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Zhao D, Deshpande R, Wu K, Tyagi A, Sharma S, Wu SY, Xing F, O'Neill S, Ruiz J, Lyu F, Watabe K. Identification of TUBB3 as an immunotherapy target in lung cancer by genome wide in vivo CRISPR screening. Neoplasia 2025; 60:101100. [PMID: 39671912 PMCID: PMC11699798 DOI: 10.1016/j.neo.2024.101100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/27/2024] [Accepted: 12/02/2024] [Indexed: 12/15/2024]
Abstract
Recent development of immune checkpoint inhibitors has revolutionized cancer immunotherapy. Although these drugs show dramatic effects on a subset of cancer patients, many other tumors are non-responsive and the pathological mechanism of the resistance is largely unknown. To identify genes underlying anti-PD-1 immunotherapy resistance using a systematic approach, we performed an in vivo genome wide CRISPR screening in lung cancer cells. We integrated our results with multi-omics clinical data and performed both in vitro and in vivo assays to evaluate the role of the top candidate in regulating cytotoxic T cell killing. We identified TUBB3 as a potential target to overcome the resistance and enhance the efficacy of anti-PD-1 immunotherapy. TUBB3 expression is upregulated in lung cancer patients, and its higher expression correlates with poorer patients' survival. We found that TUBB3 expression was significantly elevated in the non-responders compared to responders in our patient cohort that received immunotherapies. Importantly, the results of our preclinical experiments showed that inhibition of TUBB3 with a small molecule inhibitor synergized with anti-PD-1 treatment and enhanced tumor cell killing by cytotoxic T cells. Consistently, anti-PD-1 resistant cells showed significantly higher expression of TUBB3; however, TUBB3 inhibition rendered the resistant cells more susceptible to T cell killing. Mechanistic studies revealed that blocking TUBB3 suppressed the expression of PD-L1 through the EMT-related SNAI1 gene. Our results provide a rationale for a novel combination therapy consisting of the TUBB3 inhibition and anti-PD-1 immunotherapy for lung cancer.
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Affiliation(s)
- Dan Zhao
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA; Baylor College of Medicine, 1 Baylor Plz, Houston, TX 77030, USA
| | - Ravindra Deshpande
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
| | - Kerui Wu
- University of North Carolina, Greensboro, NC, 27412, USA
| | - Abhishek Tyagi
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
| | | | - Shih-Ying Wu
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
| | - Fei Xing
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
| | | | - Jimmy Ruiz
- Department of Medicine (Hematology & Oncology), Wake Forest School of Medicine, Winston Salem, NC 27157, USA
| | - Feng Lyu
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
| | - Kounosuke Watabe
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA.
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Drejeriene I, Gruode J, Cicenas S, Loizides C, Eliades A, Achilleos A, Kypri E, Tsangaras K, Ioannides M, Koumbaris G, Stanciute D, Krasauskas A, Patsalis PC. Comparison of targeted next generation sequencing assays in non-small cell lung cancer patients. Discov Oncol 2024; 15:757. [PMID: 39692940 DOI: 10.1007/s12672-024-01640-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 09/18/2024] [Indexed: 12/19/2024] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer the mutational spectrum of which has been extensively characterized. Treatment of patients with NSCLC based on their molecular profile is now part of the standard clinical care. The aim of this study was firstly to investigate two different NGS-based tumor profile genetic tests and secondly to assess the clinical actionability of the mutations and their association with survival and clinicopathological characteristics. Overall, 52 mutations were identified in 31 patients by either one or both assays. The most frequently mutated genes were TP53 (40.4%), KRAS (13.46%) and EGFR (9.62%). TP53 and KRAS mutations were associated with worst overall survival while KRAS was positively correlated with adenocarcinoma. The two methods showed a high concordance for the commonly covered genomic regions (97.14%). Ten mutations were identified in a genomic region exclusively covered by the MEDICOVER Genetics custom tumor profile assay. Likewise, one MET mutation was identified by the Ion Amliseq assay in a genomic region exclusively covered by Ion Amliseq. In conclusion both assays showed highly similar results in the commonly covered genomic areas, however, the MEDICOVER Genetics assay identified additional clinically actionable mutations that can be applied in clinical practice for personalized treatment decision making for patients with NSCLC.
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Affiliation(s)
- Ieva Drejeriene
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
- Klaipeda University Hospital, Klaipeda, Lithuania.
| | - Jurate Gruode
- Klaipeda University Hospital, Klaipeda, Lithuania
- Faculty of Medicine, Klaipeda University, Klaipeda, Lithuania
| | | | | | | | | | | | - Kyriakos Tsangaras
- MEDICOVER Genetics, Nicosia, Cyprus
- Department of Life and Health Sciences, University of Nicosia, Nicosia, Cyprus
| | | | | | | | - Arnoldas Krasauskas
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
- National Cancer Institute, Vilnius, Lithuania
| | - Philippos C Patsalis
- MEDICOVER Genetics, Nicosia, Cyprus.
- Department of Human Genetics, School of Medicine, University of Nicosia Medical School, Nicosia, Cyprus.
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Kartal B, Alimoğulları E, Akkurt G, Alimogulları M, Çaylı S. The histological investigation of the effects of electromagnetic radiation on rat ovaries. J Mol Histol 2024; 56:29. [PMID: 39630206 DOI: 10.1007/s10735-024-10319-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 11/20/2024] [Indexed: 02/07/2025]
Abstract
People are now exposed to higher levels of electromagnetic radiation (EMR) due to the widespread use of mobile phones in recent years. The possible effects of this exposure on human health are related to EMR. It has been suggested that exposure to EMR has serious effects on reproduction. The study aimed to investigate the impact of exposure to EMR (4.5 GB; 2600 MHz) emitted by mobile phones on rat ovaries. 18 adult female Wistar albino rats were used in the study, and the animals were divided into three groups (n = 6): control, stand-by, and dialing. For 8 weeks, the experimental groups were subjected to 4.5 GB EMR at 2600 MHz while on standby and making 10-min calls every hour. The rats in the control group received no exposure. Hematoxylin-eosin (H&E) staining of ovarian tissues was performed for histomorphological examinations. Additionally, immunoexpression of autophagy-related protein Beclin-1, apoptosis marker Caspase-3, ovarian reserve marker FSH, and oxidative stress marker iNOS were investigated in the rat ovaries. Microscopic examinations showed follicular degeneration in the ovaries of the rats in the stand-by and dialing groups. The immunoexpression of Beclin-1, Caspase-3, FSH, and iNOS was detected in granulosa cells and the corpus luteum in ovarian tissues obtained from the two EMR-exposed groups. There was a significant increase in the immunoexpression of Beclin-1 and Caspase-3 in the dialing group compared to the other two groups. Additionally, the iNOS and FSH expressions were increased in both EMR exposure groups compared to the control. Our results suggest that EMR exposure harms the ovaries, and autophagy and apoptosis are involved in this process.
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Affiliation(s)
- Bahar Kartal
- Department of Histology and Embryology, Medical Faculty, Ankara Yıldırım Beyazıt University, Ankara, Turkey.
| | - Ebru Alimoğulları
- Department of Histology and Embryology, Medical Faculty, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Gökhan Akkurt
- Department of General Surgery, Ankara City Hospital, Cankaya/Ankara, Turkey
| | - Mustafa Alimogulları
- University of Health Sciences Ankara Atatürk Sanatorium Training and Research Hospital/General Surgery Clinic, Ankara, Turkey
| | - Sevil Çaylı
- Department of Histology and Embryology, Medical Faculty, Ankara Yıldırım Beyazıt University, Ankara, Turkey
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Ma H, Yu T, Li ZC, Zhang L, Chen RX, Ren ZG. An Oxidative Stress-Related Prognostic Signature Predicts Treatment Response and Outcomes for Hepatocellular Carcinoma After Transarterial Chemoembolization. J Hepatocell Carcinoma 2024; 11:1569-1580. [PMID: 39156675 PMCID: PMC11330244 DOI: 10.2147/jhc.s465592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 08/01/2024] [Indexed: 08/20/2024] Open
Abstract
Purpose Oxidative stress plays a critical role in promoting tumor resistance to hypoxia and chemotherapeutic drugs. However, the prognostic role of oxidative stress-related genes (OSRGs) in hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) has not been fully explored. Methods We used transcriptome data from the GSE104580 cohort containing patients marked as responders or nonresponders to TACE therapy to identify differentially expressed OSRGs associated with TACE response (TR-OSRGs). We created a TR-OSRG prognostic signature based on TR-OSRGs using least absolute shrinkage and selection operator Cox and stepwise Cox regression analyses in a training cohort of patients with HCC (TCGA-LIHC). We verified this prognostic signature in two external cohorts of patients who received TACE for HCC (GSE14520-TACE and ZS-TACE-37). Finally, we constructed a prognostic nomogram model for predicting survival probability of patients with HCC based on Cox regression analysis. Results The TR-OSRG prognostic signature was created and shown to be a robust independent prognostic factor for treatment response and outcomes for HCC after TACE therapy. Risk scores based on this signature correlated with tumor stage and grade. Tumor samples from patients with higher risk scores exhibited more infiltration of immune cells and significantly increased expression of immune checkpoint genes. We also developed a nomogram for patients with HCC based on the TR-OSRG prognostic signature and clinical parameters; this nomogram was a useful quantitative analysis tool for predicting patient survival. Conclusion The TR-OSRGs signature exhibited good performance in predicting treatment response and outcomes in patients with HCC treated with TACE.
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Affiliation(s)
- Hui Ma
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
- Department of Hepatic Oncology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, People’s Republic of China
| | - Ting Yu
- Department of Pathology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Zhong-Chen Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Lan Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
- Department of Hepatic Oncology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, People’s Republic of China
| | - Rong-Xin Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Zheng-Gang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
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Zhang Q, Dunbar KB, Odze RD, Agoston AT, Wang X, Su T, Nguyen AD, Zhang X, Spechler SJ, Souza RF. Hypoxia-inducible factor-1α mediates reflux-induced epithelial-mesenchymal plasticity in Barrett's oesophagus patients. Gut 2024; 73:1269-1279. [PMID: 38641363 PMCID: PMC11239289 DOI: 10.1136/gutjnl-2023-331467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 04/06/2024] [Indexed: 04/21/2024]
Abstract
INTRODUCTION Epithelial-mesenchymal plasticity (EMP), the process through which epithelial cells acquire mesenchymal features, is needed for wound repair but also might contribute to cancer initiation. Earlier, in vitro studies showed that Barrett's cells exposed to acidic bile salt solutions (ABS) develop EMP. Now, we have (1) induced reflux oesophagitis in Barrett's oesophagus (BO) patients by stopping proton pump inhibitors (PPIs), (2) assessed their biopsies for EMP and (3) explored molecular pathways underlying reflux-induced EMP in BO cells and spheroids. METHODS 15 BO patients had endoscopy with biopsies of Barrett's metaplasia while on PPIs, and 1 and 2 weeks after stopping PPIs; RNA-seq data were assessed for enrichments in hypoxia-inducible factors (HIFs), angiogenesis and EMP pathways. In BO biopsies, cell lines and spheroids, EMP features (motility) and markers (vascular endothelial growth factor (VEGF), ZEB1, miR-200a&b) were evaluated by morphology, migration assays, immunostaining and qPCR; HIF-1α was knocked down with siRNA or shRNA. RESULTS At 1 and/or 2 weeks off PPIs, BO biopsies exhibited EMP features and markers, with significant enrichment for HIF-1α, angiogenesis and EMP pathways. In BO cells, ABS induced HIF-1α activation, which decreased miR-200a&b while increasing VEGF, ZEB1 and motility; HIF-1α knockdown blocked these effects. After ABS treatment, BO spheroids exhibited migratory protrusions showing nuclear HIF-1α, increased VEGF and decreased miR-200a&b. CONCLUSIONS In BO patients, reflux oesophagitis induces EMP changes associated with increased HIF-1α signalling in Barrett's metaplasia. In Barrett's cells, ABS trigger EMP via HIF-1α signalling. Thus, HIF-1α appears to play a key role in mediating reflux-induced EMP that might contribute to cancer in BO. TRIAL REGISTRATION NUMBER NCT02579460.
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Affiliation(s)
- Qiuyang Zhang
- Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA
- Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas, USA
| | - Kerry B Dunbar
- Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Internal Medicine, VA North Texas Health Care System, Dallas, Texas, USA
| | - Robert D Odze
- Department of Pathology, Tufts Medical Center, Boston, Massachusetts, USA
- Robert D Odze Pathology, LLC, Boston, Massachusetts, USA
| | - Agoston T Agoston
- Department of Pathology, Brigham and Womens Hospital, Boston, Massachusetts, USA
| | - Xuan Wang
- Biostatistics Core, Baylor Scott & White Research Insitute, Dallas, Texas, USA
| | - Tianhong Su
- Department of Oncology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, China
| | - Anh D Nguyen
- Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA
- Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas, USA
| | - Xi Zhang
- Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA
- Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas, USA
| | - Stuart Jon Spechler
- Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA
- Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas, USA
| | - Rhonda F Souza
- Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA
- Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas, USA
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Xi Y, Xi L, Tan J, Yu C, Shen W, Yu B. Comprehensive analysis of lung adenocarcinoma: Unveiling differential gene expression, survival-linked genes, subtype stratification, and immune landscape implications. ENVIRONMENTAL TOXICOLOGY 2024. [PMID: 38619376 DOI: 10.1002/tox.24282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 03/05/2024] [Accepted: 03/31/2024] [Indexed: 04/16/2024]
Abstract
This study offers a detailed exploration of lung adenocarcinoma (LUAD), addressing its heterogeneity and treatment challenges through a multi-faceted analysis that includes gene expression, genetic subtyping, pathway analysis, immune assessment, and drug sensitivity. It identifies 165 genes with significant expression differences and 46 genes associated with survival, revealing insights into oxidative stress and autophagy. LUAD samples were divided into three subtypes using consensus clustering on these 46 genes, with distinct survival outcomes. Gene Set Enrichment Analysis (GSEA) on HALLMARK gene sets indicated pathway variations with survival implications. The immune landscape, analyzed using the CIBERSORT algorithm, showed different immune cell distributions across subtypes, with the first subtype exhibiting a better immune environment and survival prospects. Advanced machine learning techniques developed a risk model from a set of four genes, effectively categorizing patients into high and low-risk groups, validated through external datasets and analyses. This model linked lower risk scores to better clinical stages, with a higher mutation rate and potential immunotherapy benefits observed in the high-risk group. Drug sensitivity assessments highlighted varied treatment responses between risk groups, suggesting avenues for personalized therapy. This comprehensive analysis enhances the understanding of LUAD's molecular and clinical nuances, offering valuable insights for tailored treatment approaches.
