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1.
Acta Neuropathol ; 138(6): 1053-1074, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31428936

RESUMO

Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease.


Assuntos
Neoplasias Encefálicas/metabolismo , Epigênese Genética , Glioma/metabolismo , Metiltransferases/metabolismo , Proteínas Musculares/metabolismo , Biossíntese de Proteínas/fisiologia , Ribossomos/metabolismo , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Metilação de DNA , Humanos , Metiltransferases/genética , Camundongos Nus , Proteínas Musculares/genética , Transplante de Neoplasias , RNA Ribossômico 28S
2.
J Immunol ; 193(7): 3470-91, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25172496

RESUMO

GATA-3 expression is crucial for T cell development and peaks during commitment to the T cell lineage, midway through the CD4(-)CD8(-) (double-negative [DN]) stages 1-3. We used RNA interference and conditional deletion to reduce GATA-3 protein acutely at specific points during T cell differentiation in vitro. Even moderate GATA-3 reduction killed DN1 cells, delayed progression to the DN2 stage, skewed DN2 gene regulation, and blocked appearance of the DN3 phenotype. Although a Bcl-2 transgene rescued DN1 survival and improved DN2 cell generation, it did not restore DN3 differentiation. Gene expression analyses (quantitative PCR, RNA sequencing) showed that GATA-3-deficient DN2 cells quickly upregulated genes, including Spi1 (PU.1) and Bcl11a, and downregulated genes, including Cpa3, Ets1, Zfpm1, Bcl11b, Il9r, and Il17rb with gene-specific kinetics and dose dependencies. These targets could mediate two distinct roles played by GATA-3 in lineage commitment, as revealed by removing wild-type or GATA-3-deficient early T lineage cells from environmental Notch signals. GATA-3 worked as a potent repressor of B cell potential even at low expression levels, so that only full deletion of GATA-3 enabled pro-T cells to reveal B cell potential. The ability of GATA-3 to block B cell development did not require T lineage commitment factor Bcl11b. In prethymic multipotent precursors, however, titration of GATA-3 activity using tamoxifen-inducible GATA-3 showed that GATA-3 inhibits B and myeloid developmental alternatives at different threshold doses. Furthermore, differential impacts of a GATA-3 obligate repressor construct imply that B and myeloid development are inhibited through distinct transcriptional mechanisms. Thus, the pattern of GATA-3 expression sequentially produces B lineage exclusion, T lineage progression, and myeloid-lineage exclusion for commitment.


Assuntos
Fator de Transcrição GATA3/imunologia , Células Precursoras de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Regulação para Cima/imunologia , Animais , Antineoplásicos Hormonais/farmacologia , Linhagem Celular , Fator de Transcrição GATA3/genética , Camundongos , Células Mieloides/citologia , Células Mieloides/imunologia , Células Precursoras de Linfócitos T/citologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Receptores Notch/genética , Receptores Notch/imunologia , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tamoxifeno/farmacologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/imunologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
3.
Cancer Cell ; 11(2): 147-60, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17292826

RESUMO

TGFbeta acts as a tumor suppressor in normal epithelial cells and early-stage tumors and becomes an oncogenic factor in advanced tumors. The molecular mechanisms involved in the malignant function of TGFbeta are not fully elucidated. We demonstrate that high TGFbeta-Smad activity is present in aggressive, highly proliferative gliomas and confers poor prognosis in patients with glioma. We discern the mechanisms and molecular determinants of the TGFbeta oncogenic response with a transcriptomic approach and by analyzing primary cultured patient-derived gliomas and human glioma biopsies. The TGFbeta-Smad pathway promotes proliferation through the induction of PDGF-B in gliomas with an unmethylated PDGF-B gene. The epigenetic regulation of the PDGF-B gene dictates whether TGFbeta acts as an oncogenic factor inducing PDGF-B and proliferation in human glioma.


