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1.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638901

RESUMO

Among the mechanisms leading to progression to Adult T-cell Leukaemia/Lymphoma in Human T-cell Leukaemia Virus type 1 (HTLV-1)-infected subjects, the contribution of stromal components remains poorly understood. To dissect the role of fibroblasts in HTLV-1-mediated lymphomagenesis, transcriptome studies, cytofluorimetric and qRT-PCR analyses of surface and intracellular markers linked to plasticity and stemness in coculture, and in vivo experiments were performed. A transcriptomic comparison between a more lymphomagenic (C91/III) and the parental (C91/PL) cell line evidenced hyperactivation of the PI3K/Akt pathway, confirmed by phospho-ELISA and 2-DE and WB analyses. C91/III cells also showed higher expression of mesenchymal and stemness genes. Short-term coculture with human foreskin fibroblasts (HFF) induced these features in C91/PL cells, and significantly increased not only the cancer stem cells (CSCs)-supporting CD10+GPR77+ HFF subpopulation, but also the percentage of ALDH1bright C91/PL cells. A non-cytotoxic acetylsalicylic acid treatment decreased HFF-induced ALDH1bright C91/PL cells, downregulated mesenchymal and stemness genes in cocultured cells, and delayed lymphoma growth in immunosuppressed mice, thus hindering the supportive activity of HFF on CSCs. These data suggest that crosstalk with HFF significantly intensifies the aggressiveness and plasticity of C91/PL cells, leading to the enrichment in lymphoma-initiating cells. Additional research is needed to better characterize these preliminary findings.

2.
Sci Rep ; 11(1): 19655, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34608258

RESUMO

COVID-19 represents the most severe global crisis to date whose public conversation can be studied in real time. To do so, we use a data set of over 350 million tweets and retweets posted by over 26 million English speaking Twitter users from January 13 to June 7, 2020. We characterize the retweet network to identify spontaneous clustering of users and the evolution of their interaction over time in relation to the pandemic's emergence. We identify several stable clusters (super-communities), and are able to link them to international groups mainly involved in science and health topics, national elites, and political actors. The science- and health-related super-community received disproportionate attention early on during the pandemic, and was leading the discussion at the time. However, as the pandemic unfolded, the attention shifted towards both national elites and political actors, paralleled by the introduction of country-specific containment measures and the growing politicization of the debate. Scientific super-community remained present in the discussion, but experienced less reach and became more isolated within the network. Overall, the emerging network communities are characterized by an increased self-amplification and polarization. This makes it generally harder for information from international health organizations or scientific authorities to directly reach a broad audience through Twitter for prolonged time. These results may have implications for information dissemination along the unfolding of long-term events like epidemic diseases on a world-wide scale.


Assuntos
COVID-19/epidemiologia , Isolamento Social , Mídias Sociais , COVID-19/patologia , COVID-19/virologia , Humanos , Pandemias , Política , SARS-CoV-2/isolamento & purificação , Análise de Rede Social , Rede Social
3.
Adv Protein Chem Struct Biol ; 127: 217-248, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34340768

RESUMO

Protein structure characterization is fundamental to understand protein properties, such as folding process and protein resistance to thermal stress, up to unveiling organism pathologies (e.g., prion disease). In this chapter, we provide an overview on how the spectral properties of the networks reconstructed from the Protein Contact Map (PCM) can be used to generate informative observables. As a specific case study, we apply two different network approaches to an example protein dataset, for the aim of discriminating protein folding state, and for the reconstruction of protein 3D structure.


Assuntos
Bases de Dados de Proteínas , Dobramento de Proteína , Mapas de Interação de Proteínas , Proteínas/química , Proteínas/metabolismo , Animais , Humanos , Domínios Proteicos , Estabilidade Proteica
4.
Phys Med ; 89: 80-92, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34352679

