610 Medizin und Gesundheit
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Institute
Human endogenous retrovirus (HERV) genomes are chromosomally integrated in all cells of an individual. They are normally transcriptionally silenced and transmitted only vertically. Enhanced expression of HERV-K accompanied by the emergence of anti-HERV-K-directed immune responses has been observed in tumor patients and HIV-infected individuals. As HERV-K is usually not expressed and immunological tolerance development is unlikely, it is an appropriate target for the development of immunotherapies. We generated a recombinant vaccinia virus (MVA-HKenv) expressing the HERV-K envelope glycoprotein (ENV), based on the modified vaccinia virus Ankara (MVA), and established an animal model to test its vaccination efficacy. Murine renal carcinoma cells (Renca) were genetically altered to express E. coli beta-galactosidase (RLZ cells) or the HERV-K ENV gene (RLZ-HKenv cells). Intravenous injection of RLZ-HKenv cells into syngenic BALB/c mice led to the formation of pulmonary metastases, which were detectable by X-gal staining. A single vaccination of tumor-bearing mice with MVA-HKenv drastically reduced the number of pulmonary RLZ-HKenv tumor nodules compared to vaccination with wild-type MVA. Prophylactic vaccination of mice with MVA-HKenv precluded the formation of RLZ-HKenv tumor nodules, whereas wild-type MVA-vaccinated animals succumbed to metastasis. Protection from tumor formation correlated with enhanced HERV-K ENV-specific killing activity of splenocytes. These data demonstrate for the first time that HERV-K ENV is a useful target for vaccine development and might offer new treatment opportunities for diverse types of cancer.
Characteristically, most solid tumors exhibit an increased tumor interstitial fluid pressure (TIFP) that directly contributes to the lowered uptake of macromolecular therapeutics into the tumor interstitium. Abnormalities in the tumor-associated lymph vessels are a central brick in the development and prolonged sustaining of an increased TIFP. In the current study, vascular endothelial growth factor C (VEGF-C) was used to enhance tumor-associated lymphangiogenesis as a new mechanism to actively reduce the TIFP by increased lymphatic drainage of the tumor tissue. Human A431 epidermoid vulva carcinoma cells were inoculated in NMRI nu/nu mice to generate a xenograft mouse model. Seven days after tumor cell injection, VEGF-C was peritumorally injected to induce lymphangiogenesis. Tumor growth and TIFP was lowered significantly over time in VEGF-C-treated tumors in comparison to control or VEGF-A-treated animals. These data demonstrate for the first time that actively induced lymphangiogenesis can lower the TIFP in a xenograft tumor model and apparently reduce tumor growth. This model represents a novel approach to modulate biomechanical properties of the tumor interstitium enabling a lowering of TIFP in vivo.
Zieht man die vergeblichen Versuche der Mediziner und Philosophen in Betracht, eine sowohl praktikable, theoretisch konsistente und ethisch vertretbare Definition von Krankheit zu erarbeiten, wird die Differenz von Krankheitsbegriff und -metapher insgesamt problematisch. Der aktuell gebräuchliche, systemtheoretische Krankheitsbegriff bezieht sich beispielsweise gar nicht mehr auf Lebewesen, sondern auf die Kopplung bio-psycho-sozialer Systeme. Die Bindestriche in diesem Begriff übernehmen gewissermaßen die Funktion der Metapher: den Sprung über Kategoriengrenzen. Wenn Metaphern in den Wissenschaften grundsätzlich keinen guten Ruf genießen, gilt dies insbesondere für Krankheitsmetaphern. Zuletzt ist ihre Bedeutung für die pseudo-medizinische Legitimation und Durchführung des Holocaust umfangreich erforscht worden. Mit dem Paradigmenwechsel von der Hygiene zur Bakteriologie wurden Krankheiten demnach nicht mehr auf äußere Umstände, sondern auf labortechnisch identifizierbare Kontagien zurückgeführt. Diese medizinische 'Visualisierung des Feindes', welche Robert Koch durch die Markierung von Gewebeschnitten mit Annelinfarbe entscheidend voranbrachte, bot zusammen mit der monokausalen und ontologisierenden Erklärung von Krankheiten große metaphorische Anschlussflächen für die (bio-)politischen Diskurse, die sich seit dem 19. Jahrhundert mehr und mehr mit der Sicherung und Steigerung des Lebens beschäftigten.
