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The impact of a high fat diet and platelet activation on pre-metastatic niche formation
Get PDFFat diet; Platelet activation; Pre-metastatic niche formationDieta rica en grasas; Activación plaquetaria; Nicho premetastásicoDieta rica en greixos; Activació plaquetària; Nínxol premetàsticThere is active crosstalk between tumor cells and the tumor microenvironment during metastatic progression, a process that is significantly affected by obesity, particularly in breast cancer. Here we analyze the impact of a high fat diet (HFD) on metastasis, focusing on the role of platelets in the formation of premetastatic niches (PMNs). We find that a HFD provokes pre-activation of platelets and endothelial cells, promoting the formation of PMNs in the lung. These niches are characterized by increased vascular leakiness, platelet activation and overexpression of fibronectin in both platelets and endothelial cells. A HFD promotes interactions between platelets, tumor cells and endothelial cells within PMNs, enhancing tumor cell homing and metastasis. Importantly, therapeutic interventions like anti-platelet antibody administration or a dietary switch reduce metastatic cell homing and outgrowth. Moreover, blocking fibronectin reduces the interaction of tumor cells with endothelial cells. Importantly, when coagulation parameters prior to neoadjuvant treatment are considered, triple negative breast cancer (TNBC) female patients with reduced Partial Thromboplastin time (aPTT) had a significantly shorter time to relapse. These findings highlight how diet and platelet activation in pre-metastatic niches affect tumor cell homing and metastasis, suggesting potential therapeutic interventions and prognostic markers for TNBC patients.This work was supported by the Worldwide Cancer Research UK (24-0197, 16-1244), Agencia Estatal de Investigación/Ministerio de Ciencia e Innovación (AEI/MCIN: PID2020-118558RB-I00/AEI/10.13039/501100011033), WHRI-ACADEMY, a COFUND of Marie Curie action (WHRI-309), Fundación Bancaria “la Caixa” (HR18-00256) granted to HP. This work was also supported by grants from the Spanish National Research and Development Plan, Instituto de Salud Carlos III, and FEDER (PI20/01837 and PI23/01932 to S.R-P.); and AECC (AECC_Lab 2020) to S.R-P and ISCIII/FEDER (PI21/01641) to R.T-R. The CNIO is a certified Severo Ochoa Center of Excellence, supported by the Spanish Government through the Instituto de Salud Carlos III (ISCIII). We thank Drs. Cyrus Ghajar, Luuke Hawinkels and Inge Verbrugge for providing cell lines, and we are grateful to Beatriz Salinas (Hospital General Universitario Gregorio Marañon) for synthetizing the NIR-IF dextran. We also thank the CNIO Histopathology Unit for their technical support and Alicia Garcia Arroyo (Centro de Investigaciones Biologicas) for her help in isolating MLECs. Figures were partially created with Servier Medical Art (https://smart.servier.com/) and Adobe Illustrator 24.1
Immune profiling of gastric adenocarcinomas in EU and LATAM countries identifies global differences in immune subgroups and microbiome influence
Get PDFImmune profiling; Gastric adenocarcinomas; MicrobiomePerfil inmunológico; Adenocarcinomas gástricos; MicrobiomaPerfil immunològic; Adenocarcinomes gàstrics; MicrobiomaBackground
Gastric cancer (GC) patients from European (EU) and especially Latin American (LATAM) countries are underrepresented in previous large-scale multi-omic studies that have identified clinically relevant subgroups. The LEGACY study aimed to profile the molecular and immunological features of GCs from EU and LATAM countries.
Methods
Tumor biopsies from 95 EU and 56 LATAM GCs were profiled with immunohistochemistry (CD3, CD8, FOXP3, PD-L1, MSI and HER2), Nanostring mRNA expression analyses, and microbiome sequencing.
Results
Immune profiling identified four distinct immune clusters: a T cell dominant cluster with enriched activation pathways, a macrophage dominant cluster and an immune excluded microenvironment which were equally distributed among the countries. A fourth cluster of mostly Mexican patients consisted of excessive T cell numbers accompanied by enhanced cytokine signaling in absence of enhanced antigen presentation and cytotoxicity signatures and a strong association with H. pylori infection.
