Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Développement et caractérisation de modèles précliniques de carcinomes hépatocellulaires pour l'évaluation de la réponse thérapeutique et l'étude des mécanismes de l'hépatocarcinogenèse

Hepatocellular carcinoma (HCC) is a very aggressive malignancy, which is resistant to current therapeutic options for advanced stages. In addition, most of recent phase 2 or 3 clinical trials failed due to the development of multiple resistance mechanisms. In this context, preclinical models are very useful to understand the molecular biology of HCC and looking for new therapeutic targets or specific biomarkers of treatment response. Thus, in this work, the study of HCC cell lines that represent a subgroup of aggressive tumors but recapitulate the molecular diversity of HCC enabled us to show associations between specific molecular contexts and response to treatments allowing to establish several new therapeutic hypotheses. Thanks to these cell lines we also understand that the overexpression of MET as a criterion for inclusion of patients in tivantinib clinical trials explained its failures and to propose the expression of Ki67 as a better biomarker predictive of its antitumor efficacy. Finally, by studying murine models of oncogenic cooperation, we highlighted for the first time the tumor suppressor role of RSK2 in hepatic carcinogenesis, in cooperation with the inactivation of AXIN1 or the activation of the Wnt/β-catenin pathway. Overall, this study shows that preclinical models are extremely informative, despite their various limitations, they allow to bring new therapeutic hypotheses. In particular we demonstrated the crucial role of the RAS-MAPK pathway activation in HCC development reinforcing the interest of the use of MEK1/2 inhibitors in future clinical trials in candidate subgroups.Le carcinome hépatocellulaire (CHC), souvent diagnostiqué tardivement, est un cancer extrêmement agressif et résistant aux traitements proposés pour les stades avancés. De plus, la majorité des récents essais cliniques de phase 2 ou 3 se sont soldés par des échecs liés au développement de multiples mécanismes de résistance. Dans ce contexte l’étude de modèles précliniques est très utile pour comprendre la biologie moléculaire du CHC et chercher de nouvelles cibles thérapeutiques ou biomarqueurs spécifiques de la réponse aux traitements. Ainsi, dans ce travail, l’étude de lignées cellulaires dérivées de CHC qui représentent un sous-groupe de tumeurs agressives mais récapitulent une diversité moléculaire du CHC, nous a permis d’associer certains contextes moléculaires spécifiques à la réponse aux traitements et d’établir plusieurs nouvelles hypothèses thérapeutiques. Ces lignées nous ont également permis de comprendre que la surexpression de MET comme critère d'inclusion des patients expliquait les échecs des essais cliniques du tivantinib et de proposer l’expression de Ki67 comme un meilleur biomarqueur prédictif de son efficacité antitumorale. Enfin, l’étude de modèles murins de coopération oncogénique a permis de mettre en évidence pour la première fois le rôle suppresseur de tumeurs de RSK2 dans la carcinogenèse hépatique, en coopération avec l’inactivation d’AXIN1 ou l’activation de la voie Wnt/β-caténine. Dans l’ensemble, cette étude montre que les modèles précliniques sont extrêmement informatifs, malgré leurs différentes limites, ils permettent d’apporter de nouvelles hypothèses thérapeutiques. En particulier dans ce travail, la mise en évidence du rôle crucial de l’activation de la voie RAS-MAPK dans le développement du CHC renforce l’intérêt de l’utilisation d’inhibiteurs de MEK1/2 dans de futurs essais cliniques dans des sous-groupes candidats

Development and characterization of hepatocellular carcinoma preclinical models to evaluate therapeutic response and to study molecular mechanism of hepatocarcinogenesis

