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Cheng CY, Chen YL, Ho H, Huang CY, Chu SE, Liang YJ. Prognostic Significance of DNAJB4 Expression in Gastric Cancer: Correlation with CD31, Caspase-3, and Tumor Progression. Diagnostics (Basel) 2025; 15:652. [PMID: 40149995 PMCID: PMC11941126 DOI: 10.3390/diagnostics15060652] [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: 10/10/2024] [Revised: 02/28/2025] [Accepted: 03/03/2025] [Indexed: 03/29/2025] Open
Abstract
Background/Objectives: Gastric cancer is one of the most common and lethal cancers worldwide, with particularly high incidence and mortality rates in East Asia and Europe. DNAJB4 has been shown to have prognostic implications in other cancer types; however, its expression patterns and role in gastric cancer have not been extensively studied. This study aimed to analyze DNAJB4 expression in gastric cancer and explore its association with clinical characteristics, molecular markers, and patient outcomes. Methods: We selected suitable tumor samples from 189 gastric cancer patients who had not undergone chemotherapy or radiotherapy, with 188 patients ultimately included in the analysis. Tissue microarray and immunohistochemistry were used to evaluate DNAJB4 expression, and the samples were divided into high- and low-expression groups based on the H-score. Multivariate logistic regression and survival analysis were conducted to identify influencing factors. Results: High DNAJB4 expression was significantly correlated with increased CD31 levels but was inversely associated with advanced cancer stages. Subgroup analysis revealed that in patients with advanced gastric cancer, high DNAJB4 expression was associated with increased caspase-3 levels and with elevated CD31 and decreased E-cadherin levels. Conclusions: High DNAJB4 expression was associated with both angiogenesis and apoptosis, indicating its complex role in gastric cancer progression. Although DNAJB4 promoted angiogenesis by increasing CD31 levels, it may also enhance apoptosis in tumor cells through caspase-3-induced apoptosis.
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Affiliation(s)
- Chiao-Yin Cheng
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei 242062, Taiwan; (C.-Y.C.); (C.-Y.H.)
- Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan; (H.H.); (S.-E.C.)
| | - Yen-Lin Chen
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114201, Taiwan;
| | - Hua Ho
- Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan; (H.H.); (S.-E.C.)
| | - Chun-Yen Huang
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei 242062, Taiwan; (C.-Y.C.); (C.-Y.H.)
- Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan; (H.H.); (S.-E.C.)
| | - Sheng-En Chu
- Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan; (H.H.); (S.-E.C.)
- Department of Emergency Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliu City 640203, Taiwan
| | - Yao-Jen Liang
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei 242062, Taiwan; (C.-Y.C.); (C.-Y.H.)
- Department and Institute of Life Science, Fu-Jen Catholic University, New Taipei 242062, Taiwan
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2
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Manoharan R. Salt-inducible kinases (SIKs) in cancer: mechanisms of action and therapeutic prospects. Drug Discov Today 2025; 30:104279. [PMID: 39710233 DOI: 10.1016/j.drudis.2024.104279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 12/24/2024]
Abstract
Salt-inducible kinases (SIKs), a group of serine/threonine kinases in the adenosine monophosphate-activated protein kinase (AMPK) family, exist in three isoforms: SIK1, SIK2 and SIK3. These kinases are crucial in various physiological processes. Emerging evidence indicates that dysregulation of SIK expression and activation significantly contributes to carcinogenesis by promoting cellular proliferation, metabolic dysregulation, metastasis and chemoresistance through the modulation of crucial signaling pathways. The role of SIKs in cancer progression and metastasis involves complex mechanisms that vary among cancer types. Additionally, research on SIK inhibitors suggests that targeting these kinases might offer promising avenues for improving cancer treatment outcomes.
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Affiliation(s)
- Ravi Manoharan
- Cell Signaling and Cancer Biology Laboratory, Department of Biochemistry, Guindy Campus, University of Madras, Chennai 600025, India.
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3
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Kuang W, Xu J, Xu F, Huang W, Majid M, Shi H, Yuan X, Ruan Y, Hu X. Current study of pathogenetic mechanisms and therapeutics of chronic atrophic gastritis: a comprehensive review. Front Cell Dev Biol 2024; 12:1513426. [PMID: 39720008 PMCID: PMC11666564 DOI: 10.3389/fcell.2024.1513426] [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: 10/18/2024] [Accepted: 11/25/2024] [Indexed: 12/26/2024] Open
Abstract
Chronic atrophic gastritis (CAG) is a prevalent digestive system disease characterized by atrophy of the gastric mucosa and the disappearance of inherent gastric glands. According to the theory of Correa's cascade, CAG is an important pathological stage in the transformation from normal condition to gastric carcinoma. In recent years, the global incidence of CAG has been increasing due to pathogenic factors, including Helicobacter pylori infection, bile reflux, and the consumption of processed meats. In this review, we comprehensively described the etiology and clinical diagnosis of CAG. We focused on elucidating the regulatory mechanisms and promising therapeutic targets in CAG, with the expectation of providing insights and theoretical support for future research on CAG.
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Affiliation(s)
- Weihong Kuang
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Jialin Xu
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
| | - Fenting Xu
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
| | - Weizhen Huang
- Cancer Center, The First Huizhou Affiliated Hospital, Guangdong Medical University, Huizhou, China
| | - Muhammad Majid
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
| | - Hui Shi
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
| | - Xia Yuan
- Cancer Center, The First Huizhou Affiliated Hospital, Guangdong Medical University, Huizhou, China
| | - Yongdui Ruan
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
- Cancer Center, The First Huizhou Affiliated Hospital, Guangdong Medical University, Huizhou, China
| | - Xianjing Hu
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Department of Acupuncture, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
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4
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Akhtar A, Hameed Y, Ejaz S, Abdullah I. Identification of gastric cancer biomarkers through in-silico analysis of microarray based datasets. Biochem Biophys Rep 2024; 40:101880. [PMID: 39655267 PMCID: PMC11626535 DOI: 10.1016/j.bbrep.2024.101880] [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: 08/31/2024] [Revised: 11/02/2024] [Accepted: 11/18/2024] [Indexed: 12/12/2024] Open
Abstract
Gastric cancer is among the most prevalent cancers worldwide including in Pakistan. Late diagnosis of gastric cancer leads to reduced survival. The present study aimed to investigate biomarkers for early diagnosis and prognosis of gastric cancer. For this purpose, the ten microarray-based gene expression datasets (GSE54129, GSE79973, GSE161533, GSE103236, GSE33651, GSE19826, GSE118916, GSE112369, GSE13911, and GSE81948) were retrieved from GEO database and analyzed by GEO2R to identify differentially expressed genes. Datasets were arranged in subsets of different dataset combinations to identify common DEGs. The gene ontology and functional pathway enrichment analysis of common DEGs was performed by DAVID tool. Pan-cancer analysis was conducted by UALCAN database. Survival analysis of common DEGs was done by Kaplan-Meier plotter. A total of 71 common DEGs were identified in different combinations of datasets. Among them, only 5 DEGs namely ATP4B, ATP4A, CCKBR, KCNJ15, and KCNJ16 were detected to be common in all the datasets. The GO and pathway analysis represented that the identified DEGs are involved in gastric acid secretion and collecting duct acid secretion pathways. Further expression validation of these five genes using three additional datasets (GSE31811, GSE26899, and GSE26272) confirmed their differential expression in gastric cancer samples. The pan-cancer analysis also revealed aberrant expression of DEGs in various cancers. The survival analysis showed the association of these 5 DEGs with poor survival of gastric cancer patients. To conclude, this study revealed a panel of 5 genes, which can be employed as diagnostic and prognostic biomarkers of gastric cancer patients.
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Affiliation(s)
- Arbaz Akhtar
- Department of Biochemistry & Molecular Biology, Institute of Biochemistry, Biotechnology and Bioinformatics (IBBB), The Islamia University of Bahawalpur, Bahawalpur, (63100), Pakistan
| | - Yasir Hameed
- Department of Biotechnology & Molecular Biology, Institute of Biochemistry, Biotechnology and Bioinformatics (IBBB), The Islamia University of Bahawalpur, Bahawalpur, (63100), Pakistan
| | - Samina Ejaz
- Department of Biochemistry & Molecular Biology, Institute of Biochemistry, Biotechnology and Bioinformatics (IBBB), The Islamia University of Bahawalpur, Bahawalpur, (63100), Pakistan
| | - Iqra Abdullah
- Department of Biochemistry & Molecular Biology, Institute of Biochemistry, Biotechnology and Bioinformatics (IBBB), The Islamia University of Bahawalpur, Bahawalpur, (63100), Pakistan
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Kurimoto M, Honjo H, Yoshida S, Okai N, Otsuka Y, Masuta Y, Masaki S, Kamata K, Minaga K, Maenishi O, Kudo M, Watanabe T. Enlargement of Gastric Hyperplastic Polyps Arising from Helicobacter heilmannii sensu strico-infected Mucosa after the Successful Eradication of Helicobacter pylori and the Long-Term Use of a Proton Pump Inhibitor. Intern Med 2024:4230-24. [PMID: 39523000 DOI: 10.2169/internalmedicine.4230-24] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2024] Open
Abstract
Helicobacter pylori eradication is effective for the regression of gastric hyperplastic polyps (GHPs). We report a case which demonstrated an enlargement of GHPs after H. pylori eradication. The patient, who received long-term proton-pump inhibitor (PPI) therapy, lived with a dog, a natural host of Helicobacter heilmanii sensu stricto. Gastric colonization with Helicobacter heilmannii s.s. was observed after H. pylori eradication, thus suggesting the involvement of non-H. pylori Helicobacter species (NHPHs) infection for the enlargement of GHPs, in addition to the proliferative effects of PPI use on the gastric epithelium. Screening for NHPHs may be necessary in dog lovers to avoid paradoxical responses to H. pylori eradication.
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Affiliation(s)
- Masayuki Kurimoto
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan
| | - Hajime Honjo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan
| | - Saki Yoshida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan
| | - Natsuki Okai
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan
| | - Yasuo Otsuka
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan
| | - Yasuhiro Masuta
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan
| | - Sho Masaki
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan
| | - Ken Kamata
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan
| | - Osamu Maenishi
- Department of Pathology, Kindai University Faculty of Medicine, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan
| | - Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan
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Meguro S, Kawasaki H, Kosugi I, Enomoto Y, Osawa S, Sugimoto K, Baba S, Iwashita T. A Case of Brunner's Gland Hyperplasia Accompanied by an Increase in Endocrine Cells and Endocrine Cell Micronests. Cureus 2024; 16:e68688. [PMID: 39246633 PMCID: PMC11378870 DOI: 10.7759/cureus.68688] [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] [Accepted: 09/03/2024] [Indexed: 09/10/2024] Open
Abstract
Endocrine cell micronests (ECMs) are aggregates of endocrine cells known as enterochromaffin-like cells, typically measuring approximately 50 μm and usually observed in the mucosal layer of atrophic gastric fundic glands associated with hypergastrinemia. Although there are numerous reports on gastric ECMs, reports on duodenal ECMs are exceedingly rare. We report a rare case of Brunner's gland hyperplasia with increased endocrine cells and ECMs. An approximately 40 mm polyp was found in the duodenal bulb of a 57-year-old Japanese male patient during an upper gastrointestinal endoscopy, and a polypectomy was performed. Microscopic examination revealed hyperplasia of Brunner's glands in the duodenal polyp. Compared to normal Brunner's glands, hyperplastic Brunner's glands exhibited more endocrine cells. Additionally, many ECMs were observed in the fibromuscular connective tissue, comprising smooth muscle cells and myofibroblasts, adjacent to the hyperplastic Brunner's glands. The patient presented with hypergastrinemia (2,500 pg/mL; normal range: 30-140 pg/mL), and the ECMs were considered related to this condition. This case represents the first instance of a benign duodenal lesion with an increase in endocrine cells and the presence of ECMs.
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Affiliation(s)
- Shiori Meguro
- Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine, Hamamatsu, JPN
| | - Hideya Kawasaki
- Department of Preeminent Bioimaging Research, Hamamatsu University School of Medicine, Hamamatsu, JPN
| | - Isao Kosugi
- Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine, Hamamatsu, JPN
| | - Yasunori Enomoto
- Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine, Hamamatsu, JPN
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University Hospital, Hamamatsu, JPN
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, JPN
| | - Satoshi Baba
- Department of Diagnostic Pathology, Hamamatsu University Hospital, Hamamatsu, JPN
| | - Toshihide Iwashita
- Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine, Hamamatsu, JPN
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Isakov V. Autoimmune gastritis studies and gastric cancer: True renaissance or bibliometric illusion. World J Gastroenterol 2024; 30:3783-3790. [PMID: 39221066 PMCID: PMC11362875 DOI: 10.3748/wjg.v30.i32.3783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 08/08/2024] [Accepted: 08/13/2024] [Indexed: 08/26/2024] Open
Abstract
A bibliometric analysis of studies dedicated to autoimmune gastritis (AIG) recently published demonstrated a noteworthy surge in publications over the last three years. This can be explained by numerous publications from different regions of the world reporting the results of several studies that stimulated reassessment of our view of AIG as a precancerous condition. Follow-up studies and retrospective analyses showed that the risk of gastric cancer (GC) in AIG patients is much lower than expected if the patients ever being infected with Helicobacter pylori (H. pylori) were excluded. The low prevalence of precancerous lesions, such as the incomplete type of intestinal metaplasia, may explain the low risk of GC in AIG patients because the spasmolytic polypeptide-expressing metaplasia commonly observed in AIG does not involve clonal reprogramming of the gastric gland and can be considered as an adaptive change rather than a true precancerous lesion. However, changes in gastric secretion due to the progression of gastric atrophy during the course of AIG cause changes in the gastric mic-robiome, stimulating the growth of bacterial species such as streptococci, which may promote the development of precancerous lesions and GC. Thus, Streptococcus anginosus exhibited a robust proinflammatory response and induced the gastritis-atrophy-metaplasia-dysplasia sequence in mice, reproducing the well-established process for carcinogenesis associated with H. pylori. Prospective studies in H. pylori-naïve patients evaluating gastric microbiome changes during the long-term course of AIG might provide an explanation for the enigmatic increase in GC incidence in the last decades in younger cohorts, which has been reported in economically developed countries.
