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Guiyun Song, Daniel Banov, August S Bassani, Benigno C Valdez
The efficacy of active pharmaceutical ingredients (API) in compounded medications for oral mucosa greatly depends on the composition of the base. Here, we assessed the safety, facilitation of cell migration, and mucoadhesive properties of a newly developed mucoadhesive polymer blend (MPB) which contains pullulan, tamarindus indica polysaccharide, and sodium hyaluronate. No cell death was observed when human oral keratinocyte (HOK) and fibroblast (HOrF) cells were exposed to 1% MPB for 24 h. Epithelial cells in a 3D buccal tissue model (EpiOral) were unaffected when exposed to 50% MPB for 20 h whereas 1% Triton X-100 killed 93% cells after 4...
September 19, 2016: AAPS PharmSciTech
Cristóbal Chaidez, Juan R Ibarra-Rodríguez, José Benigno Valdez-Torres, Marcela Soto, Charles P Gerba, Nohelia Castro-Del Campo
OBJECTIVE: In developing countries, rural communities often face the lack of potable water infrastructure and must rely on untreated sources for drinking, which are often contaminated with waterborne pathogens. The use of home water treatment devices is seen as one means of reducing the risk of exposure to waterborne pathogens. The aim of this study was to evaluate the microbiological and physicochemical performance of a simple in-home point-of-use device based on gravity ultrafiltration through an ultrafilter membrane...
September 2016: Wilderness & Environmental Medicine
Benigno C Valdez, Yang Li, David Murray, Jonathan E Brammer, Yan Liu, Chitra Hosing, Yago Nieto, Richard E Champlin, Borje S Andersson
HDAC inhibitors, DNA alkylators and nucleoside analogs are effective components of combination chemotherapy. To determine a possible mechanism of their synergism, we analyzed the effects of HDAC inhibitors on the expression of drug transporters which export DNA alkylators. Exposure of PEER lymphoma T-cells to 15 nM romidepsin (Rom) resulted in 40%-50% reduction in mRNA for the drug transporter MRP1 and up to ~500-fold increase in the MDR1 mRNA within 32-48 hrs. MRP1 protein levels concomitantly decreased while MDR1 increased...
August 24, 2016: Oncotarget
Gheath Alatrash, Peter F Thall, Benigno C Valdez, Patricia S Fox, Jing Ning, Haven R Garber, Selma Janbey, Laura L Worth, Uday Popat, Chitra Hosing, Amin M Alousi, Partow Kebriaei, Elizabeth J Shpall, Roy B Jones, Marcos de Lima, Gabriela Rondon, Julianne Chen, Richard E Champlin, Borje S Andersson
Pretransplant conditioning regimens critically determine outcomes in the setting of allogeneic stem cell transplantation (allo-SCT). The use of nucleoside analogs such as fludarabine (Flu) in combination with i.v. busulfan (Bu) has been shown to be highly effective as a pretransplant conditioning regimen in acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS). Because leukemia relapse remains the leading cause of death after allo-SCT, we studied whether clofarabine (Clo), a nucleoside analog with potent antileukemia activity, can be used to complement Flu...
October 2016: Biology of Blood and Marrow Transplantation
Benigno C Valdez, Jonathan E Brammer, Yang Li, David Murray, Esmeralda C Teo, Yan Liu, Chitra Hosing, Yago Nieto, Richard E Champlin, Borje S Andersson
Novel approaches to pre-transplant conditioning are needed to improve treatment of advanced T-cell malignancies. We investigated the synergism of fludarabine (Flu), clofarabine (Clo), busulfan (Bu), and romidepsin (Rom) in T-cell lines and patient-derived cell samples. [Flu+Clo+Bu+Rom] had combination indexes of 0.4-0.5 at ∼50% cytotoxicity in PEER and SUPT1 cells, suggesting synergism. Drug exposure resulted in histone modifications, DNA-damage response (DDR), increased reactive oxygen species (ROS), decreased glutathione (GSH) and mitochondrial membrane (MM) potential, and apoptosis...
