Adult B-Cell Acute Lymphoblastic Leukemia Cells Display Decreased PTEN Activity and Constitutive Hyperactivation of PI3K/Akt Pathway Despite High PTEN Protein Levels

Adult B-cell acute lymphoblastic leukemia remains a major therapeutic challenge, requiring a better characterization of the molecular determinants underlying disease progression and resistance to treatment. Here, using a phospho-flow cytometry approach we show that adult diagnostic B-cell acute lymphoblastic leukemia specimens display PI3K/Akt pathway hyperactivation, irrespective of their BCR-ABL status and despite paradoxically high basal expression of PTEN, the major negative regulator of the pathway. Protein kinase CK2 is known to phosphorylate PTEN thereby driving PTEN protein stabilization and concomitant PTEN functional inactivation. In agreement, we found that adult B-cell acute lymphoblastic leukemia samples show significantly higher CK2 kinase activity and lower PTEN lipid phosphatase activity than healthy controls. Moreover, the clinical-grade CK2 inhibitor CX-4945 (Silmitasertib) reversed PTEN levels in leukemia cells to those observed in healthy controls, and promoted leukemia cell death without significantly affecting normal bone marrow cells. Our studies indicate that CK2-mediated PTEN posttranslational inactivation, associated with PI3K/Akt pathway hyperactivation, are a common event in adult B-cell acute lymphoblastic leukemia and suggest that CK2 inhibition may constitute a valid, novel therapeutic tool in this malignancy.

Dynamics of Epileptic Activity in a Peculiar Case of Childhood Absence Epilepsy and Correlation with Thalamic Levels of GABA

Childhood absence epilepsy (CAE) is a syndrome with well-defined electroclinical features but unknown pathological basis. An increased thalamic tonic GABA inhibition has recently been discovered on animal models (Cope et al., 2009), but its relevance for human CAE is unproven. METHODS: We studied an 11-year-old boy, presenting the typical clinical features of CAE, but spike-wave discharges (SWD) restricted to one hemisphere. RESULTS: High-resolution EEG failed to demonstrate independent contralateral hemisphere epileptic activity. Consistently, simultaneous EEG-fMRI revealed the typical thalamic BOLD activation, associated with caudate and default mode network deactivation, but restricted to the hemisphere with SWD. Cortical BOLD activations were localized on the ipsilateral pars transverse. Magnetic resonance spectroscopy, using MEGA-PRESS, showed that the GABA/creatine ratio was 2.6 times higher in the hemisphere with SWD than in the unaffected one, reflecting a higher GABA concentration. Similar comparisons for the patient's occipital cortex and thalamus of a healthy volunteer yielded asymmetries below 25%. SIGNIFICANCE: In a clinical case of CAE with EEG and fMRI-BOLD manifestations restricted to one hemisphere, we found an associated increase in thalamic GABA concentration consistent with a role for this abnormality in human CAE.

Sintomatologia intestinal na fase crônica da esquistossomose mansoni

Com o objetivo de investigar os sintomas intestinais na fase crônica da esquistossomose mansoni, estudamos 102 indivíduos na faixa etária de nove a dezenove anos, dos 144previamente selecionados entre os moradores autóctones dos distritos de Lagoa Redonda e Menezes, portadores de Schistosoma mansoni. Todos foram submetidos a uma anamnese segmentar com a finalidade de detectara presença de cinco sintomas intestinais: dor abdominal, diarréia, muco e rajas de sangue nas fezes e enterorragia. Metade dos pacientes foi medicada com mebendazole e posteriormente com oxamniquine, constituindo-se no grupo caso, enquanto a outra metade, tratada apenas com mebendazole, constituiu-se no grupo controle. Os resultados mostram que a esquistossomose é provavelmente a responsável pelas queixas de muco e/ou rajas de sangue nas fezes, ocorrendo uma redução dessas queixas, estatisticamente significante, após a terapêutica específica.

