ABSTRACT
Gastric cancer is a leading cause of cancer mortality and health disparities in Latinos. We evaluated gastric intratumoral heterogeneity using multiregional sequencing of >700 cancer genes in 115 tumor biopsies from 32 patients, 29 who were Latinos. Analyses focused on comparisons with The Cancer Genome Atlas (TCGA) and on mutation clonality, druggability, and signatures. We found that only approximately 30% of all mutations were clonal and that only 61% of the known TCGA gastric cancer drivers harbored clonal mutations. Multiple clonal mutations were found in new candidate gastric cancer drivers such as EYS, FAT4, PCDHA1, RAD50, EXO1, RECQL4, and FSIP2. The genomically stable (GS) molecular subtype, which has the worse prognosis, was identified in 48% of our Latino patients, a fraction that was >2.3-fold higher than in TCGA Asian and White patients. Only a third of all tumors harbored clonal pathogenic mutations in druggable genes, with most (93%) GS tumors lacking actionable clonal mutations. Mutation signature analyses revealed that, in microsatellite-stable (MSS) tumors, DNA repair mutations were common for both tumor initiation and progression, while tobacco, POLE, and inflammation signatures likely initiate carcinogenesis. MSS tumor progression was likely driven by aging- and aflatoxin-associated mutations, as these latter changes were usually nonclonal. In microsatellite-unstable tumors, nonclonal tobacco-associated mutations were common. Our study, therefore, contributed to advancing gastric cancer molecular diagnostics and suggests clonal status is important to understanding gastric tumorigenesis. Our findings of a higher frequency of a poor prognosis associated molecular subtype in Latinos and a possible new aflatoxin gastric cancer etiology also advance cancer disparities research. Significance: Our study contributes to advancing our knowledge of gastric carcinogenesis, diagnostics, and cancer health disparities.
Subject(s)
Genetic Heterogeneity , Hispanic or Latino , Stomach Neoplasms , Humans , Carcinogenesis , Eye Proteins/genetics , Hispanic or Latino/genetics , Mutation , Stomach Neoplasms/genetics , Asian , White , PrognosisABSTRACT
Fundamentos: A pesar de los múltiples beneficios atribuidos a la Dieta Mediterránea (DM), diversos estudios han señalado una disminución en su seguimiento. Describir el grado de adherencia a la DM que presentan los adolescentes escolarizados en la Comunidad Autónoma de Cantabria. Métodos: Estudio transversal que analiza una muestra de 1829 adolescentes, de entre 10 y 17 años, escolarizados en 37 centros de enseñanza públicos y concertados, mediante el test KidMed. Resultados: El 6% de los adolescentes mantiene una dieta de muy baja adhesión, el 42% una adhesión media y el 52 % goza de una alta adhesión a la dieta mediterránea. El porcentaje de mujeres que presenta una alta adhesión a la dieta mediterránea es más elevado que el de los varones (54% vs50%). No se observan diferencias estadísticamente significativas en el grado de adherencia a la Dieta Mediterránea entre sexos. La alta adherencia a la Dieta Mediterránea disminuye notablemente a medida que la edad aumenta, principalmente en el paso de 10 y 11 años (57,7%)al tramo de 12 a 15 años (46,7%).Conclusiones: La mitad de los adolescentes mantienen una alta adherencia a la DM, que disminuye con el aumento de la edad, siendo especialmente significativa en el paso de los adolescentes de 10 y 11 años a los jóvenes de 12 a 15 años
Background: Despite the multiple benefits attributed to the Mediterranean Diet (DM), several studies have indicated a decrease in its follow-up. To describe the Adherence to DM, among primary and secondary education adolescents from Cantabria. Methods: A cross-sectional study was carried out, analysing a sample of 1,829 adolescents: 924 (50,5%) were women and 905 (49,5%) were men, aged 10 to 17, attending 37 different primary and secondary education centres, by means of KidMed questionnaire. Results:6% of adolescents maintain a very low adherence to Mediterranean Diet, 42% shows an average adherence, and 52% keep a high adherence. The percentage of women with a high adherence to Mediterranean Diet is higher than men (54 % vs 50 %). There arenot noticeably significant statistical differences of the Adherence to a Mediterranean Diet regarding gender. The high adherence to Mediterranean Diet decreases with age, especially from 10 -11 years to 12-15 years. Conclusions: Half of adolescents keep a high adherence to a Mediterranean Diet. Nevertheless, a major age related decline this high adherence, especially when the adolescents pass from 10-11 years old to 12-15 years old
Subject(s)
