Browsing by Author "Owen, Gareth Ivor"

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    2-Methoxyestradiol and Disorders of Female Reproductive Tissues
    (2014) Pinto, M.; Medina, R.; Owen, Gareth Ivor
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    2-Methoxyestradiol inhibits progesterone-dependent tissue factor expression and activity in breast cancer cells
    (2010) Quezada, M.; Diaz, J.; Henriquez, S.; Bravo Castillo, María Loreto; Aranda, E.; Oliva, B.; Villalón, Manuel J.; Kato Cardemil, Sumie Rode; Cuello F., Mauricio; Brosens, J. J.; Lange, C. A.; Owen, Gareth Ivor
    2-Methoxyestradiol (2ME) is an endogenous metabolite of 17β-estradiol with antiangiogenic and antitumor properties, although its mechanisms of action remain unclear. Progestins in hormone replacement therapy increase the risk of breast cancer. Progesteron
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    2-Methoxyestradiol mediates apoptosis through caspase-dependent and independent mechanisms in ovarian cancer cells but not in normal counterparts
    (2008) Kato Cardemil, Sumie Rode; Sadarangani, Anil; Lange Smith, María Soledad; Delpiano, Ana M.; Vargas, Macarena; Brañes, Jorge; Carvajal Cabrera, Jorge Andrés; Lipkowitz, Stanley; Owen, Gareth Ivor; Cuello Fredes, Mauricio Arturo
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    A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer
    (2021) Cordova-Delgado, Miguel; Bravo Castillo, María Loreto; Cumsille, Elisa; Hill Machado, Charlotte Nicole; Pinto, Mauricio P.; Miquel P., Juan Francisco; Rodríguez-Fernández, María; Corvalán R., Alejandro; Garrido S., Marcelo; Owen, Gareth Ivor
    Background: Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3–4 toxicity. Methods: Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. Results; Reported grade ≤ 2 and 3–4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70–10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19–1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. Conclusion: Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.
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    A Molecular Stratification of Chilean Gastric Cancer Patients with Potential Clinical Applicability
    (2020) Pinto Paganini, Mauricio Arturo; Bravo Castillo, Maria Loreto; Sánchez Rojel, César Giovanni; Acevedo, Francisco; Mondaca Contreras, Sebastián Patricio; Ibañez, Carolina; Galindo A., Héctor; Madrid Arenas, Jorge; Nervi Nattero, Bruno; Peña Durán, José Esteban; Torres Montes, Paula Javiera; Owen, Gareth Ivor; Corvalán R., Alejandro; Garrido S., Marcelo; Córdova Delgado, M.; Retamal, I. N.; Muñoz Medel, M.; Durán, D.; Villanueva, F.; Koch, E.; Armisen, R.
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    Advances towards the use of gastrointestinal tumor patient-derived organoids as a therapeutic decision-making tool
    (2023) Obreque Castro, Javiera Constanza; Vergara Gómez, Luis; Venegas Labra, Nicolás; Weber, Helga; Owen, Gareth Ivor; Pérez Moreno, Pablo; Leal, Pamela; Roa Strauch, Juan Carlos Enrique; Bizama, Carolina
    In December 2022 the US Food and Drug Administration (FDA) removed the requirement that drugs in development must undergo animal testing before clinical evaluation, a declaration that now demands the establishment and verification of ex vivo preclinical models that closely represent tumor complexity and that can predict therapeutic response. Fortunately, the emergence of patient-derived organoid (PDOs) culture has enabled the ex vivo mimicking of the pathophysiology of human tumors with the reassembly of tissue-specific features. These features include histopathological variability, molecular expression profiles, genetic and cellular heterogeneity of parental tissue, and furthermore growing evidence suggests the ability to predict patient therapeutic response. Concentrating on the highly lethal and heterogeneous gastrointestinal (GI) tumors, herein we present the state-of-the-art and the current methodology of PDOs. We highlight the potential additions, improvements and testing required to allow the ex vivo of study the tumor microenvironment, as well as offering commentary on the predictive value of clinical response to treatments such as chemotherapy and immunotherapy.