Assuntos
Proliferação de Células/efeitos dos fármacos , Metilação de DNA , Glioma/patologia , Proteínas Proto-Oncogênicas c-sis/genética , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Adolescente , Adulto , Idoso , Astrocitoma/metabolismo , Astrocitoma/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioma/metabolismo , Humanos , Lactente , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação , Prognóstico , Proteínas Proto-Oncogênicas c-sis/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Proteína Smad7/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas
4.
J Heart Lung Transplant ; 43(7): 1051-1058, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38823968

RESUMO

Cardiogenic shock (CS) is a heterogeneous clinical syndrome characterized by low cardiac output leading to end-organ hypoperfusion. Organ dysoxia ranging from transient organ injury to irreversible organ failure and death occurs across all CS etiologies but differing by incidence and type. Herein, we review the recognition and management of respiratory, renal and hepatic failure complicating CS. We also discuss unmet needs in the CS care pathway and future research priorities for generating evidence-based best practices for the management of extra-cardiac sequelae. The complexity of CS admitted to the contemporary cardiac intensive care unit demands a workforce skilled to care for these extra-cardiac critical illness complications with an appreciation for how cardio-systemic interactions influence critical illness outcomes in afflicted patients.


Assuntos
Unidades de Terapia Intensiva , Choque Cardiogênico , Humanos , Choque Cardiogênico/terapia , Choque Cardiogênico/etiologia , Cuidados Críticos/métodos , Insuficiência Respiratória/terapia , Insuficiência Respiratória/etiologia
5.
Clin Cancer Res ; 30(19): 4505-4516, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39078728

RESUMO

PURPOSE: Cervical cancer is a viral-associated tumor caused by the infection with the human papilloma virus. Cervical cancer is an immunogenic cancer that expresses viral antigens. Despite being immunogenic, cervical cancer does not fully respond to immune checkpoint inhibitors (ICI). LIF is a crucial cytokine in embryo implantation, involved in maternal tolerance that acts as an immunomodulatory factor in cancer. LIF is expressed in cervical cancer and high levels of LIF is associated with poor prognosis in cervical cancer. EXPERIMENTAL DESIGN: We evaluated the impact of LIF on the immune response to ICI using primary plasmocytoid dendritic cells (pDC) and macrophage cultures, syngeneic animals and patient-derived models that recapitulate the human tumor microenvironment. RESULTS: We found that the viral proteins E6 and E7 induce the expression of LIF via the NFκB pathway. The secreted LIF can then repress type I interferon expressed in pDCs and CXCL9 expressed in tumor-associated macrophages. Blockade of LIF promotes the induction of type I interferon and CXCL9 inducing the tumor infiltration of CD8 T cells. This results in the sensitization of the tumor to ICI. Importantly, we observed that patients with cervical cancer expressing high levels of LIF tend to be resistant to ICI. CONCLUSIONS: Our data show that the HPV virus induces the expression of LIF to provide a selective advantage to the tumor cell by generating local immunosuppression via the repression of type I interferon and CXCL9. Combinatory treatment with blocking antibodies against LIF and ICI could be effective against cervical cancer expressing high levels of LIF.


Assuntos
Quimiocina CXCL9 , Interferon Tipo I , Fator Inibidor de Leucemia , Microambiente Tumoral , Neoplasias do Colo do Útero , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Feminino , Humanos , Animais , Interferon Tipo I/metabolismo , Quimiocina CXCL9/metabolismo , Quimiocina CXCL9/genética , Quimiocina CXCL9/imunologia , Camundongos , Microambiente Tumoral/imunologia , Fator Inibidor de Leucemia/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/complicações , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Evasão Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral , Macrófagos/imunologia , Macrófagos/metabolismo , Proteínas E7 de Papillomavirus/imunologia , Proteínas E7 de Papillomavirus/genética
6.
Clin Cancer Res ; 29(4): 791-804, 2023 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-36441800

