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1.
BMJ Open ; 10(1): e029642, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31919123

RESUMO

INTRODUCTION: Acute myeloblastic leukaemia (AML) constitutes the second most common haematological malignancy in the paediatric population. Current treatment regimens are based on the administration of polychemotherapy, combining high doses of cytarabine with anthracyclines and topoisomerase inhibitors. Allogeneic haematopoietic stem cell transplantation (HSCT) is an option for high-risk patients with AML (and for intermediate-risk patients if a sibling donor is available). With this strategy, AML survival has increased substantially; however, it has remained stagnant at approximately 60%, with relapse being the principal culprit. The predominant role of the immune system and natural killer (NK) cells in controlling paediatric AML has gained importance within the context of HSCT. In this protocol, we propose incorporating this cell therapy as an adjuvant treatment through the infusion of activated and expanded haploidentical NK (NKAE) cells in paediatric patients with AML who are in cytological remission after completing consolidation therapy, and with no indication for HSCT. METHODS AND ANALYSIS: Patients up to 30 years of age, diagnosed with AML, in their first cytological remission, who have completed both the induction and the consolidation phases of chemotherapy and do not meet the criteria for allogeneic HSCT are eligible. The patients will receive two doses of NKAE cells once a week, using a GMP K562-mbIL15-41BBL stimulus from a haploidentical donor and interleukin 2 subcutaneously. The patients will then be followed up for 36 months to assess the primary endpoint, which is the probability of relapse after NK cell infusion. ETHICS AND DISSEMINATION: This clinical trial was approved by the Clinical Research Ethics Committee of La Paz University Hospital and The Spanish Agency of Medicines and Medical Devices. Findings will be disseminated through peer-reviewed publications, conference presentations and community reporting. TRIAL REGISTRATION NUMBER: EudraCT code: 2015-001901-15, ClinicalTrials.gov Identifier: NCT02763475.

2.
Epigenomics ; 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31833405

RESUMO

Despite remarkable improvements in survival of childhood acute lymphoblastic leukemia (ALL), nonresponding or relapsing patients still represent one of the most frequent causes of death by disease in children. Accurate patient risk stratification based on genetic markers could increases survival rates. miRNAs can represent novel candidates with diagnostic, predictive and prognostic potential; however, many groups investigated their involvement with contradictory results. Aim: To clarify the role of miRNAs as biomarkers through a systematic review. Results: From a revision of 45 manuscripts, we found that miR-128 and miR-181 overexpression could represent markers for ALL diagnosis and underexpression of miR-708 and miR-99a could be markers for bad prognosis. Conclusion: These signatures could refine classification and risk stratification of patients and improve ALL outcome.

3.
Blood ; 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31738823

RESUMO

Pediatric large B-cell lymphomas (LBCL) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children, suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse large B-cell lymphomas, not otherwise specified (DLBCL, NOS), 20 LBCL-IRF4, and 12 high grade B-cell lymphomas, NOS (HGBCL, NOS) in patients {less than or equal to}25 years-old using an integrated approach including targeted gene sequencing, copy number arrays and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-kB pathway genes (CARD11, CD79B and MYD88), losses of 17p13 and gains of chr7, 11q12.3-q25 whereas DLBCL,NOS were predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (e.g. SOCS1 and KMT2D), gains of 2p16/REL and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma related genes such as MYC, ID3 and DDX3X and homozygous deletions of 9p21/CDKN2A whereas other cases were genetically closer to GCB-DLBCL. Factors related to unfavorable outcome were age >18y old, activated B-cell DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric/young-adult LBCL, improve the classification of this group of tumors and provide new parameters for risk stratification.

4.
Sci Rep ; 9(1): 13067, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506554

RESUMO

Inborn errors of metabolism (IEMs) are rare diseases produced by the accumulation of abnormal amounts of metabolites, toxic to the newborn. When not detected on time, they can lead to irreversible physiological and psychological sequels or even demise. Metabolomics has emerged as an efficient and powerful tool for IEM detection in newborns, children, and adults with late onset. In here, we screened urine samples from a large set of neonates (470 individuals) from a homogeneous population (Basque Country), for the identification of congenital metabolic diseases using NMR spectroscopy. Absolute quantification allowed to derive a probability function for up to 66 metabolites that adequately describes their normal concentration ranges in newborns from the Basque Country. The absence of another 84 metabolites, considered abnormal, was routinely verified in the healthy newborn population and confirmed for all but 2 samples, of which one showed toxic concentrations of metabolites associated to ketosis and the other one a high trimethylamine concentration that strongly suggested an episode of trimethylaminuria. Thus, a non-invasive and readily accessible urine sample contains enough information to assess the potential existence of a substantial number (>70) of IEMs in newborns, using a single, automated and standardized 1H- NMR-based analysis.

