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1.
BMC Genomics ; 25(1): 955, 2024 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-39402493

RESUMO

BACKGROUND: Archaea and Bacteria are distinct domains of life that are adapted to a variety of ecological niches. Several genome-based methods have been developed for their accurate classification, yet many aspects of the specific genomic features that determine these differences are not fully understood. In this study, we used publicly available whole-genome sequences from bacteria ( N = 2546 ) and archaea ( N = 109 ). From these, a set of genomic features (nucleotide frequencies and proportions, coding sequences (CDS), non-coding, ribosomal and transfer RNA genes (ncRNA, rRNA, tRNA), Chargaff's, topological entropy and Shannon's entropy scores) was extracted and used as input data to develop machine learning models for the classification of archaea and bacteria. RESULTS: The classification accuracy ranged from 0.993 (Random Forest) to 0.998 (Neural Networks). Over the four models, only 11 examples were misclassified, especially those belonging to the minority class (Archaea). From variable importance, tRNA topological and Shannon's entropy, nucleotide frequencies in tRNA, rRNA and ncRNA, CDS, tRNA and rRNA Chargaff's scores have emerged as the top discriminating factors. In particular, tRNA entropy (both topological and Shannon's) was the most important genomic feature for classification, pointing at the complex interactions between the genetic code, tRNAs and the translational machinery. CONCLUSIONS: tRNA, rRNA and ncRNA genes emerged as the key genomic elements that underpin the classification of archaea and bacteria. In particular, higher nucleotide diversity was found in tRNA from bacteria compared to archaea. The analysis of the few classification errors reflects the complex phylogenetic relationships between bacteria, archaea and eukaryotes.


Assuntos
Archaea , Bactérias , Genoma Arqueal , Genômica , Aprendizado de Máquina , Archaea/genética , Archaea/classificação , Bactérias/genética , Bactérias/classificação , Genômica/métodos , Genoma Bacteriano , RNA de Transferência/genética , Filogenia
2.
J Cell Biochem ; 125(5): e30557, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38501160

RESUMO

Over recent years, the investigation of transposable elements (TEs) has granted researchers a deeper comprehension of their characteristics and functions, particularly regarding their significance in the mechanisms contributing to cancer development. This manuscript focuses on prostate carcinoma cell lines and offers a comprehensive review intended to scrutinize the associations and interactions between TEs and genes, as well as their response to treatment using various chemical drugs, emphasizing their involvement in cancer progression. We assembled a compendium of articles retrieved from the PubMed database to construct networks demonstrating correlations with genes and pharmaceuticals. In doing so, we linked the transposition of certain TE types to the expression of specific transcripts directly implicated in carcinogenesis. Additionally, we underline that treatment employing different drugs revealed unique patterns of TE reactivation. Our hypothesis gathers the current understanding and guides research toward evidence-based investigations, emphasizing the association between antiviral drugs, chemotherapy, and the reduced expression of TEs in patients affected by prostate cancer.


Assuntos
Elementos de DNA Transponíveis , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata , Humanos , Neoplasias da Próstata/genética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Masculino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral
3.
Int J Mol Sci ; 25(11)2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38892374

RESUMO

Melanoma is the fifth most common cancer in the United States. Conventional drug discovery methods are inherently time-consuming and costly, which imposes significant limitations. However, the advent of Artificial Intelligence (AI) has opened up new possibilities for simulating and evaluating numerous drug candidates, thereby mitigating the requisite time and resources. In this context, normalizing flow models by employing machine learning techniques to create new molecular structures holds promise for accelerating the discovery of effective anticancer therapies. This manuscript introduces TumFlow, a novel AI model designed to generate new molecular entities with potential therapeutic value in cancer treatment. It has been trained on the NCI-60 dataset, encompassing thousands of molecules tested across 60 tumour cell lines, with an emphasis on the melanoma SK-MEL-28 cell line. The model successfully generated new molecules with predicted improved efficacy in inhibiting tumour growth while being synthetically feasible. This represents a significant advancement over conventional generative models, which often produce molecules that are challenging or impossible to synthesize. Furthermore, TumFlow has also been utilized to optimize molecules known for their efficacy in clinical melanoma treatments. This led to the creation of novel molecules with a predicted enhanced likelihood of effectiveness against melanoma, currently undocumented on PubChem.


