Deleterious and oncogenic mutations in the IL7RA

Interleukin 7 (IL-7) is a critical cytokine that plays a fundamental role in B- and T-cell development and in acute lymphoblastic leukemia (ALL). Its receptor (IL7R) is a transmembrane heterodimer formed by the IL7R alpha and the IL2R gamma chain (gamma c). The IL7R signals through the JAK/STAT pathway. Loss-of-function mutations and some polymorphisms of the IL7R alpha were associated to immunodeficiency and inflammatory diseases, respectively. Gain-of-function mutations were described in T-cell ALL and in high risk precursor B-cell ALL. Most confirmed loss-of-function mutations occur in the extracellular part of the IL7R alpha while oncogenic mutations are exclusively found in the extracellular juxtamembrane (EJM) or transmembrane regions. Oncogenic mutations promote either IL7R alpha/IL7R alpha homodimerization and constitutive signaling, or increased affinity to gamma c or IL-7. This work presents a review on IL7R alpha polymorphisms/mutations and attempts to present a classification based on their structural consequences and resulting biological activity1112CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP305896/2013-0; 301596/2017-4sem informação2/12802-1; 14/20015-

Oral mucositis in pediatric acute lymphoblastic leukemia patients: evaluation of microbiological and hematological factors

To investigate the associations of oral microbiota, leucocytes count, neutrophil count, platelet counts and hemoglobin level, and the severity of oral mucositis in pediatric patients with acute lymphoblastic leukemia (ALL) receiving chemotherapy. 71 prospective patients were included. Analyses of oral microbiota and blood sample were conducted on days 14 (D14) and 56 (D56) of the Brazilian GBTLI-99 treatment protocol. Herpes simplex virus (HSV) identification was performed by PCR followed by DNA sequencing analysis. Bacteria and fungi identification was obtained by standard microbiological culture tests. 103 episodes of mucositis occurred, being 65 at D14 and 38 at D56. Most cases positive for herpes viral DNA sequences were identified as HSV-1. At D14, we found a significant association between the severity of mucositis and presence of HSV-1 (p = 0.0347), Candida spp. (p = 0.0078), and low platelet count (p = 0.0064). At D56, we found a significant association between the severity of mucositis and the presence of HSV-1 (p = 0.0317), previous HSV-1 presence on D14 (p < 0.0001) and neutrophil count (p = 0.0211). Clinical relevance: the identification of risk factors for mucositis in children and adolescents may contribute to the development of new strategies for prevention and/or treatment, reducing the complications associated with this condition. The presence of HSV, platelet count, and Candida spp. presence at D14 of ALL induction treatment is associated with increased severity of mucositis in children and adolescents. At D56 of ALL treatment, mucositis severity was associated with neutrophil count, HSV presence, and previous presence of HSV (at D14).325322330FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPES

Downregulation Of 14q32 Micrornas In Primary Human Desmoplastic Medulloblastoma.

Medulloblastoma (MB) is one of the most common pediatric cancers, likely originating from abnormal development of cerebellar progenitor neurons. MicroRNA (miRNA) has been shown to play an important role in the development of the central nervous system. Microarray analysis was used to investigate miRNA expression in desmoplastic MB from patients diagnosed at a young age (1 or 2 years old). Normal fetal or newborn cerebellum was used as control. A total of 84 differentially expressed miRNAs (64 downregulated and 20 upregulated) were found. Most downregulated miRNAs (32/64) were found to belong to the cluster of miRNAs at the 14q32 locus, suggesting that this miRNA locus is regulated as a module in MB. Possible mechanisms of 14q32 miRNAs downregulation were investigated by the analysis of publicly available gene expression data sets. First, expression of estrogen-related receptor-γ (ESRRG), a reported positive transcriptional regulator of some 14q32 miRNAs, was found downregulated in desmoplastic MB. Second, expression of the parentally imprinted gene MEG3 was lower in MB in comparison to normal cerebellum, suggesting a possible epigenetic silencing of the 14q32 locus. miR-129-5p (11p11.2/7q32.1), miR-206 (6p12.2), and miR-323-3p (14q32.2), were chosen for functional studies in DAOY cells. Overexpression of miR-129-5p using mimics decreased DAOY proliferation. No effect was found with miR-206 or miR-323 mimics.325

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Downregulation of 14q32 microRNAs in primary human desmoplastic medulloblastoma.

