Background
Cell adhesion molecules (CAMs) orchestrate leukocyte trafficking and could link peripheral and neuroinflammation in patients with severe mental illness (SMI), by promoting inflammatory and ...immune-mediated responses and mediating signals across blood-brain barrier. We hypothesized that CAMs would be dysregulated in SMI and evaluated plasma levels of different vascular and neural CAMs. Dysregulated CAMs in plasma were further evaluated in vivo in leukocytes and brain tissue and in vitro in induced pluripotent stem cells.
Methods
We compared plasma soluble levels of different vascular (VCAM-1, ICAM-1, P-SEL) and neural (JAM-A, NCAD) CAMs in circulating leukocytes in a large SMI sample of schizophrenia (SCZ) spectrum disorder (n = 895) and affective disorder (n = 737) and healthy control participants (n = 1070) controlling for age, sex, body mass index, C-reactive protein, and freezer storage time. We also evaluated messenger RNA expression of ICAM1 and related genes encoding ICAM-1 receptors in leukocytes using microarray (n = 842) and in available RNA sequencing data from the CommonMind Consortium (CMC) in postmortem samples from the dorsolateral prefrontal cortex (n = 474). The regulation of soluble ICAM-1 in induced pluripotent stem cell–derived neurons and astrocytes was assessed in patients with SCZ and healthy control participants (n = 8 of each).
Results
Our major findings were 1) increased soluble ICAM-1 in patients with SMI compared with healthy control participants; 2) increased ITGB2 messenger RNA, encoding the beta chain of the ICAM-1 receptor, in circulating leukocytes from patients with SMI and increased prefrontal cortex messenger RNA expression of ICAM1 in SCZ; and 3) enhanced soluble ICAM-1 release in induced pluripotent stem cell–derived neurons from patients with SCZ.
Conclusions
Our results support a systemic and cerebral dysregulation of soluble ICAM-1 expression in SMI and especially in patients with SCZ.
Abnormal DNA methylation is observed as an early event in breast carcinogenesis. However, how such alterations arise is still poorly understood. microRNAs (miRNAs) regulate gene expression at the ...post-transcriptional level and play key roles in various biological processes. Here, we integrate miRNA expression and DNA methylation at CpGs to study how miRNAs may affect the breast cancer methylome and how DNA methylation may regulate miRNA expression.
miRNA expression and DNA methylation data from two breast cancer cohorts, Oslo2 (n = 297) and The Cancer Genome Atlas (n = 439), were integrated through a correlation approach that we term miRNA-methylation Quantitative Trait Loci (mimQTL) analysis. Hierarchical clustering was used to identify clusters of miRNAs and CpGs that were further characterized through analysis of mRNA/protein expression, clinicopathological features, in silico deconvolution, chromatin state and accessibility, transcription factor binding, and long-range interaction data.
Clustering of the significant mimQTLs identified distinct groups of miRNAs and CpGs that reflect important biological processes associated with breast cancer pathogenesis. Notably, two major miRNA clusters were related to immune or fibroblast infiltration, hence identifying miRNAs associated with cells of the tumor microenvironment, while another large cluster was related to estrogen receptor (ER) signaling. Studying the chromatin landscape surrounding CpGs associated with the estrogen signaling cluster, we found that miRNAs from this cluster are likely to be regulated through DNA methylation of enhancers bound by FOXA1, GATA2, and ER-alpha. Further, at the hub of the estrogen cluster, we identified hsa-miR-29c-5p as negatively correlated with the mRNA and protein expression of DNA methyltransferase DNMT3A, a key enzyme regulating DNA methylation. We found deregulation of hsa-miR-29c-5p already present in pre-invasive breast lesions and postulate that hsa-miR-29c-5p may trigger early event abnormal DNA methylation in ER-positive breast cancer.
We describe how miRNA expression and DNA methylation interact and associate with distinct breast cancer phenotypes.
