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1.
Artif Intell Med ; 122: 102212, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34823837

RESUMO

Computational approaches to detect the signals of adverse drug reactions are powerful tools to monitor the unattended effects that users experience and report, also preventing death and serious injury. They apply statistical indices to affirm the validity of adverse reactions reported by users. The methodologies that scan fixed duration intervals in the lifetime of drugs are among the most used. Here we present a method, called TEDAR, in which ranges of varying length are taken into account. TEDAR has the advantage to detect a greater number of true signals without significantly increasing the number of false positives, which are a major concern for this type of tools. Furthermore, early detection of signals is a key feature of methods to prevent the safety of the population. The results show that TEDAR detects adverse reactions many months earlier than methodologies based on a fixed interval length.

2.
PLoS Comput Biol ; 17(9): e1009444, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34570769

RESUMO

Transcription factors (TFs) are proteins that promote or reduce the expression of genes by binding short genomic DNA sequences known as transcription factor binding sites (TFBS). While several tools have been developed to scan for potential occurrences of TFBS in linear DNA sequences or reference genomes, no tool exists to find them in pangenome variation graphs (VGs). VGs are sequence-labelled graphs that can efficiently encode collections of genomes and their variants in a single, compact data structure. Because VGs can losslessly compress large pangenomes, TFBS scanning in VGs can efficiently capture how genomic variation affects the potential binding landscape of TFs in a population of individuals. Here we present GRAFIMO (GRAph-based Finding of Individual Motif Occurrences), a command-line tool for the scanning of known TF DNA motifs represented as Position Weight Matrices (PWMs) in VGs. GRAFIMO extends the standard PWM scanning procedure by considering variations and alternative haplotypes encoded in a VG. Using GRAFIMO on a VG based on individuals from the 1000 Genomes project we recover several potential binding sites that are enhanced, weakened or missed when scanning only the reference genome, and which could constitute individual-specific binding events. GRAFIMO is available as an open-source tool, under the MIT license, at https://github.com/pinellolab/GRAFIMO and https://github.com/InfOmics/GRAFIMO.


Assuntos
Variação Genética , Motivos de Nucleotídeos , Software , Fatores de Transcrição/metabolismo , Sequência de Bases , Sítios de Ligação/genética , Biologia Computacional , Gráficos por Computador , Genoma Humano , Genômica , Haplótipos , Humanos , Ligação Proteica/genética
3.
BMC Bioinformatics ; 22(1): 209, 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888059

RESUMO

BACKGROUND: Graphs are mathematical structures widely used for expressing relationships among elements when representing biomedical and biological information. On top of these representations, several analyses are performed. A common task is the search of one substructure within one graph, called target. The problem is referred to as one-to-one subgraph search, and it is known to be NP-complete. Heuristics and indexing techniques can be applied to facilitate the search. Indexing techniques are also exploited in the context of searching in a collection of target graphs, referred to as one-to-many subgraph problem. Filter-and-verification methods that use indexing approaches provide a fast pruning of target graphs or parts of them that do not contain the query. The expensive verification phase is then performed only on the subset of promising targets. Indexing strategies extract graph features at a sufficient granularity level for performing a powerful filtering step. Features are memorized in data structures allowing an efficient access. Indexing size, querying time and filtering power are key points for the development of efficient subgraph searching solutions. RESULTS: An existing approach, GRAPES, has been shown to have good performance in terms of speed-up for both one-to-one and one-to-many cases. However, it suffers in the size of the built index. For this reason, we propose GRAPES-DD, a modified version of GRAPES in which the indexing structure has been replaced with a Decision Diagram. Decision Diagrams are a broad class of data structures widely used to encode and manipulate functions efficiently. Experiments on biomedical structures and synthetic graphs have confirmed our expectation showing that GRAPES-DD has substantially reduced the memory utilization compared to GRAPES without worsening the searching time. CONCLUSION: The use of Decision Diagrams for searching in biochemical and biological graphs is completely new and potentially promising thanks to their ability to encode compactly sets by exploiting their structure and regularity, and to manipulate entire sets of elements at once, instead of exploring each single element explicitly. Search strategies based on Decision Diagram makes the indexing for biochemical graphs, and not only, more affordable allowing us to potentially deal with huge and ever growing collections of biochemical and biological structures.


