ABSTRACT
Chemotherapies allow complete remission in more than 50 % of patients with acute myeloid leukemia (AML), however, with frequent relapse. This suggests that residual leukemic cells may escape to chemotherapy and immune system. Natural killer (NK) cells from AML patients (AML-NK) have a weaker natural cytotoxicity-activating receptors (NCRs) expression than NK cells from healthy donors (HD-NK). Coding genes for NCR1/NKp46, NCR2/NKp44 and NCR3/NKp30 are located at different loci on two different chromosomes; however, their expression is tightly coordinated. Most NK cells express either high (NCRbright) or low levels (NCRdull) of all three NCRs. This suggests the existence of negative/positive regulation factor(s) common to the three receptors. In order to find transcription factor(s) or pathway(s) involved in NCRs co-regulation, this study compared the transcriptomic signature of HD-NK and AML-NK cells, before and after in vitro NK cells culture. Microarrays analysis revealed a specific NK cells transcriptomic signature in patients with AML. However, in vitro NK cells expansion erased this signature and up-regulated expression of central molecules of NK functions, such as NCR, NKG2D and also ETS-1, regardless of their origin, i.e., AML-NK vs HD-NK. ETS-1 transcription factor was shown to bind to a specific and common region in the NCRs promoters, thus appearing as a good candidate to explain the coordinated regulation of three NCRs. Such results are encouraging regarding in vitro AML-NK cytotoxicity restoration and provide a new conceptual support for innovative cellular therapy based on in vitro NK cells expansion before their reinfusion in AML patients.
Subject(s)
Killer Cells, Natural/immunology , Leukemia, Myeloid, Acute/immunology , Receptors, Natural Cytotoxicity Triggering/metabolism , Adult , Aged , Aged, 80 and over , Cells, Cultured , Cytotoxicity, Immunologic , Female , Gene Expression Regulation , Humans , Immunophenotyping , Male , Middle Aged , Proto-Oncogene Protein c-ets-1/genetics , Proto-Oncogene Protein c-ets-1/metabolism , Receptors, Natural Cytotoxicity Triggering/genetics , Tissue Array Analysis , Transcriptome , Young AdultABSTRACT
To date, it remains impossible to guarantee that short-term treatment given to a patient suffering from a major depressive episode (MDE) will improve long-term efficacy. Objective biological measurements and biomarkers that could help in predicting the clinical evolution of MDE are still warranted. To better understand the reason nearly half of MDE patients respond poorly to current antidepressive treatments, we examined the gene expression profile of peripheral blood samples collected from 16 severe MDE patients and 13 matched controls. Using a naturalistic and longitudinal design, we ascertained mRNA and microRNA (miRNA) expression at baseline, 2 and 8 weeks later. On a genome-wide scale, we detected transcripts with roles in various biological processes as significantly dysregulated between MDE patients and controls, notably those involved in nucleotide binding and chromatin assembly. We also established putative interactions between dysregulated mRNAs and miRNAs that may contribute to MDE physiopathology. We selected a set of mRNA candidates for quantitative reverse transcriptase PCR (RT-qPCR) to validate that the transcriptional signatures observed in responders is different from nonresponders. Furthermore, we identified a combination of four mRNAs (PPT1, TNF, IL1B and HIST1H1E) that could be predictive of treatment response. Altogether, these results highlight the importance of studies investigating the tight relationship between peripheral transcriptional changes and the dynamic clinical progression of MDE patients to provide biomarkers of MDE evolution and prognosis.
Subject(s)
Antidepressive Agents/therapeutic use , Depressive Disorder, Major , RNA, Messenger/analysis , Adult , Aged , Case-Control Studies , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/genetics , Female , Gene Expression Profiling , Histones/genetics , Humans , Interleukin-1beta/genetics , Longitudinal Studies , Male , Membrane Proteins/genetics , MicroRNAs/analysis , Middle Aged , Prognosis , Reverse Transcriptase Polymerase Chain Reaction , Thiolester Hydrolases , Treatment Failure , Treatment Outcome , Tumor Necrosis Factor-alpha/geneticsSubject(s)
alpha-Mannosidosis/diagnosis , Child, Preschool , Diagnosis, Differential , Health Status , Humans , Male , Phenotype , Severity of Illness IndexABSTRACT
No disponible
Subject(s)
Humans , Male , Child , alpha-Mannosidosis/complications , alpha-Mannosidosis/diagnosis , Hernia, Umbilical/diagnosis , Hearing Loss, Sensorineural/complications , Chromatography/methods , Intellectual Disability/complications , Intellectual Disability/diagnosis , Prenatal Diagnosis/methods , Prenatal Diagnosis/trends , Oligosaccharides/urine , Dysostoses/complications , Splenomegaly/complications , Craniosynostoses/complications , Hernia/complications , Hypertelorism/complications , Oligosaccharides/analysis , alpha-Mannosidase/deficiencyABSTRACT
Introducción. La enfermedad de Hunter es una mucopolisacaridosis (MPS) recesiva ligada al cromosoma X, causada por la deficiencia de la enzima iduronato-2-sulfatasa.Objetivo: Estudiamos los niños con enfermedad de Hunter evaluados en nuestro hospital en el período 1994-2000, y analizamos las principales características clínicas, diagnósticas y terapéuticas de esta mucopolisacaridosis. Pacientes y métodos. Revisamos los antecedentes familiares, motivo de consulta, hallazgos clínicos, estudio diagnóstico, tratamiento y evolución de 4 niños con este trastorno. Resultados. En tres de los pacientes había antecedentes familiares sugestivos de mucopolisacaridosis. El cuadro clínico característico (fenotipo Hurler) era llamativo desde el inicio de la enfermedad en los tres casos severos. En todos los pacientes se constató un aumento de glucosaminoglucanos en orina y una disminución de la actividad de iduronato-2-sulfatasa en suero y/o fibroblastos. En los 4 niños se realizó análisis molecular mediante amplificación por reacción en cadena de la polimerasa (PCR). En el caso moderado se llevó a cabo trasplante de médula ósea de un donante idéntico familiar, falleciendo 33 días después. (AU)
Subject(s)
Child, Preschool , Infant , Male , Humans , Mucopolysaccharidosis II/diagnosis , Glycosaminoglycans/urine , Iduronate Sulfatase/metabolism , Mucopolysaccharidosis II/physiopathology , Mucopolysaccharidosis II/genetics , Polymerase Chain ReactionABSTRACT
Gaucher's disease is caused by mutations in the gene encoding glucocerebrosidase. The D409H mutation is the third most frequent mutation in Spain and has been associated with a particular phenotype, including oculomotor apraxia and cardiac valvular calcifications in late childhood. We report a 4-year-old patient, homozygous for the D409H mutation, who was diagnosed with Gaucher's disease at the age of 45days. Enzyme replacement therapy was started at the age of 2months. We report the patient's evolution after 4years of treatment.
Subject(s)
Gaucher Disease/drug therapy , Gaucher Disease/genetics , Glucosylceramidase/therapeutic use , Child, Preschool , Genotype , Humans , Infant , Male , SpainABSTRACT
La enfermedad de Gaucher se debe a mutaciones en el gen que codifica la glucocerebrosidasa. La mutación D409H es la tercera más frecuente en España y produce un fenotipo particular con apraxia oculomotora y calcificaciones cardiovasculares de presentación tardía. Se comunica un paciente de 4 años de edad, homozigoto para la mutación D409H, que fue díagnosticado a los 45 días de vida y que inició tratamiento enzimático sustitutivo a la edad de 2 meses. Se expone su evolución a los 4años de tratamiento (AU)