Discussion
Both EU and LATAM countries have GCs with a T cell inflamed microenvironment that might benefit from checkpoint inhibition. We identified a highly inflamed GC subgroup that lacked antigen presentation and cytotoxicity associated with H. pylori CagA-positive strains, suggesting their contribution to tumor immune tolerance. Future studies are needed to unravel whether these cancers benefit from immunotherapy as well.This study was funded by the European Union’s Horizon 2020 research and innovation program (Grant agreement No GA825832). The European Union was not involved in the collection, analysis and interpretation of data, in writing future manuscripts or deciding to submit manuscripts for publication. SD is supported by the Dutch Cancer Society, the Netherlands Organization for Scientific Research (NWO) and Oncode Institute. This work was supported in Chile by ANID-FONDAP-152220002 & 15130011 (1523A0008), PROGRAMA ICM-ANID, ICN2021_045, ANID FONDECYT 1220586. The funding for Mexico was supported by CONAHCyT N°297681 (CELAC and European Consortium for Personalized Medicine Approach to Gastric Cancer (LEGACy)
Molecular determinants of response to neoadjuvant pembrolizumab plus chemotherapy in patients with high-risk, early-stage, triple-negative breast cancer: exploratory analysis of the open-label, multicohort phase 1b KEYNOTE-173 study
Get PDFImmunohistochemistry; Triple-negative breast cancer; Tumor microenvironmentImmunohistoquímica; Càncer de mama triple negatiu; Microambient tumoralInmunohistoquímica; Cáncer de mama triple negativo; Microambiente tumoralBackground
The multicohort, open-label, phase 1b KEYNOTE-173 study was conducted to investigate pembrolizumab plus chemotherapy as neoadjuvant therapy for triple-negative breast cancer (TNBC). This exploratory analysis evaluated features of the tumor microenvironment that might be predictive of response.
Methods
Cell fractions from 20 paired samples collected at baseline and after one cycle of neoadjuvant pembrolizumab prior to chemotherapy initiation were analyzed by spatial localization (tumor compartment, stromal compartment, or sum of tumor and stromal compartments [total tumor]) using three six-plex immunohistochemistry panels with T-cell, myeloid cell, and natural killer cell components. Area under the receiver operating characteristic curve (AUROC) was used to assess associations between immune subsets and gene expression signatures (T-cell–inflamed gene expression profile [TcellinfGEP] and 10 non-TcellinfGEP signatures using RNA sequencing) and pathologic complete response (pCR).
Results
At baseline, six immune subsets quantitated within the tumor compartment showed AUROC with 95% CIs not crossing 0.5, including CD11c+ cells (macrophage and dendritic cell [DC]: AUROC, 0.85; 95% confidence interval [CI] 0.63–1.00), CD11c+/MHCII+/CD163−/CD68− cells (DC: 0.76; 95% CI, 0.53–0.99), CD11c+/MHCII−/CD163−/CD68− cells (nonactivated/immature DC: 0.80; 95% CI 0.54–1.00), and CD11c+/CD163+ cells (M2 macrophage: 0.77; 95% CI 0.55–0.99). Other associations with pCR included baseline CD11c+/MHCII−/CD163−/CD68− (nonactivated/immature DC) within the total tumor (AUROC, 0.76; 95% CI 0.51–1.00) and the baseline CD11c/CD3 ratio within the tumor compartment (0.75; 95% CI 0.52–0.98). Changes in immune subsets following one cycle of pembrolizumab were not strongly associated with pCR. Although T-cell associations were relatively weak, specific CD8 subsets trended toward association. The AUROC for discriminating pCR based on TcellinfGEP was 0.55 (95% CI 0.25–0.85); when detrended by TcellinfGEP, AUROC varied for the non-TcellinfGEP signatures. TcellinfGEP expression trended higher in responders than in nonresponders when evaluating pCR.
Conclusions
Myeloid cell populations within the tumor compartment at baseline and TcellinfGEP show a promising trend toward an association with pCR in a small subgroup of patients with early-stage TNBC treated with neoadjuvant pembrolizumab plus chemotherapy.
Trial registration
ClinicalTrials.gov, NCT02622074; registration date, December 2, 2015.Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA
Progressive systemic inflammation precedes decompensation in compensated cirrhosis
Get PDFBacterial translocation; Chronic advanced liver disease; Portal hypertensionTranslocació bacteriana; Malaltia hepàtica crònica avançada; Hipertensió portalTranslocación bacteriana; Enfermedad hepática crónica avanzada; Hipertensión portalBackground & Aims
Systemic inflammation is a driver of decompensation in cirrhosis with unclear relevance in the compensated stage. We evaluated inflammation and bacterial translocation markers in compensated cirrhosis and their dynamics in relation to the first decompensation.
