Preliminary evidence for the phosphodiesterase type-4 inhibitor, roflumilast, in ameliorating cognitive flexibility deficits in patients with schizophrenia

Background: Cognitive flexibility deficits are present in patients with schizophrenia and are strong predictors of functional outcome but, as yet, have no pharmacological treatments. Aims: The purpose of this study was to investigate whether the phosphodiesterase type-4 inhibitor, roflumilast, can improve cognitive flexibility performance and functional brain activity in patients with schizophrenia. Methods: This was a within-subject, randomised, double-blind, placebo-controlled, three-period crossover study using a version of the Intradimensional/Extradimensional (ID/ED) task, optimised for functional magnetic resonance imaging (fMRI), in 10 patients with schizophrenia who were scanned after receiving placebo, 100 µg or 250 µg roflumilast for 8 consecutive days. Data from an additional fMRI ID/ED study of 18 healthy participants on placebo was included to contextualise the schizophrenia-related performance and activations. The fMRI analyses included a priori driven region of interest (ROI) analysis of the dorsal frontoparietal attention network. Results: Patients on placebo demonstrated broad deficits in task performance compared to the healthy comparison group, accompanied by preserved network activity for solution search, but reduced activity in left ventrolateral prefrontal cortex (VLPFC) and posterior parietal cortex for attentional set-shifting and reduced activity in left dorsolateral prefrontal cortex (DLPFC) for reversal learning. These ROI deficits were ameliorated by 250 µg roflumilast, whereas during solution search 100 µg roflumilast reduced activity in the left orbitofrontal cortex, right DLPFC and bilateral PPC, which was associated with an improvement in formation of attentional sets. Conclusions: The results suggest roflumilast has dose-dependent cognitive enhancing effects on the ID/ED task in patients with schizophrenia, and provides sufficient support for larger studies to test roflumilast’s role in improving cognitive flexibility deficits in this clinical population

Patient and Public Involvement Refines the Design of ProtOeus: A Proposed Phase II Trial of Proton Beam Therapy in Oesophageal Cancer

Background: Neoadjuvant chemoradiotherapy for oesophageal cancer significantly improves overall survival but is associated with severe post-operative complications. Proton beam therapy may reduce these toxicities by sparing normal tissues compared with standard radiotherapy. ProtOeus is a proposed randomised phase II study of neoadjuvant chemoradiotherapy in oesophageal cancer that compares proton beam therapy to standard radiotherapy techniques. As proton beam therapy services are often centralised in academic centres in major cities, proton beam therapy trials raise distinct challenges including patient acceptance of travelling for proton beam therapy, coordination of treatments with local centres and ensuring equity of access for patients. Methods: Focus groups were held early in the trial development process to establish patients’ views on the trial proposal. Topics discussed include perception of proton beam therapy, patient acceptability of the trial pathway and design, patient-facing materials, and common clinical scenarios. Focus groups were led by the investigators and facilitated by patient involvement teams from the institutions who are involved in this research. Responses for each topic were analysed, and fed back to the trial’s development group. Results: Three focus groups were held in separate locations in the UK (Manchester, Cardiff, Wigan). Proton beam therapy was perceived as superior to standard radiotherapy making the trial attractive. Patients felt strongly that travel costs should be reimbursed to ensure equity of access to proton beam therapy. They were very supportive of a shorter treatment schedule and felt that toxicity reduction was the most important endpoint. Discussion and Conclusions: Incorporating patient views early in the trial development process resulted in significant trial design refinements including travel/accommodation provisions, choice of primary endpoint, randomisation ratio and fractionation schedule. Focus groups are a reproducible and efficient method of incorporating the patient and public voice into research

Comparative Dosimetric Analysis and Normal Tissue Complication Probability Modelling of Four-Dimensional Computed Tomography Planning Scans Within the UK NeoSCOPE Trial

Aims: NeoSCOPE is a trial of two different neoadjuvant chemoradiotherapy regimens for resectable oesophageal cancer and was the first multicentre trial in the UK to incorporate four-dimensional computed tomography (4D-CT) into radiotherapy planning. Despite 4D-CT being increasingly accepted as a standard of care for lower third and junctional oesophageal tumours, there is limited evidence of its benefit over standard three-dimensional computed tomography (3D-CT). // Materials: Using NeoSCOPE 4D-CT cases, we undertook a dosimetric comparison study of 3D-CT versus 4D-CT plans comparing target volume coverage and dose to organs at risk. We used established normal tissue complication probability models to evaluate the potential toxicity reduction of using 4D-CT plans in oesophageal cancer. // Results: 4D-CT resulted in a smaller median absolute PTV volume and lower dose levels for all reported constraints with comparable target volume coverage. NTCP modelling suggests a significant relative risk reduction of cardiac and pulmonary toxicity endpoints with 4D-CT. // Conclusion: Our work shows that incorporating 4D-CT into treatment planning may significantly reduce the toxicity burden from this treatment

