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1
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Zheng H, Pan Y. Transcriptome-proteome integration analysis identifies elevated expression of LARP7 promoting the tumorigenesis and development of gastrointestinal stromal tumors. Transl Oncol 2025; 53:102316. [PMID: 39933393 DOI: 10.1016/j.tranon.2025.102316] [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: 06/11/2024] [Revised: 01/16/2025] [Accepted: 01/31/2025] [Indexed: 02/13/2025] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract, with c-kit and PDGFRA mutations being the primary causes. However, GIST pathogenesis is not still fully understood. Differential expression analysis, Univariate Cox regression and Kaplan-Meier curves were utilized to screen for up-regulated and prognostically relevant genes. The expression distribution was compared across various demographics and clinical groups. The relationship between gene expression and cytokine pathway activation was assessed via CytoSig. Immune cell infiltration was analyzed using TIMER2.0. Four paired GIST and adjacent normal tissues were collected to validate the expression trend. CCK8 assays and scratch wound healing assays were conducted in GIST-T1 and GIST-882 cells. Results indicated that LARP7 was up-regulated in GISTs at both mRNA and protein levels. This elevated expression was associated with poor prognosis, particularly in GISTs located in the small intestine and those with larger tumor sizes. LARP7 was implicated in the expression of IFN-induced genes and the negative regulation of viral processes. Predictions of cytokine pathways supported these findings, and immune cell infiltration analysis revealed a higher presence of CD8+ T cells in GISTs with high LARP7 expression. The lncRNA (H19 or LINC00665)-miRNA(hsa-miR-138-5p) axis targeted LARP7. Furthermore, LARP7 was elevated in imatinib-resistant GISTs, with some other drugs predicted to aid in therapy. LARP7 knockdown resulted in reduced proliferation and migration of GIST-T1 and GIST-882 cells. Overall, high expression of LARP7 correlates with poor prognosis in GISTs, highlighting its potential as a therapeutic target.
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Affiliation(s)
- Heng Zheng
- Department of Gastrointestinal Surgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Qingyang District, Chengdu, 610072 China
| | - Yong Pan
- Department of Gastrointestinal Surgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Qingyang District, Chengdu, 610072 China.
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2
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Zhu E, Xie Q, Huang X, Zhang Z. Application of spatial omics in gastric cancer. Pathol Res Pract 2024; 262:155503. [PMID: 39128411 DOI: 10.1016/j.prp.2024.155503] [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: 04/27/2024] [Revised: 07/25/2024] [Accepted: 07/27/2024] [Indexed: 08/13/2024]
Abstract
Gastric cancer (GC), a globally prevalent and lethal malignancy, continues to be a key research focus. However, due to its considerable heterogeneity and complex pathogenesis, the treatment and diagnosis of gastric cancer still face significant challenges. With the rapid development of spatial omics technology, which provides insights into the spatial information within tumor tissues, it has emerged as a significant tool in gastric cancer research. This technology affords new insights into the pathology and molecular biology of gastric cancer for scientists. This review discusses recent advances in spatial omics technology for gastric cancer research, highlighting its applications in the tumor microenvironment (TME), tumor heterogeneity, tumor genesis and development mechanisms, and the identification of potential biomarkers and therapeutic targets. Moreover, this article highlights spatial omics' potential in precision medicine and summarizes existing challenges and future directions. It anticipates spatial omics' continuing impact on gastric cancer research, aiming to improve diagnostic and therapeutic approaches for patients. With this review, we aim to offer a comprehensive overview to scientists and clinicians in gastric cancer research, motivating further exploration and utilization of spatial omics technology. Our goal is to improve patient outcomes, including survival rates and quality of life.
