Molecular Oncology

Team Publications

Year of publication 2018

Tom Baladi, Jessy Aziz, Florent Dufour, Valentina Abet, Véronique Stoven, François Radvanyi, Florent Poyer, Ting-Di Wu, Jean-Luc Guerquin-Kern, Isabelle Bernard-Pierrot, Sergio Marco Garrido, Sandrine Piguel (2018 Nov 1)

Design, synthesis, biological evaluation and cellular imaging of imidazo[4,5-b]pyridine derivatives as potent and selective TAM inhibitors.

Bioorganic & medicinal chemistry : 26 : 5510-5530 : DOI : 10.1016/j.bmc.2018.09.031 Learn more
Summary

The TAM kinase family arises as a new effective and attractive therapeutic target for cancer therapy, autoimmune and viral diseases. A series of 2,6-disubstituted imidazo[4,5-b]pyridines were designed, synthesized and identified as highly potent TAM inhibitors. Despite remarkable structural similarities within the TAM family, compounds 28 and 25 demonstrated high activity and selectivity in vitro against AXL and MER, with IC value of 0.77 nM and 9 nM respectively and a 120- to 900-fold selectivity. We also observed an unexpected nuclear localization for compound 10Bb, thanks to nanoSIMS technology, which could be correlated to the absence of cytotoxicity on three different cancer cell lines being sensitive to TAM inhibition.

design,synthesis

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Year of publication 2016

Simone Benhamou, Julia Bonastre, Karine Groussard, François Radvanyi, Yves Allory, Thierry Lebret (2016 Nov 5)

A prospective multicenter study on bladder cancer: the COBLAnCE cohort.

BMC cancer : 837 Learn more
Summary

Bladder cancer is a very heterogeneous disease as regards natural history. Environmental exposures, constitutional genetic and/or epigenetic background may affect not only the likelihood of bladder tumor occurrence, but also the histologic type of cancer and its outcome. Currently, only a few data are available to study the prognostic role of genetic and environmental factors. Likewise, data on the economic burden of bladder cancer and the longitudinal impact of the disease and the treatments on patient quality of life are scarce.

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Philippine Eloy, Catherine Dehainault, Meriem Sefta, Isabelle Aerts, François Doz, Nathalie Cassoux, Livia Lumbroso le Rouic, Dominique Stoppa-Lyonnet, François Radvanyi, Gaël A Millot, Marion Gauthier-Villars, Claude Houdayer (2016 Mar 2)

A Parent-of-Origin Effect Impacts the Phenotype in Low Penetrance Retinoblastoma Families Segregating the c.1981C>T/p.Arg661Trp Mutation of RB1.

PLoS genetics : e1005888 : DOI : 10.1371/journal.pgen.1005888 Learn more
Summary

Retinoblastoma (Rb), the most common pediatric intraocular neoplasm, results from inactivation of both alleles of the RB1 tumor suppressor gene. The second allele is most commonly lost, as demonstrated by loss of heterozygosity studies. RB1 germline carriers usually develop bilateral tumors, but some Rb families display low penetrance and variable expressivity. In order to decipher the underlying mechanisms, 23 unrelated low penetrance pedigrees segregating the common c.1981C>T/p.Arg661Trp mutation and other low penetrance mutations were studied. In families segregating the c.1981C>T mutation, we demonstrated, for the first time, a correlation between the gender of the transmitting carrier and penetrance, as evidenced by Fisher’s exact test: the probability of being unaffected is 90.3% and 32.5% when the mutation is inherited from the mother and the father, respectively (p-value = 7.10-7). Interestingly, a similar correlation was observed in families segregating other low penetrance alleles. Consequently, we investigated the putative involvement of an imprinted, modifier gene in low penetrance Rb. We first ruled out a MED4-driven mechanism by MED4 methylation and expression analyses. We then focused on the differentially methylated CpG85 island located in intron 2 of RB1 and showing parent-of-origin-specific DNA methylation. This differential methylation promotes expression of the maternal c.1981C>T allele. We propose that the maternally inherited c.1981C>T/p.Arg661Trp allele retains sufficient tumor suppressor activity to prevent retinoblastoma development. In contrast, when the mutation is paternally transmitted, the low residual activity would mimic a null mutation and subsequently lead to retinoblastoma. This implies that the c.1981C>T mutation is not deleterious per se but needs to be destabilized in order to reach pRb haploinsufficiency and initiate tumorigenesis. We suggest that this phenomenon might be a general mechanism to explain phenotypic differences in low penetrance Rb families.

