A new, more efficient waterwheel design for very-low-head hydropower schemes

Very-low-head hydropower constitutes a large untapped renewable energy source, estimated at 1 GW in the UK alone. A new type of low-impact waterwheel has been developed and tested at Abertay University in Scotland to improve the economic viability of such schemes. For example, on a 2·5 m high weir in the UK with 5 m3/s mean flow, one waterwheel could produce an annual investment return of 7·5% for over 100 years. This paper describes the evolution of the design and reports on scale-model tests. These show that the new design harnesses significant potential and kinetic energy to generate power and handles over four times as much water per metre width compared to traditional designs

Response to ionising radiation of glioblastoma stem-like cells

Introduction: Glioblastoma (GBM) is characterised by local recurrence following surgery, radiotherapy and chemotherapy. GBM has a poor prognosis and novel approaches are required. Recently, a hierarchical organisation of tumour cells in GBM has been proposed. This hypothesis suggests only a subset of cancer cells, termed ‘cancer stem-like cells’ (CSCs) drive tumour growth and possess properties of self renewal and unlimited proliferative capacity. CSCs have been described as radioresistant, implicating CSCs as a determinant of tumour recurrence following therapy. Therefore improved patient outcomes could potentially be achieved by targeting GBM CSCs. Nevertheless, reports of GBM CSC radioresistance have been conflicting, with some authors demonstrating CSC radiosensitivity. Furthermore, investigations of GBM CSC radioresponse have lacked robust radiobiological quantification and this aspect of the CSC phenotype remains controversial. Aims: To investigate the radioresponse of GBM CSCs in comparison to non CSCs, characterise the DNA damage response (DDR) in GBM CSCs to radiation and investigate effects of inhibition of DNA damage response (DDR) in GBM CSCs. Methods: Primary GBM cells were cultured in CSC enriching conditions and differentiating (‘tumour bulk’) conditions. The radioresponse of CSC and tumour bulk cultures derived from single parental tumours were thus compared by clonogenic survival assay. DDR was analysed in CSC and tumour bulk cells via Western blotting for DDR phosphoproteins and flow cytometric quantification of mitotic cells. DNA double strand break (DSB) repair was quantified by analysis of gamma H2AX foci. CSCs and tumour bulk response to irradiation in combination with inhibition of key DDR elements (ataxia telangiectasia mutated, (ATM); ataxia telangiectasia and Rad3 related, (ATR); and poly (ADP-ribose) polymerase, (PARP) by small molecule inhibitor agents was characterised. Results: CSC cultures were tumourigenic or recapitulated pathological features of parental tumours in orthotopic mouse models, whereas differentiated tumour bulk cultures did not. CSC cultures exhibited upregulation of putative CSC markers relative to tumour bulk. CSC cultures were radioresistant, demonstrated upregulated DDR and more efficient activation of the G2/M checkpoint compared to tumour bulk. CSC cultures repaired DNA DSBs more efficiently at 24 hours following irradiation. Inhibition of ATM in CSCs led to abrogation of the G2/M checkpoint response, reduced efficiency of DNA DSB repair and potent radiosensitisation. Inhibition of PARP in CSCs produced an increase in unresolved DNA DSBs in GBM CSCs at 24 hours post irradiation in G2 phase cells and modest levels of radiosensitisation. Inhibition of ATR in CSCs abrogated the G2/M checkpoint in CSCs efficiently and was associated with modest radiosensitisation. Dual ATR and PARP inhibition provided highly potent radiosensitisation of GBM CSCs. Conclusions: GBM CSCs were shown to be radioresistant relative to tumour bulk cells due to upregulated DDR, in support of the hypothesis that CSCs contribute to local recurrence, implying a need for CSC targeted therapies. The inhibition of G2/M checkpoint activation and DNA DSB repair via ATM inhibition or combined ATR/PARP inhibition potently radiosensitised GBM CSCs suggesting targeting both checkpoint and DNA DSB repair is important for optimal radiosensitisation of GBM CSCs. This study has demonstrated that DDR is a potential therapeutic target for radiosensitisation of GBM CSCs

Replication Stress Drives Constitutive Activation of the DNA Damage Response and Radioresistance in Glioblastoma Stem-like Cells

Glioblastoma (GBM) is a lethal primary brain tumor characterized by treatment resistance and inevitable tumor recurrence, both of which are driven by a subpopulation of GBM cancer stem-like cells (GSC) with tumorigenic and self-renewal properties. Despite having broad implications for understanding GSC phenotype, the determinants of upregulated DNA damage response (DDR) and subsequent radiation resistance in GSC are unknown and represent a significant barrier to developing effective GBM treatments. In this study, we show that constitutive DDR activation and radiation resistance are driven by high levels of DNA replication stress (RS). CD133+ GSC exhibited reduced DNA replication velocity and a higher frequency of stalled replication forks than CD133- non-GSC in vitro; immunofluorescence studies confirmed these observations in a panel of orthotopic xenografts and human GBM specimens. Exposure of non-GSC to low-level exogenous RS generated radiation resistance in vitro, confirming RS as a novel determinant of radiation resistance in tumor cells. GSC exhibited DNA double strand breaks (DSB) which co-localized with 'replication factories' and RNA: DNA hybrids. GSC also demonstrated increased expression of long neural genes (>1Mbp) containing common fragile sites, supporting the hypothesis that replication/transcription collisions are the likely cause of RS in GSC. Targeting RS by combined inhibition of ATR and PARP (CAiPi) provided GSC-specific cytotoxicity and complete abrogation of GSC radiation resistance in vitro. These data identify RS as a cancer stem cell-specific target with significant clinical potential