Medulloblastoma (MB) is one of the most common pediatric cancers, likely originating from abnormal development of cerebellar progenitor neurons. MicroRNA (miRNA) has been shown to play an important role in the development of the central nervous system. Microarray analysis was used to investigate miRNA expression in desmoplastic MB from patients diagnosed at a young age (1 or 2 years old). Normal fetal or newborn cerebellum was used as control. A total of 84 differentially expressed miRNAs (64 downregulated and 20 upregulated) were found. Most downregulated miRNAs (32/64) were found to belong to the cluster of miRNAs at the 14q32 locus, suggesting that this miRNA locus is regulated as a module in MB. Possible mechanisms of 14q32 miRNAs downregulation were investigated by the analysis of publicly available gene expression data sets. First, expression of estrogen-related receptor γ (ESRRG), a reported positive transcriptional regulator of some 14q32 miRNAs, was found downregulated in desmoplastic MB. Second, expression of the parentally imprinted gene MEG3 was lower in MB in comparison to normal cerebellum, suggesting a possible epigenetic silencing of the 14q32 locus. miR-129-5p (11p11.2/7q32.1), miR-206 (6p12.2), and miR-323-3p (14q32.2), were chosen for functional studies in DAOY cells. Overexpression of miR-129-5p using mimics decreased DAOY proliferation. No effect was found with miR-206 or miR-323 mimics

SequÊncias De Dna, Kit E Uso Para A DetecÇÃo Da MutaÇÃo Tp53 R337h

Resumo não disponível.BR102012031182 (A2)C12N15/11C12Q1/68BR20121031182C12N15/11C12Q1/6

Detection of Clonal Immunoglobulin and T-Cell Receptor Gene Rearrangements in Childhood Acute Lymphoblastic Leukemia Using a Low-Cost PCR Strategy

Background Imunoglobulin (Ig) and T cell receptor (TCR) gene rearrangements function as specific markers for minimal residual disease (MRD) which is one of the best predictors of outcome in childhood acute lymphoblastic leukemia (ALL) We recently reported on the prognostic value of MRD during the induction of remission through a simplified PCR method Here we report on gene rearrangement frequencies and offer guidelines for the application of the technique Procedure Two hundred thirty three children had DNA extracted from bone marrow Ig and TCR gene rearrangements were amplified using consensus primers and conventional PCR PCR products were submitted to homo/heteroduplex analysis A computer program was designed to define combinations of targets for clonal detection using a minimum set of primers and reactions Results At least one clonal marker could be detected in 98% of the patients and two markers in approximately 80% the most commonly rear ringed genes in precursor B cell ALL were IgH (75%) TCRD (59%) IgK (55%), and TCRG (54%) the most commonly rearranged genes for TALL were TCRG (100%) and TCRD (24%) the sensitivity of primers was limited to the detection of 1 leukemic cell among 100 normal cells Conclusions We propose that eight PCR reactions per ALL subtype would allow for the detection of two markers in most cases in addition these reactions ire suitable for MRD monitoring especially when aiming the selection of patients with high MRD levels (>= 10(-2)) at the end of induction therapy Such an approach would be very useful in centers with limited financial resources Pediatr Blood Cancer 2010 55 1278-1286 (C) 2010 Wiley Liss IncFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Ctr Infantil Boldrini, Mol Biol Lab, BR-13083210 Campinas, SP, BrazilH Lee Moffitt Canc Ctr & Res Inst, Dept Integrat Math Oncol, Tampa, FL USAUniv São Paulo, Dept Pediat, Ribeirao Preto Med Sch, BR-14049 Ribeirao Preto, BrazilUniv Estadual Campinas, Dept Pediat, Campinas, SP, BrazilFAPESP: 05/02279-6Web of Scienc

Oncogenic basic amino acid insertions at the extracellular juxtamembrane region of IL7Rα cause receptor hypersensitivity

sem informação1331112591263CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP305896/2013-0; 301596/2017-4sem informação12/12802-1; 14/20015-5; 10/16947-9; 13/08293-7Fundacao de Amparo a Pesquisa do Estado de Sao PauloFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [12/12802-1, 14/20015-5, 10/16947-9, 13/08293-7]; National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [APP1084797]; Fundacao de Amparo a Pesquisa do Estado de Sao PauloFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); Coordenacao de Aperfeicoamento de Pessoal de Nivel SuperiorCAPES; Brazilian National Counsel of Technological and Scientific Development (CNPq)National Council for Scientific and Technological Development (CNPq) [305896/2013-0, 301596/2017-4