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Li M, Cui Y, Wu X, Yang X, Huang C, Yu L, Yi P, Chen C. Integrating network pharmacology to investigate the mechanism of quercetin's action through AKT inhibition in co-expressed genes associated with polycystic ovary syndrome and endometrial cancer. Int J Biol Macromol 2025; 297:139468. [PMID: 39765297 DOI: 10.1016/j.ijbiomac.2025.139468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/14/2024] [Revised: 12/30/2024] [Accepted: 01/01/2025] [Indexed: 01/30/2025]
Abstract
Endometrial cancer (EC) is a common gynecological malignancy for which polycystic ovarian syndrome (PCOS) has been identified as a significant risk factor. Quercetin, a widely distributed natural flavonoid, has demonstrated potential therapeutic effects in managing both PCOS and EC. However, the specific molecular targets of quercetin in the context of PCOS comorbid with EC (PCOS-EC) remain poorly defined. This study aims to elucidate the therapeutic potential of quercetin for treating PCOS-EC using network pharmacology, molecular dynamics simulations, and in vitro assays. The intersection of 379 PCOS-EC-associated targets with 361 quercetin targets identified 47 potential therapeutic targets of quercetin for PCOS-EC. Gene Ontology enrichment analysis revealed the biological functions, while Kyoto Encyclopedia of Genes and Genomes identified the pathways potentially involved in quercetin's effects against PCOS-EC. Protein-protein interaction network analysis highlighted six overlapping targets, namely, ACTB, AKT1, EGFR, ESR1, PTGS2, and TP53. Molecular docking and molecular dynamics simulations indicated that quercetin bound with high affinity to the hub genes, with AKT1 emerging as a central target. In vitro experiments confirmed that quercetin treatment significantly downregulated AKT expression in EC cells. These findings elucidate potential targets and molecular mechanisms through which quercetin exerts its therapeutic effects.
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Affiliation(s)
- Mengyuan Li
- Department of Obstetrics and Gynecology, Chongqing General Hospital, Chongqing University, Chongqing 401147, China; Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Yewei Cui
- School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Xingfan Wu
- School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Xunmei Yang
- Department of Orthopedics, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Chenglong Huang
- Department of Clinical Laboratory, Medical Sciences Research Center, University-Town Hospital of Chongqing Medical University, Chongqing 401331, China
| | - Lili Yu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Ping Yi
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China.
| | - Cheng Chen
- Department of Obstetrics and Gynecology, Chongqing General Hospital, Chongqing University, Chongqing 401147, China.
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Wang F, Yu X, Han Y, Zhang L, Liu S. Prognostic value of upper paratracheal lymph node resection in stage IB right‑sided lung cancer: A retrospective cohort study. Oncol Lett 2025; 29:137. [PMID: 39839609 PMCID: PMC11747950 DOI: 10.3892/ol.2025.14883] [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] [Academic Contribution Register] [Received: 08/21/2024] [Accepted: 12/06/2024] [Indexed: 01/23/2025] Open
Abstract
The aim of the present study was to investigate the impact of upper paratracheal lymph node resection on the prognosis of patients with stage IB non-small cell lung cancer (NSCLC). A retrospective analysis of 339 patients with upper lobe stage IB NSCLC who underwent surgery at Sun Yat-Sen University Cancer Center (Guangzhou, China) between 1999 and 2009 was conducted. The Cox regression model was used to investigate prognostic factors. Variables with P<0.1 in univariate analysis were incorporated into multivariate analysis. A 1-to-1 propensity score matching (PSM) was conducted to decrease potential bias when comparing the impact of upper paratracheal lymph node resection on survival outcomes. Following PSM, 202 cases were identified. Kaplan-Meier analysis and log-rank test were used to assess recurrence-free survival (RFS) and overall survival (OS). Of the 339 patients identified, 152 did not undergo resection of upper paratracheal lymph node, while 187 did undergo the surgery. Cases were separated into two groups based on the resection of the upper paratracheal lymph node. Cox regression analysis demonstrated that a family history of malignant tumors and smoking were considered significant prognostic variables for OS. Age and family history of malignant tumors were significant independent prognostic variables for RFS. Resection of the upper paratracheal lymph node was not significantly associated with OS and RFS. Additionally, resection of the upper paratracheal lymph node was not significantly associated with OS and RFS. In conclusion, there was no statistical association between upper paratracheal lymph node resection and OS or RFS for patients with stage IB NSCLC. Therefore, upper paratracheal lymph node resection may not be necessary for patients with early stage NSCLC, and application of this knowledge could reduce unnecessary surgical trauma and decrease lymph node-related complications.
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Affiliation(s)
- Feng Wang
- Department of Minimally Invasive Surgery, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, P.R. China
| | - Xiangyang Yu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer, Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong 518116, P.R. China
| | - Yi Han
- Department of Minimally Invasive Surgery, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, P.R. China
| | - Lanjun Zhang
- State Key Laboratory of Oncology in South China, Department of Thoracic Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Shuku Liu
- Department of Minimally Invasive Surgery, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, P.R. China
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Talatapeh SP, Rezaie J, Nejati V. Extracellular Vesicle-based Delivery of Paclitaxel to Lung Cancer Cells: Uptake, Anticancer Effects, Autophagy and Mitophagy Pathways. Arch Med Res 2025; 56:103194. [PMID: 39922153 DOI: 10.1016/j.arcmed.2025.103194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/08/2024] [Revised: 01/10/2025] [Accepted: 01/28/2025] [Indexed: 02/10/2025]
Abstract
BACKGROUND Due to their unique properties, extracellular vesicles (EVs) are promising nanocarriers for exogenous drug delivery. AIM We prepared a drug delivery system based on large EVs (LEVs) containing paclitaxel (PTX) (LEVs-PTX) to investigate anticancer effects on lung cancer cells with a focus on autophagy. METHODS LEVs-PTX were isolated from lung cancer cells by ultracentrifugation and characterized using different techniques. Rhodamine B dye (Rh B) was used to label LEVs-PTX for cell tracking. MTT assay was performed to investigate the cellular toxicity of PTX and LEVs-PTX for 24 h and 48 h. The uptake of LEVs-PTX was monitored by immunofluorescence microscopy in breast and lung cancer cells. A colorimetric assay was performed to evaluate apoptosis, while Western blotting assays were used to investigate autophagy proteins. Real-time PCR was used to measure mitophagy genes. RESULTS Characterization techniques showed that LEVs were isolated and loaded with PTX. Rh B labeled LEVs, which was confirmed by a fluorescence spectrophotometer. Immunofluorescence microscopy showed that the lung and breast cancer cells had captured LEVs. Cell viability was decreased in LEVs-PTX cells which coincided with an increase in caspase-3 activity in LEVs-PTX cells. The Beclin-1 protein level and LC3 II/I ratio decreased, while the P62 protein level was increased in LEVs-PTX cells. The mitophagy genes such as Pink-1 and Parkin were upregulated in LEVs-PTX cells. CONCLUSION The data show that LEVs-PTX induced apoptosis, which inhibited the autophagy pathway and increased mitophagy markers, suggesting damage to cell organelles through intracellular delivery of PTX.
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Affiliation(s)
| | - Jafar Rezaie
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia, Iran.
| | - Vahid Nejati
- Department of Biology, Urmia University, Urmia, Iran
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Zhang Z, Xia Y, Wang Z, Sun Y, Pu D, He Y, Liu R, Zhang Y, Liu Y, Yu J, Ning S, Feng B, Wang Y, Wang N. Ddx21 mutant peptide is an effective neoantigen in prophylactic lung cancer vaccines and activates long-term anti-tumor immunity. Front Immunol 2025; 16:1500417. [PMID: 39981234 PMCID: PMC11839773 DOI: 10.3389/fimmu.2025.1500417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/23/2024] [Accepted: 01/16/2025] [Indexed: 02/22/2025] Open
Abstract
Introduction Lung cancer is the leading cause of cancer-related death worldwide, and its morbidity and mortality are increasing. Although low-dose CT lung cancer screening has been shown to reduce lung cancer mortality, its adoption rate is limited and the pace of its promotion is slow, highlighting the urgent need for more effective prevention measures. Prophylactic vaccines play a crucial role in cancer prevention. Our previous studies indicated that mice immunized with a prophylactic vaccine based on lung cancer cell lines KPL 160302S, derived from early-stage murine lung cancer tissues, exhibited a significantly extended survival period, with a strong anti-tumor immune response. While the vaccine based on KPL 160424S, derived from advanced-stage murine lung cancer tissues, failed to extend survival time and demonstrated limited capacity to stimulate anti-tumor immunity. Methods To investigate the fundamental reason for the difference between KPL 160302S and KPL 160424S vaccines, we employed bioinformatics methods and immune related experiments to explore the effects and mechanisms of the screened neoantigens. Results Our findings demonstrated that immunization with the Ddx21 mutant peptide (Ddx21MT), unique to KPL 160302S, could significantly increase the proportion of central memory T cells (TCM) in mice and activate anti-tumor immunity. Discussion These results suggest that the Ddx21MT is a highly effective neoantigen that can activate anti-tumor immunity, which can serve as an important component in developing a lung cancer vaccine and is expected to be used in combination with other immunotherapy approaches.
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Affiliation(s)
- Zhe Zhang
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yimeng Xia
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Zhihong Wang
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yaxing Sun
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dan Pu
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yijia He
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Ruixian Liu
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanru Zhang
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan Liu
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Junzhi Yu
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shiyang Ning
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Baisui Feng
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yaohe Wang
- Centre for Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Na Wang
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
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Jiang F, Yu M, Wang Y. Design, synthesis and biological evaluation of novel diaryl-substituted fused nitrogen heterocycles as tubulin polymerization inhibitors to overcome multidrug resistance in vitro and in vivo. Eur J Med Chem 2025; 283:117130. [PMID: 39662283 DOI: 10.1016/j.ejmech.2024.117130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/18/2024] [Revised: 11/12/2024] [Accepted: 12/01/2024] [Indexed: 12/13/2024]
Abstract
Microtubule-targeting agents (MTAs) are considered as one of the most successful chemotherapy drugs for lung adenocarcinoma (LUAD). However, the clinical application of MTAs is often significantly plagued by multidrug resistance (MDR). To overcome this limitation in the quest of more effective MTAs for tumor therapy, a series of novel diaryl-substituted nitrogenous fused heterocycles were designed, synthesized and evaluated. Through four rounds of structure-activity relationship studies, the benzoimidazole derivative 37 was identified as a potent cytotoxic agent against both paclitaxel-sensitive and -resistant A549 (A549/T) cells, effectively overcoming multidrug resistance of A549/T cells against various MTAs. Mechanistic investigations revealed that 37 could disrupt microtubule assembly and induce cell cycle arrest at the G2/M phase, and hence trigger the cell apoptosis. Furthermore, 37 was found to be a poor substrate for P-glycoprotein (P-gp), a major contributor to multidrug resistance, and could reduce the level of P-gp in resistant cells, thereby effectively overcoming P-gp-mediated multidrug resistance. Notably, 37 exhibited higher liver microsomal stability and better water solubility than those of the reference combretastatin A-4 (CA-4). In vivo studies using an A549/T xenograft model demonstrated that 37 significantly inhibited tumor growth without obvious toxicity, outperforming the positive controls CA-4 and paclitaxel. As a novel tubulin polymerization inhibitor, compound 37 is marked by potent anticancer activity and remarkable anti-MDR properties. These salient features, coupled with the low toxicity of 37, would render it quite promising as a lead for further drug development towards clinical treatment of multidrug-resistant LUAD.
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MESH Headings
- Humans
- Drug Resistance, Multiple/drug effects
- Drug Design
- Drug Resistance, Neoplasm/drug effects
- Tubulin Modulators/pharmacology
- Tubulin Modulators/chemical synthesis
- Tubulin Modulators/chemistry
- Structure-Activity Relationship
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/chemical synthesis
- Antineoplastic Agents/chemistry
- Animals
- Tubulin/metabolism
- Heterocyclic Compounds/chemistry
- Heterocyclic Compounds/pharmacology
- Heterocyclic Compounds/chemical synthesis
- Mice
- Drug Screening Assays, Antitumor
- Cell Proliferation/drug effects
- Polymerization/drug effects
- Molecular Structure
- Apoptosis/drug effects
- Dose-Response Relationship, Drug
- Nitrogen/chemistry
- Mice, Nude
- Cell Line, Tumor
- Mice, Inbred BALB C
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/pathology
- Neoplasms, Experimental/metabolism
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Affiliation(s)
- Fuhao Jiang
- School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Min Yu
- School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Yang Wang
- School of Pharmacy, Fudan University, Shanghai, 201203, China; School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, 453007, China.
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6
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Wang Z, Zhu J, Wu Y, Wei C, Fang Y. Global, regional and national burden of lung cancer attributable to occupational carcinogens, 1990-2019: A study of trends, inequalities and predictions based on GBD 2019. Cancer Epidemiol 2025; 94:102737. [PMID: 39718282 DOI: 10.1016/j.canep.2024.102737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/17/2024] [Revised: 11/29/2024] [Accepted: 12/17/2024] [Indexed: 12/25/2024]
Abstract
BACKGROUND Lung cancer, a leading cause of cancer-related mortality, is significantly influenced by occupational carcinogens. This study aimed to assess and predict global, regional and national trends of lung cancer burden attributable to occupational carcinogens. METHODS Data on the lung cancer burden attributable to nine occupational carcinogens were obtained from the Global Burden of Disease Study 2019. Regions were categorized by the Socio-Demographic Index (SDI). Descriptive statistics, Joinpoint regression, and Age-Period-Cohort (APC) models were employed to analyze trends in mortality and Disability-Adjusted Life Years (DALYs). Using the Slope Index of Inequality and Concentration Index, health inequalities were quantified. The ARIMA-LSTM model was developed to predict the burden from 2020 to 2030. RESULTS From 1990-2019, lung cancer deaths and DALYs due to occupational carcinogens increased. Global age-standardized mortality (ASMR) and DALY (ASDR) rates declined, while middle and lower SDI regions increased. Joinpoint regression and APC analysis revealed that the local drift, period, and cohort effects exhibited increasingly unfavorable trends in lower SDI regions, while they were decreasing trends in higher SDI regions. Conversely, age effects increased similarly across all SDI regions. Health inequalities worsened over time. The ARIMA-LSTM model demonstrated global ASMR and ASDR would decrease, while low-middle and low SDI regions were expected to experience substantial increases from 2020 to 2030. CONCLUSION Health inequality of lung cancer burden attributable to occupational carcinogens remained a critical concern, underscoring the urgent need for targeted occupational health policies for low and low-middle SDI regions.
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Affiliation(s)
- Zongjie Wang
- School of Public Health, Xiamen University, Xiamen, Fujian, China; Key Laboratory of Health Technology Assessment of Fujian Province, Xiamen University, Xiamen, Fujian, China
| | - Junmin Zhu
- School of Public Health, Xiamen University, Xiamen, Fujian, China; Key Laboratory of Health Technology Assessment of Fujian Province, Xiamen University, Xiamen, Fujian, China
| | - Yafei Wu
- School of Public Health, Xiamen University, Xiamen, Fujian, China; School of Nursing, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Chongtao Wei
- School of Public Health, Xiamen University, Xiamen, Fujian, China; Key Laboratory of Health Technology Assessment of Fujian Province, Xiamen University, Xiamen, Fujian, China
| | - Ya Fang
- School of Public Health, Xiamen University, Xiamen, Fujian, China; Key Laboratory of Health Technology Assessment of Fujian Province, Xiamen University, Xiamen, Fujian, China; National Institute of Big Data for Health Care, Xiamen University, Xiamen, Fujian, China.
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Hoang Nguyen KH, Le NV, Nguyen PH, Nguyen HHT, Hoang DM, Huynh CD. Human immune system: Exploring diversity across individuals and populations. Heliyon 2025; 11:e41836. [PMID: 39911431 PMCID: PMC11795082 DOI: 10.1016/j.heliyon.2025.e41836] [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] [Academic Contribution Register] [Received: 07/21/2024] [Revised: 12/23/2024] [Accepted: 01/08/2025] [Indexed: 02/07/2025] Open
Abstract
The immune response is an intricate system that involves the complex connection of cellular and molecular components, each with distinct functional specialisations. It has a distinct capacity to adjust and mould the immune response in accordance with specific stimuli, influenced by both genetic and environmental factors. The presence of genetic diversity, particularly across different ethnic and racial groups, significantly contributes to the impact of incidence of diseases, disease susceptibility, autoimmune disorders, and cancer risks in specific regions and certain populations. Environmental factors, including geography and socioeconomic status, further modulate the variety of the immune system responses. These, in turn, affect the susceptibility to infectious diseases and development of autoimmune disorders. Despite the complexity of the relationship, there remains a gap in understanding the specificity of immune indices across races, immune reference ranges among populations, highlighting the need for deeper understanding of immune diversity for personalized approaches in diagnostics and therapeutics. This review systematically organizes these findings, with the goal of emphasizing the potential of targeted interventions to address health disparities and advance translational research, enabling a more comprehensive strategy. This approach promises significant advancements in identifying specific immunological conditions, focusing on personalized interventions, through both genetic and environmental factors.
