Article
Medicine, Research & Experimental
Xilang Chen, Jie Chen, Weibo Feng, Wenjie Huang, Guodong Wang, Mengyu Sun, Xiangyuan Luo, Yijun Wang, Yongzhan Nie, Daiming Fan, Kaichun Wu, Limin Xia
Summary: Elevated ELF4 expression is positively correlated with distant metastasis, advanced AJCC stages, and poor prognosis in colorectal cancer patients. ELF4 promotes CRC metastasis by transactivating its downstream target genes FGFR4 and SRC. FGF19 upregulates ELF4 expression through the ERK1/2/SP1 axis. Combination therapy with the FGFR4 inhibitor BLU-554 and the SRC inhibitor KX2-391 effectively suppresses ELF4-mediated CRC metastasis.
Article
Medicine, General & Internal
Bei-Hao Shiu, Ming-Hong Hsieh, Wen-Chien Ting, Ming-Chih Chou, Lun-Ching Chang, Chi-Chou Huang, Shih-Chi Su, Shun-Fa Yang
Summary: This study investigated the impact of FGFR4 gene polymorphisms on the risk and progression of CRC, finding that certain SNPs were associated with a lower likelihood of metastasis in rectal cancer patients. Additionally, analysis using databases showed that a specific SNP may regulate FGFR4 expression, influencing the occurrence and metastasis of colon adenocarcinoma.
Article
Chemistry, Medicinal
Bo Fang, Yinshuang Lai, Hao Yan, Yue Ma, Zefeng Ni, Qianqian Zhu, Jianxia Zhang, Yanfei Ye, Mengying Wang, Peipei Wang, Yan Wang, Shuyuan Zhang, Min Hui, Dalong Wang, Yunjie Zhao, Xiaokun Li, Kun Wang, Zhiguo Liu
Summary: Aberrant FGFR4 signaling is implicated in cancer development, and this study reports a novel series of selective inhibitors targeting FGFR4 kinase. Compound 19g showed excellent kinase selectivity and cytotoxicity against colorectal cancer cell lines. It also demonstrated significant tumor inhibition in a mouse model and disrupted FGFR4 phosphorylation and downstream signaling. Compound 19g could be a potential candidate for colorectal cancer treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Cardiac & Cardiovascular Systems
Hiroshi Kishimoto, Toshiaki Nakano, Kumiko Torisu, Masanori Tokumoto, Yushi Uchida, Shunsuke Yamada, Masatomo Taniguchi, Takanari Kitazono
Summary: This study found that Indoxyl Sulfate (IS) increases fibroblast growth factor 23 (FGF23) protein expression through upregulation of polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) and hypoxia-inducible factor 1 alpha expression. Meanwhile, IS activates the FGF23-FGFR4 signaling pathway in cardiomyocytes, leading to left ventricular hypertrophy (LVH).
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Youxi Yu, Xiaoju Shi, Qianqian Zheng, Xingtong Wang, Xingkai Liu, Min Tan, Guoyue Lv, Ping Zhang, Robert C. Martin, Yan Li
Summary: The study found that increased FGF15 in NASH-FGF21KO mice could not substitute for FGF21 to prevent NASH development. Up-regulated FGFR4 signaling in NASH-FGF21KO mice was associated with proliferation and epithelial-mesenchymal transition events, which are commonly linked to carcinogenic transformation.
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
(2021)
Article
Chemistry, Medicinal
Xiaomeng Zhang, Yazhou Wang, Jianfeng Ji, Dongjuan Si, Xueting Bao, Zhuangzhuang Yu, Yueyue Zhu, Liwen Zhao, Wei Li, Jian Liu
Summary: Fibroblast growth factor receptor 4 (FGFR4) has been identified as a potential target for hepatocellular carcinoma (HCC). A novel family of potent FGFR4 inhibitors, represented by compound A34, was designed and synthesized. A34 exhibited improved FGFR4 inhibitory capability and excellent anti-proliferative activities against FGFR4-dependent HCC cell lines, indicating its potential as a novel anticancer agent for HCC.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Oncology
Jin-Fen Xiao, Andrew W. Caliri, Jason E. Duex, Dan Theodorescu
Summary: This review discusses the presence of unfavorable genetic alterations in the FGFR3 gene in 20% of advanced bladder cancer patients and explores the potential therapeutic strategies targeting these alterations and mechanisms of drug resistance. It also highlights the clinical findings of combining FGFR inhibition with other targeted inhibitors and/or immunotherapy to improve outcomes for patients with suboptimal responses to FGFR3-directed monotherapy.
