Genetic and Epigenetic Factors of Takotsubo Syndrome: A Systematic Review.

Takotsubo syndrome (TTS), recognized as stress's cardiomyopathy, or as left ventricular apical balloon syndrome in recent years, is a rare pathology, described for the first time by Japanese researchers in 1990. TTS is characterized by an interindividual heterogeneity in onset and progression, and by strong predominance in postmenopausal women. The clear causes of these TTS features are uncertain, given the limited understanding of this intriguing syndrome until now. However, the increasing frequency of TTS cases in recent years, and particularly correlated to the SARS-CoV-2 pandemic, leads us to the imperative necessity both of a complete knowledge of TTS pathophysiology for identifying biomarkers facilitating its management, and of targets for specific and effective treatments. The suspect of a genetic basis in TTS pathogenesis has been evidenced. Accordingly, familial forms of TTS have been described. However, a systematic and comprehensive characterization of the genetic or epigenetic factors significantly associated with TTS is lacking. Thus, we here conducted a systematic review of the literature before June 2021, to contribute to the identification of potential genetic and epigenetic factors associated with TTS. Interesting data were evidenced, but few in number and with diverse limitations. Consequently, we concluded that further work is needed to address the gaps discussed, and clear evidence may arrive by using multi-omics investigations.

On the Road to Accurate Biomarkers for Cardiometabolic Diseases by Integrating Precision and Gender Medicine Approaches.

The need to facilitate the complex management of cardiometabolic diseases (CMD) has led to the detection of many biomarkers, however, there are no clear explanations of their role in the prevention, diagnosis or prognosis of these diseases. Molecules associated with disease pathways represent valid disease surrogates and well-fitted CMD biomarkers. To address this challenge, data from multi-omics types (genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiomics, and nutrigenomics), from human and animal models, have become available. However, individual omics types only provide data on a small part of molecules involved in the complex CMD mechanisms, whereas, here, we propose that their integration leads to multidimensional data. Such data provide a better understanding of molecules related to CMD mechanisms and, consequently, increase the possibility of identifying well-fitted biomarkers. In addition, the application of gender medicine also helps to identify accurate biomarkers according to gender, facilitating a differential CMD management. Accordingly, the impact of gender differences in CMD pathophysiology has been widely demonstrated, where gender is referred to the complex interrelation and integration of sex (as a biological and functional marker of the human body) and psychological and cultural behavior (due to ethnical, social, and religious background). In this review, all these aspects are described and discussed, as well as potential limitations and future directions in this incipient field.

Role of TGF-ß pathway polymorphisms in sporadic thoracic aortic aneurysm: rs900 TGF-ß2 is a marker of differential gender susceptibility.

Thoracic aortic aneurysm (TAA) is a progressive disorder involving gradual dilation of ascending and/or descending thoracic aorta with dissection or rupture as complications. It occurs as sporadic or defined syndromes/familial forms.Genetic, molecular and cellular mechanims of sporadic TAA forms are poorly characterized and known. Thus, our interest has been focused on investigating the role of genetic variants of transforming growth factor-ß (TGF-ß) pathways in TAA risk. On the other hand, no data on the role of genetic variants of TGF-ß pathway in sporadic TAA exist until now. In addition, other cytokines, including IL-10, orchestrate TAA pathophysiology. Their balance determines the ultimate fate of the aortic wall as healing atherosclerosis or aneurysm formation. Thus, in this paper it was analyzed the role of ten polymorphisms of genes encoding TGF-ß isoforms and receptors, and IL-10 in sporadic TAA. Our study included cases affected by sporadic TAA and two control groups. The most relevant finding obtained allows us to propose that rs900 TGF-ß2 SNP is associated with sporadic TAA in women. This might open new perspectives for the analysis of sporadic TAA susceptibility factors and prevention.

CAR, mGPS and hs-mGPS: What is among them the best gero-biomarker for age-related diseases? And for what clinical application?