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    Antiangiogenic, antimigratory and antiinflammatory effects of 2-methoxyestradiol in zebrafish larvae
    (2013) Quezada, Marisol; Alvarez, Marjorie; Peña, Oscar A.; Henríquez, Soledad; D' Alencon, Claudia A.; Lange, Soledad; Oliva, Barbara; Owen, Gareth Ivor; Allende, Miguel L.
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    Assessing the Occurrence and Influence of Cancer Chemotherapy-Related Pharmacogenetic Alleles in the Chilean Population
    (2024) Owen, Gareth Ivor; Córdova-Delgado, Miguel; Bustos, Bernabé I.; Cerpa Castro, Leslie; González Hevia, Pamela Andrea; Morales-Pison, Sebastián; García-Bloj, Benjamín; Garrido, Marcelo; Miquel, Juan Francisco; Quiñones, Luis A.
    Background: Pharmacogenomic knowledge as a biomarker for cancer care has transformed clinical practice, however, as current guidelines are primarily derived from Eurocentric populations, this limits their application in Latin America, particularly among Hispanic or Latino groups. Despite advancements, systemic chemotherapy still poses challenges in drug toxicity and suboptimal response. This study explores pharmacogenetic markers related to anticancer drugs in a Chilean cohort, filling a gap in Latin American research. Notably, the influence of native South American Mapuche-Huilliche ancestry. Methods: To explore pharmacogenetic markers related to anticancer drugs, we utilized an ethnically Admixed Chilean genome-wide association studies (GWAS) dataset of 1095 unrelated individuals. Pharmacogenomic markers were selected from PharmGKB, totaling 36 level 1 and 2 evidence single nucleotide polymorphisms (SNPs) and 571 level 3 SNPs. Comparative analyses involved assessing SNP frequencies across diverse populations from the 1000 Genomes Project. Haplotypes were estimated, and linkage disequilibrium was examined. Ancestry-based association analyses explored relationships between SNPs and Mapuche-Huilliche and European ancestries. Chi-square distribution with p ≤ 0.05 and Bonferroni’s multiple adjustment tests determined statistical differences between allele frequencies. Results: Our study reveals significant disparities in SNP frequency within the Chilean population. Notably, dihydropyrimidine dehydrogenase (DPYD) variants (rs75017182 and rs67376798), linked to an increased risk of severe fluoropyrimidine toxicity, exhibit an exceptionally low frequency (minor allele frequency (MAF) < 0.005). Nudix hydrolase 15 (NUDT15) rs116855232, associated with hematological mercaptopurine toxicity, is relatively common (MAF = 0.062), and is further linked to Mapuche-Huilliche ancestry. Thiopurine methyltransferase enzyme (TPMT), implicated in severe toxicity to mercaptopurines, SNPs rs1142345 and rs1800460 of TMPT gene demonstrate higher MAFs in Admixed Americans and the Chilean population (MAF range 0.031–0.057). Finally, the variant in the UDP-glucuronosyltransferase 1 gene (UGT1A1) rs4148323, correlated with irinotecan neutropenia, exhibits the highest MAF in East Asian (MAF = 0.136) and Chilean (MAF = 0.025) populations, distinguishing them from other investigated populations. Conclusions: This study provides the first comprehensive pharmacogenetic characterization of cancer therapy-related SNPs and highlights significant disparities in SNP frequencies within the Chilean population. Our findings underscore the necessity for inclusive research and personalized therapeutic strategies to ensure the equitable and effective application of precision medicine across diverse global communities.
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    Beyond tobacco: genomic disparities in lung cancer between smokers and never-smokers
    (Springer Nature, 2024) Garrido, Javiera; Bernal, Yanara; González, Evelin; Blanco, Alejandro; Sepúlveda-Hermosilla, Gonzalo; Freire, Matías; Oróstica, Karen; Rivas, Solange; Marcelain, Katherine; Owen, Gareth Ivor; Ibáñez Cáceres, Carolina; Corvalán Rodríguez, Alejandro; Garrido, Marcelo; Assar, Rodrigo; Lizana, Rodrigo; Cáceres-Molina, Javier; Ampuero, Diego; Ramos, Liliana; Pérez, Paola; Aren, Osvaldo; Chernilo, Sara; Fernández, Cristina; Spencer, María L.; Aguila, Jacqueline F.; Dossetto, Giuliano B.; Olea, Mónica A.; Rasse, Germán; Sánchez, Carolina; Amorim, Maria Galli de; Bartelli, Thais F.; Nunes, Diana N.; Dias-Neto, Emmanuel; Freitas, Helano C.; Armisén, Ricardo
    Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10–20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile. Methods We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment. Results Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1. Conclusions We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.
