Browsing by Author "Espinoza, Karena"
Now showing 1 - 7 of 7
Results Per Page
Sort Options
Publication A Novel Gemcitabine-Resistant Gallbladder Cancer Model Provides Insights into Molecular Changes Occurring during Acquired Resistance(2023) Vergara, Luis; Bizama, Carolina; Zhong, Jun; Buchegger, Kurt; Suárez, Felipe; Rosa, Lorena; Ili, Carmen; Weber, Helga; Obreque, Javiera; Espinoza, Karena; Repetto, Gabriela; Roa, Juan; Leal, Pamela; García, PatriciaTreatment options for advanced gallbladder cancer (GBC) are scarce and usually rely on cytotoxic chemotherapy, but the effectiveness of any regimen is limited and recurrence rates are high. Here, we investigated the molecular mechanisms of acquired resistance in GBC through the development and characterization of two gemcitabine-resistant GBC cell sublines (NOZ GemR and TGBC1 GemR). Morphological changes, cross-resistance, and migratory/invasive capabilities were evaluated. Then, microarray-based transcriptome profiling and quantitative SILAC-based phosphotyrosine proteomic analyses were performed to identify biological processes and signaling pathways dysregulated in gemcitabine-resistant GBC cells. The transcriptome profiling of parental and gemcitabine-resistant cells revealed the dysregulation of protein-coding genes that promote the enrichment of biological processes such as epithelial-to-mesenchymal transition and drug metabolism. On the other hand, the phosphoproteomics analysis of NOZ GemR identified aberrantly dysregulated signaling pathways in resistant cells as well as active kinases, such as ABL1, PDGFRA, and LYN, which could be novel therapeutic targets in GBC. Accordingly, NOZ GemR showed increased sensitivity toward the multikinase inhibitor dasatinib compared to parental cells. Our study describes transcriptome changes and altered signaling pathways occurring in gemcitabine-resistant GBC cells, which greatly expands our understanding of the underlying mechanisms of acquired drug resistance in GBC.Item Adaptation to Extreme Environments in an Admixed Human Population from the Atacama Desert(2019) Vicuña, Lucas; Fernández, Mario; Vial, Cecilia; Valdebenito, Patricio; Chaparro, Eduardo; Espinoza, Karena; Ziegler, Annmarie; Bustamante, Alberto; Eyheramendy, SusanaInorganic arsenic (As) is a toxic xenobiotic and carcinogen associated with severe health conditions. The urban population from the Atacama Desert in northern Chile was exposed to extremely high As levels(upto600 mg/l)in drink ing water between 1958 and 1971, leading to increased incidence of urinary bladder cancer (BC), skin cancer, kidney cancer, and coronary thrombosis decades later. Besides, the Andean Native-American ancestors of the Atacama population were previously exposed for millennia to elevated As levels in water (120 mg/l) for at least 5,000 years, suggesting adaptation to this selective pressure. Here, we performed two genome-wide selection tests—PBSn1 and an ancestry-enrichment test—in an admixed population from Atacama, to identify adaptation signatures to As exposure acquired before and after admixture with Europeans, respectively. The top second variant selected by PBSn1 was associated with LCE4A-C1orf68, a gene that may be involved in the immune barrier of the epithelium during BC. We performed association tests between the top PBSn1 hits and BC occurrence in our population. The strongest association (P1⁄4 0.012) was achieved by the LCE4A-C1orf68 variant. The ancestry-enrichment test detected highly significant signals (P1⁄4 1.3 109 ) mapping MAK16, a gene with important roles in ribosome biogenesis during the G1 phase of the cell cycle. Our results contribute to a better understanding of the genetic factors involved in adaptation to the pathophysiological consequences of As exposure.Item Case fatality rate and associated factors in patients with 22q11 microdeletion syndrome: a retrospective cohort study(BMJ Publishing Group, 2014) Repetto, Gabriela; Guzmán, Maria Luisa; Delgado, Iris; Loyola, Hugo; Palomares, Mirta; Lay-Son, Guillermo; Vial, Cecilia; Benavides, Felipe; Espinoza, Karena; Alvarez, PatriciaOBJECTIVE: Chromosome 22q11.2 deletion is the