The identification of biomarkers linked to the onset, progression, and prevention of age-related diseases (ARD), in the era of personalized medicine, represents the best goal of geroscience. Geroscience has the fundamental role of exploring and identifying the biological mechanisms of aging to suggest interventions capable of stopping/delaying the many pathological conditions and disabilities related to age. Therefore, it has become its key priority, as well as that of clinical practice and research, based on identifying and validating a range of biomarkers, geromarkers, which can be used to diagnostic, prognostic, or predictive clinical purposes. Indeed, geromarkers have, the potential to predict ARD trajectories and facilitate targeted interventions to slow down the related disabilities. Here our attention is paid to the inflammatory indexes (CAR, mGPS, hs-mGPS) linked to the relationship between the plasma levels of two inflammatory analytes, the typical positive protein of the acute phase, and the negative one, i.e. c-reactive protein (CRP) and albumin, respectively. These indexes allow us to understand the magnitude of the two main mechanisms predicted to influence the aging process, including inflammation and immunosenescence, as well as the degree of ARD severity. Evidence on their relationship with ARD is widely reported and discussed, to understand which can represent the best ARD geromarker, and its clinical application.

Myocardial infarction marker levels are influenced by prothrombin and tumor necrosis factor-α gene polymorphisms in young patients.

Polymorphisms of genes encoding key factors for the control and activation of inflammatory response and coagulation cascade regulation may play a role in genetic susceptibility to acute myocardial infarction (AMI). This study sought to analyze the effect of TNF -308G/A and pro-thrombin (FII) 20210G/A polymorphisms on the laboratory parameters of young patients affected by AMI. Results indicated that TNF -308A positive genotype frequencies were increased in these patients and that a genetically determined higher production of TNF-α is associated in young subjects to a more severe cardiac damage as depicted by higher levels of troponin, Creatine kinase-MB Isoenzyme (mCK-MB) and a significant increased plasma fibrinogen levels. Similar and probably additive effects on might have a genetically determined increased production of pro-thrombin even if no significant differences in genotype frequencies of pro-thrombin (FII) 20210G/A polymorphisms were observed in this study. All together these results, indicating the relationship among genetically determined TNFα and FII production and increased levels of tissue damage markers of AMI, suggest that a complex genetic background, might be involved in susceptibility to AMI in young men influencing the extension and severity of the disease.

Age and Cytokine Gene Variants Modulate the Immunogenicity and Protective Effect of SARS-CoV-2 mRNA-Based Vaccination.

The introduction of anti-SARS-CoV-2 vaccines in late 2020 substantially changed the pandemic picture, inducing effective protection in the population. However, individual variability was observed with different levels of cellular response and neutralizing antibodies. We report data on the impact of age, gender, and 16 single nucleotide polymorphisms (SNPs) of cytokine genes on the anti-SARS-CoV-2 IgG titers measured 31 and 105 days after administration of the second dose of BNT162b2 vaccine to 122 healthy subjects from the health care staff of the Palermo University Hospital, Italy. The higher titers at 31 days were measured in the younger subjects and in subjects bearing T-positive genotypes of IL-1R1 rs2234650 or the GG homozygous genotype of IL-6 rs1800795 SNP. T-positive genotypes are also significantly more common in subjects with higher titers at day 105. In addition, in this group of subjects, the frequency of the CT genotype of IL-4 rs2243250 is higher among those vaccinated with higher titers. Moreover, these SNPs and TNFA rs1800629 are differently distributed in a group of subjects that were found infected by SARS-CoV-2 at day 105 of evaluation. Finally, subjects that were found to be infected by SARS-CoV-2 at day 105 were significantly older than the uninfected subjects. Taken together, these data seem to suggest that age and polymorphisms of key cytokines, which regulate inflammation and humoral immune response, might influence the magnitude of the antibody response to vaccination with BNT162B2, prompting speculation about the possible benefit of a genetic background-based assessment of a personalized approach to the anti-COVID vaccination schedule.

Prevalence and risk of new-onset diabetes mellitus after COVID-19: a systematic review and meta-analysis.

