Thromboxane A2 receptor (TBXA2R) is a potent survival factor for triple negative breast cancers (TNBCs)

Triple Negative Breast Cancer (TNBC) is defined by the lack of ERα, PR expression and HER2 overexpression and is the breast cancer subtype with the poorest clinical outcomes. Our aim was to identify genes driving TNBC proliferation and/or survival which could represent novel therapeutic targets. We performed microarray profiling of primary TNBCs and generated differential genelists based on clinical outcomes following the chemotherapy regimen FEC (5-Fluorouracil/Epirubicin/Cyclophosphamide -‘good’ outcome no relapse > 3 years; ‘poor’ outcome relapse < 3 years). Elevated expression of thromboxane A2 receptor (TBXA2R) was observed in ‘good’ outcome TNBCs. TBXA2R expression was higher specifically in TNBC cell lines and TBXA2R knockdowns consistently showed dramatic cell killing in TNBC cells. TBXA2R mRNA and promoter activities were up-regulated following BRCA1 knockdown, with c-Myc being required for BRCA1-mediated transcriptional repression. We demonstrated that TBXA2R enhanced TNBC cell migration, invasion and activated Rho signalling, phenotypes which could be reversed using Rho-associated Kinase (ROCK) inhibitors. TBXA2R also protected TNBC cells from DNA damage by negatively regulating reactive oxygen species levels. In summary, TBXA2R is a novel breast cancer-associated gene required for the survival and migratory behaviour of a subset of TNBCs and could provide opportunities to develop novel, more effective treatments

Potential prognostic marker ubiquitin carboxyl-terminal hydrolase-L1 does not predict patient survival in non-small cell lung carcinoma

<p>Abstract</p> <p>Background</p> <p>Ubiquitin Carboxyl-Terminal Hydrolase-L1 (UCH-L1) is a deubiquitinating enzyme that is highly expressed throughout the central and peripheral nervous system and in cells of the diffuse neuroendocrine system. Aberrant function of UCH-L1 has been associated with neurological disorders such as Parkinson's disease and Alzheimer's disease. Moreover, UCH-L1 exhibits a variable expression pattern in cancer, acting either as a tumour suppressor or promoter, depending on the type of cancer. In non-small cell lung carcinoma primary tumour samples, UCH-L1 is highly expressed and is associated with an advanced tumour stage. This suggests UCH-L1 may be involved in oncogenic transformation and tumour invasion in NSCLC. However, the functional significance of UCH-L1 in the progression of NSCLC is unclear. The aim of this study was to investigate the role of UCH-L1 using NSCLC cell line models and to determine if it is clinically relevant as a prognostic marker for advanced stage disease.</p> <p>Methods</p> <p>UCH-L1 expression in NSCLC cell lines H838 and H157 was modulated by siRNA-knockdown, and the phenotypic changes were assessed by flow cytometry, haematoxylin & eosin (H&E) staining and poly (ADP-ribose) polymerase (PARP) cleavage. Metastatic potential was measured by the presence of phosphorylated myosin light chain (MLC2). Tumour microarrays were examined immunohistochemically for UCH-L1 expression. Kaplan-Meier curves were generated using UCH-L1 expression levels and patient survival data extracted from Gene Expression Omnibus data files.</p> <p>Results</p> <p>Expression of UCH-L1 was decreased by siRNA in both cell lines, resulting in increased cell death in H838 adenocarcinoma cells but not in the H157 squamous cell line. However, metastatic potential was reduced in H157 cells. Immunohistochemical staining of UCH-L1 in patient tumours confirmed it was preferentially expressed in squamous cell carcinoma rather than adenocarcinoma. However the Kaplan-Meier curves generated showed no correlation between UCH-L1 expression levels and patient outcome.</p> <p>Conclusions</p> <p>Although UCH-L1 appears to be involved in carcinogenic processes in NSCLC cell lines, the absence of correlation with patient survival indicates that caution is required in the use of UCH-L1 as a potential prognostic marker for advanced stage and metastasis in lung carcinoma.</p

A Learning Approach to Monitoring and Evaluation

This article draws on literature from both monitoring and evaluation (M&amp;E) and organisational learning to explore synergies between these two fields in support of organisational performance. Two insights from the organisational learning literature are that organisations learn through ‘double?loop’ learning: reflecting on experience and using this to question critically underlying assumptions; and that power relations within an organisation will influence what and whose learning is valued and shared. This article identifies four incentives that can help link M&amp;E with organisational learning: the incentive to learn why; the incentive to learn from below; the incentive to learn collaboratively; and the incentive to take risks. Two key elements are required to support these incentives: (1) establishing and promoting an ‘evaluative culture’ within an organisation; and (2) having accountability relationships where value is placed on learning ‘why’, as well as on learning from mistakes, which requires trust

