Department, Shanghai University, Shanghai, 200444, China.
| | - Mengchao Yao
- Center for Quantitative Life Sciences and Physics Department, Shanghai University, Shanghai, 200444, China
| | - Ruiqi Xiong
- Center for Quantitative Life Sciences and Physics Department, Shanghai University, Shanghai, 200444, China
| | - Bingya Liu
- Department of General Surgery, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Cancer, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xiaomei Zhu
- Shanghai Key Laboratory of Modern Optical Systems, School of Optoelectronic Information and Computer Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China
| | - Ping Ao
- School of Biomedical Engineering, Sichuan University, Chengdu, 610065, China
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8
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Yang X, Wu C. Systemic immune inflammation index and gastric cancer prognosis: A systematic review and meta‑analysis. Exp Ther Med 2024; 27:122. [PMID: 38410191 PMCID: PMC10895464 DOI: 10.3892/etm.2024.12410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 12/01/2023] [Indexed: 02/28/2024] Open
Abstract
The present study aimed to pool the available data on the associations between the systemic immune inflammation index (SII) and overall survival (OS) or recurrence-free survival (RFS) in patients with gastric cancer (GC). A systematic search was conducted in the PubMed, EMBASE and Scopus databases for observational studies, and a random effects model was used to conduct the statistical analysis. Pooled effect sizes were reported as hazard ratios (HRs) with corresponding 95% confidence intervals (CI). Data from 30 studies (24 conducted in China) with follow-ups ranging between 15.5 and 65.6 months were analyzed. Patients with GC and high SII levels had poor OS (HR, 1.53; 95% CI, 1.34-1.75) and recurrence free survival (HR, 1.41; 95% CI, 1.17-1.70). These increased risks were present irrespective of the treatment strategy (surgical or non-surgical management), the sample size (<500 and ≥500) and the cut-off used to define high and low SII (<600 and ≥600 x109 cells/l). The results of this meta-analysis suggest that high pretreatment SII levels were associated with poor OS and RFS in patients with GC.
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Affiliation(s)
- Xiaomao Yang
- Department of Gastrointestinal Hernia, Huzhou Central Hospital, The Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang 313000, P.R. China
| | - Chen Wu
- Department of Gastrointestinal Hernia, Huzhou Central Hospital, The Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang 313000, P.R. China
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9
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Zhai J, Nie C, Wang W, Liu C, Liu T, Sun L, Li W, Wang W, Ren X, Han X, Zhou H, Li X, Tian W. Comprehensive Analysis on Prognostic Signature Based on T Cell-Mediated Tumor Killing Related Genes in Gastric Cancer. Biochem Genet 2024; 62:504-529. [PMID: 37386336 DOI: 10.1007/s10528-023-10436-3] [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: 04/13/2023] [Accepted: 06/18/2023] [Indexed: 07/01/2023]
Abstract
Although immunotherapy is a valuable treatment for gastric cancer (GC), identifying the patients who would benefit most from this approach presents a challenge. In this study, GC patients were divided into two subtypes by consensus clustering according to T cell-mediated tumor killing related genes (TTKRGs), and there were significant differences in tumor-infiltrating immune cells, signaling pathways, and gene expression of immunomodulators and inhibitory immune checkpoints between the two subtypes. Then, we developed an individualized signature based on TTKRGs, and its clinical and predictive value in GC patients for chemotherapeutic and immunotherapeutic responses was assessed. We confirmed the expression levels of signature genes in GC tumor tissue using quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, to improve the accuracy of GC prognosis predictions, we established a nomogram. We further identified some compounds as sensitive drugs targeting GC risk groups. The signature showed significant predictive ability across RNA-seq, microarray, and qRT-PCR cohorts, which could assist in predicting survival, immunotherapeutic and chemotherapeutic outcomes in GC patients.
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Affiliation(s)
- Jiabao Zhai
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Road, 150081, Harbin, China
| | - Chuang Nie
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Road, 150081, Harbin, China
| | - Wanyu Wang
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Road, 150081, Harbin, China
| | - Chang Liu
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Road, 150081, Harbin, China
| | - Tianyu Liu
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Road, 150081, Harbin, China
| | - Lishuang Sun
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Road, 150081, Harbin, China
| | - Wei Li
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Road, 150081, Harbin, China
| | - Wentong Wang
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Road, 150081, Harbin, China
| | - Xiyun Ren
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Road, 150081, Harbin, China
| | - Xu Han
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Road, 150081, Harbin, China
| | - Haibo Zhou
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Road, 150081, Harbin, China
| | - Xin Li
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Road, 150081, Harbin, China
| | - Wenjing Tian
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Road, 150081, Harbin, China.
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Zheng Q, Gong Z, Li B, Cheng R, Luo W, Huang C, Wang H. Identification and characterization of CLEC11A and its derived immune signature in gastric cancer. Front Immunol 2024; 15:1324959. [PMID: 38348052 PMCID: PMC10859539 DOI: 10.3389/fimmu.2024.1324959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 01/05/2024] [Indexed: 02/15/2024] Open
Abstract
Introduction C-type lectin domain family 11 member A (CLEC11A) was characterized as a growth factor that mainly regulates hematopoietic function and differentiation of bone cells. However, the involvement of CLEC11A in gastric cancer (GC) is not well understood. Methods Transcriptomic data and clinical information pertaining to GC were obtained and analyzed from publicly available databases. The relationships between CLEC11A and prognoses, genetic alterations, tumor microenvironment (TME), and therapeutic responses in GC patients were analyzed by bioinformatics methods. A CLEC11A-derived immune signature was developed and validated, and its mutational landscapes, immunological characteristics as well as drug sensitivities were explored. A nomogram was established by combining CLEC11A-derived immune signature and clinical factors. The expression and carcinogenic effects of CLEC11A in GC were verified by qRT-PCR, cell migration, invasion, cell cycle analysis, and in vivo model analysis. Myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), M2 macrophages, and T cells in tumor samples extracted from mice were analyzed utilizing flow cytometry analysis. Results CLEC11A was over-expressed in GC, and the elevated CLEC11A expression indicated an unfavorable prognosis in GC patients. CLEC11A was involved in genomic alterations and associated with the TME in GC. Moreover, elevated CLEC11A was found to reduce the benefit of immunotherapy according to immunophenoscore (IPS) and the tumor immune dysfunction, exclusion (TIDE). After validation, the CLEC11A-derived immune signature demonstrated a consistent ability to predict the survival outcomes in GC patients. A nomogram that quantifies survival probability was constructed to improve the accuracy of prognosis prediction in GC patients. Using shRNA to suppress the expression of CLEC11A led to significant inhibitions of cell cycle progression, migration, and invasion, as well as a marked reduction of in vivo tumor growth. Moreover, the flow cytometry assay showed that the knock-down of CLEC11A increased the infiltration of cytotoxic CD8+ T cells and helper CD4+ T into tumors while decreasing the percentage of M2 macrophages, MDSCs, and Tregs. Conclusion Collectively, our findings revealed that CLEC11A could be a prognostic and immunological biomarker in GC, and CLEC11A-derived immune signature might serve as a new option for clinicians to predict outcomes and formulate personalized treatment plans for GC patients.
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Affiliation(s)
- Qing Zheng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
- Shantou University Medical College, Shantou, China
| | - Zhenqi Gong
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
- Shantou University Medical College, Shantou, China
| | - Baizhi Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
- Shantou University Medical College, Shantou, China
| | - Runzi Cheng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
- Shantou University Medical College, Shantou, China
| | - Weican Luo
- Shantou University Medical College, Shantou, China
| | - Cong Huang
- Department of Ultrasound, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Huaiming Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
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11
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Wang Z, Chen C, Ai J, Shu J, Ding Y, Wang W, Gao Y, Jia Y, Qin Y. Identifying mitophagy-related genes as prognostic biomarkers and therapeutic targets of gastric carcinoma by integrated analysis of single-cell and bulk-RNA sequencing data. Comput Biol Med 2023; 163:107227. [PMID: 37413850 DOI: 10.1016/j.compbiomed.2023.107227] [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: 04/03/2023] [Revised: 06/01/2023] [Accepted: 06/30/2023] [Indexed: 07/08/2023]
Abstract
Gastric carcinoma (GC) is the fourth leading cause of cancer-related mortality worldwide. Patients with advanced GC tend to have poor prognoses and shortened survival. Finding novel predictive biomarkers for GC prognosis is an urgent need. Mitophagy is the selection degradation of damaged mitochondria to maintain cellular homeostasis, which has been shown to play both pro- and anti-tumor effects. This study combined single-cell sequencing data and transcriptomics to screen mitophagy-related genes (MRGs) associated with GC progression and analyze their clinical values. Reverse transcription-quantitative PCR (RT-qPCR) and immunochemistry (IHC) further verified gene expression profiles. A total of 18 DE-MRGs were identified after taking an intersection of single-cell sequencing data and MRGs. Cells with a higher MRG score were mainly distributed in the epithelial cell cluster. Cell-to-cell communications among epithelial cells with other cell types were significantly upregulated. We established and validated a reliable nomogram model based on DE-MRGs (GABARAPL2 and CDC37) and traditional clinicopathological parameters. GABARAPL2 and CDC37 displayed different immune infiltration states. Given the significant correlation between hub genes and immune checkpoints, targeting MRGs in GC may supplement more benefits to patients who received immunotherapy. In conclusion, GABARAPL2 and CDC37 may be prognostic biomarkers and candidate therapeutic targets of GC.
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Affiliation(s)
- Zehua Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chen Chen
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiaoyu Ai
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jiao Shu
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yi Ding
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wenjia Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yaping Gao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yongxu Jia
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Yanru Qin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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12
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Liu B, Li K, Ma R, Zhang Q. Two web-based dynamic prediction models for the diagnosis and prognosis of gastric cancer with bone metastases: evidence from the SEER database. Front Endocrinol (Lausanne) 2023; 14:1136089. [PMID: 37293503 PMCID: PMC10244808 DOI: 10.3389/fendo.2023.1136089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 04/03/2023] [Indexed: 06/10/2023] Open
Abstract
Purpose Our aim was to identify the clinical characteristics and develop and validate diagnostic and prognostic web-based dynamic prediction models for gastric cancer (GC) with bone metastasis (BM) using the SEER database. Method Our study retrospectively analyzed and extracted the clinical data of patients aged 18-85 years who were diagnosed with gastric cancer between 2010 and 2015 in the SEER database. We randomly divided all patients into a training set and a validation set according to the ratio of 7 to 3. Independent factors were identified using logistic regression and Cox regression analyses. Furthermore, we developed and validated two web-based clinical prediction models. We evaluated the prediction models using the C-index, ROC, calibration curve, and DCA. Result A total of 23,156 patients with gastric cancer were included in this study, of whom 975 developed bone metastases. Age, site, grade, T stage, N stage, brain metastasis, liver metastasis, and lung metastasis were identified as independent risk factors for the development of BM in GC patients. T stage, surgery, and chemotherapy were identified as independent prognostic factors for GC with BM. The AUCs of the diagnostic nomogram were 0.79 and 0.81 in the training and test sets, respectively. The AUCs of the prognostic nomogram at 6, 9, and 12 months were 0.93, 0.86, 0.78, and 0.65, 0.69, 0.70 in the training and test sets, respectively. The calibration curve and DCA showed good performance of the nomogram. Conclusions We established two web-based dynamic prediction models in our study. It could be used to predict the risk score and overall survival time of developing bone metastasis in patients with gastric cancer. In addition, we also hope that these two web-based applications will help physicians comprehensively manage gastric cancer patients with bone metastases.