Methods
This study is nested within the PREDESCI trial, which investigated non-selective beta-blockers for preventing decompensation in compensated cirrhosis and clinically significant portal hypertension (CSPH: hepatic venous pressure gradient ≥10 mmHg). Blood biomarkers were measured at baseline and at 1 and 2 years in patients who remained compensated and had available samples (n = 164). Values of patients with CSPH were split at each time point by decompensation development in the next time interval after sampling. We also included 54 patients with cirrhosis and subclinical portal hypertension (PH) and 35 controls. We assessed markers of inflammation (interleukin-6 [IL-6], tumor necrosis factor-alpha, von Willebrand factor [vWF], C-reactive protein), macrophage activation (CD14, CD163), intestinal barrier integrity (fatty acid-binding protein [FABP], haptoglobin), and bacterial translocation (lipopolysaccharide [LPS]).
Results
IL-6, CD163, and vWF were higher (p <0.01) at baseline in patients with cirrhosis and CSPH compared to those with subclinical PH and controls. IL-6 increased (p <0.05) at 1 year in patients with CSPH, with a greater rise in those who developed decompensation. CD163 was higher (p <0.01) in patients who decompensated at baseline and 1 and 2 years. FABP was elevated (p <0.01) in patients with CSPH compared to subclinical PH and controls at baseline and 1 year, while haptoglobin was lower (p <0.01). LPS was higher (p <0.01) in patients with CSPH than in those with subclinical PH and controls and increased at 1 year regardless of decompensation development.
Conclusions
Inflammation and bacterial products are present in the systemic circulation in patients with compensated cirrhosis and CSPH. Progressive inflammation precedes the first decompensation.
Impact and implications
Systemic inflammation drives cirrhosis progression during the decompensated stage, but its role in the compensated stage is unclear. We evaluated biomarkers of systemic inflammation, intestinal barrier integrity and bacterial translocation in patients with compensated cirrhosis and their dynamics in relation to the first decompensation. We demonstrate that low-grade inflammation and bacterial products are present in the systemic circulation in compensated cirrhosis, provided clinically significant portal hypertension has developed. We also show that worsening of systemic inflammation precedes the development of first clinical decompensation.Supported by grants from the Ministerio de Ciencia e Innovación and Instituto de Salud Carlos III (PI20/01302 to A.A., PI21/01995 to E.A.T.). R.S.A. and E.A.T. are recipients of grants from the Ministerio de Ciencia e Innovación and Instituto de Salud Carlos III (CM20/00020, JR20/00047). Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD) is funded by the Instituto de Salud Carlos III with grants cofinanced by the European Development Regional Fund “A way to achieve Europe” (EDRF)
Fostering Collaboration for Paediatric Demand-Driven Innovation: Insights and Strategies from the ADD4KIDS Working Groups
Get PDFInnovació pediàtrica; Col·laboració en salut infantil; Innovació impulsada per la demandaPediatric innovation; Collaboration in child health; Demand-driven innovation (DDI)Innovación pediátrica; Colaboración en salud infantil; Innovación impulsada por la demandaThe ADD4KIDS project aimed to enhance demand-driven innovation (DDI) in paediatric
healthcare by addressing key barriers to adoption, including regulatory complexities,
limited stakeholder awareness, risk aversion, and budget constraints. While innovation in
healthcare has been growing, a European consensus on paediatric DDI remains absent.
Launched in 2024 and funded by the European Innovation Council and SMEs Executive
Agency, under the Horizon Europe Programme, ADD4KIDS brought together leading
institutions to develop a collaborative roadmap for integrating DDI in paediatrics. Using
structured working groups and the Theory of Change (ToC) methodology, the project
identified challenges, proposed strategic interventions, and fostered cross-border
collaboration.
The ADD4KIDS working groups served as a cornerstone of this initiative, bringing together
clinicians, researchers, policymakers, procurement specialists, innovators and industry
leaders to analyse barriers, define best practices, and develop actionable strategies.
