Circular RNAs (circRNAs) are covalently closed, endogenous biomolecules in eukaryotes with tissue-specific and cell-specific expression patterns, whose biogenesis is regulated by specific cis-acting ...elements and trans-acting factors. Some circRNAs are abundant and evolutionarily conserved, and many circRNAs exert important biological functions by acting as microRNA or protein inhibitors ('sponges'), by regulating protein function or by being translated themselves. Furthermore, circRNAs have been implicated in diseases such as diabetes mellitus, neurological disorders, cardiovascular diseases and cancer. Although the circular nature of these transcripts makes their detection, quantification and functional characterization challenging, recent advances in high-throughput RNA sequencing and circRNA-specific computational tools have driven the development of state-of-the-art approaches for their identification, and novel approaches to functional characterization are emerging.
Purpose
Chemotherapy-induced gastrointestinal toxicity is a common adverse event during chemotherapeutic treatment. No uniformly applicable strategies exist to predict, prevent, or treat ...gastrointestinal toxicity. Thus, a goal of mucositis research is to identify targets for therapeutic interventions and individualized risk prediction. Fibrinogen C domain containing 1 (FIBCD1) is a transmembrane protein expressed in human intestinal epithelial cells with functions in the innate immune system. Previous observations have shown that FIBCD1 ameliorates dextran sulfate sodium (DSS)–induced intestinal inflammation in vivo. We evaluated the effect of FIBCD1 in a murine model of chemotherapy-induced gastrointestinal toxicity and inflammation.
Methods
Transgenic (Tg) mice overexpressing FIBCD1 in the intestinal epithelium (
Fibcd1
Tg
) and wild-type (WT) littermates (
C57BL/6N
) were randomized to receive an intraperitoneal injection of doxorubicin 20 mg/kg or saline and were terminated 2 or 7 days after the injection. Gastrointestinal toxicity was evaluated by weight change, intestinal length, villus height/crypt depth, and histological mucositis score. Expression of inflammatory markers (
IL-6
,
IL-1β
, and
Tnfα
) was measured by quantitative real-time PCR in intestinal tissue samples.
Results
Following doxorubicin treatment, WT mice exhibited an increased weight loss compared with Tg littermates (
p
< 0.001). No differences between genotypes were seen in mucositis score, intestinal length, villus height/crypt depth, or
IL-6
,
IL-1β
, and
Tnfα
expression.
Conclusion
Our findings suggest that FIBCD1 could ameliorate chemotherapy-induced gastrointestinal toxicity by reducing weight loss; however, the mechanism of this possible protective effect remains to be defined warranting additional investigations.
Highlights • ApoE−/− mice was exposed to MWCNT-7 by oral gavage or intratracheal instillation. • Pulmonary exposure was associated with oxidative damage to DNA in lung tissue. • Oral exposure did not ...affect the composition of the gut microbiome. • The exposure was not associated with accelerated atherosclerosis in aorta or BCA. • There was increased outer and inner aortic diameter in MWCNT exposed mice.
In June, 2022, 25 scientists from eight countries met at the International Agency for Research on Cancer (IARC) in Lyon, France, to finalise their evaluation of the carcinogenicity of occupational ...exposure as a firefighter. Firefighters can be exposed to combustion products from fires (eg, polycyclic aromatic hydrocarbons PAHs and particulates), building materials (eg, asbestos), chemicals in firefighting foams (eg, perfluorinated and polyfluorinated substances PFAS), flame retardants, diesel exhaust, and other hazards (eg, night shift work and ultraviolet or other radiation). Dermal absorption of chemicals can occur even in firefighters wearing PPE due to limitations of its design, fit, maintenance, or decontamination. Since the previous classification of firefighting (as “possibly carcinogenic to humans,” Group 2B) by the IARC Monographs in 2007,2 many new studies have investigated the association between occupational exposure as a firefighter and cancer risk in humans. Airway and systemic inflammatory markers, such as IL-6 and IL-8, were associated with firefighting-related exposures. ...declines in lung function associated with changes in inflammatory markers and exposure-associated bronchial hyperreactivity were reported in firefighters.
