Fraunhofer Institute for Toxicology and Experimental Medicine

Hannover, Germany

Fraunhofer Institute for Toxicology and Experimental Medicine

Hannover, Germany

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HANOVRE & REGENSBURG, Allemagne--(BUSINESS WIRE)--Des chercheurs du projet « Group for Personalized Tumor Therapy » basé à Regensburg (Fraunhofer ITEM/University of Regensburg) et leurs collègues de l' Icahn School of Medicine at Mount Sinai ont découvert de nouveaux mécanismes de propagation précoce dans le cas du cancer du sein. Les résultats ont été publiés dans la dernière publication du journal bien connu Nature (doi:10.1038/nature20785, doi:10.1038/nature20609). Pendant des décennies, les recherches sur le cancer ont entretenu le dogme selon lequel les cellules cancéreuses proviennent principalement de tumeurs avancées – découlant du fait que le diagnostic précoce et l’ablation chirurgicale jouent un rôle important dans la guérison des patients du cancer. Toutefois de plus en plus la validité de cette explication du succès du traitement est de plus en plus remise en question car les patients ayant de petites tumeurs développent aussi des métastases. De plus, le profil génétique des cellules cancéreuses disséminées n’indique pas la similarité espérée avec la tumeur principale. Il semblerait qu’une dérivation des cellules cancéreuses disséminées, comme des précurseurs des métastases, se réaliserait fréquemment déjà au cours des premières étapes de l’évolution de la tumeur. Des équipes de chercheurs dirigées par le professeur Christoph Klein (Regensburg) et le professeur Julio Aguirre-Ghiso (New York) ont étudié pour la toute première fois les mécanismes de la propagation précoce métastatique dans le cas du cancer du sein. Ils ont trouvé que la formation du cancer du sein prend en otage des processus physiologiques qui contrôlent la ramification mammaire et l’expansion pendant l’adolescence et la grossesse, les embrouille et les utilise pour la dissémination des cellules tumorales. Une fois disséminées, ces cellules s’installent dans d’autres tissus et, après des altérations génétiques, elles peuvent devenir des métastases souvent mortelles dans l’organe cible. Les deux équipes de recherche ont au début travaillé en autonome, mais elles ont ensuite collaboré et publié leurs résultats simultanément dans le journal Nature. « Nous espérons que nos résultats, qui sont tout à fait inédits, feront considérablement avancer la recherche sur le cancer, affirme Klein. Les chercheurs espèrent que le mécanisme proposé fournira un cadre général qui pourrait permettre de comprendre la formation de la métastase. Selon leurs résultats les cellules cancéreuses partent d’abord d’une phase initiale de dissémination de faible densité cellulaire sur le site primaire pour passer ensuite à une phase de prolifération lorsqu’une forte densité cellulaire est atteinte. Cependant les chercheurs de Regensburg ont également trouvé que les cellules tumorales peuvent réapprendre à se disséminer en cours de phases plus tardives, notamment à partir de zones de faible densité cellulaire. Cela pourrait expliquer pourquoi les métastases proviennent de différentes phases de l’évolution primaire de la tumeur, aussi bien phase précoce et tardive. Etant donné que ces étapes comprennent des cellules génétiquement différentes et que les approches thérapeutiques modernes ciblent souvent les altérations génétiques, les thérapies ciblant l’origine de la métastase doivent prendre en considération cette hétérogénéité des cellules afin de réussir.

