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1
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Zhang WJ, Luo HL, Liu JP, Xu YS, Wang WL, Huang C. P2X7 receptor promotes the growth and metastasis of gastric cancer by activating P13/AKT/GSK-3 beta signaling (experimental research). Int J Surg 2025; 111:3752-3766. [PMID: 40265472 PMCID: PMC12165481 DOI: 10.1097/js9.0000000000002406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 04/03/2025] [Indexed: 04/24/2025]
Abstract
OBJECTIVE This study investigated the role of P2X7 receptor (P2X7R) in the proliferation and metastasis of gastric cancer (GC). METHODS The functional role and possible mechanism of P2X7R in the progression of GC were investigated through in vitro and in vivo experiments. RESULTS The results showed that ATP and its analogue BzATP increased calcium current in AGS and HGC-27 cells, while P2X7R antagonists A438079 and AZD9056 decreased the ATP-induced calcium influx. Activation of P2X7R increased the glycogen accumulation in GC cells, enhanced the stress ability of actin fibers and cell morphology changes, and promoted the proliferation, migration and invasion of GC cells. Conversely, the application of A438079, AZD9056 or siP2X7R inhibited the proliferation, migration and invasion of GC cells. Moreover, activation of P2X7R increased the expression levels of EMT/metastasis related genes MMP-2, MMP-9, N-cadherin, Zeb1, Vimentin and Snail, hut decreased the E-cadherin expression. While A438069, AZD9056, LY294002 or siP2X7R reversed the expression of the above genes. Activation of P2X7R activated P13/AKT/GSK-3beta signaling to promote the proliferation, migration and invasion of GC. Additionally, in vivo experiments showed that ATP activated P2X7R to induce the growth of tumors. CONCLUSIONS Our conclusion is that activation of P2X7R promotes the proliferation, metastasis and EMT of GC cells by activating P13/AKT/GSK-3beta signaling, and indicates that P2X7R may become a new potential target for GC treatment.
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Affiliation(s)
- Wen-Jun Zhang
- Department of Rehabilitation Medicine, The second affiliated hospital, Jiangxi Medical College, Nanchang University, Nanchang city, Jiangxi province, China
| | - Hong-Liang Luo
- Department of Gastrointestinal Surgery, The second affiliated hospital, Jiangxi Medical College, Nanchang University, Nanchang city, Jiangxi province, China
| | - Ji-Peng Liu
- Department of Gastrointestinal Surgery, The second affiliated hospital, Jiangxi Medical College, Nanchang University, Nanchang city, Jiangxi province, China
| | - Yong-Sheng Xu
- Department of Gastrointestinal Surgery, The second affiliated hospital, Jiangxi Medical College, Nanchang University, Nanchang city, Jiangxi province, China
| | - Wen-Long Wang
- Department of Emergency Medical, The second affiliated hospital, Jiangxi Medical College, Nanchang University, Nanchang city, Jiangxi province, China
| | - Chao Huang
- Department of Gastrointestinal Surgery, The second affiliated hospital, Jiangxi Medical College, Nanchang University, Nanchang city, Jiangxi province, China
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2
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Di Benedetto G, Varvarà P, Drago SE, Cantone AF, Mauro N, Gaudio G, Burgaletto C, Bellanca CM, Broggi G, Caltabiano R, Pitarresi G, Cantarella G, Giammona G, Bernardini R. Targeted delivery of sorafenib via biotin decorated polyaminoaspartamide-based nanoparticles for the hepatocarcinoma treatment. Int J Pharm 2025; 678:125729. [PMID: 40379225 DOI: 10.1016/j.ijpharm.2025.125729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2025] [Revised: 05/12/2025] [Accepted: 05/13/2025] [Indexed: 05/19/2025]
Abstract
Hepatocellular carcinoma (HCC), the most common primary liver cancer, faces treatment challenges due to drug resistance and poor bioavailability, with sorafenib, a key therapy, characterized by rapid clearance and significant side effects. This paper describes the development of amphiphilic graft copolymers for efficient loading and delivery of sorafenib through controlled Atom Transfer Radical Polymerization (ATRP). The amphiphilic graft copolymer PHEA-g-IB-(pButMA)-g-PEG-Bt was synthesized to enhance tumor specificity via biotin-mediated targeting. The synthesis involved a three-step process, with successful functionalization confirmed through NMR and Size Exclusion Chromatography (SEC) analyses. Sorafenib-loaded nanoparticles, prepared via dialysis-based nanoprecipitation, exhibited a mean size of ∼ 300 nm, suitable for oral and parenteral administration, while drug release studies confirmed a sustained release profile, minimizing premature systemic loss and reducing the need for frequent administration. Evaluation of cytocompatibility and anticancer efficacy tested in vitro on HepG2 and HuH-7 cell lines revealed that biotinylated sorafenib-loaded nanoparticles had the highest ability to reduce cell viability. The enhanced anticancer effect of biotinylated NPs was validated in vivo using a murine tumor xenograft model, as evidenced by reduced tumor growth, lower Ki-67 proliferation index, and diminished CD31-positive vasculature. Protein expression analysis demonstrated that PBB-Bt@SOR elicited the strongest activation of p-p38 MAPK and caspase-8-mediated apoptosis, while enhancing the expression of the pro-survival AKT pathway. Overall, the study confirms that biotinylated sorafenib-loaded nanoparticles improve tumor suppression in HCC models, demonstrating their effectiveness in targeted drug delivery. These findings suggest biotin decorated polyamino aspartamide-based nanoparticles as a promising strategy to optimize chemotherapy regimens, minimizing systemic toxicity in HCC treatment.
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Affiliation(s)
- Giulia Di Benedetto
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Via Santa Sofia 97, 95123 Catania, Italy
| | - Paola Varvarà
- Laboratory of Biocompatible Polymers, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy
| | - Salvatore Emanuele Drago
- Laboratory of Biocompatible Polymers, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy
| | - Anna Flavia Cantone
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Via Santa Sofia 97, 95123 Catania, Italy
| | - Nicolò Mauro
- Laboratory of Biocompatible Polymers, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy
| | - Gabriella Gaudio
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Via Santa Sofia 97, 95123 Catania, Italy
| | - Chiara Burgaletto
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Via Santa Sofia 97, 95123 Catania, Italy
| | - Carlo Maria Bellanca
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Via Santa Sofia 97, 95123 Catania, Italy
| | - Giuseppe Broggi
- Department of Medical, Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Anatomic Pathology, University of Catania, Via Santa Sofia 87, 95123 Catania, Italy
| | - Rosario Caltabiano
- Department of Medical, Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Anatomic Pathology, University of Catania, Via Santa Sofia 87, 95123 Catania, Italy
| | - Giovanna Pitarresi
- Laboratory of Biocompatible Polymers, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy.
| | - Giuseppina Cantarella
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Via Santa Sofia 97, 95123 Catania, Italy.
| | - Gaetano Giammona
- Laboratory of Biocompatible Polymers, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy
| | - Renato Bernardini
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Via Santa Sofia 97, 95123 Catania, Italy
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3
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Bai Y, Osmundson EC, Donahue MJ, De Vis JB. Magnetic resonance imaging to detect tumor hypoxia in brain malignant disease: A systematic review of validation studies. Clin Transl Radiat Oncol 2025; 52:100940. [PMID: 40093743 PMCID: PMC11908384 DOI: 10.1016/j.ctro.2025.100940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 02/17/2025] [Accepted: 02/25/2025] [Indexed: 03/19/2025] Open
Abstract
Tumor hypoxia indicates a worse prognosis in brain malignancies; however, current gold-standard methods for assessing tumor hypoxia are invasive and often inaccessible. Magnetic Resonance Imaging (MRI) is widely available, but its validity for identifying tumor hypoxia or hypoxia-related neoangiogenesis is not well characterized. A systematic literature search was performed across PubMed and Embase Databases. The search query identified MRI studies that validated hypoxia-surrogate imaging sequences against gold-standard hypoxia or neoangiogenesis detection methods in patients with brain malignancies. Literature screen identified 23 manuscripts published between 2007 and 2022. Among conventional MRI sequences, peritumoral edema and signal change after contrast administration were associated with gold-standard oxygen-assessment methods. T2*- and T2'-derived measures were associated with gold-standard methods, while reports on quantitative measures of oxygen extraction fraction were conflicting. Fiber density, tissue cellularity, blood volume, vascular transit time, and permeability measurements were associated with gold-standard methods, whereas blood flow measurements yielded conflicting results. MRI measures are promising surrogates for tumor hypoxia or hypoxia-related neoangiogenesis. Additional studies are needed to reconcile disparate findings. Future sensitivity analyses are needed to establish the MRI methods most accurate at identifying tumor hypoxia.
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Affiliation(s)
- Y Bai
- Vanderbilt School of Medicine, Vanderbilt University, Nashville, TN, USA
| | - E C Osmundson
- Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - M J Donahue
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, TN, USA
| | - J B De Vis
- Department of Radiation Oncology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA
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4
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Maheu MG, James N, Clark Z, Yang A, Patel R, Beaudette SM, MacPherson REK, Duarte-Guterman P. Running to remember: The effects of exercise on perineuronal nets, microglia, and hippocampal angiogenesis in female and male mice. Behav Brain Res 2025; 484:115478. [PMID: 39956366 DOI: 10.1016/j.bbr.2025.115478] [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: 07/30/2024] [Revised: 01/24/2025] [Accepted: 02/08/2025] [Indexed: 02/18/2025]
Abstract
Exercise is accepted as a positive health behaviour; however, the mechanisms of exercise on neuroprotection and cognitive health are not completely understood. The purpose of this study was to explore the neurobiological benefits of chronic treadmill exercise in female and male mice through its role in microglial content and morphology, cerebral vascularization, and perineuronal net (PNN) expression. We further examined how these neurobiological changes relate to spatial memory outcomes. Adult mice were assigned to a sedentary or treadmill exercise group for eight weeks. During the final week, all mice were trained on a spatial memory task (Barnes maze) and brains were collected for immunohistochemistry. Exercised mice made fewer errors than sedentary mice during the first two days of training and probe trial. Females, regardless of exercise training, made fewer errors during Barnes maze training and demonstrated a greater frequency of spatial strategy use compared to males. Exercised mice, regardless of sex, had fewer PNNs in the dentate gyrus of the hippocampus compared to sedentary controls. The number of PNNs in the dorsal dentate gyrus was positively correlated with total errors during training. During the probe, greater errors correlated with more PNNs among the exercised group only. Microglia count and cerebral vascularization were not affected by exercise, although proportions of microglia type (ameboid, stout/thick, and thick/thin) were regulated by exercise in the ventral dentate gyrus. We conclude that exercise decreases PNNs in the dentate gyrus in both sexes and this may be related to better spatial learning and memory.
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Affiliation(s)
- Madeleine G Maheu
- Department of Psychology, Brock University, St. Catharines, ON, Canada; Department of Health Sciences, Brock University, St. Catharines, ON, Canada; Centre for Neuroscience, Brock University, St. Catharines, ON, Canada
| | - Noah James
- Department of Health Sciences, Brock University, St. Catharines, ON, Canada
| | - Zach Clark
- Department of Psychology, Brock University, St. Catharines, ON, Canada
| | - Alex Yang
- Department of Health Sciences, Brock University, St. Catharines, ON, Canada
| | - Ridhi Patel
- Centre for Neuroscience, Brock University, St. Catharines, ON, Canada
| | - Shawn M Beaudette
- Centre for Neuroscience, Brock University, St. Catharines, ON, Canada; Department of Kinesiology, Brock University, St. Catharines, ON, Canada
| | - Rebecca E K MacPherson
- Department of Health Sciences, Brock University, St. Catharines, ON, Canada; Centre for Neuroscience, Brock University, St. Catharines, ON, Canada.
| | - Paula Duarte-Guterman
- Department of Psychology, Brock University, St. Catharines, ON, Canada; Centre for Neuroscience, Brock University, St. Catharines, ON, Canada.
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5
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Cao L, Tian W, Zhao Y, Song P, Zhao J, Wang C, Liu Y, Fang H, Liu X. Gene Mutations in Gastrointestinal Stromal Tumors: Advances in Treatment and Mechanism Research. Glob Med Genet 2024; 11:251-262. [PMID: 39176108 PMCID: PMC11341198 DOI: 10.1055/s-0044-1789204] [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: 08/24/2024] Open
Abstract
Although gastrointestinal stromal tumors (GISTs) has been reported in patients of all ages, its diagnosis is more common in elders. The two most common types of mutation, receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor a (PDGFRA) mutations, hold about 75 and 15% of GISTs cases, respectively. Tumors without KIT or PDGFRA mutations are known as wild type (WT)-GISTs, which takes up for 15% of all cases. WT-GISTs have other genetic alterations, including mutations of the succinate dehydrogenase and serine-threonine protein kinase BRAF and neurofibromatosis type 1. Other GISTs without any of the above genetic mutations are named "quadruple WT" GISTs. More types of rare mutations are being reported. These mutations or gene fusions were initially thought to be mutually exclusive in primary GISTs, but recently it has been reported that some of these rare mutations coexist with KIT or PDGFRA mutations. The treatment and management differ according to molecular subtypes of GISTs. Especially for patients with late-stage tumors, developing a personalized chemotherapy regimen based on mutation status is of great help to improve patient survival and quality of life. At present, imatinib mesylate is an effective first-line drug for the treatment of unresectable or metastatic recurrent GISTs, but how to overcome drug resistance is still an important clinical problem. The effectiveness of other drugs is being further evaluated. The progress in the study of relevant mechanisms also provides the possibility to develop new targets or new drugs.
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Affiliation(s)
- Lei Cao
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Wencong Tian
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Yongjie Zhao
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Peng Song
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Jia Zhao
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Chuntao Wang
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Yanhong Liu
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Hong Fang
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Xingqiang Liu
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
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6
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Snijesh VP, Krishnamurthy S, Bhardwaj V, Punya KM, Niranjana Murthy AS, Almutadares M, Habhab WT, Nasser KK, Banaganapalli B, Shaik NA, Albaqami WF. SHH Signaling as a Key Player in Endometrial Cancer: Unveiling the Correlation with Good Prognosis, Low Proliferation, and Anti-Tumor Immune Milieu. Int J Mol Sci 2024; 25:10443. [PMID: 39408773 PMCID: PMC11477284 DOI: 10.3390/ijms251910443] [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: 07/26/2024] [Revised: 09/11/2024] [Accepted: 09/24/2024] [Indexed: 10/19/2024] Open
Abstract
Endometrial Cancer (EC) is one of the most common gynecological malignancies. Despite its prevalence, molecular pathways, such as the Sonic Hedgehog (SHH) pathway, have not been extensively studied in the context of EC. This study aims to explore the clinical implications of SHH expression in EC, potentially uncovering new insights into the disease's pathogenesis and offering valuable insights for therapeutic strategies in EC. We utilized data from The Cancer Genome Atlas (TCGA) to divide the dataset into 'High SHH' and 'Low SHH' groups based on a gene signature score derived from SHH pathway-related genes. We explored the clinical and tumor characteristics of these groups, focusing on key cancer hallmarks, including stemness, proliferation, cytolytic activity, tumor micro-environment, and genomic instability. 'High SHH' tumors emerged as a distinct category with favorable clinical and molecular features. These tumors exhibited lower proliferation rates, reduced angiogenesis, and diminished genomic instability, indicating a controlled and less aggressive tumor growth pattern. Moreover, 'High SHH' tumors displayed lower stemness, highlighting a less invasive phenotype. The immune micro-environment in 'High SHH' tumors was enriched with immune cell types, such as macrophage M0, monocytes, B cells, CD8 T cells, CD4 T cells, follicular helper T cells, and natural killer cells. This immune enrichment, coupled with higher cytolytic activity, suggested an improved anti-tumor immune response. Our study sheds light on the clinical significance of Sonic signaling in EC. 'High SHH' tumors exhibit a unique molecular and clinical profile associated with favorable cancer hallmarks, lower grades, and better survival. These findings underscore the potential utility of SHH expression as a robust prognostic biomarker, offering valuable insights for tailored therapeutic strategies in EC. Understanding the SHH pathway's role in EC contributes to our growing knowledge of this cancer and may pave the way for more effective treatment strategies in the future.
