Masking and triggered unmasking of targeting ligands on nanocarriers to improve drug delivery to brain tumors

Long-circulating nanocarriers have been extensively studied to deliver chemotherapeutics; however, the inclusion of targeting agents compromises circulation times thereby offsetting the benefits of active targeting. Here, we formulated cysteine-cleavable phospholipid–polyethylene glycol (PEG) to ‘mask’ nanocarrier bound targeting ligands from RES clearance and prolong circulation times of liposomes to allow passive targeting to tumors. This detachable polymer coating can be removed after nanocarrier extravasation to tumor is achieved to expose targeting ligands and promote active targeting to tumor cells. In vivo studies on folate receptor-targeted liposomes demonstrated our ability to prolong circulation in the bloodstream using this system thereby verifying the ‘masking’ capacity of cleavable phospholipid–PEG₅₀₀₀. Controlled modulation of uptake and cytotoxicity of targeted nanocarriers using cleavable phospholipid–PEG was demonstrated through in vitro studies. Finally, studies analyzing uptake by tumor cells in vivo confirmed enhanced intracellular delivery when tumor-inoculated animals received targeted liposomes containing cleavable phospholipid–PEG₅₀₀₀ followed by a cysteine infusion to expose folate after liposomes had extravasated to tumor. These results indicate that cleavable phospholipid–PEG can be used in nanocarrier formulations for controlled exposure of targeting ligands to ensure that circulation times remain uncompromised by the inclusion of targeting agents while enabling active targeting to tumors after removal of the polymer coating.     

Bio-inspired design of dental multilayers: Experiments and model

This paper combines experiments, simulations and analytical modeling that are inspired by the stress reductions associated with the functionally graded structures of the dentin–enamel-junctions (DEJs) in natural teeth. Unlike conventional crown structures in which ceramic crowns are bonded to the bottom layer with an adhesive layer, real teeth do not have a distinct “adhesive layer” between the enamel and the dentin layers. Instead, there is a graded transition from enamel to dentin within a 10 to 100 μm thick regime that is called the Dentin Enamel Junction (DEJ). In this paper, a micro-scale, bio-inspired functionally graded structure is used to bond the top ceramic layer (zirconia) to a dentin-like ceramic-filled polymer substrate. The bio-inspired functionally graded material (FGM) is shown to exhibit higher critical loads over a wide range of loading rates. The measured critical loads are predicted using a rate dependent slow crack growth (RDEASCG) model. The implications of the results are then discussed for the design of bio-inspired dental multilayers.     

Life Stressors as Mediators of the Relation Between Socioeconomic Position and Mental Health Problems in Early Adolescence: The TRAILS Study

ObjectiveLife stressors and family socioeconomic position have often been associated with mental health status. The aim of the present study is to contribute to the understanding of the pathways from low socioeconomic position and life stressors to mental problems.MethodIn a cross-sectional analysis using data from a longitudinal study of early adolescents (N = 2,149, 51% girls; mean age 13.6 years, SD 0.53, range 12–15), we assessed the extent of mediation of the association between family socioeconomic position and mental health problems by different types of life stressors in multiple regression models. Stressors were rated as environment related or person related. Information on socioeconomic position was obtained directly from parents, and internalizing and externalizing problem behaviors were assessed by reports from multiple informants (parents, self, and teachers).ResultsLow socioeconomic position was associated with more mental health problems and more life stressors. Both environment-related and person-related stressors predicted mental health problems independently of socioeconomic position. The associations between socioeconomic position and all mental health outcomes were partly mediated by environment-related life stressors. Mediation by environment-related and person-related stressors as assessed by linear regression amounted to 56% (95% confidence interval [CI] 35%–78%) and 7% (95% CI ?25% to 38%) for internalizing problems and 13% (95% CI 7%–19%) and 5% (95% CI ?2% to 13%) for externalizing problems, respectively.ConclusionsEnvironment-related, but not person-related, stressors partly mediated the association between socio economic position and adolescent mental problems. The extent of mediation was larger for internalizing than for externalizing problems. Because the effect sizes of the associations were relatively small, targeted interventions to prevent impaired mental health may have only modest benefits to adolescents from low socioeconomic background.     

Barriers to procreational intentions among cancer survivors 2 years after diagnosis: a French national cross‐sectional survey

Objectives: To determine the procreational intention rates among cancer survivors whose fertility was unimpaired and to identify the factors associated with their procreational intentions. Methods: Six thousand nine hundred and fifty‐seven adult cancer patients treated between September and October 2002 were randomly selected from the French National Health Insurance Fund's Chronic Disease File. Of the 6957, 4270 responded to a cross‐sectional questionnaire 2 years after diagnosis, of whom 959 reported being fertile and responded to a question about their procreational intentions. Results: Among the 257 male and female survivors aged 20–44, 86 (33.5%) had procreational intentions. After adjusting for age, gender, and already having children, only a high educational level (adjusted odds ratio: 3.1, 95% confidence interval 1.3–7.8) and stable or increasing financial resources (2.4, 1.0–5.7) were independently associated with the respondents' procreational intentions. Neither cancer stage at diagnosis nor the present stage significantly affected their plans in this respect. Conclusions: Two years after cancer diagnosis, the reasons why some survivors who are still fertile have no parenthood projects were similar to those earlier given by members of the general population. Copyright © 2010 John Wiley & Sons, Ltd.     

Delayed Hemolytic Transfusion Reaction in Sickle Cell Disease

Delayed hemolytic transfusion reactions are potentially life-threatening complications observed in patients with sickle cell disease. We review the clinical features, pathophysiology, laboratory evaluation, and management of this complication. It is important that delayed hemolytic transfusion reactions be included in the differential diagnosis of acute pain episodes following a red blood cell transfusion in a patient with sickle cell disease.     

DNA repair mechanisms in eukaryotes: Special focus in Entamoeba histolytica and related protozoan parasites

Eukaryotic cell viability highly relies on genome stability and DNA integrity maintenance. The cellular response to DNA damage mainly consists of six biological conserved pathways known as homologous recombination repair (HRR), non-homologous end-joining (NHEJ), base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER), and methyltransferase repair that operate in a concerted way to minimize genetic information loss due to a DNA lesion. Particularly, protozoan parasites survival depends on DNA repair mechanisms that constantly supervise chromosomes to correct damaged nucleotides generated by cytotoxic agents, host immune pressure or cellular processes. Here we reviewed the current knowledge about DNA repair mechanisms in the most relevant human protozoan pathogens. Additionally, we described the recent advances to understand DNA repair mechanisms in Entamoeba histolytica with special emphasis in the use of genomic approaches based on bioinformatic analysis of parasite genome sequence and microarrays technology.