Pablo J. González

National University of the Littoral

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Carlos D. Brondino

Consejo Nacional de Investigaciones Científicas y Técnicas

José J. G. Moura

Universidade Nova de Lisboa

Alberto C. Rizzi

National University of the Littoral

María G. Rivas

National University of the Littoral

Isabel Moura

Universidade Nova de Lisboa

Sergio D. Dalosto

Instituto de Física del Litoral

Maria João Romão

Universidade Nova de Lisboa

Pedro T. Gomes

University of Lisbon

Félix M. Ferroni

Consejo Nacional de Investigaciones Científicas y Técnicas

Teresa Avilés

Universidade Nova de Lisboa

Cooperative Institutions

Rede de Química e Tecnologia

Consejo Nacional de Investigaciones Científicas y Técnicas

Universidade Nova de Lisboa

National University of the Littoral

Experimental Medicine and Biology Institute

University of Buenos Aires

University of Lisbon

Centre National de la Recherche Scientifique

Faculdade de Tecnologia e Ciências

Magdalena Villegas de Martínez el Hospital

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Abstract P5-09-19: Progesterone receptor isoform A as a predictive marker of antiprogestin therapy in breast cancer: A tissue culture method to evaluate drug responsiveness

Cancer Research (2013)

María May Paola Rojas Gonzalo R. Sequeira Paula Martínez Pablo J. González

Abstract Two thirds of breast cancers express steroid hormone receptors and are susceptible to an endocrine therapy usually aimed to target the estrogen receptors (ER). There is however compelling evidence suggesting that progesterone receptors (PR) participate together with ER, modulating breast cancer growth. Based on our results obtained in an experimental breast cancer model in which antiprogestins induce complete regression of carcinomas with higher levels of PR isoform A (PR-A) than isoform B (PR-B), we propose that antiprogestins such as mifepristone (MFP) might be a possible therapeutic option for patients expressing high levels of PR-A. The goal of our study is to correlate the ratio of PR isoform expression, with the in vitro responsiveness of human breast cancer samples to MFP. Preliminary studies indicated that primary cultures of breast cancer samples overexpressing PR-A were responsive to MFP (10 nM) in vitro. However, since the rate of successful primary cultures was not encouraging (7%), we decided to develop a tissue culture assay to evaluate MFP responsiveness of breast cancer samples in vitro. Forty five breast cancer samples obtained from the General Pacheco´s Hospital, Buenos Aires, were kept in culture medium at room temperature and in dry ice. The former were cut in slices of 100 μm using a tissue chopper usually used to slice mouse nervous tissue for short incubations, and were incubated on filters in the presence of growth medium (fetal calf serum 10%) with or without MFP (10 nM), for 48 hs at 37º C. The slices were then fixed, paraffin embedded, and processed for Ki-67 staining to evaluate proliferating cells. Frozen samples were processed for Western blotting and the ratio of both PR isoforms was determined in nuclear extracts. In 17/45 (38%) of the samples valuable information was obtained. This was related with the quality (size and amount of viable cells) of the sample. The number of Ki-67 positive cells over the total viable cells was evaluated by a pathologist (M. May) in at least six different control or MFP-treated slices. From nine cases in which the Ki-67 index in control slices doubled the value obtained in MFP-treated slices (p<0.05), 8 were samples in which PR-A was higher than PR-B. MFP increased (p<0.05) the Ki-67 index in one sample with higher levels of PR-B than PR-A. No significant differences were observed in the remaining cases (null, equimolar or higher levels of PR-B than PR-A). We still plan to increase the number of samples in our study. Our data suggest that the tissue culture method developed is much more efficient than the primary cultures to evaluate drug or hormone responsiveness in breast cancer tissue. The results obtained herein support the proposal of PR-A as a predictive marker of antiprogestin therapy in breast cancer patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-19.