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Affiliation(s)
| | - Nghi Vinh Le
- College of Health Sciences, VinUniversity, Hanoi, Viet Nam
| | | | - Hien Hau Thi Nguyen
- College of Health Sciences, VinUniversity, Hanoi, Viet Nam
- Institute of Research and Development, Duy Tan University, Da Nang, Viet Nam
- School of Medicine and Pharmacy, Duy Tan University, Da Nang, Viet Nam
| | - Duy Mai Hoang
- College of Health Sciences, VinUniversity, Hanoi, Viet Nam
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Liao C, Bai L, He T, Liang Q, Hu D, Lei S, He Y, Wang Y. Efficacy and Safety of Chemotherapy or EGFR-TKIs as First-Line Therapy in NSCLC Patients Harboring Non-Ex 20 Ins Uncommon EGFR Mutations: A Retrospective Study in China. Cancer Med 2025; 14:e70542. [PMID: 39739938 DOI: 10.1002/cam4.70542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/01/2023] [Revised: 12/07/2024] [Accepted: 12/13/2024] [Indexed: 01/02/2025] Open
Abstract
BACKGROUND Uncommon EGFR mutations are a kind of heterogeneous group of mutations with various responses to EGFR-TKIs and are often excluded from most prospective clinical trials. In this real-world retrospective study, we retrospectively compared the efficacy and safety of chemotherapy or various generations of EGFR-TKIs as first-line therapy in NSCLC Chinese patients harboring non-ex 20 ins uncommon EGFR mutations. METHODS We enrolled 139 NSCLC patients with non-ex 20 ins uncommon EGFR mutations in this study retrospectively. Patients' clinical characteristics and the efficacy and safety of different first-line therapies were analyzed and compared. RESULTS Our data reviewed that for first-line therapy, NSCLC patients harboring non-ex 20 ins uncommon EGFR mutations benefited more from EGFR-TKIs compared with chemotherapy. Afatinib performed with great efficacy for the majority of non-ex 20 ins uncommon EGFR mutations (N = 43, ORR = 41.86%, mPFS = 13.5 months, mOS = 20.8 months), especially in L861Q mutation (mPFS = 18.4 months). Osimertinib also demonstrated efficacy in patients harboring non-ex 20 ins uncommon EGFR mutations (N = 36, ORR = 27.78%, mPFS = 10.0 months, mOS = 21.0 months), especially in those without L861Q and G719X mutations (mPFS = 12.1 months). When treated with afatinib, patients harboring non-ex 20 ins uncommon EGFR mutations should pay attention to the management of safety, especially for gastrointestinal-related AE and rash, while osimertinib was safer. CONCLUSION Taking into account both efficacy and safety, afatinib and osimertinib are better choices than chemotherapy and first-generation EGFR-TKIs for NSCLC patients with non-ex 20 ins uncommon EGFR mutations. L861Q showed a trend toward a better response to afatinib, while in those without L861Q and G719X mutations, osimertinib might be a better choice. Safety also should be a concern when choosing EGFR-TKI for treatment, patients should pay attention to the management of safety when using afatinib while osimertinib is safer.
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Affiliation(s)
- Chen Liao
- Department of Respiratory and Critical Care Medicine, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Li Bai
- Department of Respiratory and Critical Care Medicine, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Tingting He
- Department of Respiratory and Critical Care Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Qingle Liang
- Department of Clinical Laboratory Medicine, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Defeng Hu
- Department of Respiratory and Critical Care Medicine, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Shipeng Lei
- Department of Respiratory and Critical Care Medicine, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Yong He
- Department of Respiratory and Critical Care Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Yubo Wang
- Department of Respiratory and Critical Care Medicine, Chongqing University Jiangjin Hospital, Chongqing, China
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9
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Majernikova SM. Risk and safety profile in checkpoint inhibitors on non-small-cel lung cancer: A systematic review. Hum Vaccin Immunother 2024; 20:2365771. [PMID: 38932682 PMCID: PMC11212564 DOI: 10.1080/21645515.2024.2365771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/08/2023] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
Treating non-small-cell lung cancer (NSCLC) has gained increased importance in recent years due to the high mortality rate and dismal five-year survival rate. Immune checkpoint inhibitors (ICI) are a promising approach with exceptional outcomes in NSCLC thanks to the antigenic nature of cells. Conversely, immune system over-stimulation with ICI is a double-edged sword that can lead to various negative effects ranging from mild to life-threatening. This review explores current breakthroughs in nanoparticle-based ICI and their limitations. The PubMed, Scopus and Web of Science were examined for relevant publications. Thirty-eight trials (N = 16,781) were included in the analyses. The mixed effects analyses on quantifying the treatment effect contributed significantly to the subgroups within studies for ICI treatment effect. Models confirmed ICI's higher impact on treatment effectivity and the decrease in respondents' mortality compared to conventional treatment regiments. ICI might be used as first-line therapy due to their proven effectiveness and safety profile.
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Affiliation(s)
- Sara Maria Majernikova
- Department for Continuing Education, The University of Oxford, Oxford, UK
- Department of Neuroscience, Physiology & Pharmacology, Division of Biosciences, Faculty of Life Sciences, University College London, London, UK
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10
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Liang H, Deng J, Luo T, Luo H, Li F, Wu K, Lin C. Chromatin accessibility reveals potential prognostic value of the peak set associated with smoking history in patients with lung adenocarcinoma. Heliyon 2024; 10:e41006. [PMID: 39720074 PMCID: PMC11665461 DOI: 10.1016/j.heliyon.2024.e41006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/05/2023] [Revised: 12/03/2024] [Accepted: 12/04/2024] [Indexed: 12/26/2024] Open
Abstract
Considerable differences in molecular characteristics have been defined between non-smoker and smokers in patients with lung adenocarcinoma (LUAD), yet studies on open chromatin patterns associated with LUAD progression caused by smoking are still lacking. Here, we constructed a novel network based on correlations between each ATAC-seq peak from TCGA data using our previously developed algorithm. Subsequently, principal component analysis was performed on LUAD samples with retained peaks filtered by the correlation network, and pathway analysis was conducted to identify potential pathways involved. We identified a set of peaks that discriminated smokers in LUAD patients according to levels of exposure to tobacco quantified in pack-years. These peaks were also significantly associated with progression-free survival and overall survival of these patients. Further examination of the gene set related to those peaks revealed that the comprising genes, such as KRT19, B3GNT3, CLDN7 and CLDN3 are strongly associated with LUAD development. They are consistent with the important roles of the associated pathways in LUAD oncogenesis induced by smoking, including estrogen response, apical junction and glycolysis pathways. In summary, our study may provide valuable insights into exploring ATAC-seq peaks and understanding smoking-related LUAD carcinogenesis from a perspective of open chromatin changes.
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Affiliation(s)
- Han Liang
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou 310000, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, BGI Research, Shenzhen 518083, China
- BGI Genomics, Shenzhen 518083, China
| | - Jianlian Deng
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Tian Luo
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou 310000, China
- BGI Genomics, Shenzhen 518083, China
| | - Huijuan Luo
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou 310000, China
- BGI Genomics, Shenzhen 518083, China
| | - Fuqiang Li
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou 310000, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, BGI Research, Shenzhen 518083, China
- BGI Genomics, Shenzhen 518083, China
| | - Kui Wu
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou 310000, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, BGI Research, Shenzhen 518083, China
- BGI Genomics, Shenzhen 518083, China
| | - Cong Lin
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou 310000, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, BGI Research, Shenzhen 518083, China
- BGI Genomics, Shenzhen 518083, China
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11
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Ma Y, Zhang F, Li J, Li J, Li Y. Diverse perspectives on proteomic posttranslational modifications to address EGFR-TKI resistance in non-small cell lung cancer. Front Cell Dev Biol 2024; 12:1436033. [PMID: 39777265 PMCID: PMC11703921 DOI: 10.3389/fcell.2024.1436033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/21/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025] Open
Abstract
Non-small cell lung cancer (NSCLC) is the main histological subtype of lung cancer. For locally advanced and advanced NSCLC, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-targeted therapy has been the first choice for NSCLC patients with EGFR mutations. TKIs, as targeted drugs, inhibit kinase activity and autophosphorylation by competitively binding to the ATP binding site of the EGFR tyrosine kinase domain, which blocks the signal transduction mediated by EGFR and thus inhibits the proliferation of tumor cells. However, drug resistance to TKIs is inevitable. EGFR is also a highly glycosylated receptor tyrosine kinase, and a wide range of crosstalk occurs between phosphorylation and glycosylation. Therefore, can the phosphorylation state be altered by glycosylation to improve drug resistance? In this review, we summarize phosphorylation, glycosylation and the crosstalk between these processes as well as the current research status and methods. We also summarize the autophosphorylation and glycosylation sites of the EGFR protein and their crosstalk. By exploring the relationship between EGFR glycosylation and autophosphorylation in targeted TKI therapy, we find that research on EGFR glycosylation is crucial for targeted NSCLC treatment and will become a research direction for identifying potential targets related to regulating TKI drug sensitivity.
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Affiliation(s)
- Yuhong Ma
- Department of Radiotherapy Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Feng Zhang
- Department of Radiotherapy Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jin Li
- Department of Radiotherapy Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Juan Li
- Department of Radiotherapy Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yanhua Li
- Department of International Medical Department, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
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12
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Cutty SJ, Hughes FA, Ortega-Prieto P, Desai S, Thomas P, Fets LV, Secrier M, Barr AR. Pro-survival roles for p21(Cip1/Waf1) in non-small cell lung cancer. Br J Cancer 2024:10.1038/s41416-024-02928-9. [PMID: 39706988 DOI: 10.1038/s41416-024-02928-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/03/2024] [Revised: 11/12/2024] [Accepted: 12/04/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND Quiescence is reversible proliferative arrest. Multiple mechanisms regulate quiescence that are not fully understood. High expression of the CDK inhibitor p21Cip1/Waf1 correlates with a poor prognosis in non-small cell lung cancer (NSCLC) and, in non-transformed cells, p21 promotes quiescence after replication stress. We tested whether NSCLC cells enter p21-dependent quiescence and if this is advantageous to NSCLC cells. METHODS Through analysis of patient data and quantitative, single-cell, timelapse imaging of genetically-engineered NSCLC reporter cell lines we investigated the role of p21 in NSCLC during normal proliferation and after chemotherapy. RESULTS High p21 expression correlates with a poor prognosis in TP53 wild-type, but not TP53 mutant, NSCLC patients and TP53 wild-type NSCLC cells can enter p21-dependent quiescence, downstream of replication stress. Without p21, unrepaired DNA damage propagates into S-phase and cells display increased genomic instability. p21 expression confers survival advantages to TP53 wild-type NSCLC cells, during proliferation and after chemotherapy. p21 can promote tumour relapse by allowing recovery from both G1 and G2 arrests after chemotherapy. CONCLUSIONS p21-dependent quiescence exists in TP53 wild-type NSCLC cells and provides survival advantages to these cells. Targeting p21 function in TP53 wild-type tumours could lead to better outcomes for chemotherapy treatment in NSCLC patients.
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Affiliation(s)
- S J Cutty
- Institute of Clinical Sciences, Imperial College London, London, UK
| | - F A Hughes
- Department of Mathematics, Imperial College London, London, UK
- MRC Laboratory of Medical Sciences, London, UK
| | | | - S Desai
- Charing Cross Hospital, Imperial College London, London, UK
| | - P Thomas
- Department of Mathematics, Imperial College London, London, UK
| | - L V Fets
- MRC Laboratory of Medical Sciences, London, UK
| | - M Secrier
- UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London, UK
| | - A R Barr
- Institute of Clinical Sciences, Imperial College London, London, UK.
- MRC Laboratory of Medical Sciences, London, UK.
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13
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Huang G, Liu Y, Li L, Li B, Jiang T, Cao Y, Yang X, Liu X, Qu H, Li S, Zheng X. Integration analysis of microRNAs as potential biomarkers in early-stage lung adenocarcinoma: the diagnostic and therapeutic significance of miR-183-3p. Front Oncol 2024; 14:1508715. [PMID: 39759146 PMCID: PMC11697600 DOI: 10.3389/fonc.2024.1508715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/09/2024] [Accepted: 12/03/2024] [Indexed: 01/07/2025] Open
Abstract
Introduction Lung adenocarcinoma (LUAD) poses a significant therapeutic challenge, primarily due to delayed diagnosis and the limited efficacy of existing treatments. Methods To understand the pathogenesis and identify diagnostic biomarkers for LUAD in the early stage, we investigated differential miRNA expression in 33 stage I LUAD patients between tumor and matched paracancerous tissues by Illumina Sequencing. Target genes of differentially expressed miRNAs were predicted using TargetScan and miRDB databases and further analyzed by GO and KEGG pathway enrichment analysis. The miRNAs expression results were verified using qRT-PCR. Additionally, we evaluated the clinical significance of miRNAs by the TCGA database. miR-183-3p was chosen for subsequent biological functional studies by cell proliferation assays, cell migration and cell invasion assays, cell apoptosis and cell cycle assays in LUAD cells. The clinical relevance target genes of miR-183-3p were predicted by TargetScan databases and bioinformatics assays. Gene-specific experimental validation was performed using qRT-PCR, western blotting and luciferase reporter assays. Results We identified 36 differentially expressed miRNAs between LUAD tissues and matched paracancerous tissues. Target genes for these miRNAs revealed associations with processes and pathways such as RNA biosynthesis, intracellular signaling, protein transport, and the Ras, MAPK, and PI3K-AKT pathways. The qRT-PCR results were in alignment with the sequencing data for 19 out of these 21 miRNAs which not yet implicated in LUAD, 13 were up-regulated, 6 were down-regulated. The clinical relevance assays showed that 5 up-regulated miRNAs have diagnostic value for LUAD. miR-183-3p showed significant advantages in the result of sequencing, qRT-PCR, and clinical relevance assay. Biological functional assays showed that miR-183-3p emerged as a key regulator, promoting LUAD cell proliferation, decreasing apoptosis, and augmenting migration and invasion capabilities. The clinical relevance assays and experimental validation showed SESN1 as a clinical significance target of miR-183-3p. Discussion Our study lays the foundation for investigating miRNAs with diagnostic significance in early-stage LUAD, pointing out that inhibition of miR-183-3p may serve as a novel therapeutic in LUAD.
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Affiliation(s)
- Guodong Huang
- Central Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Hospital of Traditional Chinese Medicine), Qingdao, Shandong, China
| | - Yuxia Liu
- Department of Respiration, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Lisha Li
- Department of Respiration, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Hospital of Traditional Chinese Medicine), Qingdao, Shandong, China
| | - Bing Li
- Central Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Hospital of Traditional Chinese Medicine), Qingdao, Shandong, China
| | - Ting Jiang
- Central Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Hospital of Traditional Chinese Medicine), Qingdao, Shandong, China
| | - Yufeng Cao
- Cancer Center, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Hospital of Traditional Chinese Medicine), Qingdao, Shandong, China
| | - Xiaoping Yang
- Department of Respiration, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Hospital of Traditional Chinese Medicine), Qingdao, Shandong, China
| | - Xinning Liu
- Central Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Hospital of Traditional Chinese Medicine), Qingdao, Shandong, China
| | - Honglin Qu
- Central Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Hospital of Traditional Chinese Medicine), Qingdao, Shandong, China
| | - Shitao Li
- Department of Respiration, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Xin Zheng
- Central Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Hospital of Traditional Chinese Medicine), Qingdao, Shandong, China
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14
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Chen J, Wang T, Zhang D, Wang H, Huang Z, Yang Z, Li J, Hu T, Wang X, Li X. KDM5D histone demethylase mediates p38α inactivation via its enzymatic activity to inhibit cancer progression. Proc Natl Acad Sci U S A 2024; 121:e2402022121. [PMID: 39636854 DOI: 10.1073/pnas.2402022121] [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] [Academic Contribution Register] [Received: 03/07/2024] [Accepted: 10/16/2024] [Indexed: 12/07/2024] Open
Abstract
The p38 MAP kinase (MAPK) signaling pathway plays pivotal roles in various cellular processes. Phosphorylation serves as a canonical way to regulate p38α activation through a phosphorylation cascade. Thus, understanding the mechanism governing p38α phosphorylation is important. The present study demonstrated that p38α undergoes methylation at K165, which promote its phosphorylation in tumor cells. Inhibition of p38α methylation impairs p38α phosphorylation, repressing tumor progression in vitro and in vivo. Mechanistically, KDM5D is a demethylase that interacts with p38α, mediating demethylation at K165 and inhibiting p38α phosphorylation. Moreover, KDM5D is expressed at low levels in non-small cell lung cancer (NSCLC), and high KDM5D expression is positively correlated with cancer survival. KDM5D markedly inhibits cell proliferation and migration via inactivating p38α, thereby slowing cancer progression in xenograft models. In summary, these findings highlight KDM5D as a demethylase of p38α at K165, elucidating a unique role for lysine demethylation in integrating cytoplasmic kinase-signaling cascades. The present results revealed the critical role of KDM5D in suppressing tumor progression, suggesting that KDM5D can serve as a potential drug target for combating hyperactive p38α-driven lung cancer.
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Affiliation(s)
- Jingying Chen
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Medicine, Henan University, Kaifeng 475004, China
- Institute of Translational Medicine, Henan University, Kaifeng 475004, China
| | - Ting Wang
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Medicine, Henan University, Kaifeng 475004, China
| | - Dongzhe Zhang
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Medicine, Henan University, Kaifeng 475004, China
| | - Huiling Wang
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Medicine, Henan University, Kaifeng 475004, China
| | - Zhiang Huang
- The First Affiliated Hospital, Henan University, Kaifeng 475004, China
| | - Zhongxin Yang
- The First Affiliated Hospital, Henan University, Kaifeng 475004, China
| | - Jizhuo Li
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Medicine, Henan University, Kaifeng 475004, China
| | - Tianyi Hu
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Medicine, Henan University, Kaifeng 475004, China
| | - Xin Wang
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Medicine, Henan University, Kaifeng 475004, China
| | - Xia Li
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Medicine, Henan University, Kaifeng 475004, China
- Institute of Translational Medicine, Henan University, Kaifeng 475004, China
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15
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Zhou R, Tang X, Wang Y. Emerging strategies to investigate the biology of early cancer. Nat Rev Cancer 2024; 24:850-866. [PMID: 39433978 DOI: 10.1038/s41568-024-00754-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Accepted: 09/06/2024] [Indexed: 10/23/2024]
Abstract
Early detection and intervention of cancer or precancerous lesions hold great promise to improve patient survival. However, the processes of cancer initiation and the normal-precancer-cancer progression within a non-cancerous tissue context remain poorly understood. This is, in part, due to the scarcity of early-stage clinical samples or suitable models to study early cancer. In this Review, we introduce clinical samples and model systems, such as autochthonous mice and organoid-derived or stem cell-derived models that allow longitudinal analysis of early cancer development. We also present the emerging techniques and computational tools that enhance our understanding of cancer initiation and early progression, including direct imaging, lineage tracing, single-cell and spatial multi-omics, and artificial intelligence models. Together, these models and techniques facilitate a more comprehensive understanding of the poorly characterized early malignant transformation cascade, holding great potential to unveil key drivers and early biomarkers for cancer development. Finally, we discuss how these new insights can potentially be translated into mechanism-based strategies for early cancer detection and prevention.
