Development and clinical validation of a blood test based on 29-gene expression for early detection of colorectal cancer

A blood test for colorectal cancer (CRC) screening is a valuable tool to for testing asymptomatic individuals and reducing CRC-related mortality. The objective of this study was to develop and validate a novel blood test able to differentiate patients with CRC and adenomatous polyps (AP) from individuals with a negative colonoscopy. Experimental Design: A case-control, multicenter clinical study was designed to collect blood samples from patients referred for colonoscopy or surgery. Predictive algorithms were developed on 75 controls, 61 large AP (LAP) {greater than or equal to}1cm, 45 CRC, and independently validated on 74 controls, 42 LAP, 52 CRC (23 Stages I-II) as well as on 245 cases including other colorectal findings and diseases other than CRC. The test is based on a 29-gene panel expressed in peripheral blood mononuclear cells alone or in combination with established plasma tumor markers. Results: The 29-gene algorithm detected CRC and LAP with a sensitivity of 79.5% and 55.4%, respectively, with 90.0% specificity. Combination with the protein tumor markers CEA and CYFRA21-2 resulted in a specificity increase (92.2%) with a sensitivity for CRC and LAP detection of 78.1% and 52.3%, respectively. Conclusions: We report the validation of a novel blood test, Colox®, for the detection of CRC and LAP based on a 29-gene panel and the CEA and CYFRA21-1 plasma biomarkers. The performance and convenience of this routine blood test provides physicians a useful tool to test average risk individuals unwilling to undergo upfront colonoscopy

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Statut viral et immunité muqueuse (des marqueurs prédictifs de l'histoire naturelle des lésions cervicales associées aux HPV)

