Browsing by Author "Nervi, Bruno"
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Item A Molecular Stratification of Chilean Gastric Cancer Patients with Potential Clinical Applicability(MDPI, Basel Sz., 2020) Pinto, Mauricio; Córdova-Delgado, Miguel; Retamal, Ignacio; Muñoz-Medel, Matías; Bravo, Loreto; Durán, Doris; Villanueva, Francisco; Sánchez, César; Acevedo, Francisco; Mondaca, Sebastián; Érica, Koch; Ibáñez, Carolina; Galindo, Héctor; Madrid, Jorge; Nervi, Bruno; Peña, José; Torres, Javiera; Garrido, Marcelo; Owen, Gareth I.; Corvalán, Alejandro H.; Armisén, RicardoGastric cancer (GC) is a complex and heterogeneous disease. In recent decades, The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) defined GC molecular subtypes. Unfortunately, these systems require high-cost and complex techniques and consequently their impact in the clinic has remained limited. Additionally, most of these studies are based on European, Asian, or North American GC cohorts. Herein, we report a molecular classification of Chilean GC patients into five subtypes, based on immunohistochemical (IHC) and in situ hybridization (ISH) methods. These were Epstein–Barr virus positive (EBV+), mismatch repair-deficient (MMR-D), epithelial to mesenchymal transition (EMT)-like, and accumulated (p53+) or undetected p53 (p53−). Given its lower costs this system has the potential for clinical applicability. Our results confirm relevant molecular alterations previously reported by TCGA and ACRG. We confirm EBV+ and MMR-D patients had the best prognosis and could be candidates for immunotherapy. Conversely, EMT-like displayed the poorest prognosis; our data suggest FGFR2 or KRAS could serve as potential actionable targets for these patients. Finally, we propose a low-cost step-by-step stratification system for GC patients. To the best of our knowledge, this is the first Latin American report on a molecular classification for GC. Pending further validation, this stratification system could be implemented into the routine clinicPublication Development and internal validation of a multifactorial riskprediction model for gallbladder cancer in a high-incidencecountry(2023) Boekstegers, Felix; Scherer, Dominique; Barahona, Carol; Marcelain, Katherine; Gárate, Valentina; Waldenberge, Melanie; Morales, Erik; Rojas, Armando; Munoz, César; Retamales, Javier; De Toro, Gonzalo; Barajas, Olga; Rivera, María; Cortés, Analía; Loader, Denisse; Saavedra, Javiera; Gutiérrez, Lorena; Ortega, Alejandro; Bertrán, Maria; Bartolotti, Leonardo; Gabler, Fernando; Campos, Monica; Alvarado, Juan; Moisán, Fabricio; Spencer, Loreto; Nervi, Bruno; Carvajal-Hausdorf, Daniel; Losada, Héctor; Almau, Mauricio; Fernández, Plinio; Olloquequi, Jordi; Fuentes, Macarena; Gonzalez, Rolando; Bortolin, Maria; Acuña, Victor; Gallo, Carla; Ruiz, Andres; Rothhamme, Francisco; Bermejo, JustoSince 2006, Chile has been implementing a gallbladder cancer (GBC) prevention program based on prophylactic cholecystectomy for gallstone patients aged 35 to 49 years. The effectiveness of this prevention program has not yet been comprehensively evaluated. We conducted a retrospective study of 473 Chilean GBC patients and 2137 population-based controls to develop and internally validate three GBC risk prediction models. The Baseline Model accounted for gallstones while adjusting for sex and birth year. Enhanced Model I also included the non-genetic risk factors: body mass index, educational level, Mapuche surnames, number of children and family history of GBC. Enhanced Model II further included Mapuche ancestry and the genotype for rs17209837. Multiple Cox regression was applied to assess the predictive performance, quantified by the area under the precision-recall curve (AUC-PRC) and the number of cholecystectomies needed (NCN) to prevent one case of GBC at age 70 years. The AUC-PRC for the Baseline Model (0.44%, 95%CI 0.42-0.46) increased by 0.22 (95%CI 0.15-0.29) when non-genetic factors were included, and by 