Assuntos
Antineoplásicos , Inteligência Artificial , Descoberta de Drogas , Melanoma , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma/patologia , Linhagem Celular Tumoral , Descoberta de Drogas/métodos , Aprendizado de Máquina
4.
Brief Bioinform ; 22(2): 2172-2181, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-32266404

RESUMO

Most living organisms rely on double-stranded DNA (dsDNA) to store their genetic information and perpetuate themselves. This biological information has been considered as the main target of evolution. However, here we show that symmetries and patterns in the dsDNA sequence can emerge from the physical peculiarities of the dsDNA molecule itself and the maximum entropy principle alone, rather than from biological or environmental evolutionary pressure. The randomness justifies the human codon biases and context-dependent mutation patterns in human populations. Thus, the DNA 'exceptional symmetries,' emerged from the randomness, have to be taken into account when looking for the DNA encoded information. Our results suggest that the double helix energy constraints and, more generally, the physical properties of the dsDNA are the hard drivers of the overall DNA sequence architecture, whereas the selective biological processes act as soft drivers, which only under extraordinary circumstances overtake the overall entropy content of the genome.


Assuntos
DNA/genética , Evolução Molecular , Análise de Sequência de DNA/métodos , Humanos
5.
Proc Natl Acad Sci U S A ; 117(11): 6075-6085, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123074

RESUMO

MicroRNA-31 (miR-31) is overexpressed in esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary Zn deficiency and inflammation. In a Zn deficiency-promoted rat ESCC model with miR-31 up-regulation, cancer-associated inflammation, and a high ESCC burden following N-nitrosomethylbenzylamine (NMBA) exposure, systemic antimiR-31 delivery reduced ESCC incidence from 85 to 45% (P = 0.038) and miR-31 gene knockout abrogated development of ESCC (P = 1 × 10-6). Transcriptomics, genome sequencing, and metabolomics analyses in these Zn-deficient rats revealed the molecular basis of ESCC abrogation by miR-31 knockout. Our identification of EGLN3, a known negative regulator of nuclear factor κB (NF-κB), as a direct target of miR-31 establishes a functional link between oncomiR-31, tumor suppressor target EGLN3, and up-regulated NF-κB-controlled inflammation signaling. Interaction among oncogenic miR-31, EGLN3 down-regulation, and inflammation was also documented in human ESCCs. miR-31 deletion resulted in suppression of miR-31-associated EGLN3/NF-κB-controlled inflammatory pathways. ESCC-free, Zn-deficient miR-31-/- rat esophagus displayed no genome instability and limited metabolic activity changes vs. the pronounced mutational burden and ESCC-associated metabolic changes of Zn-deficient wild-type rats. These results provide conclusive evidence that miR-31 expression is necessary for ESCC development.


Assuntos
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , MicroRNAs/metabolismo , Neoplasias Experimentais/genética , Animais , Carcinógenos/toxicidade , Linhagem Celular Tumoral , Suplementos Nutricionais , Neoplasias Esofágicas/induzido quimicamente , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/prevenção & controle , Carcinoma de Células Escamosas do Esôfago/induzido quimicamente , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/prevenção & controle , Esôfago/patologia , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , NF-kappa B/metabolismo , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/patologia , Neoplasias Experimentais/prevenção & controle , Nitrosaminas/toxicidade , Ratos , Ratos Transgênicos , Transdução de Sinais/genética , Zinco/administração & dosagem , Zinco/deficiência
6.
Proc Natl Acad Sci U S A ; 115(47): E11091-E11100, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30397150

RESUMO

Prostate cancer is a leading cause of cancer death in men over 50 years of age, and there is a characteristic marked decrease in Zn content in the malignant prostate cells. The cause and consequences of this loss have thus far been unknown. We found that in middle-aged rats a Zn-deficient diet reduces prostatic Zn levels (P = 0.025), increases cellular proliferation, and induces an inflammatory phenotype with COX-2 overexpression. This hyperplastic/inflammatory prostate has a human prostate cancer-like microRNA profile, with up-regulation of the Zn-homeostasis-regulating miR-183-96-182 cluster (fold change = 1.41-2.38; P = 0.029-0.0003) and down-regulation of the Zn importer ZIP1 (target of miR-182), leading to a reduction of prostatic Zn. This inverse relationship between miR-182 and ZIP1 also occurs in human prostate cancer tissue, which is known for Zn loss. The discovery that the Zn-depleted middle-aged rat prostate has a metabolic phenotype resembling that of human prostate cancer, with a 10-fold down-regulation of citric acid (P = 0.0003), links citrate reduction directly to prostatic Zn loss, providing the underlying mechanism linking dietary Zn deficiency with miR-183-96-182 overexpression, ZIP1 down-regulation, prostatic Zn loss, and the resultant citrate down-regulation, changes mimicking features of human prostate cancer. Thus, dietary Zn deficiency during rat middle age produces changes that mimic those of human prostate carcinoma and may increase the risk for prostate cancer, supporting the need for assessment of Zn supplementation in its prevention.


