Azienda Ospedaliera Universitaria Università degli Studi della Campania Luigi Vanvitelli

Significance: Oxidative stress represents the common hallmark of pathological conditions associated with cardiovascular disease (CVD), including atherosclerosis, heart failure, hypertension, aging, diabetes, and other vascular system-related diseases. The sirtuin (SIRT) family, comprising seven proteins (SIRT1–SIRT7) sharing a highly conserved nicotinamide adenine dinucleotide (NAD + )-binding catalytic domain, attracted a great attention for the past few years as stress adaptor and epigenetic enzymes involved in the cellular events controlling aging-related disorder, cancer, and CVD. Recent Advances: Among sirtuins, SIRT1 and SIRT6 are the best characterized for their protective roles against inflammation, vascular aging, heart disease, and atherosclerotic plaque development. This latest role has been only recently unveiled for SIRT6. Of interest, in recent years, complex signaling networks controlled by SIRT1 and SIRT6 common to stress resistance, vascular aging, and CVD have emerged. Critical Issues: We provide a comprehensive overview of recent developments on the molecular signaling pathways controlled by SIRT1 and SIRT6, two post-translational modifiers proven to be valuable tools to dampen inflammation and oxidative stress at the cardiovascular level. Future Directions: A deeper understanding of the epigenetic mechanisms through which SIRT1 and SIRT6 act in the signalings responsible for onset and development CVD is a prime scientific endeavor of the upcoming years. Multiple “omic” technologies will have widespread implications in understanding such mechanisms, speeding up the achievement of selective and efficient pharmacological modulation of sirtuins for future applications in the prevention and treatment of CVD. Antioxid. Redox Signal . 28, 711–732.

Abstract This paper responds to the need for a deeper empirical investigation of the impact of corporate social responsibility pillars on the financial performance of banks. To address this question, this study first analyzes the factors that encourage banks to be more environmentally friendly and then investigates the relationship between a bank's environmental engagement and its risk. Using a sample of 142 banks from 35 countries covering the period from 2011 to 2015, we document the positive impact of effective corporate governance mechanisms on banks' environmental engagement. Moreover, by using the Heckman's two‐stage model for the treatment of sample selection bias, we find that banks that are more sensitive to environmental issues also exhibit less risk. Stakeholder theory and the conflict resolution hypothesis are useful frameworks to overcome the trade‐off between economy and ecology in the banking industry.

The cancer burden is rising globally, exerting significant strain on populations and health systems at all income levels. In May 2017, world governments made a commitment to further invest in cancer control as a public health priority, passing the World Health Assembly Resolution 70.12 on cancer prevention and control within an integrated approach. In this manuscript, the 2016 European Society for Medical Oncology Leadership Generation Programme participants propose a strategic framework that is in line with the 2017 WHO Cancer Resolution and consistent with the principle of universal health coverage, which ensures access to optimal cancer care for all people because health is a basic human right. The time for action is now to reduce barriers and provide the highest possible quality cancer care to everyone regardless of circumstance, precondition or geographic location. The national actions and the policy recommendations in this paper set forth the vision of its authors for the future of global cancer control at the national level, where the WHO Cancer Resolution must be implemented if we are to reduce the cancer burden, avoid unnecessary suffering and save as many lives as possible.

Abstract The current study aims to answer dual, related questions: Does corporate environmental policy affect corporate reputation, and does this link also influence risk‐adjusted profitability and company's risk? With a comprehensive framework involving analyses of each question, among a sample of firms traced by the Reputation Institute, this study reveals several notable results, after correcting for endogeneity biases. First, environmental engagement and green product innovation are both antecedents of corporate reputation. Second, corporate reputation has a positive impact on risk‐adjusted profitability and Z score indicator of financial distress risk. Thus, corporate environmental responsibility and green practices represent cospecialized assets that enhances an intangible asset, namely, corporate reputation. The latter influence constitutes a missing link between sustainable development and the firm's financial performance. Overall, environmental engagement and corporate reputation act as insurance‐like protections of firm competitiveness.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the α-galactosidase A (GLA) gene that leads to reduced or undetectable α-galactosidase A enzyme activity and progressive accumulation of globotriaosylceramide and its deacylated form globotriaosylsphingosine in cells throughout the body. FD can be multisystemic with neurological, renal, cutaneous and cardiac involvement or be limited to the heart. Cardiac involvement is characterized by progressive cardiac hypertrophy, fibrosis, arrhythmias, heart failure and sudden cardiac death. The cardiac management of FD requires specific measures including enzyme replacement therapy or small pharmacological chaperones in patients carrying amenable pathogenic GLA gene variants and more general management of cardiac symptoms and complications. In this paper, we summarize current knowledge of FD-related heart disease and expert consensus recommendations for its management.

