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

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

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

BRCA1 Deficiency Exacerbates Estrogen-Induced DNA Damage and Genomic Instability

Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell cycle arrest and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here we report that estrogen and estrogen metabolites can cause DNA double strand breaks (DSB) in estrogen receptor-α negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability. We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolising enzymes, such as CYP1A1, in breast cells. Lastly, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumours in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types

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

Objectives: Serogroup W and Y invasive meningococcal disease (IMD) increased globally from 2000 onwards. Responding to a rapid increase in serogroup W clonal complex 11 (W:cc11) IMD, the UK replaced an adolescent booster dose of meningococcal C conjugate vaccine with quadrivalent MenACWY conjugate vaccine in 2015. By 2018, vaccine coverage in the eligible school cohorts aged 14-19 years-old 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 15–19 years, using two cross-sectional studies: 2014–15 “UKMenCar4” and 2018 “Be on the TEAM” (ISRCTN75858406). Results: A total of 10625 participants pre-implementation and 13434 post-implementation 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&lt;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 = 7/10625 vs 17/13488, 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%–79.8%, p=0·016) and for genogroup Y by 30·1% (95% CI 8·9%–46·3%, p=0·0025). Conclusions: 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