Assuntos
Adenocarcinoma/patologia , Proteínas de Transporte de Cátions/metabolismo , Próstata/patologia , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologia , Zinco/deficiência , Adenocarcinoma/genética , Animais , Proliferação de Células , Ácido Cítrico/metabolismo , Dieta , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/biossíntese , Hiperplasia Prostática/genética , Neoplasias da Próstata/genética , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Transdução de Sinais/genética , Transcrição Gênica/genética , Células Tumorais Cultivadas , Zinco/metabolismo
7.
BMC Genomics ; 21(1): 619, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912170

RESUMO

BACKGROUND: Precision medicine is a medical approach that takes into account individual genetic variability and often requires Next Generation Sequencing data in order to predict new treatments. Here we present GMIEC, Genomic Modules Identification et Characterization for genomics medicine, an application that is able to identify specific drugs at the level of single patient integrating multi-omics data such as RNA-sequencing, copy-number variation, methylation, Chromatin Immuno-Precipitation and Exome/Whole Genome sequencing. It is also possible to include clinical data related to each patient. GMIEC has been developed as a web-based R-Shiny platform and gives as output a table easy to use and explore. RESULTS: We present GMIEC, a Shiny application for genomics medicine. The tool allows the users the integration of two or more multiple omics datasets (e.g. gene-expression, copy-number), at sample level, to identify groups of genes that share common genomic and corresponding drugs. We demonstrate the characteristics of our application by using it to analyze a prostate cancer data set. CONCLUSIONS: GMIEC provides a simple interface for genomics medicine. GMIEC was develop with Shiny to provide an application that does not require advanced programming skills. GMIEC consists of three sub-application for the analysis (GMIEC-AN), the visualization (GMIEC-VIS) and the exploration of results (GMIEC-RES). GMIEC is an open source software and is available at https://github.com/guidmt/GMIEC-shiny.


Assuntos
Testes Genéticos/métodos , Genômica/métodos , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Software , Variações do Número de Cópias de DNA , Humanos , Masculino , Variantes Farmacogenômicos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , RNA-Seq/métodos
8.
J Mol Evol ; 86(5): 303-310, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29855654

RESUMO

Transposable elements (TEs) play an essential role in shaping eukaryotic genomes and generating variability. Speciation and TE activity bursts could be strongly related in mammals, in which simple gradualistic models of differentiation do not account for the currently observed species variability. In order to test this hypothesis, we designed two parameters: the Density of insertion (DI) and the Relative rate of speciation (RRS). DI is the ratio between the number of TE insertions in a genome and its size, whereas the RRS is a conditional parameter designed to identify potential speciation bursts. Thus, by analyzing TE insertions in mammals, we defined the genomes as "hot" (high DI) and "cold" (low DI). Then, comparing TE activity among 29 taxonomical families of the whole Mammalia class, 16 intra-order pairs of mammalian species, and four superorders of Eutheria, we showed that taxa with high rates of speciation are associated with "hot" genomes, whereas taxa with low ones are associated with "cold" genomes. These results suggest a remarkable correlation between TE activity and speciation, also being consistent with patterns describing variable rates of differentiation and accounting for the different time frames of the speciation bursts.


Assuntos
Elementos de DNA Transponíveis/genética , Especiação Genética , Mamíferos/genética , Animais , Extinção Biológica , Mutagênese Insercional/genética , Filogenia , Especificidade da Espécie
9.
J Mol Evol ; 86(5): 311, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29943091

RESUMO

The original version of the article unfortunately contained tagging error in Given and Surname of all the authors.