Visible light is a better co-inducer of apoptosis for curcumin-treated human melanoma cells than UVA
(2013)
Curcumin attracts worldwide scientific interest due to its anti-proliferative and apoptosis inducing effects on different tumor cells at concentrations ranging from 10 to 150 µM (3.7–55 µg/ml). Unfortunately, because of a low oral bioavailability, only low and pharmacologically ineffective serum levels are achievable. In this study, an alternative treatment concept consisting of low concentration curcumin (0.2–5 µg/ml) and irradiation with UVA or visible light (VL) has been tested. The experimental results show clearly that this treatment decreases the proliferation and the viability of human melanoma cells while the cell membrane integrity remains intact. We identified the onset of apoptosis characterized by typical markers such as active caspases 8, 9 and 3 as well as DNA fragmentation accompanied by the loss of cell adhesion. The mitochondrial apoptosis signaling pathway is predominant due to an early activation of caspase-9. The present data indicate a higher efficacy of a combination of curcumin and VL than curcumin and UVA. Reduced effects as a result of light absorption by heavily pigmented skin are unlikely if VL is used. These results indicate that a combination of curcumin and light irradiation may be a useful additional therapy in the treatment of malignant disease.
Von Killerzellen und Kurzzeitweckern : ein Laborbesuch bei der "AG Koch" im Georg-Speyer-Haus
(2013)
Eins vorweg: Killerzellen sind in dieser Geschichte die Guten. In Laborräumen der Sicherheitsstufe eins werden Kittel und Handschuhe getragen, um das Material vor den Wissenschaftlern zu schützen. Kurzzeitwecker und Handcremetuben sind allgegenwärtig. Und wie das Experiment ausgegangen ist, wird noch nicht verraten. Doch jetzt der Reihe nach.
Wassergefiltertes Infrarot A (wIRA) bezeichnet eine spezielle Form der Infrarotstrahlung (Wärmestrahlung) im Bereich von 780 bis 1.400 nm, die aufgrund ihrer sehr guten Verträglichkeit in der Medizin zur Prävention und Therapie verwendet wird. wIRA steigert Temperatur, Sauerstoffpartialdruck und Durchblutung im Gewebe. Wesentliche klinische Wirkungen von wIRA sind – indikationsübergreifend – eine ausgeprägte Minderung von Schmerzen, Entzündung und vermehrter Flüssigkeitsabgabe sowie eine Verbesserung der Infektabwehr und der Regeneration.
Gen- und Stammzelltherapie stehen für das, wovon die Medizin schon immer geträumt hat: geschädigtes Gewebe durch gesundes ersetzen und die Wirkung defekter Gene durch intakte Kopien korrigieren. Wie ist der Stand der weltweiten Forschung? Welche Hindernisse sind zu überwinden, damit mehr Patienten von der regenerativen Medizin profi tieren werden?
Wenn Zellen zu Medikamenten werden : neue Zelltherapien verbessern die Heilungschancen bei Leukämien
(2013)
Die Transplantation von Zellen aus dem Knochenmark oder von Stammzellen aus dem Blut gehört zu den bekanntesten Therapien bei Leukämie. Doch dabei treten Immunreaktionen als Nebenwirkung auf. Deshalb nehmen Forscher seit Kurzem auch die Transplantation bestimmter Immunzellen in den Blick. Im Labor gentechnisch aufgerüstet, werden sie zu äußerst effizienten "Krebs-Medikamenten".
Bei seiner Einschulung hatte Wolfgang Niedecken ein besonderes Erlebnis, als er im Alter von 6 Jahren bemerkte, dass es höchste Zeit war, ordentlich sprechen zu lernen. Im Elternhaus war ausschließlich Kölsch gesprochen worden. Hochdeutsch war seine erste Fremdsprache, die sie in letzter Konsequenz auch immer geblieben ist. Denken, empfinden und träumen tut Niedecken nach wie vor auf Kölsch, wie er selbst beteuert.
Im Sommer 1976 schreibt Wolfgang Niedecken seinen ersten Song auf Kölsch: "Helfe kann dir keiner". 1979 erscheint sein erstes Album mit dem Titel: "Wolfgang Niedecken’s BAP rockt andere kölsche Leeder".
Nie hat sich BAP auf seinen Tourneen vor den „Karren politischer Machthaber“ spannen lassen. Zu Zeiten zweier deutscher Staaten sorgten die offenen Worte von „Deshalv spill`mer he“ für einen Eklat. Das Lied sprach sich unmissverständlich nicht nur für die westdeutsche Friedensbewegung, sondern ebenfalls für die ostdeutschen Friedens- und Menschenrechtsinitiativen aus. Als die DDR-Kulturbehörden BAP verboten, den Song zu spielen, platzt am Vorabend des ersten Konzertes im Berliner Palast der Republik die über 14 Stationen geplante und längst ausverkaufte DDR-Tournee.