RESUMO

PURPOSE: Leukemia inhibitory factor (LIF) is a multifunctional cytokine with numerous reported roles in cancer and is thought to drive tumor development and progression. Characterization of LIF and clinical-stage LIF inhibitors would increase our understanding of LIF as a therapeutic target. EXPERIMENTAL DESIGN: We first tested the association of LIF expression with transcript signatures representing multiple processes regulating tumor development and progression. Next, we developed MSC-1, a high-affinity therapeutic antibody that potently inhibits LIF signaling and tested it in immune competent animal models of cancer. RESULTS: LIF was associated with signatures of tumor-associated macrophages (TAM) across 7,769 tumor samples spanning 22 solid tumor indications. In human tumors, LIF receptor was highly expressed within the macrophage compartment and LIF treatment drove macrophages to acquire immunosuppressive capacity. MSC-1 potently inhibited LIF signaling by binding an epitope that overlaps with the gp130 receptor binding site on LIF. MSC-1 showed monotherapy efficacy in vivo and drove TAMs to acquire antitumor and proinflammatory function in syngeneic colon cancer mouse models. Combining MSC-1 with anti-PD1 leads to strong antitumor response and a long-term tumor-free survival in a significant proportion of treated mice. CONCLUSIONS: Overall, our findings highlight LIF as a therapeutic target for cancer immunotherapy.


Assuntos
Neoplasias , Microambiente Tumoral , Animais , Humanos , Camundongos , Terapia de Imunossupressão , Fator Inibidor de Leucemia/genética , Fator Inibidor de Leucemia/metabolismo , Macrófagos/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Microambiente Tumoral/genética
7.
Cancer Res ; 82(14): 2552-2564, 2022 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-35584009

RESUMO

The therapeutic benefit of approved BRAF and MEK inhibitors (BRAFi/MEKi) in patients with brain metastatic BRAF V600E/K-mutated melanoma is limited and transient. Resistance largely occurs through the restoration of MAPK signaling via paradoxical BRAF activation, highlighting the need for more effective therapeutic options. Aiming to address this clinical challenge, we characterized the activity of a potent, brain-penetrant paradox breaker BRAFi (compound 1a, C1a) as first-line therapy and following progression upon treatment with approved BRAFi and BRAFi/MEKi therapies. C1a activity was evaluated in vitro and in vivo in melanoma cell lines and patient-derived models of BRAF V600E-mutant melanoma brain metastases following relapse after treatment with BRAFi/MEKi. C1a showed superior efficacy compared with approved BRAFi in both subcutaneous and brain metastatic models. Importantly, C1a manifested potent and prolonged antitumor activity even in models that progressed on BRAFi/MEKi treatment. Analysis of mechanisms of resistance to C1a revealed MAPK reactivation under drug treatment as the predominant resistance-driving event in both subcutaneous and intracranial tumors. Specifically, BRAF kinase domain duplication was identified as a frequently occurring driver of resistance to C1a. Combination therapies of C1a and anti-PD-1 antibody proved to significantly reduce disease recurrence. Collectively, these preclinical studies validate the outstanding antitumor activity of C1a in brain metastasis, support clinical investigation of this agent in patients pretreated with BRAFi/MEKi, unveil genetic drivers of tumor escape from C1a, and identify a combinatorial treatment that achieves long-lasting responses. SIGNIFICANCE: A brain-penetrant BRAF inhibitor demonstrates potent activity in brain metastatic melanoma, even upon relapse following standard BRAF inhibitor therapy, supporting further investigation into its clinical utility.


Assuntos
Neoplasias Encefálicas , Melanoma , Encéfalo/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf
8.
Mol Cancer Ther ; 21(10): 1499-1509, 2022 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-35915983

RESUMO

T-cell bispecific antibodies (TCB) are engineered molecules that bind both the T-cell receptor and tumor-specific antigens. Epidermal growth factor receptor variant III (EGFRvIII) mutation is a common event in glioblastoma (GBM) and is characterized by the deletion of exons 2-7, resulting in a constitutively active receptor that promotes cell proliferation, angiogenesis, and invasion. EGFRvIII is expressed on the surface of tumor cells and is not expressed in normal tissues, making EGFRvIII an ideal neoantigen target for TCBs. We designed and developed a novel 2+1 EGFRvIII-TCB with optimal pharmacologic characteristics and potent antitumor activity. EGFRvIII-TCB showed specificity for EGFRvIII and promoted tumor cell killing as well as T-cell activation and cytokine secretion only in patient-derived models expressing EGFRvIII. Moreover, EGFRvIII-TCB promoted T-cell recruitment into intracranial tumors. EGFRvIII-TCB induced tumor regression in GBM animal models, including humanized orthotopic GBM patient-derived xenograft models. Our results warrant the clinical testing of EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.