August 2016: Leukemia Research
Yago Nieto, Benigno C Valdez, Peter F Thall, Roy B Jones, Wei Wei, Alan Myers, Chitra Hosing, Sairah Ahmed, Uday Popat, Elizabeth J Shpall, Muzaffar Qazilbash, Alison Gulbis, Paolo Anderlini, Nina Shah, Qaiser Bashir, Amin Alousi, Yasuhiro Oki, Michelle Fanale, Bouthaina Dabaja, Chelsea Pinnix, Richard Champlin, Borje S Andersson
BACKGROUND: More active high-dose chemotherapy (HDC) regimens are needed for refractory lymphomas. The authors previously combined infusional gemcitabine with busulfan and melphalan (Gem/Bu/Mel) pursuing DNA damage repair inhibition. Subsequently, they combined Gem/Bu/Mel with vorinostat, which facilitates chemotherapy access to DNA. The resulting regimen was safe and synergistic. However, vorinostat induced DNA methyltransferase up-regulation, which could be preclinically abrogated by azacitidine, increasing tumor-cell kill...
September 1, 2016: Cancer
Esmeralda C Teo, Benigno C Valdez, Jie Ji, Yang Li, Yan Liu, Jonathan E Brammer, Chitra Hosing, Yago Nieto, Richard E Champlin, Borje S Andersson
DNA alkylators busulfan (B) and melphalan (M) act synergistically with gemcitabine (G) against lymphoma cells. To further improve the cytotoxicity, we combined them with the histone deacetylase inhibitor panobinostat (P) and proteasome inhibitor bortezomib (V). Lymphoma cell lines U937 and J45.01, and patient-derived cell samples were exposed to these drugs and the effects on cell proliferation and apoptosis were quantified. The combination BMGPV was found to exert strong synergistic cytotoxicity. Drug exposure to these cells activated the ATM pathway and modified histones at the epigenetic level...
November 2016: Leukemia & Lymphoma
Jie Ji, Benigno C Valdez, Yang Li, Yan Liu, Esmeralda C Teo, Yago Nieto, Richard E Champlin, Borje S Andersson
Hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with refractory lymphomas. Nucleoside analogs (NAs) and DNA alkylating agents are efficacious in treating hematologic malignancies. To design an efficacious and more economical pretransplant regimen for lymphoma patients, we analyzed the cytotoxicity of cladribine (Clad), gemcitabine (Gem), busulfan (Bu), and suberoylanilide hydroxamic acid (SAHA) in lymphoma cell lines. J45.01 and U937 lymphoma cell lines were exposed to drugs, alone or in combination, for 48 hours and analyzed with the MTT and annexin V assays, Western blotting, and flow cytometry...
June 2016: Experimental Hematology
Dalmira Félix-Urquídez, Melina Pérez-Urquiza, José-Benigno Valdez Torres, Josefina León-Félix, Raymundo García-Estrada, Abraham Acatzi-Silva
Certified reference materials (CRMs) are required to guarantee the reliability of analytical measurements. The CRMs available in the field of genetically modified organisms (GMOs) are characterized using real-time polymerase chain reaction (qPCR). This technology has limited application, because of its dependence on a calibrant. The objective of this study was to obtain a method with higher metrological quality, to characterize the CRMs for their contents of T-nos/hmg copy number ratio in maize. A duplex droplet digital PCR (ddPCR) assay was developed and optimized by a central composite design...
January 5, 2016: Analytical Chemistry
Yago Nieto, Benigno C Valdez, Peter F Thall, Sairah Ahmed, Roy B Jones, Chitra Hosing, Uday Popat, Elizabeth J Shpall, Muzaffar Qazilbash, Alison Gulbis, Paolo Anderlini, Amin Alousi, Nina Shah, Qaiser Bashir, Yan Liu, Yasuhiro Oki, Frederick Hagemeister, Michelle Fanale, Bouthaina Dabaja, Chelsea Pinnix, Richard Champlin, Borje S Andersson
More active high-dose regimens are needed for refractory/poor-risk relapsed lymphomas. We previously developed a regimen of infusional gemcitabine/busulfan/melphalan, exploiting the synergistic interaction. Its encouraging activity in refractory lymphomas led us to further enhance its use as a platform for epigenetic modulation. We previously observed increased cytotoxicity in refractory lymphoma cell lines when the histone deacetylase inhibitor vorinostat was added to gemcitabine/busulfan/melphalan, which prompted us to clinically study this four-drug combination...
November 2015: Biology of Blood and Marrow Transplantation
Benigno C Valdez, Yang Li, David Murray, Jie Ji, Yan Liu, Uday Popat, Richard E Champlin, Borje S Andersson
Clofarabine (Clo), fludarabine (Flu), and busulfan (Bu) combinations are efficacious in hematopoietic stem cell transplantation for myeloid leukemia. We sought to determine whether the more affordable drug cladribine (Clad) can provide a viable alternative to Clo, with or without panobinostat (Pano) and 5-aza-2'-deoxycytidine (DAC). Both Clad+Flu+Bu and Clo+Flu+Bu combinations showed synergistic cytotoxicity in KBM3/Bu250(6), HL60, and OCI-AML3 cell lines. Cell exposure to these drug combinations resulted in 60%-80% inhibition of proliferation; activation of the ATM pathway; increase in histone modifications; decrease in HDAC3, HDAC4, HDAC5 and SirT7 proteins; decrease in mitochondrial membrane potential; activation of apoptosis and stress signaling pathways; and downregulation of the AKT pathway...
June 2015: Experimental Hematology
Guiyun Song, Benigno C Valdez, Yang Li, Yan Liu, Richard E Champlin, Borje S Andersson
Clofarabine (Clo), fludarabine (Flu), and busulfan (Bu) are used in pretransplantation conditioning therapy for patients with myeloid leukemia. To further improve their efficacy in FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD)-positive acute myeloid leukemia (AML), we investigated their synergism with sorafenib (Sor). Exposure of FLT3-ITD-positive MV-4-11 and MOLM 13 cells to Bu+Clo+Flu+Sor resulted in synergistic cytotoxicity; no such synergism was observed in the FLT3-wild type THP-1 and KBM3/Bu250(6) cell lines...
November 2014: Biology of Blood and Marrow Transplantation
Guiyun Song, Benigno C Valdez, Yang Li, Jose R Dominguez, Paul Corn, Richard E Champlin, Borje S Andersson
Fludarabine (Flu), clofarabine (Clo) and busulfan (Bu) are used in allogeneic hematopoietic stem cell transplant (allo-HSCT). We reported that combining [Flu + Clo + Bu] had a synergistic cytotoxicity in AML cells. We hypothesized that combining [Flu + Clo + Bu] with the histone deacetylase inhibitor SAHA will further enhance cytotoxicity. We exposed the acute myeloid leukemia (AML) cell lines KBM3/Bu250(6) and OCI-AML3 to Flu, Clo, Bu and SAHA alone and in various combinations. [Flu + Clo + Bu + SAHA] resulted in synergistic cytotoxicity, which can be attributed to (1) activated DNA-damage response and cell cycle checkpoint activation through the ATM-CHK2-P53 (or P73) pathway or ATM-CHK2-cdc25-cdc2 pathway, (2) histone modifications and (3) activated apoptosis pathway...
July 2014: Leukemia & Lymphoma
Benigno C Valdez, Guiyun Wang, David Murray, Yago Nieto, Yang Li, Jatin Shah, Francesco Turturro, Michael Wang, Donna M Weber, Richard E Champlin, Muzaffar H Qazilbash, Borje S Andersson
Hematopoietic stem cell transplantation (HSCT) is an established treatment for multiple myeloma (MM), a plasma cell malignancy. To identify an improved pretransplant conditioning regimen, we investigated the cytotoxicity of gemcitabine (Gem) and clofarabine (Clo) combinations toward MM cell lines and patient cell samples. A strong synergism of the two nucleoside analogs, when combined at their approximate IC10 concentrations, was observed. This synergism could be partly due to the observed Gem-mediated phosphorylation and activation of deoxycytidine kinase, resulting in enhanced phosphorylation of Gem and Clo...