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Affiliation(s)
- Erran Zhu
- Department of Clinical Medicine, Grade 20, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Qi Xie
- Department of Clinical Medicine, Grade 20, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Xinqi Huang
- Excellent Class, Clinical Medicine, Grade 20, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Zhiwei Zhang
- Cancer Research Institute of Hengyang Medical College, University of South China; Key Laboratory of Cancer Cellular and Molecular Pathology of Hunan; Department of Pathology, Department of Pathology of Hengyang Medical College, University of South China; The First Affiliated Hospital of University of South China, China.
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3
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Pan GH, Zhou F, Chen WB, Pan ZJ. Advancing gastrointestinal stromal tumor management: The role of imagomics features in precision risk assessment. World J Gastrointest Surg 2024; 16:2942-2952. [PMID: 39351558 PMCID: PMC11438807 DOI: 10.4240/wjgs.v16.i9.2942] [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: 03/25/2024] [Revised: 05/24/2024] [Accepted: 07/17/2024] [Indexed: 09/18/2024] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) vary widely in prognosis, and traditional pathological assessments often lack precision in risk stratification. Advanced imaging techniques, especially magnetic resonance imaging (MRI), offer potential improvements. This study investigates how MRI imagomics can enhance risk assessment and support personalized treatment for GIST patients. AIM To assess the effectiveness of MRI imagomics in improving GIST risk stratification, addressing the limitations of traditional pathological assessments. METHODS Analyzed clinical and MRI data from 132 GIST patients, categorizing them by tumor specifics and dividing into risk groups. Employed dimension reduction for optimal imagomics feature selection from diffusion-weighted imaging (DWI), T1-weighted imaging (T1WI), and contrast enhanced T1WI with fat saturation (CE-T1WI) fat suppress (fs) sequences. RESULTS Age, lesion diameter, and mitotic figures significantly correlated with GIST risk, with DWI sequence features like sphericity and regional entropy showing high predictive accuracy. The combined T1WI and CE-T1WI fs model had the best predictive efficacy. In the test group, the DWI sequence model demonstrated an area under the curve (AUC) value of 0.960 with a sensitivity of 80.0% and a specificity of 100.0%. On the other hand, the combined performance of the T1WI and CE-T1WI fs models in the test group was the most robust, exhibiting an AUC value of 0.834, a sensitivity of 70.4%, and a specificity of 85.2%. CONCLUSION MRI imagomics, particularly DWI and combined T1WI/CE-T1WI fs models, significantly enhance GIST risk stratification, supporting precise preoperative patient assessment and personalized treatment plans. The clinical implications are profound, enabling more accurate surgical strategy formulation and optimized treatment selection, thereby improving patient outcomes. Future research should focus on multicenter studies to validate these findings, integrate advanced imaging technologies like PET/MRI, and incorporate genetic factors to achieve a more comprehensive risk assessment.
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Affiliation(s)
- Gui-Hai Pan
- Department of Radiology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, Guangdong Province, China
| | - Fei Zhou
- Department of Endocrinology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, Guangdong Province, China
| | - Wu-Biao Chen
- Department of Radiology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, Guangdong Province, China
| | - Ze-Jun Pan
- Department of Radiology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, Guangdong Province, China
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Popoiu TA, Pîrvu CA, Popoiu CM, Iacob ER, Talpai T, Voinea A, Albu RS, Tãban S, Bãlãnoiu LM, Pantea S. Gastrointestinal Stromal Tumors (GISTs) in Pediatric Patients: A Case Report and Literature Review. CHILDREN (BASEL, SWITZERLAND) 2024; 11:1040. [PMID: 39334573 PMCID: PMC11429550 DOI: 10.3390/children11091040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/18/2024] [Accepted: 08/23/2024] [Indexed: 09/30/2024]
Abstract
Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms that primarily affect adults, with pediatric cases constituting only 0.5-2.7% of the total. Pediatric GISTs present unique clinical, genetic, and pathological features that distinguish them from adult cases. This literature review aims to elucidate these differences, emphasizing diagnostic and therapeutic challenges. We discuss the resistance of pediatric GISTs to conventional chemotherapy and highlight the importance of surgical intervention, especially in emergency situations involving intra-abdominal bleeding. The review also explores the molecular characteristics of pediatric GISTs, including rare mutations such as quadruple-negative wild-type GIST with an FGF3 gene gain mutation. To illustrate these points, we conclude with a case from our clinic involving a 15-year-old female with multiple CD117-positive gastric GISTs and a quadruple-negative wild-type genetic profile who required urgent surgical intervention following a failed tumor embolization. This case underscores the critical need for early diagnosis and individualized therapeutic strategies combining oncologic and surgical care to improve outcomes in pediatric GIST patients.