Le carcinome hépatocellulaire (CHC), souvent diagnostiqué tardivement, est un cancer extrêmement agressif et résistant aux traitements proposés pour les stades avancés. De plus, la majorité des récents essais cliniques de phase 2 ou 3 se sont soldés par des échecs liés au développement de multiples mécanismes de résistance. Dans ce contexte l’étude de modèles précliniques est très utile pour comprendre la biologie moléculaire du CHC et chercher de nouvelles cibles thérapeutiques ou biomarqueurs spécifiques de la réponse aux traitements. Ainsi, dans ce travail, l’étude de lignées cellulaires dérivées de CHC qui représentent un sous-groupe de tumeurs agressives mais récapitulent une diversité moléculaire du CHC, nous a permis d’associer certains contextes moléculaires spécifiques à la réponse aux traitements et d’établir plusieurs nouvelles hypothèses thérapeutiques. Ces lignées nous ont également permis de comprendre que la surexpression de MET comme critère d'inclusion des patients expliquait les échecs des essais cliniques du tivantinib et de proposer l’expression de Ki67 comme un meilleur biomarqueur prédictif de son efficacité antitumorale. Enfin, l’étude de modèles murins de coopération oncogénique a permis de mettre en évidence pour la première fois le rôle suppresseur de tumeurs de RSK2 dans la carcinogenèse hépatique, en coopération avec l’inactivation d’AXIN1 ou l’activation de la voie Wnt/β-caténine. Dans l’ensemble, cette étude montre que les modèles précliniques sont extrêmement informatifs, malgré leurs différentes limites, ils permettent d’apporter de nouvelles hypothèses thérapeutiques. En particulier dans ce travail, la mise en évidence du rôle crucial de l’activation de la voie RAS-MAPK dans le développement du CHC renforce l’intérêt de l’utilisation d’inhibiteurs de MEK1/2 dans de futurs essais cliniques dans des sous-groupes candidats.Hepatocellular carcinoma (HCC) is a very aggressive malignancy, which is resistant to current therapeutic options for advanced stages. In addition, most of recent phase 2 or 3 clinical trials failed due to the development of multiple resistance mechanisms. In this context, preclinical models are very useful to understand the molecular biology of HCC and looking for new therapeutic targets or specific biomarkers of treatment response. Thus, in this work, the study of HCC cell lines that represent a subgroup of aggressive tumors but recapitulate the molecular diversity of HCC enabled us to show associations between specific molecular contexts and response to treatments allowing to establish several new therapeutic hypotheses. Thanks to these cell lines we also understand that the overexpression of MET as a criterion for inclusion of patients in tivantinib clinical trials explained its failures and to propose the expression of Ki67 as a better biomarker predictive of its antitumor efficacy. Finally, by studying murine models of oncogenic cooperation, we highlighted for the first time the tumor suppressor role of RSK2 in hepatic carcinogenesis, in cooperation with the inactivation of AXIN1 or the activation of the Wnt/β-catenin pathway. Overall, this study shows that preclinical models are extremely informative, despite their various limitations, they allow to bring new therapeutic hypotheses. In particular we demonstrated the crucial role of the RAS-MAPK pathway activation in HCC development reinforcing the interest of the use of MEK1/2 inhibitors in future clinical trials in candidate subgroups

Développement et caractérisation de modèles précliniques de carcinomes hépatocellulaires pour l'évaluation de la réponse thérapeutique et l'étude des mécanismes de l'hépatocarcinogenèse