Progesterone receptor

CA 15-3

10.1158/0008-5472.sabcs13-p5-09-19

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Littoral Cell Angioma in a Patient with Epstein Syndrome

Acta Haematologica (1997)

Sabah Sallah Pablo J. González Diane M. Maia Nikolaos Kelekis Richard C. Semelka

A 61-year-old male with Epstein syndrome and chronic renal failure was admitted to our institution for kidney transplantation. He was asymptomatic at the time of evaluation. Physical examination revealed pallor and marked splenomegaly measuring approximately 12 × 10 cm below the left costal margin. Because of this finding, and a history of resected non-small lung cancer, a CT scan of the abdomen was obtained. This demonstrated massive, diffusely nodular splenomegaly. This article describes the histopathologic and immunohistochemical findings of littoral cell angioma, a novel splenic tumor. Also, we discuss the differential diagnosis and include a description of the imaging study performed. To our knowledge, this is the first case report of littoral cell angioma occurring in a patient with Epstein syndrome, and the first radiographic appearance of this rare tumor.

Pallor

Angioma

10.1159/000203601

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Citations (17)

Antioxidant and Anticancer Activities and Protein Interaction of the Oxidovanadium(IV) Naringin Complex

Inorganics (2022)

Gonzalo Restrepo-Guerrero Helen Goitia Luciana G. Naso Marilín Rey Pablo J. González

The complex of oxidovanadium(IV) with naringin (Narg) [VO(Narg)2] 8H2O (VONarg) was prepared according to the literature improving the synthetic procedure and physicochemical characterization. In addition, biological activities (cytotoxic, antioxidant, and BSA interaction) were determined. The metal coordinated through the 5-hydroxy and 4-carbonyl groups of rings A and C of naringin, respectively. The antioxidant activity of VONarg, determined in vitro, was higher than those of the flavonoid against superoxide and peroxyl reactive oxygen species (ROS) and DPPH radical. The cytotoxic properties were determined by a MTT assay on adenocarcinoma human alveolar basal epithelial cells (A549). VONarg exerted a 20% decrease in cancer cells viability at 24 h incubation, while naringin and oxidovanadium(IV) cation did not show cytotoxicity. Measurements with the normal HEK293 cell line showed that the inhibitory action of the complex is selective. VONarg generated intracellular reactive oxygen species (ROS), depletion of reduced glutathione and depolarization of mitochondrial membrane potential, typical for apoptotic pathway, producing cell death by oxidative stress mechanism. Moreover, naringin interacted with bovine serum albumin (BSA) through hydrophobic interactions in a spontaneous process, and VONarg showed greater affinity for the protein but can still be transported and delivered by it (Ka 104 L·mol−1 order).

Naringin

Bovine serum albumin

10.3390/inorganics10010013

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Citations (8)

EPR characterization of the molybdenum(V) forms of formate dehydrogenase from Desulfovibrio desulfuricans ATCC 27774 upon formate reduction

Journal of Inorganic Biochemistry (2007)

María G. Rivas Pablo J. González Carlos D. Brondino José J. G. Moura Isabel Moura

Formate dehydrogenase

Characterization

10.1016/j.jinorgbio.2007.04.011

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Citations (46)

EPR and redox properties of periplasmic nitrate reductase from Desulfovibrio desulfuricans ATCC 27774

JBIC Journal of Biological Inorganic Chemistry (2006)

Pablo J. González María G. Rivas Carlos D. Brondino Sergey A. Bursakov Isabel Moura

Redox titration

Desulfovibrio

10.1007/s00775-006-0110-0

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Citations (42)

CCDC 297433: Experimental Crystal Structure Determination

The Cambridge Structural Database (2007)

V. Rosa Pablo J. González Teresa Avilés Pedro T. Gomes R. Welter

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

10.5517/cc9zhmc

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Histamine receptors in human mammary gland, different benign lesions and mammary carcinomas

Inflammation Research (1995)