Pharmacokinetics, safety and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial

Background: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide chemotherapy in pre-clinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side-effects of temozolomide. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib, and assess the safety and tolerability of its combination with temozolomide. Methods: Pre-clinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose temozolomide in a 3+3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumour core and tumour margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines. Results: Olaparib was a substrate for multi-drug resistance protein-1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients, median 496nM) and 21/21 tumor margin specimens (9 patients, median 512.3nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150mg (3 days/week) with TMZ 75mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression-free at 6 months. Olaparib radiosensitized six glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM. Conclusions: Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better pre-clinical models

Real world uptake, safety profile and outcomes of docetaxel in newly diagnosed metastatic prostate cancer

Objectives: To investigate the uptake, safety and efficacy of docetaxel chemotherapy in hormone-naïve metastatic prostate cancer (mPC) in the first year of use outside of a clinical trial. Subjects/patients and Methods: Patients in the West of Scotland Cancer Network (WoSCAN) with newly diagnosed mPC were identified from the regional multidisciplinary team (MDT) meetings and their treatment details were collected from electronic patient records. The rate of febrile neutropenia, hospitalisations, time to progression and overall survival were compared between those patients who received docetaxel and androgen deprivation therapy (ADT), or ADT alone using survival analysis. Results: Out of 270 eligible patients, 103 received docetaxel (38.1%). 35 patients (34%) were hospitalised and there were 17 episodes of febrile neutropenia (16.5%). Two patients (1.9%) died within 30 days of chemotherapy. Patients who received ADT alone had an increased risk of progression (HR 2.03, 95% CI (1.27, 3.25), log-rank test, p= 0.002) and had an increased risk of death (HR 5.88, 95% CI 2.52, 13.72, log-rank p=0.001) compared to the docetaxel group. The risk of febrile neutropenia was nine times greater if chemotherapy was started within three weeks of ADT initiation (95% CI (1.22,77.72) p= 0.032). Conclusion: Docetaxel chemotherapy in hormone-naïve mPC has significant toxicities, but has a similar effect on time to progression and overall survival as seen in randomised trials. Chemotherapy should be started 3 weeks or more after androgen deprivation

An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ∼90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo

Language as an instrument of thought

I show that there are good arguments and evidence to boot that support the language as an instrument of thought hypothesis. The underlying mechanisms of language, comprising of expressions structured hierarchically and recursively, provide a perspective (in the form of a conceptual structure) on the world, for it is only via language that certain perspectives are avail- able to us and to our thought processes. These mechanisms provide us with a uniquely human way of thinking and talking about the world that is different to the sort of thinking we share with other animals. If the primary function of language were communication then one would expect that the underlying mechanisms of language will be structured in a way that favours successful communication. I show that not only is this not the case, but that the underlying mechanisms of language are in fact structured in a way to maximise computational efficiency, even if it means causing communicative problems. Moreover, I discuss evidence from comparative, neuropatho- logical, developmental, and neuroscientific evidence that supports the claim that language is an instrument of thought

Distinct External Signals Trigger Sequential Release of Apical Organelles during Erythrocyte Invasion by Malaria Parasites

The invasion of erythrocytes by Plasmodium merozoites requires specific interactions between host receptors and parasite ligands. Parasite proteins that bind erythrocyte receptors during invasion are localized in apical organelles called micronemes and rhoptries. The regulated secretion of microneme and rhoptry proteins to the merozoite surface to enable receptor binding is a critical step in the invasion process. The sequence of these secretion events and the external signals that trigger release are not known. We have used time-lapse video microscopy to study changes in intracellular calcium levels in Plasmodium falciparum merozoites during erythrocyte invasion. In addition, we have developed flow cytometry based methods to measure relative levels of cytosolic calcium and study surface expression of apical organelle proteins in P. falciparum merozoites in response to different external signals. We demonstrate that exposure of P. falciparum merozoites to low potassium ion concentrations as found in blood plasma leads to a rise in cytosolic calcium levels through a phospholipase C mediated pathway. Rise in cytosolic calcium triggers secretion of microneme proteins such as the 175 kD erythrocyte binding antigen (EBA175) and apical membrane antigen-1 (AMA-1) to the merozoite surface. Subsequently, interaction of EBA175 with glycophorin A (glyA), its receptor on erythrocytes, restores basal cytosolic calcium levels and triggers release of rhoptry proteins. Our results identify for the first time the external signals responsible for the sequential release of microneme and rhoptry proteins during erythrocyte invasion and provide a starting point for the dissection of signal transduction pathways involved in regulated exocytosis of these key apical organelles. Signaling pathway components involved in apical organelle discharge may serve as novel targets for drug development since inhibition of microneme and rhoptry secretion can block invasion and limit blood-stage parasite growth