Serum biomarkers of inflammation and vascular damage upon SARS-Cov-2 mRNA vaccine in patients with thymic epithelial tumors.

OBJECTIVES: Thymic epithelial tumors (TET) patients are at high risk of autoimmune and hypoimmune complications. Limited evidence is available on the potential risk of immune-related and inflammatory reactions induced by SARS-Cov-2 vaccine in this patient population. METHODS: In order to identify subjects at higher risk for vaccine complications, we prospectively evaluated a panel of serum biomarkers related to inflammation (TNF-α, IL-1ß, -6, -10, -12, and -17A, IFN-α, ß and γ, MPO, MMP-9), and vascular damage (E- and P-selectin, VEGF-A, P-ANCA and MCP-1) in 44 TET patients and in 30 healthy controls along the whole SARS-Cov-2 vaccine cycle. RESULTS: About 50 % of subjects (either TET and controls) showed an increase of serum biochemical markers of inflammation and endothelial damage with a large heterogeneity of values. Such increase appeared early, after the first dose in control subjects and later, after the second dose in TET patients (in which we observed mainly an increase of inflammatory biomarkers). The values normalized after about 3 months and did not increase after the third, booster dose. No autoimmune or vascular complications were observed in the study subjects and no difference was observed in terms of vaccine response among subjects showing serum biomarkers increase and those who experienced no changes. CONCLUSIONS: Our data highlight the relevance of Sars-Cov-2 vaccine in TET patients, as it resulted safe and prevented severe COVID-19. However, further studies are awaited to explore the mechanisms and the potential consequences of the observed increase of serum inflammatory and vascular damage biomarkers.

Isolated Valve Amyloid Deposition in Aortic Stenosis: Potential Clinical and Pathophysiological Relevance.

Amyloid deposition within stenotic aortic valves (AVs) also appears frequent in the absence of cardiac amyloidosis, but its clinical and pathophysiological relevance has not been investigated. We will elucidate the rate of isolated AV amyloid deposition and its potential clinical and pathophysiological significance in aortic stenosis (AS). In 130 patients without systemic and/or cardiac amyloidosis, we collected the explanted AVs during cardiac surgery: 57 patients with calcific AS and 73 patients with AV insufficiency (41 with AV sclerosis and 32 without, who were used as controls). Amyloid deposition was found in 21 AS valves (37%), 4 sclerotic AVs (10%), and none of the controls. Patients with and without isolated AV amyloid deposition had similar clinical and echocardiographic characteristics and survival rates. Isolated AV amyloid deposition was associated with higher degrees of AV fibrosis (p = 0.0082) and calcification (p < 0.0001). Immunohistochemistry analysis suggested serum amyloid A1 (SAA1), in addition to transthyretin (TTR), as the protein possibly involved in AV amyloid deposition. Circulating SAA1 levels were within the normal range in all groups, and no difference was observed in AS patients with and without AV amyloid deposition. In vitro, AV interstitial cells (VICs) were stimulated with interleukin (IL)-1ß which induced increased SAA1-mRNA both in the control VICs (+6.4 ± 0.5, p = 0.02) and the AS VICs (+7.6 ± 0.5, p = 0.008). In conclusion, isolated AV amyloid deposition is frequent in the context of AS, but it does not appear to have potential clinical relevance. Conversely, amyloid deposition within AV leaflets, probably promoted by local inflammation, could play a role in AS pathophysiology.

Umbrella Review: Association Between Antipsychotic Drugs and Metabolic Syndrome Hallmarks in Children and Adolescents.

