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1.
Cell ; 162(4): 727-37, 2015 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-26276629

RESUMEN

Chronic infection with Plasmodium falciparum was epidemiologically associated with endemic Burkitt's lymphoma, a mature B cell cancer characterized by chromosome translocation between the c-myc oncogene and Igh, over 50 years ago. Whether infection promotes B cell lymphoma, and if so by which mechanism, remains unknown. To investigate the relationship between parasitic disease and lymphomagenesis, we used Plasmodium chabaudi (Pc) to produce chronic malaria infection in mice. Pc induces prolonged expansion of germinal centers (GCs), unique compartments in which B cells undergo rapid clonal expansion and express activation-induced cytidine deaminase (AID), a DNA mutator. GC B cells elicited during Pc infection suffer widespread DNA damage, leading to chromosome translocations. Although infection does not change the overall rate, it modifies lymphomagenesis to favor mature B cell lymphomas that are AID dependent and show chromosome translocations. Thus, malaria infection favors mature B cell cancers by eliciting protracted AID expression in GC B cells. PAPERCLIP.


Asunto(s)
Inestabilidad Genómica , Linfoma de Células B/genética , Malaria/complicaciones , Malaria/genética , Plasmodium chabaudi/fisiología , Animales , Linfocitos B/patología , Enfermedad Crónica , Citidina Desaminasa/metabolismo , Replicación del ADN , Genes p53 , Centro Germinal/parasitología , Malaria/parasitología , Malaria/patología , Ratones , Translocación Genética
2.
Cell ; 160(3): 420-32, 2015 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-25635456

RESUMEN

The barrier to curing HIV-1 is thought to reside primarily in CD4(+) T cells containing silent proviruses. To characterize these latently infected cells, we studied the integration profile of HIV-1 in viremic progressors, individuals receiving antiretroviral therapy, and viremic controllers. Clonally expanded T cells represented the majority of all integrations and increased during therapy. However, none of the 75 expanded T cell clones assayed contained intact virus. In contrast, the cells bearing single integration events decreased in frequency over time on therapy, and the surviving cells were enriched for HIV-1 integration in silent regions of the genome. Finally, there was a strong preference for integration into, or in close proximity to, Alu repeats, which were also enriched in local hotspots for integration. The data indicate that dividing clonally expanded T cells contain defective proviruses and that the replication-competent reservoir is primarily found in CD4(+) T cells that remain relatively quiescent.


Asunto(s)
Linfocitos T CD4-Positivos/virología , Infecciones por VIH/virología , VIH-1/fisiología , Integración Viral , Latencia del Virus , Elementos Alu , Células Clonales , Virus Defectuosos/genética , Virus Defectuosos/fisiología , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Memoria Inmunológica , Provirus/fisiología , Análisis de la Célula Individual
3.
BMC Biol ; 21(1): 205, 2023 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-37784185

RESUMEN

BACKGROUND: After the eradication of smallpox in China in 1979, vaccination with the vaccinia virus (VACV) Tiantan strain for the general population was stopped in 1980. As the monkeypox virus (MPXV) is rapidly spreading in the world, we would like to investigate whether the individuals with historic VACV Tiantan strain vaccination, even after more than 40 years, could still provide ELISA reactivity and neutralizing protection; and whether the unvaccinated individuals have no antibody reactivity against MPXV at all. RESULTS: We established serologic ELISA to measure the serum anti-MPXV titer by using immunodominant MPXV surface proteins, A35R, B6R, A29L, and M1R. A small proportion of individuals (born before 1980) with historic VACV Tiantan strain vaccination exhibited serum ELISA cross-reactivity against these MPXV surface proteins. Consistently, these donors also showed ELISA seropositivity and serum neutralization against VACV Tiantan strain. However, surprisingly, some unvaccinated young adults (born after 1980) also showed potent serum ELISA activity against MPXV proteins, possibly due to their past infection by some self-limiting Orthopoxvirus (OPXV). CONCLUSIONS: We report the serum ELISA cross-reactivity against MPXV surface protein in a small proportion of individuals both with and without VACV Tiantan strain vaccination history. Combined with our serum neutralization assay against VACV and the recent literature about mice vaccinated with VACV Tiantan strain, our study confirmed the anti-MPXV cross-reactivity and cross-neutralization of smallpox vaccine using VACV Tiantan strain. Therefore, it is necessary to restart the smallpox vaccination program in high risk populations.


