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1.
J Immunol ; 211(5): 721-726, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37486206

RESUMO

CTL differentiation is controlled by the crosstalk of various transcription factors and epigenetic modulators. Uncovering this process is fundamental to improving immunotherapy and designing novel therapeutic approaches. In this study, we show that polycomb repressive complex 1 subunit chromobox (Cbx)4 favors effector CTL differentiation in a murine model. Cbx4 deficiency in CTLs induced a transcriptional signature of memory cells and increased the memory CTL population during acute viral infection. It has previously been shown that besides binding to H3K27me3 through its chromodomain, Cbx4 functions as a small ubiquitin-like modifier (SUMO) E3 ligase in a SUMO-interacting motifs (SIM)-dependent way. Overexpression of Cbx4 mutants in distinct domains showed that this protein regulates CTL differentiation primarily in an SIM-dependent way and partially through its chromodomain. Our data suggest a novel role of a polycomb group protein Cbx4 controlling CTL differentiation and indicated SUMOylation as a key molecular mechanism connected to chromatin modification in this process.


Assuntos
Complexo Repressor Polycomb 1 , Ubiquitina-Proteína Ligases , Animais , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas do Grupo Polycomb/genética , Proteínas do Grupo Polycomb/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
2.
Oncologist ; 29(8): e1098-e1099, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38785402

RESUMO

Uveal melanoma is a rare malignancy originating from extracutaneous melanocytes on the uveal layer of the eyes. The incidence varies depending on the ethnic and racial global distribution, as uveal melanoma is more frequently diagnosed in non-Hispanic White subjects when compared with Hispanic, Asian, or Black individuals. Despite all the local effective management of uveal melanoma, roughly 50% of the cases will develop distant metastases. For these cases, the historical median overall survival is around 12 months. Recently, tebentafusp became the first therapy to receive Food and Drug Administration approval following a phase 3 trial demonstrating a continued long-term benefit for overall survival among adult HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma. Since 2021, high-resolution sequence-based HLA typing has been considered the gold standard for determining HLA alleles and haplotypes for the Brazilian Bone Marrow Donor Registry (REDOME) donors. To depict the HLA-A*02:01-positivity in Brazilian individuals, the REDOME database was queried out for the donors included from 2021 to 2023 and tested for HLA in high-resolution platforms. A total of 203, 44 donors were included and the frequency of the HLA-A*02:01 was 21.01%, much lower compared to the frequency in North Americans and Europeans (around 45%). Despite tebentafusp has demonstrated promising results in the treatment of uveal melanoma, the number of patients to benefit from this new approach can strongly vary by ethnic and racial issues. New strategies for the systemic treatment of advanced uveal melanoma have to be developed and tested as this disease still represents an unmet medical need.


Assuntos
Melanoma , Neoplasias Uveais , Humanos , Neoplasias Uveais/genética , Neoplasias Uveais/patologia , Melanoma/genética , Melanoma/patologia , Melanoma/tratamento farmacológico , Brasil/epidemiologia , Antígeno HLA-A2/genética , Masculino , Feminino , Adulto
3.
Cell Biol Int ; 45(3): 662-673, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33300198

RESUMO

Transforming growth factor-ß (TGF-ß) plays a dual role acting as tumor promoter or suppressor. Along with cyclooxygenase-2 (COX-2) and oncogenic Ras, this multifunctional cytokine is deregulated in colorectal cancer. Despite their individual abilities to promote tumor growth and invasion, the mechanisms of cross regulation between these pathways is still unclear. Here, we investigate the effects of TGF-ß, Ras oncogene and COX-2 in the colorectal cancer context. We used colon adenocarcinoma cell line HT-29 and Ras-transformed IEC-6 cells, both treated with prostaglandin E2 (PGE2 ), TGF-ß or a combined treatment with these agents. We demonstrated that PGE2 alters the subcellular localization of E-cadherin and ß-catenin and enhanced the tumorigenic potential in HT-29 cells. This effect was inhibited by TGF-ß, indicating a tumor suppressor role. Conversely, in Ras-transformed IEC-6 cells, TGF-ß induced COX-2 expression and increased invasiveness, acting as a tumor promoter. In IEC-6 Ras-transformed cells, TGF-ß increased nuclear ß-catenin and Wnt/ß-catenin activation, opposite to what was seen in the PGE2 and TGF-ß joint treatment in HT-29 cells. Together, our findings show that TGF-ß increases COX-2 levels and induces invasiveness cooperating with Ras in a Wnt/ß-catenin activation-dependent manner. This shows TGF-ß dual regulation over COX-2/PGE2 tumor promotion depending on the H-Ras and Wnt/ß-catenin pathways activation status in intestinal cancer cells.