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Affiliation(s)
- Tudor-Alexandru Popoiu
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Department III of Functional Sciences, Discipline of Medical Informatics and Biostatistics, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Cãtãlin-Alexandru Pîrvu
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Cãlin-Marius Popoiu
- Department of Pediatric Surgery, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Emil Radu Iacob
- Department of Pediatric Surgery, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Tamas Talpai
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Amalia Voinea
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Rãzvan-Sorin Albu
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Sorina Tãban
- Department of Pathology, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Larisa-Mihaela Bãlãnoiu
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Stelian Pantea
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
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5
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Sicinska E, Sudhakara Rao Kola V, Kerfoot JA, Taddei ML, Al-Ibraheemi A, Hsieh YH, Church AJ, Landesman-Bollag E, Landesman Y, Hemming ML. ASPSCR1::TFE3 Drives Alveolar Soft Part Sarcoma by Inducing Targetable Transcriptional Programs. Cancer Res 2024; 84:2247-2264. [PMID: 38657118 PMCID: PMC11250573 DOI: 10.1158/0008-5472.can-23-2115] [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: 07/15/2023] [Revised: 02/09/2024] [Accepted: 04/19/2024] [Indexed: 04/26/2024]
Abstract
Alveolar soft part sarcoma (ASPS) is a rare mesenchymal malignancy driven by the ASPSCR1::TFE3 fusion. A better understanding of the mechanisms by which this oncogenic transcriptional regulator drives cancer growth is needed to help identify potential therapeutic targets. In this study, we characterized the transcriptional and chromatin landscapes of ASPS tumors and preclinical models, identifying the essential role of ASPSCR1::TFE3 in tumor cell viability by regulating core transcriptional programs involved in cell proliferation, angiogenesis, and mitochondrial biology. ASPSCR1::TFE3 directly interacted with key epigenetic regulators at enhancers and promoters to support ASPS-associated transcription. Among the effector programs driven by ASPSCR1::TFE3, cell proliferation was driven by high levels of cyclin D1 expression. Disruption of cyclin D1/CDK4 signaling led to a loss of ASPS proliferative capacity, and combined inhibition of CDK4/6 and angiogenesis halted tumor growth in xenografts. These results define the ASPS oncogenic program, reveal mechanisms by which ASPSCR1::TFE3 controls tumor biology, and identify a strategy for therapeutically targeting tumor cell-intrinsic vulnerabilities. Significance: The ASPSCR1::TFE3 fusion propels the growth of alveolar soft part sarcoma by activating transcriptional programs that regulate proliferation, angiogenesis, mitochondrial biogenesis, and differentiation and can be therapeutically targeted to improve treatment.