Review
Cell Biology
Shivangi Pande, Xuehui Yang, Robert Friesel
Summary: IL17RD, also known as Sef, is a transmembrane protein that regulates multiple signaling pathways, particularly in developmental and pathobiological contexts, including the modulation of proinflammatory pathways such as IL17A. Despite its known functions, there are still gaps in our understanding of IL17RD, presenting opportunities for further research.
CELL COMMUNICATION AND SIGNALING
(2021)
Article
Biochemistry & Molecular Biology
Min Wang, Li Lan, Yu-Wei Wang, Jin-Yang Zhang, Lei Shi, Li-Ping Sun
Summary: Aberrant FGF19/FGFR4 signaling is a driver of growth and survival in hepatocellular carcinoma. Selective FGFR4 inhibitors are being researched as potential drugs for targeted therapy, but none have been approved by the FDA. In this study, a series of arylurea derivatives were designed and synthesized as novel irreversible covalent FGFR4 inhibitors. Compound 6v demonstrated significant inhibition of FGFR4 phosphorylation and downstream signaling in Hep3B cells, indicating its potential for further research and optimization.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Xiaolu Chen, Yanan Liu, Liting Zhang, Daoxing Chen, Zhaojun Dong, Chengguang Zhao, Zhiguo Liu, Qinqin Xia, Jianzhang Wu, Yongheng Chen, Xiaohui Zheng, Yuepiao Cai
Summary: In this study, a series of indazole derivatives were designed and synthesized, with F-30 showing subtle selectivity for FGFR4 and affecting cell growth and migration in HCC cell lines by inhibiting FGFR4 pathways.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Tianli Chen, Hongda Liu, Zengli Liu, Kangshuai Li, Ruixi Qin, Yue Wang, Jialiang Liu, Zhipeng Li, Qinglun Gao, Chang Pan, Fan Yang, Wei Zhao, Zongli Zhang, Yunfei Xu
Summary: The study revealed that FGF19 and FGFR4 are adverse prognostic biomarkers for gallbladder carcinoma, with their co-expression being a more sensitive predictor. FGF19 can promote GBC progression by stimulating FGFR4 activation via an autocrine pathway with bile as a potential carrier.
Review
Gastroenterology & Hepatology
Raffaella Maria Gadaleta, Antonio Moschetta
Summary: FGFR4 and its ligand FGF19 play crucial roles in cellular processes, including the development of liver tumors. FGFR4 inhibitors are a promising treatment option for HCC, while using FGF19 analogues to activate FGFR4-KLOTHO represents a novel therapeutic strategy for other liver diseases.
JOURNAL OF HEPATOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Xuexiang Li, Yunxue Li, Bing Liu, Liang Chen, Fang Lyu, Pu Zhang, Qingliu He, Lulin Cheng, Chunyu Liu, Yarong Song, Yifei Xing
Summary: In this study, it was found that Erdafitinib induces incomplete autophagy and increases intracellular reactive oxygen species levels to kill cells. A resistant cell line, RT-112-RS, was established and P4HA2 was identified as a key player in Erdafitinib resistance. Further investigation revealed that P4HA2 stabilizes HIF-1a protein and activates downstream target genes to reduce reactive oxygen species levels in bladder cancer. These findings highlight the significant role of P4HA2 in mediating acquired resistance to Erdafitinib and suggest it as a potential target for bladder cancer treatment.
Article
Biochemistry & Molecular Biology
Leilei Wang, Yuxiong Su, Wing Shan Choi
Summary: The study showed that melatonin suppresses invasion and migration of OSCC cells by blocking the FGF19/FGFR4 pathway, suggesting a potential alternative for OSCCs prevention and management.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Haojian Li, Yue Liu, Yunjie Xiao, Crystal N. Wilson, Hui Jen Bai, Maxwell D. Jones, Shihchun Wang, Jennie E. DeVore, Esther Y. Maier, Stephen T. Durant, Myriem Boufraqech, Urbain Weyemi
Summary: Cancer treatments targeting DNA repair deficiencies often encounter drug resistance, likely due to alternative metabolic pathways that counteract the most damaging effects. In this study, we identified KEAP1 as a key factor that desensitizes cancer cells to ATM inhibition, leading to increased sensitivity to DNA damage. Moreover, we found a negative correlation between ATM levels and KEAP1 levels in multiple solid malignancies, suggesting the potential of targeting ATM and KEAP1 as vulnerabilities in solid tumors.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Gastroenterology & Hepatology
Jonathan W. J. Lee, Feng Zhu, Supriya Srivastava, Stephen Kk Tsao, Christopher Khor, Khek Yu Ho, Kwong Ming Fock, Wee Chian Lim, Tiing Leong Ang, Wan Cheng Chow, Jimmy Bok Yan So, Calvin J. Koh, Shijia Joy Chua, Andrew S. Y. Wong, Jaideepraj Rao, Lee Guan Lim, Khoon Lin Ling, Chung-King Chia, Choon Jin Ooi, Andrea Rajnakova, Wai Ming Yap, Manuel Salto-Tellez, Bow Ho, Richie Soong, Kee Seng Chia, Yik Ying Teo, Ming Teh, Khay-Guan Yeoh
Summary: This study found that gastric intestinal metaplasia (IM) is a significant risk factor for early gastric neoplasia (EGN) in regions with low-intermediate incidence of gastric cancer. Based on the results, it is recommended that high-risk patients (OLGIM III-IV) undergo endoscopic surveillance every 2 years, and intermediate-risk patients (OLGIM II) every 5 years.
