Dual FGFR-targeting and pH-activatable ruthenium-peptide conjugates for targeted therapy of breast cancer.

Dysregulation of Fibroblast Growth Factor Receptors (FGFRs) signaling has been associated with breast cancer, yet employing FGFR-targeted delivery systems to improve the efficacy of cytotoxic agents is still sparsely exploited. Herein, we report four new bi-functional ruthenium-peptide conjugates (RuPCs) with FGFR-targeting and pH-dependent releasing abilities, envisioning the selective delivery of cytotoxic Ru complexes to FGFR(+)-breast cancer cells, and controlled activation at the acidic tumoral microenvironment. The antiproliferative potential of the RuPCs and free Ru complexes was evaluated in four breast cancer cell lines with different FGFR expression levels (SKBR-3, MDA-MB-134-VI, MCF-7, and MDA-MB-231) and in human dermal fibroblasts (HDF), at pH 6.8 and pH 7.4 aimed at mimicking the tumor microenvironment and normal tissues/bloodstream pHs, respectively. The RuPCs showed higher cytotoxicity in cells with higher level of FGFR expression at acidic pH. Additionally, RuPCs showed up to 6-fold higher activity in the FGFR(+) breast cancer lines compared to the normal cell line. The release profile of Ru complexes from RuPCs corroborates the antiproliferative effects observed. Remarkably, the cytotoxicity and releasing ability of RuPCs were shown to be strongly dependent on the conjugation of the peptide position in the Ru complex. Complementary molecular dynamic simulations and computational calculations were performed to help interpret these findings at the molecular level. In summary, we identified a lead bi-functional RuPC that holds strong potential as a FGFR-targeted chemotherapeutic agent.

Exploiting Co(III)-Cyclopentadienyl Complexes To Develop Anticancer Agents.

In recent years, organometallic complexes have attracted much attention as anticancer therapeutics aiming at overcoming the limitations of platinum drugs that are currently marketed. Still, the development of half-sandwich organometallic cobalt complexes remains scarcely explored. Four new cobalt(III)-cyclopentadienyl complexes containing N,N-heteroaromatic bidentate, and phosphane ligands were synthesized and fully characterized by elemental analysis, spectroscopic techniques, and DFT methods. The cytotoxicity of all complexes was determined in vitro by the MTS assay in colorectal (HCT116), ovarian (A2780), and breast (MDA-MB-231 and MCF-7) human cancer cell lines and in a healthy human cell line (fibroblasts). The complexes showed high cytotoxicity in cancer cell lines, mostly due to ROS production, apoptosis, autophagy induction, and disruption of the mitochondrial membrane. Also, these complexes were shown to be nontoxic in vivo in an ex ovo chick embryo yolk sac membrane (YSM) assay.

Mortalidad y readmisión en la unidad de cuidados intensivos / Mortality and readmission to the intensive care unit

INTRODUCCIÓN: la readmisión en las unidades de cuidados intensivos durante la hospitalización se asocia con una significativa mortalidad y un incremento de la estadía y los costos, por lo que existe un creciente interés en identificar los elementos predictores de la readmisión. OBJETIVO: caracterizar las readmisiones y la mortalidad asociadas a factores de riesgo en la Unidad de Cuidados Intensivos Polivalente del Hospital Militar Central "Dr. Carlos J. Finlay". MÉTODOS: estudio descriptivo, longitudinal y retrospectivo, entre el 1ro. de enero al 31 de diciembre de 2008. La muestra estuvo constituida por todos los pacientes readmitidos en el periodo señalado. Se aplicó el estadígrafo t de Student para las variables edad, estadía hospitalaria al ingreso, readmisión o egreso. RESULTADOS: predominaron los pacientes del sexo masculino mayores de 40 años. Hubo un 37,8 % de mortalidad global, principalmente de fallecidos en entidades clínicas. Los pacientes con mayor período entre ingreso-readmisión, presentaron una elevada mortalidad. La sepsis respiratoria fue la causa más frecuente de readmisiones. La tasa de readmisión fue de 3,31 %. CONCLUSIÓN: la escala APACHE II constituyó un adecuado predictor de riesgo de morir en la Unidad de Cuidados Intensivos. Las variables con impacto sobre la mortalidad fueron edad, sexo masculino, ventilación mecánica y la presencia de enfermedades clínicas. La tasa de readmisiones se comportó por debajo de la media internacional, lo que evidencia un buen trabajo de la Unidad de Cuidados Intensivos en este indicador de calidad.

