•Altered maternal inflammatory responses mayconfer increased risk of early-onset preeclampsia (EOP).•Maternal TLR4Asp299GlyandThre399Ilealleles confer susceptibility to EOP.•Adjusted EOP risk ...ofTLR4Asp299Glycarriersis 2.94.•Adjusted EOP risk ofTLR4Thre399Ilecarriersis 3.52.
Altered maternal inflammatory responses may play a role in the development of hypertensive disorders of pregnancy like preeclampsia, its more severe early-onset form and intrauterine growth restriction. We evaluated the relation of common allelic variants of Toll-like receptor 4 (TLR4), known to impair the inflammatory response, with the susceptibility to early-onset preeclampsia in Central Greece.
We compared the occurrence of TLR4 (Asp299Gly and Thr399Ile) alleles in heterozygous (A/G, C/T) and homozygous (G/G, T/T) states in 84 women with a history of early-onset preeclampsia and 94 age matched controls with a history of only uneventful pregnancies, by direct sequencing.
Heterozygous TLR4 allelic variants were more common in women with a history of early-onset preeclampsia than in controls (GA for Asp299Gly: 14.3% vs 6.4% (AA), p = 0.053 & CT for Thr399Ile: 16.7% vs. 6.4% (CC), p = 0.019) and a stronger association was obtained when homozygous allelic carriers were also included (GA/GG for Asp299Gly: 16.7% vs. 6.4% (AA), p = 0.03 & TC/TT for Thr399Ile: 19.0% vs. 6.4% (CC), p = 0.01).
We recorded association between common TLR4 gene variants and early-onset preeclampsia. Our findings support the involvement of maternal innate immune system in severe hypertensive disorders of pregnancy and point to the potential value of maternal TLR4 polymorphisms as predictors-risk factors of susceptibility to early-onset preeclampsia in Central Greece.
The objectives of our explorative study were to (i) evaluate the immunohistochemical expression of sex steroid hormone receptors (estrogen receptor a ERα, estrogen receptor β ERβ, progesterone ...receptor PR and androgen receptor AR), angiogenesis factors (vascular endothelial growth factor VEGF and inhibitor of differentiation/DNA synthesis 1 Id-1) and cell-cycle regulators (cyclin D1, p16 and p27) in intraductal papillary mucinous neoplasms (IPMNs) in comparison to normal adjacent pancreatic tissues and (ii) assess their correlation with the grade and histological sub-type of those lesions.
Paraffin-embedded specimens from 12 consecutive patients with IPMNs were immunostained for the studied markers and staining quantification was assessed by an image analysis system.
AR H-score and cyclin D1 H-score were significantly higher in the IPMN lesions (0.86±0.33 vs. 0.57±0.12 in the normal tissue, p=0.010 and 0.47±0.23 vs. 0.21±0.20 in the normal tissue, p=0.019, respectively). No significant differences were noted regarding the expression of ERα, ERβ, PR, p16, p27, VEGF, Id-1 or MVD. Moreover, no significant associations were found between the expression of studied markers and grade or histological subtype.
Our study showed higher expression of AR and cyclin D1 in IPMNs compared to normal pancreatic ducts without any association between AR and cyclin D1 expression and IPMNs' grade or subtype.
Immature gut motility in very low birth weight infants causes feeding intolerance. We evaluated the effect of domperidone, a prokinetic agent, on gastric emptying in very low birth weight infants.
...The study was conducted in a crossover design. Gastric emptying was assessed ultrasonographically by measuring the time it took the antral cross sectional area of the stomach to reach half of the value of the 1st measurement on 2 occasions: (1) upon administration of domperidone (0.3 mg/kg/8 h p.o.) for at least 2 days and (2) while patients received an equal quantity of sterile water. 11 infants were randomly assigned to receive domperidone before the 1st measurement and the remaining afterwards. There was a 3-5 day interval between the 2 measurements. At the time when both measurements were performed, every neonate had been receiving the same quantity and quality of milk. 12 infants were formula-fed while 10 were fed their own mother's supplemented milk.