Article
Biochemical Research Methods
John Graf, Sanghee Cho, Elizabeth McDonough, Alex Corwin, Anup Sood, Andreas Lindner, Manuela Salvucci, Xanthi Stachtea, Sandra Van Schaeybroeck, Philip D. Dunne, Pierre Laurent-Puig, Daniel Longley, Jochen H. M. Prehn, Fiona Ginty
Summary: The study presented a new immunoFLuorescence Image NOrmalization method and evaluated it against alternative methods using multiround immunofluorescence staining with DAPI. Comparison of multiple normalization methods showed that upper quartile normalization of grid objects in log space had nearly equivalent performance to normalizing segmented cell objects by the middle quantile.
Article
Oncology
Mursheda Begum, Grant Lewison, Xiang Wang, Philip D. Dunne, Tim Maughan, Richard Sullivan, Mark Lawler
Summary: The purpose of this study was to provide an evidence base for colorectal cancer research activity that might influence policy. The study found that the volume and funding of global research on colorectal cancer are relatively low, with increased international collaboration except in China. The leading research domains are genetics, surgery, and prognosis, while research on palliative care and quality-of-life is lacking. In terms of funding, Western Europe relies on the charity sector, while China and the USA rely on government funding. Certain Asian countries provide minimal contestable funding, potentially reducing the impact of their colorectal cancer research.
INTERNATIONAL JOURNAL OF CANCER
(2023)
Article
Oncology
Raheleh Amirkhah, Kathryn Gilroy, Sudhir B. B. Malla, Tamsin R. M. Lannagan, Ryan M. M. Byrne, Natalie C. C. Fisher, Shania M. M. Corry, Noha-Ehssan Mohamed, Hojjat Naderi-Meshkin, Megan L. L. Mills, Andrew D. D. Campbell, Rachel A. A. Ridgway, Baharak Ahmaderaghi, Richard Murray, Antoni Berenguer Llergo, Rebeca Sanz-Pamplona, Alberto Villanueva, Eduard Batlle, Ramon Salazar, Mark Lawler, Owen J. J. Sansom, Philip D. D. Dunne
Summary: In this study, three approaches for classifying human-to-mouse CRC tissue were developed, with MmCMS-C, a combined pathway system, showing the best accuracy in classifying epithelial-like subtypes (CMS2/3) of tumors. The results provide guidance for researchers to select suitable mouse models for studying human CRC subtypes.
BRITISH JOURNAL OF CANCER
(2023)
Article
Oncology
Praveen Vikas, Hans Messersmith, Carolyn Compton, Lynette Sholl, Russell R. Broaddus, Anjee Davis, Maria Estevez-Diz, Rohan Garje, Panagiotis A. Konstantinopoulos, Aliza Leiser, Anne M. Mills, Barbara Norquist, Michael J. Overman, Davendra Sohal, Richard C. Turkington, Tyler Johnson
Summary: The College of American Pathologists (CAP) has developed a guideline on testing for mismatch repair (MMR) and microsatellite instability (MSI) for patients considered for immune checkpoint inhibitor therapy. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. ASCO endorses the recommendations from the CAP guideline.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Article
Pathology
Matthew Phillip Humphries, Victoria Bingham, Fatima Abdullah Sidi, Stephanie Craig, Beatrize Lara, Hesham El-daly, Nicole O'Doherty, Perry Maxwell, Claire Lewis, Stephen McQuaid, James Lyness, Jacqueline James, David R. J. Snead, Manuel Salto-Tellez
Summary: In this study, a validated protocol using multiplex immunofluorescence (mIF) was described for the exploration of the molecular physiopathology of SARS-CoV-2 pulmonary disease. Validated assays originally developed for the detection of SARS-CoV-2 in tissues were applied to map the adaptive immune response at protein and mRNA levels. The mIF panels showed robust, reliable, and quantifiable performance in detecting topographic variations in inflammation related to pathological processes in formalin-fixed, paraffin-embedded pneumonia material.
