Perturbations in levels of amino acids (AA) and their derivatives are observed in hepatocellular carcinoma (HCC). Yet, it is unclear whether these alterations precede or are a consequence of the ...disease, nor whether they pertain to anatomically related cancers of the intrahepatic bile duct (IHBC), and gallbladder and extrahepatic biliary tract (GBTC). Circulating standard AA, biogenic amines and hexoses were measured (Biocrates AbsoluteIDQ‐p180Kit) in a case‐control study nested within a large prospective cohort (147 HCC, 43 IHBC and 134 GBTC cases). Liver function and hepatitis status biomarkers were determined separately. Multivariable conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI) for log‐transformed standardised (mean = 0, SD = 1) serum metabolite levels and relevant ratios in relation to HCC, IHBC or GBTC risk. Fourteen metabolites were significantly associated with HCC risk, of which seven metabolites and four ratios were the strongest predictors in continuous models. Leucine, lysine, glutamine and the ratio of branched chain to aromatic AA (Fischer's ratio) were inversely, while phenylalanine, tyrosine and their ratio, glutamate, glutamate/glutamine ratio, kynurenine and its ratio to tryptophan were positively associated with HCC risk. Confounding by hepatitis status and liver enzyme levels was observed. For the other cancers no significant associations were observed. In conclusion, imbalances of specific AA and biogenic amines may be involved in HCC development.
What's new?
Perturbations in levels of circulating amino acid metabolites are observed in hepatocellular carcinoma (HCC). Yet it is unclear whether these imbalances are apparent from earlier stages of the disease. In this study nested within a prospective cohort, and based on pre‐diagnostically collected blood samples, here the authors show strong HCC risk associations for circulating levels of some aromatic, branched‐chain and glucogenic amino acids and biogenic amines. This observation of impaired metabolism in early HCC development may be applied towards further research into the aetiology of, and pathways leading to, this disease.
To investigate trends in obesity prevalence in recent years and to predict the obesity prevalence in 2015 in European populations.
Data of 97,942 participants from seven cohorts involved in the ...European Prospective Investigation into Cancer and Nutrition (EPIC) study participating in the Diogenes project (named as "Diogenes cohort" in the following) with weight measurements at baseline and follow-up were used to predict future obesity prevalence with logistic linear and non-linear (leveling off) regression models. In addition, linear and leveling off models were fitted to the EPIC-Potsdam dataset with five weight measures during the observation period to find out which of these two models might provide the more realistic prediction.
During a mean follow-up period of 6 years, the obesity prevalence in the Diogenes cohort increased from 13% to 17%. The linear prediction model predicted an overall obesity prevalence of about 30% in 2015, whereas the leveling off model predicted a prevalence of about 20%. In the EPIC-Potsdam cohort, the shape of obesity trend favors a leveling off model among men (R² = 0.98), and a linear model among women (R² = 0.99).
Our data show an increase in obesity prevalence since the 1990ies, and predictions by 2015 suggests a sizeable further increase in European populations. However, the estimates from the leveling off model were considerably lower.
Serum metabolites have been linked to higher risk of chronic diseases but determinants of serum metabolites are not clear. We aimed to investigate the association between habitual diet as a ...modifiable risk factor and relevant serum metabolites.
This cross-sectional study comprised 2380 EPIC-Potsdam participants. Intake of 45 food groups was assessed by food frequency questionnaire and concentrations of 127 serum metabolites were measured by targeted metabolomics. Reduced rank regression was used to find dietary patterns that explain the maximum variation of metabolites.
In the multivariable-adjusted model, the proportion of explained variation by habitual diet was ranked as follows: acyl-alkyl-phosphatidylcholines (5.7%), sphingomyelins (5.1%), diacyl-phosphatidylcholines (4.4%), lyso-phosphatidylcholines (4.1%), acylcarnitines (3.5%), amino acids (2.2%) and hexose (1.6%). A pattern with high intake of butter and low intake of margarine was related to acylcarnitines, acyl-alkyl-phosphatidylcholines, lyso-phosphatidylcholines and hydroxy-sphingomyelins, particularly with saturated and monounsaturated fatty acid side chains. A pattern with high intake of red meat and fish and low intake of whole-grain bread and tea was related to hexose and phosphatidylcholines. A pattern consisting of high intake of potatoes, dairy products and cornflakes particularly explained methionine and branched chain amino acids. Dietary patterns related to type 2 diabetes-relevant metabolites included high intake of red meat and low intake of whole-grain bread, tea, coffee, cake and cookies, canned fruits and fish.
