Publications by authors named "Stephanie Maldonado"

8 Publications

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Understanding the occurrence and distribution of emerging pollutants and endocrine disruptors in sensitive coastal South Florida Ecosystems.

Sci Total Environ 2021 Feb 21;757:143720. Epub 2020 Nov 21.

Institute of Environment, Florida International University, 11200 SW 8th Street, Modesto A. Maidique Campus, Miami, FL 33199, USA; Department of Chemistry and Biochemistry, Florida International University, 11200 SW 8th Street, Modesto A. Maidique Campus, Miami, FL 33199, USA.

Environmental exposure risk to different xenobiotics, which can potentially alter the function of the endocrine system, remains a great health and safety concern for aquatic species and humans. Steroid hormones, pharmaceuticals and personal care products (PPCPs) have been identified as important aquatic contaminants due to their widespread occurrence in surface waters and their endocrine disrupting properties. Heavily populated areas in South Florida not served by municipal wastewater collection present an unexpected high risk of anthropogenic contaminants to nearby coastal systems through surface runoff and groundwater flow. Previous studies in South Florida have been largely concentrated on assessing the relevance of the fate and transport of inorganic nutrients, heavy metals and pesticides with regulatory criteria. Therefore, a significant gap exists in assessing occurrence, distribution and biological significance of the presence of human related organic contaminants in natural surface waters. In this study, we have developed a fast and sensitive online solid-phase extraction followed by liquid chromatography-high resolution mass spectrometry (SPE-LC-HRMS) method using a Q-Exactive system for the determination of the occurrence and distribution of selected wastewater tracers/indicators, recalcitrant PPCPs and steroid hormones in South Florida surface waters. Seasonal and spatial variations of these contaminants were monitored from 2017 to 2019. The presence of total coliforms and E. coli were also evaluated in order to further assess water quality. Correlations between hormones and anthropogenic tracers were explored to better elucidate the sources, pathways and exposure risks to these contaminants. Caffeine, sucralose, Diethyl-m-toluamide (DEET) and carbamazepine were frequently detected in the water samples, which is indicative of extensive wastewater intrusion impacting the surface water. Estrone (E1), 17-β-estradiol (E2), and 17-α-ethynylestradiol (EE2) levels found in surface water raises concern of potential endocrine disruption effects in the aquatic ecosystem. Hazard quotient has been calculated to identify areas with high ecological risks to aquatic organisms.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143720DOI Listing
February 2021

Diversity and Evolutionary Dynamics of Antiphage Defense Systems in Species Complex.

Front Microbiol 2020 20;11:961. Epub 2020 May 20.

School of Biological Sciences and Engineering, Yachay Tech University, San Miguel de Urcuquí, Ecuador.

Over the years, many researchers have reported a great diversity of bacteriophages infecting members of the species complex (RSSC). This diversity has driven bacterial evolution by leading the emergence and maintenance of bacterial defense systems to combat phage infection. In this work, we present an study of the arsenal of defense systems that RSSC harbors and their evolutionary history. For this purpose, we used a combination of genomic, phylogenetic and associative methods. We found that in addition to the CRISPR-Cas system already reported, there are eight other antiphage defense systems including the well-known Restriction-Modification and Toxin-Antitoxin systems. Furthermore, we found a tenth defense system, which is dedicated to reducing the incidence of plasmid transformation in bacteria. We undertook an analysis of the gene gain and loss patterns of the defense systems in 15 genomes of RSSC. Results indicate that the dynamics are inclined toward the gain of defense genes as opposed to the rest of the genes that were preferably lost throughout evolution. This was confirmed by evidence on independent gene acquisition that has occurred by profuse horizontal transfer. The mutation and recombination rates were calculated as a proxy of evolutionary rates. Again, genes encoding the defense systems follow different rates of evolution respect to the rest of the genes. These results lead us to conclude that the evolution of RSSC defense systems is highly dynamic and responds to a different evolutionary regime than the rest of the genes in the genomes of RSSC.
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http://dx.doi.org/10.3389/fmicb.2020.00961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251935PMC
May 2020

A Tat/Rev Induced Limiting Dilution Assay to Measure Viral Reservoirs in Non-Human Primate Models of HIV Infection.