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Affiliation(s)
- Ran Zhou
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiwen Tang
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yuan Wang
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
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16
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Wallen ZD, Nesline MK, Tierno M, Roos A, Schnettler E, Husain H, Sathyan P, Caveney B, Eisenberg M, Severson EA, Ramkissoon SH. Genomic profiling of NSCLC tumors with the TruSight oncology 500 assay provides broad coverage of clinically actionable genomic alterations and detection of known and novel associations between genomic alterations, TMB, and PD-L1. Front Oncol 2024; 14:1473327. [PMID: 39664186 PMCID: PMC11631745 DOI: 10.3389/fonc.2024.1473327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/30/2024] [Accepted: 11/05/2024] [Indexed: 12/13/2024] Open
Abstract
Introduction Matching patients to an effective targeted therapy or immunotherapy is a challenge for advanced and metastatic non-small cell lung cancer (NSCLC), especially when relying on assays that test one marker at a time. Unlike traditional single marker tests, comprehensive genomic profiling (CGP) can simultaneously assess NSCLC tumors for hundreds of genomic biomarkers and markers for immunotherapy response, leading to quicker and more precise matches to therapeutics. Methods In this study, we performed CGP on 7,606 patients with advanced or metastatic NSCLC using the Illumina TruSight Oncology 500 (TSO 500) CGP assay to show its coverage and utility in detecting known and novel features of NSCLC. Results Testing revealed distinct genomic profiles of lung adenocarcinoma and squamous cell carcinomas and detected variants with a current targeted therapy or clinical trial in >72% of patient tumors. Known associations between genomic alterations and immunotherapy markers were observed including significantly lower TMB levels in tumors with therapy-associated alterations and significantly higher PD-L1 levels in tumors with ALK, MET, BRAF, or ROS1 driver mutations. Co-occurrence analysis followed by network analysis with gene module detection revealed known and novel co-occurrences between genomic alterations. Further, certain modules of genes with co-occurring genomic alterations had dose-dependent relationships with histology and increasing or decreasing levels of PD-L1 and TMB, suggesting a complex relationship between PD-L1, TMB, and genomic alterations in these gene modules. Discussion This study is the largest clinical study to date utilizing the TSO 500. It provides an opportunity to further characterize the landscape of NSCLC using this newer technology and show its clinical utility in detecting known and novel facets of NSCLC to inform treatment decision-making.
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Affiliation(s)
| | | | | | | | | | - Hatim Husain
- Moores Cancer Center at UC San Diego Health, La Jolla, CA, United States
| | | | | | | | | | - Shakti H. Ramkissoon
- Labcorp Oncology, Durham, NC, United States
- Wake Forest Comprehensive Cancer Center, Wake Forest School of Medicine, Department of Pathology, Winston-Salem, NC, United States
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17
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Xu R, Han F, Zhao Y, Liu A, An N, Wang B, Zardo P, Sanz-Santos J, Franssen AJPM, de Loos ER, Zhao M. Role of CENPL, DARS2, and PAICS in determining the prognosis of patients with lung adenocarcinoma. Transl Lung Cancer Res 2024; 13:2729-2745. [PMID: 39507047 PMCID: PMC11535832 DOI: 10.21037/tlcr-24-696] [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] [Academic Contribution Register] [Received: 08/09/2024] [Accepted: 10/15/2024] [Indexed: 11/08/2024]
Abstract
Background Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancers, and is the leading cause of tumor-related death. Lung adenocarcinoma (LUAD) is the most prevalent subtype of NSCLC. Although significant progress of LUAD treatment has been made under multimodal strategies, the prognosis of advanced LUAD is still poor due to recurrence and metastasis. There is still a lack of reliable markers to evaluate the LUAD prognosis. This study aims to explore novel biomarkers and construct a prognostic model to predict the prognosis of LUAD patients. Methods The Genomic Data Commons-The Cancer Genome Atlas-Lung Adenocarcinoma (GDC-TCGA-LUAD) dataset was downloaded from the University of California, Santa Cruz (UCSC) Xena browser. The GSE72094 and GSE13213 datasets and corresponding clinical information were downloaded from the Gene Expression Omnibus (GEO) database. By analyzing these datasets using DESeq2 R package and Limma R package, differentially expressed genes (DEGs) were found. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to analyze possible enrichment pathways. A protein-protein interaction (PPI) network was constructed to explore possible relationship among DEGs by using the STRING database. A survival analysis was performed to identify reliable prognostic genes using the Kaplan-Meier method. A multi-omics analysis was performed using the Gene Set Cancer Analysis (GSCA). The Tumor Immune Estimation Score (TIMER) database was used to analyze the association between prognostic genes and immune infiltration. A Spearman correlation analysis was conducted to examine the correlation between prognostic genes and drug sensitivity. A multivariate Cox regression was used to identify independent prognostic factors. Next, a nomogram was constructed using the rms R package. Finally, the expressions of aspartyl-tRNA synthetase 2 (DARS2) and phosphoribosyl aminoimidazole carboxylase (PAICS) were detected using immunohistochemistry (IHC). Results We screened out 30 DEGs prior to functional enrichment and PPI network analysis revealing potential enrichment pathways and interactions of these DEGs. Then survival analysis revealed the CENPL, DARS2, and PAICS expression was negatively correlated with LUAD prognosis. Additionally, multi-omics analysis showed CENPL, DARS2, and PAICS expressions were significantly higher in LUAD tissues than normal tissues. CENPL, DARS2, and PAICS were all up-regulated in late stage and M1 stage. Correlation analysis indicated CENPL, DARS2, and PAICS may not be associated with activation or suppression of immune cells. Drug sensitivity analysis revealed many potentially effective drugs and small molecule compounds. Moreover, we successfully constructed a robust and stable nomogram by combining the DARS2 and PAICS expression with other clinicopathological variables. Finally, IHC results showed DARS2 and PAICS were significantly up-regulated in LUAD. Conclusions The CENPL, DARS2, and PAICS expression was negatively correlated with LUAD prognosis. A prognostic model, which integrated DARS2, PAICS, and other clinicopathological variables, was able to effectively predict LUAD patients prognosis.
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Affiliation(s)
- Rongjian Xu
- Department of Medical Microbiology, School of Basic Medicine, Qingdao University, Qingdao, China
- Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Fengyi Han
- Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yandong Zhao
- Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ao Liu
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Ning An
- Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Baogang Wang
- Department of Thoracic Surgery, The Anqiu Hospital of Traditional Chinese Medicine, Weifang, China
| | - Patrick Zardo
- Department of Cardiothoracic Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - José Sanz-Santos
- Pulmonology Department, Hospital Universitari Mútua Terrassa, University of Barcelona, Terrassa, Spain
| | - Aimée J. P. M. Franssen
- Division of General Thoracic Surgery, Department of Surgery, Zuyderland Medical Center, Heerlen, The Netherlands
| | - Erik R. de Loos
- Division of General Thoracic Surgery, Department of Surgery, Zuyderland Medical Center, Heerlen, The Netherlands
| | - Min Zhao
- Center of Laboratory Medicine, Qilu Hospital of Shandong University (Qingdao), Qingdao, China
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Xiong Y, Wang L, Zhang W, Meng Y, Wang Y, Shen M, Zhou L, Li R, Lv Y, Wang S, Ren X, Liu L. First-line treatment with gefitinib in combination with bevacizumab and chemotherapy in advanced non-squamous NSCLC with EGFR-mutation. BMC Cancer 2024; 24:1326. [PMID: 39472861 PMCID: PMC11520869 DOI: 10.1186/s12885-024-13084-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/08/2024] [Accepted: 10/22/2024] [Indexed: 11/02/2024] Open
Abstract
BACKGROUND The safety and efficacy of combination of gefitinib with chemotherapy and bevacizumab in treatment patients with epidermal growth factor receptor (EGFR) mutations are currently unknown. This study was designed to evaluate the safety and preliminary efficacy of a combination therapy consisting of gefitinib, bevacizumab, pemetrexed, and carboplatin in patients with advanced non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations. METHODS Eligible patients with EGFR-mutated advanced non-squamous NSCLC were recruited and received gefitinib combination with bevacizumab plus pemetrexed and carboplatin treatment. The primary endpoints were safety and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and overall survival (OS). RESULTS From June 2019 to June 2021, 20 patients were enrolled in this study. The median follow-up was 33.8 months (95% CI, 31.0-36.6). Grade ≥ 3 adverse events was 65%, including neutropenia (30%), thrombocytopenia (20%), nausea (20%), skin rash (20%), bleeding (10%), and increased ALT (10%). There was no death related to toxicity occurred. The median PFS was 28 months (95% CI, 20.4-35.6). the ORR was 95% (95% CI, 75.1-99.9%), the DCR was 100% (95% CI, 83.2-100%), and the median DOR was 26.4 months (95% CI, 18.9-33.9). The median OS has not been reached. CONCLUSION The results of this study demonstrate that the four-drug combination regimen, led by gefitinib, is manageable and tolerated and effective for patients with EGFR-mutated advanced non-squamous NSCLC.
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Affiliation(s)
- Yanjuan Xiong
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
- Department of Biotherapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Lu Wang
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
- Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
- Department of Oncology, Jiujiang No.1 People's Hospital, Jiujiang, Jiangxi, China
| | - Weihong Zhang
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
- Department of Biotherapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Yuan Meng
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
- Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Yang Wang
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
- Department of Biotherapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Meng Shen
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
- Department of Biotherapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Li Zhou
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
- Department of Biotherapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Runmei Li
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
- Department of Biotherapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Yingge Lv
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
- Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Shengguang Wang
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China.
- Tianjin's Clinical Research Center for Cancer, Tianjin, China.
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
| | - Xiubao Ren
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China.
- Tianjin's Clinical Research Center for Cancer, Tianjin, China.
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.
- Department of Biotherapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China.
- Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China.
| | - Liang Liu
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China.
- Tianjin's Clinical Research Center for Cancer, Tianjin, China.
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.
- Department of Biotherapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China.
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19
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Behera R, Arora S, Ish P, Khanna G. Common epidermal growth factor receptor mutations in north Indian patients with non-small cell lung carcinoma: evidence from real-time polymerase chain reaction. Monaldi Arch Chest Dis 2024. [PMID: 39470226 DOI: 10.4081/monaldi.2024.3202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/12/2024] [Accepted: 09/13/2024] [Indexed: 10/30/2024] Open
Abstract
Lung carcinoma was the ace cause of cancer deaths globally in 2022, with non-small cell lung carcinoma (NSCLC) accounting for 81% of the burden. Due to promising tyrosine kinase inhibitor (TKI) trials, NSCLC patients harboring epidermal growth factor receptor (EGFR) gene mutations are of interest. Our aim was to determine EGFR mutation prevalence in north India and its histologic and demographic correlations. We investigated the frequency of EGFR mutations in 40 patients with histologically confirmed NSCLC using real-time polymerase chain reaction. A 15% mutation frequency was observed in the study sample, involving 32 males and 8 females with a median age of 59 years. Squamous cell carcinoma (SCC) patients had only EXON20 (T790M, exon20 insertion) mutations, while adenocarcinoma patients had mutations in both EXON20 (T790M) and 21 (L858R) with mutation frequencies of 22% and 10%, respectively. 28% of the SCC patients were non-smokers, and 60% of these non-smokers had an EGFR mutation. South Indian and Asian studies have identified EXON19 (19-Del) and EXON21 (L858R) mutations as "common mutations" that account for nearly 80-90% of all mutations and respond well to TKIs. Interestingly, "common mutations" were found seldom in our study population, while the uncommon variants constitute 83% of all mutations, which we assume is due to diverse Indian genetics and ethnicity and co-existing signature mutations that involve the tyrosine kinase domain of EXON20. We suggest future genome-wide association studies to identify plausible genetic polymorphisms responsible for interethnic differences in EGFR mutation, which will contribute to better treatment and prevention of NSCLCs.
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Affiliation(s)
- Rakesh Behera
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi
| | - Sheetal Arora
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi
| | - Pranav Ish
- Department of Pulmonary Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi
| | - Geetika Khanna
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi
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20
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Gregory MD, Ofosu-Asante K, Lazarte JMS, Puente PE, Tawfeeq N, Belony N, Huang Y, Offringa IA, Lamango NS. Treatment of a mutant KRAS lung cancer cell line with polyisoprenylated cysteinyl amide inhibitors activates the MAPK pathway, inhibits cell migration and induces apoptosis. PLoS One 2024; 19:e0312563. [PMID: 39436906 PMCID: PMC11495567 DOI: 10.1371/journal.pone.0312563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/27/2023] [Accepted: 09/11/2024] [Indexed: 10/25/2024] Open
Abstract
KRAS mutations are the most common oncogenic mutations in lung adenocarcinoma in Black Americans. Polyisoprenylated Cysteinyl amide Inhibitors (PCAIs) constitute a group of potential cancer therapy agents that we designed to specifically disrupt and suppress hyperactive G-protein signaling, such as that caused by mutated RAS proteins. Here we determine the effects of PCAIs on the viability, G-protein levels, downstream mediators, and apoptosis-related proteins on the KRAS-mutated, Black American-derived lung adenocarcinoma cell line, NCI-H23. Of the 17 PCAIs tested, compounds NSL-YHJ-2-27 and NSL-YHJ-2-46 showed the most potency with EC50 values of 2.7 and 3.3 μM, respectively. Western blotting was used to determine the effect of the PCAIs on the phosphorylation levels of MAPK pathway enzymes. After 48 h exposure to 5 μM of the PCAIs, NSL-YHJ-2-46, the MAPK proteins BRAF, MEK1/2, ERK1/2, and p90RSK were activated through phosphorylation by 90, 190, 150 and 120%, respectively. However, CRAF/RAF1 phosphorylation decreased by 40%, suggesting significant changes in the KRAS/MAPK signaling patterns. Furthermore, 5 μM of NSL-YHJ-2-27 depleted the singly polyisoprenylated monomeric G-proteins RAC 1/2/3 and CDC42 by 77 and 76%, respectively. The depletion of these key cytoskeletal proteins may account for the observed inhibition of cell migration and invasion, and spheroid invasion observed on exposure to NSL-YHJ-2-27 and NSL-YHJ-2-46. Treatment with 5 μM of NSL-YHJ-2-27 suppressed full-length inactive caspase 3 and 7 levels by 72 and 91%, respectively. An analysis of cells treated with the fluorescently labeled active caspase 3/7 irreversible inhibitor, CaspaTagTM Caspase-3/7 in situ reagent revealed a 124% increase in active caspase at 3 μM over controls. These findings clearly show the direct effects of the PCAIs on the RAS signaling pathway. Given the profound increases observed in RPS6KA1/p90RSK phosphorylation, future work will involve a determination whether the proapoptotic isoforms of RPS6KA1/p90RSK are phosphorylated due to the PCAIs treatments. These results support the potential use of the PCAIs as targeted therapies against cancers with KRAS mutations.
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Affiliation(s)
- Matthew D. Gregory
- Institute of Public Health, Florida A&M University College of Pharmacy Pharmaceutical Sciences, Tallahassee, FL, United States of America
| | - Kweku Ofosu-Asante
- Institute of Public Health, Florida A&M University College of Pharmacy Pharmaceutical Sciences, Tallahassee, FL, United States of America
| | - Jassy Mary S. Lazarte
- Institute of Public Health, Florida A&M University College of Pharmacy Pharmaceutical Sciences, Tallahassee, FL, United States of America
| | - Pablo E. Puente
- Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, United States of America
| | - Nada Tawfeeq
- Institute of Public Health, Florida A&M University College of Pharmacy Pharmaceutical Sciences, Tallahassee, FL, United States of America
| | - Nadine Belony
- University of Florida Department of Mechanical and Aerospace Engineering, Gainesville, FL, United States of America
| | - Yong Huang
- University of Florida Department of Mechanical and Aerospace Engineering, Gainesville, FL, United States of America
| | - Ite A. Offringa
- Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, United States of America
| | - Nazarius S. Lamango
- Institute of Public Health, Florida A&M University College of Pharmacy Pharmaceutical Sciences, Tallahassee, FL, United States of America
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21
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Liao X, He T, Wan X, Liu P, Li J, He Y, Wang Y. Clinical Management in NSCLC Patients With EGFR Mutation After Osimertinib Progression With Unknown Resistance Mechanisms. THE CLINICAL RESPIRATORY JOURNAL 2024; 18:e70025. [PMID: 39406371 PMCID: PMC11479601 DOI: 10.1111/crj.70025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Academic Contribution Register] [Received: 03/08/2024] [Revised: 09/23/2024] [Accepted: 09/26/2024] [Indexed: 10/20/2024]
Abstract
BACKGROUND Osimertinib is approved as a standard treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation by FDA. However, the mechanisms of resistance for nearly half of patients after osimertinib progression are still unknown, and the optimal therapies for these patients are still controversial. In this retrospective study, we compared efficacy and safety between immunotherapy + chemotherapy, chemotherapy alone, and osimertinib + bevacizumab in NSCLC patients after osimertinib progression with unknown resistance mechanisms. METHODS Advanced NSCLC patients with unknown resistance mechanisms after osimertinib progression were retrospectively reviewed and divided into immunotherapy + chemotherapy, chemotherapy alone, and osimertinib + bevacizumab treatment groups according to the treatment they received after osimertinib progression. Clinicopathological features, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between groups. RESULTS A total of 121 patients were enrolled in this study, 22 in the immunotherapy + chemotherapy group, 72 in the chemotherapy group, and 27 in the osimertinib + bevacizumab group. The ORR was much higher in the immunotherapy + chemotherapy group compared with chemotherapy or osimertinib + bevacizumab group (55.56% vs. 14.81% vs. 0% in patients after progression on 1st line osimertinib treatment; 30.77% vs. 6.67% vs. 13.33% in patients after progression on 2nd/3rd line osimertinib treatment). Median PFS was also significantly longer in the immunotherapy + chemotherapy group compared with other groups (8.2 months vs. 4.0 months vs. 6.0 months in all patients, p = 0.0066). The median OS did not reach remarkable difference among groups, although osimertinib + bevacizumab group had a numerically longer median OS (37.0 months vs. 37.0 months vs. 47.6 months in all patients, p = 0.6357). Compared with immunotherapy + chemotherapy and chemotherapy, treatment-related adverse events (AEs) of osimertinib + bevacizumab were milder, especially in AEs related to gastrointestinal and bone marrow suppression. CONCLUSION Our study provides clinical evidence that NSCLC patients after osimertinib progression with unknown resistance mechanisms may benefit from immunotherapy + chemotherapy, with higher ORR and longer PFS compared with osimertinib + bevacizumab or chemotherapy groups. Osimertinib + bevacizumab treatment was also an optional option for patients because OS was numerically longer and safer in this group.