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Year of publication 2015

Elisabeth Remy, Sandra Rebouissou, Claudine Chaouiya, Andrei Zinovyev, François Radvanyi, Laurence Calzone (2015 Aug 5)

A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis.

Cancer research : 4042-52 : DOI : 10.1158/0008-5472.CAN-15-0602 Learn more
Summary

Relationships between genetic alterations, such as co-occurrence or mutual exclusivity, are often observed in cancer, where their understanding may provide new insights into etiology and clinical management. In this study, we combined statistical analyses and computational modeling to explain patterns of genetic alterations seen in 178 patients with bladder tumors (either muscle-invasive or non-muscle-invasive). A statistical analysis on frequently altered genes identified pair associations, including co-occurrence or mutual exclusivity. Focusing on genetic alterations of protein-coding genes involved in growth factor receptor signaling, cell cycle, and apoptosis entry, we complemented this analysis with a literature search to focus on nine pairs of genetic alterations of our dataset, with subsequent verification in three other datasets available publicly. To understand the reasons and contexts of these patterns of associations while accounting for the dynamics of associated signaling pathways, we built a logical model. This model was validated first on published mutant mice data, then used to study patterns and to draw conclusions on counter-intuitive observations, allowing one to formulate predictions about conditions where combining genetic alterations benefits tumorigenesis. For example, while CDKN2A homozygous deletions occur in a context of FGFR3-activating mutations, our model suggests that additional PIK3CA mutation or p21CIP deletion would greatly favor invasiveness. Furthermore, the model sheds light on the temporal orders of gene alterations, for example, showing how mutual exclusivity of FGFR3 and TP53 mutations is interpretable if FGFR3 is mutated first. Overall, our work shows how to predict combinations of the major gene alterations leading to invasiveness through two main progression pathways in bladder cancer.

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Rémy Nicolle, François Radvanyi, Mohamed Elati (2015 May 17)

CoRegNet: reconstruction and integrated analysis of co-regulatory networks.

Bioinformatics (Oxford, England) : 3066-8 : DOI : 10.1093/bioinformatics/btv305 Learn more
Summary

CoRegNet is an R/Bioconductor package to analyze large-scale transcriptomic data by highlighting sets of co-regulators. Based on a transcriptomic dataset, CoRegNet can be used to: reconstruct a large-scale co-regulatory network, integrate regulation evidences such as transcription factor binding sites and ChIP data, estimate sample-specific regulator activity, identify cooperative transcription factors and analyze the sample-specific combinations of active regulators through an interactive visualization tool. In this study CoRegNet was used to identify driver regulators of bladder cancer.

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Year of publication 2014

Stéphane Oudard, Stéphane Culine, Yann Vano, François Goldwasser, Christine Théodore, Thierry Nguyen, Eric Voog, Eugeniu Banu, Annick Vieillefond, Franck Priou, Gaël Deplanque, Gwenaëlle Gravis, Alain Ravaud, Jean Michel Vannetzel, Jean-Pascal Machiels, Xavier Muracciole, Marie-France Pichon, Jacques-Olivier Bay, Reza Elaidi, Corine Teghom, François Radvanyi, Philippe Beuzeboc (2014 Dec 3)

Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2.

European journal of cancer (Oxford, England : 1990) : 45-54 : DOI : 10.1016/j.ejca.2014.10.009 Learn more
Summary

To investigate the efficacy and safety of gemcitabine and platinum salt, with or without trastuzumab, in patients with locally advanced or metastatic urothelial carcinoma overexpressing Her2.

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C Winterhalter, R Nicolle, A Louis, C To, F Radvanyi, M Elati (2014 Aug 21)

Pepper: cytoscape app for protein complex expansion using protein-protein interaction networks.

Bioinformatics (Oxford, England) : 3419-20 : DOI : 10.1093/bioinformatics/btu517 Learn more
Summary

We introduce Pepper (Protein complex Expansion using Protein-Protein intERactions), a Cytoscape app designed to identify protein complexes as densely connected subnetworks from seed lists of proteins derived from proteomic studies. Pepper identifies connected subgraph by using multi-objective optimization involving two functions: (i) the coverage, a solution must contain as many proteins from the seed as possible, (ii) the density, the proteins of a solution must be as connected as possible, using only interactions from a proteome-wide interaction network. Comparisons based on gold standard yeast and human datasets showed Pepper’s integrative approach as superior to standard protein complex discovery methods. The visualization and interpretation of the results are facilitated by an automated post-processing pipeline based on topological analysis and data integration about the predicted complex proteins. Pepper is a user-friendly tool that can be used to analyse any list of proteins.

