Live or Let Die: CCM2 Provides the Link

TrkA receptors are well known for promoting neuronal cell survival. However, in some neuroblastic tumors, TrkA activation can instead induce apoptosis. In this issue of Neuron, Harel et al. identify CCM2 as a mediator of TrkA-dependent cell death, suggesting that CCM2 is a distinctive type of tumor suppressor that modulates tyrosine kinase signaling

Inflammation-Induced Cell Proliferation Potentiates DNA Damage-Induced Mutations In Vivo

Mutations are a critical driver of cancer initiation. While extensive studies have focused on exposure-induced mutations, few studies have explored the importance of tissue physiology as a modulator of mutation susceptibility in vivo. Of particular interest is inflammation, a known cancer risk factor relevant to chronic inflammatory diseases and pathogen-induced inflammation. Here, we used the fluorescent yellow direct repeat (FYDR) mice that harbor a reporter to detect misalignments during homologous recombination (HR), an important class of mutations. FYDR mice were exposed to cerulein, a potent inducer of pancreatic inflammation. We show that inflammation induces DSBs (γH2AX foci) and that several days later there is an increase in cell proliferation. While isolated bouts of inflammation did not induce HR, overlap between inflammation-induced DNA damage and inflammation-induced cell proliferation induced HR significantly. To study exogenously-induced DNA damage, animals were exposed to methylnitrosourea, a model alkylating agent that creates DNA lesions relevant to both environmental exposures and cancer chemotherapy. We found that exposure to alkylation damage induces HR, and importantly, that inflammation-induced cell proliferation and alkylation induce HR in a synergistic fashion. Taken together, these results show that, during an acute bout of inflammation, there is a kinetic barrier separating DNA damage from cell proliferation that protects against mutations, and that inflammation-induced cell proliferation greatly potentiates exposure-induced mutations. These studies demonstrate a fundamental mechanism by which inflammation can act synergistically with DNA damage to induce mutations that drive cancer and cancer recurrence.Austrian Academy of Sciences (APART Fellowship)Singapore-MIT Alliance for Research and TechnologySingapore. National Research FoundationNational Institutes of Health (U.S.) (NIH R33-CA112151)National Institutes of Health (U.S.) (grant R01-CA079827

Germline mutations in the DNA damage response genes BRCA1, BRCA2, BARD1 and TP53 in patients with therapy related myeloid neoplasms

Therapy related myeloid neoplasms (t-MNs) are complex diseases originating from an interplay between exogenous toxicities and a susceptible organism. It has been hypothesised that in a subset of cases t-MNs develop in the context of hereditary cancer predisposition syndromes

Systemic chemotherapy induces microsatellite instability in the peripheral blood mononuclear cells of breast cancer patients

INTRODUCTION: Systemic chemotherapy is an important part of treatment for breast cancer. We conducted the present study to evaluate whether systemic chemotherapy could produce microsatellite instability (MSI) in the peripheral blood mononuclear cell fraction of breast cancer patients. METHODS: We studied 119 sequential blood samples from 30 previously untreated breast cancer patients before, during and after chemotherapy. For comparison, we also evaluated 20 women who had no relevant medical history (control group). RESULTS: In 27 out of 30 patients we observed MSI in at least one sample, and six patients had loss of heterozygosity. We found a significant correlation between the number of MSI events per sample and chemotherapy with alkylating agents (P < 0.0001). We also observed an inverse correlation between the percentage of cells positive for hMSH2 and the number of MSI events per sample (P = 0.00019) and use of alkylating agents (P = 0.019). CONCLUSION: We conclude that systemic chemotherapy may induce MSI and loss of heterozygosity in peripheral blood mononuclear cells from breast cancer patients receiving alkylating agents, possibly mediated by a chemotherapy-induced decrease in the expression of hMSH2. These effects may be related to the generation of secondary leukaemia in some patients, and may also intensify the genetic instability of tumours and increase resistance to treatment