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Affiliation(s)
- Vasily Isakov
- Department of Gastroenterology and Hepatology, Federal Research Center of Nutrition, Biotechnology and Food Safety, Moscow 115446, Russia
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8
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Lei C, Xu Y, Zhang S, Huang C, Qin J. The role of microbiota in gastric cancer: A comprehensive review. Helicobacter 2024; 29:e13071. [PMID: 38643366 DOI: 10.1111/hel.13071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 02/19/2024] [Accepted: 03/25/2024] [Indexed: 04/22/2024]
Abstract
BACKGROUND Gastric cancer (GC) continues to pose a significant global threat in terms of cancer-related fatalities. Despite notable advancements in medical research and therapies, further investigation is warranted to elucidate its underlying etiology and risk factors. Recent times have witnessed an escalated emphasis on comprehending the role of the microbiota in cancer development. METHODS This review briefly delves into recent developments in microbiome-related research pertaining to gastric cancer. RESULTS According to studies, the microbiota can influence GC growth by inciting inflammation, disrupting immunological processes, and generating harmful microbial metabolites. Furthermore, there is ongoing research into how the microbiome can impact a patient's response to chemotherapy and immunotherapy. CONCLUSION The utilization of the microbiome for detecting, preventing, and managing stomach cancer remains an active area of exploration.
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Affiliation(s)
- Changzhen Lei
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yitian Xu
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shaopeng Zhang
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chen Huang
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Qin
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Peng Z, Wang R, Wu N, Gao H, Gao H, Li D. Assessment of the risk factors of duodenogastric reflux in relation to different dietary habits in a Chinese population of the Zhangjiakou area. Food Nutr Res 2023; 67:9385. [PMID: 37920676 PMCID: PMC10619390 DOI: 10.29219/fnr.v67.9385] [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: 02/05/2023] [Revised: 05/21/2023] [Accepted: 06/26/2023] [Indexed: 11/04/2023] Open
Abstract
Objective To explore the risk factors of duodenogastric reflux (DGR) in relation to different dietary habits. Methods A total of 106 patients with symptoms of DGR who underwent electronic gastroscopy from June 2019 to June 2020 were selected and divided into the DGR group (n = 33) and the non-DGR group (n = 73) according to the diagnosis of bile reflux. Questionnaires were used to collect the basic information and dietary habits of the patients, including age, gender, body mass index, place of residence, comorbidities, dietary composition, salt intake, smoking and drinking consumption. The total bile acid (TBA) and cholesterol (CHO) of the gastric juice were measured using a fully automated biochemical analyser, with an enzyme-linked immunosorbent assay used for the serum cholecystokinin, gastrin and gastrin levels. Univariate analysis and multivariate logistic regression analysis were used to predict the attendant DGR risk factors. Results There was no significant difference in age or gender between the DGR and the non-DGR groups (P > 0.05). The proportion of patients living in the Bashang region was significantly higher in the DGR group (78.79%) than in the non-DGR group (38.36%) (P < 0.05). The levels of TBA and CHO in the gastric juice and the cholecystokinin and gastrin levels in the serum of the DGR group were higher than those in the non-DGR group, while the serum motilin levels were significantly lower in the DGR group than in the non-DGR group (P < 0.05). The univariate analysis indicated that the proportion of patients with daily consumption of dairy products and fried foods, a high salt intake and smoking and drinking consumption were significantly higher in the DGR than in the non-DGR group (P < 0.05). Conclusion The daily consumption of dairy products and a preference for fried food are independent risk factors for the occurrence of DGR (odds ratio ≥ 1, P < 0.05).
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Affiliation(s)
- Zhao Peng
- Department of Gastroenterology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China
| | - Rui Wang
- Department of Gastroenterology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China
| | - Na Wu
- Department of Gastroenterology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China
| | - Huiru Gao
- Department of Gastroenterology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China
| | - Huibin Gao
- Department of Gastroenterology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China
| | - Duo Li
- Department of Gastroenterology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China
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10
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Gašenko E, Bogdanova I, Sjomina O, Aleksandraviča I, Kiršners A, Ancāns G, Rudzīte D, Vangravs R, Sīviņš A, Škapars R, Tzivian L, Polaka I, Folkmanis V, Leja M. Assessing the utility of pepsinogens and gastrin-17 in gastric cancer detection. Eur J Cancer Prev 2023; 32:478-484. [PMID: 36912185 DOI: 10.1097/cej.0000000000000791] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
Abstract
OBJECTIVES The aim of the study was to determine the proportion of gastric cancer patients with decreased levels of pepsinogen and gastrin-17 in plasma, with the goal of providing indirect evidence of the sensitivity of these biomarkers when applied in a cancer screening setting. METHODS The levels of pepsinogens I and II, gastrin-17, and Helicobacter pylori immunoglobulin antibodies in plasma samples of gastric cancer patients were evaluated using the GastroPanel test system (Biohit Oyj, Helsinki, Finland). A decreased level of the pepsinogen I/II ratio was defined as less than three, while a decrease in gastrin-17 was defined as less than 1 pmol/L. Univariate analysis using non-parametric tests was used to investigate differences between normal and low concentrations of biomarkers. RESULTS In total, 481 plasma samples from patients (59.9% male) with a median age of 64 years (ranging from 27 to 88 years) were analyzed. Out of the 400 cases of gastric cancer (83.2% of the total), 182 were categorized as the intestinal type, 141 as the diffuse type, 60 as the mixed type, and 17 as indeterminate according to the Lauren classification system. The H. pylori immunoglobulin test was positive in 74.0% of the patients. Pepsinogen I/II ratio was decreased in 32.4% (36.8% of the intestinal type); gastrin-17 in 12.3% (10.1% of the antral region) of all cases. CONCLUSION The majority of gastric cancer patients had normal levels of pepsinogen and gastrin-17, suggesting that these biomarkers have limited application as screening tools in the Caucasian population.
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Affiliation(s)
| | | | - Olga Sjomina
- Department of Internal Medicine, Riga East University Hospital
| | - Ilona Aleksandraviča
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Arnis Kiršners
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Guntis Ancāns
- Department of Surgery, Jēkabpils Regional Hospital, Jēkabpils
| | | | - Reinis Vangravs
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Armands Sīviņš
- Department of Abdominal and Soft Tissue Surgery, Clinic of Oncological Surgery
| | - Roberts Škapars
- Department of Abdominal and Soft Tissue Surgery, Clinic of Oncological Surgery
| | - Lilian Tzivian
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Inese Polaka
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Valdis Folkmanis
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Mārcis Leja
- Department of Research, Riga East University Hospital, Riga, Latvia
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11
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Haruma K, Kinoshita Y, Yao T, Kushima R, Akiyama J, Aoyama N, Kanoo T, Miyata K, Kusumoto N, Uemura N. Randomised clinical trial: 3-year interim analysis results of the VISION trial to evaluate the long-term safety of vonoprazan as maintenance treatment in patients with erosive oesophagitis. BMC Gastroenterol 2023; 23:139. [PMID: 37127558 PMCID: PMC10152792 DOI: 10.1186/s12876-023-02772-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 04/18/2023] [Indexed: 05/03/2023] Open
Abstract
BACKGROUND VISION is a randomised, phase 4, open-label, parallel-group, multicentre study conducted in 33 centres in Japan. The aim of this study was to assess the long-term safety of vonoprazan for maintenance treatment of healed erosive oesophagitis versus lansoprazole. METHODS Patients with endoscopically diagnosed erosive oesophagitis were randomised 2:1 to once-daily vonoprazan 20 mg or lansoprazole 30 mg, for a 4- to 8-week healing phase. Patients with endoscopically confirmed healing entered a 260-week maintenance phase with a once-daily starting dose of vonoprazan 10 mg or lansoprazole 15 mg. Primary endpoint was change in gastric mucosal histopathology. RESULTS Of 208 patients (vonoprazan, n = 139; lansoprazole, n = 69) entering the healing phase, 202 entered the maintenance phase (vonoprazan, n = 135; lansoprazole, n = 67). At 3 years, 109 vonoprazan-treated and 58 lansoprazole-treated patients remained on treatment. Histopathological evaluation of gastric mucosa showed that hyperplasia of parietal, foveolar and G cells was more common with vonoprazan than lansoprazole at week 156 of the maintenance phase. There was no marked increase in the occurrence of parietal, foveolar and G cell hyperplasia among patients in the vonoprazan group from week 48 to week 156. Histopathological evaluation of the gastric mucosa also showed no neoplastic changes in either group. No new safety issues were identified. CONCLUSIONS In this interim analysis of VISION, no new safety concerns were identified in Japanese patients with healed erosive oesophagitis receiving vonoprazan or lansoprazole as maintenance treatment for 3 years. (CT.gov identifier: NCT02679508; JapicCTI-163153; Japan Registry of Clinical Trials: jRCTs031180040).
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Affiliation(s)
- Ken Haruma
- Department of General Internal Medicine 2, Kawasaki Medical School, General Medical Center, Okayama, Japan
| | - Yoshikazu Kinoshita
- General Internal Medicine, Hyogo Prefectural Harima-Himeji General Medical Center, Himeji, Hyogo, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ryoji Kushima
- Department of Clinical Laboratory Medicine, Shiga University of Medical Science Hospital, Otsu, Shiga, Japan
| | - Junichi Akiyama
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Nobuo Aoyama
- GI Endoscopy and IBD Center, Aoyama Medical Clinic, Kobe, Hyogo, Japan
| | | | | | | | - Naomi Uemura
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Kohnodai Hospital, Ichikawa, Chiba, Japan
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12
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Bhattacharya A. Epigenetic modifications and regulations in gastrointestinal diseases. EPIGENETICS IN ORGAN SPECIFIC DISORDERS 2023:497-543. [DOI: 10.1016/b978-0-12-823931-5.00005-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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13
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Zhang Z, Liu N, Sun M. Research Progress of Immunotherapy for Gastric Cancer. Technol Cancer Res Treat 2023; 22:15330338221150555. [PMID: 37042029 PMCID: PMC10102952 DOI: 10.1177/15330338221150555] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 10/16/2022] [Accepted: 12/22/2022] [Indexed: 04/13/2023] Open
Abstract
Gastric cancer (GC) is one of the most common gastrointestinal tract cancers worldwide, which has high incidence and mortality rates and poor prognosis. Although multidisciplinary comprehensive therapies consisting of surgery, chemotherapy, radiotherapy, and targeted therapy have made great progress in GC treatment, a satisfactory curative effect still cannot be achieved in many circumstances, and the 5-year survival of patients with GC remains to be very low. In China, about 75% of patients with GC are diagnosed in the advanced stage and thus miss the opportunity of surgical resection. Although the conventional treatment of GC has improved the survival time of advanced patients to a certain extent, the clinical efficacy has encountered a bottleneck and cannot bring higher survival benefits to patients. With the development of immunologic and molecular biologic technologies, immunotherapy has gradually become a new essential treatment for GC, which has attracted extensive attention in the field of oncology. The US Food and Drug Administration (USFDA) and China Food and Drug Administration (CFDA) have approved a variety of immune-related drugs for the treatment of GC, and all of which have achieved good efficacy. In this review, we summarize the recent development in nonspecific enhancer therapy, adoptive immunocell therapy, tumor vaccine therapy, oncolytic virus therapy, and immune checkpoint inhibitor therapy, and their roles in the treatment of GC.
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Affiliation(s)
- Zhipeng Zhang
- Key Laboratory of Liver and Kidney
Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai,
China
| | - Ningning Liu
- Department of Medical Oncology and
Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai,
China
| | - Mingyu Sun
- Key Laboratory of Liver and Kidney
Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai,
China
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14
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Huber MA, Nadella S, Cao H, Kallakury B, Tucker RD, Gay MD, Shivapurkar N, Edmondson EF, Yue Y, Dou W, Fang HB, Smith JP. Does Chronic Use of High Dose Proton Pump Inhibitors Increase Risk for Pancreatic Cancer? Pancreas 2022; 51:1118-1127. [PMID: 37078934 PMCID: PMC10119745 DOI: 10.1097/mpa.0000000000002145] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Abstract
OBJECTIVES To analyze whether use of proton pump inhibitors increase the risk for pancreatic cancer in a mouse model and human clinical cohorts. METHODS p48-Cre/LSL-KrasG12D mice that develop precancerous pancreatic intraepithelial neoplasia (PanINs) were treated with low- or high-dose proton pump inhibitors (PPIs) orally for 1 and 4 months. The mechanism for the cholecystokinin receptor 2 (CCK-2R) activation was investigated in vitro. Two resources were employed to analyze the risk of pancreatic cancer in human subjects with PPI use. RESULTS Serum gastrin levels were increased 8-fold (P < 0.0001) in mice treated with chronic high-dose PPIs, and this change correlated with an increase (P = 0.02) in PanIN grade and the development of microinvasive cancer. The CCK-2R expression was regulated by microRNA-148a in the p48-Cre/LSL-KrasG12D mice pancreas and in human pancreatic cancer cells in vitro. Proton pump inhibitor consumption in human subjects was correlated with pancreatic cancer risk (odds ratio, 1.54). A validation analysis conducted using the large-scale United Kingdom Biobank database confirmed the correlation (odds ratio, 1.9; P = 0.00761) of pancreatic cancer risk with PPI exposure. CONCLUSIONS This investigation revealed in both murine models and human subjects, PPI use is correlated with a risk for development of pancreatic cancer.