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    Breaking through an epigenetic wall Re-activation of Oct4 by KRAB-containing designer zinc finger transcription factors
    (2013) Juárez Moreno, Karla; Erices, Rafaela; Beltrán, Adriana S.; Stolzenburg, Sabine; Cuello F., Mauricio; Owen, Gareth Ivor; Qian, Haili; Blancafort, Pilar
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    Cancer's new Achilles'hell
    (2017) Owen, Gareth Ivor
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    Characterization and phenotypic variation with passage number of cultured human endometrial adenocarcinoma cells
    (2008) Kato Cardemil, Sumie Rode; Villalón, Manuel J.; Cuello F., Mauricio; Owen, Gareth Ivor; Espinoza, Natalia; Lange, Soledad
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    Coagulation factor Xa promotes metastasis through endothelial cell activation
    (2019) Arce Arata, Maximiliano Amadeo; Owen, Gareth Ivor; Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas
    Diversos estudios han demostrado una alta asociación entre hipercoagulabilidad sanguínea y la progresión del cáncer. La principal consecuencia de esta asociación es el desarrollo de cuadros de trombosis venosa, la cual es la segunda causa de muerte en pacientes oncológicos. Sin embargo, se desconocen ciertos mecanismos asociados al efecto de la vía de coagulación en diversos aspectos relacionados a la progresión del cáncer. Por lo tanto, analizamos el efecto del factor de coagulación Xa (FXa), una proteína central de la vía de coagulación, sobre el crecimiento tumoral y en la metástasis experimental de células de cáncer. El tratamiento intravenoso con FXa aumentó el crecimiento tumoral y la metástasis de células de melanoma murino (B16F10) al hígado, riñón y ganglios linfáticos. Tras la administración concomitante del anticoagulante anti-FXa Dalteparina, la metástasis pulmonar se redujo significativamente y no se observó metástasis en otros órganos. FXa no alteró directamente la proliferación, migración o invasión de células cancerosas in vitro. Por otro lado, FXa aumentó la formación de fibras de estrés, promoviendo así la disrupción de la VEcadherina en la membrana y en consecuencia un aumento en la permeabilidad endotelial. Adicionalmente, células endoteliales tratadas con FXa mostraron un aumento en las moléculas de adhesión ICAM-1 y VCAM-1, lo cual promovió la adhesión de células B16F10. Un análisis realizado mediante un Microarray demostró que células endoteliales tratadas con FXa expresaron mayores niveles de transcritos inflamatorios en comparación al control, lo cual se relacionó con un incremento en la infiltración de células inmunes en los pulmones de ratones tratados con FXa. En conjunto, nuestros resultados sugieren que FXa incrementa la metástasis de células B16F10 a través de la activación de células endoteliales, lo cual apoya el concepto de que el sistema de coagulación no es simplemente un espectador en el proceso de metástasis del cáncer.
