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1.
Clin Infect Dis ; 73(7): e1445-e1453, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33119064

RESUMO

BACKGROUND: Hemotropic mycoplasmas, previously classified in the genus Eperythrozoon, have been reported as causing human infections in Brazil, China, Japan, and Spain. METHODS: In 2017, we detected DNA from Candidatus Mycoplasma haemohominis in the blood of a Melanesian patient from New Caledonia presenting with febrile splenomegaly, weight loss, life-threatening autoimmune hemolytic anemia, and hemophagocytosis. The full genome of the bacterium was sequenced from a blood isolate. Subsequently, we retrospectively (2011-2017) and prospectively (2018-2019) tested patients who had been hospitalized with a similar clinico-biological picture. In addition, as these patients had been in contact with frugivorous bats (authorized under conditions for hunting and eating in New Caledonia), we investigated the role of these animals and their biting flies by testing them for hemotropic mycoplasmas. RESULTS: There were 15 patients found to be infected by this hemotropic mycoplasma. Among them, 4 (27%) died following splenectomy performed either for spontaneous spleen rupture or to cure refractory autoimmune hemolytic anemia. The bacterium was cultivated from the patient's blood. The full genome of the Neocaledonian Candidatus M. haemohominis strain differed from that of a recently identified Japanese strain. Of 40 tested Pteropus bats, 40% were positive; 100% of collected bat flies Cyclopodia horsfieldi (Nycteribiidae, Diptera) were positive. Human, bat, and dipteran strains were highly similar. CONCLUSIONS: The bacterium being widely distributed in bats, Candidatus M. haemohominis, should be regarded as a potential cause of severe infections in humans.


Assuntos
Quirópteros , Infecções por Mycoplasma , Mycoplasma , Animais , Humanos , Mycoplasma/genética , Infecções por Mycoplasma/diagnóstico , Infecções por Mycoplasma/veterinária , Filogenia , Estudos Retrospectivos
2.
Blood ; 127(24): 3040-53, 2016 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-27060168

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive leukemia for which knowledge on disease mechanisms and effective therapies are currently lacking. Only a handful of recurring genetic mutations have been identified and none is specific to BPDCN. In this study, through molecular cloning in an index case that presented a balanced t(3;5)(q21;q31) and molecular cytogenetic analyses in a further 46 cases, we identify monoallelic deletion of NR3C1 (5q31), encoding the glucocorticoid receptor (GCR), in 13 of 47 (28%) BPDCN patients. Targeted deep sequencing in 36 BPDCN cases, including 10 with NR3C1 deletion, did not reveal NR3C1 point mutations or indels. Haploinsufficiency for NR3C1 defined a subset of BPDCN with lowered GCR expression and extremely poor overall survival (P = .0006). Consistent with a role for GCR in tumor suppression, functional analyses coupled with gene expression profiling identified corticoresistance and loss-of-EZH2 function as major downstream consequences of NR3C1 deletion in BPDCN. Subsequently, more detailed analyses of the t(3;5)(q21;q31) revealed fusion of NR3C1 to a long noncoding RNA (lncRNA) gene (lincRNA-3q) that encodes a novel, nuclear, noncoding RNA involved in the regulation of leukemia stem cell programs and G1/S transition, via E2F. Overexpression of lincRNA-3q was a consistent feature of malignant cells and could be abrogated by bromodomain and extraterminal domain (BET) protein inhibition. Taken together, this work points to NR3C1 as a haploinsufficient tumor suppressor in a subset of BPDCN and identifies BET inhibition, acting at least partially via lncRNA blockade, as a novel treatment option in BPDCN.


Assuntos
Células Dendríticas/patologia , Haploinsuficiência , Leucemia/genética , Receptores de Glucocorticoides/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Células Dendríticas/metabolismo , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica , RNA Longo não Codificante/genética , Receptores de Glucocorticoides/química , Neoplasias Cutâneas/patologia , Células Tumorais Cultivadas , Adulto Jovem
3.
Br J Haematol ; 158(2): 186-197, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22626453