Hepatocellular carcinoma (HCC) is a very aggressive malignancy, which is resistant to current therapeutic options for advanced stages. In addition, most of recent phase 2 or 3 clinical trials failed due to the development of multiple resistance mechanisms. In this context, preclinical models are very useful to understand the molecular biology of HCC and looking for new therapeutic targets or specific biomarkers of treatment response. Thus, in this work, the study of HCC cell lines that represent a subgroup of aggressive tumors but recapitulate the molecular diversity of HCC enabled us to show associations between specific molecular contexts and response to treatments allowing to establish several new therapeutic hypotheses. Thanks to these cell lines we also understand that the overexpression of MET as a criterion for inclusion of patients in tivantinib clinical trials explained its failures and to propose the expression of Ki67 as a better biomarker predictive of its antitumor efficacy. Finally, by studying murine models of oncogenic cooperation, we highlighted for the first time the tumor suppressor role of RSK2 in hepatic carcinogenesis, in cooperation with the inactivation of AXIN1 or the activation of the Wnt/β-catenin pathway. Overall, this study shows that preclinical models are extremely informative, despite their various limitations, they allow to bring new therapeutic hypotheses. In particular we demonstrated the crucial role of the RAS-MAPK pathway activation in HCC development reinforcing the interest of the use of MEK1/2 inhibitors in future clinical trials in candidate subgroups.Le carcinome hépatocellulaire (CHC), souvent diagnostiqué tardivement, est un cancer extrêmement agressif et résistant aux traitements proposés pour les stades avancés. De plus, la majorité des récents essais cliniques de phase 2 ou 3 se sont soldés par des échecs liés au développement de multiples mécanismes de résistance. Dans ce contexte l’étude de modèles précliniques est très utile pour comprendre la biologie moléculaire du CHC et chercher de nouvelles cibles thérapeutiques ou biomarqueurs spécifiques de la réponse aux traitements. Ainsi, dans ce travail, l’étude de lignées cellulaires dérivées de CHC qui représentent un sous-groupe de tumeurs agressives mais récapitulent une diversité moléculaire du CHC, nous a permis d’associer certains contextes moléculaires spécifiques à la réponse aux traitements et d’établir plusieurs nouvelles hypothèses thérapeutiques. Ces lignées nous ont également permis de comprendre que la surexpression de MET comme critère d'inclusion des patients expliquait les échecs des essais cliniques du tivantinib et de proposer l’expression de Ki67 comme un meilleur biomarqueur prédictif de son efficacité antitumorale. Enfin, l’étude de modèles murins de coopération oncogénique a permis de mettre en évidence pour la première fois le rôle suppresseur de tumeurs de RSK2 dans la carcinogenèse hépatique, en coopération avec l’inactivation d’AXIN1 ou l’activation de la voie Wnt/β-caténine. Dans l’ensemble, cette étude montre que les modèles précliniques sont extrêmement informatifs, malgré leurs différentes limites, ils permettent d’apporter de nouvelles hypothèses thérapeutiques. En particulier dans ce travail, la mise en évidence du rôle crucial de l’activation de la voie RAS-MAPK dans le développement du CHC renforce l’intérêt de l’utilisation d’inhibiteurs de MEK1/2 dans de futurs essais cliniques dans des sous-groupes candidats

Développement et caractérisation de modèles précliniques de carcinomes hépatocellulaires pour l'évaluation de la réponse thérapeutique et l'étude des mécanismes de l'hépatocarcinogenèse

