YES1 drives lung cancer growth and progression and predicts sensitivity to dasatinib

Rationale: The characterization of new genetic alterations is essential to assign effective personalized therapies in non–small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer. Objectives: To evaluate YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC. Methods: Functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts. The efficacy of pharmacological and genetic (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival, and invasion were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples. Measurements and Main Results: We demonstrated that YES1 is essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1 effects were mainly driven by mTOR (mammalian target of rapamycin) signaling. Interestingly, cell lines and patient-derived xenograft models with YES1 gene amplifications presented a high sensitivity to dasatinib, an SFK inhibitor, pointing out YES1 status as a stratification biomarker for dasatinib response. Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer. Conclusions: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy

Preliminary results of BIOFAD project: testing designs and identifying options to mitigate impacts of drifting Fish Aggregating Devices on the ecosystem

The EU project BIOFAD was launched in August 2017. This 28-months EU project is coordinated by a Consortium comprising three European research centers: AZTI, IRD (Institut de recherche pour le développement) and IEO (Instituto Español de Oceanografía). The International Seafood Sustainability Foundation (ISSF) is also actively collaborating by providing the biodegradable materials needed to test biodegradable dFADs (drifting FADs). Following IOTC, along with other tuna RFMOs, recommendations and resolutions to promote the use of natural or biodegradable materials for dFADs, this project is seeking to develop and implement the use of dFADs with both characteristics, non-entangling and biodegradable, in the IOTC Convention Area. However, there are no technical guidelines on the type of materials and FAD designs to be used. The main objectives of the project are: (1) to test the use of specific biodegradable materials and designs for the construction of dFADs in real fishing conditions; (2) to identify options to mitigate dFADs impacts on the ecosystem; and (3) to assess the socio-economic viability of the use of biodegradable dFADs in the purse seine tropical tuna fishery. This document shows the preliminary results regarding the effectiveness of around 716 BIOFADs deployed, in terms of tuna aggregation, drift, materials’ durability, etc. in comparison to currently deployed NEFADs (non-entangling dFADs). The project BIOFAD has counted since its inception with the support of the whole EU purse seine tuna fishery and, more recently, with the collaboration of the Korean purse seine fleet

Results of the BIOFAD Project: Testing Designs and Identify Options to Mitigate Impacts of Drifting Fish Aggregating Devices on the Ecosystem

The EU project BIOFAD was launched in August 2017. This 28-months EU project is coordinated by a Consortium comprising three European research centers: AZTI, IRD (Institut de recherche pour le développement) and IEO (Instituto Español de Oceanografía). The International Seafood Sustainability Foundation (ISSF) is also actively collaborating by providing the biodegradable materials needed to test biodegradable dFADs (drifting FADs). Following IOTC, along with other tuna RFMOs, recommendations and resolutions to promote the use of natural or biodegradable materials for dFADs, this project is seeking to develop and implement the use of dFADs with both characteristics, non-entangling and biodegradable, in the IOTC Convention Area. However, there are no technical guidelines on the type of materials and FAD designs to be used. The main objectives of the project are: (1) to test the use of specific biodegradable materials and designs for the construction of dFADs in real fishing conditions; (2) to identify options to mitigate dFADs impacts on the ecosystem; and (3) to assess the socioeconomic viability of the use of biodegradable dFADs in the purse seine tropical tuna fishery. This document shows the results regarding the effectiveness of 771 BIOFADs deployed within the project, in terms of FAD lifespan, drift, materials’ durability, catch and tuna aggregation in comparison to currently deployed NEFADs (non-entangling dFADs). The project BIOFAD has been supported since its inception by the whole EU purse seine tuna fishery and, more recently, with the collaboration of the Korean purse seine fleet

Id1 and PD-1 Combined Blockade Impairs Tumor Growth and Survival of KRAS-mutant Lung Cancer by Stimulating PD-L1 Expression and Tumor Infiltrating CD8+ T Cells

The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because of immunosuppression. New immunotherapy-based combinations are under investigation in an attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition and pharmacological PD-L1 blockade in three different syngeneic murine KRAS-mutant lung adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro in human and murine KRAS-driven lung cancer cell lines. In vivo experiments in KRAS-mutant syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth impairment and overall survival improvement. Mechanistically, multiplex quantification of CD3+/CD4+/CD8+ T cells and flow cytometry analysis showed that combined therapy favors tumor infiltration by CD8+ T cells, whilst in vivo CD8+ T cell depletion led to tumor growth restoration. Co-culture assays using CD8+ cells and tumor cells showed that T cells present a higher antitumor effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1 expression and harnessing tumor infiltration of CD8+ T lymphocytes

Id1 and PD-1 Combined Blockade Impairs Tumor Growth and Survival of KRAS-mutant Lung Cancer by Stimulating PD-L1 Expression and Tumor Infiltrating CD8+ T Cells

The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because of immunosuppression. New immunotherapy-based combinations are under investigation in an attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition and pharmacological PD-L1 blockade in three different syngeneic murine KRAS-mutant lung adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro in human and murine KRAS-driven lung cancer cell lines. In vivo experiments in KRAS-mutant syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth impairment and overall survival improvement. Mechanistically, multiplex quantification of CD3+/CD4+/CD8+ T cells and flow cytometry analysis showed that combined therapy favors tumor infiltration by CD8+ T cells, whilst in vivo CD8+ T cell depletion led to tumor growth restoration. Co-culture assays using CD8+ cells and tumor cells showed that T cells present a higher antitumor effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1 expression and harnessing tumor infiltration of CD8+ T lymphocytes

YES1 drives lung cancer growth and progression and predicts sensitivity to dasatinib

Rationale: The characterization of new genetic alterations is essential to assign effective personalized therapies in non–small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer. Objectives: To evaluate YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC. Methods: Functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts. The efficacy of pharmacological and genetic (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival, and invasion were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples. Measurements and Main Results: We demonstrated that YES1 is essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1 effects were mainly driven by mTOR (mammalian target of rapamycin) signaling. Interestingly, cell lines and patient-derived xenograft models with YES1 gene amplifications presented a high sensitivity to dasatinib, an SFK inhibitor, pointing out YES1 status as a stratification biomarker for dasatinib response. Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer. Conclusions: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy

Misidentification of bluefin tuna larvae: a call for caution and taxonomic reform

The international effort to prevent the collapse of Atlantic bluefin tuna (BFT, Thunnus thynnus, Scombridae) stocks exemplifies the challenges associated with modern marine resource conservation. Rampant mismanagement, under-reporting and illegal, unreported and unregulated fishing led to decades of over-exploitation in the BFT fishery. Surveys of larval abundance in the Gulf of Mexico and the Mediterranean Sea have been used as a proxy for both spawning biomass and recruitment by researchers working to improve estimates of stock abundance. Recent genetic barcoding studies have revealed that species identification errors are common among larvae surveys that use morphology-based taxonomy alone. Misidentification of larvae can lead to uncertainty about the spatial distribution of a species, confusion over life history traits and population dynamics, and potentially disguise the collapse or recovery of localized spawning sites. In an effort to identify the source of these errors, we review several weaknesses in modern morphology-based taxonomy including demographic decline of expert taxonomists, flawed identification keys, reluctance of the taxonomic community to embrace advances in digital communications and a general scarcity of modern user-friendly materials. Recent advances in molecular techniques useful for specimen identification and population studies are discussed at length. We advocate a more constructive integration of morphology-based taxonomy and barcoding in order to add confidence to larval surveys and to strengthen associated fisheries managementVersión del editor2,270