Characterisation of the carboxypeptidase G2 catalytic site and design of new inhibitors for cancer therapy

The enzyme carboxypeptidase G2 (CPG2) is used in antibody‐directed enzyme prodrug therapy (ADEPT) to catalyse the formation of an active drug from an inert prodrug. Free CPG2 in the bloodstream must be inhibited before administration of the prodrug in order to avoid a systemic reaction in the patient. Although a few small‐molecule CPG2 inhibitors have been reported, none has been taken forward thus far. This lack of progress is due in part to a lack of structural understanding of the CPG2 active site as well as the absence of small molecules that can block the active site whilst targeting the complex for clearance. The work described here aimed to address both areas. We report the structural/functional impact of extensive point mutation across the putative CPG2 catalytic site and adjacent regions for the first time, revealing that residues outside the catalytic region (K208A, S210A and T357A) are crucial to enzyme activity. We also describe novel molecules that inhibit CPG2 whilst maintaining the accessibility of galactosylated moieties aimed at targeting the enzyme for clearance. This work acts as a platform for the future development of high‐affinity CPG2 inhibitors that occupy new chemical space and will advance the safe application of ADEPT in cancer treatment

The Potential Clinical and Economic Value of Primary Tumour Identification in Metastatic Cancer of Unknown Primary Tumour: A Population-Based Retrospective Matched Cohort Study.

PurposeSeveral genomic tests have recently been developed to identify the primary tumour in cancer of unknown primary tumour (CUP). However, the value of identifying the primary tumour in clinical practice for CUP patients remains questionable and difficult to prove in randomized trials.ObjectiveWe aimed to assess the clinical and economic value of primary tumour identification in CUP using a retrospective matched cohort study.MethodsWe used the Manitoba Cancer Registry to identify all patients initially diagnosed with metastatic cancer between 2002 and 2011. We defined patients as having CUP if their primary tumour was found 6 months or more after initial diagnosis or never found during the course of disease. Otherwise, we considered patients to have metastatic cancer from a known primary tumour (CKP). We linked all patients with Manitoba Health databases to estimate their direct healthcare costs using a phase-of-care approach. We used the propensity score matching technique to match each CUP patient with a CKP patient on clinicopathologic characteristics. We compared treatment patterns, overall survival (OS) and phase-specific healthcare costs between the two patient groups and assessed association with OS using Cox regression adjustment.ResultsOf 5839 patients diagnosed with metastatic cancer, 395 had CUP (6.8%); 1:1 matching created a matched group of 395 CKP patients. CUP patients were less likely to receive surgery, radiation, hormonal and targeted therapy and more likely to receive cytotoxic empiric chemotherapeutic agents. Having CUP was associated with reduced OS (hazard ratio [HR] 1.31; 95% confidence interval 1.1-1.58), but this lost statistical significance with adjustment for treatment differences. CUP patients had a significant increase in the mean net cost of initial diagnostic workup before diagnosis and a significant reduction in the mean net cost of continuing cancer care.ConclusionIdentifying the primary tumour in CUP patients might enable the use of more effective therapies, improve OS and allow more efficient allocation of healthcare resources

Data-parallel agent-based microscopic road network simulation using graphics processing units

Road network microsimulation is computationally expensive, and existing state of the art commercial tools use task parallelism and coarse-grained data-parallelism for multi-core processors to achieve improved levels of performance. An alternative is to use Graphics Processing Units (GPUs) and fine-grained data parallelism. This paper describes a GPU accelerated agent based microsimulation model of a road network transport system. The performance for a procedurally generated grid network is evaluated against that of an equivalent multi-core CPU simulation. In order to utilise GPU architectures effectively the paper describes an approach for graph traversal of neighbouring information which is vital to providing high levels of computational performance. The graph traversal approach has been integrated within a GPU agent based simulation framework as a generalised message traversal technique for graph-based communication. Speed-ups of up to 43 ×  are demonstrated with increased performance scaling behaviour. Simulation of over half a million vehicles and nearly two million detectors at a rate of 25 ×  faster than real-time is obtained on a single GPU

A realistic two-lane traffic model for highway traffic

A two-lane extension of a recently proposed cellular automaton model for traffic flow is discussed. The analysis focuses on the reproduction of the lane usage inversion and the density dependence of the number of lane changes. It is shown that the single-lane dynamics can be extended to the two-lane case without changing the basic properties of the model which are known to be in good agreement with empirical single-vehicle data. Therefore it is possible to reproduce various empirically observed two-lane phenomena, like the synchronization of the lanes, without fine-tuning of the model parameters

The matrix protein Fibulin-3 promotes KISS1R induced triple negative breast cancer cell invasion

