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

Insects as Stem Engineers: Interactions Mediated by the Twig-Girdler Oncideres albomarginata chamela Enhance Arthropod Diversity

Background: Ecosystem engineering may influence community structure and biodiversity by controlling the availability of resources and/or habitats used by other organisms. Insect herbivores may act as ecosystem engineers but there is still poor understanding of the role of these insects structuring arthropod communities. Methodology/Principal Findings: We evaluated the effect of ecosystem engineering by the stem-borer Oncideres albomarginata chamela on the arthropod community of a tropical dry forest for three consecutive years. The results showed that ecosystem engineering by O. albomarginata chamela had strong positive effects on the colonization, abundance, species richness and composition of the associated arthropod community, and it occurred mainly through the creation of a habitat with high availability of oviposition sites for secondary colonizers. These effects cascade upward to higher trophic levels. Overall, ecosystem engineering by O. albomarginata chamela was responsible for nearly 95 % of the abundance of secondary colonizers and 82 % of the species richness. Conclusions/Significance: Our results suggest that ecosystem engineering by O. albomarginata chamela is a keystone process structuring an arthropod community composed by xylovores, predators and parasitoids. This study is the first to empirically demonstrate the effect of the ecosystem engineering by stem-boring insects on important attributes o

Unilateral Exoskeleton Imposes Significantly Different Hemispherical Effect in Parietooccipital Region, but Not in Other Regions

In modern society, increasing people suffering from locomotor disabilities need an assistive exoskeleton to help them improve or restore ambulation. When walking is assisted by an exoskeleton, brain activities are altered as the closed-loop between brain and lower limbs is affected by the exoskeleton. Intuitively, a unilateral exoskeleton imposes differential effect on brain hemispheres (i.e., hemispherical effect) according to contralateral control mechanism. However, it is unclear whether hemispherical effect appears in whole hemisphere or particular region. To this end, we explored hemispherical effect on different brain regions using EEG data collected from 30 healthy participants during overground walking. The results showed that hemispherical effect was significantly different between regions when a unilateral exoskeleton was employed for walking assistance and no significance was observed for walking without the exoskeleton. Post-hoc t-test analysis revealed that hemispherical effect in the parietooccipital region significantly differed from other regions. In the parietooccipital region, a greater hemispherical effect was observed in beta band for exoskeleton-assisted walking compared to walking without exoskeleton, which was also found in the source analysis. These findings deepen the understanding of hemispherical effect of unilateral exoskeleton on brain and could aid the development of more efficient and suitable exoskeleton for walking assistance

Protective effects of N-acetylcysteine on acetic acid-induced colitis in a porcine model

BACKGROUND: Ulcerative colitis is a chronic inflammatory disease and involves multiple etiological factors. Acetic acid (AA)-induced colitis is a reproducible and simple model, sharing many characteristics with human colitis. N-acetylcysteine (NAC) has been widely used as an antioxidant in vivo and in vitro. NAC can affect several signaling pathways involving in apoptosis, angiogenesis, cell growth and arrest, redox-regulated gene expression, and inflammatory response. Therefore, NAC may not only protect against the direct injurious effects of oxidants, but also beneficially alter inflammatory events in colitis. This study was conducted to investigate whether NAC could alleviate the AA-induced colitis in a porcine model. METHODS: Weaned piglets were used to investigate the effects of NAC on AA-induced colitis. Severity of colitis was evaluated by colon histomorphology measurements, histopathology scores, tissue myeloperoxidase activity, as well as concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon. The protective role of NAC was assessed by measurements of antioxidant status, growth modulator, cell apoptosis, and tight junction proteins. Abundances of caspase-3 and claudin-1 proteins in colonic mucosae were determined by the Western blot method. Epidermal growth factor receptor, amphiregulin, tumor necrosis factor-alpha (TNF-α), and toll-like receptor 4 (TLR4) mRNA levels in colonic mucosae were quantified using the real-time fluorescent quantitative PCR. RESULTS: Compared with the control group, AA treatment increased (P < 0.05) the histopathology scores, intraepithelial lymphocyte (IEL) numbers and density in the colon, myeloperoxidase activity, the concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon, while reducing (P < 0.05) goblet cell numbers and the protein/DNA ratio in the colonic mucosa. These adverse effects of AA were partially ameliorated (P < 0.05) by dietary supplementation with NAC. In addition, NAC prevented the AA-induced increase in caspase-3 protein, while stimulating claudin-1 protein expression in the colonic mucosa. Moreover, NAC enhanced mRNA levels for epidermal growth factor and amphiregulin in the colonic mucosa. CONCLUSION: Dietary supplementation with NAC can alleviate AA-induced colitis in a porcine model through regulating anti-oxidative responses, cell apoptosis, and EGF gene expression

Statin use and the risk of Clostridium difficile in academic medical centres

ObjectivesTo estimate the possible relationship between statin use and the risk of healthcare facility onset Clostridium difficile.MethodsPatients over 18 years of age admitted to hospitals contributing data to the University HealthSystem Consortium between 2002 and 2009 were eligible. Patients with the ICD-9-CM code 008.45 who received a minimum 3-day course of either metronidazole or oral vancomycin on/after day 5 of admission were considered incident cases of C difficile infection. 31\u2008472 incident cases of C difficile infection were identified and matched to five controls, on hospital, year/quarter of admission date, and age \ub110 years (N=78\u2008096). Patients who were administered one drug in the statin class (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin or simvastatin) before the index date were considered to be exposed. Conditional logistic regression modelling provided adjusted odds ratios and 95% CI.ResultsCompared with non-users, users of any drug within the statin class were 0.78 times less likely to develop C difficile infection in the hospital (95% CI 0.75 to 0.81) adjusting for potential confounders. Differences in estimates for specific statins were minimal. Niacin, fibrates and selective cholesterol absorption inhibitors showed no association with the risk of C difficile infection.ConclusionsOur data were consistent with a growing body of literature demonstrating a reduced risk of infections with statin use. Statins' pleiotropic properties may provide protection against C difficile infection

Achieving the promise of transdisciplinarity: A critical exploration of the relationship between transdisciplinary research and societal problem solving

Transdisciplinarity is often presented as a way to effectively use scientific research to contribute to societal problem solving for sustainability. The aim of this paper is to critically explore this statement. This is done in two ways. First, a literature survey of transdisciplinary research is used to identify the assumptions that underlie the positive relationship between transdisciplinarity and societal problem solving for sustainability. This mapping identifies the claim that in-depth participation of users and the integration of relevant knowledge from both practice and research in real-world problem contexts produce socially robust results that contribute to sustainability. Second, the ability to live up to this claim is presented and discussed in five case study projects from Mistra Urban Futures, a transdisciplinary center in G\uf6teborg, Sweden. The conclusions show that transdisciplinary processes, which fulfill the above conditions, do produce different types of socially robust knowledge, but this does not necessarily result in the ability to influence change in a sustainable direction. This instead creates a paradox in that the participation of stakeholders and the integration of knowledge from diverse sources require spaces that are both embedded in and insulated from practice and science proper. Such spaces produce results that are not easily aligned with sector-based target groups and formal policy processes. Institutionalizing transdisciplinarity in a boundary organization therefore solves some problems regarding participation and balanced problem ownership. However, it also creates new, hybrid problems, regarding knowledge transfer and scalability, which bridge the boundaries and challenge the praxis of planning and policy-making