August 2013: Experimental Hematology
Benigno C Valdez, Yago Nieto, David Murray, Yang Li, Guiyun Wang, Richard E Champlin, Borje S Andersson
Hematopoietic stem cell transplantation is used for treatment of lymphoma. In an attempt to design an efficacious and safe prehematopoietic stem cell transplantation conditioning regimen, we investigated the cytotoxicity of the combination of busulfan (B), melphalan (M), and gemcitabine (G) in lymphoma cell lines in the absence or presence of drugs that induce epigenetic changes. Cells were exposed to drugs individually or in combination and analyzed by the MTT proliferation assay, flow cytometry, and Western blotting...
October 2012: Experimental Hematology
Carey L Shive, Angélique Biancotto, Nicholas T Funderburg, Heather A Pilch-Cooper, Hernan Valdez, Leonid Margolis, Scott F Sieg, Grace A McComsey, Benigno Rodriguez, Michael M Lederman
OBJECTIVE: Increased plasma IL-6 levels have been associated with HIV-1 disease progression risk, yet the drivers of IL-6 production in HIV-1 infection are not known. This study was designed to explore the relationship between HIV-1 replication and IL-6 induction. DESIGN: Correlations between plasma levels of IL-6 and HIV-1 RNA were examined in 2 clinical studies. To more directly assess the induction of IL-6 by HIV-1, several cell and tissue types that support HIV-1 replication in vivo were infected with HIV-1, and expression of IL-6 was measured...
October 1, 2012: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Benigno C Valdez, David Murray, Yago Nieto, Yang Li, Guiyun Wang, Richard E Champlin, Borje S Andersson
Hematopoietic stem cell transplant (HSCT) is a promising treatment for lymphomas. Its success depends on effective pre-transplant conditioning regimens. We previously reported on the efficacy of DNA alkylating agent-nucleoside analog (NA) combinations for conditioning in acute myeloid leukemia (AML). We hypothesized that a similar combinatory approach can be used for lymphomas. A combination of busulfan (Bu) with two NAs - clofarabine (Clo), fludarabine (Flu) or gemcitabine (Gem) - resulted in synergistic cytotoxicity in lymphoma cell lines...
May 2012: Leukemia & Lymphoma
Borje S Andersson, Benigno C Valdez, Marcos de Lima, Xuemei Wang, Peter F Thall, Laura L Worth, Uday Popat, Timothy Madden, Chitra Hosing, Amin Alousi, Gabriela Rondon, Partow Kebriaei, Elizabeth J Shpall, Roy B Jones, Richard E Champlin
Although a combination of i.v. busulfan (Bu) and fludarabine (Flu) is a safe, reduced-toxicity conditioning program for acute myelogenous leukemia/myelodysplastic syndromes (AML/MDS), recurrent leukemia posttransplantation remains a problem. To enhance the conditioning regimen's antileukemic effect, we decided to supplant Flu with clofarabine (Clo), and assayed the interactions of these nucleoside analogs alone and in combination with Bu in Bu-resistant human cell lines in vitro. We found pronounced synergy between each nucleoside and the alkylator but even more enhanced cytotoxic synergy when the nucleoside analogs were combined prior to exposing the cells to Bu...
June 2011: Biology of Blood and Marrow Transplantation
Benigno C Valdez, Yang Li, David Murray, Richard E Champlin, Borje S Andersson
DNA alkylating agents alone or with ionizing radiation have been the preferred conditioning treatment in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In search of less toxic alternatives, we hypothesized that combination of busulfan (Bu), fludarabine (Flu) and clofarabine (Clo) would provide superior efficacy. At low concentrations, these drugs show synergistic cytotoxicity in Bu-resistant AML KBM3/Bu250(6) cells. Similar molecular responses were observed in other AML cell lines and in primary explanted AML cells...
January 15, 2011: Biochemical Pharmacology
Benigno C Valdez, Borje S Andersson
Despite successful molecularly targeted, highly specific, therapies for hematologic malignancies, the DNA interstrand crosslinking agents, which are among the oldest and least specific cytotoxic drugs, still have an important role. This is particularly true in stem cell transplantation, where virtually every patient receives conditioning therapy with a DNA-alkylating agent-based program. However, due to concern about serious additive toxicities with combinations of different alkylating drugs, the last several years have seen nucleoside analogs, whose cytotoxic action follows vastly different molecular pathways, introduced in combination with alkylating agents...
July 2010: Environmental and Molecular Mutagenesis
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