Chest CT scan plus x-ray versus chest x-ray for the follow-up of completely resected non-small-cell lung cancer (IFCT-0302): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Even after resection of early-stage non-small-cell lung cancer (NSCLC), patients have a high risk of developing recurrence and second primary lung cancer. We aimed to assess efficacy of a follow-up approach including clinic visits, chest x-rays, chest CT scans, and fibre-optic bronchoscopy versus clinical visits and chest x-rays after surgery for resectable NSCLC. METHODS: In this multicentre, open-label, randomised, phase 3 trial (IFCT-0302), patients aged 18 years or older and after complete resection of pathological stage I-IIIA NSCLC according to the sixth edition of the TNM classification were enrolled within 8 weeks of resection from 122 hospitals and tertiary centres in France. Patients were randomly assigned (1:1) to CT-based follow-up (clinic visits, chest x-rays, thoraco-abdominal CT scans, and fibre-optic bronchoscopy for non-adenocarcinoma histology) or minimal follow-up (visits and chest x-rays) after surgery for NSCLC, by means of a computer-generated sequence using the minimisation method. Procedures were repeated every 6 months for the first 2 years and yearly until 5 years. The primary endpoint was overall survival analysed in the intention-to-treat population. Secondary endpoints, also analysed in the intention-to-treat population, included disease-free survival. This trial is registered with ClinicalTrials.gov, NCT00198341, and is active, but not enrolling. FINDINGS: Between Jan 3, 2005, and Nov 30, 2012, 1775 patients were enrolled and randomly assigned to a follow-up group (888 patients to the minimal follow-up group; 887 patients to the CT-based follow-up group). Median overall survival was not significantly different between follow-up groups (8·5 years [95% CI 7·4-9·6] in the minimal follow-up group vs 10·3 years [8·1-not reached] in the CT-based follow-up group; adjusted hazard ratio [HR] 0·95, 95% CI 0·83-1·10; log-rank p=0·49). Disease-free survival was not significantly different between follow-up groups (median not reached [95% CI not estimable-not estimable] in the minimal follow-up group vs 4·9 [4·3-not reached] in the CT-based follow-up group; adjusted HR 1·14, 95% CI 0·99-1·30; log-rank p=0·063). Recurrence was detected in 246 (27·7%) of 888 patients in the minimal follow-up group and in 289 (32·6%) patients of 887 in the CT-based follow-up group. Second primary lung cancer was diagnosed in 27 (3·0%) patients in the minimal follow-up group and 40 patients (4·5%) in the CT-based follow-up group. No serious adverse events related to the trial procedures were reported. INTERPRETATION: The addition of thoracic CT scans during follow-up, which included clinic visits and chest x-rays after surgery, did not result in longer survival among patients with NSCLC. However, it did enable the detection of more cases of early recurrence and second primary lung cancer, which are more amenable to curative-intent treatment, supporting the use of CT-based follow-up, especially in countries where lung cancer screening is already implemented, alongside with other supportive measures. FUNDING: French Health Ministry, French National Cancer Institute, Weisbrem-Benenson Foundation, La Ligue Nationale Contre Le Cancer, and Lilly Oncology. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Validity of the TBApp mobile application for self-care management for people with tuberculosis.

OBJECTIVES: to describe the validity process of the TBApp mobile application for self-care management for people with tuberculosis linked to Primary Health Care. METHODS: methodological research developed with ten expert judges, carried out virtually. The application was assessed in relation to content and technology quality in seven domains (objectivity; structure and appearance; relevance; functionality; reliability; usability; and efficiency), using an instrument with a Likert scale. RESULTS: TBApp was considered valid, relevant, functional, reliable and effective by expert judges. The objectives, structure and presentation and relevance domains presented an overall Content Validity Index of 0.93, and the functionality, reliability, usability and efficiency domains presented characteristics and sub-characteristics values greater than 0.80. CONCLUSIONS: TBApp is a creative and innovative tool that can be used by people with TB and disseminated in the scientific community.

