Association between local immune cell infiltration, mismatch repair status and systemic inflammatory response in colorectal cancer

Systemic inflammatory response in colorectal cancer (CRC) has been established as a prognostic factor for impaired cancer-specific survival, predominantly in patients with right-sided tumors. On the other hand, defective mismatch repair (dMMR) tumors, primarily located in the right colon, are known to have favorable survival and dense local immune infiltration. The aim of this study was to see if there is any form of relationship between these seemingly diverse entities.Peer reviewe

The Relationship between the Tissue Expression of TLR2, TLR4, TLR5, and TLR7 and Systemic Inflammatory Responses in Colorectal Cancer Patients

Background: Colorectal cancer (CRC) is the third most commonly diagnosed malignancy globally. CRC patients with elevated plasma C-reactive protein (CRP) levels exhibit compromised prognoses. Toll-like receptors (TLRs), activating the innate and adaptive immune systems, may contribute to pro- and antitumorigenic inflammatory responses. We aimed to identify a possible link between local and systemic inflammatory responses in CRC patients by investigating the association between tissue TLRs and plasma CRP. Methods: Tissue expressions of TLR2, TLR4, TLR5, and TLR7 were assessed using immunohistochemistry of tissue microarray slides from 549 CRC patients surgically treated between 1998 and 2005. Blood samples were drawn preoperatively, centrifuged, aliquoted, and stored at -80 degrees C until analysis. Plasma CRP was determined through high-sensitivity time-resolved immunofluorometric assay. We investigated the association of TLRs to clinicopathologic variables, plasma CRP, and survival. Results: High TLR2 expression (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.41-0.85; p = 0.005), high TLR5 expression (HR 0.60; 95% CI 0.45-0.83; p = 0.002), positive TLR7 expression (HR 0.49; 95% CI 0.33-0.72; p < 0.001), and low CRP (HR 1.48; 95% CI 1.08-2.11; p = 0.017) were associated with a better prognosis. A high TLR2 immunoexpression was associated with a better prognosis among low-CRP patients (HR 0.53; 95% CI 0.35-0.80; p = 0.002), high TLR4 expression among high-CRP patients (HR 2.04; 95% CI 1.04-4.00; p = 0.038), high TLR5 expression among low-CRP patients (HR 0.059; 95% CI 0.37-0.92; p = 0.021), and positive TLR7 expression among low-CRP patients (HR 0.53; 95% CI 0.28-1.00; p = 0.049). In multivariate analyses, no biomarkers emerged as significant independent variables. Conclusions: High tissue TLR2, TLR5, and TLR7 levels were associated with a better prognosis. Among low-CRP patients, those with high TLR2, TLR5, and TLR7 immunoexpressions exhibited a better prognosis. Among high CRP patients, a high TLR4 immunoexpression was associated with a better prognosis.Peer reviewe

The Prognostic Importance of CD20(+) B lymphocytes in Colorectal Cancer and the Relation to Other Immune Cell subsets

The anti-tumour immune response is critical to patient prognosis in colorectal cancer (CRC). The aim of this study was to investigate infiltration of B lymphocytes into CRC tumours, and their clinical relevance, prognostic value and relation to other immune cell subsets. We used multiplexed immunohistochemistry and multispectral imaging to assay the amount of infiltrating CD20(+) B lymphocytes along with infiltration of CD8(+) cytotoxic T cells, FOXP3(+) T regulatory cells, CD68(+) macrophages and CD66b(+) neutrophils, in 316 archival CRC tissue specimens. A higher density of infiltrating CD20(+) B lymphocytes was associated with tumours of the right colon (P = 0.025) and of lower stages (P = 0.009). Furthermore, patients whose tumours were highly infiltrated by CD20(+) B lymphocytes had a significantly improved disease-specific survival (HR = 0.45, 95% CI 0.28-0.73, P = 0.001), which remained significant in multivariable analysis. CD20(+) B lymphocytes were highly and positively associated with CD8(+) T lymphocytes (P <0.001), and part of the prognostic role was found to be a cooperative effect between these lymphocyte subsets. Our results support a favourable prognostic value of tumour-infiltrating CD20(+) B lymphocytes in CRC. Furthermore, a cooperative prognostic effect between CD20(+) B lymphocytes and CD8(+) T lymphocytes is suggested.Peer reviewe