RESUMO

Molecular minimal residual disease (MRD) analysis is fast emerging as an essential clinical decision-making tool for the treatment and follow-up of mature B cell malignancies. Current EuroMRD consensus IGH real-time quantitative polymerase chain reaction RQ-PCR assays rely on flow cytometric assessment of diagnostic tumour burdens to construct 'normalized', patient-specific, diagnostic DNA-based MRD quantification standards. Here, we propose a new 'hybrid' assay that relies on plasmid-based quantification of patient-specific IGH VDJ targets by consensus IGH real time (RQ)-PCR, combined with EuroMRD guidelines, for MRD monitoring in lymphoid malignancies. This assay was evaluated for MRD assessment in a total of 273 samples from 29 mantle cell lymphoma (MCL) patients treated within a Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang (GOELAMS) Phase II trial and was feasible, reliable and consistently comparable to gold-standard MRD techniques (99% concordance across all samples including 32 samples within the quantitative range) when analysed in parallel (117 samples). Integrating clinical prognostic parameters and MRD status in peripheral blood at the post-induction stage was predictive of progression-free survival (P = 0·034) thus demonstrating the clinical utility of the approach. Plasmid-based standards for the quantification of IGH VDJ targets are therefore confirmed to offer new opportunities for further standardization and clinical evaluation of MRD-guided management of patients with mature B cell malignancies.


Assuntos
Cadeias Pesadas de Imunoglobulinas/genética , Linfoma de Célula do Manto/diagnóstico , Recombinação V(D)J/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , DNA de Neoplasias/genética , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Rearranjo Gênico de Cadeia Pesada de Linfócito B/genética , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Plasmídeos/genética , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real/métodos
4.
Mod Pathol ; 25(9): 1246-57, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22627740

RESUMO

Multiparametric flow cytometry has proven to be a powerful method for detection and immunophenotypic characterization of clonal subsets, particularly in lymphoproliferative disorders of the B-cell lineage. Although in theory promising, this approach has not been comparably fulfilled in mature T-cell malignancies. Specifically, the T-cell receptor-Vß repertoire analysis in blood can provide strong evidence of clonality, particularly when a single expanded Vß family is detected. The purpose of this study was to determine the relevance of this approach when applied to biopsies, at the site of tumor involvement. To this end, 30 peripheral T-cell lymphoma and 94 control biopsies were prospectively studied. Vß expansions were commonly detected within CD4+ or CD8+ T cells (97% of peripheral T-cell lymphoma and 54% of non-peripheral T-cell lymphoma cases); thus, not differentiating malignant from reactive processes. Interestingly, we demonstrated that using a standardized evaluation, the detection of a high Vß expansion was closely associated with diagnosis of peripheral T-cell lymphoma, with remarkable specificity (98%) and sensitivity (90%). This approach also identified eight cases of peripheral T-cell lymphoma that were not detectable by other forms of immunophenotyping. Moreover, focusing Vß expression analysis to T-cell subsets with aberrant immunophenotypes, we demonstrated that the T-cell clone might be heterogeneous with regard to surface CD7 or CD10 expression (4/11 cases), providing indication on 'phenotypic plasticity'. Finally, among the wide variety of Vß families, the occurrence of a Vß17 expansion in five cases was striking. To our knowledge, this is the first report demonstrating the power of T-cell receptor-Vß repertoire analysis by flow cytometry in biopsies as a basis for peripheral T-cell lymphoma diagnosis and precise T-cell clone identification and characterization.


Assuntos
Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Citometria de Fluxo/métodos , Linfoma de Células T Periférico/diagnóstico , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Biópsia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Células Clonais , Feminino , Humanos , Imunofenotipagem , Tecido Linfoide/metabolismo , Tecido Linfoide/patologia , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
5.
PLoS One ; 16(8): e0254964, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34383759

RESUMO

INTRODUCTION: Eosinophilic meningitis is a rare form of meningitis with sequelae or death occurring in approximately 2-3% of cases. The most frequent etiological agent is the parasite Angiostrongylus cantonensis. The aim of this study was to characterize New Caledonian cases and to assess the extent to which of A. cantonensis was involved. MATERIAL AND METHODS: We performed a retrospective study of all cases of eosinophilic meningitis (EM) admitted to the Territorial Hospital of New Caledonia, from 2004 to 2019. We performed a descriptive and a multivariate analysis to identify association of variables with severe and fatal cases (or cases with sequelae). CONCLUSION: Angiostrongyliasis was confirmed as being responsible for 17 of the 92 reported EM cases in New Caledonia from 2004 to 2019 with most being young adults and non-walking infants, and with two peaks of incidence one during the dry season and one during the rainy season. Considering the high incidence and regularity of cases, the potential reservoirs should be identified to target prevention campaigns.


