The incidence and pathogenesis of 'recurrent' Barrett's metaplasia following oesophagectomy (neo-Barrett's)

MD ThesisAims Columnar metaplasia in the oesophageal remnant occurring after subtotal oesophagectomy (neo-Barrett’s) has been proposed as a human model for the development of Barrett’s oesophagus. This study aimed to assess the incidence of this phenomenon and it’s accuracy as a model as well as looking for evidence of field cancerisation in the oesophagus. Methods Patients underwent prospective endoscopic evaluation having previously undergone oesophagectomy. The presence or absence of columnar epithelium above the surgical anastomosis was noted and biopsies taken. Specimens were stained using H&E and, where consent was granted, with immunohistochemical stains for proteins which have a well described expression pattern in Barrett’s oesophagus. Tumours and adjacent Barrett’s oesophagus from patients who subsequently developed neo-Barrett’s were screened for genetic mutations. Where these were present, subsequent neo- Barrett’s samples were evaluated for the presence of these mutatations Results Of 126 eligible patients, 45 (36%) had confirmed neo-Barrett’s. Median time from surgery was greater for patients with neo-Barrett’s (5.7 vs 2.2yrs, p<0.001). There were no cases of dysplasia. Non-intestinalised columnar epithelium occurred earlier than neo-Barrett’s with specialised intestinal metaplasia. Surgery for dysplastic Barrett’s or adenocarcinoma was associated with a similar prevalence of neo-Barrett’s to other indications (41% vs 27%, p=0.157). 37 samples underwent molecular analysis. Typical, Barrett’s like CK7/20 staining pattern was present in 23 cases (62%). Chromogranin A and trefoil factors 1 and 2 were were present in all cases. TFF3 expression was significantly associated with increasing time from surgery (median 8.1yrs vs 3.4yrs, p=0.004). Genetic mutations identified in the resection specimen were not present in the neo-Barrett’s tissue. Conclusions Columnar metaplasia is common following oesophagectomy. Cellular protein expression is similar to that of sporadic Barrett’s suggesting this is an accurate model. Presence of intestinal metaplasia and TFF3 expression appear to represent later stages in the development of Barrett’s. No evidence of field cancerisation was found

Paths to wider adoption of e-infrastructure services

This paper presents work conducted as part of the e-Uptake project, which aims to widen the uptake of e-Infrastructure services for research. We will discuss our fieldwork conducted so far, give examples of the barriers and enablers identified and discuss how using the accumulated knowledge can lead to paving the way for wider adoption of e Infrastructure Services

Development of autobiographical memory in children with autism spectrum disorders: Deficits, gains, and predictors of performance

Autobiographical memory (AM) was assessed in 63 children (aged 8–17 years) with an autism spectrum disorder (ASD) and compared with 63 typically developing children matched for age, gender, IQ, and verbal ability. A range of methodologies was employed for eliciting past experience with particular focus on the ability to recall (a) specific events, (b) the recent and remote past, and (c) semantic versus episodic memories across different lifetime periods. Results indicated that the ASD group manifested difficulties in retrieving specific memories to word cues and had poorer access to the remote past. Deficits were found in the context of intact recent memory and preserved general memory abilities, with some impairment of visual memory. Problems in retrieving episodic and semantic AMs across the life span were also evident. Qualitative analysis of memory reports suggested that the ASD group was less likely to refer to emotion in their remote memories but more likely to describe emotions in their recent memories. Important predictors of AM performance in the ASD group were central executive abilities, in particular cognitive flexibility and verbal fluency

Capivasertib combines with docetaxel to enhance anti-tumour activity through inhibition of AKT-mediated survival mechanisms in prostate cancer

