Thesis deals with relationship between histomorphological and molecular-genetic findings of selected salivary gland tumors. Author, as a molecular-cytogeneticist mainly focused on detection of tumor-specific translocations of the salivary gland tumors which can serve as differential diagnostic markers. The thesis is composed as a commented files of authors own publications, and it is divided into four parts. First part deepens the knowledge of salivary adenoid cystic carcinoma. It was proved, that t(6;9)(q22-23;p23-24) resulting in fusion of transcription factors MYB-NFIB, or more rarely t(8;9) resulting in MYBL1-NFIB fusion represent robust differential diagnostic marker of adenoid cystic carcinoma. Further it was proved, that the 1p36 deletion can serve as an unfavorable prognostic indicator of adenoid cystic carcinoma, as the patients with 1p36 deletion had significantly lower survival. Second part summarizes new developments about mammary analogue secretory carcinoma (MASC), which was described by our group as a new salivary tumor entity characterized by translocation t(12;15)(p13;q25) resulting in ETV6-NTRK3 fusion. Another novel observation is a discovery of ETV6-RET fusion in a subset of MASC cases. Further, the first two MASCs of nasal mucosa origin have been described. Third part consists...

Acute leukemias (AL) comprise a heterogeneous group of hematologic malignancies, and individual patient responses to treatment can be difficult to predict. Monitoring of minimal residual disease (MRD) is thus very important and holds great potential for improving treatment strategies. Common MRD targets include immunoglobulin heavy chain or T-cell receptor gene rearrangements, recurrent cytogenetic abnormalities and mutations in important hematological genes. Whereas in the majority of adult acute lymphoblastic leukemia patients a suitable MRD target can be identified, in adult acute myeloid leukemia patients well-characterized targets are found in only half of cases. The identification of new specific molecular markers of leukemic blasts for MRD assessment, particularly in AML patients, is therefore highly desirable. Our aim was to develop a flexible strategy for mapping of cytogenetically identified unique clone-specific abnormalities down to the single nucleotide level and, based on the sequence, design a specific real-time PCR assay for MRD assessment in AL patients without any previously described MRD marker. Using a combination of cytogenetic (chromosome banding, chromosome microdissection), molecular cytogenetic (mFISH, mBAND) and molecular biological (next- generation sequencing, long-range...

1. Einleitung Multipotente mesenchymale Stromazellen (MSC) stellen eine interessante Therapieoption in der regenerativen Medizin verschiedener Erkrankungen dar. Aufgrund ihrer Herkunft aus mesodermalem Gewebe ist ihr Einsatz in der Therapie von Sehnenerkrankungen als günstig anzusehen, wo sie bei Pferden bereits erfolgreich verwendet werden. Da dieser Erkrankungskomplex mit degenerativen Veränderungen der Achillessehne des Menschen vergleichbar ist, wäre eine Translation der gewonnenen Ergebnisse in die Humanmedizin wünschenswert. Die zugrunde liegenden Wirkmechanismen bei der Sehnenregeneration sind allerdings bis zum heutigen Tage noch nicht vollständig geklärt. Unter anderem wird eine tenogene Differenzierung der MSC mit nachfolgender Produktion von extrazellulärer Matrix (EZM) diskutiert. Als Nachweis hierfür wird die Genexpression von Matrixproteinen sowie Transkriptionsfaktoren angesehen. Die Isolation von MSC ist aus verschiedenen Geweben möglich; allerdings haben Untersuchungen deutliche Unterschiede in den in-vitro-Charakteristika zwischen den Zellquellen aufgezeigt. Trotz dieser unterschiedlichen Eigenschaften fasst die International Society for Cellular Therapy (ISCT) seit 2006 humane MSC als plastikadhärente Zellen mit tripotentem Differenzierungspotential sowie einem