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MESH Headings
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics
- Sarcoma, Alveolar Soft Part/genetics
- Sarcoma, Alveolar Soft Part/pathology
- Sarcoma, Alveolar Soft Part/metabolism
- Humans
- Animals
- Mice
- Cell Proliferation/genetics
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/metabolism
- Gene Expression Regulation, Neoplastic
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Cell Line, Tumor
- Xenograft Model Antitumor Assays
- Cyclin-Dependent Kinase 4/genetics
- Cyclin-Dependent Kinase 4/metabolism
- Cyclin-Dependent Kinase 4/antagonists & inhibitors
- Female
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/metabolism
- Intracellular Signaling Peptides and Proteins
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Affiliation(s)
- Ewa Sicinska
- Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Vijaya Sudhakara Rao Kola
- Department of Medicine, Division of Hematology and Oncology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Joseph A. Kerfoot
- Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Madeleine L. Taddei
- Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Alyaa Al-Ibraheemi
- Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Yi-Hsuan Hsieh
- Department of Medicine, Division of Hematology and Oncology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Alanna J. Church
- Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Esther Landesman-Bollag
- Department of Medicine, Section of Hematology and Oncology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Yosef Landesman
- Cure Alveolar Soft Part Sarcoma International, Brookline, Massachusetts, USA
| | - Matthew L. Hemming
- Department of Medicine, Division of Hematology and Oncology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
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6
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Gu Y, Chen G, Ning X. Homeobox Protein BarH-like 1 Promotes Gastric Cancer Progression by Activating Coiled-Coil Domain-Containing Protein 178. Dig Dis Sci 2024; 69:1182-1199. [PMID: 38358459 DOI: 10.1007/s10620-024-08312-0] [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: 09/27/2023] [Accepted: 01/22/2024] [Indexed: 02/16/2024]
Abstract
BACKGROUND Coiled-coil domain-containing protein 178 (CCDC178) has been revealed to exert metastasis-promoting properties in hepatocellular carcinoma, whereas its function in gastric cancer (GC) has not been fully understood. AIMS We evaluated its role in GC and the molecular mechanism. METHODS The differentially expressed genes in datasets related to GC metastasis were intersected with survival-related genes in GC, followed by prognostic significance prediction. Loss- and gain-of-function assays were conducted to examine the involvement of CCDC178, Homeobox protein BarH-like 1 (BARX1), and the extracellular signal-regulated kinase (ERK) pathway in GC cell malignant phenotype and the polarization of tumor-associated macrophages (TAM). The corresponding functions were verified in the in vivo animal experiment. RESULTS High CCDC178 expression predicted a poor prognosis for GC patients, and CCDC178 correlated significantly with macrophage infiltration in GC tissues. CCDC178 activated the ERK pathway in GC. Silencing of CCDC178 reduced the colony formation, migratory and invasive potential of GC cells, and the M2-like polarization of TAM, which was reversed by TBHQ (an ERK activator). BARX1 bound to the promoter region of CCDC178, thus inducing its transcriptional level. Silencing of BARX1 suppressed the M2-type polarization of TAM in vitro and in vivo, and CCDC178 mitigated the repressing role of BARX1 knockdown. CONCLUSIONS BARX1 activates the transcription of CCDC178 to induce the ERK pathway, thereby supporting macrophage recruitment and M2-like polarization in GC.
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Affiliation(s)
- Yue Gu
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37, Yiyuan Street, Nangang District, 150001, Harbin, Heilongjiang, People's Republic of China.