Assuntos
Carcinogênese/metabolismo , Carcinogênese/patologia , Neoplasias Colorretais/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Via de Sinalização Wnt , Caderinas/metabolismo , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/patologia , Células HT29 , Humanos , Invasividade Neoplásica , Fatores de Transcrição TCF/metabolismo , Transcrição Gênica , beta Catenina/metabolismo
4.
Biochem Biophys Res Commun ; 504(1): 270-276, 2018 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-30172372

RESUMO

Protease-activated receptor 2 (PAR2) is a G-protein coupled receptor which is activated upon cleavage of its N-terminal region. PAR2 has been associated with many aspects regarding tumor progression, such as the production of pro-tumoral cytokines. Granulocyte colony-stimulating factor (G-CSF) is a cytokine essential to neutrophil production and maturation, and it is often overexpressed in tumors. In this study, we evaluated the ability of PAR2 to modulate G-CSF expression. PAR2 and G-CSF were significantly more expressed in metastatic (4T1 and MDA-MB-231) as compared to non-metastatic (67NR and MCF7) breast cancer cell lines. In addition, PAR2 stimulation by a synthetic agonist peptide significantly increased G-CSF gene expression in the metastatic cell lines. Knockdown of PAR2 in 4T1 cells decreased G-CSF expression and secretion. In addition, treatment of 4T1 with the commercial PAR2 antagonist, ENMD-1068, significantly decreased G-CSF expression. cBioPortal analyses of the TCGA database showed a significant co-occurrence of G-CSF and PAR2 gene overexpression in breast cancer samples. In conclusion, our data suggest that PAR2 contributes to G-CSF expression in breast cancer cells, possibly favoring tumor progression.


Assuntos
Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos/metabolismo , Receptor PAR-2/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Linhagem Celular Tumoral , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Camundongos , Ativação Transcricional , Regulação para Cima
5.
J Cell Biochem ; 117(2): 458-69, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26224641

RESUMO

Lithium is a well-established non-competitive inhibitor of glycogen synthase kinase-3ß (GSK-3ß), a kinase that is involved in several cellular processes related to cancer progression. GSK-3ß is regulated upstream by PI3K/Akt, which is negatively modulated by PTEN. The role that lithium plays in cancer is controversial because lithium can activate or inhibit survival signaling pathways depending on the cell type. In this study, we analyzed the mechanisms by which lithium can modulate events related to colorectal cancer (CRC) progression and evaluated the role that survival signaling pathways such as PI3K/Akt and PTEN play in this context. We show that the administration of lithium decreased the proliferative potential of CRC cells in a GSK-3ß-independent manner but induced the accumulation of cells in G2/M phase. Furthermore, high doses of lithium increased apoptosis, which was accompanied by decreased proteins levels of Akt and PTEN. Then, cells that were induced to overexpress PTEN were treated with lithium; we observed that low doses of lithium strongly increased apoptosis. Additionally, PTEN overexpression reduced proliferation, but this effect was minor compared with that in cells treated with lithium alone. Furthermore, we demonstrated that PTEN overexpression and lithium treatment separately reduced cell migration, colony formation, and invasion, and these effects were enhanced when lithium treatment and PTEN overexpression were combined. In conclusion, our findings indicate that PTEN overexpression and lithium treatment cooperate to reduce the malignancy of CRC cells and highlight lithium and PTEN as potential candidates for studies to identify new therapeutic approaches for CRC treatment.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Colorretais/enzimologia , Expressão Gênica , Cloreto de Lítio/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Adesão Celular , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Células HCT116 , Células HT29 , Humanos , Invasividade Neoplásica , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Ativação Transcricional
6.
Cancer Sci ; 106(1): 60-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25457412