definierten Antigenprofil zusammen. Um eine Vergleichbarkeit equiner und humaner MSC und somit eine bessere Übertragbarkeit gewonnener Erkenntnisse aus der Pferdemedizin zu erreichen, steht aktuell die Untersuchung der geforderten Antigenexpression noch aus. 2. Ziele der Untersuchung In der vorliegenden Arbeit sollte daher erstmalig eine vollständige Charakterisierung des geforderten Antigenprofils equiner MSC aus fünf verschiedenen Quellen durchgeführt werden, um einen Vergleich mit humanen Zellen zu ermöglichen. Zudem sollte eine vergleichende Darstellung der Sehnenmarkerexpression durchgeführt werden, welche das Wissen um die in-vitro-Eigenschaften von MSC erweitern und in Folge zur Auswahl einer optimal für die Therapie von Sehnenerkrankungen geeigneten Zellquelle beitragen soll. 3. Materialien und Methoden In der ersten Studie wurden equine MSC aus Knochenmark, Fettgewebe, Nabelschnurblut, Nabelschnurgewebe und Sehnengewebe bis zur Passage 3 kultiviert und anschließend mittels Durchflusszytometrie auf das Vorkommen der Antigene CD 29, CD 44, CD 73, CD 90 und CD 105 sowie das Fehlen der Antigene CD 14, CD 34, CD 45, CD 79α und MHC II untersucht. In der zweiten Studie wurde eine Genexpressionsanalyse der Sehnenmarker Kollagen 1A2, Kollagen 3A1, Decorin, Tenascin-C und Skleraxis vergleichend mittels Echtzeitpolymerasekettenreaktion an den isolierten Zellen durchgeführt. In beiden Studien wurde eine Probenzahl von n= 6 für jede Zellquelle untersucht. 4. Ergebnisse Keine der untersuchten Zellquellen erfüllte die MSC-Definition der ISCT bezüglich des Antigenprofils. Insbesondere durch den fehlenden Nachweis CD 73 (< 3,07 %) in allen untersuchten Proben unterscheiden sich equine und humane MSC. Die einzigen stabil exprimierten Antigene sind die zusätzlich untersuchten Proteine CD 29 (37,5 % - 65,42 %) und CD 44 (32,2 % - 97,18 %). Das Vorkommen CD 105 konnte in MSC aus Fett- und Sehnengewebe belegt werden. Zusätzlich war ein Nachweis von CD 90 in MSC aus Fettgewebe möglich, welche somit die größte Ähnlichkeit mit der humanen Zellpopulation aufweisen. Die Studie zur Genexpressionsanalyse weist auf eine Basisexpression von Kollagen 1A2, 3A1 und Decorin in MSC aus verschiedenen Quellen hin, welche über der von nativem Sehnengewebe liegt. Auch hier weisen wiederum MSC aus Fettgewebe die höchste Expression auf. 5. Schlussfolgerungen Die vorliegende Arbeit leistet einen Beitrag zu einer vertiefenden in-vitroCharakterisierung equiner MSC. Das Antigenprofil equiner MSC ist nicht vollständig mit dem humaner identisch. Eine abschließende Beurteilung sollte durch Untersuchungen mit spezies-spezifischen Antikörpern erfolgen. Die Ergebnisse der Genexpressionsanalyse unterstützen die Theorie, dass MSC die Sehnenheilung durch Produktion von extrazellulärer Matrix beeinflussen. Der Einsatz von MSC aus Fettgewebe in der Therapie von Sehnenerkrankungen sollte forciert werden, da ihre hohe Sehnenmarkerexpression einen Hinweis auf eine Verbesserung der Sehnenregeneration darstellt.

International Telemetering Conference Proceedings / October 26-29, 1998 / Town & Country Resort Hotel and Convention Center, San Diego, California / An Improved AMI (Alternate Mark Inverse) Code used in telemetry system is proposed, its implementation and properties analysis are reported, including error performance analysis, power spectrum analysis, the relationship between acqusition probability of the first frame marker and error threshold and length of frame marker, etc. This type of code has the approximately identical power spectrum performance as the AMI Code. In addition, there have no long continuous zeroes in the data stream, which will cause phase-locked loop to fail. Using the Improved AMI Code, the equal probability of 0 and 1 is changed, which will increase acqusition probability of the first frame marker. Detailed description about how to create the Improved AMI Code is also discussed in this paper.