The energy and mass balance of Peruvian glaciers

Peruvian glaciers are important contributors to dry season runoff for agriculture and hydropower, but they are at risk of disappearing due to climate change. We applied a physically based, energy balance melt model at five on-glacier sites within the Peruvian Cordilleras Blanca and Vilcanota. Net shortwave radiation dominates the energy balance, and despite this flux being higher in the dry season, melt rates are lower due to losses from net longwave radiation and the latent heat flux. The sensible heat flux is a relatively small contributor to melt energy. At three of the sites the wet season snowpack was discontinuous, forming and melting within a daily to weekly timescale, and resulting in highly variable melt rates closely related to precipitation dynamics. Cold air temperatures due to a strong La Niña year at Shallap Glacier (Cordillera Blanca) resulted in a continuous wet season snowpack, significantly reducing wet season ablation. Sublimation was most important at the highest site in the accumulation zone of the Quelccaya Ice Cap (Cordillera Vilcanota), accounting for 81% of ablation, compared to 2%–4% for the other sites. Air temperature and precipitation inputs were perturbed to investigate the climate sensitivity of the five glaciers. At the lower sites warmer air temperatures resulted in a switch from snowfall to rain, so that ablation was increased via the decrease in albedo and increase in net shortwave radiation. At the top of Quelccaya Ice Cap warming caused melting to replace sublimation so that ablation increased nonlinearly with air temperature

A future of extreme precipitation and droughts in the Peruvian Andes

Runoff from glacierised Andean river basins is essential for sustaining the livelihoods of millions of people. By running a high-resolution climate model over the two most glacierised regions of Peru we unravel past climatic trends in precipitation and temperature. Future changes are determined from an ensemble of statistically downscaled global climate models. Projections under the high emissions scenario suggest substantial increases in temperature of 3.6 °C and 4.1 °C in the two regions, accompanied by a 12% precipitation increase by the late 21st century. Crucially, significant increases in precipitation extremes (around 75% for total precipitation on very wet days) occur together with an intensification of meteorological droughts caused by increased evapotranspiration. Despite higher precipitation, glacier mass losses are enhanced under both the highest emission and stabilization emission scenarios. Our modelling provides a new projection of combined and contrasting risks, in a region already experiencing rapid environmental change

Quantifying the controls of Peruvian glacier response to climate

Peruvian glaciers are important contributors to dry season runoff for agriculture and hydropower, but they are at risk of disappearing due to climate warming. Their energy balance and ablation characteristics have previously been studied only for individual glaciers, with no comparisons between regions. We applied the physically-based, energy balance melt component of the model Tethys-Chloris at five on-glacier meteorological stations: three in the Cordillera Blanca near Huaraz (with glaciers above ~4300 m a.s.l.), and two in the Cordillera Vilcanota east of Cusco (with glaciers above ~ 4800 m). The climate of these regions is strongly seasonal, with an austral summer wet season and winter dry season. Our results revealed that at most sites the energy available for melt is greatest in the wet season. This is a consequence of the dry season energy losses from the latent heat flux and net longwave radiation which counter-balance the high dry season net shortwave radiation, which otherwise dominates the energy balance. The sensible heat flux is a relatively small contributor to melt energy in both seasons. Comparison of the five sites suggests that there is more energy available for melt at a given elevation in the Cordillera Vilcanota compared to the Cordillera Blanca. At three of the sites the wet season snowpack was discontinuous, forming and melting within a daily to weekly timescale. Albedo and melt are thus highly variable in the wet season and closely related to the precipitation dynamics. At the highest site, in the accumulation zone of the Quelccaya Ice Cap, 81% of ablation was from sublimation. Sublimation was less important at the lower sites, but it reduces dry season melt. Correlation of the NOAA Oceanic El Niño Index (ONI) to the outputs of the two sites with the longest records revealed that the warmer wet season temperatures characteristic of a positive ONI were associated with a decreased albedo, greater net shortwave radiation, a more positive sensible heat flux and increased melt rates. Air temperature and precipitation inputs were also perturbed at all five sites to understand their sensitivity to climate change. Enhanced mass loss was predicted with a static increase of 2°C or more, even with a +30% precipitation increase, with the lower elevation Cordillera Blanca sites at risk of the greatest mass loss due to warming

A Genome-Wide Analysis Reveals No Nuclear Dobzhansky-Muller Pairs of Determinants of Speciation between S. cerevisiae and S. paradoxus, but Suggests More Complex Incompatibilities