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Sandra Rebouissou, Isabelle Bernard-Pierrot, Aurélien de Reyniès, May-Linda Lepage, Clémentine Krucker, Elodie Chapeaublanc, Aurélie Hérault, Aurélie Kamoun, Aurélie Caillault, Eric Letouzé, Nabila Elarouci, Yann Neuzillet, Yves Denoux, Vincent Molinié, Dimitri Vordos, Agnès Laplanche, Pascale Maillé, Pascale Soyeux, Karina Ofualuka, Fabien Reyal, Anne Biton, Mathilde Sibony, Xavier Paoletti, Jennifer Southgate, Simone Benhamou, Thierry Lebret, Yves Allory, François Radvanyi (2014 Jul 11)

EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype.

Science translational medicine : 244ra91 : DOI : 10.1126/scitranslmed.3008970 Learn more
Summary

Muscle-invasive bladder carcinoma (MIBC) constitutes a heterogeneous group of tumors with a poor outcome. Molecular stratification of MIBC may identify clinically relevant tumor subgroups and help to provide effective targeted therapies. From seven series of large-scale transcriptomic data (383 tumors), we identified an MIBC subgroup accounting for 23.5% of MIBC, associated with shorter survival and displaying a basal-like phenotype, as shown by the expression of epithelial basal cell markers. Basal-like tumors presented an activation of the epidermal growth factor receptor (EGFR) pathway linked to frequent EGFR gains and activation of an EGFR autocrine loop. We used a 40-gene expression classifier derived from human tumors to identify human bladder cancer cell lines and a chemically induced mouse model of bladder cancer corresponding to human basal-like bladder cancer. We showed, in both models, that tumor cells were sensitive to anti-EGFR therapy. Our findings provide preclinical proof of concept that anti-EGFR therapy can be used to target a subset of particularly aggressive MIBC tumors expressing basal cell markers and provide diagnostic tools for identifying these tumors.

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Thorunn Rafnar, Patrick Sulem, Gudmar Thorleifsson, Sita H Vermeulen, Hannes Helgason, Jona Saemundsdottir, Sigurjon A Gudjonsson, Asgeir Sigurdsson, Simon N Stacey, Julius Gudmundsson, Hrefna Johannsdottir, Kristin Alexiusdottir, Vigdis Petursdottir, Sigfus Nikulasson, Gudmundur Geirsson, Thorvaldur Jonsson, Katja K H Aben, Anne J Grotenhuis, Gerald W Verhaegh, Aleksandra M Dudek, J Alfred Witjes, Antoine G van der Heijden, Alina Vrieling, Tessel E Galesloot, Ana De Juan, Angeles Panadero, Fernando Rivera, Carolyn Hurst, D Timothy Bishop, Sei C Sak, Ananya Choudhury, Mark T W Teo, Cecilia Arici, Angela Carta, Elena Toninelli, Petra de Verdier, Peter Rudnai, Eugene Gurzau, Kvetoslava Koppova, Kirstin A van der Keur, Irene Lurkin, Mieke Goossens, Eliane Kellen, Simonetta Guarrera, Alessia Russo, Rossana Critelli, Carlotta Sacerdote, Paolo Vineis, Clémentine Krucker, Maurice P Zeegers, Holger Gerullis, Daniel Ovsiannikov, Frank Volkert, Jan G Hengstler, Silvia Selinski, Olafur T Magnusson, Gisli Masson, Augustine Kong, Daniel Gudbjartsson, Annika Lindblom, Ellen Zwarthoff, Stefano Porru, Klaus Golka, Frank Buntinx, Giuseppe Matullo, Rajiv Kumar, José I Mayordomo, D Gunnar Steineck, Anne E Kiltie, Eirikur Jonsson, François Radvanyi, Margaret A Knowles, Unnur Thorsteinsdottir, Lambertus A Kiemeney, Kari Stefansson (2014 May 28)

Genome-wide association study yields variants at 20p12.2 that associate with urinary bladder cancer.

Human molecular genetics : 5545-57 : DOI : 10.1093/hmg/ddu264 Learn more
Summary

Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 × 10(-11) for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS.

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Harish Srinivasan, Yves Allory, Martin Sill, Dimitri Vordos, Mohamed Saiel Saeed Alhamdani, Francois Radvanyi, Jörg D Hoheisel, Christoph Schröder (2014 Mar 11)

Prediction of recurrence of non muscle-invasive bladder cancer by means of a protein signature identified by antibody microarray analyses.

