Impact of KRASG12D subtype and concurrent pathogenic mutations on advanced non-small cell lung cancer outcomes

Propósito: Las mutaciones en el oncogén viral del sarcoma de rata de Kirsten (KRAS) constituyen un importante impulsor del adenocarcinoma de pulmón, presente en el 10-40% de los pacientes, que exhiben resultados clínicos heterogéneos, principalmente impulsados por alteraciones genéticas concurrentes. Sin embargo, la caracterización de los subtipos mutacionales de KRAS y su impacto en los resultados clínicos en Latinoamérica es limitada. Métodos: Se realizó un estudio de cohorte en el Instituto Nacional de Cancerología (INCan) de México. Se incluyeron para el análisis individuos con estadios avanzados de adenocarcinoma y mutaciones de KRAS, detectadas por secuenciación de próxima generación, que habían sido sometidos al menos a una línea de terapia. Las características clínicas y patológicas se recuperaron de la base de datos institucional de junio de 2014 a marzo de 2023. Resultados: KRAS fue identificado en cincuenta y cuatro (15,6%) de 346 pacientes, entre los cuales 50 casos fueron incluidos para el análisis. KRASG12D (n = 16, 32%) y KRASG12C (n = 16, 32%) representaron los subtipos más prevalentes. Las mutaciones en KRASG12D se asociaron con el sexo femenino (p = 0,018), con no haber fumado nunca (p = 0,108) y con concurrencias con EGFR (25,0% frente a 17,6%, p = 0,124) y CDKN2A (18,8% frente a 14,7%, p = 0,157). Los pacientes con KRASG12D mostraron una mejor ORR (66,6% vs. 30,0%; OR 4,66; IC 95% 1,23-17,60; p = 0,023) y en el análisis multivariante se asoció significativamente con una mejor SLP (HR 0,36; IC 95% 0,16-0,80; p = 0,012) y SG (HR 0,24; IC 95% 0,08-0,70; p = 0,009). Conclusiones: Hasta donde sabemos, este estudio representa el primer esfuerzo por caracterizar exhaustivamente la heterogeneidad molecular del CPCNP con mutación de KRAS en pacientes latinoamericanos. Nuestros datos refuerzan la opinión actual de que el CPNM con mutación de KRAS no es una enfermedad impulsada por un único oncogén y enfatiza el impacto pronóstico de los diversos perfiles moleculares en este subconjunto genómicamente definido de CPNM. Se justifica una mayor validación en cohortes latinoamericanas multicéntricas más grandes para confirmar nuestros hallazgos. 2023, El Autor (es).Purpose: Mutations in the Kirsten rat sarcoma viral (KRAS) oncogene constitute a significant driver of lung adenocarcinoma, present in 10–40% of patients, which exhibit heterogeneous clinical outcomes, mainly driven by concurrent genetic alterations. However, characterization of KRAS mutational subtypes and their impact on clinical outcomes in Latin America is limited. Methods: A cohort study was conducted at the National Cancer Institute (INCan) of Mexico. Individuals with advance-staged of adenocarcinoma and KRAS mutations, detected by next-generation sequencing, having undergone at least one line of therapy were included for analysis. Clinical and pathological characteristics were retrieved from institutional database from June 2014 to March 2023. Results: KRAS was identified in fifty-four (15.6%) of 346 patients, among which 50 cases were included for analysis. KRASG12D (n = 16, 32%) and KRASG12C (n = 16, 32%) represented the most prevalent subtypes. KRASG12D mutations were associated with female (p = 0.018), never smokers (p = 0.108), and concurrences with EGFR (25.0% vs. 17.6%, p = 0.124) and CDKN2A (18.8% vs. 14.7%, p = 0.157). KRASG12D patients showed a better ORR (66.6% vs. 30.0%; OR 4.66, 95% CI 1.23–17.60, p = 0.023) and on multivariate analysis was significantly associated with better PFS (HR 0.36, 95% CI 0.16–0.80; p = 0.012) and OS (HR 0.24, 95% CI 0.08–0.70; p = 0.009). Conclusions: To our knowledge, this study represents the first effort to comprehensively characterize the molecular heterogeneity of KRAS-mutant NSCLC in Latin American patients. Our data reinforce the current view that KRAS-mutated NSCLC is not a single oncogene-driven disease and emphasizes the prognostic impact of diverse molecular profiles in this genomically defined subset of NSCLC. Further validation is warranted in larger multicenter Latin American cohorts to confirm our findings. © 2023, The Author(s)

