RESUMO
CONTEXT: Melanoma is one of the cancers with the highest mortality rate for its ability to metastasize. Several targets have undergone investigation for the development of drugs against this pathology. One of the main targets is the kinase BRAF (RAF, rapidly accelerated fibrosarcoma). The most common mutation in melanoma is BRAFV600E and has been reported in 50-90% of patients with melanoma. Due to the relevance of the BRAFV600E mutation, inhibitors to this kinase have been developed, vemurafenib-OMe and dabrafenib. Ursolic acid (UA) is a pentacyclic triterpene with a privileged structure, the pentacycle scaffold, which allows to have a broad variety of biological activity; the most studied is its anticancer capacity. In this work, we reported the interaction profile of vemurafenib-OMe, dabrafenib, and UA, to define whether UA has binding capacity to BRAFWT, BRAFV600E, and BRAFV600K. Homology modeling of BRAFWT, V600E, and V600K; molecular docking; and molecular dynamics simulations were carried out and interactions and residues relevant to the binding of the inhibitors were obtained. We found that UA, like the inhibitors, presents hydrogen bond interactions, and hydrophobic interactions of van der Waals, and π-stacking with I463, Q530, C532, and F583. The ΔG of ursolic acid in complex with BRAFV600K (- 63.31 kcal/mol) is comparable to the ΔG of the selective inhibitor dabrafenib (- 63.32 kcal/mol) in complex to BRAFV600K and presents a ΔG like vemurafenib-OMe with BRAFWT and V600E. With this information, ursolic acid could be considered as a lead compound for design cycles and to optimize the binding profile and the selectivity towards mutations for the development of new selective inhibitors for BRAFV600E and V600K to new potential melanoma treatments. METHODS: The homology modeling calculations were executed on the public servers I-TASSER and ROBETTA, followed by molecular docking calculations using AutoGrid 4.2.6, AutoDockGPU 1.5.3, and AutoDockTools 1.5.6. Molecular dynamics and metadynamics simulations were performed in the Desmond module of the academic version of the Schrödinger-Maestro 2020-4 program, utilizing the OPLS-2005 force field. Ligand-protein interactions were evaluated using Schrödinger-Maestro program, LigPlot + , and PLIP (protein-ligand interaction profiler). Finally, all of the protein figures presented in this article were made in the PyMOL program.
Assuntos
Melanoma , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas Proto-Oncogênicas B-raf , Triterpenos , Ácido Ursólico , Triterpenos/química , Triterpenos/farmacologia , Proteínas Proto-Oncogênicas B-raf/química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Imidazóis/química , Imidazóis/farmacologia , Ligação Proteica , Vemurafenib/farmacologia , Vemurafenib/química , Oximas/química , Oximas/farmacologia , Mutação , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Sítios de LigaçãoRESUMO
BACKGROUND: Tooth loss (TL) affects quality of life and general health. The literature suggesting that tamoxifen treatment in patients with breast cancer (BC) could be associated with alterations in oral health, increasing the risk of TL, is still scarce. This work aimed to determine the relationship between TL and tamoxifen consumption in patients with BC. MATERIAL AND METHODS: This cross-sectional observational study was carried out from July to September 2023 in the medical oncology services of the "Virgen de la Puerta" - ESSALUD High Complexity Hospital and "Dr. Luis Pinillos Ganoza" - IREN Norte - Regional Institute of Neoplastic Diseases, in Trujillo - Peru. Overall, 200 adult patients diagnosed with BC were evaluated, of which 100 consumed tamoxifen and 100 did not. Inter- and intra-rater reliability was determined with respect to TL, resulting in intra-class correlation values RHO = 0.971 and interclass RHO = 0.938. The oncologist of the corresponding service performed BC diagnosis and stage. Poisson regression was used to analyze results with a significance level of p<0.05. RESULTS: No relationship was found between TL and tamoxifen consumption in patients with breast cancer (p= 0.221); however, greater TL was observed in women who consumed tamoxifen for more than one year compared to those who did not use it (p=0.025) and in older adult women compared to young women (p=0.030). CONCLUSIONS: There is a relationship between TL and time of use of tamoxifen in patients with BC, concluding that patients who consumed tamoxifen for more than one year had greater TL than those who did not. Furthermore, no relationship was found between TL and cancer stages, but there was greater TL in older adult patients and also in those who consumed tamoxifen and did not receive chemotherapy or radiotherapy.
Assuntos
Antineoplásicos Hormonais , Neoplasias da Mama , Tamoxifeno , Perda de Dente , Humanos , Tamoxifeno/uso terapêutico , Tamoxifeno/efeitos adversos , Estudos Transversais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/complicações , Feminino , Pessoa de Meia-Idade , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Hormonais/efeitos adversos , Perda de Dente/etiologia , Idoso , AdultoRESUMO
SQUAMOSA promoter-binding protein-like (SPL) proteins play crucial roles in plant growth, development, and responses to environmental stressors. The peanut (Arachis hypogaea L.) is a globally important oil crop. In this study, we cloned the full-length cDNA of 15 SPLs in the peanut by transcriptome sequencing and rapid amplification of cDNA ends, and analyzed their genomic DNA sequences. cDNA lengths varied significantly, from 369 to 3102 bp. The SBP domain of the peanut SPL proteins was highly conserved compared to SPLs in other plant species. Based on their sequence similarity to SPLs from other plant species, the peanut SPLs could be grouped into five subgroups. In each subgroup, lengths of individual genes, conserved motif numbers, and distribution patterns were similar. Seven of the SPLs were predicted to be targets of miR156. The SPLs were ubiquitously expressed in the roots, leaves, flowers, gynophores, and seeds, with different expression levels and accumulation patterns. Significant differences in the expression of most of the SPLs were observed between juvenile and adult leaves, suggesting that they are involved in developmental regulation. Dynamic changes occurred in transcript levels at stage 1 (aerial grown green gynophores), stage 2 (gynophores buried in soil for about three days), and stage 3 (gynophores buried in soil for about nine days with enlarged pods). Possible roles that these genes play in peanut pod initiation are discussed.