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Affiliation(s)
- Yong Xi
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Thoracic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, China
| | - Liu Xi
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jian Tan
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chaoqun Yu
- Department of Thoracic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, China
| | - Weiyu Shen
- Department of Thoracic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, China
| | - Bentong Yu
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Shen J, Chen L, Liu J, Li A, Zheng L, Chen S, Li Y. EGFR degraders in non-small-cell lung cancer: Breakthrough and unresolved issue. Chem Biol Drug Des 2024; 103:e14517. [PMID: 38610074 DOI: 10.1111/cbdd.14517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 03/02/2024] [Accepted: 03/16/2024] [Indexed: 04/14/2024]
Abstract
The epidermal growth factor receptor (EGFR) has been well validated as a therapeutic target for anticancer drug discovery. Osimertinib has become the first globally accessible third-generation EGFR inhibitor, representing one of the most advanced developments in non-small-cell lung cancer (NSCLC) therapy. However, a tertiary Cys797 to Ser797 (C797S) point mutation has hampered osimertinib treatment in patients with advanced EGFR-mutated NSCLC. Several classes of fourth-generation EGFR inhibitors were consequently discovered with the aim of overcoming the EGFRC797S mutation-mediated resistance. However, no clinical efficacy data of the fourth-generation EGFR inhibitors were reported to date, and EGFRC797S mutation-mediated resistance remains an "unmet clinical need." Proteolysis-targeting chimeric molecules (PROTACs) obtained from EGFR-TKIs have been developed to target drug resistance EGFR in NSCLC. Some PROTACs are from nature products. These degraders compared with EGFR inhibitors showed better efficiency in their cellular potency, inhibition, and toxicity profiles. In this review, we first introduce the structural properties of EGFR, the resistance, and mutations of EGFR, and then mainly focus on the recent advances of EGFR-targeting degraders along with its advantages and outstanding challenges.
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Affiliation(s)
- Jiayi Shen
- Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan Normal University, Ganzhou, Jiangxi, China
| | - Liping Chen
- Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan Normal University, Ganzhou, Jiangxi, China
| | - Jihu Liu
- Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan Normal University, Ganzhou, Jiangxi, China
| | - Anzhi Li
- Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan Normal University, Ganzhou, Jiangxi, China
| | - Lüyin Zheng
- Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan Normal University, Ganzhou, Jiangxi, China
| | - Sheng Chen
- Jiangxi Chiralsyn Biological Medicine Co., Ltd, Ganzhou, Jiangxi, China
| | - Yongdong Li
- Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan Normal University, Ganzhou, Jiangxi, China
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Srivastava S, Jayaswal N, Kumar S, Sharma PK, Behl T, Khalid A, Mohan S, Najmi A, Zoghebi K, Alhazmi HA. Unveiling the potential of proteomic and genetic signatures for precision therapeutics in lung cancer management. Cell Signal 2024; 113:110932. [PMID: 37866667 DOI: 10.1016/j.cellsig.2023.110932] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/15/2023] [Accepted: 10/18/2023] [Indexed: 10/24/2023]
Abstract
Lung cancer's enduring global significance necessitates ongoing advancements in diagnostics and therapeutics. Recent spotlight on proteomic and genetic biomarker research offers a promising avenue for understanding lung cancer biology and guiding treatments. This review elucidates genetic and proteomic lung cancer biomarker progress and their treatment implications. Technological strides in mass spectrometry-based proteomics and next-generation sequencing enable pinpointing of genetic abnormalities and abnormal protein expressions, furnishing vital data for precise diagnosis, patient classification, and customized treatments. Biomarker-driven personalized medicine yields substantial treatment improvements, elevating survival rates and minimizing adverse effects. Integrating omics data (genomics, proteomics, etc.) enhances understanding of lung cancer's intricate biological milieu, identifying novel treatment targets and biomarkers, fostering precision medicine. Liquid biopsies, non-invasive tools for real-time treatment monitoring and early resistance detection, gain popularity, promising enhanced management and personalized therapy. Despite advancements, biomarker repeatability and validation challenges persist, necessitating interdisciplinary efforts and large-scale clinical trials. Integrating artificial intelligence and machine learning aids analyzing vast omics datasets and predicting treatment responses. Single-cell omics reveal cellular connections and intratumoral heterogeneity, valuable for combination treatments. Biomarkers enable accurate diagnosis, tailored medicines, and treatment response tracking, significantly impacting personalized lung cancer care. This approach spurs patient-centered trials, empowering active patient engagement. Lung cancer proteomic and genetic biomarkers illuminate disease biology and treatment prospects. Progressing towards individualized efficient therapies is imminent, alleviating lung cancer's burden through ongoing research, omics integration, and technological strides.
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Affiliation(s)
- Shriyansh Srivastava
- Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University (DPSRU), Sector 3 Pushp Vihar, New Delhi 110017, India; Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida 203201, India
| | - Nandani Jayaswal
- Accurate College of Pharmacy, 49, Knowledge Park-III, Greater Noida, UP, India
| | - Sachin Kumar
- Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University (DPSRU), Sector 3 Pushp Vihar, New Delhi 110017, India
| | - Pramod Kumar Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida 203201, India
| | - Tapan Behl
- Amity School of Pharmaceutical Sciences, Amity University, Sahibzada Ajit Singh Nagar, Punjab, India.
| | - Asaad Khalid
- Substance Abuse and Toxicology Research Centre, Jazan University, Jazan 45142, Saudi Arabia; Medicinal and Aromatic Plants Research Institute, National Center for Research, P.O. Box: 2424, Khartoum 11111, Sudan
| | - Syam Mohan
- Substance Abuse and Toxicology Research Centre, Jazan University, Jazan 45142, Saudi Arabia; Center for Global Health Research, Saveetha Medical College, and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India; School of Health Sciences, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India.
| | - Asim Najmi
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan, Saudi Arabia
| | - Khalid Zoghebi
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan, Saudi Arabia
| | - Hassan A Alhazmi
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan, Saudi Arabia
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Ma H, Li Z, Chen R, Ren Z. Development of a Combined Oxidative Stress and Endoplasmic Reticulum Stress-Related Prognostic Signature for Hepatocellular Carcinoma. Comb Chem High Throughput Screen 2024; 27:2850-2860. [PMID: 37957902 PMCID: PMC11497145 DOI: 10.2174/0113862073257308231026073951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 09/17/2023] [Accepted: 10/04/2023] [Indexed: 11/15/2023]
Abstract
BACKGROUND Oxidative stress and endoplasmic reticulum stress are important components of the cellular stress process, which plays a critical role in tumor initiation and progression. METHODS First, the correlation between oxidative stress and endoplasmic reticulum stress was detected in 68 human hepatocellular carcinoma (HCC) tissue microarray samples by immunohistochemistry. Differentially expressed oxidative stress- and endoplasmic reticulum stressrelated genes (OESGs) then were screened in HCC. Next, an OESGs prognostic signature was constructed for HCC in the training cohort (TCGA-LIHC from The Cancer Genome Atlas), by least absolute shrinkage and selection operator Cox and stepwise Cox regression analyses, and was verified in the external cohort (GSE14520 from the Gene Expression Omnibus). The MCP counter was employed to evaluate immune cell infiltration. The C-index was used to evaluate the predictive power of prognostic signature. Finally, a prognostic nomogram model was constructed to predict the survival probability of patients with HCC based on the results of Cox regression analysis. RESULTS We demonstrated a positive correlation between oxidative stress and endoplasmic reticulum stress in human HCC samples. We then identified five OESGs as a prognostic signature consisting of IL18RAP, ECT2, PPARGC1A, STC2, and NQO1 for HCC. Related risk scores correlated with tumor stage, grade, and response to transcatheter arterial chemoembolization therapy, and the higher risk score group had less T cells, CD8+ T cells, cytotoxic lymphocytes and natural killer cell infiltration. The C-index of our OESGs prognostic signature was superior to four previously published signatures. Furthermore, we developed a nomogram based on the OESGs prognostic signature and clinical parameters for patients with HCC that is an effective quantitative analysis tool to predict patient survival. CONCLUSION The OESGs signature showed excellent performance in predicting survival and therapeutic responses for patients with HCC.
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Affiliation(s)
- Hui Ma
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
| | - Zhongchen Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Rongxin Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhenggang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
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Cho BC, Kim DW, Spira AI, Gomez JE, Haura EB, Kim SW, Sanborn RE, Cho EK, Lee KH, Minchom A, Lee JS, Han JY, Nagasaka M, Sabari JK, Ou SHI, Lorenzini P, Bauml JM, Curtin JC, Roshak A, Gao G, Xie J, Thayu M, Knoblauch RE, Park K. Amivantamab plus lazertinib in osimertinib-relapsed EGFR-mutant advanced non-small cell lung cancer: a phase 1 trial. Nat Med 2023; 29:2577-2585. [PMID: 37710001 PMCID: PMC10579096 DOI: 10.1038/s41591-023-02554-7] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 08/21/2023] [Indexed: 09/16/2023]
Abstract
Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) often develop resistance to current standard third-generation EGFR tyrosine kinase inhibitors (TKIs); no targeted treatments are approved in the osimertinib-relapsed setting. In this open-label, dose-escalation and dose-expansion phase 1 trial, the potential for improved anti-tumor activity by combining amivantamab, an EGFR-MET bispecific antibody, with lazertinib, a third-generation EGFR TKI, was evaluated in patients with EGFR-mutant NSCLC whose disease progressed on third-generation TKI monotherapy but were chemotherapy naive (CHRYSALIS cohort E). In the dose-escalation phase, the recommended phase 2 combination dose was established; in the dose-expansion phase, the primary endpoints were safety and overall response rate, and key secondary endpoints included progression-free survival and overall survival. The safety profile of amivantamab and lazertinib was generally consistent with previous experience of each agent alone, with 4% experiencing grade ≥3 events; no new safety signals were identified. In an exploratory cohort of 45 patients who were enrolled without biomarker selection, the primary endpoint of investigator-assessed overall response rate was 36% (95% confidence interval, 22-51). The median duration of response was 9.6 months, and the median progression-free survival was 4.9 months. Next-generation sequencing and immunohistochemistry analyses identified high EGFR and/or MET expression as potential predictive biomarkers of response, which will need to be validated with prospective assessment. ClinicalTrials.gov identifier: NCT02609776 .
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Affiliation(s)
- Byoung Chul Cho
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Dong-Wan Kim
- Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea
| | - Alexander I Spira
- Virginia Cancer Specialists Research Institute, US Oncology Research, Fairfax, VA, USA
| | - Jorge E Gomez
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Eric B Haura
- H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Sang-We Kim
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Rachel E Sanborn
- Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA
| | - Eun Kyung Cho
- Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Ki Hyeong Lee
- Chungbuk National University Hospital, Cheongju, Republic of Korea
| | - Anna Minchom
- Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, UK
| | - Jong-Seok Lee
- Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Ji-Youn Han
- National Cancer Center, Gyeonggi-do, Republic of Korea
| | - Misako Nagasaka
- University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange, CA, USA
| | | | - Sai-Hong Ignatius Ou
- University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange, CA, USA
| | | | | | | | | | | | - John Xie
- Janssen R&D, Spring House, PA, USA
| | | | | | - Keunchil Park
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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11
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Umeda I, Kitamura Y, Yokouchi H, Baba T. Effect of the First-Line Therapy with Osimertinib for a Metastatic Choroidal Tumor in Advanced-Stage Lung Cancer: A Case Report. Case Rep Ophthalmol 2023; 14:331-339. [PMID: 37496595 PMCID: PMC10368102 DOI: 10.1159/000531255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 05/20/2023] [Indexed: 07/28/2023] Open
Abstract
Although the advent of molecular-targeted drugs has improved the prognosis of various cancers, the long-term prognosis and side effects as the first-line therapy for metastatic choroidal tumors remain unclear. We describe a case in which the first-line therapy of osimertinib has shown long-term successful and minimum side effect responses for metastatic choroidal tumors in a patient with advanced-stage lung cancer. The patient was a 62-year-old man who complained of foggy vision and visual field defects in his left eye for 1 month. When he visited his local doctor, a serous retinal detachment was noted in the left eye, and he was referred to our hospital for further examination. The patient had no history of systemic disease. A fundus examination of his left eye showed a slightly elevated choroidal lesion along with the superior retinal vascular arcade. Optical coherence tomography showed a serous retinal detachment around the lesion. Fluorescein angiography showed that the site of the lesion had spotty and mottled hyperfluorescence in the early phase and ring hypofluorescence in the late phase. We suspected a metastatic choroidal tumor and performed a whole-body computed tomography scan, which indicated lung cancer and metastasis to the left iliac bone. The patient was referred to the department of respiratory medicine of our hospital, and after a thorough examination, a diagnosis of lung adenocarcinoma (stage IV-B, epidermal growth factor receptor [EGFR] gene mutation positive) was made. Treatment with osimertinib was initiated, and shrinkage of the primary tumor was observed. The elevated choroidal lesion and serous retinal detachment resolved after 2 months of treatment, and no recurrence was observed during the 20 months of treatment. The use of osimertinib as primary treatment for EGFR mutation-positive lung cancer was found to significantly reduce the size of metastatic choroidal tumors and to have a relatively long-lasting antitumor effect without serious ocular complications.
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Affiliation(s)
- Ikuko Umeda
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, Chiba, Japan
- Department of Ophthalmology, National Hospital Organization Chiba Medical Center,Chiba, Japan
| | - Yuta Kitamura
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hirotaka Yokouchi
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Takayuki Baba
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, Chiba, Japan
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12
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Prostate-Specific Membrane Antigen Targeted Pet/CT Imaging in Patients with Colon, Gastric and Pancreatic Cancer. Cancers (Basel) 2022; 14:cancers14246209. [PMID: 36551695 PMCID: PMC9777210 DOI: 10.3390/cancers14246209] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/08/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Current imaging modalities frequently misjudge disease stage in colorectal, gastric and pancreatic cancer. As treatment decisions are dependent on disease stage, incorrect staging has serious consequences. Previous preclinical research and case reports indicate that prostate-specific membrane antigen (PSMA)-targeted PET/CT imaging might provide a solution to some of these challenges. This prospective clinical study aims to assess the feasibility of [18F]DCFPyL PET/CT imaging to target and visualize primary colon, gastric and pancreatic cancer. In this prospective clinical trial, patients with colon, gastric and pancreatic cancer were included and underwent both [18F]DCFPyL and [18F]FDG PET/CT scans prior to surgical resection or (for gastric cancer) neoadjuvant therapy. Semiquantitative analysis of immunohistochemical PSMA staining was performed on the surgical resection specimens, and the results were correlated to imaging parameters. The results of this study demonstrate detection of the primary tumor by [18F]DCFPyL PET/CT in 7 out of 10 patients with colon, gastric and pancreatic cancer, with a mean tumor-to-blood pool ratio (TBR) of 3.3 and mean SUVmax of 3.6. However, due to the high surrounding uptake, visual distinction of these tumors was difficult, and the SUVmax and TBR on [18F]FDG PET/CT were significantly higher than on [18F]DCFPyL PET/CT. In addition, no correlation between PSMA expression in the resection specimen and SUVmax on [18F]DCFPyL PET/CT was found. In conclusion, the detection of several gastrointestinal cancers using [18F]DCFPyL PET/CT is feasible. However, low tumor expression and high uptake physiologically in organs/background hamper the clear distinction of the tumor. As a result, [18F]FDG PET/CT was superior in detecting colon, gastric and pancreatic cancers.
