Improved pharmacokinetic profile of lipophilic anti-cancer drugs using ανβ3-targeted polyurethane-polyurea nanoparticles

Glutathione degradable polyurethane-polyurea nanoparticles (PUUa NP) with a disulfide-rich multiwalled structure and a cyclic RGD peptide as a targeting moiety were synthesized, incorporating a very lipophilic chemotherapeutic drug named Plitidepsin. In vitro studies indicated that encapsulated drug maintained and even improved its cytotoxic activity while in vivo toxicity studies revealed that the maximum tolerated dose (MTD) of Plitidepsin could be increased three-fold after encapsulation. We also found that pharmacokinetic parameters such as maximum concentration (Cmax), area under the curve (AUC) and plasma half-life were significantly improved for Plitidepsin loaded in PUUa NP. Moreover, biodistribution assays in mice showed that RGD-decorated PUUa NP accumulate less in spleen and liver than non-targeted conjugates, suggesting that RGD-decorated nanoparticles avoid sequestration by macrophages from the reticuloendothelial system. Overall, our results indicate that polyurethane-polyurea nanoparticles represent a very valuable nanoplatform for the delivery of lipophilic drugs by improving their toxicological, pharmacokinetic and whole-body biodistribution profiles.     

Effect of bariatric surgery on cardiac structure and function in obese patients: Role of the renin‐angiotensin system

Echocardiographic alterations have been described in obesity, but their modifications after bariatric surgery (BS) and mechanisms are little known, mostly in normotensive patients. We aimed to analyze cardiac changes 1 year post‐BS and to explore possible mechanisms. A cohort of patients with severe obesity (58% normotensives) were prospectively recruited and examined before surgery and after 12 months. Clinical and echocardiographic data, 24 h BP, renin‐angiotensin‐aldosterone system (RAAS) components, cytokines, and inflammatory markers were analyzed at these two time points. Overall reduction in body weight was mean (IQR) = 30.0% (25.9–33.8). There were statistically significant decreases in left ventricle mass index^2.7(LVMI)^2.7, septum thickness (ST), posterior wall thickness (PWT), relative wall thickness (RWT), and E/e’, both in the whole cohort and in patients without RAAS blockers (p ≤ .04 for all). Plasma renin activity (PRA) decreased from (median, IQR) = 0.8 (0.3;1.35) to 0.4 (0.2;0.93) ng/ml/h, plasma aldosterone from 92 (58.6;126) to 68.1 (56.2;83.4) ng/dl, and angiotensin‐converting enzyme (ACE)‐2 activity from 7.7 (5.7;11.8) to 6.8 (5.3;11.2) RFU/µl/h, p < .05. The body weight loss correlated with a decrease in both 24 h SBP and 24 h DBP (Pearson''s coefficient 0.353, p = .022 and 0.384, p = .012, respectively). Variation (Δ) of body weight correlated with ΔE/e’ (Pearson''s coeff. 0.414, p = .008) and with Δ lateral e’ (Pearson''s coeff. = −0.363, p = .018). Generalized linear models showed that ΔPRA was an independent variable for the final (12‐months post‐BS) LVMI^2.7 (p = .028). No other changes in cardiac parameters correlated with ΔBP. In addition to the respective baseline value, final values of PWT and RWT were dependent on 12‐month Δ of PRA, ACE, and ACE/ACE2 (p < .03 for all). We conclude that there are cardiac changes post‐BS in patients with severe obesity, normotensives included. Structural changes appear to be related to modifications in the renin‐angiotensin axis.     

PPARβ/δ attenuates palmitate-induced endoplasmic reticulum stress and induces autophagic markers in human cardiac cells

Background

Chronic endoplasmic reticulum (ER) stress contributes to the apoptotic cell death in the myocardium, thereby playing a critical role in the development of cardiomyopathy. ER stress has been reported to be induced after high-fat diet feeding in mice and also after saturated fatty acid treatment in vitro. Therefore, since several studies have shown that peroxisome proliferator-activated receptor (PPAR)β/δ inhibits ER stress, the main goal of this study consisted in investigating whether activation of this nuclear receptor was able to prevent lipid-induced ER stress in cardiac cells.

Methods and results

Wild-type and transgenic mice with reduced PPARβ/δ expression were fed a standard diet or a high-fat diet for two months. For in vitro studies, a cardiomyocyte cell line of human origin, AC16, was treated with palmitate and the PPARβ/δ agonist GW501516. Our results demonstrate that palmitate induced ER stress in AC16 cells, a fact which was prevented after PPARβ/δ activation with GW501516. Interestingly, the effect of GW501516 on ER stress occurred in an AMPK-independent manner. The most striking result of this study is that GW501516 treatment also upregulated the protein levels of beclin 1 and LC3II, two well-known markers of autophagy. In accordance with this, feeding on a high-fat diet or suppression of PPARβ/δ in knockout mice induced ER stress in the heart. Moreover, PPARβ/δ knockout mice also displayed a reduction in autophagic markers.

Conclusion

Our data indicate that PPARβ/δ activation might be useful to prevent the harmful effects of ER stress induced by saturated fatty acids in the heart by inducing autophagy.     