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Affiliation(s)
| | | | | | - Qiang Zhang
- Department of Orthopedics, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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13
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Chen T, zhao L, Chen J, Jin G, Huang Q, Zhu M, Dai R, Yuan Z, Chen J, Tang M, Chen T, Lin X, Ai W, Wu L, Chen X, Qin L. Identification of three metabolic subtypes in gastric cancer and the construction of a metabolic pathway-based risk model that predicts the overall survival of GC patients. Front Genet 2023; 14:1094838. [PMID: 36845398 PMCID: PMC9950121 DOI: 10.3389/fgene.2023.1094838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 01/31/2023] [Indexed: 02/12/2023] Open
Abstract
Gastric cancer (GC) is highly heterogeneous and GC patients have low overall survival rates. It is also challenging to predict the prognosis of GC patients. This is partly because little is known about the prognosis-related metabolic pathways in this disease. Hence, our objective was to identify GC subtypes and genes related to prognosis, based on changes in the activity of core metabolic pathways in GC tumor samples. Differences in the activity of metabolic pathways in GC patients were analyzed using Gene Set Variation Analysis (GSVA), leading to the identification of three clinical subtypes by non-negative matrix factorization (NMF). Based on our analysis, subtype 1 showed the best prognosis while subtype 3 exhibited the worst prognosis. Interestingly, we observed marked differences in gene expression between the three subtypes, through which we identified a new evolutionary driver gene, CNBD1. Furthermore, we used 11 metabolism-associated genes identified by LASSO and random forest algorithms to construct a prognostic model and verified our results using qRT-PCR (five matched clinical tissues of GC patients). This model was found to be both effective and robust in the GSE84437 and GSE26253 cohorts, and the results from multivariate Cox regression analyses confirmed that the 11-gene signature was an independent prognostic predictor (p < 0.0001, HR = 2.8, 95% CI 2.1-3.7). The signature was found to be relevant to the infiltration of tumor-associated immune cells. In conclusion, our work identified significant GC prognosis-related metabolic pathways in different GC subtypes and provided new insights into GC-subtype prognostic assessment.
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Affiliation(s)
- Tongzuan Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Liqian zhao
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Junbo Chen
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Gaowei Jin
- Second School of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qianying Huang
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ming Zhu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ruixia Dai
- Second School of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhengxi Yuan
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Junshuo Chen
- College of International Education, Henan University, Kaifeng, Henan, China
| | - Mosheng Tang
- Scientific Research Laboratory, Lishui City People’s Hospital, Lishui, Zhejiang, China
| | - Tongke Chen
- Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaokun Lin
- The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Weiming Ai
- Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Le Qin, ; Xiangjian Chen, ; Liang Wu, ; Weiming Ai,
| | - Liang Wu
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Le Qin, ; Xiangjian Chen, ; Liang Wu, ; Weiming Ai,
| | - Xiangjian Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Le Qin, ; Xiangjian Chen, ; Liang Wu, ; Weiming Ai,
| | - Le Qin
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Le Qin, ; Xiangjian Chen, ; Liang Wu, ; Weiming Ai,
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14
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Ma H, Zhou C, Ge J, Yu W, Zhou Y, Wang P, Zhang X, Zhang J, Shi G. Identification of molecular subtypes and a prognostic signature based on chromatin regulators related genes in prostate cancer. Front Genet 2023; 13:1110723. [PMID: 36704352 PMCID: PMC9871366 DOI: 10.3389/fgene.2022.1110723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 12/22/2022] [Indexed: 01/12/2023] Open
Abstract
The clinical and molecular phenotypes of prostate cancer (PCa) exhibit substantial heterogeneity, ranging from indolent to metastatic disease. In this study, we aimed to identify PCa subtypes and construct a gene signature that can predict the recurrence-free survival (RFS) of PCa patients based on chromatin regulators genes (CRGs). Strikingly, we identified two heterogeneous subtypes with distinct clinical and molecular characteristics. Furthermore, by performing differential analysis between the two CRGs subtypes, we successfully constructed a gene signature to predict PCa prognosis. The signature, comprising four genes (MXD3, SSTR1, AMH and PPFIA2), was utilized to classify PCa patients into two risk groups; the high-risk group was characterized by poor prognosis and more aggressive clinical features. Moreover, we investigated the immune profile, mutation landscape and molecular pathways in each of the groups. Additionally, drug-susceptibility testing was performed to explore sensitive drugs for high-risk patients. Furthermore, we found that MXD3 downregulation suppressed the proliferation of PCa cell lines in vitro. Overall, our results highlight the signature based on CRGs as a powerful tool for predicting RFS of PCa patients, as well as an indicator for personalized treatment of those patients.
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Affiliation(s)
| | | | | | | | | | | | | | - Jun Zhang
- *Correspondence: Jun Zhang, ; Guowei Shi,
| | - Guowei Shi
- *Correspondence: Jun Zhang, ; Guowei Shi,
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15
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Jeon K, Kim SH, Yoo J, Kim SW. Added Value of the Sliding Sign on Right Down Decubitus CT for Determining Adjacent Organ Invasion in Patients with Advanced Gastric Cancer. JOURNAL OF THE KOREAN SOCIETY OF RADIOLOGY 2022; 83:1312-1326. [PMID: 36545416 PMCID: PMC9748461 DOI: 10.3348/jksr.2021.0166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/02/2021] [Accepted: 11/08/2021] [Indexed: 12/24/2022]
Abstract
Purpose To investigate the added value of right down decubitus (RDD) CT when determining adjacent organ invasion in cases of advanced gastric cancer (AGC). Materials and Methods A total of 728 patients with pathologically confirmed T4a (pT4a), surgically confirmed T4b (sT4b), or pathologically confirmed T4b (pT4b) AGCs who underwent dedicated stomach-protocol CT, including imaging of the left posterior oblique (LPO) and RDD positions, were included in this study. Two radiologists scored the T stage of AGCs using a 5-point scale on LPO CT with and without RDD CT at 2-week intervals and recorded the presence of "sliding sign" in the tumors and adjacent organs and compared its incidence of appearance. Results A total of 564 patients (77.4%) were diagnosed with pT4a, whereas 65 (8.9%) and 99 (13.6%) patients were diagnosed with pT4b and sT4b, respectively. When RDD CT was performed additionally, both reviewers deemed that the area under the curve (AUC) for differentiating T4b from T4a increased (p < 0.001). According to both reviewers, the AUC for differentiating T4b with pancreatic invasion from T4a increased in the subgroup analysis (p < 0.050). Interobserver agreement improved from fair to moderate (weighted kappa value, 0.296-0.444). Conclusion RDD CT provides additional value compared to LPO CT images alone for determining adjacent organ invasion in patients with AGC due to their increased AUC values and improved interobserver agreement.
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Xu H, Xu B, Hu J, Xia J, Tong L, Zhang P, Yang L, Tang L, Chen S, Du J, Wang Y, Li Y. Development of a novel autophagy-related gene model for gastric cancer prognostic prediction. Front Oncol 2022; 12:1006278. [PMID: 36276067 PMCID: PMC9585256 DOI: 10.3389/fonc.2022.1006278] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 09/23/2022] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is a major global health issue and one of the leading causes of tumor-associated mortality worldwide. Autophagy is thought to play a critical role in the development and progression of GC, and this process is controlled by a set of conserved regulators termed autophagy-related genes (ATGs). However, the complex contribution of autophagy to cancers is not completely understood. Accordingly, we aimed to develop a prognostic model based on the specific role of ATGs in GC to improve the prediction of GC outcomes. First, we screened 148 differentially expressed ATGs between GC and normal tissues in The Cancer Genome Atlas (TCGA) cohort. Consensus clustering in these ATGs was performed, and based on that, 343 patients were grouped into two clusters. According to Kaplan–Meier survival analysis, cluster C2 had a worse prognosis than cluster C1. Then, a disease risk model incorporating nine differentially expressed ATGs was constructed based on the least absolute shrinkage and selection operator (LASSO) regression analysis, and the ability of this model to stratify patients into high- and low-risk groups was verified. The predictive value of the model was confirmed using both training and validation cohorts. In addition, the results of functional enrichment analysis suggested that GC risk is correlated with immune status. Moreover, autophagy inhibition increased sensitivity to cisplatin and exacerbated reactive oxygen species accumulation in GC cell lines. Collectively, the results indicated that this novel constructed risk model is an effective and reliable tool for predicting GC outcomes and could help with individual treatment through ATG targeting.
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Affiliation(s)
- Haifeng Xu
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
| | - Bing Xu
- Department of Clinical Laboratory, Hangzhou Women’s Hospital, Hangzhou, China
| | - Jiayu Hu
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Jun Xia
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Le Tong
- College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Ping Zhang
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Lei Yang
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
| | - Lusheng Tang
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Sufeng Chen
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Jing Du
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
- *Correspondence: Jing Du, ; Ying Wang, ; Yanchun Li,
| | - Ying Wang
- Department of Central Laboratory, Affiliated Hangzhou first people’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Jing Du, ; Ying Wang, ; Yanchun Li,
| | - Yanchun Li
- Department of Central Laboratory, Affiliated Hangzhou first people’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Jing Du, ; Ying Wang, ; Yanchun Li,
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Hu CG, Hu BE, Zhu JF, Zhu ZM, Huang C. Prognostic significance of the preoperative hemoglobin to albumin ratio for the short-term survival of gastric cancer patients. World J Gastrointest Surg 2022; 14:580-593. [PMID: 35979426 PMCID: PMC9258240 DOI: 10.4240/wjgs.v14.i6.580] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/20/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hemoglobin and albumin are associated with the prognosis of gastric cancer (GC) patients. However, the prognostic value of the hemoglobin to albumin ratio (HAR) for the short-term survival of GC patients with D2 radical resection has not been studied.
AIM To investigate the significance of the HAR in evaluating the short-term survival of GC patients after D2 radical resection and to construct a nomogram to predict the prognosis in GC patients after surgery, thus providing a reference for the development of postoperative individualized treatment and follow-up plans.
METHODS Cox regression and Kaplan-Meier analysis was used for prognostic analysis. Logistic regression was used to analyze the relationships between HAR and the clinicopathological characteristics of the GC patients. A prognostic nomogram model for the short-term survival of GC patients was constructed by R software.
RESULTS HAR was an independent risk factor for the short-term survival of GC patients. GC patients with a low HAR had a poor prognosis (P < 0.001). Low HAR was markedly related to high stage [odds ratio (OR) = 0.45 for II vs I; OR = 0.48 for III vs I], T classification (OR = 0.52 for T4 vs T1) and large tumor size (OR = 0.51 for ≥ 4 cm vs < 4 cm) (all P < 0.05). The nomogram model was based on HAR, age, CA19-9, CA125 and stage, and the C-index was 0.820.
CONCLUSION Preoperative low HAR was associated with short-term survival in GC patients. The prognostic nomogram model can accurately predict the short-term survival of GC patients with D2 radical resection.
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Affiliation(s)
- Ce-Gui Hu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Bai-E Hu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jin-Feng Zhu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Zheng-Ming Zhu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Chao Huang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
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Menon S, Parakh S, Scott AM, Gan HK. Antibody-drug conjugates: beyond current approvals and potential future strategies. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:252-277. [PMID: 36046842 PMCID: PMC9400743 DOI: 10.37349/etat.2022.00082] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 02/07/2022] [Indexed: 11/19/2022] Open
Abstract
The recent approvals for antibody-drug conjugates (ADCs) in multiple malignancies in recent years have fuelled the ongoing development of this class of drugs. These novel agents combine the benefits of high specific targeting of oncogenic cell surface antigens with the additional cell kill from high potency cytotoxic payloads, thus achieving wider therapeutic windows. This review will summarise the clinical activity of ADCs in tumour types not covered elsewhere in this issue, such as gastrointestinal (GI) and genitourinary (GU) cancers and glioblastoma (GBM). In addition to the ongoing clinical testing of existing ADCs, there is substantial preclinical and early phase testing of newer ADCs or ADC incorporating strategies. This review will provide selected insights into such future development, focusing on the development of novel ADCs against new antigen targets in the tumour microenvironment (TME) and combination of ADCs with immuno-oncology (IO) agents.