OBJECTIVE: To summarize the available evidence on metabolic parameters indicating metabolic adverse effects and risk of metabolic syndrome in children and adolescents treated with antipsychotics, following a pre-specified protocol (PROSPERO ID 252336). METHOD: We searched PubMed, Embase and PsycINFO until May 14, 2021, to identify systematic reviews (SR), meta-analyses (MA) and network meta-analyses (NMA) examining symptoms associated to metabolic syndrome in patients <18 years of age who required treatment with oral antipsychotic drugs. Evidence from quantitative analyses for all outcomes related to anthropometric, glyco-metabolic, and blood pressure parameters (measured from baseline to intervention-end and/or follow-up, in subjects exposed to antipsychotics and placebo) was reported on the basis of their metrics (median difference [medianD], mean difference [MD], standardized mean difference [SMD], odds ratio [OR], risk ratio ([RR]). A qualitative synthesis was also made. A formal quality assessment of the included studies was carried out by using the AMSTAR 2. We also provided a hierarchical stratification of the evidence from meta-analyses based on the class of evidence. RESULTS: A total of 23 articles (13 MA, 4 NMA and 6 SR) were included for review. As compared with placebo, an increase in triglyceride levels was associated with olanzapine (medianD [95% CI]: 37 [12.27, 61.74] mg/dL; MD [95% CI]: 38.57 [21.44, 55.77] mg/dL) and quetiapine (medianD [95% CI]: 21.58 [95% CI]: 4.27, 38.31 mg/dL; MD [95% CI]: 34.87 [20.08, 49.67] mg/dL; SMD [95% CI]: 0.37 [0.06, 0.068]), whereas decreased triglyceride levels were found for lurasidone. Increased total cholesterol level was associated with asenapine (medianD [95% CI]: 9.1 [1.73, 16.44] mg/dL), quetiapine (medianD [95% CI]: 15.60 [7.30, 24.05] mg/dL; olanzapine (MD [95% CI] from 3.67 [1.43, 5.92] mg/dL to 20.47 [13.97, 26.94] mg/dL]; and lurasidone (medianD [95% CI]: 8.94 [1.27, 16.90] mg/dL). Change in glucose levels did not differ among antipsychotics or placebo. Lurasidone, molindone, and ziprasidone were the best tolerated in terms of weight gain. According to the AMSTAR 2 scoring system, 13 (56.5%) reviews were rated as very low quality. According to classes of evidence, most MA were level 4, especially because of their limited total sample size. CONCLUSION: By collating meta-analyses assessing biochemical markers of metabolic syndrome in antipsychotic-treated children, we conclude that olanzapine should not be the antipsychotic of choice in patients at risk for hypertriglyceridemia or hypercholesterolemia. Aripiprazole and lurasidone appear to be better tolerated in terms of metabolic adverse events. Insufficient meta-analytic data are available to provide a precise risk estimate of metabolic syndrome, and, overall, the quality of evidence is low. STUDY REGISTRATION INFORMATION: Association between the use of antipsychotic drugs and alterations of the parameters defining the Metabolic Syndrome (MetS) in children and adolescents: an umbrella review; https://www.crd.york.ac.uk/prospero/; CRD42021252336.

Design, Synthesis and Biological Evaluation of Novel N-Arylpiperazines Containing a 4,5-Dihydrothiazole Ring.

Arylpiperazines represent one of the most important classes of 5-HT1AR ligands and have attracted considerable interests for their versatile properties in chemistry and pharmacology, leading to the research of new derivatives that has been focused on the modification of one or more portions of such pharmacophore. An efficient protocol for the synthesis of novel thiazolinylphenyl-piperazines (2a-c) and the corresponding acetylated derivatives was used (3a-c). The new compounds were tested for their functional activity and affinity at 5-HT1A receptors, showing an interesting affinity profile with a Ki value of 412 nM for compound 2b. The cytotoxic activity of novel thiazolinylphenyl-piperazines (2a-c) and corresponding N-acetyl derivatives (3a-c) against human prostate and breast cancer cell lines (LNCAP, DU-145 and PC-3, MCF-7, SKBR-3 and MDA-MB231) was investigated according to the procedure described in the literature. The reported data showed a cytotoxic effect for 2a-c and 3a-c compounds (IC50 values ranging from 15 µM to 73 µM) on the investigated cancer cell lines, with no effect on noncancer cells. Future studies will be aimed to investigate the mechanism of action and therapeutic prospects of these new scaffolds.

Immunocytometric analysis of patients with thymic epithelial tumors revealed that COVID-19 vaccine booster strongly enhanced the immune response.