Risks and Benefits of Green Spaces for Children: A Cross-Sectional Study of Associations with Sedentary Behavior,Obesity, Asthma,and Allergy

Background: Green spaces have been associated with both health benefits and risks in children; however, available evidence simultaneously investigating these conflicting influences, especially in association with different types of greenness, is scarce.Objectives: We aimed to simultaneously evaluate health benefits and risks associated with different types of greenness in children, in terms of sedentary behavior (represented by excessive screen time), obesity, current asthma, and allergic rhinoconjunctivitis.Methods: We conducted a cross-sectional study of a population-based sample of 3,178 schoolchildren (9–12 years old) in Sabadell, Spain, in 2006. Information on outcomes and covariates was obtained by questionnaire. We measured residential surrounding greenness as the average of satellite-derived Normalized Difference Vegetation Index (NDVI) in buffers of 100 m, 250 m, 500 m, and 1,000 m around each home address. Residential proximity to green spaces was defined as living within 300 m of a forest or a park, as separate variables. We used logistic regression models to estimate associations separately for each exposure–outcome pair, adjusted for relevant covariates.Results: An interquartile range increase in residential surrounding greenness was associated with 11–19% lower relative prevalence of overweight/obesity and excessive screen time, but was not associated with current asthma and allergic rhinoconjunctivitis. Similarly, residential proximity to forests was associated with 39% and 25% lower relative prevalence of excessive screen time and overweight/obesity, respectively, but was not associated with current asthma. In contrast, living close to parks was associated with a 60% higher relative prevalence of current asthma, but had only weak negative associations with obesity/overweight or excessive screen time.Conclusion: We observed two separable patterns of estimated health benefits and risks associated with different types of greenness.Citation: Dadvand P, Villanueva CM, Font-Ribera L, Martinez D, Basagaña X, Belmonte J, Vrijheid M, Gražulevičienė R, Kogevinas M, Nieuwenhuijsen MJ. 2014. Risks and benefits of green spaces for children: a cross-sectional study of associations with sedentary behavior, obesity, asthma, and allergy. Environ Health Perspect 122:1329–1335; http://dx.doi.org/10.1289/ehp.1308038     

Ethnic Density and Depressive Symptoms Among African Americans: Threshold and Differential Effects Across Social and Demographic Subgroups