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Affiliation(s)
- Xin Liao
- Department of Respiratory and Critical Care MedicineChongqing University Jiangjin HospitalChongqingChina
| | - Tingting He
- Department of Respiratory and Critical Care MedicineDaping Hospital, Army Medical UniversityChongqingChina
| | - Xiong Wan
- Department of Respiratory and Critical Care MedicineChongqing University Jiangjin HospitalChongqingChina
| | - Pian Liu
- Department of Respiratory and Critical Care MedicineChongqing University Jiangjin HospitalChongqingChina
| | - Jing Li
- Department of Respiratory and Critical Care MedicineChongqing University Jiangjin HospitalChongqingChina
| | - Yong He
- Department of Respiratory and Critical Care MedicineDaping Hospital, Army Medical UniversityChongqingChina
| | - Yubo Wang
- Department of Respiratory and Critical Care MedicineChongqing University Jiangjin HospitalChongqingChina
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van de Worp WRPH, Theys J, Wolfs CJA, Verhaegen F, Schols AMWJ, van Helvoort A, Langen RCJ. Targeted nutritional intervention attenuates experimental lung cancer cachexia. J Cachexia Sarcopenia Muscle 2024; 15:1664-1676. [PMID: 38965830 PMCID: PMC11446694 DOI: 10.1002/jcsm.13520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/25/2023] [Revised: 04/12/2024] [Accepted: 04/29/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND Cachexia, a syndrome with high prevalence in non-small cell lung cancer patients, impairs quality of life and reduces tolerance and responsiveness to cancer therapy resulting in decreased survival. Optimal nutritional care is pivotal in the treatment of cachexia and a recommended cornerstone of multimodal therapy. Here, we investigated the therapeutic effect of an intervention diet consisting of a specific combination of high protein, leucine, fish oil, vitamin D, galacto-oligosaccharides, and fructo-oligosaccharides on the development and progression of cachexia in an orthotopic lung cancer mouse model. METHODS Eleven-week-old male 129S2/Sv mice were orthotopically implanted with 344P lung epithelial tumour cells or vehicle (control). Seven days post-implantation tumour-bearing (TB) mice were allocated to either intervention- or isocaloric control diet. Cachexia was defined as 5 days of consecutive body weight loss, after which mice were euthanized for tissue analyses. RESULTS TB mice developed cachexia accompanied by significant loss of skeletal muscle mass and epididymal fat mass compared with sham operated mice. The cachectic endpoint was significantly delayed (46.0 ± 15.2 vs. 34.7 ± 11.4 days), and the amount (-1.57 ± 0.62 vs. -2.13 ± 0.57 g) and progression (-0.26 ± 0.14 vs. -0.39 ± 0.11 g/day) of body weight loss were significantly reduced by the intervention compared with control diet. Moreover, systemic inflammation (pentraxin-2 plasma levels) and alterations in molecular markers for proteolysis and protein synthesis, indicative of muscle atrophy signalling in TB-mice, were suppressed in skeletal muscle by the intervention diet. CONCLUSIONS Together, these data demonstrate the potential of this multinutrient intervention, targeting multiple components of cachexia, as integral part of lung cancer management.
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Affiliation(s)
- Wouter R. P. H. van de Worp
- Department of Respiratory Medicine, NUTRIM – Institute of Nutrition and Translational Research in MetabolismMaastricht University Medical CenterMaastrichtThe Netherlands
| | - Jan Theys
- Department of Precision Medicine, GROW – Institute for Oncology and ReproductionMaastricht University Medical CenterMaastrichtThe Netherlands
| | - Cecile J. A. Wolfs
- Department of radiation Oncology (Maastro), GROW – Institute for Oncology and ReproductionMaastricht University Medical Centre+MaastrichtThe Netherlands
| | - Frank Verhaegen
- Department of radiation Oncology (Maastro), GROW – Institute for Oncology and ReproductionMaastricht University Medical Centre+MaastrichtThe Netherlands
| | - Annemie M. W. J. Schols
- Department of Respiratory Medicine, NUTRIM – Institute of Nutrition and Translational Research in MetabolismMaastricht University Medical CenterMaastrichtThe Netherlands
| | - Ardy van Helvoort
- Department of Respiratory Medicine, NUTRIM – Institute of Nutrition and Translational Research in MetabolismMaastricht University Medical CenterMaastrichtThe Netherlands
- Danone Nutricia ResearchUtrechtThe Netherlands
| | - Ramon C. J. Langen
- Department of Respiratory Medicine, NUTRIM – Institute of Nutrition and Translational Research in MetabolismMaastricht University Medical CenterMaastrichtThe Netherlands
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Singh J, Narayan G, Dixit VK. The long intergenic non-coding RNA LINC01140 modulates gastric cancer phenotypes and cancer cell lines aggressiveness. Dig Liver Dis 2024; 56:1776-1783. [PMID: 38556409 DOI: 10.1016/j.dld.2024.03.006] [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] [Academic Contribution Register] [Received: 01/13/2024] [Revised: 03/06/2024] [Accepted: 03/09/2024] [Indexed: 04/02/2024]
Abstract
BACKGROUND Long-intergenic non-protein coding gene 01140 (LINC01140) a long non-coding RNA is highly expressed in various cancers. However, its biological functions in gastric cancer progression is still unknown. METHOD To elucidate LINC01140 function, 70 GC tumor samples and 30 normal gastric tissues were collected. LINC01140 expression level were determined by qRT-PCR analysis and correlated with different clinico-pathological parameters. Then we tried to see the impact of LINC01140 on gastric cell line aggressiveness by knocking down the target gene and performing cell viability assay, migration assay and invasive capacity of the cell lines along with immunoblotting to check several protein levels. RESULT LINC01140 RNA is found to be positively correlated with FGF9 and significantly up regulated in GC tissues. LINC01140 knockdown inhibited the viability, migratory capacity and invasive capacity of AGS cells. LINC01140 targets miR-140-5p, while miR-140-5p targeted FGF9 to form lncRNA-miRNA-mRNA axis. The affect of miR-140-5p inhibition on gastric cancer cell aggressiveness were opposite to those of LINC01140 or FGF9 knockdown. Additionally, inhibition partially reversed the effects of LINC01140 knockdown on FGF9 protein levels, gastric cancer cell phenotypes. CONCLUSION LINC01140, miR-140-5p and FGF9 form a lncRNA-miRNA-mRNA axis that modulates the gastric cancer phenotypes and in turn affects gastric cancer cell aggressiveness.
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Affiliation(s)
- Juhi Singh
- Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Gopeshwar Narayan
- Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, 221005, India
| | - Vinod Kumar Dixit
- Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India.
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24
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Xie K, Cui C, Li X, Yuan Y, Wang Z, Zeng L. MRI-Based Clinical-Imaging-Radiomics Nomogram Model for Discriminating Between Benign and Malignant Solid Pulmonary Nodules or Masses. Acad Radiol 2024; 31:4231-4241. [PMID: 38644089 DOI: 10.1016/j.acra.2024.03.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/29/2024] [Revised: 03/29/2024] [Accepted: 03/30/2024] [Indexed: 04/23/2024]
Abstract
RATIONALE AND OBJECTIVES Pulmonary nodules or masses are highly prevalent worldwide, and differential diagnosis of benign and malignant lesions remains difficult. Magnetic resonance imaging (MRI) can provide functional and metabolic information of pulmonary lesions. This study aimed to establish a nomogram model based on clinical features, imaging features, and multi-sequence MRI radiomics to identify benign and malignant solid pulmonary nodules or masses. MATERIALS AND METHODS A total of 145 eligible patients (76 male; mean age, 58.4 years ± 13.7 [SD]) with solid pulmonary nodules or masses were retrospectively analyzed. The patients were randomized into two groups (training cohort, n = 102; validation cohort, n = 43). The nomogram was used for predicting malignant pulmonary lesions. The diagnostic performance of different models was evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS Of these patients, 95 patients were diagnosed with benign lesions and 50 with malignant lesions. Multivariate analysis showed that age, DWI value, LSR value, and ADC value were independent predictors of malignant lesions. Among the radiomics models, the multi-sequence MRI-based model (T1WI+T2WI+ADC) achieved the best diagnosis performance with AUCs of 0.858 (95%CI: 0.775, 0.919) and 0.774 (95%CI: 0.621, 0.887) for the training and validation cohorts, respectively. Combining multi-sequence radiomics, clinical and imaging features, the predictive efficacy of the clinical-imaging-radiomics model was significantly better than the clinical model, imaging model and radiomics model (all P < 0.05). CONCLUSION The MRI-based clinical-imaging-radiomics model is helpful to differentiate benign and malignant solid pulmonary nodules or masses, and may be useful for precision medicine of pulmonary diseases.
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Affiliation(s)
- Kexin Xie
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210002, China
| | - Can Cui
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210002, China
| | - Xiaoqing Li
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210002, China
| | - Yongfeng Yuan
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210002, China
| | - Zhongqiu Wang
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210002, China
| | - Liang Zeng
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210002, China.
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25
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Melosky B, Vincent MD, McGuire AL, Brade AM, Chu Q, Cheema P, Martins I, Spicer JD, Snow S, Juergens RA. Modern era systemic therapies: Expanding concepts of cure in early and locally advanced non-small cell lung cancer. Int J Cancer 2024; 155:963-978. [PMID: 38900018 DOI: 10.1002/ijc.35031] [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] [Academic Contribution Register] [Received: 12/04/2023] [Revised: 03/19/2024] [Accepted: 04/17/2024] [Indexed: 06/21/2024]
Abstract
Cure of cancer is a sensitive and multidimensional concept that is challenging to define, difficult to assert at the individual patient level, and often surrounded by controversy. The notion of cure in non-small cell lung cancer (NSCLC) has changed and continues to evolve with improvements in diagnosis and treatment. Targeted and immune therapies have recently entered the treatment landscape of stage I-III NSCLC. While some initial pivotal trials of such agents failed to improve survival, recently approved epidermal growth factor receptor (EGFR) inhibitors (in EGFR-mutated NSCLC) and immune checkpoint inhibitors have shown delays in disease recurrence or progression and unprecedented survival gains compared to previous standards of care. Additional data is now emerging supporting the benefit of treatment strategies based on alternation-matched targeting (anaplastic lymphoma kinase [ALK] inhibition in ALK-altered disease) and immune checkpoint inhibition in stage I-III NSCLC. Similar to previous developments in the treatment of early and locally advanced NSCLC, it is expected that statistically significant and clinically meaningful trial-level benefits will translate into real-world benefits, including improvements in cure measures. Parallel advances in molecular testing (e.g., circulating tumor DNA analyses) are also allowing for a deeper and more comprehensive characterization of disease status and treatment response. Given the impact that curative-intent treatments have on survival, it is critical that various stakeholders, including clinicians and patients, are aware of new opportunities to pursue cure in stage I-III NSCLC.
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Affiliation(s)
- Barbara Melosky
- BCCA Vancouver Centre, University of British Columbia, Vancouver, British Columbia, Canada
| | - Mark D Vincent
- London Regional Cancer Centre, University of Western Ontario, London, Ontario, Canada
| | - Anna L McGuire
- Vancouver Coastal Health Research Institute, University of British Colombia, Vancouver, British Columbia, Canada
| | - Anthony M Brade
- Trillium Health Partners, University of Toronto, Mississauga, Ontario, Canada
| | - Quincy Chu
- Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Parneet Cheema
- William Osler Health System, University of Toronto, Brampton, Ontario, Canada
| | | | - Jonathan D Spicer
- McGill University Health Centre, McGill University, Montreal, Quebec, Canada
| | - Stephanie Snow
- QEII Health Sciences Centre, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Rosalyn A Juergens
- Juravinski Cancer Centre, McMaster University, Hamilton, Ontario, Canada
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26
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Roelofsz D, Rampon G. Lung Cancer in Missouri. MISSOURI MEDICINE 2024; 121:368-372. [PMID: 39421481 PMCID: PMC11482853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Academic Contribution Register] [Indexed: 10/19/2024]
Abstract
Lung Cancer remains one of the leading causes of cancer related diagnoses and deaths in Missouri and across the United States. It is a major source of morbidity, mortality, and economic impact in Missouri. Over the past several years, major insights to the underlying risk factors of lung cancer have been discovered. Lung cancer screening has evolved and there are new updates to guideline recommendations on screenings. Here we outline the epidemiology and etiology of lung cancer, mitigation strategies for risk factor reduction, and review updates to lung cancer screening recommendations.
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Affiliation(s)
- David Roelofsz
- Assistant Professor of Medicine, Department of Pulmonary and Critical Care Medicine, University Health Hospital, University of Missouri-Kansas City, Kansas City, Missouri
| | - Garrett Rampon
- Pulmonary and Critical Care Fellow, Department of Pulmonary and Critical Care Medicine, University Health Hospital, University of Missouri-Kansas City, Kansas City, Missouri
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27
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Paudel KR, Singh M, De Rubis G, Kumbhar P, Mehndiratta S, Kokkinis S, El-Sherkawi T, Gupta G, Singh SK, Malik MZ, Mohammed Y, Oliver BG, Disouza J, Patravale V, Hansbro PM, Dua K. Computational and biological approaches in repurposing ribavirin for lung cancer treatment: Unveiling antitumorigenic strategies. Life Sci 2024; 352:122859. [PMID: 38925223 DOI: 10.1016/j.lfs.2024.122859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/07/2024] [Revised: 03/11/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024]
Abstract
Lung cancer is among leading causes of death worldwide. The five-year survival rate of this disease is extremely low (17.8 %), mainly due to difficult early diagnosis and to the limited efficacy of currently available chemotherapeutics. This underlines the necessity to develop innovative therapies for lung cancer. In this context, drug repurposing represents a viable approach, as it reduces the turnaround time of drug development removing costs associated to safety testing of new molecular entities. Ribavirin, an antiviral molecule used to treat hepatitis C virus infections, is particularly promising as repurposed drug for cancer treatment, having shown therapeutic activity against glioblastoma, acute myeloid leukemia, and nasopharyngeal carcinoma. In the present study, we thoroughly investigated the in vitro anticancer activity of ribavirin against A549 human lung adenocarcinoma cells. From a functional standpoint, ribavirin significantly inhibits cancer hallmarks such as cell proliferation, migration, and colony formation. Mechanistically, ribavirin downregulates the expression of numerous proteins and genes regulating cell migration, proliferation, apoptosis, and cancer angiogenesis. The anticancer potential of ribavirin was further investigated in silico through gene ontology pathway enrichment and protein-protein interaction networks, identifying five putative molecular interactors of ribavirin (Erb-B2 Receptor Tyrosine Kinase 4 (Erb-B4); KRAS; Intercellular Adhesion Molecule 1 (ICAM-1); amphiregulin (AREG); and neuregulin-1 (NRG1)). These interactions were characterized via molecular docking and molecular dynamic simulations. The results of this study highlight the potential of ribavirin as a repurposed chemotherapy against lung cancer, warranting further studies to ascertain the in vivo anticancer activity of this molecule.
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Affiliation(s)
- Keshav Raj Paudel
- Centre of Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW 2007, Australia
| | - Manisha Singh
- Department of Biotechnology, Jaypee Institute of Information Technology (JIIT), Noida, Uttar Pradesh, India; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2007, Australia; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Gabriele De Rubis
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2007, Australia; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Popat Kumbhar
- Department of Pharmaceutics, Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur, Maharashtra 416113, India
| | - Samir Mehndiratta
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2007, Australia; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Sofia Kokkinis
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2007, Australia; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Tammam El-Sherkawi
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2007, Australia; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India; Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Sachin Kumar Singh
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia; School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi GT Road, Phagwara 144411, Punjab, India
| | - Md Zubbair Malik
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman, Kuwait city 15462, Kuwait
| | - Yousuf Mohammed
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, Australia
| | - Brian G Oliver
- Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia; School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - John Disouza
- Department of Pharmaceutics, Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur, Maharashtra 416113, India
| | - Vandana Patravale
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai 400019, Maharashtra, India
| | - Philip Michael Hansbro
- Centre of Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW 2007, Australia.
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2007, Australia; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia.
