GeneRanger and TargetRanger: processed gene and protein expression levels across cells and tissues for target discovery.

Several atlasing efforts aim to profile human gene and protein expression across tissues, cell types and cell lines in normal physiology, development and disease. One utility of these resources is to examine the expression of a single gene across all cell types, tissues and cell lines in each atlas. However, there is currently no centralized place that integrates data from several atlases to provide this type of data in a uniform format for visualization, analysis and download, and via an application programming interface. To address this need, GeneRanger is a web server that provides access to processed data about gene and protein expression across normal human cell types, tissues and cell lines from several atlases. At the same time, TargetRanger is a related web server that takes as input RNA-seq data from profiled human cells and tissues, and then compares the uploaded input data to expression levels across the atlases to identify genes that are highly expressed in the input and lowly expressed across normal human cell types and tissues. Identified targets can be filtered by transmembrane or secreted proteins. The results from GeneRanger and TargetRanger are visualized as box and scatter plots, and as interactive tables. GeneRanger and TargetRanger are available from https://generanger.maayanlab.cloud and https://targetranger.maayanlab.cloud, respectively.

Osteogenic circulating endothelial progenitor cells are linked to electrocardiographic conduction abnormalities in rheumatic patients.

BACKGROUND: Osteogenic circulating endothelial progenitor cells (EPC) play a pathogenic role in cardiovascular system degeneration through promulgating vasculature calcification, but its role in conduction disorders as part of the cardiovascular degenerative continuum remained unknown. AIM: To investigate the role of osteocalcin (OCN)-expressing circulating EPCs in cardiac conduction disorders in the unique clinical sample of rheumatoid arthritis (RA) susceptible to both abnormal bone metabolism and cardiac conduction disorders. METHODS: We performed flow cytometry studies in 134 consecutive asymptomatic patients with rheumatoid arthritis to derive osteogenic circulating OCN-positive (OCN+) CD34+KDR+ vs. CD34+CD133+KDR+ conventional EPC. Study endpoint was the prespecified combined endpoint of electrocardiographic conduction abnormalities. RESULTS: Total prevalence of cardiac conduction abnormality was 9% (n = 12). All patients except one had normal sinus rhythm. One patient had atrial fibrillation. No patient had advanced atrioventricular (AV) block. Prevalence of first-degree heart block (>200 ms), widened QRS duration (>120 ms) and right bundle branch block were 6.7%, 2.1%, and 2.2% respectively. Circulating osteogenic OCN+ CD34+ KDR+ EPCs were significantly higher among patients with cardiac conduction abnormalities (p = 0.039). Elevated OCN+ CD34+ KDR+ EPCs> 75th percentile was associated with higher prevalence of cardiac conduction abnormalities (58.3% vs. 20.02%, p = 0.003). Adjusted for potential confounders, elevated OCN+ CD34+ KDR+ EPCs> 75th percentile remained independently associated with increased risk of cardiac conduction abnormalities (OR = 4.4 [95%CI 1.2-16.4], p = 0.028). No significant relation was found between conventional EPCs CD34+CD133+KDR+ and conduction abnormalities (p = 0.36). CONCLUSIONS: Elevated osteogenic OCN+ CD34+ KDR+ EPCs are independently associated with the presence of electrocardiographic conduction abnormalities in patients with rheumatoid arthritis, unveiling a potential novel pathophysiological mechanism.

Osteogenic Circulating Endothelial Progenitor Cells are Associated with Vascular Aging of the Large Arteries in Rheumatoid Arthritis.