Background: Thymic epithelial tumors (TETs) are rare malignancies with heterogeneous clinical manifestations. The high frequency of autoimmune paraneoplastic disorders observed in such patients requires caution when using COVID-19 vaccines. Furthermore, TETs are often associated with severe immunodeficiency, making it difficult to predict vaccine immunization. Therefore, we aimed to evaluate immune response to COVID-19 vaccine in patients with TETs. Methods: We conducted a prospective study enrolling patients who underwent the SARS-Cov-2 mRNA full vaccine cycle (two doses plus a booster after 6 months of BNT162b2). All patients were enrolled before receiving 1st vaccine dose and were followed over the vaccination cycle for up to 6 months after the booster dose to i) assess humoral and cellular responses, ii) define biomarkers predictive of effective immunization, and iii) evaluate the safety of the vaccine. Results: At the end of the full vaccine cycle, 27 (61.4%) patients developed humoral and 38 (86.4%) cellular responses (IFN γ release by stimulated cells) and showed an increase in activated TH1 and TH17 cells, particularly significant after the booster dose. The number of B and T lymphocytes at baseline was predictive of humoral and cellular responses, respectively. Patients with no evidence of tumor lesions had a higher probability of achieving a humoral response than those with evidence of the disease. Furthermore, the percentage of patients with immune-related disorders (75%), particularly Good's syndrome (47.7%) and myasthenia gravis (29.5%), did not change over the entire vaccine cycle. Overall, 19 of the 44 enrolled patients (43.2%) had COVID-19 during the observation period; none required hospitalization or oxygen support, and no fatalities were observed. Conclusion: SARS-Cov-2 mRNA vaccine determines the immune responses in patients with TET, particularly after the booster dose, and in patients with no evidence of tumor lesions. Preliminary analysis of B and T lymphocytes may help identify patients who have a lower probability of achieving effective humoral and cellular responses and thus may need passive immunization. The vaccine prevented severe COVID-19 infection and is safe.

Preliminary Results of a Double-Blind Randomized Controlled Trial Evaluating the Cardiometabolic Effects of Levothyroxine and Liothyronine Compared to Levothyroxine with Placebo in Athyreotic Low-Risk Thyroid Cancer Patients.

Background: Evidence is needed on the risks and benefits of combination therapy with levothyroxine (LT4)+liothyronine (LT3) for the treatment of hypothyroidism. Objective and Methods: We performed a randomized, double-blind placebo-controlled study to assess the effects of LT4+LT3 therapy versus LT4+placebo in a homogeneous group of athyreotic patients, without cardiovascular risk factors during long-term replacement monotherapy with LT4. The primary objective of the study was to assess the effects of combination LT4+LT3 therapy on heart rate, cardiac rhythm, and sensitive cardiovascular parameters of cardiac morphology and function by means of electrocardiography and Doppler echocardiography. The secondary objective of the study was to evaluate patient compliance, tolerability, and potential adverse events. Results: Thirty-eight patients with postsurgical hypothyroidism satisfying the inclusion criteria were selected from a group of 300 patients with low-risk thyroid cancer followed for a routine follow-up; they were randomized to receive LT4+LT3 or LT4+placebo. Twenty-four patients were evaluated after 1 year of treatment. All clinical and laboratory parameters were compared with the results obtained from 50 healthy euthyroid volunteers without comorbidities, matched for gender, age, physical activity, and lifestyle. Participants and clinicians remained blinded to the treatment allocation. After 1 year of combination therapy, a significant improvement in the diastolic function, evidenced by a significant reduction in the E/e' ratio (p = 0.046) and its positive trend over time, was observed in the LT4+LT3 group versus the LT4+placebo group. In addition, the univariate analyses showed a significant relationship between free triiodothyronine (fT3) levels (in pg/mL) with Δ of variation of the E/e' ratio in the LT4+LT3 group (standardized ß coefficient = 0.603 [confidence interval: 0.001-1.248], p = 0.050) after combination therapy. No adverse events including tachycardia, arrhythmias, atrial fibrillation, or other important events occurred between the first administration and the end of the study. Conclusions: In this preliminary report, combination treatment with LT4+LT3 induced favorable changes in cardiovascular parameters of diastolic function without any adverse cardiovascular events. Trial Registration: EUDRACT number: 2017-001261-25.

Resveratrol Improves Endothelial Function by A PREP1-Mediated Pathway in Mouse Aortic Endothelial Cells.

