The Expression and Activation of the NF-κB Pathway Correlate with Methotrexate Resistance and Cell Proliferation in Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although its prognosis continually improves with time, a significant proportion of patients still relapse from the disease because of the leukemia's resistance to therapy. Methotrexate (MTX), a folic-acid antagonist, is a chemotherapy agent commonly used against ALL and as an immune-system suppressant for rheumatoid arthritis that presents multiple and complex mechanisms of action and resistance.

Glutathione levels are associated with methotrexate resistance in acute lymphoblastic leukemia cell lines.

Introduction: Methotrexate (MTX), a folic acid antagonist and nucleotide synthesis inhibitor, is a cornerstone drug used against acute lymphoblastic leukemia (ALL), but its mechanism of action and resistance continues to be unraveled even after decades of clinical use.

Methods: To better understand the mechanisms of this drug, we accessed the intracellular metabolic content of 13 ALL cell lines treated with MTX by 1H-NMR, and correlated metabolome data with cell proliferation and gene expression. Further, we validated these findings by inhibiting the cellular antioxidant system of the cells in vitro and in vivo in the presence of MTX.

Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population.

Background: The Hereditary Breast and Ovarian Cancer Syndrome (HBOC) occurs in families with a history of breast/ovarian cancer, presenting an autosomal dominant inheritance pattern. BRCA1 and BRCA2 are high penetrance genes associated with an increased risk of up to 20-fold for breast and ovarian cancer. However, only 20-30% of HBOC cases present pathogenic variants in those genes, and other DNA repair genes have emerged as increasing the risk for HBOC.

Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia.

Tubulin is one of the best validated anti-cancer targets, but most anti-tubulin agents have unfavorable therapeutic indexes. Here, we characterized the tubulin-binding activity, the mechanism of action, and the in vivo anti-leukemia efficacy of three 3,4,5-trimethoxy-N-acylhydrazones. We show that all compounds target the colchicine-binding site of tubulin and that none is a substrate of ABC transporters.

Synthesis and evaluation of 2-carboxy indole derivatives as potent and selective anti-leukemic agents.

Despite the success achieved in the treatment of acute lymphoblastic leukemia (ALL), the search for new drugs featuring selectivity against leukemia cells and effectiveness to prevent relapsed ALL is still highly desirable. Here, we described the synthesis of several novel 3-substituted and 3,6-disubstituted-2-carboalkoxy indoles followed by the elucidation of their mechanism of action and in vivo anti-leukemia efficacy. The synthesis of 3-substituted-2-carboalkoxy indoles relied on two Heck arylations of methyl acrylate and methyl cinnamates respectively, to generate β,β-disubstituted acrylates followed by an efficient Cadogan-Sundberg reaction of these latter intermediates.

Up-regulation of SPINT2/HAI-2 by Azacytidine in bone marrow mesenchymal stromal cells affects leukemic stem cell survival and adhesion.

The role of tumour microenvironment in neoplasm initiation and malignant evolution has been increasingly recognized. However, the bone marrow mesenchymal stromal cell (BMMSC) contribution to disease progression remains poorly explored. We previously reported that the expression of serine protease inhibitor kunitz-type2 (SPINT2/HAI-2), an inhibitor of hepatocyte growth factor (HGF) activation, is significantly lower in BMMSC from myelodysplastic syndromes (MDS) patients compared to healthy donors (HD).

Low Bioavailability and High Immunogenicity of a New Brand of E. colil-Asparaginase with Active Host Contaminating Proteins.

The drug l-asparaginase is a cornerstone in the treatment of acute lymphoblastic leukemia (ALL). The native E. colil-asparaginase used in Brazil until recently has been manufactured by Medac/Kyowa.

The Ala55Val and -866G>A polymorphisms of the UCP2 gene could be biomarkers for weight loss in patients who had Roux-en-Y gastric bypass.

Objective: The aim of this study was to investigate whether the Ala55Val and -866G>A polymorphisms of the UCP2 gene are related to weight loss and changes in body composition after bariatric surgery performed by Roux-en-Y gastric bypass (RYGB).

Methods: This longitudinal study enrolled obese patients submitted to RYGB. Data regarding weight (kg), body mass index (kg/m), fat-free mass (FFM; kg), fat mass (kg), weight loss (kg and %), and percent excess weight loss were collected from both preoperative and 1-y postoperative medical records.

Polymorphisms of the CYP1A1 and CYP2E1 genes in head and neck squamous cell carcinoma risk.

Polymorphisms in genes that encode P450 cytochrome enzymes may increase carcinogen activation or decrease their inactivation and consequently, promote the development of cancer. The aims of this study were to identify the MspI-CYP1A1, PstI-CYP2E1 and DraI-CYP2E1 polymorphisms in patients with head and neck cancer and to compare with individuals without cancer; to evaluate the association of these polymorphisms with risk factors and clinical histopathological parameters. In the study group, 313 patients were evaluated for CYP1A1, 217 for CYP2E1 (PstI) and 211 for CYP2E1 (DraI) and in the control group 417, 334 and 374 individuals, respectively.