Background Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) that are part of a psychosis continuum, and dysregulated innate immune responses have been suggested to be ...involved in their pathophysiology. However, disease-specific immune mechanisms in SMI are not known yet. Recently, dyslipidemia has been linked to systemic inflammasome activation, and elevated atherogenic lipid ratios have been shown to correlate with circulating levels of inflammatory biomarkers in SMI. It is, however, not yet known if increased systemic cholesterol load leads to inflammasome activation in these patients. Methods We tested the hypothesis that patients with SCZ and BD display higher circulating levels compared to healthy individuals of key members of the IL-18 system using a large patient cohort (n = 1632; including 737 SCZ and 895 BD), and healthy controls (CTRL; n = 1070). In addition, we assessed associations with coronary artery disease risk factors in SMI, focusing on relevant inflammasome-related, neuroendocrine, and lipid markers. Results We report higher baseline levels of circulating IL-18 system components (IL-18, IL-18BPA, IL-18R1), and increased expression of inflammasome-related genes (NLRP3 and NLRC4) in the blood of patients relative to CTRL. We demonstrate a cholesterol dyslipidemia pattern in psychotic disorders, and report correlations between levels of blood cholesterol types and the expression of inflammasome system elements in SMI. Conclusions Based on these results, we suggest a role for inflammasome activation/dysregulation in SMI. Our findings further the understanding of possible underlying inflammatory mechanisms and may expose important therapeutic targets in SMI.
Measuring the aneurysm sac’s size is vital in postoperative surveillance following endovascular treatment of aortic aneurysms. A three-dimensional ultrasound technique may enable accurate volume ...measurements. However, there is no validation of any commercially available electro-mechanical 3D ultrasound equipment or of the software used when measuring the volume of the aortic aneurysm sac. This investigation used a phantom model to study a three-dimensional ultrasound technique on aortic aneurysm sac volume measurements. High volume measurement accuracy indicates that this method may be useful for postoperative surveillance following endovascular aortic aneurysm operations. These results must be confirmed in clinical studies.
Ductal carcinoma in situ (DCIS) is a non-invasive type of breast cancer with highly variable potential of becoming invasive and affecting mortality. Currently, many patients with DCIS are overtreated ...due to the lack of specific biomarkers that distinguish low risk lesions from those with a higher risk of progression. In this study, we analyzed 57 pure DCIS and 313 invasive breast cancers (IBC) from different patients. Three levels of genomic data were obtained; gene expression, DNA methylation, and DNA copy number. We performed subtype stratified analyses and identified key differences between DCIS and IBC that suggest subtype specific progression. Prominent differences were found in tumors of the basal-like subtype: Basal-like DCIS were less proliferative and showed a higher degree of differentiation than basal-like IBC. Also,
tumors (characterized by high correlation to the basal-like centroid) were not identified amongst DCIS as opposed to IBC. At the copy number level, basal-like DCIS exhibited fewer copy number aberrations compared with basal-like IBC. An intriguing finding through analysis of the methylome was hypermethylation of multiple protocadherin genes in basal-like IBC compared with basal-like DCIS and normal tissue, possibly caused by long range epigenetic silencing. This points to silencing of cell adhesion-related genes specifically in IBC of the basal-like subtype. Our work confirms that subtype stratification is essential when studying progression from DCIS to IBC, and we provide evidence that basal-like DCIS show less aggressive characteristics and question the assumption that basal-like DCIS is a direct precursor of basal-like invasive breast cancer.
Abstract Objectives This study aims at evaluating and comparing mechanical, chemical, and cytotoxicological parameters of a commercial brand name composite material against two ‘own brand label’ ...(OBL) composites. Methods Parameters included depth of cure, flexural strength, degree of conversion, polymerization shrinkage, filler particle morphology and elemental analyzes, Vickers hardness, surface roughness parameters after abrasion, monomer elution, and cytotoxicity. Results The conventional composite outperformed the OBLS in terms of depth of cure (p < 0.001), degree of cure at the first and last time intervals (p < 0.001), hardness (p < 0.001), and post-abrasion roughness (p < 0.05). The polymerization volumetric shrinkage ranged from 2.86% to 4.13%, with the highest shrinkage seen among the OBLs. Both Monomer elution from the OBLs was statistically significantly higher (p < 0.001). Statistically significantly higher cytotoxicity combined with altered morphology and loss of confluence was detected in the cells exposed to extracts from the OBLs. Conclusions The OBLs were in general outdone by the conventional composite. Clinical significance OBLs restorative materials have become pervasive in the dental market. Manufacturers often promise equal or better characteristics than existing brand-name composites, but at a lower price. Dentists are highly recommended to reconsider utilization of OBLs lacking sound scientific scrutiny, and our findings underscore this recommendation.