PREP1 is a homeodomain transcription factor that impairs metabolism and is involved in age-related aortic thickening. In this study, we evaluated the role of PREP1 on endothelial function. Mouse Aortic Endothelial Cells (MAECs) transiently transfected with a Prep1 cDNA showed a 1.5- and 1.6-fold increase in eNOSThr495 and PKCα phosphorylation, respectively. Proinflammatory cytokines Tnf-α and Il-6 increased by 3.5 and 2.3-fold, respectively, in the presence of Prep1, while the antioxidant genes Sod2 and Atf4 were significantly reduced. Bisindolylmaleimide reverted the effects induced by PREP1, suggesting PKCα to be a mediator of PREP1 action. Interestingly, resveratrol, a phenolic micronutrient compound, reduced the PREP1 levels, eNOSThr495, PKCα phosphorylation, and proinflammatory cytokines and increased Sod2 and Atf4 mRNA levels. The experiments performed on the aorta of 18-month-old Prep1 hypomorphic heterozygous mice (Prep1i/+) expressing low levels of this protein showed a 54 and 60% decrease in PKCα and eNOSThr495 phosphorylation and a 45% reduction in Tnf-α levels, with no change in Il-6, compared to same-age WT mice. However, a significant decrease in Sod2 and Atf4 was observed in Prep1i/+ old mice, indicating the lack of age-induced antioxidant response. These results suggest that Prep1 deficiency partially improved the endothelial function in aged mice and suggested PREP1 as a novel target of resveratrol.

The therapeutic potential of an allosteric non-competitive CXCR1/2 antagonist for diabetic nephropathy.

AIMS: Diabetic nephropathy is a major consequence of inflammation developing in type 1 diabetes, with interleukin-8 (IL-8)-CXCR1/2 axis playing a key role in kidney disease progression. In this study, we investigated the therapeutic potential of a CXCR1/2 non-competitive allosteric antagonist (Ladarixin) in preventing high glucose-mediated injury in human podocytes and epithelial cells differentiated from renal stem/progenitor cells (RSC) cultured as nephrospheres. MATERIALS AND METHODS: We used human RSCs cultured as nephrospheres through a sphere-forming functional assay to investigate hyperglycemia-mediated effects on IL-8 signalling in human podocytes and tubular epithelial cells. RESULTS: High glucose impairs RSC self-renewal, induces an increase in IL-8 transcript expression and protein secretion and induces DNA damage in RSC-differentiated podocytes, while exerting no effect on RSC-differentiated epithelial cells. Accordingly, the supernatant from epithelial cells or podocytes cultured in high glucose was able to differentially activate leucocyte-mediated secretion of pro-inflammatory cytokines, suggesting that the crosstalk between immune and non-immune cells may be involved in disease progression in vivo. CONCLUSIONS: Treatment with Ladarixin during RSC differentiation prevented high glucose-mediated effects on podocytes and modulated either podocyte or epithelial cell-dependent leucocyte secretion of pro-inflammatory cytokines, suggesting CXCR1/2 antagonists as possible pharmacological approaches for the treatment of diabetic nephropathy.

Visceral Obesity and Cytokeratin-18 Antigens as Early Biomarkers of Liver Damage.

Visceral obesity is linked to the progression of fatty liver to nonalcoholic steatohepatitis (NASH). Cytokeratin-18 (CK18) epitopes M30 (CK18M30) and M65 (CK18M65) represent accurate markers for detecting NASH. The aim of this study was to evaluate the association of CK18M30 and CK18M65 levels with anthropometric and metabolic characteristics, liver stiffness, and liver indices of steatosis and fibrosis in a cohort of subjects with visceral obesity; in this cross-sectional study, transient elastography (TE-Fibroscan®), anthropometric measurements, metabolic parameters, High Sensitivity C-Reactive Protein (hsCRP), and CK18M30 and CK18M65 levels (Apoptosense ELISA, PEVIVA, Germany) were evaluated. Fatty Liver Index (FLI), Fibrosis 4 (FIB-4), and Aspartate transaminase (AST)-platelet ratio index (APRI) were calculated; among 48 subjects, 47.2% presented metabolic syndrome, 93.8% hepatic steatosis, 60.4% high liver stiffness, and 14.6% hypertransminasemia, while FIB-4 and APRI were normal. CK18M30 and CK18M65 levels were significantly correlated with waist circumference, AST, ALT, HoMA-IR, liver stiffness, and APRI (p < 0.001). Subjects with CK18 fragments above the median values showed significantly higher waist circumference, HbA1c, AST, ALT, HoMA-IR, FLI, and APRI compared to those with values below the median; CK18M30 and CK18M65 levels correlated well with anthropometric and metabolic characteristics, representing good biomarkers for early identification of NASH in subjects with visceral obesity.