RESUMO

Multidrug resistance (MDR) is considered a multifactorial event that favors cancer cells becoming resistant to several chemotherapeutic agents. Numerous mechanisms contribute to MDR, such as P-glycoprotein (Pgp/ABCB1) activity that promotes drug efflux, overexpression of inhibitors of apoptosis proteins (IAP) that contribute to evasion of apoptosis, and oncogenic pathway activation that favors cancer cell survival. MDR molecules have been identified in membrane microparticles (MP) and can be transferred to sensitive cancer cells. By co-culturing MP derived from MDR-positive cells with recipient cells, we showed that sensitive cells accumulated Pgp, IAP proteins and mRNA. In addition, MP promoted microRNA transfer and NFκB and Yb-1 activation. Therefore, our results indicate that MP can induce a multifactorial phenotype in sensitive cancer cells.


Assuntos
Micropartículas Derivadas de Células/fisiologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Transdução de Sinais , Antineoplásicos/farmacologia , Carcinogênese/metabolismo , Técnicas de Cocultura , Humanos , Células K562 , Células MCF-7 , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
7.
Biochim Biophys Acta ; 1833(8): 2016-28, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23583303

RESUMO

Nuclear factor of activated T cells (NFAT) was described as an activation and differentiation factor in T cells. NFAT1 protein is expressed in several cell types and has been implicated in the control of the cell cycle, death and migration. Overexpression or activation of NFAT1 has been demonstrated to induce cell death in different cell types, such as T lymphocytes, Burkitt's lymphoma, and fibroblasts. Although these findings indicate a role for NFAT1 transcription factor in control of cell death, the precise mechanisms involved in this process regulated by NFAT1 are still poorly understood. The Ras/Raf/MEK/ERK pathway is activated by many growth factors and cytokines that are important in driving proliferation and preventing apoptosis and is widely implicated in cell transformation and cancer development. We show that NFAT1 protein can cooperate with Ras/Raf/MEK/ERK, but not with the JNK, p38 or NFκB pathways in cell death induction. NFAT1 can induce a cell death pathway consistent with apoptosis, which can be shifted to programmed necrosis by caspase inhibitors. Finally, through screening genes involved in cell death regulation, although we determined that TNF-α, TRAIL and PAK7 genes were up-regulated, only TNF-α expression was responsible for cell death in this context. These data suggest that NFAT1 protein activation can shift oncogenic Ras/Raf/MEK/ERK signaling to acting as a tumor suppressor pathway. These data support a potential role for regulating NFAT1 expression in gene therapy in tumors that display an activated Ras pathway, which could lead to more specific, target-directed TNF-α expression and, thus, tumor suppression.


Assuntos
Apoptose/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Fatores de Transcrição NFATC/metabolismo , Proteínas Proto-Oncogênicas c-raf/genética , Fatores de Transcrição/genética , Fator de Necrose Tumoral alfa/genética , Proteínas ras/metabolismo , Animais , Caspases/genética , Caspases/metabolismo , Morte Celular/genética , Linhagem Celular , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Fatores de Transcrição NFATC/genética , Células NIH 3T3 , Necrose/genética , Necrose/metabolismo , Proteínas Proto-Oncogênicas c-raf/metabolismo , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Fatores de Transcrição/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo , Proteínas ras/genética
8.
Nat Commun ; 14(1): 199, 2023 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639383