Proteomics : 1333-42 : DOI : 10.1002/pmic.201300320 Learn more
Summary

About 70% of newly diagnosed cases of bladder cancer are low-stage, low-grade, non muscle-invasive. Standard treatment is transurethral resection. About 60% of the tumors will recur, however, and in part progress to become invasive. Therefore, surveillance cystoscopy is performed after resection. However, in the USA and Europe alone, about 54 000 new patients per year undergo repeated cystoscopies over several years, who do not experience recurrence. Analysing in a pilot study resected tumors from patients with (n = 19) and without local recurrence (n = 6) after a period of 5 years by means of an antibody microarray that targeted 724 cancer-related proteins, we identified 255 proteins with significantly differential abundance. Most are involved in the regulation and execution of apoptosis and cell proliferation. A multivariate classifier was constructed based on 20 proteins. It facilitates the prediction of recurrence with a sensitivity of 80% and a specificity of 100%. As a measure of overall accuracy, the area under the curve value was found to be 91%. After validation in additional sample cohorts with a similarly long follow-up, such a signature could support decision making about the stringency of surveillance or even different treatment options.

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C Vallot, A Hérault, S Boyle, W A Bickmore, F Radvanyi (2014 Jan 29)

PRC2-independent chromatin compaction and transcriptional repression in cancer.

Oncogene : 741-51 : DOI : 10.1038/onc.2013.604 Learn more
Summary

The silencing of large chromosomal regions by epigenetic mechanisms has been reported to occur frequently in cancer. Epigenetic marks, such as histone methylation and acetylation, are altered at these loci. However, the mechanisms of formation of such aberrant gene clusters remain largely unknown. Here, we show that, in cancer cells, the epigenetic remodeling of chromatin into hypoacetylated domains covered with histone H3K27 trimethylation is paralleled by changes in higher-order chromatin structures. Using fluorescence in situ hybridization, we demonstrate that regional epigenetic silencing corresponds to the establishment of compact chromatin domains. We show that gene repression is tightly correlated to the state of chromatin compaction and not to the levels of H3K27me3-its removal through the knockdown of EZH2 does not induce significant gene expression nor chromatin decompaction. Moreover, transcription can occur with intact high-H3K27me3 levels; treatment with histone deacetylase inhibitors can relieve chromatin compaction and gene repression, without altering H3K27me3 levels. Our findings imply that compaction and subsequent repression of large chromatin domains are not direct consequences of PRC2 deregulation in cancer cells. By challenging the role of EZH2 in aberrant gene silencing in cancer, these findings have therapeutical implications, notably for the choice of epigenetic drugs for tumors with multiple regional epigenetic alterations.

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Anne Biton, Isabelle Bernard-Pierrot, Yinjun Lou, Clémentine Krucker, Elodie Chapeaublanc, Carlota Rubio-Pérez, Nuria López-Bigas, Aurélie Kamoun, Yann Neuzillet, Pierre Gestraud, Luca Grieco, Sandra Rebouissou, Aurélien de Reyniès, Simone Benhamou, Thierry Lebret, Jennifer Southgate, Emmanuel Barillot, Yves Allory, Andrei Zinovyev, François Radvanyi (2014 Jan 25)

Independent component analysis uncovers the landscape of the bladder tumor transcriptome and reveals insights into luminal and basal subtypes.

Cell reports : 1235-45 : DOI : 10.1016/j.celrep.2014.10.035 Learn more
Summary

Extracting relevant information from large-scale data offers unprecedented opportunities in cancerology. We applied independent component analysis (ICA) to bladder cancer transcriptome data sets and interpreted the components using gene enrichment analysis and tumor-associated molecular, clinicopathological, and processing information. We identified components associated with biological processes of tumor cells or the tumor microenvironment, and other components revealed technical biases. Applying ICA to nine cancer types identified cancer-shared and bladder-cancer-specific components. We characterized the luminal and basal-like subtypes of muscle-invasive bladder cancers according to the components identified. The study of the urothelial differentiation component, specific to the luminal subtypes, showed that a molecular urothelial differentiation program was maintained even in those luminal tumors that had lost morphological differentiation. Study of the genomic alterations associated with this component coupled with functional studies revealed a protumorigenic role for PPARG in luminal tumors. Our results support the inclusion of ICA in the exploitation of multiscale data sets.

