Role of ADAM17 in the non-cell autonomous effects of oncogene-induced senescence

Proteomic analysis of the secretome of p95HER2-induced senescence. a MCF7 Tet-Off p95HER2 cells were cultured with or without doxycycline for 1 week and stained for senescence-associated β-galactosidase. Representative images of the stained cultures are shown. b The secretomes of the same cells as in a were analyzed by label-free quantitative proteomics. The results are shown as unsupervised hierarchical clustering analysis corresponding to three technical replicas (a-c) of two independent experiments (1 and 2). c The proteins identified in b were classified according to the presence of transmembrane or glycophosphatidylinositol domains (cell membrane), signal peptide but not transmembrane domain (secreted, canonical), or the lack of these domains (secreted, unknown). See also Additional file 2: Table S1. Doxy doxycycline. (JPEG 585 kb

Modeling anti-IL-6 therapy using breast cancer patient-derived xenografts

The pleiotropic cytokine IL-6 accelerates the progression of breast cancer in a variety of preclinical models through the activation of the STAT3 (signal transducer and activator of transcription 3) signaling pathway. However, the proportion of breast cancers sensitive to anti-IL-6 therapies is not known. This study evaluates the efficacy of anti-IL-6 therapies using breast cancer patient derived xenografts (PDXs). During the generation of our collection of PDXs, we showed that the successful engraftment of tumor tissue in immunodeficient mice correlates with bad prognosis. Four PDXs out of six were resistant to anti-IL-6 therapies and the expression of IL-6, its receptor or the levels of phospho-STAT3 (the active form of the signal transducer) did not correlate with sensitivity. Using cell cultures established from the PDXs as well as samples from in vivo treatments, we showed that only tumors in which the activation of STAT3 depends on IL-6 respond to the blocking antibodies. Our results indicate that only a fraction of breast tumors are responsive to anti-IL-6 therapies. In order to identify responsive tumors, a functional assay to determine the dependence of STAT3 activation on IL-6 should be performed

Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors

Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients. We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR). We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib. ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics

Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation

Gasdermin B (GSDMB) over-expression promotes poor prognosis and aggressive behavior in HER2 breast cancer by increasing resistance to therapy. Decoding the molecular mechanism of GSDMB-mediated drug resistance is crucial to identify novel effective targeted treatments for HER2/GSDMB aggressive tumors. Different in vitro approaches (immunoblot, qRT-PCR, flow cytometry, proteomic analysis, immunoprecipitation, and confocal/electron microscopy) were performed in HER2 breast and gastroesophageal carcinoma cell models. Results were then validated using in vivo preclinical animal models and analyzing human breast and gastric cancer samples. GSDMB up-regulation renders HER2 cancer cells more resistant to anti-HER2 agents by promoting protective autophagy. Accordingly, the combination of lapatinib with the autophagy inhibitor chloroquine increases the therapeutic response of GSDMB-positive cancers in vitro and in zebrafish and mice tumor xenograft in vivo models. Mechanistically, GSDMB N-terminal domain interacts with the key components of the autophagy machinery LC3B and Rab7, facilitating the Rab7 activation during pro-survival autophagy in response to anti-HER2 therapies. Finally, we validated these results in clinical samples where GSDMB/Rab7/LC3B co-expression associates significantly with relapse in HER2 breast and gastric cancers. Our findings uncover for the first time a functional link between GSDMB over-expression and protective autophagy in response to HER2-targeted therapies. GSDMB behaves like an autophagy adaptor and plays a pivotal role in modulating autophagosome maturation through Rab7 activation. Finally, our results provide a new and accessible therapeutic approach for HER2/GSDMB + cancers with adverse clinical outcome. The online version contains supplementary material available at 10.1186/s13046-022-02497-w

Mitigation of coupled wind-wave-earthquake responses of a 10 MW fixed-bottom offshore wind turbine