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Affiliation(s)
- V. P. Snijesh
- Division of Molecular Medicine, St. John’s Research Institute, St. John’s National Academy of Health Sciences, Bangalore 560034, Karnataka, India;
| | - Shivakumar Krishnamurthy
- Division of Molecular Medicine, St. John’s Research Institute, St. John’s National Academy of Health Sciences, Bangalore 560034, Karnataka, India;
| | - Vipul Bhardwaj
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China;
| | - K. M. Punya
- Electronics & Communication Engineering, Excel College of Technology, Namakkal 637303, Tamilnadu, India;
| | - Ashitha S. Niranjana Murthy
- Department of Psychiatry, National Institute of Mental Health And Neuro Sciences, Bangalore 560029, Karnataka, India;
| | - Mahmoud Almutadares
- Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (M.A.); (W.T.H.); (B.B.); (N.A.S.)
| | - Wisam Tahir Habhab
- Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (M.A.); (W.T.H.); (B.B.); (N.A.S.)
- Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Khalidah Khalid Nasser
- Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Babajan Banaganapalli
- Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (M.A.); (W.T.H.); (B.B.); (N.A.S.)
- Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Noor Ahmad Shaik
- Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (M.A.); (W.T.H.); (B.B.); (N.A.S.)
- Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Walaa F. Albaqami
- Department of Science, Prince Sultan Military College of Health Sciences, Dhahran 31932, Saudi Arabia
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Adeleye K, Li A, Xie Y, Pochampally S, Hamilton D, Garcia-Godoy F, Miller D, Li W. Novel Antimitotic Agent SP-1-39 Inhibits Head and Neck Squamous Cell Carcinoma. J Dent Res 2024; 103:926-936. [PMID: 39101715 PMCID: PMC11465348 DOI: 10.1177/00220345241261982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/06/2024] Open
Abstract
Effective management of head and neck cancer (HNC) poses a significant challenge in the field of oncology, due to its intricate pathophysiology and limited treatment options. The most common HNC malignancy is head and neck squamous cell carcinoma (HNSCC). HNSCC treatment includes a combination of surgery, radiation, and chemotherapy. While HNSCC is treatable if diagnosed early, this is often not the case and is considered incurable once in its late stages and metastatic disease has developed. Therapies are also limited once resistant disease has occurred. SP-1-39, a novel colchicine-binding site inhibitor (CBSI), has been recently reported for its potential efficacy in a variety of cancer cell lines including breast, melanoma, pancreatic, and prostate. SP-1-39 also shows abilities to overcome paclitaxel resistance in a paclitaxel-resistant prostate cancer xenograft model. To evaluate the potential of SP-1-39 as a new HNSCC treatment option, herein we systematically performed preclinical studies in HNSCC models using SP-1-39 and demonstrated that, in vitro, SP-1-39 inhibits the proliferation of 2 HNSCC cell lines with low nanomolar IC50 values (1.4 to 2.1 nM), induces HNSCC cell apoptosis in a dose-dependent manner, interferes with migration of HNSCC cells, and leads to HNSCC cell cycle arrest in the G2/M phase. In vivo, SP-1-39 suppresses the primary tumor growth of a Detroit 562 subcutaneous xenograft mouse model in 6- to 8-wk-old, male NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice, with no detectable cytotoxic effects at a low dose of 2.5 mg/kg. This efficacy of SP-1-39 is better when compared with the treatment using a reference chemotherapy drug, paclitaxel at 10 mg/kg. Collectively, these data demonstrate that SP-1-39 is a promising candidate for further development for more efficacious HNSCC treatment.
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Affiliation(s)
- K.L. Adeleye
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - A.R. Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Y. Xie
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - S. Pochampally
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - D. Hamilton
- Department of Comparative Medicine, College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN, USA
| | - F. Garcia-Godoy
- Department of Bioscience Research, College of Dentistry, University of Tennessee Health Science Center, Memphis, TN, USA
| | - D.D. Miller
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - W. Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
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8
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Elechalawar CK, Gulla SK, Roy RV, Means N, Zhang Y, Asifa S, Robertson DJ, Xu C, Bhattacharya R, Mukherjee P. Biodistribution and therapeutic efficacy of a gold nanoparticle-based targeted drug delivery system against pancreatic cancer. Cancer Lett 2024; 589:216810. [PMID: 38494151 PMCID: PMC11793163 DOI: 10.1016/j.canlet.2024.216810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 02/22/2024] [Accepted: 03/07/2024] [Indexed: 03/19/2024]
Abstract
Pancreatic cancer is characterized by desmoplasia; crosstalk between pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs) leads to the deposition of extracellular matrix proteins in the tumor environment resulting in poor vascularity. Targeting either PCCs or PSCs individually has produced mixed results, and there is currently no effective strategy to target both cell types simultaneously. Previously, we demonstrated, through in vitro cell culture experiments, that a specific gold nanoparticle-based nanoformulation containing the anti-EGFR antibody cetuximab (C225) as a targeting agent and gemcitabine as a chemotherapeutic agent effectively targets both PCCs and PSCs simultaneously. Herein, we extend our studies to test the ability of these in vitro tested nano formulations to inhibit tumor growth in an orthotopic co-implantation model of pancreatic cancer in vivo. Orthotopic tumors were established by co-implantation of equal numbers of PCCs and PSCs in the mouse pancreas. Among the various formulations tested, 5 nm gold nanoparticles coated with gemcitabine, cetuximab and poly-ethylene glycol (PEG) of molecular weight 1000 Da, which we named ACGP441000, demonstrated optimal efficacy in inhibiting tumor growth. The current study reveals an opportunity to target PCCs and PSCs simultaneously, by exploiting their overexpression of EGFR as a target, in order to inhibit pancreatic cancer growth.
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Affiliation(s)
- Chandra Kumar Elechalawar
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Suresh Kumar Gulla
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Ram Vinod Roy
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Nicolas Means
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Yushan Zhang
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Sima Asifa
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - David J Robertson
- Department of Chemistry and University of Missouri Research Reactor, University of Missouri, Columbia, MO 65211, USA
| | - Chao Xu
- Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Resham Bhattacharya
- Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Priyabrata Mukherjee
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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Zhou S, Abdihamid O, Tan F, Zhou H, Liu H, Li Z, Xiao S, Li B. KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST. Cell Commun Signal 2024; 22:153. [PMID: 38414063 PMCID: PMC10898159 DOI: 10.1186/s12964-023-01411-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 11/25/2023] [Indexed: 02/29/2024] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common sarcoma located in gastrointestinal tract and derived from the interstitial cell of Cajal (ICC) lineage. Both ICC and GIST cells highly rely on KIT signal pathway. Clinically, about 80-90% of treatment-naive GIST patients harbor primary KIT mutations, and special KIT-targeted TKI, imatinib (IM) showing dramatic efficacy but resistance invariably occur, 90% of them was due to the second resistance mutations emerging within the KIT gene. Although there are multiple variants of KIT mutant which did not show complete uniform biologic characteristics, most of them have high KIT expression level. Notably, the high expression level of KIT gene is not correlated to its gene amplification. Recently, accumulating evidences strongly indicated that the gene coding, epigenetic regulation, and pre- or post- protein translation of KIT mutants in GIST were quite different from that of wild type (WT) KIT. In this review, we elucidate the biologic mechanism of KIT variants and update the underlying mechanism of the expression of KIT gene, which are exclusively regulated in GIST, providing a promising yet evidence-based therapeutic landscape and possible target for the conquer of IM resistance. Video Abstract.
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Affiliation(s)
- Shishan Zhou
- Division of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China, Xiangya road 87
| | - Omar Abdihamid
- Garissa Cancer Center, Garissa County Referral Hospital, Kismayu road, Garissa town, P.O BOX, 29-70100, Kenya
| | - Fengbo Tan
- Division of Surgery, Xiangya Hospital, Central South University, China, Hunan, Changsha
| | - Haiyan Zhou
- Division of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Heli Liu
- Division of Surgery, Xiangya Hospital, Central South University, China, Hunan, Changsha
| | - Zhi Li
- Center for Molecular Medicine of Xiangya Hospital, Collaborative Innovation Center for Cancer Medicine, Central South University, Changsha, Hunan, China, 410008
| | - Sheng Xiao
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, 410008, MA, USA
| | - Bin Li
- Division of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China, Xiangya road 87#.
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10
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Li B, Zhang J, Ma N, Li W, You G, Chen G, Zhao L, Wang Q, Zhou H. PEG-conjugated bovine haemoglobin enhances efficiency of chemotherapeutic agent doxorubicin with alleviating DOX-induced splenocardiac toxicity in the breast cancer. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2023; 51:120-130. [PMID: 36905212 DOI: 10.1080/21691401.2023.2176865] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 01/17/2023] [Accepted: 01/22/2023] [Indexed: 03/12/2023]
Abstract
Doxorubicin (DOX) is an effective chemotherapeutic agent widely used for cancer treatment. However, hypoxia in tumour tissue and obvious adverse effects particularly cardiotoxicity restricts the clinical usage of DOX. Our study is based on the co-administration of haemoglobin-based oxygen carriers (HBOCs) and DOX in a breast cancer model to investigate HBOCs' ability to enhance chemotherapeutic effectiveness and its capabilities to alleviate the side effects induced by DOX. In an in-vitro study, the results suggested the cytotoxicity of DOX was significantly improved when combined with HBOCs in a hypoxic environment, and produced more γ-H2AX indicating higher DNA damage than free DOX did. Compared with administration of free DOX, combined therapy exhibited a stronger tumour suppressive effect in an in-vivo study. Further mechanism studies showed that the expression of various proteins such as hypoxia-inducible factor-1α (HIF-1α), CD31, CD34, and vascular endothelial growth factor (VEGF) in tumour tissues was also significantly reduced in the combined treatment group. In addition, HBOCs can significantly reduce the splenocardiac toxicity induced by DOX, according to the results of the haematoxylin and eosin (H&E) staining and histological investigation. This study suggested that PEG-conjugated bovine haemoglobin may not only reduce the hypoxia in tumours and increase the efficiency of chemotherapeutic agent DOX, but also alleviate the irreversible heart toxicity caused by DOX-inducted splenocardiac dysregulation.
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Affiliation(s)
- Bingting Li
- Institute of Health Service and Transfusion Medicine, Beijing, P. R. China
| | - Jun Zhang
- Institute of Health Service and Transfusion Medicine, Beijing, P. R. China
- The Western Theater General Hospital, Chengdu, P. R. China
| | - Ning Ma
- Clinical Laboratory of Beijing Huairou Hospital, Beijing, P. R. China
| | - Weidan Li
- Institute of Health Service and Transfusion Medicine, Beijing, P. R. China
| | - Guoxing You
- Institute of Health Service and Transfusion Medicine, Beijing, P. R. China
| | - Gan Chen
- Institute of Health Service and Transfusion Medicine, Beijing, P. R. China
| | - Lian Zhao
- Institute of Health Service and Transfusion Medicine, Beijing, P. R. China
| | - Quan Wang
- Institute of Health Service and Transfusion Medicine, Beijing, P. R. China
| | - Hong Zhou
- Institute of Health Service and Transfusion Medicine, Beijing, P. R. China
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11
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Perivoliotis K, Baloyiannis I, Samara AA, Koutoukoglou P, Ntellas P, Dadouli K, Ioannou M, Tepetes K. Microvessel density in patients with gastrointestinal stromal tumors: A systematic review and meta-analysis. World J Methodol 2023; 13:153-165. [PMID: 37456971 PMCID: PMC10348082 DOI: 10.5662/wjm.v13.i3.153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 04/30/2023] [Accepted: 05/16/2023] [Indexed: 06/20/2023] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) are considered the most common mesenchymal tumors of the gastrointestinal tract. Microvessel density (MVD) constitutes a direct method of vascularity quantification and has been associated with survival rates in multiple malignancies. AIM To appraise the effect of MVD on the survival of patients with GIST. METHODS This study adhered to Systematic reviews and Meta-Analyses guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. Electronic scholar databases and grey literature repositories were systematically screened. The Fixed Effects or Random Effects models were used according to the Cochran Q test. RESULTS In total, 6 eligible studies were identified. The pooled hazard ratio (HR) for disease free survival (DFS) was 8.52 (95%CI: 1.69-42.84, P = 0.009). The odds ratios of disease-free survival between high and low MVD groups at 12 and 60 mo did not reach statistical significance. Significant superiority of the low MVD group in terms of DFS was documented at 36 and 120 mo (OR: 8.46, P < 0.0001 and OR: 22.71, P = 0.0003, respectively) as well as at metastases rate (OR: 0.11, P = 0.0003). CONCLUSION MVD significantly correlates with the HR of DFS and overall survival rates at 36 and 120 mo. Further prospective studies of higher methodological quality are required.
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Affiliation(s)
| | - Ioannis Baloyiannis
- Department of Surgery, University Hospital of Larissa, Larissa 41110, Greece
| | - Athina A Samara
- Department of Surgery, University Hospital of Larissa, Larissa 41110, Greece
| | - Prodromos Koutoukoglou
- Research Methodology in Biomedicine, Biostatistics and Clinical Bioinformatics, University of Thessaly, 41110 41110, Greece
| | - Panagiotis Ntellas
- Department of Pathology, University Hospital of Larissa, Larissa 41110, Greece
| | - Katerina Dadouli
- Research Methodology in Biomedicine, Biostatistics and Clinical Bioinformatics, University of Thessaly, 41110 41110, Greece
| | - Maria Ioannou
- Department of Pathology, University Hospital of Larissa, Larissa 41110, Greece
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12
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Nematollahi-Mahani SN, Ganjalikhan-Hakemi S, Abdi Z. The Regression of Glioblastoma Multiforme is Time Dependent in the Wild-type Rat Xenograft Model. Basic Clin Neurosci 2023; 14:263-272. [PMID: 38107534 PMCID: PMC10719980 DOI: 10.32598/bcn.2021.3370.1] [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: 05/01/2021] [Revised: 06/22/2021] [Accepted: 09/06/2021] [Indexed: 12/19/2023] Open
Abstract
Introduction Glioblastoma multiforme (GBM) is an aggressive case of primary brain cancer which remains among the most fatal tumors worldwide. Although, some in vitro and in vivo models have been developed for a better understanding of GBM behavior; a natural model of GBM would improve the efficiency of experimental models of human GBM tumors. We aimed the present study to examine the survival and durability of U87 cells in the brain of wild-type rats. Methods U87 cells were intracranially implanted in twenty-one wild-type rats. Tumor size and morphology as well as infiltration of immune cells were investigated at three-time points by H&E and immunohistochemistry (IHC). Results The results demonstrated that the inoculation of GBM cells led to the infiltration of host defense system cells which caused immunological regression of the tumor mass after six weeks. While the tumors successfully developed without any sign of host defense invasion in the second week of GBM inoculation. Also, a decrease in tumor size and infiltration of immune system cells were observed in the fourth week. Conclusion These data remarkably suggest that time plays a crucial role in activating the immune system against human GBM tumors in rats; it shows that the regression of tumor mass depends on a time slope. Highlights A noticeable proliferation of tumor cells was observed in the rat's brain by the second week.The distant metastatic masses of cancer infiltrated into the adjacent normal tissue by the second week.Tumor mass underwent a noticeable diminution in the size by the fourth week.Cancer cells completely regressed by the sixth week due to immunological reactions.In tumor rejection, the effective mechanism depends on immune system activity and the slope of time. Plain Language Summary One of the most malignant tumors is the brain tumor in the world. Unfortunately, no effective treatment has yet been found for it. Of course, researchers need efficient animal models to find the appropriate treatment. The xenograft model is one of the tumor models in the laboratory. However, the main challenge is the interaction of the animal's immune system with induced-cancer cells so that the immune system finally rejects the tumor. In this study, we investigated how long the immune system needs to reject induced tumors in the xenograft model completely. For this purpose, we studied the animals in three periods (second week, fourth week, and sixth week). We concluded that the immune system does not recognize the induced cancer cells until the second week of the experiment. It results in the growth of cancer cells and the formation of tumors in the animal brain. However, the immune system begins to recognize the tumor mass after the fourth week which leads to a reduction in metastasis and tumor size. Eventually, the immune system completely rejects the formed tumor in the sixth week.
