Epidémiologie et prise en charge du cancer colorectal: une étude de population en Valais

Entre 2006 et 2009, 774 cas de cancer colorectal in situ ou invasif ont été diagnostiqués en Valais. La proportion des hommes (59%) est plus élevée que celle des femmes (41%). L'âge moyen au diagnostic est de 70 ans. 79% des tumeurs sont invasives. Le côlon est la localisation la plus fréquente (71%). 20% des cas sont de stade 0, 36% de stade I et II, 18% de stade III et 22% de stade IV. Le mode de présentation le plus fréquent est de loin la consultation pour symptômes non urgents (75%). Toutefois, 9% des patients sont pris en charge en urgence. 95% des patients traités le sont par de la chirurgie seule ou en combinaison avec d'autres traitements. 82% des patients avec un cancer colorectal invasif ont été traités dans les 30 jours. En première intention, 95% des cancers du côlon invasifs ont un traitement chirurgical alors que 53% des cancers du rectum invasifs ont un traitement chirurgical et 36% une radio-chimiothérapie. La survie du cancer colorectal invasif est de 95% à 30 jours et de 79% à 1 an. La survie est plus basse chez les personnes de 70 ans et plus (à 30 jours: 92%; à 1 an: 70%) que chez les personnes de moins de 70 ans (à 30 jours: 99%; à 1 an: 90%). Elle est également moins bonne pour les stades IV de la maladie (à 30 jours: 91%; à 1 an: 54%) que pour les stades I-II (à 30 jours: 97%; à 1 an: 91%) ou III (à 30 jours: 98%; à 1 an: 92%). Ces observations indiquent que l'épidémiologie du cancer colorectal dans la population valaisanne est similaire à ce qui est décrit dans d'autres populations en Europe, que les modalités de prise en charge sont proches de celles proposées dans les guidelines et que la survie est similaire à celle observée en Suisse et dans d'autres pays européens.

Acoustic transport of charge and spins in GaAs-based heterostructures

Report for the scientific sojourn carried out at the Paul Drude Institut für Festkörperelektronik of the Stanford University, USA, from 2010 to 2012. The objective of this project is the transport and control of electronic charge and spin along GaAs-based semiconductor heterostructures. The electronic transport has been achieved by taking advantage of the piezolectric field induced by surface acoustic waves in non-centrosymmetric materials like GaAs. This piezolectric field separates photogenerated electrons and holes at different positions along the acoustic wave, where they acummulate and are transported at the same velocity as the wave. Two different kinds of structures have been studied: quantum wells grown along the (110) direction, both intrinsic and n-doped, as well as GaAs nanowires. The analysis of the charge acoustic transport was performed by micro-photoluminescence, whereas the detection of the spin transport was done either by analyzing the polarization state of the emitted photoluminescence or by Kerr reflectometry. Our results in GaAs quantum wells show that charge and spin transport is clearly observed at the non-doped structures,obtaining spin lifetimes of the order of several nanoseconds, whereas no acoutically induced spin transport was detected for the n-doped quantum wells. In the GaAs nanowires, we were able of transporting successfully both electrons and holes along the nanowire axis, but no conservation of the spin polarization has been observed until now. The photoluminescence emitted by these structures after acoustic transport, however, shows anti-bunching characteristics, making this system a very good candidate for its use as single photon emitters.

Neuron-to-neuron wild-type Tau protein transfer through a trans-synaptic mechanism: relevance to sporadic tauopathies.

BACKGROUND: In sporadic Tauopathies, neurofibrillary degeneration (NFD) is characterised by the intraneuronal aggregation of wild-type Tau proteins. In the human brain, the hierarchical pathways of this neurodegeneration have been well established in Alzheimer's disease (AD) and other sporadic tauopathies such as argyrophilic grain disorder and progressive supranuclear palsy but the molecular and cellular mechanisms supporting this progression are yet not known. These pathways appear to be associated with the intercellular transmission of pathology, as recently suggested in Tau transgenic mice. However, these conclusions remain ill-defined due to a lack of toxicity data and difficulties associated with the use of mutant Tau. RESULTS: Using a lentiviral-mediated rat model of hippocampal NFD, we demonstrated that wild-type human Tau protein is axonally transferred from ventral hippocampus neurons to connected secondary neurons even at distant brain areas such as olfactory and limbic systems indicating a trans-synaptic protein transfer. Using different immunological tools to follow phospho-Tau species, it was clear that Tau pathology generated using mutated Tau remains near the IS whereas it spreads much further using the wild-type one. CONCLUSION: Taken together, these results support a novel mechanism for Tau protein transfer compared to previous reports based on transgenic models with mutant cDNA. It also demonstrates that mutant Tau proteins are not suitable for the development of experimental models helpful to validate therapeutic intervention interfering with Tau spreading.

