Binding Modes of Peptidomimetics Designed to Inhibit STAT3

STAT3 is a transcription factor that has been found to be constitutively activated in a number of human cancers. Dimerization of STAT3 via its SH2 domain and the subsequent translocation of the dimer to the nucleus leads to transcription of anti-apoptotic genes. Prevention of the dimerization is thus an attractive strategy for inhibiting the activity of STAT3. Phosphotyrosine-based peptidomimetic inhibitors, which mimic pTyr-Xaa-Yaa-Gln motif and have strong to weak binding affinities, have been previously investigated. It is well-known that structures of protein-inhibitor complexes are important for understanding the binding interactions and designing stronger inhibitors. Experimental structures of inhibitors bound to the SH2 domain of STAT3 are, however, unavailable. In this paper we describe a computational study that combined molecular docking and molecular dynamics to model structures of 12 peptidomimetic inhibitors bound to the SH2 domain of STAT3. A detailed analysis of the modeled structures was performed to evaluate the characteristics of the binding interactions. We also estimated the binding affinities of the inhibitors by combining MMPB/GBSA-based energies and entropic cost of binding. The estimated affinities correlate strongly with the experimentally obtained affinities. Modeling results show binding modes that are consistent with limited previous modeling studies on binding interactions involving the SH2 domain and phosphotyrosine(pTyr)-based inhibitors. We also discovered a stable novel binding mode that involves deformation of two loops of the SH2 domain that subsequently bury the C-terminal end of one of the stronger inhibitors. The novel binding mode could prove useful for developing more potent inhibitors aimed at preventing dimerization of cancer target protein STAT3

Nosocomial infections in a Brazilian neonatal intensive care unit: a 4-year surveillance study Infecções hospitalares em uma unidade de terapia intensiva neonatal brasileira: vigilância de quatro anos

INTRODUCTION: Report the incidence of nosocomial infections, causative microorganisms, risk factors associated with and antimicrobial susceptibility pattern in the NICU of the Uberlândia University Hospital. METHODS: Data were collected through the National Healthcare Safety Network surveillance from January 2006 to December 2009. The patients were followed five times/week from their birth to their discharge or death. RESULTS: The study included 1,443 patients, 209 of these developed NIs, totaling 293 NI episodes, principally bloodstream infections (203; 69.3%) and conjunctivitis (52; 17.7%). Device-associated infection rates were as follows: 17.3 primary bloodstream infections per 1,000 central line-days and 3.2 pneumonias per 1000 ventilator-days. The mortality rate in neonates with NI was 11.9%. Mechanical ventilation, total parenteral nutrition, orogastric tube, previous antibiotic therapy, use of CVC and birth weight of 751-1,000g appeared to be associated with a significantly higher risk of NI (p < 0.05). In multiple logistic regression analysis for NI, mechanical ventilation and the use of CVC were independent risk factors (p < 0.05). Coagulase- negative Staphylococcus (CoNS) (36.5%) and Staphylococcus aureus (23.6%) were the most common etiologic agents isolated from cultures. The incidences of oxacillin-resistant CoNS and S. aureus were 81.8% and 25.3%, respectively. CONCLUSIONS: Frequent surveillance was very important to evaluate the association of these well-known risk factors with NIs and causative organisms, assisting in drawing the attention of health care professionals to this potent cause of morbidity.<br>INTRODUÇÃO: Relatar a incidência das infecções hospitalares, microrganismos causadores, fatores de risco associados e o padrão de susceptibilidade aos antimicrobianos na UTI neonatal do Hospital Universitário de Uberlândia. MÉTODOS: Realizou-se vigilância National Healthcare Safety Network de janeiro de 2006 a dezembro de 2009. Os pacientes foram acompanhados cinco vezes por semana desde o seu nascimento até a alta ou óbito. RESULTADOS: O estudo incluiu 1.443 pacientes dos quais 209 desenvolveram infecção hospitalar, totalizando 293 episódios de IHs, com destaque para as infecções de corrente sanguínea (203; 69,3%) e conjuntivite (52; 17,7%). As taxas de infecção associadas a dispositivos foram as seguintes: 17,3 infecções da corrente sanguínea primária por 1.000 CVC dia e 3,2 pneumonias por 1.000 ventiladores-dia. A taxa de mortalidade em recém-nascidos com infecções hospitalares foi de 11,9%. A ventilação mecânica, nutrição parenteral total, sonda orogástrica, antibioticoterapia prévia, uso de CVC e peso de 751-1.000g pareceu estar associado com um risco significativamente maior de IH (p < 0,05). Na análise de regressão logística múltipla para IH, ventilação mecânica e uso de CVC foram fatores de risco independentes (p < 0,05). Staphylococcus coagulase-negativo (SCoN) (36,5%) e Staphylococcus aureus (23,6%) foram os agentes etiológicos mais comumente isolados. A incidência de SCoN e S. aureus resistente à oxacilina foram de 81,8% e 25,3%, respectivamente. CONCLUSÕES: Uma vigilância frequente foi importante para avaliar a associação de fatores de risco bem conhecidos com as IHs e etiologia com a finalidade de chamar a atenção dos profissionais de saúde para esta grande causa de morbidade