22 infants with a mean (SD) birth weight of 1,377 g (319) and a mean (SD) gestational age of 30.2 weeks (2.1) were studied. The mean (SD) antral cross sectional area half-value time (in minutes) was 47.6 (23.9) in the domperidone group and 68.2 (25.5) in the control group (p = 0.008). There was no significant difference between formula-fed neonates and neonates fed their own mother's milk in either group.
Domperidone significantly reduces gastric emptying in preterm neonates, and this may account for its effect in cases of disturbances related to gut motility.
Continuous outlier detection in data streams Georgiadis, Dimitrios; Kontaki, Maria; Gounaris, Anastasios ...
Proceedings of the 2013 ACM SIGMOD International Conference on Management of Data,
06/2013
Conference Proceeding
Anomaly detection is an important data mining task, aiming at the discovery of elements that show significant diversion from the expected behavior; such elements are termed as outliers. One of the ...most widely employed criteria for determining whether an element is an outlier is based on the number of neighboring elements within a fixed distance (R), against a fixed threshold (k). Such outliers are referred to as distance-based outliers and are the focus of this work. In this demo, we show both an extendible framework for outlier detection algorithms and specific outlier detection algorithms for the demanding case where outlier detection is continuously performed over a data stream. More specifically: i) first we demonstrate a novel flavor of an open-source publicly available tool for Massive Online Analysis (MOA) that is endowed with capabilities to encapsulate algorithms that continuously detect outliers and ii) second, we present four online outlier detection algorithms. Two of these algorithms have been designed by the authors of this demo, with a view to improving on key aspects related to outlier mining, such as running time, flexibility and space requirements.
Heat-shock protein 90 (HSP90) is an abundant protein in mammalian cells. It interacts with a variety of proteins that play key roles in breast neoplasia. This is the first study to assess serum ...levels of HSP90 in atypical ductal hyperplasia (ADH), lobular neoplasia (LN), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and infiltrative lobular carcinoma (ILC).
Serum concentrations of HSP90 in women with benign (n=34), ADH (n=26), DCIS (n=30), IDC (n=29), LN (n=20) and ILC (n=9) lesions were determined with immunoenzymatic assays. For the evaluation of serum concentrations along the transition from benign through precursor and preinvasive to invasive lesion, the severity of diagnosis was treated as an ordinal variable.
No significant association was demonstrated between serum HSP90 levels and the severity of the lesion in ductal and lobular series. The post hoc comparison between the lobular and ductal precursor lesions (i.e. ADH vs. LN) did not yield a statistically significant difference. Similarly, the post hoc comparison between the lobular and ductal invasive carcinomas (i.e. IDC vs. ILC) did not point to a statistically significant difference.
This is the first study evaluating HSP90 serum levels in both lobular and ductal lesions of the breast. Contrary to published pathological findings according to which HSP90 exhibits significant variability along both series, such a finding was not replicated for the level of serum HSP90 concentrations.
To address the role of Tpl2, a MAP3K8 that regulates innate/adaptive immunity and inflammation, in intestinal tumorigenesis, we crossed a Tpl2 KO allele into the Apc min/+ genetic background. Here, ...we show that Apc min/+ /Tpl2 −/− mice exhibit a fivefold increase in the number of intestinal adenomas. Bone marrow transplantation experiments revealed that the enhancement of polyposis was partially hematopoietic cell-driven. Consistent with this observation, Tpl2 ablation promoted intestinal inflammation. IL-10 levels and regulatory T-cell numbers were lower in the intestines of Tpl2 −/− mice, independent of Apc and polyp status, suggesting that they were responsible for the initiation of the enhancement of tumorigenesis caused by the ablation of Tpl2 . The low IL-10 levels correlated with defects in mTOR activation and Stat3 phosphorylation in Toll-like receptor-stimulated macrophages and with a defect in inducible regulatory T-cell generation and function. Both polyp numbers and inflammation increased progressively with time. The rate of increase of both, however, was more rapid in Apc min/+ /Tpl2 −/− mice, suggesting that the positive feedback initiated by inflammatory signals originating in developing polyps is more robust in these mice. This may be because these mice have a higher intestinal polyp burden as a result of the enhancement of tumor initiation.