5.
An Pediatr (Barc) ; 91(2): 127.e1-127.e10, 2019 Aug.
Artigo em Espanhol | MEDLINE | ID: mdl-31178291

RESUMO

Primary immune thrombocytopenia, formerly known as immune thrombocytopenic purpura, is a disease for which the clinical and therapeutic management has always been controversial. The ITP working group of the Spanish Society of Paediatric Haematology and Oncology has updated its guidelines for diagnosis and treatment of primary immune thrombocytopenia in children, based on current guidelines, bibliographic review, clinical assays, and member consensus. The main objective is to reduce clinical variability in diagnostic and therapeutic procedures, in order to obtain best clinical results with minimal adverse events and good quality of life.

6.
Pharmacogenomics J ; 19(6): 564-569, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30723315

RESUMO

Vincristine is an important drug of acute lymphoblastic leukemia (ALL) treatment protocols that can cause neurotoxicity. Patients treated with LAL/SHOP protocols often suffer from vincristine-related neurotoxicity in early phases of treatment. A genetic variant in CEP72, a gene involved in vincristine pharmacodynamics, was recently associated with neurotoxicity after prolonged vincristine treatment. This association was not replicated in our Spanish population during induction phase. To test the possibility that other variants in genes involved in vincristine pharmacodynamics were associated with vincristine neuropathy in early phases of the treatment, we evaluated the correlation with toxicity of 24 polymorphisms in 9 key genes in a large cohort of 152 Spanish children with B-ALL homogeneously treated. Results showed no association between any genetic variant in the TUBB1, TUBB2A, TUBB2B, TUBB3, TUBB4, MAPT, MIR146a, MIR202, and MIR411 genes and vincristine-related neurotoxicity. These results are in line with the hypothesis that there are different mechanisms causing pheripheral neurotoxicity after prolonged and short-term vincristine treatments.

7.
Haematologica ; 104(9): 1822-1829, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30733272

RESUMO

Burkitt-like lymphoma with 11q aberration is characterized by pathological features and gene expression profile resembling those of Burkitt lymphoma but lacks the MYC rearrangement and carries an 11q-arm aberration with proximal gains and telomeric losses. Whether this lymphoma is a distinct category or a particular variant of other recognized entities is controversial. To improve the understanding of Burkitt-like lymphoma with 11q aberration we performed an analysis of copy number alterations and targeted sequencing of a large panel of B-cell lymphoma-related genes in 11 cases. Most patients had localized nodal disease and a favorable outcome after therapy. Histologically, they were high grade B-cell lymphoma, not otherwise specified (8 cases), diffuse large B-cell lymphoma (2 cases) and only one was considered as atypical Burkitt lymphoma. All cases had a germinal center B-cell signature and phenotype with frequent LMO2 expression. The patients with Burkitt-like lymphoma with 11q aberration had frequent gains of 12q12-q21.1 and losses of 6q12.1-q21, and lacked common Burkitt lymphoma or diffuse large B-cell lymphoma alterations. Potential driver mutations were found in 27 genes, particularly involving BTG2, DDX3X, ETS1, EP300, and GNA13 However, ID3, TCF3, or CCND3 mutations were absent in all cases. These results suggest that Burkitt-like lymphoma with 11q aberration is a germinal center-derived lymphoma closer to high-grade B-cell lymphoma or diffuse large B-cell lymphoma than to Burkitt lymphoma.