Assuntos
Vitis , Indexação e Redação de Resumos , Algoritmos , Bases de Dados Factuais
4.
Noncoding RNA ; 7(2)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923420

RESUMO

Stressful conditions induce the cell to save energy and activate a rescue program modulated by mammalian target of rapamycin (mTOR). Along with transcriptional and translational regulation, the cell relies also on post-transcriptional modulation to quickly adapt the translation of essential proteins. MicroRNAs play an important role in the regulation of protein translation, and their availability is tightly regulated by RNA competing mechanisms often mediated by long noncoding RNAs (lncRNAs). In our paper, we simulated the response to growth adverse condition by bimiralisib, a dual PI3K/mTOR inhibitor, in diffuse large B cell lymphoma cell lines, and we studied post-transcriptional regulation by the differential analysis of exonic and intronic RNA expression. In particular, we observed the upregulation of a lncRNA, lncTNK2-2:1, which correlated with the stabilization of transcripts involved in the regulation of translation and DNA damage after bimiralisib treatment. We identified miR-21-3p as miRNA likely sponged by lncTNK2-2:1, with consequent stabilization of the mRNA of p53, which is a master regulator of cell growth in response to DNA damage.

5.
Brief Bioinform ; 22(3)2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32893299

RESUMO

Given a group of genomes, represented as the sets of genes that belong to them, the discovery of the pangenomic content is based on the search of genetic homology among the genes for clustering them into families. Thus, pangenomic analyses investigate the membership of the families to the given genomes. This approach is referred to as the gene-oriented approach in contrast to other definitions of the problem that takes into account different genomic features. In the past years, several tools have been developed to discover and analyse pangenomic contents. Because of the hardness of the problem, each tool applies a different strategy for discovering the pangenomic content. This results in a differentiation of the performance of each tool that depends on the composition of the input genomes. This review reports the main analysis instruments provided by the current state of the art tools for the discovery of pangenomic contents. Moreover, unlike previous works, the presented study compares pangenomic tools from a methodological perspective, analysing the causes that lead a given methodology to outperform other tools. The analysis is performed by taking into account different bacterial populations, which are synthetically generated by changing evolutionary parameters. The benchmarks used to compare the pangenomic tools, in addition to the computational pipeline developed for this purpose, are available at https://github.com/InfOmics/pangenes-review. Contact: V. Bonnici, R. Giugno Supplementary information: Supplementary data are available at Briefings in Bioinformatics online.

6.
Aging Cell ; 20(1): e13287, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33369048

RESUMO

Ischemic stroke, the third leading cause of death in the Western world, affects mainly the elderly and is strongly associated with comorbid conditions such as atherosclerosis or diabetes, which are pathologically characterized by increased inflammation and are known to influence the outcome of stroke. Stroke incidence peaks during influenza seasons, and patients suffering from infections such as pneumonia prior to stroke exhibit a worse stroke outcome. Earlier studies have shown that comorbidities aggravate the outcome of stroke, yet the mediators of this phenomenon remain obscure. Here, we show that acute peripheral inflammation aggravates stroke-induced neuronal damage and motor deficits specifically in aged mice. This is associated with increased levels of plasma proinflammatory cytokines, rather than with an increase of inflammatory mediators in the affected brain parenchyma. Nascent transcriptomics data with mature microRNA sequencing were used to identify the neuron-specific miRNome, in order to decipher dysregulated miRNAs in the brains of aged animals with stroke and co-existing inflammation. We pinpoint a previously uninvestigated miRNA in the brain, miR-127, that is highly neuronal, to be associated with increased cell death in the aged, LPS-injected ischemic mice. Target prediction tools indicate that miR-127 interacts with several basally expressed neuronal genes, and of these we verify miR-127 binding to Psmd3. Finally, we report reduced expression of miR-127 in human stroke brains. Our results underline the impact of peripheral inflammation on the outcome of stroke in aged subjects and pinpoint molecular targets for restoring endogenous neuronal capacity to combat ischemic stroke.


