SPARC, FOXP3, CD8 and CD45 Correlation with Disease Recurrence and Long-Term Disease-Free Survival in Colorectal Cancer

BACKGROUND: SPARC is a matricellular protein involved in tissue remodelling, cell migration and angiogenesis, while forkhead box P3 (FOXP3) protein functions as a transcription factor involved in immune cell regulation. Both SPARC and FOXP3 can play an anti-tumorigenic role in cancer progression. The aim was to determine if SPARC, FOXP3, CD8 and CD45RO expression levels are associated with colorectal cancer (CRC) stage, disease outcome and long-term cancer-specific survival (CSS) in stage II and III CRC. METHODS AND FINDINGS: SPARC expression was initially assessed in 120 paired normal and stage I-IV CRCs. Subsequently, approximately 1000 paired patient samples of stage II or III CRCs in tissue microarrays were stained for SPARC, FOXP3, CD8 or CD45RO. Proportional hazards modelling assessed correlations between these markers and clinicopathological data, including disease outcome and cancer specific survival (CSS). Both SPARC and FOXP3 expression were significantly greater in CRC than normal colon (p<0.0001). High SPARC expression correlated with good disease outcome (≥60 mths without disease recurrence, p = 0.0039) and better long-term CSS in stage II CRC (<0.0001). In stage III CRC, high SPARC expression correlated with better long-term CSS (p<0.0001) and less adjuvant chemotherapy use (p = 0.01). High FOXP3 correlated with a good disease outcome, better long-term CSS and less adjuvant chemotherapy use in stage II (p<0.0037, <0.0001 and p = 0.04 respectively), but not in stage III CRC. High CD8 and CD45RO expression correlated with better disease outcome in stage II CRC, and better CSS, but the differences were not as marked as for SPARC and FOXP3. CONCLUSIONS: These data suggest that high SPARC and FOXP3 are associated with better disease outcome in stage II CRC and may be prognostic indicators of CSS. Further assessment of whether these markers predict patients at high risk of recurrence with stage II CRC and functional studies of these effects are underway

High Dose Vitamin D supplementation alters faecal microbiome and predisposes mice to more severe colitis

Vitamin D has been suggested as a possible adjunctive treatment to ameliorate disease severity in human inflammatory bowel disease. In this study, the effects of diets containing high (D++, 10,000 IU/kg), moderate (D+, 2,280 IU/kg) or no vitamin D (D-) on the severity of dextran sodium sulphate (DSS) colitis in female C57Bl/6 mice were investigated. The group on high dose vitamin D (D++) developed the most severe colitis as measured by blinded endoscopic (p < 0.001) and histologic (p < 0.05) assessment, weight loss (p < 0.001), drop in serum albumin (p = 0.05) and increased expression of colonic TNF-α (p < 0.05). Microbiota analysis of faecal DNA showed that the microbial composition of D++ control mice was more similar to that of DSS mice. Serum 25(OH)D3 levels reduced by 63% in the D++ group and 23% in the D+ group after 6 days of DSS treatment. Thus, high dose vitamin D supplementation is associated with a shift to a more inflammatory faecal microbiome and increased susceptibility to colitis, with a fall in circulating vitamin D occurring as a secondary event in response to the inflammatory process

Enhancing the resilience capacity of SENSitive mountain FORest ecosystems under environmental change (SENSFOR): COST Action ES1203: SENSFOR Deliverable 5