most commonly occurring known microdeletion syndrome. Deaths related to the syndrome have been reported, but the magnitude of death has not been quantified. This study evaluated the deletion's impact on survival and its clinical manifestations in a large cohort of Chilean patients. DESIGN: Demographic and clinical data of individuals with 22q11 deletions diagnosed between 1998 and 2013 were collected from medical records and death certificates. Case fatality rate was calculated and compared with national vital statistics. OR with 95% CI analysis was used to assess the association between clinical manifestations and death. SETTING: Genetic services in tertiary care centres in Chile, following patients with 22q11.2 deletion. OUTCOMES: Fatality rate and associated factors. RESULTS: 59 of 419 patients (14.1%) died during the study period at a median of 3.4 months (range 0 to 32 years of age). Factors associated with death included congenital heart disease (OR 5.27; 95% CI 2.06 to 13.99; p<0.0001), hypocalcaemia (OR 4.27; 95% CI 1.67 to 11.15; p<0.002) and airway malacia (OR 13.37; 95% CI 1.19 to 110.51; p<0.002). Patients with deletions and defects such as tetralogy of Fallot with or without pulmonary atraesia, truncus arteriosus or ventricular septal defect, had a 2.6-fold to 4.6-fold higher death rate compared with nationwide reports for the same types of defects. CONCLUSIONS: In this cohort, we observed a death rate of 14.1%, implying that one in seven patients with 22q11 deletion died during the study period. Significant associations with cardiac defects, hypocalcaemia and airway malacia were observed. Furthermore, the death risk in patients with 22q11 deletion and cardiac defects exceeded the global figures observed in Chile for infants with structurally similar but apparently isolated anomalies. These observations indicate a need to identify patients who may require specific perioperative management to improve survival.Item Chromosomal microarrays testing in children with developmental disabilities and congenital anomalies(Sociedad Brasileira de Pediatria with Elsevier, 2015) Lay-Son, Guillermo; Espinoza, Karena; Vial, Cecilia; Rivera, Juan; Guzmán, María; Repetto, GabrielaObjectives Clinical use of microarray-based techniques for the analysis of many developmental disorders has emerged during the last decade. Thus, chromosomal microarray has been positioned as a first-tier test. This study reports the first experience in a Chilean cohort. Methods Chilean patients with developmental disabilities and congenital anomalies were studied with a high-density microarray (CytoScan™ HD Array, Affymetrix, Inc., Santa Clara, CA, USA). Patients had previous cytogenetic studies with either a normal result or a poorly characterized anomaly. Results This study tested 40 patients selected by two or more criteria, including: major congenital anomalies, facial dysmorphism, developmental delay, and intellectual disability. Copy number variants (CNVs) were found in 72.5% of patients, while a pathogenic CNV was found in 25% of patients and a CNV of uncertain clinical significance was found in 2.5% of patients. Conclusion Chromosomal microarray analysis is a useful and powerful tool for diagnosis of developmental diseases, by allowing accurate diagnosis, improving the diagnosis rate, and discovering new etiologies. The higher cost is a limitation for widespread use in this setting.Item Diagnóstico de intolerancia a la lactosa en adultos: rendimiento comparativo de la clínica, test de hidrógeno espirado y test genético(Sociedad Medica de Santiago, 2012) Rollan, Antonio; Vial, Cecilia; Quesada, Soledad; Espinoza, Karena; Hatton, Mary; Puga, Alonso; Repetto, GabrielaBackground: Genetically programmed adult-type hypolactasia affects 56% of Chilean population. Ideally, diagnosis should be confirmed. Aim: To compare diagnostic yield of genetic test, hydrogen (H2) expiratory test and a validated symptomatic structured survey (SS). Material and Methods: Patients submitted to H2 test answered a historic (anamnestic) and current SS (after the ingestion of 25 g of lactose). A blood sample was obtained for determination