These groups focused on key areas such as aligning innovation with paediatric needs,
streamlining procurement processes, enhancing cross-border collaboration, and improving
funding mechanisms. Their insights informed a European action plan designed to facilitate
sustainable DDI adoption and improve long-term paediatric healthcare outcomes
Pla funcional d’higienistes dentals del procés d’atenció a la salut bucodental en els equips d’atenció primària i comunitària
Get PDFHigienistes dentals; Salut bucodental; Atenció primàriaHigienistas dentales; Salud bucodental; Atención primariaDental hygienists; Oral health; Primary careAquest document és una eina de suport per a l’acollida i la incorporació, a tots els centres de l’atenció primària i comunitària (CAP), dels higienistes dentals. És un document dinàmic que evolucionarà quan se’n detecti la necessitat, incorporant-hi propostes de millora.Este documento es una herramienta de apoyo para la acogida e incorporación de los higienistas dentales en todos los centros de atención primaria y comunitaria (CAP). Es un documento dinámico que irá evolucionando cuando se detecte la necesidad, incorporando propuestas de mejora.This document is a support tool for the onboarding and integration of dental hygienists in all primary and community care centers. It is a dynamic document that will evolve as needed, incorporating improvement proposals
Actionable NSCLC Mutation Identification by Comprehensive Genomic Profiling for Clinical Trial Enrollment: The European Program for the Routine Testing of Patients With Advanced Lung Cancer (EPROPA)
Get PDFProves de biomarcadors; Càncer de pulmó; Teràpia dirigidaBiomarker testing; Lung cancer; Targeted therapyPruebas de biomarcadores; Cáncer de pulmón; Terapia dirigidaIntroduction
The advocacy Women Against Lung Cancer in Europe (WALCE) promoted the European Program for the Routine Testing of Patients With Advanced Lung Cancer (EPROPA) and provided a free-of-charge molecular profiling platform for NSCLC sample characterization with the aim of increasing the detection of targetable drivers and improving patients’ access to clinical trials in Europe.
Methods
From January 2021 to December 2023, 20 centers located at five different European countries (Greece, Slovenia, Romania, Albania, and Italy) joined EPROPA, with 555 patients with advanced NSCLC registered to the program. Anonymized patients’ clinical-pathological data were shared through the EPROPA web platform and tissue samples were collected at the Molecular Pathology Unit of the Reference Center (University of Turin) for molecular analyses. A comprehensive genomic profiling by a targeted next-generation sequencing approach has been performed and molecular reports have been discussed within the molecular tumor board to assess patients’ eligibility for clinical trials.
Results
The average turnaround time was eight days, with only 30 out of 555 tissue samples (6%) not suitable for molecular analysis. In the 525 analyzed samples, a total of 570 molecular alterations have been identified, including 264 pathogenic targetable oncogenic alterations and 113 cases with co-occurring mutations. A total of 18 molecular alterations with potential germline and hereditary cancer syndrome implications have been reported. The identification of a clinical trial was considered for 205 patients. After molecular tumor board discussion, 30 patients were enrolled and treated in clinical studies available in Europe. Survival outcomes were significantly improved in patients with targetable molecular alterations receiving a matched targeted therapy.
Conclusion
This data confirmed the feasibility and usefulness of the program in the real-world practice scenario, supporting the implementation of next-generation sequencing–based molecular characterization of NSCLC samples, to reduce the unequal access to tests, drugs, and clinical trials in Europe.This work was supported by an unrestricted educational grant by AstraZeneca, Amgen, BeiGene, Blueprint Medicines, Boeringher Ingelheim, Gilead, Incyte, Eli Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Thermo Fisher Scientific with no role in study design, data collection, data analysis, data interpretation and report writing. To the Women Against Lung Cancer Europe (WALCE) Advocacy Group, Francesca Arizio, Cristina Destro, Ewelina Smzytke (LuCE), Angela Dicorato (SC Oncology – ASU GI, Trieste, Italy), Ravzan Curca (Spitalul Juedetean de Urgenta, Alba Iulia, Romania) and Daniela Elvira Sirbu (Centrul de Oncologie Oncohelp, Timisoara, Romania)
Representació per gènere en càrrecs directius i comandaments al sistema públic de salut de Catalunya: resultat enquesta 2024
Get PDFCàrrecs directius; Representació per gènere; Sistema de Salut de CatalunyaCargos directivos; Representación de sexo; Sistema de Salud de CataluñaManagement positions; Gender representation; Catalan Health SystemEn base al Pla de Govern de la XIV Legislatura, i més en concret el Pla d'acció del Departament de Salut, es va definir el Pla d’acció per a la millora de l’atracció i fidelització de professionals al sistema de salut de Catalunya.