Aims: After the acute phase of SARS-CoV-2 infection, the onset of glycemic impairment and diabetes have been reported. Nevertheless, the exact burden of glycemic impairment and diabetes after COVID-19 has not been clearly described. Materials and methods: Electronic search was run in Pubmed (MEDLINE), Web of Science, Scopus, and ClinicalTrial.org for reports published from database inception to September 2022. We included observational studies reporting quantitative data on diabetes prevalence or its onset in subjects with a history of SARS-CoV-2 infection from at least 60 days. Risk of bias was assessed by the JBI's critical appraisal checklist. Random effect model was used to calculate pooled data. The review protocol was registered on PROSPERO (CRD42022310722). Results: Among 1,630 records screened, 20 studies were included in the analysis. The mean or median age of participants ranged from ~ 35 to 64 years, with a percentage of males ranging from 28% to 80%. Only two studies were considered at low risk of bias. The estimate of diabetes prevalence, calculated on a total of 320,948 participants pooled with 38,731 cases, was 16% (95%CI: 11-22%). The estimate of proportion of incident cases of diabetes was 1.6% (95%CI: 0.8-2.7%). Subgroup analysis showed that previous hospitalization increased the prevalence of diabetes and the proportion of incident cases. Conclusion: Diabetes is common in individuals who have experienced SARS-CoV-2 infection, especially if they required hospitalization. This data may be helpful to screen for diabetes and manage its complications in individuals who experienced COVID-19. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022310722, identifier CRD42022310722.

Could the Combination of eGFR and mGPS Facilitate the Differential Diagnosis of Age-Related Renal Decline from Diseases? A Large Study on the Population of Western Sicily.

The assessment of renal function is critical to diagnosing and managing renal age-related decline, disease (KD), and failure, which are prevalent in the elderly population. The glomerular filtration rate (GFR) is widely used as an indicator of kidney function, but its direct measurement is challenging, as are its age and gender caveats. This makes difficult the differential diagnosis between age-related physiological decline and KD and/or failure. Currently, the inflammation-based modified Glasgow prognostic score (mGPS) is emerging as a promising biomarker of several inflammatory acute/chronic diseases. In this study, the large variability of eGFR with age and gender was evaluated as the association of eGFR values with mGPS levels. A population of 57,449 adult participants (age ≥ 18 years) was enrolled. Appropriate circulating biomarkers were measured to detect eGFR and mGPS values. The data obtained demonstrated a significant decrease in eGFR in men vs. women across the four selected age classes (18-40, 40-60, 60-80, 80-100 years); eGFR classes were significantly associated with mGPS (p < 0.001), as were age classes and gender with mGPS categories. Accordingly, the percentage of people having an mGPS score = 2 significantly increased across the eGFR classes: with an 11% in the G1/eGFR class needed to achieve 44% in G5/eGFR. Thus, the combination of mGPS with eGFR could represent the best benchmark risk model for the differential diagnosis of kidney disease from the age-related eGFR reduction.

Single nucleotide polymorphisms (SNPs) of pro-inflammatory/anti-inflammatory and thrombotic/fibrinolytic genes in patients with acute ischemic stroke in relation to TOAST subtype.

BACKGROUND: The genetic basis of complex diseases like ischemic stroke probably consists of several predisposing risk factors, such as genes involved in inflammation and thrombotic pathways. On this basis the aim of our study was to evaluate the role of SNPs (single nucleotide polymorphisms) of some pro-inflammatory/anti-inflammatory and coagulation/fibrinolytic genes in patients with acute ischemic stroke. METHODS: The study population consisted of 144 consecutive Caucasian adult patients who were hospitalized in the Internal Medicine Department at the University of Palermo between November 2006 and January 2008, and who met inclusion criteria. The cases were patients admitted with a diagnosis of acute ischemic stroke, and age-matched (± 3 years) control subjects: patients admitted to our Internal Medicine Department for any cause other than acute cardiovascular and cerebrovascular events and for routine checkup examinations. Molecular analysis of alleles at the -308 nucleotide (-308G/A) of TNF-α gene, -1082/-819 haplotypes of IL-10 gene, IL-1RN exon 2 VNR polymorphism, alleles at the -174 nucleotide (-174G/C) of IL-6 gene, PAI-1675 5G/4G polymorphism, alleles at the -7351 nucleotide (-7351C/T) of tPA gene was undertaken in both patient groups. RESULTS: We analyzed 96 subjects with acute ischemic stroke and 48 control subjects. We observed a significantly higher frequency of IL-10 1082 AA genotype in stroke patients with a significant risk trend. We also reported a higher frequency in stroke subjects with a significant risk trend of the TPA 7351-CT genotype and of IL-1RN-VNTR 86 bp 2/2 genotype. Moreover, we observed a significant relationship with TOAST subtype only with regard to CC TPA genotype and 1/1 IL-1 VNTR 86 bp and lacunar strokes. CONCLUSIONS: Ischemic stroke is a common multifactor disease, which is affected by a number of genetic mutations and environmental factors. Our findings showing a relationship between pro-inflammatory/anti-inflammatory and thrombotic/fibrinolytic genes SNPs and ischemic stroke may contribute to delineate a possible stroke risk profile in subjects with cerebrovascular risk factors.