Dietary patterns characterized by intakes of red meat, whole-grain bread, tea and coffee were linked to relevant metabolites and could be potential targets for chronic disease prevention.
We present the first full water column Nd isotope (εNd) and concentration data for Caribbean seawater, as well as for stations close to the Orinoco River mouth and in the Florida Straits. The surface ...inflow into the southeastern Caribbean via the Guyana Current is characterized by an εNd signature of −10.9, which is a consequence of the mixing of relatively unradiogenic εNd signatures (−13.6) supplied by the Orinoco River with contributions from the Amazon River (∼−10). Despite the proximity to land, sub-surface and intermediate waters within the Caribbean largely retain the εNd signatures of their source water masses in the Atlantic. In contrast, the deep waters of the Caribbean show εNd signatures at least 3 εNd units more radiogenic than the inflowing Upper North Atlantic Deep Water (UNADW). A εNd shift from −13 to −9.7 can be explained by addition of radiogenic Nd to the deep Caribbean through weathering inputs from land. However, in order to balance such large shifts in εNd with at the same time modest increases in Nd concentrations, Nd must also be removed from seawater within the basin. It is suggested that the long residence time of deep waters in the Caribbean allows significant interaction of seawater with sinking particles and seafloor sediments resulting in more radiogenic values. These findings have implications for the use of εNd as a proxy for paleocirculation in restricted basins, in which the residence times of the deep waters are long.
•First seawater Nd isotope measurements for the Caribbean.•Surface and intermediate waters have Atlantic-like Nd isotope compositions.•Deep water Nd isotope compositions are shifted towards more radiogenic values.
Abstract
Study objective:
The activity of linsitinib, a small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF-1R), was assessed in a mouse model of Graves’ orbitopathy (GO). GO ...is the most common extra-thyroidal manifestation of Graves’ disease (GD), which is caused by autoantibodies against the thyroid stimulating hormone receptor (TSHR).
Methods:
GD was induced in mice by immunization with a human TSHR A-subunit encoding plasmid. Linsitinib was administered orally for four weeks either in parallel to or after disease induction. Endocrine orbitopathy and inflammation were determined by histology and MRI.
Results:
Immunization with the TSHR A-subunit induced hyperthyroidism, as well as CD3+ T-cell infiltration and macrophage infiltration into orbital muscle/adipose tissue. Linsitinib reduced these effects by up to 80% whether given prophylactically or after disease induction. In addition, linsitinib reduced the formation of brown adipose tissue in the orbit and displayed an additional effect on the immune system. An MRI using F19 imaging confirmed marked orbital inflammation, significant muscle edema and formation of brown fat in experimental GO, events that were abrogated upon application of linsitinib. Linsitinib’s pharmacologic effects were observed at a dose that did not impact the concentration of plasma glucose.
Conclusion:
Linsitinib improved GO-related endpoints in a TSHR autoantibody dependent mouse model of Graves’ disease. Both prophylactic and therapeutic intervention with linsitinib improved clinically relevant endpoints in the orbita and thyroid gland. Our results are consistent with the therapeutic hypothesis being evaluated in an ongoing Phase 2b clinical study (NCT05276063).
This work was funded by Sling Therapeutics, Inc.
RATIONALE:Immediate changes in the ECM (extracellular matrix) microenvironment occur after myocardial ischemia and reperfusion (I/R) injury.
OBJECTIVE:Aim of this study was to unravel the role of the ...early hyaluronan (HA)-rich ECM after I/R.
METHODS AND RESULTS:Genetic deletion of Has2 and Has1 was used in a murine model of cardiac I/R. Chemical exchange saturation transfer imaging was adapted to image cardiac ECM post-I/R. Of note, the cardiac chemical exchange saturation transfer signal was severely suppressed by Has2 deletion and pharmacological inhibition of HA synthesis 24 hours after I/R. Has2 KO (Has2 deficient) mice showed impaired hemodynamic function suggesting a protective role for endogenous HA synthesis. In contrast to Has2 deficiency, Has1-deficient mice developed no specific phenotype compared with control post-I/R. Importantly, in Has2 KO mice, cardiac macrophages were diminished after I/R as detected by F MRI (magnetic resonance imaging) of perfluorcarbon-labeled immune cells, Mac-2/Galectin-3 immunostaining, and FACS (fluorescence-activated cell sorting) analysis (CD45CD11bLy6GCD64F4/80cells). In contrast to macrophages, cardiac Ly6C and Ly6C monocytes were unaffected post-I/R compared with control mice. Mechanistically, inhibition of HA synthesis led to increased macrophage apoptosis in vivo and in vitro. In addition, α-SMA (α-smooth muscle actin)–positive cells were reduced in the infarcted myocardium and in the border zone. In vitro, the myofibroblast response as measured by Acta2 mRNA expression was reduced by inhibition of HA synthesis and of CD44 signaling. Furthermore, Has2 KO fibroblasts were less able to contract collagen gels in vitro. The effects of HA/CD44 on fibroblasts and macrophages post-I/R might also affect intercellular cross talk because cardiac fibroblasts were activated by monocyte/macrophages and, in turn, protected macrophages from apoptosis.