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Year of publication 2013

Luca Grieco, Laurence Calzone, Isabelle Bernard-Pierrot, François Radvanyi, Brigitte Kahn-Perlès, Denis Thieffry (2013 Nov 20)

Integrative modelling of the influence of MAPK network on cancer cell fate decision.

PLoS computational biology : e1003286 : DOI : 10.1371/journal.pcbi.1003286 Learn more
Summary

The Mitogen-Activated Protein Kinase (MAPK) network consists of tightly interconnected signalling pathways involved in diverse cellular processes, such as cell cycle, survival, apoptosis and differentiation. Although several studies reported the involvement of these signalling cascades in cancer deregulations, the precise mechanisms underlying their influence on the balance between cell proliferation and cell death (cell fate decision) in pathological circumstances remain elusive. Based on an extensive analysis of published data, we have built a comprehensive and generic reaction map for the MAPK signalling network, using CellDesigner software. In order to explore the MAPK responses to different stimuli and better understand their contributions to cell fate decision, we have considered the most crucial components and interactions and encoded them into a logical model, using the software GINsim. Our logical model analysis particularly focuses on urinary bladder cancer, where MAPK network deregulations have often been associated with specific phenotypes. To cope with the combinatorial explosion of the number of states, we have applied novel algorithms for model reduction and for the compression of state transition graphs, both implemented into the software GINsim. The results of systematic simulations for different signal combinations and network perturbations were found globally coherent with published data. In silico experiments further enabled us to delineate the roles of specific components, cross-talks and regulatory feedbacks in cell fate decision. Finally, tentative proliferative or anti-proliferative mechanisms can be connected with established bladder cancer deregulations, namely Epidermal Growth Factor Receptor (EGFR) over-expression and Fibroblast Growth Factor Receptor 3 (FGFR3) activating mutations.

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Ténin Traoré, Andrea Cavagnino, Nicolas Saettel, François Radvanyi, Sandrine Piguel, Isabelle Bernard-Pierrot, Véronique Stoven, Michel Legraverend (2013 Nov 19)

New aminopyrimidine derivatives as inhibitors of the TAM family.

European journal of medicinal chemistry : 789-801 : DOI : 10.1016/j.ejmech.2013.10.037 Learn more
Summary

In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.

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Julien Calderaro, Sandra Rebouissou, Leanne de Koning, Asma Masmoudi, Aurélie Hérault, Thierry Dubois, Pascale Maille, Pascale Soyeux, Mathilde Sibony, Alexandre de la Taille, Dimitri Vordos, Thierry Lebret, François Radvanyi, Yves Allory (2013 Oct 15)

PI3K/AKT pathway activation in bladder carcinogenesis.

International journal of cancer : 1776-84 : DOI : 10.1002/ijc.28518 Learn more
Summary

The PI3K/AKT pathway is considered to play a major role in bladder carcinogenesis, but its relationships with other molecular alterations observed in bladder cancer remain unknown. We investigated PI3K/AKT pathway activation in a series of human bladder urothelial carcinomas (UC) according to PTEN expression, PTEN deletions and FGFR3, PIK3CA, KRAS, HRAS, NRAS and TP53 gene mutations. The series included 6 normal bladder urothelial samples and 129 UC (Ta n = 25, T1 n = 34, T2-T3-T4 n = 70). Expression of phospho-AKT (pAKT), phospho-S6-Ribosomal Protein (pS6) (one downstream effector of PI3K/AKT pathway) and PTEN was evaluated by reverse phase protein Array. Expression of miR-21, miR-19a and miR-222, known to regulate PTEN expression, was also evaluated. pAKT expression levels were higher in tumors than in normal urothelium (p < 0.01), regardless of stage and showed a weak and positive correlation with pS6 (Spearman coefficient RS = 0.26; p = 0.002). No association was observed between pAKT or pS6 expression and the gene mutations studied. PTEN expression was decreased in PTEN-deleted tumors, and in T1 (p = 0.0089) and T2-T3-T4 (p < 0.001) tumors compared to Ta tumors; it was also negatively correlated with miR-19a (RS = -0.50; p = 0.0088) and miR-222 (RS = -0.48; p = 0.0132), but not miR-21 (RS = -0.27; p = 0.18) expression. pAKT and PTEN expressions were not negatively correlated, and, on the opposite, a positive and moderate correlation was observed in Ta (RS = 0.54; p = 0.0056) and T1 (RS = 0.56; p = 0.0006) tumors. Our study suggests that PI3K/AKT pathway activation occurs in the entire spectrum of bladder UC regardless of stage or known most frequent molecular alterations, and independently of low PTEN expression.

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