Influence of omega-3 PUFAs on the metabolism of proanthocyanidins in rats

Studies of the bioavailability of proanthocyanidins usually consider them independently of other dietary constituents, while there is a tendency in the field of functional foods towards the combination of different bioactive compounds in a single product. This study examined the long-term effects of ω-3 polyunsaturated fatty acids of marine origin on the metabolic fate of grape proanthocyanidins. For this, female adult Wistar-Kyoto rats were fed (18 weeks) with a standard diet supplemented or not with eicosapentaenoic acid/docosahexaenoic acid (1:1, 16.6 g/kg feed), proanthocyanidin-rich grape seed extract (0.8 g/kg feed) or both. A total of 39 microbial-derived metabolites and 16 conjugated metabolites were detected by HPLC-MS/MS either in urine or in the aqueous fraction of feces. An unexpected significant increase in many proanthocyanidin metabolites in urine and feces was observed in the group supplemented with ω-3 polyunsaturated fatty acids group as compared to the animals fed a standard diet, which contains a small amount of polyphenols. However, proanthocyanidin metabolites in rats given ω-3 polyunsaturated fatty acids and grape seed extract did not significantly differ from those in the group supplemented only with grape seed extract. It was concluded that ω-3 polyunsaturated fatty acids collaborate in the metabolism of polyphenols when present at low doses in the feed matrix, while the capacity of ω-3 polyunsaturated fatty acids to induce microbiota transformations when proanthocyanidins are present at high doses is not relevant compared to that of polyphenols themselves

A high-fat high-sucrose diet affects the long-term metabolic fate of grape proanthocyanidins in rats

Purpose Polyphenol metabolites are key mediators of the biological activities of polyphenols. This study aimed to evaluate the long-term effects of a high-fat high-sucrose (HFHS) diet on the metabolism of proanthocyanidins from grape seed extract (GSE). Methods Adult female Wistar-Kyoto rats were fed a standard (STD) or HFHS diet supplemented or not with GSE for 16 weeks. PA metabolites were determined by targeted HPLC-MS/MS analysis. Results A lower concentration of total microbial-derived PA metabolites was present in urine and the aqueous fraction of faeces in the HFHS + GSE group than in the STD + GSE group. In contrast, a tendency towards the formation of conjugated (epi)catechin metabolites in the HFHS + GSE group was observed. Conclusions These results show that a HFHS diet significantly modifies PA metabolism, probably via: (1) a shift in microbial communities not counteracted by the polyphenols themselves; and (2) an up-regulation of hepatic enzymes

Environmental gradients and the evolution of successional habitat specialization: A test case with 14 Neotropical forest sites

© 2015 British Ecological Society. Successional gradients are ubiquitous in nature, yet few studies have systematically examined the evolutionary origins of taxa that specialize at different successional stages. Here we quantify successional habitat specialization in Neotropical forest trees and evaluate its evolutionary lability along a precipitation gradient. Theoretically, successional habitat specialization should be more evolutionarily conserved in wet forests than in dry forests due to more extreme microenvironmental differentiation between early and late-successional stages in wet forest. We applied a robust multinomial classification model to samples of primary and secondary forest trees from 14 Neotropical lowland forest sites spanning a precipitation gradient from 788 to 4000 mm annual rainfall, identifying species that are old-growth specialists and secondary forest specialists in each site. We constructed phylogenies for the classified taxa at each site and for the entire set of classified taxa and tested whether successional habitat specialization is phylogenetically conserved. We further investigated differences in the functional traits of species specializing in secondary vs. old-growth forest along the precipitation gradient, expecting different trait associations with secondary forest specialists in wet vs. dry forests since water availability is more limiting in dry forests and light availability more limiting in wet forests. Successional habitat specialization is non-randomly distributed in the angiosperm phylogeny, with a tendency towards phylogenetic conservatism overall and a trend towards stronger conservatism in wet forests than in dry forests. However, the specialists come from all the major branches of the angiosperm phylogeny, and very few functional traits showed any consistent relationships with successional habitat specialization in either wet or dry forests. Synthesis. The niche conservatism evident in the habitat specialization of Neotropical trees suggests a role for radiation into different successional habitats in the evolution of species-rich genera, though the diversity of functional traits that lead to success in different successional habitats complicates analyses at the community scale. Examining the distribution of particular lineages with respect to successional gradients may provide more insight into the role of successional habitat specialization in the evolution of species-rich taxa