Assuntos
Arachis/metabolismo , Clonagem Molecular , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Fatores de Transcrição/genética , Arachis/genética , Sequência de Bases , Regulação da Expressão Gênica no Desenvolvimento , Genes de Plantas , MicroRNAs , Especificidade de Órgãos , Filogenia , Componentes Aéreos da Planta/genética , Componentes Aéreos da Planta/metabolismo , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , RNA Mensageiro , Alinhamento de Sequência , Análise de Sequência de DNA , Análise de Sequência de RNA , Fatores de Transcrição/química , Fatores de Transcrição/metabolismoRESUMO
This article presents the preliminary findings of the Survey on Teenagers and Youth Reproductive Behavior in the Metropolitan Area of Mexico City, which contains information on 1,010 teenagers and young adults from 10 to 25 years of age interviewed in 1987. The average age was 17 years; 51.7 per cent of those interviewed were male and 48.3 per cent were female. A total of 14.6 per cent were married, being the average age at marriage 19.2 years for males and 17.8 years for females. Menarche occurred at an average age of 12.4 years, and spermarche at 14. Of those interviewed, 32.7 per cent have had sexual intercourse at least once in their lives. The average age at which sexual activity had begun, in the case of males, was 16 years and for females, 17 years. Of this group, 33.8 per cent stated that they had used some form of contraception during the first sexual intercourse; the contraceptive methods used most often were rhythm and withdrawal. The main source of supply of other methods is the pharmacy, in 67 per cent. 18.4 per cent of women had been pregnant, and 20.4 per cent of men's partners had presented this same condition. The first pregnancy occurred at 17.8 years for women and 18.7 for men. Of those men and women with a pregnancy experience 66.1 per cent and 57.3 per cent, respectively, stated that their first pregnancy was an unplanned one. Also, first pregnancy was related to their first marriage in 48.1 per cent of women and 82.4 per cent of male. The data presented here will reinforce current knowledge and will enable us to obtain a profile of the reproductive behavior of teenagers and young adults in the metropolitan area of Mexico City.
Assuntos
Reprodução , Comportamento Sexual , População Urbana , Adolescente , Adulto , Criança , Comportamento Contraceptivo/estatística & dados numéricos , Feminino , Humanos , Masculino , México , Gravidez , Gravidez na Adolescência/estatística & dados numéricos , Puberdade , Comportamento Sexual/estatística & dados numéricos , População Urbana/estatística & dados numéricosRESUMO
The purpose of this article is to provide a brief description of the information that the adolescent and youth population of Mexico City has concerning the knowledge and use of contraceptive methods, as well as the reasons why they do not adopt some contraceptive method during their sexual relations. The data obtained from the Survey on Adolescent and Youth Reproductive Behavior in the Metropolitan Area of Mexico City serves as a basis for pointing out several behavior patterns of the male and female population from 10 to 25 years of age. Of those interviewed, 32.7 per cent had had at least one sexual contact; the average age at which sexual relations had begun was 16 years for males and 17 for females. A total of 33.8 per cent of those who had had sexual contact stated that they had used some form of contraception, the principal methods used during first sexual intercourse being rhythm (36.9%); withdrawal (23.6%), and condoms (12.3%). The reasons for not using any contraceptive method were as follows: lack of knowledge regarding the methods, how to use them or where to obtain them (39.4%), and unplanned sexual intercourse (28.9%). During the last sexual contact they had, 70.5 per cent had used a contraceptive. The methods most frequently used were hormonal contraceptives and IUD (40.9%); rhythm (23.8%), and withdrawal and condoms. The reasons why no contraceptive was used in the last sexual contact were: neither partner thought that pregnancy would occur (27.1%) and the sexual contact was unplanned.
Assuntos
Comportamento do Adolescente , Comportamento Contraceptivo , Adolescente , Adulto , Criança , Dispositivos Anticoncepcionais Masculinos , Anticoncepcionais Orais Hormonais/administração & dosagem , Feminino , Humanos , Masculino , México , Gravidez , Comportamento Sexual , População UrbanaRESUMO
Two simple screening instruments for mental disorders in adults and children respectively were developed in the course of an evaluative study on mental health care in developing countries. Two research teams have attempted to use these same instruments as training tools for primary health care workers. Their experience has shown that the design of the instruments with short, easily understandable questions to which an answer "yes" or "no" can be given is also highly appropriate in the training situation and in daily work. The adaptation and use of these new training tools for primary health care workers in Manila (Philippines) and Cali (Colombia) is described.