RESUMO
Background: Overweight and obesity are prevalent in schoolchildren due to dietary habits and lack of exercise. These children are prone to metabolic syndrome (MS) and future risk of type 2 diabetes mellitus and cardiovascular diseases. Materials and Methods: This cross-sectional study was conducted in Bhubaneswar City, Eastern India, among schoolchildren. Obesity and overweight were determined by the Indian Academy of Pediatrics guideline. Fasting venous blood samples were taken for insulin, blood glucose, and lipid levels measurement. Blood pressure was measured as per the protocol. The International Diabetic Federation (IDF) criteria for the definition of MS were followed. Insulin resistance was determined by a homeostatic model assessment (HOMA-IR). Results: A total of 1,930 children were screened, of which 545 (28.2%) were overweight and obese. The male to female ratio was 1.27. The overall prevalence of MS was 21.8% (11% in 6 to ≤10 years old and 30.6% in 11 to 16 years old). A history of cardiovascular disease, diabetes, obesity, and hypertension in the family was present in 42.7%. Acanthosis nigricans was present in 46.4%. A history of exclusive breast feeding for 6 months was present in 68.1%. The mean HOMA-IR in children with MS was 5.46 compared to 2.18 in those without MS (insulin resistance was more common in children with MS). Conclusions: The present study found a higher prevalence of MS and insulin resistance in schoolchildren from Eastern India who are overweight/obese.
RESUMO
Most breast cancer deaths occur in women with recurrent, estrogen receptor (ER)-α(+), metastatic tumors. There is a critical need for therapeutic approaches that include novel, targetable mechanism-based strategies by which ERα (+) tumors can be resensitized to endocrine therapies. The objective of this study was to validate a group of nuclear transport genes as potential biomarkers to predict the risk of endocrine therapy failure and to evaluate the inhibition of XPO1, one of these genes as a novel means to enhance the effectiveness of endocrine therapies. Using advanced statistical methods, we found that expression levels of several of nuclear transport genes including XPO1 were associated with poor survival and predicted recurrence of tamoxifen-treated breast tumors in human breast cancer gene expression data sets. In mechanistic studies we showed that the expression of XPO1 determined the cellular localization of the key signaling proteins and the response to tamoxifen. We demonstrated that combined targeting of XPO1 and ERα in several tamoxifen-resistant cell lines and tumor xenografts with the XPO1 inhibitor, Selinexor, and tamoxifen restored tamoxifen sensitivity and prevented recurrence in vivo. The nuclear transport pathways have not previously been implicated in the development of endocrine resistance, and given the need for better strategies for selecting patients to receive endocrine modulatory reagents and improving therapy response of relapsed ERα(+) tumors, our findings show great promise for uncovering the role these pathways play in reducing cancer recurrences.
Assuntos
Antineoplásicos Hormonais/farmacologia , Receptor alfa de Estrogênio/metabolismo , Carioferinas/metabolismo , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Tamoxifeno/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/genética , Núcleo Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Carioferinas/genética , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína Quinase 7 Ativada por Mitógeno/genética , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteína Exportina 1RESUMO
BACKGROUND: Depending on chemical features residues have preferred locations -- interior or exterior -- in protein structures, which also determine how many other residues are found around them. The close packing of residues is the hallmark of protein interior and protein-protein interaction sites. RESULTS: The average values of accessible surface area (ASA) and partner number (PN, the number of other residues within a distance of 4.5 A from any atom of a given residue) of different residues have been determined and a webserver, ContPlot has been designed to display these values (relative to the average values) along the protein sequence. This would be useful to visually identify residues that are densely packed, or those involved in protein-protein interactions. The skewness observed in the distribution of PNs is indicative of the hydrophobic or hydrophilic nature of the residue. The variation of ASA with PN can be analytically expressed in terms of a cubic equation. These equations (one for each residue) can be used to estimate the ASA of a polypeptide chain using the PNs of the individual residues in the structure. CONCLUSION: The atom-based PNs (obtained by counting surrounding atoms) are highly correlated to the residue-based PN, indicating that the latter can adequately capture the atomic details of packing. The average values of ASA and PN associated with each residue should be useful in protein structure prediction or fold-recognition algorithm. ContPlot would provide a handy tool to assess the importance of a residue in the protein structure or interaction site.