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13
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Hisada T, Kondo N, Wanifuchi-Endo Y, Osaga S, Fujita T, Asano T, Uemoto Y, Nishikawa S, Katagiri Y, Terada M, Kato A, Sugiura H, Okuda K, Kato H, Komura M, Morita S, Takahashi S, Toyama T. Co-expression effect of LLGL2 and SLC7A5 to predict prognosis in ERα-positive breast cancer. Sci Rep 2022; 12:16515. [PMID: 36192404 PMCID: PMC9529905 DOI: 10.1038/s41598-022-20225-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 09/09/2022] [Indexed: 11/09/2022] Open
Abstract
Lethal giant larvae homolog 2 (LLGL2) and solute carrier family 7 member 5 (SLC7A5) have been reported to be involved in resistance to endocrine therapy. This study aimed to assess the effects of LLGL2/SLC7A5 co-expression in predicting prognosis and response to tamoxifen therapy in ERα-positive breast cancer patients according to LLGL2/SLC7A5 mRNA and protein expression in long-term follow-up invasive breast cancer tissues. We identified that low LLGL2/SLC7A5 mRNA co-expression (LLGL2low/SLC7A5low) was associated with disease-free survival (DFS) compared with other combination groups in all breast cancer patients. In ERα-positive breast cancer patients, LLGL2low/SLC7A5low showed longer DFS and overall survival (OS) compared with LLGL2high/SLC7A5high and a positive trend of longer survival compared with the other combination groups. We also observed that LLGL2low/SLC7A5low showed longer survival compared with LLGL2high/SLC7A5high in ERα-positive breast cancer patients receiving adjuvant tamoxifen therapy. Multivariate analysis demonstrated that LLGL2low/SLC7A5low was an independent favorable prognostic factor of both DFS and OS, not only in all breast cancer patients, but also in ERα-positive breast cancer patients. High co-expression of LLGL2 and SLC7A5 protein showed a positive trend of shorter survival. Our study showed that co-expression of LLGL2 and SLC7A5 mRNA is a promising candidate biomarker in early breast cancer patients.
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Affiliation(s)
- Tomoka Hisada
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Naoto Kondo
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Yumi Wanifuchi-Endo
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Satoshi Osaga
- Clinical Research Management Center, Nagoya City University Hospital, Nagoya, Aichi, Japan
| | - Takashi Fujita
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Tomoko Asano
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Yasuaki Uemoto
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Sayaka Nishikawa
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Yusuke Katagiri
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Mitsuo Terada
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Akiko Kato
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Hiroshi Sugiura
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.,Department of Breast and Endocrine Surgery, Nagoya City University West Medical Center, Nagoya, Aichi, Japan
| | - Katsuhiro Okuda
- Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Hiroyuki Kato
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Masayuki Komura
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Satoru Takahashi
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Tatsuya Toyama
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.
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14
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Kartal B, Bozkurt MF, Alimoğullari E, Saçık U. The protective effect of erythropoietin on ischemia- reperfusion injury caused by ovarian torsion-detorsion in the experimental rat model. J Histotechnol 2022; 46:57-64. [DOI: 10.1080/01478885.2022.2122653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Affiliation(s)
- Bahar Kartal
- Medical Faculty, Department of Histology and Embryology, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Mehmet Fatih Bozkurt
- Department of Pathology, Faculty of Veterinary Medicine, Afyon Kocatepe University, Afyon, Turkey
| | - Ebru Alimoğullari
- Department of Histology and Embryology, Medical Faculty, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Uygar Saçık
- Department of Histology and Embryology, Medical Faculty, Ankara Yıldırım Beyazıt University, Ankara, Turkey
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15
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Zhang S, Gao J, Niu R, Ye J, Ma J, Jiang L, Shao X. Association between squamous cell carcinoma antigen level and EGFR mutation status in Chinese lung adenocarcinoma patients. J Clin Lab Anal 2022; 36:e24613. [PMID: 35838003 PMCID: PMC9459300 DOI: 10.1002/jcla.24613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/02/2022] [Accepted: 07/05/2022] [Indexed: 12/24/2022] Open
Abstract
Background To investigate the association between squamous cell carcinoma antigen (SCCAg) level and epidermal growth factor receptor (EGFR) mutation status in Chinese lung adenocarcinoma patients. Methods We retrospectively analyzed 293 patients with lung adenocarcinoma, divided into EGFR mutant group (n = 178) and EGFR wild‐type group (n = 115). The general data and laboratory parameters of the two groups were compared. We used univariable and multivariable logistic regression to analyze the association between SCCAg level and EGFR mutation. Generalized additive model was used for curve fitting, and a hierarchical binary logistic regression model was used for interaction analysis. Results Squamous cell carcinoma antigen level in the EGFR wild‐type group was significantly higher than that in the mutant group (p < 0.001). After adjusting for confounding factors, we found that elevated SCCAg was associated with a lower probability of EGFR mutation, with an OR of 0.717 (95% CI: 0.543–0.947, p = 0.019). For the tripartite SCCAg groups, the increasing trend of SCCAg was significantly associated with the decreasing probability of EGFR mutation (p for trend = 0.015), especially for Tertile 3 versus Tertile 1 (OR = 0.505; 95% CI: 0.258–0.986; p = 0.045). Curve fitting showed that there was an approximate linear negative relationship between continuous SCCAg and EGFR mutation probability (p = 0.020), which was first flattened and then decreased (p < 0.001). The association between the two was consistent among different subgroups, suggesting no interaction (all p > 0.05). Conclusion There is a negative association between SCCAg level and EGFR mutation probability in Chinese lung adenocarcinoma patients.
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Affiliation(s)
- Shuying Zhang
- Department of Clinical Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jianxiong Gao
- Department of Nuclear Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Changzhou Key Laboratory of Molecular Imaging, Changzhou, China
| | - Rong Niu
- Department of Nuclear Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Changzhou Key Laboratory of Molecular Imaging, Changzhou, China
| | - Jiru Ye
- Department of Respiratory and Critical Care Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jinhong Ma
- Department of Clinical Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Lijuan Jiang
- Department of Clinical Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xiaonan Shao
- Department of Nuclear Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Changzhou Key Laboratory of Molecular Imaging, Changzhou, China
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16
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Field MG, Boldt HC, Abu Hejleh T, Binkley EM. Successful response to first-line treatment with osimertinib for choroidal metastasis from EGFR-mutated non-small-cell lung cancer. Am J Ophthalmol Case Rep 2022; 26:101459. [PMID: 35265776 PMCID: PMC8899229 DOI: 10.1016/j.ajoc.2022.101459] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 01/21/2022] [Accepted: 02/24/2022] [Indexed: 11/05/2022] Open
Abstract
Purpose Describe the use of osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, as the first-line treatment in a patient with choroidal and central nervous system metastases from EGFR-mutated non-small cell lung cancer. Observations A 68-year-old man presented with an amelanotic choroidal lesion in the left eye concerning for choroidal metastasis. Systemic evaluation identified widely metastatic adenocarcinoma of the lung with EGFR exon 19 mutation. Within one month of initiating treatment with osimertinib, there was complete resolution of the subretinal fluid over the choroidal lesion and decreased thickness of the lesion. At follow-up after three months of treatment, the lesion was clinically involuted. Positron emission tomography at two months and magnetic resonance imaging of the brain at three months showed significant interval decrease in size and activity of the primary right lung lesion, central nervous system lesions, and other metastatic sites with no new metastatic lesions. After 17 months of follow up, the lesion remained involuted. Conclusions and Importance Osimertinib may be considered as a first-line treatment option in patients with choroidal metastases from an EGFR-mutated non-small cell lung cancer.
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17
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Kir MC, Onal MO, Uluer ET, Ulman C, Inan S. Continuous and intermittent parathyroid hormone administration promotes osteogenic differentiation and activity of programmable cells of monocytic origin. Biotech Histochem 2022; 97:593-603. [PMID: 35473476 DOI: 10.1080/10520295.2022.2049876] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Bone healing deficiencies are challenging for orthopedic practice. The use of stem cells with scaffolds to treat bone tissue losses currently is popular for promoting regeneration of tissue. Programmable cells of monocytic origin (PCMO) may differentiate into three germ layers and may be a promising alternative treatment due to their stem cell-like properties. Parathyroid hormone (PTH) participates in bone metabolism. Intermittent administration of PTH promotes osteogenic activity of mesenchymal stem cdells (MSC). We investigated the osteogenic effects of continuous and intermittent administration of PTH on PCMO. Mononuclear cells were harvested from the peripheral blood of healthy donors. Isolated cells were cultured for six days in a de-differentiation medium. Indirect immunocytochemistry using anti-CD14, anti-CD45 and anti-CD90 primary antibodies, as well as electron microscopy were used to detect PCMO. PCMO then were cultured in an osteogenic differentiation medium supplemented with continuous or intermittent 50 ng/ml PTH. The PTH-free control group (CG), intermittent PTH treated group (IPG) and continuous PTH treated group (CPG) were cultured and assessed for their differentiation into osteogenic lineage cells by indirect immunocytochemistry using anti-collagen I, anti-osteonectin and anti-osteocalcin primary antibodies. Osteoblast-like cells obtained by continuous or intermittent PTH administration exhibited increased levels of collagen I, osteonectin and osteocalcin immunoreactivity. We found that continuous and intermittent PTH administration to PCMO enhanced their differentiation to osteogenic lineage cells and increased osteoblastic activity.
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Affiliation(s)
- M C Kir
- Department of Orthopedics and Traumatology, Okmeydani Training and Research Hospital, Istanbul, Turkey
| | - M O Onal
- Department of Histology & Embryology, Faculty of Medicine, Mugla Sitki Kocman University, Mugla, Turkey
| | - E T Uluer
- Department of Histology & Embryology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey
| | - C Ulman
- Department of Biochemistry, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey
| | - S Inan
- Department of Histology & Embryology, Faculty of Medicine, Izmir University of Economics, Izmir, Turkey
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18
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Nikas IP, Lee C, Song MJ, Kim B, Ryu HS. Biomarkers expression among paired serous ovarian cancer primary lesions and their peritoneal cavity metastases in treatment-naïve patients: A single-center study. Cancer Med 2022; 11:2193-2203. [PMID: 35212471 PMCID: PMC9160817 DOI: 10.1002/cam4.4600] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/30/2021] [Accepted: 01/04/2022] [Indexed: 12/17/2022] Open
Abstract
Background High‐grade serous ovarian carcinoma (HGSOC), the most common histologic subtype of ovarian epithelial cancer, is associated with treatment resistance, enhanced recurrence rates, and poor prognosis. HGSOCs often metastasize to the peritoneal cavity, while fluid cytology examination could identify such metastases. This retrospective study aimed to identify potential biomarker discrepancies between paired HGSOC primary tissues and metastatic peritoneal fluid cytology samples, processed as cell blocks (CBs). Methods Twenty‐four pairs of formalin‐fixed, paraffin‐embedded primary tissues and metastatic CBs from an equal number of treatment‐naïve patients were used, and immunohistochemistry (IHC) for epidermal growth factor receptor (EGFR), human epidermal growth factor receptor, programmed cell death‐1 ligand 1 (PD‐L1), and CD147 was applied. Results 13/24 pairs showed discordant EGFR IHC results; in all these 13 patients, EGFR was positive (≥1+ membranous staining intensity found in at least 10% of the cancer cells) in the peritoneal, yet negative in the primary tissue samples. Notably, EGFR IHC was positive in 15/24 of the metastatic, whereas in just 2/24 of the primary HGSOC samples (p < 0.001). Although most PD‐L1 results were concordant, 5/24 and 6/24 pairs exhibited discordant results when stained with the E1L3N and 22C3 clones, respectively. Lastly, CD147 overexpression was found more often in the metastatic rather than the matched primary HGSOCs stained with CD147, though the difference was not significant. Conclusions Cytology from effusions could be considered for biomarker testing when present, even when tissue from the primary cancer is also available and adequately cellular, as it could provide additional information of potential clinical significance.
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Affiliation(s)
- Ilias P. Nikas
- School of Medicine, European University CyprusNicosiaCyprus
| | - Cheol Lee
- Department of Pathology, Seoul National University HospitalSeoulRepublic of Korea
| | - Min Ji Song
- Center for Medical Innovation, Biomedical Research Institute, Seoul National University HospitalSeoulRepublic of Korea
| | - Bohyun Kim
- Department of Pathology, Seoul National University HospitalSeoulRepublic of Korea
| | - Han Suk Ryu
- Department of Pathology, Seoul National University HospitalSeoulRepublic of Korea
- Center for Medical Innovation, Biomedical Research Institute, Seoul National University HospitalSeoulRepublic of Korea
- Department of Pathology, Seoul National University College of MedicineSeoulRepublic of Korea
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19
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Lee WY, Gutierrez-Lanz EA, Xiao H, McClintock D, Chan MP, Bixby DL, Shao L. ERG amplification is a secondary recurrent driver event in myeloid malignancy with complex karyotype and TP53 mutations. Genes Chromosomes Cancer 2022; 61:399-411. [PMID: 35083818 DOI: 10.1002/gcc.23027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 01/06/2022] [Accepted: 01/09/2022] [Indexed: 11/09/2022] Open
Abstract
ERG is a transcription factor encoded on chromosome 21q22.2 with important roles in hematopoiesis and oncogenesis of prostate cancer. ERG amplification has been identified as one of the most common recurrent events in acute myeloid leukemia with complex karyotype (AML-CK). In this study, we uncover 3 different modes of ERG amplification in AML-CK. Importantly, we present evidence to show that ERG amplification is distinct from intrachromosomal amplification of chromosome 21 (iAMP21), a hallmark segmental amplification frequently encompassing RUNX1 and ERG in a subset of high-risk B-lymphoblastic leukemia. We also characterize the association with TP53 aberrations and other chromosomal aberrations, including chromothripsis. Lastly, we show that ERG amplification can initially emerge as subclonal events in low grade myeloid neoplasms. These findings demonstrate that ERG amplification is a recurrent secondary driver event in AML and raise the tantalizing possibility of ERG as a therapeutic target. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Winston Y Lee
- Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Efrain A Gutierrez-Lanz
- Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Hong Xiao
- Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - David McClintock
- Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - May P Chan
- Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Dale L Bixby
- Division of Hematology and Medical Oncology, Department of Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Lina Shao
- Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
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20
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Endometrial stromal cell ferroptosis promotes angiogenesis in endometriosis. Cell Death Dis 2022; 8:29. [PMID: 35039492 PMCID: PMC8763888 DOI: 10.1038/s41420-022-00821-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 12/09/2021] [Accepted: 12/23/2021] [Indexed: 02/07/2023]
Abstract
Endometriosis, a chronic disorder characterised by the presence of endometrial-like tissue outside the uterus, is associated with iron overload and oxidative stress in the lesion. Although it is well established that iron overload can trigger ferroptosis, the results of previous studies on ferroptosis resistance and ferroptosis in endometriotic lesions are paradoxical. Here, we found that some stromal cells of the cyst walls that were in contact with the cyst fluid underwent ferroptosis. Surprisingly, endometrial stromal cell ferroptosis triggered the production of angiogenic, inflammatory and growth cytokines. In particular, angiogenic cytokines, such as vascular endothelial growth factor A (VEGFA) and interleukin 8 (IL8), promoted human umbilical vein endothelial cell (HUVEC) vascular formation in vitro. Moreover, we found that inhibition of p38 mitogen-activated protein kinase/signal transducer and activator of transcription 6 (p38 MAPK/STAT6) signalling represses VEGFA and IL8 expression when endometrial stromal cells undergo ferroptosis. Notably, VEGFA and IL8 showed localised expression and were significantly upregulated in ectopic lesions compared to control and eutopic endometrium samples from patients with endometriosis. Thus, our study reveals that endometrial stromal cell ferroptosis in the ovarian endometrioma may trigger cytokine secretion and promote angiogenesis of adjacent lesions via paracrine actions to drive the development of endometriosis, providing a rationale for translation into clinical practice and developing drugs for endometriosis.