The effect of dose escalation on gastric toxicity when treating lower oesophageal tumours: a radiobiological investigation

Purpose Using radiobiological modelling to estimate normal tissue toxicity, this study investigates the effects of dose escalation for concurrent chemoradiation therapy (CRT) in lower third oesophageal tumours on the stomach. Methods and materials 10 patients with lower third oesophageal cancer were selected from the SCOPE 1 database (ISCRT47718479) with a mean planning target volume (PTV) of 348 cm3. The original 3D conformal plans (50Gy3D) were compared to newly created RapidArc plans of 50GyRA and 60GyRA, the latter using a simultaneous integrated boost (SIB) technique using a boost volume, PTV2. Dose-volume metrics and estimates of normal tissue complication probability (NTCP) were compared. Results There was a significant increase in NTCP of the stomach wall when moving from the 50GyRA to the 60GyRA plans (11–17 %, Wilcoxon signed rank test, p = 0.01). There was a strong correlation between the NTCP values of the stomach wall and the volume of the stomach wall/PTV 1 and stomach wall/PTV2 overlap structures (R = 0.80 and R = 0.82 respectively) for the 60GyRA plans. Conclusion Radiobiological modelling suggests that increasing the prescribed dose to 60Gy may be associated with a significantly increased risk of toxicity to the stomach. It is recommended that stomach toxicity be closely monitored when treating patients with lower third oesophageal tumours with 60Gy

Photometric Selection of Emission Line Galaxies, Clustering Analysis and a Search for the ISW effect

We investigate the use of simple colour cuts applied to the SDSS optical imaging to perform photometric selections of emission line galaxies out to z<1. From colour-cuts using the SDSS g, r and i bands, we obtain mean photometric redshifts of z=0.32+-0.08, z=0.44+-0.12 and z=0.65+-0.21. We further calibrate our high redshift selection using spectroscopic observations with the AAOmega spectrograph on the 4m Anglo-Australian Telescope (AAT), observing ~50-200 galaxy candidates in 4 separate fields. With just 1-hour of integration time and with seeing of ~1.6", we successfully determined redshifts for ~65% of the targeted candidates. We calculate the angular correlation functions of the samples and find correlation lengths of r0=2.64 h-1 Mpc, r0=3.62 h-1 Mpc and r0=5.88 h-1 Mpc for the low, mid and high redshift samples respectively. Comparing these results with predicted dark matter clustering, we estimate the bias parameter for each sample to be b=0.70, b=0.92 and b=1.46. We calculate the 2-point redshift-space correlation function at z~0.6 and find a clustering amplitude of s0=6.4 h-1 Mpc. Finally, we use our photometric sample to search for the Integrated Sachs-Wolfe signal in the WMAP 5yr data. We cross-correlate our three redshift samples with the WMAP W, V, Q and K bands and find an overall trend for a positive signal similar to that expected from models. However, the signal in each is relatively weak. Combining all three galaxy samples we find a signal of wTg(<100')=0.20+-0.12 microK in the WMAP W-band, a significance of 1.7sigma.Comment: 14 pages, 17 figures, submitted to MNRA

Preliminary evidence for the phosphodiesterase type-4 inhibitor, roflumilast, in ameliorating cognitive flexibility deficits in patients with schizophrenia.

BACKGROUND: Cognitive flexibility deficits are present in patients with schizophrenia and are strong predictors of functional outcome but, as yet, have no pharmacological treatments. AIMS: The purpose of this study was to investigate whether the phosphodiesterase type-4 inhibitor, roflumilast, can improve cognitive flexibility performance and functional brain activity in patients with schizophrenia. METHODS: This was a within-subject, randomised, double-blind, placebo-controlled, three-period crossover study using a version of the Intradimensional/Extradimensional (ID/ED) task, optimised for functional magnetic resonance imaging (fMRI), in 10 patients with schizophrenia who were scanned after receiving placebo, 100 µg or 250 µg roflumilast for 8 consecutive days. Data from an additional fMRI ID/ED study of 18 healthy participants on placebo was included to contextualise the schizophrenia-related performance and activations. The fMRI analyses included a priori driven region of interest (ROI) analysis of the dorsal frontoparietal attention network. RESULTS: Patients on placebo demonstrated broad deficits in task performance compared to the healthy comparison group, accompanied by preserved network activity for solution search, but reduced activity in left ventrolateral prefrontal cortex (VLPFC) and posterior parietal cortex for attentional set-shifting and reduced activity in left dorsolateral prefrontal cortex (DLPFC) for reversal learning. These ROI deficits were ameliorated by 250 µg roflumilast, whereas during solution search 100 µg roflumilast reduced activity in the left orbitofrontal cortex, right DLPFC and bilateral PPC, which was associated with an improvement in formation of attentional sets. CONCLUSIONS: The results suggest roflumilast has dose-dependent cognitive enhancing effects on the ID/ED task in patients with schizophrenia, and provides sufficient support for larger studies to test roflumilast's role in improving cognitive flexibility deficits in this clinical population

Luminous Red Galaxy Clustering at z~0.7 - First Results using AAOmega

We report on the AAT-AAOmega LRG Pilot observing run to establish the feasibility of a large spectroscopic survey using the new AAOmega instrument. We have selected Luminous Red Galaxies (LRGs) using single epoch SDSS riz-photometry to i<20.5 and z<20.2. We have observed in 3 fields including the COSMOS field and the COMBO-17 S11 field, obtaining a sample of ~600 redshift z>=0.5 LRGs. Exposure times varied from 1 - 4 hours to determine the minimum exposure for AAOmega to make an essentially complete LRG redshift survey in average conditions. We show that LRG redshifts to i<20.5 can measured in approximately 1.5hr exposures and present comparisons with 2SLAQ and COMBO-17 (photo-)redshifts. Crucially, the riz selection coupled with the 3-4 times improved AAOmega throughput is shown to extend the LRG mean redshift from z=0.55 for 2SLAQ to z=0.681+/- 0.005 for riz-selected LRGs. This extended range is vital for maximising the S/N for the detection of the baryon acoustic oscillations (BAOs). Furthermore, we show that the amplitude of LRG clustering is s_0 = 9.9+/-0.7 h^-1 Mpc, as high as that seen in the 2SLAQ LRG Survey. Consistent results for the real-space amplitude are found from projected and semi-projected correlation functions. This high clustering amplitude is consistent with a long-lived population whose bias evolves as predicted by a simple ``high-peaks'' model. We conclude that a redshift survey of 360 000 LRGs over 3000deg^2, with an effective volume some 4 times bigger than previously used to detect BAO with LRGs, is possible with AAOmega in 170 nights.Comment: 12 pages, 7 figures, 8 tables, minor changes, matches published versio

Pathogenic germline MCM9 variants are rare in Australian Lynch-like syndrome patients

Lynch syndrome is a hereditary cancer syndrome caused by the autosomal dominant inheritance of loss-of-function mutations in DNA mismatch repair (MMR) genes. Approximately one quarter of clinically suspected cases have no identifiable germline mutation in any MMR gene, a condition known as Lynch-like syndrome (LLS). MCM9 was recently identified as the DNA helicase in the mammalian MMR complex and loss of helicase activity results in microsatellite instability. We hypothesized that pathogenic variants in MCM9 may account for LLS. The 5′UTR and coding region of MCM9 were sequenced in germline DNA of 109 Australian patients with LLS and variants were cross-referenced with three population-based databases (dbSNP144, 1000 Genomes, ExAC). The functional effect of variants was assessed in silico with PolyPhen-2, SIFT and CONDEL. Fifteen variants that included six common SNPs and nine variants of unknown significance (VUS) were identified. We conclude that VUS occur in MCM9 in a small proportion of LLS patients and MCM9 mutations are unlikely to explain most LLS cases

Ethanol exposure perturbs sea urchin development and disrupts developmental timing

Ethanol is a known vertebrate teratogen that causes craniofacial defects as a component of fetal alcohol syndrome (FAS). Our results show that sea urchin embryos treated with ethanol similarly show broad skeletal patterning defects, potentially analogous to the defects associated with FAS. The sea urchin larval skeleton is a simple patterning system that involves only two cell types: the primary mesenchymal cells (PMCs) that secrete the calcium carbonate skeleton and the ectodermal cells that provide migratory, positional, and differentiation cues for the PMCs. Perturbations in RA biosynthesis and Hh signaling pathways are thought to be causal for the FAS phenotype in vertebrates. Surprisingly, our results indicate that these pathways are not functionally relevant for the teratogenic effects of ethanol in developing sea urchins. We found that developmental morphology as well as the expression of ectodermal and PMC genes was delayed by ethanol exposure. Temporal transcriptome analysis revealed significant impacts of ethanol on signaling and metabolic gene expression, and a disruption in the timing of GRN gene expression that includes both delayed and precocious gene expression throughout the specification network. We conclude that the skeletal patterning perturbations in ethanol-treated embryos likely arise from a loss of temporal synchrony within and between the instructive and responsive tissues.IOS-1656752 - National Science Foundation; National Science FoundationFirst author draf