RESUMO

MR fingerprinting (MRF) is an innovative approach to quantitative MRI. A typical disadvantage of dictionary-based MRF is the explosive growth of the dictionary as a function of the number of reconstructed parameters, an instance of the curse of dimensionality, which determines an explosion of resource requirements. In this work, we describe a deep learning approach for MRF parameter map reconstruction using a fully connected architecture. Employing simulations, we have investigated how the performance of the Neural Networks (NN) approach scales with the number of parameters to be retrieved, compared to the standard dictionary approach. We have also studied optimal training procedures by comparing different strategies for noise addition and parameter space sampling, to achieve better accuracy and robustness to noise. Four MRF sequences were considered: IR-FISP, bSSFP, IR-FISP-B1, and IR-bSSFP-B1. A comparison between NN and the dictionary approaches in reconstructing parameter maps as a function of the number of parameters to be retrieved was performed using a numerical brain phantom. Results demonstrated that training with random sampling and different levels of noise variance yielded the best performance. NN performance was at least as good as the dictionary-based approach in reconstructing parameter maps using Gaussian noise as a source of artifacts: the difference in performance increased with the number of estimated parameters because the dictionary method suffers from the coarse resolution of the parameter space sampling. The NN proved to be more efficient in memory usage and computational burden, and has great potential for solving large-scale MRF problems.


Assuntos
Aprendizado Profundo , Processamento de Imagem Assistida por Computador , Algoritmos , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Imagens de Fantasmas
5.
Leukemia ; 35(10): 2813-2826, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34193978

RESUMO

Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1-mutated(mut), chromatin/spliceosome-mut and TP53-mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1-mut AML. One was enriched for mutations in cohesin/DNA damage-related genes (NPM1/cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1/cohesin-mut and NPM1-mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1/cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored.

6.
Brief Bioinform ; 2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34010955

RESUMO

The complex web of macromolecular interactions occurring within cells-the interactome-is the backbone of an increasing number of studies, but a clear consensus on the exact structure of this network is still lacking. Different genome-scale maps of human interactome have been obtained through several experimental techniques and functional analyses. Moreover, these maps can be enriched through literature-mining approaches, and different combinations of various 'source' databases have been used in the literature. It is therefore unclear to which extent the various interactomes yield similar results when used in the context of interactome-based approaches in network biology. We compared a comprehensive list of human interactomes on the basis of topology, protein complexes, molecular pathways, pathway cross-talk and disease gene prediction. In a general context of relevant heterogeneity, our study provides a series of qualitative and quantitative parameters that describe the state of the art of human interactomes and guidelines for selecting interactomes in future applications.

7.
Vaccines (Basel) ; 9(2)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670697

RESUMO

While the SARS-CoV-2 pandemic continues to strike and collect its death toll throughout the globe, as of 31 January 2021, the vaccine candidates worldwide were 292, of which 70 were in clinical testing. Several vaccines have been approved worldwide, and in particular, three have been so far authorized for use in the EU. Vaccination can be, in fact, an efficient way to mitigate the devastating effect of the pandemic and offer protection to some vulnerable strata of the population (i.e., the elderly) and reduce the social and economic burden of the current crisis. Regardless, a question is still open: after vaccination availability for the public, will vaccination campaigns be effective in reaching all the strata and a sufficient number of people in order to guarantee herd immunity? In other words: after we have it, will we be able to use it? Following the trends in vaccine hesitancy in recent years, there is a growing distrust of COVID-19 vaccinations. In addition, the online context and competition between pro- and anti-vaxxers show a trend in which anti-vaccination movements tend to capture the attention of those who are hesitant. Describing this context and analyzing its possible causes, what interventions or strategies could be effective to reduce COVID-19 vaccine hesitancy? Will social media trend analysis be helpful in trying to solve this complex issue? Are there perspectives for an efficient implementation of COVID-19 vaccination coverage as well as for all the other vaccinations?

8.
J Clin Oncol ; 39(11): 1223-1233, 2021 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-33539200

RESUMO

PURPOSE: Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication. METHODS: We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed. RESULTS: We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations (SF3B1, SRSF2, and U2AF1) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with SF3B1 mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within SF3B1- and SRSF2-related MDS. MDS with complex karyotype and/or TP53 gene abnormalities and MDS with acute leukemia-like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of TP53 mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features. CONCLUSION: Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.