Assuntos
Isquemia Encefálica/genética , Inflamação/genética , MicroRNAs/metabolismo , Envelhecimento , Animais , Isquemia Encefálica/mortalidade , Modelos Animais de Doenças , Humanos , Masculino , Camundongos
7.
J Extracell Vesicles ; 10(1): e12002, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33304471

RESUMO

Hypoxia is an essential hallmark of several serious diseases such as cardiovascular and metabolic disorders and cancer. A decline in the tissue oxygen level induces hypoxic responses in cells which strive to adapt to the changed conditions. A failure to adapt to prolonged or severe hypoxia can trigger cell death. While some cell types, such as neurons, are highly vulnerable to hypoxia, cancer cells take advantage of a hypoxic environment to undergo tumour growth, angiogenesis and metastasis. Hypoxia-induced processes trigger complex intercellular communication and there are now indications that extracellular vesicles (EVs) play a fundamental role in these processes. Recent developments in EV isolation and characterization methodology have increased the awareness of the importance of EV purity in functional and cargo studies. Cell death, a hallmark of severe hypoxia, is a known source of intracellular contaminants in isolated EVs. In this review, methodological aspects of studies investigating hypoxia-induced EVs are critically evaluated. Key concerns and gaps in the current knowledge are highlighted and future directions for studies are set. To accelerate and advance research, an in-depth analysis of the functions and cargo of hypoxic EVs, compared to normoxic EVs, is provided with the focus on the altered microRNA contents of the EVs.

8.
Front Neurol ; 11: 926, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33041963

RESUMO

The current COVID-19 pandemic presents unprecedented new challenges to public health and medical care delivery. To control viral transmission, social distancing measures have been implemented all over the world, interrupting the access to routine medical care for many individuals with neurological diseases. Cognitive disorders are common in many neurological conditions, e.g., stroke, traumatic brain injury, Alzheimer's disease, and other types of dementia, Parkinson's disease and parkinsonian syndromes, and multiple sclerosis, and should be addressed by cognitive rehabilitation interventions. To be effective, cognitive rehabilitation programs must be intensive and prolonged over time; however, the current virus containment measures are hampering their implementation. Moreover, the reduced access to cognitive rehabilitation might worsen the relationship between the patient and the healthcare professional. Urgent measures to address issues connected to COVID-19 pandemic are, therefore, needed. Remote communication technologies are increasingly regarded as potential effective options to support health care interventions, including neurorehabilitation and cognitive rehabilitation. Among them, telemedicine, virtual reality, augmented reality, and serious games could be in the forefront of these efforts. We will briefly review current evidence-based recommendations on the efficacy of cognitive rehabilitation and offer a perspective on the role of tele- and virtual rehabilitation to achieve adequate cognitive stimulation in the era of social distancing related to COVID-19 pandemic. In particular, we will discuss issues related to their diffusion and propose a roadmap to address them. Methodological and technological improvements might lead to a paradigm shift to promote the delivery of cognitive rehabilitation to people with reduced mobility and in remote regions.

9.
J Neuroinflammation ; 17(1): 194, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32560730

RESUMO

BACKGROUND: Ischemic stroke is a devastating disease without a cure. The available treatments for ischemic stroke, thrombolysis by tissue plasminogen activator, and thrombectomy are suitable only to a fraction of patients and thus novel therapeutic approaches are urgently needed. The neuroinflammatory responses elicited secondary to the ischemic attack further aggravate the stroke-induced neuronal damage. It has been demonstrated that these responses are regulated at the level of non-coding RNAs, especially miRNAs. METHODS: We utilized lentiviral vectors to overexpress miR-669c in BV2 microglial cells in order to modulate their polarization. To detect whether the modulation of microglial activation by miR-669c provides protection in a mouse model of transient focal ischemic stroke, miR-669c overexpression was driven by a lentiviral vector injected into the striatum prior to induction of ischemic stroke. RESULTS: Here, we demonstrate that miR-669c-3p, a member of chromosome 2 miRNA cluster (C2MC), is induced upon hypoxic and excitotoxic conditions in vitro and in two different in vivo models of stroke. Rather than directly regulating the neuronal survival in vitro, miR-669c is capable of attenuating the microglial proinflammatory activation in vitro and inducing the expression of microglial alternative activation markers arginase 1 (Arg1), chitinase-like 3 (Ym1), and peroxisome proliferator-activated receptor gamma (PPAR-γ). Intracerebral overexpression of miR-669c significantly decreased the ischemia-induced cell death and ameliorated the stroke-induced neurological deficits both at 1 and 3 days post injury (dpi). Albeit miR-669c overexpression failed to alter the overall Iba1 protein immunoreactivity, it significantly elevated Arg1 levels in the ischemic brain and increased colocalization of Arg1 and Iba1. Moreover, miR-669c overexpression under cerebral ischemia influenced several morphological characteristics of Iba1 positive cells. We further demonstrate the myeloid differentiation primary response gene 88 (MyD88) transcript as a direct target for miR-669c-3p in vitro and show reduced levels of MyD88 in miR-669c overexpressing ischemic brains in vivo. CONCLUSIONS: Collectively, our data provide the evidence that miR-669c-3p is protective in a mouse model of ischemic stroke through enhancement of the alternative microglial/macrophage activation and inhibition of MyD88 signaling. Our results accentuate the importance of controlling miRNA-regulated responses for the therapeutic benefit in conditions of stroke and neuroinflammation.


