Examining the efficacy of localised gemcitabine therapy for the treatment of pancreatic cancer using a hybrid agent-based model.

The prognosis for pancreatic ductal adenocarcinoma (PDAC) patients has not significantly improved in the past 3 decades, highlighting the need for more effective treatment approaches. Poor patient outcomes and lack of response to therapy can be attributed, in part, to a lack of uptake of perfusion of systemically administered chemotherapeutic drugs into the tumour. Wet-spun alginate fibres loaded with the chemotherapeutic agent gemcitabine have been developed as a potential tool for overcoming the barriers in delivery of systemically administrated drugs to the PDAC tumour microenvironment by delivering high concentrations of drug to the tumour directly over an extended period. While exciting, the practicality, safety, and effectiveness of these devices in a clinical setting requires further investigation. Furthermore, an in-depth assessment of the drug-release rate from these devices needs to be undertaken to determine whether an optimal release profile exists. Using a hybrid computational model (agent-based model and partial differential equation system), we developed a simulation of pancreatic tumour growth and response to treatment with gemcitabine loaded alginate fibres. The model was calibrated using in vitro and in vivo data and simulated using a finite volume method discretisation. We then used the model to compare different intratumoural implantation protocols and gemcitabine-release rates. In our model, the primary driver of pancreatic tumour growth was the rate of tumour cell division. We were able to demonstrate that intratumoural placement of gemcitabine loaded fibres was more effective than peritumoural placement. Additionally, we quantified the efficacy of different release profiles from the implanted fibres that have not yet been tested experimentally. Altogether, the model developed here is a tool that can be used to investigate other drug delivery devices to improve the arsenal of treatments available for PDAC and other difficult-to-treat cancers in the future.

Learning supervised embeddings for large scale sequence comparisons.

Similarity-based search of sequence collections is a core task in bioinformatics, one dominated for most of the genomic era by exact and heuristic alignment-based algorithms. However, even efficient heuristics such as BLAST may not scale to the data sets now emerging, motivating a range of alignment-free alternatives exploiting the underlying lexical structure of each sequence. In this paper, we introduce two supervised approaches-SuperVec and SuperVecX-to learn sequence embeddings. These methods extend earlier Representation Learning (RepL) based methods to include class-related information for each sequence during training. Including class information ensures that related sequence fragments have proximal representations in the target space, better reflecting the structure of the domain. We show the quality of the embeddings learned through these methods on (i) sequence retrieval and (ii) classification tasks. We also propose an hierarchical tree-based approach specifically designed for the sequence retrieval problem. The resulting methods, which we term H-SuperVec or H-SuperVecX, according to their respective use of SuperVec or SuperVecX, learn embeddings across a range of feature spaces based on exclusive and exhaustive subsets of the class labels. Experiments show that the proposed methods perform better for retrieval and classification tasks over existing (unsupervised) RepL-based approaches. Further, the new methods are an order of magnitude faster than BLAST for the database retrieval task, supporting hybrid approaches that rapidly filter the collection so that only potentially relevant records remain. Such filtering of the original database allows slower but more accurate methods to be executed quickly over a far smaller dataset. Thus, we may achieve faster query processing and higher precision than before.

Rapid analysis of metagenomic data using signature-based clustering.

BACKGROUND: Sequencing highly-variable 16S regions is a common and often effective approach to the study of microbial communities, and next-generation sequencing (NGS) technologies provide abundant quantities of data for analysis. However, the speed of existing analysis pipelines may limit our ability to work with these quantities of data. Furthermore, the limited coverage of existing 16S databases may hamper our ability to characterise these communities, particularly in the context of complex or poorly studied environments. RESULTS: In this article we present the SigClust algorithm, a novel clustering method involving the transformation of sequence reads into binary signatures. When compared to other published methods, SigClust yields superior cluster coherence and separation of metagenomic read data, while operating within substantially reduced timeframes. We demonstrate its utility on published Illumina datasets and on a large collection of labelled wound reads sourced from patients in a wound clinic. The temporal analysis is based on tracking the dominant clusters of wound samples over time. The analysis can identify markers of both healing and non-healing wounds in response to treatment. Prominent clusters are found, corresponding to bacterial species known to be associated with unfavourable healing outcomes, including a number of strains of Staphylococcus aureus. CONCLUSIONS: SigClust identifies clusters rapidly and supports an improved understanding of the wound microbiome without reliance on a reference database. The results indicate a promising use for a SigClust-based pipeline in wound analysis and prediction, and a possible novel method for wound management and treatment.