Understanding Social Situations (USS): A proof-of-concept social–cognitive intervention targeting theory of mind and attributional bias in individuals with psychosis.

In this proof-of-concept trial, we examined the feasibility and preliminary efficacy of Understanding Social Situations (USS), a new social cognitive intervention that targets higher-level social cognitive skills using methods common to neurocognitive remediation, including drill and practice and hierarchically structured training, which may compensate for the negative effects of cognitive impairment on learning

Withania somnifera Root Extract Enhances Chemotherapy through ‘Priming’

Withania somnifera extracts are known for their anti-cancerous, anti-inflammatory and antioxidative properties. One of their mechanisms of actions is to modulate mitochondrial function through increasing oxidative stress. Recently ‘priming’ has been suggested as a potential mechanism for enhancing cancer cell death. In this study we demonstrate that ‘priming’, in HT-29 colon cells, with W. somnifera root extract increased the potency of the chemotherapeutic agent cisplatin. We have also showed the W. somnifera root extract enhanced mitochondrial dysfunction and that the underlying mechanism of ‘priming’ was selectively through increased ROS. Moreover, we showed that this effect was not seen in non-cancerous cells

HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's Disease

Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.This article is freely available via Open Access. Click on Publisher URL to access the full-text

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

In vivo monitoring of liposomal encapsulated siRNA delivery

RNA interference (RNAi) is being widely explored as a means of tumour therapy due to the specific and potent silencing of targeted genes. However, in vivo delivery of RNAi effectors, such as small interfering RNA (siRNA) and detection of delivery is fraught with problems. In this thesis a novel theranostic PEGylated siRNA nanoparticle, termed liposome encapsulated siRNA (LEsiRNA) was developed and tested in vitro and in vivo. The LEsiRNA nanoparticles were formulated to be MR sensitive and contain labels for fluorescence microscopy/histology. The nanoparticles were shown to be an ideal size for in vivo delivery, under 100 nm, stable over 4 days and have a MR relaxivity better than the clinically used contrast agent Dotarem. The LEsiRNA nanoparticles were tested in vitro to assess their suitability for use in vivo. It was found that incubation of the particles with cells led to a decrease in protein level of the targeted cancer gene, Survivin, an inhibitor of apoptosis. In vivo assessment of the LEsiRNA nanoparticles demonstrated their potential as a theranostic agent, delivering therapy, while simultaneously allowing monitoring of tumour delivery. The LEsiRNA nanoparticles, administered by intravenous injection, were shown to accumulate in xenograft tumours by MRI at 16 and 24 hours post administration. Fluorescence microscopy of ex vivo tumour samples was used to corroborate the MR results and simultaneously demonstrate co-localisation of nanoparticles and siRNA within the tumours. The LEsiRNA nanoparticle-mediated delivery of the anti-cancer Survivin siRNA caused a significant reduction in both Survivin expression and tumour growth when compared to controls. These results suggest that LEsiRNA nanoparticles can be valuable as an in vivo delivery agent for siRNA therapy to tumours. As a way to non-invasively assess the tumour therapy effect caused by the Survivin LEsiRNA nanoparticles, an MR contrast agent targeted to apoptotic cells was investigated. This agent was tested in vitro and found, by MRI, to selectively bind to apoptotic cells. This suggests that the agent could be used in vivo to give an early prognosis, after a therapeutic intervention, without the need for an invasive biopsy. The favourable biodistribution of the LEsiRNA nanoparticles to tumours and the subsequent successful functional delivery of Survivin siRNA, with simultaneous monitoring by MRI, suggests that these LEsiRNA nanoparticles have real potential for the future treatment of cancer. The ability to non-invasively detect the effect of the LEsiRNA nanoparticles on tumours in vivo, afforded by the apoptotic targeted contrast agent, is also paramount for future clinical applications. Therefore, these two agents have great potential in the treatment and prognosis of cancer.EThOS - Electronic Theses Online ServiceBBSRC, MRC and AstraZenecaGBUnited Kingdo

miRWoods: Enhanced precursor detection and stacked random forests for the sensitive detection of microRNAs.

