Efficient chemotherapy of rat glioblastoma using Doxorubicin-loaded PLGA nanoparticles with different stabilizers

Background: Chemotherapy of glioblastoma is largely ineffective as the blood-brain barrier (BBB) prevents entry of most anticancer agents into the brain. For an efficient treatment of glioblastomas it is necessary to deliver anti-cancer drugs across the intact BBB. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with poloxamer 188 hold great promise as drug carriers for brain delivery after their intravenous injection. In the present study the anti-tumour efficacy of the surfactant-coated doxorubicin-loaded PLGA nanoparticles against rat glioblastoma 101/8 was investigated using histological and immunohistochemical methods. Methodology: The particles were prepared by a high-pressure solvent evaporation technique using 1% polyvinylalcohol (PLGA/PVA) or human serum albumin (PLGA/HSA) as stabilizers. Additionally, lecithin-containing PLGA/HSA particles (Dox-Lecithin-PLGA/HSA) were prepared. For evaluation of the antitumour efficacy the glioblastoma-bearing rats were treated intravenously with the doxorubicin-loaded nanoparticles coated with poloxamer 188 using the following treatment regimen: 3×2.5 mg/kg on day 2, 5 and 8 after tumour implantation; doxorubicin and poloxamer 188 solutions were used as controls. On day 18, the rats were sacrificed and the antitumour effect was determined by measurement of tumour size, necrotic areas, proliferation index, and expression of GFAP and VEGF as well as Isolectin B4, a marker for the vessel density. Conclusion: The results reveal a considerable anti-tumour effect of the doxorubicin-loaded nanoparticles. The overall best results were observed for Dox-Lecithin-PLGA/HSA. These data demonstrate that the poloxamer 188-coated PLGA nanoparticles enable delivery of doxorubicin across the blood-brain barrier in the therapeutically effective concentrations

Effekte der Nitrifikationsinhibierung auf die N2O-Freisetzung nach Mineraldüngung auf einem sandigen Lehm-Standort (Leipziger Tieflandsbucht)

In einem randomisierten Feldversuch (4 Wdh.) wurden mittels closed chamber Methode die N2O-Emissionen aus KAS, Harnstoff (HS) und HS + Nitrifikationsinhibitor (NI) ermittelt. Der Versuchsstandort (614 mm NS; 9,5 °C Jahresmittel; 140 m ü. NN; Fahlerde-/Staugleybodengesellschaften; 41-50 BP; Marktfruchtanbau; keine Wirtschaftsdünger) ist repräsentativ für ca. 50 % der Ackerbaustandorte Mitteldeutschlands. N2O-Emissionen und resultierende Dünger-N-Verluste wurden im Feldversuch bei Düngung von 200 kg N/ha (2011) bzw. 220 kg N/ha (2012) und praxisüblicher Gabenteilung anhand ereignisbezogener Messungen erfasst. Im anschließenden Modellversuch auf der gleichen Fläche wurde die N2O-Bildung nach N-Applikation unter induzierten Verlustbedingungen (100 kg N/ha + Bewässerung nach Stoppelumbruch) ermittelt. Vom Vegetationsbeginn bis zur Nachernte traten 2011 und 2012 nur sehr geringe N2O-Emissionen auf. In den Modellversuchen lagen die N2O-Emissionen um ein Vielfaches höher. In einem ersten Emissionsereignis waren die signifikant höchsten N-Verluste für die Variante KAS zu verzeichnen. Insgesamt wies KAS tendenziell höhere N2O-Verluste als HS auf. Der Einsatz eines NI (Variante HS + NI) reduzierte die Emissionen gegenüber HS und KAS im Modellversuch signifikant um > 50 %

Effekte der Nitrifikationsinhibierung auf die N2O-Freisetzung nach Mineraldüngung auf einem sandigen Lehm-Standort: Versuchsergebnisse 2011-2014

In einem randomisierten Versuch wurden mittels der closed-chamber Methode die N2O-Emissionen unter Feldversuchsbedingungen sowie anschließend unter homogenisierten Feldbedingungen (Modellversuch) nach Düngung mit KAS, Harnstoff (HS) und HS + Nitrifikationsinhibitor (NI) ermittelt. Der Versuchsstandort Cunnersdorf ist repräsentativ für ca. 50 % der Ackerbaustandorte Mitteldeutschlands. In den Feldversuchen wurden die N2O-Emissionen und resultierenden Dünger-N-Verluste bei Düngung von 200 kg (2011) bzw. 220 kg N/ha (2012-2014) und praxisüblicher Gabenteilung anhand ereignisbezogener Messungen erfasst. In den anschließenden Modellversuchen wurde die N2O-Bildung unter Verlustbedingungen (Stoppelumbruch; 100 kg N/ha; Bewässerung) ermittelt. In den Feldversuchen traten vom Vegetationsbeginn bis zur Nachernte in den Jahren 2011, 2012 und 2014 in den gedüngten Varianten nur geringe N2O-Emissionen auf. Im Jahr 2013 wurden nach einer N-Gabe und der folgenden Starkniederschlagsperiode (Mai/Juni) in allen Düngungsvarianten relativ hohe N2O-Verluste detektiert. In allen vier Jahren waren die Unterschiede in den kumulativen N2O-Emissionen zwischen den Düngervarianten im Feldversuch nicht signifikant. In den Modellversuchen wurden im Vergleich zu den Feldversuchen höhere Emissions-Peaks erfasst. In vier Versuchen unter Verlustbedingungen zeigte HS + NI geringere N2O-Verluste als KAS. Dieser Effekt war in drei Jahren signifikant. Durch den Einsatz eines Düngers mit NI (DCD/TZ sowie MPA) konnten N2O-Verluste unter starken Verlustbedingungen im dreijährigen Mittel (2012-2014 gleiche Fläche) um 56 % reduziert werden