Sci Rep 2019 08 19;9(1):12078. Epub 2019 Aug 19.

Center for Biomedical Research, Population Council, New York, NY, USA.

The establishment of latent infection and poorly characterized viral reservoirs in tissues represent major obstacles to a definitive cure for HIV. Non-human primate (NHP) models of HIV infection are critical to elucidate pathogenic processes and an essential tool to test novel therapeutic strategies. Thus, the availability of novel assays to measure residual viral replication and reservoirs in NHP models may increase their utility in the search for an HIV cure. We developed a tat/rev induced limiting dilution assay to measure the frequency of CD4 T cells that express multiply-spliced(ms)_SIV RNA in presence and absence of stimulation. We validated the assay using cell lines and cells from blood and lymph nodes of SIV infected macaques. In vitro, SIV/SHIV TILDA detects only cells expressing viral proteins. In SIV/SHIV-infected macaques, CD4 T cells that express msSIV/SHIV RNA (TILDA data) were detected also in the setting of very low/undetectable viremia. TILDA data were significantly higher after stimulation and correlated with plasma viral load (pVL). Interestingly, TILDA data from early cART initiation correlated with peak and AUC pVL post-cART interruption. In summary, we developed an assay that may be useful in characterizing viral reservoirs and determining the effect of HIV interventions in NHP models.
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http://dx.doi.org/10.1038/s41598-019-48354-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700126PMC
August 2019

Delayed vaginal SHIV infection in VRC01 and anti-α4β7 treated rhesus macaques.

PLoS Pathog 2019 05 13;15(5):e1007776. Epub 2019 May 13.

Center for Biomedical Research, Population Council, New York, New York, United States of America.

VRC01 protects macaques from vaginal SHIV infection after a single high-dose challenge. Infusion of a simianized anti-α4β7 mAb (Rh-α4β7) just prior to, and during repeated vaginal exposures to SIVmac251 partially protected macaques from vaginal SIV infection and rescued CD4+ T cells. To investigate the impact of combining VRC01 and Rh-α4β7 on SHIV infection, 3 groups of macaques were treated with a suboptimal dosing of VRC01 alone or in combination with Rh-α4β7 or with control antibodies prior to the initiation of weekly vaginal exposures to a high dose (1000 TCID50) of SHIVAD8-EO. The combination Rh-α4β7-VRC01 significantly delayed SHIVAD8-EO vaginal infection. Following infection, VRC01-Rh-α4β7-treated macaques maintained higher CD4+ T cell counts and exhibited lower rectal SIV-DNA loads compared to controls. Interestingly, VRC01-Rh-α4β7-treated macaques had fewer IL-17-producing cells in the blood and the gut during the acute phase of infection. Moreover, higher T cell responses to the V2-loop of the SHIVAD8-EO envelope in the VRC01-Rh-α4β7 group inversely correlated with set point viremia. The combination of suboptimal amounts of VRC01 and Rh-α4β7 delayed infection, altered antiviral immune responses and minimized CD4+ T cell loss. Further exploration of the effect of combining bNAbs with Rh-α4β7 on SIV/HIV infection and antiviral immune responses is warranted and may lead to novel preventive and therapeutic strategies.
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http://dx.doi.org/10.1371/journal.ppat.1007776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533011PMC
May 2019

Mechanisms of MAFG Dysregulation in Cholestatic Liver Injury and Development of Liver Cancer.

Gastroenterology 2018 08 5;155(2):557-571.e14. Epub 2018 May 5.

Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Background & Aims: MAF bZIP transcription factor G (MAFG) is activated by the farnesoid X receptor to repress bile acid synthesis. However, expression of MAFG increases during cholestatic liver injury in mice and in cholangiocarcinomas. MAFG interacts directly with methionine adenosyltransferase α1 (MATα1) and other transcription factors at the E-box element to repress transcription. We studied mechanisms of MAFG up-regulation in cholestatic tissues and the pathways by which S-adenosylmethionine (SAMe) and ursodeoxycholic acid (UDCA) prevent the increase in MAFG expression. We also investigated whether obeticholic acid (OCA), an farnesoid X receptor agonist, affects MAFG expression and how it contributes to tumor growth in mice.

Methods: We obtained 7 human cholangiocarcinoma specimens and adjacent non-tumor tissues from patients that underwent surgical resection in California and 113 hepatocellular carcinoma (HCC) specimens and adjacent non-tumor tissues from China, along with clinical data from patients. Tissues were analyzed by immunohistochemistry. MAT1A, MAT2A, c-MYC, and MAFG were overexpressed or knocked down with small interfering RNAs in MzChA-1, KMCH, Hep3B, and HepG2 cells; some cells were incubated with lithocholic acid (LCA, which causes the same changes in gene expression observed during chronic cholestatic liver injury in mice), SAMe, UDCA (100 μM), or farnesoid X receptor agonists. MAFG expression and promoter activity were measured using real-time polymerase chain reaction, immunoblot, and transient transfection. We performed electrophoretic mobility shift, and chromatin immunoprecipitation assays to study proteins that occupy promoter regions. We studied mice with bile-duct ligation, orthotopic cholangiocarcinomas, cholestasis-induced cholangiocarcinoma, diethylnitrosamine-induced liver tumors, and xenograft tumors.

Results: LCA activated expression of MAFG in HepG2 and MzChA-1 cells, which required the activator protein-1, nuclear factor-κB, and E-box sites in the MAFG promoter. LCA reduced expression of MAT1A but increased expression of MAT2A in cells. Overexpression of MAT2A increased activity of the MAFG promoter, whereas knockdown of MAT2A reduced it. MAT1A and MAT2A had opposite effects on the activator protein-1, nuclear factor-κB, and E-box-mediated promoter activity. Expression of MAFG and MAT2A increased, and expression of MAT1A decreased, in diethylnitrosamine-induced liver tumors in mice. SAMe and UDCA had shared and distinct mechanisms of preventing LCA-mediated increased expression of MAFG. OCA increased expression of MAFG, MAT2A, and c-MYC, but reduced expression of MAT1A. Incubation of human liver and biliary cancer cells lines with OCA promoted their proliferation; in nude mice given OCA, xenograft tumors were larger than in mice given vehicle. Levels of MAFG were increased in human HCC and cholangiocarcinoma tissues compared with non-tumor tissues. High levels of MAFG in HCC samples correlated with hepatitis B, vascular invasion, and shorter survival times of patients.

Conclusions: Expression of MAFG increases in cells and tissues with cholestasis, as well as in human cholangiocarcinoma and HCC specimens; high expression levels correlate with tumor progression and reduced survival time. SAMe and UDCA reduce expression of MAFG in response to cholestasis, by shared and distinct mechanisms. OCA induces MAFG expression, cancer cell proliferation, and growth of xenograft tumors in mice.
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http://dx.doi.org/10.1053/j.gastro.2018.04.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067975PMC
August 2018

Relevance of CEA and LDH in relation to KRAS status in patients with unresectable colorectal liver metastases.

J Surg Oncol 2017 Mar 23;115(4):480-487. Epub 2016 Dec 23.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: While the significance of carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH), and Kirsten rat sarcoma (KRAS) status as individual prognostic factors for patients with metastatic colorectal cancer has been addressed, the relationship and interdependence between these prognostic factors on survival is limited.

Methods: Patients with unresectable colorectal liver metastases with known KRAS status, and with baseline CEA and LDH levels who were treated with hepatic arterial infusion and systemic chemotherapy were identified. Patients were divided into two groups: hepatic-only disease and extra-hepatic disease.

