131 Cancer and takotsubo syndrome: clinical features, outcome, and inflammatory patterns. Results from a multicentre prospective registry

Aims Cancer represents one of the major determinants of prognosis in patients with Takotsubo Syndrome (TTS). Aim of this study was therefore to compare clinical features, short- and long-term outcome and inflammatory pattern among TTS patients with history of cancer. Methods and results 412 consecutive patients with TTS were enrolled in a multicentre prospective registry from July 2007 to February 2021. Clinical features, in and out of hospital MACE, laboratory and imaging data were collected. A sub-analysis evaluating serum interleukins levels among 12 patients with cancer vs. a propensity score matched cohort was performed. Prevalence of history of cancer was 12% (N = 51 pts). Patients with history of cancer were older (77 vs. 72 years, P = 0.01), with a higher percentage of male (23.5% vs. 8.8%, P = 0.01). Diabetes, dyslipidemia, and obesity were more prevalent in patients with cancer (29% vs. 22%, 49% vs. 42%, 25.5% vs. 18.5%, P = 0.01 respectively), while a similar prevalence was found for hypertension and smoke. Left ventricular ejection fraction (LVEF) at admission and discharge was lower in patients with history of cancer (33% vs. 37%, 44% vs. 50%. P = 0.03 respectively). Patients with cancer showed higher incidence of in hospital events (41% vs. 33%, P = 0.01) mainly driven by cardiogenic shock (21.5% vs. 8.5% P = 0.01), in hospital death (13.7% vs. 4.7%, P = 0.01), left ventricular thrombi (9.8% vs. 3.3%, P = 0.01) and ventricular arrhythmias (13.7% vs. 7.4%, P = 0.01). The long-term mortality was higher in patients with history of cancer (31.3% vs. 11.3%, P = 0.01). A distinct inflammatory pattern was found in cancer patients: at admission there were higher levels of IL 2 and VEGF levels (IL-2 3.3 vs. 0.7 pg/ml, P = 0.05, VEGF 476.3 vs. 249.5 pg/ml, P = 0.03); at discharge IL-4 was lower (1.17 pg/ml vs. 2.49 pg/ml, P = 0.04) while VEGF remained higher in subjects with TTS and cancer (406 vs. 128 pg/ml, P = 0.03). Conclusions Cancer patients with TTS are characterized by different clinical features, epidemiological characteristics, worse prognosis and higher long-term mortality when compared to patients with TTS without history of malignancy. A distinct inflammatory pattern can be found in this subset of TTS patients.

Opposite Effects of Chronic Central Leptin Infusion on Activation of Insulin Signaling Pathways in Adipose Tissue and Liver Are Related to Changes in the Inflammatory Environment

Leptin modulates insulin signaling and this involves the Akt pathway, which is influenced by changes in the inflammatory environment and with leptin regulating cytokine synthesis. We evaluated the association between activation of the insulin-signaling pathway and alterations in pro- and anti-inflammatory cytokine levels in inguinal fat and liver of chronic central leptin infused (L), pair-fed (PF), and control rats. Signal transducer and activator of transcription 3 (STAT3) phosphorylation was increased in inguinal fat and reduced in liver of L rats. Phosphorylation of c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NFkB) was increased in inguinal fat of L rats, together with a pro-inflammatory cytokine profile, while in the liver activation of JNK and NFkB were reduced and an anti-inflammatory pattern was found. Phosphorylation of the insulin receptor, Akt and mechanistic target of rapamycin was decreased in inguinal fat and increased in liver of L rats. There was a direct relationship between pSTAT3 and JNK and a negative correlation of Akt with pSTAT3 and JNK in both tissues. These results indicate that the effects of chronically increased leptin on insulin-related signaling are tissue-specific and suggest that inflammation plays a relevant role in the crosstalk between leptin and insulin signaling.

miRNA-205-5p can be related to T2-polarity in Chronic Rhinosinusitis with Nasal Polyps