Genetics of longevity. data from the studies on Sicilian centenarians.

The demographic and social changes of the past decades have determined improvements in public health and longevity. So, the number of centenarians is increasing as a worldwide phenomenon. Scientists have focused their attention on centenarians as optimal model to address the biological mechanisms of "successful and unsuccessful ageing". They are equipped to reach the extreme limits of human life span and, most importantly, to show relatively good health, being able to perform their routine daily life and to escape fatal age-related diseases, such as cardiovascular diseases and cancer. Thus, particular attention has been centered on their genetic background and immune system. In this review, we report our data gathered for over 10 years in Sicilian centenarians. Based on results obtained, we suggest longevity as the result of an optimal performance of immune system and an over-expression of anti-inflammatory sequence variants of immune/inflammatory genes. However, as well known, genetic, epigenetic, stochastic and environmental factors seem to have a crucial role in ageing and longevity. Epigenetics is associated with ageing, as demonstrated in many studies. In particular, ageing is associated with a global loss of methylation state. Thus, the aim of future studies will be to analyze the weight of epigenetic changes in ageing and longevity.

Cytokine serum profile in a group of Sicilian nonagenarians.

The aim of our study was to evaluate the possibility of using multiplex analysis of the cytokine profile as a marker for successful aging by comparing cytokine plasmatic levels of a group of Sicilian nonagenarians with those of young controls. We analyzed a panel of 17 cytokines, comprehensive of haematopoietic factors T helper 1 (Th1), Th2, inflammation regulatory cytokines, and chemokines. The assay was carried out using the Luminex system. Interleukin (IL)-6 levels (p = 0.01) were increased in nonagenarians, whereas no modifications of other proinflammatory cytokines and chemokines were observed. Interferon-gamma (IFN-γ) and IL-2 levels are unmodified, suggesting a substantial maintenance of relevant T cell functions. In addition, a significant increase of IL-12 serum levels in nonagenarians versus young controls that might be related to the increase of natural killer (NK) cell functions characterizing aging processes was observed. The analysis of Th2 cytokines show an increase of IL-13 and a reduction of IL-4 levels mirroring the maintenance of some effector's mechanisms of the immunoresponse in advanced ages. Our results suggest that the multiplex analysis of cytokine levels might be useful in defining a successful aging profile.

TGF-ß/VEGF-A Genetic Variants Interplay in Genetic Susceptibility to Non-Melanocytic Skin Cancer.

