Increased Toll-like receptor 9 expression indicates adverse prognosis in oesophageal adenocarcinoma

Kauppila J H, Takala H, Selander K S, Lehenkari P P, Saarnio J & Karttunen T J
(2011) Histopathology 59 , 643–649 Increased Toll‐like receptor 9 expression indicates adverse prognosis in oesophageal adenocarcinoma Aims: Toll‐like receptor 9 (TLR‐9) is a cellular DNA receptor that has been linked previously to invasion in various cancers. The aim of this study was to investigate TLR‐9 expression and its possible association with prognosis in oesophageal adenocarcinoma. Methods and results: Immunohistochemical TLR‐9 expression was graded in clinical specimens (n = 76) of oesophageal adenocarcinoma. The TLR‐9 immunostaining intensity was compared with tumour grade, stage and indicators of proliferation, apoptosis and tumour vascular supply. High TLR‐9 expression correlated with advanced tumour stage, tumour unresectability, poor differentiation and high proliferation. Strong immunoreactivity of TLR‐9 also indicated poor overall survival. Conclusions: High TLR‐9 expression is associated with poor differentiation, a high proliferation rate and disseminated disease. Accordingly, increased TLR‐9 expression may contribute to the growth and metastatic properties of oesophageal adenocarcinoma.     

Evaluation of STOX1 as a preeclampsia candidate gene in a population-wide sample

Preeclampsia is a common, pregnancy-specific vascular disorder characterised by hypertension and proteinuria. A recent report suggested association of the STOX1 gene on chromosome 10q22.1 with preeclampsia in the Dutch population. Here, we present a comprehensive assessment of STOX1 as a candidate gene for preeclampsia in the Finnish population by re-examining our previous genetic linkage analysis results for both chromosome 10 and paralogous loci, by genotyping representative markers in a nationwide data set, and by studying STOX1 expression in placentas from preeclamptic and uncomplicated pregnancies. In conclusion, we are unable to validate STOX1 as a common preeclampsia susceptibility gene.     

The human GIMAP5 gene has a common polyadenylation polymorphism increasing risk to systemic lupus erythematosus

Background

Several members of the GIMAP gene family have been suggested as being involved in different aspects of the immune system in different species. Recently, a mutation in the GIMAP5 gene was shown to cause lymphopenia in a rat model of autoimmune insulin‐dependent diabetes. Thus it was hypothesised that genetic variation in GIMAP5 may be involved in susceptibility to other autoimmune disorders where lymphopenia is a key feature, such as systemic lupus erythematosus (SLE).

Material and methods

To investigate this, seven single nucleotide polymorphisms in GIMAP5 were analysed in five independent sets of family‐based SLE collections, containing more than 2000 samples.

Result

A significant increase in SLE risk associated with the most common GIMAP5 haplotype was found (OR 1.26, 95% CI 1.02 to 1.54, p = 0.0033). In families with probands diagnosed with trombocytopenia, the risk was increased (OR 2.11, 95% CI 1.09 to 4.09, p = 0.0153). The risk haplotype bears a polymorphic polyadenylation signal which alters the 3′ part of GIMAP5 mRNA by producing an inefficient polyadenylation signal. This results in higher proportion of non‐terminated mRNA for homozygous individuals (p<0.005), a mechanism shown to be causal in thalassaemias. To further assess the functional effect of the polymorphic polyadenylation signal in the risk haplotype, monocytes were treated with several cytokines affecting apoptosis. All the apoptotic cytokines induced GIMAP5 expression in two monocyte cell lines (1.5–6 times, p<0.0001 for all tests).

Conclusion

Taken together, the data suggest the role of GIMAP5 in the pathogenesis of SLE.     

Novel parameters indicate significant differences in severity of obstructive sleep apnea with patients having similar apnea–hypopnea index

Sleep apnea–hypopnea syndrome (SAHS) causes impairment of daytime functions and increases risk of cardiovascular diseases. Apnea–hypopnea index (AHI), currently used for the estimation of the severity of SAHS, does not contain information on the morphology or duration aspects of the breathing cessations and related oxygen desaturations. Longer breathing cessations and deeper desaturations may have more severe consequences than shorter and shallower ones. To address these issues, novel parameters containing information on the duration and morphology of breathing cessations and oxygen desaturations were calculated and evaluated on 160 male patients (40 patients in normal, mild, moderate and severe AHI severity categories). Obstruction and desaturation duration parameters consist of sum of event durations normalized with the total analysed time. Desaturation severity is a sum of desaturation event areas normalized with total analysed time and obstruction severity parameter is a sum of the products of apnea and hypopnea durations and related desaturation areas normalized with total analysed time. The median follow-up time of the patients was 183 months (range 154–215 months). The 40 patients in each category were further divided into subgroups A and B with lowest and highest novel parameter values, respectively. AHI showed no differences between the subgroups. Mortality was increased in subgroups B compared to subgroups A. The correlation of the novel parameters with AHI was only moderate and the parameter values were partially overlapping between the AHI severity categories. This suggests that patients with similar AHI may in fact suffer from SAHS of very different severity. Thus, the present results suggest that the novel parameters could bring new insight to the individual estimation of the severity of SAHS.     