Breast cancer is a leading cause of cancer mortality. In particular, triple negative breast cancer (TNBC) comprise a heterogeneous group of basal-like tumors lacking estrogen receptor (ERa), progesterone receptor (PR) and HER2 (ErbB2). TNBC represents 15-20% of all breast cancers and occurs frequently in women under 50 years of age. Unfortunately, these patients lack targeted therapy, are typically high grade and metastatic at time of diagnosis. The mechanisms regulating metastasis remain poorly understood. We have previously shown that the kisspeptin receptor, KISS1R stimulates invasiveness of TNBC cells. In this report, we demonstrate that KISS1R signals via the secreted extracellular matrix protein, fibulin-3, to regulate TNBC invasion. We found that the fibulin-3 gene is amplified in TNBC primary tumors and that plasma fibulin-3 levels are elevated in TNBC patients compared to healthy subjects. In this study, we show that KISS1R activation increases fibulin-3 expression and secretion. We show that fibulin-3 regulates TNBC metastasis in a mouse experimental metastasis xenograft model and signals downstream of KISS1R to stimulate TNBC invasion, by activating matrix metalloproteinase 9 (MMP-9) and the MAPK pathway. These results identify fibulin-3 as a new downstream mediator of KISS1R signaling and as a potential biomarker for TNBC progression and metastasis, thus revealing KISS1R and fibulin-3 as novel drug targets in TNBC

Cost-effectiveness of using a gene expression profiling test to aid in identifying the primary tumour in patients with cancer of unknown primary.

We aimed to investigate the cost-effectiveness of a 2000-gene-expression profiling (GEP) test to help identify the primary tumor site when clinicopathological diagnostic evaluation was inconclusive in patients with cancer of unknown primary (CUP). We built a decision-analytic-model to project the lifetime clinical and economic consequences of different clinical management strategies for CUP. The model was parameterized using follow-up data from the Manitoba Cancer Registry, cost data from Manitoba Health administrative databases and secondary sources. The 2000-GEP-based strategy compared to current clinical practice resulted in an incremental cost-effectiveness ratio (ICER) of $44,151 per quality-adjusted life years (QALY) gained. The total annual-budget impact was$36.2 million per year. A value-of-information analysis revealed that the expected value of perfect information about the test\u27s clinical impact was $4.2 million per year. The 2000-GEP test should be considered for adoption in CUP. Field evaluations of the test are associated with a large societal benefit.The Pharmacogenomics Journal advance online publication, 29 March 2016; doi:10.1038/tpj.2015.94

OmniCAV : a simulation and modelling system that enables “CAVs for All”

OmniCAV is laying the foundations for the development of a comprehensive, robust and secure simulator, aimed at providing a certification tool for Connected Autonomous Vehicles (CAVs) that can be used by regulatory and accreditation bodies, insurers and manufacturers to accelerate the safe development of CAVs. To achieve this, OmniCAV is using highly detailed road maps, together with a powerful combination of traffic management, accident and CCTV data, to create a high-fidelity traffic and driving simulation environment to interact with the AV under test. Scenarios for testing are developed and randomised in a holistic way to avoid CAVs training to specific conditions. Critically, the simulator offers coverage of a representative element of the U.K. road network, through encompassing rural roads, peri-urban and urban roads to enable autonomy for all. The validity of the synthetic test environment compared to the real-world is of particular importance, and OmniCAV will be tested and refined through an iterative approach involving real-world comparisons and working in conjunction with a CAV testbed

The clinical significance of occult gastrointestinal primary tumours in metastatic cancer: A population retrospective cohort study

© 2018 by the Korean Cancer Association. Purpose The purpose of this study was to estimate the incidence of occult gastrointestinal (GI) primary tumours in patients with metastatic cancer of uncertain primary origin and evaluate their influence on treatments and overall survival (OS). Materials and Methods We used population heath data from Manitoba, Canada to identify all patients initially diagnosed with metastatic cancer between 2002 and 2011. We defined patients to have occult primary tumour if the primary was found at least 6 months after initial diagnosis. Otherwise, we considered primary tumours as obvious. We used propensity-score methods to match each patient with occult GI tumour to four patients with obvious GI tumour on all known clinicopathologic features. We compared treatments and 2-year survival data between the two patient groups and assessed treatment effect on OS using Cox regression adjustment. Results Eighty-three patients had occult GI primary tumours, accounting for 17.6% of men and 14% of women with metastatic cancer of uncertain primary. A 1:4 matching created a matched group of 332 patients with obvious GI primary tumour. Occult cases compared to the matched group were less likely to receive surgical interventions and targeted biological therapy, and more likely to receive cytotoxic empiric chemotherapeutic agents. Having an occult GI tumour was associated with reduced OS and appeared to be a nonsignificant independent predictor of OS when adjusting for treatment differences. Conclusion GI tumours are the most common occult primary tumours in men and the second most common in women. Patients with occult GI primary tumours are potentially being undertreated with available GI site-specific and targeted therapies

A Gaussian Theory of Superfluid--Bose-Glass Phase Transition

We show that gaussian quantum fluctuations, even if infinitesimal, are sufficient to destroy the superfluidity of a disordered boson system in 1D and 2D. The critical disorder is thus finite no matter how small the repulsion is between particles. Within the gaussian approximation, we study the nature of the elementary excitations, including their density of states and mobility edge transition. We give the gaussian exponent $\eta$ at criticality in 1D and show that its ratio to $\eta$ of the pure system is universal.Comment: Revtex 3.0, 11 pages (4 figures will be sent through airmail upon request