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NKX3.1 is a multifaceted protein with roles in prostate development and protection from oxidative stress. Acting as a pioneer factor, NKX3.1 interacts with chromatin at enhancers to help integrate androgen regulated signalling. In prostate cancer, NKX3.1 activity is frequently reduced through a combination of mutational and post-translational events. Owing to its specificity for prostate tissue, NKX3.1 has found use as an immunohistochemical marker in routine histopathology practice.

Tumour hypoxia is associated with poor patient prognosis and therapy resistance. A unique transcriptional response is initiated by hypoxia which includes the rapid activation of numerous transcription factors in a background of reduced global transcription. Here, we show that the biological response to hypoxia includes the accumulation of R-loops and the induction of the RNA/DNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. Therefore, suggesting that, SETX plays a role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we propose that the mechanism of SETX induction in hypoxia is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to hypoxia, which includes both a replication stress-dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways. Hypoxia induces a change in transcriptional response in mammalian cells. Here the authors reveal a role for the RNA/DNA helicase Senataxin in protecting cells from DNA damage induced during transcription in hypoxia.

Up to 10% of Bladder Cancers may arise following occupational exposure to carcinogens. We hypothesised that different cancer phenotypes reflected different patterns of occupational exposure. Consecutive participants, with bladder cancer, self-completed a structured questionnaire detailing employment, tasks, exposures, smoking, lifestyle and family history. Our primary outcome was association between cancer phenotype and occupational details. We collected questionnaires from 536 patients, of whom 454 (85%) participants (352 men and 102 women) were included. Women were less likely to be smokers (68% vs. 81% Chi sq. p<0.001), but more likely than men to inhale environmental tobacco smoke at home (82% vs. 74% p = 0.08) and use hair dye (56% vs. 3%, p<0.001). Contact with potential carcinogens occurred in 282 (62%) participants (mean 3.1 per worker (range 0-14)). High-grade cancer was more common than low-grade disease in workers from the steel, foundry, metal, engineering and transport industries (p<0.05), and in workers exposed to crack detection dyes, chromium, coal/oil/gas by-products, diesel fumes/fuel/aircraft fuel and solvents (such as trichloroethylene). Higher staged cancers were frequent in workers exposed to Chromium, coal products and diesel exhaust fumes/fuel (p<0.05). Various workers (e.g. exposed to diesel fuels or fumes (Cox, HR 1.97 (95% CI 1.31-2.98) p = 0.001), employed in a garage (HR 2.19 (95% CI 1.31-3.63) p = 0.001), undertaking plumbing/gas fitting/ventilation (HR 2.15 (95% CI 1.15-4.01) p = 0.017), undertaking welding (HR 1.85 (95% CI 1.24-2.77) p = 0.003) and exposed to welding materials (HR 1.92 (95% CI 1.27-2.91) p = 0.002)) were more likely to have disease progression and receive radical treatment than others. Fewer than expected deaths were seen in healthcare workers (HR 0.17 (95% CI 0.04-0.70) p = 0.014). We identified multiple occupational tasks and contacts associated with bladder cancer. There were some associations with phenotype, although our study design precludes robust assessment.

The GUSTO clinical trial (Gene expression subtypes of Urothelial carcinoma: Stratified Treatment and Oncological outcomes) uses molecular subtypes to guide neoadjuvant therapies in participants with muscle‐invasive bladder cancer (MIBC). Before commencing the GUSTO trial, we needed to determine the reliability of a commercial subtyping platform (Decipher Bladder; Veracyte) when performed in an external trial laboratory as this has not been done previously. Here, we report our pre‐trial verification of the TCGA molecular subtyping model using gene expression profiling. Formalin‐fixed paraffin‐embedded tissue blocks of MIBC were used for gene expression subtyping by gene expression microarrays. Intra‐ and inter‐laboratory technical reproducibilities, together with quality control of laboratory and bioinformatics processes, were assessed. Eighteen samples underwent analysis. RNA of sufficient quality and quantity was successfully extracted from all samples. All subtypes were represented in the cohort. Each sample was subtyped twice in our laboratory and once in a separate reference laboratory. No clinically significant discordance in subtype occurred between intra‐ or inter‐laboratory replicates. Examination of sample histopathology showed variability of morphological appearances within and between subtypes. Overall, these results show that molecular subtyping by gene expression profiling is reproducible, robust and suitable for use in the GUSTO clinical trial.