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21
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Wanifuchi-Endo Y, Kondo N, Dong Y, Fujita T, Asano T, Hisada T, Uemoto Y, Nishikawa S, Katagiri Y, Kato A, Terada M, Sugiura H, Okuda K, Kato H, Takahashi S, Toyama T. Discovering novel mechanisms of taxane resistance in human breast cancer by whole-exome sequencing. Oncol Lett 2022; 23:60. [PMID: 34992692 PMCID: PMC8721851 DOI: 10.3892/ol.2021.13178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 11/12/2021] [Indexed: 11/17/2022] Open
Abstract
Taxanes are important drugs used in the treatment of breast cancer; however, some cancer types are taxane-resistant. The aim of the present study was to investigate the underlying mechanisms of taxane resistance using whole-exome sequencing (WES). Six patients with breast cancer whose tumors responded well to anthracycline treatment but grew rapidly during neoadjuvant taxane-based chemotherapy, were included in the present study. WES of samples from these patients was carried out to identify somatic mutations of candidate genes thought to affect taxane resistance, and the candidate proteins were structurally modeled. The mRNA and protein expression levels of these candidate genes in other breast cancers treated with taxanes were also examined. Nine variants common to all six patients were identified and two of these [R552P in V-type proton ATPase catalytic subunit A (ATP6V1A) and T114P in apolipoprotein B MRNA editing enzyme catalytic subunit 3F (APOBEC3F)] were selected. The results also showed that, protein-structure visualization suggested that these mutations may cause structural changes. The Kaplan-Meier analyses revealed that higher APT6V1A and APOBEC3F expression levels were significantly associated with poorer disease-free survival (DFS) and overall survival. Moreover, multivariate analysis identified high ATP6V1A mRNA expression as an independent risk factor for poor DFS. Two specific mutations that might affect taxane resistance were identified. Thus, these results suggest that breast cancer patients receiving taxanes who have high ATP6V1A or APOBEC3F expression levels may have shorter survival.
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Affiliation(s)
- Yumi Wanifuchi-Endo
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Naoto Kondo
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Yu Dong
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Takashi Fujita
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Tomoko Asano
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Tomoka Hisada
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Yasuaki Uemoto
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Sayaka Nishikawa
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Yusuke Katagiri
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Akiko Kato
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Mitsuo Terada
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Hiroshi Sugiura
- Education and Research Center for Advanced Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Katsuhiro Okuda
- Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Hiroyuki Kato
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Satoru Takahashi
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Tatsuya Toyama
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
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22
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Qu S, Fetsch P, Thomas A, Pommier Y, Schrump DS, Miettinen MM, Chen H. Molecular Subtypes of Primary SCLC Tumors and Their Associations With Neuroendocrine and Therapeutic Markers. J Thorac Oncol 2022; 17:141-153. [PMID: 34534680 PMCID: PMC8692365 DOI: 10.1016/j.jtho.2021.08.763] [Citation(s) in RCA: 95] [Impact Index Per Article: 31.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 07/27/2021] [Accepted: 08/27/2021] [Indexed: 01/03/2023]
Abstract
INTRODUCTION A new molecular subtype classification was recently proposed for SCLC. It is necessary to validate it in primary SCLC tumors by immunohistochemical (IHC) staining and define its clinical relevance. METHODS We used IHC to assess four subtype markers (ASCL1, NEUROD1, POU2F3, and YAP1) in 194 cores from 146 primary SCLC tumors. The profiles of tumor-associated CD3+ and CD8+ T-cells, MYC paralogs, SLFN11, and SYP were compared among different subtypes. Validation was performed using publicly available RNA sequencing data of SCLC. RESULTS ASCL1, NEUROD1, POU2F3, and YAP1 were the dominant molecular subtypes in 78.2%, 5.6%, 7%, and 2.8% of the tumors, respectively; 6.3% of the tumors were negative for all four subtype markers. Notably, three cases were uniquely positive for YAP1. Substantial intratumoral heterogeneity was observed, with 17.6% and 2.8% of the tumors being positive for two and three subtype markers, respectively. The non-ASCL1/NEUROD1 tumors had more CD8+ T-cells and manifested more frequently an "inflamed" immunophenotype. L-MYC and MYC were more often associated with ASCL1/NEUROD1 subtypes and non-ASCL1/NEUROD1 subtypes, respectively. SLFN11 expression was absent in 40% of the tumors, especially those negative for the four subtype markers. SYP was often expressed in the ASCL1 and NEUROD1 subtypes and was associated with less tumor-associated CD8+ T-cells and a "desert" immunophenotype. CONCLUSIONS We validated the new molecular subtype classification in primary SCLC tumors by IHC and identified several intriguing associations between subtypes and therapeutic markers. The new subtype classification may potentially assist treatment decisions in SCLC.
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Affiliation(s)
- Song Qu
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Patricia Fetsch
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Anish Thomas
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Yves Pommier
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - David S Schrump
- Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Markku M Miettinen
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Haobin Chen
- Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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23
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Perdrizet K, Sutradhar R, Li Q, Liu N, Earle CC, Leighl NB. Second and later-line erlotinib use in non-small cell lung cancer: real world outcomes and practice patterns overtime in Canada. J Thorac Dis 2021; 13:5419-5429. [PMID: 34659808 PMCID: PMC8482335 DOI: 10.21037/jtd-21-804] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 08/06/2021] [Indexed: 12/25/2022]
Abstract
Background In Canada, epidermal growth factor receptor (EGFR) inhibitor therapies in advanced non-small cell lung cancer (NSCLC) were initially approved regardless of EGFR status. The purpose of this study is to characterise the use of second or later-line erlotinib therapy in Ontario, Canada from 2007–2016, as well as evaluate the impact of erlotinib therapy on survival and emergency department (ED) visits in a real-world population. Methods This is a retrospective cohort study derived at ICES (formerly known as the Institute for Clinical and Evaluative Sciences) of advanced NSCLC patients diagnosed from 2007–2016 in Ontario, Canada, over the age of 65, who received at least one dose of first-line chemotherapy. The exposure of interest was receipt of second or later-line erlotinib. The primary outcome was the hazard ratio for mortality evaluated using a Cox proportional hazards model, and the secondary outcome, ED visits, was evaluated using a Poisson model. Results First-line chemotherapy was administered in 30.4% of stage IV NSCLC patients. Of these patients, 19.7% received second or later-line erlotinib. The proportion of patients prescribed second or later-line erlotinib decreased over the course of the study (P<0.0001). Unadjusted median overall survival in the entire cohort was 325 days (95% CI: 314–337 days), 513 days (95% CI: 485–539 days) in the erlotinib cohort, and 282 days (95% CI: 270–291 days) in the non-erlotinib cohort. Despite this, the adjusted hazard ratio for death was 1.89 (95% CI: 1.73–2.07, P<0.0001) for patients on erlotinib. Patients receiving erlotinib also had a marginally higher relative rates of ED visits with an adjusted relative risk of 1.10 (95% CI: 1.02–1.19, P=0.013). Conclusions This study highlights the importance of using EGFR targeted treatments in NSCLC patients with a predictive biomarker, and suggests that treatment with erlotinib therapy is unlikely to benefit unselected patients with advanced NSCLC.
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Affiliation(s)
- Kirstin Perdrizet
- Department of Oncology and Hematology, Princess Margaret Cancer Centre/University Health Network, Toronto, Canada.,Division of Oncology, William Osler Health System, Brampton, Canada.,Department of Medicine, University of Toronto, Toronto, ON, Canada.,Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
| | - Rinku Sutradhar
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada.,ICES (formerly the Institute for Clinical and Evaluates Sciences), Toronto, Canada.,Department of Biostatistics, Dalla Lana School of Public Health at the University of Toronto, Toronto, Canada
| | - Qing Li
- ICES (formerly the Institute for Clinical and Evaluates Sciences), Toronto, Canada
| | - Ning Liu
- ICES (formerly the Institute for Clinical and Evaluates Sciences), Toronto, Canada
| | - Craig C Earle
- Department of Medicine, University of Toronto, Toronto, ON, Canada.,ICES (formerly the Institute for Clinical and Evaluates Sciences), Toronto, Canada.,Department of Oncology and Hematology, Sunnybrook Health Sciences Centre, Toronto, Canada
| | - Natasha B Leighl
- Department of Oncology and Hematology, Princess Margaret Cancer Centre/University Health Network, Toronto, Canada.,Department of Medicine, University of Toronto, Toronto, ON, Canada.,Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
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24
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Wang B, Zhang W, Zhang G, Kwong L, Lu H, Tan J, Sadek N, Xiao M, Zhang J, Labrie M, Randell S, Beroard A, Sugarman E, Rebecca VW, Wei Z, Lu Y, Mills GB, Field J, Villanueva J, Xu X, Herlyn M, Guo W. Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma. Oncogene 2021; 40:5590-5599. [PMID: 34304249 PMCID: PMC8445818 DOI: 10.1038/s41388-021-01911-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 06/14/2021] [Accepted: 06/17/2021] [Indexed: 12/30/2022]
Abstract
Targeting MAPK pathway using a combination of BRAF and MEK inhibitors is an efficient strategy to treat melanoma harboring BRAF-mutation. The development of acquired resistance is inevitable due to the signaling pathway rewiring. Combining western blotting, immunohistochemistry, and reverse phase protein array (RPPA), we aim to understanding the role of the mTORC1 signaling pathway, a center node of intracellular signaling network, in mediating drug resistance of BRAF-mutant melanoma to the combination of BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) therapy. The mTORC1 signaling pathway is initially suppressed by BRAFi and MEKi combination in melanoma but rebounds overtime after tumors acquire resistance to the combination therapy (CR) as assayed in cultured cells and PDX models. In vitro experiments showed that a subset of CR melanoma cells was sensitive to mTORC1 inhibition. The mTOR inhibitors, rapamycin and NVP-BEZ235, induced cell cycle arrest and apoptosis in CR cell lines. As a proof-of-principle, we demonstrated that rapamycin and NVP-BEZ235 treatment reduced tumor growth in CR xenograft models. Mechanistically, AKT or ERK contributes to the activation of mTORC1 in CR cells, depending on PTEN status of these cells. Our study reveals that mTOR activation is essential for drug resistance of melanoma to MAPK inhibitors, and provides insight into the rewiring of the signaling networks in CR melanoma.
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Affiliation(s)
- Beike Wang
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Wei Zhang
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Gao Zhang
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
- Department of Neurosurgery, The Preston Robert Tisch Brain Tumor Center and Department of Pathology, Duke University Medical Center, Durham, NC, USA
| | - Lawrence Kwong
- Department of Translation Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hezhe Lu
- Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Jiufeng Tan
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Norah Sadek
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Min Xiao
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Jie Zhang
- Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA
| | - Marilyne Labrie
- Department of Cell, Developmental and Cancer Biology, School of Medicine, and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Sergio Randell
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Aurelie Beroard
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Eric Sugarman
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Vito W Rebecca
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Zhi Wei
- Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA
| | - Yiling Lu
- Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Gordon B Mills
- Department of Cell, Developmental and Cancer Biology, School of Medicine, and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Jeffrey Field
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jessie Villanueva
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Xiaowei Xu
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Meenhard Herlyn
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
| | - Wei Guo
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, USA.
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25
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Han S, Cicek AF, Tokmak A, Yildirir Ustun T, Ercan Gokay N, Uludag MO, Demirel MA. Effects of Resveratrol on Receptor Expression and Serum Levels of Estrogen and Progesterone in the Rat Endometritis Model. Reprod Sci 2021; 28:2610-2622. [PMID: 33966185 DOI: 10.1007/s43032-021-00586-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 04/15/2021] [Indexed: 11/24/2022]
Abstract
Endometritis is characterized by inflammation of the endometrial lining that leads to reduced reproductive potential. Restoring the impaired hormonal balance is an important component of endometritis treatment. The purpose of the current study was to evaluate the effects of resveratrol on estrogen and progesterone hormone status in endometritis. Mature female Sprague Dawley rats were used, and endometritis was induced by intrauterine infusion of Escherichia coli. Animals were treated with resveratrol alone or combined with marbofloxacin. Compared to the non-treated endometritis group, resveratrol treatment reduced serum oestradiol levels, increased serum progesterone levels, enhanced estrogen receptor (ER) expression in the uterine stroma, decreased ESR1 gene expression, and raised ESR2 gene expression. Resveratrol administration combined with marbofloxacin also increased ER expression in the uterine gland and progesterone receptor expression in the uterine epithelium. The findings of this study suggest that the actions of resveratrol on progesterone levels and estrogen receptor expression might be responsible for its beneficial effect in rats with endometritis.
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Affiliation(s)
- Sevtap Han
- Department of Pharmacology, Faculty of Pharmacy, Gazi University, Etiler, 06330, Ankara, Turkey.
| | - Ali Fuat Cicek
- Department of Pathology, Gülhane Research and Education Hospital, Etlik, 06010, Ankara, Turkey
| | - Aytekin Tokmak
- Department of Obstetrics and Gynecology, Zekai Tahir Burak Women's Health Research and Education Hospital, Altindag, 06230, Ankara, Turkey
| | - Tugce Yildirir Ustun
- Department of Microbiology, Faculty of Veterinary, Ankara University, Dışkapı, 06110, Ankara, Turkey
| | - Nilufer Ercan Gokay
- Department of Obstetrics and Gynecology, Zekai Tahir Burak Women's Health Research and Education Hospital, Altindag, 06230, Ankara, Turkey
| | - Mecit Orhan Uludag
- Department of Pharmacology, Faculty of Pharmacy, Gazi University, Etiler, 06330, Ankara, Turkey
| | - Murside Ayse Demirel
- Laboratory Animal Care and Research Unit, Department of Pharmacology, Faculty of Pharmacy, Gazi University, Etiler, 06330, Ankara, Turkey
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26
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Wiedenmann S, Breunig M, Merkle J, von Toerne C, Georgiev T, Moussus M, Schulte L, Seufferlein T, Sterr M, Lickert H, Weissinger SE, Möller P, Hauck SM, Hohwieler M, Kleger A, Meier M. Single-cell-resolved differentiation of human induced pluripotent stem cells into pancreatic duct-like organoids on a microwell chip. Nat Biomed Eng 2021; 5:897-913. [PMID: 34239116 PMCID: PMC7611572 DOI: 10.1038/s41551-021-00757-2] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 06/01/2021] [Indexed: 02/06/2023]
Abstract
Creating in vitro models of diseases of the pancreatic ductal compartment requires a comprehensive understanding of the developmental trajectories of pancreas-specific cell types. Here we report the single-cell characterization of the differentiation of pancreatic duct-like organoids (PDLOs) from human induced pluripotent stem cells (hiPSCs) on a microwell chip that facilitates the uniform aggregation and chemical induction of hiPSC-derived pancreatic progenitors. Using time-resolved single-cell transcriptional profiling and immunofluorescence imaging of the forming PDLOs, we identified differentiation routes from pancreatic progenitors through ductal intermediates to two types of mature duct-like cells and a few non-ductal cell types. PDLO subpopulations expressed either mucins or the cystic fibrosis transmembrane conductance regulator, and resembled human adult duct cells. We also used the chip to uncover ductal markers relevant to pancreatic carcinogenesis, and to establish PDLO co-cultures with stellate cells, which allowed for the study of epithelial-mesenchymal signalling. The PDLO microsystem could be used to establish patient-specific pancreatic duct models.