RESUMO

Orally available antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary because of the continuous circulation of new variants that challenge immunized individuals. Because severe COVID-19 is a virus-triggered immune and inflammatory dysfunction, molecules endowed with both antiviral and anti-inflammatory activity are highly desirable. We identified here that kinetin (MB-905) inhibits the in vitro replication of SARS-CoV-2 in human hepatic and pulmonary cell lines. On infected monocytes, MB-905 reduced virus replication, IL-6 and TNFα levels. MB-905 is converted into its triphosphate nucleotide to inhibit viral RNA synthesis and induce error-prone virus replication. Coinhibition of SARS-CoV-2 exonuclease, a proofreading enzyme that corrects erroneously incorporated nucleotides during viral RNA replication, potentiated the inhibitory effect of MB-905. MB-905 shows good oral absorption, its metabolites are stable, achieving long-lasting plasma and lung concentrations, and this drug is not mutagenic nor cardiotoxic in acute and chronic treatments. SARS-CoV-2-infected hACE-mice and hamsters treated with MB-905 show decreased viral replication, lung necrosis, hemorrhage and inflammation. Because kinetin is clinically investigated for a rare genetic disease at regimens beyond the predicted concentrations of antiviral/anti-inflammatory inhibition, our investigation suggests the opportunity for the rapid clinical development of a new antiviral substance for the treatment of COVID-19.


Assuntos
Antivirais , COVID-19 , Animais , Humanos , Camundongos , Antivirais/farmacologia , Antivirais/uso terapêutico , SARS-CoV-2 , Cinetina/farmacologia , Inflamação/tratamento farmacológico , Nucleotídeos , Replicação Viral
9.
Front Microbiol ; 13: 946549, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35958144

RESUMO

Chronically immunosuppressed patients infected with SARS-CoV-2 often experience prolonged virus shedding, and may pave the way to the emergence of mutations that render viral variants of concern (VOC) able to escape immune responses induced by natural infection or by vaccination. We report herein a SARS-CoV-2+ cancer patient from the beginning of the COVID-19 pandemic whose virus quasispecies across multiple timepoints carried several immune escape mutations found in more contemporary VOC, such as alpha, delta and omicron, that appeared to be selected for during infection. We hypothesize that immunosuppressed patients may represent the source of VOC seen throughout the COVID-19 pandemics.

10.
Front Microbiol ; 13: 1074382, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36713167

RESUMO

Due to immunosuppressive cancer therapies, cancer patients diagnosed with COVID-19 have a higher chance of developing severe symptoms and present a higher mortality rate in comparison to the general population. Here we show a comparative analysis of the microbiome from naso-oropharyngeal samples of breast cancer patients with respect to SARS-CoV-2 status and identified bacteria associated with symptom severity. Total DNA of naso-oropharyngeal swabs from 74 women with or without breast cancer, positive or negative for SARS-CoV-2 were PCR-amplified for 16S-rDNA V3 and V4 regions and submitted to massive parallel sequencing. Sequencing data were analyzed with QIIME2 and taxonomic identification was performed using the q2-feature-classifier QIIME2 plugin, the Greengenes Database, and amplicon sequence variants (ASV) analysis. A total of 486 different bacteria were identified. No difference was found in taxa diversity between sample groups. Cluster analysis did not group the samples concerning SARS-CoV-2 status, breast cancer diagnosis, or symptom severity. Three taxa (Pseudomonas, Moraxella, and Klebsiella,) showed to be overrepresented in women with breast cancer and positive for SARS-CoV-2 when compared to the other women groups, and five bacterial groups were associated with COVID-19 severity among breast cancer patients: Staphylococcus, Staphylococcus epidermidis, Scardovia, Parasegitibacter luogiensis, and Thermomonas. The presence of Staphylococcus in COVID-19 breast cancer patients may possibly be a consequence of nosocomial infection.

11.
Front Immunol ; 13: 840203, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35677061

RESUMO

Long-term immunological protection relies on the differentiation and maintenance of memory lymphocytes. Since the knowledge of memory generation has been centered on in vivo models of infection, there are obstacles to deep molecular analysis of differentiating subsets. Here we defined a novel in vitro CD8 T cell activation and culture regimen using low TCR engagement and cytokines to generate differentiated cells consistent with central memory-like cells, as shown by surface phenotype, gene expression profile and lack of cytotoxic function after challenge. Our results showed an effector signature expressed by in vitro memory precursors and their plasticity under specific conditions. Moreover, memory CD8 T cells conferred long-term protection against bacterial infection and slowed in vivo tumor growth more efficiently than effector cells. This model may allow further understanding of CD8 T cell memory molecular differentiation subsets and be suited for generating cells to be used for immunotherapy.