EZH2 Depletion Blocks the Proliferation of Colon Cancer Cells

The Enhancer of Zeste 2 (EZH2) protein has been reported to stimulate cell growth in some cancers and is therefore considered to represent an interesting new target for therapeutic intervention. Here, we investigated a possible role of EZH2 for the growth control of colon cancer cells. RNA interference (RNAi)-mediated intracellular EZH2 depletion led to cell cycle arrest of colon carcinoma cells at the G1/S transition. This was associated with a reduction of cell numbers upon transient transfection of synthetic EZH2-targeting siRNAs and with inhibition of their colony formation capacity upon stable expression of vector-borne siRNAs. We furthermore tested whether EZH2 may repress the growth-inhibitory p27 gene, as reported for pancreatic cancer. However, expression analyses of colon cancer cell lines and colon cancer biopsies did not reveal a consistent correlation between EZH2 and p27 levels. Moreover, EZH2 depletion did not re-induce p27 expression in colon cancer cells, indicating that p27 repression by EZH2 may be cell- or tissue-specific. Whole genome transcriptome analyses identified cellular genes affected by EZH2 depletion in colon cancer cell lines. They included several cancer-associated genes linked to cellular proliferation or invasion, such as Dag1, MageD1, SDC1, Timp2, and Tob1. In conclusion, our results demonstrate that EZH2 depletion blocks the growth of colon cancer cells. These findings might provide benefits for the treatment of colon cancer

Baicalin Downregulates Porphyromonas gingivalis Lipopolysaccharide-Upregulated IL-6 and IL-8 Expression in Human Oral Keratinocytes by Negative Regulation of TLR Signaling

published_or_final_versio

Soil Management Strategies to Establish Vegetation and Groundwater Recharge when Restoring Gravel Pits

The removal of vegetation and overburden changes the naturalwater purifying processes and thus decreases the groundwaterprotection in gravel pit areas. The sand and gravel depositsusedfor aggregate extraction in Sweden are also often valuablefor extraction of groundwater as a drinking water resource. TheSwedish legislation requires that gravel pits be restored afterthe cessation of extraction, the aim being to reestablishvegetation and to reinstate groundwater purifyingprocesses. The objective of this study was to improve our understandingof the processes governing groundwater protection andvegetation establishment so that these could be applied toimproving restoration methods for reestablishing naturalgroundwater protection. The focus was on the importance of soilphysical properties of the topsoil for vegetation establishmentand groundwater recharge. Actual field methods for restoration were reviewed.Conflicts between aggregate extraction and groundwaterinterests were common. In many cases the actual restorationcarried out differed from pre-planned specifications in permitdocumentation. Commonly available substrates that might be used forrestoration of gravel pits were investigated. The soils weredescribed as regards texture, organic content, porosity, waterretention and hydraulic conductivity. The way in which acombination of the water retention characteristic and theunsaturated conductivity influenced the behaviour of thesoil-plant-atmosphere system was demonstrated using aprocess-orientated simulation model. Plants with well-developedaboveground characteristics and shallow roots in particularexerted the highest requirements on the soil physicalproperties. Key words:groundwater protection, soil physicalproperties, CoupModel, unsaturated conductivity, waterretention, transpiration, soil evaporatio

Scale-up of high-solid enzymatic hydrolysis of steam-pretreated softwood : the effects of reactor flow conditions

The importance of flow conditions during scale-up of high-solid enzymatic hydrolysis of steam-pretreated spruce was demonstrated by comparing hydrolysis rates between laboratory (2 L) and demonstration (4 m3) scale. A positive effect of increased agitation speed on the rate of enzymatic hydrolysis was found regardless of scale. Importantly, the hydrolysis rate was higher at the larger scale when compared at similar specific power inputs. Changes in the rheological properties of the pretreated material during the hydrolysis were followed by off-line measurements of apparent viscosity. This information was used to estimate the flow conditions in the reactors, i.e., average Reynolds numbers, which together with measured mixing power consumptions enabled a more detailed comparison between the scales. The hydrolysis yields correlated better with average Reynolds numbers than specific power input over the different scales. This indicates that mass transport limitations, caused by insufficient bulk flow, likely play a decisive role in determining the rate of enzymatic hydrolysis