B. O. Lemos Carlos Davio Hugo Gass Pablo J. González G. Cricco

Mammary carcinoma

10.1007/bf01674400

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Citations (27)

Study of the Cys-His bridge electron transfer pathway in a copper-containing nitrite reductase by site-directed mutagenesis, spectroscopic, and computational methods

Biochimica et Biophysica Acta (BBA) - General Subjects (2017)

Julio C. Cristaldi María Cecilia Gómez Pablo J. González Félix M. Ferroni Sergio D. Dalosto

Site-directed mutagenesis

Bridge (graph theory)

10.1016/j.bbagen.2017.10.011

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Citations (9)

The effect of the sixth sulfur ligand in the catalytic mechanism of periplasmic nitrate reductase

Journal of Computational Chemistry (2009)

Nuno M. F. S. A. Cerqueira Pablo J. González Carlos D. Brondino Maria João Romão Carlos C. Romão

Abstract The catalytic mechanism of nitrate reduction by periplasmic nitrate reductases has been investigated using theoretical and computational means. We have found that the nitrate molecule binds to the active site with the Mo ion in the +6 oxidation state. Electron transfer to the active site occurs only in the proton‐electron transfer stage, where the Mo V species plays an important role in catalysis. The presence of the sulfur atom in the molybdenum coordination sphere creates a pseudo‐dithiolene ligand that protects it from any direct attack from the solvent. Upon the nitrate binding there is a conformational rearrangement of this ring that allows the direct contact of the nitrate with Mo VI ion. This rearrangement is stabilized by the conserved methionines Met141 and Met308. The reduction of nitrate into nitrite occurs in the second step of the mechanism where the two dimethyl‐dithiolene ligands have a key role in spreading the excess of negative charge near the Mo atom to make it available for the chemical reaction. The reaction involves the oxidation of the sulfur atoms and not of the molybdenum as previously suggested. The mechanism involves a molybdenum and sulfur‐based redox chemistry instead of the currently accepted redox chemistry based only on the Mo ion. The second part of the mechanism involves two protonation steps that are promoted by the presence of Mo V species. Mo VI intermediates might also be present in this stage depending on the availability of protons and electrons. Once the water molecule is generated only the Mo VI species allow water molecule dissociation, and, the concomitant enzymatic turnover. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009

Molybdenum Cofactor

10.1002/jcc.21280

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Citations (50)

Heterologous production and functional characterization of Bradyrhizobium japonicum copper-containing nitrite reductase and its physiological redox partner cytochrome c550

Metallomics (2020)

Julio C. Cristaldi Félix M. Ferroni Andrea B. Duré Cintia Soledad Ramírez Sergio D. Dalosto

Abstract Two domain copper-nitrite reductases (NirK) contain two types of copper centers, one electron transfer (ET) center of type 1 (T1) and a catalytic site of type 2 (T2). NirK activity is pH-dependent, which has been suggested to be produced by structural modifications at high pH of some catalytically relevant residues. To characterize the pH-dependent kinetics of NirK and the relevance of T1 covalency in intraprotein ET, we studied the biochemical, electrochemical, and spectroscopic properties complemented with QM/MM calculations of Bradyrhizobium japonicum NirK (BjNirK) and of its electron donor cytochrome c550 (BjCycA). BjNirK presents absorption spectra determined mainly by a S(Cys)3pπ → Cu2+ ligand-to-metal charge-transfer (LMCT) transition. The enzyme shows low activity likely due to the higher flexibility of a protein loop associated with BjNirK/BjCycA interaction. Nitrite is reduced at high pH in a T1-decoupled way without T1 → T2 ET in which proton delivery for nitrite reduction at T2 is maintained. Our results are analyzed in comparison with previous results found by us in Sinorhizobium meliloti NirK, whose main UV-vis absorption features are determined by S(Cys)3pσ/π → Cu2+ LMCT transitions.

Bradyrhizobium japonicum

Heterologous

10.1039/d0mt00177e

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Citations (8)