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Affiliation(s)
- Sandra Wiedenmann
- Helmholtz Pioneer Campus, Helmholtz Zentrum München, Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany
| | - Markus Breunig
- Department of Internal Medicine I, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany
| | - Jessica Merkle
- Department of Internal Medicine I, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany
| | - Christine von Toerne
- Research Unit Protein Science, Helmholtz Zentrum München, Heidemannstraße 1, 80939 Müunich, Germany
| | - Tihomir Georgiev
- Helmholtz Pioneer Campus, Helmholtz Zentrum München, Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany
| | - Michel Moussus
- Helmholtz Pioneer Campus, Helmholtz Zentrum München, Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany
| | - Lucas Schulte
- Department of Internal Medicine I, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany
| | - Thomas Seufferlein
- Department of Internal Medicine I, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany
| | - Michael Sterr
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany,German Center for Diabetes Research (DZD), Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany
| | - Heiko Lickert
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany,German Center for Diabetes Research (DZD), Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany,Institute of Stem Cell Research, Helmholtz Zentrum München, Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany,Technical University of Munich, School of Medicine, Ismaninger Straße 22, 81675 Munich, Germany
| | | | - Peter Möller
- Institute for Pathology, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany
| | - Stefanie M. Hauck
- Research Unit Protein Science, Helmholtz Zentrum München, Heidemannstraße 1, 80939 Müunich, Germany
| | - Meike Hohwieler
- Department of Internal Medicine I, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany,Corresponding authors: ; ;
| | - Alexander Kleger
- Department of Internal Medicine I, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany,Corresponding authors: ; ;
| | - Matthias Meier
- Helmholtz Pioneer Campus, Helmholtz Zentrum München, Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany,Technical University of Munich, School of Medicine, Ismaninger Straße 22, 81675 Munich, Germany,Corresponding authors: ; ;
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27
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Winham SJ, Wang C, Heinzen EP, Bhagwate A, Liu Y, McDonough SJ, Stallings-Mann ML, Frost MH, Vierkant RA, Denison LA, Carter JM, Sherman ME, Radisky DC, Degnim AC, Cunningham JM. Somatic mutations in benign breast disease tissues and association with breast cancer risk. BMC Med Genomics 2021; 14:185. [PMID: 34261476 PMCID: PMC8278587 DOI: 10.1186/s12920-021-01032-8] [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] [Scholar Register] [Received: 10/12/2020] [Accepted: 07/06/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Benign breast disease (BBD) is a risk factor for breast cancer (BC); however, little is known about the genetic alterations present at the time of BBD diagnosis and how these relate to risk of incident BC. METHODS A subset of a long-term BBD cohort was selected to examine DNA variation across three BBD groups (42 future estrogen receptor-positive (ER+) BC, 36 future estrogen receptor-negative (ER-) BC, and 42 controls cancer-free for at least 16 years post-BBD). DNA extracted from archival formalin fixed, paraffin-embedded (FFPE) tissue blocks was analyzed for presence of DNA alterations using a targeted panel of 93 BC-associated genes. To address artifacts frequently observed in FFPE tissues (e.g., C>T changes), we applied three filtering strategies based on alternative allele frequencies and nucleotide substitution context. Gene-level associations were performed using two types of burden tests and adjusted for clinical and technical covariates. RESULTS After filtering, the variant frequency of SNPs in our sample was highly consistent with population allele frequencies reported in 1 KG/ExAC (0.986, p < 1e-16). The top ten genes found to be nominally associated with later cancer status by four of 12 association methods(p < 0.05) were MED12, MSH2, BRIP1, PMS1, GATA3, MUC16, FAM175A, EXT2, MLH1 and TGFB1, although these were not statistically significant in permutation testing. However, all 10 gene-level associations had OR < 1 with lower mutation burden in controls compared to cases, which was marginally statistically significant in permutation testing (p = 0.04). Comparing between the three case groups, BBD ER+ cases were closer to controls in mutation profile, while BBD ER- cases were distinct. Notably, the variant burden was significantly higher in controls than in either ER+ or ER- cases. CD45 expression was associated with mutational burden (p < 0.001). CONCLUSIONS Somatic mutations were more frequent in benign breast tissue from women who did not develop cancer, opening questions of clonal diversity or immune-mediated restraint on future cancer development. CD45 expression was positively associated with mutational burden, most strongly in controls. Further studies in both normal and premalignant tissues are needed to better understand the role of somatic gene mutations and their contribution to future cancer development.
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Affiliation(s)
- Stacey J Winham
- Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Chen Wang
- Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Ethan P Heinzen
- Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Aditya Bhagwate
- Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Yuanhang Liu
- Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Samantha J McDonough
- Medical Genome Facility, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | | | - Marlene H Frost
- Women's Cancer Program, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Robert A Vierkant
- Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Lori A Denison
- Information Technology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Jodi M Carter
- Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Mark E Sherman
- Epidemiology and Laboratory Medicine and Pathology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, 32224, USA
| | - Derek C Radisky
- Cancer Biology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, 32224, USA
| | - Amy C Degnim
- Breast, Endocrine, Metabolic and GI Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Julie M Cunningham
- Experimental Pathology and Laboratory Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
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Kol A, Lubbers JM, Terwindt ALJ, Workel HH, Plat A, Wisman GBA, Bart J, Nijman HW, De Bruyn M. Combined STING levels and CD103+ T cell infiltration have significant prognostic implications for patients with cervical cancer. Oncoimmunology 2021; 10:1936391. [PMID: 34178428 PMCID: PMC8205031 DOI: 10.1080/2162402x.2021.1936391] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Activation of STimulator of INterferon Genes (STING) is important for induction of anti-tumor immunity. A dysfunctional STING pathway is observed in multiple cancer types and associates with poor prognosis and inferior response to immunotherapy. However, the association between STING and prognosis in virally induced cancers such as HPV-positive cervical cancer remains unknown. Here, we investigated the prognostic value of STING protein levels in cervical cancer using tumor tissue microarrays of two patient groups, primarily treated with surgery (n = 251) or radio(chemo)therapy (n = 255). We also studied CD103, an integrin that marks tumor-reactive cytotoxic T cells that reside in tumor epithelium and that is reported to associate with improved prognosis. Notably, we found that a high level of STING protein was an independent prognostic factor for improved survival in both the surgery and radio(chemo)therapy group. High infiltration of CD103+ T cells was associated with improved survival in the radio(chemo)therapy group. The combination of STING levels and CD103+ T cell infiltration is strongly associated with improved prognosis. We conclude that combining the prognostic values of STING and CD103 may improve the risk stratification of cervical cancer patients, independent from established clinical prognostic parameters.
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Affiliation(s)
- Arjan Kol
- University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands
| | - Joyce M Lubbers
- University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands
| | - Anouk L J Terwindt
- University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands
| | - Hagma H Workel
- University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands
| | - Annechien Plat
- University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands
| | - G Bea A Wisman
- University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands
| | - Joost Bart
- University of Groningen, University Medical Center Groningen, Department of Pathology, The Netherlands
| | - Hans W Nijman
- University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands
| | - Marco De Bruyn
- University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands
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Tampakis A, Weixler B, Rast S, Tampaki EC, Cremonesi E, Kancherla V, Tosti N, Kettelhack C, Ng CKY, Delko T, Soysal SD, von Holzen U, Felekouras E, Nikiteas N, Bolli M, Tornillo L, Terracciano L, Eppenberger-Castori S, Spagnoli GC, Piscuoglio S, von Flüe M, Däster S, Droeser RA. Nestin and CD34 expression in colorectal cancer predicts improved overall survival. Acta Oncol 2021; 60:727-734. [PMID: 33734917 DOI: 10.1080/0284186x.2021.1891280] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Nestin, a class VI intermediate filament protein of the cytoskeleton, and CD34, a transmembrane phosphoglycoprotein, are markers of progenitor cells. This study aimed to evaluate their expression and clinical significance in colorectal cancer. METHODS A clinically annotated tissue microarray, including 599 patients with colorectal cancer, was analyzed by immunohistochemistry. Furthermore, nestin and CD34 correlations with HIF-1a and a panel of cytokines and chemokines were assessed using quantitative reverse transcription PCR and The Cancer Genome Atlas dataset. RESULTS Expression of nestin and CD34 was observed only in the tumor stroma. Patients displaying high expression of nestin and CD34 demonstrated higher rates of T1 and T2 tumors (p = .020), lower vascular invasion (p < .001) and improved 5-year overall survival (65%; 95% CI = 55-73 vs 45%; 95% CI = 37-53) after adjusting for clinicopathological characteristics (HR: 0.67; 95% CI = 0.46-0.96). A moderate to strong correlation (r = 0.37-0.78, p < .03) of nestin and CD34 was demonstrated for the following markers; HIF-1α, CD4, CD8, FOXP3, IRF1, GATA3, CCL2, CCL3, CXCL12 and CCL21. CONCLUSIONS Combined expression of nestin and CD34 expression is associated with better overall survival possibly by modulating a favorable immune response.
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Affiliation(s)
- Athanasios Tampakis
- Clarunis, University Centre for Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital of Basel, Basel, Switzerland
| | - Benjamin Weixler
- Clarunis, University Centre for Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital of Basel, Basel, Switzerland
- Department of Surgery, Charité University Hospital, Campus Benjamin Franklin, Berlin, Germany
| | - Silvan Rast
- Clarunis, University Centre for Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital of Basel, Basel, Switzerland
| | - Ekaterini-Christina Tampaki
- National Organization for the Provision of Healthcare Services, Department of Planning and Monitoring of Medicines Dispencing, Medicines Division, Athens, Greece
- 2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
| | | | | | - Nadia Tosti
- Clarunis, University Centre for Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital of Basel, Basel, Switzerland
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Christoph Kettelhack
- Clarunis, University Centre for Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital of Basel, Basel, Switzerland
| | - Charlotte K. Y. Ng
- Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Tarik Delko
- Clarunis, University Centre for Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital of Basel, Basel, Switzerland
| | - Savas D. Soysal
- Clarunis, University Centre for Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital of Basel, Basel, Switzerland
| | - Urs von Holzen
- Indiana University School of Medicine South Bend, Goshen Center for Cancer Care, Goshen, IN, USA
- Harper Cancer Research Institute, South Bend, IN, USA
- School of Medicine, University of Basel, Basel, Switzerland
| | - Evangelos Felekouras
- 1st Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
| | - Nikolaos Nikiteas
- 2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
| | - Martin Bolli
- Clarunis, University Centre for Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital of Basel, Basel, Switzerland
| | - Luigi Tornillo
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Luigi Terracciano
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | | | | | - Salvatore Piscuoglio
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
- Department of Biomedicine, Visceral Surgery Research Laboratory, Clarunis, Basel, Switzerland
| | - Markus von Flüe
- Clarunis, University Centre for Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital of Basel, Basel, Switzerland
- Department of Biomedicine, Visceral Surgery Research Laboratory, Clarunis, Basel, Switzerland
| | - Silvio Däster
- Clarunis, University Centre for Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital of Basel, Basel, Switzerland
| | - Raoul A. Droeser
- Clarunis, University Centre for Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital of Basel, Basel, Switzerland
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Deneka AY, Kopp MC, Nikonova AS, Gaponova AV, Kiseleva AA, Hensley HH, Flieder DB, Serebriiskii IG, Golemis EA. Nedd9 Restrains Autophagy to Limit Growth of Early Stage Non-Small Cell Lung Cancer. Cancer Res 2021; 81:3717-3726. [PMID: 34006524 DOI: 10.1158/0008-5472.can-20-3626] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 03/16/2021] [Accepted: 04/26/2021] [Indexed: 01/22/2023]
Abstract
Non-small cell lung cancer (NSCLC) is the most common cancer worldwide. With overall 5-year survival estimated at <17%, it is critical to identify factors that regulate NSCLC disease prognosis. NSCLC is commonly driven by mutations in KRAS and TP53, with activation of additional kinases such as SRC promoting tumor invasion. In this study, we investigated the role of NEDD9, a SRC activator and scaffolding protein, in NSCLC tumorigenesis. In an inducible model of NSCLC dependent on Kras mutation and Trp53 loss (KP mice), deletion of Nedd9 (KPN mice) led to the emergence of larger tumors characterized by accelerated rates of tumor growth and elevated proliferation. Orthotopic injection of KP and KPN tumors into the lungs of Nedd9-wild-type and -null mice indicated the effect of Nedd9 loss was cell-autonomous. Tumors in KPN mice displayed reduced activation of SRC and AKT, indicating that activation of these pathways did not mediate enhanced growth of KPN tumors. NSCLC tumor growth has been shown to require active autophagy, a process dependent on activation of the kinases LKB1 and AMPK. KPN tumors contained high levels of active LKB1 and AMPK and increased autophagy compared with KP tumors. Treatment with the autophagy inhibitor chloroquine completely eliminated the growth advantage of KPN tumors. These data for the first time identify NEDD9 as a negative regulator of LKB1/AMPK-dependent autophagy during early NSCLC tumor growth. SIGNIFICANCE: This study demonstrates a novel role for the scaffolding protein NEDD9 in regulating LKB1-AMPK signaling in early stage non-small cell lung cancer, suppressing autophagy and tumor growth.
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Affiliation(s)
- Alexander Y Deneka
- Program in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA.,Kazan Federal University, Kazan, Russian Federation, Kazan, Tatarstan, Russia
| | - Meghan C Kopp
- Program in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA.,Cancer Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Anna S Nikonova
- Program in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA
| | - Anna V Gaponova
- Program in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA
| | - Anna A Kiseleva
- Program in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA
| | - Harvey H Hensley
- Program in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA
| | - Douglas B Flieder
- Program in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA.,Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | | | - Erica A Golemis
- Program in Molecular Therapeutics Fox Chase Cancer Center, Philadelphia, PA.
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Chung TK, Lee HA, Park S, Oh D, Lee K, Kim JW, Kim JH, Woo A, Lee SJ, Bang Y, Lee H. A target-mediated drug disposition population pharmacokinetic model of GC1118, a novel anti-EGFR antibody, in patients with solid tumors. Clin Transl Sci 2021; 14:990-1001. [PMID: 33382918 PMCID: PMC8212746 DOI: 10.1111/cts.12963] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/18/2020] [Accepted: 12/03/2020] [Indexed: 11/29/2022] Open
Abstract
GC1118 is a monoclonal antibody for epidermal growth factor receptor (EGFR) that is currently under clinical development to treat patients with solid tumors. In this study, the pharmacokinetics (PKs) of GC1118 were modeled in solid tumor patients who received a 2-h intravenous infusion of GC1118 at 0.3, 1, 3, 5, or 4 mg/kg once-weekly (Q1W) on days 1, 8, 15, and 22 or 8 mg/kg every other week on days 1 and 15. A target-mediated drug disposition population PK model adequately described the concentration-time profiles of GC1118. Monte-Carlo simulation experiments of the PK profiles and EGFR occupancies (ROs) by GC1118 based on the final model showed that Q1W at 4 or 5 mg/kg will produce a better antitumor effect than Q2W at 8 mg/kg. Because GC1118 was safer at 4 mg/kg than 5 mg/kg in the phase I study, we suggest to test the 4 mg/kg Q1W regimen in further clinical trials with GC1118. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? GC1118, a fully human IgG1 monoclonal antibody (mAb) for epidermal growth factor receptor (EGFR), showed a nonlinear pharmacokinetic (PK) profile in monkeys and humans. The total clearance of GC1118 decreased as the dose was increased up to 3-4 mg/kg in humans, beyond which it remained stable. The recommended phase II dose for GC1118 was 4 mg/kg intravenously infused over 2 h once weekly. WHAT QUESTION DID THIS STUDY ADDRESS? We developed a target-mediated drug disposition (TMDD) population PK model that described the nonlinear PK profile of GC1118 in patients with solid tumors. We also simulated the PK profiles and receptor occupancies for different dosage regimens. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The TMDD population PK model adequately described the nonlinear and multiphasic PK profiles of GC1118 in humans. The simulation experiment showed that once-weekly GC1118 at 4-5 mg/kg could be more efficacious than the biweekly regimen at 8 mg/kg. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The pharmacometrics analysis could support better informed drug development decisions for GC1118, particularly for determining an optimal dosage regimen.