Abstract Purpose: Histone deacetylase inhibitors (HDACi) are promising anticancer drugs. Although some HDACi have entered the clinic, the mechanism(s) underlying their tumor selectivity are poorly understood. Experimental Design and Results: Using gene expression analysis, we define a core set of six genes commonly regulated in acute myeloid leukemia (AML) blasts and cell lines. MYC, the most prominently modulated, is preferentially altered in leukemia. Upon HDACi treatment, c-Myc is acetylated at lysine 323 and its expression decreases, leading to TRAIL activation and apoptosis. c-Myc binds to the TRAIL promoter on the proximal GC box through SP1 or MIZ1, impairing TRAIL activation. HDACi exposure triggers TRAIL expression, altering c-Myc-TRAIL binding. These events do not occur in normal cells. Excitingly, this inverse correlation between TRAIL and c-Myc is supported by HDACi treatment ex vivo of AML blasts and primary human breast cancer cells. The predictive value of c-Myc to HDACi responsiveness is confirmed in vivo in AML patients undergoing HDACi-based clinical trials. Conclusions: Collectively, our findings identify a key role for c-Myc in TRAIL deregulation and as a biomarker of the anticancer action of HDACi in AML. The potential improved patient stratification could pave the way toward personalized therapies. Clin Cancer Res; 23(10); 2542–55. ©2016 AACR.

In recent months, Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread throughout the world. COVID-19 patients show mild, moderate or severe symptoms with the latter ones requiring access to specialized intensive care. SARS-CoV-2 infections, pathogenesis and progression have not been clearly elucidated yet, thus forcing the development of many complementary approaches to identify candidate cellular pathways involved in disease progression. Host lipids play a critical role in the virus life, being the double-membrane vesicles a key factor in coronavirus replication. Moreover, lipid biogenesis pathways affect receptor-mediated virus entry at the endosomal cell surface and modulate virus propagation. In this study, targeted lipidomic analysis coupled with proinflammatory cytokines and alarmins measurement were carried out in serum of COVID-19 patients characterized by different severity degree. Serum IL-26, a cytokine involved in IL-17 pathway, TSLP and adiponectin were measured and correlated to lipid COVID-19 patient profiles. These results could be important for the classification of the COVID-19 disease and the identification of therapeutic targets.

OBJECTIVE: To grade the evidence about risk factors for eating disorders (anorexia nervosa, bulimia nervosa, and binge eating disorder) with an umbrella review approach. METHODS: This was a systematic review of observational studies on risk factors for eating disorders published in PubMed/PsycInfo/Embase until December 11th, 2019. We recalculated random-effect meta-analyses, heterogeneity, small-study effect, excess significance bias and 95% prediction intervals, grading significant evidence (p < 0.05) from convincing to weak according to established criteria. Quality was assessed with the Assessment of Multiple Systematic Reviews 2 (AMSTAR-2) tool. RESULTS: Of 2,197 meta-analyses, nine were included, providing evidence on 50 risk factors, 29,272 subjects with eating disorders, and 1,679,385 controls. Although no association was supported by convincing evidence, highly suggestive evidence supported the association between childhood sexual abuse and bulimia nervosa (k = 29, 1,103 cases with eating disorders, 8,496 controls, OR, 2.73, 95%CI 1.96-3.79, p = 2.1 x 10-9, AMSTAR-2 moderate quality) and between appearance-related teasing victimization and any eating disorder (k = 10, 1,341 cases with eating disorders, 3,295 controls, OR 2.91, 95%CI 2.05-4.12, p = 1.8x10-9, AMSTAR-2 moderate quality). Suggestive, weak, or no evidence supported 11, 29, and 8 associations, respectively. CONCLUSIONS: The most credible evidence indicates that early traumatic and stressful events are risk factors for eating disorders. Larger collaborative prospective cohort studies are needed to identify risk factors for eating disorders, particularly anorexia nervosa.