Asunto(s)
Reacciones Cruzadas , Monkeypox virus , Vacuna contra Viruela , Vacunación , Animales , Humanos , Ratones , Adulto Joven , Formación de Anticuerpos , Pueblos del Este de Asia , Proteínas de la Membrana , Viruela/prevención & control , Virus Vaccinia , Vacuna contra Viruela/inmunología , Vacuna contra Viruela/uso terapéutico , China
4.
Mol Cell ; 49(4): 623-31, 2013 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-23290917

RESUMEN

Deficiencies in factors that regulate the DNA damage response enhance the incidence of malignancy by destabilizing the genome. However, the precise influence of the DNA damage response on regulation of cancer-associated rearrangements is not well defined. Here we examine the genome-wide impact of tumor protein P53-binding protein 1 (53BP1) deficiency in lymphoma and translocation. While both activation-induced cytidine deaminase (AID) and 53BP1 have been associated with cancer in humans, neither AID overexpression nor loss of 53BP1 is sufficient to produce malignancy. However, the combination of 53BP1 deficiency and AID deregulation results in B cell lymphoma. Deep sequencing of the genome of 53BP1(-/-) cancer cells and translocation capture sequencing (TC-Seq) of primary 53BP1(-/-) B cells revealed that their chromosomal rearrangements differ from those found in wild-type cells in that they show increased DNA end resection. Moreover, loss of 53BP1 alters the translocatome by increasing rearrangements to intergenic regions.


Asunto(s)
Transformación Celular Neoplásica/genética , Proteínas Cromosómicas no Histona/fisiología , Citidina Desaminasa/fisiología , Proteínas de Unión al ADN/fisiología , Reordenamiento Génico , Linfoma de Células B/metabolismo , Animales , Células Cultivadas , Proteínas Cromosómicas no Histona/deficiencia , Proteínas Cromosómicas no Histona/genética , Cromosomas de los Mamíferos/genética , Citidina Desaminasa/genética , Citidina Desaminasa/metabolismo , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Epigénesis Genética , Genes Supresores de Tumor , Estudio de Asociación del Genoma Completo , Linfoma de Células B/genética , Ratones , Ratones Noqueados , Mutación , Análisis de Secuencia de ADN , Transcripción Genética , Translocación Genética , Proteína 1 de Unión al Supresor Tumoral P53
5.
Mol Cell Proteomics ; 18(10): 1950-1966, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31332097

RESUMEN

Mesenchymal stem/stromal cells (MSCs) are self-renewing multipotent cells with regenerative, secretory and immunomodulatory capabilities that are beneficial for the treatment of various diseases. To avoid the issues that come with using tissue-derived MSCs in therapy, MSCs may be generated by the differentiation of human embryonic stems cells (hESCs) in culture. However, the changes that occur during the differentiation process have not been comprehensively characterized. Here, we combined transcriptome, proteome and phosphoproteome profiling to perform an in-depth, multi-omics study of the hESCs-to-MSCs differentiation process. Based on RNA-to-protein correlation, we determined a set of high confidence genes that are important to differentiation. Among the earliest and strongest induced proteins with extensive differential phosphorylation was AHNAK, which we hypothesized to be a defining factor in MSC biology. We observed two distinct expression waves of developmental HOX genes and an AGO2-to-AGO3 switch in gene silencing. Exploring the kinetic of noncoding ORFs during differentiation, we mapped new functions to well annotated long noncoding RNAs (CARMN, MALAT, NEAT1, LINC00152) as well as new candidates which we identified to be important to the differentiation process. Phosphoproteome analysis revealed ESC and MSC-specific phosphorylation motifs with PAK2 and RAF1 as top predicted upstream kinases in MSCs. Our data represent a rich systems-level resource on ESC-to-MSC differentiation that will be useful for the study of stem cell biology.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Células Madre Embrionarias Humanas/citología , Células Madre Mesenquimatosas/citología , Proteómica/métodos , Diferenciación Celular , Células Cultivadas , Cromatografía Liquida , Regulación de la Expresión Génica , Células Madre Embrionarias Humanas/metabolismo , Humanos , Espectrometría de Masas , Células Madre Mesenquimatosas/metabolismo , Fosforilación , Mapas de Interacción de Proteínas , Análisis de Secuencia de ARN
6.
Int J Cancer ; 146(1): 181-191, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31090066