8.
J Allergy Clin Immunol ; 143(2): 700-711.e5, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29906528

RESUMO

BACKGROUND: Basophils express high-affinity IgE receptors (FcεRI), which play an essential role in allergic diseases. It is important to characterize new cell-surface receptors that modulate IgE-mediated basophil activation threshold to design promising immunomodulatory therapies. OBJECTIVES: We sought to analyze the expression of CD300 receptors on human basophils and their implication in IgE-mediated basophil activation processes. METHODS: Blood samples from healthy subjects and patients with cow's milk allergy were collected through the Basque Biobank under an institutional review board-approved protocol. PBMCs were obtained by means of density centrifugation, basophils were purified with a specific isolation kit, and phenotypic and functional studies were performed by using flow cytometry. RESULTS: We demonstrate that basophils express the activating receptor CD300c, which is specifically upregulated in response to IL-3. CD300c works as a costimulatory molecule during IgE-mediated basophil activation, as shown by a significant increase in degranulation and cytokine production when basophils are activated in the presence of CD300c cross-linking compared with activation through the IgE/FcεRI axis alone. Coligation of FcεRI and CD300c increased intracellular calcium mobilization and phosphorylation of signaling intermediates evoked only by FcεRI ligation. We show that the natural ligands of CD300c, phosphatidylserine and phosphatidylethanolamine, modulate IgE-mediated basophil activation. Furthermore, we have observed that CD300c expression in children with cow's milk allergy is increased compared with that in healthy control subjects and that the intensity of expression correlates with the severity of the hypersensitivity symptoms. CONCLUSION: CD300c could be considered a biomarker and therapeutic target in patients with IgE-mediated allergic diseases because it seems to be involved in the modulation of IgE-mediated basophil activation.

9.
Cancer ; 125(6): 963-971, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30521100

RESUMO

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the presence of abnormal CD1a-positive (CD1a+ )/CD207+ histiocytes. Hemophagocytic lymphohistiocytosis (HLH) represents a spectrum of hyperinflammatory syndromes typified by the dysregulated activation of the innate and adaptive immune systems. Patients with LCH, particularly those with multisystem (MS) involvement, can develop severe hyperinflammation mimicking that observed in HLH. Nevertheless, to the authors' knowledge, little is known regarding the prevalence, timing, risk factors for development, and outcomes of children and young adults who develop HLH within the context of MS-LCH (hereafter referred to LCH-associated HLH). METHODS: To gain further insights, the authors conducted a retrospective, multicenter study and collected data regarding all patients diagnosed with MS-LCH between 2000 and 2015. RESULTS: Of 384 patients with MS-LCH, 32 were reported by their primary providers to have met the diagnostic criteria for HLH, yielding an estimated 2-year cumulative incidence of 9.3% ± 1.6%. The majority of patients developed HLH at or after the diagnosis of MS-LCH, and nearly one-third (31%) had evidence of an intercurrent infection. Patient age <2 years at the time of diagnosis of LCH; female sex; LCH involvement of the liver, spleen, and hematopoietic system; and a lack of bone involvement each were found to be independently associated with an increased risk of LCH-associated HLH. Patients with MS-LCH who met the criteria for HLH had significantly poorer 5-year survival compared with patients with MS-LCH who did not meet the criteria for HLH (69% vs 97%; P < .0001). CONCLUSIONS: Given its inferior prognosis, further efforts are warranted to enhance the recognition and optimize the treatment of patients with LCH-associated HLH.

10.
Pharmacogenomics ; 19(18): 1403-1412, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30479191

RESUMO

AIM: Mucositis, linked to methotrexate, daunorubicin or cyclophosphamide, is a frequent childhood acute lymphoblastic leukemia (ALL) therapy side effect. miRNAs regulate the expression of pharmacokinetic/pharmacodynamic pathway genes. SNPs in miRNAs could affect their levels or function, and affect their pharmacokinetic/pharmacodynamic pathway target genes. Our aim was to determine the association between miRNA genetic variants targeting mucositis-related genes and mucositis-developing risk. PATIENTS & METHODS: We analyzed 160 SNPs in 179 Spanish children with B-cell precursor ALL homogeneously treated with LAL/SHOP protocols. RESULTS: We identified three SNPs in miR-4268, miR-4751 and miR-3117 associated with mucositis, diarrhea and vomiting, respectively. CONCLUSION: The effect of these SNPs on genes related to drug pharmacokinetics/pharmacodynamics could explain mucositis, diarrhea and vomiting development during ALL therapy.


Assuntos
Predisposição Genética para Doença/genética , MicroRNAs/genética , Mucosite/genética , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pré-Escolar , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Estudos Retrospectivos
11.
J Allergy Clin Immunol Pract ; 6(5): 1508-1517, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30201097