OBJECTIVES: To assess whether multiple observers can identify the same pigmented lesion(s) as being different from a patient's other moles ("ugly duckling" [UD] sign) and to explore whether the UD sign is sensitive for melanoma detection. DESIGN: Baseline back images of 12 patients were obtained from a database of standardized patient images. All patients had at least 8 atypical moles on the back, and in 5 patients, one of the lesions was a histologically confirmed melanoma. The overview back images were supplemented with close-up clinical images of lesions. Participants were asked to evaluate whether the images showed any lesions on the back that differed from other nevi. SETTING: Dermatology clinic specializing in pigmented lesions. PARTICIPANTS: Images were evaluated by 34 participants, including 8 pigmented lesion experts, 13 general dermatologists, 5 dermatology nurses, and 8 nonclinical medical staff. MAIN OUTCOME MEASURES: A lesion was considered a generally apparent UD if it was perceived as different by at least two-thirds of the participants. Sensitivity was defined as the fraction of melanomas identified as different. RESULTS: All 5 melanomas (100%) and only 3 of 140 benign lesions (2.1%) were generally apparent as different. The sensitivity of the UD sign for melanoma detection was 0.9 for the whole group, 1.0 for experts, 0.89 for general dermatologists, 0.88 for nurses, and 0.85 for nonclinicians. A limitation of the study is that assessment was done in virtual settings. CONCLUSIONS: In the present study, melanomas were generally apparent as UDs. The potential of the UD sign for melanoma screening should be further assessed.

The endogenous fatty acid amide palmitoylethanolamide (PEA) has been shown to exert anti-inflammatory actions mainly through inhibition of the release of pro-inflammatory molecules from mast cells, monocytes and macrophages. Indirect activation of the endocannabinoid (eCB) system is among the several mechanisms of action that have been proposed to underlie the different effects of PEA in vivo. In this study, we used cultured rat microglia and human macrophages to evaluate whether PEA affects eCB signaling. PEA was found to increase CB2 mRNA and protein expression through peroxisome proliferator-activated receptor-α (PPAR-α) activation. This novel gene regulation mechanism was demonstrated through: (i) pharmacological PPAR-α manipulation, (ii) PPAR-α mRNA silencing, (iii) chromatin immunoprecipitation. Moreover, exposure to PEA induced morphological changes associated with a reactive microglial phenotype, including increased phagocytosis and migratory activity. Our findings suggest indirect regulation of microglial CB2R expression as a new possible mechanism underlying the effects of PEA. PEA can be explored as a useful tool for preventing/treating the symptoms associated with neuroinflammation in CNS disorders.

Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD) which sets the stage for further liver damage. The mechanism for the progression of NASH involves multiple parallel hits including oxidative stress, mitochondrial dysfunction, inflammation and others. Manipulation of any of these pathways may be an approach to prevent NASH development and progression. Aramchol (arachidyl-amido cholanoic acid) is presently in a phase IIb NASH study. The aim of this study was to investigate Aramchol's mechanism of action and its effect on fibrosis using the methionine- and choline-deficient (MCD) diet model of NASH. We collected liver and serum from mice fed a MCD diet containing 0.1% methionine (0.1MCD) for four weeks, which developed steatohepatitis and fibrosis, as well as mice receiving a control diet; the metabolomes and proteomes were determined. 0.1MCD fed mice were given Aramchol (5mg/kg/day for the last 2 weeks); liver samples were analyzed histologically. Aramchol administration reduced features of steatohepatitis and fibrosis in 0.1MCD fed mice. Aramchol downregulated stearoyl-CoA desaturase 1 (SCD1), a key enzyme involved in triglyceride biosynthesis whose loss enhances fatty acid β-oxidation. Aramchol increased the flux through the transsulfuration pathway, leading to a rise in glutathione (GSH) and GSH/GSSG ratio, the main cellular antioxidant that maintains intracellular redox status. Comparison of serum metabolomic pattern between 0.1MCD fed mice and NAFLD patients showed a substantial overlap. CONCLUSIONS: Aramchol treatment improved steatohepatitis and fibrosis by 1) decreasing SCD1, and 2) increasing the flux through the transsulfuration pathway maintaining cellular redox homeostasis. We also demonstrated that the 0.1MCD model resembles the metabolic phenotype observed in about 50% of NAFLD patients, which supports the potential use of Aramchol in NASH treatment.