Results: A total of 193 patients were included: 121 with hepatic-only and 72 with extra-hepatic disease. In the hepatic-only group, median overall survival (OS) was 55 months. On multivariate analysis, KRAS mutated tumors (HR 1.7, P < 0.05), LDH >200 U/L (HR 2.0, P < 0.05), and prior chemotherapy (HR 2.1, P < 0.05) had lower OS. In patients with extra-hepatic disease, median OS was 32 months. On multivariate analysis, baseline CEA >200 ng/mL (HR 2.1, P = 0.051), LDH >200 U/L (HR 3.8, P < 0.05), and right-sided tumors (HR 2.8, P < 0.05) had lower OS.

Conclusions: This analysis verifies two distinct patterns in terms of biomarkers in patients with unresectable colorectal liver metastases. In patients with hepatic-only disease, KRAS mutation and elevated LDH negatively influenced survival. In patients with extra-hepatic disease, elevated LDH negatively impacted survival.
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http://dx.doi.org/10.1002/jso.24536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400688PMC
March 2017

Study of As(III) and As(V) Oxoanion Adsorption onto Single and Mixed Ferrite and Hausmannite Nanomaterials.

Microchem J 2014 Nov;117:52-60

Department of Chemistry the University of Texas-Pan American 1201 W University Dr. Edinburg TX, 78539.

The removal of arsenic(III) and arsenic(V) from an aqueous solution through adsorption on to FeO, MnFeO, 50% Mn substituted FeO, 75% Mn substituted FeO, and MnO nanomaterials was investigated. Characterization of the nanomaterials using XRD showed only pure phases for MnO, MnFeO, and FeO. The 50% and 75% substituted nanomaterials were found to be mixtures of MnO and FeO. From batch studies the optimum binding pH of arsenic(III) and arsenic(V) to the nanomaterials was determined to be pH 3. The binding capacity for As(III) and As(VI) to the various nanomaterials was determined using Isotherm studies. The binding capacity of FeO was determined to be 17.1 mg/g for arsenic(III) and 7.0 mg/g for arsenic(V). The substitution of 25% Mn into the FeO lattice showed a slight increase in the binding capacity for As(III) and As(VI) to 23.8 mg/g and 7.9 mg/g, respectively. The 50% substituted showed the maximum binding capacity of 41.5 mg/g and 13.9 mg/g for arsenic(III) and arsenic(V). The 75% Mn substituted FeO capacities were 16.7 mg/g for arsenic(III) and 8.2 mg/g for arsenic(V). The binding capacity of the MnO was determined to be 13.5 mg/g for arsenic(III) and 7.5 mg/g for arsenic(V). In addition, interference studies on the effects of SO, PO, Cl, and NO investigated. All the interferences had very minimal effects on the As(III) and As(V) binding never fell below 20% even in the presence of 1000 ppm interfering ions.
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http://dx.doi.org/10.1016/j.microc.2014.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119443PMC
November 2014

A microwave-assisted bismuth nitrate-catalyzed unique route toward 1,4-dihydropyridines.

Molecules 2012 Mar 5;17(3):2643-62. Epub 2012 Mar 5.

Department of Chemistry, The University of Texas-Pan American, 1201 West University Drive, Edinburg, TX 78539, USA.

The classical Hantzsch reaction is one of the simplest and most economical methods for the synthesis of biologically important and pharmacologically useful 1,4-dihydropyridine derivatives. Bismuth nitrate pentahydrate under microwave irradiation is proven to act as a very efficient catalyst for a one-pot, three-component synthesis of 1,4-dihydropyridines in excellent yields from diverse amines/ammonium acetate, aldehydes and 1,3-dicarbonyl compounds within 1-3 min under solvent-free conditions. The present environmentally benign procedure for the synthesis of 1,4-dihydropyridines is suitable for library synthesis and it will find application in the synthesis of potent biologically active molecules. The excellent yield and extreme rapidity of the method is due to a concurrent effect of the catalyst and microwave irradiation.
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http://dx.doi.org/10.3390/molecules17032643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6268638PMC
March 2012