Exogenous mRNA delivery and bioavailability in gene transfer mediated by piggyBac transposition.

BACKGROUND: Up to now, the different uptake pathways and the subsequent intracellular trafficking of plasmid DNA have been largely explored. By contrast, the mode of internalization and the intracellular routing of an exogenous mRNA in transfected cells are poorly investigated and remain to be elucidated. The bioavailability of internalized mRNA depends on its intracellular routing and its potential accumulation in dynamic sorting sites for storage: stress granules and processing bodies. This question is of particular significance when a secure transposon-based system able to integrate a therapeutic transgene into the genome is used. Transposon vectors usually require two components: a plasmid DNA, carrying the gene of interest, and a source of transposase allowing the integration of the transgene. The principal drawback is the lasting presence of the transposase, which could remobilize the transgene once it has been inserted. Our study focused on the pharmacokinetics of the transposition process mediated by the piggyBac transposase mRNA transfection. Exogenous mRNA internalization and trafficking were investigated towards a better apprehension and fine control of the piggyBac transposase bioavailability. RESULTS: The mRNA prototype designed in this study provides a very narrow expression window of transposase, which allows high efficiency transposition with no cytotoxicity. Our data reveal that exogenous transposase mRNA enters cells by clathrin and caveolae-mediated endocytosis, before finishing in late endosomes 3 h after transfection. At this point, the mRNA is dissociated from its carrier and localized in stress granules, but not in cytoplasmic processing bodies. Some weaker signals have been observed in stress granules at 18 h and 48 h without causing prolonged production of the transposase. So, we designed an mRNA that is efficiently translated with a peak of transposase production 18 h post-transfection without additional release of the molecule. This confines the integration of the transgene in a very small time window. CONCLUSION: Our results shed light on processes of exogenous mRNA trafficking, which are crucial to estimate the mRNA bioavailability, and increase the biosafety of transgene integration mediated by transposition. This approach provides a new way for limiting the transgene copy in the genome and their remobilization by mRNA engineering and trafficking.

CAV2 vector gene transfer into central nervious System

Estudi realitzat a partir d’una estada al Institut de Génétique Moléculaire de Montpellier, França, entre 2010 i 2012. En aquest projecte s’ha avaluat les avantatges dels vectors adenovirals canins tipus 2 (CAV2) com a vectors de transferència gènica al sistema nerviós central (SNC) en un model primat no-humà i en un model caní del síndrome de Sly (mucopolisacaridosis tipus 7, MPS VII), malaltia monogènica que cursa amb neurodegeneració. En una primera part del projecte s’ha avaluat la biodistribució, l’eficàcia i la durada de l’expressió del transgen en un model primat no humà, (Microcebus murinus). Com ha vector s’ha utilitzat un CAV2 de primera generació que expressa la proteïna verda fluorescent (CAVGFP). Els resultats aportats en aquesta memòria demostren que en primats no humans, com en d’altres espècies testades anteriorment per l’equip de l’EJ Kremer, la injecció intracerebral de CAV2 resulta en una extensa transducció del SNC, siguent les neurones i els precursors neuronals les cèl•lules preferencialment transduïdes. Els vectors canins, servint-se de vesícules intracel•lulars són transportats, majoritàriament, des de les sinapsis cap al soma neuronal, aquest transport intracel•lular permet una extensa transducció del SNC a partir d’una única injecció intracerebral dels vectors virals. En una segona part d’aquest projecte s’ha avaluat l’ús terapèutic dels CAV2. S’ha injectat un vector helper-dependent que expressa el gen la b-glucuronidasa i el gen de la proteïna verda fluorescent (HD-RIGIE), en el SNC del model caní del síndrome de Sly (MPS VII). La biodistribució i la eficàcia terapèutica han estat avaluades. Els nivells d’activitat enzimàtica en animals malalts injectats amb el vector terapèutic va arribar a valors similars als dels animals no afectes. A més a més s’ha observat una reducció en la quantitat dels GAGs acumulats en les cèl•lules dels animals malalts tractats amb el vector terapèutic, demostrant la potencialitat terapèutica dels CAV2 per a malalties que afecten al SNC. Els resultats aportats en aquest treball ens permeten dir que els CAV2 són unes bones eines terapèutiques per al tractament de malalties que afecten al SNC.