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Affiliation(s)
- Siddharth Menon
- Olivia Newton-John Cancer Centre at Austin Health, Olivia Newton-John Cancer Wellness & Research Centre, Heidelberg Victoria 3084, Australia;College of Science, Health and Engineering, La Trobe University, Melbourne Victoria 3086, Australia
| | - Sagun Parakh
- Olivia Newton-John Cancer Centre at Austin Health, Olivia Newton-John Cancer Wellness & Research Centre, Heidelberg Victoria 3084, Australia;College of Science, Health and Engineering, La Trobe University, Melbourne Victoria 3086, Australia
| | - Andrew M. Scott
- Olivia Newton-John Cancer Centre at Austin Health, Olivia Newton-John Cancer Wellness & Research Centre, Heidelberg Victoria 3084, Australia;College of Science, Health and Engineering, La Trobe University, Melbourne Victoria 3086, Australia
| | - Hui K. Gan
- Olivia Newton-John Cancer Centre at Austin Health, Olivia Newton-John Cancer Wellness & Research Centre, Heidelberg Victoria 3084, Australia;College of Science, Health and Engineering, La Trobe University, Melbourne Victoria 3086, Australia
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Identification of Five N6-Methylandenosine-Related ncRNA Signatures to Predict the Overall Survival of Patients with Gastric Cancer. DISEASE MARKERS 2022; 2022:7765900. [PMID: 35774851 PMCID: PMC9239763 DOI: 10.1155/2022/7765900] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 03/15/2022] [Indexed: 01/19/2023]
Abstract
Noncoding ribonucleic acids (ncRNAs) are involved in various functions in the formation and progression of different tumors. However, the association between N6-methyladenosine-related ncRNAs (m6A-related ncRNAs) and gastric cancer (GC) prognosis remains elusive. As such, this research was aimed at identifying m6A-related ncRNAs (lncRNAs and miRNAs) in GC and developing prognostic models of relevant m6A-related ncRNAs and identifying potential biomarkers regulated by m6A. In this study, the m6A2Target database, Starbase database, and The Cancer Genome Atlas (TCGA) were used to screen m6A-related ncRNAs. And then, we performed integrated bioinformatics analyses to determine prognosis-associated ncRNAs and to develop the m6A-related ncRNA prognostic signature (m6A-NPS) for GC patients. Finally, five m6A-related ncRNAs (including lnc-ARHGAP12, lnc-HYPM-1, lnc-WDR7-11, LINC02266, and lnc-PRIM2-7) were identified to establish m6A-NPS. The predictive power of m6A-NPS was better in the receiver operating characteristic (ROC) curve analysis of the training set (area under the curve (AUC), >0.6). The m6A-NPS could be utilized to classify patients into high- and low-risk cohorts, and the Kaplan-Meier analysis indicated that participants in the high-risk cohort had a poorer prognosis. The entire TCGA dataset substantiated the predictive value of m6A-NPS. Significant differences in TCGA molecular GC subtypes were observed between high- and low-risk cohorts. The ROC curve analysis indicated that m6A-NPS had better predictive power than other clinical characteristics of GC prognosis. Uni- and multivariate regression analyses indicated m6A-NPS as an independent prognostic factor. Furthermore, the m6A status between the low-risk cohort and high-risk cohort was significantly different. Differential genes between them were enriched in multiple tumor-associated signaling pathways. In summary, five m6A-related ncRNA signatures that could forecast the overall survival of patients with GC were identified.
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Nie C, Zhai J, Wang Q, Zhu X, Xiang G, Liu C, Liu T, Wang W, Wang Y, Zhao Y, Tian W, Xue Y, Zhou H. Comprehensive Analysis of an Individualized Immune-Related lncRNA Pair Signature in Gastric Cancer. Front Cell Dev Biol 2022; 10:805623. [PMID: 35273959 PMCID: PMC8902466 DOI: 10.3389/fcell.2022.805623] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 02/02/2022] [Indexed: 12/26/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) have diverse functions, including immune regulation. Increasing studies have reported immune-related lncRNAs in the prognosis of multiple cancers. In this study, we developed an individualized signature containing 13 immune-related lncRNA pairs (IRLPs) which could predict the overall survival, disease-free survival, progression-free survival, and disease-specific survival of gastric cancer (GC) patients in The Cancer Genome Atlas (TCGA) cohort, and internal and external validations, signature comparisons, and subgroup analyses further confirmed its superiority, stability, and generalizability. Notably, this signature also showed good applicability in discriminating the prognosis of pan-cancer patients. Then, we constructed and validated a nomogram for overall survival based on the signature and clinical factors, which allowed more accurate predictions of GC prognosis. In addition, we revealed that the low survival rate of patients with high-risk scores may be due to their aggressive clinical features, enriched cancer-related signaling pathways, the infiltration of specific immunosuppressive cells, and low tumor mutation burden. We further predicted obviously worse immunotherapeutic responses in the high-risk groups and identified some candidate compounds targeting GC risk group differentiation. This signature based on the IRLPs may be promising for predicting the survival outcomes and immunotherapeutic responses of GC patients in clinical practice.
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Affiliation(s)
- Chuang Nie
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Jiabao Zhai
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Qi Wang
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Xiaojie Zhu
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Guanghui Xiang
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Chang Liu
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Tianyu Liu
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Wanyu Wang
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Yimin Wang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yashuang Zhao
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Wenjing Tian
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Yingwei Xue
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Haibo Zhou
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
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21
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Mao C, Ma L, Huang Y, Yang X, Huang H, Cai W, Sitrakiniaina A, Gu R, Xue X, Shen X. Immunogenomic Landscape and Immune-Related Gene-Based Prognostic Signature in Asian Gastric Cancer. Front Oncol 2021; 11:750768. [PMID: 34804939 PMCID: PMC8602354 DOI: 10.3389/fonc.2021.750768] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 10/01/2021] [Indexed: 12/24/2022] Open
Abstract
Background Asians have the highest incidence of gastric cancer (GC), and the prognosis of Asian GC is poor. Furthermore, the therapeutics for Asian GC is limited because of genetic heterogeneity and screening difficulty at the early stage. This study aimed to develop an immune-related gene (IRG)-based prognostic signature and to explore prognosis-related regulatory mechanism and therapeutic target for Asian GC. Methods To elucidate the prognostic value of IRGs in Asian GC, a comprehensive analysis of IRG expression profiles and overall survival times in 364 Asian GC patients from the Asian Cancer Research Group (ACRG) and The Cancer Genome Atlas (TCGA) databases was performed, and a novel prognostic index was established. To further explore regulatory prognosis mechanisms and therapeutic targets, a tumor immunogenomic landscape analysis, including stromal and immune subcomponents, cell types, panimmune gene sets, and immunomodulatory genes, was performed. Result Our analysis allowed the creation of an optimal risk assessment model, the Asian-specific IRG-based prognostic index (ASIRGPI), which showed a high accuracy in predicting survival in Asian GC. We also developed an ASIRGPI-based nomogram to predict the 3- and 5-year overall survival (OS) of Asian GC patients. The impact of the ASIRGPI on the worse prognosis of Asian GC was possibly related to the stromal component remodeling. Specifically, TGFβ gene sets were significantly associated with the ASIRGPI and worse prognosis. Immunomodulatory gene analysis further revealed that TGFβ1 and EDNRB may be the novel potential therapeutic targets for Asian GC. Conclusions As a tumor microenvironment-relevant gene set-based prognostic signature, the ASIRGPI model provides an effective approach for evaluating the prognosis of Asian GC and may even prolong OS by enabling the selection of individualized therapy with the novel targets.
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Affiliation(s)
- Chenchen Mao
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liangliang Ma
- Department of Vascular Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yingpeng Huang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xinxin Yang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - He Huang
- Department of General Surgery, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Wentao Cai
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Andriamifehimanjaka Sitrakiniaina
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, China
| | - Ruihong Gu
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, China
| | - Xiangyang Xue
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, China
| | - Xian Shen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Human telomerase reverse transcriptase (hTERT) synergistic with Sp1 upregulate Gli1 expression and increase gastric cancer invasion and metastasis. J Mol Histol 2021; 52:1165-1175. [PMID: 34601664 DOI: 10.1007/s10735-021-10019-9] [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: 11/30/2020] [Accepted: 09/14/2021] [Indexed: 11/12/2022]
Abstract
Abnormal expression of human telomerase reverse transcriptase (hTERT) has been widely identified in tumors, but the relevant mechanism is not well known. This study aims to investigate the role and mechanism of hTERT in gastric cancer metastasis. Gastric cancer and adjacent non-tumor tissues were collected and the expression levels of hTERT and Gli1 were detected by immunohistochemistry. The results demonstrated that hTERT and Gli1 expression levels in gastric cancer tissue were significantly higher than adjacent non-tumor tissues. Western blot and quantitative real-time PCR were used to an identified expression of the related protein in BGC-823 and SGC-7901 cells. The interactions between hTERT and Sp1 were tested by co-immunoprecipitation experiments. Chromatin immunoprecipitation was performed to confirm that Sp1 and hTERT could bind to the Gli1 promoter. Chromatin reimmunoprecipitation assay further demonstrated that both hTERT and Sp1 bind to the Sp1 site of the Gli1 promoter. Moreover, the hTERT, Sp1, and Gli1 were upregulate was verified in human gastric cancer tissues. These results showed that the expression levels of hTERT in GC tissues were strongly closed to the depth of invasion, lymph node metastasis, TNM (tumor, node, metastasis) stage, and distant metastasis. By combining Sp1 and Gli1 promoter, hTERT upregulated Gli1 expression and promoted invasion and metastasis of GC cells. Overall, these data provide a new molecular mechanism of hTERT to promotes gastric cancer progression. Targeting the hTERT/Sp1/Gli1 axis may represent a new therapeutic strategy.
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LncRNA SNHG7 Regulates Gastric Cancer Progression by miR-485-5p. JOURNAL OF ONCOLOGY 2021; 2021:6147962. [PMID: 34512753 PMCID: PMC8424243 DOI: 10.1155/2021/6147962] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 08/20/2021] [Indexed: 12/14/2022]
Abstract
Background Long noncoding ribonucleic acids (lncRNAs) were closely related to the development of gastric cancer. This study investigated the effect of SNHG7 on gastric cancer progression and its potential molecular mechanism. Methods SNHG7 and microRNA-485-5p (miR-485-5p) expressions in gastric cancer tissues and cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell counting kit-8 (CCK-8), wound healing, and transwell experiments were used to detect cell proliferation, migration, and invasion. The dual luciferase reporter assay, RNA immunoprecipitation (RIP) experiment, and Pearson's correlation analysis were used to confirm the relationship between SNHG7 and miR-485-5p. Results SNHG7 expression was increased in human gastric cancer tissues and cells. Knockdown of SNHG7 could notably inhibit the gastric cancer cells proliferation, migration, and invasion. The dual-luciferase reporter assay and RIP experiments proved that miR-485-5p was a direct target of SNHG7. At the same time, further experiments demonstrated that miR-485-5p inhibition reversed the suppression of SNHG7 knockdown on gastric cancer cells proliferation, migration, and invasion. Conclusions SNHG7 knockdown could hamper gastric cancer progression via inhibiting miR-485-5p expression, providing a novel understanding for gastric cancer development.