Background and Aim: Rheumatoid arthritis is associated with both abnormal bone metabolism and accelerated vascular aging but a mechanistic link was lacking. This study aims to investigate the role of osteocalcin (OCN)-expressing circulating endothelial progenitor cells (EPCs) in vascular aging, as determined by arterial calcifications in rheumatoid arthritis. Methods: We performed flow cytometry studies in 145 consecutive patients with rheumatoid arthritis to determine osteogenic circulating levels of OCN-positive (OCN+) CD34+KDR+ and OCN+CD34+ versus conventional early EPC CD34+CD133+KDR+. Total calcium load of the thoracic aorta (ascending plus descending) and the carotid arteries were assessed by non-contrast computed tomography (CT) and contrast CT angiography. Results: Osteogenic EPCs OCN+CD34+KDR+ (P = 0.002) and OCN+CD34+ (P = 0.001), together with clinical parameters of age, history of hypertension, systolic blood pressure, serum levels of triglycerides, HbA1c and creatinine, use of leflunomide and brachial-ankle pulse-wave velocity (all P < 0.05), were associated with the clustered presence of aortic and carotid calcification. Multivariable analyses revealed that circulating OCN+CD34+KDR+ (B = 14.4 [95% CI 4.0 to 24.8], P = 0.007) and OCN+CD34+ (B = 9.6 [95% CI 4.9 to 14.3], P < 0.001) remained independently associated with increased aortic calcium load. OCN+CD34+ EPC (B = 0.8 [95% CI 0.1 to 1.5], P = 0.023), but not OCN+CD34+KDR+ EPC (B = 1.2 [95% CI -0.2 to 2.6], P = 0.09), was further independently associated with carotid calcium load. In comparison, conventional early EPC CD34+CD133+KDR+ had no significant association with aortic or carotid calcium load (P = 0.46 and 0.88, respectively). Conclusion: Circulating level of osteogenic EPC is associated with increased vascular aging in terms of calcification of the large arteries in patients with rheumatoid arthritis. The findings may suggest a role of the bone-vascular axis underlying vascular aging in rheumatic diseases. Further research is needed to characterize the mechanistic links and basis of these observations.

Cumulative Rheumatic Inflammation Modulates the Bone-Vascular Axis and Risk of Coronary Calcification.

Background Rheumatic diseases are related to both abnormal bone turnover and atherogenesis, but a mechanistic link was missing. Methods and Results We investigated the effect of cumulative rheumatic inflammation ( CRI ) on risk of coronary calcification in a retrospective cohort of 145 rheumatoid arthritis patients. A time-adjusted aggregate CRI score was derived by conglomerating all quarterly biomarker encounters of serum C-reactive protein over 60 months immediately preceding computed tomography coronary angiography. Flow cytometry was performed to measure the osteocalcin-positive ( OCN +) CD 34+ KDR + and OCN + CD 34+ circulating endothelial progenitor cells ( EPCs ). Conventional early circulating EPCs CD 34+ CD 133+ KDR + was determined. Coronary calcification was defined as any Agatston score >0. 50% of patients (n=72/145) had coronary calcification. CRI score was associated with presence of coronary calcification ( P=0.004) (multivariable-adjusted: highest versus lowest quartile: odds ratio=5.6 [95% CI 1.1-28.9], P=0.041). Receiver operating characteristics curve revealed divergent behavior of OCN -expressing circulating EPCs ( OCN + CD 34+ EPCs : area under the curve=0.60, P=0.034; OCN + CD 34+ KDR + EPCs : area under the curve=0.59, P=0.053, positive predictors) versus conventional early EPCs ( CD 34+ CD 133+ KDR +: area under the curve=0.60, P=0.034, negative predictor) for coronary calcification, which persisted after multivariable adjustments ( OCN + CD 34+ KDR + [>75th percentile]: odds ratio=7.2 [95% CI 1.8-27.9], P=0.005; OCN + CD 34+ EPCs [>75th percentile]: odds ratio=6.0 [95% CI 1.5-23.3], P=0.010; CD 34+ CD 133+ KDR + [>75th percentile: odds ratio=0.3 [95% CI 0.1-1.0], P=0.053). Intriguingly, the CRI score was associated with increased OCN + CD 34+ EPCs (highest versus lowest quartile: B=+25.6 [95% CI 0.8-50.5] [×103/mL peripheral blood], P=0.043), but reduced CD 34+ CD 133+ KDR + EPCs (highest versus lowest quartile: B=-16.2 [95% CI -31.5 to -0.9], P=0.038). Conclusions Preceding 60 months of CRI is associated with increased risk of coronary calcification and altered OCN expression in circulating EPCs .