Background: microRNAs (miRNAs) are directly associated with inflammatory response, but their direct role in CRSwNP (chronic rhinosinusitis with nasal polyps) remains evasive. This study aimed to compare the expression of several miRNAs in tissue samples obtained from patients with CRSwNP and controls and to evaluate if miRNAs correlate to a specific inflammatory pattern (T1, T2, T17, and Treg) or intensity of symptoms in CRSwNP. Methods: nasal polyps (from patients with CRSwNP – n=36) and middle turbinate mucosa (from control patients – n=41) were collected. Microarray determined human mature miRNA expression, and the results obtained were validated by qPCR. miRNAs that were differentially expressed were then correlated to cytokine proteins (by Luminex), tissue eosinophilia, and SNOT-22. Results: After microarray and qPCR analyses, six microRNAs were up-regulated in CRSwNP samples when compared with controls: miR-205-5p, miR-221-3p, miR-222-3p, miR-378a-3p, miR-449a and miR-449b-5p. All these miRNAs are directly implicated with cell cycle regulation and apoptosis, and to a minor extent, with inflammation. Importantly, miR-205-5p showed a significantly positive correlation with IL-5 concentration and eosinophil count at the tissue and with the worst SNOT-22 score. Conclusions: miRNA 205-5p was increased in CRSwNP compared to controls, and it was especially expressed in CRSwNP patients with higher T2 inflammation (measured by both IL-5 levels and local eosinophilia) and worst clinical presentation. This miRNA may be an interesting target to be explored in patients with CRSwNP.

Proinflammatory and Hyperinsulinemic Dietary Patterns Are Associated With Specific Profiles of Biomarkers Predictive of Chronic Inflammation, Glucose-Insulin Dysregulation, and Dyslipidemia in Postmenopausal Women

Background: Dietary patterns promoting hyperinsulinemia and chronic inflammation, including the empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP), have been shown to strongly influence risk of weight gain, type 2 diabetes, cardiovascular disease, and cancer. EDIH was developed using plasma C-peptide, whereas EDIP was based on plasma C-reactive protein (CRP), interleukin-6, and tumor necrosis factor alpha receptor 2 (TNF-αR2). We investigated whether these dietary patterns were associated with a broader range of relevant biomarkers not previously tested.Methods: In this cross-sectional study, we included 35,360 women aged 50–79 years from the Women's Health Initiative with baseline (1993–1998) fasting blood samples. We calculated EDIH and EDIP scores from baseline food frequency questionnaire data and tested their associations with 40 circulating biomarkers of insulin response/insulin-like growth factor (IGF) system, chronic systemic inflammation, endothelial dysfunction, lipids, and lipid particle size. Multivariable-adjusted linear regression was used to estimate the percent difference in biomarker concentrations per 1 standard deviation increment in dietary index. FDR-adjusted p < 0.05 was considered statistically significant.Results: Empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) were significantly associated with altered concentrations of 25 of the 40 biomarkers examined. For EDIH, the percent change in biomarker concentration in the insulin-related biomarkers ranged from +1.3% (glucose) to +8% (homeostatic model assessment for insulin resistance) and −9.7% for IGF-binding protein-1. EDIH impacted inflammation and endothelial dysfunction biomarkers from +1.1% (TNF-αR2) to +7.8% (CRP) and reduced adiponectin by 2.4%; and for lipid biomarkers: +0.3% (total cholesterol) to +3% (triglycerides/total cholesterol ratio) while reducing high-density lipoprotein cholesterol by 2.4%. EDIP showed a similar trend of associations with most biomarkers, although the magnitude of association was slightly weaker for the insulin-related biomarkers and stronger for lipids and lipid particle size.Conclusions: Dietary patterns with high potential to contribute to insulin hypersecretion and to chronic systemic inflammation, based on higher EDIH and EDIP scores, were associated with an unfavorable profile of circulating biomarkers of glucose-insulin dysregulation, chronic systemic inflammation, endothelial dysfunction and dyslipidemia. The broad range of biomarkers further validates EDIH and EDIP as mechanisms-based dietary patterns for use in clinical and population-based studies of metabolic and inflammatory diseases.

Estimating the Effects of Dental Caries and Its Restorative Treatment on Periodontal Inflammatory and Oxidative Status: A Short Controlled Longitudinal Study

Dental caries and periodontitis are among the most common health conditions that are currently recognized as growing socio-economic problems relating to their increasing prevalence, negative socio-economic impact, and harmful effects on systemic health. So far, the exact effects of caries and standard restorative materials on periodontal inflammatory and oxidative status are not established. The present study aimed to investigate the effect of caries and its restoration using standard temporary and permanent filling materials on a panel of 16 inflammatory and oxidative markers in gingival crevicular fluid (GCF) of periodontally healthy individuals, 7 (D7) and 30 (D30) days post-restoration, while the intact teeth represented the control. One hundred ninety systemically and periodontally healthy patients with occlusal caries underwent standard cavity preparation and restorations with one of six standard temporary or permanent restorative material according to indication and randomization scheme. Interleukin (IL)-2, IFN- γ, IL-12, IL-17A, IL-13, IL-9, IL-10, IL-6, IL-5, IL-4, IL-22, TNF-α, IL1- β, thiobarbituric acid reactive substances, superoxide dismutase, and reduced form of glutathione were measured in GCF samples by flowcytometry and spectrophotometry in aid of commercial diagnostic assays. Caries affected teeth exhibited significantly increased IL-1 β, IL-17, IL-22, and TBARS and decreased IL-9 concentrations compared to healthy controls. Treatment generally resulted in an increased antioxidant capacity with exception of zinc-polycarboxylate cement showing distinctive inflammatory pattern. Comparison of inflammatory and oxidative profiles in temporary and permanent restorations showed material-specific patterning which was particularly expressed in temporary materials plausibly related to greater caries extension. Caries affected teeth exhibited a balanced inflammatory pattern in GCF, with a general tendency of homeostatic re-establishment following treatment. Restorative materials did not provide specific pathological effects, although some material groups did exhibit significantly elevated levels of inflammatory and oxidative markers compared to healthy controls, while the material-specific patterning was observed as well.

