ABSTRACT
The drug, 5-fluorouracil (5FU) is a standard first-line treatment for colorectal cancer (CRC) patients. However, drug resistance acquisition remains an important challenge for effective clinical outcomes. Here, we established a long-term drug-resistant CRC model and explored the cellular events underlying 5FU resistance. We showed that 5FU-treated cells (HCT-116 5FUR) using a prolonged treatment protocol were significantly more resistant than parental cells. Likewise, cell viability and IC50 values were also observed to increase in HCT-116 5FUR cells when treated with increasing doses of oxaliplatin, indicating a cross-resistance mechanism to other cytotoxic agents. Moreover, HCT-116 5FUR cells exhibited metabolic and molecular changes, as evidenced by increased thymidylate synthase levels and upregulated mRNA levels of ABCB1. HCT-116 5FUR cells were able to overcome S phase arrest and evade apoptosis, as well as activate autophagy, as indicated by increased LC3B levels. Cells treated with low and high doses displayed epithelial-mesenchymal transition (EMT) features, as observed by decreased E-cadherin and claudin-3 levels, increased vimentin protein levels, and increased SLUG, ZEB2 and TWIST1 mRNA levels. Furthermore, HCT-116 5FUR cells displayed enhanced migration and invasion capabilities. Interestingly, we found that the 5FU drug-resistance gene signature is positively associated with the mesenchymal signature in CRC samples, and that ABCB1 and ZEB2 co-expressed at high levels could predict poor outcomes in CRC patients. Overall, the 5FU long-term drug-resistance model established here induced various cellular events, and highlighted the importance of further efforts to identify promising targets involved in more than one cellular event to successfully overcome drug-resistance.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Apoptosis , Autophagy , Cadherins/genetics , Cell Line, Tumor , Cell Proliferation , Claudin-3 , Colonic Neoplasms/drug therapy , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Cytotoxins , Drug Resistance, Neoplasm , Epithelial-Mesenchymal Transition , Fluorouracil/pharmacology , Humans , Oxaliplatin/pharmacology , RNA, Messenger , Thymidylate Synthase , VimentinABSTRACT
Triple-negative breast cancer represents about 15% of all cases of breast cancer, and still represents a therapeutic challenge. 3'-Azido-3'-deoxythymidine (AZT) is a nucleoside reverse transcriptase inhibitor with antitumor activity. Chalcogenides compounds, such as selenium, are very important intermediates applied in organic synthesis. Our objective was to investigate the effect and the underlying cell death mechanisms of AZT and its derivatives, in human breast cancer cell lines. The inhibitory effect of AZT and derivatives (1072, 1073, and 1079) was determined by MTT assay (0.1, 1, 10, 50, and 100 µM for concentrations and times 4, 24, 48, and 72 h) and Live/Dead in tumor cell lines MCF-7, MDA-MB 231 and also in non-tumor cell line CHO. Gene expression profiles related to apoptosis were investigated by qRT-PCR and induction of apoptosis was investigated by flow cytometry. MTT and Live/Dead assays showed that AZT derivatives decreased the rate of cell proliferation at concentrations of 50 and 100 µM in tumor cell lines MCF-7 and MDA-MB 231 while the commercial AZT presented a low antitumoral potential in all strains tested. In flow cytometry analysis we demonstrated that derivatives of AZT induced apoptosis, with an increase in both initial and late stages in both tumor cell lines evaluated, especially in MDA-MB 231. Our data show that the AZT derivative 1072 increased the expression of transcripts of the genes caspase 3 and 8 in MDA-MB 231 cell line when compared to control, suggesting that the extrinsic pathway of apoptosis was activated. In conclusion, derivatives of AZT, especially 1072, induce cytotoxicity in vitro in the triple negative breast cancer cell line through activation of the extrinsic pathway of apoptosis. These compounds containing selenium in its formulation are potential therapeutic agents for breast cancer.