Humans , Male , Female , Child , Adolescent , Feeding Behavior , Food Preferences , Diet, Mediterranean/statistics & numerical data , Adolescent Nutrition , Adolescent Behavior , Diet, Healthy/statistics & numerical data , Cross-Sectional Studies , Nutrition Surveys/statistics & numerical data , Food and Nutrition EducationABSTRACT
Disintegrins are small peptides produced in viper venom that act as integrin antagonists. When bound to integrins, disintegrins induce altered cellular behaviors, such as apoptotic induction. Disintegrins with RGDDL or RGDDM motifs induce apoptosis of normal and cancer cells. We hypothesized that a second aspartate (D) carboxyl to the RGD is sufficient to induce apoptosis. Five recombinant mojastin D mutants were produced by site-directed mutagenesis (r-Moj-DA, r-Moj-DG, r-Moj-DL, r-Moj-DN, and r-Moj-DV). Stable αv integrin knockdown and shRNA scrambled control SK-Mel-28 cell lines were produced to test a second hypothesis: r-Moj-D_ peptides bind to αv integrin. Only r-Moj-DL, r-Moj-DM, and r-Moj-DN induced apoptosis of SK-Mel-28 cells (at 29.4%, 25.6%, and 36.2%, respectively). Apoptotic induction was significantly reduced in SK-Mel-28 cells with a stable αv integrin knockdown (to 2%, 17%, and 2%, respectively), but not in SK-Mel-28 cells with a stable scrambled shRNA. All six r-Moj-D_ peptides inhibited cell proliferation; ranging from 49.56% (r-Moj-DN) to 75.6% (r-Moj-DA). Cell proliferation inhibition by r-Moj-D_ peptides was significantly reduced in SK-Mel-28 cells with a stable αv integrin knockdown. All six r-Moj-D_ peptides inhibited SK-Mel-28 cell migration at high levels (69%-100%). As a consequence, rac-1 mRNA expression levels were significantly reduced as early as 1 h after treatment, suggesting that rac-1 is involved in the cell migration activity of SK-Mel-28.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Disintegrins/pharmacology , Drug Design , Melanoma/drug therapy , Mutant Proteins/pharmacology , Amino Acid Motifs , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Aspartic Acid/chemistry , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Disintegrins/genetics , Disintegrins/metabolism , Enzyme Repression/drug effects , Humans , Integrin alpha Chains/antagonists & inhibitors , Integrin alpha Chains/genetics , Integrin alpha Chains/metabolism , Integrin alphaV/chemistry , Integrin alphaV/genetics , Integrin alphaV/metabolism , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutant Proteins/metabolism , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/genetics , Peptide Fragments/metabolism , Peptide Fragments/pharmacology , RNA Interference , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Recombinant Proteins/pharmacology , Reptilian Proteins/antagonists & inhibitors , Reptilian Proteins/genetics , Reptilian Proteins/metabolism , Reptilian Proteins/pharmacology , Viper Venoms/chemistry , rac1 GTP-Binding Protein/antagonists & inhibitors , rac1 GTP-Binding Protein/genetics , rac1 GTP-Binding Protein/metabolismABSTRACT
Objetivo. Describir cuales son los eventos moleculares que intervienen en la génesis del cáncer colorrectal (CCR) y describir el estado actual en la detección, el diagnóstico y en el tratamiento. Antecedentes. El CCR es una de las neoplasias malignas más frecuentes en los países industrialzados. en México, es la segunda neoplasia maligna del aparato digestivo. Material y métodos. Se efectuó una revisión de la literatura para conocer la utilidad de los procedimientos de detección, diagnóstico y tratamiento del CCR. Además, se describen algunas de las normas vigentes en nuestro servicio. Resultados. Los programas actuales de detección de CCR en la población de bajo riesgo, no han demostrado que tengan impacto en la reducción de la mortalidad por CCR. El tratamiento actual del CCR en etapas tempranas (Duker'A y B1) es quirúrgico. En los pacientes con cáncer del colon con ganglios linfáticos metastásicos (Dukes'C) se recomienda utilizar quimioterapia. En los pacientes con cáncer de recto que han penetrado hasta la grasa perirrectal o que tienen ganglios linfáticos metastásicos (Dukes'B2 y C), el tratamiento recomendado es la utilización de quimioterapia + radioterapia. Hasta la fecha es motivo de debate si estos tratamientos complementarios a la cirugía deben de ser utilizados en el pre o en el postoperatorio. Conclusión. El proceso de carcinogénesis en el colon y en el recto incluyen una serie de pasos donde están involucrados genes activadores y supresores. El tratamiento actual de cáncer colorrectal en etapas tempranas es quirúrgico y en las etapas avanzadas es multidisciplinario (cirugía + quimioterapia ñ radioterapia)