RESUMEN

Mechanisms of viral oncogenesis are diverse and include the off-target activity of enzymes expressed by the infected cells, which evolved to target viral genomes for controlling their infection. Among these enzymes, the single-strand DNA editing capability of APOBECs represent a well-conserved viral infection response that can also cause untoward mutations in the host DNA. Here we show, after evaluating somatic single-nucleotide variations and transcriptome data in 240 gastric cancer samples, a positive correlation between APOBEC3s mRNA-expression and the APOBEC-mutation signature, both increased in EBV+ tumors. The correlation was reinforced by the observation of APOBEC mutations preferentially occurring in the genomic loci of the most active transcripts. This EBV infection and APOBEC3 mutation-signature axis were confirmed in a validation cohort of 112 gastric cancer patients. Our findings suggest that APOBEC3 upregulation in EBV+ cancer may boost the mutation load, providing further clues to the mechanisms of EBV-induced gastric carcinogenesis. After further validation, this EBV-APOBEC axis may prove to be a secondary driving force in the mutational evolution of EBV+ gastric tumors, whose consequences in terms of prognosis and treatment implications should be vetted.


Asunto(s)
Citidina Desaminasa/genética , ADN de Neoplasias/genética , Herpesvirus Humano 4/patogenicidad , Neoplasias Gástricas/virología , Desaminasas APOBEC , Carcinogénesis , Genes Virales , Herpesvirus Humano 4/genética , Humanos , Mutación , Neoplasias Gástricas/patología
7.
Bioinformatics ; 33(1): 8-16, 2017 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-27591080

RESUMEN

MOTIVATION: Mutational signatures can be used to understand cancer origins and provide a unique opportunity to group tumor types that share the same origins and result from similar processes. These signatures have been identified from high throughput sequencing data generated from cancer genomes by using non-negative matrix factorisation (NMF) techniques. Current methods based on optimization techniques are strongly sensitive to initial conditions due to high dimensionality and nonconvexity of the NMF paradigm. In this context, an important question consists in the determination of the actual number of signatures that best represent the data. The extraction of mutational signatures from high-throughput data still remains a daunting task. RESULTS: Here we present a new method for the statistical estimation of mutational signatures based on an empirical Bayesian treatment of the NMF model. While requiring minimal intervention from the user, our method addresses the determination of the number of signatures directly as a model selection problem. In addition, we introduce two new concepts of significant clinical relevance for evaluating the mutational profile. The advantages brought by our approach are shown by the analysis of real and synthetic data. The later is used to compare our approach against two alternative methods mostly used in the literature and with the same NMF parametrization as the one considered here. Our approach is robust to initial conditions and more accurate than competing alternatives. It also estimates the correct number of signatures even when other methods fail. Results on real data agree well with current knowledge. AVAILABILITY AND IMPLEMENTATION: signeR is implemented in R and C ++, and is available as a R package at http://bioconductor.org/packages/signeR CONTACT: itojal@cipe.accamargo.org.brSupplementary information: Supplementary data are available at Bioinformatics online.


Asunto(s)
Análisis Mutacional de ADN/métodos , Mutación , Neoplasias/genética , Programas Informáticos , Algoritmos , Animales , Teorema de Bayes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos
8.
Proc Natl Acad Sci U S A ; 111(52): 18667-72, 2014 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-25512519