ABSTRACT
Pictures of facial expressions of emotion are used in a wide range of experiments. The last decade has seen an increase in the number of studies presenting local sets of emotion stimuli. However, only a few existing sets contain pictures of Latin Americans, despite the growing attention emotion research is receiving in this region. Here we present the development and validation of the Universidad Nacional de Cordoba, Expresiones de Emociones Faciales (UNCEEF), a Facial Action Coding System (FACS)-verified set of pictures of Argentineans expressing the six basic emotions, plus neutral expressions. FACS scores, recognition rates, Hu scores, and discrimination indices are reported. Evidence of convergent validity was obtained using the Pictures of Facial Affect in an Argentine sample. However, recognition accuracy was greater for UNCEEF. The importance of local sets of emotion pictures is discussed.
Subject(s)
Databases, Factual , Emotions , Facial Expression , Photic Stimulation/methods , Adolescent , Adult , Argentina , Female , Humans , Male , Recognition, Psychology , Young AdultABSTRACT
Most human populations are undergoing a demographic transition regarding their age structure. This transition is reflected in chronic non-communicable diseases featuring among the main contributors to burden of disease. Considering that the aging process is a major risk factor for such conditions, understanding the mechanisms underlying aging and age-related diseases is critical to develop strategies to impact human health at population and/or individual-levels. Two different aspects of aging process (namely, telomere shortening and DNA damage accumulation) were shown to interact in positively impacting mice median survival. However, strategies aimed at translating such knowledge into actual human health benefits have not yet been discussed. In this manuscript, we present potential exposures that are suited for population-level interventions, and contextualize the roles of population (based on behavioral exposures) and individual-level (based on small-molecule administration) anti-aging interventions in different levels of disease prevention. We suggest that exposures such as moderate wine consumption, reducing calorie intake and active lifestyle are potentially useful for primordial and primary prevention, while small-molecules that activate telomerase and/or tumor suppression responses are more suited for secondary and tertiary prevention (although important for primary prevention in specific population subgroups). We also indicate the need of studying the impacts, on aging and age-related diseases, of different combinations of these exposures in well-conducted randomized controlled trials, and propose Mendelian randomization as a valuable alternative to gather information in human populations regarding the effects of potential anti-aging interventions.
ABSTRACT
A tireoidite supurativa aguda (TSA) é uma condição rara, potencialmente ameaçadora da vida, que acomete geralmente mulheres na idade adulta, sendo mais comum em pacientes com doença tireoideana pré-existente. Os autores apresentam o caso de uma paciente pediátrica, previamente hígida, com quadro clínico e exames complementares sugestivos de TSA durante sua internação no Hospital Universitário da Universidade Luterana do Brasil.
Acute suppurative thyroiditis (AST) is a rare life-threatening condition that usually affects women in adulthood, being more common in patients with pre-existing thyroid disease. The authors report the case of a previously healthy pediatric patient with clinical and laboratory tests suggestive of AST during her hospitalization at the University Hospital of the Lutheran University of Brazil.
Subject(s)
Humans , Female , Child , Neck/pathology , Thyroiditis, Suppurative/diagnosis , Thyroiditis, Suppurative/pathology , Child , Diagnostic Imaging/methods , Thyroiditis, Suppurative/therapyABSTRACT
En esta publicación, se presenta el análisis de algunos datos relacionados con la marihuana como ser: la distribución de los estudiantes que probaron marihuana, de los que saben donde conseguirla, de los que probaron y saben donde conseguirla, de los que no probaron pero saben donde conseguirla, según sexo y edad. Se plantea la necesidad de implementar reales y efectivos programas preventivos, los cuales son menos costosos que los asistenciales y los de reinserción social. En próximos trabajos, se irán analizando otras variables de interés relacionadas con esta sustancia
Subject(s)
Humans , Male , Female , Adolescent , Adolescent , Marijuana Smoking/epidemiology , Social Problems , Substance-Related Disorders , Uruguay , Health EducationABSTRACT
En esta publicación, se presenta el análisis de algunos datos relacionados con la cocaína como ser: la distribución de los estudiantes que probaron cocaína, de los que saben donde conseguirla, de los que no probaron y saben donde conseguirla, según sexo y edad. Se plantea el hecho que existen adolescentes que han probado la droga, lo que significa que la sociedad uruguaya está ante un problema con urgencia de elaboración y planificación de medidas de atención primaria en salud.En próximos trabajos se irán analizando otras variables de interés relacionadas con esta sustancia