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The drug l-asparaginase is a cornerstone in the treatment of acute lymphoblastic leukemia (ALL). The native E. coli l-asparaginase used in Brazil until recently has been manufactured by Medac/Kyowa. Then a decision was taken by the Ministry of Health in 2017 to supply the National Health System with a cheaper alternative l-asparaginase manufactured by Beijing SL Pharmaceutical, called Leuginase®. As opposed to Medac, the asparaginase that has been in use in Brazil under the trade name of Aginasa®, it was not possible to find a single entry with the terms Leuginase in the Pubmed repository. The apparent lack of clinical studies and the scarcity of safety information provided to the hospitals by the drug distributor created a debate among Brazilian pediatric oncologists about issues of safety and efficacy that culminated eventually in a court decision to halt the distribution of the new drug all over the country. Boldrini Children's Center, a non-profit pediatric oncohematology hospital, has conducted its own evaluation of Leuginase®. Mass spectrometry analyses found at least 12 different contaminating host-cell proteins (HCP) in Leuginase®. The presence of two HCP (beta-lactamase and malate dehydrogenase) was confirmed by orthogonal methodologies. The relative number of HCP peptides ranged from 19 to 37% of the total peptides identified by mass spectrometry. In vivo studies in mice injected with Leuginase® revealed a 3 times lower plasma bioavailability and the development of higher antibody titres against l-asparaginase in comparison to Aginasa®-injected animals. The decision to buy a new drug based on its price alone is not safe. Developing countries are especially vulnerable to cheaper alternatives that lack solid quality assurance. Keywords: l-Asparaginase, Host contaminant proteins, Mass spectrometry, Bioavailability, Immunogenicity

Abstract Background The spontaneous immortalization of primary malignant cells is frequently assigned to their genetic instability during in vitro culturing. In this study, the new epithelial ovarian cancer cell line CAISMOV24 was described and compared with its original low-grade serous ovarian carcinoma. Methods The in vitro culture was established with cells isolated from ascites of a 60-year-old female patient with recurrent ovarian cancer. The CAISMOV24 line was assessed for cell growth, production of soluble biomarkers, expression of surface molecules and screened for typical mutations found in serous ovarian carcinoma. Additionally, comparative genomic hybridization was employed to compare genomic alterations between the CAISMOV24 cell line and its primary malignant cells. Results CAISMOV24 has been in continuous culture for more than 30 months and more than 100 in vitro passages. The cell surface molecules EpCAM, PVR and CD73 are overexpressed on CAISMOV24 cells compared to the primary malignant cells. CAISMOV24 continues to produce CA125 and HE4 in vitro. Although the cell line had developed alongside the accumulation of genomic alterations (28 CNV in primary cells and 37 CNV in CAISMOV24), most of them were related to CNVs already present in primary malignant cells. CAISMOV24 cell line harbored KRAS mutation with wild type TP53, therefore it is characterized as low-grade serous carcinoma. Conclusion Our results corroborate with the idea that genomic alterations, depicted by CNVs, can be used for subtyping epithelial ovarian carcinomas. Additionally, CAISMOV24 cell line was characterized as a low-grade serous ovarian carcinoma, which still resembles its primary malignant cells.

Increased glycolytic metabolism plays an important role in B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL). We previously showed that IGFBP7 exerts mitogenic and prosuvival effects in ALL by promoting IGF1 receptor (IGF1R) permanence on the cell surface, thus prolonging Akt activation upon IGFs/insulin stimulation. Here, we show that sustained activation of the IGF1R–PI3K–Akt axis concurs with GLUT1 upregulation, which enhances energy metabolism and increases glycolytic metabolism in BCP-ALL. IGFBP7 neutralization with a monoclonal antibody or the pharmacological inhibition of the PI3K–Akt pathway was shown to abrogate this effect, restoring the physiological levels of GLUT1 on the cell surface. The metabolic effect described here may offer an additional mechanistic explanation for the strong negative impact seen in ALL cells in vitro and in vivo after the knockdown or antibody neutralization of IGFBP7, while reinforcing the notion that it is a valid target for future therapeutic interventions. [ABSTRACT FROM AUTHOR]

Vaccinium ashei Reade, popularly known as Rabbiteye blueberry, has several therapeutic properties attributed to the phenolic compounds present in its leaves and fruits. Here, we sought to evaluate the effects of the hydroalcoholic extract from V. ashei leaves (Bluegem cultivar, VAB) in T-cell Acute lymphoblastic leukemia (T-ALL). The VAB extract was toxic to T-ALL cells at the ∼60 µg/ml concentration. T-ALL cell death occurred through apoptosis. VAB extract was found to induce micronuclei formation, p53 pathway activation, and cell cycle arrest. Those mutagenic effects were evidenced through microscopy analysis and molecular p53 pathway activation. A series of phenolic compounds were identified in VAB extract by mass spectrometry, such as vanillic acid, catechin, caffeic acid, chlorogenic acid, rutin, coumaric acid, taxifolin, quercetin and naringenin, some of which are presumed to induce DNA damage. In conclusion, the V. ashei leaves extract may have important secondary metabolites with antileukemic properties. [ABSTRACT FROM AUTHOR]

Process related to power generation, i.e., extraction and burning of coal, strongly affects the soil, water resources, and air quality. Pollutants generated by the coal mining can lead to a number of environmental problems and has become matter of global concern. This study has focused on to evaluate the cytotoxicity and phytotoxicity of surface waters collected in the surroundings of the Thermoelectric Power Plant President Médici-UTPM (Candiota, Brazil), through Allium cepa bioassay and physicochemical analyzes. Three water samples collected at points P1, P2, and P3 were compared to the negative control (NC) for all variables analyzed. The P2 sample resulted in the lowest mitotic index (MI) values (23, 33.1, and 40.7%), followed by P1 (23, 33.1, and 40.7%). However, the P3 sample had the highest MI values (50.2, 40.1, and 36.3%) and was the most mutagenic sample compared to NC and other treatments. Samples P1, P2, and P3 were phytotoxic to A. cepa, resulting in abnormal seedlings. Through physicochemical analysis, all collected water samples showed high electrical conductivity and turbidity, indicating an increase in the deposition of metallic ions and organic compounds in these samples. Based on these findings, we can conclude that the analysis of surface water is an important step for screening mining areas potentially contaminated by coal compounds. Therefore, our study points out some consequences of mining process, in terms of A. cepa bioassay as well as their harmful effect on physicochemical constituents of surface waters, indicating the need for environmental monitoring of this region. [ABSTRACT FROM AUTHOR]