Hybridization, the process of interbreeding between individuals of different species, is one method by which plants and animals adapt to a changing environment. One example of such adaptation through hybridization may be occurring on the California Channel Islands with two species of Castilleja. While United State Geological Survey (USGS) researchers have been studying the populations of Castilleja affinis and Castilleja mollis to determine if hybridization is occurring on Santa Rosa Island since the early 1990s, up until this point primarily overt phenotypic characteristics have been used to differentiate between the two species. Genetic methods of differentiation were adopted to confirm that hybridization is in fact occurring on the island, possibly in response to climate change. Hybrids may be expanding into areas once occupied by pure C. mollis, because they might carry some of C. affinis’ traits like an ability to survive warmer, drier climates as parts of the island are starting to become warmer and drier. In this study, I have developed a cleaved amplified polymorphic sequences (CAPS) marker based on internal transcribed spacer (ITS) regions to differentiate between the two species and hybrids and have applied these CAPS markers to genotype DNA samples isolated from 132 individuals. This protocol was used to determine the extent of hybridization on Santa Rosa Island in conjunction with ongoing surveys conducted by the USGS. Work focused on genotyping previously collected samples from two main sites on the island, which allowed confirmation that patterns observed based on phenotype in the field are supported by genetic data. In the future, findings will link genetic type with survivorship and growth data, to test whether hybrids perform differently than pure C. mollis. Broadly, this will determine if the two species are in fact hybridizing as a method for adapting to climate change, the most severe threat to Channel Island biodiversity.

International Telemetering Conference Proceedings / October 22-25, 2001 / Riviera Hotel and Convention Center, Las Vegas, Nevada / The Jet Propulsion Laboratory’s (JPL) Advanced Multi-Mission Operations System (AMMOS) system processes data received from deep-space spacecraft, where error rates are high, bit rates are low, and every bit is precious. Frame synchronization and data extraction as performed by AMMOS enhance data acquisition and reliability for maximum data return and validity. Unique aspects of data phase determination, sync acquisition and sync loss and other bit-level topics are covered.

Antal cancerfall ökar ständigt. Samtidigt ses en ökning av antalet cancerpatienter som lever längre tack vare tidig diagnostisering och bättre behandlingsmetoder. Neuroendokrina tumörsjukdomar diagnostiseras med hjälp av tumörmarkören chromogranin A. Syftet med studien var att redogöra för och jämföra kliniskt biokemiska metoder för analys av chromogranin A i plasma och serum. I samband med detta gjordes verifiering av KRYPTOR, BRAHMS automated immunofluorescent assay (KRYPTOR) för chromogranin A. Förekomst av analysmetoder undersöktes genom fördjupad litteraturgenomgång. Metodverifieringen innefattade smittöverföringstest mellan prover, mellanliggande precision, inomserieprecision samt jämförelse med samma metod respektive radioimmunoassay-metoden. I litteraturgenomgången erhölls analysmetoderna radioimmunoassay, immunoradiometric assay, enzymed linked immunosorbent assay och KRYPTOR/immunochemiluminometric assay. Metodverifieringens smittöverföringsrisk blev 0.04%, mellanliggande precision gav total CV på 1.96% respektive 2.33%, inomserieprecisions total CV 2.85%. Fem av sex analysresultat överrensstämde vid jämförelse med radioimmunoassay, medan jämförelse med samma metod gav en genomsnittlig skillnad på 17.6%. Sammanfattningsvis konstaterades att inom forskning används fyra immunologiska metoder för analys av chromogranin A i plasma och serum. Dess utveckling har gått från radioaktiv manuell till icke-radioaktiv automatiserad analysmetod med förkortad analystid. Metodverifieringen med KRYPTOR visade god mellanliggande- och inomserieprecision, men otillräckligt provunderlag resulterade i låg reliabilitet. / Title: Verification on KRYPTOR compact PLUS and an in-depth literature overview of clinical biochemical assays for the detection of Chromogranin A in plasma and serum.   Cancer is constantly increasing. Simultaneously, there is an increase in survival for cancer patients due to early diagnosis and better treatment.  