Assuntos
Anticorpos Biespecíficos , Neoplasias Encefálicas , Glioblastoma , Animais , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Citocinas , Receptores ErbB/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/metabolismo
9.
Arch Argent Pediatr ; 119(5): e540-e544, 2021 10.
Artigo em Espanhol | MEDLINE | ID: mdl-34569759

RESUMO

The infection by Bartonela henselae (BH), the cause of cat scratch disease, it could be asymptomatic or produce local and multisystem illness. The objective of this case report is to document that the hepato-splenic involvement is unusual in BH infection, and the treatment is discussed and individualized in each patient. This case is about an eleven-year girl who presented with findings in abdominal tomography and ultrasound of hepato-splenic abscesses, with later positive serology for BH. In this way, a bibliographic review is carried out to show the low prevalence and incidence of hepato-splenic involvement where the anamnesis and the physical examination are essential to make an early diagnosis and treatment.


La infección por Bartonella henselae (BH) que causa la enfermedad por arañazo de gato puede cursar de manera asintomática, así como presentar manifestaciones locales y sistémicas. El objetivo de este caso es documentar que el compromiso hepatoesplénico es poco habitual en este tipo de infección y el tratamiento, que debe ser personalizado, aún genera controversia. Se presenta un caso de una paciente de 11 años con fiebre de origen de desconocido con hallazgos en tomografía y ecografía abdominal de abscesos hepatoesplénicos, y confirmación de infección por BH a través de métodos serológicos. Se realiza una revisión bibliográfica donde se evidencia la baja frecuencia de compromiso hepatoesplénico. De esta manera, la anamnesis y el examen físico son fundamentales para realizar un rápido diagnóstico y tratamiento.


Assuntos
Bartonella henselae , Doença da Arranhadura de Gato , Esplenopatias , Abscesso , Doença da Arranhadura de Gato/complicações , Doença da Arranhadura de Gato/diagnóstico , Criança , Feminino , Humanos , Fígado , Esplenopatias/diagnóstico por imagem
10.
Nat Commun ; 12(1): 1503, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33686071

RESUMO

Brain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the degree and phenotype of the immune cell infiltration has been used to predict response to ICI. However, the anatomical location of brain lesions limits access to tumor material to characterize the immune phenotype. Here, we characterize immune cells present in brain lesions and matched cerebrospinal fluid (CSF) using single-cell RNA sequencing combined with T cell receptor genotyping. Tumor immune infiltration and specifically CD8+ T cell infiltration can be discerned through the analysis of the CSF. Consistently, identical T cell receptor clonotypes are detected in brain lesions and CSF, confirming cell exchange between these compartments. The analysis of immune cells of the CSF can provide a non-invasive alternative to predict the response to ICI, as well as identify the T cell receptor clonotypes present in brain metastasis.


Assuntos
Neoplasias Encefálicas/imunologia , Líquido Cefalorraquidiano/imunologia , Leucócitos , Microambiente Tumoral/imunologia , Adenocarcinoma de Pulmão , Encéfalo/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linfócitos T CD8-Positivos/imunologia , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Prognóstico
11.
Games Health J ; 9(3): 164-181, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32027184