Hepatocellular carcinoma (HCC) is a very aggressive malignancy, which is resistant to current therapeutic options for advanced stages. In addition, most of recent phase 2 or 3 clinical trials failed due to the development of multiple resistance mechanisms. In this context, preclinical models are very useful to understand the molecular biology of HCC and looking for new therapeutic targets or specific biomarkers of treatment response. Thus, in this work, the study of HCC cell lines that represent a subgroup of aggressive tumors but recapitulate the molecular diversity of HCC enabled us to show associations between specific molecular contexts and response to treatments allowing to establish several new therapeutic hypotheses. Thanks to these cell lines we also understand that the overexpression of MET as a criterion for inclusion of patients in tivantinib clinical trials explained its failures and to propose the expression of Ki67 as a better biomarker predictive of its antitumor efficacy. Finally, by studying murine models of oncogenic cooperation, we highlighted for the first time the tumor suppressor role of RSK2 in hepatic carcinogenesis, in cooperation with the inactivation of AXIN1 or the activation of the Wnt/β-catenin pathway. Overall, this study shows that preclinical models are extremely informative, despite their various limitations, they allow to bring new therapeutic hypotheses. In particular we demonstrated the crucial role of the RAS-MAPK pathway activation in HCC development reinforcing the interest of the use of MEK1/2 inhibitors in future clinical trials in candidate subgroups.Le carcinome hépatocellulaire (CHC), souvent diagnostiqué tardivement, est un cancer extrêmement agressif et résistant aux traitements proposés pour les stades avancés. De plus, la majorité des récents essais cliniques de phase 2 ou 3 se sont soldés par des échecs liés au développement de multiples mécanismes de résistance. Dans ce contexte l’étude de modèles précliniques est très utile pour comprendre la biologie moléculaire du CHC et chercher de nouvelles cibles thérapeutiques ou biomarqueurs spécifiques de la réponse aux traitements. Ainsi, dans ce travail, l’étude de lignées cellulaires dérivées de CHC qui représentent un sous-groupe de tumeurs agressives mais récapitulent une diversité moléculaire du CHC, nous a permis d’associer certains contextes moléculaires spécifiques à la réponse aux traitements et d’établir plusieurs nouvelles hypothèses thérapeutiques. Ces lignées nous ont également permis de comprendre que la surexpression de MET comme critère d'inclusion des patients expliquait les échecs des essais cliniques du tivantinib et de proposer l’expression de Ki67 comme un meilleur biomarqueur prédictif de son efficacité antitumorale. Enfin, l’étude de modèles murins de coopération oncogénique a permis de mettre en évidence pour la première fois le rôle suppresseur de tumeurs de RSK2 dans la carcinogenèse hépatique, en coopération avec l’inactivation d’AXIN1 ou l’activation de la voie Wnt/β-caténine. Dans l’ensemble, cette étude montre que les modèles précliniques sont extrêmement informatifs, malgré leurs différentes limites, ils permettent d’apporter de nouvelles hypothèses thérapeutiques. En particulier dans ce travail, la mise en évidence du rôle crucial de l’activation de la voie RAS-MAPK dans le développement du CHC renforce l’intérêt de l’utilisation d’inhibiteurs de MEK1/2 dans de futurs essais cliniques dans des sous-groupes candidats

RSK2 inactivation cooperates with AXIN1 inactivation or ß-catenin activation to promote hepatocarcinogenesis

Background & Aims : Recurrent somatic mutations of RPS6KA3 gene encoding for the serine/threonine kinase RSK2 were identified in hepatocellular carcinomas (HCC) suggesting its tumor suppressive function. Our goal was to demonstrate the tumor suppressor role of RSK2 in the liver and investigate the functional consequences of its inactivation.Methods : We analyzed a series of 1151 human HCCs for RSK2 mutations and 20 other driver genetic alterations. We then modeled RSK2 inactivation in mice in various mutational contexts recapitulating or not those naturally found in human HCC, using transgenic mice and liver-specific carcinogens. These models were monitored for liver tumor appearance and subjected to phenotypic and transcriptomic analyzes. Functional consequences of RSK2 rescue were also investigated in a human RSK2 deficient HCC cell line.Results : RSK2 inactivating mutations are specific of human HCC and frequently co-occur with AXIN1 inactivating or ß-catenin activating mutations. Modeling of these co-occurrences in mice showed cooperative effect in promoting liver tumors with transcriptomic profiles recapitulating those of human HCCs. By contrast, there was no cooperation in liver tumor induction between RSK2 loss and BRAF activating mutations chemically induced by diethylnitrosamine. In human liver cancer cells, we also showed that RSK2 inactivation confers some dependency to the activation of the RAS/MAPK signaling that can be targeted by MEK inhibitors.Conclusions : Our study newly demonstrated the tumor suppressor role of RSK2 and its specific synergistic effect in hepatocarcinogenesis when its loss of function is specifically combined with AXIN1 inactivation or ß-catenin activation. Furthermore, we identified the RAS/MAPK pathway as a potential therapeutic target for RSK2-inactivated liver tumors.Impact and implications : This study demonstrated the tumor suppressor role of RSK2 in the liver and showed that its inactivation specifically synergizes with AXIN1 inactivation or ß-catenin activation to promote the development of HCC with similar transcriptomic profiles as found in humans. Furthermore, this study highlights that activation of the RAS/MAPK pathway is one of the key signaling pathways mediating the oncogenic effect of RSK2 inactivation that can be targeted with already available anti-MEK therapies