Levels of zinc, along with its mechanistically related metabolites citrate and aspartate, are widely reported as reduced in prostate cancer compared to healthy tissue and are therefore pointed out as ...potential cancer biomarkers. Previously, it has only been possible to analyze zinc and metabolites by separate detection methods. Through matrix-assisted laser desorption/ionization mass spectrometry imaging (MSI), we were for the first time able to demonstrate, in two different sample sets (n = 45 and n = 4), the simultaneous spatial detection of zinc, in the form of ZnCl3 –, together with citrate, aspartate, and N-acetylaspartate on human prostate cancer tissues. The reliability of the ZnCl3 – detection was validated by total zinc determination using laser ablation inductively coupled plasma MSI on adjacent serial tissue sections. Zinc, citrate, and aspartate were correlated with each other (range r = 0.46 to 0.74) and showed a significant reduction in cancer compared to non-cancer epithelium (p < 0.05, log2 fold change range: −0.423 to −0.987), while no significant difference between cancer and stroma tissue was found. Simultaneous spatial detection of zinc and its metabolites is not only a valuable tool for analyzing the role of zinc in prostate metabolism but might also provide a fast and simple method to detect zinc, citrate, and aspartate levels as a biomarker signature for prostate cancer diagnostics and prognostics.
i
Classical Heritage and European Identities examines how the heritages of classical antiquity have been used to construct European identities, and especially the concept of citizenship, in Denmark ...from the eighteenth century to the present day. It implements a critical historiographical perspective in line with recent work on the “reception” of classical antiquity that has stressed the dialectic relationship between past, present and future.
Arguing that the continuous employment and appropriation of classical heritages in the Danish context constitute an interesting case of an imagined geography that is simultaneously based on both national and European identities, this book shows how Denmark’s imagined geography is naturalised through very distinctive uses of classical heritages within the educational and heritage sectors. It does so by exploring three significant and interrelated arenas where the heritages of classical antiquity are used to shape Danes as European citizens. Together, these three cases emphasise different but interconnected ways in which classical heritages are being put to use in order to construct Denmark’s own distinctive national identity within Europe. Finally, the book also sheds light on some of the challenges that face unified and homogenous conceptions of European heritage and identity, as well as the notion of the “classical” itself.
Classical Heritage and European Identities is the first English-language monograph to situate the Danish case within the wider European context. As such, the book should be essential reading for researchers and students engaged in the study of heritage and museums, classics, education and modern European history.
Reactive stroma is a tissue feature commonly observed in the tumor microenvironment of prostate cancer and has previously been associated with more aggressive tumors. The aim of this study was to ...detect differentially expressed genes and metabolites according to reactive stroma content measured on the exact same prostate cancer tissue sample. Reactive stroma was evaluated using histopathology from 108 fresh frozen prostate cancer samples gathered from 43 patients after prostatectomy (Biobank1). A subset of the samples was analyzed both for metabolic (n = 85) and transcriptomic alterations (n = 78) using high resolution magic angle spinning magnetic resonance spectroscopy (HR-MAS MRS) and RNA microarray, respectively. Recurrence-free survival was assessed in patients with clinical follow-up of minimum five years (n = 38) using biochemical recurrence (BCR) as endpoint. Multivariate metabolomics and gene expression analysis compared low (≤15%) against high reactive stroma content (≥16%). High reactive stroma content was associated with BCR in prostate cancer patients even when accounting for the influence of Grade Group (Cox hazard proportional analysis, p = 0.013). In samples with high reactive stroma content, metabolites and genes linked to immune functions and extracellular matrix (ECM) remodeling were significantly upregulated. Future validation of these findings is important to reveal novel biomarkers and drug targets connected to immune mechanisms and ECM in prostate cancer. The fact that high reactive stroma grading is connected to BCR adds further support for the clinical integration of this histopathological evaluation.