CONCLUSIONS:Increased HA synthesis contributes to postinfarct healing by supporting macrophage survival and by promoting the myofibroblast response. Additionally, imaging of cardiac HA by chemical exchange saturation transfer post-I/R might have translational value.
The aim was to investigate the association between pre-diagnostic intakes of polyphenol classes (flavonoids, lignans, phenolic acids, stilbenes, and other polyphenols) in relation to breast cancer ...survival (all-cause and breast cancer-specific mortality). We used data from the European Prospective Investigation into Cancer and Nutrition cohort. Pre-diagnostic usual diet was assessed using dietary questionnaires, and polyphenol intakes were estimated using the Phenol-Explorer database. We followed 11,782 breast cancer cases from time of diagnosis until death, end of follow-up or last day of contact. During a median of 6 years, 1482 women died (753 of breast cancer). We related polyphenol intake to all-cause and breast cancer-specific mortality using Cox proportional hazard models with time since diagnosis as underlying time and strata for age and country. Among postmenopausal women, an intake of lignans in the highest versus lowest quartile was related to a 28 % lower risk of dying from breast (adjusted model: HR, quartile 4 vs. quartile 1, 0.72, 95 % CI 0.53; 0.98). In contrast, in premenopausal women, a positive association between lignan intake and all-cause mortality was found (adjusted model: HR, quartile 4 vs. quartile 1, 1.63, 95 % CI 1.03; 2.57). We found no association for other polyphenol classes. Intake of lignans before breast cancer diagnosis may be related to improved survival among postmenopausal women, but may on the contrary worsen the survival for premenopausal women. This suggests that the role of phytoestrogens in breast cancer survival is complex and may be dependent of menopausal status.
The key goal of metabolomic studies is to identify relevant individual biomarkers or composite metabolic patterns associated with particular disease status or patho-physiological conditions. There ...are currently very few approaches to evaluate the variability of metabolomic data in terms of characteristics of individuals or aspects pertaining to technical processing. To address this issue, a method was developed to identify and quantify the contribution of relevant sources of variation in metabolomic data prior to investigation of etiological hypotheses. The Principal Component Partial R-square (PC-PR2) method combines features of principal component and of multivariable linear regression analyses. Within the European Prospective Investigation into Cancer and nutrition (EPIC), metabolic profiles were determined by
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H NMR analysis on 807 serum samples originating from a nested liver cancer case–control study. PC-PR2 was used to quantify the variability of metabolomic profiles in terms of study subjects age, sex, body mass index, country of origin, smoking status, diabetes and fasting status, as well as factors related to sample processing. PC-PR2 enables the evaluation of important sources of variations in metabolomic studies within large-scale epidemiological investigations.
Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is difficult to diagnose and has limited treatment options with a low survival rate. Aside from a few key risk factors, such ...as hepatitis, high alcohol consumption, smoking, obesity, and diabetes, there is incomplete etiologic understanding of the disease and little progress in identification of early risk biomarkers.
To address these aspects, an untargeted nuclear magnetic resonance metabolomic approach was applied to pre-diagnostic serum samples obtained from first incident, primary HCC cases (n = 114) and matched controls (n = 222) identified from amongst the participants of a large European prospective cohort.
A metabolic pattern associated with HCC risk comprised of perturbations in fatty acid oxidation and amino acid, lipid, and carbohydrate metabolism was observed. Sixteen metabolites of either endogenous or exogenous origin were found to be significantly associated with HCC risk. The influence of hepatitis infection and potential liver damage was assessed, and further analyses were made to distinguish patterns of early or later diagnosis.
Our results show clear metabolic alterations from early stages of HCC development with application for better etiologic understanding, prevention, and early detection of this increasingly common cancer.
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