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28
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Tamiya A, Osuga M, Harada D, Isa SI, Taniguchi Y, Nakamura K, Mizumori Y, Shinohara T, Yanai H, Nakatomi K, Oki M, Mori M, Kuwako T, Yamazaki K, Tamura A, Ando M, Koh Y. Mechanisms of resistance and correlation between pre-treatment co-alterations and p-prognosis to osimertinib in chemo-naïve advanced non-small cell lung cancer. Lung Cancer 2024; 195:107917. [PMID: 39116552 DOI: 10.1016/j.lungcan.2024.107917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/26/2024] [Revised: 07/22/2024] [Accepted: 08/01/2024] [Indexed: 08/10/2024]
Abstract
BACKGROUND Several patients treated with osimertinib experience progressive disease. The aim was to clarify the mechanisms underlying resistance to osimertinib. METHODS ELUCIDATOR: A multi-centre, prospective, observational study involved chemotherapy-naive patients with advanced non-small cell lung cancer receiving osimertinib. Mutations in cancer-associated genes, detected via ultrasensitive next-generation sequencing of circulating tumour deoxyribonucleic acid samples, were collected at baseline and after progressive disease detection. These paired plasma samples were compared. RESULTS Of 188 patients enrolled (May 2019-January 2021), 178 (119 females [67 %]) median age 74 years, were included. Patients, n = 95 (53 %) had epidermal growth factor receptor exon 19 deletion mutations. Among 115 patients with progressive disease, circulating tumour deoxyribonucleic acid levels of 85 patients were analysed. MET amplification (n = 4), TP53 mutations (n = 4), PIK3CA mutations (n = 3), BRINP3 mutation (n = 2), BRAF mutation (n = 2), APC mutation (n = 1), RET mutation (n = 1) and epidermal growth factor receptor (EGFR) resistance mutation, and C797S (n = 1) were detected. Patients with baseline TP53 mutations, with MET or EGFR amplification had shorter progression-free (PFS) and overall survival. Patients with PIK3CA mutations tended to shorter PFS. CONCLUSION MET amplification and PIK3CA mutation mechanisms underly resistance to osimertinib in patients. Patients with coexisting mutations or amplifications at baseline had shorter PFS and overall survival.
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Affiliation(s)
- Akihiro Tamiya
- Department of Internal Medicine, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Osaka, Japan
| | - Mitsuo Osuga
- Center for Biomedical Sciences, Wakayama Medical University, Wakayama, Japan
| | - Daijiro Harada
- Department of Thoracic Oncology and Medicine, National Hospital Organization Shikoku Cancer Center, Matsuyama, Ehime, Japan
| | - Shun-Ichi Isa
- Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Osaka, Japan
| | - Yoshihiko Taniguchi
- Department of Internal Medicine, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Osaka, Japan
| | - Keiichi Nakamura
- Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, Asahikawa, Hokkaido, Japan
| | - Yasuyuki Mizumori
- Department of Respiratory Medicine, National Hospital Organization Himeji Medical Center, Himeji, Hyogo, Japan
| | - Tsutomu Shinohara
- Department of Respiratory Medicine, National Hospital Organization Kochi Hospital, Kochi, Japan
| | - Hidetoshi Yanai
- Department of Respiratory Medicine, National Hospital Organization Mito Medical Center, Ibaraki, Japan
| | - Katsumi Nakatomi
- Department of Respiratory Medicine, National Hospital Organization Ureshino Medical Center, Ureshino, Saga, Japan
| | - Masahide Oki
- Department of Respiratory Medicine, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi, Japan
| | - Masahide Mori
- Department of Thoracic Oncology, National Hospital Organization Osaka Toneyama Medical Center, Toyonaka, Osaka, Japan
| | - Tomohito Kuwako
- Department of Respiratory Medicine, National Hospital Organization Shibukawa Medical Center, Shibukawa, Gunma, Japan
| | - Koji Yamazaki
- Department of Thoracic Surgery, National Hospital Organization Kyushu Medical Center, Fukuoka, Kyushu, Japan
| | - Atsuhisa Tamura
- Department of Respiratory Medicine, National Hospital Organization Tokyo National Hospital, Tokyo, Japan
| | - Masahiko Ando
- Department of Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
| | - Yasuhiro Koh
- Center for Biomedical Sciences, Wakayama Medical University, Wakayama, Japan; Internal Medicine III, Wakayama Medical University, Wakayama, Japan.
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Calvo V, Niazmand E, Carcereny E, Rodriguez-Abreu D, Cobo M, López-Castro R, Guirado M, Camps C, Laura Ortega A, Bernabé R, Massutí B, Garcia-Campelo R, Del Barco E, Luis González-Larriba J, Bosch-Barrera J, Martínez M, Torrente M, Vidal ME, Provencio M. Family history of cancer and lung cancer: Utility of big data and artificial intelligence for exploring the role of genetic risk. Lung Cancer 2024; 195:107920. [PMID: 39137596 DOI: 10.1016/j.lungcan.2024.107920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/06/2024] [Revised: 08/02/2024] [Accepted: 08/05/2024] [Indexed: 08/15/2024]
Abstract
OBJECTIVES Lung Cancer (LC) is a multifactorial disease for which the role of genetic susceptibility has become increasingly relevant. Our aim was to use artificial intelligence (AI) to analyze differences between patients with LC based on family history of cancer (FHC). MATERIALS AND METHODS From August 2016 to June 2020 clinical information was obtained from Thoracic Tumors Registry (TTR), a nationwide database sponsored by the Spanish Lung Cancer Group. In addition to descriptive statistical analysis, an AI-assisted analysis was performed. The German Technical Information Library supported the merging of data from the electronic medical records and database of the TTR. The results of the AI-assisted analysis were reported using Knowledge Graph, Unified Schema and descriptive and predictive analyses. RESULTS Analyses were performed in two phases: first, conventional statistical analysis including 11,684 patients of those 5,806 had FHC. Median overall survival (OS) for the global population was 23 months (CI 95 %: 21.39-24.61) in patients with FHC versus 21 months (CI 95 %: 19.53-22.48) in patients without FHC (NFHC), p < 0.001. The second AI-assisted analysis included 5,788 patients of those 939 had FHC. 58.48 % of women with FHC had LC. 9.53 % of patients had an EGFR or HER2 mutation or ALK translocation and at least one relative with cancer. A family history of LC was associated with an increased risk of smoking-related LC. Non-smokers with a family history of LC were more likely to have an EGFR mutation in NSCLC. In Bayesian network analysis, 55 % of patients with a family history of LC and never-smokers had an EGFR mutation. CONCLUSION In our population, the incidence of LC in patients with a FHC is higher in women and younger patients. FHC is a risk factor and predictor of LC development, especially in people ≤ 50 years. These results were confirmed by conventional statistics and AI-assisted analysis.
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Affiliation(s)
- Virginia Calvo
- Medical Oncology Department, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
| | - Emetis Niazmand
- TIB Leibniz Information Centre for Science and Technology, Hannover, Germany; L3S Research, Hannover, Germany
| | - Enric Carcereny
- Medical Oncology Department, Catalan Institute of Oncology (ICO)-Badalona Badalona-Applied Research Group in Oncology (B-ARGO), Barcelona, Spain
| | - Delvys Rodriguez-Abreu
- Medical Oncology Department, Hospital Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - Manuel Cobo
- BIONAND, Unidad de Gestión Clínica Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen de la Victoria, IBIMA, Málaga. Spain
| | - Rafael López-Castro
- Medical Oncology Department, Hospital Clínico Universitario de Valladolid, Valladolid, Spain
| | - María Guirado
- Medical Oncology Department, Hospital General Universitario de Elche, Elche, Spain
| | - Carlos Camps
- Medical Oncology Departametnt, Hospital General Universitario de Valencia, Valencia, Spain
| | - Ana Laura Ortega
- Medical Oncology Department, Hospital Universitario de Jaen, Jaen, Spain
| | - Reyes Bernabé
- Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Bartomeu Massutí
- Medical Oncology Department, Hospital General Universitario Doctor Balmis, Alicante, Spain
| | | | - Edel Del Barco
- Medical Oncology Department, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain
| | | | - Joaquim Bosch-Barrera
- Medical Oncology Department, Catalan Institute of Oncology, University Hospital Dr. Josep Trueta, Precision Oncology Group (OncoGIR-Pro), Girona BiomedicaI Research Institute (IDIBGI-CERCA), Girona, Spain
| | - Marta Martínez
- Medical Oncology Department, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - María Torrente
- Medical Oncology Department, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - María-Esther Vidal
- TIB Leibniz Information Centre for Science and Technology, Hannover, Germany; L3S Research, Hannover, Germany
| | - Mariano Provencio
- Medical Oncology Department, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
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Ma Y, Wang Y, He L, Du J, Li L, Bie Z, Li Y, Xu X, Zhou W, Wu X, Yang L, Di J, Li C, Li X, Liu D, Wang Z. Preservation of cfRNA in cytological supernatants for cfDNA & cfRNA double detection in non-small cell lung cancer patients. Cancer Med 2024; 13:e70197. [PMID: 39233657 PMCID: PMC11375324 DOI: 10.1002/cam4.70197] [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] [Academic Contribution Register] [Received: 02/08/2024] [Revised: 08/23/2024] [Accepted: 08/26/2024] [Indexed: 09/06/2024] Open
Abstract
BACKGROUD Supernatants from various cytological samples, including body cavity effusion, sputum, bronchoalveolar lavage fluid (BALF), and needle aspiration, have been validated for detecting genetic alterations using cell-free DNA (cfDNA) in patients with non-small cell lung cancer (NSCLC). However, the sensitivity of fusion variations detection remains challenging. The protection of cell-free RNA (cfRNA) is critical for resolving the issue. METHODS A protective solution (PS) was applied for preserving cfRNA in cytological supernatant (CS), and the quality of protected cfRNA was assessed by cycle threshold (CT) values from reverse transcription quantitative polymerase chain reaction (RT-qPCR). Furthermore, we collected an additional set of malignant cytological and matched tumor samples from 84 NSCLC patients, cfDNA & cfRNA extraction and double detection for driver gene mutations was validated using the multi-gene mutations detection by RT-qPCR. RESULTS Under the optimal protection system, 91.0% (101/111) of cfRNA were protected effectively. Among the 84 NSCLC patient samples, seven cytological samples failed the tests. In comparison with tumor samples, the overall sensitivity and specificity of detecting driver genes of supernatant cfDNA and cfRNA were 93.8% (74/77) and 100% (77/77), respectively. Notably, when focusing exclusively on patients with fusion gene changes, both sensitivity and specificity reached 100% (11/11) for EML4-ALK, ROS1, RET fusions, and MET ex14 skipping. CONCLUSION These findings suggest that cfDNA & cfRNA extraction and double detection strategy recommended in this study improve the accuracy of driver genes mutations test, especially for RNA-based assay.
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Affiliation(s)
- Yidan Ma
- Department of Pathology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Yifei Wang
- Department of Pathology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Lei He
- Department of Pathology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Jun Du
- Department of Pathology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Lin Li
- Department of Oncology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Zhixin Bie
- Department of Minimally Invasive Tumor Therapies Center, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Yuanming Li
- Department of Minimally Invasive Tumor Therapies Center, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Xiaomao Xu
- Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Wei Zhou
- Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Xiaonan Wu
- Department of Oncology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Li Yang
- Department of Pathology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Jing Di
- Department of Pathology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Chenyang Li
- Department of Pathology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Xiaoguang Li
- Department of Minimally Invasive Tumor Therapies Center, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Dongge Liu
- Department of Pathology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Zheng Wang
- Department of Pathology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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Mavroeidi IA, Romanowicz A, Haake T, Wienker J, Metzenmacher M, Darwiche K, Oezkan F, Bölükbas S, Stuschke M, Umutlu L, Opitz M, Nader M, Hamacher R, Siveke J, Winantea J, Fendler WP, Wiesweg M, Eberhardt WEE, Herrmann K, Theegarten D, Schuler M, Hautzel H, Kersting D. Theranostics with somatostatin receptor antagonists in SCLC: Correlation of 68Ga-SSO120 PET with immunohistochemistry and survival. Theranostics 2024; 14:5400-5412. [PMID: 39310095 PMCID: PMC11413793 DOI: 10.7150/thno.98819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/23/2024] [Accepted: 07/16/2024] [Indexed: 09/25/2024] Open
Abstract
Rationale: Positron Emission Tomography (PET) using the somatostatin receptor 2 (SSTR2)-antagonist satoreotide trizoxetan (68Ga-SSO120) is a novel, promising imaging modality for small-cell lung cancer (SCLC), which holds potential for theranostic applications. This study aims to correlate uptake in PET imaging with SSTR2 expression in immunohistochemistry (IHC) and to assess the prognostic value of 68Ga-SSO120 PET at initial staging of patients with SCLC. Methods: We analyzed patients who underwent 68Ga-SSO120 PET/CT during initial diagnostic workup of SCLC as part of institutional standard-of-care. SSTR2 expression in IHC was evaluated on a 4-level scale and correlated with normalized standardized uptake values and tumor-to-liver ratios (SUVmax and TLRpeak) in 68Ga-SSO120 PET on a lesion level. Highest lesion SUVmax/TLRpeak per patient, SSTR2 score in IHC, M status according to TNM classification, and other parameters were analyzed for association with overall survival (OS) and time to treatment failure (TTF) by univariate, multivariate (cut-off values were identified on data for best separation), and stratified Cox regression. Results: We included 54 patients (24 men/30 women, median age 65 years, 21 M0/33 M1 according to TNM classification). In 43 patients with available surplus tumor tissue samples, hottest lesion SUVmax/TLRpeak showed a significant correlation with the level of SSTR2-expression by tumor cells in IHC (Spearman's rho 0.86/0.81, both p < 0.001; ANOVA p < 0.001). High SSTR2 expression in IHC, 68Ga-SSO120 SUVmax and TLRpeak of the hottest lesion per patient, whole-body TLRmean, MTV, TLG, M status, and serum LDH showed a significant association with inferior TTF/OS in univariate analysis. In separate multivariate Cox regression (including sex, age, M stage, and LDH) higher hottest-lesion TLRpeak showed a significant association with shorter OS (HR = 0.26, 95%CI: 0.08-0.84, p = 0.02) and SSTR2 expression in IHC with significantly shorter TTF (HR = 0.24, 95%CI: 0.08-0.71, p = 0.001) and OS (HR = 0.22, 95%CI: 0.06-0.84, p = 0.03). In total, 12 patients (22.2%) showed low (< 1), 21 (38.9%) intermediate (≥ 1 but < 2), 14 (25.9%) high (≥ 2 but < 5), and 7 (13.0%) very high (≥ 5) whole-body mean TLRmean. Conclusion: In patients with SCLC, SSTR2 expression assessed by 68Ga-SSO120 PET and by IHC were closely correlated and associated with shorter survival. More than 75% of patients showed higher whole-body 68Ga-SSO120 tumor uptake than liver uptake and almost 40% high or very high uptake, possibly paving the way towards theranostic applications.
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Affiliation(s)
- Ilektra Antonia Mavroeidi
- Department of Medical Oncology, West German Cancer Center (WTZ), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Anna Romanowicz
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Department of Nuclear Medicine, West German Cancer Center (WTZ), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Tristan Haake
- Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Johannes Wienker
- Department of Pulmonary Medicine, Section of Interventional Pulmonology, West German Cancer Center (WTZ), University Medicine Essen - Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
- Division of Thoracic Oncology, West German Lung Center, University Medicine Essen - Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
| | - Martin Metzenmacher
- Department of Medical Oncology, West German Cancer Center (WTZ), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Division of Thoracic Oncology, West German Lung Center, University Medicine Essen - Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
| | - Kaid Darwiche
- Department of Pulmonary Medicine, Section of Interventional Pulmonology, West German Cancer Center (WTZ), University Medicine Essen - Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
- Division of Thoracic Oncology, West German Lung Center, University Medicine Essen - Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
| | - Filiz Oezkan
- Department of Pulmonary Medicine, Section of Interventional Pulmonology, West German Cancer Center (WTZ), University Medicine Essen - Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
- Division of Thoracic Oncology, West German Lung Center, University Medicine Essen - Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
| | - Servet Bölükbas
- National Center for Tumor Diseases (NCT) West, Essen, Germany
- Department of Thoracic Surgery and Thoracic Endoscopy, West German Cancer Center (WTZ), University Medicine Essen - Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
| | - Martin Stuschke
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- National Center for Tumor Diseases (NCT) West, Essen, Germany
- Department of Radiotherapy, West German Cancer Center (WTZ), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Lale Umutlu
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Institute of Diagnostic, Interventional Radiology and Neuroradiology, West German Cancer Center (WTZ), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Marcel Opitz
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Institute of Diagnostic, Interventional Radiology and Neuroradiology, West German Cancer Center (WTZ), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Michael Nader
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Department of Nuclear Medicine, West German Cancer Center (WTZ), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Rainer Hamacher
- Department of Medical Oncology, West German Cancer Center (WTZ), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
| | - Jens Siveke
- Department of Medical Oncology, West German Cancer Center (WTZ), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jane Winantea
- Department of Pulmonary Medicine, Section of Interventional Pulmonology, West German Cancer Center (WTZ), University Medicine Essen - Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
- Division of Thoracic Oncology, West German Lung Center, University Medicine Essen - Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
| | - Wolfgang P. Fendler
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Department of Nuclear Medicine, West German Cancer Center (WTZ), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Marcel Wiesweg
- Department of Medical Oncology, West German Cancer Center (WTZ), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Division of Thoracic Oncology, West German Lung Center, University Medicine Essen - Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
| | - Wilfried E. E. Eberhardt
- Department of Medical Oncology, West German Cancer Center (WTZ), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Division of Thoracic Oncology, West German Lung Center, University Medicine Essen - Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
| | - Ken Herrmann
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Department of Nuclear Medicine, West German Cancer Center (WTZ), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- National Center for Tumor Diseases (NCT) West, Essen, Germany
| | - Dirk Theegarten
- Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Martin Schuler
- Department of Medical Oncology, West German Cancer Center (WTZ), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Division of Thoracic Oncology, West German Lung Center, University Medicine Essen - Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
- National Center for Tumor Diseases (NCT) West, Essen, Germany
| | - Hubertus Hautzel
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Department of Nuclear Medicine, West German Cancer Center (WTZ), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - David Kersting
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
- Department of Nuclear Medicine, West German Cancer Center (WTZ), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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Huang X, Zhu D, Cao Y, Li W, Lai J, Ren Y. Protocol for a systematic review and meta-analysis of recurrence and metastasis of different surgical techniques for non-small cell lung cancer. BMJ Open 2024; 14:e086503. [PMID: 39179278 PMCID: PMC11344504 DOI: 10.1136/bmjopen-2024-086503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/16/2024] [Accepted: 08/02/2024] [Indexed: 08/26/2024] Open
Abstract
INTRODUCTION Lung cancer remains the primary cause of cancer-related deaths on a global scale. Surgery is the main therapeutic option for non-small cell lung cancer (NSCLC). However, the optimal surgical approach for lymph node assessment in NSCLC resection remains controversial, and it is still uncertain whether lymph node dissection (LND) is more effective in reducing recurrence and metastasis rates in NSCLC compared with lymph node sampling (LNS). Therefore, we will conduct a meta-analysis to evaluate the recurrence and metastasis of LND versus LNS in patients with NSCLC. METHODS AND ANALYSIS This systematic review and meta-analysis will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analysis: The PRISMA Statement. According to the predefined inclusion criteria, we will conduct a comprehensive search for randomised controlled trials and non-randomised studies examining the recurrence and metastasis of LND compared with LNS in patients with NSCLC. A literature search from inception in PubMed, EMBASE, the Cochrane Library, CNKI, Wanfang, SINOMED, VIP and Web of Science will be done. There will be no limitations on language, and the search will be undertaken on 30 August 2024, with regular search for new studies. Additionally, relevant literature references will be retrieved and hand-searching of pertinent journals will be conducted. The main outcomes include overall recurrence rate, local recurrence rate and distant metastasis rate. The supplementary outcomes encompass the rates of regional recurrence and lymph node metastasis. Two independent reviewers will perform screening, data extraction and quality assessment. Our reviewers will perform subgroup analysis, sensitivity analysis and publication bias analysis to evaluate the heterogeneity and robustness. Review Manager 5.4 will be applied in analysing and synthesising. The Grading of Recommendations Assessment, Development and Evaluation will be used to assess the quality of evidence for the whole study. ETHICS AND DISSEMINATION Ethical approval is dispensable for this study since no private information of the participants will be involved. The findings of the present study will be disseminated through a peer-reviewed journal or conference presentation. STUDY REGISTRATION The protocol of the systematic review has been registered on Open Science Framework, with a registration doi: https://doi.org/10.17605/OSF.IO/S2FT5.