RESUMEN

Activation-induced cytidine deaminase (AID) initiates class switch recombination (CSR) and somatic hypermutation (SHM) by deaminating cytosine residues in immunoglobulin genes (Igh, Igκ, and Igλ). At a lower frequency, AID also causes collateral DNA damage at non-Ig loci, including genes that are rearranged or mutated in B-cell lymphoma. Precisely how AID is recruited to these off-target sites is not entirely understood. To gain further insight into how AID selects its targets, we compared AID-mediated translocations in two different cell types, B cells and mouse embryonic fibroblasts (MEFs). AID targets a distinct set of hotspots in the two cell types. In both cases, hotspots are concentrated in highly transcribed but stalled genes. However, transcription alone is insufficient to recruit AID activity. Comparison of genes similarly transcribed in B cells and MEFs but targeted in only one of the two cell types reveals a common set of epigenetic features associated with AID recruitment in both cells. AID target genes are enriched in chromatin modifications associated with active enhancers (such as H3K27Ac) and marks of active transcription (such as H3K36me3) in both fibroblasts and B cells, indicating that these features are universal mediators of AID recruitment.


Asunto(s)
Linfocitos B/enzimología , Citidina Desaminasa , Embrión de Mamíferos/enzimología , Epigénesis Genética , Marcación de Gen , Transcripción Genética/fisiología , Animales , Linfocitos B/citología , Línea Celular , Citidina Desaminasa/genética , Citidina Desaminasa/metabolismo , Embrión de Mamíferos/citología , Fibroblastos/citología , Fibroblastos/enzimología , Histonas/genética , Histonas/metabolismo , Inmunoglobulinas/biosíntesis , Inmunoglobulinas/genética , Ratones , Ratones Noqueados
9.
Bioinformatics ; 30(18): 2551-8, 2014 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-24860160

RESUMEN

MOTIVATION: The detection of genomic regions unusually rich in a given pattern is an important undertaking in the analysis of next-generation sequencing data. Recent studies of chromosomal translocations in activated B lymphocytes have identified regions that are frequently translocated to c-myc oncogene. A quantitative method for the identification of translocation hotspots was crucial to this study. Here we improve this analysis by using a simple probabilistic model and the framework provided by scan statistics to define the number and location of translocation breakpoint hotspots. A key feature of our method is that it provides a global chromosome-wide nominal control level to clustering, as opposed to previous methods based on local criteria. While being motivated by a specific application, the detection of unusual clusters is a widespread problem in bioinformatics. We expect our method to be useful in the analysis of data from other experimental approaches such as of ChIP-seq and 4C-seq. RESULTS: The analysis of translocations from B lymphocytes with the method described here reveals the presence of longer hotspots when compared with those defined previously. Further, we show that the hotspot size changes substantially in the absence of DNA repair protein 53BP1. When 53BP1 deficiency is combined with overexpression of activation-induced cytidine deaminase, the hotspot length increases even further. These changes are not detected by previous methods that use local significance criteria for clustering. Our method is also able to identify several exclusive translocation hotspots located in genes of known tumor supressors. AVAILABILITY AND IMPLEMENTATION: The detection of translocation hotspots is done with hot_scan, a program implemented in R and Perl. Source code and documentation are freely available for download at https://github.com/itojal/hot_scan.


Asunto(s)
Biometría/métodos , Genómica/métodos , Translocación Genética/genética , Linfocitos B/metabolismo , Puntos de Rotura del Cromosoma , Análisis por Conglomerados , Citidina Desaminasa/genética , Reparación del ADN , Secuenciación de Nucleótidos de Alto Rendimiento , Modelos Estadísticos
10.
Elife ; 122023 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-36645410