Assuntos
Genômica/métodos , Síndromes Mielodisplásicas/classificação , Feminino , Humanos , Masculino , Síndromes Mielodisplásicas/genética , Prognóstico , Estudos Retrospectivos
9.
BMC Bioinformatics ; 22(1): 60, 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33563206

RESUMO

BACKGROUND: Current high-throughput technologies-i.e. whole genome sequencing, RNA-Seq, ChIP-Seq, etc.-generate huge amounts of data and their usage gets more widespread with each passing year. Complex analysis pipelines involving several computationally-intensive steps have to be applied on an increasing number of samples. Workflow management systems allow parallelization and a more efficient usage of computational power. Nevertheless, this mostly happens by assigning the available cores to a single or few samples' pipeline at a time. We refer to this approach as naive parallel strategy (NPS). Here, we discuss an alternative approach, which we refer to as concurrent execution strategy (CES), which equally distributes the available processors across every sample's pipeline. RESULTS: Theoretically, we show that the CES results, under loose conditions, in a substantial speedup, with an ideal gain range spanning from 1 to the number of samples. Also, we observe that the CES yields even faster executions since parallelly computable tasks scale sub-linearly. Practically, we tested both strategies on a whole exome sequencing pipeline applied to three publicly available matched tumour-normal sample pairs of gastrointestinal stromal tumour. The CES achieved speedups in latency up to 2-2.4 compared to the NPS. CONCLUSIONS: Our results hint that if resources distribution is further tailored to fit specific situations, an even greater gain in performance of multiple samples pipelines execution could be achieved. For this to be feasible, a benchmarking of the tools included in the pipeline would be necessary. It is our opinion these benchmarks should be consistently performed by the tools' developers. Finally, these results suggest that concurrent strategies might also lead to energy and cost savings by making feasible the usage of low power machine clusters.


Assuntos
Biologia Computacional , Sequenciamento de Nucleotídeos em Larga Escala , Software , Sequenciamento Completo do Exoma , Sequenciamento de Cromatina por Imunoprecipitação , Biologia Computacional/métodos , Sequenciamento Completo do Exoma/normas , Fluxo de Trabalho
10.
Sci Rep ; 11(1): 3030, 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33542369

RESUMO

In this paper we compared taxonomic results obtained by metataxonomics (16S rRNA gene sequencing) and metagenomics (whole shotgun metagenomic sequencing) to investigate their reliability for bacteria profiling, studying the chicken gut as a model system. The experimental conditions included two compartments of gastrointestinal tracts and two sampling times. We compared the relative abundance distributions obtained with the two sequencing strategies and then tested their capability to distinguish the experimental conditions. The results showed that 16S rRNA gene sequencing detects only part of the gut microbiota community revealed by shotgun sequencing. Specifically, when a sufficient number of reads is available, Shotgun sequencing has more power to identify less abundant taxa than 16S sequencing. Finally, we showed that the less abundant genera detected only by shotgun sequencing are biologically meaningful, being able to discriminate between the experimental conditions as much as the more abundant genera detected by both sequencing strategies.

11.
Sci Rep ; 10(1): 19756, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33184391

RESUMO

Photoplethysmography (PPG) measured by smartphone has the potential for a large scale, non-invasive, and easy-to-use screening tool. Vascular aging is linked to increased arterial stiffness, which can be measured by PPG. We investigate the feasibility of using PPG to predict healthy vascular aging (HVA) based on two approaches: machine learning (ML) and deep learning (DL). We performed data preprocessing, including detrending, demodulating, and denoising on the raw PPG signals. For ML, ridge penalized regression has been applied to 38 features extracted from PPG, whereas for DL several convolutional neural networks (CNNs) have been applied to the whole PPG signals as input. The analysis has been conducted using the crowd-sourced Heart for Heart data. The prediction performance of ML using two features (AUC of 94.7%) - the a wave of the second derivative PPG and tpr, including four covariates, sex, height, weight, and smoking - was similar to that of the best performing CNN, 12-layer ResNet (AUC of 95.3%). Without having the heavy computational cost of DL, ML might be advantageous in finding potential biomarkers for HVA prediction. The whole workflow of the procedure is clearly described, and open software has been made available to facilitate replication of the results.