RESUMO

Objective: Differences in cultural background between health providers and patients can reduce effective access to health services in multicultural settings. Health sciences educators have recently suggested that game-based learning may be effective for cross-cultural care training. This scoping review maps published knowledge on educational games intended to foster cross-cultural care training and highlights the research gaps for future research. Materials and Methods: A scoping review searched PubMed, Eric, Embase, Lilacs, PsycINFO, and Google Scholar for theoretical and empirical research, using terms relevant to cross-cultural care and game-based learning. A participatory research framework engaged senior medical students and participatory research experts in conducting and evaluating the review. Results: Forty-one documents met the inclusion criteria, all from developed countries. The most common source of publication was nursing and medicine (39%; 16/41) and used the cultural competence approach (44%; 18/41). Around one-half of the publications (51%; 21/41) were theoretical and 39% (16/41) were empirical. Empirical studies most commonly used mixed methods (44%; 7/16), followed by strictly quantitative (31%; 5/16) or qualitative (25%; 4/16) approaches. There were no randomized controlled trials and only one study engaged end-users in the design. Empirical studies most frequently assessed role-play-related games (44%; 7/16) and used game evaluation-related outcomes or learning-related outcomes. None used patient-oriented outcomes. Findings suggest that educational games are an effective and engaging educational intervention for cross-cultural care training. Conclusions: The paucity of studies on educational games and cross-cultural care training precludes a systematic review. Future empirical studies should focus on randomized counterfactual designs and patient-related outcomes. We encourage involving end-users in developing content for educational games.


Assuntos
Assistência à Saúde Culturalmente Competente , Pessoal de Saúde/educação , Jogos de Vídeo , Comunicação , Humanos , Assistência Centrada no Paciente , Relações Profissional-Paciente
12.
Nat Commun ; 11(1): 5376, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33110059

RESUMO

The molecular characterisation of medulloblastoma, the most common paediatric brain tumour, is crucial for the correct management and treatment of this heterogenous disease. However, insufficient tissue sample, the presence of tumour heterogeneity, or disseminated disease can challenge its diagnosis and monitoring. Here, we report that the cerebrospinal fluid (CSF) circulating tumour DNA (ctDNA) recapitulates the genomic alterations of the tumour and facilitates subgrouping and risk stratification, providing valuable information about diagnosis and prognosis. CSF ctDNA also characterises the intra-tumour genomic heterogeneity identifying small subclones. ctDNA is abundant in the CSF but barely present in plasma and longitudinal analysis of CSF ctDNA allows the study of minimal residual disease, genomic evolution and the characterisation of tumours at recurrence. Ultimately, CSF ctDNA analysis could facilitate the clinical management of medulloblastoma patients and help the design of tailored therapeutic strategies, increasing treatment efficacy while reducing excessive treatment to prevent long-term secondary effects.


Assuntos
Neoplasias Encefálicas/líquido cefalorraquidiano , DNA Tumoral Circulante/líquido cefalorraquidiano , Meduloblastoma/líquido cefalorraquidiano , Biomarcadores Tumorais/líquido cefalorraquidiano , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , DNA Tumoral Circulante/genética , DNA de Neoplasias/líquido cefalorraquidiano , DNA de Neoplasias/genética , Genômica , Humanos , Meduloblastoma/diagnóstico , Meduloblastoma/genética
13.
Nat Commun ; 10(1): 2416, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186412

RESUMO

Cancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8+ T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8+ T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Quimiocina CXCL9/metabolismo , Fator Inibidor de Leucemia/imunologia , Macrófagos/imunologia , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Anticorpos Neutralizantes/farmacologia , Linfócitos T CD8-Positivos/metabolismo , Quimiocina CCL2/metabolismo , Epigênese Genética , Humanos , Memória Imunológica , Fator Inibidor de Leucemia/antagonistas & inibidores , Fator Inibidor de Leucemia/metabolismo , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos SCID , Transplante de Neoplasias , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral/imunologia
14.
Cell Rep ; 27(9): 2690-2708.e10, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141692

RESUMO

The detailed molecular characterization of lethal cancers is a prerequisite to understanding resistance to therapy and escape from cancer immunoediting. We performed extensive multi-platform profiling of multi-regional metastases in autopsies from 10 patients with therapy-resistant breast cancer. The integrated genomic and immune landscapes show that metastases propagate and evolve as communities of clones, reveal their predicted neo-antigen landscapes, and show that they can accumulate HLA loss of heterozygosity (LOH). The data further identify variable tumor microenvironments and reveal, through analyses of T cell receptor repertoires, that adaptive immune responses appear to co-evolve with the metastatic genomes. These findings reveal in fine detail the landscapes of lethal metastatic breast cancer.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Mutação , Neoplasias da Mama/secundário , Feminino , Perfilação da Expressão Gênica , Humanos , Perda de Heterozigosidade , Metástase Neoplásica , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Sequenciamento do Exoma
15.
Oncotarget ; 9(29): 20617-20630, 2018 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-29755676