OBJECTIVE: To investigate predictors of response, remission, low disease activity, damage, and drug discontinuation in patients with systemic lupus erythematosus (SLE) who were treated with belimumab. METHODS: In this retrospective study of a multicenter cohort of SLE patients who received intravenous belimumab, the proportion of patients who achieved remission, low disease activity, and treatment response according to the SLE Responder Index 4 (SRI-4) was determined, and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) was used to score disease damage yearly over the follow-up. Predictors of outcomes were analyzed by multivariate logistic regression with the results expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: The study included 466 patients with active SLE from 24 Italian centers, with a median follow-up period of 18 months (range 1-60 months). An SRI-4 response was achieved by 49.2%, 61.3%, 69.7%, 69.6%, and 66.7% of patients at 6, 12, 24, 36, and 48 months, respectively. Baseline predictors of response at 6 months included a score of ≥10 on the SLE Disease Activity Index 2000 (SLEDAI-2K) (OR 3.14 [95% CI 2.033-4.860]) and a disease duration of ≤2 years (OR 1.94 [95% CI 1.078-3.473). Baseline predictors of response at 12 months included a score of ≥10 on the SLEDAI-2K (OR 3.48 [95% CI 2.004-6.025]) and an SDI score of 0 (OR 1.74 [95% CI 1.036-2.923]). Baseline predictors of response at 24 months included a score of ≥10 on the SLEDAI-2K (OR 4.25 [95% CI 2.018-8.940]) and a disease duration of ≤2 years (OR 3.79 [95% CI 1.039-13.52]). Baseline predictors of response at 36 months included a score of ≥10 on the SLEDAI-2K (OR 14.59 [95% CI 3.54-59.79) and baseline status of current smoker (OR 0.19 [95% CI 0.039-0.69]). Patients who were in remission for ≥25% of the follow-up period (44.3%) or who had low disease activity for ≥50% of the follow-up period (66.1%) accrued significantly less damage (P = 0.046 and P = 0.007). A baseline SDI score of 0 was an independent predictor of achieving low disease activity in ≥50% of the follow-up period and remission in ≥25% of the follow-up period. Our findings suggest that the lower the baseline damage, the greater the probability of achieving remission over the course of ≥25% of the follow-up. Further, there was a negative association between the number of flares reported prior to belimumab initiation and the frequency of belimumab discontinuation due to inefficacy (P = 0.009). CONCLUSION: In patients with active SLE and low damage at baseline, treatment with belimumab early in the disease may lead to favorable outcomes in a real-life setting.

The role of shared identity in predicting both ingroup helping behaviour and adherence to protective norms during COVID-19 has been extensively theorized, but remains largely under-investigated. We build upon previous Social Identity research into community resilience by testing the role of pre-existing local community (or 'neighbourhood') identity as a predictor of these outcomes, via the mediator of perceived social support. Community residents in the UK completed a longitudinal online survey four months before lockdown (T1; N = 253), one month before lockdown (T2; N = 217), and two months into lockdown (T3; N = 149). The cross-lagged panel analysis shows that T1 community identification predicts T3 giving and receiving of pandemic-related support, and that these effects occur via the perception of community support at the second time point (while the alternative pathway from T1 support via T2 identification is non-significant). Moreover, we show that T1 community identification also directly predicts lockdown adherence at T3. Our findings point to the pivotal role played by community identity in effective behavioural responses to the pandemic, and the need to support and foster community development to facilitate local community resilience as the crisis continues to unfold.