News Article | December 14, 2016

HANNOVER & REGENSBURG, Germany--(BUSINESS WIRE)--Scientists of the Regensburg-based Project Group for Personalized Tumor Therapy (Fraunhofer ITEM/University of Regensburg) and colleagues from Icahn School of Medicine at Mount Sinai discovered new mechanisms of early metastatic spread in breast cancer. Results have been published in the latest issue of the renowned journal Nature (doi:10.1038/nature20785, doi:10.1038/nature20609). Over decades, cancer research pursued the dogma that cancer cells seed mainly from advanced tumors – based on the finding that early diagnosis and surgical removal are decisive for curing cancer patients. Recently, however, the validity of this concept in explaining treatment success has been questioned increasingly, because patients with small tumors also develop metastases. Furthermore, the genetic profile of disseminated cancer cells often does not show the expected similarity to the primary tumor. Derivation of disseminated cancer cells, as precursors of metastases, frequently seems to occur at early tumor evolution stages already. Researcher teams under Prof. Christoph Klein (Regensburg) and Prof. Julio Aguirre-Ghiso (New York) for the first time ever studied mechanisms of early metastatic spread in breast cancer. They found that breast cancer formation hijacks physiological processes controlling mammary epithelial branching and expansion during adolescence and pregnancy, deregulates and uses them for tumor cell dissemination. Once disseminated, these cells settle in other tissues and, after further genetic alterations, can grow to often life-threatening metastases in the target organ. The two research teams initially worked independently, but then collaborated and published their results simultaneously in Nature. “Our fundamentally new findings will hopefully advance cancer research substantially,” Klein explains. The researchers hope that the proposed mechanism will provide a general framework for understanding metastasis formation. According to their findings, cancer cells first go through an early dissemination stage at low cell density at the primary site and later on switch to a proliferation stage when high cell density is reached. However, the Regensburg scientists also found that tumor cells can “relearn” to disseminate even at later stages – from areas of low cell density. This is probably why metastases may derive from different stages of primary tumor evolution, both early and late. Since these stages comprise genetically different cells and modern therapeutic approaches often target genetic alterations, therapies targeting the seed of metastasis need to address this heterogeneity of cells to be successful.

Hoymann H.G.,Fraunhofer Institute for Toxicology and Experimental Medicine
Frontiers in Pharmacology | Year: 2012

The ICH guideline S7A requires safety pharmacology tests including measurements of pulmonary function. In the first step-as part of the "core battery" - lung function tests in conscious animals are requested. If potential adverse effects raise concern for human safety, these should be explored in a second step as a "follow-up study." For these two stages of safety pharmacology testing, both non-invasive and invasive techniques are needed which should be as precise and reliable as possible. A short overview of typical in vivo measurement techniques is given, their advantages and disadvantages are discussed and out of these the non-invasive head-out body plethysmography and the invasive but repeatable body plethysmography in orotracheally intubated rodents are presented in detail. For validation purposes the changes in the respective parameters such as tidal midexpiratory flow (EF50) or lung resistance have been recorded in the same animals in typical bronchoconstriction models and compared. In addition, the technique of head-out body plethysmography has been shown to be useful to measure lung function in juvenile rats starting from day two of age. This allows safety pharmacology testing and toxicological studies in juvenile animals as a model for the young developing organism as requested by the regulatory authorities (e.g., EMEA Guideline 1/2008). It is concluded that both invasive and non-invasive pulmonary function tests are capable of detecting effects and alterations on the respiratory system with different selectivity and area of operation. The use of both techniques in a large number of studies in mice and rats in the last years have demonstrated that they provide useful and reliable information on pulmonary mechanics in safety pharmacology and toxicology testing, in investigations of respiratory disorders, and in pharmacological efficacy studies. © 2012 Hoymann.

Hahn T.,Fraunhofer Institute for Toxicology and Experimental Medicine
Integrated environmental assessment and management | Year: 2014