Assuntos
Linfócitos T CD8-Positivos , Memória Imunológica , Diferenciação Celular/genética , Expressão Gênica , Subpopulações de Linfócitos T
12.
Front Immunol ; 13: 820131, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35251001

RESUMO

Coronavirus disease 2019 (COVID-19) is currently a worldwide emergency caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). In observational clinical studies, statins have been identified as beneficial to hospitalized patients with COVID-19. However, experimental evidence of underlying statins protection against SARS-CoV-2 remains elusive. Here we reported for the first-time experimental evidence of the protective effects of simvastatin treatment both in vitro and in vivo. We found that treatment with simvastatin significantly reduced the viral replication and lung damage in vivo, delaying SARS-CoV-2-associated physiopathology and mortality in the K18-hACE2-transgenic mice model. Moreover, simvastatin also downregulated the inflammation triggered by SARS-CoV-2 infection in pulmonary tissue and in human neutrophils, peripheral blood monocytes, and lung epithelial Calu-3 cells in vitro, showing its potential to modulate the inflammatory response both at the site of infection and systemically. Additionally, we also observed that simvastatin affected the course of SARS-CoV-2 infection through displacing ACE2 on cell membrane lipid rafts. In conclusion, our results show that simvastatin exhibits early protective effects on SARS-CoV-2 infection by inhibiting virus cell entry and inflammatory cytokine production, through mechanisms at least in part dependent on lipid rafts disruption.


Assuntos
Tratamento Farmacológico da COVID-19 , Regulação para Baixo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Microdomínios da Membrana/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Sinvastatina/farmacologia , Animais , COVID-19/virologia , Modelos Animais de Doenças , Humanos , Inflamação/virologia , Pulmão/virologia , Camundongos , Camundongos Transgênicos , Replicação Viral/efeitos dos fármacos
13.
Cancer Immunol Immunother ; 60(4): 537-46, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21225259

RESUMO

Members of the nuclear factor of activated T cell (NFAT) family of transcription factors were originally described in T lymphocytes but later shown to be expressed in several immune and non-immune cell types. NFAT proteins can modulate cellular transformation intrinsically, and NFAT-deficient (NFAT1-/-) mice are indeed more susceptible to transformation than wild-type counterparts. However, the contribution of an NFAT1-/- microenvironment to tumor progression has not been studied. We have addressed this question by inoculating NFAT1-/- mice with B16F10 melanoma cells intravenously, an established model of tumor homing and growth. Surprisingly, NFAT1-/- animals sustained less tumor growth in the lungs after melanoma inoculation than wild-type counterparts. Even though melanoma cells equally colonize NFAT1-/- and wild-type lungs, tumors do not progress in the absence of NFAT1 expression. A massive mononuclear perivascular infiltrate and reduced expression of TGF-ß in the absence of NFAT1 suggested a role for tumor-infiltrating immune cells and the cytokine milieu. However, these processes are independent of an IL-4-induced regulatory tumor microenvironment, since lack of this cytokine does not alter the phenotype in NFAT1-/- animals. Bone marrow chimera experiments meant to differentiate the contributions of stromal and infiltrating cells to tumor progression demonstrated that NFAT1-induced susceptibility to pulmonary tumor growth depends on NFAT1-expressing parenchyma rather than on bone marrow-derived cells. These results suggest an important role for NFAT1 in radio-resistant tumor-associated parenchyma, which is independent of the anti-tumor immune response and Th1 versus Th2 cytokine milieu established by the cancer cells, but able to promote site-specific tumor growth.


