Deciphering Genomic Heterogeneity and the Internal Composition of Tumour Activities through a Hierarchical Factorisation Model

Genomic heterogeneity constitutes one of the most distinctive features of cancer diseases, limiting the efficacy and availability of medical treatments. Tumorigenesis emerges as a strongly stochastic process, producing a variable landscape of genomic configurations. In this context, matrix factorisation techniques represent a suitable approach for modelling such complex patterns of variability. In this work, we present a hierarchical factorisation model conceived from a systems biology point of view. The model integrates the topology of molecular pathways, allowing to simultaneously factorise genes and pathways activity matrices. The protocol was evaluated by using simulations, showing a high degree of accuracy. Furthermore, the analysis with a real cohort of breast cancer patients depicted the internal composition of some of the most relevant altered biological processes in the disease, describing gene and pathway level strategies and their observed combinations in the population of patients. We envision that this kind of approaches will be essential to better understand the hallmarks of cancer.Peer ReviewedPostprint (published version

A first approach to the Paleoentomology present in the Quaternarian sites of Atapuerca (Burgos, Spain): the subfossil oribatid fauna (Acari, Oribatida)

8 páginas, 3 figuras, 2 tablas.[ES] Los yacimientos cuaternarios de la Sierra de Atapuerca ofrecen interés mundial por haber hospedado varias especies de homínidos que vivieron en el último millón de años. En este contexto, durante la campaña de excavaciones de 2003 se realizó un muestreo puntual en algunos de sus yacimientos para obtener los primeros datos de restos de artrópodos que pudieran conservarse en los mismos. En este trabajo se presentan los resultados obtenidos de ácaros subfósiles pertenecientes al suborden de los oribátidos (Acari, Oribatida). Después de procesar los sedimentos, se obtuvieron un total de 7 individuos en el conjunto de los yacimientos muestreados, de los cuales 6 aparecieron en Gran Dolina en un nivel con datación en torno a los 300.000 años. Los ejemplares, identificados en su mayoría a nivel taxonómico de especie, pertenecen a las familias Cosmochthoniidae, Scheloribatidae, Oribatulidae y Hemileiidae. Dado el conocimiento que se dispone de la biología de los taxones encontrados, que pertenecen a géneros y especies presentes en la actualidad, se han realizado inferencias sobre los ambientes pretéritos en que los animales vivieron.[EN] The Atapuerca Quaternarian sites are of worldwide interest due to the presence of human remains belonging to the last million years. The oribatid mites (Acari, Oribatida) found in several archaeological samples extracted from the Atapuerca Quaternarian deposits, have been analyzed during the 2003 excavation campaign to study the Palaeoentomology of the site. The oribatid mite fauna consists of 7 individuals, 6 of which were obtained from Gran Dolina site (about 300.000 years old) and belong to families Cosmochthoniidae, Scheloribatidae, Oribatulidae and Hemileiidae. Most of the taxa were identified to species level. The results obtained were used as a basis to reconstruct the paleo-environments of the site in correspondence with the biological and ecological preferences of the taxa.Las investigaciones entomológicas de Atapuerca se realizaron dentro del Proyecto BOS2003-08938-C03-02.Peer reviewe

C/EBPα mediates the growth inhibitory effect of progestins on breast cancer cells

Steroid hormones are key gene regulators in breast cancer cells. While estrogens stimulate cell proliferation, progestins activate a single cell cycle followed by proliferation arrest. Here, we use biochemical and genome‐wide approaches to show that progestins achieve this effect via a functional crosstalk with C/EBPα. Using ChIP‐seq, we identify around 1,000 sites where C/EBPα binding precedes and helps binding of progesterone receptor (PR) in response to hormone. These regions exhibit epigenetic marks of active enhancers, and C/EBPα maintains an open chromatin conformation that facilitates loading of ligand‐activated PR. Prior to hormone exposure, C/EBPα favors promoter–enhancer contacts that assure hormonal regulation of key genes involved in cell proliferation by facilitating binding of RAD21, YY1, and the Mediator complex. Knockdown of C/EBPα disrupts enhancer–promoter contacts and decreases the presence of these architectural proteins, highlighting its key role in 3D chromatin looping. Thus, C/EBPα fulfills a previously unknown function as a potential growth modulator in hormone‐dependent breast cancer.The experimental work was supported by grants from the Departament d'Innovació Universitat i Empresa (DIUiE), and the Spanish Ministry of Economy and Competitiveness (SAF2016‐75006P), “Centro de Excelencia Severo Ochoa 2013‐2017”, SEV‐2012‐0208 and ERC Synergy Grant “4DGenome” nr: 609989