Am 9. November 1992 findet das „Arsch huh“-Konzert gegen Ausländerfeindlichkeit und Rassismus auf dem Kölner Chlodwigplatz vor über 100.000 Menschen statt. Danach ähnliche Konzerte in Frankfurt „Heute die, morgen Du“ und in Leipzig „Gewalt ätzt“ vor ähnlich großer Kulisse. Für sein gesellschaftspolitisches Engagement bekommt Niedecken 1998 das Bundesverdienstkreuz von Bundespräsident Roman Herzog überreicht. In der Laudatio heißt es: „Kölsch-Rock, BAP und Kölner Dialekt sind untrennbar mit ihm verbunden. Er ist einer der profiliertesten Rockmusiker Deutschlands. Als engagierter Künstler hat er sich nachhaltig für Frieden, Toleranz, Demokratie und gegen Fremdenfeindlichkeit eingesetzt.“
Zu Niedeckens 60. Geburtstag, den er am 30. März 2011 mit etwa 500 Gästen auf einem Rheinschiff feiert, sendet der WDR die „Niedecken-Nacht“. Zu seinem Geburtstag erscheint im Verlag Hoffmann und Campe auch das Buch „Für 'ne Moment. Autobiographie“. Auf über 500 Seiten erzählt der Musiker von seiner Familie, einer behüteten frühen Kindheit und der schwierigen Zeit als Heranwachsender im katholischen Internat, von seinem Kunststudium und Aufenthalten in der New Yorker Kunstszene, der ehe zufälligen Gründung von BAP, die zur erfolgreichsten Mundartgruppe Deutschlands wurde.
Und dann das: Am 2. November gegen 13 Uhr bemerkt Wolfgang Niedecken beim Lesen, „dass ich nichts mehr kapierte. Ich musste die Seiten immer wieder neu lesen. Dann wurde es nebelig vor den Augen, alles sah merkwürdig aus, mein ganzes Umfeld hatte amorphe Formen. Und dann begegnete ich Gott sei Dank meinem Schutzengel.“ Wolfgang Niedecken hatte einen Schlaganfall erlitten, obwohl er eigentlich kein typischer Schlaganfallpatient war. Es kann also jeden treffen! Dank des schnellen Reagierens seiner Frau Tina konnte das Schlimmste verhindert werden.
Erkrankungen des Herz-Kreislauf-Systems sind für die größte Zahl der Todesfälle in Deutschland verantwortlich. Das liegt nicht zuletzt daran, dass das menschliche Herz kaum Selbstheilungskräfte besitzt. Wissenschaftler suchen deshalb nach Möglichkeiten, die Regenerationsfähigkeit des Organs zu steigern. Dabei helfen ihnen der Blick ins Tierreich und modernste molekularbiologische Verfahren.
Reproducing the characteristics and the functional responses of the blood–brain barrier (BBB) in vitro represents an important task for the research community, and would be a critical biotechnological breakthrough. Pharmaceutical and biotechnology industries provide strong demand for inexpensive and easy-to-handle in vitro BBB models to screen novel drug candidates. Recently, it was shown that canonical Wnt signaling is responsible for the induction of the BBB properties in the neonatal brain microvasculature in vivo. In the present study, following on from earlier observations, we have developed a novel model of the BBB in vitro that may be suitable for large scale screening assays. This model is based on immortalized endothelial cell lines derived from murine and human brain, with no need for co-culture with astrocytes. To maintain the BBB endothelial cell properties, the cell lines are cultured in the presence of Wnt3a or drugs that stabilize β-catenin, or they are infected with a transcriptionally active form of β-catenin. Upon these treatments, the cell lines maintain expression of BBB-specific markers, which results in elevated transendothelial electrical resistance and reduced cell permeability. Importantly, these properties are retained for several passages in culture, and they can be reproduced and maintained in different laboratories over time. We conclude that the brain-derived endothelial cell lines that we have investigated gain their specialized characteristics upon activation of the canonical Wnt pathway. This model may be thus suitable to test the BBB permeability to chemicals or large molecular weight proteins, transmigration of inflammatory cells, treatments with cytokines, and genetic manipulation.
Background: Only few studies deal with the workload of physical therapists and the health consequences, although this occupational group is quite important for the health care system in many industrialized countries (e.g. ca. 136 000 people are currently employed as physical therapists in Germany). Therefore, the current state of knowledge of work-related diseases and disorders of physical therapists is insufficient. The aim of the "Physical Therapist Cohort" (PTC) study is to analyze the association between work-related exposures and diseases among physical therapists in Germany. This article describes the protocol of the baseline assessment of the PTC study.