Assuntos
Fatores de Transcrição NFATC/metabolismo , Neoplasias Experimentais/patologia , Microambiente Tumoral/imunologia , Animais , Western Blotting , Citocinas/biossíntese , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Fatores de Transcrição NFATC/deficiência , Fatores de Transcrição NFATC/imunologia , Invasividade Neoplásica/imunologia , Metástase Neoplásica/imunologia , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
14.
Front Cell Dev Biol ; 9: 655307, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33996817

RESUMO

Interferon regulatory factor 2-binding protein 2 (IRF2BP2) encodes a member of the IRF2BP family of transcriptional regulators, which includes IRF2BP1, IRF2BP2, and IRF2BPL (EAP1). IRF2BP2 was initially identified as a transcriptional corepressor that was dependent on Interferon regulatory factor-2 (IRF-2). The IRF2BP2 protein is found in different organisms and has been described as ubiquitously expressed in normal and tumor cells and tissues, indicating a possible role for this transcriptional cofactor in different cell signaling pathways. Recent data suggest the involvement of IRF2BP2 in the regulation of several cellular functions, such as the cell cycle, cell death, angiogenesis, inflammation and immune response, thereby contributing to physiological cell homeostasis. However, an imbalance in IRF2BP2 function may be related to the pathophysiology of cancer. Some studies have shown the association of IRF2BP2 expression in hematopoietic and solid tumors through mechanisms based on gene fusion and point mutations in gene coding sequences, and although the biological functions of these types of hybrid and mutant proteins are not yet known, they are thought to be involved in an increase in the likelihood of tumor development. In this review, we address the possible involvement of IRF2BP2 in tumorigenesis through its regulation of important pathways involved in tumor development.

15.
Virus Evol ; 7(1): veab013, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33738124

RESUMO

Numerous factors have been identified to influence susceptibility to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and disease severity. Cancer patients are more prone to clinically evolve to more severe COVID-19 conditions, but the determinants of such a more severe outcome remain largely unknown. We have determined the full-length SARS-CoV-2 genomic sequences of cancer patients and healthcare workers (non-cancer controls) by deep sequencing and investigated the within-host viral population of each infection, quantifying intrahost genetic diversity. Naso- and oropharyngeal SARS-CoV-2+ swabs from 57 cancer patients and 14 healthcare workers from the Brazilian National Cancer Institute were collected in April to May 2020. Complete genome amplification using ARTIC network V3 multiplex primers was performed followed by next-generation sequencing. Assemblies were conducted in Geneious R11, where consensus sequences were extracted and intrahost single nucleotide variants were identified. Maximum likelihood phylogenetic analysis was performed using PhyMLv.3.0 and lineages were classified using Pangolin and CoV-GLUE. Phylogenetic analysis showed that all but one strain belonged to clade B1.1. Four genetically linked mutations known as the globally dominant SARS-CoV-2 haplotype (C241T, C3037T, C14408T and A23403G) were found in the majority of consensus sequences. SNV signatures of previously characterized Brazilian genomes were also observed in most samples. Another 85 SNVs were found at a lower frequency (1.4%-19.7%) among the consensus sequences. Cancer patients displayed a significantly higher intrahost viral genetic diversity compared to healthcare workers. This difference was independent of SARS-CoV-2 Ct values obtained at the diagnostic tests, which did not differ between the two groups. The most common nucleotide changes of intrahost SNVs in both groups were consistent with APOBEC and ADAR activities. Intrahost genetic diversity in cancer patients was not associated with disease severity, use of corticosteroids, or use of antivirals, characteristics that could influence viral diversity. Moreover, the presence of metastasis, either in general or specifically in the lung, was not associated with intrahost diversity among cancer patients. Cancer patients carried significantly higher numbers of minor variants compared to non-cancer counterparts. Further studies on SARS-CoV-2 diversity in especially vulnerable patients will shed light onto the understanding of the basis of COVID-19 different outcomes in humans.

16.
Infect Genet Evol ; 94: 104998, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34252616

RESUMO

After a one-year rollout of the pandemic caused by SARS-CoV-2, the continuous dissemination of the virus has generated a number of variants with increased transmissibility and infectivity, called variants of concern (VOC), which now predominate worldwide. Concerns about the susceptibility of humans that have already been infected before or those already vaccinated to infection by VOC rise among scientists and clinicians. Herein, we assessed the prevalence of different VOC among recent infections at the Brazilian National Cancer Institute (Rio de Janeiro, Brazil). By using a Sanger-based sequencing approach targeting the viral S gene to identify VOC, we have analyzed 72 recent infections. The overall prevalence of VOC was 97%. Among the subjects analyzed, six had been vaccinated with the ChAdOx1-S/nCoV-19 (n = 4; one with two doses and three with one dose) or the CoronaVac (n = 2; both with 2 doses) vaccine, while five subjects represented reinfection cases, being two of them also part of the vaccinated group (each one with one vaccine type). All vaccinated and re-infected subjects carried VOC irrespective of the vaccine type taken, the number of doses taken, IgG titers or being previously infected during the first wave of the Brazilian pandemic. Importantly, all six vaccinees only had mild symptoms. We present here several examples of how natural infections or vaccination may not be fully capable of conferring sterilizing immunity against VOC.