Low total haemoglobin mass, blood volume and aerobic capacity in men with type 1 diabetes

Blood O₂ carrying capacity affects aerobic capacity (VO_2max). Patients with type 1 diabetes have a risk for anaemia along with renal impairment, and they often have low VO_2max. We investigated whether total haemoglobin mass (tHb-mass) and blood volume (BV) differ in men with type 1 diabetes (T1D, n = 12) presently without complications and in healthy men (CON, n = 23) (age-, anthropometry-, physical activity-matched), to seek an explanation for low VO_2max. We determined tHb-mass, BV, haemoglobin concentration ([Hb]), and VO_2max in T1D and CON. With similar (mean ± SD) [Hb] (144 vs. 145 g l^?1), T1D had lower tHb-mass (10.1 ± 1.4 vs. 11.0 ± 1.1 g kg^?1, P < 0.05), BV (76.8 ± 9.5 vs. 83.5 ± 8.3 ml kg^?1, P < 0.05) and VO_2max (35.4 ± 4.8 vs. 44.9 ± 7.5 ml kg^?1 min^?1, P < 0.001) than CON. VO_2max correlated with tHb-mass and BV both in T1D (r = 0.71, P < 0.01 and 0.67, P < 0.05, respectively) and CON (r = 0.54, P < 0.01 and 0.66, P < 0.001, respectively), but not with [Hb]. Linear regression slopes were shallower in T1D than CON both between VO_2max and tHb-mass (2.4 and 3.6 ml kg^?1 min^?1 vs. g kg^?1, respectively) and VO_2max and BV (0.3 and 0.6 ml kg^?1 min^?1 vs. g kg^?1, respectively), indicating that T1D were unable to reach similar VO_2max than CON at a given tHb-mass and BV. In conclusion, low tHb-mass and BV partly explained low VO_2max in T1D and may provide early and more sensitive markers of blood O₂ carrying capacity than [Hb] alone.     

Short DNA sequences and bacterial DNA induce esophageal,gastric, and colorectal cancer cell invasion

Toll‐like receptor 9 (TLR9) recognizes both bacterial and self‐DNA and it is abundantly expressed in the gastrointestinal tract. In this study, we investigated the influences of both bacterial DNA and specific short DNA sequences on TLR9‐mediated gastrointestinal cancer cell invasion. We assessed the effect of various DNA ligands on cellular invasion and on TLR9 and matrix metalloproteinase expression of three gastrointestinal cancer cell lines. DNA‐ligands described in this study include CpG‐ODN M362, 9‐mer (hairpin), human telomeric sequence h‐Tel22 G‐quadruplex, and bacterial DNAs from Escherichia coli and Helicobacter pylori. All of the DNAs studied were demonstrated to induce invasion in the studied cells. The DNA‐induced invasion was inhibited with a broad‐spectrum MMP inhibitor and partly also with chloroquine suggesting that it could be mediated via MMP activation, endosomal signaling, and TLR9. Interestingly, H. pylori DNA was shown to induce a more pronounced invasion in a gastric cancer cell line than in the other cell lines. Our results suggest that bacterial DNA as well as deoxynucleotides having stable secondary structures (i.e. hairpins or G‐quadruplex structures) may serve as endogenous, invasion‐inducing TLR9‐ligands and promote local progression and metastasis of cancers in the alimentary tract.     

The middle range of the number line orients attention to the left side of visual space

Mental representation of numbers is believed to be spatial in nature, with small numbers occupying the left and large numbers the right side of a putative mental number line. Consistent with this, presentation of numbers from the low and high ends of the mental number line induces covert shifts of spatial attention to the left and right side of visual space, respectively. However, the effect of the presentation of the middle range (containing numbers below and above the midpoint) of the number line on visual perception has so far not been studied. Here we show in two experiments, using a line bisection task and a simple target detection task, that processing of middle-range numbers affects allocation of visuospatial attention in a similar way as processing of small numbers, with attention shifted to the left side of space. We suggest that this pattern of results arises due to “anchoring” heuristics that participants use in number processing.     

Mycoplasma pneumoniae may cause dyspnoea and hospitalisations in young healthy adults

European Journal of Clinical Microbiology & Infectious Diseases - Polymerase chain reaction (PCR)-based diagnostics for Mycoplasma pneumoniae (M. pneumoniae) from the respiratory tract has...     

AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan

Adenosine monophosphate-activated protein kinase (AMPK) is a crucial regulator of energy metabolic homeostasis and thus a major survival factor in a variety of metabolic stresses and also in the aging process. Metabolic syndrome is associated with a low-grade, chronic inflammation, primarily in adipose tissue. A low-level of inflammation is also present in the aging process. There are emerging results indicating that AMPK signaling can inhibit the inflammatory responses induced by the nuclear factor-κB (NF-κB) system. The NF-κB subunits are not direct phosphorylation targets of AMPK, but the inhibition of NF-κB signaling is mediated by several downstream targets of AMPK, e.g., SIRT1, PGC-1α, p53, and Forkhead box O (FoxO) factors. AMPK signaling seems to enhance energy metabolism while it can repress inflammatory responses linked to chronic stress, e.g., in nutritional overload and during the aging process. AMPK can inhibit endoplasmic reticulum and oxidative stresses which are involved in metabolic disorders and the aging process. Interestingly, many target proteins of AMPK are so-called longevity factors, e.g., SIRT1, p53, and FoxOs, which not only can increase the stress resistance and extend the lifespan of many organisms but also inhibit the inflammatory responses. The activation capacity of AMPK declines in metabolic stress and with aging which could augment the metabolic diseases and accelerate the aging process. We will review the AMPK pathways involved in the inhibition of NF-κB signaling and suppression of inflammation. We also emphasize that the capacity of AMPK to repress inflammatory responses can have a significant impact on both healthspan and lifespan.