Levels of loneliness across the world have reached epidemic proportions, and their impact upon population health is increasingly apparent. In response, policies and initiatives have attempted to reduce loneliness by targeting social isolation among residents of local communities. Yet, little is known about the social psychological processes underpinning the relationships between community belonging, loneliness, and well-being. We report three studies which apply the Social Identity Approach to Health to examine the mechanisms underpinning the relationships between community identity, health, and loneliness. Hypotheses were tested through secondary analyses of the 2014-2015 UK Community Life Survey (N = 4,314) as well as bespoke household surveys in a more (N = 408) and less (N = 143) affluent community at high risk of loneliness. Studies 1 and 2a demonstrated that the relationship between community identification and well-being was mediated by increased social support and reduced loneliness. In Study 2b, community identification predicted well-being through reduced loneliness, but not through social support. Our results are the first to evidence these relationships and suggest that community-level interventions that enhance community identification and peer support can promote a potential Social Cure for loneliness.

Background: Suspected myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) occurs in ≈5% to 10% of patients with MI referred for coronary angiography. The prognosis of these patients may differ to those with MI and obstructive coronary artery disease (MI-CAD) and those without a MI (patients without known history of MI [No-MI]). The primary objective of this study is to evaluate the 12-month all-cause mortality of patients with MINOCA. Methods: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the terms “MI,” “nonobstructive,” “angiography,” and “prognosis” were searched in PubMed and Embase databases from inception to December 2018, including original, English language MINOCA studies with &gt;100 consecutive patients. Publications with a heterogeneous cohort, unreported coronary stenosis, or exclusively focusing on MINOCA-mimicking conditions, were excluded. Unpublished data were obtained from the MINOCA Global Collaboration. Data were pooled and analyzed using Paule-Mandel, Hartung, Knapp, Sidik &amp; Jonkman, or restricted maximum-likelihood random-effects meta-analysis methodology. Heterogeneity was assessed using Cochran’s Q and I 2 statistics. The primary outcome was 12-month all-cause mortality in patients with MINOCA, with secondary comparisons to MI-CAD and No-MI. Results: The 23 eligible studies yielded 55 369 suspected MINOCA, 485 382 MI-CAD, and 33 074 No-MI. Pooled meta-analysis of 14 MINOCA studies accounting for 30 733 patients revealed an unadjusted 12-month all-cause mortality rate of 3.4% (95% CI, 2.6%–4.2%) and reinfarction (n=27 605; 10 studies) in 2.6% (95% CI, 1.7%–3.5%). MINOCA had a lower 12-month all-cause mortality than those with MI-CAD (3.3% [95% CI, 2.5%–4.1%] versus 5.6% [95% CI, 4.1%–7.0%]; odds ratio, 0.60 [95% CI, 0.52–0.70], P &lt;0.001). In contrast, there was a statistically nonsignificant trend towards increased 12-month all-cause mortality in patients with MINOCA (2.6% [95% CI, 0%–5.9%]) compared with No-MI (0.7% [95% CI, 0.1%–1.3%]; odds ratio, 3.71 [95% CI, 0.58–23.61], P =0.09). Conclusions: In the largest contemporary MINOCA meta-analysis to date, patients with suspected MINOCA had a favorable prognosis compared with MI-CAD, but statistically nonsignificant trend toward worse outcomes compared to those with No-MI. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/ ; Unique identifier: CRD42020145356.