RESUMEN

Background: We have previously shown that the long non-coding (lnc)RNA prostate cancer associated 3 (PCA3; formerly prostate cancer antigen 3) functions as a trans-dominant negative oncogene by targeting the previously unrecognized prostate cancer suppressor gene PRUNE2 (a homolog of the Drosophila prune gene), thereby forming a functional unit within a unique allelic locus in human cells. Here, we investigated the PCA3/PRUNE2 regulatory axis from early (tumorigenic) to late (biochemical recurrence) genetic events during human prostate cancer progression. Methods: The reciprocal PCA3 and PRUNE2 gene expression relationship in paired prostate cancer and adjacent normal prostate was analyzed in two independent retrospective cohorts of clinically annotated cases post-radical prostatectomy: a single-institutional discovery cohort (n=107) and a multi-institutional validation cohort (n=497). We compared the tumor gene expression of PCA3 and PRUNE2 to their corresponding expression in the normal prostate. We also serially examined clinical/pathological variables including time to disease recurrence. Results: We consistently observed increased expression of PCA3 and decreased expression of PRUNE2 in prostate cancer compared with the adjacent normal prostate across all tumor grades and stages. However, there was no association between the relative gene expression levels of PCA3 or PRUNE2 and time to disease recurrence, independent of tumor grades and stages. Conclusions: We concluded that upregulation of the lncRNA PCA3 and targeted downregulation of the protein-coding PRUNE2 gene in prostate cancer could be early (rather than late) molecular events in the progression of human prostate tumorigenesis but are not associated with biochemical recurrence. Further studies of PCA3/PRUNE2 dysregulation are warranted. Funding: We received support from the Human Tissue Repository and Tissue Analysis Shared Resource from the Department of Pathology of the University of New Mexico School of Medicine and a pilot award from the University of New Mexico Comprehensive Cancer Center. RP and WA were supported by awards from the Levy-Longenbaugh Donor-Advised Fund and the Prostate Cancer Foundation. EDN reports research fellowship support from the Brazilian National Council for Scientific and Technological Development (CNPq), Brazil, and the Associação Beneficente Alzira Denise Hertzog Silva (ABADHS), Brazil. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of New Mexico Comprehensive Cancer Center (CA118100) and the Rutgers Cancer Institute of New Jersey (CA072720).


Asunto(s)
Neoplasias de la Próstata , ARN Largo no Codificante , Humanos , Masculino , Antígenos de Neoplasias/genética , Biomarcadores de Tumor/genética , Recurrencia Local de Neoplasia/genética , Próstata/metabolismo , Neoplasias de la Próstata/metabolismo , Estudios Retrospectivos , ARN Largo no Codificante/genética
11.
Mult Scler Relat Disord ; 57: 103383, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34922254

RESUMEN

Multiple Sclerosis is an autoimmune disease with an unknown etiology. Both genetic and environmental factors are believed to trigger MS autoimmunity. Among the environmental factors, infectious agents have been extensively investigated, and the Human Endogenous Retroviruses (HERVs), especially HERV-W, are believed to be associated with MS pathogenesis. HERVs are derived from ancestral infections and comprise around 8% of the human genome. Although most HERVs are silenced, retroviral genes may be expressed with virion formation. There is extensive evidence of the relationship between HERV-W and MS, including higher levels of HERV-W expression in MS patients, HERV-W protein detection in MS plaques, and the HERV-W env protein inducing an inflammatory response in in vitro and in vivo models. Here we discuss possible links of HERVs and the pathogenesis of MS and present new data regarding the diversity of HERVs expression in samples derived from MS patients.


Asunto(s)
Retrovirus Endógenos , Esclerosis Múltiple , Retrovirus Endógenos/genética , Humanos , Esclerosis Múltiple/genética , Transcriptoma
12.
Front Oncol ; 12: 809441, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35392220

RESUMEN

The clinical and pathological responses to multimodal neoadjuvant therapy in locally advanced rectal cancers (LARCs) remain unpredictable, and robust biomarkers are still lacking. Recent studies have shown that tumors present somatic molecular alterations related to better treatment response, and it is also clear that tumor-associated bacteria are modulators of chemotherapy and immunotherapy efficacy, therefore having implications for long-term survivorship and a good potential as the biomarkers of outcome. Here, we performed whole exome sequencing and 16S ribosomal RNA (rRNA) amplicon sequencing from 44 pre-treatment LARC biopsies from Argentinian and Brazilian patients, treated with neoadjuvant chemoradiotherapy or total neoadjuvant treatment, searching for predictive biomarkers of response (responders, n = 17; non-responders, n = 27). In general, the somatic landscape of LARC was not capable to predict a response; however, a significant enrichment in mutational signature SBS5 was observed in non-responders (p = 0.0021), as well as the co-occurrence of APC and FAT4 mutations (p < 0.05). Microbiota studies revealed a similar alpha and beta diversity of bacteria between response groups. Yet, the linear discriminant analysis (LDA) of effect size indicated an enrichment of Hungatella, Flavonifractor, and Methanosphaera (LDA score ≥3) in the pre-treatment biopsies of responders, while non-responders had a higher abundance of Enhydrobacter, Paraprevotella (LDA score ≥3) and Finegoldia (LDA score ≥4). Altogether, the evaluation of these biomarkers in pre-treatment biopsies could eventually predict a neoadjuvant treatment response, while in post-treatment samples, it could help in guiding non-operative treatment strategies.