Neuroendocrine tumour disease is diagnosed with help of tumour marker chromogranin A. The aim of this study was to narrate and compare clinical biochemical methods for the detection of chromogranin A in plasma and serum. In addition, a verification of KRYPTOR, BRAHMS automated immunofluorescent assay (KRYPTOR) for chromogranin A was performed. Occurring methods for analysis was investigated by in-depth literature overview. Verification contained tests for carry over, intra- and inter-assay, comparison with same method and radioimmunoassay method respectively. The literature overview resulted in radioimmunoassay, immunoradiometric assay, enzyme linked immunosorbent assay and KRYPTOR/immunochemiluminometric assay. Verification gave carry over 0.04%, inter-assay CV 1.96% and 2.33%, intra-assay CV 2.85%. Comparison with the same method gave a mean difference of 17.6% and five samples out of six correlated for comparison with radioimmunoassay. In summary, four immunological methods are used for analysis of chromogranin A, within research. Their development ranges from radioactive manual to non-radioactive automated method with shortened analysis times. Verification for KRYPTOR showed god intra- and inter-assay but an insufficient number of samples resulted in low reliability.

Theoretical procedures are developed to account for the effect of emotion and perception in strategic conflict. The <em>possibility principle</em> facilitates modeling the effects of emotions on future scenarios contemplated by decision makers; <em>perceptual graph models</em> and a <em>graph model system</em> permit the decision makers (DMs) to experience and view the conflict independently; and <em>perceptual stability analysis</em>, which is based on individual- and meta-stability analysis techniques, is employed in analyzing graph model systems when the DMs have inconsistent perceptions. These developments improve the methodology of the Graph Model for Conflict Resolution by reconciling emotion, perception, and strategy to make predictions consistent with the actual unfolding of events. <br /><br /> Current research in neuroscience suggests that emotions are a necessary component of cognitive processes such as memory, attention, and reasoning. The somatic marker hypothesis, for example, holds that feelings are necessary to reasoning, especially during social interactions (Damasio, 1994, 2003). Somatic markers are memories of past emotions: we use them to predict future outcomes. To incorporate the effect of emotion in conflict, the underlying principle of Damasio?s hypothesis is used in developing the possibility principle, which significantly expands the paradigm of the Graph Model for Conflict Resolution of Fang, Hipel, and Kilgour (1993). <br /><br /> State identification is a crucial step in determining future scenarios for DMs. The possibility principle is integrated into the modeling stage of the Graph Model by refining the method of determining feasible states. The possibility principle enables analysts and DMs to include emotion in a conflict model, without sacrificing the parsimonious design of the Graph Model methodology, by focusing attention on two subsets of the set of feasible states: <em>hidden</em> and <em>potential</em> states. Hidden states are logically valid, feasible states that are invisible because of the presence of negative emotions such as anger and fear; potential states are logically valid, feasible states that are invisible because of missing positive emotions. Dissipating negative emotions will make the hidden states visible, while expressing the appropriate positive emotions will make the potential states visible. The possibility principle has been applied to a number of real world conflicts. In all cases, eliminating logically valid states not envisioned by any DM simplifies a conflict model substantially, expedites the analysis, and makes it an intuitive and a realistic description of the DMs' conceptualizations of the conflict. <br /><br /> A fundamental principle of the Graph Model methodology is that all DMs' directed graphs must have the same set of feasible states, which are integrated into a <em>standard</em> graph model. The possibility principle may modify the set of feasible states perceived by each DM according to his or her emotion, making it impossible to construct a single standard graph model. When logically valid states are no longer achievable for one or more DMs due to emotions, the apprehension of conflict becomes inconsistent, and resolution may become difficult to predict. Therefore, reconciling emotion and strategy requires that