INTRODUCTION: reentry to the ICU during hospitalization is associated with significant mortality and an increase of stay and costs, so that there is a growing interest in identifying predictors of readmission elements. OBJECTIVE: to characterize reentries and mortality associated to risk factors in the Intensive Care Unit at "Dr. Carlos J. Finlay" Central Military Hospital. METHODS: a descriptive, longitudinal and retrospective study was conducted from January 1st December to 31st 2008. The sample consisted of all patients readmitted within the given period. The Student t statistic for the variables such as age, hospital admission, hospital stay, hospital readmission or discharge was applied. RESULTS: male patients over 40 years were in majority. There was 37.8 % overall mortality, mainly of deaths in clinical entities. Patients with higher admission- readmission period showed a high mortality. Respiratory sepsis was the most frequent cause of readmissions. The readmission rate was 3.31 %. CONCLUSION: APACHE II scale is an adequate predictor of risk of deceases in ICU. Variables with impact on mortality were age, male gender, mechanical ventilation, and the presence of clinical disease. The rate of readmissions was below the international average, which demonstrates good performance of ICU in this quality indicator.

Relação entre índice de resistência obtido pela ultra-sonografia Doppler transfortanela e o neurodesenvolvimento até o primeiro ano de vida em recém-nascidos a termo com encefalopatia hipóxico-isquêmica leve e moderada / Relation between the resistance index obtained by the transfontanellar Doppler ultrasonography and the neurological development until the first year of life in term infants with mild or moderate hypoxic-ischaemic encephalopathy

OBJETIVO: Avaliar a relação do índice de resistência (IR) obtido pela ultra-sonografia Doppler transfontanela com o neurodesenvolvimento até um ano de idade, em recém-nascidos (RN) a termo com encefalopatia hipóxica-isquêmica (EHI) leve a moderada, secundária à asfixia intra-parto. MÉTODO: Estudo prospectivo em 20 RN com EHI leve a moderada, IR elevado no primeiro exame de Doppler, e sem doenças associadas ou anormalidades morfológicas cerebrais. Foram realizados exames seriados bimensais de Doppler transfontanela a partir do sétimo dia de vida, e avaliações clínicas mensais do neurodesenvolvimento no primeiro ano de vida. RESULTADOS: Houve normalização progressiva dos valores de IR até o último exame realizado. Cinco pacientes apresentaram normalização clínico-neurológica no período neonatal, após o primeiro exame de Doppler. Quinze lactentes apresentaram alterações neurológicas com resolução a partir do segundo trimestre de vida. CONCLUSÃO: Houve relação entre os períodos em que ocorreu a normalização dos valores de IR e a melhora clínica-neurológica.

OBJECTIVE: To evaluate the relation between the resistance index (RI) obtained by transfontanellar Doppler ultrasonography, and the neurodevelopment until one year of life, at term newborns with mild or moderate hypoxic-ischaemic encephalopathy due to intrapartum asphyxia. METHOD: 20 term newborns, with mild or moderate hypoxic-ischemic encephalopathy, high values of resistance index in the first exam, and without cerebral morfologic abnormalities or other diseases. They were submitted to serial bimonthly transfontanellar Doppler ultrasonography, from the seventh day of life on, and monthly clinical neurodevelopment assessment until one year of life. RESULTS: There was a progressive normalization of RI values until the last examination. In five cases there were clinical neurologic normalization in the neonatal period after the first Doppler exam. Fifteen infants presented neurologic abnormalities, with normalization after the second trimester of life. CONCLUSION: There was a relation between the normal RI values with the normalization of the clinical assessment.

Utilizaçäo de recurso tecnológico como agente facilitador do trabalho de enfermagem / The utilization of technological resources as a facilitator agent for nursing work

Atualmente recursos tecnológicos vêm sendo empregados no sentido de facilitar a execuçäo de diversas atividades laborais, entre eles encontra-se o elevador de pacientes impossibilitados, cujo uso visa evitar o desgaste físico ao trabalhador de enfermagem. Os objetivos deste estudo foram averiguar o motivo da näo utilizaçäo de tal recurso disponível em uma clínica de neurologia e elaborar um roteiro de orientaçäo e treinamento para sua utilizaçäo...