10.
Blood ; 125(18): 2865-74, 2015 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-25736310

RESUMO

Memory stem T cells (TSCM) have been proposed as key determinants of immunologic memory. However, their exact contribution to a mounting immune response, as well as the mechanisms and timing of their in vivo generation, are poorly understood. We longitudinally tracked TSCM dynamics in patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT), thereby providing novel hints on the contribution of this subset to posttransplant immune reconstitution in humans. We found that donor-derived TSCM are highly enriched early after HSCT. We showed at the antigen-specific and clonal level that TSCM lymphocytes can differentiate directly from naive precursors infused within the graft and that the extent of TSCM generation might correlate with interleukin 7 serum levels. In vivo fate mapping through T-cell receptor sequencing allowed defining the in vivo differentiation landscapes of human naive T cells, supporting the notion that progenies of single naive cells embrace disparate fates in vivo and highlighting TSCM as relevant novel players in the diversification of immunological memory after allogeneic HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Memória Imunológica , Linfopoese , Linfócitos T/imunologia , Linfócitos T/fisiologia , Adulto , Doadores de Sangue , Diferenciação Celular/imunologia , Proliferação de Células , Haplótipos , Humanos , Memória Imunológica/imunologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia , Transplante Homólogo
11.
PLoS Genet ; 9(3): e1003311, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23505378

RESUMO

MicroRNAs (miRNAs), single-stranded non-coding RNAs, influence myriad biological processes that can contribute to cancer. Although tumor-suppressive and oncogenic functions have been characterized for some miRNAs, the majority of microRNAs have not been investigated for their ability to promote and modulate tumorigenesis. Here, we established that the miR-191/425 cluster is transcriptionally dependent on the host gene, DALRD3, and that the hormone 17ß-estradiol (estrogen or E2) controls expression of both miR-191/425 and DALRD3. MiR-191/425 locus characterization revealed that the recruitment of estrogen receptor α (ERα) to the regulatory region of the miR-191/425-DALRD3 unit resulted in the accumulation of miR-191 and miR-425 and subsequent decrease in DALRD3 expression levels. We demonstrated that miR-191 protects ERα positive breast cancer cells from hormone starvation-induced apoptosis through the suppression of tumor-suppressor EGR1. Furthermore, enforced expression of the miR-191/425 cluster in aggressive breast cancer cells altered global gene expression profiles and enabled us to identify important tumor promoting genes, including SATB1, CCND2, and FSCN1, as targets of miR-191 and miR-425. Finally, in vitro and in vivo experiments demonstrated that miR-191 and miR-425 reduced proliferation, impaired tumorigenesis and metastasis, and increased expression of epithelial markers in aggressive breast cancer cells. Our data provide compelling evidence for the transcriptional regulation of the miR-191/425 cluster and for its context-specific biological determinants in breast cancers. Importantly, we demonstrated that the miR-191/425 cluster, by reducing the expression of an extensive network of genes, has a fundamental impact on cancer initiation and progression of breast cancer cells.


Assuntos
Neoplasias da Mama , Proteína 1 de Resposta de Crescimento Precoce , Receptor alfa de Estrogênio , MicroRNAs , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Estrogênios , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo
12.
BMC Med Genet ; 16: 46, 2015 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-26138095

RESUMO

BACKGROUND: P19 H-Ras, a second product derived from the H-Ras gene by alternative splicing, induces a G1/S phase delay, thereby maintaining cells in a reversible quiescence state. When P21 H-Ras is mutated in tumour cells, the alternative protein P19 H-Ras is also mutated. The H-Ras mutation Q61L is frequently detected in different tumours, which acts as constitutive activator of Ras functions and is considered to be a strong activating mutant. Additionally, a rare congenital disorder named Costello Syndrome, is described as a H-Ras disorder in children, mainly due to mutation G12S in p19 and p21 H-Ras proteins, which is present in 90 % of the Costello Syndrome patients. Our aim is to better understand the role of p19 and p21 H-Ras proteins in the cancer and Costello Syndrome development, concerning the miRNAs expression. METHODS: Total miRNAs expression regulated by H-Ras proteins were first analyzed in human miRNA microarrays assays. Previously selected miRNAs, were further analyzed in developed cell lines containing H-Ras protein mutants, that included the G12S Costello Syndrome mutant, with PCR Real-Time Taq Man miRNA Assays primers. RESULTS: This study describes how p19 affects the RNA world and shows that: i) miR-342, miR-206, miR-330, miR-138 and miR-99b are upregulated by p19 but not by p19W164A mutant; ii) anti-miR-206 can restore the G2 phase in the presence of p19; iii) p19 and p21Q61L regulate their own alternative splicing; iv) miR-206 and miR-138 are differentially regulated by p19 and p21 H-Ras and v) P19G12S Costello mutants show a clear upregulation of miR-374, miR-126, miR-342, miR-330, miR-335 and let-7. CONCLUSIONS: These results allow us to conclude that the H-Ras G12S mutation plays an important role in miRNA expression and open up a new line of study to understand the consequences of this mutation on Costello syndrome. Furthermore, they suggest that oncogenes may have a sufficiently important impact on miRNA expression to promote the development of numerous cancers.