Validity of the TBApp mobile application for self-care management for people with tuberculosis / Validación de la aplicación móvil TBApp para la gestión del autocuidado de personas con tuberculosis / Validação do aplicativo móvel TBApp para a gestão do autocuidado de pessoas com tuberculose

ABSTRACT Objectives: to describe the validity process of the TBApp mobile application for self-care management for people with tuberculosis linked to Primary Health Care. Methods: methodological research developed with ten expert judges, carried out virtually. The application was assessed in relation to content and technology quality in seven domains (objectivity; structure and appearance; relevance; functionality; reliability; usability; and efficiency), using an instrument with a Likert scale. Results: TBApp was considered valid, relevant, functional, reliable and effective by expert judges. The objectives, structure and presentation and relevance domains presented an overall Content Validity Index of 0.93, and the functionality, reliability, usability and efficiency domains presented characteristics and sub-characteristics values greater than 0.80. Conclusions: TBApp is a creative and innovative tool that can be used by people with TB and disseminated in the scientific community.

RESUMEN Objetivos: describir el proceso de validación de la aplicación móvil TBApp para la gestión del autocuidado de personas con tuberculosis, vinculada a la atención primaria de salud. Métodos: investigación metodológica desarrollada con diez jueces expertos, realizada de forma virtual. La aplicación fue evaluada en relación con la calidad del contenido y la tecnología en siete dominios (objetividad; estructura y apariencia; relevancia; funcionalidad; fiabilidad; usabilidad; y eficiencia), mediante un instrumento con escala Likert. Resultados: la TBApp fue considerada válida, relevante, funcional, confiable y eficaz por los jueces expertos. Los dominios de objetivos, estructura y presentación y relevancia presentaron un Índice de Validez de Contenido general de 0,93, y los dominios de funcionalidad, confiabilidad, usabilidad y eficiencia presentaron características y subcaracterísticas valores superiores a 0,80. Conclusiones: la TBApp es una herramienta creativa e innovadora que puede ser utilizada por personas con TB y difundida en la comunidad científica.

RESUMO Objetivos: descrever o processo de validação do aplicativo móvel TBApp para a gestão do autocuidado de pessoas com tuberculose vinculadas à Atenção Primária à Saúde. Métodos: pesquisa metodológica, desenvolvida com dez juízes especialistas, realizada por meio virtual. O aplicativo foi avaliado em relação a conteúdo e qualidade da tecnologia, em sete domínios (objetividade; estrutura e aparência; relevância; funcionalidade; confiabilidade; usabilidade; e eficiência), por meio de instrumento com escala tipo Likert. Resultados: o TBApp foi considerado válido, relevante, funcional, confiável e eficaz pelos juízes especialistas. Os domínios de objetivos, estrutura e apresentação e relevância apresentaram Índice de Validade de Conteúdo global de 0,93, e os domínios de funcionalidade, confiabilidade, usabilidade e eficiência apresentaram valores de características e subcaracterísticas maiores que 0,80. Conclusões: o TBApp é uma ferramenta criativa e inovadora, podendo ser utilizado por pessoas com TB e divulgado no meio científico.

Predominant expression of the long isoform of GP130-like (GPL) receptor is required for interleukin-31 signaling.

Gp130-like receptor (GPL) is a newly identified cytokine receptor. A recent study reported the involvement of GPL, together with OSMR, in the formation of the receptor complex for IL-31, a novel immune cytokine with a skin tropism. In the present work, we analyzed the signaling properties of IL-31 in glioblastoma and melanoma tumor cells. We demonstrate that in response to IL-31, its receptor complex recruits Jak1, Jak2, STAT1, -3, -5 signaling pathways, as well as the Pi3 kinase / AKT cascade. SHP-2 and Shc adapter molecules are also recruited and contribute to an increased activation of the MAP kinase pathway in response to IL-31. Different responses were observed depending on the expression of short or long GPL receptor isoform within the studied cell lines. We show that the short form of GPL receptor exerts a profound inhibitory effect on the signaling of IL-31 and behaves as a dominant negative receptor.

Kaposi sarcoma-associated viral cyclin K overrides cell growth inhibition mediated by oncostatin M through STAT3 inhibition.