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Affiliation(s)
- Tae Kyu Chung
- Department of Transdisciplinary StudiesGraduate School of Convergence Science and TechnologySeoul National UniversitySeoulKorea
| | - Hyun A. Lee
- Department of Transdisciplinary StudiesGraduate School of Convergence Science and TechnologySeoul National UniversitySeoulKorea
| | - Sang‐In Park
- Department of PharmacologyCollege of MedicineKangwon National UniversityChuncheonKorea
| | - Do‐Youn Oh
- Department of Internal MedicineSeoul National University HospitalCancer Research InstituteSeoul National University College of MedicineSeoulKorea
| | - Keun‐Wook Lee
- Department of Internal MedicineSeoul National University College of MedicineSeoul National University Bundang HospitalSeongnamKorea
| | - Jin Won Kim
- Department of Internal MedicineSeoul National University College of MedicineSeoul National University Bundang HospitalSeongnamKorea
| | - Jee Hyun Kim
- Department of Internal MedicineSeoul National University College of MedicineSeoul National University Bundang HospitalSeongnamKorea
| | | | | | - Yung‐Jue Bang
- Department of Internal MedicineSeoul National University HospitalCancer Research InstituteSeoul National University College of MedicineSeoulKorea
| | - Howard Lee
- Department of Transdisciplinary StudiesGraduate School of Convergence Science and TechnologySeoul National UniversitySeoulKorea
- Department of Clinical Pharmacology and TherapeuticsSeoul National University College of Medicine and HospitalSeoulKorea
- Department of Molecular Medicine and Biopharmaceutical SciencesGraduate School of Convergence Science and TechnologySeoul National UniversitySeoulKorea
- Center for Convergence Approaches in Drug DevelopmentSeoul National UniversitySeoulKorea
- Advanced Institute of Convergence TechnologySuwonKorea
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32
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Reduction in Alveolar Macrophage Size in Refractory Autoimmune Pulmonary Alveolar Proteinosis After Treatment With Pioglitazone. J Bronchology Interv Pulmonol 2021; 27:219-222. [PMID: 32569076 DOI: 10.1097/lbr.0000000000000686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Koomen BM, van der Starre‐Gaal J, Vonk JM, von der Thüsen JH, van der Meij JJC, Monkhorst K, Willems SM, Timens W, ’t Hart NA. Formalin fixation for optimal concordance of programmed death-ligand 1 immunostaining between cytologic and histologic specimens from patients with non-small cell lung cancer. Cancer Cytopathol 2021; 129:304-317. [PMID: 33108706 PMCID: PMC8246726 DOI: 10.1002/cncy.22383] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/28/2020] [Accepted: 09/30/2020] [Indexed: 12/29/2022]
Abstract
BACKGROUND Immunohistochemical staining of programmed death-ligand 1 (PD-L1) is used to determine which patients with non-small cell lung cancer (NSCLC) may benefit most from immunotherapy. Therapeutic management of many patients with NSCLC is based on cytology instead of histology. In this study, concordance of PD-L1 immunostaining between cytology cell blocks and their histologic counterparts was analyzed. Furthermore, the effect of various fixatives and fixation times on PD-L1 immunoreactivity was studied. METHODS Paired histologic and cytologic samples from 67 patients with NSCLC were collected by performing fine-needle aspiration on pneumonectomy/lobectomy specimens. Formalin-fixed, agar-based or CytoLyt/PreservCyt-fixed Cellient cell blocks were prepared. Sections from cell blocks and tissue blocks were stained with SP263 (standardized assay) and 22C3 (laboratory-developed test) antibodies. PD-L1 scores were compared between histology and cytology. In addition, immunostaining was compared between PD-L1-expressing human cell lines fixed in various fixatives at increasing increments in fixation duration. RESULTS Agar cell blocks and tissue blocks showed substantial agreement (κ = 0.70 and κ = 0.67, respectively), whereas fair-to-moderate agreement was found between Cellient cell blocks and histology (κ = 0.28 and κ = 0.49, respectively). Cell lines fixed in various alcohol-based fixatives showed less PD-L1 immunoreactivity compared with those fixed in formalin. In contrast to SP263, additional formalin fixation after alcohol fixation resulted in preserved staining intensity using the 22C3 laboratory-developed test and the 22C3 pharmDx assay. CONCLUSIONS Performing PD-L1 staining on cytologic specimens fixed in alcohol-based fixatives could result in false-negative immunostaining results, whereas fixation in formalin leads to higher and more histology-concordant PD-L1 immunostaining. The deleterious effect of alcohol fixation could be reversed to some degree by postfixation in formalin.
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Affiliation(s)
- Bregje M. Koomen
- Department of PathologyUniversity Medical Center UtrechtUtrecht UniversityUtrechtthe Netherlands
| | | | - Judith M. Vonk
- Department of EpidemiologyUniversity Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
| | | | | | - Kim Monkhorst
- Department of PathologyNetherlands Cancer Institute‐Antoni van Leeuwenhoek HospitalAmsterdamthe Netherlands
| | - Stefan M. Willems
- Department of PathologyUniversity Medical Center UtrechtUtrecht UniversityUtrechtthe Netherlands
- Department of Pathology and Medical BiologyUniversity Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
| | - Wim Timens
- Department of Pathology and Medical BiologyUniversity Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
| | - Nils A. ’t Hart
- Department of PathologyIsala HospitalsZwollethe Netherlands
- Department of Pathology and Medical BiologyUniversity Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
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Musashi-2 (MSI2) regulates epidermal growth factor receptor (EGFR) expression and response to EGFR inhibitors in EGFR-mutated non-small cell lung cancer (NSCLC). Oncogenesis 2021; 10:29. [PMID: 33723247 PMCID: PMC7961039 DOI: 10.1038/s41389-021-00317-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/04/2021] [Accepted: 02/19/2021] [Indexed: 01/21/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) has limited treatment options. Expression of the RNA-binding protein (RBP) Musashi-2 (MSI2) is elevated in a subset of non-small cell lung cancer (NSCLC) tumors upon progression, and drives NSCLC metastasis. We evaluated the mechanism of MSI2 action in NSCLC to gain therapeutically useful insights. Reverse phase protein array (RPPA) analysis of MSI2-depleted versus control KrasLA1/+; Trp53R172HΔG/+ NSCLC cell lines identified EGFR as a MSI2-regulated protein. MSI2 control of EGFR expression and activity in an NSCLC cell line panel was studied using RT-PCR, Western blots, and RNA immunoprecipitation. Functional consequences of MSI2 depletion were explored for cell growth and response to EGFR-targeting drugs, in vitro and in vivo. Expression relationships were validated using human tissue microarrays. MSI2 depletion significantly reduced EGFR protein expression, phosphorylation, or both. Comparison of protein and mRNA expression indicated a post-transcriptional activity of MSI2 in control of steady state levels of EGFR. RNA immunoprecipitation analysis demonstrated that MSI2 directly binds to EGFR mRNA, and sequence analysis predicted MSI2 binding sites in the murine and human EGFR mRNAs. MSI2 depletion selectively impaired cell proliferation in NSCLC cell lines with activating mutations of EGFR (EGFRmut). Further, depletion of MSI2 in combination with EGFR inhibitors such as erlotinib, afatinib, and osimertinib selectively reduced the growth of EGFRmut NSCLC cells and xenografts. EGFR and MSI2 were significantly co-expressed in EGFRmut human NSCLCs. These results define MSI2 as a direct regulator of EGFR protein expression, and suggest inhibition of MSI2 could be of clinical value in EGFRmut NSCLC.
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Lan Q, Tan X, He P, Li W, Tian S, Dong W. TRIM11 Promotes Proliferation, Migration, Invasion and EMT of Gastric Cancer by Activating β-Catenin Signaling. Onco Targets Ther 2021; 14:1429-1440. [PMID: 33658804 PMCID: PMC7920621 DOI: 10.2147/ott.s289922] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 01/28/2021] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Gastric cancer (GC) is the sixth most common malignant tumor and the third leading cause of cancer-related death in the world. Studies have shown that TRIM protein can regulate transcription factor activity and is associated with many cancers. However, the role of TRIM11 in gastric cancer remains unclear. METHODS TRIM11 protein levels were examined in 36 cases of GC tissues and 4 gastric cancer cell lines. TRIM11 overexpression and knockdown cells were constructed in MGC-803, HGC-27 and SGC-7901, respectively. The biological roles and mechanisms of TRIM11 were examined using CCK8, colony formation, transwell migration assay, invasion assay, Western blotting, Immunohistochemistry and in vivo nude mice experiments. RESULTS We found that TRIM11 was upregulated in gastric cancer tissues and gastric cancer cell lines. Functionally, TRIM11 overexpression increased growth rate, colony formation, invasion and migration ability, EMT and β-catenin protein level and its downstream proteins such as CyclinD1 and C-myc, while TRIM11 knockdown shows the opposite effects. CONCLUSION In summary, our data show that TRIM11 is overexpressed in GC. TRIM11 promotes proliferation, migration, invasion and EMT of gastric cancer by activating β-catenin signaling.
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Affiliation(s)
- Qingzhi Lan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
- Central Laboratory of Renmin Hospital, Wuhan, People’s Republic of China
| | - Xiaoping Tan
- Department of Gastroenterology, The First Affiliated Hospital of Yangtze University, Jingzhou, People’s Republic of China
| | - Pengzhan He
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
- Central Laboratory of Renmin Hospital, Wuhan, People’s Republic of China
| | - Wei Li
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
- Central Laboratory of Renmin Hospital, Wuhan, People’s Republic of China
| | - Shan Tian
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
- Central Laboratory of Renmin Hospital, Wuhan, People’s Republic of China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
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Delen K, Sırav B, Oruç S, Seymen CM, Kuzay D, Yeğin K, Take Kaplanoğlu G. Effects of 2600 MHz Radiofrequency Radiation in Brain Tissue of Male Wistar Rats and Neuroprotective Effects of Melatonin. Bioelectromagnetics 2021; 42:159-172. [PMID: 33440456 DOI: 10.1002/bem.22318] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 12/06/2020] [Accepted: 12/20/2020] [Indexed: 02/05/2023]
Abstract
The debate on the biological effects of radiofrequency radiation (RFR) still continues due to differences in the design of studies (frequency, power density, specific absorption rate [SAR], exposure duration, cell, tissue, or animal type). The current study aimed to investigate the effects of 2,600 MHz RFR and melatonin on brain tissue biochemistry and histology of male rats. Thirty-six rats were divided into six groups randomly: cage-control, sham, RFR, melatonin, sham melatonin, and RFR melatonin. In RFR groups, animals were exposed to 2,600 MHz RFR for 30 days (30 min/day, 5 days/week) and the melatonin group animals were subcutaneously injected with melatonin (7 days/week, 10 mg/kg/day) for 30 days. SAR in brain gray matter was calculated as 0.44 and 0.295 W/kg for 1 and 10 g averaging, respectively. RFR exposure decreased the GSH, GSH-Px, and SOD levels and increased the MPO, MDA, and NOx levels (P < 0.005) significantly. RFR exposure also led to an increase in structural deformation and apoptosis in the brain tissue. This study revealed that exogenous high-dose melatonin could reduce these adverse effects of RFR. Limiting RFR exposure as much as possible is recommended, and taking daily melatonin supplements may be beneficial. Bioelectromagnetics. © 2021 Bioelectromagnetics Society.
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Affiliation(s)
- Kevser Delen
- Department of Biophysics, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Bahriye Sırav
- Department of Biophysics, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Sinem Oruç
- Department of Biophysics, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Cemile M Seymen
- Department of Histology and Embryology Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Dilek Kuzay
- Department of Physiology, Kırşehir Ahi Evran University, Kırşehir, Turkey
| | - Korkut Yeğin
- Department of Electrical and Electronics Engineering, Ege University, Izmir, Turkey
| | - Gülnur Take Kaplanoğlu
- Department of Histology and Embryology Faculty of Medicine, Gazi University, Ankara, Turkey
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Chen HJ, Tu CY, Huang KY, Chien CR, Hsia TC. Early serum tumor marker levels after fourteen days of tyrosine kinase inhibitor targeted therapy predicts outcomes in patients with advanced lung adenocarcinoma. PLoS One 2020; 15:e0240736. [PMID: 33306683 PMCID: PMC7732093 DOI: 10.1371/journal.pone.0240736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 10/01/2020] [Indexed: 11/19/2022] Open
Abstract
Objective Image evaluation strategy for lung cancer patients has difficulty obtaining the appropriate quantity of diffuse lung nodules and bone metastases. The study was to demonstrate whether early variations in the levels of serum 4-tumor markers (4-TMs)(carcinoembryonic antigen [CEA], cancer antigen [CA]125, CA19-9, and CA15-3) after TKI targeted therapy were associated with treatment response in patients with lung adenocarcinoma. Methods Patients with stage IIIB-IV lung adenocarcinoma taking epidermal growth factor receptor (EGFR) TKIs or anaplastic lymphoma kinase (ALK) inhibitors were enrolled prospectively from June 2012 to February 2015. According to the variations of the percentage of change in 4-TM levels (4-TMpc), we divided patients into ascending (increases in 4-TMpc over the 7th- 14th day) and descending (decreases in 4-TMpc over the 7th- 14th day) groups. Results 184 patients were enrolled, and 89% had at least one of the pre-treatment evaluable TMs and were further analyzed. An excellent response to the TKI targeted therapy was accurately predicted in the descending group, as determined using receiver operating characteristic curve analysis (an area under the curve, 0.83). Multivariate Cox hazards model analyses demonstrated that the type of 4-TMpc and mutation status were the strongest predictors of progression-free survival (PFS)(descending versus ascending, hazard ratios [HR] 0.30, 95% confidence interval [CI], 0.19–0.47; sensitive mutation versus wide type, HR 0.30, 95% CI, 0.19–0.48). Conclusions Type of 4-TMpc 14 days after TKI targeted therapy is associated with an image response and PFS, without regarding mutation status, in patients with advanced lung adenocarcinoma.