Assuntos
Síndrome de Costello/genética , Síndrome de Costello/patologia , MicroRNAs/genética , Neoplasias/genética , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Proteínas ras/fisiologia , Animais , Transformação Celular Neoplásica/genética , Células Cultivadas , Embrião de Mamíferos , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Camundongos , Modelos Biológicos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Neoplasias/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas ras/genética
13.
Cancer Cell ; 12(3): 215-29, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17785203

RESUMO

Noncoding RNA (ncRNA) transcripts are thought to be involved in human tumorigenesis. We report that a large fraction of genomic ultraconserved regions (UCRs) encode a particular set of ncRNAs whose expression is altered in human cancers. Genome-wide profiling revealed that UCRs have distinct signatures in human leukemias and carcinomas. UCRs are frequently located at fragile sites and genomic regions involved in cancers. We identified certain UCRs whose expression may be regulated by microRNAs abnormally expressed in human chronic lymphocytic leukemia, and we proved that the inhibition of an overexpressed UCR induces apoptosis in colon cancer cells. Our findings argue that ncRNAs and interaction between noncoding genes are involved in tumorigenesis to a greater extent than previously thought.


Assuntos
Carcinoma/genética , Leucemia/genética , RNA não Traduzido/química , Sequência de Bases , Análise por Conglomerados , Sequência Conservada , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/fisiologia , Dados de Sequência Molecular , Oncogenes/fisiologia , Análise de Sequência de RNA
14.
J Mol Biol ; 436(10): 168569, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38604527

RESUMO

Transglutaminase 2 (TG2) performs many functions both under physiological and pathological conditions. In cancer, its expression is associated with aggressiveness, propensity to epithelial-mesenchymal transition, and metastasis. Since TG2 performs key functions both outside and inside the cell, using inhibitors with different membrane permeability we analyzed the changes in the transcriptome induced in two triple-negative cell lines (MDA-MB-436 and MDA-MB-231) with aggressive features. By characterizing pathways and gene networks, we were able to define the effects of TG2 inhibitors (AA9, membrane-permeable, and NCEG2, impermeable) in relation to the roles of the enzyme in the intra- and extracellular space within the context of breast cancer. The deregulated genes revealed p53 and integrin signaling to be the common pathways with some genes showing opposite changes in expression. In MDA-MB-436, AA9 induced apoptosis, modulated cadherin, Wnt, gastrin and cholecystokinin receptors (CCKR) mediated signaling, with RHOB and GNG2 playing significant roles, and affected the Warburg effect by decreasing glycolytic enzymes. In MDA-MB-231 cells, AA9 strongly impacted HIF-mediated hypoxia, including AKT and mTOR pathway. These effects suggest an anti-tumor activity by blocking intracellular TG2 functions. Conversely, the use of NCEG2 stimulated the expression of ATP synthase and proteins involved in DNA replication, indicating a potential promotion of cell proliferation through inhibition of extracellular TG2. To effectively utilize these molecules as an anti-tumor strategy, an appropriate delivery system should be evaluated to target specific functions and avoid adverse effects. Additionally, considering combinations with other pathway modulators is crucial.