DNA viruses have evolved a number of mechanisms to inhibit the major cellular tumor-suppressor pathways. Viral oncogenes can override growth suppressive signals and extend the virus proliferative capacity. The Kaposi sarcoma-associated human herpesvirus 8 (KSHV) encodes a protein, cyclin K, that is similar to cellular cyclin D1 but behaves atypically. Cyclin K resists the actions of the p16 INK4a and p27Kip1 inhibitors and extends the range of cdk6 substrates, thereby inducing cell-cycle progression toward S phase. In this study, we show that cyclin K overrides growth suppressive signals through signal transducer and activator of transcription 3 (STAT3) inactivation. Cyclin K was found to associate with the activation domain of STAT3 to inhibit its DNA-binding and transcriptional activities. Overexpression of cyclin K and inhibition of STAT3 prevents the growth suppressive effect imposed by the interleukin 6-type cytokine, oncostatin M. Altogether, these results suggest that KSHV is able to override growth suppressive effects through multiple mechanisms, and they further indicate that cyclin K plays an important role in the oncogenic activity of these viruses.

Functionally active fusion protein of the novel composite cytokine CLC/soluble CNTF receptor.

The heterodimeric cytokine composed of the soluble ciliary neurotrophic factor receptor (sCNTFR) and the IL-6 family member cardiotrophin-like cytokine (CLC) was recently identified as a new ligand for gp130-leukemia inhibitory factor receptor (LIFR) complex [Plun-Favreau, H., Elson, G., Chabbert, M., Froger, J., deLapeyriere, O., Lelievre, E., Guillet, C., Hermann, J., Gauchat, J. F., Gascan, H. & Chevalier, S. (2001) EMBO J. 20, 1692-1703]. This heterodimer shows overlapping biological properties with LIF. Although CLC contains a putative signal peptide and therefore should enter into the classical secretory pathway, the protein has been shown to be retained within transfected mammalian cells, unless coexpressed with either sCNTFR or cytokine like factor (CLF) [Elson, G. C., Lelievre, E., Guillet, C., Chevalier, S., Plun-Favreau, H., Froger, J., Suard, I., de Coignac, A. B., Delneste, Y., Bonnefoy, J. Y., Gauchat, J. F. & Gascan, H. (2000) Nat. Neurosci. 3, 867-872]. In the present study, we demonstrate that a fusion protein comprising CLC covalently coupled through a glycine/serine linker to sCNTFR (CC-FP) is efficiently secreted from transfected mammalian cells. CC-FP shows enhanced activities in respect to the CLC/sCNTFR native complex, on a number of cells expressing gp130 and LIFR on their surface. In addition, CC-FP is able to compete with CNTF for cell binding, indicating that both cytokines share binding epitope(s) expressed by their receptor complex. Analysis of the downstream signaling events revealed the recruitment by CC-FP of the signal transducer and activator of transcription (STAT)-3, Akt and mitogen-activated protein (MAP) kinase pathways. The monomeric bioactive CLC/sCNTFR fusion protein is therefore a powerful tool to study the biological role of the recently described cytokine CLC.

Neuropoietin, a new IL-6-related cytokine signaling through the ciliary neurotrophic factor receptor.

A structural profile-based computational screen was used to identify neuropoietin (NP), a new cytokine. The np gene is localized in tandem with the cardiotrophin-1 gene on mouse chromosome 7. NP shares structural and functional features with ciliary neurotrophic factor (CNTF), cardiotrophin-1, and cardiotrophin-like cytokine. It acts through a membrane receptor complex comprising CNTF receptor-alpha component (CNTFRalpha), gp130, and leukemia inhibitory factor receptor to activate signal transducer and activator of transcription 3 signaling pathway. NP is highly expressed in embryonic neuroepithelia. Strikingly, CNTFRalpha, but not its alternate ligands, CNTF and cardiotrophin-like cytokine, is expressed at the same developmental stages. NP is also observed in retina and to a lesser extent in skeletal muscle. Moreover, NP could sustain the in vitro survival of embryonic motor neurons and could increase the proliferation of neural precursors when associated to epidermal growth factor and fibroblast growth factor 2. Thus, NP is a new ligand for CNTFRalpha, with important implications for murine nervous system development.