Differential genetically determined expression of transforming growth factor-ß (TGF-ß pathway and of vascular endothelial growth factor-A (VEGF-A) might modulate the molecular "milieu" involved in the etio-pathogenesis of non-melanoma skin cancer (NMSC). We have evaluated the frequency of some functionally relevant SNPs of TGF-ß and VEGF-A genes in 70 NMSC patients and 161 healthy controls, typed for TGF-ß1 rs1800471, TGF-ß2 rs900, TGF-ßR1 rs334348 and rs334349, TGF-ßR2 rs4522809 and VEGF-A rs3025039 SNPs. TGF-ßR2 rs1800629G allele and related genotypes were found to be associated with a possible protective role against NMSC, whereas VEGF-A rs3025039T was associated with an increased risk. To evaluate the effect of genotype combinations on NMSC susceptibility, we determined the frequencies of 31 pseudo-haplotypes due to non-random linkage among alleles of loci not lying on the same chromosome. Two pseudo-haplotypes that imply a minor allele of TGF-ßR2 or minor allele of VEGF-A SNPs combined with major alleles of the other SNPs were, respectively, associated with a protective effect, and susceptibility to NMSC. In addition, a pseudo-haplotype involving minor alleles of TGF-ß2 rs900, TGF-ßR1 rs334348 and rs4522809 SNPs might be a susceptibility marker for NMSC. In conclusion, our data suggest that a complex interplay among the genetic polymorphisms of TGF-ß, TGF-ß receptors and VEGF-A genes might influence the net effect of genetic background of the patients on NMSC development. This might be relevant in the risk evaluation, diagnosis and treatment of NMSC.

MIF rs755622 and IL6 rs1800795 Are Implied in Genetic Susceptibility to End-Stage Renal Disease (ESRD).

Chronic kidney disease (CKD) is characterized by an increased risk of kidney failure and end-stage renal disease (ESRD). Aging and comorbidities as cardiovascular diseases, metabolic disorders, infectious diseases, or tumors, might increase the risk of dialysis. In addition, genetic susceptibility factors might modulate kidney damage evolution. We have analyzed, in a group of ESRD patients and matched controls, a set of SNPs of genes (Klotho rs577912, rs564481, rs9536314; FGF23 rs7955866; IGF1 rs35767; TNFA rs1800629; IL6 rs1800795; MIF rs755622, rs1007888) chosen in relation to their possible involvement with renal disease and concomitant pathologies. Analysis of the raw data did indicate that IL6 rs180795 and MIF rs755622 SNPs might be markers of genetic susceptibility to ESRD. In particular, the C positive genotypes of MIF rs755622, (dominant model) seem to be an independent risk factor for ESDR patients (data adjusted for age, gender, and associated pathologies). Stratifying results according to age MIF rs755622 C positive genotype frequencies are increased in both the two age classes considered (<59 and ≥59-year-old subjects). Analyses of data according to gender allowed us to observe that ESRD women shoved a significantly reduced frequency of genotypes bearing IL6 rs180795 C allele. In addition, MIF rs755622 might interact with diabetes or hypercholesterolemia in increasing susceptibility to ESRD. In conclusion, our data indicate that some polymorphisms involved in the regulation of both renal function and inflammatory response can influence the evolution of chronic kidney disease and suggest that the modulation of the activities of these and other genes should also be considered as therapeutic targets on to intervene with innovative therapies.

IL-1 Superfamily Member (IL-1A, IL-1B and IL-18) Genetic Variants Influence Susceptibility and Clinical Course of Mediterranean Spotter Fever.

Mediterranean Spotted Fever (MSF) is one of the most common spotted fever Rickettsioses. Most cases of MSF follow a benign course, with a minority of cases being fatal. The severity of the infection depends on bacterial virulence, dose and host factors such as effective immune response and genetic background. Herein, we reported data on typing by competitive allele-specific PCR of functionally relevant polymorphisms of genes coding for MyD88 adapter-like (Mal/TIRAP) protein (rs8177374), interleukin(IL)-1 cluster (IL-1A rs1800587, IL-1B rs16944 and rs1143634) and IL-18 (rs187238), which might be crucial for an efficient immune response. The results enlighten the role that IL-1 gene cluster variants might play in susceptibility against Rickettsia conorii infection. In particular, the IL-1A rs1800587TT genotype was significantly increased in patients alone and combined in a haplotype composed by minor alleles rs1800587T, rs16944A and rs1143634A. This result was confirmed using the decision tree heuristic approach. Using this methodology, IL-1A rs1800587TT genotype was the better discrimination key among MSF patients and controls. In addition, the IL-1 gene cluster SNP genotypes containing minor alleles and IL-18 rs187238G positive genotypes were found as associated with risk of severe complications such as sepsis, septic shock, acute respiratory distress syndrome and coma. In conclusion, these data suggest that the evaluation of IL-1A, IL-1B and IL-18 gene SNPs can add useful information on the clinical course of patients affected by Mediterranean Spotted Fever, even if further confirmatory studies will be necessary.