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    Concanavalin-A Induces Granulosa Cell Death and Inhibits FSH-Mediated Follicular Growth and Ovarian Maturation in Female Rats
    (2013) Velásquez Opazo, Ethel Virginia; Ríos Raggio, Mariana; Ortíz Scarlazetta, María Elena; Lizama, Carlos; Orge, Felipe; Oliva, Barbara; Orellana Walden, Renán Felipe; Villalón, Manuel J.; Moreno Mauro, Ricardo D.; Owen, Gareth Ivor; Núñez, Elizabeth; Abramovich, Dalhia; Tesone, Marta, Rokka, Anne; Corthals, Garry; Croxatto A., Horacio; Parborell, Fernanda
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    Conflicts of CpG density and DNA methylation are proximally and distally involved in gene regulation in human and mouse tissues
    (2018) Li, Zhiguang; Chen, Fushun; Zhang, Qingzheng; Deng, Xiaodi; Zhang, Xia; Chen, Chengjun; Lv, Dekang; Li, Yulong; Li, Dan; Owen, Gareth Ivor; Zhang, Yu; Li, Peiying; Diao, Yunpeng; Kang, Lan; Chen, Jun; Li, Zhiguang
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    Correction to : MicroRNA‑335‑5p is a potential suppressor of metastasis and invasion in gastric cancer
    (2021) Sandoval Bórquez, Alejandra; Polakovicova, Iva; Carrasco Véliz, Nicolás; Lobos González, Lorena; Riquelme, Ismael; Carrasco Avino, Gonzalo; Bizama, Carolina; Norero Muñoz, Enrique; Owen, Gareth Ivor; Roa Strauch, Juan Carlos Enrique; Corvalán R., Alejandro
    An amendment to this paper has been published and can be accessed via the original article.
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    Different effects of progesterone and estradiol on chimeric and wild type aldosterone synthase in vitro
    (2013) Vecchiola Cárdenas, Andrea Paola; Lagos Arévalo, Carlos Fernando; Fuentes Zúñiga, Cristóbal Andrés; Allende, Fidel; Campino Johnson, María del Carmen; Valdivia, Carolina.; Tapia Castillo, Alejandra.; Owen, Gareth Ivor; Solari Gajardo, Sandra; Carvajal Maldonado, Cristián Andrés; Fardella B., Carlos; Ogishima, Tadashi.; Mukai, Kuniaki.
    Abstract Background Familial hyperaldosteronism type I (FH-I) is caused by the unequal recombination between the 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, resulting in the generation of a CYP11B1/B2 chimeric gene and abnormal adrenal aldosterone production. Affected patients usually show severe hypertension and an elevated frequency of stroke at a young age. Aldosterone levels rise during pregnancy, yet in pregnant women with FH-1, their hypertensive condition either remains unchanged or may even improve. The purpose of this study was to investigate in vitro whether female sex steroids modulate the activity of chimeric (ASCE) or wild type (ASWT) aldosterone synthase enzymes. Methods We designed an in vitro assay using HEK-293 cell line transiently transfected with vectors containing the full ASCE or ASWT cDNAs. Progesterone or estradiol effects on AS enzyme activities were evaluated in transfected cells incubated with deoxycorticosterone (DOC) alone or DOC plus increasing doses of these steroids. Results In our in vitro model, both enzymes showed similar apparent kinetic parameters (Km = 1.191 microM and Vmax = 27.08 microM/24 h for ASCE and Km = 1.163 microM and Vmax = 36.98 microM/24 h for ASWT; p = ns, Mann–Whitney test). Progesterone inhibited aldosterone production by ASCE- and ASWT-transfected cells, while estradiol demonstrated no effect. Progesterone acted as a competitive inhibitor for both enzymes. Molecular modelling studies and binding affinity estimations indicate that progesterone might bind to the substrate site in both ASCE and ASWT, supporting the idea that this steroid could regulate these enzymatic activities and contribute to the decay of aldosterone synthase activity in chimeric gene-positive patients. Conclusions Our results show an inhibitory action of progesterone in the aldosterone synthesis by chimeric or wild type aldosterone synthase enzymes. This is a novel regulatory mechanism of progesterone action, which could be involved in protecting pregnant women with FH-1 against hypertension. In vitro, both enzymes showed comparable kinetic parameters, but ASWT was more strongly inhibited than ASCE. This study implicates a new role for progesterone in the regulation of aldosterone levels that could contribute, along with other factors, to the maintenance of an adequate aldosterone-progesterone balance in pregnancy.Abstract Background Familial hyperaldosteronism type I (FH-I) is caused by the unequal recombination between the 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, resulting in the