Methods/Design: A cross-sectional study will be conducted as baseline assessment and will include a representative random sample of approximately 300 physical therapists employed in Germany (exposure group), and a population-based comparison group (n = 300). The comparison group will comprise a sample of working aged (18–65 years) inhabitants of a German city. Variables of interest will be assessed using a questionnaire manual including questions regarding musculoskeletal, dermal, and infectious diseases and disorders as well as psychosocial exposures, diseases and disorders. In addition to subjective measures, a clinical examination will be used to objectify the questionnaire-based results (n = 50).
Discussion: The study, which includes extensive data collection, provides a unique opportunity to study the prospective association of work-related exposures and associated complaints of physical therapists. Baseline results will give first clues with regard to whether and how prevalent main exposures of physiotherapeutic work and typical work areas of physical therapists are associated with the development of work-related diseases. Thereby, this baseline assessment provides the basis for further investigations to examine causal relationships in accordance with a longitudinal design.
Background: The brain cancer stem cell (CSC) model describes a small subset of glioma cells as being responsible for tumor initiation, conferring therapy resistance and tumor recurrence. In brain CSC, the PI3-K/AKT and the RAS/mitogen activated protein kinase (MAPK) pathways are found to be activated. In consequence, the human transcription factor YB-1, knowing to be responsible for the emergence of drug resistance and driving adenoviral replication, is phosphorylated and activated. With this knowledge, YB-1 was established in the past as a biomarker for disease progression and prognosis. This study determines the expression of YB-1 in glioblastoma (GBM) specimen in vivo and in brain CSC lines. In addition, the capacity of Ad-Delo3-RGD, an YB-1 dependent oncolytic adenovirus, to eradicate CSC was evaluated both in vitro and in vivo.
Methods: YB-1 expression was investigated by immunoblot and immuno-histochemistry. In vitro, viral replication as well as the capacity of Ad-Delo3-RGD to replicate in and, in consequence, to kill CSC was determined by real-time PCR and clonogenic dilution assays. In vivo, Ad-Delo3-RGD-mediated tumor growth inhibition was evaluated in an orthotopic mouse GBM model. Safety and specificity of Ad-Delo3-RGD were investigated in immortalized human astrocytes and by siRNA-mediated downregulation of YB-1.
Results: YB-1 is highly expressed in brain CSC lines and in GBM specimen. Efficient viral replication in and virus-mediated lysis of CSC was observed in vitro. Experiments addressing safety aspects of Ad-Delo3-RGD showed that (i) virus production in human astrocytes was significantly reduced compared to wild type adenovirus (Ad-WT) and (ii) knockdown of YB-1 significantly reduced virus replication. Mice harboring othotopic GBM developed from a temozolomide (TMZ)-resistant GBM derived CSC line which was intratumorally injected with Ad-Delo3-RGD survived significantly longer than mice receiving PBS-injections or TMZ treatment.
Conclusion: The results of this study supported YB-1 based virotherapy as an attractive therapeutic strategy for GBM treatment which will be exploited further in multimodal treatment concepts.
Background: A number of scientific papers on yellow fever have been published but no broad scientometric analysis on the published research of yellow fever has been reported. The aim of the article based study was to provide an in-depth evaluation of the yellow fever field using large-scale data analysis and employment of bibliometric indicators of production and quantity.
Methods: Data were retrieved from the Web of Science database (WoS) and analyzed as part of the NewQis platform. Then data were extracted from each file, transferred to databases and visualized as diagrams. Partially by means of density-equalizing mapping makes the findings clear and emphasizes the output of the analysis.
Results: In the study period from 1900 to 2012 a total of 5,053 yellow fever-associated items were published by 79 countries. The United States (USA) having the highest publication rate at 42% (n = 751) followed by far from Brazil (n = 203), France (n = 149) and the United Kingdom (n = 113). The most productive journals are the "Public Health Reports", the "American Journal of Tropical Medicine and Hygiene" and the "Journal of Virology". The gender analysis showed an overall steady increase of female authorship from 1950 to 2011. Brazil is the only country of the five most productive countries with a higher proportion of female scientists.
Conclusions: The present data shows an increase in research productivity over the entire study period, in particular an increase of female scientists. Brazil shows a majority of female authors, a fact that is confirmed by other studies.