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Jiang S, Zhang Y, Zhang X, Lu B, Sun P, Wu Q, Ding X, Huang J. GARP Correlates With Tumor-Infiltrating T-Cells and Predicts the Outcome of Gastric Cancer. Front Immunol 2021; 12:660397. [PMID: 34421887 PMCID: PMC8378229 DOI: 10.3389/fimmu.2021.660397] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 05/04/2021] [Indexed: 12/12/2022] Open
Abstract
Accepting the crucial role of the immune microenvironment (TME) in tumor progression enables us to identify immunotherapeutic targets and develop new therapies. Glycoprotein A repetitions predominant (GARP) plays a vital part in maintaining regulatory T cell (Treg)-mediated immune tolerance. The impact of GARP in TME of gastric cancer is still worth exploring. We investigated public genomic datasets from The Cancer Genome Atlas and Gene Expression Omnibus to analyze the possible role of GARP and its relationship with TME of gastric cancer. Fluorescence-based multiplex immunohistochemistry and immunohistochemistry for T-cell immune signatures in a series of tissue microarrays were used to validate the value of GARP in the TME. We initially found that GARP expression was upregulated in gastric carcinoma cells, and diverse levels o3f immune cell infiltration and immune checkpoint expression were detected. Gene expression profiling revealed that GARP expression was related to the TME of gastric cancer. GARP upregulation was usually accompanied by increased FOXP3+ Treg and CD4+ T cell infiltration. In addition, GARP expression had positive relationships with CTLA-4 and PD-L1 expression in gastric cancer. Cox regression analysis and a nomogram highlighted that the probability of poor overall survival was predicted well by GARP or GARP+CD4+ T cell. Taken together, this research underlines the potential effect of GARP in regulating survival and tumor-infiltrating T-cells. In addition, the function of CD4+ T cell immune signatures in the prognosis can be clinically meaningful, thereby providing a new idea for the immunotherapeutic approach.
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Affiliation(s)
- Sutian Jiang
- Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, China.,Department of Pathology and Pathophysiology, School of Medicine, Nantong University, Nantong, China
| | - Yifan Zhang
- Clinical Medicine, Xian Medical University, Xi'an, China
| | - Xiaojing Zhang
- Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, China
| | - Bing Lu
- Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, China
| | - Pingping Sun
- Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, China
| | - Qianqian Wu
- Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, China
| | - Xuzhong Ding
- Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, China
| | - Jianfei Huang
- Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, China.,Translational Medicine Center, The Affiliated Kezhou People's Hospital of Nanjing Medical University, Kezhou, China
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Pei JP, Zhang CD, Yusupu M, Zhang C, Dai DQ. Screening and Validation of the Hypoxia-Related Signature of Evaluating Tumor Immune Microenvironment and Predicting Prognosis in Gastric Cancer. Front Immunol 2021; 12:705511. [PMID: 34249015 PMCID: PMC8267919 DOI: 10.3389/fimmu.2021.705511] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 06/08/2021] [Indexed: 12/17/2022] Open
Abstract
Background Hypoxia is one driving factor of gastric cancer. It causes a series of immunosuppressive processes and malignant cell responses, leading to a poor prognosis. It is clinically important to identify the molecular markers related to hypoxia. Methods We screened the prognostic markers related to hypoxia in The Cancer Genome Atlas database, and a risk score model was developed based on these markers. The relationships between the risk score and tumor immune microenvironment were investigated. An independent validation cohort from Gene Expression Omnibus was applied to validate the results. A nomogram of risk score model and clinicopathological factor was developed to individually predict the prognosis. Results We developed a hypoxia risk score model based on SERPINE1 and EFNA3. Quantified real-time PCR was further applied to verified gene expressions of SERPINE1 and EFNA3 in gastric cancer patients and cell lines. A high-risk score is associated with a poor prognosis through the immunosuppressive microenvironment and immune escape mechanisms, including infiltration of immunosuppressive cells, expression of immune checkpoint molecules, and enrichment of signal pathways related to cancer and immunosuppression. The nomogram basing on the hypoxia-related risk score model showed a good ability to predict prognosis and high clinical net benefits. Conclusions The hypoxia risk score model revealed a close relationship between hypoxia and tumor immune microenvironment. The current study potentially provides new insights of how hypoxia affects the prognosis, and may provide a new therapeutic target for patients with gastric cancer.
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Affiliation(s)
- Jun-Peng Pei
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Chun-Dong Zhang
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.,Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Maimaititusun Yusupu
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Cheng Zhang
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Dong-Qiu Dai
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.,Cancer Center, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
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Díaz del Arco C, Ortega Medina L, Estrada Muñoz L, Molina Roldán E, Cerón Nieto MÁ, García Gómez de las Heras S, Fernández Aceñero MJ. Are Borrmann's Types of Advanced Gastric Cancer Distinct Clinicopathological and Molecular Entities? A Western Study. Cancers (Basel) 2021; 13:3081. [PMID: 34205546 PMCID: PMC8234739 DOI: 10.3390/cancers13123081] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 06/17/2021] [Accepted: 06/18/2021] [Indexed: 12/21/2022] Open
Abstract
Most studies on the clinicopathological impact of Borrmann classification for gastric cancer (GC) have been performed in Asian patients with type IV tumors, and immunohistochemical features of Borrmann types have scarcely been analyzed. We assessed the clinicopathological, molecular features and prognostic value of Borrmann types in all patients with advanced GC resected in a Western institution (n = 260). We observed a significant relationship between Borrmann types and age, systemic symptoms, tumor size, Laurén subtype, presence of signet-ring cells, infiltrative growth, high grade, tumor necrosis, HERCEPTEST positivity, microsatellite instability (MSI) and molecular subtypes. Polypoid GC showed systemic symptoms, intestinal-type histology, low grade, expansive growth and HERCEPTEST positivity. Fungating GC occurred in symptomatic older patients. It presented intestinal-type histology, infiltrative growth and necrosis. Ulcerated GC showed smaller size, intestinal-type histology, high grade and infiltrative growth. Most polypoid and ulcerated tumors were stable-p53-not overexpressed or microsatellite unstable. Flat lesions were high-grade diffuse tumors with no MSI, and occurred in younger and less symptomatic patients. No association was found between Borrmann classification and prognosis. According to our results, Borrmann types may represent distinct clinicopathological and biological entities. Further research should be conducted to confirm the role of Borrmann classification in the stratification of patients with advanced GC.
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Affiliation(s)
- Cristina Díaz del Arco
- Department of Surgical Pathology, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (L.O.M.); (M.J.F.A.)
- Department of Pathology, Hospital Clínico San Carlos, 28040 Madrid, Spain; (E.M.R.); (M.Á.C.N.)
| | - Luis Ortega Medina
- Department of Surgical Pathology, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (L.O.M.); (M.J.F.A.)
- Department of Pathology, Hospital Clínico San Carlos, 28040 Madrid, Spain; (E.M.R.); (M.Á.C.N.)
| | - Lourdes Estrada Muñoz
- Department of Pathology, Hospital Rey Juan Carlos, Móstoles, 28933 Madrid, Spain;
- Department of Basic Medical Sciences, School of Medicine, Rey Juan Carlos University, Móstoles, 28933 Madrid, Spain;
| | - Elena Molina Roldán
- Department of Pathology, Hospital Clínico San Carlos, 28040 Madrid, Spain; (E.M.R.); (M.Á.C.N.)
| | - M. Ángeles Cerón Nieto
- Department of Pathology, Hospital Clínico San Carlos, 28040 Madrid, Spain; (E.M.R.); (M.Á.C.N.)
| | | | - M. Jesús Fernández Aceñero
- Department of Surgical Pathology, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (L.O.M.); (M.J.F.A.)
- Department of Pathology, Hospital Clínico San Carlos, 28040 Madrid, Spain; (E.M.R.); (M.Á.C.N.)
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Ning ZK, Hu CG, Huang C, Liu J, Zhou TC, Zong Z. Molecular Subtypes and CD4 + Memory T Cell-Based Signature Associated With Clinical Outcomes in Gastric Cancer. Front Oncol 2021; 10:626912. [PMID: 33816214 PMCID: PMC8011500 DOI: 10.3389/fonc.2020.626912] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 12/08/2020] [Indexed: 12/26/2022] Open
Abstract
Background CD4+ memory T cells are an important component of the tumor microenvironment (TME) and affect tumor occurrence and progression. Nevertheless, there has been no systematic analysis of the effect of CD4+ memory T cells in gastric cancer (GC). Methods Three datasets obtained from microarray and the corresponding clinical data of GC patients were retrieved and downloaded from the Gene Expression Omnibus (GEO) database. We uploaded the normalize gene expression data with standard annotation to the CIBERSORT web portal for evaluating the proportion of immune cells in the GC samples. The WGCNA was performed to identify the modules the CD4+ memory T cell related module (CD4+ MTRM) which was most significantly associated with CD4+ memory T cell. Univariate Cox analysis was used to screen prognostic CD4+ memory T cell-related genes (CD4+ MTRGs) in CD4+ MTRM. LASSO analysis and multivariate Cox analysis were then performed to construct a prognostic gene signature whose effect was evaluated by Kaplan-Meier curves and receiver operating characteristic (ROC), Harrell’s concordance index (C-index), and decision curve analyses (DCA). A prognostic nomogram was finally established based on the CD4+ MTRGs. Result We observed that a high abundance of CD4+ memory T cells was associated with better survival in GC patients. CD4+ MTRM was used to stratify GC patients into three clusters by unsupervised clustering analysis and ten CD4+ MTRGs were identified. Overall survival, five immune checkpoint genes and 17 types of immunocytes were observed to be significantly different among the three clusters. A ten-CD4+ MTRG signature was constructed to predict GC patient prognosis. The ten-CD4+ MTRG signature could divide GC patients into high- and low-risk groups with distinct OS rates. Multivariate Cox analysis suggested that the ten-CD4+ MTRG signature was an independent risk factor in GC. A nomogram incorporating this signature and clinical variables was established, and the C-index was 0.73 (95% CI: 0.697–0.763). Calibration curves and DCA presented high credibility for the OS nomogram. Conclusion We identified three molecule subtypes, ten CD4+ MTRGs, and generated a prognostic nomogram that reliably predicts OS in GC. These findings have implications for precise prognosis prediction and individualized targeted therapy.
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Affiliation(s)
- Zhi-Kun Ning
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Department of Day Ward, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ce-Gui Hu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chao Huang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jiang Liu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Tai-Cheng Zhou
- Department of Gastroenterological Surgery and Hernia Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, China
| | - Zhen Zong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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Li W, Li M, Wang H, Peng Y, Dong S, Lu Y, Wang F, Xu F, Liu L, Zhao Q. Infiltrating Immune Cells in Gastric Cancer: A Novel Predicting Model for Prognosis. J Cancer 2021; 12:965-975. [PMID: 33442396 PMCID: PMC7797666 DOI: 10.7150/jca.51079] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 11/01/2020] [Indexed: 02/07/2023] Open
Abstract
Objective: Immune cells infiltrating has been proved to be associated with prognosis in gastric cancer (GC) by studies. This study aims to explore the prognosis value of infiltrating immune cells in gastric cancer. Methods: In our study, the CIBERSORT algorithm was used to calculate the fraction of 22 tumor-infiltrating immune cells (TIIC) in 100 normal and 300 tumor samples from the GEO cohort and 30 normal and 344 tumor samples from the TCGA cohort. Univariate and multivariate Cox regression were used to construct an immune risk score model. Multivariate cox regression was also used to validate whether our risk score model could predict prognosis in GC independently. Furthermore, the model was validated in different patient subgroups to test its independence. P<0.05 was considered statistically significant. Results: The results showed that the fraction of 3 immune cells increased in tumor tissues compared with normal tissues in both the GEO and TCGA cohort. Univariate cox regression analysis showed four cells significantly correlated with survival rate in GC (P<0.05). The immune risk score model was constructed based on the four cells through multivariate cox regression and further validated. The KM survival curve suggested that patients with high risk had poor prognosis than patients with low risk (P<0.05). ROC curve indicated the model was reliable (AUC= 0.67 in the GEO cohort, AUC = 0.65 in the TCGA cohort). Furthermore, multivariate Cox regression showed the model was an independent factor for overall survival predicting in GC (hazard ratio (HR) = 2.35, 95% confidence interval (CI) = 1.63~3.40 in the GEO cohort, HR = 2.87, 95% CI = 1.94~4.25 in the TCGA cohort). Finally, we validated the model in patient subgroups by the KM survival curve. Conclusion: In summary, tumor-infiltrating immune cells play an essential role in GC progression and affect the outcome of GC patients. The immune risk score can predict overall survival for GC independently, and high immune risk score is associated with poor prognosis.