Image en fluorescence en endoscopie: contribution dans la prise en charge des tumeurs de vessie [Fluorescence guided endoscopy: improvement in the management of bladder cancer].

White-light cystoscopy and cytology are the standard tools to diagnose bladder cancer. White-light cystoscopy is excellent to detect macroscopic exophytic tumors, but its sensitivity is poor for flat tumors such as carcinoma in situ. Use of fluorescence cystoscopy during transurethral bladder resection improve tumor detection, particulary for carcinoma in situ. Fluorescence cystoscopy reduce residual tumor rate, especially for voluminous and multifocal tumors with consecutive lower recurrence. Fluorescence is now recommended to diagnose and treat bladder cancer.

Allergie alimentaire chez l'enfant: quelle prise en charge en 2011 [Food allergy in children: anything new in its management?].

The prevalence of food allergy in children is increasing, in particular in its most severe presentation, i.e. anaphylaxis. Food allergy has an important impact on children's and their parent's quality of life, because of the fear of accidental ingestion and limitations of social activities. Quality of life questionnaires adapted to food allergy are now available, as well as new diagnostic procedures using recombinant technology. Their interpretation and their clinical correlation remain difficult, especially in children, in the absence of references values. Various oral and subcutaneous immunotherapy strategies are currently under evaluation, using modified or native allergens.

Evaluating thermal treeline indicators based on air and soil temperature using an air-to-soil temperature transfer model

In recent research, both soil (root-zone) and air temperature have been used as predictors for the treeline position worldwide. In this study, we intended to (a) test the proposed temperature limitation at the treeline, and (b) investigate effects of season length for both heat sum and mean temperature variables in the Swiss Alps. As soil temperature data are available for a limited number of sites only, we developed an air-to-soil transfer model (ASTRAMO). The air-to-soil transfer model predicts daily mean root-zone temperatures (10cm below the surface) at the treeline exclusively from daily mean air temperatures. The model using calibrated air and root-zone temperature measurements at nine treeline sites in the Swiss Alps incorporates time lags to account for the damping effect between air and soil temperatures as well as the temporal autocorrelations typical for such chronological data sets. Based on the measured and modeled root-zone temperatures we analyzed. the suitability of the thermal treeline indicators seasonal mean and degree-days to describe the Alpine treeline position. The root-zone indicators were then compared to the respective indicators based on measured air temperatures, with all indicators calculated for two different indicator period lengths. For both temperature types (root-zone and air) and both indicator periods, seasonal mean temperature was the indicator with the lowest variation across all treeline sites. The resulting indicator values were 7.0 degrees C +/- 0.4 SD (short indicator period), respectively 7.1 degrees C +/- 0.5 SD (long indicator period) for root-zone temperature, and 8.0 degrees C +/- 0.6 SD (short indicator period), respectively 8.8 degrees C +/- 0.8 SD (long indicator period) for air temperature. Generally, a higher variation was found for all air based treeline indicators when compared to the root-zone temperature indicators. Despite this, we showed that treeline indicators calculated from both air and root-zone temperatures can be used to describe the Alpine treeline position.

Technology Transfer of As-Built and Preliminary Surveys Using GPS, Soft Photogrammetry, and Video Logging, 2002

This research involved two studies: one to determine the local geoid to obtain mean sea level elevation from a global positioning system (GPS) to an accuracy of ±2 cm, and the other to determine the location of roadside features such as mile posts and stop signs for safety studies, geographic information systems (GIS), and maintenance applications, from video imageries collected by a van traveling at traffic speed.

Use of a short hPDE6b promoter for rod gene transfer in a model of severe retinal cystrophy, the Rd10 mouse