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Affiliation(s)
| | | | | | | | - Robin D Tucker
- Department of Pathology, Georgetown University, Washington, DC
| | | | | | | | - Yuanzhen Yue
- Biostatistics, Bioinformatics and Biomathematics, Georgetown University, Washington, DC
| | - Wenyu Dou
- Biostatistics, Bioinformatics and Biomathematics, Georgetown University, Washington, DC
| | - Hong-Bin Fang
- Biostatistics, Bioinformatics and Biomathematics, Georgetown University, Washington, DC
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15
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Mommersteeg MC, Yu BT, van den Bosch TPP, von der Thüsen J, Kuipers EJ, Doukas M, Spaander M, Peppelenbosch MP, Fuhler GM. Constitutive programmed death ligand 1 expression protects gastric G-cells from Helicobacter pylori-induced inflammation. Helicobacter 2022; 27:e12917. [PMID: 35899973 PMCID: PMC9542424 DOI: 10.1111/hel.12917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 05/20/2022] [Accepted: 06/23/2022] [Indexed: 12/09/2022]
Abstract
INTRODUCTION Gastric intestinal metaplasia (GIM) is a premalignant lesion, highly associated with Helicobacter pylori infection. Previous studies have shown that H. pylori is able to induce the expression of programmed death ligand 1 (PD-L1), an inhibitory immune modulator, in gastric cells. Our aim was to investigate whether tissues from GIM patients may exploit PD-L1 expression upon H. pylori infection to evade immunosurveillance. METHODS Immunohistochemistry was performed for PD-L1 and enteroendocrine markers somatostatin and gastrin on samples derived from a cohort of patients with known GIM, both before and after H. pylori eradication. To determine the identity of any observed PD-L1-positive cells, we performed multiplex immunofluorescent staining and analysis of single-cell sequencing data. RESULTS GIM tissue was rarely positive for PD-L1. In normal glands from GIM patients, PD-L1 was mainly expressed by gastrin-positive G-cells. While the D-cell and G-cell compartments were both diminished 2-fold (p = .015 and p = .01, respectively) during H. pylori infection in the normal antral tissue of GIM patients, they were restored 1 year after eradication. The total number of PD-L1-positive cells was not affected by H. pylori, but the percentage of PD-L1-positive G-cells was 30% higher in infected subjects (p = .011), suggesting that these cells are preferentially rescued from destruction. CONCLUSIONS Antral G-cells frequently express PD-L1 during homeostasis. G-cells seem to be protected from H. pylori-induced immune destruction by PD-L1 expression. GIM itself does not express PD-L1 and is unlikely to escape immunosurveillance via expression of PD-L1.
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Affiliation(s)
- Michiel C. Mommersteeg
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - Bing Ting Yu
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | | | | | - Ernst J. Kuipers
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - Michael Doukas
- Department of PathologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - Manon C. W. Spaander
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - Maikel P. Peppelenbosch
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - Gwenny M. Fuhler
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands
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16
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Islas JF, Quiroz-Reyes AG, Delgado-Gonzalez P, Franco-Villarreal H, Delgado-Gallegos JL, Garza-Treviño EN, Gonzalez-Villarreal CA. Cancer Stem Cells in Tumor Microenvironment of Adenocarcinoma of the Stomach, Colon, and Rectum. Cancers (Basel) 2022; 14:3948. [PMID: 36010940 PMCID: PMC9405851 DOI: 10.3390/cancers14163948] [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: 06/30/2022] [Revised: 07/29/2022] [Accepted: 08/09/2022] [Indexed: 11/17/2022] Open
Abstract
Gastrointestinal adenocarcinomas are one of the world's deadliest cancers. Cancer stem cells and the tissue microenvironment are highly regulated by cell and molecular mechanisms. Cancer stem cells are essential for maintenance and progression and are associated with resistance to conventional treatments. This article reviews the current knowledge of the role of the microenvironment during the primary establishment of gastrointestinal adenocarcinomas in the stomach, colon, and rectum and its relationship with cancer stem cells. We also describe novel developments in cancer therapeutics, such as targeted therapy, and discuss the advantages and disadvantages of different treatments for improving gastrointestinal cancer prognosis.
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Affiliation(s)
- Jose Francisco Islas
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico
| | - Adriana G. Quiroz-Reyes
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico
| | - Paulina Delgado-Gonzalez
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico
| | | | - Juan Luis Delgado-Gallegos
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico
| | - Elsa N. Garza-Treviño
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico
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17
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Xu R, Höß C, Swiercz JM, Brandt DT, Lutz V, Petersen N, Li R, Zhao D, Oleksy A, Creigh-Pulatmen T, Trokter M, Fedorova M, Atzberger A, Strandby RB, Olsen AA, Achiam MP, Matthews D, Huber M, Gröne HJ, Offermanns S, Worzfeld T. A semaphorin-plexin-Rasal1 signaling pathway inhibits gastrin expression and protects against peptic ulcers. Sci Transl Med 2022; 14:eabf1922. [PMID: 35857828 DOI: 10.1126/scitranslmed.abf1922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Peptic ulcer disease is a frequent clinical problem with potentially serious complications such as bleeding or perforation. A decisive factor in the pathogenesis of peptic ulcers is gastric acid, the secretion of which is controlled by the hormone gastrin released from gastric G cells. However, the molecular mechanisms regulating gastrin plasma concentrations are poorly understood. Here, we identified a semaphorin-plexin signaling pathway that operates in gastric G cells to inhibit gastrin expression on a transcriptional level, thereby limiting food-stimulated gastrin release and gastric acid secretion. Using a systematic siRNA screening approach combined with biochemical, cell biology, and in vivo mouse experiments, we found that the RasGAP protein Rasal1 is a central mediator of plexin signal transduction, which suppresses gastrin expression through inactivation of the small GTPase R-Ras. Moreover, we show that Rasal1 is pathophysiologically relevant for the pathogenesis of peptic ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs), a main risk factor of peptic ulcers in humans. Last, we show that application of recombinant semaphorin 4D alleviates peptic ulcer disease in mice in vivo, demonstrating that this signaling pathway can be harnessed pharmacologically. This study unravels a mode of G cell regulation that is functionally important in gastric homeostasis and disease.
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Affiliation(s)
- Rui Xu
- Institute of Pharmacology, University of Marburg, Marburg 35043, Germany.,Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany
| | - Carsten Höß
- Institute of Pharmacology, University of Marburg, Marburg 35043, Germany
| | - Jakub M Swiercz
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany
| | - Dominique T Brandt
- Institute of Pharmacology, University of Marburg, Marburg 35043, Germany
| | - Veronika Lutz
- Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, Marburg 35043, Germany
| | - Natalia Petersen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Rui Li
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany
| | - Dandan Zhao
- Institute of Pharmacology, University of Marburg, Marburg 35043, Germany
| | | | | | | | | | - Ann Atzberger
- Flow Cytometry Facility, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany
| | - Rune B Strandby
- Department of Surgical Gastroenterology, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark
| | - August A Olsen
- Department of Surgical Gastroenterology, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark
| | - Michael P Achiam
- Department of Surgical Gastroenterology, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark
| | | | - Magdalena Huber
- Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, Marburg 35043, Germany
| | - Hermann-Josef Gröne
- Institute of Pharmacology, University of Marburg, Marburg 35043, Germany.,Medical Faculty, University of Heidelberg, Heidelberg 69120, Germany
| | - Stefan Offermanns
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.,Medical Faculty, University of Frankfurt, Frankfurt 60590, Germany
| | - Thomas Worzfeld
- Institute of Pharmacology, University of Marburg, Marburg 35043, Germany.,Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany
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18
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Abstract
Like most solid tumours, the microenvironment of epithelial-derived gastric adenocarcinoma (GAC) consists of a variety of stromal cell types, including fibroblasts, and neuronal, endothelial and immune cells. In this article, we review the role of the immune microenvironment in the progression of chronic inflammation to GAC, primarily the immune microenvironment driven by the gram-negative bacterial species Helicobacter pylori. The infection-driven nature of most GACs has renewed awareness of the immune microenvironment and its effect on tumour development and progression. About 75-90% of GACs are associated with prior H. pylori infection and 5-10% with Epstein-Barr virus infection. Although 50% of the world's population is infected with H. pylori, only 1-3% will progress to GAC, with progression the result of a combination of the H. pylori strain, host susceptibility and composition of the chronic inflammatory response. Other environmental risk factors include exposure to a high-salt diet and nitrates. Genetically, chromosome instability occurs in ~50% of GACs and 21% of GACs are microsatellite instability-high tumours. Here, we review the timeline and pathogenesis of the events triggered by H. pylori that can create an immunosuppressive microenvironment by modulating the host's innate and adaptive immune responses, and subsequently favour GAC development.
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19
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Zhao Y, Wang Q, Zeng Y, Xie Y, Zhou J. Gastrin/CCK-B Receptor Signaling Promotes Cell Invasion and Metastasis by Upregulating MMP-2 and VEGF Expression in Gastric Cancer. J Cancer 2022; 13:134-145. [PMID: 34976177 PMCID: PMC8692687 DOI: 10.7150/jca.51854] [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: 08/12/2020] [Accepted: 11/09/2021] [Indexed: 11/05/2022] Open
Abstract
Accumulated evidence suggests that a functional loop composed of gastrin and cholecystokinin B receptor (CCK-BR) may exist in gastric carcinogenesis. However, this suggestion is not completely supported due to a lack of direct evidence, and the underlying mechanism is not completely understood. Here, we evaluated the effects of gastrin/CCK-BR signaling on the cell growth, invasion, and expression of MMP-2 and VEGF, as well as xenograft growth in vivo. Furthermore, we detected gastrin mRNA content in human gastric cancer tissues, metastatic lymph nodes, and adjacent nontumor tissues. We found that the forced gastrin could promote the proliferation, migration, and invasion of gastric cancer cells by upregulating the expression of MMP-2 and VEGF. Blocking gastrin/CCK-BR signal using either Proglumide, a CCK-BR antagonist, or shRNA against GASTRIN significantly inhibited the gastrin-promoting effects. In vivo study revealed that the tumor growth in nude mice inoculated with gastrin-overexpressed cells was significantly faster than control cells. The gastrin mRNA content in metastatic lymph nodes was higher in patients with gastric cancer than in primary gastric cancer and adjacent nontumor tissues. In conclusion, we provided direct evidence and possible mechanism of gastrin/CCK-BR signaling in the initiation and progression of gastric cancer.
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Affiliation(s)
- Yan Zhao
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang, Guizhou, China
| | - Qinrong Wang
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang, Guizhou, China
| | - Yi Zeng
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang, Guizhou, China
| | - Yuan Xie
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang, Guizhou, China
| | - Jianjiang Zhou
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang, Guizhou, China
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20
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Smith JP, Cao H, Chen W, Mahmood K, Phillips T, Sutton L, Cato A. Gastrin Vaccine Alone and in Combination With an Immune Checkpoint Antibody Inhibits Growth and Metastases of Gastric Cancer. Front Oncol 2021; 11:788875. [PMID: 34926305 PMCID: PMC8672297 DOI: 10.3389/fonc.2021.788875] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 11/10/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer is a leading cause of cancer-related deaths worldwide. Recently, clinical studies have demonstrated that many of those with advanced gastric cancer are responsive to immune checkpoint antibody therapy, although the median survival even with these new agents is less than 12 months for advanced disease. The gastrointestinal peptide gastrin has been shown to stimulate growth of gastric cancer in a paracrine and autocrine fashion through the cholecystokinin-B receptor (CCK-BR), a receptor that is expressed in at least 56.6% of human gastric cancers. In the current investigation, we studied the role of the gastrin-CCK-BR pathway in vitro and in vivo as well as the expression of the CCK-BR in a human gastric cancer tissue array. CCK-BR and PD-L1 receptor expression and gastrin peptide was found in two murine gastric cancer cells (NCC-S1 and YTN-16) by qRT-PCR and immunocytochemistry. Treatment of NCC-S1 cells with gastrin resulted in increased growth. In vivo, the effects of a cancer vaccine that targets gastrin peptide (polyclonal antibody stimulator-PAS) alone or in combination with a Programed Death-1 antibody (PD-1 Ab) was evaluated in immune competent mice (N = 40) bearing YTN-16 gastric tumors. Mice were treated with PBS, PD-1 Ab (50 µg), PAS (250 µg), or the combination of PD-1 Ab with PAS. Tumor growth was significantly slower than controls in PAS-treated mice, and tumor growth was decreased even more in combination-treated mice. There were no metastases in any of the mice treated with PAS either alone or in combination with PD-1 Ab. Tumor proliferation by the Ki67 staining was significantly decreased in mice treated with PAS monotherapy or the combination therapy. PAS monotherapy or combined with PD-1 Ab increased tumor CD8+ T-lymphocytes and decreased the number of immunosuppressive M2-polarized tumor-associated macrophages. CCK-BR expression was identified in samples from a human tissue array by immunohistochemistry confirming the clinical relevance of this study. These results confirm the significance of the gastrin-CCK-BR signaling pathway in gastric cancer and suggest that the addition of a gastrin vaccine, PAS, to therapy with an immune checkpoint antibody may decrease growth and metastases of gastric cancer by altering the tumor microenvironment.