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Affiliation(s)
- Wenjie Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Mengting Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Haizhou Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Yanan Peng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Shouquan Dong
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Yuanyuan Lu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Fan Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Fei Xu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Lan Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
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Zhang T, Zhang K, Ji K, Zhang C, Jiang Y, Zhang Q, Tian Z, Wang X, Zhang M, Li X. microRNA-365 inhibits YAP through TLR4-mediated IRF3 phosphorylation and thereby alleviates gastric precancerous lesions. Cancer Cell Int 2020; 20:549. [PMID: 33292210 PMCID: PMC7664090 DOI: 10.1186/s12935-020-01578-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 09/25/2020] [Indexed: 12/18/2022] Open
Abstract
Background Gastric carcinoma (GC) is currently one of the most common malignant tumors of the digestive system, and gastric precancerous lesions play a vital role in studying the mechanism of GC. Multiple microRNAs (miRNAs) have been documented to be potential biomarkers to indicate progression of gastric precancerous lesions. In this study, we explained the anti-cancer effect of miR-365 in gastric precancerous lesions via regulation of the TLR4/IRF3/YAP/CDX2 axis. Methods miR-365, TLR4, CDX2 and IPF3 expression was determined in GC and atrophic gastritis tissues and cells. After transfection of shRNA and overexpression plasmids, in vitro experiments detected the alteration of cell viability, apoptosis and inflammatory factors. Bioinformatics analysis, Co-IP and dual luciferase reporter gene assay were conducted to evaluate the binding between miR-365 and TLR4 as well as IRF3 and YAP. Rat models were established to explore the effect of the miR-365 and TLR4 on gastric precancerous lesions. Results miR-365 was poorly expressed in GC and atrophic gastritis tissues and GC cell lines, while TLR4, CDX2 and IRF3 were overexpressed. Of note, miR-365 was indicated to target TLR4 and thereby suppressed cancer progression and increased hemoglobin content. Interestingly, silencing of TLR4 was accompanied by decreased IRF3 phosphorylation and reduced expression with less binding between CDX2 and IRF3. Downregulation of YAP resulted in declined CDX2 expression in cancer cells. Moreover, the inhibitory role of miR-365 was further confirmed in animal models. Conclusion Taken together, miR-365-mediated TLR4 inhibition reduces IRF3 phosphorylation and YAP-mediated CDX2 transcription to impede progression of gastric precancerous lesions.
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Affiliation(s)
- Tianqi Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao, 266000, Shandong, People's Republic of China
| | - Kunpeng Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao, 266000, Shandong, People's Republic of China
| | - Kaiyue Ji
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao, 266000, Shandong, People's Republic of China
| | - Cuiping Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao, 266000, Shandong, People's Republic of China
| | - Yueping Jiang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao, 266000, Shandong, People's Republic of China
| | - Qi Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao, 266000, Shandong, People's Republic of China
| | - Zibin Tian
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao, 266000, Shandong, People's Republic of China
| | - Xinyu Wang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao, 266000, Shandong, People's Republic of China
| | - Mengyuan Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao, 266000, Shandong, People's Republic of China
| | - Xiaoyu Li
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao, 266000, Shandong, People's Republic of China.
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Cai WY, Dong ZN, Fu XT, Lin LY, Wang L, Ye GD, Luo QC, Chen YC. Identification of a Tumor Microenvironment-relevant Gene set-based Prognostic Signature and Related Therapy Targets in Gastric Cancer. Am J Cancer Res 2020; 10:8633-8647. [PMID: 32754268 PMCID: PMC7392024 DOI: 10.7150/thno.47938] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 06/23/2020] [Indexed: 12/22/2022] Open
Abstract
Rationale: The prognosis of gastric cancer (GC) patients is poor, and there is limited therapeutic efficacy due to genetic heterogeneity and difficulty in early-stage screening. Here, we developed and validated an individualized gene set-based prognostic signature for gastric cancer (GPSGC) and further explored survival-related regulatory mechanisms as well as therapeutic targets in GC. Methods: By implementing machine learning, a prognostic model was established based on gastric cancer gene expression datasets from 1699 patients from five independent cohorts with reported full clinical annotations. Analysis of the tumor microenvironment, including stromal and immune subcomponents, cell types, panimmune gene sets, and immunomodulatory genes, was carried out in 834 GC patients from three independent cohorts to explore regulatory survival mechanisms and therapeutic targets related to the GPSGC. To prove the stability and reliability of the GPSGC model and therapeutic targets, multiplex fluorescent immunohistochemistry was conducted with tissue microarrays representing 186 GC patients. Based on multivariate Cox analysis, a nomogram that integrated the GPSGC and other clinical risk factors was constructed with two training cohorts and was verified by two validation cohorts. Results: Through machine learning, we obtained an optimal risk assessment model, the GPSGC, which showed higher accuracy in predicting survival than individual prognostic factors. The impact of the GPSGC score on poor survival of GC patients was probably correlated with the remodeling of stromal components in the tumor microenvironment. Specifically, TGFβ and angiogenesis-related gene sets were significantly associated with the GPSGC risk score and poor outcome. Immunomodulatory gene analysis combined with experimental verification further revealed that TGFβ1 and VEGFB may be developed as potential therapeutic targets of GC patients with poor prognosis according to the GPSGC. Furthermore, we developed a nomogram based on the GPSGC and other clinical variables to predict the 3-year and 5-year overall survival for GC patients, which showed improved prognostic accuracy than clinical characteristics only. Conclusion: As a tumor microenvironment-relevant gene set-based prognostic signature, the GPSGC model provides an effective approach to evaluate GC patient survival outcomes and may prolong overall survival by enabling the selection of individualized targeted therapy.
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Liu Y, Wu J, Huang W, Weng S, Wang B, Chen Y, Wang H. Development and validation of a hypoxia-immune-based microenvironment gene signature for risk stratification in gastric cancer. J Transl Med 2020; 18:201. [PMID: 32410620 PMCID: PMC7226948 DOI: 10.1186/s12967-020-02366-0] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 05/07/2020] [Indexed: 12/23/2022] Open
Abstract
Background Increasing evidences have found that the clinical importance of the interaction between hypoxia and immune status in gastric cancer microenvironment. However, reliable prognostic signatures based on combination of hypoxia and immune status have not been well-established. This study aimed to develop a hypoxia-immune-based gene signature for risk stratification in gastric cancer. Methods Hypoxia and immune status was estimated with transcriptomic profiles for a discovery cohort from GEO database using the t-SNE and ESTIMATE algorithms, respectively. The Cox regression model with the LASSO method was applied to identify prognostic genes and to develop a hypoxia-immune-based gene signature. The TCGA cohort and two independent cohorts from GEO database were used for external validation. Results Low hypoxia status (p < 0.001) and high immune status (p = 0.005) were identified as favorable factors for patients’ overall survival. By using the LASSO model, four genes, including CXCR6, PPP1R14A and TAGLN, were identified to construct a gene signature for risk stratification. In the discovery cohort (n = 357), patients with low risk yielded better outcomes than those with high risk regarding overall survival across and within TNM stage subgroups. Multivariate analysis identified the hypoxia-immune-based gene signature as an independent prognostic factor (p < 0.001). A nomogram integrating the gene signature and known risk factors yielded better performance and net benefits in calibration and decision curve analyses. Similar results were validated in the TCGA (n = 321) and two independent GEO (n = 300 and n = 136, respectively) cohorts. Conclusions The hypoxia-immune-based gene signature represents a promising tool for risk stratification tool in gastric cancer. It might serve as a prognostic classifier for clinical decision-making regarding individualized prognostication and treatment, and follow-up scheduling.
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Affiliation(s)
- Yifan Liu
- The First Department of Gastrointestinal Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China.,Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianhua Wu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weiwei Huang
- The First Department of Gastrointestinal Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Shaowen Weng
- The First Department of Gastrointestinal Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Baochun Wang
- The First Department of Gastrointestinal Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Yiming Chen
- The First Department of Gastrointestinal Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Hao Wang
- The First Department of Gastrointestinal Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China.
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Xue W, Xu X, Tan Y, Wang Y, Wang H, Xu Y, Xi C, Jiang P, Ding W. Evaluation and validation of the prognostic value of nutrition and immunity parameters in gastric cancer after R0 resection. Medicine (Baltimore) 2020; 99:e19270. [PMID: 32080137 PMCID: PMC7034686 DOI: 10.1097/md.0000000000019270] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Precise predictive tools are critical for choosing the individualized treatment protocols and follow-up procedures for patients with gastric cancer (GC). In this study, we aimed to evaluate and validate the prognostic abilities of preoperative nutrition and immunity parameters in GC after curative R0 resection.We established two nomograms based on 437 patients who underwent curative radical gastrectomy for gastric cancer to predict the postoperative overall survival (OS) and recurrence-free survival (RFS), and then compared the predictive accuracy and discriminative ability of the nomograms with the TNM stage systems for GC. An internal validation cohort of 141 patients and an external validation cohort of 116 patients were used to validate the result.The independent predictive factors for OS or RFS, including T stage, N stage, differentiated degree, neutrophil monocyte lymphocyte ratio (NMLR) and albumin globulin ratio (AGR) were used to establish the 2 nomograms. The C-index of the OS nomogram was 0.802, which was higher than that of the AGR, the NMLR and the TNM stage. The C-index of the RFS nomogram was 0.850, which was higher than that of the AGR, the NMLR and the TNM stage. Analogously, the areas under the receiver operating characteristics curves (AUROCs, 0.920 for OS and 0.897 for RFS, respectively) of the two nomograms were higher than that of the NMLR, the AGR and the TNM stage. In the internal validation cohort, the C-indexes of the OS and RFS nomograms were 0.812 and 0.826, respectively. In the external validation cohort, the C-indexes of the OS and RFS nomograms were 0.866 and 0.880, respectively.The proposed nomograms including nutrition and immunity parameters were proved to have excellent predictive ability in survival and recurrence for patients with GC after R0 resection.
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Affiliation(s)
- Wenbo Xue
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu Province
- The Wujin Clinical college of Xuzhou Medical University, Changzhou
| | - Xuezhong Xu
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu Province
- The Wujin Clinical college of Xuzhou Medical University, Changzhou
| | - Yulin Tan
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu Province
- The Wujin Clinical college of Xuzhou Medical University, Changzhou
| | - Yibo Wang
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu Province
- The Wujin Clinical college of Xuzhou Medical University, Changzhou
| | - Hao Wang
- The Wujin Clinical college of Xuzhou Medical University, Changzhou
- Department of Medical Record, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu Province, China
| | - Yixin Xu
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu Province
- The Wujin Clinical college of Xuzhou Medical University, Changzhou
| | - Cheng Xi
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu Province
- The Wujin Clinical college of Xuzhou Medical University, Changzhou
| | - Peng Jiang
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu Province
- The Wujin Clinical college of Xuzhou Medical University, Changzhou
| | - Wei Ding
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu Province
- The Wujin Clinical college of Xuzhou Medical University, Changzhou
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Tang B, Yang S. Involvement of Heparanase in Gastric Cancer Progression and Immunotherapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1221:351-363. [PMID: 32274717 DOI: 10.1007/978-3-030-34521-1_13] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Heparanase is upregulated in various tumors, and its expression is closely associated with tumor growth, angiogenesis and metastasis, which accomplishes this mainly through degrading heparan sulfate and releasing heparin-binding growth factors thereby influencing multiple signaling pathways. In addition to its enzymatic degrading activity, heparanase can act via its non-enzymatic mechanisms that directly regulate various signaling. This review mainly focuses on the expression levels and role of heparanase in gastric cancer, and multiple genes and mechanisms regulating heparanase expression in gastric cancer. Furthermore, the development of heparanase-targeted immunotherapy and its potential application for treating gastric cancer are discussed.