Assuntos
Ventrículos Cerebrais/metabolismo , AVC Isquêmico/metabolismo , Ativação de Macrófagos/fisiologia , Macrófagos/metabolismo , MicroRNAs/metabolismo , Microglia/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , AVC Isquêmico/genética , Camundongos , MicroRNAs/genética , Neurônios/metabolismo , Transdução de Sinais/fisiologia
10.
Vet Comp Oncol ; 18(4): 645-655, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32154977

RESUMO

Marginal zone lymphoma (MZL) and follicular lymphoma (FL) are classified as indolent B-cell lymphomas in dogs. Aside from the clinical and histopathological similarities with the human counterpart, the molecular pathogenesis remains unclear. We integrated transcriptome, genome-wide DNA methylation and copy number aberration analysis to provide insights on the pathogenesis of canine MZL (n = 5) and FL (n = 7), also comparing them with diffuse large B-cell lymphoma (DLBCL). Transcriptome profiling highlighted the presence of similar biological processes affecting both histotypes, including BCR and TLR signalling pathways. However, FLs showed an enrichment of E2F targets, whereas MZLs were characterized by MYC-driven transcriptional activation signatures. FLs showed a distinctive loss on chr1 containing CEACAM23 and 24, conversely MZLs presented multiple recurrent gains on chr13, where MYC is located. The distribution of methylation peaks was similar between the two histotypes. Integrating data from the three omics, FLs resulted clearly separated from MZLs and DLBCL dataset. MZLs showed the enrichment of FoxM1 network and TLR associated TICAM1-dependent IRFs activation pathway. However, no specific signatures differentiated MZLs from DLBCLs. In conclusion, our study presents the first comprehensive analysis of molecular and epigenetic pathogenesis of canine FL and MZL.


Assuntos
Aberrações Cromossômicas/veterinária , Doenças do Cão/genética , Linfoma de Zona Marginal Tipo Células B/veterinária , Linfoma Folicular/veterinária , Linfoma Difuso de Grandes Células B/veterinária , Animais , Variações do Número de Cópias de DNA , Doenças do Cão/patologia , Cães , Epigênese Genética , Itália , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Folicular/genética , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Metanfetamina/análogos & derivados , Transcriptoma
11.
Bioinformatics ; 36(7): 2001-2008, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31764961

RESUMO

MOTIVATION: Clustered regularly interspaced short palindromic repeats (CRISPR) technologies allow for facile genomic modification in a site-specific manner. A key step in this process is the in silico design of single guide RNAs to efficiently and specifically target a site of interest. To this end, it is necessary to enumerate all potential off-target sites within a given genome that could be inadvertently altered by nuclease-mediated cleavage. Currently available software for this task is limited by computational efficiency, variant support or annotation, and assessment of the functional impact of potential off-target effects. RESULTS: To overcome these limitations, we have developed CRISPRitz, a suite of software tools to support the design and analysis of CRISPR/CRISPR-associated (Cas) experiments. Using efficient data structures combined with parallel computation, we offer a rapid, reliable, and exhaustive search mechanism to enumerate a comprehensive list of putative off-target sites. As proof-of-principle, we performed a head-to-head comparison with other available tools on several datasets. This analysis highlighted the unique features and superior computational performance of CRISPRitz including support for genomic searching with DNA/RNA bulges and mismatches of arbitrary size as specified by the user as well as consideration of genetic variants (variant-aware). In addition, graphical reports are offered for coding and non-coding regions that annotate the potential impact of putative off-target sites that lie within regions of functional genomic annotation (e.g. insulator and chromatin accessible sites from the ENCyclopedia Of DNA Elements [ENCODE] project). AVAILABILITY AND IMPLEMENTATION: The software is freely available at: https://github.com/pinellolab/CRISPRitzhttps://github.com/InfOmics/CRISPRitz. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Edição de Genes , Sistemas CRISPR-Cas , RNA Guia , Software
12.
F1000Res ; 9: 1239, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33628435