The Dobzhansky-Muller (D-M) model of speciation by genic incompatibility is widely accepted as the primary cause of interspecific postzygotic isolation. Since the introduction of this model, there have been theoretical and experimental data supporting the existence of such incompatibilities. However, speciation genes have been largely elusive, with only a handful of candidate genes identified in a few organisms. The Saccharomyces sensu stricto yeasts, which have small genomes and can mate interspecifically to produce sterile hybrids, are thus an ideal model for studying postzygotic isolation. Among them, only a single D-M pair, comprising a mitochondrially targeted product of a nuclear gene and a mitochondrially encoded locus, has been found. Thus far, no D-M pair of nuclear genes has been identified between any sensu stricto yeasts. We report here the first detailed genome-wide analysis of rare meiotic products from an otherwise sterile hybrid and show that no classic D-M pairs of speciation genes exist between the nuclear genomes of the closely related yeasts S. cerevisiae and S. paradoxus. Instead, our analyses suggest that more complex interactions, likely involving multiple loci having weak effects, may be responsible for their post-zygotic separation. The lack of a nuclear encoded classic D-M pair between these two yeasts, yet the existence of multiple loci that may each exert a small effect through complex interactions suggests that initial speciation events might not always be mediated by D-M pairs. An alternative explanation may be that the accumulation of polymorphisms leads to gamete inviability due to the activities of anti-recombination mechanisms and/or incompatibilities between the species' transcriptional and metabolic networks, with no single pair at least initially being responsible for the incompatibility. After such a speciation event, it is possible that one or more D-M pairs might subsequently arise following isolation

Towards advancing scientific knowledge of climate change impacts on short-duration rainfall extremes

A large number of recent studies have aimed at understanding short-duration rainfall extremes, due to their impacts on flash floods, landslides and debris flows and potential for these to worsen with global warming. This has been led in a concerted international effort by the INTENSE Crosscutting Project of the GEWEX (Global Energy and Water Exchanges) Hydroclimatology Panel. Here, we summarize the main findings so far and suggest future directions for research, including: the benefits of convection-permitting climate modelling; towards understanding mechanisms of change; the usefulness of temperature-scaling relations; towards detecting and attributing extreme rainfall change; and the need for international coordination and collaboration. Evidence suggests that the intensity of long-duration (1 day+) heavy precipitation increases with climate warming close to the Clausius–Clapeyron (CC) rate (6–7% K−1), although large-scale circulation changes affect this response regionally. However, rare events can scale at higher rates, and localized heavy short-duration (hourly and sub-hourly) intensities can respond more strongly (e.g. 2 × CC instead of CC). Day-to-day scaling of short-duration intensities supports a higher scaling, with mechanisms proposed for this related to local-scale dynamics of convective storms, but its relevance to climate change is not clear. Uncertainty in changes to precipitation extremes remains and is influenced by many factors, including large-scale circulation, convective storm dynamics andstratification. Despite this, recent research has increased confidence in both the detectability and understanding of changes in various aspects of intense short-duration rainfall. To make further progress, the international coordination of datasets, model experiments and evaluations will be required, with consistent and standardized comparison methods and metrics, and recommendations are made for these frameworks

Impact of meningococcal ACWY conjugate vaccines on pharyngeal carriage in adolescents: evidence for herd protection from the UK MenACWY programme

Objective: Serogroup W and Y invasive meningococcal disease increased globally from 2000 onwards. Responding to a rapid increase in serogroup W clonal complex 11 (W:cc11) invasive meningococcal disease, the UK replaced an adolescent booster dose of meningococcal C conjugate vaccine with quadrivalent MenACWY conjugate vaccine in 2015. By 2018, the vaccine coverage in the eligible school cohorts aged 14 to 19 years was 84%. We assessed the impact of the MenACWY vaccination programme on meningococcal carriage. Methods: An observational study of culture-defined oropharyngeal meningococcal carriage prevalence before and after the start of the MenACWY vaccination programme in UK school students, aged 15 to 19 years, using two cross-sectional studies: 2014 to 2015 “UKMenCar4” and 2018 “Be on the TEAM” (ISRCTN75858406). Results: A total of 10 625 participants preimplementation and 13 434 postimplementation were included. Carriage of genogroups C, W, and Y (combined) decreased from 2.03 to 0.71% (OR 0.34 [95% CI 0.27–0.44], p < 0.001). Carriage of genogroup B meningococci did not change (1.26% vs 1.23% [95% CI 0.77–1.22], p = 0.80) and genogroup C remained rare (n = 7/10 625 vs 17/13 488, p = 0.135). The proportion of serogroup positive isolates (i.e. those expressing capsule) decreased for genogroup W by 53.8% (95% CI –5.0 to 79.8, p = 0.016) and for genogroup Y by 30.1% (95% CI 8.9–46·3, p = 0.0025). Discussion: The UK MenACWY vaccination programme reduced carriage acquisition of genogroup and serogroup Y and W meningococci and sustained low levels of genogroup C carriage. These data support the use of quadrivalent MenACWY conjugate vaccine for indirect (herd) protection