Molecular classification and survival analysis of late-stage serous ovarian carcinoma

BACKGROUND: Setting a molecular classification for serous ovarian carcinoma from transcriptomic data has been proved to be troublesome due to the high specimen heterogeneity. Consequently, it made difficult the identification of survival prognosis gene markers. In this study, we proposed a tumor classification based on gene expression profiling and we derived a 10-gene survival Cox predictive model. METHODS: We selected eleven clinically-annotated microarray-based gene expression studies conducted in the last decade to collect gene expression values from 1'409 late-stage serous ovarian carcinoma specimens obtained from cytoreductive surgery. The 2'000 genes with the highest expression variability were selected for the analysis. The expression data were batch-harmonized using the method combat and then split into a training set (n=715) and two test sets (n=226 and n=468). The non-negative matrix factorization (NMF) clustering algorithm was used to derive four stable molecular clusters. Subsequently, twenty genes (five per cluster) were selected by penalized generalized linear models (GLMs) to build a predictive subtype classifier. The test set samples were used to validate the classifier. We also selected 10 genes by penalized Cox regressions to build a survival predictive model which performance was evaluated by log-rank tests and C-index computation using the test set samples. All computations and data analyses were conducted in R language. RESULTS: The NMF algorithm yielded four stable subtypes which molecular gene expression features were very similar to the clusters described by TCGA and obtained from a distinct tumor dataset. Thus, we attributed the same names as the TCGA subtypes: Differentiated, Immunoreactive, Mesenchymal and Proliferative. Survival differed significantly between the subtypes (log-rank test p-value of 0.00012) with the best vital prognosis for the Immunoreactive and the worst for the Mesenchymal group. Moreover, we observed 84% of concordance between the subtypes obtained using the NMF algorithm on the 2'000 genes and those using the 20-gene classifier; that supports the possibility to reduce the number of subtype gene markers for further classification systems. The 10-gene multivariable Cox regression survival model allowed segregating significantly good and poor prognosis samples from the largest test set (log-rank test p-value of 0.0002, n=468) and displayed a C-index of 0.543. However, the results on the smallest test set were not significant. Using the survival Cox model, we also identified predictive genes such as CXCL9, SERPINA1 or PTX3 which associated molecular pathways could be involved on cancer progression processes. CONCLUSION: The existence of the serous ovarian carcinoma subtypes previously described by TCGA was confirmed using gene expression profiling on a large multiplatform dataset. Several survival predictive genes and their associated pathways were identified and are valuable candidates for targeted therapies

Learning curves of the Glidescope, the McGrath and the Airtraq laryngoscopes: a manikin study

BACKGROUND AND OBJECTIVE: Several video and optical laryngoscopes have been developed but few have been compared in terms of their learning curves and efficacy. Using a manikin with normal airways we compared the Glidescope, the McGrath, the Airtraq and the Macintosh laryngoscopes. METHODS: Sixty anaesthetists (20 staff, 20 residents and 20 nurses) participated in the study. All subjects were novice with the new devices. They intubated a Laerdal SimMan manikin (with normal airway) five times in a row with all laryngoscopes. The sequence of use of the devices was randomized. Before using a device, a presentation and a demonstration were provided. Outcome measures were: duration of intubation attempt, modified Cormack grades, dental trauma and difficulty of use. RESULTS: The Airtraq had the most favourable learning curve and mirrored the Macintosh after two intubation attempts. The Glidescope and McGrath had steep learning curves but, after five attempts, differences persisted when compared with the Macintosh and Airtraq. Time taken to visualize the glottis was similar but time taken to position the endotracheal tube was shorter for the Airtraq when compared with the Glidescope and McGrath. Indirect laryngoscopes seemed to have advantages over the Macintosh blade in terms of laryngeal exposure and potential dental trauma. CONCLUSIONS: In a 'normal airway' model, intubation skills with the new devices appeared to be rapidly mastered. The three indirect laryngoscopes provided a better glottic exposure than the Macintosh. The Airtraq displayed the most favourable learning curve, probably reflecting differences in the techniques of endotracheal tube placement: guiding channel versus steering technique

Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models

Aggregation of α-synuclein (α-syn) is neuropathologically and genetically linked to Parkinson's disease (PD). Since stereotypic cell-to-cell spreading of α-syn pathology is believed to contribute to disease progression, immunotherapy with antibodies directed against α-syn is considered a promising therapeutic approach for slowing disease progression. Here we report the identification, binding characteristics, and efficacy in PD mouse models of the human-derived α-syn antibody BIIB054, which is currently under investigation in a Phase 2 clinical trial for PD. BIIB054 was generated by screening human memory B-cell libraries from healthy elderly individuals. Epitope mapping studies conducted using peptide scanning, X-ray crystallography, and mutagenesis show that BIIB054 binds to α-syn residues 1-10. BIIB054 is highly selective for aggregated forms of α-syn with at least an 800-fold higher apparent affinity for fibrillar versus monomeric recombinant α-syn and a strong preference for human PD brain tissue. BIIB054 discriminates between monomers and oligomeric/fibrillar forms of α-syn based on high avidity for aggregates, driven by weak monovalent affinity and fast binding kinetics. In efficacy studies in three different mouse models with intracerebrally inoculated preformed α-syn fibrils, BIIB054 treatment attenuated the spreading of α-syn pathology, rescued motor impairments, and reduced the loss of dopamine transporter density in dopaminergic terminals in striatum. The preclinical data reported here provide a compelling rationale for clinical development of BIIB054 for the treatment and prevention of PD