Purpose: Gene therapy of severe retinal dystrophies directly affecting photoreceptor is still a challenge in terms of clinical application. One of the main hurdles is to generate high transgene expression specifically in rods or cones. In the present study, we are investigating the possibility to drive hPDE6b expression in the Rd10 mouse retina using a specific sequence of the human PDE6b promoter. Methods: Two 5' flanking fragments of the human PDE6b gene: (-93 to +53 (146 bp) and -297 to +53 (350 bp, see Di Polo and Farber, 1995) were cloned in different plasmids in order to check their expression in vitro and in vivo. These elements drove the activity of either luciferase (pGL3 plasmids) or EGFP (AAV2/8 backbone). Then, an AAV2/8 vector carrying the PDE6b cDNA was tested with subretinal injections at P9 in the Rd10 eyes. Eye fundus, OCT, ERG recordings and histological investigations were performed to assess the efficacy of the gene transfer. Results: The short PDE6b promoter containing 146bp (-93 to +53) showed the highest activity in the Y-79 cells, as described previously (Di Polo and Farber, 1995). Subretinal administrations of AAV2/8-PDE6bpromoter-EGFP allowed a rapid expression specifically in rods and not in cones. The expression is faster than a vector containing the CMV promoter. The AAV2/8-PDE6bpromoter-PDE6b and the control vector were injected at P9 in the Rd10 mouse retina and investigated 5 weeks post-injection. Out of 14 eyes, 6 presented an increased rod sensitivity of about 300 fold, and increased a- and b-wave responses in ERG recordings. Flicker stimulations revealed that cones are also functional. OCT images and histological analyses revealed an increased ONL size in the injected area. The retina treated with the therapeutic vector presented 4-6 rows of photoreceptors with outersegments containing PDE6b. In the control eyes, only 2-4 rows of photoreceptors with almost no OS were observed . Conclusions: The 146 bp promoter sequence (-93 to + 53) is the shortest regulatory element described to date which allows to obtain efficient rod-specific expression in the context of somatic gene transfer. This first result is of great interest for AAV vector design in general allowing more space for the accommodation of transgenes of interest and good expression in rods. Moreover we showed the proof of principle of the efficacy of AAV2/8-PDE6bp-PDE6b vector in the Rd10 mouse model of severe photoreceptor degeneration without using neither AAV mutated capsids, nor self-complementary vectors.

Les sinusites d'origine dentaire: diagnostic et prise en charge [Diagnosis and management of sinusitis of odontogenic origin]

Les sinusites maxillaires sont des infections fréquentes de la sphère ORL. On retrouve une étiologie dentaire dans environ 10% des cas. L'extension des infections dentaires dans le sinus maxillaire est possible en raison de la proximité des racines des dents postérieures avec le bas fond sinusien. Une source odontogène doit être suspectée chez les patients ayant une anamnèse de douleur ou d'infection dentaires, de soins dentaires récents et qui présentent une sinusite unilatérale prolongée ou résistant à un traitement conservateur habituel. Les infections d'origine dentaire possèdent une flore bactérienne mixte. Le diagnostic et la prise en charge nécessitent un bilan radiologique précis. Le traitement doit prendre en charge conjointement la cause dentaire et la sinusite. Un geste chirurgical peut être indiqué dans un deuxième temps afin de restaurer la fonction sinusienne. Maxillary sinusitis are common infections. A dental origin is found in about 10% of the cases. The roots of the posterior maxillary teeth are adjacent to the sinus floor. Extensions of dental infections are therefore possible to the sinus. An odontogenic source should be considered in patients with a history of dental pain or recent oral surgery and those with extended unilateral sinusitis or unilateral sinusitis resistant to conventional treatment. Maxillary sinusitis of dental origin are polymicrobial infections. Conventional radiographs and CT-scans are required for the diagnosis and proper management. Dental treatments to remove the underlying cause combined with oral antibiotics to treat the infection are required. Endoscopic or open surgery may be necessary to complete the treatment and restore adequate sinusal function.

Technology transfer of an oil-in-water vaccine-adjuvant for strengthening pandemic influenza preparedness in Indonesia.

With the current enzootic circulation of highly pathogenic avian influenza viruses, the ability to increase global pandemic influenza vaccine production capacity is of paramount importance. This has been highlighted by, and is one of the main pillars of, the WHO Global Action Plan for Influenza Vaccines (GAP). Such capacity expansion is especially relevant in developing countries. The Vaccine Formulation Laboratory at University of Lausanne is engaged in the technology transfer of an antigen-sparing oil-in-water adjuvant in order to empower developing countries vaccine manufacturers to increase pandemic influenza vaccine capacity. In a one-year project funded by United States Department of Health and Human Services, the Vaccine Formulation Laboratory transferred the process know-how and associated equipment for the pilot-scale manufacturing of an oil-in-water adjuvant to Bio Farma, Indonesia's state-owned vaccine manufacturer, for subsequent formulation with H5N1 pandemic influenza vaccines. This paper describes the experience acquired and lessons learnt from this technology transfer project.