JOURNAL OF CLINICAL PATHOLOGY
(2023)
Editorial Material
Oncology
Manuel Salto-Tellez, Jorge S. Reis-Filho
Article
Cell Biology
Hannah Egan, Oliver Treacy, Kevin Lynch, Niamh A. Leonard, Grace O'Malley, Eileen Reidy, Aoise O'Neill, Shania M. Corry, Kim De Veirman, Karin Vanderkerken, Laurence J. Egan, Thomas Ritter, Aisling M. Hogan, Keara Redmond, Li Peng, Jenny Che, Wayne Gatlin, Pushpa Jayaraman, Margaret Sheehan, Aoife Canney, Sean O. Hynes, Emma M. Kerr, Philip D. Dunne, Michael E. O'Dwyer, Aideen E. Ryan
Summary: Immunosuppressive tumor microenvironments (TMEs) in cancer reduce immune responses, and mesenchymal stromal cells (MSCs) promote tumor progression through enhancing immune cell suppression in colorectal cancer (CRC). The hyper-sialylation of glycans promotes immune evasion by binding sialic acids to Siglecs receptors on immune cells, resulting in inhibition of their functions. However, the role of sialylation in MSC/CAF immunosuppression in the TME is not well characterized.
Article
Oncology
Toshiyasu Suzuki, Anna Kilbey, Nuria Casa-Rodriguez, Amy Lawlor, Anastasia Georgakopoulou, Hannah Hayman, Kyi Lai Yin Swe, Anna Nordin, Claudio Cantu, Pierre Vantourout, Rachel A. Ridgway, Ryan M. Byrne, Lei Chen, Michael P. Verzi, David M. Gay, Ester Gil Vazquez, Hayley L. Belnoue-Davis, Kathryn Gilroy, Anne Helene Kostner, Christian Kersten, Chanitra Thuwajit, Ditte K. Andersen, Robert Wiesheu, Anett Jandke, Karen Blyth, Antonia K. Roseweir, Simon J. Leedham, Philip D. Dunne, Joanne Edwards, Adrian Hayday, Owen J. Sansom, Seth B. Coffelt
Summary: Colon cancer cells evade immune surveillance by suppressing the expression of y8 T cells and Butyrophilin-like (BTNL) molecules. Reexpression of BTNL enhances the survival and activation of y8 T cells, but it does not affect their cancer-killing ability or recruitment to orthotopic tumors. However, inhibition of 13-catenin signaling through genetic deletion of Bcl9/Bcl9L restores the expression of Hnf4a, Hnf4g, and Btnl genes as well as infiltration of y8 T cells into tumors.
CANCER IMMUNOLOGY RESEARCH
(2023)
Article
Oncology
Jonathan L. Moore, Michael Green, Aida Santaolalla, Harriet Deere, Richard P. T. Evans, Mona Elshafie, Anita Lavery, Damian T. McManus, Andrew McGuigan, Rosalie Douglas, Joanne Horne, Robert Walker, Hira Mir, Monica Terlizzo, Sivesh K. Kamarajah, Mieke Van Hemelrijck, Nick Maisey, Ailsa Sita-Lumsden, Sarah Ngan, Mark Kelly, Cara R. Baker, Sacheen Kumar, Jesper Lagergren, William H. Allum, James A. Gossage, Ewen A. Griffiths, Heike I. Grabsch, Richard C. Turkington, Tim J. Underwood, Elizabeth C. Smyth, Rebecca C. Fitzgerald, David Cunningham, Andrew R. Davies
Summary: This study aimed to evaluate the influence of lymph node (LN) regression on survival after surgery for esophageal adenocarcinoma. The results showed that patients with complete LN regression, partial LN regression, or negative LNs had a lower mortality rate compared to those with poor/no LN regression.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Alice Geaney, Paul O'Reilly, Perry Maxwell, Jacqueline A. James, Darragh Mcart, Manuel Salto-Tellez
Summary: Digital pathology and artificial intelligence have transformed oncology research and cancer diagnostics, allowing for better interpretation of pathology images and improved quantitation of biomarkers. Different approaches of artificial intelligence can solve various problems in pathology workflows and have the potential to revolutionize clinical trials and create complex biomarkers for cancer patients.