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Affiliation(s)
- Jill P Smith
- Department of Medicine, Georgetown University, Washington, DC, United States
| | - Hong Cao
- Department of Medicine, Georgetown University, Washington, DC, United States
| | - Wenqiang Chen
- Department of Medicine, Georgetown University, Washington, DC, United States
| | - Kanwal Mahmood
- Department of Medicine, Georgetown University, Washington, DC, United States
| | | | - Lynda Sutton
- Cancer Advances, Inc., Durham, NC, United States
| | - Allen Cato
- Cancer Advances, Inc., Durham, NC, United States
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21
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Duan S, Rico K, Merchant JL. Gastrin: From Physiology to Gastrointestinal Malignancies. FUNCTION (OXFORD, ENGLAND) 2021; 3:zqab062. [PMID: 35330921 PMCID: PMC8788842 DOI: 10.1093/function/zqab062] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/14/2021] [Accepted: 11/16/2021] [Indexed: 01/07/2023]
Abstract
Abetted by widespread usage of acid-suppressing proton pump inhibitors (PPIs), the mitogenic actions of the peptide hormone gastrin are being revisited as a recurring theme in various gastrointestinal (GI) malignancies. While pathological gastrin levels are intricately linked to hyperplasia of enterochromaffin-like cells leading to carcinoid development, the signaling effects exerted by gastrin on distinct cell types of the gastric mucosa are more nuanced. Indeed, mounting evidence suggests dichotomous roles for gastrin in both promoting and suppressing tumorigenesis. Here, we review the major upstream mediators of gastrin gene regulation, including inflammation secondary to Helicobacter pylori infection and the use of PPIs. We further explore the molecular biology of gastrin in GI malignancies, with particular emphasis on the regulation of gastrin in neuroendocrine neoplasms. Finally, we highlight tissue-specific transcriptional targets as an avenue for targetable therapeutics.
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Affiliation(s)
- Suzann Duan
- Department of Medicine, Division of Gastroenterology and Hepatology, Arizona Comprehensive Cancer Center, University of Arizona, Tucson, AZ 85724, USA
| | - Karen Rico
- Department of Medicine, Division of Gastroenterology and Hepatology, Arizona Comprehensive Cancer Center, University of Arizona, Tucson, AZ 85724, USA
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22
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Weidle UH, Birzele F, Brinkmann U, Auslaender S. Gastric Cancer: Identification of microRNAs Inhibiting Druggable Targets and Mediating Efficacy in Preclinical In Vivo Models. Cancer Genomics Proteomics 2021; 18:497-514. [PMID: 34183383 DOI: 10.21873/cgp.20275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/30/2021] [Accepted: 05/05/2021] [Indexed: 01/06/2023] Open
Abstract
In addition to chemotherapy, targeted therapies have been approved for treatment of locally advanced and metastatic gastric cancer. The therapeutic benefit is significant but more durable responses and improvement of survival should be achieved. Therefore, the identification of new targets and new approaches for clinical treatment are of paramount importance. In this review, we searched the literature for down-regulated microRNAs which interfere with druggable targets and exhibit efficacy in preclinical in vivo efficacy models. As druggable targets, we selected transmembrane receptors, secreted factors and enzymes. We identified 38 microRNAs corresponding to the criteria as outlined. A total of 13 miRs target transmembrane receptors, nine inhibit secreted proteins and 16 attenuate enzymes. These microRNAs are targets for reconstitution therapy of gastric cancer. Further target validation experiments are mandatory for all of the identified microRNAs.
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Affiliation(s)
- Ulrich H Weidle
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany;
| | - Fabian Birzele
- Pharmaceutical Sciences, Roche Pharma Research and Early Development (pRed), Roche Innovation Center Basel, Basel, Switzerland
| | - Ulrich Brinkmann
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany;
| | - Simon Auslaender
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
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23
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Yan Z, Xu T, Xu Y, Chen W, An Z, Zhu F. Jianpiyiqi formula ameliorates chronic atrophic gastritis in rats by modulating the Wnt/β-catenin signaling pathway. Exp Ther Med 2021; 22:878. [PMID: 34194556 PMCID: PMC8237394 DOI: 10.3892/etm.2021.10310] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 04/23/2021] [Indexed: 12/14/2022] Open
Abstract
Jianpiyiqi formula is a Traditional Chinese Medicine (TCM) prescription and is used for the clinical treatment of patients with chronic atrophic gastritis (CAG). The aim of the present study was to examine the underlying mechanisms of Jianpiyiqi formula treatment for CAG via the Wnt/β-catenin signaling pathway. The high-performance liquid chromatography (HPLC) chromatogram of Jianpiyiqi formula was constructed. A CAG rat model induced by N-methyl-N'-nitro-N-nitrosoguanidine and ranitidine was established. The body weight and food intake of the rats was recorded and rat gastric morphology was visually examined. Pathological analysis of rat gastric tissue was also performed. The levels of gastrin (GAS), pepsin (PP), somatostatin (SS) and prostaglandin E2 (PGE2) in rat serum were detected using ELISAs. The expression levels of proteins and genes associated with the Wnt/β-catenin signaling pathway were measured via immunohistochemistry and reverse transcription-quantitative PCR. The HPLC chromatogram of Jianpiyiqi formula was determined and as active components, liquiritin and hesperidin were identified from the chromatogram. Compared with the blank group, the body weight and feed intake of the rats were decreased, and gastric mucosal atrophy and inflammation appeared in the model group. Treatment with Jianpiyiqi formula increased the body weight and feed intake of the rats, as well as relieved the gastric atrophy and inflammation. The contents of GAS, PP, SS and PGE2 were significantly reduced in the model group compared with the blank group. Jianpiyiqi formula significantly increased GAS, PP, SS and PGE2 levels in serum of rats with CAG. In the model group, Wnt1, β-catenin and cyclin D1 protein expression levels were increased, and glycogen synthase kinase-3β (GSK-3β) protein expression levels were decreased. Jianpiyiqi formula decreased the protein expression levels of Wnt1, β-catenin and cyclin D1 and increased the protein expression levels of GSK-3β. Compared with the blank group, the mRNA expression levels of Wnt1, Wnt5a, β-catenin, cyclin D1 and MMP7 were upregulated, and the mRNA expression levels of GSK-3β were downregulated in the model group. Treatment with Jianpiyiqi formula downregulated the mRNA expression levels of Wnt1, Wnt5a, β-catenin, cyclin D1 and MMP7 and upregulated the mRNA expression levels of GSK-3β. All of the experimental results indicated that Jianpiyiqi formula exerted a therapeutic effect on rats with CAG and inhibited the activation of the Wnt/β-catenin signaling pathway. Thus, Jianpiyiqi formula, as an effective TCM prescription for treating patients with CAG, may be more widely used in the clinic.
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Affiliation(s)
- Zhanpeng Yan
- Clinical Research Department of Chinese and Western Medicine, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China.,Clinical Research Department of Chinese and Western Medicine, Jiangsu Province Institute of Traditional Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China
| | - Tingting Xu
- Clinical Research Department of Chinese and Western Medicine, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China.,Clinical Research Department of Chinese and Western Medicine, Jiangsu Province Institute of Traditional Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China
| | - Yuxuan Xu
- Clinical Research Department of Chinese and Western Medicine, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China
| | - Wanzhen Chen
- Clinical Research Department of Chinese and Western Medicine, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China
| | - Zhentao An
- Clinical Research Department of Chinese and Western Medicine, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China.,Clinical Research Department of Chinese and Western Medicine, Jiangsu Province Institute of Traditional Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China
| | - Fangshi Zhu
- Clinical Research Department of Chinese and Western Medicine, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China.,Clinical Research Department of Chinese and Western Medicine, Jiangsu Province Institute of Traditional Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China
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Friedman AJ, Elseth AJ, Brockmeyer JR. Proton Pump Inhibitors, Associated Complications, and Alternative Therapies: A Shifting Risk Benefit Ratio. Am Surg 2021; 88:20-27. [PMID: 33560890 DOI: 10.1177/0003134821991988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVE Our goal was to compile the most recent and accurate data on the side effects of proton pump inhibitors (PPI). We also compared the efficacy of PPI to the efficacy of different surgical options for acid reflux control. BACKGROUND Proton pump inhibitors are the primary therapy for chronic control of gastroesophageal reflux disease (GERD), but newer studies demonstrate deleterious side effects. Collating this information and contrasting it with surgical therapy for GERD provides evidence for possible practice changes in treatment. METHODS A literature search utilizing PubMed was performed evaluating for PPI and anti-reflux surgery (ARS), focusing on articles that reflected information regarding the usage and efficacy of symptom control of both PPI and ARS. Search terms included "ARS, fundoplication, MSA, acute interstitial nephritis, acute kidney injury, chronic kidney disease, meta-analysis, PPI, H2 blocker, cardiovascular risk, and gut dysbiosis." We evaluated 271 articles by title, abstract, and data for relevance and included 70. RESULTS Long-term control of GERD with PPI may have a greater than expected side effect profile than initially thought. Surgical options may provide greater symptom control than PPI without the side effects of long-term medical therapy. CONCLUSIONS Anti-reflux control can be safely achieved with either PPI or surgical options; however, the long-term side effects noted in the review such as increased risk of cardiovascular events, renal disease, and gut dysbiosis may suggest surgical anti-reflux control as a better long-term option.
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Affiliation(s)
- Alexander J Friedman
- General Surgery Department, 19911Dwight D. Eisenhower Army Medical Center, Fort Gordon, GA, USA
| | - Anna J Elseth
- General Surgery Department, 19911Dwight D. Eisenhower Army Medical Center, Fort Gordon, GA, USA
| | - Joel R Brockmeyer
- General Surgery Department, 19911Dwight D. Eisenhower Army Medical Center, Fort Gordon, GA, USA
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25
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Liu J, Geng Z, Zhang Y, Alharbi SA, Shi Y. Sesquiterpenoid bilobalide inhibits gastric carcinoma cell growth and induces apoptosis both in vitro and in vivo models. J Biochem Mol Toxicol 2021; 35:e22723. [PMID: 33511709 DOI: 10.1002/jbt.22723] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/15/2020] [Accepted: 11/26/2020] [Indexed: 12/15/2022]
Abstract
Gastric carcinoma is one of the most aggressive types of cancer that ranks fifth among all cancer incidences and third in cancer mortality. As it exhibits a prolonged asymptomatic condition and high recurrence rate, it is a great challenge to treat gastric cancer. Traditional medicine that utilizes herbal phytochemicals to treat various diseases is a potent alternative for current allopathic treatment. Hence, we evaluated the potency of a phytochemical bilobalide for treating gastric cancer in in vitro and in vivo models. Bilobalide, a sesquiterpenoid, is present in the Ginkgo biloba plant that belongs to the family of Ginkgoaceae. The cytotoxicity effect of bilobalide was evaluated in both gastric cancer (AGS) cells and normal gastric epithelial cells. Apoptosis-inducing property of bilobalide against the AGS cell line was analyzed with different fluorescent staining techniques and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and cell cycle analysis was carried out by flow cytometry. The in vivo studies were assessed with N-methyl-N-nitrosourea (MNU)-induced gastric cancer in rats. Serum-specific gastric markers were quantified and histopathological analysis of stomach tissue was performed. The expression of target-signaling molecules was analyzed by a reverse-transcription polymerase chain reaction. The in vitro results proved that bilobalide effectively suppressed the AGS cell growth and induced cell death by nuclear damage and apoptosis induction. The bilobalide treatment effectively arrested the cell cycle of AGS cells via inhibiting the PI3K-signaling pathway. Our in vivo results also confirmed that the bilobalide persuasively inhibited the MNU-induced gastric carcinoma via inhibiting the thioredoxin-fold family proteins and inflammatory markers' expression. Overall, our results authentically prove that bilobalide possesses therapeutic potency to cure gastric carcinoma.
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Affiliation(s)
- Jinglei Liu
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
| | - Zhen Geng
- Department of Gastrointestinal Surgery, Binzhou People's Hospital, Binzhou, Shandong Province, China
| | - Yingying Zhang
- Department of Oncology, Binzhou People's Hospital, Binzhou, Shandong Province, China
| | - Sulaiman Ali Alharbi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Yulong Shi
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
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26
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van Tilborg D, Saccenti E. Cancers in Agreement? Exploring the Cross-Talk of Cancer Metabolomic and Transcriptomic Landscapes Using Publicly Available Data. Cancers (Basel) 2021; 13:393. [PMID: 33494351 PMCID: PMC7865504 DOI: 10.3390/cancers13030393] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/12/2021] [Accepted: 01/19/2021] [Indexed: 12/13/2022] Open
Abstract
One of the major hallmarks of cancer is the derailment of a cell's metabolism. The multifaceted nature of cancer and different cancer types is transduced by both its transcriptomic and metabolomic landscapes. In this study, we re-purposed the publicly available transcriptomic and metabolomics data of eight cancer types (breast, lung, gastric, renal, liver, colorectal, prostate, and multiple myeloma) to find and investigate differences and commonalities on a pathway level among different cancer types. Topological analysis of inferred graphical Gaussian association networks showed that cancer was strongly defined in genetic networks, but not in metabolic networks. Using different statistical approaches to find significant differences between cancer and control cases, we highlighted the difficulties of high-level data-merging and in using statistical association networks. Cancer transcriptomics and metabolomics and landscapes were characterized by changed macro-molecule production, however, only major metabolic deregulations with highly impacted pathways were found in liver cancer. Cell cycle was enriched in breast, liver, and colorectal cancer, while breast and lung cancer were distinguished by highly enriched oncogene signaling pathways. A strong inflammatory response was observed in lung cancer and, to some extent, renal cancer. This study highlights the necessity of combining different omics levels to obtain a better description of cancer characteristics.