Background: Genetic polymorphisms in metabolizing enzymes may modify the association of environmental exposure on colorectal
cancer (CRC) and adenoma risk. Materials and Methods: One hundred and ...ninety-eight CRC cases, 422 adenomas (206 low-risk and
216 high-risk adenomas) and 222 controls were genotyped for the CYP1A2 164 A âC polymorphism and questionnaires were used
to assess environmental exposure. Results: The smoking parameter âcurrent smokingâ was significantly associated with CRC risk,
and all the smoking parameters related to current smoking, having ever smoked or high numbers of cigarette years were significantly
associated with risk of adenomas. No association was detected between red meat consumption or how well red meat was cooked
and colorectal carcinogenesis. When stratifying the case groups based on CYP1A2 genotype, all the smoking parameters yielded
stronger risk association in carriers of the C allele. Conclusion: These findings may indicate that the association between
cigarette smoking and colorectal carcinogenesis can be modified by the CYP1A2 genotype.
Abstract
Long non-coding RNAs (lncRNAs) are involved in breast cancer pathogenesis through chromatin remodeling, transcriptional and post-transcriptional gene regulation. We report robust ...associations between lncRNA expression and breast cancer clinicopathological features in two population-based cohorts: SCAN-B and TCGA. Using co-expression analysis of lncRNAs with protein coding genes, we discovered three distinct clusters of lncRNAs. In silico cell type deconvolution coupled with single-cell RNA-seq analyses revealed that these three clusters were driven by cell type specific expression of lncRNAs. In one cluster lncRNAs were expressed by cancer cells and were mostly associated with the estrogen signaling pathways. In the two other clusters, lncRNAs were expressed either by immune cells or fibroblasts of the tumor microenvironment. To further investigate the cis-regulatory regions driving lncRNA expression in breast cancer, we identified subtype-specific transcription factor (TF) occupancy at lncRNA promoters. We also integrated lncRNA expression with DNA methylation data to identify long-range regulatory regions for lncRNA which were validated using ChiA-Pet-Pol2 loops. lncRNAs play an important role in shaping the gene regulatory landscape in breast cancer. We provide a detailed subtype and cell type-specific expression of lncRNA, which improves the understanding of underlying transcriptional regulation in breast cancer.
Summary Childhood asthma and wheeze is more common among boys than girls, while the opposite is found in adults. The main objective was to study the incidence and the course of wheeze and asthma ...during adolescence with focus on gender differences. In addition, we explored associations between lifestyle factors at baseline and wheeze at follow-up. A total of 2399 adolescents answered validated questionnaires on respiratory symptoms and lifestyle in 1995–1997 (13–15 years) and at follow-up in 2000–2001 (17–19 years). The risk of reporting wheeze and asthma at follow-up was greater in girls compared to boys among subjects reporting no respiratory symptoms at baseline; Relative risk: 1.4 and 2.4, respectively. More girls than boys reported current wheeze at follow-up, both among those with current wheeze (girls 60%, boys 48%) and previous wheeze (girls 33%, boys 28%) at baseline. In girls, development of current wheeze was significantly associated with current smoking ( OR = 2.8 ) and stable current wheeze was significantly associated with overweight ( OR = 2.4 ). Similar associations were not significant in boys. More girls than boys developed wheeze, had stable wheeze or had relapse of previous symptoms during the four year follow-up. The impact of smoking and overweight may put girls at a higher risk of respiratory symptoms than boys. Awareness of the gender difference in respiratory symptoms is important for diagnosis and preventive strategies during adolescence.
The objective was to study sex differences in adolescence regarding prevalence of asthma and current wheeze and to explore the association between respiratory symptoms and hereditary, lifestyle and ...socioeconomic factors.
Young-HUNT included data comprehensive questionnaire on health, disease, lifestyle and social factors from 8817 teenagers 13–19 years conducted in 1995/97 (89% response rate). Questionnaire on respiratory symptoms was based on the International Study of Asthma and Allergy in Childhood (ISAAC).
In age groups 13–16 and 17–19 years, current wheeze was reported by 29.0% and 33.5% among girls and 20.4% and 22.1% among boys, whilst the corresponding figures for asthma were 8.5% and 12.2% among girls and 7.1% and 7.0% among boys. Both wheeze and asthma were significantly more prevalent and increased with age in girls compared to boys. Heredity was associated with asthma, but the association was strongest between parents and children of the same sex. Environmental smoking was associated with asthma and wheeze in girls only. Girls reported more asthma and wheeze in association with overweight compared to boys.
Girls reported more wheeze and asthma than boys and seemed more susceptible to risk factors such as environmental smoking and overweight than boys. Moreover, girls with mothers having asthma were more likely to be diagnosed as asthmatics themselves.
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