© 2020 Elsevier Ltd In this paper we present a study on the mitigation of dynamic responses of a 10 MW monopile offshore wind turbine under coupled wind-wave-earthquake excitations. We have developed and validated the generic seismic coupled analysis and structural control architecture tool to overcome the limitation of numerical tools when examining the wind-wave-earthquake coupling effects. We investigated the dynamic responses of a 10 MW monopile offshore wind turbine under different loading combinations and found that the earthquake loading increases the tower-top displacement and pile-cap moment by 47.6% and 95.1%, respectively, compared to the wind-wave-only condition. It is found that the earthquake-induced vibration in the fore-aft direction is mitigated by the wind and wave loadings due to the energy dissipated by the aerodynamic and hydrodynamic damping. In addition, the tower responses are dominated by the earthquake excitation. In order to alleviate the tower vibration induced by the earthquake, we implemented the structural control capability within the tool using tuned mass dampers. The tuned mass dampers with appropriately selected design parameters achieve a larger mitigation on the tower-top displacement for the earthquake-only condition compared to the coupled-loading scenario. The reason is that the tuned mass damper is only effective in mitigating tower vibration, and it is not capable of reducing the tower elastic deformation which is the major contribution of the tower displacement for the coupled-loading condition. In addition, we have found that a heavier tuned mass damper requires a lower tuned frequency to achieve a larger mitigation. A configuration for the mitigation control of the 10 MW offshore wind turbine is suggested by using a 5% mass ratio of the tuned mass damper

Revista de Vertebrados de la Estación Biológica de Doñaña

Alimentación de la boga del Guadiana (Chondrostoma polylepis wi/lkommi, Stein. 1866) en la interfase río-embalse de Sierra Boyera (Córdoba. España)Predación del búho real (Bubo bubo) sobre la perdiz roja (Alectoris rufa): selección de edad y sexoAlimentación de la nutria (Lutra lufra L, 1758)en el Nordeste de la Península IbéricaDatos sobre la distribución espacialde micromamíferos en el Parque Nacionalde DoñanaGuía para el reconocimiento microscópico de los pelos de los mamíferos de la Patagonia.Sobre la distribución geográfica de Anaecypris hispanica (STEINDACHNER, 1866) (OSTEICHTHYES, CYPRINIDAE)Cronología del periodo reproductor de Rana temporaria L. en La Coruña (NW de España).Un nuevo caso de melanismo en Natrix natrix (LINNAEUS 1758) procedente de Fuente Dé (Santander)Nuevas citas de anfibios y reptiles para el SE de la Península Ibérica.Datos sobre la dieta invernal del Búho chico (Asia atus) en la provinvia de LeónLa Distribucióndel Mara (Dolichotis patagonum) según criterios ecológicos e históricosSolapamiento entre la dieta de la cabra montés (Capra pyrenaica) y la del muflón (Ovis musimon)Nota sobre dietas de carnívoros e índices de abundancia en una Reserva de caza del norte de España.Discriminación osteométrica en el géneroTalpa (LINNEO, 1758), en el norte IbéricoObservaciones sobre el comportamiento depredativo de algunos colúbridos Ibéricos en estado salvajePeer reviewe

High HER2 protein levels correlate with increased survival in breast cancer patients treated with anti-HER2 therapy

Introduction: Current methods to determine HER2 (human epidermal growth factor receptor 2) status are affected by reproducibility issues and do not reliably predict benefit from anti-HER2 therapy. Quantitative measurement of HER2 may more accurately identify breast cancer (BC) patients who will respond to anti-HER2 treatments. Methods: Using selected reaction monitoring mass spectrometry (SRM-MS), we quantified HER2 protein levels in formalin-fixed, paraffin-embedded (FFPE) tissue samples that had been classified as HER2 0, 1+, 2+ or 3+ by immunohistochemistry (IHC). Receiver operator curve (ROC) analysis was conducted to obtain optimal HER2 protein expression thresholds predictive of HER2 status (by standard IHC or in situ hybridization [ISH]) and of survival benefit after anti-HER2 therapy. Results: Absolute HER2 amol/μg levels were significantly correlated with both HER2 IHC and amplification status by ISH (p 2200 amol/μg were significantly associated with longer disease-free survival (DFS) and overall survival (OS) in an adjuvant setting and with longer OS in a metastatic setting. Conclusion: Quantitative HER2 measurement by SRM-MS is superior to IHC and ISH in predicting outcome after treatment with anti-HER2 therapy

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Proteinasa multicatalítica y autoinmunidad

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 8-12-199