different apprehensions of the underlying decision problem be permitted, which can be accomplished using a perceptual graph model for each DM. A perceptual graph model inherits its primitive ingredients from a standard graph model, but reflects a DM's emotion and perception with no assumption of complete knowledge of other DMs' perceptions. <br /><br /> Each DM's perceptual graph model constitutes a complete standard graph model. Hence, conclusions drawn from a perceptual graph model provide a limited view of equilibria and predicted resolutions. A graph model system, which consists of a list of DMs' perceptual graph models, is defined to reconcile perceptions while facilitating conclusions that reflect each DM's viewpoint. However, since a DM may or may not be aware that other graph models differ from his or her own, different variants of graph model systems are required to describe conflicts. Each variant of graph model system corresponds to a configuration of awareness, which is a set of ordered combinations of DMs' viewpoints. <br /><br /> Perceptual stability analysis is a new procedure that applies to graph model systems. Its objective is to help an <em>outside</em> analyst predict possible resolutions, and gauge the robustness and sustainability of these predictions. Perceptual stability analysis takes a two-phase approach. In Phase 1, the stability of each state in each perceptual graph model is assessed from the point of view of the owner of the model, for each DM in the model, using standard or perceptual solution concepts, depending on the owner's awareness of others' perceptions. (In this research, only perceptual solution concepts for the 2-decision maker case are developed. ) In Phase 2, meta-stability analysis is employed to consolidate the stability assessments of a state in all perceptual graph models and across all variants of awareness. Distinctive modes of equilibria are defined, which reflect incompatibilities in DMs' perceptions and viewpoints but nonetheless provide important insights into possible resolutions of conflict. <br /><br /> The possibility principle and perceptual stability analysis are integrative techniques that can be used as a basis for empathetically studying the interaction of emotion and reasoning in the context of strategic conflict. In general, these new techniques expand current modeling and analysis capabilities, thereby facilitating realistic, descriptive models without exacting too great a cost in modeling complexity. In particular, these two theoretical advances enhance the applicability of the Graph Model for Conflict Resolution to real-world disputes by integrating emotion and perception, common ingredients in almost all conflicts. <br /><br /> To demonstrate that the new developments are practical, two illustrative applications to real-world conflicts are presented: the US-North Korea conflict and the confrontation between Russia and Chechen Rebels. In both cases, the analysis yields new strategic insights and improved advice.

The overall aim of this thesis was to investigate the genetic control of beef quality in a commercial population of Aberdeen Angus-sired cattle with a view to trait improvement. The population studied included 500 Angus-cross animals, all with purebred Aberdeen Angus sires, from a selection of farms throughout Scotland. A number of carcass-related weight traits and taste panel assessed sensory traits were measured on these animals. A population of 265 Charolais cross cattle (all with purebred sires) was then used to explore the extrapolation of results across breeds. The first aim of this thesis was to investigate heritabilities for important carcass and meat quality traits and to assess the quality of a number of taste-panel derived meat quality traits by calculating three consistency statistics. Consistency statistics (parameter range 0 to 1) for the taste panel traits were moderately high, particularly for panel member consistency and reproducibility, with values ranging from 0.48 to 0.81 and 0.43 to 0.73, respectively. Estimated heritabilities were low for most of the sensory taste-panel-evaluated traits, where the maximum value was 0.16 for overall liking, but were higher for carcass traits where carcass weight heritability was 0.7. To perform these analyses it was first necessary to confirm paternity using a number of genetic markers. Therefore, a comparison of the power of both microsatellite and SNP markers for paternity exclusion was carried out to determine the more effective method. Results indicated that approximately three