Essentials
Protease activated receptor‐1 (PAR‐1) has been proposed to drive cancer progression.
Surprisingly, PAR‐1 deletion accelerated tumor progression in two distinct experimental settings.
PAR‐1 ...deletion was shown to limit the apoptosis of transformed epithelial cells.
Thrombin‐ and activated protein C‐mediated PAR‐1 activation have unique effects on tumor cell biology.
Summary
Background
Multiple studies have implicated protease‐activated receptor‐1 (PAR‐1), a G‐protein‐coupled receptor activated by proteolytic cleavage of its N‐terminus, as one target coupling thrombin‐mediated proteolysis to tumor progression.
Objective
To analyze the role of PAR‐1 in the setting of two distinct spontaneously developing tumor models in mice.
Methods
We interbred PAR‐1‐deficient mice with Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, which spontaneously develop prostate tumors, and adenomatous polyposis coli Min (APCMin/+) mice, which spontaneously develop intestinal adenomas.
Results
Analyses of TRAMP mice with advanced disease (30 weeks) revealed that PAR‐1 deficiency resulted in significantly larger and more aggressive prostate tumors. Prostates collected at an earlier time point (12 weeks of age) revealed that PAR‐1 promotes apoptosis in transformed epithelia. In vitro analyses of TRAMP‐derived cells revealed that activated protein C‐mediated PAR‐1 cleavage can induce tumor cell apoptosis, suggesting that tumor cell‐intrinsic PAR‐1 functions can limit tumor progression. Paralleling results in TRAMP mice, PAR‐1‐deficient APCMin/+ mice developed three‐fold more adenomas than PAR‐1‐expressing mice, and the adenomas that formed were significantly larger. Moreover, loss of PAR‐1 expression was shown to limit apoptosis in transformed intestinal epithelial cells.
Conclusions
Together, these results demonstrate a previously unrecognized role for PAR‐1 in impeding tumor progression in vivo. These results also offer a cautionary note suggesting that long‐term PAR‐1 inhibition could increase malignancy risk in some contexts.
The aim of this study was to investigate the association between inflammatory markers and 28-day mortality in patients with ST-elevation myocardial infarction (STEMI).
In 398 STEMI patients recorded ...between 2009 and 2013 by the population-based Myocardial Infarction Registry Augsburg, 92 protein biomarkers were measured in admission arterial blood samples using the OLINK inflammatory panel. In multivariable-adjusted logistic regression models, the association between each marker and 28-day mortality was investigated. The values of the biomarkers most significantly associated with mortality were standardized and summarized to obtain a prediction score for 28-day mortality. The predictive ability of this biomarker score was compared to the established GRACE score using ROC analysis. Finally, a combined total score was generated by adding the standardized biomarker score to the standardized GRACE score.
The markers IL-6, IL-8, IL-10, FGF-21, FGF-23, ST1A1, MCP-1, 4E-BP1, and CST5 were most significantly associated with 28-day mortality, each with FDR-adjusted (false discovery rate adjusted) p-values of < 0.01 in the multivariable logistic regression model. In a ROC analysis, the biomarker score and the GRACE score showed comparable predictive ability for 28-day mortality (biomarker score AUC: 0.7859 CI: 0.6735-0.89, GRACE score AUC: 0.7961 CI: 0.6965-0.8802). By combining the biomarker score and the Grace score, the predictive ability improved with an AUC of 0.8305 CI: 0.7269-0.9187. A continuous Net Reclassification Improvement (cNRI) of 0.566 (CI: 0.192-0.94, p-value: 0.003) and an Integrated Discrimination Improvement (IDI) of 0.083 ((CI: 0.016-0.149, p-value: 0.015) confirmed the superiority of the combined score over the GARCE score.
Inflammatory biomarkers may play a significant role in the pathophysiology of acute myocardial infarction (AMI) and AMI-related mortality and might be a promising starting point for personalized medicine, which aims to provide each patient with tailored therapy.
Aims
Prior studies demonstrated an association between hospital admission blood glucose and mortality in acute myocardial infarction (AMI). Because stress hyperglycemia ratio (SHR) has been suggested ...as a more reliable marker of stress hyperglycemia this study investigated to what extent SHR in comparison with admission blood glucose is associated with short- and long-term mortality in diabetic and non-diabetic AMI patients.
Methods
The analysis was based on 2,311 AMI patients aged 25–84 years from the population-based Myocardial Infarction Registry Augsburg (median follow-up time 6.5 years IQR: 4.9–8.1). The SHR was calculated as admission glucose (mg/dl)/(28.7 × HbA1c (%)—46.7). Using logistic and COX regression analyses the associations between SHR and admission glucose and mortality were investigated.
Result
Higher admission glucose and higher SHR were significantly and nonlinearly associated with higher 28-day mortality in AMI patients with and without diabetes. In patients without diabetes, the AUC for SHR was significantly lower than for admission glucose (SHR: 0.6912 95%CI 0.6317–0.7496, admission glucose: 0.716 95%CI 0.6572–0.7736,
p
-value: 0.0351). In patients with diabetes the AUCs were similar for SHR and admission glucose. Increasing admission glucose and SHR were significantly nonlinearly associated with higher 5-year all-cause mortality in AMI patients with diabetes but not in non-diabetic patients. AUC values indicated a comparable prediction of 5-year mortality for both measures in diabetic and non-diabetic patients.