of genetic polymorphisms C/T_13910, C/G_13907 and G/A_22018 by polymerase chain reaction. The gold standard for diagnosis of lactose intolerance (LI) was the agreement of at least two of three tests. Results: Sixty-one participants aged 39 ± 12 years (21 males), were studied. Anamnestic SS was diagnostic of LI in all cases (score > 7), while current SS detected LI in 27/61 (46%). H2 test (an increase > 15 ppm after ingestion of 25 g of lactose) showed LI in 31/61 (51%). The locus C/G_13907 showed no polymorphism and locus G/A_22018 was in complete linkage disequilibrium with C/T_13910. Genotype C/C_13910, associated to hypolactasia, was present in 30/58 (52%). According to the gold-standard, 32/61 (52.5%) patients were diagnosed as LI. Sensitivity and specificity were, respectively, 79% and 69% for current SS, 93% and 93% for H2 test and 97% and 93% for the genetic test. The last two showed a positive likelihood ratio (LR) > 10 and a negative LR < 0.1, figures within the range considered clinically useful. Conclusions: Genotype C/C_13910 is responsible for hypolactasia in this population. Anamnestic report of symptoms after milk ingestion and symptoms after lactose ingestion, are not accurate enough. H2 and genetic tests are simple and similarly accurate to diagnose lactose intolerance in adults.Item Efecto de las variantes de VKORC1 y CYP2C9 sobre la dosis de anticoagulantes orales en individuos chilenos(Sociedad Medica de Santiago, 2015) Benavides, Felipe; Grossman, Nicole; Poggi, Helena; Nieto, Elena; Bertrán, Antonio; Araos, Daniel; Vásquez, Marcos; Ibarra, Ignaz; Caceres, Felipe; Espinoza, Karena; Lagos, Marcela; Repetto, GabrielaBACKGROUND: The dose of oral anticoagulants (OAC) shows great variability among patients. Pharmacogenetic studies have shown that common variants in genes CYP2C9 (*2 and *3) and VKORC1 (-1639G>A) are associated with lower requirements of OAC. AIM: To study the association between average maintenance doses of oral anticoagulant therapy required to maintain a stable INR and CYP2C9 and VKORC1 gene variants in Chilean adults. MATERIAL AND METHODS: Prospective study of patients on anticoagulant treatment and with a stable international normalized ratio (INR) for prothrombin time for at least three months. Patients were classified as having high or low acenocoumarol or warfarin requirements. Peripheral blood DNA genotyping was performed by polymerase chain reaction and restriction fragment polymorphism or sequencing and electrophoresis. RESULTS: The study included 185 patients, 125 on acenocoumarol and 60 on warfarin. Patients with VKORC1-1639A allele were more likely to require lower doses of both drugs than patients with the G allele (Odds ratio [OR] for acenocoumarol 9.06, and OR for warfarin = 18.7). There was no association between CYP2C9*2 and*3 and acenocoumarol or warfarin requirements. CONCLUSIONS: There is an association between VKORC1-1639A variant and anticoagulant doses.Item Proximal Deletion of 6q Overlapping with Toriello-Carey Facial Phenotype: Prenatal Findings, Clinical Course, Differential Diagnosis, and Review(2017) Catena, Sofía; Aracena, Mariana; Pizarro, Oscar; Espinoza, Karena; Lay-Son, GuillermoProximal deletion of 6q is a relatively rare chromosomal abnormality. Reported patients have deletions of different sizes but share partial overlap and present with similar clinical features, and some of them were described prior to the introduction of chromosome microarrays. We describe a male patient with prenatal sonographic findings of nuchal edema, intrauterine growth restriction, renal pelvis dilatation, and oligohydramnios. At birth, facial dysmorphism, retro/micrognathia, a short and wide neck as well as cardiovascular and renal anomalies were noted. His clinical evolution has been marked by failure to thrive, severe developmental delay, and cognitive impairment. The diagnosis of Toriello-Carey syndrome (TCS) was based on his “gestalt.” aCGH identified a de novo proximal deletion of 17 Mb in 6q (6q12q14.3). Deletion 6q13q14 seems to be responsible for the main facial features and should be considered within the differential diagnosis of TCS.