13.
Genes (Basel) ; 13(2)2022 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-35205282

RESUMEN

Whereas targeted and shotgun sequencing approaches are both powerful in allowing the study of tissue-associated microbiota, the human: microorganism abundance ratios in tissues of interest will ultimately determine the most suitable sequencing approach. In addition, it is possible that the knowledge of the relative abundance of bacteria and fungi during a treatment course or in pathological conditions can be relevant in many medical conditions. Here, we present a qPCR-targeted approach to determine the absolute and relative amounts of bacteria and fungi and demonstrate their relative DNA abundance in nine different human tissue types for a total of 87 samples. In these tissues, fungi genomes are more abundant in stool and skin samples but have much lower levels in other tissues. Bacteria genomes prevail in stool, skin, oral swabs, saliva, and gastric fluids. These findings were confirmed by shotgun sequencing for stool and gastric fluids. This approach may contribute to a more comprehensive view of the human microbiota in targeted studies for assessing the abundance levels of microorganisms during disease treatment/progression and to indicate the most informative methods for studying microbial composition (shotgun versus targeted sequencing) for various samples types.


Asunto(s)
Bacterias , Metagenómica , Bacterias/genética , ADN de Hongos , Hongos/genética , Humanos , Metagenómica/métodos , Análisis de Secuencia de ADN
14.
Obes Res Clin Pract ; 15(2): 124-132, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33622623

RESUMEN

BACKGROUND: Pathogenic variants involving the MYT1L gene lead to an autosomal dominant form of syndromic obesity, characterized by polyphagia, intellectual disability/developmental delay, and behavioral problems, and that a characteristic facial phenotype does not seem to be recognizable. METHODS: Trio whole exome sequencing was performed in a 10-year-old Brazilian male presenting polyphagia, severe early-onset obesity, intellectual disability, speech delay, macrocephaly, frontal bossing, telecanthus, strabismus, and hypogenitalism. Additionally, we performed a literature review of patients carrying non-copy number MYT1L variants. RESULTS: A de novo genetic variant not previously reported in MYT1L (NM_015025.4:c.2990C>A) was identified in the proband and classified as pathogenic. From a literature search, 22 further patients carrying non-copy number MYT1L variants were identified, evidencing that although the associated phenotype is quite variable, intellectual disability/developmental and speech delays are always present. Further, most patients have obesity or overweight due to polyphagia. Macrocephaly, strabismus, behavioral problems, and hand/feet malformations are also recurrent features. CONCLUSIONS: We described the first Brazilian case of MYT1L related syndrome and highlighted clinical characteristics based on the literature. Other syndromic forms of obesity such as Prader-Willi, Bardet-Biedl, Börjeson-Forssman-Lehmann, MORM, Cohen, Alstrom, and Kleefstra type 1 syndromes should be considered in the differential diagnosis. Further, although obesity is frequent, it is not an obligatory feature of all carriers of MYT1L mutations.


Asunto(s)
Discapacidad Intelectual , Proteínas del Tejido Nervioso/genética , Obesidad Infantil/genética , Factores de Transcripción/genética , Brasil , Niño , Humanos , Masculino , Mutación , Fenotipo
15.
Cell Rep ; 34(5): 108699, 2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33485405