0.25 (95%CI 0.20-0.30) when incorporating non-genetic and genetic factors. The overall NCN for Chileans with gallstones (115, 95%CI 104-131) decreased to 92 (95%CI 60-128) for Chileans with a higher risk than the median according to Enhanced Model I, and to 80 (95%CI 59-110) according to Enhanced Model II. In conclusion, age, sex and gallstones are strong risk factors for GBC, but consideration of other non-genetic factors and individual genotype data improves risk prediction and may optimize allocation of financial resources and surgical capacity.Publication Differential Effects of a Telemonitoring Platform in the Development of Chemotherapy-Associated Toxicity: A Randomized Trial Protocol(2024) Martínez, Felipe; Taramasco, Carla; Espinoza, Manuel; Acevedo, Johanna; Goic, Carolina; Nervi, BrunoChemotherapy requires careful monitoring, but traditional follow-up approaches face significant challenges that were highlighted by the COVID-19 pandemic. Hence, exploration into telemonitoring as an alternative emerged. The objective is to assess the impact of a telemonitoring platform that provides clinical data to physicians overseeing solid tumor patients, aiming to enhance the care experience. The methodology outlines a parallel-group randomized clinical trial involving recently diagnosed patients with solid carcinomas preparing for curative intent chemotherapy. Eligible adult patients diagnosed with specific carcinoma types and proficient in Spanish, possessing smartphones, will be invited to participate. They will be randomized using concealed allocation sequences into two groups: one utilizing a specialized smartphone application called Contigo for monitoring chemotherapy toxicity symptoms and accessing educational content, while the other receives standard care. Primary outcome assessment involves patient experience during chemotherapy using a standardized questionnaire. Secondary outcomes include evaluating severe chemotherapy-associated toxicity, assessing quality of life, and determining user satisfaction with the application. The research will adhere to intention-to-treat principles. This study has been registered at ClinicalTrials.govPublication Effects on Quality of Life of a Telemonitoring Platform amongst Patients with Cancer (EQUALITE): A Randomized Trial Protocol(2024) Martínez, Felipe; Taramasco, Carla; Espinoza, Manuel; Acevedo, Johanna; Goic, Carolina; Nervi, BrunoCancer, a pervasive global health challenge, necessitates chemotherapy or radiotherapy treatments for many prevalent forms. However, traditional follow-up approaches encounter limitations, exacerbated by the recent COVID-19 pandemic. Consequently, telemonitoring has emerged as a promising solution, although its clinical implementation lacks comprehensive evidence. This report depicts the methodology of a randomized trial which aims to investigate whether leveraging a smartphone app called Contigo for disease monitoring enhances self-reported quality of life among patients with various solid cancers compared to standard care. Secondary objectives encompass evaluating the app's impact on depressive symptoms and assessing adherence to in-person appointments. Randomization will be performed independently using an allocation sequence that will be kept concealed from clinical investigators. Contigo offers two primary functions: monitoring cancer patients' progress and providing educational content to assist patients in managing common clinical situations related to their disease. The study will assess outcomes such as quality of life changes and depressive symptom development using validated scales, and adherence to in-person appointments. Specific scales include the EuroQol Group's EQ-5D questionnaire and the Patient Health Questionnaire (PHQ-9). We hypothesize that the use of Contigo will assist and empower patients receiving cancer treatment, which will translate to better quality of life scores and a reduced incidence of depressive symptoms. All analyses will be