generation of a CYP11B1/B2 chimeric gene and abnormal adrenal aldosterone production. Affected patients usually show severe hypertension and an elevated frequency of stroke at a young age. Aldosterone levels rise during pregnancy, yet in pregnant women with FH-1, their hypertensive condition either remains unchanged or may even improve. The purpose of this study was to investigate in vitro whether female sex steroids modulate the activity of chimeric (ASCE) or wild type (ASWT) aldosterone synthase enzymes. Methods We designed an in vitro assay using HEK-293 cell line transiently transfected with vectors containing the full ASCE or ASWT cDNAs. Progesterone or estradiol effects on AS enzyme activities were evaluated in transfected cells incubated with deoxycorticosterone (DOC) alone or DOC plus increasing doses of these steroids. Results In our in vitro model, both enzymes showed similar apparent kinetic parameters (Km = 1.191 microM and Vmax = 27.08 microM/24 h for ASCE and Km = 1.163 microM and Vmax = 36.98 microM/24 h for ASWT; p = ns, Mann–Whitney test). Progesterone inhibited aldosterone production by ASCE- and ASWT-transfected cells, while estradiol demonstrated no effect. Progesterone acted as a competitive inhibitor for both enzymes. Molecular modelling studies and binding affinity estimations indicate that progesterone might bind to the substrate site in both ASCE and ASWT, supporting the idea that this steroid could regulate these enzymatic activities and contribute to the decay of aldosterone synthase activity in chimeric gene-positive patients. Conclusions Our results show an inhibitory action of progesterone in the aldosterone synthesis by chimeric or wild type aldosterone synthase enzymes. This is a novel regulatory mechanism of progesterone action, which could be involved in protecting pregnant women with FH-1 against hypertension. In vitro, both enzymes showed comparable kinetic parameters, but ASWT was more strongly inhibited than ASCE. This study implicates a new role for progesterone in the regulation of aldosterone levels that could contribute, along with other factors, to the maintenance of an adequate aldosterone-progesterone balance in pregnancy.
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    Enhanced caveolin-1 expression increases migration, anchorage-independent growth and invasion of endometrial adenocarcinoma cells
    (2015) Diaz Valdivia, Natalia.; Owen, Gareth Ivor; Bravo, Denisse.; Huerta, Hernán.; Henriquez, Soledad.; Gabler, Fernando.; Vega, Margarita.; Romero, Carmen.; Calderon, Claudia.; Leyton, Lisette.; Quest, Andrew F. G.
    Abstract Background Caveolin-1 (CAV1) has been implicated both in tumor suppression and progression, whereby the specific role appears to be context dependent. Endometrial cancer is one of the most common malignancies of the female genital tract; however, little is known about the role of CAV1 in this disease. Methods Here, we first determined by immunohistochemistry CAV1 protein levels in normal proliferative human endometrium and endometrial tumor samples. Then using two endometrial cancer cell lines (ECC: Ishikawa and Hec-1A) we evaluated mRNA and protein levels of CAV1 by real time qPCR and Western blot analysis, respectively. The role of CAV1 expression in ECC malignancy was further studied by either inducing its expression in endometrial cancer cells with the tumor promotor 12-O-tetradecanoyl-phorbol-13-acetate (4β-TPA) or decreasing expression using short-hairpin RNA constructs, and then evaluating the effects of these changes on ECC proliferation, transmigration, matrigel invasion, and colony formation in soft agar. Results Immunohistochemical analysis of endometrial epithelia revealed that substantially higher levels of CAV1 were present in endometrial tumors than the normal proliferative epithelium. Also, in Ishikawa and Hec-1A endometrial cancer cells CAV1 expression was readily detectable. Upon treatment with 4β-TPA CAV1 levels increased and coincided with augmented cell transmigration, matrigel invasion, as well as colony formation in soft agar. Reduction of CAV1 expression using short-hairpin RNA constructs ablated these effects in both cell types whether treated or not with 4β-TPA. Alternatively, CAV1 expression appeared not to modulate significantly proliferation of these cells. Conclusion Our study shows that elevated CAV1, observed in patients with endometrial cancer, is linked to enhanced malignancy of endometrial cancer cells, as evidenced by increased migration, invasion and anchorage-independent growth.