Impaired Seroconversion After Severe Acute Respiratory Syndrome Coronavirus 2 mRNA Vaccine in Patients With Thymic Epithelial Tumors.

INTRODUCTION: Thymic epithelial tumors (TETs) are rare malignancies associated with dysregulation of the immune system and humoral- and cell-mediated immunity abnormalities. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine is effective in preventing coronavirus disease 2019 morbidity and mortality. The aim of this study was to evaluate the seroconversion in patients with TET after two doses of mRNA vaccine. METHODS: This is a prospective study in which consecutive patients with TET were enrolled before receiving the first dose of SARS-CoV-2 mRNA vaccine (BNT162b2 by Pfizer-BioNTech). SARS-CoV-2 spike-binding immunoglobulin (Ig)G antibody serologic levels were analyzed at different time points, including before first vaccine dose (T0), 1 month after the second dose (T2), and 3 months after the second dose (T3). RESULTS: Overall, 39 patients were included in the analysis. All patients had negative antibody titer results at T0. There were 19 patients (48.7%) in the follow-up with no residual tumor lesion/s (referred as no evidence of disease), and 20 (51.3%) had evidence of disease (ED) and were receiving systemic treatment. Dysregulations of the immune system were diagnosed in 29 patients (74.4%) with Good syndrome (GS) being the most frequent immune disorder (48.7%). At univariate analysis, lack of seroconversion at T2 was significantly associated with ED (p < 0.001) and with GS (p = 0.043). A significant association with impaired seroconversion was confirmed at multivariate analysis for ED (p = 0.00101) but not for GS (p = 0.625). CONCLUSIONS: Our data revealed that patients with TET with ED had substantially higher probability of impaired seroconversion after SARS-CoV-2 mRNA vaccine as compared with patients with no evidence of disease.

Human Platelet-Rich Plasma Regulates Canine Mesenchymal Stem Cell Migration through Aquaporins.

Platelet products are commonly used in regenerative medicine due to their effects on the acceleration and promotion of wound healing, reduction of bleeding, synthesis of new connective tissue, and revascularization. Furthermore, a novel approach for the treatment of damaged tissues, following trauma or other pathological damages, is represented by the use of mesenchymal stem cells (MSCs). In dogs, both platelet-rich plasma (PRP) and MSCs have been suggested to be promising options for subacute skin wounds. However, the collection of canine PRP is not always feasible. In this study, we investigated the effect of human PRP (hPRP) on canine MSCs (cMSCs). We isolated cMSCs and observed that hPRP did not modify the expression levels of the primary class of major histocompatibility complex genes. However, hPRP was able to increase cMSC viability and migration by at least 1.5-fold. hPRP treatment enhanced both Aquaporin (AQP) 1 and AQP5 protein levels, and their inhibition by tetraethylammonium chloride led to a reduction of PRP-induced migration of cMSCs. In conclusion, we have provided evidence that hPRP supports cMSC survival and may promote cell migration, at least through AQP activation. Thus, hPRP may be useful in canine tissue regeneration and repair, placing as a promising tool for veterinary therapeutic approaches.

Targeting G-quadruplex motifs interferes with differentiation of adipose-derived mesenchymal stem cells.