times as many SNP markers than microsatellite markers were required for parentage exclusion, and a panel of 15 microsatellite markers was used to assign paternity before subsequent data analysis was carried out. The remaining aims of this thesis centred on exploring genetic markers for carcass and meat quality. Firstly, the Angus animals were genotyped for the del11 myostatin mutation which was found to be segregating at a relatively low frequency (0.04) and was shown to be associated with a 17.4 kg increase in carcass weight (P < 0.05) in the heterozygous animals when compared to the homozygous wild-type animals. By analysing the haplotype associated with the mutant allele, it was determined that there have been at least two separate introductions of the mutant allele into the Aberdeen Angus breed. A number of SNPs were also tested for their effects on the carcass and meat quality traits in the Angus animals. The SNPs fell into two groups: eight that have been incorporated into commercially available tests and a further 28 from alternative candidate genes that have effects in different breeds and species. In total, 17 SNPs significantly affected at least one of the traits measured. Of these significant associations, a number have been seen previously, such as the association between calpain and tenderness (P = 0.01) and growth hormone and eye muscle area (P = 0.05), and some of which were novel, such as the association between growth hormone receptor and steak odour (P = 0.02) and corticotrophin releasing hormone and gristle distance from fat (P = 0.004). A further six SNPs, identified by resequencing of the malic enzyme 1 (ME1) and small heterodimer partner (SHP) genes, were tested for their effects on the traits measured in this thesis. Five of the SNPs, including one which caused a non-synonymous amino acid change, had a significant effect on at least one of the traits tested including fat class (P = 0.002), eye muscle area (P = 0.01), sirloin weight before maturation (P = 0.03), sirloin steak tail length (P = 0.004) and juiciness (P = 0.004) where the effect sizes were 1.79 units, 565 mm2, 0.36 kg, 17.12 mm and 0.23 taste panel units, respectively. To assess the effect of the genotyped SNPs on intramuscular fat (IMF), a simple method of visible IMF quantification in the sirloin steak was developed using digital photographs and an image analysis program. Results showed that two SNPs in the calpain gene, known to be linked with an increase in meat tenderness, were associated with an increase in visible IMF% and the del11 mutation was associated with a reduction in visible IMF%. The heritabilities, SNP association validations and novel SNP-trait associations identified in this thesis provide tools for use in breeding programs, possibly via marker assisted selection to improve meat quality traits. However, the results seem breed-specific, as most of the significant effects were not replicated in the Charolais population.

L'expansion d'une tumeur résulte d'une multiplication non contrôlée des cellules tumorales, de l'acquisition de leur capacité à migrer, ainsi que de la genèse du réseau vasculaire nécessaire à leur survie. Ces propriétés reposent en partie sur la mise en jeu de molécules impliquées dans le guidage cellulaire telles que les sémaphorines, initialement décrites pour leur implication dans le guidage axonal au cours du développement du système nerveux. Leurs fonction s'étendent actuellement au contrôle de l'angiogénèse de la migration des précurseurs nerveux ainsi que du cycle cellulaire. Les voies de signalisation intra-cellulaires des sémaphorines ne sont que partiellement connues. Les CRMP (CollapsinResponse Mediator Protein) font partie de leurs médiateurs intracytoplasmiques, décrites au cours de la rétraction du cône de croissance induit par la sémaphorine 3A (Sema3A). L'implication en pathologie tumorale de ces voies de signalisation a été découverte par l!