RESUMEN

Several potent neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus have been identified. However, antibody-dependent enhancement (ADE) has not been comprehensively studied for SARS-CoV-2, and the relationship between enhancing versus neutralizing activities and antibody epitopes remains unknown. Here, we select a convalescent individual with potent IgG neutralizing activity and characterize his antibody response. Monoclonal antibodies isolated from memory B cells target four groups of five non-overlapping receptor-binding domain (RBD) epitopes. Antibodies to one group of these RBD epitopes mediate ADE of entry in Raji cells via an Fcγ receptor-dependent mechanism. In contrast, antibodies targeting two other distinct epitope groups neutralize SARS-CoV-2 without ADE, while antibodies against the fourth epitope group are poorly neutralizing. One antibody, XG014, potently cross-neutralizes SARS-CoV-2 variants, as well as SARS-CoV-1, with respective IC50 (50% inhibitory concentration) values as low as 5.1 and 23.7 ng/mL, while not exhibiting ADE. Therefore, neutralization and ADE of human SARS-CoV-2 antibodies correlate with non-overlapping RBD epitopes.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Acrecentamiento Dependiente de Anticuerpo , Epítopos/inmunología , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/inmunología , Anticuerpos Antivirales/uso terapéutico , Reacciones Antígeno-Anticuerpo , COVID-19/inmunología , COVID-19/virología , Línea Celular , Niño , Análisis por Conglomerados , Femenino , Humanos , Concentración 50 Inhibidora , Masculino , Persona de Mediana Edad , Dominios Proteicos/inmunología , SARS-CoV-2/aislamiento & purificación , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto Joven , Tratamiento Farmacológico de COVID-19
16.
Elife ; 102021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-34060472

RESUMEN

Triple-negative breast cancer (TNBC) is an aggressive tumor with limited treatment options and poor prognosis. We applied the in vivo phage display technology to isolate peptides homing to the immunosuppressive cellular microenvironment of TNBC as a strategy for non-malignant target discovery. We identified a cyclic peptide (CSSTRESAC) that specifically binds to a vitamin D receptor, protein disulfide-isomerase A3 (PDIA3) expressed on the cell surface of tumor-associated macrophages (TAM), and targets breast cancer in syngeneic TNBC, non-TNBC xenograft, and transgenic mouse models. Systemic administration of CSSTRESAC to TNBC-bearing mice shifted the cytokine profile toward an antitumor immune response and delayed tumor growth. Moreover, CSSTRESAC enabled ligand-directed theranostic delivery to tumors and a mathematical model confirmed our experimental findings. Finally, in silico analysis showed PDIA3-expressing TAM in TNBC patients. This work uncovers a functional interplay between a cell surface vitamin D receptor in TAM and antitumor immune response that could be therapeutically exploited.


Asunto(s)
Antineoplásicos/farmacología , Oligopéptidos/farmacología , Proteína Disulfuro Isomerasas/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Macrófagos Asociados a Tumores/efectos de los fármacos , Proteína de Unión a Vitamina D/metabolismo , Animales , Línea Celular Tumoral , Activación Enzimática , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ligandos , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Biológicos , Proteína Disulfuro Isomerasas/genética , Transducción de Señal , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Carga Tumoral/efectos de los fármacos , Microambiente Tumoral , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Proteína de Unión a Vitamina D/genética , Ensayos Antitumor por Modelo de Xenoinjerto
17.
BMC Bioinformatics ; 11: 161, 2010 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-20353576

RESUMEN

BACKGROUND: The post-genomic era has brought new challenges regarding the understanding of the organization and function of the human genome. Many of these challenges are centered on the meaning of differential gene regulation under distinct biological conditions and can be performed by analyzing the Multiple Differential Expression (MDE) of genes associated with normal and abnormal biological processes. Currently MDE analyses are limited to usual methods of differential expression initially designed for paired analysis. RESULTS: We proposed a web platform named ProbFAST for MDE analysis which uses Bayesian inference to identify key genes that are intuitively prioritized by means of probabilities. A simulated study revealed that our method gives a better performance when compared to other approaches and when applied to public expression data, we demonstrated its flexibility to obtain relevant genes biologically associated with normal and abnormal biological processes. CONCLUSIONS: ProbFAST is a free accessible web-based application that enables MDE analysis on a global scale. It offers an efficient methodological approach for MDE analysis of a set of genes that are turned on and off related to functional information during the evolution of a tumor or tissue differentiation. ProbFAST server can be accessed at http://gdm.fmrp.usp.br/probfast.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Genómica/métodos , Programas Informáticos , Expresión Génica , Genoma Humano , Humanos , Internet , Probabilidad , Interfaz Usuario-Computador
18.
Mult Scler Relat Disord ; 44: 102243, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32559700