Article
Multidisciplinary Sciences
Fatima Abdullahi G. Sidi, Victoria C. Bingham, Stephen A. McQuaid, Stephanie P. Craig, Richard Turkington, Jacqueline James, Matthew Humphries, Manuel Salto-Tellez
Summary: This study analyzed the expression of immune cells and immune checkpoint biomarkers in a cohort of small bowel adenocarcinoma patients and assessed their impact on survival outcomes. The results showed that high expressions of CD3, CD4, IDO1, and ICOS were significantly associated with progression-free survival, while high PD-L1 expression in tumor cells was significantly associated with overall survival. These findings provide valuable insights for the immunotherapeutic management of small bowel adenocarcinoma patients.
Article
Multidisciplinary Sciences
Sujath Abbas, Oriol A. Pich, Ginny Devonshire, Shahriar Zamani, Annalise Katz-Summercorn, Sarah Killcoyne, Calvin Cheah, Barbara Nutzinger, Nicola Grehan, Nuria Lopez-Bigas, Paul A. W. Edwards, Elwira M. Fidziukiewicz, Aisling Redmond, Adam C. Freeman, Elizabeth Smyth, Maria O'Donovan, Ahmad Miremadi, Shalini Malhotra, Monika Tripathi, Hannah Coles, Conor Flint, Matthew Eldridge, Sriganesh Jammula, Jim Davies, Charles Crichton, Nick H. Carroll, Richard Hardwick, Peter Safranek, Andrew Hindmarsh, Vijayendran J. Sujendran, Stephen Hayes, Yeng Ang, Andrew R. Sharrocks, Shaun Preston, Izhar Bagwan, Vicki Save, Richard J. E. R. Skipworth, Ted Hupp, J. Robert O'Neill, Olga Tucker, Andrew Beggs, Philippe Taniere, Sonia Puig, Gianmarco J. Contino, Timothy C. Underwood, Robert L. Walker, Ben Grace, Jesper Lagergren, James Gossage, Andrew Davies, Fuju Chang, Ula Mahadeva, Vicky D. Goh, Francesca Ciccarelli, Grant Sanders, Richard Berrisford, David Chan, Ed Cheong, Bhaskar Kumar, L. L. Sreedharan, Simon Parsons, Irshad Soomro, Philip Kaye, John Saunders, Laurence Lovat, Rehan Haidry, Michael Scott, Sharmila Sothi, Suzy B. Lishman, George J. Hanna, Christopher Peters, Krishna Moorthy, Anna Grabowska, Richard Turkington, Damian McManus, Helen D. Coleman, Russell Petty, Freddie C. Bartlett, Rebecca Fitzgerald, Maria Secrier
Summary: The mutational processes of oesophageal adenocarcinoma (OAC) progression from Barrett's Oesophagus have been characterized, with C[T > C/G]T substitution enriched signatures SBS17a/b being dominant. TP53 mutations, increased proliferation, genomic instability, and disease progression are associated with these mutations. Alterations in DNA damage repair pathways, including base excision repair deficiencies, are also linked to poor prognosis.
NATURE COMMUNICATIONS
(2023)
Article
Cell Biology
Shun Hay Pun, Karla M. O'Neill, Kevin S. Edgar, Eleanor K. Gill, Arya Moez, Hojjat Naderi-Meshkin, Sudhir B. Malla, Michelle B. Hookham, Mohammed Alsaggaf, Vinuthna Vani Madishetti, Bianca Botezatu, William King, Coy Brunssen, Henning Morawietz, Philip D. Dunne, Derek P. Brazil, Reinhold J. Medina, Chris J. Watson, David J. Grieve
Summary: This study aimed to investigate and define the contribution of NOX4 NADPH oxidase to hypoxia-induced dysfunction and explore its potential as a therapeutic target. The results showed that activation of the PLAC8-NOX4 signaling axis improved the angiogenic functions of CB-ECFCs under hypoxic conditions.
Article
Rehabilitation
Malcolm Brown, Dominic O'Connor, Richard Turkington, Martin Eatock, Rebecca Vince, Claire Hulme, Roy Bowdery, Rebecca Robinson, Jonathan Wadsley, Anthony Maraveyas, Gillian Prue
Summary: This study aimed to investigate the feasibility and safety of concurrent exercise training during adjuvant chemotherapy. The results showed that this training method was feasible and safe, and it prevented a decline in functional fitness and patient-reported outcomes. These findings provide further evidence for including exercise training as a standard of care for surgical rehabilitation and managing treatment-related toxicities.
BMC SPORTS SCIENCE MEDICINE AND REHABILITATION
(2023)