BACKGROUND: G-quadruplex (G4) motifs are nucleic acid secondary structures observed in mammalian genomes and transcriptomes able to regulate various cellular processes. Several small molecules have been developed so far to modulate G4 stability, frequently associated with anticancer activity. However, how G4 structures are regulated over homeostatic conditions is mostly unexplored. Here, we used human adipose-derived mesenchymal stem cells (ASCs) to address the role of G4 motifs during adipogenic differentiation. METHODS: Adipocyte differentiation of ASCs was investigated in the presence or absence of a well-known G4 ligand, Braco-19. Cell viability was determined by sulforhodamine B assay. Cell dimension and granularity, DNA G4 motifs and cell cycle were detected by flow cytometry. Lipid droplet accumulation was assessed by Oil Red O staining. Cell senescence was evaluated by ß-galactosidase staining. Gene expression was measured by qPCR. Protein release in the extracellular medium was quantified by ELISA. RESULTS: Braco-19 used at non-cytotoxic concentrations induced morphological changes in mature adipocytes partially restoring an undifferentiated-like status. Braco-19 reduced lipid vacuolization and PPARG, AP2, LEP and TNFA mRNA levels in terminally differentiated cells. No effect was observed in cell senescence, fibrotic markers, IL-6 and IL-8 production, while the secretion of VEGF was dose-dependently reduced. Interestingly, G4 structures were increased in differentiated adipocytes compared to their precursors. Braco-19 treatment reduced G4 content in mature adipocytes. CONCLUSIONS: Our data highlight a new role of G4 motifs as genomic structural elements related to human ASC differentiation into mature adipocytes, with potential implications in physio-pathological processes.

SARS-CoV-2 Affects Both Humans and Animals: What Is the Potential Transmission Risk? A Literature Review.

In March 2020, the World Health Organization Department declared the coronavirus (COVID-19) outbreak a global pandemic, as a consequence of its rapid spread on all continents. The COVID-19 pandemic has been not only a health emergency but also a serious general problem as fear of contagion and severe restrictions put economic and social activity on hold in many countries. Considering the close link between human and animal health, COVID-19 might infect wild and companion animals, and spawn dangerous viral mutants that could jump back and pose an ulterior threat to us. The purpose of this review is to provide an overview of the pandemic, with a particular focus on the clinical manifestations in humans and animals, the different diagnosis methods, the potential transmission risks, and their potential direct impact on the human-animal relationship.

Adiponectin Contributes to the Inflammatory Milieu in Hidradenitis Suppurativa.

Introduction: Hidradenitis suppurativa (HS) is a severe chronic skin disease. Although the pathogenesis remains unclear, at the basis of HS there is an enhancement of the immune and inflammatory response together with a susceptibility to environmental factors. Cytokine dysregulation is crucial in HS severity and progression. Objectives: The aim of this study was to analyze serum levels of different cytokines focusing on adiponectin concentration and its oligomers in HS patients compared to both obese and healthy subjects. Methods: The concentrations of adiponectin and cytokines were measured using enzyme-linked immunosorbent assay (ELISA); the oligomeric distribution of adiponectin (low molecular weight (LMW), medium molecular weight (MMW) and high molecular weight (HMW) oligomers)was evaluated through Western Blotting analysis. Results: Total adiponectin is statistically higher in HS patients compared to matched controls and obese subjects. Interestingly, Adiponectin oligomerization state is altered in HS, with an increase of HMW oligomers. Serum levels of PDGF-BB, IL-1ß, IL-5, Il-6, IL12, IL13, IL15, IL-17, GMCSF, INFγ, VEGF and MCP-1 are statistically higher while IL-1ra and RANTES levels are statistically lower in HS patients compared to healthy controls. Interestingly, adiponectin positively correlates with PDGF-BB, and IL-13. Conclusions: Our data confirmed that the complex network that links metabolism to immune homeostasis is dysregulated in HS and that adiponectin and its HMW oligomers are actively involved in this disease. In addition, the correlation between adiponectin and PDGF-BB, and IL-13 extends the role of this adipokine in modulation of the immune response, in particular regulating the innate immune system rather that the adaptive one. Further researches are needed to clarify the complex inflammatory milieu that characterizes HS syndrome.

Glucose Enhances Pro-Tumorigenic Functions of Mammary Adipose-Derived Mesenchymal Stromal/Stem Cells on Breast Cancer Cell Lines.