Author Summary The findings in this report support a model in which Tpl2 ablation promotes intestinal inflammation in Apc min/+ mice by down-regulating the expression of the antiinflammatory cytokine IL-10 in myeloid cells in the intestinal mucosa and by interfering with the development and function of Tregs, which also inhibit inflammation. Developing polyps produce proinflammatory molecules that suppress Tregs and Tr1 cells and stimulate IL-17–producing T cells. This positive feedback loop is more robust in Apc min/+ /Tpl2 −/− mice, perhaps because the tumor burden of these mice is higher throughout life, as a result of the enhancement of tumor initiation ( Fig. P1 ). Overall, our data provide a unique genetic link between inflammation and cancer. Moreover, the animal model described here provides a valuable tool to address the pathophysiology of inflammatory bowel disease and colorectal cancer mechanistically in animals and humans. Experiments of Treg induction in culture provided evidence that the low numbers of Tregs in Tpl2 −/− mice result from a T cell-intrinsic defect in Treg generation and that only a small fraction of these Tpl2 −/− Tregs produce IL-10. Other in vivo studies reported here showed that the numbers of IL-10 + Tregs and type 1 regulatory T (Tr1) cells were lower in the intestines of Apc min/+ /Tpl2 −/− mice. The low numbers of Tregs and Tr1 cells were accompanied by high numbers of proinflammatory Foxp3 + and Foxp3 − IL-17–producing T cells. Moreover, the numbers of Tregs decreased and the numbers of IL-17–producing T cells increased with time faster in the Apc min/+ /Tpl2 −/− mice than in the Apc min/+ /Tpl2 +/+ mice. The more rapid change in the numbers of Tregs and IL-17–producing T cells in Apc min/+ /Tpl2 −/− mice parallels the increase in polyp numbers with time, which is also more rapid in these mice. This suggests that Apc min/+ /Tpl2 −/− mice may exhibit an enhanced response to proinflammatory signals triggered by the developing polyps or that Apc min/+ /Tpl2 −/− polyps may produce a more robust proinflammatory environment than Apc min/+ /Tpl2 +/+ polyps. Other cells that contribute to the abundance of IL-10 in the intestines are the Tregs, which may also produce IL-10. Our studies indeed showed that the number of Tregs is reduced in the intestines and peripheral lymphoid organs, but not in the thymus, of Tpl2 −/− mice in both the Apc +/+ and Apc min/+ genetic backgrounds. Tregs from Tpl2 −/− mice are not only low in number but express low levels of Foxp3, a transcription factor essential for Treg development and function. This suggested that the Tpl2 −/− Tregs might also be functionally defective, which was confirmed with Treg transfer experiments. These experiments showed that only the WT Tregs protect Apc min/+ /Tpl2 +/+ mice from polyposis. Interestingly, the Tpl2 +/+ Tregs failed to inhibit polyposis when transplanted into Apc min/+ /Tpl2 −/− mice, suggesting that the function of WT Tregs is intact only in the Tpl2 +/+ microenvironment. Intestinal IL-10 is produced primarily by macrophages. This observation, combined with the known defect of Tpl2 −/− macrophages in the induction of IL-10 by signals initiated by receptors triggered by bacterial products ( 4 ), suggested that the low levels of IL-10 in the intestines of Tpl2 −/− mice might be attributable to a macrophage signaling defect. Further studies showed that Tpl2 ablation in macrophages inhibits the activation of several upstream regulators of IL-10, including mTOR and Stat3 ( 5 ). Divergence in the composition of the intestinal inflammatory infiltrates of the Apc min/+ /Tpl2 −/− mice becomes apparent with the initiation of polyposis. Because polyps may stimulate inflammation ( 3 ), this observation challenged the hypothesis that the enhancement of polyposis in Apc min/+ /Tpl2 −/− mice may be secondary to the enhancement of inflammation. ELISAs addressing the expression of cytokines in the intestinal mucosa of these mice showed that the levels of intestinal IL-10 were lower in Tpl2 −/− mice than in Tpl2 +/+ mice, independent of adenomatous polyposis coli ( APC ) or polyp status. These data identified IL-10 as one of the factors that may be responsible for the initial divergence in inflammation and tumorigenesis between Apc min/+ /Tpl2 +/+ and Apc min/+ /Tpl2 −/− mice. The