RESUMO

Patient classification based on clinical and genomic data will further the goal of precision medicine. Interpretability is of particular relevance for models based on genomic data, where sample sizes are relatively small (in the hundreds), increasing overfitting risk netDx is a machine learning method to integrate multi-modal patient data and build a patient classifier. Patient data are converted into networks of patient similarity, which is intuitive to clinicians who also use patient similarity for medical diagnosis. Features passing selection are integrated, and new patients are assigned to the class with the greatest profile similarity. netDx has excellent performance, outperforming most machine-learning methods in binary cancer survival prediction. It handles missing data - a common problem in real-world data - without requiring imputation. netDx also has excellent interpretability, with native support to group genes into pathways for mechanistic insight into predictive features. The netDx Bioconductor package provides multiple workflows for users to build custom patient classifiers. It provides turnkey functions for one-step predictor generation from multi-modal data, including feature selection over multiple train/test data splits. Workflows offer versatility with custom feature design, choice of similarity metric; speed is improved by parallel execution. Built-in functions and examples allow users to compute model performance metrics such as AUROC, AUPR, and accuracy. netDx uses RCy3 to visualize top-scoring pathways and the final integrated patient network in Cytoscape. Advanced users can build more complex predictor designs with functional building blocks used in the default design. Finally, the netDx Bioconductor package provides a novel workflow for pathway-based patient classification from sparse genetic data.


Assuntos
Genômica , Software , Humanos , Aprendizado de Máquina , Medicina de Precisão , Fluxo de Trabalho
13.
Noncoding RNA ; 5(3)2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31546795

RESUMO

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL) and follicular lymphoma (FL) are the most common B-cell lymphomas (BCL) in dogs. Recent investigations have demonstrated overlaps of these histotypes with the human counterparts, including clinical presentation, biologic behavior, tumor genetics, and treatment response. The molecular mechanisms that underlie canine BCL are still unknown and new studies to improve diagnosis, therapy, and the utilization of canine species as spontaneous animal tumor models are undeniably needed. Recent work using human DLBCL transcriptomes has suggested that long non-coding RNAs (lncRNAs) play a key role in lymphoma pathogenesis and pinpointed a restricted number of lncRNAs as potential targets for further studies. RESULTS: To expand the knowledge of non-coding molecules involved in canine BCL, we used transcriptomes obtained from a cohort of 62 dogs with newly-diagnosed multicentric DLBCL, MZL and FL that had undergone complete staging work-up and were treated with chemotherapy or chemo-immunotherapy. We developed a customized R pipeline performing a transcriptome assembly by multiple algorithms to uncover novel lncRNAs, and delineate genome-wide expression of unannotated and annotated lncRNAs. Our pipeline also included a new package for high performance system biology analysis, which detects high-scoring network biological neighborhoods to identify functional modules. Moreover, our customized pipeline quantified the expression of novel and annotated lncRNAs, allowing us to subtype DLBCLs into two main groups. The DLBCL subtypes showed statistically different survivals, indicating the potential use of lncRNAs as prognostic biomarkers in future studies. CONCLUSIONS: In this manuscript, we describe the methodology used to identify lncRNAs that differentiate B-cell lymphoma subtypes and we interpreted the biological and clinical values of the results. We inferred the potential functions of lncRNAs to obtain a comprehensive and integrative insight that highlights their impact in this neoplasm.