Analysis of polymorphisms Leiden Factor V G1691A and prothrombin G20210A as risk factors for acute myocardial infarction.

Thrombotic risk increases in elderly, therefore, the understanding of the genetic predisposition of hypercoagulability could make the difference in the prevention of venous and/or arterial thrombotic events. Laboratory evaluation of hyperfibrinogenemia, increased Factor VII levels, antiphospholipid antibodies presence and hyperhomocysteinemia are considered to have a consistent high predictivity for arterial thrombophilic diseases. Anyway, a large debate exists on the validity of testing Leiden Factor V (FV) G1691A and/or prothrombin (FII) G20210A polymorphisms in patients affected by arterial thrombotic diseases, despite of the several observations described. Here we report data strongly suggesting that at least the FII G20210A polymorphism might be considered an important risk factor for acute myocardial infarction in aged patients (55-80 years old). On the other hand, in spite of a not different genotypic and allelic distribution for the Leiden FV G1691A mutation, the presence of one or both the two polymorphisms is significantly higher among cases than in controls. In conclusion, our data suggest that FII G20210A and/or Leiden FV might be involved as risk factor for arterial disorders in about 5% of old subjects, justifying the opportunity of a genetic screening and an eventual preventive treatment, in particular in old subjects in which other and major risk factors, as hypertension and atherosclerosis, are detected.

Role of prothrombotic polymorphisms in successful or unsuccessful aging.

The study of the genetic profile of centenarians aims to identify the genes and allelic variants which may influence a greater life expectancy and that can be considered as predisposing factors associated to the aging diseases, such as Alzheimer. Centenarians, that represent a cohort of selected survivors, show an hypercoagulability state characterised by striking signs of high coagulation enzyme activity, as directly assessed by the tested higher plasma level of some important factors involved in the haemostasis balance. Anyway, these individuals seem to have a reduced susceptibility to dementia, as well as to cardiovascular events. In this study we analyze the frequencies of Leiden Factor V polymorphism (G1691A), and G20210A of prothrombin (FII) in three cohorts of subjects: patients with Alzheimer's disease (unsuccessful aging), nonagenarians (successful aging) and young healthy controls, to assess whether allelic variants associated to the modification of haemostatic system function, may play a role in the protection or susceptibility to Alzheimer disease, as well as to reach a successful aging. No significant differences were observed in the frequencies of the three groups studied. These results indicate that the presence or absence of the gene variants examined did not influence the achievement of advanced age and are not risk factors for Alzheimer's disease. The state of hypercoagulability and the possession of these risk alleles appear to be compatible with the achievement of longevity and are not implied as risk factors in Alzheimer disease development.

The close link between the fetal programming imprinting and neurodegeneration in adulthood: The key role of "hemogenic endothelium" programming.

The research on neurodegenerative diseases (NeuroDegD) has been traditionally focused on later life stages. There is now an increasing evidence, that they may be programmed during early development. Here, we propose that NeuroDegD are the result of the complex process of imprinting on fetal hemogenic endothelium, from which the microglial cells make to origin. The central role of placenta and epigenetic mechanisms (methylation of DNA, histone modifications and regulation by non-coding RNAs) in mediating the short and long-term effects has been also described. Precisely, it reports their role in impacting plasticity and memory of microglial cells. In addition, we also underline the necessity of further studies for clearing all mechanisms involved and developing epigenetic methods for identifying potential targets as biomarkers, and for developing preventive measures. Such biomarkers might be used to identify individuals at risk to NeuroDegD. Finally, the sex dependence of fetal programming process has been discussed. It might justify the sex differences in the epidemiologic, imaging, biomarkers, and pathology studies of these pathologies. The discovery of related mechanisms might have important clinical implications in both the etiology of disorders and the management of pregnant women for encouraging healthy long-term outcomes for their children, and future generations. Impending research on the mechanisms related to transgenerational transmission of prenatal stress might consent the development and application of therapies and/or intervention strategies for these disorders in humans.