Le cancer du col de l'utérus demeure un problème majeur de santé publique, car il est le second cancer féminin au monde. Ce sont des virus, les papillomavirus humains (HPV) - et en particulier ceux appartenant aux génotypes à haut risque - qui sont responsables de l'apparition des lésions précancéreuses et cancéreuses du col utérin. Depuis la fin des années 80, le développement de la biologie moléculaire a permis la détection et l'étude de ce virus, apportant une approche supplémentaire dans la prévention de cette pathologie. La détection de cette infection à l'aide de tests validés cliniquement, est une méthode plus sensible et plus reproductible que la cytologie cervico-utérine dans le cadre du dépistage. Si la présence du virus est nécessaire, elle n'est pas suffisante au développement d'un cancer, et de nombreux facteurs liés à l'environnement, à l'hôte ou au virus vont influencer la persistance d'HPV au sein de la cellule. De ce fait, l'histoire naturelle de l'infection est aujourd'hui encore décrite de façon limitée et les relations entre l'hôte et le pathogène ne sont pas clairement comprises. C'est dans ce contexte que mon travail de thèse s'inscrit. - Nous avons montré la nécessité de la validation des performances d'un test de détection des HPV afin de proposer un outil supplémentaire pour le dépistage des lésions cervicales précancéreuses. Nous avons ensuite étudié des facteurs viraux influençant la persistance de l'infection. Après le développement de technique de quantification de l'HPV16 par PCR en temps réel, nous avons confirmé que le test de routine Hybrid Capture® Il fournissait des résultats pouvant être considéré comme quantitatifs. Par ailleurs, nous avons défini une valeur seuil de charge virale HPV16 de 200 copies pour 1 000 cellules comme étant cliniquement relevante, et nous avons aussi montré que l'évolution de la charge virale entre deux points de suivi pouvait constituer un élément prédictif de l'apparition des lésions précurseurs. Ces résultats nous ont permis de caractériser les infections relevantes des infections non relevantes sans pour autant connaître à quel instant de l'histoire naturelle de la pathologie se trouvaient les patientes. Nous avons montré aussi que le taux d'intégration du génome d'HPV16 dans celui de la cellule hôte constitue un marqueur de malignité de la lésion, car une augmentation de ce taux est observée avec l'augmentation du grade des lésions. De plus, des profils de taux d'intégration en fonction de la charge virale sont caractéristiques des lésions, ce qui semble montrer le lien ente ces deux facteurs, et montrer que de fortes CV pourraient induire une plus forte probabilité d'intégration. Le facteur immunitaire s'avère déterminant dans l'évolution de ces infections, et nous avons montré qu'une accumulation de cellules immunitaires de type CD4+ accompagne la régression des lésions. Inversement, la diminution du ratio CD4+/CD8+ pourrait constituer un marqueur de mauvais pronostic. Ces résultats suggèrent une défaillance probable de la réponse cellulaire dans les cancers. En revanche, l'induction d'une réponse humorale par la vaccination prophylactique anti-HPV est efficace contre le développement des lésions précurseurs, et nous avons montré qu'un vaccin dirigé contre les types 16 et 18 pourrait cibler près de 70% des lésions précurseurs et de plus de 80% des cancers en France. - La mise en évidence et l'étude de ces facteurs restent actuellement les meilleurs moyens de comprendre cette pathologie complexe qu'est le cancer du col de l'utérus, et d'améliorer ainsi la prise en charge des patientes qui échapperont à la vaccination prophylactique.Cervical cancer remains a major problem of public health, because it is the second female cancer. Human papillomavirus (HPV) and in particular from high risk genotypes are responsible for the appearance of the precancerous and cancerous lesions of the uterine cervix. Since the end Eighties, the development of molecular biology allowed the detection and the study of these viruses, providing an additional approach prevention of this patllology. Detection of this infection with clinically valid test is a more sensitive and a more reproducible method than cytology for the screening. If HPV are necessary, they are not sufficient to induce cervical cancer development, and many factors related to the environment, the host or the virus will influence the persistence of HPV infection. So the natural history of the infection is still today described in a limited way and the relations between the host and the pathogenic are not clearly understood, and it is in this context that my PhD is registered . - We showed the necessity to validate performances of an HPV detection test in order to propose an additional tool for the screening of cervical precancerous lesions. Using adapted methodologies, we studied viral factors influencing persistence of the infection. We defined a HPV16 viral load threshold value of 200 copies for 1 000 cells and we showed this value was clinically relevant. Moreover, the viral load evolution between two points of follow-up could constitute a predictive factor for the appearance of precursor lesions. These results enabled us to characterize relevant relevant infections. We also showed that the viral genome integration percentage constitutes a marker of malignity. Indeed, an increase in this rate is linked to the grade of the lesion. Moreover, profiles of integration percentage according to the viral load are characteristics of the lesions, and seem to show the link between these two factors. Thus, be hypothesized that high viral loads could induce a stronger probability of integration. The immune response proves to be determining for the infection evolution, and we showed an accumulation of CD4+ immune cells accompanying lesions potential of regression. Conversely, the decrease of the CD4+/CD8+ ratio could constitute a bad prognostic marker. These results suggest a probable failure of the cellular immune response in cancers. On the other hand, the induction of a humoral response by anti-HPV prophylactic vaccin is efficient against the development of the precursor lesions, and we showed that a vaccine directed against types 16 and 18 could target near 70% of precursors lesions and more than 80% of cancers in France. - The description and the study of these factors remain currently the best means of understanding this complex pathology, and improving the management of the patients who will escape prophylactic vaccination.BESANCON-BU Médecine pharmacie (250562102) / SudocSudocFranceF

[Vaccination against human papillomavirus infections]

International audienceThe aim of vaccination against human papillomaviruses is to fight against benign lesions as well as cancers. Two vaccine strategies have been developed: therapeutic vaccines that induce cytotoxic T cells with the ability to eliminate infected/tumoral cells, and prophylactic vaccines that induce the production of neutralizing antibodies preventing HPV to infect their target cells. While the therapeutic strategies give good results in mouse model, their efficiency in human remains to be demonstrated. In contrast, data regarding prophylactic vaccines, already promising in animal models, show a significant benefit as no HPV16 nor 18 associated high grade lesions of the cervix occurred in vaccinated subjects participating to ongoing clinical trials. Who is going to vaccinate? What is the best target population to vaccinate, at which age? With or without a booster? And what about developing countries? Several issues remain to be addressed for an efficient implementation of HPV vaccination