The modular network structure of the mutational landscape of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways

Plastome genomics in South American maize landraces: chloroplast lineages parallel the geographical structuring of nuclear gene pools

33 páginas, 2 tablas, 4 figurasBackground and aims: The number of plastome sequences has increased exponentially during the last decade. However, there is still little knowledge of the levels and distribution of intraspecific variation. The aims of this study were to estimate plastome diversity within Zea mays and analyse the distribution of haplotypes in connection with the landrace groups previously delimited for South American maize based on nuclear markers. Methods: We obtained the complete plastomes of 30 South American maize landraces and three teosintes by means of next-generation sequencing (NGS) and used them in combination with data from public repositories. After quality filtering, the curated data were employed to search for single-nucleotide polymorphisms, indels and chloroplast simple sequence repeats. Exact permutational contingency tests were performed to assess associations between plastome and nuclear variation. Network and Bayesian phylogenetic analyses were used to infer evolutionary relationships among haplotypes. Key results: Our analyses identified a total of 124 polymorphic plastome loci, with the intergenic regions psbE-rps18, petN-rpoB, trnL_UAG-ndhF and rpoC2-atpI exhibiting the highest marker densities. Although restricted in number, these markers allowed the discrimination of 27 haplotypes in a total of 51 Zea mays individuals. Andean and lowland South American landraces differed significantly in haplotype distribution. However, overall differentiation patterns were not informative with respect to subspecies diversification, as evidenced by the scattered distribution of maize and teosinte plastomes in both the network and Bayesian phylogenetic reconstructions. Conclusions: Knowledge of intraspecific plastome variation provides the framework for a more comprehensive understanding of evolutionary processes at low taxonomic levels and may become increasingly important for future plant barcoding efforts. Whole-plastome sequencing provided useful variability to contribute to maize phylogeographic studies. The structuring of haplotype diversity in the maize landraces examined here clearly reflects the distinction between the Andean and South American lowland gene pools previously inferred based on nuclear markers.This work was supported by the Agencia Nacional de Promoción Científica y Técnica (PICT 2012 0325, PICT 2016 1101), the Consejo Nacional de Investigaciones Científicas y Tecnológicas (PIP 11220120100416CO 2013–2015), the Instituto Nacional de Tecnología Agropecuaria (PNBIO 1131044) and the DEANN Project.Peer reviewe

Effects of intubation timing in patients with COVID-19 throughout the four waves of the pandemic : a matched analysis

The primary aim of our study was to investigate the association between intubation timing and hospital mortality in critically ill patients with COVID-19-associated respiratory failure. We also analysed both the impact of such timing throughout the first four pandemic waves and the influence of prior non-invasive respiratory support on outcomes. This is a secondary analysis of a multicentre, observational and prospective cohort study that included all consecutive patients undergoing invasive mechanical ventilation due to COVID-19 from across 58 Spanish intensive care units (ICU) participating in the CIBERESUCICOVID project. The study period was between 29 February 2020 and 31 August 2021. Early intubation was defined as that occurring within the first 24 h of intensive care unit (ICU) admission. Propensity score (PS) matching was used to achieve balance across baseline variables between the early intubation cohort and those patients who were intubated after the first 24 h of ICU admission. Differences in outcomes between early and delayed intubation were also assessed. We performed sensitivity analyses to consider a different timepoint (48 h from ICU admission) for early and delayed intubation. Of the 2725 patients who received invasive mechanical ventilation, a total of 614 matched patients were included in the analysis (307 for each group). In the unmatched population, there were no differences in mortality between the early and delayed groups. After PS matching, patients with delayed intubation presented higher hospital mortality (27.3% versus 37.1%, p =0.01), ICU mortality (25.7% versus 36.1%, p=0.007) and 90-day mortality (30.9% versus 40.2%, p=0.02) when compared to the early intubation group. Very similar findings were observed when we used a 48-hour timepoint for early or delayed intubation. The use of early intubation decreased after the first wave of the pandemic (72%, 49%, 46% and 45% in the first, second, third and fourth wave, respectively; first versus second, third and fourth waves p<0.001). In both the main and sensitivity analyses, hospital mortality was lower in patients receiving high-flow nasal cannula (n=294) who were intubated earlier. The subgroup of patients undergoing NIV (n=214) before intubation showed higher mortality when delayed intubation was set as that occurring after 48 h from ICU admission, but not when after 24 h. In patients with COVID-19 requiring invasive mechanical ventilation, delayed intubation was associated with a higher risk of hospital mortality. The use of early intubation significantly decreased throughout the course of the pandemic. Benefits of such an approach occurred more notably in patients who had received high-flow nasal cannul