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Affiliation(s)
| | - Donghong Zhu
- Department of Respiratory, The Ninth Hospital of Nanchang, Nanchang, China
| | - Yaoxing Cao
- Jiangxi College of Traditional Chinese Medicine, Fuzhou, China
| | - Weijuan Li
- Fuzhou Medical College, Nanchang University, Fuzhou, China
| | - Jinxing Lai
- Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, China
| | - Yuxi Ren
- Jiangxi University of Chinese Medicine, Nanchang, China
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Amilo D, Izuchukwu C, Sadri K, Yao HR, Hincal E, Shehu Y. A fractional-order model for optimizing combination therapy in heterogeneous lung cancer: integrating immunotherapy and targeted therapy to minimize side effects. Sci Rep 2024; 14:18484. [PMID: 39122747 PMCID: PMC11395867 DOI: 10.1038/s41598-024-66531-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] [Academic Contribution Register] [Received: 03/20/2024] [Accepted: 07/02/2024] [Indexed: 08/12/2024] Open
Abstract
This research presents a novel approach to address the complexities of heterogeneous lung cancer dynamics through the development of a Fractional-Order Model. Focusing on the optimization of combination therapy, the model integrates immunotherapy and targeted therapy with the specific aim of minimizing side effects. Notably, our approach incorporates a clever fusion of Proportional-Integral-Derivative (PID) feedback controls alongside the optimization process. Unlike previous studies, our model incorporates essential equations accounting for the interaction between regular and mutated cancer cells, delineates the dynamics between immune cells and mutated cancer cells, enhances immune cell cytotoxic activity, and elucidates the influence of genetic mutations on the spread of cancer cells. This refined model offers a comprehensive understanding of lung cancer progression, providing a valuable tool for the development of personalized and effective treatment strategies. the findings underscore the potential of the optimized treatment strategy in achieving key therapeutic goals, including primary tumor control, metastasis limitation, immune response enhancement, and controlled genetic mutations. The dynamic and adaptive nature of the treatment approach, coupled with economic considerations and memory effects, positions the research at the forefront of advancing precision and personalized cancer therapeutics.
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Affiliation(s)
- David Amilo
- Mathematics Research Center, Near East University TRNC, Mersin 10, 99138, Nicosia, Turkey
- Department of Mathematics, Near East University TRNC, Mersin 10, 99138, Nicosia, Turkey
- Faculty of Art and Science, University of Kyrenia, Kyrenia, TRNC, Mersin 10, Kyrenia, Turkey
| | - Chinedu Izuchukwu
- School of Mathematics, University of the Witwatersrand, Private Bag 3, Johannesburg, 2050, South Africa.
| | - Khadijeh Sadri
- Mathematics Research Center, Near East University TRNC, Mersin 10, 99138, Nicosia, Turkey
- Department of Mathematics, Near East University TRNC, Mersin 10, 99138, Nicosia, Turkey
- Faculty of Art and Science, University of Kyrenia, Kyrenia, TRNC, Mersin 10, Kyrenia, Turkey
| | - Hao-Ren Yao
- National Institutes of Health, Bethesda, MD, USA
| | - Evren Hincal
- Mathematics Research Center, Near East University TRNC, Mersin 10, 99138, Nicosia, Turkey
- Department of Mathematics, Near East University TRNC, Mersin 10, 99138, Nicosia, Turkey
- Faculty of Art and Science, University of Kyrenia, Kyrenia, TRNC, Mersin 10, Kyrenia, Turkey
| | - Yekini Shehu
- School of Mathematical Sciences, Zhejiang Normal University, Jinhua, 321004, People's Republic of China
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Lee SY, Lee E, Ryu JO, Kim K, Hwang Y, Ku B, Moon SW, Moon MH, Kim KS, Hyun K, Lim JU, Park CK, Kim SW, Yeo CD, Lee DW, Kim SJ. Histo-pillar strip for optimal histogel block construction and biomarker analysis in 3D-lung cancer patient-derived organoids. Biofabrication 2024; 16:045017. [PMID: 39074508 DOI: 10.1088/1758-5090/ad68a7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/05/2024] [Accepted: 07/29/2024] [Indexed: 07/31/2024]
Abstract
This study proposed an optimized histogel construction method for histological analysis by applying lung cancer patient-derived organoids (PDOs) to the developed histo-pillar strip. Previously, there is the cultured PDOs damage problem during the histogel construction due to forced detachment of the Matrigel spots from the 96-well plate bottom. To address this issue, we cultured PDO on the proposed Histo-pillar strips and then immersed them in 4% paraformaldehyde fixation solution to self-isolate PDO without damage. The 4μl patient-derived cell (PDC)/Matrigel mixtures were dispensed on the surface of a U-shaped histo-pillar strip, and the PDCs were aggregated by gravity and cultured into PDOs. Cultured PDOs were self-detached by simply immersing them in a paraformaldehyde fixing solution without physical processing, showing about two times higher cell recovery rate than conventional method. In addition, we proposed a method for embedding PDOs under conditions where the histogel temperature was maintained such that the histogel did not harden, thereby improving the problem of damaging the histogel block in the conventional sandwich histogel construction method. We performed histological and genotyping analyses using tumor tissues and PDOs from two patients with lung adenocarcinoma. Therefore, the PDO culture and improved histogel block construction method using the histo-pillar strip proposed in this study can be employed as useful tools for the histological analysis of a limited number of PDCs.
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Affiliation(s)
- Sang-Yun Lee
- Department of Biomedical Engineering, Gachon University, Seongnam 13120, Republic of Korea
- Central R & D Center, Medical & Bio Decision (MBD) Co., Ltd, Suwon 16229, Republic of Korea
| | - Eunyoung Lee
- Division of Pulmonology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Postech-Catholic Biomedical Engineering Institute, Songeui Multiplex Hall, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ji-O Ryu
- Department of Biomedical Engineering, Gachon University, Seongnam 13120, Republic of Korea
| | - Kyuhwan Kim
- Division of Pulmonology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Postech-Catholic Biomedical Engineering Institute, Songeui Multiplex Hall, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yongki Hwang
- Division of Pulmonology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Postech-Catholic Biomedical Engineering Institute, Songeui Multiplex Hall, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Bosung Ku
- Central R & D Center, Medical & Bio Decision (MBD) Co., Ltd, Suwon 16229, Republic of Korea
| | - Seok Whan Moon
- Department of Thoracic and Cardiovascular Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Mi Hyoung Moon
- Department of Thoracic and Cardiovascular Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Kyung Soo Kim
- Department of Thoracic and Cardiovascular Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Kwanyong Hyun
- Department of Thoracic and Cardiovascular Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jeong Uk Lim
- Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Postech-Catholic Biomedical Engineering Institute, Songeui Multiplex Hall, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Chan Kwon Park
- Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Postech-Catholic Biomedical Engineering Institute, Songeui Multiplex Hall, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung Won Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Chang Dong Yeo
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Postech-Catholic Biomedical Engineering Institute, Songeui Multiplex Hall, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Dong Woo Lee
- Department of Biomedical Engineering, Gachon University, Seongnam 13120, Republic of Korea
| | - Seung Joon Kim
- Division of Pulmonology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Postech-Catholic Biomedical Engineering Institute, Songeui Multiplex Hall, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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De Rubis G, Paudel KR, Vishwas S, Kokkinis S, Chellappan DK, Gupta G, MacLoughlin R, Gulati M, Singh SK, Dua K. Fecal microbiome extract downregulates the expression of key proteins at the interface between airway remodelling and lung cancer pathogenesis in vitro. Pathol Res Pract 2024; 260:155387. [PMID: 38870713 DOI: 10.1016/j.prp.2024.155387] [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] [Academic Contribution Register] [Received: 04/10/2024] [Revised: 05/17/2024] [Accepted: 05/31/2024] [Indexed: 06/15/2024]
Abstract
Lung cancer (LC) is the leading cause of cancer-related mortality, and it is caused by many factors including cigarette smoking. Despite numerous treatment strategies for LC, its five-year survival is still poor (<20 %), attributable to treatment resistance and lack of early diagnosis and intervention. Importantly, LC incidence is higher in patients affected by chronic respiratory diseases (CRDs) such as asthma and chronic obstructive pulmonary disorder (COPD), and LC shares with other CRDs common pathophysiological features including chronic inflammation, oxidative stress, cellular senescence, and airway remodelling. Remodelling is a complex process resulting from the aberrant activation of tissue repair secondary to chronic inflammation, oxidative stress, and tissue damage observed in the airways of CRD patients, and it is characterized by irreversible airway structural and functional alterations, concomitantly with tissue fibrosis, epithelial-to-mesenchymal transition (EMT), excessive collagen deposition, and thickening of the basement membrane. Many processes involved in remodelling, particularly EMT, are also fundamental for LC pathogenesis, highlighting a potential connection between CRDs and LC. This provides rationale for the development of novel treatment strategies aimed at targeting components of the remodelling pathways. In this study, we tested the in vitro therapeutic activity of rat fecal microbiome extract (FME) on A549 human lung adenocarcinoma cells. We show that treatment with FME significantly downregulates the expression of six proteins whose function is at the forefront between airway remodelling and LC development: Snail, SPARC, MUC-1, Osteopontin, MMP-2, and HIF-1α. The results of this study, if confirmed by further investigations, provide proof-of-concept for a novel approach in the treatment of LC, focused on tackling the airway remodelling mechanisms underlying the increased susceptibility to develop LC observed in CRD patients.
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Affiliation(s)
- Gabriele De Rubis
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2007, Australia; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia
| | - Keshav Raj Paudel
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney 2007, Australia; Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Sukriti Vishwas
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Sofia Kokkinis
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2007, Australia; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Gaurav Gupta
- Chitkara College of Pharmacy, Chitkara University, Rajpura, India; Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Ronan MacLoughlin
- Aerogen, IDA Business Park, Dangan, Galway H91 HE94, Ireland; School of Pharmacy & Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland; School of Pharmacy & Pharmaceutical Sciences, Trinity College, Dublin D02 PN40, Ireland
| | - Monica Gulati
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia; School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Sachin Kumar Singh
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia; School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India; School of Medical and Life Sciences, Sunway University, 47500 Sunway City, Malaysia.
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2007, Australia; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia; Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India.
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Pîslaru AI, Albișteanu SM, Ilie AC, Ștefaniu R, Mârza A, Moscaliuc Ș, Nicoară M, Turcu AM, Grigoraș G, Alexa ID. Lung Cancer: New Directions in Senior Patients Assessment. Geriatrics (Basel) 2024; 9:101. [PMID: 39195131 DOI: 10.3390/geriatrics9040101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/04/2024] [Revised: 07/10/2024] [Accepted: 07/30/2024] [Indexed: 08/29/2024] Open
Abstract
Age is but one significant prognostic factor in lung cancer, influencing survival, treatment response, and outcomes. This narrative review synthesizes findings from searches of 11 leading databases of research studies, systematic reviews, book chapters, and clinical trial reports on lung cancer in senior patients, with a focus on geriatric assessment as well as biomarkers. Key prognostic factors for lung cancer in seniors include biological age, functional capability, physical and psychological comorbidities, frailty, nutrition, status, and biomarkers like DNA methylation age. We identified the most valuable assessments that balance efficacy with quality of life. Optimizing care and improving outcomes with senior lung cancer patients benefits from a tailored therapeutic approach incorporating a complex geriatric assessment. A multidisciplinary collaboration between geriatricians, oncologists, and pulmonologists is crucial.
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Affiliation(s)
- Anca Iuliana Pîslaru
- Department of Medical Specialties II, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Sabinne-Marie Albișteanu
- Department of Medical Specialties II, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Adina Carmen Ilie
- Department of Medical Specialties II, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Ramona Ștefaniu
- Department of Medical Specialties II, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Aurelia Mârza
- Department of Medical Specialties II, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Ștefan Moscaliuc
- Department of Oncology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Mălina Nicoară
- Department of Oncology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Ana-Maria Turcu
- Department of Medical Specialties II, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Gabriela Grigoraș
- Department of Medical Specialties II, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Ioana Dana Alexa
- Department of Medical Specialties II, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
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Huang A, Cheng J, Zhan Y, Zhou F, Xuan Y, Wang Y, Chen Q, Wang H, Xu X, Luo S, Cheng M. Hedgehog ligand and receptor cooperatively regulate EGFR stability and activity in non-small cell lung cancer. Cell Oncol (Dordr) 2024; 47:1405-1423. [PMID: 38568419 DOI: 10.1007/s13402-024-00938-6] [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] [Academic Contribution Register] [Accepted: 03/13/2024] [Indexed: 09/25/2024] Open
Abstract
PURPOSE The hyperactivation of epidermal growth factor receptor (EGFR) plays a crucial role in non-small cell lung cancer (NSCLC). Hedgehog (Hh) signaling has been implicated in the tumorigenesis and progression of various cancers, however, its function in NSCLC cells remains controversial. Herein, we present a novel finding that challenges the current understanding of Hh signaling in tumor growth. METHODS Expression of Hh ligands and receptor were assessed using TCGA datasets, immunoblotting and immunohistochemical. Biological function of Hh ligands and receptor in NSCLC were tested using colony formation, cell count kit-8 (CCK-8) and xenograft assays. Biochemical effect of Hh ligands and receptor on regulating EGFR stability and activity were checked via immunoblotting. RESULTS Expression of Hh ligands and receptor was suppressed in NSCLC tissues, and the lower expression levels of these genes were associated with poor prognosis. Ptch1 binds to EGFR and facilitates its poly-ubiquitylation and degradation independent of downstream transcriptional signaling. Moreover, Hh ligands cooperate with Ptch1 to regulate the protein stability and activity of EGFR. This unique mechanism leads to a suppressive effect on NSCLC tumor growth. CONCLUSION Non-canonical Hh signaling pathway, involving cooperation between Hh ligands and their receptor Ptch1, facilitates the degradation of EGFR and attenuates its activity in NSCLC. These findings provide novel insights into the regulation of EGFR protein stability and activity, offer new diagnostic indicators for molecular typing of NSCLC and identify potential targets for targeted therapy of this challenging disease.
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Affiliation(s)
- Aidi Huang
- Jiangxi Clinical Research Center for Respiratory Diseases, Jiangxi Institute of Respiratory Disease, The Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China
- Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, Center for Experimental Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China
| | - Junyao Cheng
- Jiangxi Clinical Research Center for Respiratory Diseases, Jiangxi Institute of Respiratory Disease, The Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China
- Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, Center for Experimental Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China
| | - Yuan Zhan
- Institute of Molecular Pathology, Department of Pathology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China
| | - Feifei Zhou
- Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, Center for Experimental Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, Shandong, China
| | - Yanlu Xuan
- Jiangxi Clinical Research Center for Respiratory Diseases, Jiangxi Institute of Respiratory Disease, The Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China
- Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, Center for Experimental Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China
| | - Yiting Wang
- Department of Oncology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China
| | - Qingjie Chen
- Department of Nuclear Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China
| | - Hailong Wang
- Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, Center for Experimental Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China
| | - Xinping Xu
- Jiangxi Clinical Research Center for Respiratory Diseases, Jiangxi Institute of Respiratory Disease, The Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China
| | - Shiwen Luo
- Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, Center for Experimental Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China.
| | - Minzhang Cheng
- Jiangxi Clinical Research Center for Respiratory Diseases, Jiangxi Institute of Respiratory Disease, The Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China.
- Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, Center for Experimental Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China.
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Lee YF, Phua CZJ, Yuan J, Zhang B, Lee MY, Kannan S, Chiu YHJ, Koh CWQ, Yap CK, Lim EKH, Chen J, Lim Y, Lee JJH, Skanderup AJ, Wang Z, Zhai W, Tan NS, Verma CS, Tay Y, Tan DSW, Tam WL. PARP4 interacts with hnRNPM to regulate splicing during lung cancer progression. Genome Med 2024; 16:91. [PMID: 39034402 PMCID: PMC11265163 DOI: 10.1186/s13073-024-01328-1] [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] [Academic Contribution Register] [Received: 02/17/2023] [Accepted: 04/02/2024] [Indexed: 07/23/2024] Open
Abstract
BACKGROUND The identification of cancer driver genes from sequencing data has been crucial in deepening our understanding of tumor biology and expanding targeted therapy options. However, apart from the most commonly altered genes, the mechanisms underlying the contribution of other mutations to cancer acquisition remain understudied. Leveraging on our whole-exome sequencing of the largest Asian lung adenocarcinoma (LUAD) cohort (n = 302), we now functionally assess the mechanistic role of a novel driver, PARP4. METHODS In vitro and in vivo tumorigenicity assays were used to study the functional effects of PARP4 loss and mutation in multiple lung cancer cell lines. Interactomics analysis by quantitative mass spectrometry was conducted to identify PARP4's interaction partners. Transcriptomic data from cell lines and patient tumors were used to investigate splicing alterations. RESULTS PARP4 depletion or mutation (I1039T) promotes the tumorigenicity of KRAS- or EGFR-driven lung cancer cells. Disruption of the vault complex, with which PARP4 is commonly associated, did not alter tumorigenicity, indicating that PARP4's tumor suppressive activity is mediated independently. The splicing regulator hnRNPM is a potentially novel PARP4 interaction partner, the loss of which likewise promotes tumor formation. hnRNPM loss results in splicing perturbations, with a propensity for dysregulated intronic splicing that was similarly observed in PARP4 knockdown cells and in LUAD cohort patients with PARP4 copy number loss. CONCLUSIONS PARP4 is a novel modulator of lung adenocarcinoma, where its tumor suppressive activity is mediated not through the vault complex-unlike conventionally thought, but in association with its novel interaction partner hnRNPM, thus suggesting a role for splicing dysregulation in LUAD tumorigenesis.
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Affiliation(s)
- Yi Fei Lee
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore
| | - Cheryl Zi Jin Phua
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore
| | - Ju Yuan
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore
| | - Bin Zhang
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore
- Computational Bioscience Research Center, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
- Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - May Yin Lee
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore
| | - Srinivasaraghavan Kannan
- Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, Matrix, Singapore, 138671, Singapore
| | - Yui Hei Jasper Chiu
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore
| | - Casslynn Wei Qian Koh
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore
| | - Choon Kong Yap
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore
| | - Edwin Kok Hao Lim
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore
| | - Jianbin Chen
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore
| | - Yuhua Lim
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore
| | - Jane Jia Hui Lee
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore
| | - Anders Jacobsen Skanderup
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore
| | - Zhenxun Wang
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore
- Centre for Vision Research, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Weiwei Zhai
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China
| | - Nguan Soon Tan
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore, 308232, Singapore
| | - Chandra S Verma
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore
- Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, Matrix, Singapore, 138671, Singapore
- Department of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore, 117558, Singapore
| | - Yvonne Tay
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore, 117597, Singapore
| | - Daniel Shao Weng Tan
- Division of Medical Oncology, National Cancer Centre Singapore, 30 Hospital Boulevard, Singapore, 168583, Singapore
| | - Wai Leong Tam
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore.
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore.
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore.
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore, 117597, Singapore.
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Yang C, Chen W, Ye B, Nie K. An overview of 6-shogaol: new insights into its pharmacological properties and potential therapeutic activities. Food Funct 2024; 15:7252-7270. [PMID: 38287779 DOI: 10.1039/d3fo04753a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/31/2024]
Abstract
Ginger (Zingiber officinale Roscoe) has traditionally been used as a cooking spice and herbal medicine for treating nausea and vomiting. More recently, ginger was found to effectively reduce the risk of diseases such as gastroenteritis, migraine, gonarthritis, etc., due to its various bioactive compounds. 6-Shogaol, the pungent phenolic substance in ginger, is the most pharmacologically active among such compounds. The aim of the present study was to review the pharmacological characteristic of 6-shogaol, including the properties of anti-inflammatory, antioxidant and antitumour, and its corresponding molecular mechanism. With its multiple mechanisms, 6-shogaol is considered a beneficial natural compound, and therefore, this review will shed some light on the therapeutic role of 6-shogaol and provide a theoretical basis for the development and clinical application of 6-shogaol.
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Affiliation(s)
- Chenglu Yang
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Weijian Chen
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Binbin Ye
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Ke Nie
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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40
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Ren Q, Ma H, Wang L, Qin J, Tian M, Zhang W. Gene-knockdown Methods for Silencing Nuclear-localized Insulin Receptors in Lung Adenocarcinoma Cells: A Bioinformatics Approach. Curr Genomics 2024; 26:24-35. [PMID: 39911279 PMCID: PMC11793068 DOI: 10.2174/0113892029298721240627095839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/29/2024] [Revised: 05/19/2024] [Accepted: 05/22/2024] [Indexed: 02/07/2025] Open
Abstract
Background Lung adenocarcinoma, the predominant subtype of lung cancer, presents a significant challenge to public health due to its notably low five-year survival rate. Recent epidemiological data highlights a concerning trend: patients with pulmonary adenocarcinoma and comorbid diabetes exhibit substantially elevated mortality rates compared to those without diabetes, suggesting a potential link between hyperinsulinemia in diabetic individuals and accelerated progression of pulmonary adenocarcinoma. Insulin Receptor (IR) is a tyrosine-protein kinase on the cell surface, and its over-expression is considered the pathological hallmark of hyperinsulinemia in various cancer cell types. Research indicates that IR can translocate to the nucleus of lung adenocarcinoma cells to promote their proliferation, but its precise molecular targets remain unclear. This study aims to silence IRs in lung adenocarcinoma cells and identify key genes within the ERK pathway that may serve as potential molecular targets for intervention. Methods Gene expression data from lung adenocarcinoma and para cancer tissues were retrieved from the Gene Expression Omnibus (GEO) database and assessed through "pheatmap", GO annotation, KEGG analysis, R calculations, Cytoscape mapping, and Hub gene screening. Significant genes were visualized using the ggplot2 tool to compare expression patterns between the two groups. Additionally, survival analysis was performed using the R "survminer" and "survival" packages, along with the R "pathview" package for pathway visualization. Marker genes were identified and linked to relevant signaling pathways. Validation was conducted utilizing real-time quantitative polymerase chain reaction and immunoblotting assays in an A549 lung cancer cell model to determine the roles of these marker genes in associated signaling cascades. Results The study examined 58 lung adenocarcinoma samples and paired para-neoplastic tissues. Analysis of the GSE32863 dataset from GEO revealed 1040 differentially expressed genes, with 421 up-regulated and 619 down-regulated. Visualization of these differences identified 172 significant alterations, comprising 141 up-regulated and 31 down-regulated genes. Functional enrichment analysis using Gene Ontology (GO) revealed 56 molecular functions, 77 cellular components, and 816 biological processes. KEGG analysis identified 17 strongly enriched functions, including cytokine interactions and tumor necrosis factor signaling. Moreover, the ERK signaling pathway was associated with four Hub genes (FGFR4, ANGPT1, TEK, and IL1B) in cellular biological processes. Further validation demonstrated a positive correlation between IL-1B expression in the ERK signaling pathway and lung cancer through real-time fluorescence quantitative enzyme-linked reaction with immunoblotting assays. Conclusion In IR-silenced lung adenocarcinoma, the expression of the IL-1B gene exhibited a positive correlation with the ERK signaling pathway.
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Affiliation(s)
- Qiu Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, No.23 Post Street, Nangang District, Harbin 150001, China
- Department of Respiratory, Heilongjiang Province Hospital Harbin, Harbin, 150000, China
| | - Hui Ma
- Department of Respiratory Medicine, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Lingling Wang
- Department of Respiratory, Heilongjiang Province Hospital Harbin, Harbin, 150000, China
| | - Jiayu Qin
- Department of Respiratory, Heilongjiang Province Hospital Harbin, Harbin, 150000, China
| | - Miao Tian
- Heilongjiang College of Business and Technology. Harbin, Heilongjiang, People's Republic of China
| | - Wei Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, No.23 Post Street, Nangang District, Harbin 150001, China
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Sentek H, Braun A, Budeus B, Klein D. Non-small cell lung cancer cells and concomitant cancer therapy induce a resistance-promoting phenotype of tumor-associated mesenchymal stem cells. Front Oncol 2024; 14:1406268. [PMID: 39011489 PMCID: PMC11246879 DOI: 10.3389/fonc.2024.1406268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/24/2024] [Accepted: 05/30/2024] [Indexed: 07/17/2024] Open
Abstract
Introduction The tumor microenvironment gained attraction over the last decades as stromal cells significantly impact on tumor development, progression and metastasis, and immune evasion as well as on cancer therapy resistance. We previously reported that lung-resident mesenchymal stem cells (MSCs) were mobilized and activated in non-small cell lung cancer (NSCLC) progression and could even mediate radiation resistance in co-cultured NSCLC cells. Methods We investigated how MSCs were affected by NSCLC cells in combination with cancer (radiation) therapy in indirect co-cultures using tumor-conditioned medium and Transwells or direct three-dimensional NSCLC-MSC spheroid co-cultures in order to unravel the resistance-mediating action of tumor-associated MSCs. Results Although no obvious phenotypic and functional alterations in MSCs following NSCLC co-culture could be observed, MSC senescence was induced following co-applied radiotherapy (RT). Global gene expression profiling, in combination with gene set enrichment analysis upon treatment, was used to confirm the senescent phenotype of irradiated MSC and to reveal relevant senescence-associated secretory phenotype (SASP) factors that could meditate NSCLC RT resistance. We identified senescent tumor-associated MSC-derived serine proteinase inhibitor (serpin) E1/PAI1 as potential SASP factor mediating NSCLC progression and RT resistance. Discussion Specified intra-tumor-stroma interactions and cell type-specific pro-tumorigenic functions could not only improve lung cancer classification but could even be used for a more precise profiling of individual patients, finally paving an additional way for the discovery of potential drug targets for NSCLC patients.
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Affiliation(s)
| | | | | | - Diana Klein
- Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, University Hospital, Essen, Germany
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Jiang J, Berry MF, Lui NS, Liou DZ, Trope WL, Backhus LM, Shrager JB. Clinical impact of EGFR and KRAS mutations in surgically treated unifocal and multifocal lung adenocarcinoma. Transl Lung Cancer Res 2024; 13:1222-1231. [PMID: 38973951 PMCID: PMC11225054 DOI: 10.21037/tlcr-24-165] [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] [Academic Contribution Register] [Received: 02/22/2024] [Accepted: 05/07/2024] [Indexed: 07/09/2024]
Abstract
Background Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (KRAS) are the two most common oncogenic drivers in lung adenocarcinoma, and their roles still need further exploration. Here we aimed to compare the clinical impact of EGFR and KRAS mutations on disease progression in resected unifocal and multifocal lung adenocarcinoma. Methods Clinicopathologic and genomic data were collected for patients who underwent resection of lung adenocarcinoma from 2008 to 2022 at Stanford University Hospital. Retrospective review was performed in 241 patients whose tumors harbored EGFR (n=150, 62.2%) or KRAS (n=91, 37.8%) mutations. Clinical outcome was analyzed with special attention to the natural history of secondary nodules in multifocal cases wherein the dominant tumor had been resected. Results We confirm that compared with EGFR mutations, patients with KRAS mutations had more smokers, larger tumor size, higher TNM stage, higher positron emission tomography (PET)/computed tomography (CT) standard uptake value max, higher tumor mutation burden, and worse disease-free survival and overall survival on univariate analysis. For patients with multifocal pulmonary nodules, the median follow-up of unresected secondary nodules was 55 months. Secondary nodule progression-free survival (SNPFS) was significantly worse for patients with KRAS mutations than those with EGFR mutations (mean 40.3±6.6 vs. 67.7±6.5 months, P=0.004). Univariate analysis showed tumor size, tumor morphology, pathologic TNM stage, and KRAS mutations were significantly associated with SNPFS, while multivariate analysis showed only KRAS mutations were independently associated with worse SNPFS (hazard ratio 1.752, 95% confidence interval: 1.017-3.018, P=0.043). Conclusions Resected lung adenocarcinomas with KRAS mutations have more aggressive clinicopathological features and confer worse prognosis than those with EGFR mutations. Secondary pulmonary nodules in multifocal cases with dominant KRAS-mutant tumors have more rapid progression of the secondary nodules.
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Affiliation(s)
- Jiahao Jiang
- Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA
- Department of Thoracic Surgery, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Mark F. Berry
- Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA
| | - Natalie S. Lui
- Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA
| | - Douglas Z. Liou
- Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA
| | - Winston L. Trope
- Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA
| | - Leah M. Backhus
- Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA
- Veterans Affairs Palo Alto Health Care System, Palo Alto, Stanford, CA, USA
| | - Joseph B. Shrager
- Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA
- Veterans Affairs Palo Alto Health Care System, Palo Alto, Stanford, CA, USA
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Poalelungi DG, Neagu AI, Fulga A, Neagu M, Tutunaru D, Nechita A, Fulga I. Revolutionizing Pathology with Artificial Intelligence: Innovations in Immunohistochemistry. J Pers Med 2024; 14:693. [PMID: 39063947 PMCID: PMC11278211 DOI: 10.3390/jpm14070693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/12/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/28/2024] Open
Abstract
Artificial intelligence (AI) is a reality of our times, and it has been successfully implemented in all fields, including medicine. As a relatively new domain, all efforts are directed towards creating algorithms applicable in most medical specialties. Pathology, as one of the most important areas of interest for precision medicine, has received significant attention in the development and implementation of AI algorithms. This focus is especially important for achieving accurate diagnoses. Moreover, immunohistochemistry (IHC) serves as a complementary diagnostic tool in pathology. It can be further augmented through the application of deep learning (DL) and machine learning (ML) algorithms for assessing and analyzing immunohistochemical markers. Such advancements can aid in delineating targeted therapeutic approaches and prognostic stratification. This article explores the applications and integration of various AI software programs and platforms used in immunohistochemical analysis. It concludes by highlighting the application of these technologies to pathologies such as breast, prostate, lung, melanocytic proliferations, and hematologic conditions. Additionally, it underscores the necessity for further innovative diagnostic algorithms to assist physicians in the diagnostic process.
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Affiliation(s)
- Diana Gina Poalelungi
- Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati, 35 AI Cuza St., 800010 Galati, Romania; (D.G.P.); (M.N.); (D.T.); (A.N.); (I.F.)
- Saint Apostle Andrew Emergency County Clinical Hospital, 177 Brailei St., 800578 Galati, Romania
| | - Anca Iulia Neagu
- Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati, 35 AI Cuza St., 800010 Galati, Romania; (D.G.P.); (M.N.); (D.T.); (A.N.); (I.F.)
- Saint John Clinical Emergency Hospital for Children, 800487 Galati, Romania
| | - Ana Fulga
- Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati, 35 AI Cuza St., 800010 Galati, Romania; (D.G.P.); (M.N.); (D.T.); (A.N.); (I.F.)
- Saint Apostle Andrew Emergency County Clinical Hospital, 177 Brailei St., 800578 Galati, Romania
| | - Marius Neagu
- Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati, 35 AI Cuza St., 800010 Galati, Romania; (D.G.P.); (M.N.); (D.T.); (A.N.); (I.F.)
- Saint Apostle Andrew Emergency County Clinical Hospital, 177 Brailei St., 800578 Galati, Romania
| | - Dana Tutunaru
- Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati, 35 AI Cuza St., 800010 Galati, Romania; (D.G.P.); (M.N.); (D.T.); (A.N.); (I.F.)
- Saint Apostle Andrew Emergency County Clinical Hospital, 177 Brailei St., 800578 Galati, Romania
| | - Aurel Nechita
- Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati, 35 AI Cuza St., 800010 Galati, Romania; (D.G.P.); (M.N.); (D.T.); (A.N.); (I.F.)
- Saint John Clinical Emergency Hospital for Children, 800487 Galati, Romania
| | - Iuliu Fulga
- Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati, 35 AI Cuza St., 800010 Galati, Romania; (D.G.P.); (M.N.); (D.T.); (A.N.); (I.F.)
- Saint Apostle Andrew Emergency County Clinical Hospital, 177 Brailei St., 800578 Galati, Romania
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Zhang B, Li C, Wu J, Zhang J, Cheng C. DeepCG: A cell graph model for predicting prognosis in lung adenocarcinoma. Int J Cancer 2024; 154:2151-2161. [PMID: 38429627 PMCID: PMC11015971 DOI: 10.1002/ijc.34901] [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] [Academic Contribution Register] [Received: 12/27/2023] [Accepted: 01/31/2024] [Indexed: 03/03/2024]
Abstract
Lung cancer is the first leading cause of cancer-related death in the United States, with lung adenocarcinoma as the major subtype accounting for 40% of all cases. To improve patient survival, image-based prognostic models were developed due to the ready availability of pathological images at diagnosis. However, the application of these models is hampered by two main challenges: the lack of publicly available image datasets with high-quality survival information and the poor interpretability of conventional convolutional neural network models. Here, we integrated matched transcriptomic and H&E staining data from TCGA (The Cancer Genome Atlas) to develop an image-based prognostic model, termed Deep-learning based Cell Graph (DeepCG) model. Instead of survival data, we used a gene signature to predict patient prognostic risks, which was then used as labels for training DeepCG. Importantly, by employing graph structures to capture cell patterns, DeepCG can provide cell-level interpretation, which was more biologically relevant than previous region-level insights. We validated the prognostic values of DeepCG in independent datasets and demonstrated its ability to identify prognostically informative cells in images.