14.
Stem Cell Reports ; 13(4): 669-683, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31522977

RESUMO

Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Apolipoproteína E4/genética , Diferenciação Celular/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Microglia/metabolismo , Fenótipo , Presenilina-1/genética , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Apolipoproteína E4/metabolismo , Cálcio/metabolismo , Células Cultivadas , Quimiocinas/metabolismo , Citocinas/metabolismo , Hematopoese , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Mediadores da Inflamação/metabolismo , Microglia/citologia , Mutação , Fagocitose , Presenilina-1/metabolismo , Proteólise
15.
J Immunother Cancer ; 7(1): 255, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533831

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with an overall 5-year survival rate of less than 8%. New evidence indicates that PDAC cells release pro-inflammatory metabolites that induce a marked alteration of normal hematopoiesis, favoring the expansion and accumulation of myeloid-derived suppressor cells (MDSCs). We report here that PDAC patients show increased levels of both circulating and tumor-infiltrating MDSC-like cells. METHODS: The frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in three independent cohorts of PDAC patients (total analyzed patients, n = 117). Frequency of circulating MDSCs was correlated with overall survival of PDAC patients. We also analyzed the frequency of tumor-infiltrating MDSC and the immune landscape in fresh biopsies. Purified myeloid cell subsets were tested in vitro for their T-cell suppressive capacity. RESULTS: Correlation with clinical data revealed that MDSC frequency was significantly associated with a shorter patients' overall survival and metastatic disease. However, the immunosuppressive activity of purified MDSCs was detectable only in some patients and mainly limited to the monocytic subset. A transcriptome analysis of the immunosuppressive M-MDSCs highlighted a distinct gene signature in which STAT3 was crucial for monocyte re-programming. Suppressive M-MDSCs can be characterized as circulating STAT3/arginase1-expressing CD14+ cells. CONCLUSION: MDSC analysis aids in defining the immune landscape of PDAC patients for a more appropriate diagnosis, stratification and treatment.


Assuntos
Carcinoma Ductal Pancreático/imunologia , Células Supressoras Mieloides/imunologia , Neoplasias Pancreáticas/imunologia , Fator de Transcrição STAT3/metabolismo , Evasão Tumoral , Idoso , Idoso de 80 Anos ou mais , Arginase/imunologia , Arginase/metabolismo , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Separação Celular , Células Cultivadas , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Receptores de Lipopolissacarídeos/imunologia , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Células Supressoras Mieloides/metabolismo , Pâncreas/imunologia , Pâncreas/patologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Cultura Primária de Células , Prognóstico , Estudos Prospectivos , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/imunologia , Análise de Sobrevida , Microambiente Tumoral/imunologia
16.
Methods Mol Biol ; 1970: 121-167, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30963492

RESUMO

This chapter is devoted to illustrate the usage of state-of-the-art methodologies for miRNA regulatory network construction and analysis. Advantages in understanding the role of miRNAs in regulating gene expression are increasing the possibility of developing targeted therapies and drugs. This new possibility can be exploited by gaining new knowledge through analyzing interactions between a specific miRNA and a targeted gene.


Assuntos
Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , MicroRNAs/genética , RNA Mensageiro/genética , Software , Regulação da Expressão Gênica , Humanos , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo
17.
BMC Bioinformatics ; 20(Suppl 4): 125, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30999855

RESUMO

The 17th International NETTAB workshop was held in Palermo, Italy, on October 16-18, 2017. The special topic for the meeting was "Methods, tools and platforms for Personalised Medicine in the Big Data Era", but the traditional topics of the meeting series were also included in the event. About 40 scientific contributions were presented, including four keynote lectures, five guest lectures, and many oral communications and posters. Also, three tutorials were organised before and after the workshop. Full papers from some of the best works presented in Palermo were submitted for this Supplement of BMC Bioinformatics. Here, we provide an overview of meeting aims and scope. We also shortly introduce selected papers that have been accepted for publication in this Supplement, for a complete presentation of the outcomes of the meeting.