Abstract The EPHA2 tyrosine kinase receptor is implicated in tumor progression and targeted therapies resistance. We evaluated EPHA2 as a potential resistance marker to the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in colorectal cancer. We studied activation of EPHA2 in a panel of human colorectal cancer cell lines sensitive or resistant to anti-EGFR drugs. The in vitro and in vivo effects of ALW-II-41-27 (an EPHA2 inhibitor) and/or cetuximab treatment were tested. Formalin-fixed paraffin-embedded tumor specimens from 82 RAS wild-type (WT) metastatic colorectal cancer patients treated with FOLFIRI + cetuximab as first-line therapy in the CAPRI-GOIM trial were assessed for EPHA2 expression by immunohistochemistry and correlated with treatment efficacy. EPHA2 was differentially activated in colorectal cancer cell lines. Combined treatment with ALW-II-41-27 plus cetuximab reverted primary and acquired resistance to cetuximab, causing cell growth inhibition, inducing apoptosis and cell-cycle G1–G2 arrest. In tumor xenograft models, upon progression to cetuximab, ALW-II-41-27 addition significantly inhibited tumor growth. EPHA2 protein expression was detected in 55 of 82 tumor samples, frequently expressed in less-differentiated and left-sided tumors. High levels of EPHA2 significantly correlated with worse progression-free survival [8.6 months; confidence interval (CI) 95%, 6.4–10.8; vs. 12.3 months; CI 95%, 10.4–14.2; P = 0.03] and with increased progression rate (29% vs. 9%, P = 0.02). A specific EPHA2 inhibitor reverts in vitro and in vivo primary and acquired resistance to anti-EGFR therapy. EPHA2 levels are significantly associated with worse outcome in patients treated with FOLFIRI + cetuximab. These results highlight EPHA2 as a potential therapeutic target in metastatic colorectal cancer.

Epidemiological studies on the prevalence of cyberbullying and cybervictimization in different countries, using the same procedure and the same measures, are of relevance in understanding differences in results that are not due to methodological factors. The current study was conducted in 8 European countries (Bulgaria, Cyprus, France, Greece, Hungary, Italy, Poland, and Spain), involving a total of 4,847 students, using an online anonymous questionnaire (the Tabby online questionnaire). The results were analyzed by comparing differences between countries and between genders. Cyberbullying and cybervictimization were most prevalent in Bulgaria and Hungary and least prevalent in Spain. Boys committed more cyberbullying than girls in all countries, but there were no overall gender differences in cybervictimization. However, girls were more often cybervictims in four countries and boys were more often cybervictims in the other four countries. The results are discussed with regard to the importance of cross-national studies of cyberbullying and cybervictimization and the use of online data collection in order to reduce methodological bias.