Background/objective: To explore the anti-tumour activity of combining AKT inhibition and docetaxel in PTEN protein null and WT prostate tumours. Methods: Mechanisms associated with docetaxel capivasertib treatment activity in prostate cancer were examined using a panel of in vivo tumour models and cell lines. Results: Combining docetaxel and capivasertib had increased activity in PTEN null and WT prostate tumour models in vivo. In vitro short-term docetaxel treatment caused cell cycle arrest in the majority of cells. However, a sub-population of docetaxel-persister cells did not undergo G2/M arrest but upregulated phosphorylation of PI3K/AKT pathway effectors GSK3β, p70S6K, 4E-BP1, but to a lesser extent AKT. In vivo acute docetaxel treatment induced p70S6K and 4E-BP1 phosphorylation. Treating PTEN null and WT docetaxel-persister cells with capivasertib reduced PI3K/AKT pathway activation and cell cycle progression. In vitro and in vivo it reduced proliferation and increased apoptosis or DNA damage though effects were more marked in PTEN null cells. Docetaxel-persister cells were partly reliant on GSK3β as a GSK3β inhibitor AZD2858 reversed capivasertib-induced apoptosis and DNA damage. Conclusion: Capivasertib can enhance anti-tumour effects of docetaxel by targeting residual docetaxel-persister cells, independent of PTEN status, to induce apoptosis and DNA damage in part through GSK3β.</p

Clonal transitions and phenotypic evolution in Barrett esophagus

BACKGROUND & AIMS: Barrett's esophagus (BE) is a risk factor for esophageal adenocarcinoma but our understanding of how it evolves is poorly understood. We investigated BE gland phenotype distribution, the clonal nature of phenotypic change, and how phenotypic diversity plays a role in progression. METHODS: Using immunohistochemistry and histology, we analyzed the distribution and the diversity of gland phenotype between and within biopsy specimens from patients with nondysplastic BE and those who had progressed to dysplasia or had developed postesophagectomy BE. Clonal relationships were determined by the presence of shared mutations between distinct gland types using laser capture microdissection sequencing of the mitochondrial genome. RESULTS: We identified 5 different gland phenotypes in a cohort of 51 nondysplastic patients where biopsy specimens were taken at the same anatomic site (1.0-2.0 cm superior to the gastroesophageal junction. Here, we observed the same number of glands with 1 and 2 phenotypes, but 3 phenotypes were rare. We showed a common ancestor between parietal cell-containing, mature gastric (oxyntocardiac) and goblet cell-containing, intestinal (specialized) gland phenotypes. Similarly, we have shown a clonal relationship between cardiac-type glands and specialized and mature intestinal glands. Using the Shannon diversity index as a marker of gland diversity, we observed significantly increased phenotypic diversity in patients with BE adjacent to dysplasia and predysplasia compared to nondysplastic BE and postesophagectomy BE, suggesting that diversity develops over time. CONCLUSIONS: We showed that the range of BE phenotypes represents an evolutionary process and that changes in gland diversity may play a role in progression. Furthermore, we showed a common ancestry between gastric and intestinal-type glands in BE

The role of cultivated versus wild seeds in the diet of European turtle doves (Streptopelia turtur) across European breeding and African wintering grounds

Agricultural intensification is a major driver in species declines, with changes in land use resulting in widespread alteration of resource availability. An increase in anthropogenic food resources, alongside decreasing natural resources, has resulted in species undergoing dietary changes that can have important ecological consequences, particularly for declining species. Here we use high-throughput sequencing to analyze the diet of the migrant European turtle dove (Streptopelia turtur), a species that has experienced significant population decline throughout its European range. We analyze the diet of this species on both breeding and wintering grounds to gain an understanding of resource use throughout the annual cycle and compare areas of more and less intensive agriculture in western and eastern Europe, respectively. We examine associations with body condition, spatiotemporal variation and the source of food (wild or cultivated). We identified 121 taxonomic units in the diet, with significant variation across sampling seasons, and very little overlap between the breeding and wintering seasons, as well as high levels of cultivated food resources in the diet of turtle doves in both breeding and wintering grounds, with the highest proportion of wild seeds in the diet occurring in birds caught in Hungary, where agricultural intensity was lowest. We detected no association between body condition and the consumption of cultivated food resources. We demonstrate the importance of wild resources in birds on the wintering grounds as they approach migration, where body condition increased as the season progressed, concurrent with an increased consumption of wild seeds. These findings indicate the importance of habitats rich in wild seeds and the need to consider food availability on the wintering grounds, as well as the breeding grounds in turtle dove conservation strategies