Environmental hazard assessments for chemicals are carried out to define an environmentally "safe" level at which, theoretically, the chemical will not negatively affect any exposed biota. Despite this common goal, the methodologies in use are very diverse across different countries and jurisdictions. This becomes particularly obvious when international scientists work together on documents with global scope, e.g., in the World Health Organization (WHO) International Program on Chemical Safety. In this article, we present a study that describes the extent of such variability and analyze the reasons that lead to different outcomes in deriving a "safe level" (termed the predicted no effect concentration [PNEC] throughout this article). For this purpose, we chose 5 chemicals to represent well-known substances for which sufficient high-quality aquatic effects data were available: ethylene glycol, trichloroethylene, nonylphenol, hexachlorobenzene, and copper (Cu). From these data, 2 data sets for each chemical were compiled: the full data set, that contained all information from selected peer-review sources, and the base data set, a subsample of the full set simulating limited data. Scientists from the European Union (EU), United States, Canada, Japan, and Australia independently carried out hazard assessments for each of these chemicals using the same data sets. Their reasoning for key study selection, use of assessment factors, or use of probabilistic methods was comprehensively documented. The observed variation in the PNECs for all chemicals was up to 3 orders of magnitude, and this was not simply due to obvious factors such as the size of the data set or the methodology used. Rather, this was due to individual decisions of the assessors within the scope of the methodology used, especially key study selection, acute versus chronic definitions, and size of assessment factors. Awareness of these factors, together with transparency of the decision-making process, would be necessary to minimize confusion and uncertainty related to different hazard assessment outcomes, particularly in international documents. The development of a "guideline on transparency in decision-making" ensuring the decision-making process is science-based, understandable, and transparent, may therefore be a promising way forward. © 2013 SETAC.

Creutzenberg O.,Fraunhofer Institute for Toxicology and Experimental Medicine
Archives of Toxicology | Year: 2012

After deposition in the respiratory tract, nanoparticles exhibit acute, neutrophil-driven inflammatory and oxidative reactions, fibrotic responses and in chronic studies under overload conditions carcinogenic effects, more severely than the microscaled materials of the same chemistry. Besides these effects also known to be induced by microsized particles, nanoparticles principally can translocate from the site of exposure to circulation and become systemically available. This may either increase the toxic outcome (e.g. cardio-vascular effects and potential responses in remote organs) or facilitate an elimination of nanomaterials. For example, in combination with partial dissolution, a strong lung response after a short-term inhalative exposure may be followed by a rapid recovery effect. Mechanistically, in vitro and in vivo tests demonstrated that nanoparticles induce inflammation and oxidative stress after interaction with macrophages and lung epithelial cells; consequently, a cytotoxic and genotoxic potential may exist. The deposition, retention and clearance behaviour of inhaled nanomaterials and the toxic effects observed are decisively dependent on the particle agglomeration status of the aerosol. Two principally different experimental approaches are used for inhalative exposure to nanoparticles: either (1) a basic research-oriented approach using very small aerosol mass concentrations or particle formulations that result in at least partially nanoscaled aerosols; in this way, the potential hazard and the translocation potential for individual nanoparticles can be followed effectively; or (2) exposure scenarios mimicking the occupational situation (risk-oriented) with mostly agglomerated nanoparticles; consequently, the probable risk deriving from incidental/accidental exposure can be assessed more adequately. © Springer-Verlag 2012.

Buschmann J.,Fraunhofer Institute for Toxicology and Experimental Medicine
Methods in Molecular Biology | Year: 2013

In many countries the process of toxicity testing of environmental chemicals is ruled by a framework of OECD guidelines. The present paper will give an overview over the relevant OECD guidelines and guidance documents and mainly focus on methodological issues related to the prenatal toxicity testing guideline. Relevant guideline text will be provided, and practical recommendations will be given both for critical issues of experimental methodology and data interpretation. © 2013 Springer Science+Business Media, LLC.

Reamon-Buettner S.M.,Fraunhofer Institute for Toxicology and Experimental Medicine | Borlak J.,Fraunhofer Institute for Toxicology and Experimental Medicine
Human Mutation | Year: 2010