MicroRNAs are conserved, endogenous small RNAs with critical post-transcriptional regulatory functions throughout eukaryota, including prominent roles in development and disease. Despite much effort, microRNA annotations still contain errors and are incomplete due especially to challenges related to identifying valid miRs that have small numbers of reads, to properly locating hairpin precursors and to balancing precision and recall. Here, we present miRWoods, which solves these challenges using a duplex-focused precursor detection method and stacked random forests with specialized layers to detect mature and precursor microRNAs, and has been tuned to optimize the harmonic mean of precision and recall. We trained and tuned our discovery pipeline on data sets from the well-annotated human genome, and evaluated its performance on data from mouse. Compared to existing approaches, miRWoods better identifies precursor spans, and can balance sensitivity and specificity for an overall greater prediction accuracy, recalling an average of 10% more annotated microRNAs, and correctly predicts substantially more microRNAs with only one read. We apply this method to the under-annotated genomes of Felis catus (domestic cat) and Bos taurus (cow). We identified hundreds of novel microRNAs in small RNA sequencing data sets from muscle and skin from cat, from 10 tissues from cow and also from human and mouse cells. Our novel predictions include a microRNA in an intron of tyrosine kinase 2 (TYK2) that is present in both cat and cow, as well as a family of mirtrons with two instances in the human genome. Our predictions support a more expanded miR-2284 family in the bovine genome, a larger mir-548 family in the human genome, and a larger let-7 family in the feline genome

Understanding Social Situations (USS): A proof-of-concept social–cognitive intervention targeting theory of mind and attributional bias in individuals with psychosis.

OBJECTIVES: In this proof-of-concept trial, we examined the feasibility and preliminary efficacy of Understanding Social Situations (USS), a new social cognitive intervention that targets higher-level social cognitive skills using methods common to neurocognitive remediation, including drill and practice and hierarchically structured training, which may compensate for the negative effects of cognitive impairment on learning. METHODS: Thirty-eight individuals with schizophrenia spectrum disorders completed the same baseline assessment of cognitive and social cognitive functioning twice over a one month period to minimize later practice effects, then received 7–10 sessions of USS training, and then completed the same assessment again at post-treatment RESULTS: USS training was well tolerated and received high treatment satisfaction ratings. Large improvements on the USS Skills Test, which contained items similar to but not identical to training stimuli, suggest that we were effective in teaching specific training content. Content gains generalized to improvements on some of the social cognitive tasks, including select measures of attributional bias and theory of mind. Importantly, baseline neurocognition did not impact the amount of learning during USS (as indexed by USS Skills test), nor the amount of improvement on social cognitive measures. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: USS shows promise as a treatment for higher-level social cognitive skills. Given the lack of relationship between baseline cognition and treatment effects, it may be particularly appropriate for individuals with lower-range cognitive function

Understanding Social Situations (USS): A proof-of-concept social-cognitive intervention targeting theory of mind and attributional bias in individuals with psychosis

Objectives: In this proof-of-concept trial, we examined the feasibility and preliminary efficacy of Understanding Social Situations (USS), a new social–cognitive intervention that targets higher level social–cognitive skills using methods common to neurocognitive remediation, including drill and practice and hierarchically structured training, which may compensate for the negative effects of cognitive impairment on learning. Method: Thirty-eight individuals with schizophrenia spectrum disorders completed the same baseline assessment of cognitive and social–cognitive functioning twice over a 1-month period to minimize later practice effects, then received 7–10 sessions of USS training, and then completed the same assessment again at posttreatment. Results: USS training was well tolerated and received high treatment satisfaction ratings. Large improvements on the USS Skills Test, which contained items similar to but not identical to training stimuli, suggest that we were effective in teaching specific training content. Content gains generalized to improvements on some of the social–cognitive tasks, including select measures of attributional bias and theory of mind. Importantly, baseline neurocognition did not impact the amount of learning during USS (as indexed by the USS Skills Test) or the amount of improvement on social–cognitive measures. Conclusions and Implications for Practice: USS shows promise as a treatment for higher level social–cognitive skills. Given the lack of relationship between baseline cognition and treatment effects, it may be particularly appropriate for individuals with lower range cognitive function