Osteoporosis and osteoarthritis are the most common age-related diseases of the musculoskeletal system. They are responsible for high level of healthcare use and are often associated with comorbidities. Mechanisms of ageing such as senescence, inflammation and autophagy are common drivers for both diseases and molecules targeting those mechanisms (geroprotectors) have potential to prevent both diseases and their co-morbidities. However, studies to test the efficacy of geroprotectors on bone and joints are scant. The limited studies available show promising results to prevent and reverse Osteoporosis-like disease. In contrast, the effects on the development of Osteoarthritis-like disease in ageing mice has been disappointing thus far. Here we review the literature and report novel data on the effect of geroprotectors for Osteoporosis and Osteoarthritis, we challenge the notion that extension of lifespan correlates with extension of healthspan in all tissues and we highlight the need for more thorough studies to test the effects of geroprotectors on skeletal health in ageing organisms.

The pathological assessment of cystectomy specimens is important for accurate prognostic information and to inform adjuvant therapy decisions. However, there is limited evidence regarding the best approach to fixation, dissection, block selection and microscopic assessment of cystectomies. We report the results of an international survey of 212 pathologists and their approach to cystectomy pathology. There is variation at all stages of the specimen journey including in fixation and dissection techniques, and in the approach to evaluating residual tumour. This is particularly evident in the post-neoadjuvant chemotherapy setting where there is variable use of response scoring systems and differing approaches to sampling. We also find variation in the use of digital and molecular pathology in cystectomy specimens. Finally, we have suggested areas for future research in cystectomy pathological assessment.

GATA binding protein 3 (GATA3) is a zinc-finger pioneer transcription factor involved in diverse processes. GATA3 regulates gene expression through binding nucleosomal DNA and facilitating chromatin remodelling. Post-translational modifications modulate its activity. During development, GATA3 plays a key role in cell differentiation. Mutations in GATA3 are linked to breast and bladder cancer. GATA3 expression is a feature of the luminal subtype of bladder cancer and has implications for immune status and therapeutic response. It also has clinical relevance in squamous cell carcinomas and soft tissue sarcomas. This paper reviews the structure and function of GATA3, its role in cancer and its use and pitfalls as an immunohistochemical marker.

At a molecular level up to 80% of ARMS have a PAX3::FOXO1 or PAX7::FOXO1 fusion and recent data have suggested that the PAX3/7::FOXO1 fusion genes have prognostic significance, and the modern North American and European RMS trials stratify therapy on FOXO1-fusion status.6 PAX3::NCOA1 gene fusions are extremely uncommon in ARMS and were first reported in 20047 with only six cases reported subsequently.7 8 The previous cases were presented in a wide variety of sites (including the perineurium, gluteus maximus, base of skull and tongue), in patients between 2 and 22 years of age. 7 8 9 Although it has been suggested that PAX3::NCOA1 gene fusions may represent a subset of ARMS with differing pathogenesis, at present, there is insufficient evidence to determine the clinical significance of these fusions.6–9 Only two of these reported cases were in the head and neck region and neither had a sinonasal origin. [...]ARMS is one of the only soft tissue sarcomas that can metastasise to local lymph nodes and this should be considered in the differential diagnosis of poorly differentiated metastases. [...]we demonstrate the utility of RNA sequencing in clinical use for accurate tumour typing of poorly differentiated rare tumours which in this case was necessary for detecting the rare PAX3::NCOA1 fusion.

Uroplakins are a family of membrane-spanning proteins highly specific to the urothelium. There are four uroplakin proteins in humans. These are encoded by the following UPK genes: UPK1A, UPK1B, UPK2 and UPK3. Uroplakin proteins span the apical membrane of umbrella cells of the urothelium, where they associate into urothelial plaques. This provides a barrier function to prevent passage of urine across the urothelium in the renal pelvis, ureters, and bladder. Uroplakins are also involved in developmental processes such as nephrogenesis. The specific localisation of uroplakins within the urothelium means that they are often expressed in primary and metastatic urothelial cell carcinoma and may be used as an immunohistochemical marker of urothelial malignancy.