Adiposity and diabetes affect breast cancer (BC) progression. We addressed whether glucose may affect the interaction between mammary adipose tissue-derived mesenchymal stromal/stem cells (MAT-MSCs) and BC cells. Two-dimensional co-cultures and spheroids were established in 25 mM or 5.5 mM glucose (High Glucose-HG or Low Glucose-LG) by using MAT-MSCs and MCF7 or MDA-MB231 BC cells. Gene expression was measured by qPCR, while protein levels were measured by cytofluorimetry and ELISA. CD44high/CD24low BC stem-like sub-population was quantified by cytofluorimetry. An in vivo zebrafish model was assessed by injecting spheroid-derived labeled cells. MAT-MSCs co-cultured with BC cells showed an inflammatory/senescent phenotype with increased abundance of IL-6, IL-8, VEGF and p16INK4a, accompanied by altered levels of CDKN2A and LMNB1. BC cells reduced multipotency and increased fibrotic features modulating OCT4, SOX2, NANOG, αSMA and FAP in MAT-MSCs. Of note, these co-culture-mediated changes in MAT-MSCs were partially reverted in LG. Only in HG, MAT-MSCs increased CD44high/CD24low MCF7 sub-population and promoted their ability to form mammospheres. Injection in zebrafish embryos of HG spheroid-derived MCF7 and MAT-MSCs was followed by a significant cellular migration and caudal dissemination. Thus, MAT-MSCs enhance the aggressiveness of BC cells in a HG environment.

Insight on the Role of Leptin: A Bridge from Obesity to Breast Cancer.

Leptin is a peptide hormone, mainly known for its role as a mediator of adipose tissue endocrine functions, such as appetite control and energy homeostasis. In addition, leptin signaling is involved in several physiological processes as modulation of innate and adaptive immune responses and regulation of sex hormone levels. When adipose tissue expands, an imbalance of adipokines secretion may occur and increasing leptin levels contribute to promoting a chronic inflammatory state, which is largely acknowledged as a hallmark of cancer. Indeed, upon binding its receptor (LEPR), leptin activates several oncogenic pathways, such as JAK/STAT, MAPK, and PI3K/AKT, and seems to affect cancer immune response by inducing a proinflammatory immune polarization and eventually enhancing T-cell exhaustion. In particular, obesity-associated hyperleptinemia has been related to breast cancer risk development, although the underlying mechanism is yet to be completely clarified and needs to be deemed in light of multiple variables, such as menopausal state and immune response. The aim of this review is to provide an overview of the potential role of leptin as a bridge between obesity and breast cancer and to establish the physio-pathological basis of the linkage between these major health concerns in order to identify appropriate and novel therapeutic strategies to adopt in daily clinical practice.

Immunological signature of patients with thymic epithelial tumors and Good syndrome.

Background: Thymic epithelial tumors (TETs) are frequently accompanied by Good Syndrome (GS), a rare immunodeficiency, characterized by hypogammaglobulinemia and peripheral B cell lymphopenia. TETs can be also associated to other immunological disorders, both immunodeficiency and autoimmunity. Methods: In this study, we enrolled TET patients with GS to address differences between patients with or without associated autoimmune diseases (AD). We analyzed the immunophenotype from peripheral blood of these patients focusing on selected immune cell subsets (CD4+T cells, CD8+T cells, T regulatory cells, NK cells, B-cells, monocytes, eosinophils, basophils, neutrophils) and serum levels of cytokines, chemokines and growth factors. Results: We observed higher number of leucocytes, in particular lymphocytes, B lymphopenia and lower number of T regulatory cells in TET patients with associated AD compared to TET patients without AD. In the group of TET patients with AD, we also observed increased serum levels of IL-15, VEGF, IP-10, GM-CSF, IL-6, and MIP-1α. Thus, we identified considerable differences in the lymphocyte profiles of TET patients with and without ADs, in particular a reduction in the numbers of B lymphocytes and T-regulatory cells in the former, as well as differences in the serum levels of various immune modulators. Conclusions: Although the pathogenic mechanisms are still unclear, our results add new knowledge to better understand the disease, suggesting the need of surveilling the immunophenotype of TET patients to ameliorate their clinical management.

Lifestyle and Dietary Habits Affect Plasma Levels of Specific Cytokines in Healthy Subjects.