Environmental gradients and the evolution of successional habitat specialization: A test case with 14 Neotropical forest sites

https://www.scopus.com/inward/record.url?eid=2-s2.0-84939570316&partnerID=40&md5=fcadae8e6c274e8b7efca96099304a7cSuccessional gradients are ubiquitous in nature, yet few studies have systematically examined the evolutionary origins of taxa that specialize at different successional stages. Here we quantify successional habitat specialization in Neotropical forest trees and evaluate its evolutionary lability along a precipitation gradient. Theoretically, successional habitat specialization should be more evolutionarily conserved in wet forests than in dry forests due to more extreme microenvironmental differentiation between early and late-successional stages in wet forest. We applied a robust multinomial classification model to samples of primary and secondary forest trees from 14 Neotropical lowland forest sites spanning a precipitation gradient from 788 to 4000 mm annual rainfall, identifying species that are old-growth specialists and secondary forest specialists in each site. We constructed phylogenies for the classified taxa at each site and for the entire set of classified taxa and tested whether successional habitat specialization is phylogenetically conserved. We further investigated differences in the functional traits of species specializing in secondary vs. old-growth forest along the precipitation gradient, expecting different trait associations with secondary forest specialists in wet vs. dry forests since water availability is more limiting in dry forests and light availability more limiting in wet forests. Successional habitat specialization is non-randomly distributed in the angiosperm phylogeny, with a tendency towards phylogenetic conservatism overall and a trend towards stronger conservatism in wet forests than in dry forests. However, the specialists come from all the major branches of the angiosperm phylogeny, and very few functional traits showed any consistent relationships with successional habitat specialization in either wet or dry forests. Synthesis. The niche conservatism evident in the habitat specialization of Neotropical trees suggests a role for radiation into different successional habitats in the evolution of species-rich genera, though the diversity of functional traits that lead to success in different successional habitats complicates analyses at the community scale. Examining the distribution of particular lineages with respect to successional gradients may provide more insight into the role of successional habitat specialization in the evolution of species-rich taxa

Carbon sequestration potential of second-growth forest regeneration in the Latin American tropics

Regrowth of tropical secondary forests following complete or nearly complete removal of forest vegetation actively stores carbon in aboveground biomass, partially counterbalancing carbon emissions from deforestation, forest degradation, burning of fossil fuels, and other anthropogenic sources. We estimate the age and spatial extent of lowland second-growth forests in the Latin American tropics and model their potential aboveground carbon accumulation over four decades. Our model shows that, in 2008, second-growth forests (1 to 60 years old) covered 2.4 million km2 of land (28.1%of the total study area).Over 40 years, these lands can potentially accumulate a total aboveground carbon stock of 8.48 Pg C (petagrams of carbon) in aboveground biomass via low-cost natural regeneration or assisted regeneration, corresponding to a total CO2 sequestration of 31.09 Pg CO2. This total is equivalent to carbon emissions from fossil fuel use and industrial processes in all of Latin America and the Caribbean from1993 to 2014. Ten countries account for 95% of this carbon storage potential, led by Brazil, Colombia, Mexico, and Venezuela. We model future land-use scenarios to guide national carbon mitigation policies. Permitting natural regeneration on 40% of lowland pastures potentially stores an additional 2.0 Pg C over 40 years. Our study provides information and maps to guide national-level forest-based carbon mitigation plans on the basis of estimated rates of natural regeneration and pasture abandonment. Coupled with avoided deforestation and sustainable forestmanagement, natural regeneration of second-growth forests provides a low-costmechanism that yields a high carbon sequestration potential with multiple benefits for biodiversity and ecosystem services. © 2016 The Authors

Cardiovascular disease-related parameters and oxidative stress in SHROB rats, a model for metabolic syndrome

8 páginas, 3 tablas.-- Eunice Molinar Toribio ... et al.-- This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.SHROB rats have been suggested as a model for metabolic syndrome (MetS) as a situation prior to the onset of CVD or type-2 diabetes, but information on descriptive biochemical parameters for this model is limited. Here, we extensively evaluate parameters related to CVD and oxidative stress (OS) in SHROB rats. SHROB rats were monitored for 15 weeks and compared to a control group of Wistar rats. Body weight was recorded weekly. At the end of the study, parameters related to CVD and OS were evaluated in plasma, urine and different organs. SHROB rats presented statistically significant differences from Wistar rats in CVD risk factors: total cholesterol, LDL-cholesterol, triglycerides, apoA1, apoB100, abdominal fat, insulin, blood pressure, C-reactive protein, ICAM-1 and PAI-1. In adipose tissue, liver and brain, the endogenous antioxidant systems were activated, yet there was no significant oxidative damage to lipids (MDA) or proteins (carbonylation). We conclude that SHROB rats present significant alterations in parameters related to inflammation, endothelial dysfunction, thrombotic activity, insulin resistance and OS measured in plasma as well as enhanced redox defence systems in vital organs that will be useful as markers of MetS and CVD for nutrition interventions.This research was supported by the Spanish Ministries of Science and Innovation and of Economy and Competitiveness (Grants AGL2009-12374-C03-01, -02 and -03; AGL2013-49079-C2-1,2-R; respectively) and in part by the Generalitat de Catalunya regional authorities (2009SGR-1308). M.C. acknowledges ETHERPATHS (FP7-KBBE-222639) funded by the European Union and “ICREA Academia” award for excellence in research, funded by the ICREA Foundation of the Generalitat de Catalunya. The Panamanian Government (SENACYT/IFRHU) and the Spanish Ministry of Science and Innovation awarded graduate fellowships to E.M.-T. and L.M., respectively. The ISCIII and the Xunta de Galicia are also acknowledged for “Sara Borrell” and “Isidro Parga Pondal” postdoctoral contracts to J.P.-J. (CD09/00068) and M.P., respectively.Peer reviewe