RESUMO

Brain metastases constitute a challenge in the management of patients with HER2-positive breast cancer treated with anti-HER2 systemic therapies. Here we sought to define the repertoire of mutations private to or enriched for in HER2-positive brain metastases. Massively parallel sequencing targeting all exons of 254 genes frequently mutated in breast cancers and/or related to DNA repair was used to characterize the spatial and temporal heterogeneity of HER2-positive breast cancers and their brain metastases in six patients. Data were analyzed with state-of-the-art bioinformatics algorithms and selected mutations were validated with orthogonal methods. Spatial and temporal inter-lesion genetic heterogeneity was observed in the HER2-positive brain metastases from an index patient subjected to a rapid autopsy. Genetic alterations restricted to the brain metastases included mutations in cancer genes FGFR2, PIK3CA and ATR, homozygous deletion in CDKN2A and amplification in KRAS. Shifts in clonal composition and the acquisition of additional mutations in the progression from primary HER2-positive breast cancer to brain metastases following anti-HER2 therapy were investigated in additional five patients. Likely pathogenic mutations private to or enriched in the brain lesions affected cancer and clinically actionable genes, including ATR, BRAF, FGFR2, MAP2K4, PIK3CA, RAF1 and TP53. Changes in clonal composition and the acquisition of additional mutations in brain metastases may affect potentially actionable genes in HER2-positive breast cancers. Our observations have potential clinical implications, given that treatment decisions for patients with brain metastatic disease are still mainly based on biomarkers assessed in the primary tumor.

16.
Arch. argent. pediatr ; 119(5): e540-e544, oct. 2021. ilus
Artigo em Espanhol | LILACS, BINACIS | ID: biblio-1292794

RESUMO

La infección por Bartonella henselae (BH) que causa la enfermedad por arañazo de gato puede cursar de manera asintomática, así como presentar manifestaciones locales y sistémicas. El objetivo de este caso es documentar que el compromiso hepatoesplénico es poco habitual en este tipo de infección y el tratamiento, que debe ser personalizado, aún genera controversia. Se presenta un caso de una paciente de 11 años con fiebre de origen de desconocido con hallazgos en tomografía y ecografía abdominal de abscesos hepatoesplénicos, y confirmación de infección por BH a través de métodos serológicos. Se realiza una revisión bibliográfica donde se evidencia la baja frecuencia de compromiso hepatoesplénico. De esta manera, la anamnesis y el examen físico son fundamentales para realizar un rápido diagnóstico y tratamiento


The infection by Bartonela henselae (BH), the cause of cat scratch disease, it could be asymptomatic or produce local and multisystem illness. The objective of this case report is to document that the hepato-splenic involvement is unusual in BH infection, and the treatment is discussed and individualized in each patient. This case is about an eleven-year girl who presented with findings in abdominal tomography and ultrasound of hepato-splenic abscesses, with later positive serology for BH. In this way, a bibliographic review is carried out to show the low prevalence and incidence of hepato-splenic involvement where the anamnesis and the physical examination are essential to make an early diagnosis and treatment.


