Restricted T-Cell Repertoire in the Epicardial Adipose Tissue of Non-ST Segment Elevation Myocardial Infarction Patients

Aims: Human epicardial adipose tissue, a dynamic source of multiple bioactive factors, holds a close functional and anatomic relationship with the epicardial coronary arteries and communicates with the coronary artery wall through paracrine and vasocrine secretions. We explored the hypothesis that T-cell recruitment into epicardial adipose tissue (EAT) in patients with non-ST segment elevation myocardial infarction (NSTEMI) could be part of a specific antigen-driven response implicated in acute coronary syndrome onset and progression. Methods and Results: We enrolled 32 NSTEMI patients and 34 chronic coronary syndrome (CCS) patients undergoing coronary artery bypass grafting (CABG) and 12 mitral valve disease (MVD) patients undergoing surgery. We performed EAT proteome profiling on pooled specimens from three NSTEMI and three CCS patients. We performed T-cell receptor (TCR) spectratyping and CDR3 sequencing in EAT and peripheral blood mononuclear cells of 29 NSTEMI, 31 CCS, and 12 MVD patients. We then used computational modeling studies to predict interactions of the TCR beta chain variable region (TRBV) and explore sequence alignments. The EAT proteome profiling displayed a higher content of pro-inflammatory molecules (CD31, CHI3L1, CRP, EMPRINN, ENG, IL-17, IL-33, MMP-9, MPO, NGAL, RBP-4, RETN, VDB) in NSTEMI as compared to CCS (P < 0.0001). CDR3-beta spectratyping showed a TRBV21 enrichment in EAT of NSTEMI (12/29 patients; 41%) as compared with CCS (1/31 patients; 3%) and MVD (none) (ANOVA for trend P < 0.001). Of note, 11/12 (92%) NSTEMI patients with TRBV21 perturbation were at their first manifestation of ACS. Four patients with the first event shared a distinctive TRBV21-CDR3 sequence of 178 bp length and 2/4 were carriers of the human leukocyte antigen (HLA)-A*03:01 allele. A 3D analysis predicted the most likely epitope able to bind HLA-A3*01 and interact with the TRBV21-CDR3 sequence of 178 bp length, while the alignment results were consistent with microbial DNA sequences. Conclusions: Our study revealed a unique immune signature of the epicardial adipose tissue, which led to a 3D modeling of the TCRBV/peptide/HLA-A3 complex, in acute coronary syndrome patients at their first event, paving the way for epitope-driven therapeutic strategies

In silico evaluation of PCB toxicity by integrative bioinformatics approach for food contaminants biomarker identification

Many diseases are the outcome of a complex inter-relationship between multiple genetic and environmental factors. Research suggests that individual susceptibility is influenced more by certain genes than by exposure to environmental agents. The startup of Human genome project has induced the activation, by NIEHS, of a companion project: the Enviromental Genomic Project (EGP). The main goal of EGP is to better understand how individuals differ in their susceptibility to environmental agents and how these susceptibilities change over time,taking genetic variability into account. The new 'omics' technologies have enhanced the capability to massively screen thousand of genes or proteins at the same time. The capability to screen thousand genes at time allows to speed up the identification of biomarkers, not only as single molecule but also in their functional context (metabolic level). In this study we investigated, by using an integrated \u2018in silico\u2019 and \u2018in vitro\u2019 analysis, the possible use of biomarkers of exposure to Polychlorinated Biphenyls (PCBs) and Polycyclic Aromatic Hydrocarbons (PAHs) on multipotent preadipocites in a complex food matrix by using a double bioinformatics/genomics approach. Experimental data constitute the basic knowledge for \u2018integrative bioinformatics\u2019 analysis. In this study we have combined and analysed the results of two different data mining processes: 1) Bioinformatics data mining that has been performed on some publically available databases (PubChem, KEGG, PharmaKb). 2) Chemoinformatics data by screening the Chemical Abstract Systems. The results of two \u2018in silico\u2019 analysis has been used to rank food contaminant taking their preferential cellular and tissue target into account

Emotion Regulation, Physical Diseases, and Borderline Personality Disorders: Conceptual and Clinical Considerations

This perspective paper aims at discussing theoretical principles that could explain how emotion regulation and physical diseases mutually influence each other in the context of borderline personality disorder (BPD). Furthermore, this paper discusses the clinical implications of the functional relationships between emotion regulation, BPD and medical conditions considering dialectical behavior therapy (DBT) as a wellvalidated therapeutic intervention, which encompasses these issues. The inflexible use of maladaptive emotion regulation strategies (e.g., suppression, experiential avoidance, and rumination) might directly increase the probability of developing physical diseases through a physiological pathway, or indirectly through a behavioral pathway. Some metabolic and chronic medical conditions could significantly impact emotional functioning through biological alterations involved in emotion regulation. Several empirical studies have shown high co-occurrence rates between BPD and several chronic physical diseases, especially ones linked to emotion-based maladaptive behaviors. DBT addresses physical diseases reported by individuals with BPD reducing problematic behaviors functionally associated to emotion dysregulation and identifying physical health as a goal for Building a Life Worth Living

Inappropriate exercise-induced increase in pulmonary artery pressure in patients with systemic sclerosis

Background Recent data show that there is an unexpectedly high prevalence of 'inappropriate' pulmonary responses to exercise among patients with systemic sclerosis (SS). However, no consensus exists as to which threshold of pulmonary artery systolic pressure (PASP) can be considered diagnostically relevant. Aim To evaluate pulmonary vascular reserve and right ventricular function changes induced by exercise in SS patients without overt pulmonary arterial hypertension. Methods and results The study enrolled 172 consecutive SS patients in NYHA class I-II, with a peak tricuspid regurgitant jet velocity at echocardiography not greater than 3 m/s, and 88 control subjects. Echocardiography was performed at rest and at the end of a maximal exercise test. SS patients showed a higher exercise-induced PASP than control subjects (36.9 +/- 8.7 vs 25.9 +/- 3.3 mm Hg, p=0.00008). The response to effort was higher in the presence of moderate interstitial lung disease (39.7 +/- 9.3 vs 36.0 +/- 8.4 mm Hg, p=0.016) or subclinical left ventricular diastolic dysfunction (42.3 +/- 5.8 vs 37.0 +/- 8.6 mm Hg, p=0.015). In control subjects, PASP values were normally distributed at rest and after exercise. In SS patients, the distribution was normal at rest but bimodal after exercise, with a second peak at 52.2 mm Hg including 13% of the total SS population. Patients in this subgroup showed subtle abnormalities of right ventricular function at rest and, most importantly, a blunted increase in right ventricular systolic function with exercise. Conclusion Exercise echocardiography may identify a subset of SS patients with an inappropriate exercise-induced increase in PASP and early signs of right ventricular dysfunction