AURKA mRNA expression is an independent predictor of poor prognosis in patients with non-small cell lung cancer

Deregulation of mitotic spindle genes has been reported to contribute to the development and progression of malignant tumours. The aim of the present study was to explore the association between the expression profiles of Aurora kinases (AURKA, AURKB and AURKC), cytoskeleton-associated protein 5 (CKAP5), discs large-associated protein 5 (DLGAP5), kinesin-like protein 11 (KIF11), microtubule nucleation factor (TPX2), monopolar spindle 1 kinase (TTK), and β-tubulins (TUBB) and (TUBB3) genes and clinicopathological characteristics in human non-small cell lung carcinoma (NSCLC). Reverse transcription-quantitative polymerase chain reaction-based RNA gene expression profiles of 132 NSCLC and 44 adjacent wild-type tissues were generated, and Cox's proportional hazard regression was used to examine associations. With the exception of AURKC, all genes exhibited increased expression in NSCLC tissues. Of the 10 genes examined, only AURKA was significantly associated with prognosis in NSCLC. Multivariate Cox's regression analysis demonstrated that AURKA mRNA expression [hazard ratio (HR), 1.81; 95% confidence interval (CI), 1.16-2.84; P=0.009], age (HR, 1.03; 95% CI, 1.00-1.06; P=0.020), pathological tumour stage 2 (HR, 2.43; 95% CI, 1.16-5.10; P=0.019) and involvement of distal nodes (pathological node stage 2) (HR, 3.14; 95% CI, 1.24-7.99; P=0.016) were independent predictors of poor prognosis in patients with NSCLC. Poor prognosis of patients with increased AURKA expression suggests that those patients may benefit from surrogate therapy with AURKA inhibitors

Heterogeneity of PD-L1 expression in non-small cell lung cancer: Implications for specimen sampling in predicting treatment response

© 2019 The Authors Objectives: PD-L1 expression on tumour cells can guide the use of anti-PD-1/PD-L1 immune modulators to treat patients with non-small cell lung cancer (NSCLC). Heterogeneity of PD-L1 expression both within and between tumour sites is a well-documented phenomenon that compromises its predictive power. Our aim was to better characterise the pattern and extent of PD-L1 heterogeneity with a view to optimising tumour sampling and improve its accuracy as a biomarker. Materials and methods: Expression of PD-L1 was assessed by immunochemistry using the SP263 clone in 107 resected primary NSCLCs and their nodal metastases. Intra-tumoural heterogeneity, defined as ‘small-scale’ (mm²), ‘medium-scale’ (cm²) and ‘large-scale’ (between tumour blocks), was assessed by digital imaging using a novel ‘squares method’. Inter-tumoural heterogeneity between the primary tumours and their nodal metastases and between N1 and N2 nodal stages was also assessed. Results: The majority of tumours demonstrated intra-tumoural heterogeneity (small-scale 78%, medium-scale 50%, large-scale 46%). Inter-tumoural heterogeneity between the primary and nodal metastases was present in 53% of cases and, in 17%, between N1 and N2 disease. These differences were occasionally sufficient to lead to discrepancy across the ≥1%, ≥25% and ≥50% cut-offs used to guide therapy. Conclusion: Heterogeneity of PD-L1 expression is common, variable in scale and extent, and carries significant implications for its accuracy as a predictive biomarker. Extensive sampling reduces, but cannot eliminate, this inaccuracy

Lung cancer mortality reduction by LDCT screening: UKLS randomised trial results and international meta-analysis