Objective We undertook this study to evaluate the activation and functional relevance of inflammasome pathways in ankylosing spondylitis (AS) patients and rodent models and their relationship to dysbiosis. Methods An inflammasome pathway was evaluated in the gut and peripheral blood from 40 AS patients using quantitative reverse transcriptase–polymerase chain reaction (qRT‐PCR), immunohistochemistry (IHC), flow cytometry, and confocal microscopy, and was compared to that of 20 healthy controls and 10 patients with Crohn’s disease. Bacteria was visualized using silver stain in human samples, and antibiotics were administered to HLA–B27–transgenic rats. The NLRP3 inhibitor MCC950 was administered to SKG mice, and ileal and joint tissues were assessed by IHC analysis and real‐time qRT‐PCR. The role of inflammasome in modulating the interleukin‐23 (IL‐23)/IL‐17 axis was studied ex vivo. Results Expression levels of Nlrp3 , Nlrc4 , and Aim2 were increased in the gut of HLA–B27–transgenic rats and reduced by antibiotic treatment ( P &lt; 0.05). In curdlan‐treated SKG mice, NLRP3 blockade prevented ileitis and delayed arthritis onset ( P &lt; 0.05). Compared to healthy controls, AS patients demonstrated overexpression of NLRP3 (fold induction 2.33 versus 22.2; P &lt; 0.001), NLRC4 (fold induction 1.90 versus 6.47; P &lt; 0.001), AIM2 (fold induction 2.40 versus 20.8; P &lt; 0.001), CASP1 (fold induction 2.53 versus 24.8; P &lt; 0.001), IL1B (fold induction 1.07 versus 10.93; P &lt; 0.001), and IL18 (fold induction 2.56 versus 15.67; P &lt; 0.001) in the ileum, and caspase 1 activity was increased ( P &lt; 0.01). The score of adherent and invasive mucosa‐associated bacteria was higher in AS ( P &lt; 0.01) and correlated with the expression of inflammasome components in peripheral blood mononuclear cells ( P &lt; 0.001). NLRP3 expression was associated with disease activity (the Ankylosing Spondylitis Disease Activity Score using the C‐reactive protein level) (r 2 = 0.28, P &lt; 0.01) and with IL23A expression (r 2 = 0.34, P &lt; 0.001) . In vitro, inflammasome activation in AS monocytes was paralleled by increased serum levels of IL‐1β and IL‐18. Induction of IL23A , IL17A, and IL22 was IL‐1β–dependent. Conclusion Inflammasome activation occurs in rodent models of AS and in AS patients, is associated with dysbiosis, and is involved in triggering ileitis in SKG mice. Inflammasomes drive type III cytokine production with an IL‐1β–dependent mechanism in AS patients.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are widely used in the treatment of many cancers as they improve clinical outcomes. However, ICIs have also been associated with the development of immune-related adverse drug reactions (ADRs). Among immune-related ADRs, cardiac immune-related ADRs are rare, but also associated with high mortality rates. OBJECTIVE: The objective of this study was to evaluate the occurrence of cardiac ADRs reported with ICIs in the European spontaneous reporting system. METHODS: We retrieved individual case safety reports on ICI-induced cardiac ADRs from the website of suspected ADR ( www.adrreports.eu ) of the European pharmacovigilance database (Eudravigilance). Data were retrieved from the date of marketing authorization of each ICI (ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and cemiplimab) to 14 March, 2020. The reporting odds ratio and its 95% confidence interval were computed to assess the reporting frequency of cardiac ADRs for each ICI compared to all other ICIs. RESULTS: A total of 2478 individual case safety reports with at least one ICI as the suspected drug were retrieved from Eudravigilance, of which 249 (10%) reported more than one ICI. The three most reported ICIs were nivolumab (43.2%), pembrolizumab (32.5%), and the association of nivolumab/ipilimumab (9.4%). A total of 3388 cardiac ADRs were identified. Cardiac ADRs were serious (99.4%) and had a fatal outcome (30.1%). The most reported cardiac events were myocarditis, cardiac failure, atrial fibrillation, pericardial effusion, and myocardial infarction. Nivolumab was reported with a small increased reporting frequency of individual case safety reports with cardiac ADRs compared to all other ICIs (reporting odds ratio 1.09, 95% confidence interval 1.01-1.18). CONCLUSIONS: Immune checkpoint inhibitor-induced cardiac ADRs were serious and had unfavorable outcomes. In our study, nivolumab was the only ICI with a small increased reporting frequency of individual case safety reports with cardiac ADRs compared to all other ICIs. In this regard, further head-to-head studies are needed.

Ergothioneine (ESH), the betaine of 2-mercapto-L-histidine, is a water-soluble naturally occurring amino acid with antioxidant properties. ESH accumulates in several human and animal tissues up to millimolar concentration through its high affinity transporter, namely the organic cation transporter 1 (OCTN1). ESH, first isolated from the ergot fungus (Claviceps purpurea), is synthesized only by Actinomycetales and non-yeast-like fungi. Plants absorb ESH via symbiotic associations between their roots and soil fungi, whereas mammals acquire it solely from dietary sources. Numerous evidence demonstrated the antioxidant and cytoprotective effects of ESH, including protection against cardiovascular diseases, chronic inflammatory conditions, ultraviolet radiation damages, and neuronal injuries. Although more than a century after its discovery has gone by, our understanding on the in vivo ESH mechanism is limited and this compound still intrigues researchers. However, recent evidence about differences in chemical redox behavior between ESH and alkylthiols, such as cysteine and glutathione, has opened new perspectives on the role of ESH during oxidative damage. In this short review, we discuss the role of ESH in the complex machinery of the cellular antioxidant defense focusing on the current knowledge on its chemical mechanism of action in the protection against cardiovascular disease.