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Affiliation(s)
- Seyed Noureddin Nematollahi-Mahani
- Department of Anatomy, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Afzal Research Institute, Kerman, Iran
| | - Sepideh Ganjalikhan-Hakemi
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Abdi
- Department of Anatomical Sciences, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
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13
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Liu Q, Liu H, Griveau A, Li X, Eyer J, Arib C, Spadavecchia J. NFL-TBS.40-63 Peptide Gold Complex Nanovector: A Novel Therapeutic Approach to Increase Anticancer Activity by Breakdown of Microtubules in Pancreatic Adenocarcinoma (PDAC). ACS Pharmacol Transl Sci 2022; 5:1267-1278. [PMID: 36524008 PMCID: PMC9745895 DOI: 10.1021/acsptsci.2c00159] [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: 08/11/2022] [Indexed: 11/28/2022]
Abstract
The role of the NFL-TBS.40-63 peptide is to destroy the microtubule network of target glioma cancer cells. Recently, we have conceived a gold-complex biotinylated NFL-TBS.40-63 (BIOT-NFL) to form a hybrid gold nanovector (BIOT-NFL-PEG-AuNPs). This methodology showed, for the first time, the ability of the BIOT-NFL-PEG-AuNPs to target the destruction of pancreatic cancer cells (PDAC) under experimental conditions, as well as detoxification and preclinical therapeutic efficacy regulated by the steric and chemical configuration of the peptide. For this aim, a mouse transplantation tumor model induced by MIA-PACA-2 cells was applied to estimate the therapeutic efficacy of BIOT-NFL-PEG-AuNPs as a nanoformulation. Our relevant results display that BIOT-NFL-PEG-AuNPs slowed the tumor growth and decreased the tumor index without effects on the body weight of mice with an excellent antiangiogenic effect, mediated by the ability of BIOT-NFL-PEG-AuNPs to alter the metabolic profiles of these MIA-PACA-2 cells. The cytokine levels were detected to evaluate the behavior of serum inflammatory factors and the power of BIOT-NFL-PEG-AuNPs to boost the immune system.
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Affiliation(s)
- Qiqian Liu
- CNRS,
UMR 7244, NBD-CSPBAT, Laboratoire de Chimie, Structures et Propriétés de Biomatériaux et
d′Agents Thérapeutiques Université Paris 13, Sorbonne Paris Nord, Bobigny93000, France
| | - Hui Liu
- Department
of Hepatobiliary Surgery, Guangdong Provincial Key Laboratory of Regional
Immunity and Diseases & Carson International Cancer Center, Shenzhen
University General Hospital & Shenzhen University Clinical Medical
Academy Center, Shenzhen University, Shenzhen518083China
| | - Audrey Griveau
- Laboratoire
Micro et Nanomedecines Translationnelles, Inserm 1066, CNRS 6021,
Institut de Recherche en Ingénierie de la Sante, Bâtiment
IBS Institut de Biologie de la Sante, Université′
Angers, Centre Hospitalier Universitaire, Angers49100France
| | - Xiaowu Li
- Department
of Hepatobiliary Surgery, Guangdong Provincial Key Laboratory of Regional
Immunity and Diseases & Carson International Cancer Center, Shenzhen
University General Hospital & Shenzhen University Clinical Medical
Academy Center, Shenzhen University, Shenzhen518083China
| | - Joel Eyer
- Laboratoire
Micro et Nanomedecines Translationnelles, Inserm 1066, CNRS 6021,
Institut de Recherche en Ingénierie de la Sante, Bâtiment
IBS Institut de Biologie de la Sante, Université′
Angers, Centre Hospitalier Universitaire, Angers49100France
| | - Celia Arib
- CNRS,
UMR 7244, NBD-CSPBAT, Laboratoire de Chimie, Structures et Propriétés de Biomatériaux et
d′Agents Thérapeutiques Université Paris 13, Sorbonne Paris Nord, Bobigny93000, France
| | - Jolanda Spadavecchia
- CNRS,
UMR 7244, NBD-CSPBAT, Laboratoire de Chimie, Structures et Propriétés de Biomatériaux et
d′Agents Thérapeutiques Université Paris 13, Sorbonne Paris Nord, Bobigny93000, France
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14
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Guo W, Huang S, An J, Zhang J, Dong F, Dang J, Zhang J. Ultrasound-Mediated Antitumor Therapy via Targeted Acoustic Release Carrier of Carbon Monoxide (TARC-CO). ACS APPLIED MATERIALS & INTERFACES 2022; 14:50664-50676. [PMID: 36322480 DOI: 10.1021/acsami.2c16821] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
As one of the most valuable endogenous gas signaling molecules, carbon monoxide (CO) has been demonstrated in numerous studies to show excellent promise in the treatment of diseases, such as cancer. However, for many years, the inherent high affinity of CO for hemoglobin severely impeded the clinical transformation of CO-based treatments. Therefore, the controlled delivery of CO to target tissues has become a common challenge. Herein, an efficient ultrasonic-triggered and targeted CO release strategy was constructed based on a novel targeted acoustic release carrier of carbon monoxide (TARC-CO) that we synthesized in this study. The designed TARC-COs could afford a safe, stable, and ultrasound-guided delivery of CO in vivo by loading a specified dose of CO inside microbubbles, resulting in breast tumor suppression. Taking advantage of the high loading capacity of microbubbles, the unit volume of TARC-CO suspension could encapsulate up to 337.1 ± 8.0 (×103 ppm) of CO. In addition, the satisfactory ultrasound contrast-enhanced ability of TARC-COs achieved real-time interactive guidance and visual policing of CO delivery. For the in vitro antitumor study, TARC-COs with ultrasonic irradiation were demonstrated to effectively induce mitochondrial dysfunction by reducing mitochondrial membrane potential, leading to the apoptosis of 4T1 cells. In addition, we realized that TARC-CO-based treatment could significantly slow the growth rate of tumors by inducing apoptosis, inhibiting the proliferation of cancer cells, and limiting tumor angiogenesis. In summary, this proof-of-concept study demonstrates the feasibility and tremendous potential of TARC-COs for controlled release of CO, which can be expected to provide new inspirations and a promising perspective for therapy based on active gases.
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Affiliation(s)
- Wenyu Guo
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Shuo Huang
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Jian An
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Jiabin Zhang
- State Key Laboratory of Membrane Biology, National Biomedical Imaging Center, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
| | - Feihong Dong
- State Key Laboratory of Membrane Biology, National Biomedical Imaging Center, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
| | - Jie Dang
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Jue Zhang
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
- College of Engineering, Peking University, Beijing 100871, China
- National Biomedical Imaging Center, Peking University, Beijing 100871, China
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15
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Sato R, Harada R, Hashimoto K, Tsutsui T, Hattori N, Inoue M, Kobashi H, Morimoto M, Tamura M, Hayashi A, Iwamuro M. Gastrointestinal stromal tumors in the duodenum show increased contrast enhancement compared with those in the stomach on computed tomography. Mol Clin Oncol 2022; 17:144. [PMID: 36157321 PMCID: PMC9468842 DOI: 10.3892/mco.2022.2577] [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: 05/16/2022] [Accepted: 07/25/2022] [Indexed: 11/06/2022] Open
Abstract
Duodenal gastrointestinal stromal tumors (D-GISTs) are a rare and relatively small subset of GISTs whose imaging features are not well known. The present study aimed to evaluate the enhancement pattern of D-GISTs compared with that of gastric GISTs (G-GISTs) using dynamic computed tomography. This single-center, retrospective, clinicopathological analysis was conducted on 10 patients with D-GISTs who underwent surgery between June 2006 and October 2018. In the same period, 25 patients with G-GISTs underwent surgery and were enrolled. The contrast ratio was defined as the ratio between Hounsfield units in contrast enhanced and unenhanced images in different phases, and these ratios were compared between the D-GIST and G-GIST groups. Furthermore, microvessel density, analyzed by immunohistochemical staining for CD31, was compared between the D-GIST and G-GIST groups. The contrast ratio of D-GIST was significantly higher than that of G-GIST in the arterial, portal and delayed phases (P<0.01, P<0.01 and P=0.02, respectively). The microvessel density of the D-GISTs was significantly higher than that of the G-GISTs (P<0.0001). D-GISTs were more hypervascular than G-GISTs on both imaging and pathological analyses.
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Affiliation(s)
- Ryosuke Sato
- Department of Gastroenterology and Hepatology, Japanese Red Cross Okayama Hospital, Okayama 700-8607, Japan
- Department of Gastroenterology and Hepatology, Okayama University Hospital, Okayama 700-8558, Japan
| | - Ryo Harada
- Department of Gastroenterology and Hepatology, Japanese Red Cross Okayama Hospital, Okayama 700-8607, Japan
| | - Kenji Hashimoto
- Department of Gastroenterology and Hepatology, Japanese Red Cross Okayama Hospital, Okayama 700-8607, Japan
| | - Tomoaki Tsutsui
- Department of Gastroenterology and Hepatology, Japanese Red Cross Okayama Hospital, Okayama 700-8607, Japan
| | - Nao Hattori
- Department of Gastroenterology and Hepatology, Japanese Red Cross Okayama Hospital, Okayama 700-8607, Japan
| | - Masafumi Inoue
- Department of Gastroenterology and Hepatology, Japanese Red Cross Okayama Hospital, Okayama 700-8607, Japan
| | - Haruhiko Kobashi
- Department of Gastroenterology and Hepatology, Japanese Red Cross Okayama Hospital, Okayama 700-8607, Japan
| | - Mami Morimoto
- Department of Radiology, Japanese Red Cross Okayama Hospital, Okayama 700-8607, Japan
| | - Maiko Tamura
- Department of Radiology, Japanese Red Cross Okayama Hospital, Okayama 700-8607, Japan
| | - Atsushi Hayashi
- Department of Pathology, Japanese Red Cross Okayama Hospital, Okayama 700-8607, Japan
| | - Masaya Iwamuro
- Department of Gastroenterology and Hepatology, Okayama University Hospital, Okayama 700-8558, Japan
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Zhu MP, Ding QL, Xu JX, Jiang CY, Wang J, Wang C, Yu RS. Building contrast-enhanced CT-based models for preoperatively predicting malignant potential and Ki67 expression of small intestine gastrointestinal stromal tumors (GISTs). ABDOMINAL RADIOLOGY (NEW YORK) 2022; 47:3161-3173. [PMID: 33765174 DOI: 10.1007/s00261-021-03040-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 03/02/2021] [Accepted: 03/05/2021] [Indexed: 01/18/2023]
Abstract
PURPOSE To assess contrast-enhanced computed tomography (CE-CT) features for predicting malignant potential and Ki67 in small intestinal gastrointestinal stromal tumors (GISTs) and the correlation between them. METHODS We retrospectively analyzed the pathological and imaging data for 123 patients (55 male/68 female, mean age: 57.2 years) with a histopathological diagnosis of small intestine GISTs who received CE-CT followed by curative surgery from May 2009 to August 2019. According to postoperatively pathological and immunohistochemical results, patients were categorized by malignant potential and the Ki67 index, respectively. CT features were analyzed to be associated with malignant potential or the Ki67 index using univariate analysis, logistic regression and receiver operating curve analysis. Then, we explored the correlation between the Ki67 index and malignant potential by using the Spearman rank correlation. RESULTS Based on univariate and multivariate analysis, a predictive model of malignant potential of small intestine GISTs, consisting of tumor size (p < 0.001) and presence of necrosis (p = 0.033), was developed with the area under the receiver operating curve (AUC) of 0.965 (95% CI, 0.915-0.990; p < 0.001), with 91.53% sensitivity, 96.87% specificity, 96.43% PPV, 92.54% NPV, 94.31% diagnostic accuracy. For high Ki67 expression, a model made up of tumor size (p = 0.051), presence of ulceration (p = 0.054) and metastasis (p = 0.001) may be the best predictive combination with an AUC of 0.785 (95% CI, 0.702-0.854; p < 0.001), 63.33% sensitivity, 76.34% specificity, 46.34% PPV, 86.59% NPV, 73.17% diagnostic accuracy. Ki67 index showed a moderate positive correlation with mitotic count (r = 0.578, p < 0.001), a weak positive correlation with tumor size (r = 0.339, p < 0.001) and with risk stratification (r = 0.364, p < 0.001). CONCLUSION Features on CE-CT could preoperatively predict malignant potential and high Ki67 expression of small intestine GISTs, and Ki67 index may be a promising prognostic factor in predicting the prognosis of small intestine GISTs, independent of the risk stratification system.
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Affiliation(s)
- Miao-Ping Zhu
- Department of Radiology, the Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China
- Department of Radiology, Hangzhou Women's Hospital, Hangzhou, China
| | - Qiao-Ling Ding
- Department of Radiology, the Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Jian-Xia Xu
- Department of Radiology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Chun-Yan Jiang
- Department of Radiology, the Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China
- Department of Radiology, People's Hospital of Songyang County, Lishui, China
| | - Jing Wang
- Department of Radiology, Ningbo Medical Center Lihuili Hospital, Ningbo, China
| | - Chao Wang
- Department of Radiology, the Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.
| | - Ri-Sheng Yu
- Department of Radiology, the Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.
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17
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Papadakos SP, Tsagkaris C, Papadakis M, Papazoglou AS, Moysidis DV, Zografos CG, Theocharis S. Angiogenesis in gastrointestinal stromal tumors: From bench to bedside. World J Gastrointest Oncol 2022; 14:1469-1477. [PMID: 36160752 PMCID: PMC9412926 DOI: 10.4251/wjgo.v14.i8.1469] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 05/15/2022] [Accepted: 07/18/2022] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are rare neoplasms with an estimated incidence from 0.78 to 1-1.5 patients per 100000. They most commonly occur in the elderly during the eighth decade of life affecting predominantly the stomach, but also the small intestine, the omentum, mesentery and rectosigmoid. The available treatments for GIST are associated with a significant rate of recurrent disease and adverse events. Thorough understanding of GIST's pathophysiology and translation of this knowledge into novel regimens or drug repurposing is essential to counter this challenge. The present review summarizes the existing evidence about the role of angiogenesis in GIST's development and progression and discusses its clinical underpinnings.
