Toxic effects of brake wear particles on epithelial lung cells in vitro

ABSTRACT: BACKGROUND: Fine particulate matter originating from traffic correlates with increased morbidity and mortality. An important source of traffic particles is brake wear of cars which contributes up to 20% of the total traffic emissions. The aim of this study was to evaluate potential toxicological effects of human epithelial lung cells exposed to freshly generated brake wear particles. RESULTS: An exposure box was mounted around a car's braking system. Lung cells cultured at the air-liquid interface were then exposed to particles emitted from two typical braking behaviours ("full stop" and "normal deceleration"). The particle size distribution as well as the brake emission components like metals and carbons was measured on-line, and the particles deposited on grids for transmission electron microscopy were counted. The tight junction arrangement was observed by laser scanning microscopy. Cellular responses were assessed by measurement of lactate dehydrogenase (cytotoxicity), by investigating the production of reactive oxidative species and the release of the pro-inflammatory mediator interleukin-8. The tight junction protein occludin density decreased significantly (p < 0.05) with increasing concentrations of metals on the particles (iron, copper and manganese, which were all strongly correlated with each other). Occludin was also negatively correlated with the intensity of reactive oxidative species. The concentrations of interleukin-8 were significantly correlated with increasing organic carbon concentrations. No correlation was observed between occludin and interleukin-8, nor between reactive oxidative species and interleukin-8. CONCLUSION: These findings suggest that the metals on brake wear particles damage tight junctions with a mechanism involving oxidative stress. Brake wear particles also increase pro-inflammatory responses. However, this might be due to another mechanism than via oxidative stress.

The prognostic value of cytology and fluorescence in situ hybridization in the follow-up of nonmuscle-invasive bladder cancer after intravesical Bacillus Calmette-Guérin therapy

Molecular markers reliably predicting failure or success of Bacillus Calmette-Guérin (BCG) in the treatment of nonmuscle-invasive urothelial bladder cancer (NMIBC) are lacking. The aim of our study was to evaluate the value of cytology and chromosomal aberrations detected by fluorescence in situ hybridization (FISH) in predicting failure to BCG therapy. Sixty-eight patients with NMIBC were prospectively recruited. Bladder washings collected before and after BCG instillation were analyzed by conventional cytology and by multitarget FISH assay (UroVysion, Abbott/Vysis, Des Plaines, IL) for aberrations of chromosomes 3, 7, 17 and 9p21. Persistent and recurrent bladder cancers were defined as positive events during follow-up. Twenty-six of 68 (38%) NMIBC failed to BCG. Both positive post-BCG cytology and positive post-BCG FISH were significantly associated with failure of BCG (hazard ratio (HR)= 5.1 and HR= 5.6, respectively; p < 0.001 each) when compared to those with negative results. In the subgroup of nondefinitive cytology (all except those with unequivocally positive cytology), FISH was superior to cytology as a marker of relapse (HR= 6.2 and 1.4, respectively). Cytology and FISH in post-BCG bladder washings are highly interrelated and a positive result predicts failure to BCG therapy in patients with NMIBC equally well. FISH is most useful in the diagnostically less certain cytology categories but does not provide additional information in clearly malignant cytology.

"...all diese fingierten, notierten, in meinem Kopf ungefähr wieder zusammengesetzten Ichs". Autobiographie und Autofiktion

Dass jede literarische Selbstdarstellung fiktionale Elemente beinhaltet, ist in der gegenwärtigen Autobiographie-Diskussion unbestritten. Mit dem von Serge Doubrovsky geprägten Terminus »Autofiktion« hat sich die Forschung verstärkt literarischen Texten zugewendet, die fiktionales und faktuales Erzählen der eigenen Biographie mehr oder minder offensichtlich vermischen und so die Problematik literarischer Selbstthematisierung reflektieren. Ausgehend von der theoretischen Diskussion um Autobiographie und Autofiktion werden Texte und Textentwürfe von Robert Walser, Annemarie Schwarzenbach, Paul Nizon, Friedrich Dürrenmatt und Urs Widmer mit ihren je eigenen und nicht selten eigenwilligen Konzepten des literarischen Umgangs mit der Biographie untersucht. Mit Beiträgen von Peter Gasser, Wolfram Groddeck, Lucas Marco Gisi, Heidy Margrit Müller, Ulrich Weber, Reto Sorg, Elio Pellin und Irmgard Wirtz.