Assuntos
Humanos , Feminino , Criança , Esplenopatias/diagnóstico por imagem , Doença da Arranhadura de Gato/complicações , Doença da Arranhadura de Gato/diagnóstico , Bartonella henselae , Abscesso , Fígado
17.
Nat Commun ; 6: 8839, 2015 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-26554728

RESUMO

Cell-free circulating tumour DNA (ctDNA) in plasma has been shown to be informative of the genomic alterations present in tumours and has been used to monitor tumour progression and response to treatments. However, patients with brain tumours do not present with or present with low amounts of ctDNA in plasma precluding the genomic characterization of brain cancer through plasma ctDNA. Here we show that ctDNA derived from central nervous system tumours is more abundantly present in the cerebrospinal fluid (CSF) than in plasma. Massively parallel sequencing of CSF ctDNA more comprehensively characterizes the genomic alterations of brain tumours than plasma, allowing the identification of actionable brain tumour somatic mutations. We show that CSF ctDNA levels longitudinally fluctuate in time and follow the changes in brain tumour burden providing biomarkers to monitor brain malignancies. Moreover, CSF ctDNA is shown to facilitate and complement the diagnosis of leptomeningeal carcinomatosis.


Assuntos
Neoplasias Encefálicas/genética , DNA de Neoplasias/sangue , DNA de Neoplasias/líquido cefalorraquidiano , Genômica , Neoplasias Meníngeas/genética , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Glioblastoma/sangue , Glioblastoma/líquido cefalorraquidiano , Glioblastoma/genética , Humanos , Neoplasias Pulmonares/patologia , Meduloblastoma/sangue , Meduloblastoma/líquido cefalorraquidiano , Meduloblastoma/genética , Neoplasias Meníngeas/sangue , Neoplasias Meníngeas/líquido cefalorraquidiano
18.
J Am Coll Cardiol ; 62(11): 949-58, 2013 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-23850910

RESUMO

Heart failure (HF) data in Latin America (LA) were reviewed to guide health service planning in the prevention and treatment of HF. The HF epidemiology and the adequacy of relevant health service provision related to HF in LA are not well delineated. A systematic search of the electronic databases and the World Health Organization website was undertaken for HF in LA. LA countries have reduced gross income and lower total expenditure on health per capita. LA is a heterogeneous region with HF risk factors of developed and nondeveloped countries, including lower risk of raised blood glucose levels, obesity, tobacco, and aging, whereas systemic hypertension (SH), rheumatic fever, and Chagas' disease (C'D) are higher in LA. Main etiologies of HF in LA are idiopathic dilated cardiomyopathy (from 1.3% to 37%), C'D (from 1.3% to 21%), ischemic (from 68% to 17%), SH (from 14% to 76%), valvular (from 3% to 22%), and alcohol related (from 1.1% to 8%). The prognosis of C'D HF is worse than for other etiologies. Chronic HF is the cause of death in 6.3% of cases. Decompensated HF is the main cause of cardiovascular hospitalization. The prevalence of systolic HF varies from 64% to 69%. LA is under the awful paradox of having the HF risk factors and HF epidemiology of developed countries with the added factors of SH, C'D, and rheumatic fever. Overall, in the scenario of lower total expenditure on health per capita and lower gross national income per capita, new strategies are essential for prevention and treatment of HF in LA.


Assuntos
Insuficiência Cardíaca/epidemiologia , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/terapia , Hospitalização/estatística & dados numéricos , Humanos , América Latina/epidemiologia , Masculino , Prevalência , Prognóstico , Fatores de Risco
19.
Rev. Fac. Med. (Bogotá) ; 62(1): 81-90, ene.-mar. 2014. ilus, tab
Artigo em Espanhol | LILACS | ID: lil-712549