| | - Gang Chen
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37, Yiyuan Street, Nangang District, 150001, Harbin, Heilongjiang, People's Republic of China
| | - Xinwei Ning
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37, Yiyuan Street, Nangang District, 150001, Harbin, Heilongjiang, People's Republic of China
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7
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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: 0] [Impact Index Per Article: 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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8
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Wang P, Yan J, Qiu H, Huang J, Yang Z, Shi Q, Yan C. A radiomics-clinical combined nomogram-based on non-enhanced CT for discriminating the risk stratification in GISTs. J Cancer Res Clin Oncol 2023; 149:12993-13003. [PMID: 37464150 DOI: 10.1007/s00432-023-05170-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 07/09/2023] [Indexed: 07/20/2023]
Abstract
PURPOSE To discriminate the risk stratification in gastrointestinal stromal tumors (GISTs) by preoperatively constructing a model of nonenhanced computed tomography (NECT). METHODS A total of 111 GISTs patients (77 in the training group and 34 in the validation Group) from two hospitals between 2015 and 2022 were collected retrospectively. One thousand and thirty-seven radiomics features were extracted from non-contract CT images, and the optimal radiomics signature was determined by univariate analysis and LASSO regression. The radiomics model was developed and validated from the ten optimal radiomics features by three methods. Covariates (clinical features, CT findings, and immunohistochemical characteristics) were collected to establish the clinical model, and both the radiomics features and the covariates were used to build the combined model. The effectiveness of the three models was evaluated by the Delong test. RESULTS The experimental results showed that the clinical models (75.3%, 70.6%), the radiomics models (79.2%, 79.4%) and the combined models (81.8%, 82.4%) all had high accuracy in predicting the pathological risk of GIST in both training and validation groups. The AUC values of the combined models were significantly higher in both the training groups (0.921 vs 0.822, p= 0.032) and the validation groups (0.913 vs 0.792, p= 0.019) than that of the clinical models. According to the calibration curve, the combined model nomogram is clinically useful. CONCLUSIONS The clinical-radiomics combined model and based on NECT performed well in discriminating the risk stratification in GISTs. As a quantitative technique, radiomics is capable of predicting the malignant potential and guiding treatment preoperatively.
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Affiliation(s)
- Peizhe Wang
- Department of Medical Imaging, The Second Affiliated Hospital of Shandong First Medical University, Taian, 271000, Shandong, China
| | - Jingrui Yan
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Hui Qiu
- Department of Medical Imaging, The Second Affiliated Hospital of Shandong First Medical University, Taian, 271000, Shandong, China
| | - Jingying Huang
- Department of Medical Imaging, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China
| | - Zhe Yang
- Department of Medical Imaging, The Second Affiliated Hospital of Shandong First Medical University, Taian, 271000, Shandong, China
| | - Qiang Shi
- Department of Medical Imaging, The Second Affiliated Hospital of Shandong First Medical University, Taian, 271000, Shandong, China
| | - Chengxin Yan
- Department of Medical Imaging, The Second Affiliated Hospital of Shandong First Medical University, Taian, 271000, Shandong, China.
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9
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Durand M, Brehaut V, Clement G, Kelemen Z, Macé J, Feil R, Duville G, Launay-Avon A, Roux CPL, Lunn JE, Roudier F, Krapp A. The Arabidopsis transcription factor NLP2 regulates early nitrate responses and integrates nitrate assimilation with energy and carbon skeleton supply. THE PLANT CELL 2023; 35:1429-1454. [PMID: 36752317 PMCID: PMC10118280 DOI: 10.1093/plcell/koad025] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 01/04/2023] [Indexed: 06/18/2023]
Abstract
Nitrate signaling improves plant growth under limited nitrate availability and, hence, optimal resource use for crop production. Whereas several transcriptional regulators of nitrate signaling have been identified, including the Arabidopsis thaliana transcription factor NIN-LIKE PROTEIN7 (NLP7), additional regulators are expected to fine-tune this pivotal physiological response. Here, we characterized Arabidopsis NLP2 as a top-tier transcriptional regulator of the early nitrate response gene regulatory network. NLP2 interacts with NLP7 in vivo and shares key molecular features such as nitrate-dependent nuclear localization, DNA-binding motif, and some target genes with NLP7. Genetic, genomic, and metabolic approaches revealed a specific role for NLP2 in the nitrate-dependent regulation of carbon and energy-related processes that likely influence plant growth under distinct nitrogen environments. Our findings highlight the complementarity and specificity of NLP2 and NLP7 in orchestrating a multitiered nitrate regulatory network that links nitrate assimilation with carbon and energy metabolism for efficient nitrogen use and biomass production.