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome requiring aggressive immunosuppressive therapy. Following 2 large international studies mainly targeting pediatric patients with familial disease and patients without underlying chronic or malignant disease, the HLH-94 protocol is recommended as the standard of care when using etoposide-based therapy by the Histiocyte Society. However, in clinical practice, etoposide-based therapy has been widely used beyond the study inclusion criteria, including older patients and patients with underlying diseases (secondary HLH). Many questions remain around these extended indications and published reports do not address several practical issues. To tackle these concerns, the HLH Steering Committee of the Histiocyte Society decided to issue guidance for use of the HLH-94 protocol. The group convened in a structured consensus finding process to define recommendations that are based largely on expert opinion backed up by available data from the literature. The recommendations address all main elements of HLH-94 including corticosteroids, cyclosporin, etoposide, intrathecal therapy, and hematopoietic stem cell transplantation (HSCT) and consider various forms of HLH and all age groups. Aspects covered include indications, applications, dosing, side effects, duration of therapy, salvage therapy, and HSCT. These recommendations aim to provide a framework to guide treatment decisions in this severe disease.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Transplante de Medula Óssea , Etoposídeo/uso terapêutico , Histiócitos/imunologia , Linfócitos/imunologia , Linfo-Histiocitose Hemofagocítica/terapia , Consenso , Citotoxicidade Imunológica , Diretrizes para o Planejamento em Saúde , Humanos , Ativação Linfocitária , Linfo-Histiocitose Hemofagocítica/diagnóstico , Sociedades Médicas
12.
Blood ; 132(19): 2088-2096, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30104219

RESUMO

Asymptomatic carriers (ACs) of pathogenic biallelic mutations in causative genes for primary hemophagocytic lymphohistiocytosis (HLH) are at high risk of developing life-threatening HLH, which requires allogeneic hematopoietic stem cell transplantation (HSCT) to be cured. There are no guidelines on the management of these asymptomatic patients. We analyzed the outcomes of pairs of index cases (ICs) and subsequently diagnosed asymptomatic family members carrying the same genetic defect. We collected data from 22 HSCT centers worldwide. Sixty-four children were evaluable. ICs presented with HLH at a median age of 16 months. Seven of 32 ICs died during first-line therapy, and 2 are alive after chemotherapy only. In all, 23/32 underwent HSCT, and 16 of them are alive. At a median follow-up of 36 months from diagnosis, 18/32 ICs are alive. Median age of ACs at diagnosis was 5 months. Ten of 32 ACs activated HLH while being observed, and all underwent HSCT: 6/10 are alive and in complete remission (CR). 22/32 ACs remained asymptomatic, and 6/22 have received no treatment and are in CR at a median follow-up of 39 months. Sixteen of 22 underwent preemptive HSCT: 15/16 are alive and in CR. Eight-year probability of overall survival (pOS) in ACs who did not have activated HLH was significantly higher than that in ICs (95% vs 45%; P = .02), and pOS in ACs receiving HSCT before disease activation was significantly higher than in ACs receiving HSCT after HLH activation (93% vs 64%; P = .03). Preemptive HSCT in ACs proved to be safe and should be considered.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfo-Histiocitose Hemofagocítica/terapia , Criança , Pré-Escolar , Gerenciamento Clínico , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Linfo-Histiocitose Hemofagocítica/genética , Masculino , Mutação , Análise de Sobrevida , Resultado do Tratamento
13.
An. pediatr. (2003. Ed. impr.) ; 89(2): 124.e1-124.e8, ago. 2018. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-177023

RESUMO

El síndrome hemofagocítico (SHF) o linfohistiocitosis hemofagocítica es una entidad con elevada mortalidad, típicamente reconocida en la edad pediátrica. Sin un correcto tratamiento, el SHF puede ser fatal: el riesgo de una rápida progresión a fallo multiorgánico y de afectación del sistema nervioso central con secuelas a largo plazo, son las consecuencias más graves de un retraso diagnóstico. Por lo tanto, el SHF es una urgencia médica que los pediatras deben saber identificar en un paciente con fiebre y afectación progresiva del estado general. La aplicación de los criterios diagnósticos de SHF, que consideran datos clínicos y analíticos (incluyendo un aspirado de médula ósea), y la búsqueda del factor desencadenante (infeccioso, oncológico, reumatológico, metabólico), son claves para poder instaurar un tratamiento dirigido, que neutralice el desencadenante y frene la hiperinflamación. En la presente revisión se exponen los datos más relevantes sobre la fisiopatología, diagnóstico y tratamiento de esta grave enfermedad para pediatras generales


