FK506 and spinal cord injury : investigating a mechanism of action and developing and instituting a pre-clinical trial protocol to assess FK506 as a neuroprotective agent

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Glioblastoma Multiforme in the over 70's: “To treat or not to treat with radiotherapy?”

Abstract Background The incidence of Glioblastoma Multiforme (GBM) is increasing among the older population and is associated with poor prognosis. Management guidelines are lacking in this group. The purpose of this study was to analyze survival data and determine predictors of survival in patients aged ≥70 years treated with radiotherapy (RT) and/or Temozolomide. Materials and Methods A retrospective analysis of all GBM patients treated at our institution between January 2011 and January 2017 was carried out. Results One‐hundred and four patients were eligible. Median age was 73.8 years (70‐87). Thirty‐three patients received radical RT and 71 palliative RT. Overall median survival (MS) was 6 months. The MS was 10.6 months for radical patients and 4.9 months for palliative patients (P < 0.0005). The MS was 6.9 months in patients aged 70‐75 years and 5.2 months in those aged 76‐80 years (P = 0.004). The debulked group had a statistically significantly longer survival (8.0 months) than the biopsy only group (4.9 months). Biopsy only (hazard ratio [HR] 2.4), ECOG performance status 3 vs 0 (HR 6.4), and increasing age (HR 1.06) were associated with statistically significant shorter survival after adjustment for the effects of concurrent chemo, delay in starting RT, and RT dose. Conclusion The MS for radical patients was favorable and approaching current literature for the under 70 age group. Radical treatment should be considered for good performance patients aged 70‐75 years. Increasing age was associated with shorter MS in patients aged ≥76 years. Debulking and good performance status were associated with improved survival

Water quality as a threat to aquatic plants: discriminating between the effects of nitrate, phosphate, boron and heavy metals on charophytes

Eutrophication is a threat to wetlands worldwide. Elevated phosphorus concentration is often the main driver of loss of biodiversity and ecosystem function, but effects of phosphorus and nitrogen have proved largely inseparable, because they vary colinearly. Charophytes, aquatic algae that are very close to the evolutionary link with the land–plant lineage, provide a sensitive system for disentangling complex pollutant threats. Here, we investigated aquatic vegetation and water quality at the principal sites for charophyte biodiversity in the UK and used hierarchical partitioning to discriminate independent effects of pollutants on their occurrence. A laboratory experiment examined the growth responses of a representative species (Chara globularis) to nitrate. Nitrate-N exerted the greatest detrimental effect on charophyte occurrence in the field. Furthermore, growth of C. globularis in the laboratory was inhibited above very low concentrations. Smaller independent effects of copper (Cu), cadmium (Cd), cobalt (Co), phosphate-P, nickel (Ni), boron (B) and manganese (Mn) on charophyte occurrence were discriminated. It is possible to separate the deleterious effects of phosphorus and nitrogen on aquatic organisms in the field. Nitrate is a critical factor and a mean annual average concentration limit of c. 2 mg l-1 nitrate-N is necessary to protect charophytes and their services within wetland ecosystems

The weekend effect in aneurysmal subarachnoid haemorrhage: a single centre experience and review

Clinical outcomes for patients admitted to hospital during weekend hours have been reported to be poorer than for those admitted during the week. Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating form of haemorrhagic stroke, with a mortality rate greater than 30%. A number of studies have reported higher mortality for patients with aSAH who are admitted during weekend hours. This study evaluates the effect of weekend admission on patients in our unit with aSAH in terms of time to treatment, treatment type, rebleeding rates, functional outcome, and mortality. We analysed a retrospective database of all patients admitted to our tertiary referral centre with aneurysmal subarachnoid haemorrhage between February 2016 and February 2020. Chi-square tests and t-tests were used to compare weekday and weekend demographic and clinical variables. Univariate and multivariate logistic regression analyses were performed to assess for any association between admission during weekend hours and increased neurological morbidity (assessed via Glasgow Outcome Scale at 3 months) and mortality. Of the 571 patients included in this study, 191 were admitted during on-call weekend hours. There were no significant differences found in time to treatment, type of treatment, rebleeding rates, neurological morbidity, or mortality rates between patients admitted during the week and those admitted during weekend hours. Weekend admission was not associated with worsened functional outcome or increased mortality in this cohort. These results suggest that provision of 7-day cover by vascular neurosurgeons and interventional neuroradiologists in high-volume centres could mitigate the weekend effect sometimes reported in the aSAH cohort. </p

RET overexpression leads to increased brain metastatic competency in luminal breast cancer

Background: Breast cancer brain metastasis is a rising occurrence, necessitating a better understanding of the mechanisms involved for effective management. Breast cancer brain metastases diverge notably from the primary tumor, with gains in kinase and concomitant losses of steroid signaling observed. In this study, we explored the role of the kinase receptor RET in promoting breast cancer brain metastases and provide a rationale for targeting this receptor. Methods: RET expression was characterized in a cohort of patients with primary and brain metastatic tumors. RET functionality was assessed using pharmacological inhibition and gene silencing in patient-derived brain metastatic tumor explants and in vivo models, organoid models, and brain organotypic cultures. RNA sequencing was used to uncover novel brain metastatic relevant RET mechanisms of action. Results: A statistically significant enrichment of RET in brain metastases was observed in estrogen receptor-positive breast cancer, where it played a role in promoting cancer cell adhesion, survival, and outgrowth in the brain. In vivo, RET overexpression enhanced brain metastatic competency in patient-derived models. At a mechanistic level, RET overexpression was found to enhance the activation of gene programs involved in cell adhesion, requiring EGFR cooperation to deliver a pro-brain metastatic phenotype. Conclusion: Our results illustrate, for the first time, the role of RET in regulating colonization and outgrowth of breast cancer brain metastasis and provide data to support the use of RET inhibitors in the management strategy for patients with breast cancer brain metastases.</p

Plant functional types and traits as biodiversity indicators for tropical forests: two biogeographically separated case studies including birds, mammals and termites

Multi-taxon surveys were conducted in species-rich, lowland palaeotropical and neotropical forested landscapes in Sumatra, Indonesia and Mato Grosso, Brazil. Gradient-directed transects (gradsects) were sampled across a range of forested land use mosaics, using a uniform protocol to simultaneously record vegetation (vascular plant species, plant functional types (PFTs) and vegetation structure), vertebrates (birds, mammals) and invertebrates (termites), in addition to measuring site and soil properties, including carbon stocks. At both sites similar correlations were detected between major components of structure (mean canopy height, woody basal area and litter depth) and the diversities of plant species and PFTs. A plant species to PFT ratio [spp.:PFTs] was the best overall predictor of animal diversity, especially termite species richness in Sumatra. To a notable extent vegetation structure also correlated with animal diversity. These surrogates demonstrate generic links between habitat structural elements, carbon stocks and biodiversity. They may also offer practical low-cost indicators for rapid assessment in tropical forest landscapes