étude de gènes tel que celui de la sémaphorine 3F (Sema3F), présents dans les régions délétées du chromosome 3 de certains types de tumeurs non neuroendocrines du poumon L'implication des CRMP a été également révélée par les syndromes neurologiques paranéoplasiques (SNP). Ces syndromes résultent d'une auto-immunisation humorale des patients contre des antigènes exprimés par la tumeur dont ils sont atteints. C'est le cas de CRMP5, protéine, identifiée dans notre laboratoire comme cible des auto-anticorps anti-CV2/ CRMP5 dans le cadre des SNP associés à des tumeurs neuroendocrines du poumon, les carcinomes à petites cellules (CPC) ainsi qu'à des thymomes. Alors que les thymomes sont des tumeurs bénignes, les CPC représentent 20% des carcinomes pulmonaires et sont, avec les carcinomes neuroendocrines à grandes cellules, les formes les plus agressives des tumeurs du poumon. Notre objectif était d'étudier l'implication physiopathologique des CRMP dans les différents types de carcinomes du poumon et dans les thymomes ainsi que dans les tumeurs du système nerveux central en relation avec la signalisation des sémaphorines. Nous avons ainsi démontré une expression exclusive de CRMP5 par les carcinomes neuroendocrines du poumon et les gliomes de haut grade par comparaison aux carcinomes non neuroendocrines et aux thymomes. CRMP5 n'est pas exprimée dans les carcinomes non neuroendocrines du poumon desquels sont dérivés les lignées H460 et H157. Ces observations ont été complétées par deux collaborations à des études portant sur les voies de signalisation des sémaphorines dans des modèles cellulaires de ces tumeurs. La première étude a montré que Sema3F, surexprimée dans la lignée H157 possède un effet anti-tumoral. La voie de signalisation de Sema3F nécessite neuropiline 2, l'inactivation de la MAPK (Mitogen Activated Protein Kinase) Erk 1/2 et entraîne l!inhibition de l'adhésion des intégrines !vß3, avec participation de CRMP1 et CRMP4 mais pas de CRMP5. La deuxième étude a établi que sous Sema3A la voie de signalisation d'Erk ½ est activée par le complexe de récepteur NRP1/VEGFR1 lors de la migration de précurseurs nerveux. Dans ces conditions Sema3A entraîne des modulations des expressions des CRMP2, CRMP4 et CRMP5 suggérant leur implication. Ainsi, ce travail montre que l!activation de certaines voies de signalisation des sémaphorines sont spécifiques des types histopathologiques et des grades des tumeurs. Ces voies de signalisations sont médiées par des complexes de récepteurs précis et mettent souvent en jeu les CRMP / Tumour growth is a consequence of uncontrolled cell proliferation, cell migration and angiogenesis. These functions are partly controlled by molecules involved in cellular guidance. Among these molecules, the semaphorins, previously described in axonal guidance during development, interestingly control cell migration, angiogenesis, apoptosis and proliferation. Signalling pathways of Semaphorins are only partially known. CRMP (Collapsin Response Mediator Protein) are involved in the signalling semaphoring pathway, precisely as mediator of Sema3A induced growth cone collapse. Implication of these signalling pathways in tumour growth was initially discovered with Sema3F localised in frequently deleted regions of the third chromosome found in non neuroendocrine lung carcinoma. CRMP involvement was also discovered in neurological paraneoplastic syndromes (NPS). These syndromes result of an auto-immunisation against tumour antigens present in some patients. CRMP5 was identified by our laboratory as a target of anti-CV2/CRMP5 auto-antibodies seen in some NPS associated with small cell lung carcinoma (SCLC) and thymoma. While thymoma are benign tumours, SCLC account for 20% of all lung tumour pathological subtypes and represent with large cell neuroendocrine carcinoma the most clinically aggressive subtypes of lung tumours. Our aim was to study the physiopathological role of CRMP among the different subtypes of lung carcinoma, thymoma and central nervous system tumours and their relationship with semaphorin signalling pathways. We showed a specific diffuse expression of CRMP5 by high grade neuroendocrine carcinoma and high grade glioma tumour cells. CRMP5 is neither expressed by non neuroendocrine lung carcinoma nor H460 or H157 derived cell lines, nor thymoma. Additionally, 2 collaborative studies were undertaken, focusing on semaphorin cell signalling in tumour derived cell lines. The first study showed an anti tumour effect of Sema3F over-expressed in H157 cell line mediated by neuropilin 2, CRMP2 and CRMP4 but not by CRMP5. It showed that Sema3F stimulation led to the inactivation of Erk1/2 MAPK (Mitogen Activated Protein Kinase) and inhibition of !vß3 integrin mediated adhesion. The second study showed that Sema3A induced DEV cells migration was mediated by neuropilin1/VEGFR1 receptor complex and activated Erk1/2 pathway. CRMP2, CRMP4 and CRMP5 expression changes suggested their involvement in that pathway. Thus, these data show that some semaphorin pathways activation were specific of tumour pathological subtype and grade. These signalling pathways were precisely mediated by specific receptor complexes and different CRMPs isoforms