RESUMEN

BACKGROUND: Multiple sclerosis (MS) is an inflammatory autoimmune neurologic disease that causes progressive destruction of myelin sheath and axons. Affecting more than 2 million people worldwide, MS may presents distinct clinical courses. However, information regarding key gene expression and genic pathways related to each clinical form is still limited. OBJECTIVE: To assess the whole transcriptome of blood leukocytes from patients with remittent-recurrent (RRMS) and secondary-progressive (SPMS) forms to explore the gene expression profile of each form. METHODS: Total RNA was obtained and sequenced in Illumina HiSeq platform. Reads were aligned to human genome (GRCh38/hg38), BAM files were mapped and differential expression was obtained with DeSeq2. Up or downregulated pathways were obtained through Ingenuity IPA. Pro-inflammatory cytokines levels were also assessed. RESULTS: The transcriptome was generated for nine patients (6 SPMS and 3 RRMS) and 5 healthy controls. A total of 731 and 435 differentially expressed genes were identified in SPMS and RRMS, respectively. RERE, IRS2, SIPA1L1, TANC2 and PLAGL1 were upregulated in both forms, whereas PAD2 and PAD4 were upregulated in RRMS and downregulated in SPMS. Inflammatory and neuronal repair pathways were upregulated in RRMS, which was also observed in cytokine analysis. Conversely, SPMS patients presented IL-8, IL-1, Neurothrophin and Neuregulin pathways down regulated. CONCLUSIONS: Overall, the transcriptome of RRMS and SPMS clearly indicated distinct inflammatory profiles, where RRMS presented marked pro-inflammatory profile but SPMS did not. SPMS individuals also presented a decrease on expression of neuronal repair pathways.


Asunto(s)
Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Regulación hacia Abajo , Perfilación de la Expresión Génica , Humanos , Esclerosis Múltiple Crónica Progresiva/genética , Esclerosis Múltiple Recurrente-Remitente/genética , Recurrencia
19.
Nat Med ; 24(5): 604-609, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29686423

RESUMEN

Despite suppressive combination antiretroviral therapy (ART), latent HIV-1 proviruses persist in patients. This latent reservoir is established within 48-72 h after infection, has a long half-life1,2, enables viral rebound when ART is interrupted, and is the major barrier to a cure for HIV-1 3 . Latent cells are exceedingly rare in blood (∼1 per 1 × 106 CD4+ T cells) and are typically enumerated by indirect means, such as viral outgrowth assays4,5. We report a new strategy to purify and characterize single reactivated latent cells from HIV-1-infected individuals on suppressive ART. Surface expression of viral envelope protein was used to enrich reactivated latent T cells producing HIV RNA, and single-cell analysis was performed to identify intact virus. Reactivated latent cells produce full-length viruses that are identical to those found in viral outgrowth cultures and represent clones of in vivo expanded T cells, as determined by their T cell receptor sequence. Gene-expression analysis revealed that these cells share a transcriptional profile that includes expression of genes implicated in silencing the virus. We conclude that reactivated latent T cells isolated from blood can share a gene-expression program that allows for cell division without activation of the cell death pathways that are normally triggered by HIV-1 replication.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Perfilación de la Expresión Génica , VIH-1/fisiología , Latencia del Virus/fisiología , Células Clonales , Humanos , Análisis de Componente Principal , ARN Viral/metabolismo , Análisis de Secuencia de ARN , Análisis de la Célula Individual
20.
Nanoscale ; 10(3): 881-906, 2018 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-29265147

RESUMEN

Extracellular Vesicles (EVs) are gaining interest as central players in liquid biopsies, with potential applications in diagnosis, prognosis and therapeutic guidance in most pathological conditions. These nanosized particles transmit signals determined by their protein, lipid, nucleic acid and sugar content, and the unique molecular pattern of EVs dictates the type of signal to be transmitted to recipient cells. However, their small sizes and the limited quantities that can usually be obtained from patient-derived samples pose a number of challenges to their isolation, study and characterization. These challenges and some possible options to overcome them are discussed in this review.


Asunto(s)
Vesículas Extracelulares/química , Carbohidratos , Humanos , Lípidos , Ácidos Nucleicos , Pronóstico , Proteínas
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