Objectives. We examined the association between Black ethnic density and depressive symptoms among African Americans. We sought to ascertain whether a threshold exists in the association between Black ethnic density and an important mental health outcome, and to identify differential effects of this association across social, economic, and demographic subpopulations.Methods. We analyzed the African American sample (n = 3570) from the National Survey of American Life, which we geocoded to the 2000 US Census. We determined the threshold with a multivariable regression spline model. We examined differential effects of ethnic density with random-effects multilevel linear regressions stratified by sociodemographic characteristics.Results. The protective association between Black ethnic density and depressive symptoms changed direction, becoming a detrimental effect, when ethnic density reached 85%. Black ethnic density was protective for lower socioeconomic positions and detrimental for the better-off categories. The masking effects of area deprivation were stronger in the highest levels of Black ethnic density.Conclusions. Addressing racism, racial discrimination, economic deprivation, and poor services—the main drivers differentiating ethnic density from residential segregation—will help to ensure that the racial/ethnic composition of a neighborhood is not a risk factor for poor mental health.Recent years have seen an increase in the number of studies examining the association between the residential concentration of racial/ethnic minorities (ethnic density) and health, with increasingly sophisticated statistical techniques and theoretical frameworks helping to identify the relevance of ethnic density effects. Despite these improvements, the association between ethnic density and health, given the concentration of poverty in areas of higher ethnic density, is still a puzzling phenomenon.The literature is characterized by inconclusive findings in both the direction and the size of ethnic density effects. Reviews have asserted that ethnic density effects are stronger for mental health1 than for physical health, mortality, and health behaviors,2 but even among the latter set of outcomes, protective ethnic density effects are more common than adverse associations.2 One common finding among ethnic density studies, regardless of health outcome, is the variation in results across and within racial/ethnic groups. For example, US studies often report protective associations among Latinos but mostly detrimental associations for African Americans,2 and the few studies that have examined subgroups among broad “US Black” ethnic categories have found differences by age,3 gender,4,5 and nativity.6,7 Determining the specific populations for which ethnic density effects are protective or detrimental can help in achieving a greater understanding of the potential mechanisms by which ethnic density is associated with health.Another methodological improvement that would clarify the association between ethnic density and health is adequate adjustment for area resource deprivation. The positive correlation that exists between ethnic density and deprivation, and the established association between area deprivation and poor health,8 may have a twofold effect in concealing ethnic density effects: first, by overriding protective effects of ethnic density; second, by complicating analytical attempts at disentangling harmful deprivation effects from protective ethnic density benefits, even with the use of multilevel methods. Reviews of the literature have highlighted the inadequate adjustment for area deprivation as one of the main limitations in current studies, most of which control for only 1 measure of area deprivation (e.g., median income) or, in some cases, do not adjust for any relevant confounders.1,2Although the appropriate adjustment for area deprivation is critical for detecting ethnic density effects, it is not sufficient. To properly capture the associations between ethnic density, area resource deprivation, and health, the potential suppressing effects of area deprivation in the association between ethnic density and health should be modeled. Detrimental ethnic density effects may not be due to the concentration of ethnic minorities in an area but to the concurrent concentration of poverty and social adversity,9 and appropriate modeling can portray the relative contribution of ethnic density and area deprivation to health.In addition to differentiating ethnic density effects between subgroups and accurately modeling and adjusting for area deprivation, the possible nonlinearity in the association between ethnic density and health, and the potential thresholds at which ethnic density exerts protective or nonprotective effects on health, need to be addressed.10 The combination of methods and theoretical frameworks aiming to understand the importance of concentrated poverty and threshold effects for ethnic density might also be useful in clarifying the difference between ethnic density and residential segregation. Although ethnic density is framed in terms of social support, racial/ethnic diversity, and a stronger sense of community, residential segregation is a direct consequence of current and historical racism and discrimination, and is recognized as a determinant of racial/ethnic health inequalities.11 However, both ethnic density and residential segregation are conceptualized through use of a measure of racial/ethnic residential concentration, and it is unclear at what point the hypothesized protective benefits of ethnic density are overcome by the pernicious effects of racial residential segregation. Understanding this difference and its drivers has important implications for social and public health policy, as it would allow the promotion of factors that harness the protective effects of ethnic density while targeting the factors related to racial residential segregation.We examined the association between Black ethnic density and depressive symptoms among African Americans in the National Survey of American Life (NSAL), to ascertain (1) the differential effects of ethnic density across subgroups of African American NSAL respondents and (2) the protective or detrimental thresholds of Black ethnic density. We addressed these 2 study aims while accounting for, and adequately modeling, the potential suppressing effects of area resource deprivation on the association between ethnic density and an important mental health outcome.We selected depressive symptoms as the mental health outcome in this study because the literature is consistent regarding the ethnic density effects of outcomes such as psychoses, but not about the association between Black ethnic density and depression.5 Although the prevalence of major depression is lower among African Americans than among the White majority, the prevalence of depressive symptoms and chronic low mood is high among this population,12–14 and understanding any protective or risk factors of psychological distress, including at the neighborhood level, remains a priority.We focused on African Americans because most ethnic density studies have been conducted in this population, and it is the group in which ethnic density effects have been found to be the most detrimental.1,2 Some previous studies have modeled nonlinear associations between Black ethnic density and several physical health indicators,15–18 but not mental health ones. In all of these prior studies, potential cutoff points have not been based on formal threshold examinations. In addition, prior studies have analyzed non-Hispanic Black respondents. In this study, we focused specifically on African Americans because of the documented heterogeneity of sociodemographic characteristics,19 health profiles,20–22 and ethnic density effects23 in the non-Hispanic Black population.     

Chromosome microarray analysis should be offered to all invasive prenatal diagnostic testing following a normal rapid aneuploidy test result

Chromosomal microarray analysis (CMA) has now replaced karyotyping in the analysis of prenatal cases with a fetal structural anomaly, whereas in those pregnancies undergoing invasive prenatal diagnosis with a normal fetal ultrasound, conventional karyotyping is still performed. The aims of this study were to establish the diagnostic yield of CMA in prenatal diagnosis, and to provide new data that might contribute to reconsider current practices. We reviewed 2905 prenatal samples with a normal rapid aneuploidy detection test referred for evaluation by CMA testing. Our study revealed pathogenic and reported susceptibility copy number variants associated with syndromic disorders in 4.8% (n = 138/2905) of cases, being 2.8% (n = 81/2905) the estimated added diagnostic value of CMA over karyotyping. Clinically significant CMA abnormality was detected in 5.4% (107/1975) of the fetuses with ultrasound anomalies and in 1.4% (5/345) of those considered as low-risk pregnancies. Our series shows that in prenatal samples, CMA increases 2-fold the diagnostic yield achieved by conventional karyotyping.     

Gene expression profiles of breast cancer metastasis according to organ site

In advanced breast cancer, biomarker identification and patient selection using a metastatic tumor biopsy is becoming more necessary. However, the biology of metastasis according to the organ site is largely unknown. Here, we evaluated the expression of 771 genes in 184 metastatic samples across 11 organs, including liver, lung, brain, and bone, and made the following observations. First, all PAM50 molecular intrinsic subtypes were represented across organs and within immunohistochemistry‐based groups. Second, HER2‐low disease was identified across all organ sites, including bone, and HER2 expression significantly correlated with ERBB2 expression. Third, the majority of expression variation was explained by intrinsic subtype and not organ of metastasis. Fourth, subtypes and individual subtype‐related genes/signatures were significantly associated with overall survival. Fifth, we identified 74 genes whose expression was organ‐specific and subtype‐independent. Finally, immune profiles were found more expressed in lung compared to brain or liver metastasis. Our results suggest that relevant tumor biology can be captured in metastatic tissues across a variety of organ sites; however, unique biological features according to organ site were also identified and future studies should explore their implications in diagnostic and therapeutic interventions.