Assuntos
Inibidores Enzimáticos , Proteína 2 Glutamina gama-Glutamiltransferase , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Ligação ao GTP/antagonistas & inibidores , Proteínas de Ligação ao GTP/metabolismo , Proteína 2 Glutamina gama-Glutamiltransferase/antagonistas & inibidores , Proteína 2 Glutamina gama-Glutamiltransferase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/enzimologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
15.
Genome Res ; 20(5): 589-99, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20439436

RESUMO

We studied miRNA profiles in 4419 human samples (3312 neoplastic, 1107 nonmalignant), corresponding to 50 normal tissues and 51 cancer types. The complexity of our database enabled us to perform a detailed analysis of microRNA (miRNA) activities. We inferred genetic networks from miRNA expression in normal tissues and cancer. We also built, for the first time, specialized miRNA networks for solid tumors and leukemias. Nonmalignant tissues and cancer networks displayed a change in hubs, the most connected miRNAs. hsa-miR-103/106 were downgraded in cancer, whereas hsa-miR-30 became most prominent. Cancer networks appeared as built from disjointed subnetworks, as opposed to normal tissues. A comparison of these nets allowed us to identify key miRNA cliques in cancer. We also investigated miRNA copy number alterations in 744 cancer samples, at a resolution of 150 kb. Members of miRNA families should be similarly deleted or amplified, since they repress the same cellular targets and are thus expected to have similar impacts on oncogenesis. We correctly identified hsa-miR-17/92 family as amplified and the hsa-miR-143/145 cluster as deleted. Other miRNAs, such as hsa-miR-30 and hsa-miR-204, were found to be physically altered at the DNA copy number level as well. By combining differential expression, genetic networks, and DNA copy number alterations, we confirmed, or discovered, miRNAs with comprehensive roles in cancer. Finally, we experimentally validated the miRNA network with acute lymphocytic leukemia originated in Mir155 transgenic mice. Most of miRNAs deregulated in these transgenic mice were located close to hsa-miR-155 in the cancer network.


Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Leucemia , MicroRNAs/genética , Neoplasias , Adenocarcinoma/metabolismo , Animais , Linhagem Celular Tumoral , Dosagem de Genes , Humanos , Leucemia/genética , Leucemia/metabolismo , Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , Camundongos , MicroRNAs/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
16.
Blood ; 118(11): 3072-9, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21636858

RESUMO

MicroRNAs play a crucial role in chronic lymphocytic leukemia. We investigated whether microRNAs can discriminate patients with a progressive disease from patients with a stable disease. We analyzed microRNA expression on leukemic cells isolated from 358 sequential samples of 114 patients with either stable or progressive disease. We found that during the course of the disease the expression values of miR-181b, the most dysregulated microRNA, decreased in samples of patients with a progressive (P < .001, training and validation sets) but not in samples of patients with a stable disease (P = .3, training set; P = .2, validation set) over time. A drop of ≥ 50% between sequential samples and/or a miR-181b value ≤ 0.005 at the starting time point were significant to differentiate progressive from stable disease (P = .004, training set; P < .001, validation set). These parameters were associated with high risk of requiring treatment (risk ratio, 5.8; 95% confidence interval, 2.5-14.9). We also observed that miR-181b targets Mcl-1 protein and that the decrease of its expression inversely correlated with increased protein levels of MCL1 and BCL2 target genes. We conclude that parameters defined on the basis of the miR-181b expression values specify disease progression in chronic lymphocytic leukemia and are associated with clinical outcome.


Assuntos
Leucemia Linfocítica Crônica de Células B/genética , MicroRNAs/fisiologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/fisiologia , Estudos de Coortes , Progressão da Doença , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Células HeLa , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Análise em Microsséries , Prognóstico , Estudos de Validação como Assunto
17.
Sci Rep ; 13(1): 9039, 2023 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-37270634

RESUMO

The presence in nature of species showing drastic differences in lifespan and cancer incidence has recently increased the interest of the scientific community. In particular, the adaptations and the genomic features underlying the evolution of cancer-resistant and long-lived organisms have recently focused on transposable elements (TEs). In this study, we compared the content and dynamics of TE activity in the genomes of four rodent and six bat species exhibiting different lifespans and cancer susceptibility. Mouse, rat, and guinea pig genomes (short-lived and cancer-prone organisms) were compared with that of naked mole rat (Heterocephalus glaber) which is a cancer-resistant organism and the rodent with the longest lifespan. The long-lived bats of the genera Myotis, Rhinolophus, Pteropus and Rousettus were instead compared with Molossus molossus, which is one of the organisms with the shortest lifespan among the order Chiroptera. Despite previous hypotheses stating a substantial tolerance of TEs in bats, we found that long-lived bats and the naked mole rat share a marked decrease of non-LTR retrotransposons (LINEs and SINEs) accumulation in recent evolutionary times.