Low-grade chronic inflammation (LGCI) is a common feature of non-communicable diseases. Cytokines play a crucial role in LGCI. This study aimed to assess how LGCI risk factors [e.g., age, body mass index (BMI), smoke, physical activity, and diet] may impact on specific cytokine levels in a healthy population. In total, 150 healthy volunteers were recruited and subjected to questionnaires about the last 7-day lifestyle, including smoking habit, physical activity, and food frequency. A panel of circulating cytokines, chemokines, and growth factors was analyzed by multiplex ELISA. BMI showed the heaviest impact on the correlation between LGCI-related risk factors and cytokines and was significantly associated with CRP levels. Aging was characterized by an increase in IL-1b, eotaxin, MCP-1, and MIP-1α. Smoking was related to higher levels of IL-1b and CCL5/RANTES, while physical activity was related to MIP-1α. Within the different eating habits, CRP levels were modulated by eggs, red meat, shelled fruits, and greens consumption; however, these associations were not confirmed in a multivariate model after adjusting for BMI. Nevertheless, red meat consumption was associated with an inflammatory pattern, characterized by an increase in IL-6 and IL-8. IL-8 levels were also increased with the frequent intake of sweets, while a higher intake of shelled fruits correlated with lower levels of IL-6. Moreover, IL-6 and IL-8 formed a cluster that also included IL-1b and TNF-α. In conclusion, age, BMI, smoke, physical activity, and dietary habits are associated with specific cytokines that may represent potential markers for LGCI.

Epicardial Adipose Tissue and Cardiac Arrhythmias: Focus on Atrial Fibrillation.

Atrial Fibrillation (AF) is the most frequent cardiac arrhythmia and its prevalence increases with age. AF is strongly associated with an increased risk of stroke, heart failure and cardiovascular mortality. Among the risk factors associated with AF onset and severity, obesity and inflammation play a prominent role. Numerous recent evidence suggested a role of epicardial adipose tissue (EAT), the visceral fat depot of the heart, in the development of AF. Several potential arrhythmogenic mechanisms have been attributed to EAT, including myocardial inflammation, fibrosis, oxidative stress, and fat infiltration. EAT is a local source of inflammatory mediators which potentially contribute to atrial collagen deposition and fibrosis, the anatomical substrate for AF. Moreover, the close proximity between EAT and myocardium allows the EAT to penetrate and generate atrial myocardium fat infiltrates that can alter atrial electrophysiological properties. These observations support the hypothesis of a strong implication of EAT in structural and electrical atrial remodeling, which underlies AF onset and burden. The measure of EAT, through different imaging methods, such as echocardiography, computed tomography and cardiac magnetic resonance, has been proposed as a useful prognostic tool to predict the presence, severity and recurrence of AF. Furthermore, EAT is increasingly emerging as a promising potential therapeutic target. This review aims to summarize the recent evidence exploring the potential role of EAT in the pathogenesis of AF, the main mechanisms by which EAT can promote structural and electrical atrial remodeling and the potential therapeutic strategies targeting the cardiac visceral fat.

Epicardial Adipose Tissue-Derived IL-1ß Triggers Postoperative Atrial Fibrillation.

Background and aims: Post-operative atrial fibrillation (POAF), defined as new-onset AF in the immediate period after surgery, is associated with poor adverse cardiovascular events and a higher risk of permanent AF. Mechanisms leading to POAF are not completely understood and epicardial adipose tissue (EAT) inflammation could be a potent trigger. Here, we aim at exploring the link between EAT-secreted interleukin (IL)-1ß, atrial remodeling, and POAF in a population of coronary artery disease (CAD) patients. Methods: We collected EAT and atrial biopsies from 40 CAD patients undergoing cardiac surgery. Serum samples and EAT-conditioned media were screened for IL-1ß and IL-1ra. Atrial fibrosis was evaluated at histology. The potential role of NLRP3 inflammasome activation in promoting fibrosis was explored in vitro by exposing human atrial fibroblasts to IL-1ß and IL-18. Results: 40% of patients developed POAF. Patients with and without POAF were homogeneous for clinical and echocardiographic parameters, including left atrial volume and EAT thickness. POAF was not associated with atrial fibrosis at histology. No significant difference was observed in serum IL-1ß and IL-1ra levels between POAF and no-POAF patients. EAT-mediated IL-1ß secretion and expression were significantly higher in the POAF group compared to the no-POAF group. The in vitro study showed that both IL-1ß and IL-18 increase fibroblasts' proliferation and collagen production. Moreover, the stimulated cells perpetuated inflammation and fibrosis by producing IL-1ß and transforming growth factor (TGF)-ß. Conclusion: EAT could exert a relevant role both in POAF occurrence and in atrial fibrotic remodeling.