Neutrophils: homing in on the myeloid mechanisms of metastasis

The metastasis cascade is complex and comprises several stages including local invasion into surrounding tissue, intravasation and survival of tumour cells in the circulation, and extravasation and colonisation of a distant site. It is increasingly clear that these processes are driven not only by signals within the tumour cells, but are also profoundly influenced by stromal cells and signals in the tumour microenvironment. Amongst the many cell types within the tumour microenvironment, immune cells such as lymphocytes, macrophages and neutrophils play a prominent role in tumour development and progression. Neutrophils, however, have only recently emerged as important players, particularly in metastasis. Here we review the current evidence suggesting a multi-faceted role for neutrophils in the metastatic cascade

Characterising the tumour microenvironment in pancreatic cancer and the changes elicited by targeted therapies

Pancreatic cancer represents less than 3% of cancers diagnosed each year in the United Kingdom yet despite this low number, it is the fifth highest cause of death by cancer. This situation has changed little in the past few decades with median survival barely altering between 1971 and 2007. The availability of well characterised in vivo models that histologically recapitulate pancreatic ductal adenocarcinoma (PDAC) have revolutionised the field of PDAC research. These models not only recapitulate the central epithelial component of human pancreatic cancer but also the incredibly complex microenvironment, a feature for which PDAC is well known. Due to the failure of therapies targeting the neoplastic epithelial cells within PDAC, increasing interest has been given to targeting the tumour microenvironment. The tumour microenvironment is extremely complex and consists of both cellular and non-cellular components and in PDAC exhibits a number of characteristic features including the presence of pancreatic stellate cells. Work in our lab has also highlighted stromal constituents such as lysyl-oxidase and tenascin C which are vital for PDAC viability and/or metastasis. In recent years increasing numbers of stromal targets have been evaluated in mouse models of PDAC with varying success. To date work characterising the stromal changes elicited by targeted therapies has utilised methods which we believe lack the required fastidiousness required to obtain reliable and meaningful results. In this work we have established reliable methods for stromal characterisation, we have established methods to characterise the expression of tenascin C on formalin fixed specimens and we have applied these methods to determine the changes elicited by stromal targeting therapies

Final report: Prototyping a combustion corridor

The Combustion Corridor is a concept in which researchers in combustion and thermal sciences have unimpeded access to large volumes of remote computational results. This will enable remote, collaborative analysis and visualization of state-of-the-art combustion science results. The Engine Research Center (ERC) at the University of Wisconsin - Madison partnered with Lawrence Berkeley National Laboratory, Argonne National Laboratory, Sandia National Laboratory, and several other universities to build and test the first stages of a combustion corridor. The ERC served two important functions in this partnership. First, we work extensively with combustion simulations so we were able to provide real world research data sets for testing the Corridor concepts. Second, the ERC was part of an extension of the high bandwidth based DOE National Laboratory connections to universities

Towards Device Agnostic Detection of Stress and Craving in Patients with Substance Use Disorder

Novel technologies have great potential to improve the treatment of individuals with substance use disorder (SUD) and to reduce the current high rate of relapse (i.e. return to drug use). Wearable sensor-based systems that continuously measure physiology can provide information about behavior and opportunities for real-time interventions. We have previously developed an mHealth system which includes a wearable sensor, a mobile phone app, and a cloud-based server with embedded machine learning algorithms which detect stress and craving. The system functions as a just-in-time intervention tool to help patients de-escalate and as a tool for clinicians to tailor treatment based on stress and craving patterns observed. However, in our pilot work we found that to deploy the system to diverse socioeconomic populations and to increase usability, the system must be able to work efficiently with cost-effective and popular commercial wearable devices. To make the system device agnostic, methods to transform the data from a commercially available wearable for use in algorithms developed from research grade wearable sensor are proposed. The accuracy of these transformations in detecting stress and craving in individuals with SUD is further explored

Rice Galaxy: An open resource for plant science

Background: Rice molecular genetics, breeding, genetic diversity, and allied research (such as rice-pathogen interaction) have adopted sequencing technologies and high-density genotyping platforms for genome variation analysis and gene discovery. Germplasm collections representing rice diversity, improved varieties, and elite breeding materials are accessible through rice gene banks for use in research and breeding, with many having genome sequences and high-density genotype data available. Combining phenotypic and genotypic information on these accessions enables genome-wide association analysis, which is driving quantitative trait loci discovery and molecular marker development. Comparative sequence analyses across quantitative trait loci regions facilitate the discovery of novel alleles. Analyses involving DNA sequences and large genotyping matrices for thousands of samples, however, pose a challenge to non−computer savvy rice researchers. Findings: The Rice Galaxy resource has shared datasets that include high-density genotypes from the 3,000 Rice Genomes project and sequences with corresponding annotations from 9 published rice genomes. The Rice Galaxy web server and deployment installer includes tools for designing single-nucleotide polymorphism assays, analyzing genome-wide association studies, population diversity, rice−bacterial pathogen diagnostics, and a suite of published genomic prediction methods. A prototype Rice Galaxy compliant to Open Access, Open Data, and Findable, Accessible, Interoperable, and Reproducible principles is also presented. Conclusions: Rice Galaxy is a freely available resource that empowers the plant research community to perform state-of-the-art analyses and utilize publicly available big datasets for both fundamental and applied science

Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest

Oncogene-induced senescence (OIS) is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signaling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here, we show that multinucleate OIS cells originate mostly from failed mitosis. Prior to senescence, mutant H-RasV12 activation in primary human fibroblasts compromised mitosis, concordant with abnormal expression of mitotic genes functionally linked to the observed mitotic spindle and chromatin defects. Simultaneously, H-RasV12 activation enhanced survival of cells with damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional upregulation of Mcl1 was, at least in part, responsible for enhanced survival and slippage of cells with mitotic defects. Importantly, mitotic slippage and oncogene signaling cooperatively induced senescence and key senescence effectors p21 and p16. In summary, activated Ras coordinately triggers mitotic disruption and enhanced cell survival to promote formation of multinucleate senescent cells

Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer‐related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1‐Cre KrasG12D/+ Trp53R172H/+ (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor‐free survival in KPC mice with early‐stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease

Proof of concept and feasibility studies examining the influence of combination ribose, adenine and allopurinol treatment on stroke outcome in the rat

Background: Cerebral ischaemia results in a rapid and profound depletion of adenosine triphosphate (ATP), the energy currency of the cell. This depletion leads to disruption of cellular homeostasis and cell death. Early replenishment of ATP levels might therefore have a neuroprotective effect in the injured brain. We have previously shown that the ATP precursors, D-ribose and adenine (RibAde), restored the reduced ATP levels in rat brain slices to values similar to those measured in the intact rodent brain. The aim of this study was to assess whether RibAde, either alone or in combination with the xanthine oxidase inhibitor allopurinol (RibAdeAll; to further increase the availability of ATP precursors), could improve outcome in an in vivo rodent model of transient cerebral ischaemia. Methods: After 60 min occlusion of the middle cerebral artery, and upon reperfusion, rats were administered saline, RibAde, or RibAdeAll for 6 h. Baseline lesion volume was determined by diffusion-weighted MRI prior to reperfusion and final infarct volume determined by T2-weighted MRI at Day 7. Neurological function was assessed at Days 1, 3 and 7. Results: Ischaemic lesion volume decreased between Days 1 and 7: a 50% reduction was observed for the RibAdeAll group, 38% for the RibAde group and 18% in the animals that received saline. Reductions in lesion size in treatment groups were accompanied by a trend for faster functional recovery. Conclusion: These data support the potential use of ribose, adenine and allopurinol in the treatment of cerebral ischaemic injury, especially since all compounds have been used in man

Modality-Independent Effects of Phonological Neighborhood Structure on Initial L2 Sign Language Learning

The goal of the present study was to characterize how neighborhood structure in sign language influences lexical sign acquisition in order to extend our understanding of how the lexicon influences lexical acquisition in both sign and spoken languages. A referent-matching lexical sign learning paradigm was administered to a group of 29 hearing sign language learners in order to create a sign lexicon. The lexicon was constructed based on exposures to signs that resided in either sparse or dense handshape and location neighborhoods. The results of the current study indicated that during the creation of the lexicon signs that resided in sparse neighborhoods were learned better than signs that resided in dense neighborhoods. This pattern of results is similar to what is seen in child first language acquisition of spoken language. Therefore, despite differences in child first language and adult second language acquisition, these results contribute to a growing body of literature that implicates the phonological features that structure of the lexicon is influential in initial stages of lexical acquisition for both spoken and sign languages. This is the first study that uses an innovated lexicon-construction methodology to explore interactions between phonology and the lexicon in L2 acquisition of sign language

Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer.

Different thresholds of Wnt signalling are thought to drive stem cell maintenance, regeneration, differentiation and cancer. However, the principle that oncogenic Wnt signalling could be specifically targeted remains controversial. Here we examine the requirement of BCL9/9l, constituents of the Wnt-enhanceosome, for intestinal transformation following loss of the tumour suppressor APC. Although required for Lgr5+ intestinal stem cells and regeneration, Bcl9/9l deletion has no impact upon normal intestinal homeostasis. Loss of BCL9/9l suppressed many features of acute APC loss and subsequent Wnt pathway deregulation in vivo. This resulted in a level of Wnt pathway activation that favoured tumour initiation in the proximal small intestine (SI) and blocked tumour growth in the colon. Furthermore, Bcl9/9l deletion completely abrogated β-catenin driven intestinal and hepatocellular transformation. We speculate these results support the just-right hypothesis of Wnt-driven tumour formation. Importantly, loss of BCL9/9l is particularly effective at blocking colonic tumourigenesis and mutations that most resemble those that occur in human cancer