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Affiliation(s)
- Stavros P Papadakos
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens 10679, Greece
| | | | - Marios Papadakis
- University Hospital Witten-Herdecke, University of Witten-Herdecke, Wuppertal 42283, Germany
| | - Andreas S Papazoglou
- First Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki 54636, Greece
| | - Dimitrios V Moysidis
- First Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki 54636, Greece
| | - Constantinos G Zografos
- First Department of Surgery, Athens Medical School, National and Kapodistrian University of Athens, Laikon General Hospital, Athens 11527, Greece
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, University of Athens, Athens 11527, Greece
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18
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Mancinelli R, Ceci L, Kennedy L, Francis H, Meadows V, Chen L, Carpino G, Kyritsi K, Wu N, Zhou T, Sato K, Pannarale L, Glaser S, Chakraborty S, Alpini G, Gaudio E, Onori P, Franchitto A. The Effects of Taurocholic Acid on Biliary Damage and Liver Fibrosis Are Mediated by Calcitonin-Gene-Related Peptide Signaling. Cells 2022; 11:1591. [PMID: 35563897 PMCID: PMC9104610 DOI: 10.3390/cells11091591] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/07/2022] [Accepted: 05/04/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND & AIMS Cholangiocytes are the target cells of liver diseases that are characterized by biliary senescence (evidenced by enhanced levels of senescence-associated secretory phenotype, SASP, e.g., TGF-β1), and liver inflammation and fibrosis accompanied by altered bile acid (BA) homeostasis. Taurocholic acid (TC) stimulates biliary hyperplasia by activation of 3',5'-cyclic cyclic adenosine monophosphate (cAMP) signaling, thereby preventing biliary damage (caused by cholinergic/adrenergic denervation) through enhanced liver angiogenesis. Also: (i) α-calcitonin gene-related peptide (α-CGRP, which activates the calcitonin receptor-like receptor, CRLR), stimulates biliary proliferation/senescence and liver fibrosis by enhanced biliary secretion of SASPs; and (ii) knock-out of α-CGRP reduces these phenotypes by decreased cAMP levels in cholestatic models. We aimed to demonstrate that TC effects on liver phenotypes are dependent on changes in the α-CGRP/CALCRL/cAMP/PKA/ERK1/2/TGF-β1/VEGF axis. METHODS Wild-type and α-CGRP-/- mice were fed with a control (BAC) or TC diet for 1 or 2 wk. We measured: (i) CGRP levels by both ELISA kits in serum and by qPCR in isolated cholangiocytes (CALCA gene for α-CGRP); (ii) CALCRL immunoreactivity by immunohistochemistry (IHC) in liver sections; (iii) liver histology, intrahepatic biliary mass, biliary senescence (by β-GAL staining and double immunofluorescence (IF) for p16/CK19), and liver fibrosis (by Red Sirius staining and double IF for collagen/CK19 in liver sections), as well as by qPCR for senescence markers in isolated cholangiocytes; and (iv) phosphorylation of PKA/ERK1/2, immunoreactivity of TGF-β1/TGF- βRI and angiogenic factors by IHC/immunofluorescence in liver sections and qPCR in isolated cholangiocytes. We measured changes in BA composition in total liver by liquid chromatography/mass spectrometry. RESULTS TC feeding increased CALCA expression, biliary damage, and liver inflammation and fibrosis, as well as phenotypes that were associated with enhanced immunoreactivity of the PKA/ERK1/2/TGF-β1/TGF-βRI/VEGF axis compared to BAC-fed mice and phenotypes that were reversed in α-CGRP-/- mice fed TC coupled with changes in hepatic BA composition. CONCLUSION Modulation of the TC/ α-CGRP/CALCRL/PKA/ERK1/2/TGF-β1/VEGF axis may be important in the management of cholangiopathies characterized by BA accumulation.
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Affiliation(s)
- Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy; (R.M.); (L.P.); (E.G.); (P.O.)
| | - Ludovica Ceci
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Vik Meadows
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
| | - Lixian Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, 00135 Rome, Italy;
| | - Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
| | - Nan Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
| | - Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
| | - Keisaku Sato
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
| | - Luigi Pannarale
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy; (R.M.); (L.P.); (E.G.); (P.O.)
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University, Bryan, TX 77807, USA; (S.G.); (S.C.)
| | - Sanjukta Chakraborty
- Department of Medical Physiology, Texas A&M University, Bryan, TX 77807, USA; (S.G.); (S.C.)
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy; (R.M.); (L.P.); (E.G.); (P.O.)
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy; (R.M.); (L.P.); (E.G.); (P.O.)
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy; (R.M.); (L.P.); (E.G.); (P.O.)
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Reis NRP, Barbosa LER. Prognostic Factors and Management of Colorectal Gastrointestinal Stromal Tumors. JOURNAL OF COLOPROCTOLOGY 2022. [DOI: 10.1055/s-0041-1740297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Abstract
Introduction The gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. Even though it can be found in any location of the digestive tract, the colorectal GIST is rare. With this study, we aim to review the current knowledge regarding the prognosis and management of colorectal GIST.
Methods A literature search was conducted in PubMed, and 717 articles were collected. After analyzing these studies, 60 articles were selected to use in this review.
Results The mitotic index, as well as tumor size and location were identified as good discriminators of prognosis in various studies. Surgery remains the only curative therapy for potentially resectable tumors. However, even after surgical resection, some patients develop disease recurrence and metastasis, especially those with high-risk tumors. Therefore, surgical resection alone might be inadequate for the management of all colorectal GISTs. The discovery of GIST's molecular pathway led to a shift in its therapy, insofar as tyrosine kinase inhibitors became part of the treatment schemes for this tumor, revolutionizing the treatment's outcome and prognosis.
Discussion/Conclusion The controversy concerning colorectal GIST prognosis and treatment can be, in part, attributed to the limited number of studies in the literature. In this review, we gathered the most recent knowledge about the prognosis and management of GIST in this rare location and propose two algorithms for its approach. Lastly, we highlight the importance of an individualized approach in the setting of a multidisciplinary team.
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Affiliation(s)
- Nuno Rafael Pereira Reis
- Department of Surgery and Physiology, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - Laura Elisabete Ribeiro Barbosa
- Department of Surgery and Physiology, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
- Department of General Surgery, Centro Hospitalar Universitário São João, Serviço de Cirurgia Geral, Porto, Portugal
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20
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Dong Y, Gong Y, Kuo F, Makarov V, Reznik E, Nanjangud GJ, Aras O, Zhao H, Qu R, Fagin JA, Sherman EJ, Xu B, Ghossein R, Chan TA, Ganly I. Targeting the mTOR Pathway in Hurthle Cell Carcinoma Results in Potent Anti-Tumor Activity. Mol Cancer Ther 2021; 21:382-394. [PMID: 34789562 DOI: 10.1158/1535-7163.mct-21-0224] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 08/29/2021] [Accepted: 11/10/2021] [Indexed: 11/16/2022]
Abstract
Hurthle cell carcinomas (HCC) are refractory to radioactive iodine and unresponsive to chemotherapeutic agents, with a fatality rate that is the highest among all types of thyroid cancer after anaplastic thyroid cancer. Our previous study on the genomic landscape of HCCs identified a high incidence of disruptions of mTOR pathway effectors. Here, we report a detailed analysis of mTOR signaling in cell line and patient-derived xenograft (PDX) mouse models of HCCs. We show that mTOR signaling is upregulated and that targeting mTOR signaling using mTOR inhibitors suppresses tumor growth in primary tumors and distant metastasis. Mechanistically, ablation of mTOR signaling impaired the expression of p-S6 and cyclin A2, resulting in the decrease of S phase and blocking of cancer cell proliferation. Strikingly, mTOR inhibitor treatment significantly reduced lung metastatic lesions, with the decreased expression of Snail in xenograft tumors. Our data demonstrates that mTOR pathway blockade represents a novel treatment strategy for HCC.
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Affiliation(s)
- Yiyu Dong
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
| | | | - Fengshen Kuo
- Immunogenomics & Precision Oncology Platform, Memorial Sloan Kettering Cancer Center
| | | | - Ed Reznik
- Computational Oncology, Memorial Sloan Kettering Cancer Center
| | - Gouri J Nanjangud
- Molecular Cytogenetics Core Facility, Memorial Sloan Kettering Cancer Center
| | - Omer Aras
- Radiology, Memorial Sloan Kettering Cancer Center
| | - HuiYong Zhao
- Anti-tumor assessment facility, Memorial Sloan Kettering Cancer Center
| | - Rui Qu
- Anti-tumor assessment facility, Memorial Sloan Kettering Cancer Center
| | - James A Fagin
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
| | - Eric J Sherman
- Medical Oncology, Memorial Sloan Kettering Cancer Center
| | - Bin Xu
- Pathology, Memorial Sloan Kettering Cancer Center
| | | | | | - Ian Ganly
- Head and Neck Surgery, Memorial Sloan Kettering Cancer Center
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21
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Guo X, Zhang M, Guo Y, Liu H, Yang B, Gou J, Yin T, Zhang Y, He H, Liu D, Tang X. Impact of jet pulverization and wet milling techniques on properties of aripiprazole long-acting injection and absorption mechanism research in vivo. Int J Pharm 2021; 612:121300. [PMID: 34793936 DOI: 10.1016/j.ijpharm.2021.121300] [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: 08/09/2021] [Revised: 10/31/2021] [Accepted: 11/11/2021] [Indexed: 11/25/2022]
Abstract
This study aims to explore the influence of wet milling and jet pulverization on the aripiprazole microcrystalline long-acting injection. Crystal form and particle size distribution were taken as inspection indicators in vitro, and process parameters were optimized. The formulation prepared by wet milling (AMLAI-WM) was shown to undergo a slight conversion of crystal form by DSC, PXRD, TG, FT-IR and have a wider particle size distribution with D50 and Span values of 2.967 μm and 3.457 compared to the formulation fabricated by jet pulverization (AMLAI-JP) with 2.887 μm and 2.258 respectively. In addition, the in vitro release of AMLAI-WM was faster, whereby the pharmacokinetic data indicated that AMLAI-WM was absorbed more quickly within five days with AUC0-5d of 5243.7 μg·L-1·h and 4818.28 μg·L-1·h, respectively. Furthermore, no statistically significant differences in Cmax, tmax and AUC between AMLAI-JP and the commercial formulation (Abilify Maintena™) were found. The absorption mechanism was studied and showed a 1.4-fold later Tmax after depletion of macrophages and significantly lower Cmax and AUC after inhibiting angiogenesis, indicating inflammatory granuloma could facilitate drug plasma exposure. Overall, we demonstrated that jet pulverization was a good strategy for long-acting microcrystalline injection, and that the absorption behavior was affected by both particle size distribution and inflammatory granuloma.
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Affiliation(s)
- Xueting Guo
- Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Maolian Zhang
- Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yibin Guo
- Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Hao Liu
- Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Bing Yang
- Department of Traditional Chinese Pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Jingxin Gou
- Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Tian Yin
- Department of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yu Zhang
- Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Haibing He
- Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Dongchun Liu
- Department of Traditional Chinese Pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
| | - Xing Tang
- Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang 110016, China.
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22
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Xia Y, Wang WC, Shen WH, Xu K, Hu YY, Han GH, Liu YB. Thalidomide suppresses angiogenesis and immune evasion via lncRNA FGD5-AS1/miR-454-3p/ZEB1 axis-mediated VEGFA expression and PD-1/PD-L1 checkpoint in NSCLC. Chem Biol Interact 2021; 349:109652. [PMID: 34520751 DOI: 10.1016/j.cbi.2021.109652] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/01/2021] [Accepted: 09/09/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) accounts for about 80-85% of total lung cancer cases. Identifying the molecular mechanisms of anti-tumor drugs is essential for improving therapeutic effects. Herein, we aim to investigate the role of thalidomide in the tumorigenicity of NSCLC. METHODS The A549 xenograft nude mouse model was established to explore therapeutic effects of thalidomide. The expression of FGD5-AS1 was evaluated in carcinomatous and paracarcinomatous tissues from NSCLC patients as well as NSCLC cell lines. CCK-8 assay was performed to assess cell viability. The invasive capacity was examined using transwell assay. The tube formation assay was applied to determine cell angiogenesis. Flow cytometry was subjected to validate CD8+ T cell activity. The FGD5-AS1/miR-454-3p/ZEB1 regulatory network was analyzed using luciferase reporter, RIP and ChIP assays. RESULTS Thalidomide reduced tumor growth and angiogenesis and increased CD8+ T cell ratio in a mouse model. Enhanced expression of FGD5-AS1 was positively correlated with the poor survival of NSCLC patients. Knockdown of FGD5-AS1 notably suppressed the proliferation, invasion and angiogenesis of cancer cells as well as the apoptosis of CD8+ T cells. Thalidomide targeted FGD5-AS1 to exert its anti-tumor activity in NSCLC. FGD5-AS1 acted as a sponge of miR-454-3p to upregulate ZEB1, thus increasing the expression of PD-L1 and VEGFA. Simultaneous overexpression of FGD5-AS1 and silencing of miR-454-3p reversed thalidomide-mediated anti-tumor effects in NSCLC. CONCLUSION Thalidomide inhibits NSCLC angiogenesis and immune evasion via FGD5-AS1/miR-454-3p/ZEB1 axis-mediated regulation of VEGFA expression and PD-1/PD-L1 checkpoint.
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Affiliation(s)
- Yang Xia
- Department of Oncology, Taizhou Clinical Medical School of Nanjing Medical University; Taizhou People's Hospital, Taizhou, 225300, Jiangsu Province, China; Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Wei-Cheng Wang
- Department of Oncology, Taizhou Clinical Medical School of Nanjing Medical University; Taizhou People's Hospital, Taizhou, 225300, Jiangsu Province, China
| | - Wen-Hao Shen
- Department of Oncology, Taizhou Clinical Medical School of Nanjing Medical University; Taizhou People's Hospital, Taizhou, 225300, Jiangsu Province, China
| | - Kun Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Yang-Yang Hu
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Gao-Hua Han
- Department of Oncology, Taizhou Clinical Medical School of Nanjing Medical University; Taizhou People's Hospital, Taizhou, 225300, Jiangsu Province, China.
| | - Yong-Biao Liu
- Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China.
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Fujinaga A, Ohta M, Masuda T, Itai Y, Nakanuma H, Kawasaki T, Kawano Y, Hirashita T, Endo Y, Inomata M. Recurrence of gastric gastrointestinal stromal tumor 12 years after repeat hepatectomies for liver metastases: report of a case. Clin J Gastroenterol 2021; 14:1637-1641. [PMID: 34486081 DOI: 10.1007/s12328-021-01513-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 08/31/2021] [Indexed: 10/20/2022]
Abstract
No consensus has been reached on the postoperative treatment and follow-up duration for high-risk malignant gastrointestinal stromal tumor (GIST). We herein report a case of recurrent liver metastasis from gastric GIST in a patient who had been receiving adjuvant chemotherapy with imatinib mesylate for 10 years. A 78-year-old woman underwent local gastrectomy for a 20-cm gastric GIST with a mitotic index of 25/50 high-power fields (HPF) 17 years before. Partial hepatectomy for recurrent liver metastases was repeatedly performed 14 and 12 years before. After the second hepatectomy, postoperative adjuvant chemotherapy with imatinib mesylate was given for 10 years, during which no recurrence was observed. Two years after the completion of adjuvant chemotherapy, computed tomography revealed a 2-cm hepatic tumor; thus, laparoscopic partial hepatectomy was performed. Histopathological findings revealed a liver metastasis of gastric GIST with a mitotic count of 20/50 HPF and MIB-1 labeling index of 20%. Mutation analysis of the KIT gene revealed an exon 11 mutation. The patient is currently undergoing postoperative adjuvant chemotherapy with imatinib mesylate. The combination of surgery and long-term adjuvant chemotherapy for high-risk malignant GIST and liver metastases may be effective to achieve a good prognosis.