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Affiliation(s)
- Baoyi Zhang
- Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX 77030
| | - Chenyang Li
- Genomic Medicine Department, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
- Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center UTHealth Houston, Houston, TX 77030
| | - Jia Wu
- Department of Imaging Physics, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Jianjun Zhang
- Genomic Medicine Department, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
- Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center UTHealth Houston, Houston, TX 77030
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Chao Cheng
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030
- The Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX 77030
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Lu T, Ma R, Mansour AG, Bustillos C, Li Z, Li Z, Ma S, Teng KY, Chen H, Zhang J, Villalona-Calero MA, Caligiuri MA, Yu J. Preclinical Evaluation of Off-The-Shelf PD-L1+ Human Natural Killer Cells Secreting IL15 to Treat Non-Small Cell Lung Cancer. Cancer Immunol Res 2024; 12:731-743. [PMID: 38572955 PMCID: PMC11218741 DOI: 10.1158/2326-6066.cir-23-0324] [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] [Academic Contribution Register] [Received: 04/12/2023] [Revised: 01/04/2024] [Accepted: 03/27/2024] [Indexed: 04/05/2024]
Abstract
We described previously a human natural killer (NK) cell population that upregulates PD-L1 expression upon recognizing and reacting to tumor cells or exposure to a combination of IL12, IL18, and IL15. Here, to investigate the safety and efficacy of tumor-reactive and cytokine-activated (TRACK) NK cells, human NK cells from umbilical cord blood were expanded, transduced with a retroviral vector encoding soluble (s) IL15, and further cytokine activated to induce PD-L1 expression. Our results show cryopreserved and thawed sIL15_TRACK NK cells had significantly improved cytotoxicity against non-small cell lung cancer (NSCLC) in vitro when compared with non-transduced (NT) NK cells, PD-L1+ NK cells lacking sIL15 expression (NT_TRACK NK), or NK cells expressing sIL15 without further cytokine activation (sIL15 NK cells). Intravenous injection of sIL15_TRACK NK cells into immunodeficient mice with NSCLC significantly slowed tumor growth and improved survival when compared with NT NK and sIL15 NK cells. The addition of the anti-PD-L1 atezolizumab further improved control of NSCLC growth by sIL15_TRACK NK cells in vivo. Moreover, a dose-dependent efficacy was assessed for sIL15_TRACK NK cells without observed toxicity. These experiments indicate that the administration of frozen, off-the-shelf allogeneic sIL15_TRACK NK cells is safe in preclinical models of human NSCLC and has potent antitumor activity without and with the administration of atezolizumab. A phase I clinical trial modeled after this preclinical study using sIL15_TRACK NK cells alone or with atezolizumab for relapsed or refractory NSCLC is currently underway (NCT05334329).
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MESH Headings
- Carcinoma, Non-Small-Cell Lung/immunology
- Carcinoma, Non-Small-Cell Lung/therapy
- Humans
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Interleukin-15
- Animals
- Lung Neoplasms/immunology
- Lung Neoplasms/therapy
- B7-H1 Antigen/metabolism
- Mice
- Xenograft Model Antitumor Assays
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/pharmacology
- Cell Line, Tumor
- Mice, SCID
- Mice, Inbred NOD
- Female
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Affiliation(s)
- Ting Lu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA
- Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA
| | - Rui Ma
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA
| | - Anthony G. Mansour
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA
| | - Christian Bustillos
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA
| | - Zhiyao Li
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA
| | - Zhenlong Li
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA
| | - Shoubao Ma
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA
| | - Kun-Yu Teng
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA
| | - Hanyu Chen
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA
| | - Jianying Zhang
- Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA 91010, USA
| | - Miguel A. Villalona-Calero
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Los Angeles, CA 91010, USA
- City of Hope Comprehensive Cancer Center, Los Angeles, CA 91010, USA
| | - Michael A. Caligiuri
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA
- Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA
- City of Hope Comprehensive Cancer Center, Los Angeles, CA 91010, USA
| | - Jianhua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA
- Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA
- City of Hope Comprehensive Cancer Center, Los Angeles, CA 91010, USA
- Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Los Angeles, CA 91010, USA
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Ma W, Hu J. Downregulated CDH3 is correlated with a better prognosis for LUAD and decreases proliferation and migration of lung cancer cells. Genes Genomics 2024; 46:713-731. [PMID: 38064156 DOI: 10.1007/s13258-023-01476-5] [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] [Academic Contribution Register] [Received: 05/04/2023] [Accepted: 11/05/2023] [Indexed: 05/19/2024]
Abstract
BACKGROUND CDH3 is a glycoprotein with a single-span transmembrane domain that mediates cell-to-cell adhesion. Abnormal expression of CDH3 is associated with a poor prognosis in patients with breast, thyroid, colorectal carcinomas and glioblastoma. Soluble CDH3 in pleural effusions can be used as a marker for real-time monitoring of resistance to first- and second-generation EGFR-TKIs. The CDH3 mechanism underlying lung adenocarcinomas (LUADs) has not been established. OBJECTIVE This study analyzed the correlation between CDH3 expression and lung cancer prognosis and the effect of down-regulation CDH3 expression on the proliferation and migration of lung cancer cells. METHODS CDH3 expression was studied using the Oncomine, TIMER, PanglaoDB, and GEPIA databases. The effect of CDH3 on clinical prognosis was assessed with GEPIA, the PrognoScan database, and Kaplan-Meier plotter. The relationship between CDH3 to immune infiltrating cells was explored using TIMER and TISIDB. The function of CDH3 in lung cancer cell lines was determined by CCK-8 and wound healing assays in vitro. Furthermore, RNA sequencing was used to identify key signaling pathways and differentially-expressed genes. RESULTS LUAD tissues had higher CDH3 expression compared with normal tissues and were associated with worse overall survival in patients with LUAD. CDH3 expression had positive associations with infiltration of CD4 + T cells, Tregs and exhausted T cells, but negative associations with infiltration of B cells in patients with LUAD. CCK-8 and wound healing assays revealed that downregulation of CDH3 inhibited the proliferation and migration of cells. KEGG analysis revealed that the TGF-beta signaling pathways were demonstrated to be enriched pathways for genes negatively regulated by knockdown of CDH3. CONCLUSION CDH3 expression affects proliferation and migration of lung cancer cells and might serve as a potential prognostic marker in LUAD patients.
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Affiliation(s)
- Wanru Ma
- Department of Blood Transfusion, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 Da Hua Road, Dong Dan, Beijing, 100730, People's Republic of China
| | - Junhua Hu
- Department of Blood Transfusion, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 Da Hua Road, Dong Dan, Beijing, 100730, People's Republic of China.
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Li W, Wu J, Jia Q, Shi Y, Li F, Zhang L, Shi F, Wang X, Wu S. PD-L1 knockdown suppresses vasculogenic mimicry of non-small cell lung cancer by modulating ZEB1-triggered EMT. BMC Cancer 2024; 24:633. [PMID: 38783271 PMCID: PMC11118770 DOI: 10.1186/s12885-024-12390-8] [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] [Academic Contribution Register] [Received: 11/03/2023] [Accepted: 05/15/2024] [Indexed: 05/25/2024] Open
Abstract
BACKGROUND PD-L1 overexpression is commonly observed in various malignancies and is strongly correlated with poor prognoses for cancer patients. Moreover, PD-L1 has been shown to play a significant role in promoting angiogenesis and epithelial-mesenchymal transition (EMT) processes across different cancer types. METHODS The relationship between PD-L1 and vasculogenic mimicry as well as epithelial-mesenchymal transition (EMT) was explored by bioinformatics approach and immunohistochemistry. The functions of PD-L1 in regulating the expression of ZEB1 and the EMT process were assessed by Western blotting and q-PCR assays. The impact of PD-L1 on the migratory and proliferative capabilities of A549 and H1299 cells was evaluated through wound healing, cell invasion, and CCK8 assays following siRNA-mediated PD-L1 knockdown. Tube formation assay was utilized to evaluate the presence of VM structures. RESULTS In this study, increased PD-L1 expression was observed in A549 and H1299 cells compared to normal lung epithelial cells. Immunohistochemical analysis revealed a higher prevalence of VM structures in the PD-L1-positive group compared to the PD-L1-negative group. Additionally, high PD-L1 expression was also found to be significantly associated with advanced TNM stage and increased metastasis. Following PD-L1 knockdown, NSCLC cells exhibited a notable reduction in their ability to form tube-like structures. Moreover, the levels of key EMT and VM-related markers, including N-cadherin, MMP9, VE-cadherin, and VEGFA, were significantly decreased, while E-cadherin expression was upregulated. In addition, the migration and proliferation capacities of both cell lines were significantly inhibited after PD-L1 or ZEB1 knockdown. CONCLUSIONS Knockdown PD-L1 can inhibit ZEB1-mediated EMT, thereby hindering the formation of VM in NSCLC.
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Affiliation(s)
- Wenjuan Li
- Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Molecular Diagnosis Center, First Affiliated Hospital, Bengbu Medical University, 287 Changhuai Road, Bengbu, Anhui, 233004, China
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, People's Republic of China
| | - Jiatao Wu
- Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Molecular Diagnosis Center, First Affiliated Hospital, Bengbu Medical University, 287 Changhuai Road, Bengbu, Anhui, 233004, China
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, People's Republic of China
| | - Qianhao Jia
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, People's Republic of China
| | - Yuqi Shi
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, People's Republic of China
| | - Fan Li
- Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Molecular Diagnosis Center, First Affiliated Hospital, Bengbu Medical University, 287 Changhuai Road, Bengbu, Anhui, 233004, China
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, People's Republic of China
| | - Linxiang Zhang
- Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Molecular Diagnosis Center, First Affiliated Hospital, Bengbu Medical University, 287 Changhuai Road, Bengbu, Anhui, 233004, China
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, People's Republic of China
| | - Fan Shi
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, People's Republic of China
| | - Xiaojing Wang
- Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Molecular Diagnosis Center, First Affiliated Hospital, Bengbu Medical University, 287 Changhuai Road, Bengbu, Anhui, 233004, China.
| | - Shiwu Wu
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, People's Republic of China.
- Department of Pathology, Bengbu Medical University, Bengbu, 233030, Anhui, China.
- Department of Pathology, Anhui No.2 Provincial People's Hospital, Hefei, China.
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Li Z, Chen J, Xu B, Zhao W, Zha H, Han Y, Shen W, Dong Y, Zhao N, Zhang M, He K, Li Z, Liu X. Correlation between small-cell lung cancer serum protein/peptides determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and chemotherapy efficacy. Clin Proteomics 2024; 21:35. [PMID: 38764042 PMCID: PMC11103996 DOI: 10.1186/s12014-024-09483-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/13/2023] [Accepted: 04/22/2024] [Indexed: 05/21/2024] Open
Abstract
BACKGROUND Currently, no effective measures are available to predict the curative efficacy of small-cell lung cancer (SCLC) chemotherapy. We expect to develop a method for effectively predicting the SCLC chemotherapy efficacy and prognosis in clinical practice in order to offer more pertinent therapeutic protocols for individual patients. METHODS We adopted matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and ClinPro Tools system to detect serum samples from 154 SCLC patients with different curative efficacy of standard chemotherapy and analyze the different peptides/proteins of SCLC patients to discover predictive tumor markers related to chemotherapy efficacy. Ten peptide/protein peaks were significantly different in the two groups. RESULTS A genetic algorithm model consisting of four peptides/proteins was developed from the training group to separate patients with different chemotherapy efficacies. Among them, three peptides/proteins (m/z 3323.35, 6649.03 and 6451.08) showed high expression in the disease progression group, whereas the peptide/protein at m/z 4283.18 was highly expressed in the disease response group. The classifier exhibited an accuracy of 91.4% (53/58) in the validation group. The survival analysis showed that the median progression-free survival (PFS) of 30 SCLC patients in disease response group was 9.0 months; in 28 cases in disease progression group, the median PFS was 3.0 months, a statistically significant difference (χ2 = 46.98, P < 0.001). The median overall survival (OS) of the two groups was 13.0 months and 7.0 months, a statistically significant difference (χ2 = 40.64, P < 0.001). CONCLUSIONS These peptides/proteins may be used as potential biological markers for prediction of the curative efficacy and prognosis for SCLC patients treated with standard regimen chemotherapy.
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Affiliation(s)
- Zhihua Li
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Junnan Chen
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Bin Xu
- National Center of Biomedical Analysis, Beijing, 100850, China
| | - Wei Zhao
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Haoran Zha
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Yalin Han
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Wennan Shen
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Yuemei Dong
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Nan Zhao
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Manze Zhang
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Kun He
- National Center of Biomedical Analysis, Beijing, 100850, China
| | - Zhaoxia Li
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China.
| | - Xiaoqing Liu
- Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, 100071, China.
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Du W, Qiu T, Liu H, Liu A, Wu Z, Sun X, Qin Y, Su W, Huang Z, Yun T, Jiao W. The predictive value of serum tumor markers for EGFR mutation in non-small cell lung cancer patients with non-stage IA. Heliyon 2024; 10:e29605. [PMID: 38707478 PMCID: PMC11066585 DOI: 10.1016/j.heliyon.2024.e29605] [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] [Academic Contribution Register] [Received: 02/01/2024] [Revised: 04/07/2024] [Accepted: 04/10/2024] [Indexed: 05/07/2024] Open
Abstract
Objective The predictive value of serum tumor markers (STMs) in assessing epidermal growth factor receptor (EGFR) mutations among patients with non-small cell lung cancer (NSCLC), particularly those with non-stage IA, remains poorly understood. The objective of this study is to construct a predictive model comprising STMs and additional clinical characteristics, aiming to achieve precise prediction of EGFR mutations through noninvasive means. Materials and methods We retrospectively collected 6711 NSCLC patients who underwent EGFR gene testing. Ultimately, 3221 stage IA patients and 1442 non-stage IA patients were analyzed to evaluate the potential predictive value of several clinical characteristics and STMs for EGFR mutations. Results EGFR mutations were detected in 3866 patients (57.9 %) of all NSCLC patients. None of the STMs emerged as significant predictor for predicting EGFR mutations in stage IA patients. Patients with non-stage IA were divided into the study group (n = 1043) and validation group (n = 399). In the study group, univariate analysis revealed significant associations between EGFR mutations and the STMs (carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), and cytokeratin-19 fragment (CYFRA21-1)). The nomogram incorporating CEA, CYFRA 21-1, pathology, gender, and smoking history for predicting EGFR mutations with non-stage IA was constructed using the results of multivariate analysis. The area under the curve (AUC = 0.780) and decision curve analysis demonstrated favorable predictive performance and clinical utility of nomogram. Additionally, the Random Forest model also demonstrated the highest average C-index of 0.793 among the eight machine learning algorithms, showcasing superior predictive efficiency. Conclusion CYFRA21-1 and CEA have been identified as crucial factors for predicting EGFR mutations in non-stage IA NSCLC patients. The nomogram and 8 machine learning models that combined STMs with other clinical factors could effectively predict the probability of EGFR mutations.
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Affiliation(s)
- Wenxing Du
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tong Qiu
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hanqun Liu
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ao Liu
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhe Wu
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiao Sun
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yi Qin
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenhao Su
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhangfeng Huang
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tianxiang Yun
- Department of Thoracic Surgery, The Second Affiliated Hospital, Shandong First Medical University, Taian, China
| | - Wenjie Jiao
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
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Sbrana A, Cappelli S, Petrini I, Bernardini L, Massa V, Carrozzi L, Chella A. Dabrafenib-trametinib in BRAF V600-mutated non-small-cell lung cancer: a single center real world experience. Future Oncol 2024; 20:1745-1751. [PMID: 38709118 PMCID: PMC11486151 DOI: 10.1080/14796694.2024.2340898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/14/2023] [Accepted: 04/05/2024] [Indexed: 05/07/2024] Open
Abstract
Aim: We retrospectively evaluated the effect of dabrafenib/trametinib combination in patients with BRAF-mutated non-small-cell lung cancer (NSCLC) treated in a single center from 2017 to 2022.Patients: The response and safety data of 42 patients (27 treated in first-line and 15 as second/subsequent lines) were analyzed.Results: The objective response was 73.8%, with no differences between patients undergoing first- or second-line. A longer, statistically significant median progression-free survival (PFS) was observed in patients receiving the combination in first-line vs those in the second/subsequent lines (19.9 months [95% CI: 19.7-20] vs 13.1 months [95% CI: 8.6-17.6], respectively; p = 0.012). The median overall survival (OS) was 29.9 months (95% CI: 14.1-45.7) for patients treated with the combination in first-line and 22.4 months (95% CI: 14.6-30.2) for those treated in subsequent lines. The combination was well toleratedConclusion: We confirm the efficacy of dabrafenib/trametinib in BRAF-V600-mutated NSCLC.
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Affiliation(s)
- Andrea Sbrana
- Service of Pneumo-Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
- Department of Surgical, Medical & Molecular Pathology & Critical Care Medicine, University of Pisa, Pisa, Italy
| | - Sabrina Cappelli
- Service of Pneumo-Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Iacopo Petrini
- Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
- Department of Translational Research & of New Surgical & Medical Technologies, University of Pisa, Pisa, Italy
| | - Laura Bernardini
- Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
- Department of Translational Research & of New Surgical & Medical Technologies, University of Pisa, Pisa, Italy
| | - Valentina Massa
- Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
- Department of Translational Research & of New Surgical & Medical Technologies, University of Pisa, Pisa, Italy
| | - Laura Carrozzi
- Department of Surgical, Medical & Molecular Pathology & Critical Care Medicine, University of Pisa, Pisa, Italy
- Pneumology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Antonio Chella
- Service of Pneumo-Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
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