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Affiliation(s)
| | - Edoardo Saccenti
- Laboratory of Systems and Synthetic Biology, Wageningen University & Research, Stippeneng, 6708 WE Wageningen, The Netherlands;
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Chin JL, O'Connell J, Muldoon C, Swan N, Reynolds JV, Ravi N, Geoghegan J, Conlon KC, O'Shea D, O'Toole D. Selective Resection of Type 1 Gastric Neuroendocrine Neoplasms and the Risk of Progression in an Endoscopic Surveillance Programme. Dig Surg 2020; 38:38-45. [PMID: 33260173 DOI: 10.1159/000510962] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 08/17/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Current guidance for type 1 gastric neuroendocrine neoplasms (gNENs) recommends either resection of all visible lesions or selective resection of gNENs >10 mm. We adopt a selective strategy targeting lesions approaching 10 mm for endoscopic mucosal resection (EMR) and provide surveillance for smaller lesions. OBJECTIVES This study aimed to describe the incidence of type 1 gNENs requiring endoscopic/surgical resection and the risk of disease progression (both considered significant disease) on endoscopic surveillance. The secondary objective was to assess the risk factors for disease progression during surveillance and the incidence of gastric dysplasia/adenoma/adenocarcinoma. METHODS We collected consecutive patients with type 1 gNENs and obtained demographic and clinical data through the electronic patient record. RESULTS In our cohort of 57 patients, 12 patients had EMR at index gastroscopy; 7 patients had surgery (4: large/multiple gNENs and 3: nodal metastases) (5.2% [3/57] risk of nodal metastases); and a patient with nodal and liver metastases (1.8% [1/57] risk of distant metastases). The prevalence of gastric adenocarcinoma in our study was 3.5% with an incidence rate of 9.59 per 1,000 persons per year. For patients undergoing surveillance, 29.5% (13/44) of patients progressed requiring resection. Serum gastrin was significantly higher in patients who progressed to resection (p value = 0.023). CONCLUSION We concluded that up to a third of patients with type 1 gNENs have significant disease requiring resection. Hence, endoscopic surveillance and resect strategy would benefit patients.
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Affiliation(s)
- Jun Liong Chin
- ENETS Neuroendocrine Tumour Centre of Excellence, St. Vincent's University Hospital, University College, Dublin, Ireland, .,St. James's Hospital, Trinity College, Dublin, Ireland,
| | - Jim O'Connell
- St. James's Hospital, Trinity College, Dublin, Ireland
| | - Cian Muldoon
- St. James's Hospital, Trinity College, Dublin, Ireland
| | - Niall Swan
- ENETS Neuroendocrine Tumour Centre of Excellence, St. Vincent's University Hospital, University College, Dublin, Ireland
| | | | | | - Justin Geoghegan
- ENETS Neuroendocrine Tumour Centre of Excellence, St. Vincent's University Hospital, University College, Dublin, Ireland
| | - Kevin C Conlon
- ENETS Neuroendocrine Tumour Centre of Excellence, St. Vincent's University Hospital, University College, Dublin, Ireland.,Tallaght Hospital, Trinity College, Dublin, Ireland
| | - Donal O'Shea
- ENETS Neuroendocrine Tumour Centre of Excellence, St. Vincent's University Hospital, University College, Dublin, Ireland
| | - Dermot O'Toole
- ENETS Neuroendocrine Tumour Centre of Excellence, St. Vincent's University Hospital, University College, Dublin, Ireland.,St. James's Hospital, Trinity College, Dublin, Ireland
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28
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Qiu Y, Cui L, Lin Y, Gao B, Li J, Zhao X, Zhu X, Hu S, Lin L. Development and Validation of a Robust Immune Prognostic Signature for Head and Neck Squamous Cell Carcinoma. Front Oncol 2020; 10:1502. [PMID: 33224866 PMCID: PMC7667274 DOI: 10.3389/fonc.2020.01502] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 07/14/2020] [Indexed: 12/12/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is among the most destructive of tumors, leading to considerable morbidity and mortality. Abnormal immune microenvironment is closely associated with tumor progression. This study aimed to construct a robust immune prognostic model for HNSCC. The RNA-seq transcriptome data and clinical information of HNSCC were downloaded from The Cancer Genome Atlas (TCGA) database. The key pathways and transcriptional factors (TFs) that are correlated with significantly altered immune related genes were identified. A robust immune prognostic model was constructed and further validated using a discovery-validation cohort design. An immune prognostic signature-based nomogram model was also developed. We have identified 400 significantly changed immune related genes in HNSCC. In addition, functional analysis of the altered immune related genes revealed many biological functions and pathways that might affect the tumor immune microenvironment. FOXP3, SNAI2, and STAT1 were identified as the hub TFs for regulating immunological changes in HNSCC. Moreover, an immune related gene-based prognostic signature significantly associated with the overall survival (OS) of HNSCC was constructed in the discovery cohort, and successfully validated in the validation cohort. Finally, a nomogram model based on immune prognostic signature was built and exhibited good performance for predicting the OS of HNSCC. In conclusion, the immune prognostic model is robust for predicting the prognosis of HNSCC and may evolve as a promising tool for risk evaluation and therapeutic selection.
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Affiliation(s)
- Yu Qiu
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Maxillofacial Medicine Center of Fujian Province, Fuzhou, China
| | - Li Cui
- School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
| | - Yang Lin
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Maxillofacial Medicine Center of Fujian Province, Fuzhou, China
| | - Bingju Gao
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Maxillofacial Medicine Center of Fujian Province, Fuzhou, China
| | - Jun Li
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Maxillofacial Medicine Center of Fujian Province, Fuzhou, China
| | - Xinyuan Zhao
- Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Xiaofeng Zhu
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Maxillofacial Medicine Center of Fujian Province, Fuzhou, China
| | - Shen Hu
- School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
| | - Lisong Lin
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Maxillofacial Medicine Center of Fujian Province, Fuzhou, China
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29
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Camilo SMP, Almeida ÉCDS, Sousa JB, Camilo LP, Etchebehere RM. CHRONIC USE OF PROTON PUMP INHIBITORS AND THE QUANTITY OF G, D, AND ECL CELLS IN THE STOMACH. ARQUIVOS BRASILEIROS DE CIRURGIA DIGESTIVA : ABCD = BRAZILIAN ARCHIVES OF DIGESTIVE SURGERY 2020; 33:e1506. [PMID: 32844883 PMCID: PMC7448853 DOI: 10.1590/0102-672020190001e1506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 04/02/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Acid inhibition from chronic proton pump inhibitor use and a possible increase in gastrin can lead to changes in the regulation of hydrochloric acid production. However, it has not known whether such chronic use changes the presence of gastrin, delta, and enterochromaffin-like cells in the stomach or the relationship between gastrin and delta cells. AIM To analyze the number of gastrin-producing gastrin cells, somatostatin-producing cells, and histamine-producing cells in patients who were chronic users of proton pump inhibitor, with or without related Helicobacter pylori infection. METHODS Biopsies from 105 patients, including 81 chronic proton pump inhibitor users (experimental group) and 24 controls, were processed immunohistochemically and subjected to counting of gastrin, delta, and enterochromaffin-like cells in high-magnification microscopic fields and in 10 glands. RESULTS Gastrin cell, delta cell, and enterochromaffin-like cells counts were similar across the groups and appeared to be unaffected by Helicobacter pylori infection. The ratio between gastrin cells and delta cells was higher in the chronic users of proton pump inhibitor group than in controls. CONCLUSION Chronic users of proton pump inhibitor does not affect gastrin cell, delta cell, and enterochromaffin-like cell counts significantly, but may alter the ratio between gastrin cells and delta cells.
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Affiliation(s)
- Silvia Maria Perrone Camilo
- Post-Graduate Program in Health Sciences, Clinical Hospital, Triângulo Mineiro Federal University, Uberaba, MG, Brazil
| | - Élia Cláudia de Souza Almeida
- Post-Graduate Program in Health Sciences, Clinical Hospital, Triângulo Mineiro Federal University, Uberaba, MG, Brazil
| | - Jacqueline Batista Sousa
- Post-Graduate Program in Health Sciences, Triângulo Mineiro Federal University, Uberaba, MG, Brazil
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30
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Huang S, Cao Y, Guo H, Yao Y, Li L, Chen J, Li J, Xiang X, Deng J, Xiong J. Up-regulated acylglycerol kinase (AGK) expression associates with gastric cancer progression through the formation of a novel YAP1-AGK-positive loop. J Cell Mol Med 2020; 24:11133-11145. [PMID: 32827244 PMCID: PMC7576242 DOI: 10.1111/jcmm.15613] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 06/20/2020] [Accepted: 06/23/2020] [Indexed: 12/31/2022] Open
Abstract
Acylglycerol kinase (AGK) uses adenosine triphosphate (ATP) and acylglycerol to generate adenosine diphosphate (ADP) and acyl‐sn‐glycerol 3‐phosphate in cells. Recent evidence has demonstrated that dysregulated AGK expression is associated with the development of various human cancers. This study investigated the effects of AGK on gastric cancer cell proliferation and carcinogenesis and explored the underlying molecular events. AGK expression was up‐regulated in gastric cancer and was associated with poor prognosis in gastric cancer patients. AGK overexpression increased gastric cancer proliferation, invasion capacity and the expression of the epithelial‐mesenchymal transition markers in vitro. Conversely, the knockdown of AGK expression reduced gastric cancer cell proliferation in vitro and in nude mouse tumour cell xenografts. Importantly, AGK expression was associated with the YAP1 expression in gastric cancer cells and tissues. YAP1 expression also transcriptionally induced AGK expression through the binding of TEAD to the AGK gene promoter. However, AGK expression inhibited the activation of the Hippo pathway proteins and induced YAP1 nuclear localization to enhance the transcription activity of YAP1/TEADs. In conclusion, the study demonstrates that AGK is not only a novel target of the Hippo‐YAP1 pathway, but that it also positively regulates YAP1 expression, thus forming a YAP1‐AGK–positive feedback loop.
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Affiliation(s)
- Shanshan Huang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yuan Cao
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hui Guo
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yangyang Yao
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Li Li
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jun Chen
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Junhe Li
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiaojun Xiang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jun Deng
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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31
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Does the Use of Proton Pump Inhibitors Increase the Risk of Pancreatic Cancer? A Systematic Review and Meta-Analysis of Epidemiologic Studies. Cancers (Basel) 2020; 12:cancers12082220. [PMID: 32784492 PMCID: PMC7463819 DOI: 10.3390/cancers12082220] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 12/24/2022] Open
Abstract
Background: One of the most frequently used medications for treating gastrointestinal disorders is proton pump inhibitor (PPI), which reportedly has potential adverse effects. Although the relationship between the use of PPIs and the risk of pancreatic cancer has been extensively investigated, the results remain inconsistent. Hence, this meta-analysis aimed to evaluate such relationship. Methods: We searched for literature and subsequently included 10 studies (seven case–control and three cohort studies; 948,782 individuals). The pooled odds ratio (OR) and 95% confidence intervals (CI) for pancreatic cancer were estimated using a random-effects model. We also conducted sensitivity analysis and subgroup analysis. Results: The pooled OR of the meta-analysis was 1.698 (95% CI: 1.200–2.402, p = 0.003), with a substantial heterogeneity (I2 = 98.75%, p < 0.001). Even when studies were excluded one by one, the pooled OR remained statistically significant. According to the stratified subgroup analyses, PPI use, and pancreatic cancer incidence were positively associated, regardless of the study design, quality of study, country, and PPI type. Conclusion: PPI use may be associated with the increased risk of pancreatic cancer. Hence, caution is needed when using PPIs among patients with a high risk of pancreatic cancer.
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32
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The association between acid-suppressive agent use and the risk of cancer: a systematic review and meta-analysis. Eur J Clin Pharmacol 2020; 76:1437-1456. [PMID: 32548678 DOI: 10.1007/s00228-020-02927-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 06/01/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Acid-suppressive agents (ASAs) may be associated with cancer; previous studies reported that the risk of cancer with acid suppressants has differed depending on the site of cancer. Here, we conducted a systematic review and meta-analysis of the association between ASA use and the type of cancer risk. METHODS MEDLINE, EMBASE, and Cochrane library databases were searched for publications up to the end of September 2019 for MeSH terms and text words related to cancer and ASAs. Studies on the association between ASAs and cancer risk, which included a control group and reported the relative risk of cancer, were included. The inverse-variance random effect model was used to estimate the pooled relative risk (RR) and 95% confidence interval (CI), and subgroup analysis for type of acid suppressants, drug uptake duration, and cumulative doses was performed. Heterogeneity was assessed using the I2 test and Q statistic. RESULTS Thirty-nine cohort and case-control studies were included. ASA use was found to be significantly associated with a 46% higher risk of gastric cancer (RR, 1.46; 95% CI, 1.18-1.80) and a 53% higher risk of liver cancer (RR, 1.53; 95% CI, 1.31-1.78) compared with nonuse; however, there was no significant association for esophageal, colorectal, pancreatic, lung, breast, prostate, and kidney cancer; melanoma; and lymphoma. CONCLUSIONS ASAs were significantly associated with an increased risk of gastric and liver cancer; therefore, special attention of ASA use considering the potential risk of gastric and liver cancer is needed.