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Affiliation(s)
- Bo Tang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Shiming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
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Xue W, Xu X, Tan Y, Qian Y, Wang H, Wang Y, Xu Y, Zhu X, Jiang P, Ding W. Evaluating and validating the predictive ability of preoperative systemic inflammatory/immune cells in gastric cancer following R0 resection. Oncol Lett 2019; 18:5205-5214. [PMID: 31612031 PMCID: PMC6781767 DOI: 10.3892/ol.2019.10867] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 08/29/2019] [Indexed: 01/17/2023] Open
Abstract
The present study aimed to compare the predictive abilities of preoperative systemic inflammatory/immune cell ratios in gastric cancer (GC) following curative R0 resection, and to screen the optimal parameter incorporated into nomograms to predict the postoperative overall survival (OS) and recurrence-free survival (RFS). A total of 679 patients with GC were included in the study, divided into a primary cohort (300 cases), an internal validation cohort (278 cases), and an external validation cohort (101 cases). In the primary cohort, the prognostic abilities of all systemic inflammatory/immune cell accounts or ratios were compared by receiver operating characteristic (ROC) curve analysis. The area under the ROC curve (AUC) of the neutrophil-monocyte-lymphocyte ratio (NMLR) was largest for the prediction of OS (AUC=0.728) and RFS (AUC=0.695). The independent predictive factors for OS or RFS, including NMLR, degree of differentiation (DD), T-stage and N-stage were used to establish the 2 nomograms. The comprehensive predictive power of nomograms was compared with that of the tumor-nodes-metastasis (TNM) staging system and validated by bootstrap resampling. The concordance indexes (C-indexes) of the nomograms for OS [C-index, 0.851; 95% confidence interval (CI), 0.817-0.883] and RFS (C-index, 0.860; 95% CI, 0.831-0.889), were increased compared with those for the DD, the NMLR and the TNM stage. The AUCs of the 2 nomograms (0.933 for OS and 0.944 for RFS) were largest among all predictive scoring systems. In the internal validation cohort, the C-indexes of the nomograms for OS and RFS were 0.840 and 0.916, respectively. In the external validation cohort, the C-indexes of the nomograms for OS and RFS nomograms were 0.827 and 0.891, respectively. The present study demonstrated that the NMLR was an independent prognostic factor for patients with GC. The proposed nomograms were demonstrated to have a good predictive ability with improved sensitivity and accuracy in survival and recurrence in patients with GC undergoing R0 resection.
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Affiliation(s)
- Wenbo Xue
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu 213002, P.R. China
| | - Xuezhong Xu
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu 213002, P.R. China
| | - Yulin Tan
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu 213002, P.R. China
| | - Yan Qian
- Department of Respiration, Changzhou Second People's Hospital Affiliated to Nanjing Medical University, Changzhou, Jiangsu 213164, P.R. China
| | - Hao Wang
- Department of Medical Records, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu 213002, P.R. China
| | - Yibo Wang
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu 213002, P.R. China
| | - Yixin Xu
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu 213002, P.R. China
| | - Xiaojun Zhu
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu 213002, P.R. China
| | - Peng Jiang
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu 213002, P.R. China
| | - Wei Ding
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu 213002, P.R. China
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Zhang Y, Zhu JY, Zhou LN, Tang M, Chen MB, Tao M. Predicting the Prognosis of Gastric Cancer by Albumin/Globulin Ratio and the Prognostic Nutritional Index. Nutr Cancer 2019; 72:635-644. [PMID: 31423840 DOI: 10.1080/01635581.2019.1651347] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Affiliation(s)
- Yan Zhang
- Department of Oncology, the first Affiliated Hospital of Soochow University, Jiangsu, China
- Department of Oncology, Affiliated Kunshan Hospital of Jiangsu University, Jiangsu, China
| | - Jia-Yao Zhu
- Department of Oncology, Affiliated Kunshan Hospital of Jiangsu University, Jiangsu, China
| | - Li-Na Zhou
- Department of Oncology, Affiliated Kunshan Hospital of Jiangsu University, Jiangsu, China
| | - Min Tang
- Department of Oncology, Affiliated Kunshan Hospital of Jiangsu University, Jiangsu, China
| | - Min-Bin Chen
- Department of Oncology, Affiliated Kunshan Hospital of Jiangsu University, Jiangsu, China
| | - Min Tao
- Department of Oncology, the first Affiliated Hospital of Soochow University, Jiangsu, China
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Koh J, Lee KW, Nam SK, Seo AN, Kim JW, Kim JW, Park DJ, Kim HH, Kim WH, Lee HS. Development and Validation of an Easy-to-Implement, Practical Algorithm for the Identification of Molecular Subtypes of Gastric Cancer: Prognostic and Therapeutic Implications. Oncologist 2019; 24:e1321-e1330. [PMID: 31371521 DOI: 10.1634/theoncologist.2019-0058] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 06/10/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is a heterogeneous disease, and substantial efforts have been made to develop a molecular biology-based classification system for GC. Analysis of the genomic signature is not always feasible, and thus, we aimed to (i) develop and validate a practical immunohistochemistry (IHC)- and polymerase chain reaction (PCR)-based molecular classification of GC and (ii) to assess HER2 status according to this classification. MATERIALS AND METHODS A total of 894 consecutive patients with GC from two individual cohorts (training, n = 507; validation, n = 387) were classified using Epstein-Barr virus (EBV) in situ hybridization, microsatellite instability (MSI) testing, and IHC for E-cadherin and p53. RESULTS We were able to classify patients into five groups in the training cohort: group 1 (MSI+), group 2 (EBV-, MSI-, non-epithelial-mesenchymal transition [non-EMT]-like, p53-), group 3 (EBV+), group 4 (EBV-, MSI-, non-EMT-like, p53+), and group 5 (EBV-, MSI-, EMT-like). In the training cohort, each group showed different overall survival (OS) after gastrectomy (p < .001); group 1 had the best prognosis, and group 5 showed the worst survival outcome. The significant impact of the classification system on OS was also verified in the validation cohort (p = .004). HER2 positivity was observed in 6.5% of total population, and most of HER2-positive cases (93.1%) were included in groups 2 and 4. CONCLUSION We developed and validated a modified IHC- and PCR-based molecular classification system in GC, which showed significant impact on survival, irrespective of stage or other clinical variables. We also found close association between HER2 status and non-EMT phenotype in our classification system. IMPLICATIONS FOR PRACTICE Molecular classification of gastric cancer suggested by previous studies mostly relies on extensive genomic data analysis, which is not always available in daily practice. The authors developed a simplified immunohistochemistry- and polymerase chain reaction-based molecular classification of gastric cancer and proved the prognostic significance of this classification, as well as the close association between HER2 status and certain groups of the classification, in the largest consecutive cohort of gastric cancer. Results of this study suggest that this scheme is a cost-effective, easy-to-implement, and feasible way of classifying gastric cancer in daily clinical practice, also serving as a practical tool for aiding therapeutic decisions and predicting prognosis.
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Affiliation(s)
- Jiwon Koh
- Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Keun-Wook Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Soo Kyung Nam
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea
| | - Ji-Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jin Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Do Joong Park
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Hyung-Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
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Joo I, Kim SH, Lee DH, Han JK. Dynamic Contrast-Enhanced Ultrasound of Gastric Cancer: Correlation with Perfusion CT and Histopathology. Korean J Radiol 2019; 20:781-790. [PMID: 30993929 PMCID: PMC6470092 DOI: 10.3348/kjr.2018.0273] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 12/10/2018] [Indexed: 02/06/2023] Open
Abstract
Objective To assess the relationship between contrast-enhanced ultrasound (CEUS) parameters and perfusion CT (PCT) parameters of gastric cancers and their correlation with histologic features. Materials and Methods This prospective study was approved by our Institutional Review Board. We included 43 patients with pathologically-proven gastric cancers undergoing CEUS using SonoVue® (Bracco) and PCT on the same day. Correlation between the CEUS parameters (peak intensity [PI], area under the curve [AUC], rise time [RT] from 10% to 90% of PI, time to peak [TTPUS], and mean transit time [MTTUS]) and PCT parameters (blood flow, blood volume, TTPCT, MTTCT, and permeability surface product) of gastric cancers were analyzed using Spearman's rank correlation test. In cases of surgical resection, the CEUS and PCT parameters were compared according to histologic features using Mann-Whitney test. Results CEUS studies were of diagnostic quality in 88.4% (38/43) of patients. Among the CEUS parameters of gastric cancers, RT and TTPUS showed significant positive correlations with TTPCT (rho = 0.327 and 0.374, p = 0.045 and 0.021, respectively); PI and AUC were significantly higher in well-differentiated or moderately-differentiated tumors (n = 4) than poorly-differentiated tumors (n = 18) (p = 0.026 and 0.033, respectively), whereas MTTCT showed significant differences according to histologic types (poorly cohesive carcinoma [PCC] vs. non-PCC), T-staging (≤ T2 vs. ≥ T3), N-staging (N0 vs. N-positive), and epidermal growth factor receptor expression (≤ faint vs. ≥ moderate staining) (p values < 0.05). Conclusion In patients with gastric cancers, CEUS is technically feasible for the quantification of tumor perfusion and may provide correlative and complementary information to that of PCT, which may allow prediction of histologic features.
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Affiliation(s)
- Ijin Joo
- Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Se Hyung Kim
- Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
| | - Dong Ho Lee
- Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Joon Koo Han
- Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.,Institute of Radiation Medicine, Seoul National University Hospital, Seoul, Korea
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Yan B, Cui M, You J, Li F, Liu H. Gastric adenocarcinoma is concurrent with metastatic neuroendocrine cancer treated with nivolumab and chemotherapy: A case report. Mol Clin Oncol 2018; 9:607-612. [PMID: 30546888 PMCID: PMC6256192 DOI: 10.3892/mco.2018.1740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 09/21/2018] [Indexed: 11/23/2022] Open
Abstract
Gastric adenocarcinoma concurrent with metastatic neuroendocrine cancer (NEC) is rare. In the present case report, a 39-year-old male was first pathologically diagnosed by gastric endoscopy as having a highly differentiated adenocarcinoma. Next, positron emission tomography-computed tomography examination and bone marrow biopsy confirmed extensive metastasis. Subsequently, the patient underwent 6 cycles of immunotherapy (nivolumab, 160 mg) and 5 cycles of chemotherapy based on the XELOX regimen (oxaliplatin + capecitabine). Following this, the patient received the final cycles of nivolumab and XELOX; however, the patient then succumbed. Further biopsy of the metastatic collarbone lymph nodes indicated NEC. Overall, the progression-free survival was ~3.5 months, and overall survival (OS) was ~6 months. The case presented the possibility of concurrent gastric adenocarcinoma and NEC in the clinic. In addition, the efficacy of a combined regimen such as immunotherapy and chemotherapy for such disorders still requires further validation in the future.