Assuntos
Angiostrongylus cantonensis/fisiologia , Eosinófilos/patologia , Meningite/epidemiologia , Meningite/parasitologia , Adolescente , Adulto , Idoso , Animais , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Nova Caledônia/epidemiologia , Chuva , Estações do Ano , Índice de Gravidade de Doença , Adulto Jovem
7.
Exp Cell Res ; 315(19): 3281-93, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19751723

RESUMO

CD95 gene and splicing aberrations have been detected in B-cell non-Hodgkin lymphoma (B-NHL) where they are thought to contribute to CD95 apoptosis resistance. To further investigate this, we have performed extensive CD95 transcript sequencing and functional analysis in B-NHL with demonstrated resistance to CD95-induced apoptosis (B-NHLr). Strikingly, instead of showing CD95 mutations per se, B cells from B-NHLr co-expressed wild-type and multiple, normal (CD95nv) and novel alternatively spliced variant CD95 transcripts (CD95av). CD95av were predicted, by sequencing, to encode soluble, potentially apoptosis inhibitory proteins. However, their overexpression, by transfection, in Jurkat cells did not interfere with endogenous CD95 death signalling. Furthermore, CD95av-expressing B-NHLr did not show mutations in CD95 splice-regulatory elements and CD95av expression was 'reversible' by CD40 activation. This, in conjunction with treatment by the protein synthesis inhibitor, cycloheximide, could sensitise a subset of B-NHLr to CD95 apoptosis. In normal and lymphoma B cells, this correlated to increased CD95 membrane expression, enhanced DISC activity and engagement of the mitochondrial death pathway via Bid cleavage, although the latter occurred less efficiently in B-NHLr. Thus, immune modulation of CD95 transcription and alternative splicing combined with enhanced engagement of mitochondrial death signalling offer potential for restoration of CD95 apoptosis sensitivity in B-NHLr.


Assuntos
Apoptose , Antígenos CD40/metabolismo , Linfoma de Células B/patologia , Receptor fas/genética , Proteínas Reguladoras de Apoptose , Sequência de Bases , Humanos , Células Jurkat , Proteínas Mitocondriais , Isoformas de Proteínas , RNA Mensageiro/genética , Transdução de Sinais , Transfecção
8.
Oncotarget ; 7(35): 56976-56985, 2016 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-27486974

RESUMO

In chronic lymphocytic leukemia (CLL), telomere dysfunction is associated with poor outcomes. TP53 is involved in cellular responses to dysfunctional telomeres, and its inactivation is the strongest adverse prognostic factor for CLL. Given the biological relationship between TP53 and telomeres, and their prognostic value, it is important to improve our understanding of the impact of TP53 alterations on telomeres. We performed a comprehensive study of the deletions and mutations of the TP53 gene and telomere parameters, including hTERT and the shelterin complex, in 115 CLL patients. We found that any type of TP53 alteration was associated with very short telomeres and high hTERT expression, independently of other biological CLL features. Patients with disrupted TP53 showed telomere deletions and chromosomal end-to-end fusions in cells with complex karyotypes. TP53 disruption was characterized by downregulation of shelterin genes. Interestingly, low expression of POT1, TPP1 and TIN2 was also found in some patients with wild-type TP53 and had an adverse impact on progression-free survival after standard genotoxic therapy. In conclusion, we have demonstrated that patients with disrupted TP53 have severe telomere dysfunction and high genomic instability. Thus, the telomeric profile could be tested as a biomarker in CLL patients treated with new therapeutic agents.


Assuntos
Leucemia Linfocítica Crônica de Células B/metabolismo , Telômero/ultraestrutura , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminopeptidases/metabolismo , Biomarcadores Tumorais , Análise Mutacional de DNA , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Intervalo Livre de Doença , Feminino , Seguimentos , Deleção de Genes , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Genômica , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Serina Proteases/metabolismo , Complexo Shelterina , Telomerase/genética , Proteínas de Ligação a Telômeros/metabolismo
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