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Affiliation(s)
- Atsuro Fujinaga
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan.
| | - Masayuki Ohta
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan.,Global Oita Medical Advanced Research Center for Health, Oita University, Oita, Japan
| | - Takashi Masuda
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan
| | - Yusuke Itai
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan.,Department of Diagnostic Pathology, Faculty of Medicine, Oita University, Oita, Japan
| | - Hiroaki Nakanuma
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan
| | - Takahide Kawasaki
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan
| | - Yoko Kawano
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan
| | - Teijiro Hirashita
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan
| | - Yuichi Endo
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan
| | - Masafumi Inomata
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan
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24
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Bovilla VR, Kuruburu MG, Bettada VG, Krishnamurthy J, Sukocheva OA, Thimmulappa RK, Shivananju NS, Balakrishna JP, Madhunapantula SV. Targeted Inhibition of Anti-Inflammatory Regulator Nrf2 Results in Breast Cancer Retardation In Vitro and In Vivo. Biomedicines 2021; 9:1119. [PMID: 34572304 PMCID: PMC8471069 DOI: 10.3390/biomedicines9091119] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/21/2021] [Accepted: 08/26/2021] [Indexed: 02/06/2023] Open
Abstract
Nuclear factor erythroid-2 related factor-2 (Nrf2) is an oxidative stress-response transcriptional activator that promotes carcinogenesis through metabolic reprogramming, tumor promoting inflammation, and therapeutic resistance. However, the extension of Nrf2 expression and its involvement in regulation of breast cancer (BC) responses to chemotherapy remain largely unclear. This study determined the expression of Nrf2 in BC tissues (n = 46) and cell lines (MDA-MB-453, MCF-7, MDA-MB-231, MDA-MB-468) with diverse phenotypes. Immunohistochemical (IHC)analysis indicated lower Nrf2 expression in normal breast tissues, compared to BC samples, although the difference was not found to be significant. However, pharmacological inhibition and siRNA-induced downregulation of Nrf2 were marked by decreased activity of NADPH quinone oxidoreductase 1 (NQO1), a direct target of Nrf2. Silenced or inhibited Nrf2 signaling resulted in reduced BC proliferation and migration, cell cycle arrest, activation of apoptosis, and sensitization of BC cells to cisplatin in vitro. Ehrlich Ascites Carcinoma (EAC) cells demonstrated elevated levels of Nrf2 and were further tested in experimental mouse models in vivo. Intraperitoneal administration of pharmacological Nrf2 inhibitor brusatol slowed tumor cell growth. Brusatol increased lymphocyte trafficking towards engrafted tumor tissue in vivo, suggesting activation of anti-cancer effects in tumor microenvironment. Further large-scale BC testing is needed to confirm Nrf2 marker and therapeutic capacities for chemo sensitization in drug resistant and advanced tumors.
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Affiliation(s)
- Venugopal R. Bovilla
- Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India; (V.R.B.); (M.G.K.); (V.G.B.); (R.K.T.)
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India
- Public Health Research Institute of India (PHRII), Mysuru 570020, Karnataka, India
| | - Mahadevaswamy G. Kuruburu
- Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India; (V.R.B.); (M.G.K.); (V.G.B.); (R.K.T.)
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India
| | - Vidya G. Bettada
- Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India; (V.R.B.); (M.G.K.); (V.G.B.); (R.K.T.)
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India
| | - Jayashree Krishnamurthy
- Department of Pathology, JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India;
| | - Olga A. Sukocheva
- College of Nursing and Health Sciences, Flinders University, Bedford Park, SA 5042, Australia
| | - Rajesh K. Thimmulappa
- Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India; (V.R.B.); (M.G.K.); (V.G.B.); (R.K.T.)
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India
| | - Nanjunda Swamy Shivananju
- Department of Biotechnology, JSS Technical Institutions Campus, JSS Science and Technology University, Mysore 570006, Karnataka, India;
| | | | - SubbaRao V. Madhunapantula
- Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India; (V.R.B.); (M.G.K.); (V.G.B.); (R.K.T.)
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India
- Leader, Special Interest Group in Cancer Biology and Cancer Stem Cells (SIG-CBCSC), JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India
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Liu H, Chen S, Huang C, Zheng Q, Ye Y, Ye Z, Lyu G. Longitudinal Changes in Knee Joint Synovial Vascularity in a Rabbit Model of Rheumatoid Arthritis: Quantification Using Power Doppler Ultrasound and Contrast-Enhanced Ultrasound. ULTRASOUND IN MEDICINE & BIOLOGY 2021; 47:2430-2441. [PMID: 33958258 DOI: 10.1016/j.ultrasmedbio.2021.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 02/24/2021] [Accepted: 03/16/2021] [Indexed: 06/12/2023]
Abstract
We studied a rabbit model of rheumatoid arthritis (RA) to examine the time course of changes in synovial neovascularization based on quantitative power Doppler ultrasound and contrast-enhanced ultrasound (CEUS). Twenty-five male New Zealand rabbits were in the ovalbumin-induced arthritis (OIA) group, and 5 were in the control group. Both rear knee joints of all rabbits were examined using conventional US and CEUS over 16 weeks. The knee synoviums of OIA rabbits were sampled by US-guided biopsy, and expression of CD31 and vascular endothelial growth factor (VEGF) was determined by immunohistochemistry. The correlation of joint damage based on multimodal US with microvessel density (CD31 positivity) and VEGF expression at different times was analyzed. OIA rabbits had increased synovial expression of CD31 and VEGF from weeks 6 to 12 (p < 0.01). During the early stage of CEUS enhancement, "dot enhancement" was more common at weeks 6 and 8, and "stripe enhancement" was more common at weeks 12 and 16 (p < 0.05). There were significant positive correlations of synovial CD31 and VEGF expression with power Doppler image grade, CEUS grade and peak intensity (p < 0.05 for all). Thus, OIA rabbits mimicked early-stage RA at 6 to 8 weeks, middle-stage RA at 8 to 12 weeks and late-stage RA at 12 to 16 weeks. Power Doppler image grade, CEUS grade and peak intensity, especially when combined with CD31 expression data, accurately characterized the extent of synovial vascularization in a rabbit model of RA. Increased vascularity based on CEUS may have value for the early diagnosis of RA.
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Affiliation(s)
- Hui Liu
- Department of Ultrasound, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Shuqiang Chen
- Department of Ultrasound, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Chao Huang
- Department of Nuclear Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Qing Zheng
- Department of Hematology and Rheumatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Yuhong Ye
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Zhen Ye
- Department of Ultrasound, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Guorong Lyu
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China; Department of Clinical Medicine, Quanzhou Medical College, Quanzhou, China.
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Asif M, Yousaf HM, Saleem M, Hussain L, Mahrukh, Zarzour RA, Chohan T, Saadullah M, Shamas MU, Yaseen HS, Yousaf MU, Khan IU, Tahir MA. Raphanus Sativus Seeds OilArrested In Vivo Inflammation and Angiogenesis Through Down-Regulation of TNF-a. Curr Pharm Biotechnol 2021; 23:728-739. [PMID: 34225619 DOI: 10.2174/1389201022666210702120956] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 01/19/2021] [Accepted: 04/13/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Raphanus sativus is traditionally used as an anti-inflammatory agent. OBJECTIVES The current study was designed to explore the in vivo anti-inflammatory and antiangiogenic properties of Raphanus sativus seeds oil. METHODS Cold press method was used for the extraction of oil (RsSO) and was characterised using GC-MS techniques. Three in vitro antioxidant assays (DPPH, ABTS, and FRAP) were performed to explore antioxidant potential of RsSO. Disc diffusion methods were used to study in vitro antimicrobial properties. In vivo anti-inflammatory properties were studied in both acute and chronic inflammation models. In ovo chicken, a chorioallantoic membrane assay was performed to study antiangiogenic effects. Molecular mechanisms were identified using serum TNF-α ELISA kit and docking tools. RESULTS GC-MS analysis of RsSO revealed the presence of hexadecanoic and octadecanoic acid. Findings of DPPH, ABTS, and FRAP models indicated relatively moderate radical scavenging properties of RsSO. Oil showed antimicrobial activity against a variety of strains tested. Data of inflammation models showed significant (p < 0.05) anti-inflammatory effects of RsSO in both acute and chronic models. 500 mg/kg RsSO halted inflammation development significantly better (p < 0.05) as compared with lower doses. Histopathological evaluations of paws showed minimal infiltration of inflammatory cells in RsSO-treated animals. Findings of TNF-α ELSIA and docking studies showed that RsSO has the potential to downregulate the expression of TNF-α, iNOS, ROS, and NF-κB, respectively. Moreover, RsSO showed in vivo antiangiogenic effects. CONCLUSION Data of the current study highlight that Raphanus sativus seeds oil has anti-inflammatory, and antiangiogenic properties and can be used as an adjunct to standard NSAIDs therapy to reduce its dose and side effects.
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Affiliation(s)
- Muhammad Asif
- Department of Pharmacy, The Islamia University of Bahawalpur, Punjab. Pakistan
| | - Hafiz Muhammad Yousaf
- Faculty of Pharmaceutical Sciences, Government College University Faisalabad. Pakistan
| | - Mohammed Saleem
- University College of Pharmacy, University of the Punjab, Lahore. Pakistan
| | - Liaqat Hussain
- Faculty of Pharmaceutical Sciences, Government College University Faisalabad. Pakistan
| | - Mahrukh
- Faculty of Pharmaceutical Sciences, Government College University Faisalabad. Pakistan
| | - Raghdaa Al Zarzour
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia. Malaysia
| | - Tahir Chohan
- Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore. Pakistan
| | - Malik Saadullah
- Faculty of Pharmaceutical Sciences, Government College University Faisalabad. Pakistan
| | | | - Hafiza Sidra Yaseen
- Faculty of Pharmaceutical Sciences, Government College University Faisalabad. Pakistan
| | - Muhammad Umair Yousaf
- Faculty of Pharmaceutical Sciences, Government College University Faisalabad. Pakistan
| | - Ikram Ullah Khan
- Faculty of Pharmaceutical Sciences, Government College University Faisalabad. Pakistan
| | - Muhammad Azam Tahir
- Department of Pharmaceutics, Institute of Pharmacy, University of Bonn, Bonn. Germany
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Yeeravalli R, Kaushik K, Das A. TWIST1-mediated transcriptional activation of PDGFRβ in breast cancer stem cells promotes tumorigenesis and metastasis. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166141. [PMID: 33845139 DOI: 10.1016/j.bbadis.2021.166141] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 03/05/2021] [Accepted: 03/30/2021] [Indexed: 12/26/2022]
Abstract
Triple-negative breast cancer (TNBC) patients often exhibit poor prognosis and breast cancer relapse due to metastasis. This results in secondary tumor generation at distant-unrelated organs that account for the majority of breast cancer-related deaths. Although breast cancer stem cells (CSCs) have been attributed to metastasis, a mechanistic understanding is essential for developing therapeutic interventions to combat breast cancer relapse. Breast CSCs are generated due to Epithelial-to-mesenchymal transition (EMT), regulated by transcription factors (EMT-TF) that are implicated in tumorigenesis and metastasis. However, the underlying mechanisms mediating these processes remain elusive. In the present study, we have reported that TWIST1, an EMT-TF, exhibits positive transcriptional regulation on PDGFRβ promoter, thus identifying PDGFRβ as one of the downstream targets of EMT regulation in breast CSCs. Breast cancer cells overexpressing PDGFRβ exhibited a significant increase in physiological and molecular properties comparable to that of breast CSCs, while molecular silencing of PDGFRβ in breast CSCs perturbed these phenomena. Mechanistically, PDGFRβ overexpression induced the activation of FAK and Src leading to cell migration and invasion. Orthotopic xenograft transplantation of stable breast cancer cells and CSCs with PDGFRβ overexpression in nude mice led to a significant increase in tumorigenesis, and metastasis to lung and liver as depicted by the significant increase in human gene-specific PDGFRβ and CD44 expression, and colocalization along with an expression of human-specific Alu sequences which were perturbed with stable silencing of PDGFRβ in breast CSCs. Thus, PDGFRβ plays a crucial role in inducing breast cancer tumorigenesis and metastasis that can be a plausible therapeutic target to treat TNBC patients.
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Affiliation(s)
- Ragini Yeeravalli
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500 007, TS, India; Academy of Science and Innovative Research (AcSIR), Ghaziabad, UP 201 002, India
| | - Komal Kaushik
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500 007, TS, India; Academy of Science and Innovative Research (AcSIR), Ghaziabad, UP 201 002, India
| | - Amitava Das
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500 007, TS, India; Academy of Science and Innovative Research (AcSIR), Ghaziabad, UP 201 002, India.
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Fudalej MM, Badowska-Kozakiewicz AM. Improved understanding of gastrointestinal stromal tumors biology as a step for developing new diagnostic and therapeutic schemes. Oncol Lett 2021; 21:417. [PMID: 33841578 DOI: 10.3892/ol.2021.12678] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/10/2021] [Indexed: 12/12/2022] Open
Abstract
A gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal tract, with an estimated incidence of 10-15 per 1 million per year. While preparing holistic care for patients with GIST diagnosis, scientists might face several difficulties - insufficient risk stratification, acquired or secondary resistance to imatinib, or the need for an exceptional therapy method associated with wild-type tumors. This review summarizes recent advances associated with GIST biology that might enhance diagnostic and therapeutic strategies. New molecules might be incorporated into risk stratification schemes due to their proven association with outcomes; however, further research is required. Therapies based on the significant role of angiogenesis, immunology, and neural origin in the GIST biology could become a valuable enhancement of currently implemented treatment schemes. Generating miRNA networks that would predict miRNA regulatory functions is a promising approach that might help in better selection of potential biomarkers and therapeutical targets in cancer, including GISTs.
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Affiliation(s)
- Marta Magdalena Fudalej
- Department of Cancer Prevention, Medical University of Warsaw, 02-091 Warsaw, Poland.,Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
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Liu F, Yang W, Hu M, Zhang Y, Sun B, Yang H, Brosius J, Deng C. Constitutive activity of GPR26 regulated by ubiquitin-dependent degradation and its antitumor role. FEBS J 2021; 288:4655-4682. [PMID: 33577134 DOI: 10.1111/febs.15763] [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: 10/15/2020] [Revised: 01/13/2021] [Accepted: 02/11/2021] [Indexed: 02/05/2023]
Abstract
G protein-coupled receptors (GPCRs) play important roles in many physiological functions and numerous diseases. In addition to the classic ligand-stimulated receptor activity, an increasing number of studies have established that many GPCRs function constitutively in a receptor dose-dependent manner. Previous observations showed that following gene transfection, little or no protein was detectable for certain GPCRs (designated apparent state A), such as GPR26, GPR39, GPR78, GPR133, GPR139, BRS3, and LGR5, which showed strong constitutive activities. When we lysed cells in the immediate presence of western blot loading buffer, a significant increase of protein levels was detected (actual state B), which was much closer to the true expression levels under physiological conditions. GPR26 was chosen for further functional experiments as the actual state B. We identified an important ubiquitination site, K286, as well as the ubiquitin ligase E3 homologous to the E6-associated protein carboxyl terminus domain containing 3 interacting with GPR26. The pronounced differences in the protein expression and constitutive activity of GPR26 were a consequence of the ubiquitin-mediated rapid degradation mechanism. Furthermore, we identified in vitro and in vivo antitumor activity associated with high expression levels and constitutive activity of GPR26 in liver cancer cells. Hence, GPR26 could act as an antitumor gene for hepatocellular carcinoma. This study also represents the actual state B of a batch of GPCRs that actually play potentially important roles in physiological functions by their constitutive activity, which is controlled by rapid ubiquitin-dependent degradation.