Identification of mechanisms controlling the transcriptional activity of nuclear factor kappa B (NF-κB) p65/RelA

Dissertação para a obtenção do grau de doutor em Biologia pelo Instituto de Tecnologia Química e Biológica. Universidade Nova de Lisboa.

Isoniazid acetylating phenotype in patients with paracoccidioidomycosis and its relationship with serum sulfadoxin levels, glucose-6-phosphate dehydrogenase and glutathione reductase activities

The authors evaluated the isoniazid acetylating phenotype and measured hematocrit, hemoglobin, glucose-6-phosphate dehydrogenase and glutathione reductase activities plus serum sulfadoxin levels in 39 patients with paracoccidioidomycosis (33 males and 6 females) aged 17 to 58 years. Twenty one (53.84%) of the patients presented a slow acetylatingphenotype and 18(46.16%) a fast acetylating phenotype. Glucose-6-phosphate- dehydrogenase (G6PD) acti vity was decreased in 5(23.80%) slow acetylators and in 4(22.22%) fast acetylators. Glutathione reductase activity was decreased in 14 (66.66%) slow acetylators and in 12 (66.66%) fast acetylators. Serum levels of free and total sulfadoxin Were higher in slow acetylator (p < 0.02). Analysis of the resultspermitted us to conclude that serum sulfadoxin levels are related to the acetylatorphenotype. Furthermore, sulfadoxin levels were always above 50 µg/ml, a value considered therapeutic. Glutathione reductase deficiency observed in 66% of patients may be related to the intestinal malabsorption of nutrients, among them riboflavin, a FAD precursor vitamin, inpatients with paracoceidioidomycosis.

Caso fatal de balantidíase intestinal

Caso fatal de balantidíase em mulher desnutrida de 63 anos, criadora de porcos, da zona rural de Uberaba. A doença evoluiu em oito dias com disenteria, náusea e vômitos, culminando em óbito por enterorragia. A necropsia constatou-se colite ulcerada causada por B. coli, facilmente identificado ao exame histológico do intestino grosso.

Intestinal helminthiases in Ecuador: the relatíonship between prevalence, genetic, and socioeconomic factors

Prevalence of infection with the intestinal helminths, Ascaris lumbricoides, Trichuris trichiura, Ancylostoma duodenale and Strongyloides stercoralis was examinedin 632 residents of communities in Esmeraldas province of Ecuador. These communities were divided into two groups according to area of habitation which reflected different socioeconomic circumstances. Attempts were made to correlate infection status with race and ABO blood group phenotype. The racial groups included blacks, Chachi amerindians, and mixed-race mestizos. Greater prevalences of infection were seen in the area oflower socioeconomic status. No racial or blood group associations with helminth infection were seen controlling for socioeconomic status.

Production and Characterization of the biological activity of peptides obtained via hydrolysis from whey proteins by cardosins

Dissertation presented to obtain the Ph.D degree in Biochemistry, Engineering and Technological Sciences

Antischistosomal activity of acridanone- hydrazones in Cebus monkeys experimentally infected with the SJ strain of Schistosoma mansoni

In this study, four compounds were utilized at the dose of 12.5mg/kg body weight, p.o., to treat Cebus monkeys experimentally infected with about 200 cercariae of Schistosoma mansoni (SJ strain), via transcutaneous route. The oograms performed with rectal snips, as well as stool examinations carried out periodically, showed no viable eggs of the parasite, from day 29 to 226post-treatment. The perfusion undertaken after killing the animals showed absence of worms in the treated monkeys, whereas 83 worms were recovered from the control, thus corroborating the results obtained by means of oograms and coproscopy. These results confirm the efficacy of 9-acridanone- hydrazones previously tested against the LE strain of S. mansoni. The low curative dose and apparent absence of toxicity render these dmgs an important therapeutic reserve, taking into consideration the reports on the resistance of S. mansoni to the modern drugs oxamniquine and praziquantel.

Enhancing physical activity coaching through personalized motivational strategies and self-adaptive goal-setting: development of self-adaptive processes in a monitoring and coaching smartphone application

Dissertação para obtenção do Grau de Mestre em Engenharia Biomédica