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33
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Sadighbayan D, Tohidkia MR, Mehdipour T, Hasanzadeh M, Yari Khosroushahi A. Bio-assay of the non-amidated progastrin-derived peptide (G17-Gly) using the tailor-made recombinant antibody fragment and phage display method: a biomedical analysis. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2020; 12:2735-2746. [PMID: 32930305 DOI: 10.1039/d0ay00627k] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
In this research, four novel and sensitive immunosensors for electrochemical determination of G17-Gly were designed based on signal amplification and tailor-made recombinant antibody technology. Anti-G17-Gly antibody fragments (i.e. scFv and VL specific to the N- and C-terminal of G17-Gly) were immobilized onto a polymeric nanocomposite comprising poly cetyl trimethyl ammonium bromide (P(CTAB)) as the conductive matrix, chitosan (CS) as a biocompatible agent and gold nanoparticles (AuNPs) as the signal amplification element. The high surface area provided by AuNPs and the small size of scFv/VL establish the basis for immobilizing a high amount of the anti-G17-Gly on the surface of the electrode for detecting G17-Gly in human plasma samples. Under optimal conditions, the designed immunosensors provide an excellent analytical capability for detecting and determining G17-Gly in human plasma samples with a linear range from 0.5 mM to 0.05 pM and a LLOQ of 0.05 pM. The sensitivity order of the immunosensors was Ag/2-mercaptoethanol/phage displaying scFv/P(CTAB-CS)-AuNP/GE, Ag/2-mercaptoethanol/phage displaying VL/P(CTAB-CS)-AuNP/GE, Ag/BSA/scFv/P(CTAB-CS)-AuNP/GE, and Ag/BSA/VL/P(CTAB-CS)-AuNP/GE. The aforementioned characteristics demonstrate that the proposed immune-devices can be used in biological and clinical diagnosis as reliable tools for identifying different oncobiomarkers.
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Affiliation(s)
- Deniz Sadighbayan
- Department of Medical Nanotechnology, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Daneshgah Street, P.O.Box 51548-53431, Tabriz, Iran.
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Tohidkia
- Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tayebeh Mehdipour
- Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hasanzadeh
- Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Food and Drug Safety Research Canter, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahmad Yari Khosroushahi
- Department of Medical Nanotechnology, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Daneshgah Street, P.O.Box 51548-53431, Tabriz, Iran.
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Sheng W, Malagola E, Nienhüser H, Zhang Z, Kim W, Zamechek L, Sepulveda A, Hata M, Hayakawa Y, Zhao CM, Chen D, Wang TC. Hypergastrinemia Expands Gastric ECL Cells Through CCK2R + Progenitor Cells via ERK Activation. Cell Mol Gastroenterol Hepatol 2020; 10:434-449.e1. [PMID: 32330731 PMCID: PMC7371950 DOI: 10.1016/j.jcmgh.2020.04.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 04/11/2020] [Accepted: 04/13/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Enterochromaffin-like (ECL) cells in the stomach express gastrin/cholecystokinin 2 receptor CCK2R and are known to expand under hypergastrinemia, but whether this results from expansion of existing ECL cells or increased production from progenitors has not been clarified. METHODS We used mice with green fluorescent protein fluorescent reporter expression in ECL cells (histidine decarboxylase [Hdc]-green fluorescent protein), as well as Cck2r- and Hdc-driven Tamoxifen inducible recombinase Cre (Cck2r-CreERT2, Hdc-CreERT2) mice combined with Rosa26Sor-tdTomato (R26-tdTomato) mice, and studied their expression and cell fate in the gastric corpus by using models of hypergastrinemia (gastrin infusion, omeprazole treatment). RESULTS Hdc-GFP marked the majority of ECL cells, located in the lower third of the gastric glands. Hypergastrinemia led to expansion of ECL cells that was not restricted to the gland base, and promoted cellular proliferation (Ki67) in the gastric isthmus but not in basal ECL cells. Cck2r-CreERT2 mice marked most ECL cells, as well as scattered cell types located higher up in the glands, whose number was increased during hypergastrinemia. Cck2r-CreERT2+ isthmus progenitors, but not Hdc+ mature ECL cells, were the source of ECL cell hyperplasia during hypergastrinemia and could grow as 3-dimensional spheroids in vitro. Moreover, gastrin treatment in vitro promoted sphere formation from sorted Cck2r+Hdc- cells, and increased chromogranin A and phosphorylated- extracellular signal-regulated kinase expression in CCK2R-derived organoids. Gastrin activates extracellular signal-regulated kinase pathways in vivo and in vitro, and treatment with the Mitogen-activated protein kinase kinase 1 inhibitor U0126 blocked hypergastrinemia-mediated changes, including CCK2R-derived ECL cell hyperplasia in vivo as well as sphere formation and chromogranin A expression in vitro. CONCLUSIONS We show here that hypergastrinemia induces ECL cell hyperplasia that is derived primarily from CCK2R+ progenitors in the corpus. Gastrin-dependent function of CCK2R+ progenitors is regulated by the extracellular signal-regulated kinase pathway.
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Affiliation(s)
- Weiwei Sheng
- Division of Digestive and Liver Diseases, Department of Medicine,Department of Gastrointestinal Surgery, the First Hospital, China Medical University, Shenyang, China
| | - Ermanno Malagola
- Division of Digestive and Liver Diseases, Department of Medicine
| | - Henrik Nienhüser
- Division of Digestive and Liver Diseases, Department of Medicine
| | - Zhengyu Zhang
- Division of Digestive and Liver Diseases, Department of Medicine
| | - Woosook Kim
- Division of Digestive and Liver Diseases, Department of Medicine
| | - Leah Zamechek
- Division of Digestive and Liver Diseases, Department of Medicine
| | - Antonia Sepulveda
- Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, New York
| | - Masahiro Hata
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Chun-Mei Zhao
- Department of Clinical and Molecular Medicine (Institutt for klinisk og molekylær medisin), Norwegian University of Science and Technology (Norges teknisk-naturvitenskaplige universitet), Trondheim, Norway
| | - Duan Chen
- Department of Clinical and Molecular Medicine (Institutt for klinisk og molekylær medisin), Norwegian University of Science and Technology (Norges teknisk-naturvitenskaplige universitet), Trondheim, Norway
| | - Timothy C. Wang
- Division of Digestive and Liver Diseases, Department of Medicine,Correspondence Address correspondence to: Timothy C. Wang, MD, Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York; fax: (212) 851-4590.
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Ko HJ, Kim KH, Lee SH, Choi CW, Kim SJ, In Choi C, Kim DH, Kim DH, Hwang SH. Can Proximal Gastrectomy with Double-Tract Reconstruction Replace Total Gastrectomy? A Propensity Score Matching Analysis. J Gastrointest Surg 2020; 24:516-524. [PMID: 30937710 DOI: 10.1007/s11605-019-04195-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 02/26/2019] [Indexed: 01/31/2023]
Abstract
BACKGROUND This retrospective cohort study compared proximal gastrectomy (PG) with double-tract reconstruction (DTR) versus total gastrectomy (TG) with Roux-en-Y reconstruction in terms of clinical outcomes. METHODS All consecutive patients with upper early gastric cancer (EGC) who underwent PG-DTR or TG in 2008-2016 were selected. TG patients who matched PG-DTR patients in age, sex, body mass index, clinical stage, and ASA score were selected by propensity score matching. Groups were compared in terms of clinicopathological characteristics, clinical outcomes, early (≤ 30 days), late (> 30 days), and severe (Clavien-Dindo grade ≥ III) postoperative complications, 1-year reflux morbidity, recurrence, and mortality. RESULTS Of 322 patients, 52 underwent PG-DTR. A matching TG group of 52 patients was selected. The PG-DTR group had smaller tumors (p = 0.02), smaller proximal and distal resection margins (p = 0.01, p < 0.01), and fewer retrieved lymph nodes (p < 0.01). PG-DTR associated with shorter times to diet and hospital stay (both p = 0.02). Groups did not differ in early (11.3 vs. 19.2%, p = 0.19), late (1.9 vs. 5.7%, p = 0.31), or severe complication rates (7.7 vs. 13.5%, p = 0.34). At 1 year, the groups did not differ in reflux symptoms (Visick score) or endoscopic esophagitis (Los Angeles Classification). There were no recurrences. Five-year overall survival rates were 100 and 81.6% (p = 0.02), respectively. CONCLUSION PG-DTR associated with better clinical outcomes and survival. Complication and reflux rates were similar. PG-DTR may be suitable for upper EGC.
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Affiliation(s)
- Hyo Jung Ko
- Department of Surgery and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea
| | - Ki Hyun Kim
- Department of Surgery and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea
| | - Si-Hak Lee
- Department of Surgery and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea
| | - Cheol Woong Choi
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
| | - Su Jin Kim
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
| | - Chang In Choi
- Department of Surgery, Pusan National University, Pusan, Republic of Korea
| | - Dae-Hwan Kim
- Department of Surgery, Pusan National University, Pusan, Republic of Korea
| | - Dong-Heon Kim
- Department of Surgery, Pusan National University, Pusan, Republic of Korea
| | - Sun-Hwi Hwang
- Department of Surgery and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea.
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George S, Lucero Y, Torres JP, Lagomarcino AJ, O'Ryan M. Gastric Damage and Cancer-Associated Biomarkers in Helicobacter pylori-Infected Children. Front Microbiol 2020; 11:90. [PMID: 32117120 PMCID: PMC7029740 DOI: 10.3389/fmicb.2020.00090] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 01/15/2020] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori (H. pylori) is well-known to be involved in gastric carcinogenesis, associated with deregulation of cell proliferation and epigenetic changes in cancer-related genes. H. pylori infection is largely acquired during childhood, persisting long-term in about half of infected individuals, a subset of whom will go on to develop peptic ulcer disease and eventually gastric cancer, however, the sequence of events leading to disease is not completely understood. Knowledge on carcinogenesis and gastric damage-related biomarkers is abundant in adult populations, but scarce in children. We performed an extensive literature review focusing on gastric cancer related biomarkers identified in adult populations, which have been detected in children infected with H. pylori. Biomarkers were related to expression levels (RNA or protein) and/or methylation levels (DNA) in gastric tissue or blood of infected children as compared to non-infected controls. In this review, we identified 37 biomarkers of which 24 are over expressed, three are under expressed, and ten genes are significantly hypermethylated in H. pylori-infected children compared to healthy controls in at least 1 study. Only four of these biomarkers (pepsinogen I, pepsinogen II, gastrin, and SLC5A8) have been studied in asymptomatically infected children. Importantly, 13 of these biomarkers (β-catenin, C-MYC, GATA-4, DAPK1, CXCL13, DC-SIGN, TIMP3, EGFR, GRIN2B, PIM2, SLC5A8, CDH1, and VCAM-1.) are consistently deregulated in infected children and in adults with gastric cancer. Future studies should be designed to determine the clinical significance of these changes in infection-associated biomarkers in children and their persistence over time. The effect of eradication therapy over these biomarkers in children if proven significant, could lead to modifications in treatment guidelines for younger populations, and eventually promote the development of preventive strategies, such as vaccination, in the near future.
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Affiliation(s)
- Sergio George
- Host-Pathogen Interaction Laboratory, Microbiology and Mycology Program, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Yalda Lucero
- Host-Pathogen Interaction Laboratory, Microbiology and Mycology Program, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile.,Department of Pediatrics and Pediatric Surgery, Dr. Roberto del Río Hospital, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Juan Pablo Torres
- Host-Pathogen Interaction Laboratory, Microbiology and Mycology Program, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile.,Department of Pediatrics and Pediatric Surgery, Dr. Luis Calvo Mackenna Hospital, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Anne J Lagomarcino
- Host-Pathogen Interaction Laboratory, Microbiology and Mycology Program, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Miguel O'Ryan
- Host-Pathogen Interaction Laboratory, Microbiology and Mycology Program, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy (IMII), Faculty of Medicine, Universidad de Chile, Santiago, Chile
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A Cholecystokinin Receptor Antagonist Halts Nonalcoholic Steatohepatitis and Prevents Hepatocellular Carcinoma. Dig Dis Sci 2020; 65:189-203. [PMID: 31297627 PMCID: PMC6946881 DOI: 10.1007/s10620-019-05722-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 07/03/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Nonalcoholic steatohepatitis (NASH) is a common inflammatory liver condition that may lead to cirrhosis and hepatocellular carcinoma (HCC). Risk factors for NASH include a saturated fat diet, altered lipid metabolism, and genetic and epigenetic factors, including microRNAs. Serum levels of cholecystokinin (CCK) are elevated in mice and humans that consume a high-saturated fat diet. CCK receptors (CCK-Rs) have been reported on fibroblasts which when activated can induce fibrosis; however, their role in hepatic fibrosis remains unknown. We hypothesized that elevated levels of CCK acting on the CCK-Rs play a role in the development of NASH and in NASH-associated HCC. METHODS We performed a NASH Prevention study and Reversal study in mice fed a saturated fat 75% choline-deficient-ethionine-supplemented (CDE) diet for 12 or 18 weeks. In each study, half of the mice received untreated drinking water, while the other half received water supplemented with the CCK-R antagonist proglumide. CCK-R expression was evaluated in mouse liver and murine HCC cells. RESULTS CCK receptor antagonist treatment not only prevented NASH but also reversed hepatic inflammation, fibrosis, and steatosis and normalized hepatic transaminases after NASH was established. Thirty-five percent of the mice on the CDE diet developed HCC compared with none in the proglumide-treated group. We found that CCK-BR expression was markedly upregulated in mouse CDE liver and HCC cells compared with normal hepatic parenchymal cells, and this expression was epigenetically regulated by microRNA-148a. CONCLUSION These results support the novel role of CCK receptors in the pathogenesis of NASH and HCC.