Treeline ecotones in mountains all over the world are dynamic and in many cases changing due to human impact, but there is considerable regional variation. Nevertheless, pressures on the treeline ecotone can be differentiated in abiotic (e.g. wind, fire, drought, avalanche), biotic (e.g. insects, browsing, pathogens) and anthropogenic ones (e.g. pollution, overgrazing, global warming). There is a need for a set of indicators but it is difficult to find indicators for entire ecosystems. Indicators within treeline ecotones can be subdivided into those indicating impact on vegetation, soil or fauna. There can be natural ecosystem responses, not triggered by human impact. One example is the influence of strong winds on the growth form of trees. However, there can be responses of the ecosystem and the related ecosystem services due to human impact. One example is the erosion due to overgrazing. The ecosystem service for decomposition and thus nutrient cycling would be hampered. The connection between pressures and indicators using the Driver, Pressure, State, Impact, Response (DPSIR) framework can be clarified by showing two examples. The first example is focusing on climate change. Precipitation is one DRIVER with heavy rain events putting PRESSURE on ecotones. In case for steep slopes (STATE), the heavy rain would lead to an IMPACT on the stability of the slope. The ecological RESPONSE to this impact would be the instability of the slope with the INDICATOR of a landslide. The anthropogenic RESPONSE may be a technical solution fixing the slope. The second example is focusing on land use change. Grazing is one DRIVER and overgrazing the PRESSURE. In case there are sandy and dry soils covered by plants used as forage for the animals (STATE) the ecological RESPONSE would be erosion. In this case, the INDICATOR would be the area with bare soil. The anthropogenic RESPONSE could be the reduction of the number of grazing animals. Due to the high vulnerability of treeline ecosystems, the ecological resilience is low. When vegetation is damaged due to natural and/or human impact, erosion removes the soil cover including most of the carbon. Above- and belowground biodiversity is getting reduced, leading to reduced ecosystem services such as carbon sequestration or decomposition providing nutrients. Meanwhile, those policy makers who have to deal with climate change have following the topics on the agenda: biodiversity, land degradation and carbon sequestration. Thus, there is a slim chance, that recommendations to preserve carbon stocks, to prevent soil erosion and to protect biodiversity (including belowground biodiversity) will be accepted by policy makers. On the other hand, most of the stakeholders are not open to be convinced this way. Most probably, economic benefits will weigh more than biodiversity issues in ecotones for the future. In this deliverable, we introduce 18 indicators that help practitioners and scientists to understand changes, sustainability issues and resilience of sensitive mountain forest ecosystems. Our aim is to identify a common set of indicators to monitor and analyze changes in treeline biodiversity and to develop monitoring methodology. Findings are based on literature, previous and in-project scientific work of the SENSFOR working groups and experimental work, testing the practicality of preliminary indicators with forest technicians (Ferranti 2015). 3 It is important to understand that especially social indicators listed here might be related to treeline issues. Conflicts can take place at local level while economic and population structure changes may not have any effect on the condition of forest ecosystems. This means that following indicators do not necessarily indicate the sustainability issues linked to treeline ecotones. However, there can be connections and causalities between these variables and in each case, potential linkages need to be tested for: 1. to identify a common set of monitoring indicators to analyze changes in the treeline ecotone which could be used for monitoring; 2. to create a holistic set of indicators for the vulnerability and resilience of coupled socio-ecological systems on the basis of the DPSIR framework analysis. The following Indicators could be used for monitoring changes in the treeline ecotone: 1. Ecological Indicators are related to plants, the soil and the fauna. Usually, trees, their growth form or seedling production, are in the focus but soil indicators like carbon stock or soil biodiversity are considered less but with increasing tendency; 2. Economic Indicators, a valuable economic indicator may be the reduction of the amount of income of the stakeholders, e.g. due to reduced tourism in high mountain areas, triggered by global warming. Also, the distribution of benefits (in most cases income) among stakeholders could be influenced. 3. Social and Cultural Indicators, an important social indicator is the conflict between people who use the land and those people who would like to protect nature and the ecological ecosystem services. The indicators are explained in detail in the following, considering several case studies in different parts of Europe

Dietary iron enhances colonic inflammation and IL-6/IL-11-Stat3 signaling promoting colonic tumor development in mice

Chronic intestinal inflammation and high dietary iron are associated with colorectal cancer development. The role of Stat3 activation in iron-induced colonic inflammation and tumorigenesis was investigated in a mouse model of inflammation-associated colorectal cancer. Mice, fed either an iron-supplemented or control diet, were treated with azoxymethane and dextran sodium sulfate (DSS). Intestinal inflammation and tumor development were assessed by endoscopy and histology, gene expression by real-time PCR, Stat3 phosphorylation by immunoblot, cytokines by ELISA and apoptosis by TUNEL assay. Colonic inflammation was more severe in mice fed an iron-supplemented compared with a control diet one week post-DSS treatment, with enhanced colonic IL-6 and IL-11 release and Stat3 phosphorylation. Both IL-6 and ferritin, the iron storage protein, co-localized with macrophages suggesting iron may act directly on IL-6 producing-macrophages. Iron increased DSS-induced colonic epithelial cell proliferation and apoptosis consistent with enhanced mucosal damage. DSS-treated mice developed anemia that was not alleviated by dietary iron supplementation. Six weeks post-DSS treatment, iron-supplemented mice developed more and larger colonic tumors compared with control mice. Intratumoral IL-6 and IL-11 expression increased in DSS-treated mice and IL-6, and possibly IL-11, were enhanced by dietary iron. Gene expression of iron importers, divalent metal transporter 1 and transferrin receptor 1, increased and iron exporter, ferroportin, decreased in colonic tumors suggesting increased iron uptake. Dietary iron and colonic inflammation synergistically activated colonic IL-6/IL-11-Stat3 signaling promoting tumorigenesis. Oral iron therapy may be detrimental in inflammatory bowel disease since it may exacerbate colonic inflammation and increase colorectal cancer risk