Assuntos
Envelhecimento/patologia , Aprendizado Profundo , Redes Neurais de Computação , Fotopletismografia/métodos , Smartphone/estatística & dados numéricos , Doenças Vasculares/diagnóstico , Adolescente , Adulto , Idoso , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Processamento de Sinais Assistido por Computador , Adulto Jovem
12.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2520-2523, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018519

RESUMO

Non-contact galvanotaxis as a way to drive the cells migration could be a promising tool for a variety of biomedical applications, such as wound healing control, avoiding the interaction between electrodes and cell cultures. To this regard, the efficacy of this electrical stimulus application has to be deeper studied to control physiological migratory phenomena in a remote way.Aim of this work is to provide an experimental investigation on the mobility of cells exposed to a static electric field in a "noncontact" mode, supported by a suitable modeling of the electric field distribution inside the experimental setup. In particular, scratch assays have been carried out placing the electrodes outside the cells medium support and changing the cells holder to study more than one configuration.Clinical Relevance- In this study the in vitro experiments on the non-contact galvanotaxis, together with the numerical simulations of the exposure setup, provide a way to investigate the effects that could affect an electrically drive cell migration.


Assuntos
Eletricidade , Resposta Táctica , Bioensaio , Movimento Celular , Eletricidade Estática
13.
PLoS One ; 15(10): e0237207, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33125392

RESUMO

In this work we propose an index to estimate the gut microbiota biodiversity using a modeling approach with the aim of describing its relationship with health and aging. The gut microbiota, a complex ecosystem that links nutrition and metabolism, has a pervasive effect on all body organs and systems, undergoes profound changes with age and life-style, and substantially contributes to the pathogenesis of age-related diseases. For these reasons, the gut microbiota is a suitable candidate for assessing and quantifying healthy aging, i.e. the capability of individuals to reach an advanced age, avoiding or postponing major age-related diseases. The importance of the gut microbiota in health and aging has been proven to be related not only to its taxonomic composition, but also to its ecological properties, namely its biodiversity. Following an ecological approach, here we intended to characterize the relationship between the gut microbiota biodiversity and healthy aging through the development a parsimonious model of gut microbiota from which biodiversity can be estimated. We analysed publicly available metagenomic data relative to subjects of different ages, countries, nutritional habits and health status and we showed that a hybrid niche-neutral model well describes the observed patterns of bacterial relative abundance. Moreover, starting from such ecological modeling, we derived an estimate of the gut microbiota biodiversity that is consistent with classical indices, while having a higher statistical power. This allowed us to unveil an increase of the gut microbiota biodiversity during aging and to provide a good predictor of health status in old age, dependent on life-style and aging disorders.


Assuntos
Envelhecimento , Microbioma Gastrointestinal , Modelos Biológicos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/fisiologia , Biodiversidade , Criança , Pré-Escolar , Bases de Dados de Ácidos Nucleicos , Feminino , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiologia , Nível de Saúde , Envelhecimento Saudável/genética , Envelhecimento Saudável/fisiologia , Humanos , Lactente , Recém-Nascido , Masculino , Metagenoma , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Adulto Jovem
14.
Sci Rep ; 10(1): 15026, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929164

RESUMO

It is important that antibiotics prescriptions are based on antimicrobial susceptibility data to ensure effective treatment outcomes. The increasing availability of next-generation sequencing, bacterial whole genome sequencing (WGS) can facilitate a more reliable and faster alternative to traditional phenotyping for the detection and surveillance of AMR. This work proposes a machine learning approach that can predict the minimum inhibitory concentration (MIC) for a given antibiotic, here ciprofloxacin, on the basis of both genome-wide mutation profiles and profiles of acquired antimicrobial resistance genes. We analysed 704 Escherichia coli genomes combined with their respective MIC measurements for ciprofloxacin originating from different countries. The four most important predictors found by the model, mutations in gyrA residues Ser83 and Asp87, a mutation in parC residue Ser80 and presence of the qnrS1 gene, have been experimentally validated before. Using only these four predictors in a linear regression model, 65% and 93% of the test samples' MIC were correctly predicted within a two- and a four-fold dilution range, respectively. The presented work does not treat machine learning as a black box model concept, but also identifies the genomic features that determine susceptibility. The recent progress in WGS technology in combination with machine learning analysis approaches indicates that in the near future WGS of bacteria might become cheaper and faster than a MIC measurement.


Assuntos
Antibacterianos/toxicidade , Ciprofloxacina/toxicidade , Farmacorresistência Bacteriana , Genes Bacterianos , Aprendizado de Máquina , DNA Girase/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Concentração Inibidora 50 , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Testes de Toxicidade/métodos
15.
Animals (Basel) ; 10(2)2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32033399

RESUMO

Paratuberculosis or Johne's disease in cattle is a chronic granulomatous gastroenteritis caused by infection with Mycobacterium avium subspecies paratuberculosis (MAP). Paratuberculosis is not treatable; therefore, the early identification and isolation of infected animals is a key point to reduce its incidence. In this paper, we analyse RNAseq experimental data of 5 ELISA-negative cattle exposed to MAP in a positive herd, compared to 5 negative-unexposed controls. The purpose was to find a small set of differentially expressed genes able to discriminate between exposed animals in a preclinical phase from non-exposed controls. Our results identified 10 transcripts that differentiate between ELISA-negative, clinically healthy, and exposed animals belonging to paratuberculosis-positive herds and negative-unexposed animals. Of the 10 transcripts, five (TRPV4, RIC8B, IL5RA, ERF, CDC40) showed significant differential expression between the three groups while the remaining 5 (RDM1, EPHX1, STAU1, TLE1, ASB8) did not show a significant difference in at least one of the pairwise comparisons. When tested in a larger cohort, these findings may contribute to the development of a new diagnostic test for paratuberculosis based on a gene expression signature. Such a diagnostic tool could allow early interventions to reduce the risk of the infection spreading.

16.
Biochim Biophys Acta Gene Regul Mech ; 1863(6): 194415, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31672524

RESUMO

Genome organization in eukaryotes during interphase stems from the delicate balance between non-random correlations present in the DNA polynucleotide linear sequence and the physico/chemical reactions which shape continuously the form and structure of DNA and chromatin inside the nucleus of the cell. It is now clear that these mechanisms have a key role in important processes like gene regulation, yet the detailed ways they act simultaneously and, eventually, come to influence each other even across very different length-scales remain largely unexplored. In this paper, we recapitulate some of the main results concerning gene regulatory and physical mechanisms, in relation to the information encoded in the 1D sequence and the 3D folding structure of DNA. In particular, we stress how reciprocal crossfeeding between 1D and 3D models may provide original insight into how these complex processes work and influence each other. This article is part of a Special Issue entitled: Transcriptional Profiles and Regulatory Gene Networks edited by Dr. Dr. Federico Manuel Giorgi and Dr. Shaun Mahony.


Assuntos
Cromossomos , Genômica/métodos , Modelos Genéticos , Sequência de Bases , Cromatina/química , DNA/química , Eucariotos/genética
17.
J Alzheimers Dis ; 72(3): 911-918, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31658056

RESUMO

BACKGROUND: Elevated peripheral levels of different cytokines and chemokines in subjects with Alzheimer's disease (AD), as compared with healthy controls (HC), have emphasized the role of inflammation in such a disease. Considering the cross-talking between the central nervous system and the periphery, the inflammatory analytes may provide utility as biomarkers to identify AD at earlier stages. OBJECTIVE: Using an advanced statistical approach, we can discriminate the interactive network of cytokines/chemokines and propose a useful tool to follow the progression and evolution of AD, also in light of sex differences. METHODS: A cohort of 289 old-age subjects was screened for cytokine and chemokine profiling, measured in plasma, after a thorough clinical and neuropsychological evaluation. A custom algorithm based on Fisher linear discriminant analysis was applied to ascertain a classification signature able to discriminate HC from mild cognitive impairment (MCI) and AD. RESULTS: We observed that a joint expression of three proteins (a "signature" composed by IFN-α2, IL-1α, TNFα) can discriminate HC from AD with an accuracy of 65.24%. Using this signature on MCI samples, 84.93% of them were classified as "non-HC". Stratifying MCI samples by sex, we observed that 87.23% of women were classified as "non-HC", and only 57.69% of males. Indeed, in a scatter plot of IFN-α2 and IL-1α, the HC group was better separated from MCI and AD in women as compared with men. CONCLUSION: These findings suggest that AD is accompanied by a peripheral inflammatory response that can already be present in MCI subjects, thus providing a mean for detecting this at-risk status and allow an anticipated intervention.


Assuntos
Doença de Alzheimer/sangue , Quimiocinas/sangue , Disfunção Cognitiva/sangue , Citocinas/sangue , Caracteres Sexuais , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Doença de Alzheimer/diagnóstico , Biomarcadores/sangue , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico , Estudos Transversais , Feminino , Humanos , Masculino
18.
Oncogene ; 38(42): 6801-6817, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31406246

RESUMO

Inhibitors of BET proteins (BETi) are anti-cancer drugs that have shown efficacy in pre-clinical settings and are currently in clinical trials for different types of cancer, including non-small cell lung cancer (NSCLC). Currently, no predictive biomarker is available to identify patients that may benefit from this treatment. To uncover the mechanisms of resistance to BETi, we performed a genome-scale CRISPR/Cas9 screening in lung cancer cells. We identified three Hippo pathway genes, LATS2, TAOK1, and NF2, as key determinants for sensitivity to BETi. The knockout of these genes induces resistance to BETi, by promoting TAZ nuclear localization and transcriptional activity. Conversely, TAZ expression promotes resistance to these drugs. We also showed that TAZ, YAP, and their partner TEAD are direct targets of BRD4 and that treatment with BETi downregulates their expression. Noticeably, molecular alterations in one or more of these genes are present in a large fraction of NSCLC patients and TAZ amplification or overexpression correlates with a worse outcome in lung adenocarcinoma. Our data define the central role of Hippo pathway in mediating resistance to BETi and provide a rationale for using BETi to counter-act YAP/TAZ-mediated pro-oncogenic activity.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Células A549 , Sistemas CRISPR-Cas , Carcinoma Pulmonar de Células não Pequenas/patologia , Núcleo Celular/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Proteínas de Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/genética
19.
Mol Syst Biol ; 15(5): e8339, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118277

RESUMO

In chronic lymphocytic leukemia (CLL), a diverse set of genetic mutations is embedded in a deregulated epigenetic landscape that drives cancerogenesis. To elucidate the role of aberrant chromatin features, we mapped DNA methylation, seven histone modifications, nucleosome positions, chromatin accessibility, binding of EBF1 and CTCF, as well as the transcriptome of B cells from CLL patients and healthy donors. A globally increased histone deacetylase activity was detected and half of the genome comprised transcriptionally downregulated partially DNA methylated domains demarcated by CTCF CLL samples displayed a H3K4me3 redistribution and nucleosome gain at promoters as well as changes of enhancer activity and enhancer linkage to target genes. A DNA binding motif analysis identified transcription factors that gained or lost binding in CLL at sites with aberrant chromatin features. These findings were integrated into a gene regulatory enhancer containing network enriched for B-cell receptor signaling pathway components. Our study predicts novel molecular links to targets of CLL therapies and provides a valuable resource for further studies on the epigenetic contribution to the disease.


Assuntos
Cromatina/química , Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes , Histonas/química , Leucemia Linfocítica Crônica de Células B/genética , Idoso , Motivos de Aminoácidos , Sítios de Ligação , Fator de Ligação a CCCTC/genética , DNA/química , Metilação de DNA , Regulação para Baixo , Elementos Facilitadores Genéticos , Histona Desacetilases/genética , Humanos , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Ligação Proteica , Transativadores/genética
20.
Mol Cell Oncol ; 6(3): 1561118, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31131304

RESUMO

Network approaches are ubiquitous, from social and ecological systems up to complex biological processes. In our recently published work we used the network framework for a Systems Medicine approach to multiple cancer types, in order to highlight similitudes and differences that can be exploited to extend existing therapeutical strategies. These approaches shed new light to oncological processes, but allow also to pose "old" questions (like the search for novel drug targets) in a "new" way.

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