Entre els àmbits d’actuació que contempla aquest Pla, es troba l’àmbit vinculat amb la formació i generació de talent, que inclou fomentar la igualtat d’oportunitats i el lideratge en relació amb el gènere(acció 1.1.9). En línia amb el Pla d’acció per a la millora de l’atracció i fidelització de professionals al sistema de salut de Catalunya, i amb la voluntat d’avançar en la igualtat d’oportunitats en el lideratge, es volen monitorar les posicions de lideratge, segons el gènere, mitjançant indicadors en els àmbits assistencials i de gestió de serveis. En aquest document es mostren els resultats de l’enquesta "Petició de gènere en posicions de lideratge" de les entitats proveïdores del SISCAT de 2024 i amb data de 31 de desembre de 2024
Transcriptional reprogramming triggered by neonatal UV radiation or Lkb1 loss prevents BRAFV600E-induced growth arrest in melanocytes
Get PDFTranscriptional reprogramming; Neonatal UV radiation; MelanocytesReprogramació transcripcional; Radiació UV neonatal; MelanòcitsReprogramación transcripcional; Radiación UV neonatal; MelanocitosThe mechanisms behind UVB-initiated, neonatal-specific melanoma linked to BRAFV600E are not well understood, particularly regarding its role in growth arrest. We found that, beyond mutations, neonatal UV irradiation or Lkb1 loss promotes a cell-autonomous transcriptional reprogramming that prevents BRAFV600E-induced growth arrest, leading to melanoma development. Using UVB-dependent and independent mouse models, genomic analyses, clinical data, and single-cell transcriptomics, we identified a transcriptional program that bypasses growth arrest, promoting melanoma. In humans, many of these genes are linked to poor survival and are upregulated in melanoma progression and other RAS pathway-driven tumors. Reconstitution experiments showed these genes cooperate with BRAFV600E in melanocyte transformation, dedifferentiation, and drug resistance. Depleting gene products like UPP1 highlights their potential as therapeutic targets. Our findings reveal that BRAFV600E-mutated melanomas can develop independently of nevus progression and identify novel targets for treatment.This work was funded by Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, “A way to make Europe”/“Investing in your future”), PI17/00043-Fondos FEDER; PI20/0384-Fondos FEDER; PI23/00428-Fondos FEDER JAR, Euronanomed2-ISCIII (AC16/00019)-Fondos FEDER; JAR, Asociación Española Contra el Cancer (AECC-GCB15152978SOEN). AGAUR, 2021-SGR00653 JAR (supported PGM, KM); Ramón Areces Foundation (supported KM and research); JAR. We thank Joan Seoane, HG Palmer, and FM Barriga for their critical comments
El bisfenol A (BPA)
Get PDFSubstàncies químiques; Policarbonat; Materials en contacte amb els alimentsSustancias químicas; Policarbonato; Materiales en contacto con los alimentosChemicals; Polycarbonate; Materials in contact with foodEl bisfenol A (2,2-bis[4-hidroxifenil] propà) és una substància química utilitzada en l’elaboració de materials plàstics i resines.
S’empra en la fabricació del policarbonat, un tipus de plàstic rígid i transparent que s’ha emprat en diferents envasos alimentaris, com ampolles, vaixella i altres contenidors per conservar aliments.
També ha format part de les resines epoxídiques utilitzades en el recobriment intern protector de llaunes d’aliments i begudes.
Com el BPA pot migrar als aliments i a les begudes s’ha prohibit la seva utilització per a l’elaboració de materials en contacte amb els aliments (MCA).El bisfenol A (2,2-bis[4-hidroxifenil] propano) es una sustancia química utilizada en la elaboración de materiales plásticos y resinas.
Se utiliza en la fabricación del policarbonato, un tipo de plástico rígido y transparente que se ha utilizado en diferentes envases alimentarios, como botellas, vajilla y otros contenedores para conservar alimentos.
También ha formado parte de las resinas epóxicas utilizadas en el recubrimiento interno protector de latas de alimentos y bebidas.
Como el BPA puede migrar a los alimentos y las bebidas se ha prohibido su uso para la elaboración de materiales en contacto con los alimentos (MCA)