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Affiliation(s)
- Mickaël Durand
- Université Paris-Saclay, INRAE, AgroParisTech, Institut Jean-Pierre Bourgin, Versailles 78000, France
- UMR CNRS 7267, EBI Ecologie et Biologie des Interactions, Université de Poitiers, Poitiers, France
| | - Virginie Brehaut
- Université Paris-Saclay, INRAE, AgroParisTech, Institut Jean-Pierre Bourgin, Versailles 78000, France
| | - Gilles Clement
- Université Paris-Saclay, INRAE, AgroParisTech, Institut Jean-Pierre Bourgin, Versailles 78000, France
| | - Zsolt Kelemen
- Université Paris-Saclay, INRAE, AgroParisTech, Institut Jean-Pierre Bourgin, Versailles 78000, France
| | - Julien Macé
- Laboratoire Reproduction et Développement des Plantes, Université de Lyon, ENS de Lyon, UCB Lyon 1, CNRS, INRAE, Lyon, France
| | - Regina Feil
- Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, Potsdam-Golm D-14476, Germany
| | - Garry Duville
- Université Paris-Saclay, INRAE, AgroParisTech, Institut Jean-Pierre Bourgin, Versailles 78000, France
| | - Alexandra Launay-Avon
- Université Paris-Saclay, CNRS, INRAE, Université Evry, Institute of Plant Sciences Paris-Saclay (IPS2), Gif sur Yvette 91190, France
- Université Paris Cité, CNRS, INRAE, Institute of Plant Sciences Paris-Saclay (IPS2), Gif sur Yvette 91190, France
| | - Christine Paysant-Le Roux
- Université Paris-Saclay, CNRS, INRAE, Université Evry, Institute of Plant Sciences Paris-Saclay (IPS2), Gif sur Yvette 91190, France
- Université Paris Cité, CNRS, INRAE, Institute of Plant Sciences Paris-Saclay (IPS2), Gif sur Yvette 91190, France
| | - John E Lunn
- Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, Potsdam-Golm D-14476, Germany
| | - François Roudier
- Laboratoire Reproduction et Développement des Plantes, Université de Lyon, ENS de Lyon, UCB Lyon 1, CNRS, INRAE, Lyon, France
| | - Anne Krapp
- Université Paris-Saclay, INRAE, AgroParisTech, Institut Jean-Pierre Bourgin, Versailles 78000, France
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10
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Yue L, Sun Y, Wang X, Hu W. Advances of endoscopic and surgical management in gastrointestinal stromal tumors. Front Surg 2023; 10:1092997. [PMID: 37123546 PMCID: PMC10130460 DOI: 10.3389/fsurg.2023.1092997] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 03/24/2023] [Indexed: 05/02/2023] Open
Abstract
As one of the most common mesenchymal malignancies in the digestive system, gastrointestinal stromal tumors (GISTs) occur throughout the alimentary tract with diversified oncological characteristics. With the advent of the tyrosine kinase inhibitor era, the treatment regimens of patients with GISTs have been revolutionized and GISTs have become the paradigm of multidisciplinary therapy. However, surgery resection remains recognized as the potentially curative management for the radical resection and provided with favorable oncological outcomes. The existing available surgery algorithms in clinical practice primarily incorporate open procedure, and endoscopic and laparoscopic surgery together with combined operation techniques. The performance of various surgery methods often refers to the consideration of risk evaluation of recurrence and metastases; the degree of disease progression; size, location, and growth pattern of tumor; general conditions of selected patients; and indications and safety profile of various techniques. In the present review, we summarize the fundamental principle of surgery of GISTs based on risk assessment as well as tumor size, location, and degree of progress with an emphasis on the indications, strengths, and limitations of current surgery techniques.