Haemophagocytic syndrome, or haemophagocytic lymphohistiocytosis (HLH), is a disorder with high mortality, typically recognised at paediatric age. Without proper treatment, HLH can be fatal. The risk of a rapid progression to multi-organ failure and central nervous system involvement leading to long-term sequelae, are the most feared consequences of a diagnostic delay. Therefore, HLH is a medical emergency that paediatricians should be able to identify in a patient with fever and progressive worsening of general condition. The application of the HLH diagnostic criteria, which include clinical and analytical data (as well as a bone marrow aspirate), and the search for a trigger (infectious, oncological, rheumatological, or metabolic). These are decisive for the establishment of a targeted treatment, which aims at neutralising the trigger and reducing the hyper-inflammation. The most relevant data for general paediatricians are presented in this review, including the physiopathology, diagnosis, and treatment of this serious disease


Assuntos
Humanos , Criança , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/terapia , Síndrome de Ativação Macrofágica/diagnóstico , Diagnóstico Precoce , Sepse , Síndrome de Ativação Macrofágica/fisiopatologia
15.
An Pediatr (Barc) ; 89(2): 124.e1-124.e8, 2018 Aug.
Artigo em Espanhol | MEDLINE | ID: mdl-29871839

RESUMO

Haemophagocytic syndrome, or haemophagocytic lymphohistiocytosis (HLH), is a disorder with high mortality, typically recognised at paediatric age. Without proper treatment, HLH can be fatal. The risk of a rapid progression to multi-organ failure and central nervous system involvement leading to long-term sequelae, are the most feared consequences of a diagnostic delay. Therefore, HLH is a medical emergency that paediatricians should be able to identify in a patient with fever and progressive worsening of general condition. The application of the HLH diagnostic criteria, which include clinical and analytical data (as well as a bone marrow aspirate), and the search for a trigger (infectious, oncological, rheumatological, or metabolic). These are decisive for the establishment of a targeted treatment, which aims at neutralising the trigger and reducing the hyper-inflammation. The most relevant data for general paediatricians are presented in this review, including the physiopathology, diagnosis, and treatment of this serious disease.


Assuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/terapia , Criança , Diagnóstico Precoce , Humanos
16.
Oncotarget ; 9(33): 22907-22914, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29796161

RESUMO

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Numerous studies have shown that microRNAs (miRNAs) could play a role in this disease. Nowadays, more than 2500 miRNAs have been described, that regulate more than 50% of genes, including those involved in B-cell maturation, differentiation and proliferation. Genetic variants in miRNAs can alter their own levels or function, affecting their target gene expression, and then, may affect ALL risk. Therefore, the aim of this study was to determine the role of miRNA genetic variants in B-ALL susceptibility. We analyzed all variants in pre-miRNAs (MAF > 1%) in two independent cohorts from Spain and Slovenia and inferred their functional effect by in silico analysis. SNPs rs12402181 in miR-3117 and rs62571442 in miR-3689d2 were associated with ALL risk in both cohorts, possibly through their effect on MAPK signalling pathway. These SNPs could be novel markers for ALL susceptibility.

17.
Epigenomics ; 10(4): 409-417, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29569486

RESUMO

AIM: Hepatotoxicity is one of the most common drug-related toxicities during the treatment of childhood acute lymphoblastic leukemia (ALL). Many genes involved in liver-specific signaling pathways are tightly controlled by miRNAs, and miRNA function could be modulated by SNPs. As a consequence, we hypothesized that variants in miRNAs could be associated with drug-induced hepatotoxicity. METHODS: We analyzed 213 SNPs in 206 miRNAs in a cohort of 179 children with ALL homogeneously treated. RESULTS: rs2648841 in miR-1208 was the most significant SNP during consolidation phase after false discovery rate correction, probably through an effect on its target genes DHFR, MTR and MTHFR. CONCLUSION: These results point out the possible involvement of SNPs in miRNAs in toxicity to chemotherapy in children with ALL.


Assuntos
Fígado/efeitos dos fármacos , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , MicroRNAs/química , Conformação de Ácido Nucleico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estudos Retrospectivos
18.
Pharmacogenomics ; 19(4): 361-373, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29469670

RESUMO

Childhood acute lymphoblastic leukemia survival rates have increased remarkably during last decades due, in part, to intensive treatment protocols. However, therapy resistance and toxicity are still two important barriers to survival. In this context, pharmacoepigenetics arises as a tool to identify new predictive markers, required to guide clinicians on risk stratification and dose individualization. The present study reviews current evidence about miRNA implication on childhood acute lymphoblastic leukemia therapy resistance and toxicity. A total of 12 studies analyzing differential miRNA expression in relation to drug resistance and six studies exploring the association between miRNAs-related SNPs and drug-induced toxicities were identified. We pointed out to miR-125b together with miR-99a and/or miR-100 overexpression as markers of vincristine resistance and rs2114358 in mir-1206 as mucositis marker as the most promising results.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , MicroRNAs/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animais , Humanos , Farmacogenética/métodos , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Taxa de Sobrevida
19.
Pharmacogenomics J ; 18(6): 704-712, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29282364