Attitudes to and Experiences of Physical Activity After Colon Cancer Diagnosis Amongst Physically Active Individuals : A Qualitative Study

BACKGROUND: Physical activity improves survival, reduces postoperative complications, and reduces the risk of developing colon cancer. It is important to maintain physical activity after receiving a diagnosis of colon cancer to improve postoperative recovery. Individuals who are physically active and diagnosed with colon cancer presumably have different motivations to maintain physical activity compared to their sedentary counterparts. OBJECTIVE: Enlighten how the diagnosis of colon cancer might affect physically active individuals in their attitude and experiences towards physical activity. METHODS: A qualitative study using content analysis was conducted in northern Sweden based on semi-structured telephone interviews of twenty patients diagnosed with colon cancer. All participants met the recommendations for physical activity issued by the World Health Organization. RESULTS: Participants were between 50 and 88 years and 50% were male. Three main categories were identified: I'll fight the cancer and come out stronger; The diagnosis makes no difference; and The diagnosis is an obstacle for physical activity. These main categories represent the ways the individuals reacted to the diagnosis of colon cancer regarding their physical activity. CONCLUSION: Attitudes to and experience of physical activity after colon cancer diagnosis varied from a will to increase physical activity and fight the cancer, to the diagnosis putting a stop to physical activity. It is important that healthcare professionals recommend physical activity even in already physically active individuals, to encourage continued physical activity after diagnosis of colon cancer

Structural Differences of the Semantic Network in Adolescents with Intellectual Disability

The semantic network structure is a core aspect of the mental lexicon and is, therefore, a key to understanding language development processes. This study investigated the structure of the semantic network of adolescents with intellectual disability (ID) and children with typical development (TD) using network analysis. The semantic networks of the participants (nID = 66; nTD = 49) were estimated from the semantic verbal fluency task with the pathfinder method. The groups were matched on the number of produced words. The average shortest path length (ASPL), the clustering coefficient (CC), and the network’s modularity (Q) of the two groups were compared. A significantly smaller ASPL and Q and a significantly higher CC were found for the adolescents with ID in comparison with the children with TD. Reasons for this might be differences in the language environment and differences in cognitive skills. The quality and quantity of the language input might differ for adolescents with ID due to differences in school curricula and because persons with ID tend to engage in different out-of-school activities compared to TD peers. Future studies should investigate the influence of different language environments on the language development of persons with IDFunding agencies: European Union Seventh Framework Program (FP7/2007–2013) under Grant Agreement FP7-607139 (iCARE) and by the Swedish Research Council (2013-01363 and 2016-04217)</p

Association of pre-diagnostic physical exercise and peri-diagnostic body composition with mortality in non-metastatic colorectal cancer

Purpose: Sarcopenia and myosteatosis, quantified via computed tomography (CT), are associated with poor colorectal cancer outcomes. These body composition estimates can be influenced by physical exercise. We explored the correlation between pre-diagnostic physical exercise, body composition close to diagnosis, and the combined prognosis impact of these factors. Methods: We studied 519 stage I–III colorectal cancer (CRC) cases diagnosed 2000–2016 with pre-diagnostic self-reported recreational physical exercise data collected in the prospective, population-based Northern Sweden Health and Disease Study, and CT-estimated skeletal muscle index (SMI) or skeletal muscle density (SMD). Risk estimates were calculated by multivariable logistic regression and Cox proportional hazards models. Results: No association was seen between low pre-diagnostic physical exercise and sarcopenia/myosteatosis in the multivariable model adjusted for age, sex, educational level, tumor stage, and tumor location. In multivariable Cox regression models, the combination of low pre-diagnostic physical exercise and either sarcopenia or myosteatosis at the time of diagnosis was associated with cancer-specific mortality compared to the reference group of high physical exercise combined with no sarcopenia/myosteatosis (adjusted HR 1.94 95% CI 1.00–3.76 for sarcopenia and adjusted HR 2.39 95% CI 1.16–4.94 for myosteatosis). Conclusions: The combined presence of low pre-diagnostic physical exercise and sarcopenia or myosteatosis was associated with increased CRC-specific mortality. Despite the positive effect on prognosis, physical exercise did not alter body composition estimates at diagnosis, which could indicate attenuation from other factors