Congenital heart disease (CHD) is among the most prevalent and fatal of all birth defects. Deciphering its causes, however, is complicated, as many patients affected by CHD have no family history of the disease. There is also widespread heterogeneity of cardiac malformations within affected individuals. Nonetheless, there have been tremendous efforts toward a better understanding of the molecular and cellular events leading to CHD. Notably, certain cardiac-specific transcription factors have been implicated in mammalian heart development and disruption of their activity has been demonstrated in CHD. The homeodomain transcription factor NKX2-5 is an important member of this group. Indeed, more than 40 heterozygous NKX2-5 germline mutations have been observed in individuals with CHD, and these are spread along the coding region, with many shown to impact protein function. Thus, NKX2-5 appears to be hypermutable, yet the overall detection frequency in sporadic CHD is about 2% and NKX2-5 mutations are one-time detections with single-positives or private to families. Furthermore, there is lack of genotype-phenotype correlation, in which the same cardiac malformations have been exhibited in different NKX2-5 mutations or the same NKX2-5 mutation associated with diverse malformations. Here, we summarize published NKX2-5 germline mutations and explore different avenues in disease pathogenesis to support the notion of a multifactorial cause of CHD where possibly several genes and associated pathways are involved. Hum Mutat 31:1-10, 2010. © 2010 Wiley-Liss, Inc.

Winkler C.,Fraunhofer Institute for Toxicology and Experimental Medicine
Swiss medical weekly | Year: 2013

Pulmonary surfactant is a complex mixture of unique proteins and lipids that covers the airway lumen. Surfactant prevents alveolar collapse and maintains airway patency by reducing surface tension at the air-liquid interface. Furthermore, it provides a defence against antigen uptake by binding foreign particles and enhancing cellular immune responses. Allergic asthma is associated with chronic airway inflammation and presents with episodes of airway narrowing. The pulmonary inflammation and bronchoconstriction can be triggered by exposure to allergens or pathogens present in the inhaled air. Pulmonary surfactant has the potential to interact with various immune cells which orchestrate allergen- or pathogen-driven episodes of airway inflammation. The complex nature of surfactant allows multiple sites of interaction, but also makes it susceptible to external alterations, which potentially impair its function. This duality of modulating airway physiology and immunology during inflammatory conditions, while at the same time being prone to alterations accompanied by restricted function, has stimulated numerous studies in recent decades, which are reviewed in this article.

HANNOVER & REGENSBURG, Duitsland--(BUSINESS WIRE)--Onderzoekers van de projectgroep Personalized Tumor Therapy uit Regensburg hebben samen met collega’s van de Icahn School of Medicine at Mount Sinai nieuwe mechanismen ontdekt bij vroege uitzaaiingen van borstkanker. De resultaten zijn gepubliceerd in het nieuwste nummer van het vermaarde tijdschrift Nature (doi:10.1038/nature20785, doi:10.1038/nature20609). Decennialang gold in kankeronderzoek het dogma dat kankercellen zich vooral vanuit gevorderde tumoren verspreiden. Dit idee was gebaseerd op de bevinding dat vroege diagnose en chirurgische verwijdering beslissend zijn voor de genezing van kankerpatiënten. Onlangs werd deze verklaring voor succes bij behandelingen ernstig in twijfel getrokken, omdat patiënten met kleine tumoren ook uitzaaiing hebben. Bovendien komt het genetische profiel van verspreide kankercellen vaak niet overeen met de primaire tumor. Afwijkingen van verspreide kankercellen, als voorlopers van uitzaaiing, blijken vaak al in de vroege ontwikkelingsfase van de tumor voor te komen. Deze bekendmaking is officieel geldend in de originele brontaal. Vertalingen zijn slechts als leeshulp bedoeld en moeten worden vergeleken met de tekst in de brontaal, die als enige rechtsgeldig is.

Per decenni la ricerca sul cancro ha seguito il dogma secondo cui le cellule tumorali provengono principalmente da tumori in fase avanzata, in base alla constatazione che la diagnosi precoce e la rimozione chirurgica sono fattori decisivi per la cura di pazienti affetti da tumore. Di recente, tuttavia, la validità di questo concetto nella spiegazione del successo del trattamento è stata sempre più messa in discussione, perché anche i pazienti con masse tumorali ridotte possono sviluppare metastasi.

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