Fans und Partizipation im Fußballmagazin Ballesterer

Die vorliegende Magisterarbeit beschäftigt sich mit dem österreichischen Fußballmagazin Ballesterer und den darin repräsentierten Themen im Bereich der politischen Partizipation von Fußballfans. In Anlehnung an Roose/Schäfer (2010) können Partizipationsformen institutionalisierter und nicht-institutionalisierter Mitbestimmung für Fußballfans ausgemacht werden, welche zusammen mit Unterstützungsaktivitäten die theoretische Grundlage dieser Untersuchung bilden. Konkret handelt es sich dabei um Berichte über Mitbestimmungsformen und -strukturen (z. B. Fanvereine oder Mitgliedersysteme), Fanproteste (z. B. gegen die Vereinspolitik) sowie diverse Formen der Mitwirkung in Form eines Engagements von Fans (z. B. für das Fanobjekt). Die Berichterstattung über diverse Möglichkeiten zur Teilnahme von Fußballfans wird anhand der in den Artikeln vorkommenden Akteure, Themen und ihren jeweiligen Bewertungen analysiert. Parallel dazu werden Strukturmerkmale des Ballesterer abgebildet, um folglich den Entwicklungsprozess des Mediums, vom Fanzine hin zur etablierten Fachzeitschrift, zu betrachten. Obwohl sich strukturelle Merkmale wie Organisationsstruktur, Layout und Erscheinungsweise des Magazins mittlerweile der Logik kommerzieller Medienprodukte angenähert haben, kann im Fall des Ballesterer weiterhin von einem alternativen Medium gesprochen werden. Alternative Kommunikationsformen und fußballbezogene Fanmedien stellen dabei weitere theoretische Fundamente der Arbeit dar. Als eines der zentralen Merkmale alternativer Medien ist die Repräsentation von in Massenmedien marginalisierten Personengruppen zu bezeichnen. Dies erscheint auf Fußballfans in jedem Fall zutreffend, zumal ihre organisierten Szenewelten in vielen Redaktionen wohl selten in einem positiven Kontext gesehen werden. Magazine wie der Ballesterer bieten Fußballfans jedoch ein Forum, beschäftigen sich mit ihren Anliegen und heben dabei die Bedeutung von fankulturellen Aspekten immer wieder hervor. Der Betrachtung fanspezifischer Themen in einem Medium, welches selbst einen zumindest vormaligen Fanzine-Charakter vorweisen kann, wird demnach besondere Bedeutung zugemessen.This thesis analyses the coverage of the Austrian football magazine Ballesterer in terms of fans and participation. The protagonists, topics and their evaluations featured in the articles about participation will be analysed and compared. According to Roose/Schäfer (2010) and their view on political participation research we can also differ between certain ways of fan participation. Institutionalized ways of supporters' participation focus on the decision-making process. Influence on the particular club is a very important issue for supporters' groups. Models and structures which offer such possibilities could be certain membership schemes, e. g. supporters trusts or clubs owned and democratically runned by its supporters. On the other hand protests are certain methods of participation which are not institutionalized, but generally more common in the world of football than forms of institutionalized co-management are. Together with special support activities those three different possibilities of fan participation are going to be analysed in this paper. The emphasis of the study is on the fan-related context Ballesterer offers to it's readers. Supporters, their views and football culture in general are well represented in the magazine. In contrast to mass media, where fans and their opinions are not present on the same level. The representation of marginalised groups is one of the key aspects of alternative media. Ballesterer still offers an alternative to mainstream football coverage. But the former fanzine also ran through certain steps of professionalization and is now characterized as a well-established and commercialised medium. Additionally, the thesis focuses on this process of development and particular structure characteristics, e.g. the frequency of publication, price of sale and page volume. These two aspects of participation and the development of the magazine are going to be compared. The aim is to look at the fan-related context at the same time the fanzine developed to more professional structures

Development and characterization of a novel variable low-dose rate irradiator for in vivo mouse studies

Radiation exposure of humans generally results in low doses delivered at low dose rate. Our limited knowledge of the biological effects of low dose radiation is mainly based on data from the atomic bomb Life Span Study (LSS) cohort. However, the total doses and dose rates in the LSS cohort are still higher than most environmental and occupational exposures in humans. Importantly, the dose rate is a critical determinant of health risks stemming from radiation exposure. Understanding the shape of the dose-rate response curve for different biological outcomes is thus crucial for projecting the biological hazard from radiation in different environmental and man-made conditions. A significant barrier to performing low dose-rate studies is the difficulty in creating radiation source configurations compatible with long-term cellular or animal experiments. In this study the design and characterization of a large area, 125I-based irradiator is described. The irradiator allows continuous long-term exposure of mice at variable dose rates and can be sited in standard animal care facilities. The dose rate is determined by the level of 125I activity added to a large NaOH-filled rectangular phantom. The desired dose rate is maintained at essentially constant levels by weekly additions of 125I to compensate for decay. Dosimetry results for long-term animal irradiation at targeted dose rates of 0.00021 and 0.0021 cGy min−1 are presented.United States. Dept. of Energy (Grant FG01-04ER04-21)University of California, Davis. Center for Environmental Health Sciences (P30 ES001209-26A1)National Institutes of Health (U.S.) (NIH R01-CA79827)Austrian Academy of Science