Assuntos
Quirópteros , Neoplasias , Animais , Cobaias , Camundongos , Quirópteros/genética , Retroelementos/genética , Incidência , Envelhecimento , Ratos-Toupeira/genética , Neoplasias/epidemiologia , Neoplasias/genética , Neoplasias/veterinária
18.
Animals (Basel) ; 13(11)2023 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-37889789

RESUMO

The accurate detection of behavioural changes represents a promising method of detecting the early onset of disease in dairy cows. This study assessed the performance of deep learning (DL) in classifying dairy cows' behaviour from accelerometry data acquired by single sensors on the cows' left flanks and compared the results with those obtained through classical machine learning (ML) from the same raw data. Twelve cows with a tri-axial accelerometer were observed for 136 ± 29 min each to detect five main behaviours: standing still, moving, feeding, ruminating and resting. For each 8 s time interval, 15 metrics were calculated, obtaining a dataset of 211,720 observation units and 15 columns. The entire dataset was randomly split into training (80%) and testing (20%) datasets. The DL accuracy, precision and sensitivity/recall were calculated and compared with the performance of classical ML models. The best predictive model was an 8-layer convolutional neural network (CNN) with an overall accuracy and F1 score equal to 0.96. The precision, sensitivity/recall and F1 score of single behaviours had the following ranges: 0.93-0.99. The CNN outperformed all the classical ML algorithms. The CNN used to monitor the cows' conditions showed an overall high performance in successfully predicting multiple behaviours using a single accelerometer.

19.
Animals (Basel) ; 13(9)2023 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-37174547

RESUMO

The present research was conducted to determine the optimal inclusion level of full-fat silkworm chrysalis meal (SWM) into laying quails' diets, focusing on performance traits and egg physical quality. A total of 240 31-day-old female Japanese quails were randomly assigned to four dietary groups (12 replicates/treatment; 5 quails/replicate); quails were initially fed a standard commercial diet for pullets until 63 days of age. When oviposition started, the experimental groups received the following diets: a conventional corn and soybean-based diet (control diet-C) and three other diets, including 4%, 8%, or 12% of full-fat SWM (SWM4, SWM8, SWM12, respectively). Experimental diets were provided until quails reached 119 days of age. Birds displayed satisfactory productive performance throughout the trial. SWM12 and SWM8 had higher (p < 0.001) egg production but also a higher feed conversion ratio compared to C. At the end of the trial, the eggs edible portion increased, and shell weight decreased with increasing the SWM dietary inclusion level (p < 0.001). At the same time, SWM12 displayed an increase in albumen pH (p < 0.05), even though in the normal range for quail egg. Overall, full-fat SWM (up to 12%) can be considered a promising feed ingredient for laying quails, although higher inclusion levels (>8%) require special attention because SWM also contains anti-nutritional factors.

20.
FEBS J ; 290(22): 5411-5433, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37597264

RESUMO

Transglutaminase 2 (TG2), which mediates post-translational modifications of multiple intracellular enzymes, is involved in the pathogenesis and progression of cancer. We used 1 H-NMR metabolomics to study the effects of AA9, a novel TG2 inhibitor, on two breast cancer cell lines with distinct phenotypes, MCF-7 and MDA-MB-231. AA9 can promote apoptosis in both cell lines, but it is particularly effective in MD-MB-231, inhibiting transamidation reactions and decreasing cell migration and invasiveness. This metabolomics study provides evidence of a major effect of AA9 on MDA-MB-231 cells, impacting glutamate and aspartate metabolism, rather than on MCF-7 cells, characterised by choline and O-phosphocholine decrease. Interestingly, AA9 treatment induces myo-inositol alteration in both cell lines, indicating action on phosphatidylinositol metabolism, likely modulated by the G protein activity of TG2 on phospholipase C. Considering the metabolic deregulations that characterise various breast cancer subtypes, the existence of a metabolic pathway affected by AA9 further points to TG2 as a promising hot spot. The metabolomics approach provides a powerful tool to monitor the effectiveness of inhibitors and better understand the role of TG2 in cancer.


Assuntos
Neoplasias da Mama , Proteína 2 Glutamina gama-Glutamiltransferase , Humanos , Feminino , Neoplasias da Mama/metabolismo , Células MCF-7 , Apoptose , Metabolômica , Linhagem Celular Tumoral , Transglutaminases/metabolismo
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