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Affiliation(s)
- Fang Liu
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, China
| | - Wei Yang
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, China
| | - Minghui Hu
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, China
| | - Yong Zhang
- West China - Washington Mitochondria and Metabolism Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, China
| | - Hao Yang
- Key Laboratory of Transplant Engineering and Immunology, MOH, West China Hospital, Sichuan University, Chengdu, China
| | - Juergen Brosius
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.,Institute of Experimental Pathology, ZMBE, University of Münster, Germany
| | - Cheng Deng
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, China
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Radzikowska J, Krzeski A, Czarnecka AM, Klepacka T, Rychlowska-Pruszynska M, Raciborska A, Dembowska-Baginska B, Pronicki M, Kukwa A, Sierdzinski J, Kukwa W. Endoglin Expression and Microvessel Density as Prognostic Factors in Pediatric Rhabdomyosarcoma. J Clin Med 2021; 10:jcm10030512. [PMID: 33535525 PMCID: PMC7867094 DOI: 10.3390/jcm10030512] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 01/17/2021] [Accepted: 01/23/2021] [Indexed: 12/23/2022] Open
Abstract
(1) Background: The study proposed to analyze microvessel density (MVD) in rhabdomyosarcoma (RMS) based on the expression of angiogenesis markers and define its prognostic role in this group of patients. (2) Methods: The study included forty-nine pediatric patients diagnosed with RMS. Tumor tissue expression of CD31, CD34, and CD105 was analyzed. MVD was calculated and correlated with clinical RMS prognostic parameters. (3) Results: CD31, CD34, and CD105 are expressed in all RMS cases. MVD/CD105 was significantly higher in the RMS group than in the control group. The mean and median values of MVD/CD105 in RMS were lower than MVD/CD31 and MVD/CD34. MVD/CD105 was significantly higher in patients with alveolar RMS and those with metastatic disease. Patients with higher levels of MVD/CD105 had a higher risk of death (HR = 1.009). (4) Conclusion: CD105 is a relevant angiogenesis marker in pediatric RMS, and MVD/CD105 is an independent risk factor of short overall survival in children with RMS.
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Affiliation(s)
- Joanna Radzikowska
- Department of Otorhinolaryngology, Faculty of Dental Medicine, Medical University of Warsaw, 19/25 Stepinska St., 00-739 Warsaw, Poland; (J.R.); (A.K.)
| | - Antoni Krzeski
- Department of Otorhinolaryngology, Faculty of Dental Medicine, Medical University of Warsaw, 19/25 Stepinska St., 00-739 Warsaw, Poland; (J.R.); (A.K.)
| | - Anna M. Czarnecka
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute—Oncology Center, 5 Roentgena St., 02-781 Warsaw, Poland;
- Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warsaw, Poland
| | - Teresa Klepacka
- Department of Pathology, Institute of Mother and Child, 17a Kasprzaka St., 01-211 Warsaw, Poland;
| | - Magdalena Rychlowska-Pruszynska
- Department of Oncology and Surgical Oncology for Children and Youth, Institute of Mother and Child, 17a Kasprzaka St., 01-211 Warsaw, Poland; (M.R.-P.); (A.R.)
| | - Anna Raciborska
- Department of Oncology and Surgical Oncology for Children and Youth, Institute of Mother and Child, 17a Kasprzaka St., 01-211 Warsaw, Poland; (M.R.-P.); (A.R.)
| | - Bozenna Dembowska-Baginska
- Department of Pediatric Oncology, The Children’s Memorial Health Institute, 20 Dzieci Polskich St., 04-730 Warsaw, Poland;
| | - Maciej Pronicki
- Department of Pathology, The Children’s Memorial Health Institute, 20 Dzieci Polskich St., 04-730 Warsaw, Poland;
| | - Andrzej Kukwa
- Department of Otolaryngology and Head and Neck Diseases, School of Medicine, University of Warmia and Mazury, 30 Warszawska St., 10-082 Olsztyn, Poland;
| | - Janusz Sierdzinski
- Department of Medical Informatics and Telemedicine, Medical University of Warsaw, 14/16 Litewska St., 00-581 Warsaw, Poland;
| | - Wojciech Kukwa
- Department of Otorhinolaryngology, Faculty of Dental Medicine, Medical University of Warsaw, 19/25 Stepinska St., 00-739 Warsaw, Poland; (J.R.); (A.K.)
- Correspondence: ; Tel.: +48-223186270
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Song LJ, Ge HJ, Shi XQ, Shen WW. Prognostic and predictive values of the KIT11-mutated grading system in patients with gastrointestinal stromal tumors: a retrospective study. Hum Pathol 2021; 110:31-42. [PMID: 33476644 DOI: 10.1016/j.humpath.2021.01.001] [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: 11/13/2020] [Revised: 01/05/2021] [Accepted: 01/11/2021] [Indexed: 01/10/2023]
Abstract
The KIT11 mutation is the most frequent mutation pattern in gastrointestinal stromal tumors (GISTs). However, few studies have investigated the correlation between the KIT11-mutated grading system and imatinib mesylate (IM) sensitivity (the first choice for adjuvant treatment of GISTs). Here, we elucidated the clinical value of the KIT11-mutated grading system for prognostic prediction in patients with GISTs treated with IM. A total of 106 patients with GIST were treated with IM (8: intermediate-risk, 98: high-risk; 10: KIT9-mutated, 86: KIT11-mutated, 5: wild-type, and 5: other mutations). KIT11-mutated patients were divided into 3 grades based on the KIT11-mutated site and type. Clinical backgrounds and prognostic outcomes were retrospectively compared between the 3 groups. Of 86 KIT11-mutated patients treated with IM, 32 (37.21%) had grade 1 tumors, 37 (43.02%) had grade 2 tumors, and 17 (19.77%) had grade 3 tumors. The 5-year disease-free survival (DFS) was significantly worse in patients with grade 3 KIT11-mutated GISTs (41.96%, p = 0.001) than in those with grade 1 (93%) and grade 2 (70.64%) cases. The multivariable analysis suggested that the KIT11-mutated grading system was an independent risk factor for DFS in patients treated with IM (hazard risk, 2.512; 95% confidence interval, 1.370-4.607; p = 0.003). In conclusion, the KIT11-mutated grading system provides good prognostic stratification for DFS in patients treated with IM. Grade 1 tumors predict a favorable response to IM.
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Affiliation(s)
- Ling-Jun Song
- Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080 China.
| | - Hui-Juan Ge
- Department of Pathology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 PR China
| | - Xiao-Qin Shi
- Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080 China
| | - Wei-Wei Shen
- Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080 China; Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
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Allanblackia floribunda Seed Extract Attenuates the Ethanol-Induced Gastric Ulcer in Rats via the Inhibition of TNF- α and INF- γ Levels and Modulation in the Expression of Ki67 Protein. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6694572. [PMID: 33521129 PMCID: PMC7819754 DOI: 10.1155/2021/6694572] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/15/2020] [Accepted: 12/22/2020] [Indexed: 01/12/2023]
Abstract
Allanblackia floribunda has been used to treat an upset stomach in African traditional medicine, but its efficacy and safety have not been scientifically studied. The present research is aimed at assessing the antiulcer property of the seed extract of the plant to validate its traditional claim. Rats were pretreated with three doses of aqueous extract of A. floribunda (AFE) at 30, 100, and 300 mg/kg or omeprazole 10 mg/kg for 1 hr before the acute gastric ulcer was induced by oral administration of 5 mL/kg of 98% ethanol. The animals were sacrificed under anesthesia, and the stomach and blood were collected. The gross histology of the stomach, percentage protection conferred by the treatment, gastric pH, and serum TNF-α and INF-γ were assessed as well as the expression of Ki67 antigens. The antioxidant properties as well as the acute toxicity profile of the plant extract were also assessed. The results show that A. floribunda conferred significant protection on the rats against gastric ulceration with % protection of 46.15, 57.69, and 65.38 for AFE 30, 100, and 300 mg/kg, respectively, as well as 69.23% for omeprazole 10 mg/kg. The plant extract caused marked reductions in gastric pH, TNF-α, and INF-γ with statistical significance (p < 0.001) for AFE 300 mg/kg and omeprazole 10 mg/kg. Also, the plant showed good antioxidant activity comparable to gallic acid. Furthermore, the plant extract modulated the expression of Ki67 antigens. All animals survived the 14-day delayed toxicity test with no significant differences in physical, hematological, and biochemical parameters between rats orally administered with supratherapeutic doses of AFE (5000 mg/kg) or normal saline. The study established that the gastroprotective effect of the seed extract of A. floribunda is attributable to its antisecretory, antioxidant, and anti-inflammatory properties. Additionally, the plant was found to promote ulcer healing via the modulation of the expression Ki67 and was safe at supratherapeutic doses.
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Could computed tomography be used as a surrogate of endoscopic ultrasonography in the screening and surveillance of small gastric Gastrointestinal stromal tumors? Eur J Radiol 2020; 135:109463. [PMID: 33338760 DOI: 10.1016/j.ejrad.2020.109463] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 11/26/2020] [Accepted: 11/30/2020] [Indexed: 12/18/2022]
Abstract
PURPOSE To investigate whether computed tomography (CT) could be used for screening and surveillance of small gastric gastrointestinal stromal tumors (gGISTs). METHOD A total of 162 pathologically confirmed small gGISTs (≤2 cm) between September 2007 and November 2019 were retrospectively enrolled. Thirty-six lesions received contrast-enhanced CT after they were identified by endoscopy and EUS, and forty-three lesions received CT alone before surgery. The detection rate of CT for ≤1 cm gGISTs (micro-gGISTs) and 1-2 cm gGISTs (mini-gGISTs) was investigated, and the detection rate of CT alone was compared with that of CT following endoscopy and EUS. The relationship between EUS- and CT-detected high-risk features were assessed. RESULTS CT demonstrated a favorable detection rate for mini-gGISTs previously identified by EUS and endoscopy, whereas CT alone showed an inferior detection rate (100 % vs. 75 %, p = 0.02). CT showed a poor detection rate for micro-gGISTs, both for lesions received CT after identified by EUS and endoscopy, and those received CT alone (33.3 % vs. 14.8 %, p = 0.372). CT-detected heterogeneous enhancement pattern and presence of calcification were strongly correlated with heterogeneous echotexture (Spearman's ρ=0.66, p < 0.001) and echogenic foci (Spearman's ρ=0.79, p < 0.001) on EUS, respectively. CT-detected necrosis was moderately correlated with cystic spaces on EUS (Spearman's ρ=0.42, p = 0.02). No correlation was found between EUS- and CT- assessed irregular border. CONCLUSIONS CT could potentially be considered as a surrogate of EUS for surveillance of mini-gGISTs instead of micro-gGISTs, whereas couldn't be used as a screening modality for either micro- or mini-gGISTs.
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Zhu XQ, Yang H, Lin MH, Shang HX, Peng J, Chen WJ, Chen XZ, Lin JM. Qingjie Fuzheng Granules regulates cancer cell proliferation, apoptosis and tumor angiogenesis in colorectal cancer xenograft mice via Sonic Hedgehog pathway. J Gastrointest Oncol 2020; 11:1123-1134. [PMID: 33456987 PMCID: PMC7807284 DOI: 10.21037/jgo-20-213] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 09/25/2020] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Sonic Hedgehog (SHh) signaling pathway plays a critical role in cell proliferation, apoptosis, and tumor angiogenesis in various types of malignancies including colorectal cancer (CRC). Qingjie Fuzheng Granules (QFG) is a traditional Chinese medicinal formula, which has been clinically used in various cancer treatments, including CRC. In this study, we explored the potential molecular mechanisms of QFG treatment effects on CRC via the SHh pathway. METHODS A CRC HCT-116 xenograft mouse model was utilized for all experiments. Mice were treated with intra-gastric administration of 1 g/kg of QFG or saline 6 days a week for 28 days (4 weeks). Body weight, length and shortest diameter of the tumor were measured every 3 days. At the end of the treatment, the tumor weight was measured. TUNEL staining assays were used to detect tumor apoptosis. Western blot and immunohistochemistry (IHC) assays were used to detect the expression of relative proteins. RESULTS In our results, QFG inhibited the increase of tumor volume and weight, and exhibited no impact on mouse body weight. Furthermore, QFG significantly decreased the expression of SHh, Smo and Gli proteins, indicating the action of SHh signaling. Consequently, the expression of pro-proliferative survivin, Ki-67, Cyclin-D1 and CDK4 were decreased and expression of anti-proliferative p21 was increased. The pro-apoptotic Bax/Bcl-2 ratio, cle-caspase-3 and TUNEL-positive cell percentage in tumor tissues were increased. Meanwhile, the pro-angiogenic VEGF-A and VEGFR-2 expression was down-regulated. CONCLUSIONS QFG inhibited CRC cell proliferation and promoted CRC cell apoptosis and tumor angiogenesis in vivo through the suppression of SHh pathway, suggesting that QFG could be a potential therapeutic drug for CRC.
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Affiliation(s)
- Xiao-Qin Zhu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, China
| | - Hong Yang
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, China
| | - Ming-He Lin
- Editorial Department of Rehabilitation Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Hai-Xia Shang
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, China
| | - Jun Peng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, China
| | - Wu-Jin Chen
- Department of Oncology, Affiliated People’s Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Xu-Zheng Chen
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, China
| | - Jiu-Mao Lin
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, China
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Kimura T, Togawa T, Onishi K, Iida A, Sato Y, Goi T. Efficacy of Long-Term Adjuvant Therapy With Imatinib Mesylate After Extensive Surgical Treatment for Ruptured Gastrointestinal Stromal Tumors of the Small Intestine With Peritoneal Metastases: A Case Report. J Investig Med High Impact Case Rep 2020; 8:2324709620970736. [PMID: 33228387 PMCID: PMC7691891 DOI: 10.1177/2324709620970736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal
neoplasms of the gastrointestinal tract. Although most patients with
advanced GISTs benefit from imatinib mesylate (IM) as standard
targeted therapy, the optimal duration of adjuvant IM for GIST
patients with high risk of recurrence who underwent surgical resection
remains unknown. In this article, we present a case of a ruptured GIST
of the small intestine accompanied by peritoneal metastases, which was
effectively treated by surgical procedure followed by long-term
adjuvant therapy with IM. Surgical resection was performed for the
ruptured small intestinal GIST, and multitude of peritoneal metastases
were cauterized. The patient received adjuvant therapy with IM (400
mg/day) for 12 years without an interruption or a dose change.
Peritoneal metastatic recurrence was observed by the follow-up
computed tomography scan obtained 12 years after surgery, and surgical
resection of the recurrent GIST was performed. The molecular
examination indicated a KIT exon 11 deletion mutation in both the
primary GIST and recurrent GIST. An additional point mutation was
observed in the recurrent GIST in exon 17 that caused resistance to
IM. The present case might indicate that extensive removal of the
tumor cells through surgery and long-term administration of IM without
an interruption or a dose change were important for achieving improved
recurrence-free survival in patients with ruptured GISTs of the small
intestine with peritoneal metastases.