Conclusions
Stress hyperglycemia in AMI patients plays a significant role mainly with regard to short-term prognosis, but barely so for long-term prognosis, underlining the assumption that it is a transient dynamic disorder that occurs to varying degrees during the acute event, thereby affecting prognosis.
Despite the known association of chronic cardiovascular diseases and more severe courses of COVID-19, little is known about individual risk perception of patients with a history of acute myocardial ...infarction (AMI) and resulting preventive behaviours. In May 2020, a postal survey was conducted, including 150 patients with previous AMI from the myocardial infarction registry Augsburg. The study objective was to assess COVID-19 knowledge, individual risk perception, worries, infection likelihood and preventive behaviours in this patient cohort. From the 100 respondents, 69.7% perceived themselves to be at high risk of developing a severe course of COVID-19. There was a significant positive correlation between dangerousness assessment and knowledge on COVID-19. Despite a majority (70%) of patients rating their susceptibility for an infection as moderate to very high, the individual likelihood of being infected was rated at only 3%. Almost 70% of patients with previous MI classified themselves at high risk for a severe course of COVID-19 infection. As seen in other risk groups as well, the availability of valuable information sources as well as the support in individual risk reduction strategies and psychological coping mechanisms are mandatory, especially since higher knowledge correlates with dangerousness assessment and might lead to better compliance with preventive behaviours.
Different ST-segment elevation myocardial infarction (STEMI) localizations go along with dissimilarities in the size of the affected myocardium, the causing coronary vessel occlusion, and the right ...ventricular participation. Therefore, this study aims to clarify if there is any difference in long-term survival between anterior- and non-anterior-wall STEMI.
This study included 2,195 incident STEMI cases that occurred between 2009 and 2017, recorded by the population-based Augsburg Myocardial Infarction Registry, Germany. The study population comprised 1.570 men and 625 women aged 25-84 years at acute myocardial infarction. The patients were observed from the day of their first acute event with an average follow-up period of 4.3 years, (standard deviation: 3.0). Survival analyses and multivariable Cox regression analyses were performed to examine the association between infarction localizations and long-term all-cause mortality.
Of the 2,195 patients, 1,118 had an anterior (AWS)- and 1,077 a non-anterior-wall-STEMI (NAWS). No significant associations of the STEMI localization with long-term mortality were found. When comparing AWS with NAWS, a hazard ratio of 0.91 95% confidence interval: 0.75-1.10 could be calculated after multivariable adjustment. In contrast to NAWS, AWS was associated with a greater <28 day mortality, less current or former smoking and higher creatine kinase-myocardial band levels (CK-MB) and went along with a higher frequency of impaired left ventricular ejection fraction (<30%).
Despite pathophysiological differences between AWS and NAWS, and identified differences in multiple clinical characteristics, no significant differences in long-term mortality between both groups were observed.
We applied an 8-year selection process in an attempt to determine if yearling antler quality in subsequent cohorts could be improved by selecting for yearling male white-tailed deer (Odocoileus ...virginianus) exhibiting relatively superior antler potential under suboptimal nutritional conditions. In 41 single-sire (breeding M) breeding herds, 217 yearling males were produced on an 8% protein diet of limited quantity. All antler measurements increased significantly (P < 0.001) during the study: number of points (+3.2), inside spread (+96.5 mm), main beam length (+129.1 mm), basal circumference (+21.6 mm), and total antler weight (+231.3 g). Furthermore, mean gross Boone and Crockett (GBC) score increased (P < 0.001) linearly throughout the study, with the GBC of the 1999 cohort exceeding that of the 1993 cohort by 36.4 in (923.0 mm). These data provide insight to the effectiveness of a selection process (i.e., culling) in an overall deer-management program.
The role of AMPK in regulating energy storage and depletion remains unexplored in the intestine. This study will to define its status, composition, regulation and lipid function, as well as to ...examine the impact of insulin resistance and type 2 diabetes on intestinal AMPK activation, insulin sensitivity, and lipid metabolism. Caco-2/15 cells and Psammomys obesus (P. obesus) animal models were experimented. We showed the predominance of AMPKα1 and the prevalence of α1/β2/γ1 heterotrimer in Caco-2/15 cells. The activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleoside and metformin resulted in increased phospho(p)-ACC. However, the down-regulation of p-AMPK by compound C and high glucose lowered p-ACC without affecting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Administration of metformin to P. obesus with insulin resistance and type 2 diabetes led to 1) an up-regulation of intestinal AMPK signaling pathway typified by ascending p-AMPKα-Thr172; 2) a reduction in ACC activity; 3) an elevation of carnitine palmitoyltransferase 1; 4) a trend of increase in insulin sensitivity portrayed by augmentation of p-Akt and phospho-glycogen synthetase kinase 3β; 5) a reduced phosphorylation of p38-MAPK and ERK1/2; and 6) a decrease in diabetic dyslipidemia following lowering of intracellular events that govern lipoprotein assembly. These data suggest that AMPK fulfills key functions in metabolic processes in the small intestine.
PDF