Assuntos
Vacinas contra COVID-19/administração & dosagem , COVID-19/imunologia , COVID-19/virologia , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/genética , Brasil/epidemiologia , COVID-19/diagnóstico , COVID-19/epidemiologia , Humanos , Pandemias , Filogenia , SARS-CoV-2/classificação , SARS-CoV-2/genética , Vacinação
17.
Infect Genet Evol ; 90: 104772, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33592317

RESUMO

Different groups have recently reported events of SARS-CoV-2 reinfection, where patients had a sequence of positive-negative-positive RT-PCR tests. However, such events could be explained by different scenarios such as intermittent viral shedding, bonafide re-infection or multiple infection with alternating predominance of different viruses. Analysis of minor variants is an important tool to distinguish between these scenarios. Using ARTIC network PCR amplification and next-generation sequencing, we obtained SARS-CoV-2 sequences from two timepoints (with a time span of 102 days) of a patient followed at the Brazilian National Cancer Institute. Within-host variant analysis evidenced three single nucleotide variants (SNVs) at the consensus viral sequence in the second timepoint that were already present in the first timepoint as minor variants. Another five SNVs found in the second timepoint were not detected in the first sample sequenced, suggesting an additional infection by a yet another new virus. Our observation shed light into the existence of different viral populations that are present in dynamic frequencies and fluctuate during the course of SARS-CoV-2 infection. The detection of these variants in distinct disease events of an individual highlights a complex interplay between viral reactivation from a pre-existing minority variant and reinfection by a different virus.


Assuntos
COVID-19/diagnóstico , COVID-19/virologia , Interações Hospedeiro-Patógeno , Reinfecção , SARS-CoV-2 , Idoso , Biomarcadores , Comorbidade , Suscetibilidade a Doenças , Evolução Fatal , Humanos , Masculino , SARS-CoV-2/fisiologia , Tomografia Computadorizada por Raios X , Carga Viral , Ativação Viral
18.
Pharmaceuticals (Basel) ; 15(1)2021 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-35056078

RESUMO

Atazanavir (ATV) has already been considered as a potential repurposing drug to 2019 coronavirus disease (COVID-19); however, there are controversial reports on its mechanism of action and effectiveness as anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Through the pre-clinical chain of experiments: enzymatic, molecular docking, cell-based and in vivo assays, it is demonstrated here that both SARS-CoV-2 B.1 lineage and variant of concern gamma are susceptible to this antiretroviral. Enzymatic assays and molecular docking calculations showed that SARS-CoV-2 main protease (Mpro) was inhibited by ATV, with Morrison's inhibitory constant (Ki) 1.5-fold higher than GC376 (a positive control) dependent of the catalytic water (H2Ocat) content. ATV was a competitive inhibitor, increasing the Mpro's Michaelis-Menten (Km) more than sixfold. Cell-based assays indicated that different lineages of SARS-CoV-2 is susceptible to ATV. Using oral administration of ATV in mice to reach plasmatic exposure similar to humans, transgenic mice expression in human angiotensin converting enzyme 2 (K18-hACE2) were partially protected against lethal challenge with SARS-CoV-2 gamma. Moreover, less cell death and inflammation were observed in the lung from infected and treated mice. Our studies may contribute to a better comprehension of the Mpro/ATV interaction, which could pave the way to the development of specific inhibitors of this viral protease.