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Affiliation(s)
- Hung-Jen Chen
- Division of Pulmonary and Critical Care Medicine, Taichung, Taiwan
- China Medical University Hospital, Taichung, Taiwan
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- * E-mail:
| | - Chih-Yen Tu
- Division of Pulmonary and Critical Care Medicine, Taichung, Taiwan
- China Medical University Hospital, Taichung, Taiwan
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
| | - Kuo-Yang Huang
- Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Chun-Ru Chien
- China Medical University Hospital, Taichung, Taiwan
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan
| | - Te-Chun Hsia
- Division of Pulmonary and Critical Care Medicine, Taichung, Taiwan
- China Medical University Hospital, Taichung, Taiwan
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Vizcaya D, Farahmand B, Walter AO, Kneip C, Jöhrens K, Tukiainen M, Schmitz AA. Prognosis of patients with malignant mesothelioma by expression of programmed cell death 1 ligand 1 and mesothelin in a contemporary cohort in Finland. Cancer Treat Res Commun 2020; 25:100260. [PMID: 33310366 DOI: 10.1016/j.ctarc.2020.100260] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 11/16/2020] [Accepted: 11/28/2020] [Indexed: 12/17/2022]
Abstract
OBJECTIVES We aimed to describe mesothelin (MSLN) and programmed cell death 1 ligand 1 (PD-L1) tumour overexpression amongst patients with malignant mesothelioma (MM), and their associations with survival, amongst a cohort of patients with MM in Finland. METHODS Between 2004 and 2017, 91 adults with histologically confirmed MM were identified from the Auria Biobank in Finland and followed-up using linked data from electronic health records and national statistics. Biomarker content in tumour cell membranes was determined using automated Immunohistochemistry on histological sections. Stained tumour sections were scored for MSLN and PD-L1 intensity. Adjusted associations between MSLN/PD-L1 co-expression and mortality were evaluated by estimating hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox regression. RESULTS Biomarker overexpression occurred in 52 patients for MSLN and 34 patients for PD-L1 and was associated with tumour histology and certain comorbidities. Fifteen per cent of patients had a tumour that overexpressed both biomarkers; r =-0.244, p-value: 0.02. Compared with MSLN+/PD-L1+ patients, HRs (95% CIs) for death were 4.18 (1.71-10.23) for MSLN-/PD-L1+ patients, 3.03 (1.35-6.77) for MSLN-/PD-L1- patients, and 2.13 (0.97-4.67) for MSLN+/PD-L1- patients. CONCLUSIONS Both MSLN and PD-L1 markers were independent prognostic indicators in patients with MM. Overexpression of MSLN was associated with longer survival; yet their combined expression gave a better indication of survival. The risk of death was four times higher amongst MSLN-/PD-L1+ patients than in MSLN+/PD-L1+ patients.
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Affiliation(s)
| | | | | | | | - Korinna Jöhrens
- Institute of Pathology University Hospital Carl Gustav Carus, Dresden, Germany; Provitro AG, Berlin, Germany
| | - Mikko Tukiainen
- Auria Biobank, University of Turku and Turku University Hospital, Turku, Finland
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Kondo Y, Hirabayashi K, Carreras J, Tsukinoki K, Ota Y, Okami K, Nakamura N. The significance of tyrosine kinase receptor B and brain-derived neurotrophic factor expression in salivary duct carcinoma. Ann Diagn Pathol 2020; 50:151673. [PMID: 33248386 DOI: 10.1016/j.anndiagpath.2020.151673] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 11/04/2020] [Accepted: 11/19/2020] [Indexed: 10/22/2022]
Abstract
Salivary duct carcinoma (SDC) is a high-grade salivary gland neoplasm. It may occur de novo or secondarily from pleomorphic adenoma (ex-PA), with secondary development accounting for more than 50% of the cases. In recent years, the expression of tyrosine kinase receptor B (TrkB), which is in the same family as HER2, has been confirmed in various types of carcinomas. However, there are a few studies on SDC. In order to examine the expression and role of TrkB in SDC, we investigated it. Immunohistochemistry was used to detect the expression of TrkB and its ligands, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) in 20 patients with SDC. The mRNA levels of TrkB, BDNF, and NT-4 were analyzed using quantitative polymerase chain reaction. TrkB was negative in 10 cases and positive in 10 cases, BDNF was negative in 11 cases and positive in 9 cases, and NT-4 was positive in all cases. There was a high number of TrkB-positive cases in the pT4 group and The H-score of TrkB was also significantly higher in the stage III and IV groups. There was a high number of BDNF-positive cases in the ex-PA group and Histo-score of BDNF had a trend of high expression in ex-PA. There were no significant differences or correlations in mRNA expression. Our results suggest that TrkB may be involved in SDC tumor growth.
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Affiliation(s)
- Yusuke Kondo
- Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
| | - Kenichi Hirabayashi
- Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
| | - Joaquim Carreras
- Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
| | - Keiichi Tsukinoki
- Department of Oral Science, Graduate School of Dentistry, Kanagawa Dental University, Yokosuka, Kanagawa 238-8580, Japan
| | - Yoshihide Ota
- Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
| | - Kenji Okami
- Department of Otolaryngology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
| | - Naoya Nakamura
- Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
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40
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Bondarenko G, Sorden SD, Christian BJ, Webster S, Sharma AK. Semiquantitative Methods for GFP Immunohistochemistry and In Situ Hybridization to Evaluate AAV Transduction of Mouse Retinal Cells Following Subretinal Injection. Toxicol Pathol 2020; 49:537-543. [PMID: 33167778 DOI: 10.1177/0192623320964804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The goal of this study was to develop methods for the evaluation of green fluorescent protein (GFP) and GFP transcript biodistribution in paraformaldehyde-fixed paraffin-embedded (PFPE) eye sections to assess the effectiveness of Adeno-associated virus (AAV) gene delivery in an experimental ocular toxicity study. Female C57BL/6NTac mice were administered AAV2-enhancedGFP vector once via subretinal injection. One group also received anti-inflammatory therapy (meloxicam). Immunohistochemistry (IHC) and RNA in situ hybridization (ISH) for GFP were performed on PFPE serial eye sections and evaluated using semiquantitative methods. On day 43, GFP labeling in both IHC and ISH sections was greatest in the retinal pigment epithelium, compared with other retinal layers in which expression was negative to moderate. Despite the presence of IHC GFP labeling in the photoreceptor layer (PRL) in some animals, only low numbers of transduced cells were detected by ISH in the PRL. Simultaneous analysis of IHC and ISH may be needed for comprehensive assessment of gene transduction and protein biodistribution. This study demonstrates approaches for semiquantitative evaluation of IHC and ISH that allow interpretation and reporting of GFP expression in toxicity studies.
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41
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Doescher J, Minkenberg P, Laban S, Kostezka U, von Witzleben A, Hoffmann TK, Schuler PJ, Weissinger SE. Immune checkpoint expression in HNSCC patients before and after definitive chemoradiotherapy. Head Neck 2020; 43:778-787. [PMID: 33159481 DOI: 10.1002/hed.26534] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 10/23/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Primary platinum-based chemoradiotherapy (CRT) remains the treatment of choice for nonresectable squamous cell carcinoma of the head and neck (HNSCC). Immune-checkpoint modulators are used as palliative therapy and studied in combination with definitive CRT. However, the immunological changes by CRT need yet to be understood. METHODS A cohort consisting of 67 paired tissue biopsies (N = 134) of HNSCC patients before and after CRT was created. The expression of PD-1, PD-L1, and CD27 of tumor and immune cells by immunohistochemistry was evaluated. RESULTS PD-L1 expression on immune cells of non-responders was significantly lower before CRT (P = .008). CD27 was expressed only on immune cells and not on cancer cells. A significant lower CD27-expression score was observed following CRT (P = .019). CONCLUSIONS Conventional CRT changes the expression of CD27 in the tumor microenvironment. Whether this is due to a loss of expression or a reduction of CD27+ cells must be evaluated in further analyses.
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Affiliation(s)
- Johannes Doescher
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Ulm, Ulm, Germany
| | - Peter Minkenberg
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Ulm, Ulm, Germany
| | - Simon Laban
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Ulm, Ulm, Germany
| | | | - Adrian von Witzleben
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Ulm, Ulm, Germany.,University of Southampton Faculty of Medicine, Cancer Sciences Unit Southampton, Southampton, UK
| | - Thomas Karl Hoffmann
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Ulm, Ulm, Germany
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Molecular targets for diagnostic and intraoperative imaging of pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX treatment. Sci Rep 2020; 10:16211. [PMID: 33004930 PMCID: PMC7529886 DOI: 10.1038/s41598-020-73242-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 07/14/2020] [Indexed: 12/17/2022] Open
Abstract
Neoadjuvant systemic treatment is increasingly being integrated in the standard treatment of pancreatic ductal adenocarcinoma (PDAC) patients to improve oncological outcomes. Current available imaging techniques remain unreliable in assessing response to therapies, as they cannot distinguish between (vital) tumor tissue and therapy induced fibrosis (TIF). Consequently, resections with tumor positive margins and subsequent early post-operative recurrences occur and patients eligible for potential radical resection could be missed. To optimize patient selection and monitor results of neoadjuvant treatment, PDAC-specific diagnostic and intraoperative molecular imaging methods are required. This study aims to evaluate molecular imaging targets for PDAC after neoadjuvant FOLFIRINOX treatment. Expression of integrin αvβ6, carcinoembryonic antigen cell adhesion molecule 5 (CEACAM5), mesothelin, prostate-specific membrane antigen (PSMA), urokinase-type plasminogen activator receptor, fibroblast activating receptor, integrin α5 subunit and epidermal growth factor receptor was evaluated using immunohistochemistry. Immunoreactivity was determined using the semiquantitative H-score. Resection specimens from patients after neoadjuvant FOLFIRINOX treatment containing PDAC (n = 32), tumor associated pancreatitis (TAP) and TIF (n = 15), normal pancreas parenchyma (NPP) (n = 32) and tumor positive (n = 24) and negative (n = 56) lymph nodes were included. Integrin αvβ6, CEACAM5, mesothelin and PSMA stainings showed significantly higher expression in PDAC compared to TAP and NPP. No expression of αvβ6, CEACAM5 and mesothelin was observed in TIF. Integrin αvβ6 and CEACAM5 allow for accurate metastatic lymph node detection. Targeting integrin αvβ6, CEA, mesothelin and PSMA has the potential to distinguish vital PDAC from fibrotic tissue after neoadjuvant FOLFIRINOX treatment. Integrin αvβ6 and CEACAM5 detect primary tumors and tumor positive lymph nodes.
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Sellam LS, Zappasodi R, Chettibi F, Djennaoui D, Yahi-Ait Mesbah N, Amir-Tidadini ZC, Touil-Boukoffa C, Ouahioune W, Merghoub T, Bourouba M. Silibinin down-regulates PD-L1 expression in nasopharyngeal carcinoma by interfering with tumor cell glycolytic metabolism. Arch Biochem Biophys 2020; 690:108479. [PMID: 32679194 PMCID: PMC8507490 DOI: 10.1016/j.abb.2020.108479] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/09/2020] [Accepted: 06/21/2020] [Indexed: 02/06/2023]
Abstract
The upregulation of checkpoint inhibitor PD-L1 expression has recently been associated with nasopharyngeal carcinoma (NPC) resistance to therapy. The mechanism of induction of PD-L1 has also been linked to enhanced aerobic glycolysis promoted by HIF1-α dysregulation and LDH-A activity in cancer. Here, we investigated the effect of the anti-tumoral compound Silibinin on HIF-1α/LDH-A mediated cancer cell metabolism and PD-L1 expression in NPC. Our results demonstrate that exposure to Silibinin potently inhibits tumor growth and promotes a shift from aerobic glycolysis toward oxidative phosphorylation. The EBV + NPC cell line C666-1 and glycolytic human tumor explants treated with Silibinin displayed a reduction in LDH-A activity which consistently associated with a reduction in lactate levels. This effect was accompanied by an increase in intracellular citrate levels in C666-1 cells. Accordingly, expression of HIF-1α, a critical regulator of glycolysis, was down-regulated after treatment. This event associated with a down-regulation in PD-L1. Altogether, our results provide evidence that silibinin can alter PD-L1 expression by interfering with HIF-1α/LDH-A mediated cell metabolism in NPC. These results provide a new perspective for Silibinin use to overcome PD-L1 mediated NPC resistance to therapy.
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Affiliation(s)
- Leïla Sarah Sellam
- Cell and Molecular Biology Laboratory (LBCM), Team Cytokines and Nitric oxide Synthase: Immunity and Pathogeny, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Bab Ezzouar, Algiers, Algeria
| | - Roberta Zappasodi
- Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Fayçal Chettibi
- Otorhinolaryngology Department, Mustapha Pacha Hospital, Algiers, Algeria
| | - Djamel Djennaoui
- Otorhinolaryngology Department, Mustapha Pacha Hospital, Algiers, Algeria
| | | | | | - Chafia Touil-Boukoffa
- Cell and Molecular Biology Laboratory (LBCM), Team Cytokines and Nitric oxide Synthase: Immunity and Pathogeny, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Bab Ezzouar, Algiers, Algeria
| | - Wahiba Ouahioune
- Central Laboratory for Anatomopathology, Frantz Fanon Hospital, Blida, Algeria
| | - Taha Merghoub
- Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medicine, New York, NY 10065, USA
| | - Mehdi Bourouba
- Cell and Molecular Biology Laboratory (LBCM), Team Cytokines and Nitric oxide Synthase: Immunity and Pathogeny, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Bab Ezzouar, Algiers, Algeria.
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Nkembo AT, Amissah F, Ntantie E, Poku RA, Salako OO, Ikpatt OF, Lamango NS. Polyisoprenylated Cysteinyl Amide Inhibitors Deplete K-Ras and Induce Caspase-dependent Apoptosis in Lung Cancer Cells. Curr Cancer Drug Targets 2020; 19:838-851. [PMID: 30914025 DOI: 10.2174/1568009619666190325144636] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 03/01/2019] [Accepted: 03/10/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Non-small cell lung cancers (NSCLC) harboring mutation-induced dysregulation of Ras signaling present some of the most difficult-to-manage cases, since directly targeting the constitutively active mutant Ras proteins has not resulted in clinically useful drugs. Therefore, modulating Ras activity for targeted treatment of cancer remains an urgent healthcare need. OBJECTIVE In the current study, we investigated a novel class of compounds, the polyisoprenylated cysteinyl amide inhibitors (PCAIs), for their anticancer molecular mechanisms using the NSCLC cell panel with K-Ras and/or other mutant genes. METHODS The effect of the PCAIs on intracellular K-Ras levels, cell viability, apoptosis, spheroid and colony formation were determined. RESULTS Treatment of the lung cancer cells with the PCAIs, NSL-RD-035, NSL-BA-036, NSL-BA- 040 and NSL-BA-055 resulted in concentration-dependent cell death in both K-Ras mutant (A549, NCI-H460, and NCI-H1573), N-Ras mutant (NCI-H1299) and other (NCI-H661, NCI-H1975, NCIH1563) NSCLC cells. The PCAIs at 1.0 -10 μM induced the degeneration of 3D spheroid cultures, inhibited clonogenic cell growth and induced marked apoptosis via the extrinsic pathway. The most potent of the PCAIs, NSL-BA-055, at 5 μM induced a seven-fold increase in the activity of caspase- 3/7 and a 75% selective depletion of K-Ras protein levels relative to GAPDH in A549 cells that correlated with PCAIs-induced apoptosis. NSL-BA-040 and NSL-BA-055 also induced the phosphorylation of MAP kinase (ERK 1/2). CONCLUSION Taken together, PCAIs may be potentially useful as targeted therapies that suppress NSCLC progression through disruption of Ras-mediated growth signaling.