Proliferation markers are associated with MET expression in hepatocellular carcinoma and predict tivantinib sensitivity in vitro

International audiencePurpose: Tivantinib was initially reported as a selective MET inhibitor and is under phase 3evaluation in "MET-high" hepatocellular carcinoma (HCC) patients. However, it has beenalso proposed as an antimitotic agent. We aimed to evaluate the anti-tumor effect of tivantinibin HCC cells by combining pharmacological and molecular profiling.Experimental design: Sensitivity to tivantinib, JNJ-38877605, PHA-665752, vinblastine andpaclitaxel was tested in a panel of 35 liver cancer cell lines analyzed with exome sequencing,mRNA expression of 188 genes and protein expression. Drug effect was investigated bywestern blot and mitotic index quantification. Expression of candidate biomarkers predictingdrug response was analyzed in 310 HCC.Results: Tivantinib sensitivity profiles in the 35 cell lines were similar to those obtained withantimitotic drugs. It induced blockage of cell mitosis and high cell proliferation wasassociated with sensitivity to tivantinib, vinblastine and placitaxel. In contrast, tivantinib didnot suppress MET signaling and selective MET inhibitors demonstrated an anti-proliferativeeffect only in MHCC97H, the unique cell line displaying MET gene amplification. HCCtumors with high expression of cell proliferation genes defined a group of patients with poorsurvival. Interestingly, highly proliferative tumors also demonstrated high MET expressionlikely explaining better therapeutic response of MET-high HCC patients to tivantinib.Conclusions: Tivantinib acts as an antimitotic compound and cell proliferation markers arethe best predictors of its antitumor efficacy in cell lines. Ki67 expression should be tested inclinical trials to predict tivantinib response

Analysis of Liver Cancer Cell Lines Identifies Agents With Likely Efficacy Against Hepatocellular Carcinoma and Markers of Response

International audienceBACKGROUND AND AIMS: Hepatocellular carcinomas (HCCs) are heterogeneous aggressive tumors with low rates of response to treatment at advanced stages. We screened a large panel of liver cancer cell lines (LCCLs) to identify agents that might be effective against HCC and markers of therapeutic response.METHODS: We performed whole-exome RNA and microRNA sequencing and quantification of 126 proteins in 34 LCCLs. We screened 31 anticancer agents for their ability to decrease cell viability. We compared genetic, RNA, and protein profiles of LCCLs with those of primary HCC samples and searched for markers of response.RESULTS: The protein, RNA and mutational signatures of the LCCLs were similar to those of the proliferation class of HCC, which is the most aggressive tumor type. Cell lines with alterations in genes encoding members of the Ras-MAPK signaling pathway and that required fibroblast growth factor (FGF)19 signaling via FGF receptor 4 for survival were more sensitive to trametinib than to FGF receptor 4 inhibitors. Amplification of FGF19 resulted in increased activity of FGF19 only in tumor cells that kept a gene expression pattern of hepatocyte differentiation. We identified single agents and combinations of agents that reduced viability of cells with features of the progenitor subclass of HCC. LCCLs with inactivating mutations in TSC1 and TSC2 were sensitive to the mammalian target of rapamycin inhibitor rapamycin, and cells with inactivating mutations in TP53 were sensitive to the Aurora kinase A inhibitor alisertib. Amplification of MET was associated with hypersensitivity to cabozantinib and the combination of sorafenib and inhibitors of MAP kinase 1 and MAP kinase2 had a synergistic antiproliferative effect.CONCLUSION: LCCLs can be screened for drugs and agents that might be effective for treatment of HCC. We identified genetic alterations and gene expression patterns associated with response to these agents. This information might be used to select patients for clinical trials

Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.

International audienc