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Affiliation(s)
- Lei Yue
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China
| | - Yingchao Sun
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China
| | - Xinjie Wang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China
| | - Weiling Hu
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China
- Institute of Gastroenterology, Zhejiang University (IGZJU), Hangzhou, China
- Zhejiang University Cancer Center, Hangzhou, China
- Correspondence: Weiling Hu
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Andrzejewska M, Czarny J, Derwich K. Latest Advances in the Management of Pediatric Gastrointestinal Stromal Tumors. Cancers (Basel) 2022; 14:4989. [PMID: 36291774 PMCID: PMC9599787 DOI: 10.3390/cancers14204989] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/28/2022] [Accepted: 10/10/2022] [Indexed: 11/21/2022] Open
Abstract
Gastrointestinal stromal tumor is the most common mesenchymal neoplasm of the gastrointestinal tract, usually found in elderly adults. It is infrequent among pediatric patients and usually differs biologically from adult-type diseases presenting mutations of KIT and PDGFR genes. In this population, more frequent is the wild-type GIST possessing SDH, TRK, RAS, NF1 mutations, among others. Both tumor types require individualized treatment with kinase inhibitors that are still being tested in the pediatric population due to the different neoplasm biology. We review the latest updates to the management of pediatric gastrointestinal tumors with a particular focus on the advances in molecular biology of the disease that enables the definition of possible resistance. Emerging treatment with kinase inhibitors that could serve as targeted therapy is discussed, especially with multikinase inhibitors of higher generation, the effectiveness of which has already been confirmed in the adult population.
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Affiliation(s)
- Marta Andrzejewska
- Faculty of Medicine, Poznan University of Medical Sciences, 61-701 Poznan, Poland or
| | - Jakub Czarny
- Faculty of Medicine, Poznan University of Medical Sciences, 61-701 Poznan, Poland or
| | - Katarzyna Derwich
- Department of Pediatric Oncology, Hematology and Transplantology, Institute of Pediatrics, Poznan University of Medical Sciences, 60-355 Poznan, Poland
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Sun J, Zhang Q, Sun X, Xue A, Gao X, Shen K. THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours. Cell Commun Signal 2022; 20:138. [PMID: 36076237 PMCID: PMC9454178 DOI: 10.1186/s12964-022-00928-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/05/2022] [Indexed: 11/19/2022] Open
Abstract
Background Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract and are characterized by activating mutations of c-KIT or PDGFRa receptor tyrosine kinases (RTKs). Despite the clinical success of tyrosine kinase inhibitors (TKIs), more than half of GIST patients develop resistance due to a second mutation. Cyclin-dependent kinase 7 (CDK7) is the catalytic subunit of CDK-activating kinase (CAK), and it plays an important role in the regulation of cell cycle transitions and gene transcription. THZ1, a CDK7 inhibitor, exhibits a dose-dependent inhibitory effect in various cancers. Methods Data from the public GEO database and tissue microarray were used to analyse the gene expression levels of CDKs in GISTs. The impact of CDK7 knockdown and the CDK7 inhibitor THZ1 on GIST progression was investigated in vitro using CCK-8, colony formation, and flow cytometry assays and in vivo using a xenograft mouse model. RNA sequencing was performed to investigate the mechanism of GIST cell viability impairment mediated by THZ1 treatment. Results Our study demonstrated that CDK7 is relatively overexpressed in high-risk GISTs and predicts a poor outcome. A low concentration of THZ1 exhibited a pronounced antineoplastic effect in GIST cells in vivo and in vitro. Moreover, THZ1 exerted synergistic anticancer effects with imatinib. THZ1 treatment resulted in transcriptional modulation by inhibiting the phosphorylation of Ser2, Ser5, and Ser7 within RNA polymerase II (RNAPII). c-KIT, an oncogene driver of GIST, was transcriptionally repressed by THZ1 treatment or CDK7 knockdown. Transcriptome sequencing analysis showed that OSR1 acts as a downstream target of CDK7 and regulates c-KIT expression. Taken together, our results highlight elevated CDK7 expression as a predictor of poor outcome in GIST and present the combination of CDK7 and RTK inhibitors as a potent therapeutic strategy to improve the efficacy of GIST treatment.
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