Biography:

Dr. Ben Valdez obtained his PhD in Biochemistry at Louisiana State Univ. He did his post-doctoral training at Baylor College of Medicine in Houston, TX and became an Assistant Professor. His laboratory cloned the genes and corresponding cDNAs for RNA helicase II/Gu α and β and discovered their functions. His lab identified the functions of treacle, encoded by the TCOF1 gene, in the expression and methylation of pre-ribosomal RNA. In 2005, he transferred to the Dept of  Stem Cell Transplantation and Cellular Therapy, UT MD Anderson Cancer Center where he is now an Associate Professor.  His current research focuses on the identification of safe and efficacious conditioning regimen for hematopoietic stem cell transplantation for patients with hematological disorders. He conceptualized and proved the efficacy of combined DNA alkylators, nucleoside analogs, and epigenetic modifiers in leukemia, lymphoma and multiple myeloma cells, and proposed a model called the “loop of death” to explain the cytotoxic synergism of these drugs. He developed an assay for cellular efflux of chemotherapeutic drugs which is relevant to understanding drug interactions.  Using this assay, Dr. Valdez discovered the differential effects of HDAC inhibitors on cellular drug transporters which have tremendous implications for using epigenetic modifiers in combination chemotherapy. The results of his pre-clinical studies have been used as bases for several clinical trials at UT MD Anderson Cancer Center

Abstract:

Statement of the Problem: Hematopoietic stem cell transplantation is an effective treatment for a variety of hematological disorders. Its success partly depends on the optimization of the pre-transplant conditioning regimen.

Methodology & Theoretical Orientation: To identify an efficacious regimen, we exposed cells to different drug combinations, analyzed their cytotoxicity and identified their molecular mechanisms of interaction using various techniques.

Findings: We have shown the synergistic cytotoxicity of DNA alkylating agents (AA) and nucleoside analogs (NA) in leukemia and lymphoma cells and proposed a mechanistic model called the “loop of death”. Exposure of cells to a nucleoside analog initiates DNA damage resulting in chromatin remodeling and makes genomic DNA more susceptible to DNA alkylation. DNA damage response is then activated and the loop of DNA damage, chromatin remodeling, and DNA alkylation continues until the tumor cells commit to apoptosis. Using this model and the [AA+NA] combination as a backbone to identify drugs that may further enhance its anti-tumor activity, we hypothesized that epigenetic modifiers would amplify the loop of death. Indeed, inhibitors of histone deacetylases (HDACi) and DNA methyl transferases (DNMTi), which facilitate relaxation of chromatin, were found to be synergistic with [AA+NA]. Since active DNA repair may contribute to decreased efficacy of these drug combinations, we also examined the inclusion of DNA repair inhibitors such as olaparib. Addition of olaparib to [AA+NA] caused significant apoptosis by activation of the DNA-damage response, inhibition of PARP activity and DNA repair, production of reactive oxygen species and depolarization of the mitochondrial membranes.

Conclusion & Significance: Our pre-clinical studies have been translated to the clinic and results from some of our clinical trials will be presented. Overall, our pre-clinical and clinical results suggest that the conditioning regimen for HSCT may be optimized by combining drugs that provide synergistic cytotoxicity based on their molecular mechanisms of action.

Biography:

Katarzyna Miranowicz-Dzierżawska works in Laboratory of Toxicology, a part of the Department of Chemical, Aerosol and Biological Hazards in the Central Institute for Labour Protection – National Research Institute. She was graduated from the Faculty of Pharmacy (specialization: pharmaceutical analysis) of the Medical University of Warsaw and she prepared her dissertation (Ph.D.): “The evaluation of interaction between chosen organic solvents” at the Collegium Medicum of Jagiellonian University, Cracow. The main area of her professional interest are problems of human in the working environment and the toxicity of chemical substances as well as methods of estimating the toxicity of substances in vitro. She was also engaged in preparation of documentation of maximum allowable levels of occupational exposure and characteristics of hazardous substances in the work of the Interdepartmental Committee mandated with updating and verification of the Threshold Limit Values (TLVs) for agents harmful to human health.

Abstract:

Statement of the Problem: Cell culture system could be a useful model for aging-related changes. The aim of the study was to assess whether there are differences between the results of determination of preservatives cytotoxicity obtained on senescent cells in different age.

Methodology & Theoretical Orientation: Experiments were conducted to determine the cytotoxicity of four preservatives: methylparaben, propylparaben, 2-phenoxyethanol and benzalkonium chloride on subsequent passages of senescent human lung CCD-8Lu (ATCC CCL-201TM) fibroblasts. The tests were carried out in passages no. 10 / 18. Xenobiotics cytotoxicity was evaluated using two cell viability assays: MTT assay, determining metabolic activity of cells, and NRU assay, assessing the integrity of cell membranes. The IC50 values were used as the main measure for comparing the cytotoxicity of tested compounds.

Findings: The results showed that the preservatives can be ranked according to the increasing cytotoxic potency towards the tested human diploid lung fibroblasts: 2-phenoxyethanol  methylparaben propylparaben benzalkonium chloride. Older cells became less susceptible then the younger ones with cytotoxic effects of the xenobiotics tested in the majority of cases.

Conclusion & Significance: The passage number of diploid human lung fibroblasts had an important impact on the susceptibility of cells to preservatives. The test of the integrity of cell membranes (NRU) seems to be more appropriate to assess the cytotoxic effect of the investigated preservatives on diploid fibroblasts in different ages, which may be related to the mechanism of action of these compounds.

Funding: This paper has been based on the results of a research task I.N.13 carried out within the scope of the fourth stage of the National Programme Improvement of safety and working conditions partly supported in 2017–2019 — within the scope of research and development — by the Ministry of Science and Higher Education/National Centre for Research and Development.

Biography:

Mahmoud Said has his knowledge in monitoring and counteracting the adverse effects of anti-biotics by using different antioxidant natural plants to reduce the mortality rate and health hazards resulting from antibiotic use. He has five years of experience in research, teaching and administration in hospital. His current position is director of the blood bank and he has experience in performing serological tests. 

Abstract:

Linezolid is one of the oxazolidinone anti-biotics that’s used to treat methicillin resistant staphylococcus aureus (MRSA) & vancomycin resistant staphylococcus aureus VRSA and was discovered in the 1990s and first approved for use in 2000. This study was aimed to investigate the adverse effects of linezolid on bone marrow, brain & kidney damaging effect of linezolid and counteracting these adverse effects using Phoenix dactylifera methanolic extract in rats. It was found that oral administration of linezolid (100 mg/kg body weight) given for 14 successive days induced a significant decrease in hemoglobin content (7.88±0.18 g/L) on the first day post-treatment, significant increase in serum urea (59.75±0.85) & serum creatinine (1.89±0.04) on the 14th day post- treatment and induced mild brain damage on the first day post treatment. The concurrent oral administration of Phoenix dactylifera methanolic extract (1000 mg/kg body weight) and linezolid (100 mg/kg body weight) for the same period corrected the damaging effects of linezolid of the hemoglobin content, urea, creatinine & brain condition of treated rats. It was concluded that methanolic extract of phoenix dactylifera clearly ameliorated these damaging effects of linezolid.