«Es gibt kein größeres Verbrechen als die Unschuld». Zu den Kriminalromanen von Glauser, Dürrenmatt, Highsmith und Schneider

Der Kriminalroman hat als Genre mit relativ starren erzählerischen Normen die Autoren des 20. Jahrhunderts immer wieder herausgefordert. Am Beispiel von drei Schriftstellergenerationen verfolgen die Beiträger die Öffnung des Genres: Friedrich Glauser (1896-1938) war Zeitgenosse Simenons und ein Pionier des deutschsprachigen Kriminalromans. Seine Romane zeichnen sich durch einen ungekannten Reichtum der Milieuschilderungen aus. Friedrich Dürrenmatt (1921-1990) und Patricia Highsmith (1921-1995) trugen ab Beginn der 1950er-Jahre mit ihrer Unterwanderung der regelhaften Konventionen und deren moralischer Implikationen entscheidend zur Öffnung des Genres und zu seiner literarischen Anerkennung bei. Hansjörg Schneider (*1938) schließlich schrieb seinen ersten Roman um Kommissär Hunkeler 1993 zu einem Zeitpunkt, als der Kriminalroman bereits mit einer gewissen Selbstverständlichkeit zu den postmodernen literarischen Möglichkeiten sozialkritischen Schreibens zählte Ein besonderes Augenmerk der Sommerakademie gilt, hier am Beispiel von Highsmith, auch den Manuskripten und der Textgenese. Mit Beiträgen u.a. von: Hubert Thüring, Elio Pellin, Peter Gasser, Peter Rusterholz, Jochen Vogt, Elisabeth Bronfen, Ulrich Weber

Tenascin-C downregulates wnt inhibitor dickkopf-1, promoting tumorigenesis in a neuroendocrine tumor model

The extracellular matrix molecule tenascin-C (TNC) is a major component of the cancer-specific matrix, and high TNC expression is linked to poor prognosis in several cancers. To provide a comprehensive understanding of TNC's functions in cancer, we established an immune-competent transgenic mouse model of pancreatic β-cell carcinogenesis with varying levels of TNC expression and compared stochastic neuroendocrine tumor formation in abundance or absence of TNC. We show that TNC promotes tumor cell survival, the angiogenic switch, more and leaky vessels, carcinoma progression, and lung micrometastasis. TNC downregulates Dickkopf-1 (DKK1) promoter activity through the blocking of actin stress fiber formation, activates Wnt signaling, and induces Wnt target genes in tumor and endothelial cells. Our results implicate DKK1 downregulation as an important mechanism underlying TNC-enhanced tumor progression through the provision of a proangiogenic tumor microenvironment.

Promoter- and RNA polymerase II-dependent hsp-16 gene association with nuclear pores in Caenorhabditis elegans.

Some inducible yeast genes relocate to nuclear pores upon activation, but the general relevance of this phenomenon has remained largely unexplored. Here we show that the bidirectional hsp-16.2/41 promoter interacts with the nuclear pore complex upon activation by heat shock in the nematode Caenorhabditis elegans. Direct pore association was confirmed by both super-resolution microscopy and chromatin immunoprecipitation. The hsp-16.2 promoter was sufficient to mediate perinuclear positioning under basal level conditions of expression, both in integrated transgenes carrying from 1 to 74 copies of the promoter and in a single-copy genomic insertion. Perinuclear localization of the uninduced gene depended on promoter elements essential for induction and required the heat-shock transcription factor HSF-1, RNA polymerase II, and ENY-2, a factor that binds both SAGA and the THO/TREX mRNA export complex. After induction, colocalization with nuclear pores increased significantly at the promoter and along the coding sequence, dependent on the same promoter-associated factors, including active RNA polymerase II, and correlated with nascent transcripts.

Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety Associated With Life-threatening Diseases

A double-blind, randomized, active placebo-controlled pilot study was conducted to examine safety and efficacy of lysergic acid diethylamide (LSD)-assisted psychotherapy in 12 patients with anxiety associated with life-threatening diseases. Treatment included drug-free psychotherapy sessions supplemented by two LSD-assisted psychotherapy sessions 2 to 3 weeks apart. The participants received either 200 μg of LSD (n = 8) or 20 μg of LSD with an open-label crossover to 200 μg of LSD after the initial blinded treatment was unmasked (n = 4). At the 2-month follow-up, positive trends were found via the State-Trait Anxiety Inventory (STAI) in reductions in trait anxiety (p = 0.033) with an effect size of 1.1, and state anxiety was significantly reduced (p = 0.021) with an effect size of 1.2, with no acute or chronic adverse effects persisting beyond 1 day after treatment or treatment-related serious adverse events. STAI reductions were sustained for 12 months. These results indicate that when administered safely in a methodologically rigorous medically supervised psychotherapeutic setting, LSD can reduce anxiety, suggesting that larger controlled studies are warranted.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.