Transglutaminase 2 facilitates the distant hematogenous metastasis of breast cancer by modulating interleukin-6 in cancer cells

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract Introduction Inflammation has been implicated in cancer aggressiveness. As transglutaminase 2 (TG2), which has been associated with inflammatory signaling, has been suggested to play a role in tumor behavior, we propose that TG2 may be an important linker inducing interleukin (IL)-6-mediated cancer-cell aggressiveness, including distant hematogenous metastasis. Methods To investigate the role for TG2 and IL-6, TG2-knocked-down and IL-6-knocked-down cancer cells were generated by using shRNA. Human breast cancer cell xenograft model in highly immunocompromised mice and human advanced breast cancer primary tumor tissue microarrays were used in this study. Results IL-6 production in human breast cancer cells was dependent on their TG2 expression level. In vitro tumor-sphere formation was dependent on TG2 and downstream IL-6 production from cancer cells. Primary tumor growth in the mammary fat pads and distant hematogenous metastasis into the lung was also dependent on TG2 and downstream IL-6 expression levels. The effect of TG2 expression on human breast cancer distant metastasis was investigated by analyzing a tissue microarray of primary tumors from 412 patients with their clinical data after 7 years. TG2 expression in primary tumor tissue was inversely correlated with recurrence-free survival (P = 0.019) and distant metastasis-free survival (DMFS) (P = 0.006) in patients with advanced breast cancer. Furthermore, by using public datasets that included a total of 684 breast cancer patients, we found that the combined high expression of TG2 and IL-6 was associated with shorter DMFS, compared with the high expression of IL-6 only (P = 0.013). Conclusions We provide evidence that TG2 is an important link in IL-6-mediated tumor aggressiveness, and that TG2 could be an important mediator of distant metastasis, both in a xenograft animal model and in patients with advanced breast cancer

Motor unit potential morphology differences in individuals with non-specific arm pain and lateral epicondylitis

<p>Abstract</p> <p>Background</p> <p>The pathophysiology of non-specific arm pain (NSAP) is unclear and the diagnosis is made by excluding other specific upper limb pathologies, such as lateral epicondylitis or cervical radiculopathy. The purpose of this study was to determine: (i) if the quantitative parameters related to motor unit potential morphology and/or motor unit firing patterns derived from electromyographic (EMG) signals detected from an affected muscle of patients with NSAP are different from those detected in the same muscle of individuals with lateral epicondylitis (LE) and/or control subjects and (ii) if the quantitative EMG parameters suggest that the underlying pathophysiology in NSAP is either myopathic or neuropathic in nature.</p> <p>Methods</p> <p>Sixteen subjects with NSAP, 11 subjects with LE, eight subjects deemed to be at-risk for developing a repetitive strain injury, and 37 control subjects participated. A quantitative electromyography evaluation was completed using decomposition-based quantitative electromyography (DQEMG). Needle- and surface-detected EMG signals were collected during low-level isometric contractions of the extensor carpi radialis brevis (ECRB) muscle. DQEMG was used to extract needle-detected motor unit potential trains (MUPTs), and needle-detected motor unit potential (MUP) and surface detected motor unit potential (SMUP) morphology and motor unit (MU) firing rates were compared among the four groups using one-way analysis of variance (ANOVA). Post hoc analyses were performed using Tukey's pairwise comparisons.</p> <p>Results</p> <p>Significant group differences were found for all MUP variables and for MU firing rate (<it>p</it> < 0.006). The post-hoc analyses revealed that patients with NSAP had smaller MUP amplitude and SMUP amplitude and area compared to the control and LE groups (<it>p </it>< 0.006). MUP duration and AAR values were significantly larger in the NSAP, LE and at-risk groups compared to the control group (<it>p </it>< 0.006); while MUP amplitude, duration and AAR values were smaller in the NSAP compared to the LE group. SMUP duration was significantly shorter in the NSAP group compared to the control group (<it>p </it>< 0.006). NSAP, LE and at-risk subjects had lower mean MU firing rates than the control subjects (<it>p </it>< 0.006).</p> <p>Conclusion</p> <p>The size-related parameters suggest that the NSAP group had significantly smaller MUPs and SMUPs than the control and LE subjects. Smaller MUPs and SMUPs may be indicative of muscle fiber atrophy and/or loss. A prospective study is needed to confirm any causal relationship between smaller MUPs and SMUPs and NSAP as found in this work.</p