Weight loss and outcomes in subjects with progressive pulmonary fibrosis: data from the INBUILD trial

BACKGROUND: Lower body mass index (BMI) and weight loss have been associated with worse outcomes in some studies in patients with pulmonary fibrosis. We analyzed outcomes in subgroups by BMI at baseline and associations between weight change and outcomes in subjects with progressive pulmonary fibrosis (PPF) in the INBUILD trial. METHODS: Subjects with PPF other than idiopathic pulmonary fibrosis were randomized to receive nintedanib or placebo. In subgroups by BMI at baseline (< 25, ≥ 25 to < 30, ≥ 30 kg/m2), we analyzed the rate of decline in FVC (mL/year) over 52 weeks and time-to-event endpoints indicating disease progression over the whole trial. We used a joint modelling approach to assess associations between change in weight and the time-to-event endpoints. RESULTS: Among 662 subjects, 28.4%, 36.6% and 35.0% had BMI < 25, ≥ 25 to < 30 and ≥ 30 kg/m2, respectively. The rate of decline in FVC over 52 weeks was numerically greater in subjects with baseline BMI < 25 than ≥ 25 to < 30 or ≥ 30 kg/m2 (nintedanib: - 123.4, - 83.3, - 46.9 mL/year, respectively; placebo: - 229.5; - 176.9; - 171.2 mL/year, respectively). No heterogeneity was detected in the effect of nintedanib on reducing the rate of FVC decline among these subgroups (interaction p = 0.83). In the placebo group, in subjects with baseline BMI < 25, ≥ 25 to < 30 and ≥ 30 kg/m2, respectively, 24.5%, 21.4% and 14.0% of subjects had an acute exacerbation or died, and 60.2%, 54.5% and 50.4% of subjects had ILD progression (absolute decline in FVC % predicted ≥ 10%) or died over the whole trial. The proportions of subjects with these events were similar or lower in subjects who received nintedanib versus placebo across the subgroups. Based on a joint modelling approach, over the whole trial, a 4 kg weight decrease corresponded to a 1.38-fold (95% CI 1.13, 1.68) increase in the risk of acute exacerbation or death. No association was detected between weight loss and the risk of ILD progression or the risk of ILD progression or death. CONCLUSIONS: In patients with PPF, lower BMI at baseline and weight loss may be associated with worse outcomes and measures to prevent weight loss may be required. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02999178

Uptake Mechanism of ApoE-Modified Nanoparticles on Brain Capillary Endothelial Cells as a Blood-Brain Barrier Model

Background: The blood-brain barrier (BBB) represents an insurmountable obstacle for most drugs thus obstructing an effective treatment of many brain diseases. One solution for overcoming this barrier is a transport by binding of these drugs to surface-modified nanoparticles. Especially apolipoprotein E (ApoE) appears to play a major role in the nanoparticle-mediated drug transport across the BBB. However, at present the underlying mechanism is incompletely understood. Methodology/Principal Findings: In this study, the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells was investigated to differentiate between active and passive uptake mechanism by flow cytometry and confocal laser scanning microscopy. Furthermore, different in vitro co-incubation experiments were performed with competing ligands of the respective receptor. Conclusions/Significance: This study confirms an active endocytotic uptake mechanism and shows the involvement of low density lipoprotein receptor family members, notably the low density lipoprotein receptor related protein, on the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells. This knowledge of the uptake mechanism of ApoE-modified nanoparticles enables future developments to rationally create very specific and effective carriers to overcome the blood-brain barrier

Low housing quality, unmet social needs, stress and depression among low-income smokers

Smokers are at greater risk of multiple health conditions that are exacerbated by environmental hazards associated with low housing quality. However, little is known about the prevalence of low housing quality among low-income smokers. Using correlations and logistic regression, we examined associations among eight housing quality indicators - pests, water leaks, mold, lead paint, and working smoke detectors, appliances, heating, and air conditioning - and between housing quality and social needs, depressive symptoms, perceived stress, sleep problems, and self-rated health in a community-based sample of 786 low-income smokers from 6 states. Most participants were female (68%), and White (45%) or African-American (43%). One in four (27%) completed less than high school education, and 41% reported annual pre-tax household income of less than $10,000. Housing quality problems were common. Most participants (64%) reported at least one problem in their home, and 41% reported two or more problems, most commonly pest infestations (40%), water leaks (22%), lack of air conditioning (22%) and mold (18%). Lack of heat and air conditioning were correlated, as were water leaks and mold. Using logistic regression analyses controlling for participant demographic characteristics, we found that reporting more housing quality problems was associated with greater odds of worse mental and physical health outcomes. Multiple health threats, including housing quality, depressive symptoms, stress, poor sleep, and financial strain may be mutually reinforcing and compound the health consequence of smoking. Future research should seek to replicate these findings in other samples, and examine associations longitudinally to better understand causality

Raman spectroscopy of a single ion coupled to a high-finesse cavity

We describe an ion-based cavity-QED system in which the internal dynamics of an atom is coupled to the modes of an optical cavity by vacuum-stimulated Raman transitions. We observe Raman spectra for different excitation polarizations and find quantitative agreement with theoretical simulations. Residual motion of the ion introduces motional sidebands in the Raman spectrum and leads to ion delocalization. The system offers prospects for cavity-assisted resolved-sideband ground-state cooling and coherent manipulation of ions and photons.Comment: 8 pages, 6 figure