undertaken with the intention-to-treat principle by a statistician unaware of treatment allocation. This trial is registered in ClinicalTrials under the registration number NCT06086990.Publication Gallbladder Cancer Risk and Indigenous South American Mapuche Ancestry: Instrumental Variable Analysis Using Ancestry-Informative Markers(2023) Zollner, Linda; Boekstegers, Felix; Barahona, Carol; Scherer, Dominique; Marcelain, Katherine; Gárate, Valentina; Waldenberger, Melanie; Morales, Erik; Rojas, Armando; Munoz, César; Retamales, Javier; De Toro, Gonzalo; Vera, Allan; Barajas, Olga; Rivera, María; Cortés, Analía; Loader, Denisse; Saavedra, Javiera; Gutiérrez, Lorena; Ortega, Alejandro; Bertrán, Maria; Bartolotti, Leonardo; Gabler, Fernando; Campos, Mónica; Alvarado, Juan; Moisán, Fabricio; Spencer, Loreto; Nervi, Bruno; Carvajal-Hausdorf, Daniel; Losada, Héctor; Almau, Mauricio; Fernández, Plinio; Olloquequi, Jordi; Carter, Alice; Miquel, Juan; Bustos, Bernabe; Fuentes, Macarena; Gonzalez, Rolando; Bortolini, Maria; Acuña, Victor; Gallo, Carla; Ruiz, Andres; Rothhammer, Francisco; Bermejo, JustoA strong association between the proportion of indigenous South American Mapuche ancestry and the risk of gallbladder cancer (GBC) has been reported in observational studies. Chileans show the highest incidence of GBC worldwide, and the Mapuche are the largest indigenous people in Chile. We set out to assess the confounding-free effect of the individual proportion of Mapuche ancestry on GBC risk and to investigate the mediating effects of gallstone disease and body mass index (BMI) on this association. Genetic markers of Mapuche ancestry were selected based on the informativeness for assignment measure, and then used as instrumental variables in two-sample Mendelian randomization analyses and complementary sensitivity analyses. Results suggested a putatively causal effect of Mapuche ancestry on GBC risk (inverse variance-weighted (IVW) risk increase of 0.8% per 1% increase in Mapuche ancestry proportion, 95% CI 0.4% to 1.2%, p = 6.7 × 10-5) and also on gallstone disease (3.6% IVW risk increase, 95% CI 3.1% to 4.0%), pointing to a mediating effect of gallstones on the association between Mapuche ancestry and GBC. In contrast, the proportion of Mapuche ancestry showed a negative effect on BMI (IVW estimate -0.006 kg/m2, 95% CI -0.009 to -0.003). The results presented here may have significant implications for GBC prevention and are important for future admixture mapping studies. Given that the association between the individual proportion of Mapuche ancestry and GBC risk previously noted in observational studies appears to be free of confounding, primary and secondary prevention strategies that consider genetic ancestry could be particularly efficient.Publication Identification of Circulating lncRNAs Associated with Gallbladder Cancer Risk by Tissue-Based Preselection, Cis-eQTL Validation, and Analysis of Association with Genotype-Based Expression(2022) Blandino, Alice; Scherer, Dominique; Rounge, Trine B.; Umu, Sinan U.; Boekstegers, Felix; Barahona Ponce, Carol; Marcelain, Katherine; Gárate-Calderón, Valentina; Waldenberger, Melanie; Morales, Erik; Rojas, Armando; Muñoz, César; Retamales, Javier; Toro, Gonzalo de; Barajas, Olga; Rivera, María Teresa; Cortés, Analía; Loader, Denisse; Saavedra, Javiera; Gutiérrez, Lorena; Ortega, Alejandro; Bertrán, María Enriqueta; Gabler, Fernando; Campos, Mónica; Alvarado, Juan; Fabrizio Moisán 18, Loreto Spencer 18, Bruno Nervi 19, Daniel E Carvajal-Hausdorf; Spencer, Loreto; Nervi, Bruno; Carvajal-Hausdorf, Daniel; Losada, Héctor; Almau, Mauricio; Fernández, Plinio; Gallegos, Iván; Olloquequi, Jordi; Fuentes-Guajardo, Macarena; González -Jose, Rolando; Bortolini, María Cátira; Gallo, Carla; Ruíz Linares, Andrés; Rothhammer, Francisco; Bermejo, Justo LorenzoLong noncoding RNAs (lncRNAs) play key roles in cell processes and are good candidates for cancer risk prediction. Few studies have investigated the association