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Affiliation(s)
- Toshihisa Kimura
- National Hospital Organization Tsuruga Medical Center, Tsuruga, Fukui, Japan
| | - Tamotsu Togawa
- National Hospital Organization Tsuruga Medical Center, Tsuruga, Fukui, Japan
| | - Kenji Onishi
- National Hospital Organization Tsuruga Medical Center, Tsuruga, Fukui, Japan
| | - Atsushi Iida
- National Hospital Organization Tsuruga Medical Center, Tsuruga, Fukui, Japan
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Seven G, Kochan K, Caglar E, Kiremitci S, Koker IH, Senturk H. Evaluation of Ki67 Index in Endoscopic Ultrasound-Guided Fine Needle Aspiration Samples for the Assessment of Malignancy Risk in Gastric Gastrointestinal Stromal Tumors. Dig Dis 2020; 39:407-414. [PMID: 33017820 DOI: 10.1159/000511994] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 10/05/2020] [Indexed: 02/02/2023]
Abstract
BACKGROUND The risk of malignancy in resected gastrointestinal stromal tumors (GISTs) depends on tumor size, location, and mitotic index. Reportedly, the Ki67 index has a prognostic value in resected GISTs. We aimed to analyze the accuracy of endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) samples with reference to Ki67 index, using surgical specimens as the gold standard. METHODS Fifty-five patients who underwent EUS-FNA followed by surgical resection for gastric GISTs were retrospectively analyzed. Patients' age and sex; tumors' size and location; mitotic index, cell type, cellularity, pleomorphism, presence of ulceration, hemorrhage, necrosis, mucosal or serosal invasion, growth pattern, and Ki67 index based on pathology were investigated. RESULTS Location in fundus, ulceration, hemorrhage, mucosal invasion, and Ki67 index in surgical specimens were significant in predicting high-risk groups (p < 0.05) on univariate analysis. Frequency of bleeding (p = 0.034) and the Ki67 index (p = 0.018) were the only independent significant factors in multivariate analysis. The optimal cutoff level of Ki67 was 5%, with 88.2% sensitivity and 52.8% specificity (p = 0.021). The mean Ki67 index was lower in EUS-FNA samples than in surgical specimens (2% [1-15] versus 10% [1-70], p = 0.001). The rank correlation coefficient value of Ki67 was 0.199 (p = 0.362) between EUS-FNA and surgical samples and showed no reliability for EUS-FNA samples. CONCLUSION The Ki67 index in resected specimens correlated with high-risk GISTs, although it had no additive value to the current criteria. The Ki67 index in EUS-guided FNA samples is not a reliable marker of proliferation in GISTs.
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Affiliation(s)
- Gulseren Seven
- Division of Gastroenterology, Bezmialem Vakif University, Istanbul, Turkey
| | - Koray Kochan
- Division of Gastroenterology, Bezmialem Vakif University, Istanbul, Turkey
| | - Erkan Caglar
- Division of Gastroenterology, Balikesir University School of Medicine, Balikesir, Turkey
| | - Sercan Kiremitci
- Division of Gastroenterology, Bezmialem Vakif University, Istanbul, Turkey
| | | | - Hakan Senturk
- Division of Gastroenterology, Bezmialem Vakif University, Istanbul, Turkey
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Guo CH, Hsia S, Chung CH, Lin YC, Shih MY, Chen PC, Peng CL, Henning SM, Hsu GSW, Li Z. Nutritional supplements in combination with chemotherapy or targeted therapy reduces tumor progression in mice bearing triple-negative breast cancer. J Nutr Biochem 2020; 87:108504. [PMID: 32956826 DOI: 10.1016/j.jnutbio.2020.108504] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 08/26/2020] [Accepted: 09/03/2020] [Indexed: 02/06/2023]
Abstract
The potential anti-cancer properties of selenium (Se) and eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) have been documented. However, few studies have been conducted examining anti-tumor effects of nutritional supplements (NS) containing Se and EPA/DHA in combination with anti-cancer agents, such as taxol (Tax), adriamycin (Adr), and avastin (Ava). Compared with triple-negative breast cancer (TNBC)-bearing positive control (TB) mice, a low dose of Tax, Adr, and Ava decreased tumor size and the incidence of metastasis in TB-Tax, TB-Adr, and TB-Ava groups. Combination treatment with anti-cancer agent and NS (2.7 μg Se and 5.1 mg EPA/3.7 mg DHA/g) induced additional decreases in TB-Tax-NS, TB-Adr-NS, and TB-Ava-NS groups. Th1-associated cytokines were increased, and Th2-type cytokines were decreased significantly in TB mice with combination treatment than that of anti-cancer agent treatment alone. Combination treatment with anti-cancer agents and NS has also been shown to further increased tumor malondialdehyde (MDA) levels, lowered hypoxia-inducible factor (HIF)-1α, angiogenic markers (vascular endothelial growth factor [VEGF] and CD31) and metastatic potential, as well as reduced heat shock proteins, receptor tyrosine kinase AXL, and surface markers of cancer stem cells, and increased apoptotic proteins. For immune checkpoint molecules, combination treatment was associated with a greater decrease in programmed cell death ligand-1 (PD-L1) in both tumors and mammary glands, but PD-1 level in primary tumors was increased. Our results suggest that combination treatment with low-dose anti-cancer agents (Tax, Adr, and Ava) and oral supplementation of Se/ EPA/DHA significantly decreased tumor growth and metastatic progression in TNBC mice through multiple anti-tumor mechanisms.
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Affiliation(s)
- Chih-Hung Guo
- Micronutrition and Biomedical Nutrition Lab, Institute of Biomedical Nutrition, Hung-Kuang University, Taichung 433, Taiwan; Taiwan Nutraceutical Association, Taipei 105, Taiwan.
| | - Simon Hsia
- Taiwan Nutraceutical Association, Taipei 105, Taiwan
| | | | - Yi-Chun Lin
- Taiwan Nutraceutical Association, Taipei 105, Taiwan
| | - Min-Yi Shih
- Taiwan Nutraceutical Association, Taipei 105, Taiwan
| | | | - Chia-Lin Peng
- Taiwan Nutraceutical Association, Taipei 105, Taiwan
| | - Susanne M Henning
- UCLA Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA
| | - Guoo-Shyng W Hsu
- Department of Nutritional Science, Fu Jen University, New Taipei City 242, Taiwan
| | - Zhaoping Li
- UCLA Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
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Cannella R, La Grutta L, Midiri M, Bartolotta TV. New advances in radiomics of gastrointestinal stromal tumors. World J Gastroenterol 2020; 26:4729-4738. [PMID: 32921953 PMCID: PMC7459199 DOI: 10.3748/wjg.v26.i32.4729] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/16/2020] [Accepted: 08/01/2020] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are uncommon neoplasms of the gastrointestinal tract with peculiar clinical, genetic, and imaging characteristics. Preoperative knowledge of risk stratification and mutational status is crucial to guide the appropriate patients’ treatment. Predicting the clinical behavior and biological aggressiveness of GISTs based on conventional computed tomography (CT) and magnetic resonance imaging (MRI) evaluation is challenging, unless the lesions have already metastasized at the time of diagnosis. Radiomics is emerging as a promising tool for the quantification of lesion heterogeneity on radiological images, extracting additional data that cannot be assessed by visual analysis. Radiomics applications have been explored for the differential diagnosis of GISTs from other gastrointestinal neoplasms, risk stratification and prediction of prognosis after surgical resection, and evaluation of mutational status in GISTs. The published researches on GISTs radiomics have obtained excellent performance of derived radiomics models on CT and MRI. However, lack of standardization and differences in study methodology challenge the application of radiomics in clinical practice. The purpose of this review is to describe the new advances of radiomics applied to CT and MRI for the evaluation of gastrointestinal stromal tumors, discuss the potential clinical applications that may impact patients’ management, report limitations of current radiomics studies, and future directions.
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Affiliation(s)
- Roberto Cannella
- Section of Radiology - BiND, University Hospital “Paolo Giaccone”, Palermo 90127, Italy
| | - Ludovico La Grutta
- Section of Radiology - BiND, University Hospital “Paolo Giaccone”, Palermo 90127, Italy
| | - Massimo Midiri
- Section of Radiology - BiND, University Hospital “Paolo Giaccone”, Palermo 90127, Italy
| | - Tommaso Vincenzo Bartolotta
- Section of Radiology - BiND, University Hospital “Paolo Giaccone”, Palermo 90127, Italy
- Department of Radiology, Fondazione Istituto Giuseppe Giglio, Ct.da Pietrapollastra, Cefalù (Palermo) 90015, Italy
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Cella PS, Marinello PC, Padilha CS, Testa MT, Guirro PB, Cecchini R, Duarte JA, Guarnier FA, Deminice R. Creatine supplementation does not promote tumor growth or enhance tumor aggressiveness in Walker-256 tumor-bearing rats. Nutrition 2020; 79-80:110958. [PMID: 32882636 DOI: 10.1016/j.nut.2020.110958] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 06/22/2020] [Accepted: 07/13/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVES This study aimed to analyze the effect of creatine (Cr) supplementation on tumor microenvironment, evaluating the parameters of tumor aggressiveness. METHODS Sixteen male Wistar rats were randomly assigned to 2 groups (n = 8/group): Tumor-bearing (T) and tumor-bearing supplemented with Cr (TCr). Cr supplementation was provided in drinking water for a total of 21 d. After 11 d of Cr supplementation (TCr group) or water (T group), Walker-256 tumor cells were inoculated subcutaneously in the right flank of all rats, which kept receiving Cr supplementation (TCr group) or water (T group) for 10 more days. The total period of the experiment was 21 d. RESULTS Tumor weight corresponded with approximately 3.5% ± 0.9% of animal body weight in the T group. Cr supplementation did not accelerate tumor growth or increase tumor size. The histopathological analysis demonstrated the presence of nuclear pleomorphisms and atypical nuclei, with the presence of low-differentiated tumor cells, in both groups. Cr supplementation did not alter apoptosis and cell proliferation markers, nor tumor capsule thickness and viable tumor area. CONCLUSIONS Cr supplementation in Walker-256 tumor-bearing rats did not induce significant changes in tumor development, and did not interfere with the parameters of tumor aggressiveness, such as the level of cell differentiation and proliferation.
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Affiliation(s)
- Paola Sanches Cella
- State University of Londrina, Department of Physical Education, Londrina, Paraná, Brazil.
| | - Poliana C Marinello
- State University of Londrina, Department of Physical Education, Londrina, Paraná, Brazil; State University of Londrina, Department of General Pathology, Londrina, Paraná, Brazil
| | - Camila S Padilha
- State University of Londrina, Department of Physical Education, Londrina, Paraná, Brazil
| | - Mayra T Testa
- State University of Londrina, Department of Physical Education, Londrina, Paraná, Brazil
| | - Philippe B Guirro
- State University of Londrina, Department of Physical Education, Londrina, Paraná, Brazil
| | - Rubens Cecchini
- State University of Londrina, Department of General Pathology, Londrina, Paraná, Brazil
| | - José A Duarte
- University of Porto, CIAFEL, Faculty of Sport, Porto, Portugal
| | - Flávia A Guarnier
- State University of Londrina, Department of General Pathology, Londrina, Paraná, Brazil
| | - Rafael Deminice
- State University of Londrina, Department of Physical Education, Londrina, Paraná, Brazil
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Zhong X, Yu X, Wen X, Chen L, Gu N. Activation of the LINC00242/miR-141/FOXC1 axis underpins the development of gastric cancer. Cancer Cell Int 2020; 20:272. [PMID: 32587479 PMCID: PMC7313095 DOI: 10.1186/s12935-020-01369-7] [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] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 06/19/2020] [Indexed: 02/07/2023] Open
Abstract
Background Long non-coding RNAs (LncRNAs) are a class of newly identified transcripts recognized as critical governors of gene expression during human carcinogenesis, whereas their tumor-suppressive or tumor-promoting effects on gastric cancer (GC) are required for further investigation. In the study, we identify the expression pattern of a novel lncRNA LINC00242 in GC and its possible permissive role in the development of GC. Methods The study included 68 pairs of GC and adjacent normal gastric tissue samples. The viability, migration, and invasion of cultured human GC cells HGC27 were evaluated by CCK-8 and Transwell chamber assays. In vitro tube formation of human brain microvascular endothelial cells (HBMVECs) in HGC27 cell coculture was detected. The regulatory network of LINC00242/miR-141/FOXC1 was verified using dual luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay. Subcutaneous xenografts of HGC27 cells were performed in nude mice. Results LINC00242 was highly expressed in GC tissues and cells and contributed to poor prognosis. LINC00242 knockdown inhibited HGC27 cell viability, migration and invasion, and tube formation of HBMVECs. LINC00242 interacted with miR-141 and positively regulated FOXC1, a target gene of miR-141. LINC00242 knockdown was partially lost in HGC27 cells upon miR-141 inhibition or FOXC1 overexpression. The tumor-promoting effect of LINC00242 on GC was demonstrated in nude mice. Conclusion Taken together, the present study demonstrates the oncogenic role of the LINC00242/miR-141/FOXC1 axis in GC, highlighting a theoretical basis for GC treatment.
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Affiliation(s)
- Xiongdong Zhong
- Department of General Surgery, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), No.79 Kangning Road, Xiangzhou District, Zhuhai, 519000 Guangdong China
| | - Xianchang Yu
- Department of General Surgery, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), No.79 Kangning Road, Xiangzhou District, Zhuhai, 519000 Guangdong China
| | - Xiaoyan Wen
- Department of General Surgery, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), No.79 Kangning Road, Xiangzhou District, Zhuhai, 519000 Guangdong China
| | - Lei Chen
- Department of General Surgery, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), No.79 Kangning Road, Xiangzhou District, Zhuhai, 519000 Guangdong China
| | - Ni Gu
- Department of General Surgery, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), No.79 Kangning Road, Xiangzhou District, Zhuhai, 519000 Guangdong China
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Ollauri-Ibáñez C, Núñez-Gómez E, Egido-Turrión C, Silva-Sousa L, Díaz-Rodríguez E, Rodríguez-Barbero A, López-Novoa JM, Pericacho M. Continuous endoglin (CD105) overexpression disrupts angiogenesis and facilitates tumor cell metastasis. Angiogenesis 2020; 23:231-247. [PMID: 31897911 PMCID: PMC7160077 DOI: 10.1007/s10456-019-09703-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 12/12/2019] [Indexed: 12/11/2022]
Abstract
Endoglin (CD105) is an auxiliary receptor for members of the TFG-β superfamily. Whereas it has been demonstrated that the deficiency of endoglin leads to minor and defective angiogenesis, little is known about the effect of its increased expression, characteristic of several types of cancer. Angiogenesis is essential for tumor growth, so high levels of proangiogenic molecules, such as endoglin, are supposed to be related to greater tumor growth leading to a poor cancer prognosis. However, we demonstrate here that endoglin overexpression do not stimulate sprouting or vascularization in several in vitro and in vivo models. Instead, steady endoglin overexpression keep endothelial cells in an active phenotype that results in an impairment of the correct stabilization of the endothelium and the recruitment of mural cells. In a context of continuous enhanced angiogenesis, such as in tumors, endoglin overexpression gives rise to altered vessels with an incomplete mural coverage that permit the extravasation of blood. Moreover, these alterations allow the intravasation of tumor cells, the subsequent development of metastases and, thus, a worse cancer prognosis.