Respiratory Nasal Mucosa in Chronic Rhinosinusitis with Nasal Polyps versus COVID-19: Histopathology, Electron Microscopy Analysis and Assessing of Tissue Interleukin-33

(1) Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is one of the most studied rhinological disorders. Modifications of the respiratory nasal mucosa in COVID-19 patients are so far unknown. This paper presents a comparative morphological characterization of the respiratory nasal mucosa in CRSwNP versus COVID-19 and tissue interleukin (IL)-33 concentration. (2) Methods: We analyzed CRSwNP and COVID-19 samples through histopathology, scanning and transmission electron microscopy and performed proteomic determination of IL-33. (3) Results: Histopathologically, stromal edema (p < 0.0001) and basal membrane thickening (p = 0.0768) were found more frequently in CRSwNP than in COVID-19. Inflammatory infiltrate was mainly eosinophil-dominant in CRSwNP and lymphocyte-dominant in COVID-19 (p = 0.3666). A viral cytopathic effect was identified in COVID-19. Scanning electron microscopy detected biofilms only in CRSwNP, while most COVID-19 samples showed microbial aggregates (p = 0.0148) and immune cells (p = 0.1452). Transmission electron microscopy of CRSwNP samples identified biofilms, mucous cell hyperplasia (p = 0.0011), eosinophils, fibrocytes, mastocytes, and collagen fibers. Extracellular suggestive structures for SARS-CoV-2 and multiple Golgi apparatus in epithelial cells were detected in COVID-19 samples. The tissue IL-33 concentration in CRSwNP (210.0 pg/7 μg total protein) was higher than in COVID-19 (52.77 pg/7 μg total protein) (p < 0.0001), also suggesting a different inflammatory pattern. (4) Conclusions: The inflammatory pattern is different in each of these disorders. Results suggested the presence of nasal dysbiosis in both conditions, which could be a determining factor in CRSwNP and a secondary factor in COVID-19.

Inflammatory Pattern of Eosinophilic COPD Involving 12/15-LOX Lipid Signals Expressed by Eosinophils

Background and objective:Eosinophilic chronic obstructive pulmonary disease (COPD) has been recognized as an inflammatory pattern which is importance for precise treatment interventions among COPD. However, the studies about eosinophilic COPD show conflicting results and the role of eosinophils in COPD remains unclear. In this study, LC-MS/MS-based mediator lipidomics was to determine the expression status of lipid signals in non-eosinophilic and eosinophilic COPD.Method:A totally 80 patients with COPD including 40 eosinophilic COPD and 40 non-eosinophilic COPD were enrolled over 12 months. Clinical characteristics information record, pulmonary function tests, complete blood count, serum metabolites analysis and other clinical tests were performed at baseline and follow-up. Results:There were no significant differences in pulmonary function or pulmonary function decline between eosinophilic COPD and non-eosinophilic COPD after follow-up. However, eosinophilic COPD have higher numbers of acute exacerbation patient in the last 1 year. Complete blood count (CBC) data demonstrated that Δblood eosinophil count (BEC) was significantly decreased and correlated with ΔFEV1 (% Predicted) (r = 0.314, P = 0.036) in eosinophilic COPD. Furthermore, compared to non-eosinophilic COPD, a series of 12/15-LOX-derived mediators were found increased in eosinophilic COPD. Among them, 17-HDoHE was found significantly decreased after follow-up and significantly correlated with ΔBEC (r= 0.336, P= 0.023).Conclusion:This study demonstrates that metabolic levels of non-eosinophilic COPD and eosinophilic COPD were different due to the huge difference in eosinophil level, which leads to different inflammatory patterns, and the 12/15-LOX metabolic pathway was one of them. The results might help to understand the inflammatory response and lipid metabolism of eosinophilic COPD.