Background: The NLST reported a significant 20% reduction in lung cancer mortality with three annual low-dose CT (LDCT) screens and the Dutch-Belgian NELSON trial indicates a similar reduction. We present the results of the UKLS trial. Methods: From October 2011 to February 2013, we randomly allocated 4 055 participants to either a single invitation to screening with LDCT or to no screening (usual care). Eligible participants (aged 50-75) had a risk score (LLPv2) ≥ 4.5% of developing lung cancer over five years. Data were collected on lung cancer cases to 31 December 2019 and deaths to 29 February 2020 through linkage to national registries. The primary outcome was mortality due to lung cancer. We included our results in a random-effects meta-analysis to provide a synthesis of the latest randomised trial evidence. Findings: 1 987 participants in the intervention and 1 981 in the usual care arms were followed for a median of 7.3 years (IQR 7.1-7.6), 86 cancers were diagnosed in the LDCT arm and 75 in the control arm. 30 lung cancer deaths were reported in the screening arm, 46 in the control arm, (relative rate 0.65 [95% CI 0.41-1.02]; p=0.062). The meta-analysis indicated a significant reduction in lung cancer mortality with a pooled overall relative rate of 0.84 (95% CI 0.76-0.92) from nine eligible trials. Interpretation: The UKLS trial of single LDCT indicates a reduction of lung cancer death of similar magnitude to the NELSON and NLST trials and was included in a meta-analysis of nine randomised trials which provides unequivocal support for lung cancer screening in identified risk groups. Funding: NIHR Health Technology Assessment programme; NIHR Policy Research programme; Roy Castle Lung Cancer Foundation

Lung cancer mortality reduction by LDCT screening: UKLS randomised trial results and international meta-analysis.

Background: The NLST reported a significant 20% reduction in lung cancer mortality with three annual low-dose CT (LDCT) screens and the Dutch-Belgian NELSON trial indicates a similar reduction. We present the results of the UKLS trial. Methods: From October 2011 to February 2013, we randomly allocated 4 055 participants to either a single invitation to screening with LDCT or to no screening (usual care). Eligible participants (aged 50-75) had a risk score (LLPv2) ≥ 4.5% of developing lung cancer over five years. Data were collected on lung cancer cases to 31 December 2019 and deaths to 29 February 2020 through linkage to national registries. The primary outcome was mortality due to lung cancer. We included our results in a random-effects meta-analysis to provide a synthesis of the latest randomised trial evidence. Findings: 1 987 participants in the intervention and 1 981 in the usual care arms were followed for a median of 7.3 years (IQR 7.1-7.6), 86 cancers were diagnosed in the LDCT arm and 75 in the control arm. 30 lung cancer deaths were reported in the screening arm, 46 in the control arm, (relative rate 0.65 [95% CI 0.41-1.02]; p=0.062). The meta-analysis indicated a significant reduction in lung cancer mortality with a pooled overall relative rate of 0.84 (95% CI 0.76-0.92) from nine eligible trials. Interpretation: The UKLS trial of single LDCT indicates a reduction of lung cancer death of similar magnitude to the NELSON and NLST trials and was included in a meta-analysis of nine randomised trials which provides unequivocal support for lung cancer screening in identified risk groups. Funding: NIHR Health Technology Assessment programme; NIHR Policy Research programme; Roy Castle Lung Cancer Foundation

The estrogen receptor-α A908G (K303R) mutation occurs at a low frequency in invasive breast tumors: results from a population-based study

INTRODUCTION: Evidence suggests that alterations in estrogen signaling pathways, including estrogen receptor-α (ER-α), occur during breast cancer development. A point mutation in ER-α (nucleotide A908G), producing an amino acid change from lysine to arginine at codon 303 (K303R) results in receptor hypersensitivity to estrogen. This mutation was initially reported in one-third of hyperplastic benign breast lesions, although several recent studies failed to detect it in benign or malignant breast tissues. METHODS: We screened 653 microdissected, newly diagnosed invasive breast tumors from patients in the Carolina Breast Cancer Study, a population-based case-control study of breast cancer in African American and white women in North Carolina, for the presence of the ER-α A908G mutation by using single-strand conformational polymorphism (SSCP) analysis and (33)P-cycle sequencing. RESULTS: We detected the ER-α A908G mutation in 37 of 653 (5.7%) breast tumors. The absence of this mutation in germline DNA confirmed it to be somatic. Three tumors exhibited only the mutant G base at nucleotide 908 on sequencing, indicating that the wild-type ER-α allele had been lost. The ER-α A908G mutation was found more frequently in higher-grade breast tumors (odds ratio (OR) 2.83; 95% confidence interval (CI) 1.09 to 7.34, grade II compared with grade I), and in mixed lobular/ductal tumors (OR 2.10; 95% CI 0.86 to 5.12) compared with ductal carcinomas, although the latter finding was not statistically significant. CONCLUSION: This population-based study, the largest so far to screen for the ER-α A908G mutation in breast cancer, confirms the presence of the mutant in invasive breast tumors. The mutation was associated with higher tumor grade and mixed lobular/ductal breast tumor histology