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Affiliation(s)
- Claudia Ollauri-Ibáñez
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, and the Biomedical Research Institute of Salamanca (IBSAL), Edificio Departamental, Campus Miguel de Unamuno, 37007, Salamanca, Spain
| | - Elena Núñez-Gómez
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, and the Biomedical Research Institute of Salamanca (IBSAL), Edificio Departamental, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
| | - Cristina Egido-Turrión
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, and the Biomedical Research Institute of Salamanca (IBSAL), Edificio Departamental, Campus Miguel de Unamuno, 37007, Salamanca, Spain
| | - Laura Silva-Sousa
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, and the Biomedical Research Institute of Salamanca (IBSAL), Edificio Departamental, Campus Miguel de Unamuno, 37007, Salamanca, Spain
| | - Elena Díaz-Rodríguez
- Instituto de Biología Molecular Y Celular del Cáncer. CSIC, IBSAL and CIBERONC, Salamanca, Spain
| | - Alicia Rodríguez-Barbero
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, and the Biomedical Research Institute of Salamanca (IBSAL), Edificio Departamental, Campus Miguel de Unamuno, 37007, Salamanca, Spain
| | - José M López-Novoa
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, and the Biomedical Research Institute of Salamanca (IBSAL), Edificio Departamental, Campus Miguel de Unamuno, 37007, Salamanca, Spain
| | - Miguel Pericacho
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, and the Biomedical Research Institute of Salamanca (IBSAL), Edificio Departamental, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
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Merev E, Cicin I. Effect of clinical and pathological features of gastrointestinal stromal tumors on overall survival and prognosis: Single center experience. JOURNAL OF ONCOLOGICAL SCIENCES 2019. [DOI: 10.1016/j.jons.2019.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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Ribeiro Franco PI, Rodrigues AP, de Menezes LB, Pacheco Miguel M. Tumor microenvironment components: Allies of cancer progression. Pathol Res Pract 2019; 216:152729. [PMID: 31735322 DOI: 10.1016/j.prp.2019.152729] [Citation(s) in RCA: 142] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 11/06/2019] [Accepted: 11/10/2019] [Indexed: 12/12/2022]
Abstract
Cancer is a disease that affects millions of individuals worldwide and has a great impact on public health. Therefore, the study of tumor biology and an understanding of how the components of the tumor microenvironment behave and interact is extremely important for cancer research. Factors expressed by the components of the tumor microenvironment and induce angiogenesis have important roles in the onset and progression of the tumor. These components are represented by the extracellular matrix, fibroblasts, adipocytes, immune cells, and macrophages, besides endothelial cells, which modulate tumor cells and the tumor microenvironment to favor survival and the progression of cancer. The characteristics and function of the main stromal components and their mechanisms of interaction with the tumor cells that contribute to progression, tumor invasion, and tumor spread will be addressed in this review. Furthermore, reviewing these components is expected to indicate their importance as possible prognostic markers and therapeutic targets.
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Affiliation(s)
- Pablo Igor Ribeiro Franco
- Escola de Veterinária e Zootecnia, Programa de Pós-Graduação em Ciência Animal, Universidade Federal de Goiás, Goiânia, GO, Brazil.
| | - Arthur Perillo Rodrigues
- Escola de Veterinária e Zootecnia, Programa de Pós-Graduação em Ciência Animal, Universidade Federal de Goiás, Goiânia, GO, Brazil
| | | | - Marina Pacheco Miguel
- Escola de Veterinária e Zootecnia, Programa de Pós-Graduação em Ciência Animal, Universidade Federal de Goiás, Goiânia, GO, Brazil
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Yu T, Zhuang W, Su X, Ma B, Hu J, He H, Li G, Wang Y. Dual-Responsive Micelles with Aggregation-Induced Emission Feature and Two-Photon Aborsption for Accurate Drug Delivery and Bioimaging. Bioconjug Chem 2019; 30:2075-2087. [DOI: 10.1021/acs.bioconjchem.9b00364] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Tao Yu
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China
| | - Weihua Zhuang
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China
| | - Xin Su
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China
| | - Boxuan Ma
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China
| | - Jun Hu
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China
| | - Haiyang He
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China
| | - Gaocan Li
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China
| | - Yunbing Wang
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China
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Cai Z, Chen X, Zhang B, Cao D. Apatinib Treatment in Metastatic Gastrointestinal Stromal Tumor. Front Oncol 2019; 9:470. [PMID: 31245289 PMCID: PMC6579896 DOI: 10.3389/fonc.2019.00470] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 05/16/2019] [Indexed: 02/05/2023] Open
Abstract
Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The clinical management of patients with metastatic GISTs is exceptionally challenging due to their poor prognosis. Apatinib is a multiple tyrosine kinase inhibitor. Here, we present the unique case with metastatic GISTs who derived clinical benefit from apatinib following the failure of imatinib and sunitinib. Case presentation: A 57-year-old man was admitted to our hospital diagnosed with metastatic and recurrent GISTs following surgical resection. Fifty-four months after the first-line imatinib treatment, he developed progressive disease and then was treated with cytoreductive surgery combined with imatinib. Disease progression occurred after 7 months. He then received second-line sunitinib and achieved a progression-free survival of 11 months. Apatinib mesylate was then administered. Follow-up imaging revealed a stable disease. Progression-free survival following apatinib therapy was at least 8 months. The only toxicities were hypertension and proteinuria, which were both controllable and well-tolerated. Conclusions: Treatment with apatinib provides an additional option for the treatment of patients with GISTs refractory to imatinib and sunitinib.
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Affiliation(s)
- Zhaolun Cai
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Xin Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Bo Zhang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Dan Cao
- Department of Abdominal Oncology, Cancer Center of West China Hospital, Sichuan University, Chengdu, China
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PADILHA CAMILAS, TESTA MAYRAT, MARINELLO POLIANAC, CELLA PAOLAS, VOLTARELLI FABRÍCIOA, FRAJACOMO FERNANDOT, CECHINI RUBENS, DUARTE JOSÉALBERTOR, GUARNIER FLAVIAA, DEMINICE RAFAEL. Resistance Exercise Counteracts Tumor Growth in Two Carcinoma Rodent Models. Med Sci Sports Exerc 2019; 51:2003-2011. [DOI: 10.1249/mss.0000000000002009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Giner F, López-Guerrero JA, Fernández-Serra A, Machado I, Mayordomo-Aranda E, Peydró-Olaya A, Llombart-Bosch A. Chemokine Expression Is Involved in the Vascular Neogenesis of Ewing Sarcoma: A Preliminary Analysis of the Early Stages of Angiogenesis in a Xenograft Model. Pediatr Dev Pathol 2019; 22:30-39. [PMID: 29895220 DOI: 10.1177/1093526618782497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Ewing sarcoma (EWS) is the second most common bone cancer in pediatric patients. Angiogenesis is a major factor for tumor growth and metastasis. Our aim was to carry out a histological, immunohistochemical, and molecular characterization of the neovascularization established between xenotransplanted tumors and the host during the initial phases of growth in nude mice in three angiogenesis experiments (ES2, ES3, and ES4). METHODS The original human EWS were implanted subcutaneously on the backs of three nude mice. Tumor pieces 3 mm-4 mm in size from early passages of Nu432, Nu495, and Nu471 were also implanted subcutaneously on the backs of three sets (ES2, ES3, and ES4) of athymic Balb-c nude mice (n = 14 each). The animals were sacrificed at 24, 48, and 96 hours and at 7, 14, 21, and 28 days after implantation to perform histological, immunohistochemical, and molecular studies (neovascularization experiments). RESULTS We observed histological, ultrastructural, and immunohistochemical changes in the xenografted tumor at different times after implantation. Chemokine ligand expression peaked twice, once during the first 48 hours and again in the second week. We observed that tumor cells in contact with murine peritumoral stroma presented higher expression of chemokine ligands as well as more tumor cells around the capillary vessels. Mouse serum vascular endothelial growth factor levels peaked twice, once in the first hours and then in the second week after tumor implantation. CONCLUSION Chemokines and other angiogenic factors may be relevant in the angiogenic mechanism during tumor growth. This model provides information on the early stages of the angiogenic process and could be a useful tool in researching anti-angiogenic drugs for new therapeutic strategies in EWS.
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Affiliation(s)
- Francisco Giner
- 1 Department of Pathology, Universitat de València Estudi General, Valencia, Spain
| | - José A López-Guerrero
- 2 Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain
| | - Antonio Fernández-Serra
- 2 Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain
| | - Isidro Machado
- 3 Department of Pathology, Fundación Instituto Valenciano de Oncología, Valencia, Spain
| | | | - Amando Peydró-Olaya
- 1 Department of Pathology, Universitat de València Estudi General, Valencia, Spain
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Effects of VEGFR1 + hematopoietic progenitor cells on pre-metastatic niche formation and in vivo metastasis of breast cancer cells. J Cancer Res Clin Oncol 2018; 145:411-427. [PMID: 30483898 PMCID: PMC6373264 DOI: 10.1007/s00432-018-2802-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 11/19/2018] [Indexed: 02/07/2023]
Abstract
The pre-metastatic niche has been shown to play a critical role in tumor metastasis, and its formation is closely related to the tumor microenvironment. However, the underlying molecular mechanisms remain unclear. In the present study, we successfully established a mouse model of lung metastasis using luciferase-expressing MDA-MB-435s cells. In this model, recruitment of vascular endothelial growth factor receptor-1 (VEGFR1)+CD133+ hematopoietic progenitor cells (HPCs) was gradually increased in lung but gradually decreased after the formation of tumor colonies in lung. We also established a highly metastatic MDA-MB-435s (MDA-MB-435s-HM) cell line from the mouse model. Changes in protein profiles in different culture conditions were investigated by protein microarray analysis. The levels of CXC chemokine ligand 16, interleukin (IL)-2Rα, IL-2Rγ, matrix metalloproteinase (MMP)-1, MMP-9, platelet-derived growth factor receptor (PDGFR)-α, stromal cell-derived factor (SDF)-1α, transforming growth factor (TGF)-β, platelet endothelial cell adhesion molecule (PECAM)-1 and vascular endothelial (VE)-cadherin were significantly greater (> fivefold) in the culture medium from MDA-MB-435s-HM cells than in that from MDA-MB-435s cells. Moreover, the levels of MMP-9, PDGFR-α, and PECAM-1 were significantly greater in the co-culture medium of MDA-MB-435s-HM cells and CD133+ HPCs than in that from MDA-MB-435s-HM cells. Differentially expressed proteins were validated by enzyme-linked immunosorbent assay, and expression of their transcripts was confirmed by quantitative real-time polymerase chain reaction. Moreover, inhibition of MMP-9, PDGFR-α, and PECAM-1 by their specific inhibitors or antibodies significantly decreased cell migration, delayed lung metastasis, and decreased recruitment of VEGFR1+CD133+ HPCs into lung. Intra-hepatic growth of HPCs enhanced the invasive growth of MDA-MB-435s-HM cells in the liver. Our data indicate that VEGFR1+CD133+ HPCs contribute to lung metastasis.
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Kurata Y, Hayano K, Ohira G, Narushima K, Aoyagi T, Matsubara H. Fractal analysis of contrast-enhanced CT images for preoperative prediction of malignant potential of gastrointestinal stromal tumor. Abdom Radiol (NY) 2018; 43:2659-2664. [PMID: 29500645 DOI: 10.1007/s00261-018-1526-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
PURPOSE The purpose of this study is to assess the heterogeneity of tumor enhancement using fractal analysis on contrast-enhanced computed tomography (CE-CT) for predicting malignant potential of gastrointestinal stromal tumor (GIST). METHODS We retrospectively identified 64 patients (36 M/28 W; median age: 65) with GISTs who received CE-CT and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) followed by curative surgery. Fractal analysis was applied to CE-CT image, and fractal dimension (FD) was measured. Diagnostic value of FD for malignant potential of GIST was compared with that of FDG-PET using the risk classification and Ki67 index. RESULTS 14 patients were categorized as the high risk, and 50 patients were as the very low, low or intermediate risk. FD of high-risk group was significantly higher than that of the other-risk group (p < 0.05). The areas under the ROC curves of FD and SUVmax for prediction of high-risk group were 0.82 and 0.93 (accuracy: 84.4% and 98.5%). FD showed a significant positive correlation with Ki67 index (p = 0.01). CONCLUSION Diagnostic value of CT fractal analysis for prediction of high-risk GIST is comparable with FDG-PET. In terms of cost and availability, fractal analysis has a potential to be an optimal preoperative biomarker.
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Affiliation(s)
- Yoshihiro Kurata
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8677, Japan.
| | - Koichi Hayano
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8677, Japan
| | - Gaku Ohira
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8677, Japan
| | - Kazuo Narushima
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8677, Japan
| | - Tomoyoshi Aoyagi
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8677, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8677, Japan
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Li H, Ren G, Cai R, Chen J, Wu X, Zhao J. A correlation research of Ki67 index, CT features, and risk stratification in gastrointestinal stromal tumor. Cancer Med 2018; 7:4467-4474. [PMID: 30123969 PMCID: PMC6144253 DOI: 10.1002/cam4.1737] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 07/24/2018] [Accepted: 07/25/2018] [Indexed: 12/16/2022] Open
Abstract
Background and Objectives Recurrence and metastasis are the most important factors affecting the quality of life and survival rate of patients with gastrointestinal stromal tumors (GISTs). Accurate preoperative determination of the malignant degree of GISTs and the development of a reasonable treatment plan can effectively reduce the recurrence rate. CT is currently considered the preferred imaging modality for initial assessment. Until now, there have only been a few studies investigating the relationship between CT features and recurrence of GISTs. However, the value of CT features in prognostic assessment is still unclear. In this study, we attempted to investigate the prognostic significance of CT features and the Ki67 index in GISTs. Methods We retrospectively analyzed the clinicopathological and imaging data for 151 patients with a histopathological diagnosis of GIST who had received contrast‐enhanced CT examination and surgical resection at XinHua Hospital from October 2008 to December 2015 or Sir Run Run Shaw Hospital in 2017. Then, we explored the correlation among CT features, the Ki67 index, and risk stratification of GISTs. The correlation among CT features, the Ki67 index, and risk stratification was mainly analyzed using the Spearman rank correlation. Results The incidence of high‐risk disease or metastasis was clearly higher in the group with Ki67 > 5% than that in the group with Ki67 ≤ 5% (P < 0.001). The Ki67 index was positively correlated with risk stratification (r = 0.558) or mitotic index (r = 0.619). CT imaging features including size, contour, and margin of the tumor were associated with the Ki67 index (r = 0.332, 0.333, and 0.302, respectively). The multivariate logistic regression analysis revealed that the tumor size [P = 0.043 Exp (B) = 1.150] and the presence of ulceration [P = 0.011, Exp (B) = 3.669] were effective variables in distinguishing between the groups with Ki67 ≤ 5% and >5%. The presence of necrosis or cystic degeneration, tumor contour, tumor margin, and pattern of enhancement were associated with risk stratification (r = 0.530, 0.501, 0.419, and 0.447, respectively). Conclusions Our findings suggest that the Ki67 index is an effective complementation in predicting the prognosis of GISTs, and CT features including size, contour, and margin of the tumor, presence of necrosis or cystic degeneration, and pattern of enhancement provide evidence to support the importance of preoperative assessment.
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Affiliation(s)
- Huali Li
- Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Gang Ren
- Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Rong Cai
- Department of Radiotherapy, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jian Chen
- Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiangru Wu
- Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jianxi Zhao
- Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
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