19.
Cell Death Dis ; 11(2): 105, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029741

RESUMO

Lipid droplets (also known as lipid bodies) are lipid-rich, cytoplasmic organelles that play important roles in cell signaling, lipid metabolism, membrane trafficking, and the production of inflammatory mediators. Lipid droplet biogenesis is a regulated process, and accumulation of these organelles within leukocytes, epithelial cells, hepatocytes, and other nonadipocyte cells is a frequently observed phenotype in several physiologic or pathogenic situations and is thoroughly described during inflammatory conditions. Moreover, in recent years, several studies have described an increase in intracellular lipid accumulation in different neoplastic processes, although it is not clear whether lipid droplet accumulation is directly involved in the establishment of these different types of malignancies. This review discusses current evidence related to the biogenesis, composition and functions of lipid droplets related to the hallmarks of cancer: inflammation, cell metabolism, increased proliferation, escape from cell death, and hypoxia. Moreover, the potential of lipid droplets as markers of disease and targets for novel anti-inflammatory and antineoplastic therapies will be discussed.


Assuntos
Transformação Celular Neoplásica/metabolismo , Gotículas Lipídicas/metabolismo , Neoplasias/metabolismo , Animais , Morte Celular , Proliferação de Células , Transformação Celular Neoplásica/patologia , Metabolismo Energético , Humanos , Mediadores da Inflamação/metabolismo , Gotículas Lipídicas/patologia , Neoplasias/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais , Hipóxia Tumoral , Microambiente Tumoral
20.
bioRxiv ; 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32869023

RESUMO

Numerous factors have been identified to influence susceptibility to SARS-CoV-2 infection and disease severity. Cancer patients are more prone to clinically evolve to more severe COVID-19 conditions, but the determinants of such a more severe outcome remain largely unknown. We have determined the full-length SARS-CoV-2 genomic sequences of cancer patients and healthcare workers (HCW; non-cancer controls) by deep sequencing and investigated the within-host viral quasispecies of each infection, quantifying intrahost genetic diversity. Naso- and oropharyngeal SARS-CoV-2 + swabs from 57 cancer patients and 14 healthcare workers (HCW) from the Brazilian Cancer Institute were collected in April-May 2020. Complete genome amplification using ARTIC network V3 multiplex primers was performed followed by next-generation sequencing. Assemblies were conducted in Geneious R11, where consensus sequences were extracted and intrahost single nucleotide variants (iSNVs) were identified. Maximum likelihood phylogenetic analysis was performed using PhyMLv.3.0 and lineages were classified using Pangolin and CoV-GLUE. Phylogenetic analysis showed that all but one strain belonged to clade B1.1. Four genetically linked mutations known as the globally dominant SARS-CoV-2 haplotype (C241T, C3037T, C14408T and A23403G) were found in the majority of consensus sequences. SNV signatures of previously characterized Brazilian genomes were also observed in most samples. Another 85 SNVs were found at a lower frequency (1.4-19.7%). Cancer patients displayed a significantly higher intrahost viral genetic diversity compared to HCW (p = 0.009). Intrahost genetic diversity in cancer patients was independent of SARS-CoV-2 Ct values, and was not associated with disease severity, use of corticosteroids, or use of antivirals, characteristics that could influence viral diversity. Such a feature may explain, at least in part, the more adverse outcomes to which cancer/COVID-19 patients experience. AUTHOR SUMMARY: Cancer patients are more prone to clinically evolve to more severe COVID-19 conditions, but the determinants of such a more severe outcome remain largely unknown. In this study, phylogenetic and variation analysis of SARS-CoV-2 genomes from cancer patients and non-cancer healthcare workers at the Brazilian National Cancer Institute were characterized by deep sequencing. Viral genomes showed signatures characteristic of Brazilian viruses, consistent with the hypothesis of local, community transmission rather than virus importation from abroad. Despite most genomes in patients and healthcare workers belonging to the same lineage, intrahost variability was higher in cancer patients when compared to non-cancer counterparts. The intrahost genomic diversity analysis presented in our study highlights the relaxed evolution of SARS-CoV-2 in a vulnerable population of cancer patients. The high number of minor variations can result in the selection of immune escape variants, resistance to potential drugs, and/or increased pathogenicity. The impact of this higher intrahost variability over time warrants further investigation.

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