RESUMO

Antecedentes. La hipertensión arterial sistémica es una enfermedad multifactorial que incluye la elevación de las cifras de tensión arterial, factores de riesgo cardiovascular e hipertrofia ventricular izquierda. Objetivo. Analizar los cambios electrocardiográficos en pacientes hipertensos inscritos en el programa de hipertensión arterial en ASSBASALUD Empresa Social del Estado, Manizales, Colombia, 2012. Materiales y métodos. Estudio poblacional de corte transversal. 102 pacientes. Variables electrocardiográficas analizadas: índices de Cornell, Sokolow Lyon y Macruz; cambios en la onda P y cambios en el eje. Se tomó electrocardiograma. Resultados. Edad promedio de 62 años. El 58,5% de los pacientes estudiados se clasificaron como pre-hipertensos, el 18,6% tenían frecuencia cardíaca superior a 100 latidos por minuto. Se encontraron cambios en la onda P en el 26,3%. En el 34% el eje estaba desviado. 64,6% tenían índice de Macruz anormal. 10,8% mostraron aumento en el voltaje del índice Sokolow-Lyon. En un 10,8% el voltaje de Cornell estaba elevado. En un 5,1% la fuerza terminal de onda P fue mayor a 40. Un 7,8% tenían bloqueos de rama derecha. En los pacientes con niveles altos de la presión arterial se encontró relación significativa con la elevación en los índices de Cornell (p=0,000) y de Sokolow-Lyon (p=0,016). Se encontró relación significativa entre los valores elevados de la presión arterial sistólica y los cambios en los índices de Cornell (p=0,010) y Sokolow-Lyon (p=0.001), los valores de la presión arterial diastólica se asociaron más a cambios en el Sokolow-Lyon (p=0,001). Conclusiones. Se confirma en esta población de hipertensos la asociación entre hipertensión arterial y cambios electrocardiográficos, especialmente en los índices de Cornell y de Sokolow-Lyon.


Background. Systemic blood pressure (HBP) is a multifactorial disease that includes elevated blood pressure levels, cardiovascular risk factors and left ventricular hypertrophy. Objective. To analyze the electrocardiographic changes in hypertensive patients enrolled in the hypertension surveillance and control program at ASSBASALUD ESE, Manizales, Colombia in 2012. Materials and methods. Cross-sectional study that involved 102 patients. The variables used were electrocardiogram indexes as Cornell, Sokolow Lyon, Macruz and P wave duration. It took a 12-lead electrocardiogram for each patient executed at ASBASALUD ESE, La Asunción. Results. The average age was 62 years, 58.5% were in the prehypertension range, also 18.6% had abnormal heart rate, 26.3% abnormal P wave duration, 34% abnormal cardiac axis, 64.6% abnormal Macruz index, 10.8% abnormal Sokolow-Lyon index, 10.8% abnormal Cornell index, 5.1% positive P-wave terminal force, 7.8% had right bundle branch block. The rank of hypertension showed significant relationship with the level of Cornell (p=0.000) and Sokolow-Lyon (p=0.016) indexes. A significant relationship between systolic blood pressure value and Cornell (p=0.010) and Sokolow-Lyon indexes were found (p=0.001), likewise diastolic blood pressure value and Sokolow-Lyon index value showed relationship (p=0.001). Conclusions. It is confirmed, in this population of hypertensive patients, that the indexes show variation according to level of hypertension, as well with the values of systolic and diastolic blood pressure are Cornell and Sokolow-Lyon indexes.

20.
Dev Biol ; 246(1): 103-21, 2002 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-12027437

RESUMO

PU.1 and GATA-3 are transcription factors that are required for development of T cell progenitors from the earliest stages. Neither one is a simple positive regulator for T lineage specification, however. When expressed at elevated levels at early stages of T cell development, each of these transcription factors blocks T cell development within a different, characteristic time window, with GATA-3 overexpression initially inhibiting at an earlier stage than PU.1. These perturbations are each associated with a distinct spectrum of changes in the regulation of genes needed for T cell development. Both transcription factors can interfere with expression of the Rag-1 and Rag-2 recombinases, while GATA-3 notably blocks PU.1 and IL-7Ralpha expression, and PU.1 reduces expression of HES-1 and c-Myb. A first-draft assembly of the regulatory targets of these two factors is presented as a provisional gene network. The target genes identified here provide insight into the basis of the effects of GATA-3 or PU.1 overexpression and into the regulatory changes that distinguish the developmental time windows for these effects.


Assuntos
Linhagem da Célula/fisiologia , Proteínas de Ligação a DNA/fisiologia , Genes Reguladores , Proteínas Proto-Oncogênicas/fisiologia , Linfócitos T/citologia , Transativadores/fisiologia , Animais , Sequência de Bases , Primers do DNA , Proteínas de Ligação a DNA/genética , Fator de Transcrição GATA3 , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores/genética
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