Reference genome assessment from a population scale perspective: an accurate profile of variability and noise

This work was supported by grants [BIO2014-57291-R] from the Spanish Ministry of Economy and Competitiveness and ‘Plataforma de Recursos Biomoleculares y Bioinformáticos’ [PT13/0001/0007] from ISCIII, both co-funded with European Regional Development Funds (ERDF); and [EU H2020-INFRADEV-1-2015-1 ELIXIR-EXCELERATE (ref. 676559)]. David Conesa and Antonio López-Quílez would like to thank the Spanish Ministry of Economy and Competitiveness via research grant MTM2016-77501-P (jointly financed with the European Regional Development Fund)

Prognostic implications of comorbidity patterns in critically ill COVID-19 patients: A multicenter, observational study

Background The clinical heterogeneity of COVID-19 suggests the existence of different phenotypes with prognostic implications. We aimed to analyze comorbidity patterns in critically ill COVID-19 patients and assess their impact on in-hospital outcomes, response to treatment and sequelae. Methods Multicenter prospective/retrospective observational study in intensive care units of 55 Spanish hospitals. 5866 PCR-confirmed COVID-19 patients had comorbidities recorded at hospital admission; clinical and biological parameters, in-hospital procedures and complications throughout the stay; and, clinical complications, persistent symptoms and sequelae at 3 and 6 months. Findings Latent class analysis identified 3 phenotypes using training and test subcohorts: low-morbidity (n=3385; 58%), younger and with few comorbidities; high-morbidity (n=2074; 35%), with high comorbid burden; and renal-morbidity (n=407; 7%), with chronic kidney disease (CKD), high comorbidity burden and the worst oxygenation profile. Renal-morbidity and high-morbidity had more in-hospital complications and higher mortality risk than low-morbidity (adjusted HR (95% CI): 1.57 (1.34-1.84) and 1.16 (1.05-1.28), respectively). Corticosteroids, but not tocilizumab, were associated with lower mortality risk (HR (95% CI) 0.76 (0.63-0.93)), especially in renal-morbidity and high-morbidity. Renal-morbidity and high-morbidity showed the worst lung function throughout the follow-up, with renal-morbidity having the highest risk of infectious complications (6%), emergency visits (29%) or hospital readmissions (14%) at 6 months (p<0.01). Interpretation Comorbidity-based phenotypes were identified and associated with different expression of in-hospital complications, mortality, treatment response, and sequelae, with CKD playing a major role. This could help clinicians in day-to-day decision making including the management of post-discharge COVID-19 sequelae. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd

A blood microRNA classifier for the prediction of ICU mortality in COVID-19 patients: a multicenter validation study

Background: The identification of critically ill COVID-19 patients at risk of fatal outcomes remains a challenge. Here, we first validated candidate microRNAs (miRNAs) as biomarkers for clinical decision-making in critically ill patients. Second, we constructed a blood miRNA classifier for the early prediction of adverse outcomes in the ICU. Methods: This was a multicenter, observational and retrospective/prospective study including 503 critically ill patients admitted to the ICU from 19 hospitals. qPCR assays were performed in plasma samples collected within the first 48 h upon admission. A 16-miRNA panel was designed based on recently published data from our group. Results: Nine miRNAs were validated as biomarkers of all-cause in-ICU mortality in the independent cohort of critically ill patients (FDR < 0.05). Cox regression analysis revealed that low expression levels of eight miRNAs were associated with a higher risk of death (HR from 1.56 to 2.61). LASSO regression for variable selection was used to construct a miRNA classifier. A 4-blood miRNA signature composed of miR-16-5p, miR-192-5p, miR-323a-3p and miR-451a predicts the risk of all-cause in-ICU mortality (HR 2.5). Kaplan‒Meier analysis confirmed these findings. The miRNA signature provides a significant increase in the prognostic capacity of conventional scores, APACHE-II (C-index 0.71, DeLong test p-value 0.055) and SOFA (C-index 0.67, DeLong test p-value 0.001), and a risk model based on clinical predictors (C-index 0.74, DeLong test-p-value 0.035). For 28-day and 90-day mortality, the classifier also improved the prognostic value of APACHE-II, SOFA and the clinical model. The association between the classifier and mortality persisted even after multivariable adjustment. The functional analysis reported biological pathways involved in SARS-CoV infection and inflammatory, fibrotic and transcriptional pathways. Conclusions: A blood miRNA classifier improves the early prediction of fatal outcomes in critically ill COVID-19 patients.11 página