enhancement of tumorigenesis in Tpl2 −/− mice carrying the Apc min mutation could be the result of an intrinsic defect in the intestinal epithelia. Alternatively, it may be attributable to tumor-promoting changes in the intestinal stroma (i.e., the tissue supporting the intestinal epithelia). Bone marrow transplantation experiments showed that this enhancement is driven, at least in part, by hematopoietic cells. These results, combined with the known protumorigenic effects of inflammation, also suggested that Tpl2 ablation may promote tumorigenesis by promoting inflammation. Our analysis of the intestinal inflammatory infiltrates by flow cytometry showed that the infiltrates isolated from Apc min/+ /Tpl2 −/− mice contained a higher percentage of macrophages and tumor-associated myeloid-derived suppressor cells, and that the percentages of these cells increase with time. More important, the levels of the proinflammatory mediators, TNF-α, and IL-6 were higher in extracts of the intestinal mucosa of the Apc min/+ /Tpl2 −/− mice, and polyps from the same mice expressed higher levels of the enzyme COX-2, suggesting that Tpl2 ablation promotes the establishment of a proinflammatory environment in the intestinal mucosa. The Tpl2 gene encodes an enzyme that phosphorylates proteins on serine and threonine amino acid residues (a serine-threonine protein kinase) and is activated in retrovirus-induced tumors in animals via the integration of a DNA copy of the retroviral RNA genome within the gene. The Tpl2 kinase is activated enzymatically by signals originating in receptors that recognize bacterial products and various regulators of the immune system. Tpl2 activated by such signals plays an important role in the regulation of innate and adaptive immunity and inflammation (refs. 1 and 2 and references therein). Here, we show that mice with an inactivating mutation in the Apc gene and a second inactivating mutation in Tpl2 ( Apc min/+ /Tpl2 −/− mice) exhibit a fivefold increase in the number of intestinal polyps by comparison with the mice that carry only the Apc mutation. The increase in polyp numbers was partly hematopoietic cell-driven. The ablation of Tpl2 promoted intestinal inflammation by interfering with the secretion of the antiinflammatory molecule IL-10 in the intestinal mucosa and with the generation and function of regulatory T cells (Tregs), which also inhibit inflammation and tumorigenesis. Inflammation and polyp numbers increased with time, but the increase was faster in Apc min/+ /Tpl2 −/− mice, suggesting that the positive feedback initiated by polyp-induced inflammatory signals is more robust in these mice. Given the importance of Apc mutations in human colorectal cancer, these findings provide unique insights into the role of inflammation in this disease and into the molecular mechanisms that may influence the development of inflammation.
To address the role of Tpl2, a MAP3K8 that regulates innate/adaptive immunity and inflammation, in intestinal tumorigenesis, we crossed a Tpl2 KO allele into the Apcmin/+ genetic background. Here, we ...show that Apcmin/+/Tpl2-/- mice exhibit a fivefold increase in the number of intestinal adenomas. Bone marrow transplantation experiments revealed that the enhancement of polyposis was partially hematopoietic cell-driven. Consistent with this observation, Tpl2 ablation promoted intestinal inflammation. IL-10 levels and regulatory T-cell numbers were lower in the intestines of Tpl2-/- mice, independent of Apc and polyp status, suggesting that they were responsible for the initiation of the enhancement of tumorigenesis caused by the ablation of Tpl2. The low IL-10 levels correlated with defects in mTOR activation and Stat3 phosphorylation in Toll-like receptor-stimulated macrophages and with a defect in inducible regulatory T-cell generation and function. Both polyp numbers and inflammation increased progressively with time. The rate of increase of both, however, was more rapid in Apcmin/+/Tpl2-/- mice, suggesting that the positive feedback initiated by inflammatory signals originating in developing polyps is more robust in these mice. This may be because these mice have a higher intestinal polyp burden as a result of the enhancement of tumor initiation. PUBLICATION ABSTRACT
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