between individual genotypes and lncRNA expression. Here we integrate three separate datasets with information on lncRNA expression only, both lncRNA expression and genotype, and genotype information only to identify circulating lncRNAs associated with the risk of gallbladder cancer (GBC) using robust linear and logistic regression techniques. In the first dataset, we preselect lncRNAs based on expression changes along the sequence "gallstones → dysplasia → GBC". In the second dataset, we validate associations between genetic variants and serum expression levels of the preselected lncRNAs (cis-lncRNA-eQTLs) and build lncRNA expression prediction models. In the third dataset, we predict serum lncRNA expression based on individual genotypes and assess the association between genotype-based expression and GBC risk. AC084082.3 and LINC00662 showed increasing expression levels (p-value = 0.009), while C22orf34 expression decreased in the sequence from gallstones to GBC (p-value = 0.04). We identified and validated two cis-LINC00662-eQTLs (r2 = 0.26) and three cis-C22orf34-eQTLs (r2 = 0.24). Only LINC00662 showed a genotyped-based serum expression associated with GBC risk (OR = 1.25 per log2 expression unit, 95% CI 1.04-1.52, p-value = 0.02). Our results suggest that preselection of lncRNAs based on tissue samples and exploitation of cis-lncRNA-eQTLs may facilitate the identification of circulating noncoding RNAs linked to cancer risk.Publication SARS-CoV-2 infectivity and antigenic evasion: spotlight on isolated Omicron sub-lineages(2024) Barrera, Aldo; Martínez, Constanza; Angulo, Jenniffer; Palma, Carlos; Hormazabal, Juan; Vial Cox, María Cecilia; Aguilera, Ximena; Castillo, Pablo; Pardo, Catalina; Balcells, María; Nervi, Bruno; Le Corre, Nicole; Ferrés, MarcelaSince the SARS-CoV-2 outbreak in 2019, a diversity of viral genomic variants has emerged and spread globally due to increased transmissibility, pathogenicity, and immune evasion. By the first trimester of 2023 in Chile, as in most countries, BQ and XBB were the predominant circulating sub-lineages of Omicron. The molecular and antigenic characteristics of these variants have been mainly determined using non-authentic spike pseudoviruses, which is often described as a limitation. Additionally, few comparative studies using isolates from recent Omicron sub-lineages have been conducted. In this study, we isolated SARS-CoV-2 variants from clinical samples, including the ancestral B.1.1, Delta, Omicron BA.1, and sub-lineages of BA.2 and BA.5. We assessed their infectivity through cell culture infections and their antibody evasion using neutralization assays. We observed variations in viral plaque size, cell morphology, and cytotoxicity upon infection in Vero E6-TMPRSS2 cells for each variant compared to the ancestral B.1.1 virus. BA.2-derived sub-variants, such as XBB.1.5, showed attenuated viral replication, while BA.5-derived variants, such as BQ.1.1, exhibited replication rates similar to the ancestral SARS-CoV-2 virus. Similar trends were observed in intestinal Caco-2 cells, except for Delta. Antibody neutralization experiments using sera from individuals infected during the first COVID-19 wave (FWI) showed a consistent but moderate reduction in neutralization against Omicron sub-lineages. Interestingly, despite being less prevalent, BQ.1.1 showed a 6.1-fold greater escape from neutralization than XBB.1.5. Neutralization patterns were similar when tested against sera from individuals vaccinated with 3xBNT162b2 (PPP) or Coronavac-Coronavac-BNT162b2 (CCP) schedules. However, CCP sera showed 2.3-fold higher neutralization against XBB.1.5 than FWI and PPP sera. This study provides new insights into the differences between BA.2 and BA.5-derived variants, leading to their eventual outcompetition. Our analysis offers important evidence regarding the balance between infectivity and antigenic escape that drives the evolution of second-generation SARS-CoV-2 variants in the population.