Assuntos
Biologia Computacional/métodos , Atenção à Saúde , Genômica , Humanos , Itália , Neoplasias/genética , Medicina de Precisão
18.
Front Immunol ; 10: 446, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30915084

RESUMO

Mesenchymal stromal cells (MSCs) are adult, multipotent cells of mesodermal origin representing the progenitors of all stromal tissues. MSCs possess significant and broad immunomodulatory functions affecting both adaptive and innate immune responses once MSCs are primed by the inflammatory microenvironment. Recently, the role of extracellular vesicles (EVs) in mediating the therapeutic effects of MSCs has been recognized. Nevertheless, the molecular mechanisms responsible for the immunomodulatory properties of MSC-derived EVs (MSC-EVs) are still poorly characterized. Therefore, we carried out a molecular characterization of MSC-EV content by high-throughput approaches. We analyzed miRNA and protein expression profile in cellular and vesicular compartments both in normal and inflammatory conditions. We found several proteins and miRNAs involved in immunological processes, such as MOES, LG3BP, PTX3, and S10A6 proteins, miR-155-5p, and miR-497-5p. Different in silico approaches were also performed to correlate miRNA and protein expression profile and then to evaluate the putative molecules or pathways involved in immunoregulatory properties mediated by MSC-EVs. PI3K-AKT signaling pathway and the regulation of actin cytoskeleton were identified and functionally validated in vitro as key mediators of MSC/B cell communication mediated by MSC-EVs. In conclusion, we identified different molecules and pathways responsible for immunoregulatory properties mediated by MSC-EVs, thus identifying novel therapeutic targets as safer and more useful alternatives to cell or EV-based therapeutic approaches.


Assuntos
Citoesqueleto de Actina/metabolismo , Linfócitos B/imunologia , Vesículas Extracelulares/metabolismo , Imunomodulação/imunologia , Células-Tronco Mesenquimais/metabolismo , Transdução de Sinais/fisiologia , Células Cultivadas , Perfilação da Expressão Gênica , Humanos , MicroRNAs/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteoma/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo
19.
Interdiscip Sci ; 11(1): 21-32, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30790228

RESUMO

Many scientific applications entail solving the subgraph isomorphism problem, i.e., given an input pattern graph, find all the subgraphs of a (usually much larger) target graph that are structurally equivalent to that input. Because subgraph isomorphism is NP-complete, methods to solve it have to use heuristics. This work evaluates subgraph isomorphism methods to assess their computational behavior on a wide range of synthetic and real graphs. Surprisingly, our experiments show that, among the leading algorithms, certain heuristics based only on pattern graphs are the most efficient.


Assuntos
Algoritmos , Biologia Computacional/métodos , Heurística Computacional , Humanos , Software
20.
J Neuroimaging ; 29(3): 383-393, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30714241

RESUMO

BACKGROUND AND PURPOSE: While AD can be definitively confirmed by postmortem histopathologic examination, in vivo imaging may improve the clinician's ability to identify AD at the earliest stage. The aim of the study was to test the performance of amyloid PET using new processing imaging algorithm for more precise diagnosis of AD. METHODS: Amyloid PET results using a new processing imaging algorithm (MRI-Less and AAL Atlas) were correlated with clinical, cognitive status, CSF analysis, and other imaging. The regional SUVR using the white matter of cerebellum as reference region and scores from clinical and cognitive tests were used to create ROC curves. Leave-one-out cross-validation was carried out to validate the results. RESULTS: Forty-four consecutive patients with clinical evidence of dementia, were retrospectively evaluated. Amyloid PET scan was positive in 26/44 patients with dementia. After integration with 18F-FDG PET, clinical data and CSF protein levels, 22 of them were classified as AD, the remaining 4 as vascular or frontotemporal dementia. Amyloid and FDG PET, CDR 1, CSF Tau, and p-tau levels showed the best true positive and true negative rates (amyloid PET: AUC = .85, sensitivity .91, specificity .79). A SUVR value of 1.006 in the inferior frontal cortex and of 1.03 in the precuneus region was the best cutoff SUVR value and showed a good correlation with the diagnosis of AD. Thirteen of 44 amyloid PET positive patients have been enrolled in clinical trials using antiamyloid approaches. CONCLUSIONS: Amyloid PET using SPM-normalized SUVR analysis showed high predictive power for the differential diagnosis of AD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Estilbenos , Idoso , Doença de Alzheimer/patologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética , Masculino , Estudos Retrospectivos , Sensibilidade e Especificidade
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