Glioblastoma is the most common and most aggressive type of brain tumor in adults. In contrast to epithelial cancers, glioblastomas do not metastasize. While the major treatment challenge in epithelial cancers is not the primary tumor but metastasis, glioblastoma patients die of the primary tumor.
However, there is a common theme which underlies the malignant properties of progressed epithelial cancers and glioblastoma: invasion from the primary tumor into the surrounding tissue. In the case of epithelial cancers this is the first and necessary step to metastasis, whereas invasion leads inevitably to tumor recurrence after resection in the case of glioblastoma, causing it to be incurable.
A cellular program which has been described in detail to promote the invasive phenotype in epithelial tumors, is the epithelial-mesenchymal-transition (EMT). Differentiated neural cells are not epithelial, thus, strictly speaking, EMT does not occur in glioblastoma. However, the traits acquired in the process of EMT, especially invasiveness and stemness, are highly relevant to glioblastoma. One of the key transcription factors known to induce EMT in epithelial cancers is ZEB1, which has been described only marginally in the central nervous system so far. Here, I investigate the expression and function of ZEB1 in glioblastoma and during human fetal neural development.
ZEB1 mRNA was significantly upregulated in all histological types of glioma, including glioblastoma, when compared to normal brain. There was no correlation between ZEB1 mRNA levels and tumor grade. Immunohistochemical staining of glioma samples demonstrated that ZEB1 was highly expressed in the great majority of tumor cells. In the developing human brain, intense staining for ZEB1 could be observed in the ventricular and subventricular zone, where stem- and progenitor cells reside. ZEB1 positive cells included cells stained with stem- and progenitor markers like PAX6, GFAP and Nestin. In contrast, ZEB1 was never found in early neuronal cells as identified by TUBB3 staining.
To gain insight into ZEB1 function I generated a human fetal neural stem cell line and a glioblastoma cell line with ZEB1 knockdown, which were compared with their respective control cell lines. First, I found that ZEB1 does not regulate the micro RNA 200 family in either cell line, which has been described as an essential ZEB1 target in epithelial cancers. Second, regulated target genes were identified with a genome wide microarray. The third approach was to directly identify genomic binding sites of ZEB1 by chromatin immunoprecipitation sequencing (ChIP-seq). All three approaches showed that the ZEB1 transcriptional program is surprisingly similar in the neural stem cell line and the glioblastoma cell line. In contrast, it bears only little resemblance to the program described in epithelial cancers.
The most interesting, previously unrecognized ZEB1 target gene identified in this study is integrin b1. It was regulated after ZEB1 knockdown detected by microarray analysis, and has a ZEB1 binding site in its promoter region detected by ChIP-seq. Finally, I addressed the question whether ZEB1 influences tumor growth and invasiveness in a glioblastoma model. After intracranial xenotransplantation in mice, ZEB1 knockdown glioblastoma cells formed significantly smaller and less invasive tumors than control glioblastoma cells.
This study demonstrates that ZEB1 is widely expressed in glioma and relevant for glioblastoma growth and invasion. In contrast to what is known about ZEB1 function in epithelial cancers, ZEB1 is not associated with glioma progression, but instead seems to be an early and necessary event in tumorigenesis. Also with regard to ZEB1 target genes, ZEB1 functions differently in glioblastoma than in epithelial cancers. The two most important ZEB1 targets in epithelial cancers are E-cadherin and the miR-200 family members. Both are not relevant to ZEB1 function in glioblastoma. Interestingly, while the ZEB1 transcriptional program is different from the one described in epithelial cancers, it is highly similar in glioblastoma cells and fetal neural stem cells. This suggests that an embryonic pathway restricted to stem- and progenitor cells during development is reactivated in glioblastoma.
Previously known ZEB1 target genes were tissue specific and therefore seemed unlikely to mediate ZEB1 function in the central nervous system. However, the newly identified ZEB1 target gene integrin b1 is well known to play pivotal roles in both glioblastoma tumorigenesis and invasion as well as in neural stem cells. Additionally, integrin b1 is widely expressed and seems a likely ZEB1 target in other organs than the brain.
Taken together, I demonstrate that ZEB1 is a new regulator of glioblastoma growth and invasion. The transcriptional program of ZEB1 differs from the one in epithelial cancers but is strikingly similar to the one in neural stem cells. The newly identified ZEB1 target gene integrin b1 is likely to mediate crucial ZEB1 functios. Thus, this study identifies ZEB1 as a yet unrecognized player in glioblastoma and neural development. Furthermore, it sets the stage for more research which will help to deepen our understanding of ZEB1 function in the central nervous system and beyond.