The Ferroxidase Hephaestin in Lung Cancer: Pathological Significance and Prognostic Value.

Hephaestin (HEPH) belongs to a group of exocytoplasmic ferroxidases which contribute to cellular iron homeostasis by favouring its export. Down-regulation of HEPH expression, possibly by stimulating cell proliferation due to an increase in iron availability, has shown to correlate with poor survival in breast cancer. The lung is particularly sensitive to iron-induced oxidative stress, given the high oxygen tension present, however, HEPH distribution in lung cancer and its influence on prognosis have not been investigated yet. In this study we explored the prognostic value of HEPH and its expression pattern in the most prevalent histotypes of lung cancers, namely lung adenocarcinoma and lung squamous cell carcinoma. In silico analyses, based on UALCAN, Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier plotter bioinformatics, revealed a significant correlation between higher levels of HEPH expression and favorable prognosis, in both cancer histotypes. Moreover, TIMER web platform showed a statistically significant association between HEPH expression and cell elements belonging to the tumor microenvironment identified as endothelial cells and a subpopulation of cancer-associated fibroblasts, further confirmed by double immunohistochemical labeling with cell type specific markers. Taken together, these data shed a light on the complex mechanisms of local iron handling lung cancer can exploit to support tumorigenesis.

Polymorphisms of Pro-Inflammatory IL-6 and IL-1ß Cytokines in Ascending Aortic Aneurysms as Genetic Modifiers and Predictive and Prognostic Biomarkers.

BACKGROUND: Previous studies have demonstrated that polymorphisms involved in immune genes can affect the risk, pathogenesis, and outcome of thoracic ascending aortic aneurysms (TAAA). Here, we explored the potential associations of five functional promoter polymorphisms in interleukin-6 (IL-6), IL-1B, IL-1A, IL-18, and Tumor necrosis factor (TNF)A genes with TAAA. METHODS: 144 TAAA patients and 150 age/gender matched controls were typed using KASPar assays. Effects on telomere length and levels of TAAA related histopathological and serological markers were analyzed. RESULTS: Significant associations with TAAA risk were obtained for IL-6 rs1800795G>C and IL-1B rs16944C>T SNPs. In addition, the combined rs1800795C/rs16944T genotype showed a synergic effect on TAAA pathogenesis and outcome. The combined rs1800795C/rs16944T genotype was significantly associated with: (a) higher serum levels of both cytokines and MMP-9 and -2; (b) a significant CD3+CD4+CD8+ CD68+CD20+ cell infiltration in aorta aneurysm tissues; (c) a significant shorter telomere length and alterations in telomerase activity. Finally, it significantly correlated with TAAA aorta tissue alterations, including elastic fragmentation, medial cell apoptosis, cystic medial changes, and MMP-9 levels. CONCLUSIONS: the combined rs1800795C/rs16944T genotype appears to modulate TAAA risk, pathogenesis, and outcome, and consequently can represent a potential predictive and prognostic TAAA biomarker for individual management, implementation of innovative treatments, and selection of the more proper surgical timing and approaches.

SARS CoV2 infection _The longevity study perspectives.

Like other infectious diseases, COVID-19 shows a clinical outcome enormously variable, ranging from asymptomatic to lethal. In Italy, like in other countries, old male individuals, with one or more comorbidity, are the most susceptible group, and show, consequently, the highest mortality, and morbidity, including lethal respiratory distress syndrome, as the most common complication. In addition, another extraordinary peculiarity, that is a surprising resistance to COVID-19, characterizes some Italian nonagenarians/centenarians. Despite having the typical COVID-19 signs and/or symptoms, such exceptional individuals show a surprising tendency to recover from illness and complications. On the other hand, long-lived people have an optimal performance of immune system related to an overexpression of anti-inflammatory variants in immune/inflammatory genes, as demonstrated by our and other groups. Consequently, we suggest long-lived people as an optimal model for detecting genetic profiles associated with the susceptibility and/or protection to COVID-19, to utilize as potential pharmacological targets for preventing or reducing viral infection in more vulnerable individuals.