ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA

Circulating tumour DNA; Pancreatic cancer; Tumour evolutionADN tumoral circulant; Càncer de pàncrees; Evolució tumoralADN tumoral circulante; Cáncer de páncreas; Evolución tumoralBackground Liquid biopsies and the dynamic tracking of somatic mutations within circulating tumour DNA (ctDNA) can provide insight into the dynamics of cancer evolution and the intra-tumour heterogeneity that fuels treatment resistance. However, identifying and tracking dynamic changes in somatic copy number alterations (SCNAs), which have been associated with poor outcome and metastasis, using ctDNA is challenging. Pancreatic adenocarcinoma is a disease which has been considered to harbour early punctuated events in its evolution, leading to an early fitness peak, with minimal further subclonal evolution. Methods To interrogate the role of SCNAs in pancreatic adenocarcinoma cancer evolution, we applied whole-exome sequencing of 55 longitudinal cell-free DNA (cfDNA) samples taken from 24 patients (including 8 from whom a patient-derived xenograft (PDX) was derived) with metastatic disease prospectively recruited into a clinical trial. We developed a method, Aneuploidy in Circulating Tumour DNA (ACT-Discover), that leverages haplotype phasing of paired tumour biopsies or PDXs to identify SCNAs in cfDNA with greater sensitivity. Results SCNAs were observed within 28 of 47 evaluable cfDNA samples. Of these events, 30% could only be identified by harnessing the haplotype-aware approach leveraged in ACT-Discover. The exceptional purity of PDX tumours enabled near-complete phasing of genomic regions in allelic imbalance, highlighting an important auxiliary function of PDXs. Finally, although the classical model of pancreatic cancer evolution emphasises the importance of early, homogenous somatic events as a key requirement for cancer development, ACT-Discover identified substantial heterogeneity of SCNAs, including parallel focal and arm-level events, affecting different parental alleles within individual tumours. Indeed, ongoing acquisition of SCNAs was identified within tumours throughout the disease course, including within an untreated metastatic tumour. Conclusions This work demonstrates the power of haplotype phasing to study genomic variation in cfDNA samples and reveals undiscovered intra-tumour heterogeneity with important scientific and clinical implications. Implementation of ACT-Discover could lead to important insights from existing cohorts or underpin future prospective studies seeking to characterise the landscape of tumour evolution through liquid biopsy.This work was supported by the European Research Council (ERC) no. 670582 (Call: ERC-2014-ADG) to Dr. Hidalgo. R.A.T is supported by the Miguel Servet-II Research Award and the 2021 call for Proyectos de generación de conocimiento by the Institute of Health Carlos III (ISCIII) of the Ministry of Economy [CP17/00199], the Olga Torres Foundation Award to emerging researchers [2017, to R.A.T, 2601], and received research grants from Novartis, Astrazeneca, and Beigene pharmaceuticals, not related to this study. N.M is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (Grant Number 211179/Z/18/Z), and also receives funding from Cancer Research UK Lung Cancer Centre of Excellence, Rosetrees, and the NIHR BRC at University College London Hospitals

Biocontrol of Diseases Caused by Phytophthora capsici and P. parasitica in Pepper Plants

first_pagesettingsOrder Article Reprints Open AccessArticle Biocontrol of Diseases Caused by Phytophthora capsici and P. parasitica in Pepper Plants by Mila Santos 1,*ORCID,Fernando Diánez 1ORCID,Brenda Sánchez-Montesinos 2,Victoria Huertas 1,Alejandro Moreno-Gavira 1,Belén Esteban García 3,José A. Garrido-Cárdenas 3ORCID andFrancisco J. Gea 4ORCID 1 Departamento de Agronomía, Escuela Superior de Ingeniería, Universidad de Almería, 04120 Almería, Spain 2 Departamento de Agronomía, División Ciencias de la Vida, Campus Irapuato-Salamanca, Universidad de Guanajuato, Irapuato 36500, Guanajuato, Mexico 3 Departamento de Biología y Geología, Edificio CITE IIB, Universidad de Almería, 04120 Almería, Spain 4 Centro de Investigación, Experimentación y Servicios del Champiñón (CIES), Quintanar del Rey, 16220 Cuenca, Spain * Author to whom correspondence should be addressed. J. Fungi 2023, 9(3), 360; https://doi.org/10.3390/jof9030360 Received: 6 February 2023 / Revised: 10 March 2023 / Accepted: 11 March 2023 / Published: 15 March 2023 (This article belongs to the Special Issue Isolation and Control of Fruit and Vegetable Rot Fungi) Download Browse Figures Versions Notes Abstract The main objective of this study was to evaluate the ability of Trichoderma aggressivum f. europaeum, T. longibrachiatum, Paecilomyces variotii, and T. saturnisporum as biological control agents (BCAs) against diseases caused by P. capsici and P. parasitica in pepper. For this purpose, their antagonistic activities were evaluated both in vitro and in vivo. We analysed the expression patterns of five defence related genes, CaBGLU, CaRGA1, CaBPR1, CaPTI1, and CaSAR8.2, in leaves. All BCAs showed a high in vitro antagonistic activity, significantly reducing the mycelial growth of P. capsici and P. parasitica. The treatments with T. aggressivum f. europaeum, T. longibrachiatum, and P. variotii substantially reduced the severity of the disease caused by P. capsici by 54, 76, and 70%, respectively, and of the disease caused by P. parasitica by 66, 55, and 64%, respectively. T. saturnisporum had the lowest values of disease reduction. Reinoculation with the four BCAs increased the control of both plant pathogens. Markedly different expression patterns were observed in the genes CaBGLU, CaRGA1, and CaSAR8.2. Based on the results, all four BCAs under study could be used as a biological alternative to chemicals for the control of P. capsici and P. parasitica in pepper with a high success rate