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Lee L, Ramos-Alvarez I, Ito T, Jensen RT. Insights into Effects/Risks of Chronic Hypergastrinemia and Lifelong PPI Treatment in Man Based on Studies of Patients with Zollinger-Ellison Syndrome. Int J Mol Sci 2019; 20:5128. [PMID: 31623145 PMCID: PMC6829234 DOI: 10.3390/ijms20205128] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/08/2019] [Accepted: 10/13/2019] [Indexed: 02/07/2023] Open
Abstract
The use of proton pump inhibitors (PPIs) over the last 30 years has rapidly increased both in the United States and worldwide. PPIs are not only very widely used both for approved indications (peptic ulcer disease, gastroesophageal reflux disease (GERD), Helicobacter pylori eradication regimens, stress ulcer prevention), but are also one of the most frequently off-label used drugs (25-70% of total). An increasing number of patients with moderate to advanced gastroesophageal reflux disease are remaining on PPI indefinitely. Whereas numerous studies show PPIs remain effective and safe, most of these studies are <5 years of duration and little data exist for >10 years of treatment. Recently, based primarily on observational/epidemiological studies, there have been an increasing number of reports raising issues about safety and side-effects with very long-term chronic treatment. Some of these safety issues are related to the possible long-term effects of chronic hypergastrinemia, which occurs in all patients taking chronic PPIs, others are related to the hypo-/achlorhydria that frequently occurs with chronic PPI treatment, and in others the mechanisms are unclear. These issues have raised considerable controversy in large part because of lack of long-term PPI treatment data (>10-20 years). Zollinger-Ellison syndrome (ZES) is caused by ectopic secretion of gastrin from a neuroendocrine tumor resulting in severe acid hypersecretion requiring life-long antisecretory treatment with PPIs, which are the drugs of choice. Because in <30% of patients with ZES, a long-term cure is not possible, these patients have life-long hypergastrinemia and require life-long treatment with PPIs. Therefore, ZES patients have been proposed as a good model of the long-term effects of hypergastrinemia in man as well as the effects/side-effects of very long-term PPI treatment. In this article, the insights from studies on ZES into these controversial issues with pertinence to chronic PPI use in non-ZES patients is reviewed, primarily concentrating on data from the prospective long-term studies of ZES patients at NIH.
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Affiliation(s)
- Lingaku Lee
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA.
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
| | | | - Tetsuhide Ito
- Neuroendocrine Tumor Centra, Fukuoka Sanno Hospital, International University of Health and Welfare 3-6-45 Momochihama, Sawara-Ku, Fukuoka 814-0001, Japan.
| | - Robert T Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA.
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Lyudovyk O, Shen Y, Tatonetti NP, Hsiao SJ, Mansukhani MM, Weng C. Pathway analysis of genomic pathology tests for prognostic cancer subtyping. J Biomed Inform 2019; 98:103286. [PMID: 31499184 PMCID: PMC7136846 DOI: 10.1016/j.jbi.2019.103286] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 09/01/2019] [Accepted: 09/05/2019] [Indexed: 10/26/2022]
Abstract
Genomic test results collected during the provision of medical care and stored in Electronic Health Record (EHR) systems represent an opportunity for clinical research into disease heterogeneity and clinical outcomes. In this paper, we evaluate the use of genomic test reports ordered for cancer patients in order to derive cancer subtypes and to identify biological pathways predictive of poor survival outcomes. A novel method is proposed to calculate patient similarity based on affected biological pathways rather than gene mutations. We demonstrate that this approach identifies subtypes of prognostic value and biological pathways linked to survival, with implications for precision treatment selection and a better understanding of the underlying disease. We also share lessons learned regarding the opportunities and challenges of secondary use of observational genomic data to conduct such research.
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Affiliation(s)
- Olga Lyudovyk
- Department of Biomedical Informatics, Columbia University, New York, NY, USA
| | - Yufeng Shen
- Department of Biomedical Informatics, Columbia University, New York, NY, USA
| | | | - Susan J Hsiao
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Mahesh M Mansukhani
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Chunhua Weng
- Department of Biomedical Informatics, Columbia University, New York, NY, USA.
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Jakubek M, Kejík Z, Kaplánek R, Hromádka R, Šandriková V, Sýkora D, Antonyová V, Urban M, Dytrych P, Mikula I, Martásek P, Král V. Strategy for improved therapeutic efficiency of curcumin in the treatment of gastric cancer. Biomed Pharmacother 2019; 118:109278. [PMID: 31387004 DOI: 10.1016/j.biopha.2019.109278] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 07/24/2019] [Accepted: 07/25/2019] [Indexed: 02/08/2023] Open
Abstract
Gastric cancer is a common oncological disease. Although enormous efforts have been expended, possible therapeutic modalities are still limited. For this reason, new therapeutic approaches and agents are highly requested and intensively developed. One strategy is the application of natural agents, such as curcumin, with proven anticancer effects and low toxicity for patients. Therefore, this review discusses the potential application of curcumin in the therapy of gastric cancer and its potential incorporation in therapeutic regimens. Because one of the largest impediments for widespread curcumin application is its limited bioavailability (caused mainly by its very low water solubility), studied strategies (drug delivery systems and curcumin derivatization) aimed to solve this obstacle are discussed in more detail.
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Affiliation(s)
- Milan Jakubek
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 121 00 Prague 2, Czech Republic; Department of Analytical Chemistry, Faculty of Chemical Engineering, University of Chemistry and Technology, Technická 5, 166 28 Prague 6, Czech Republic.
| | - Zdeněk Kejík
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 121 00 Prague 2, Czech Republic
| | - Robert Kaplánek
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Analytical Chemistry, Faculty of Chemical Engineering, University of Chemistry and Technology, Technická 5, 166 28 Prague 6, Czech Republic
| | - Róbert Hromádka
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Research and Development Center C2P s.r.o., Jungmannova 101, 503 51 Chlumec nad Cidlinou, Czech Republic
| | - Viera Šandriková
- Research and Development Center C2P s.r.o., Jungmannova 101, 503 51 Chlumec nad Cidlinou, Czech Republic
| | - David Sýkora
- Department of Analytical Chemistry, Faculty of Chemical Engineering, University of Chemistry and Technology, Technická 5, 166 28 Prague 6, Czech Republic
| | - Veronika Antonyová
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 121 00 Prague 2, Czech Republic
| | - Marian Urban
- Food Research Institute Prague, Radiová 1285/7, 1285/7, Prague 10, Czech Republic
| | - Petr Dytrych
- 1st Department of Surgery - Department of Abdominal, Thoracic Surgery and Traumatology, First Faculty of Medicine, Charles University and General University Hospital in Prague, U Nemocnice 2, 128 08 Prague 2, Czech Republic
| | - Ivan Mikula
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic
| | - Pavel Martásek
- Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 121 00 Prague 2, Czech Republic
| | - Vladimír Král
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 121 00 Prague 2, Czech Republic; Department of Analytical Chemistry, Faculty of Chemical Engineering, University of Chemistry and Technology, Technická 5, 166 28 Prague 6, Czech Republic
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Uchida M, Kondo Y, Suzuki S, Hosohata K. Evaluation of Acute Kidney Injury Associated With Anticancer Drugs Used in Gastric Cancer in the Japanese Adverse Drug Event Report Database. Ann Pharmacother 2019; 53:1200-1206. [PMID: 31347378 DOI: 10.1177/1060028019865870] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background: Development of acute kidney injury (AKI) depends on the severity of renal dysfunction, clinical setting, comorbid factors, and geographical location. Gastric cancer is one of the deadliest malignancies worldwide, and its incidence is significantly high in Japan. Objective: We analyzed the rank-order of the association of anticancer agents for gastric cancer with AKI using a spontaneous reporting system database, the Japanese Adverse Drug Event Report database. Methods: We performed a retrospective pharmacovigilance disproportionality analysis using the adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between April 2004 and March 2017. Results: Anticancer drug-related AKI was common in patients in their 60s and 70s (39.2% and 43.2%, respectively). AKI occurred most frequently within 1 month after anticancer drug administration. The signals of AKI were reported after treatment with S-1 (tegafur/gimeracil/oteracil), cisplatin (CDDP), and capecitabine, with significant adjusted reporting odds ratios (95% CI) of 1.50 (1.09-2.07), 3.43 (2.48-4.74), and 1.82 (1.15-2.90), respectively. CDDP-induced AKI was more likely to occur in patients who were male, hypertension, or diabetes mellitus. Conclusion and Relevance: This study showed that most AKI cases were related to S-1 and/or CDDP adjuvant chemotherapy for gastric cancer treatment. The data also clarified that AKIs occurred within 1 month and that their clinical outcomes were more severe than previous reports of drug-induced AKI in general medicine. Our study provides useful information to minimize the risks of administration to patients at high risk for S-1 and/or CDDP containing chemotherapy-induced AKI.
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Affiliation(s)
- Mayako Uchida
- Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan
| | - Yuki Kondo
- Kumamoto University, Chuo-ku, Kumamoto, Japan
| | - Shinya Suzuki
- National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Keiko Hosohata
- Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan
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Parra-Medina R, Moreno-Lucero P, Jimenez-Moreno J, Parra-Morales AM, Romero-Rojas A. Neuroendocrine neoplasms of gastrointestinal tract and secondary primary synchronous tumors: A systematic review of case reports. Casualty or causality? PLoS One 2019; 14:e0216647. [PMID: 31086397 PMCID: PMC6516644 DOI: 10.1371/journal.pone.0216647] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 04/26/2019] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Neuroendocrine neoplasms (NENs) can arise in most of the epithelial organs of the body and are not a rare condition in the gastrointestinal tract (GIT). The presence of NENs in GIT associated with other secondary primary malignancies (SPM) has been considered an exotic event. This study aims to describe the case reports of NENs accompanied by synchronous primary tumors. METHODS AND FINDINGS We performed a systematic literature search of the databases Scopus, PubMed, Scielo and LILACS to identify case reports that described the presence of NENs in GIT with SPM. 78 case reports were included. The mean of age of the cases was 60.2 years. 60% were male. 95.4% were NENs G1. 17 cases of NENs had metastasis. 80% of SPM were recognized in the GIT (36% in stomach, 27% in large intestine, 11.2% in small intestine, and 5.6% in esophagus). The most common type of SPM was adenocarcinoma (49.4%), followed by GIST (13.5%), other NENs in different GIT segment (7.9%), lymphoma (6.8%), and squamous cell carcinoma (4.5%). The most common tumor in GIT was adenocarcinoma (97.6%) and the presence of adenocarcinoma in the same segment of GIT was found in 68.4% of the cases. Association between adenocarcinomas and NENs in GIT (p:<0.0001) and adenocarcinoma and tumor in the same segment of GIT location were observed (p<0.001). CONCLUSION These results demonstrate that NENs with SPM are not a rare condition. Several theories have been proposed to explain this association; one of these is the ability of NENs to generate synchronous tumors by autocrine and paracrine effect. We observed an association between adenocarcinomas and NENs in the same segment of GIT.
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Affiliation(s)
- Rafael Parra-Medina
- Research Institute, Fundación Universitaria de Ciencias de la salud, Bogotá, Colombia
- Department of Pathology, Fundación Universitaria de Ciencias de la salud, Bogotá, Colombia
- * E-mail:
| | - Paula Moreno-Lucero
- Department of Pathology, Fundación Universitaria de Ciencias de la salud, Bogotá, Colombia
| | - Julian Jimenez-Moreno
- Department of Pathology, Fundación Universitaria de Ciencias de la salud, Bogotá, Colombia
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Yeh YC, Kuo HY, Chang WL, Yang HB, Lu CC, Cheng HC, Wu MS, Sheu BS. H. pylori isolates with amino acid sequence polymorphisms as presence of both HtrA-L171 & CagL-Y58/E59 increase the risk of gastric cancer. J Biomed Sci 2019; 26:4. [PMID: 30611258 PMCID: PMC6321681 DOI: 10.1186/s12929-019-0498-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 01/02/2019] [Indexed: 12/14/2022] Open
Abstract
Background H. pylori CagL-Y58/E59 increase gastric cancer risk by stronger binding with integrin to faciliate type IV secretory system (T4SS). H. pylori can secrete high temperature requirement A (HtrA) to mediate E-Cadherin cleavage for gastric epithelial junction disruption, so H. pylori CagL can adhere to integrin located on basolateral side of epithelium. The study test whether H. pylori HtrA amino acid polymorphisms can increase gastric cancer risk synergistically with CagL-Y58/E59. Methods One-hundred and sixty-four H. pylori-positive patients, including 71 with non-ulcer dyspepsia (NUD), 63 with peptic ulcers (PU), and 30 with gastric cancers (GC), were enrolled to receive upper gastrointestinal endoscopy to obtain gastric biopsies for H. pylori culture and histology by the updated Sydney system. Each isolate was screened for htrA & cagL genotype by polymerase chain reaction and HtrA & CagL-Y58/E59 amino acid sequence polymorphisms by sequencing. Results The prevalence rates of htrA & cagL gene were both 100%. The HtrA amino acid sequence polymorphisms were not different between NUD and PU. The H. pylori isolates of GC had higher rates of HtrA residue 171 as leucine than those of NUD (73.3% vs. 50.7%, P = 0.036, OR[95%CI] = 2.7[1.1–6.8]). The risk of the H. pylori-infected subjects to get gastric cancer was increased up to 15.4-fold, if the infected isolates had presence of both HtrA-L171 and CagL-Y58/E59 (P < 0.001). Conclusions The H. pylori isolates of gastric cancer subjects had a higher rate of HtrA-L171. H. pylori isolates with presence of both HtrA-171 & CagL-Y58/E59 can synergistically increase the risk of gastric cancer. Electronic supplementary material The online version of this article (10.1186/s12929-019-0498-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yi-Chun Yeh
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hsin-Yu Kuo
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wei-Lun Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hsiao-Bai Yang
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Pathology, Ton Yen General Hospital, Hsin-Chu, Taiwan
| | - Cheng-Chan Lu
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hsiu-Chi Cheng
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Bor-Shyang Sheu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. .,Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, 125 Chuang Shan Road, Tainan, Taiwan.