Características del síntoma de angina en un grupo de mujeres con coronariografía positiva en la clínica AMI de la ciudad de Cartagena 2007 - 2008

Tesis (Enfermero) -- Universidad de Cartagena. Facultad de Enfermería, 2008El presente trabajo de investigación tiene el concepto que La angina de pecho es un síntoma que traduce la existencia de isquemia miocárdica, y por ende de enfermedad funcional y orgánica en las arterias coronarias. Las mujeres que padecen enfermedad coronaria tienen menor riesgo de muerte que los hombres, sin embargo, la mayoría de muertes atribuibles a esta causa ocurren en pacientes de sexo femenino; debido a que estas consultan mas tarde, presentan dolores atípicos, localizaciones anormales, fatiga y el electrocardiograma se realiza con menor frecuencia

A high-fat high-sucrose diet affects the long-term metabolic fate of grape proanthocyanidins in rats

[Purpose]: Polyphenol metabolites are key mediators of the biological activities of polyphenols. This study aimed to evaluate the long-term effects of a high-fat high-sucrose (HFHS) diet on the metabolism of proanthocyanidins from grape seed extract (GSE). [Methods]: Adult female Wistar–Kyoto rats were fed a standard (STD) or HFHS diet supplemented or not with GSE for 16 weeks. PA metabolites were determined by targeted HPLC–MS/MS analysis. [Results]: A lower concentration of total microbial-derived PA metabolites was present in urine and the aqueous fraction of faeces in the HFHS + GSE group than in the STD + GSE group. In contrast, a tendency towards the formation of conjugated (epi)catechin metabolites in the HFHS + GSE group was observed. [Conclusions]: These results show that a HFHS diet significantly modifies PA metabolism, probably via: (1) a shift in microbial communities not counteracted by the polyphenols themselves; and (2) an up-regulation of hepatic enzymes.This research was supported by the Spanish Ministry of Science and Innovation (Grants: AGL2009-12374-C03-01, -02 and -03; and AGL2013-49079-C2-1, 2 and -R, and through a doctoral fellowship to L.M.). The Panamanian Government (SENACYT/IFARHU) awarded a graduate fellowship to E.M.-T. The ISCIII is acknowledged for a “Sara Borrell” postdoctoral contract to J.P.-J. (CD09/00068).Peer Reviewe

The combined action of omega-3 polyunsaturated fatty acids and grape proanthocyanidins on a rat model of diet-induced metabolic alterations

8 pages, 3 figuresIt has been suggested that food components such as ω-3 polyunsaturated fatty acids (ω-3 PUFAs) and (poly)phenols counteract diet-induced metabolic alterations by common or complementary mechanisms. To examine the effects of a combination of ω-3 PUFAs and (poly)phenols on such alterations, adult Wistar-Kyoto rats were fed an obesogenic high-fat high-sucrose diet supplemented, or not, for 24 weeks with: eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) 1 : 1 (16.6 g kg(-1) feed); proanthocyanidin-rich grape seed extract (GSE, 0.8 g kg(-1) feed); or EPA/DHA 1 : 1 + GSE. Body weight, feed intake, and plasma glucose were evaluated every 6 weeks, while adipose tissue weight, insulin, glucagon, ghrelin, leptin, adiponectin, cholesterol, and triglycerides were evaluated at the end of the experiment. ω-3 PUFAs reduced plasma leptin and cholesterol levels, but did not modify diet-induced perigonadal fat or plasma insulin levels; while GSE increased plasma triglyceride levels. The combined action of ω-3 PUFAs and the proanthocyanidins reduced plasma insulin and leptin, as well as partially prevented perigonadal fat accumulation. While separate supplementation with ω-3 PUFAs or grape proanthocyanidins may not counteract all the key metabolic changes induced by a high-energy-dense diet, the combination of both supplements reverts altered insulin, leptin and triglyceride levels to normal.This research was supported by the Spanish Ministry of Science and Innovation (through grants AGL2009-12374-C03-01, -02 and -03; and AGL2013-49079-C2-1,2-R). The Panamanian Government (SENACYT/IFRHU) and Spanish Research Council (CSIC) awarded graduate fellowships to E. M.-T. and G. D., respectively. The ISCIII is acknowledged for a “Sara Borrell” postdoctoral contract to J. P.-J. (CD09/00068).Peer reviewe