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer

Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12-0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10-0.71; P = 0.008), in patients with MSS-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients. The presence of inactivating mutations in RNF43, a negative regulator of WNT, in tumor cells predicts improved response rates and survival outcomes in patients with metastatic BRAF(V600E) colorectal cancer treated with anti-BRAF/EGFR therapy

Derecho a la alimentación: aproximaciones teóricas y prácticas para su debate

Los lectores encontrarán en este texto ponderación y buen juicio en un tema que sigue siendo discutido por muchos con gran entusiasmo. Estas narrativas jurídicas nos exponen varias visiones del derecho humano a la alimentación desde diferentes ángulos –teórico y práctico– y de diferentes latitudes –México, Colombia, Argentina y Chile–. Esta obra, y sin el afán de ser pretenciosa, evidencia un encuentro académico de personas con altas calidades académicas y profesionales, preocupadas por la protección del derecho a la alimentación en nuestros países. Sus visiones y reflexiones pueden ser un interesante punto de referencia para nuestros dirigentes, legisladores, diseñadores de políticas públicas, para el jurista y hasta para el ciudadano común

Sound Pills: Voice as a classroom innovation for equality and inclusion (podcasting, Discord, Twitter, Clubhouse)

El proyecto de innovación docente 2022-2023, titulado Píldoras sonoras: la voz como innovación en el aula para la igualdad y la inclusión (podcasting, Discord, Twitter, Clubhouse), aúna un equipo interdisciplinar de profesorado UCM y profesorado externo (de España y del extranjero), PAS, alumnado de Grado, Máster y Doctorado, una becaria de colaboración, dos becarios FPI UCM-Banco Santander y un becario FPU (doctorado). Todos sus integrantes son expertos docentes y/o investigadores en nuevas tecnologías, innovación docente y auto-aprendizaje, redes sociales, voz y podcasting. Durante la crisis de la COVID-19, se adaptaron perfectamente a la docencia virtual online y gran parte de ellos cuenta con experiencia en docencia online completa, en programas oficiales a distancia, previos al confinamiento. En este nuevo entorno, que se erige como el futuro inmediato, se ha detectado el crecimiento del uso de las redes sociales y repositorios de voz y de podcasting, frente a las redes sociales de fotografía y vídeo, que requieren de mejores dispositivos, mejor acceso Internet y en ocasiones, conocimientos avanzados de edición de vídeo y sonido. Sin embargo, la voz humana es una herramienta primordial, gratuita y accesible para todos y todas. No requiere de infraestructura, ni de logística previa y gracias a ello, elimina la brecha tecnológica por motivos de desigualdad económica, de edad, de formación y de género.Oficina para la Calidad, Vicerrectorado de Calidad, Universidad Complutense de MadridDepto. de Periodismo y Nuevos MediosFac. de Ciencias de la InformaciónFALSEsubmitte

Investigación joven con perspectiva de género V

Actas del V Congreso Internacional de Jóvenes Investigadorxs con perspectiva de género (Getafe, 3 - 5 de junio de 2020) organizado por el Instituto Universitario de Estudios de Género de la Universidad Carlos III de Madrid

Impacto de la COVID-19 en el tratamiento del infarto agudo de miocardio con elevación del segmento ST. La experiencia Española

The COVID-19 outbreak has had an unclear impact on the treatment and outcomes of patients with ST-segment elevation myocardial infarction (STEMI). The aim of this study was to assess changes in STEMI management during the COVID-19 outbreak. Using a multicenter, nationwide, retrospective, observational registry of consecutive patients who were managed in 75 specific STEMI care centers in Spain, we compared patient and procedural characteristics and in-hospital outcomes in 2 different cohorts with 30-day follow-up according to whether the patients had been treated before or after COVID-19. Suspected STEMI patients treated in STEMI networks decreased by 27.6% and patients with confirmed STEMI fell from 1305 to 1009 (22.7%). There were no differences in reperfusion strategy (> 94% treated with primary percutaneous coronary intervention in both cohorts). Patients treated with primary percutaneous coronary intervention during the COVID-19 outbreak had a longer ischemic time (233 [150-375] vs 200 [140-332] minutes, P < .001) but showed no differences in the time from first medical contact to reperfusion. In-hospital mortality was higher during COVID-19 (7.5% vs 5.1%; unadjusted OR, 1.50; 95%CI, 1.07-2.11; P < .001); this association remained after adjustment for confounders (risk-adjusted OR, 1.88; 95%CI, 1.12-3.14; P = .017). In the 2020 cohort, there was a 6.3% incidence of confirmed SARS-CoV-2 infection during hospitalization. The number of STEMI patients treated during the current COVID-19 outbreak fell vs the previous year and there was an increase in the median time from symptom onset to reperfusion and a significant 2-fold increase in the rate of in-hospital mortality. No changes in reperfusion strategy were detected, with primary percutaneous coronary intervention performed for the vast majority of patients. The co-existence of STEMI and SARS-CoV-2 infection was relatively infrequent.S