SIRT1 Undergoes Alternative Splicing in a Novel Auto-Regulatory Loop with p53

Background: The NAD-dependent deacetylase SIRT1 is a nutrient-sensitive coordinator of stress-tolerance, multiple homeostatic processes and healthspan, while p53 is a stress-responsive transcription factor and our paramount tumour suppressor. Thus, SIRT1-mediated inhibition of p53 has been identified as a key node in the common biology of cancer, metabolism, development and ageing. However, precisely how SIRT1 integrates such diverse processes remains to be elucidated. Methodology/Principal Findings: Here we report that SIRT1 is alternatively spliced in mammals, generating a novel SIRT1 isoform: SIRT1-DExon8. We show that SIRT1-DExon8 is expressed widely throughout normal human and mouse tissues, suggesting evolutionary conservation and critical function. Further studies demonstrate that the SIRT1-DExon8 isoform retains minimal deacetylase activity and exhibits distinct stress sensitivity, RNA/protein stability, and protein-protein interactions compared to classical SIRT1-Full-Length (SIRT1-FL). We also identify an auto-regulatory loop whereby SIRT1-DExon8 can regulate p53, while in reciprocal p53 can influence SIRT1 splice variation. Conclusions/Significance: We characterize the first alternative isoform of SIRT1 and demonstrate its evolutionary conservation in mammalian tissues. The results also reveal a new level of inter-dependency between p53 and SIRT1, two master regulators of multiple phenomena. Thus, previously-attributed SIRT1 functions may in fact be distributed betwee

Correction to: Pulpotomy for the Management of Irreversible Pulpitis in Mature Teeth (PIP): a feasibility study

Background Progression of dental caries can result in irreversible pulpal damage. Partial irreversible pulpitis is the initial stage of this damage, confined to the coronal pulp whilst the radicular pulp shows little or no sign of infection. Preserving the pulp with sustained vitality and developing minimally invasive biologically based therapies are key themes within contemporary clinical practice. However, root canal treatment involving complete removal of the pulp is often the only option (other than extraction) given to patients with irreversible pulpitis, with substantial NHS and patient incurred costs. The European Society of Endodontology’s (ESE 2019) recent consensus statement recommends full pulpotomy, where the inflamed coronal pulp is removed with the goal of keeping the radicular pulp vital, as a more minimally invasive technique, potentially avoiding complex root canal treatment. Although this technique may be provided in secondary care, it has not been routinely implemented or evaluated in UK General Dental Practice. Method This feasibility study aims to identify and assess in a primary care setting the training needs of general dental practitioners and clinical fidelity of the full pulpotomy intervention, estimate likely eligible patient pool and develop recruitment materials ahead of the main randomised controlled trial comparing the clinical and cost-effectiveness of full pulpotomy compared to root canal treatment in pre/molar teeth of adults 16 years and older showing signs indicative of irreversible pulpitis. The feasibility study will recruit and train 10 primary care dentists in the full pulpotomy technique. Dentists will recruit and provide full pulpotomy to 40 participants (four per practice) with indications of partial irreversible pulpitis. Discussion The Pulpotomy for the Management of Irreversible Pulpitis in Mature Teeth (PIP) study will address the lack of high-quality evidence in the treatment of irreversible pulpitis, to aid dental practitioners, patients and policymakers in their decision-making. The PIP feasibility study will inform the main study on the practicality of providing both training and provision of the full pulpotomy technique in general dental practice. Trial registration ISRCTN Registry, ISRCTN17973604. Registered on 28 January 2021. Protocol version Protocol version: 1; date: 03.02.202