RESUMO

Vincristine (VCR), an important component of childhood acute lymphoblastic leukemia (ALL) therapy, can cause sensory and motor neurotoxicity. This neurotoxicity could lead to dose reduction or treatment discontinuation, which could in turn reduce survival. In this line, several studies associated peripheral neurotoxicity and polymorphisms in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) of VCR. Nowadays, it is well known that these genes are regulated by microRNAs (miRNAs) and SNPs in miRNAs could modify their levels or function. Therefore, the aim of this study was to determine whether SNPs in miRNAs could be associated with VCR-induced neurotoxicity. To achieve this aim, we analyzed all the SNPs in miRNAs (minor allele frequency (MAF) ≥ 0.01) which could regulate VCR-related genes in a large cohort of Spanish children with B-cell precursor ALL (B-ALL) homogeneously treated with LAL/SHOP protocols. We identified the A allele of rs12402181 in the seed region of miR-3117-3p, that could affect the binding with ABCC1 and RALBP1 gene, and C allele of rs7896283 in pre-mature sequence of miR-4481, which could be involved in peripheral nerve regeneration, significantly associated with VCR-induced neurotoxicity. These findings point out the possible involvement of two SNPs in miRNA associated with VCR-related neurotoxicity.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , MicroRNAs/genética , Doença dos Neurônios Motores/induzido quimicamente , Doença dos Neurônios Motores/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Transtornos das Sensações/induzido quimicamente , Transtornos das Sensações/genética , Vincristina/efeitos adversos , Transportadores de Cassetes de Ligação de ATP/genética , Idade de Início , Antineoplásicos Fitogênicos/administração & dosagem , Criança , Pré-Escolar , Feminino , Proteínas Ativadoras de GTPase/genética , Frequência do Gene , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Doença dos Neurônios Motores/diagnóstico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Farmacogenética , Testes Farmacogenômicos , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Transtornos das Sensações/diagnóstico , Espanha , Vincristina/administração & dosagem
20.
J Microbiol Immunol Infect ; 51(4): 465-472, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28655573

RESUMO

BACKGROUND: Sepsis is a life-threatening illness with a challenging diagnosis. Current serum biomarkers are not sensitive enough for diagnosis. With the aim of finding proteins associated with sepsis, serum protein profile was compared between patients and healthy donors and serum classical inflammatory proteins were analyzed in both groups. METHODS: Serum protein profiles were characterized by two-dimensional electrophoresis (2DE). Identification of the proteins was carried out by mass spectrophotometry and their validation was performed by Enzyme-Linked-ImmunoSorbent Assay (ELISA) in a cohort of 85 patients and 67 healthy donors. Seven classical inflammatory proteins were analyzed in the same cohort by ELISA: interleukin-2 receptor α-chain (sCD25), scavenger receptor cysteine-rich-type-1 (sCD163), tumor-necrosis factor receptor superfamily-member-6 (sFas), hemeoxigenase-1 decycling (HO-1), interleukin-6 (IL-6), interleukin-18 (IL-18) and intercellular adhesion-molecule-1 (sICAM-1). RESULTS: After 2DE, 20 significantly differently expressed spots were identified by mass spectrometry analysis, revealing deregulation of six different proteins upon sepsis and 50% were validated by ELISA: Antithrombin-III (AT-III), Clusterin (CLUS) and Serum amyloid A-1 (SAA-1). Serum concentration of AT-III and CLUS was significantly lower in patients' serum, whereas SAA-1 showed higher values in septic patients. Serum concentration of the seven inflammatory proteins was significantly increased in septic patients. Functional analysis of the ten deregulated proteins revealed an enrichment of proteins related mainly to the activation of the immune response. CONCLUSION: We have identified a panel of ten potential sepsis marker proteins biologically connected and validated in a large number of patients, whose analysis could be considered as a complementary tool for the diagnosis of sepsis.


Assuntos
Biomarcadores/sangue , Proteínas Sanguíneas/análise , Sepse/diagnóstico , Estudos de Coortes , Eletroforese em Gel Bidimensional , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade
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