Managing change in complex projects: configuration management, asset information and big data

As we enter an era of ‘big data’, asset information is becoming a deliverable of complex projects. Prior research suggests digital technologies enable rapid, flexible forms of project organizing. This research analyses practices of managing change in Airbus, CERN and Crossrail, through desk-based review, interviews, visits and a cross-case workshop. These organizations deliver complex projects, rely on digital technologies to manage large data-sets; and use configuration management, a systems engineering approach with mid-20th century origins, to establish and maintain integrity. In them, configuration management has become more, rather than less, important. Asset information is structured, with change managed through digital systems, using relatively hierarchical, asynchronous and sequential processes. The paper contributes by uncovering limits to flexibility in complex projects where integrity is important. Challenges of managing change are discussed, considering the evolving nature of configuration management; potential use of analytics on complex projects; and implications for research and practice

Addressing Criticisms of Large-Scale Marine Protected Areas

Designated large-scale marine protected areas (LSMPAs, 100,000 or more square kilometers) constitute over two-thirds of the approximately 6.6% of the ocean and approximately 14.5% of the exclusive economic zones within marine protected areas. Although LSMPAs have received support among scientists and conservation bodies for wilderness protection, regional ecological connectivity, and improving resilience to climate change, there are also concerns. We identified 10 common criticisms of LSMPAs along three themes: (1) placement, governance, and management; (2) political expediency; and (3) social–ecological value and cost. Through critical evaluation of scientific evidence, we discuss the value, achievements, challenges, and potential of LSMPAs in these arenas. We conclude that although some criticisms are valid and need addressing, none pertain exclusively to LSMPAs, and many involve challenges ubiquitous in management. We argue that LSMPAs are an important component of a diversified management portfolio that tempers potential losses, hedges against uncertainty, and enhances the probability of achieving sustainably managed oceans

Global dynamic topography observations reveal limited influence of large-scale mantle flow

Convective circulation of the Earth’s mantle maintains some fraction of surface topography that varies with space and time. Most predictive models show that this dynamic topography has peak amplitudes of about ±2 km, dominated by wavelengths of 104 km. Here, we test these models against our comprehensive observational database of 2,120 spot measurements of dynamic topography that were determined by analysing oceanic seismic surveys. These accurate measurements have typical peak amplitudes of ±1 km and wavelengths of approximately 103 km, and are combined with limited continental constraints to generate a global spherical harmonic model, the robustness of which has been carefully tested and benchmarked. Our power spectral analysis reveals significant discrepancies between observed and predicted dynamic topography. At longer wavelengths (such as 104 km), observed dynamic topography has peak amplitudes of about ±500 m. At shorter wavelengths (such as 103 km), significant dynamic topography is still observed. We show that these discrepancies can be explained if short-wavelength dynamic topography is generated by temperature-driven density anomalies within a sub-plate asthenospheric channel. Stratigraphic observations from adjacent continental margins show that these dynamic topographic signals evolve quickly with time. More rapid temporal and spatial changes in vertical displacement of the Earth’s surface have direct consequences for fields as diverse as mantle flow, oceanic circulation and long-term climate change.This research was supported by a BP-Cambridge collaboration. We are grateful to ION for permission to publish partial seismic reflection profiles shown in Fig. 2 from their IndiaSPAN and Greater BrasilSPAN data sets