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Affiliation(s)
- Augustine T Nkembo
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, United States
| | - Felix Amissah
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, United States
| | - Elizabeth Ntantie
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, United States
| | - Rosemary A Poku
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, United States
| | - Olufisayo O Salako
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, United States
| | - Offiong Francis Ikpatt
- Department of Pathology, School of Medicine, University of Miami, Miami, FL, 33136, United States
| | - Nazarius S Lamango
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, United States
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Franceschini D, Rossi S, Loi M, Chiola I, Piccoli F, Lutman FR, Finocchiaro G, Toschi L, Santoro A, Scorsetti M. Lung cancer management: monitoring and treating resistance development in third-generation EGFR TKIs. Expert Rev Anticancer Ther 2020; 20:743-753. [PMID: 32755244 DOI: 10.1080/14737140.2020.1806716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
INTRODUCTION Patients treated with third-generation EGFR TKIs will develop resistance to treatment at a certain point. Early detection of resistance occurrence could allow more options for treatment. AREAS COVERED We discuss the development of third-generation EGFR TKIs, focusing on osimertinib and discuss the most common resistance mechanisms under evaluation. We also debate how this resistance can be detected; particularly we review the possible application of liquid biopsy in this scenario. Lastly we discuss available treatment options when resistance occurs, with an eye on ongoing trials and possible future developments. EXPERT OPINION As resistance will ultimately develop, a strict instrumental follow-up as per international guidelines is required with the aim of detecting this resistance in an early phase. Detecting an oligoprogression could allow the integration of local ablative therapies while further delaying the need for a systemic therapy change. By exploiting the increasing potentiality of liquid biopsy, in the near future, physicians could be able to understand why a patient develops resistance and therefore can choose the best possible individualized treatment option.
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Affiliation(s)
- D Franceschini
- Radiotherapy and Radiosurgery Department- Humanitas Clinical and Research Center, IRCCS , Rozzano, Italy
| | - S Rossi
- Medical Oncology Department, Humanitas Clinical and Research Center - IRCCS , Rozzano, Italy
| | - M Loi
- Radiotherapy and Radiosurgery Department- Humanitas Clinical and Research Center, IRCCS , Rozzano, Italy
| | - I Chiola
- Radiotherapy and Radiosurgery Department- Humanitas Clinical and Research Center, IRCCS , Rozzano, Italy
| | - F Piccoli
- Radiology Department, Humanitas University , Pieve Emanuele, Italy
| | - F R Lutman
- Radiology Department, Humanitas Clinical and Research Center - IRCCS , Rozzano, Italy
| | - G Finocchiaro
- Medical Oncology Department, Humanitas Clinical and Research Center - IRCCS , Rozzano, Italy
| | - L Toschi
- Medical Oncology Department, Humanitas Clinical and Research Center - IRCCS , Rozzano, Italy
| | - A Santoro
- Medical Oncology Department, Humanitas Clinical and Research Center - IRCCS , Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University , Pieve Emanuele, Italy
| | - M Scorsetti
- Radiotherapy and Radiosurgery Department- Humanitas Clinical and Research Center, IRCCS , Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University , Pieve Emanuele, Italy
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Gkika E, Benndorf M, Oerther B, Mohammad F, Beitinger S, Adebahr S, Carles M, Schimek-Jasch T, Zamboglou C, Frye BC, Bamberg F, Waller CF, Werner M, Grosu AL, Nestle U, Kayser G. Immunohistochemistry and Radiomic Features for Survival Prediction in Small Cell Lung Cancer. Front Oncol 2020; 10:1161. [PMID: 32903606 PMCID: PMC7438800 DOI: 10.3389/fonc.2020.01161] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 06/08/2020] [Indexed: 12/23/2022] Open
Abstract
Background: The aim of the study was to evaluate the role of different immunohistochemical and radiomics features in patients with small cell lung cancer (SCLC). Methods: Consecutive patients with histologically proven SCLC with limited (n = 47, 48%) or extensive disease (n = 51, 52%) treated with radiotherapy and chemotherapy at our department were included in the analysis. The expression of different immunohistochemical markers from the initial tissue biopsy, such as CD56, CD44, chromogranin A, synaptophysin, TTF-1, GLUT-1, Hif-1 a, PD-1, and PD-L1, and MIB-1/KI-67 as well as LDH und NSE from the initial blood sample were evaluated. H-scores were additionally generated for CD44, Hif-1a, and GLUT-1. A total of 72 computer tomography (CT) radiomics texture features from a homogenous subgroup (n = 31) of patients were correlated with the immunohistochemistry, the survival (OS), and the progression-free survival (PFS). Results: The median OS, calculated from diagnosis, was 21 months for patients with limited disease and 13 months for patients with extensive disease. The expression of synaptophysin correlated with a better OS (HR 0.546 95% CI 0.308–0.966, p = 0.03). The expression of TTF-1 (HR 0.286, 95% CI: 0.117–0.698, p = 0.006) and a lower GLUT-1 H-score (median = 50, HR: 0.511, 95% CI: 0.260–1.003, p = 0.05) correlated with a better PFS. Patients without chromogranin A expression had a higher risk for developing cerebral metastases (p = 0.02) and patients with PD 1 expression were at risk for developing metastases (p = 0.02). Our radiomics analysis did not reveal a single texture feature that correlated highly with OS or PFS. Correlation coefficients ranged between −0.48 and 0.39 for OS and between −0.46 and 0.38 for PFS. Conclusions: The role of synaptophysin should be further evaluated as synaptophysin-negative patients might profit from treatment intensification. We report an, at most, moderate correlation of radiomics features with overall and progression free survival and no correlation with the expression of different immunohistochemical markers.
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Affiliation(s)
- Eleni Gkika
- Department of Radiation Oncology, Medical Center, University Hospital Freiburg, Freiburg, Germany
| | - Matthias Benndorf
- Department of Radiology Freiburg, University Medical Center Freiburg, Freiburg, Germany
| | - Benedict Oerther
- Department of Radiology Freiburg, University Medical Center Freiburg, Freiburg, Germany
| | - Farid Mohammad
- Department of Radiology Freiburg, University Medical Center Freiburg, Freiburg, Germany
| | - Susanne Beitinger
- Department of Neurology, Medical Center, University Hospital Freiburg, Freiburg, Germany
| | - Sonja Adebahr
- Department of Radiation Oncology, Medical Center, University Hospital Freiburg, Freiburg, Germany.,German Cancer Consortium (DKTK), Freiburg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Montserrat Carles
- Department of Radiation Oncology, Medical Center, University Hospital Freiburg, Freiburg, Germany
| | - Tanja Schimek-Jasch
- Department of Radiation Oncology, Medical Center, University Hospital Freiburg, Freiburg, Germany
| | - Constantinos Zamboglou
- Department of Radiation Oncology, Medical Center, University Hospital Freiburg, Freiburg, Germany
| | - Björn C Frye
- Department of Pneumology, Medical Center, University Hospital Freiburg, Freiburg, Germany
| | - Fabian Bamberg
- Department of Radiology Freiburg, University Medical Center Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Cornelius F Waller
- Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany
| | - Martin Werner
- Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Department of Pathology, Faculty of Medicine, Medical Center, Institute of Surgical Pathology, University Hospital Freiburg, Freiburg, Germany
| | - Anca L Grosu
- German Cancer Consortium (DKTK), Freiburg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Ursula Nestle
- German Cancer Consortium (DKTK), Freiburg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Department of Radiation Oncology, Kliniken Maria Hilf, Mönchengladbach, Germany
| | - Gian Kayser
- Department of Pathology, Faculty of Medicine, Medical Center, Institute of Surgical Pathology, University Hospital Freiburg, Freiburg, Germany
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Rainey L, Deevi RK, McClements J, Khawaja H, Watson CJ, Roudier M, Van Schaeybroeck S, Campbell FC. Fundamental control of grade-specific colorectal cancer morphology by Src regulation of ezrin-centrosome engagement. J Pathol 2020; 251:310-322. [PMID: 32315081 DOI: 10.1002/path.5452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 02/27/2020] [Accepted: 04/07/2020] [Indexed: 11/11/2022]
Abstract
The phenotypic spectrum of colorectal cancer (CRC) is remarkably diverse, with seemingly endless variations in cell shape, mitotic figures and multicellular configurations. Despite this morphological complexity, histological grading of collective phenotype patterns provides robust prognostic stratification in CRC. Although mechanistic understanding is incomplete, previous studies have shown that the cortical protein ezrin controls diversification of cell shape, mitotic figure geometry and multicellular architecture, in 3D organotypic CRC cultures. Because ezrin is a substrate of Src tyrosine kinase that is frequently overexpressed in CRC, we investigated Src regulation of ezrin and morphogenic growth in 3D CRC cultures. Here we show that Src perturbations disrupt CRC epithelial spatial organisation. Aberrant Src activity suppresses formation of the cortical ezrin cap that anchors interphase centrosomes. In CRC cells with a normal centrosome number, these events lead to mitotic spindle misorientation, perturbation of cell cleavage, abnormal epithelial stratification, apical membrane misalignment, multilumen formation and evolution of cribriform multicellular morphology, a feature of low-grade cancer. In isogenic CRC cells with centrosome amplification, aberrant Src signalling promotes multipolar mitotic spindle formation, pleomorphism and morphological features of high-grade cancer. Translational studies in archival human CRC revealed associations between Src intensity, multipolar mitotic spindle frequency and high-grade cancer morphology. Collectively, our study reveals Src regulation of CRC morphogenic growth via ezrin-centrosome engagement and uncovers combined perturbations underlying transition to high-grade CRC morphology. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Lisa Rainey
- Centre for Cancer Research and Cell Biology, Queen's University Belfast and Belfast Health and Social Care Trust, Belfast, UK
| | - Ravi K Deevi
- Centre for Cancer Research and Cell Biology, Queen's University Belfast and Belfast Health and Social Care Trust, Belfast, UK
| | - Jane McClements
- Centre for Cancer Research and Cell Biology, Queen's University Belfast and Belfast Health and Social Care Trust, Belfast, UK
| | - Hajrah Khawaja
- Centre for Cancer Research and Cell Biology, Queen's University Belfast and Belfast Health and Social Care Trust, Belfast, UK
| | - Chris J Watson
- Wellcome Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK
| | - Martine Roudier
- Molecular Pathology Laboratory, AstraZeneca Oncology Translational Science, Cambridge, UK
| | - Sandra Van Schaeybroeck
- Centre for Cancer Research and Cell Biology, Queen's University Belfast and Belfast Health and Social Care Trust, Belfast, UK
| | - Frederick C Campbell
- Centre for Cancer Research and Cell Biology, Queen's University Belfast and Belfast Health and Social Care Trust, Belfast, UK
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Stemness regulation of the adrenal mixed corticomedullary tumorigenesis-a case-control study. Neoplasia 2020; 22:263-271. [PMID: 32438306 PMCID: PMC7240194 DOI: 10.1016/j.neo.2020.04.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 04/12/2020] [Accepted: 04/21/2020] [Indexed: 12/14/2022] Open
Abstract
Mixed corticomedullary tumor is an adrenal tumor intermixed with cortical and medullary cells. It is extremely rare with unclear tumorigenesis. We reported a 32-year-old female, manifested with typical Cushing’s syndrome and hypertension, to be diagnosed with right huge adrenal mixed corticomedullary tumor (8.8 cm). Right adrenalectomy was done to document the tumor intimately admixed with adrenal cortical adenoma and pheochromocytoma by biochemistry and immunohistochemistry. A case-control study was designed to explore the tumorigenesis of mixed corticomedullary tumor by whole exome sequencing. Expression of the stemness markers was controlled by a tissue array of 80 adrenal tumors. Overall, 1559 identical variants coexisted in parts of adrenal cortical adenoma and pheochromocytoma, which mainly (85.8%) originated from germline mutations. These enriched mutations were engaged in stemness control, coherent with substantial expression of the stemness markers (SOX2, CD44 and OCT4) in both parts. The differential stemness expressions were demonstrated in other adrenal tumors as well. The germline mutations were also enriched in signaling involving cancer proliferation, hypoxia inducible factor-1, focal adhesion and extracellular matrix receptor interaction. Somatic mutations affecting mitogen-activated protein kinase signaling, glycolysis and the citrate cycle were found in some tumor elements. This is the first study to verify the rare mixed corticomedullary tumor by molecular and genetic evidence to link with its phenotype. Germline mutations involving the stemness regulation and cancer proliferative signaling may drive intermixed tumor formation. Somatic mutations related to glycolysis and the citrate cycle may contribute to greater tumor outgrowth.
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Abstract
While our understanding of the biology of CD30 in lymphoma continues to evolve, our need to detect and measure its expression at the protein level remains critically important for diagnosis and patient care. In addition to its diagnostic and prognostic utility, CD30 has emerged as a vehicle for drug targeting through the antibody-drug conjugate brentuximab-vedotin (BV). Given the numerous ways that CD30 is utilized and its emergence as a predictive/prognostic biomarker, pathologists must come to a general consensus on the best reporting structure and methodology to ensure appropriate patient care. In this manuscript, we review the indications for testing, various modalities for testing, technical challenges, pitfalls, and potential standards of reporting. The following questions will try to be addressed in the current review article: What defines a "POSITIVE" level of CD30 expression?; How do we evaluate and report CD30 expression?; What are the caveats in the evaluation of CD30 expression?
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Pierce JT, Cho SS, Nag S, Zeh R, Jeon J, Holt D, Durham A, Nasrallah MP, Singhal S, Lee JYK. Folate Receptor Overexpression in Human and Canine Meningiomas-Immunohistochemistry and Case Report of Intraoperative Molecular Imaging. Neurosurgery 2020; 85:359-368. [PMID: 30113687 DOI: 10.1093/neuros/nyy356] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 06/12/2018] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Meningiomas are well-encapsulated benign brain tumors and surgical resection is often curative. Nevertheless, this is not always possible due to the difficulty of identifying residual disease intraoperatively. We hypothesized that meningiomas overexpress folate receptor alpha (FRα), allowing intraoperative molecular imaging by targeting FRα with a near-infrared (NIR) dye. OBJECTIVE To determine FRα expression in both human and canine meningioma cohorts to prepare for future clinical studies. Present a case study of a meningioma resection with intraoperative NIR fluorescence imaging. METHODS Tissue samples of 27 human meningioma specimens and 7 canine meningioma specimens were immunohistochemically stained for FRα along with normal dura, skeletal muscle, and kidney tissue. We then enrolled a patient with a pituitary adenoma and tuberculum sella meningioma in a clinical trial in which the patient received an infusion of folate-linked, NIR fluorescent dye prior to surgery. RESULTS In the cohort of human meningiomas, 9 WHO grade I, 12 grade II, and 6 grade III tumors were identified. Eighty-nine percent of WHO grade I, 67% of grade II, and 50% of grade III tumors overexpressed FRα. In the 7 canine meningioma samples, 100% stained positively for FRα. Both human and canine normal dura from autopsy samples demonstrated no evidence of FRα overexpression. In the case study, the meningioma demonstrated a high NIR signal-to-background-ratio of 4.0 and demonstrated strong FRα immunohistochemistry staining. CONCLUSION This study directly demonstrates FRα overexpression in both human and canine meningiomas. We also demonstrate superb intraoperative imaging of a meningioma using a FRα-targeting dye.
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Affiliation(s)
- John T Pierce
- Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Steve S Cho
- Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.,Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Shayoni Nag
- Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ryan Zeh
- Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jun Jeon
- Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.,Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - David Holt
- Department of Veterinary Medicine, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, Pennsylvania
| | - Amy Durham
- Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, Pennsylvania
| | - MacLean P Nasrallah
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sunil Singhal
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - John Y K Lee
- Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
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