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Affiliation(s)
- Bing Yan
- Department of Oncology, Hainan Branch of PLA General Hospital, Sanya, Hainan 572000, P.R. China
| | - Meiqi Cui
- Department of Outpatient, Hainan Branch of PLA General Hospital, Sanya, Hainan 572000, P.R. China
| | - Junhao You
- Department of Oncology, Hainan Branch of PLA General Hospital, Sanya, Hainan 572000, P.R. China
| | - Fang Li
- Department of Oncology, Hainan Branch of PLA General Hospital, Sanya, Hainan 572000, P.R. China
| | - Hui Liu
- Department of Oncology, Hainan Branch of PLA General Hospital, Sanya, Hainan 572000, P.R. China
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Park JK, Seo JS, Lee SK, Chan KK, Kuh HJ. Combinatorial Antitumor Activity of Oxaliplatin with Epigenetic Modifying Agents, 5-Aza-CdR and FK228, in Human Gastric Cancer Cells. Biomol Ther (Seoul) 2018; 26:591-598. [PMID: 30173503 PMCID: PMC6254647 DOI: 10.4062/biomolther.2018.061] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 07/13/2018] [Accepted: 07/31/2018] [Indexed: 12/13/2022] Open
Abstract
Epigenetic silencing is considered to be a major mechanism for loss of activity in tumor suppressors. Reversal of epigenetic silencing by using inhibitors of DNA methyltransferase (DNMT) or histone deacetylases (HDACs) such as 5-Aza-CdR and FK228 has shown to enhance cytotoxic activities of several anticancer agents. This study aims to assess the combinatorial effects of gene-silencing reversal agents (5-Aza-CdR and FK228) and oxaliplatin in gastric cancer cells, i.e., Epstein-Barr virus (EBV)-negative SNU-638 and EBV-positive SNU-719 cells. The doublet combinatorial treatment of 5-Aza-CdR and FK228 exhibited synergistic effects in both cell lines, and this was further corroborated by Zta expression induction in SNU-719 cells. Three drug combinations as 5-Aza-CdR/FK228 followed by oxaliplatin, however, resulted in antagonistic effects in both cell lines. Simultaneous treatment with FK228 and oxaliplatin induced synergistic and additive effects in SNU-638 and SNU-719 cells, respectively. Three drug combinations as 5-Aza-CdR prior to FK228/oxaliplatin, however, again resulted in antagonistic effects in both cell lines. This work demonstrated that efficacy of doublet synergistic combination using DNMT or HDACs inhibitors can be compromised by adding the third drug in pre- or post-treatment approach in gastric cancer cells. This implies that the development of clinical trial protocols for triplet combinations using gene-silencing reversal agents should be carefully evaluated in light of their potential antagonistic effects.
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Affiliation(s)
- Jong Kook Park
- Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chuncheon 24252, Republic of Korea
| | - Jung Seon Seo
- Department of Biomedicine & Health Science, Graduate School, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Suk Kyeong Lee
- Department of Biomedicine & Health Science, Graduate School, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Kenneth K Chan
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA
| | - Hyo-Jeong Kuh
- Department of Biomedicine & Health Science, Graduate School, The Catholic University of Korea, Seoul 06591, Republic of Korea.,Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.,Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
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Zhong M, Zhang Y, Yuan F, Peng Y, Wu J, Yuan J, Zhu W, Zhang Y. High FNDC1 expression correlates with poor prognosis in gastric cancer. Exp Ther Med 2018; 16:3847-3854. [PMID: 30402143 DOI: 10.3892/etm.2018.6731] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 08/02/2018] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer is a common human cancer worldwide. Fibronectin is an important extracellular matrix protein that has been implicated in many cancers and is known to be associated with proliferation and migration. Fibronectin type III domain containing 1 (FNDC1) contains a major component of the structural domain of fibronectin. The objectives of the present study were to measure FNDC1 expression in gastric cancer tissues and evaluate its value as a potential prognostic marker for gastric cancer. FNDC1 protein expression was analyzed by immunohistochemistry in 98 samples of gastric cancer tissue and 25 adjacent normal tissues. The associations between FNDC1 level and various clinicopathological characteristics were assessed, and the correlation between FNDC1 expression levels and prognosis of patients with gastric cancer was analyzed using a Kaplan-Meier analysis. It was demonstrated that FNDC1 expression in gastric cancer tissues and adjacent tissues was significantly different. FNDC1 expression levels were significantly higher in gastric cancer tissues compared with normal gastric tissues (P<0.001). Among the clinicopathological characteristics evaluated, clinical stage (P<0.001), T classification (P<0.001), N classification (P<0.001) and pathological differentiation (P=0.044) were significantly associated with high FNDC1 expression. Higher FNDC1 expression level was significantly correlated with poorer survival. The present findings suggest that FNDC1 expression levels may be a promising prognostic biomarker for gastric cancer.
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Affiliation(s)
- Muxiao Zhong
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yijie Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Fangfang Yuan
- Department of Intensive Care Unit, General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China
| | - Yao Peng
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
| | - Jingjing Wu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Jiawei Yuan
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Wei Zhu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yali Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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41
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Liu L, Bai Y, Gu H, Zhu H, Yu Y, Lu P, Wang Y, Zhang H, Li M. The prognostic efficacy of the 8th edition UICC TNM classifications for gastric cancer in Chinese patients: A study based on follow-up system of nursing department. Medicine (Baltimore) 2018; 97:e12284. [PMID: 30200173 PMCID: PMC6133638 DOI: 10.1097/md.0000000000012284] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
This study aimed to analyze the applicability of the Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) classification 8th edition for Chinese patients with gastric cancer.A review of all inpatient and outpatient records of patients with gastric cancer was conducted in the First Affiliated Hospital of China Medical University and Liaoning Cancer Hospital and Institute. All patients who met the inclusion criteria and were seen from January 1980 through December 2009 were included in the study. The primary outcome was 5-year survival, which was analyzed according to the decade of diagnosis and TNM classifications.Two thousand five hundred fifty-four patients were enrolled in this study. When classified according to the UICC TNM classification of gastric cancer 8th edition, the prognoses of patients with stage IIIB (n = 250) and stage IIIC (n = 101) disease were not significantly different (P = .332). However, if T4aN2 patients were classified as having stage IIIB disease, and T4bN2 and T4aN3a patients were classified as having stage IIIC disease, the prognoses of stage IIIB (n = 221) and stage IIIC (n = 172) patients were significantly different (P = .03).Classifying T4bN0 patients as having stage IIIB disease, and T4bN2 and T4aN3a patients as having stage IIIC disease according to the 8th edition of UICC gastric cancer TNM classifications better stratified Chinese patients and predicted prognoses.
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Affiliation(s)
| | - Yu Bai
- Department of Thoracic Surgery
| | - Huizi Gu
- Department of Internal Neurology, the Second Hospital of Dalian Medical University, Dalian
| | - Haitao Zhu
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute
| | - Ying Yu
- Liaoning Medical Device Test Institute
| | - Ping Lu
- Department of Surgical Oncology, the First Hospital of China Medical University, Shenyang
| | | | | | - Min Li
- Department of Nursing, the Second Hospital of Dalian Medical University, Dalian, China
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Yuan G, Quan J, Dong D, Wang Q. Long Noncoding RNA CAT104 Promotes Cell Viability, Migration, and Invasion in Gastric Carcinoma Cells Through Activation of MicroRNA-381-Inhibiting Zinc Finger E-box-Binding Homeobox 1 (ZEB1) Expression. Oncol Res 2018; 26:1037-1046. [PMID: 29295724 PMCID: PMC7844839 DOI: 10.3727/096504017x15144748428127] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Gastric carcinoma (GC) remains the second leading cause of cancer-related deaths worldwide. Good biomarkers are of paramount importance for GC therapy. This study aimed to assess the role of long noncoding RNA (lncRNA) CAT104 in GC. We found that CAT104 was highly expressed in human GC NCI-N87, SGC7901, BGC823, BGC803, and AGS cells. Suppression of CAT104 decreased NCI-N87 cell viability, migration, and invasion, but promoted apoptosis. CAT104 knockdown enhanced the expression of microRNA-381 (miR-381) expression in NCI-N87 cells. miR-381 participated in the regulatory effects of CAT104 on NCI-N87 cell viability, migration, invasion, and apoptosis. Zinc finger E-box-binding homeobox 1 (ZEB1) was identified as a direct target of miR-381. Overexpression of ZEB1 reversed the miR-381 mimic-induced cell viability, migration, and invasion inhibition. Suppression of ZEB1 reversed the miR-381 inhibitor-induced activation of the c-Jun N-terminal kinase (JNK) pathway and Wnt/β-catenin signaling pathways in NCI-N87 cells. In conclusion, CAT104 might function as an oncogenic factor in GC cells via regulating the expression of miR-381 and ZEB1.
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Affiliation(s)
- Gang Yuan
- Department of Gastroenterology, 401 Hospital of People’s Liberation Army, Qingdao, P.R. China
| | - Jingzi Quan
- Department of Gastroenterology, 401 Hospital of People’s Liberation Army, Qingdao, P.R. China
| | - Dongfang Dong
- Department of Gastroenterology, 401 Hospital of People’s Liberation Army, Qingdao, P.R. China
| | - Qunying Wang
- Department of Gastroenterology, 401 Hospital of People’s Liberation Army, Qingdao, P.R. China
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Li P, Guo YJ, Tang Q, Yang L. Effectiveness of nursing intervention for increasing hope in patients with cancer: a meta-analysis. Rev Lat Am Enfermagem 2018; 26:e2937. [PMID: 30110091 PMCID: PMC6091366 DOI: 10.1590/1518-8345.1920.2937] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Accepted: 07/04/2017] [Indexed: 12/26/2022] Open
Abstract
Objective: to evaluate the efficacy of nursing interventions to increase the level of
hope in cancer patients, in a meta-analysis. Methods: electronic databases were searched. Two of the authors independently
extracted data from the eligible studies, and Stata 13.0 software was used
to pool the data. Results: nine randomized controlled trials were included, and methodological quality
of each randomized controlled trial (RCT) was evaluated using Cochrane
handbook recommendations. A random effects model was used to combine results
from eligible studies. The pooled results using the fixed effects model
showed that scores to first effects increase significantly after the use of
nursing intervention between the groups. Heterogeneity was observed among
the studies for posttest (df = 8, P = 0.000; I2 =76.1 %). The
results indicated significant heterogeneity across the nine selected
studies. The test for heterogeneity showed no homogeneity among studies for
follow-up (df = 8, P = 0.328; I2 = 12.9 %), and there was no
statistical significance. Conclusion: the current evidence suggests that nursing intervention has a positive effect
on hope in cancer patients. However, more large-scale and high-quality
randomized controlled trials are needed to confirm these results.
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Affiliation(s)
- Ping Li
- MSc, Researcher, School of Nursing, Nantong University, Nantong, Jiangsu, China
| | - Yu-Jie Guo
- PhD, Assistant Professor, School of Nursing, Nantong University, Nantong, Jiangsu, China
| | - Qing Tang
- MSc, Researcher, School of Nursing, Nantong University, Nantong, Jiangsu, China
| | - Lei Yang
- MSc, Researcher, School of Nursing, Nantong University, Nantong, Jiangsu, China
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Wang Z, Li M, Xu Z, Jiang Y, Gu H, Yu Y, Zhu H, Zhang H, Lu P, Xin J, Xu H, Liu C. Improvements to the gastric cancer tumor-node-metastasis staging system based on computer-aided unsupervised clustering. BMC Cancer 2018; 18:706. [PMID: 29970022 PMCID: PMC6029135 DOI: 10.1186/s12885-018-4623-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 06/20/2018] [Indexed: 12/26/2022] Open
Abstract
Background The Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) classification is a key gastric cancer prognosis system. This study aimed to create a new TNM system to provide a reference for the clinical diagnosis and treatment of gastric cancer. Methods A review of gastric cancer patients’ records was conducted in The First Hospital of China Medical University and the Liaoning Cancer Hospital and Institute. Based on patients’ prognoses data, computer-aided unsupervised clustering was performed for all possible TNM staging situations to create a new staging division system. Results The primary outcome measure was 5-year survival, analyzed according to TNM classifications. Computer-aided unsupervised clustering for all TNM staging situations was used to create TNM division criteria that were more consistent with clinical situations. Furthermore, unsupervised clustering for the number of lymph node metastasis in the N stage led to the formulation of a classification method that differs from the existing N stage criteria, and unsupervised clustering for tumor size provided an additional reference for prognosis estimates. Conclusions Finally, we developed a TNM staging system based on the computer-aided unsupervised clustering method; this system was more in line with clinical prognosis data when compared with the 7th edition of UICC gastric cancer TNM classification.