Aims/hypothesis
Glucagon-like peptide 1 (GLP-1) reduces appetite and energy intake in humans, whereas the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), seems to have no ...effect on eating behaviour. Interestingly, studies in rodents have shown that concomitant activation of GIP and GLP-1 receptors may potentiate the satiety-promoting effect of GLP-1, and a novel dual GLP-1/GIP receptor agonist was recently shown to trigger greater weight losses compared with a GLP-1 receptor agonist in individuals with type 2 diabetes. The aim of this study was to delineate the effects of combined GIP and GLP-1 receptor activation on energy intake, appetite and resting energy expenditure in humans.
Methods
We examined 17 overweight/obese men in a crossover design with 5 study days. On day 1, a 50 g OGTT was performed; on the following 4 study days, the men received an isoglycaemic i.v. glucose infusion (IIGI) plus saline (154 mmol/l NaCl; placebo), GIP (4 pmol kg
−1
min
−1
), GLP-1 (1 pmol kg
−1
min
−1
) or GIP+GLP-1 (4 and 1 pmol kg
−1
min
−1
, respectively). All IIGIs were performed in a randomised order blinded for the participant and the investigators. The primary endpoint was energy intake as measured by an ad libitum meal after 240 min. Secondary endpoints included appetite ratings and resting energy expenditure, as well as insulin, C-peptide and glucagon responses.
Results
Energy intake was significantly reduced during IIGI+GLP-1 compared with IIGI+saline infusion (2715 ± 409 vs 4483 ± 568 kJ mean ± SEM,
n
= 17,
p
= 0.014), whereas there were no significant differences in energy intake during IIGI+GIP (4062 ± 520 kJ) or IIGI+GIP+GLP-1 (3875 ± 451 kJ) infusion compared with IIGI+saline (
p
= 0.590 and
p
= 0.364, respectively). Energy intake was higher during IIGI+GIP+GLP-1 compared with IIGI+GLP-1 infusion (
p
= 0.039).
Conclusions/interpretation
While GLP-1 infusion lowered energy intake in overweight/obese men, simultaneous GIP infusion did not potentiate this GLP-1-mediated effect.
Trial registration
ClinicalTrials.gov
NCT02598791
Funding
This study was supported by grants from the Innovation Fund Denmark and the Vissing Foundation.
Prostate cancer tissues are inherently heterogeneous, which presents a challenge for metabolic profiling using traditional bulk analysis methods that produce an averaged profile. The aim of this ...study was therefore to spatially detect metabolites and lipids on prostate tissue sections by using mass spectrometry imaging (MSI), a method that facilitates molecular imaging of heterogeneous tissue sections, which can subsequently be related to the histology of the same section.
Here, we simultaneously obtained metabolic and lipidomic profiles in different prostate tissue types using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MSI. Both positive and negative ion mode were applied to analyze consecutive sections from 45 fresh-frozen human prostate tissue samples (N = 15 patients). Mass identification was performed with tandem MS.
Pairwise comparisons of cancer, non-cancer epithelium, and stroma revealed several metabolic differences between the tissue types. We detected increased levels of metabolites crucial for lipid metabolism in cancer, including metabolites involved in the carnitine shuttle, which facilitates fatty acid oxidation, and building blocks needed for lipid synthesis. Metabolites associated with healthy prostate functions, including citrate, aspartate, zinc, and spermine had lower levels in cancer compared to non-cancer epithelium. Profiling of stroma revealed higher levels of important energy metabolites, such as ADP, ATP, and glucose, and higher levels of the antioxidant taurine compared to cancer and non-cancer epithelium.
This study shows that specific tissue compartments within prostate cancer samples have distinct metabolic profiles and pinpoint the advantage of methodology providing spatial information compared to bulk analysis. We identified several differential metabolites and lipids that have potential to be developed further as diagnostic and prognostic biomarkers for prostate cancer. Spatial and rapid detection of cancer-related analytes showcases MALDI-TOF MSI as a promising and innovative diagnostic tool for the clinic.
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