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Polymorphisms in RAS/RAF/MEK/ERK Pathway Are Associated with Gastric Cancer. Genes (Basel) 2018; 10:genes10010020. [PMID: 30597917 PMCID: PMC6356706 DOI: 10.3390/genes10010020] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 12/19/2018] [Accepted: 12/21/2018] [Indexed: 01/02/2023] Open
Abstract
The RAS/RAF/MEK/ERK pathway regulates certain cellular functions, including cell proliferation, differentiation, survival, and apoptosis. Dysregulation of this pathway leads to the occurrence and progression of cancers mainly by somatic mutations. This study aimed to assess if polymorphisms of the RAS/RAF/MEK/ERK pathway are associated with gastric cancer. A case-control study of 242 gastric cancer patients and 242 controls was performed to assess the association of 27 single nucleotide polymorphisms (SNPs) in the RAS/RAF/MEK/ERK pathway genes with gastric cancer. Analyses performed under the additive model (allele) showed four significantly associated SNPs: RAF1 rs3729931 (Odds ratio (OR) = 1.54, 95%, confidence interval (CI): 1.20–1.98, p-value = 7.95 × 10−4), HRAS rs45604736 (OR = 1.60, 95% CI: 1.16–2.22, p-value = 4.68 × 10−3), MAPK1 rs2283792 (OR = 1.45, 95% CI: 1.12–1.87, p-value = 4.91 × 10−3), and MAPK1 rs9610417 (OR = 0.60, 95% CI: 0.42–0.87, p-value = 6.64 × 10−3). Functional annotation suggested that those variants or their proxy variants may have a functional effect. In conclusion, this study suggests that RAF1 rs3729931, HRAS rs45604736, MAPK1 rs2283792, and MAPK1 rs9610417 are associated with gastric cancer.
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Nakano K, Nishizawa T, Komura D, Fujii E, Monnai M, Kato A, Funahashi SI, Ishikawa S, Suzuki M. Difference in morphology and interactome profiles between orthotopic and subcutaneous gastric cancer xenograft models. J Toxicol Pathol 2018; 31:293-300. [PMID: 30393433 PMCID: PMC6206286 DOI: 10.1293/tox.2018-0020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 07/22/2018] [Indexed: 01/21/2023] Open
Abstract
In xenograft models, orthotopic (ORT) engraftment is thought to provide a different tumor microenvironment compared with subcutaneous (SC) engraftment. We attempted to characterize the biological difference between OE19 (adenocarcinoma of the gastroesophageal junction) SC and ORT models by pathological analysis and CASTIN (CAncer-STromal INteractome) analysis, which is a novel method developed to analyze the tumor-stroma interactome framework. In SC models, SCID mice were inoculated subcutaneously with OE19 cells, and tumor tissues were sampled at 3 weeks. In ORT models, SCID mice were inoculated under the serosal membrane of the stomach wall, and tumor tissues were sampled at 3 and 6 weeks after engraftment. Results from the two models were then compared. Histopathologically, the SC tumors were well circumscribed from the adjacent tissue, with scant stroma and the formation of large ductal structures. In contrast, the ORT tumors were less circumscribed, with small ductal structures invading into abundant stroma. Then we compared the transcriptome profiles of human tumor cells with the mouse stromal cells of each model by species-specific RNA sequencing. With CASTIN analysis, we successfully identified several interactions that are known to affect the tumor microenvironment as being selectively enhanced in the ORT model. In conclusion, pathological analysis and CASTIN analysis revealed that ORT models of OE19 cells have a more invasive character and enhanced interaction with stromal cells compared with SC models.
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Affiliation(s)
- Kiyotaka Nakano
- Forerunner Pharma Research Co., Ltd., Komaba Open Laboratory, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
| | - Takashi Nishizawa
- Forerunner Pharma Research Co., Ltd., Komaba Open Laboratory, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
| | - Daisuke Komura
- Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Etsuko Fujii
- Forerunner Pharma Research Co., Ltd., Komaba Open Laboratory, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan.,Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan
| | - Makoto Monnai
- Chugai Research Institute for Medical Science Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan
| | - Atsuhiko Kato
- Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan
| | - Shin-Ichi Funahashi
- Forerunner Pharma Research Co., Ltd., Komaba Open Laboratory, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
| | - Shumpei Ishikawa
- Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Masami Suzuki
- Forerunner Pharma Research Co., Ltd., Komaba Open Laboratory, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
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Zu LD, Peng XC, Zeng Z, Wang JL, Meng LL, Shen WW, Hu CT, Yang Y, Fu GH. Gastrin inhibits gastric cancer progression through activating the ERK-P65-miR23a/27a/24 axis. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:115. [PMID: 29866191 PMCID: PMC5987590 DOI: 10.1186/s13046-018-0782-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 05/01/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND To test the hypothesis that activated extracellular signal-regulated kinase (ERK) regulates P65-miR23a/27a/24 axis in gastric cancer (GC) and the ERK-P65-miR23a/27a/24 axis plays an important role in the development of GC, and to evaluate the role of gastrin in GC progression and ERK-P65-miR23a/27a/24 axis. METHODS The component levels of the ERK-P65-miR23a/27a/24 axis in four fresh GC tissues, 101 paraffin-embedded GC tissues and four GC cell lines were determined by Western blotting, immunohistochemistry (IHC) or qRT-PCR. The effects of gastrin on GC were first evaluated by measuring gastrin serum levels in 30 healthy and 70 GC patients and performing a correlation analysis between gastrin levels and survival time in 27 GC patients after eight years of follow-up, then evaluated on GC cell lines, GC cell xenograft models, and patient-derived xenografts (PDX) mouse models. The roles of ERK-P65-miR23a/27a/24 axis in GC progression and in the effects of gastrin on GC were examined. RESULTS ERK- P65-miR23a/27a/24 axis was proved to be present in GC cells. The levels of components of ERK-P65-miR23a/27a/24 axis were decreased in GC tissue samples and PGC cells. The decreased levels of components of ERK-P65-miR23a/27a/24 axis were associated with poor prognosis of GC, and ERK-P65-miR23a/27a/24 axis played a suppressive role in GC progression. Low blood gastrin was correlated with poor prognosis of the GC patients and decreased expression of p-ERK and p-P65 in GC tissues. Gastrin inhibited proliferation of poorly-differentiated GC (PGC) cells through activating the ERK-P65-miR23a/27a/24 axis. Gastrin inhibited GC growth and enhanced the suppression of GC by cisplatin in mice or PGC cell culture models through activating the ERK-P65-miR23a/27a/24 axis or its components. CONCLUSIONS ERK-P65-miR23a/27a/24 axis is down-regulated, leading to excess GC growth and poor prognosis of GC. Low gastrin promoted excess GC growth and contributed to the poor prognosis of the GC patients by down-regulating ERK-P65-miR23a/27a/24 axis. Gastrin inhibits gastric cancer growth through activating the ERK-P65-miR23a/27a/24 axis.
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Affiliation(s)
- Li-Dong Zu
- Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xing-Chun Peng
- Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhi Zeng
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jing-Long Wang
- Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li-Li Meng
- Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei-Wei Shen
- Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chun-Ting Hu
- Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ye Yang
- Department of Digestive Medicine, Ningbo No. 2 Hospital, Ningbo, 315010, China
| | - Guo-Hui Fu
- Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, No. 280, South Chong-Qing Road, Shanghai, 200025, People's Republic of China.
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Vaziri F, Tarashi S, Fateh A, Siadat SD. New insights of Helicobacter pylori host-pathogen interactions: The triangle of virulence factors, epigenetic modifications and non-coding RNAs. World J Clin Cases 2018; 6:64-73. [PMID: 29774218 PMCID: PMC5955730 DOI: 10.12998/wjcc.v6.i5.64] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 02/09/2018] [Accepted: 03/07/2018] [Indexed: 02/05/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a model organism for understanding host-pathogen interactions and infection-mediated carcinogenesis. Gastric cancer and H. pylori colonization indicates the strong correlation. The progression and exacerbation of H. pylori infection are influenced by some factors of pathogen and host. Several virulence factors involved in the proper adherence and attenuation of immune defense to contribute the risk of emerging gastric cancer, therefore analysis of them is very important. H. pylori also modulates inflammatory and autophagy process to intensify its pathogenicity. From the host regard, different genetic factors particularly affect the development of gastric cancer. Indeed, epigenetic modifications, MicroRNA and long non-coding RNA received more attention. Generally, various factors related to pathogen and host that modulate gastric cancer development in response to H. pylori need more attention due to develop an efficacious therapeutic intervention. Therefore, this paper will present a brief overview of host-pathogen interaction especially emphases on bacterial virulence factors, interruption of host cellular signaling, the role of epigenetic modifications and non-coding RNAs.
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Affiliation(s)
- Farzam Vaziri
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Samira Tarashi
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Abolfazl Fateh
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Seyed Davar Siadat
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
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Mommersteeg MC, Yu J, Peppelenbosch MP, Fuhler GM. Genetic host factors in Helicobacter pylori-induced carcinogenesis: Emerging new paradigms. Biochim Biophys Acta Rev Cancer 2017; 1869:42-52. [PMID: 29154808 DOI: 10.1016/j.bbcan.2017.11.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 11/13/2017] [Accepted: 11/13/2017] [Indexed: 02/09/2023]
Abstract
Helicobacter Pylori is a gram negative rod shaped microaerophilic bacterium that colonizes the stomach of approximately half the world's population. Infection with c may cause chronic gastritis which via a quite well described process known as Correas cascade can progress through sequential development of atrophic gastritis, intestinal metaplasia and dysplasia to gastric cancer. H. pylori is currently the only bacterium that is classified as a class 1 carcinogen by the WHO, although the exact mechanisms by which this bacterium contributes to gastric carcinogenesis are still poorly understood. Only a minority of H. pylori-infected patients will eventually develop gastric cancer, suggesting that host factors may be important in determining the outcome of H. pylori infection. This is supported by a growing body of evidence suggesting that the host genetic background contributes to risk of H. pylori infection and gastric carcinogenesis. In particular single nucleotide polymorphisms in genes that influence bacterial handling via pattern recognition receptors appear to be involved, further strengthening the link between host risk factors, H. pylori incidence and cancer. Many of these genes influence cellular pathways leading to inflammatory signaling, inflammasome formation and autophagy. In this review we summarize known carcinogenic effects of H. pylori, and discuss recent findings that implicate host genetic pattern recognition pathways in the development of gastric cancer and their relation with H. pylori.
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Affiliation(s)
- Michiel C Mommersteeg
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical center Rotterdam, Office NA-619, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
| | - Jun Yu
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences and CUHK-Shenzhen Research Institute, Rm 707A, 7/F., Li Ka Shing Medical Science Building, The Chinese University of Hong Kong, Hong Kong.
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical center Rotterdam, Office NA-619, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
| | - Gwenny M Fuhler
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical center Rotterdam, Office NA-619, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
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Arin RM, Gorostidi A, Navarro-Imaz H, Rueda Y, Fresnedo O, Ochoa B. Adenosine: Direct and Indirect Actions on Gastric Acid Secretion. Front Physiol 2017; 8:737. [PMID: 29018360 PMCID: PMC5614973 DOI: 10.3389/fphys.2017.00737] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 09/11/2017] [Indexed: 12/12/2022] Open
Abstract
Composed by a molecule of adenine and a molecule of ribose, adenosine is a paradigm of recyclable nucleoside with a multiplicity of functions that occupies a privileged position in the metabolic and regulatory contexts. Adenosine is formed continuously in intracellular and extracellular locations of all tissues. Extracellular adenosine is a signaling molecule, able to modulate a vast range of physiologic responses in many cells and organs, including digestive organs. The adenosine A1, A2A, A2B, and A3 receptors are P1 purinergic receptors, G protein-coupled proteins implicated in tissue protection. This review is focused on gastric acid secretion, a process centered on the parietal cell of the stomach, which contains large amounts of H+/K+-ATPase, the proton pump responsible for proton extrusion during acid secretion. Gastric acid secretion is regulated by an extensive collection of neural stimuli and endocrine and paracrine agents, which act either directly at membrane receptors of the parietal cell or indirectly through other regulatory cells of the gastric mucosa, as well as mechanic and chemic stimuli. In this review, after briefly introducing these points, we condense the current body of knowledge about the modulating action of adenosine on the pathophysiology of gastric acid secretion and update its significance based on recent findings in gastric mucosa and parietal cells in humans and animal models.
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Affiliation(s)
- Rosa M Arin
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU)Leioa, Spain
| | - Adriana Gorostidi
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU)Leioa, Spain
| | - Hiart Navarro-Imaz
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU)Leioa, Spain
| | - Yuri Rueda
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU)Leioa, Spain
| | - Olatz Fresnedo
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU)Leioa, Spain
| | - Begoña Ochoa
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU)Leioa, Spain
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