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Affiliation(s)
- Zhiqiong Wang
- Sino-Dutch Biomedical and Information Engineering School, Northeastern University, Shenyang, 110169, China
| | - Mo Li
- Sino-Dutch Biomedical and Information Engineering School, Northeastern University, Shenyang, 110169, China
| | - Zhen Xu
- Department of General, Visceral and Transplantation Surgery, Section Surgical Research, University Clinic Heidelberg, Im Neuenheimer Feld 365, 69120, Heidelberg, Germany
| | - Yanlin Jiang
- Department of Breast and Thyroid Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, China
| | - Huizi Gu
- Department of Internal Neurology, the Second Hospital of Dalian Medical University, Dalian, 116027, China
| | - Ying Yu
- Liaoning Medical Device Test Institute, Shenyang, 110179, China
| | - Haitao Zhu
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, 110042, China
| | - Hao Zhang
- Department of Breast Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, No. 44, Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning Province, China.
| | - Ping Lu
- Department of Surgical Oncology, the first hospital of China Medical University, Shenyang, 110001, China
| | - Junchang Xin
- School of Computer Science and Engineering, Northeastern University, Shenyang, 110189, China.
| | - Hong Xu
- Department of Breast Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, No. 44, Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning Province, China.
| | - Caigang Liu
- Department of Breast Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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Zhang Y, Lu JJ, Du YP, Feng CX, Wang LQ, Chen MB. Prognostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in gastric cancer. Medicine (Baltimore) 2018; 97:e0144. [PMID: 29561419 PMCID: PMC5895303 DOI: 10.1097/md.0000000000010144] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been presented to be a prognostic indicator in several types of cancer. However, these issues have not been concluded yet. The present study was therefore performed to determine the prognostic value of NLR and PLR in gastric cancer (GC).A total of 182 GC patients, diagnosed between January 2011 and January 2014, were enrolled in the study. The clinicopathological parameters, laboratory analyses, and outcomes were collected. The association between NLR, PLR, and clinicopathological characters was analyzed with univariate and multivariate analyses.NLR was significantly related to age (P = .026), surgery (P = .006), node status (P = .004), and clinical stage (P = .009). The median overall survival (OS) and progression-free survival (PFS) were poor in the High-NLR group (OS: 36.0 vs 20.5 months, P < .001, PFS: 33.0 vs 12.0 months, P < .001) and High-PLR group (OS: 31.5 vs 18.5 months, P = .003, PFS: 26.0 vs 11.0 months, P = .01). Multivariate analyses indicated both surgery [for OS hazard ratio (HR) = 2.092, 95% confidence interval (95% CI): 1.345-3.253, P = .001; for PFS HR = 1.939, 95% CI: 1.259-2.988, P = .003] and NLR (for OS HR = 1.585, 95% CI: 1.011-2.485, P = .045) were independent prognostic factors.Elevated NLR and PLR were related with poor prognosis in GC patients before treatment. The NLR was an independent prognostic factor for OS. More studies should be conducted to address the potential prognostic value of NLR and PLR in GC.
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Fiorica F, Trovò M, Ottaiano A, Nasti G, Carandina I, Marzola M, De Paoli P, Berretta M. Can the addition of radiotherapy postoperatively increase clinical outcome of patients with gastric cancer? A systematic review of the literature and meta-analysis. Oncotarget 2018; 9. [PMID: 29535839 PMCID: PMC5828196 DOI: 10.18632/oncotarget.23754] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Although several studies have been carried out to determine the best treatment for gastric carcinoma, the data on survival rate still remain inconclusive. OBJECTIVE To evaluate the effects of postoperative radio-chemotherapy on overall and disease-free survival. DATA SOURCES MEDLINE and CANCERLIT searches of reference lists (for the period 1970 to 2016) were supplemented with hand search of reference lists. STUDY SELECTION The present work includes randomized controlled trials comparing postoperative radio-chemotherapy to postoperative chemotherapy or to surgery alone in patients with resected gastric carcinoma without evidence of metastatic disease. Ten randomized controlled trials were analyzed in total: four compared postoperative radiochemotherapy to surgery alone (708 patients), and six compared postoperative radiochemotherapy to postoperative chemotherapy (1020 patients). DATA EXTRACTION According to "intention to treat" method, three independent observers have extracted from each trial, the data on patients, intervention, and outcomes. These data were subsequently combined using DerSimonian and Laird methods. RESULTS Postoperative radiochemotherapy significantly increases 3-year and 5-year overall survival and 3-year and 5-year disease free survival rate compared to postoperative chemotherapy (RR 0.89; 95%CI 0.81-0.97 and RR 0.82; 95%CI 0.71-0.95) or surgery alone (RR 0.83; 95% CI 0.77-0.91 and RR 0.80; 95% CI 0.65-0.98). CONCLUSIONS In patients with resected gastric cancer, postoperative radiochemotherapy obtains: 1) an increase in overall survival, 2) an increase in disease free survival, and 3) a gain in 5 year disease free survival independent of surgical procedure.
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Affiliation(s)
- Francesco Fiorica
- 1 Department of Radiation Oncology, University Hospital Ferrara, Ferrara, Italy
| | - Marco Trovò
- 2 Radiotherapy Division, “Santa Maria della Misericordia” Hospital Udine, Udine, Italy
| | - Alessandro Ottaiano
- 3 Division of Abdominal Medical Oncology, National Cancer Institute, “Pascale” Naples, Naples, Italy
| | - Guglielmo Nasti
- 3 Division of Abdominal Medical Oncology, National Cancer Institute, “Pascale” Naples, Naples, Italy
| | - Ilaria Carandina
- 4 Department of Medical Oncology, University Hospital Ferrara, Ferrara, Italy
| | - Marina Marzola
- 4 Department of Medical Oncology, University Hospital Ferrara, Ferrara, Italy
| | - Paolo De Paoli
- 5 Scientific Directorate, National Cancer Institute (CRO), Aviano (PN), Italy
| | - Massimiliano Berretta
- 6 Division of Medical Oncology A, National Cancer Institute (CRO), Aviano (PN), Italy
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Human telomerase reverse transcriptase (hTERT) promotes gastric cancer invasion through cooperating with c-Myc to upregulate heparanase expression. Oncotarget 2017; 7:11364-79. [PMID: 26689987 PMCID: PMC4905479 DOI: 10.18632/oncotarget.6575] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2015] [Accepted: 11/25/2015] [Indexed: 02/07/2023] Open
Abstract
Human telomerase reverse transcriptase (hTERT) is a central regulator of multiple hallmarks of tumors. However, the potential roles of hTERT in tumor invasion and metastasis and the underlying molecular mechanisms remain poorly understood. Here, we found that the expression of hTERT in gastric cancer (GC) was significantly associated with an advanced TNM stage, lymphatic metastasis. Survival analysis identified hTERT as an independent prognostic factor for survival of GC patients. hTERT promoted the invasion and metastasis of GC cells by binding to c-Myc and recruiting the complex to heparanase promoter to upregulate heparanase expression. In addition, our data demonstrated that hTERT activated Wnt/β-catenin signaling to promote c-Myc expression which could in turn activate hTERT transcription and expression, suggesting a positive feedback regulation in GC progression. Consistently, c-Myc and heparanase expression was positively correlated with hTERT levels, and was also an independent predictor of metastasis and survival. Collectively, our data provide a novel molecular mechanism for hTERT in promotion of GC invasion and metastasis, and highlight the molecular etiology and clinical significance of hTERT in GC progression. Targeting hTERT may represent a new therapeutic strategy to improve therapy and survival of GC patients.
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Abbas M, Habib M, Naveed M, Karthik K, Dhama K, Shi M, Dingding C. The relevance of gastric cancer biomarkers in prognosis and pre- and post- chemotherapy in clinical practice. Biomed Pharmacother 2017; 95:1082-1090. [DOI: 10.1016/j.biopha.2017.09.032] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Revised: 09/07/2017] [Accepted: 09/08/2017] [Indexed: 02/07/2023] Open
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Abstract
Background: MiR-646 has been reported to be aberrantly expressed in human cancers. However, the underlying molecular mechanisms of action of miR-646 in gastric cancer (GC) have not yet been investigated. Methods: In vitro function of miR-646 in GC was evaluated using EdU assay, plate colony formation assay, and matrigel invasion assay. Real-time PCR or western blotting was performed to detect miR-646 and FOXK1 expressions. In vivo tumour growth and metastasis were conducted in nude mice. Results: MiR-646 expression was downregulated in GC tissues compared with adjacent normal tissues. Low miR-646 expression is associated with malignant progression. Transient transfection of GC cells with miR-646 inhibited their growth and migration. Moreover, miR-646 influenced the expression of epithelial–mesenchymal transition (EMT)-associated proteins. TGF-β1 treatment significantly suppressed the expression of miR-646 and overexpression of this microRNA counteracted the influence of the TGF-β1-induced EMT phenotype. In terms of the underlying mechanism, miR-646 directly targeted FOXK1. In vivo, it inhibited the FOXK1-mediated proliferation and EMT-induced metastasis. Consistently, inverse correlations were also observed between the expression of miR-646 and FOXK1 in human GC tissue samples. Furthermore, miR-646 regulated Akt/mTOR signalling after FOXK1. Conclusions: miR-646 inhibited GC cell proliferation and the EMT progression in GC cells by targeting FOXK1.
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Regorafenib inhibited gastric cancer cells growth and invasion via CXCR4 activated Wnt pathway. PLoS One 2017; 12:e0177335. [PMID: 28489887 PMCID: PMC5425213 DOI: 10.1371/journal.pone.0177335] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 04/26/2017] [Indexed: 02/06/2023] Open
Abstract
AIM Regorafenib is an oral small-molecule multi kinase inhibitor. Recently, several clinical trials have revealed that regorafenib has an anti-tumor activity in gastric cancer. However, only part of patients benefit from regorafenib, and the mechanisms of regorafenib's anti-tumor effect need further demonstrating. In this study, we would assess the potential anti-tumor effects and the underlying mechanisms of regorafenib in gastric cancer cells, and explore novel biomarkers for patients selecting of regorafenib. METHODS The anti-tumor effects of regorafenib on gastric cancer cells were analyzed via cell proliferation and invasion. The underlying mechanisms were demonstrated using molecular biology techniques. RESULTS We found that regorafenib inhibited cell proliferation and invasion at the concentration of 20μmol/L and in a dose dependent manner. The anti-tumor effects of regorafenib related to the decreased expression of CXCR4, and elevated expression and activation of CXCR4 could reverse the inhibition effect of regorafenib on gastric cancer cells. Further studies revealed that regorafenib reduced the transcriptional activity of Wnt/β-Catenin pathway and led to decreased expression of Wnt pathway target genes, while overexpression and activation of CXCR4 could attenuate the inhibition effect of regorafenib on Wnt/β-Catenin pathway. CONCLUSIONS Our findings demonstrated that regorafenib effectively inhibited cell proliferation and invasion of gastric cancer cells via decreasing the expression of CXCR4 and further reducing the transcriptional activity of Wnt/β-Catenin pathway.
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