Half-Time Strategies to Enhance Second-Half Performance in Team-Sports Players: A Review and Recommendations

The competitive demands of numerous intermittent team sports require that two consecutive periods of play are separated by a half-time break. Typically, half-time allows players to: return to the changing rooms, temporarily relax from the cognitive demands of the first half of match-play, rehydrate, re-fuel, attend to injury or equipment concerns, and to receive tactical instruction and coach feedback in preparation for the second half. These passive practices have been associated with physiological changes which impair physical and cognitive performance in the initial stages of the second half. An increased risk of injury has also been observed following half-time. On the day of competition, modification of half-time practices may therefore provide Sports Scientists and Strength and Conditioning Coaches with an opportunity to optimise second half performance. An overview of strategies that may benefit team sports athletes is presented; specifically, the efficacy of: heat maintenance strategies (including passive and active methods), hormonal priming (through video feedback), post-activation potentiation, and modified hydro-nutritional practices are discussed. A theoretical model of applying these strategies in a manner that compliments current practice is also presented

Open Data for Global Science

The global science system stands at a critical juncture. On the one hand, it is overwhelmed by a hidden avalanche of ephemeral bits that are central components of modern research and of the emerging ‘cyberinfrastructure’4 for e-Science.5 The rational management and exploitation of this cascade of digital assets offers boundless opportunities for research and applications. On the other hand, the ability to access and use this rising flood of data seems to lag behind, despite the rapidly growing capabilities of information and communication technologies (ICTs) to make much more effective use of those data. As long as the attention for data policies and data management by researchers, their organisations and their funders does not catch up with the rapidly changing research environment, the research policy and funding entities in many cases will perpetuate the systemic inefficiencies, and the resulting loss or underutilisation of valuable data resources derived from public investments. There is thus an urgent need for rationalised national strategies and more coherent international arrangements for sustainable access to public research data, both to data produced directly by government entities and to data generated in academic and not-for-profit institutions with public funding. In this chapter, we examine some of the implications of the ‘data driven’ research and possible ways to overcome existing barriers to accessibility of public research data. Our perspective is framed in the context of the predominantly publicly funded global science system. We begin by reviewing the growing role of digital data in research and outlining the roles of stakeholders in the research community in developing data access regimes. We then discuss the hidden costs of closed data systems, the benefits and limitations of openness as the default principle for data access, and the emerging open access models that are beginning to form digitally networked commons. We conclude by examining the rationale and requirements for developing overarching international principles from the top down, as well as flexible, common-use contractual templates from the bottom up, to establish data access regimes founded on a presumption of openness, with the goal of better capturing the benefits from the existing and future scientific data assets. The ‘Principles and Guidelines for Access to Research Data from Public Funding’ from the Organisation for Economic Cooperation and Development (OECD), reported on in another article by Pilat and Fukasaku,6 are the most important recent example of the high-level (inter)governmental approach. The common-use licenses promoted by the Science Commons are a leading example of flexible arrangements originating within the community. Finally, we should emphasise that we focus almost exclusively on the policy—the institutional, socioeconomic, and legal aspects of data access—rather than on the technical and management practicalities that are also important, but beyond the scope of this article

Tumour sampling method can significantly influence gene expression profiles derived from neoadjuvant window studies

Patient-matched transcriptomic studies using tumour samples before and after treatment allow inter-patient heterogeneity to be controlled, but tend not to include an untreated comparison. Here, Illumina BeadArray technology was used to measure dynamic changes in gene expression from thirty-seven paired diagnostic core and surgically excised breast cancer biopsies obtained from women receiving no treatment prior to surgery, to determine the impact of sampling method and tumour heterogeneity. Despite a lack of treatment and perhaps surprisingly, consistent changes in gene expression were identified during the diagnosis-surgery interval (48 up, 2 down; Siggenes FDR 0.05) in a manner independent of both subtype and sampling-interval length. Instead, tumour sampling method was seen to directly impact gene expression, with similar effects additionally identified in six published breast cancer datasets. In contrast with previous findings, our data does not support the concept of a significant wounding or immune response following biopsy in the absence of treatment and instead implicates a hypoxic response following the surgical biopsy. Whilst sampling-related gene expression changes are evident in treated samples, they are secondary to those associated with response to treatment. Nonetheless, sampling method remains a potential confounding factor for neoadjuvant study design

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe