Pathogenetic Determinants Research Articles

Role of microRNAs in Congenital Diaphragmatic Hernia-Associated Pulmonary Hypertension.

Epigenetic regulators such as microRNAs (miRNAs) have a key role in modulating several gene expression pathways and have a role both in lung development and function. One of the main pathogenetic determinants in patients with congenital diaphragmatic hernia (CDH) is pulmonary hypertension (PH), which is directly related to smaller lung size and pulmonary microarchitecture alterations. The aim of this review is to highlight the importance of miRNAs in CDH-related PH and to summarize the results covering this topic in animal and human CDH studies. The focus on epigenetic modulators of CDH-PH offers the opportunity to develop innovative diagnostic tools and novel treatment modalities, and provides a great potential to increase researchers' understanding of the pathophysiology of CDH.

Estrogen receptors, ERK1/2 phosphorylation and reactive oxidizing species in red blood cells from patients with rheumatoid arthritis.

Red blood cells (RBCs) are recognized to be important pathogenetic determinants in several human cardiovascular diseases (CVD). Undergoing to functional alterations when submitted to risk factors, RBCs modify their own intracellular signaling and the redox balance, shift their status from antioxidant defense to pro-oxidant agents, become a potent atherogenic stimulus playing a key role in the dysregulation of the vascular homeostasis favoring the developing and progression of CVD. Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with a significantly increased risk of cardiovascular mortality with a prevalence from two to five more likely in woman, mainly attributed to accelerated atherosclerosis. The purpose of this study was to correlate the RA disease activity and the RBCs functional characteristics. Thirty-two women (aged more than 18years) with RA, and 25 age-matched healthy women were included in this study. The disease activity, measured as the number of swollen and painful joints (DAS-28), was correlated with 1) the expression of RBCs estrogen receptors, which modulate the RBC intracellular signaling, 2) the activation of the estrogen-linked kinase ERK½, which is a key regulator of RBC adhesion and survival, and 3) the levels of inflammatory- and oxidative stress-related biomarkers, such as the acute-phase reactants, the antioxidant capacity of plasma, the reactive oxidizing species formation and 3-nitrotyrosine. All the biomarkers were evaluated in RA patients at baseline and 6months after treatment with disease-modifying anti-rheumatic drugs (DMARDs). We found, for the first times, that in RA patients 1) the DAS-28 correlated with RBC ER-α expression, and did not correlate with total antioxidant capacity of plasma; 2) the RBC ER-α expression correlated with systemic inflammatory biomarkers and oxidative stress parameters, as well as ERK½ phosphorylation; and 3) the DMARDs treatments improved the clinical condition measured by DAS-28 score decrease, although the RBCs appeared to be more prone to pro-oxidant status associated to the expression of survival molecules. These findings represent an important advance in the study of RA determinants favoring the developing of CVD, because strongly suggest that RBCs could also participate in the vascular homeostasis through fine modulation of an intracellular signal linked to the ER-α.

Quantification of Brain β-Amyloid Load in Parkinson's Disease With Mild Cognitive Impairment: A PET/MRI Study.

BackgroundMild cognitive impairment in Parkinson's disease (PD-MCI) is associated with faster cognitive decline and conversion to dementia. There is uncertainty about the role of β-amyloid (Aβ) co-pathology and its contribution to the variability in PD-MCI profile and cognitive progression.ObjectiveTo study how presence of Aβ affects clinical and cognitive manifestations as well as regional brain volumes in PD-MCI.MethodsTwenty-five PD-MCI patients underwent simultaneous PET/3T-MRI with [18F]flutemetamol and a clinical and neuropsychological examination allowing level II diagnosis. We tested pairwise differences in motor, clinical, and cognitive features with Mann–Whitney U test. We calculated [18F]flutemetamol (FMM) standardized uptake value ratios (SUVR) in striatal and cortical ROIs, and we performed a univariate linear regression analysis between the affected cognitive domains and the mean SUVR. Finally, we investigated differences in cortical and subcortical brain regional volumes with magnetic resonance imaging (MRI).ResultsThere were 8 Aβ+ and 17 Aβ- PD-MCI. They did not differ for age, disease duration, clinical, motor, behavioral, and global cognition scores. PD-MCI-Aβ+ showed worse performance in the overall executive domain (p = 0.037). Subcortical ROIs analysis showed significant Aβ deposition in PD-MCI-Aβ+ patients in the right caudal and rostral middle frontal cortex, in precuneus, in left paracentral and pars triangularis (p < 0.0001), and bilaterally in the putamen (p = 0.038). Cortical regions with higher amyloid load correlated with worse executive performances (p < 0.05). Voxel-based morphometry (VBM) analyses showed no between groups differences.ConclusionsPresence of cerebral Aβ worsens executive functions, but not motor and global cognitive abilities in PD-MCI, and it is not associated with middle-temporal cortex atrophy. These findings, together with the observation of significant proportion of PD-MCI-Aβ-, suggest that Aβ may not be the main pathogenetic determinant of cognitive deterioration in PD-MCI, but it would rather aggravate deficits in domains vulnerable to Parkinson primary pathology.

Prognostic value of pre-hospitalization stress perfusion cardiovascular magnetic resonance to predict death in patients hospitalized for COVID-19

BackgroundInducible ischaemia is a strong marker of vascular vulnerability. Knowing the important role of the vascular tropism of COVID-19 to explain its severity, the presence of a prior inducible ischaemia may be a key pathogenetic determinant of COVID-19 severity.AimsTo investigate the prognostic value of prior inducible ischaemia on stress cardiovascular magnetic resonance (CMR) to predict death in patients hospitalized for COVID-19.MethodsWe retrospectively analysed consecutive patients referred for stress perfusion CMR during 1/1/18–1/1/20 who were later hospitalized for COVID-19. The primary outcome was all-cause death, including in-hospital and post-hospitalization deaths, based on the electronic national death registry.ResultsAmong the patients referred for stress CMR, 481 were hospitalized for COVID-19 (mean age 68.4 ± 9.6 years, 61.3% male) and completed the follow-up (median [interquartile range] 73 [36–101] days). There were 93 (19.3%) all-cause deaths, of which 13.7% occurred in hospital and 5.6% were post-hospitalization deaths. Age, male sex, hypertension, diabetes, known coronary artery disease (CAD), the presence of prior inducible ischaemia, the number of ischaemic segments, the presence of late gadolinium enhancement and left ventricular ejection fraction were significantly associated with all-cause death. In multivariable stepwise Cox regression analysis, age (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 1.01–1.07; P = 0.023), hypertension (HR: 2.77; 95% CI: 1.71–4.51; P < 0.001), diabetes (HR: 1.72; 95% CI: 1.08–2.74; P = 0.022), known CAD (HR: 1.78; 95% CI: 1.07–2.94; P = 0.025) and prior inducible ischaemia (HR 2.05; 95% CI: 1.27–3.33; P = 0.004) were independent predictors of all-cause death.ConclusionsIn COVID-19 patients, prior inducible ischaemia by stress CMR during the 2 years preceding the COVID-19 pandemic was independently associated with all-cause death.

Prognostic value of pre-hospitalization stress perfusion CMR to predict death in patients hospitalized for COVID-19

Funding AcknowledgementsType of funding sources: None.BACKGROUNDInducible ischemia is a strong marker of vascular vulnerability that may be a key pathogenetic determinant of COVID-19 severity.PURPOSEThis study investigated the prognostic value of prior inducible ischemia on stress perfusion CMR to predict death in patients hospitalized for COVID-19.METHODSIn an observational study, we retrospectively analyzed consecutive patients referred for stress perfusion CMR within last two years prior to hospitalization for COVID-19. The primary outcome was all-cause death, including in-hospital and post-hospitalisation deaths, based on the electronic national death registry.RESULTSAmong the patients referred for stress perfusion CMR, 481 were hospitalized for COVID-19 (mean age =68.4 ± 9.6 years, 61.3% males) and completed the follow-up (median 73[36-101] days). There were 93 (19.3%) all-cause deaths, of which 13.7% were in-hospital and 5.6% post-hospitalisation deaths.Using Kaplan-Meier analysis, age, male gender, hypertension, diabetes, known CAD, the presence of prior inducible ischemia, the number of ischemic segments, the presence of LGE, and LVEF were significantly associated with all-cause death. In multivariable stepwise Cox regression analysis, age (HR: 1.04; 95%CI:1.01-1.07, p = 0.023), hypertension (HR: 2.77; 95%CI:1.71-4.51, p < 0.001), diabetes (HR: 1.72; 95%CI:1.08-2.74, p = 0.022), known CAD (HR: 1.78; 95%CI:1.07-2.94, p = 0.025) and the presence of prior inducible ischaemia (HR: 2.05; 95%CI:1.27-3.33, p = 0.004) were independent predictors of all-cause death.CONCLUSIONSIn COVID-19 patients, prior inducible myocardial ischemia by stress CMR over the last two years preceding the COVID-19 pandemic was independently associated with all-cause in-hospital and post-hospitalisation deaths, suggesting involvement of vasculature and endothelial dysfunction in the severity of COVID-19. Figure. Death rates (%) according to ischemia Figure. Survival curves for All-cause Death

Impact of Epigenomic Hypermethylation at TP53 on Allogeneic Hematopoietic Cell Transplantation Outcomes for Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders for which allogeneic hematopoietic cell transplantation (HCT) is currently the sole curative treatment. Epigenetic lesions are considered a major pathogenetic determinant in many cancers, and in MDS, epigenetic-based interventions have emerged as life-prolonging therapies. However, the impact of epigenomic aberrations on HCT outcomes among patients with MDS are not well understood. We hypothesized that epigenomic signatures in MDS patients before undergoing HCT serve as a novel prognostic indicator of the risk of post-HCT MDS relapse. To evaluate these epigenomic signatures in MDS patients, we analyzed reduced representation bisulfite sequencing profiles in a matched case-control population of 94 patients. Among these HCT recipients, 47 patients with MDS who relapsed post-HCT (cases) were matched 1:1 to patients with MDS who did not relapse (controls). Only patients with wild-type TP53, RAS pathway, and JAK2 mutations were included in this study to promote the discovery of novel factors. Cases were matched with controls based on conditioning regimen intensity, age, sex, Revised International Prognostic Scoring System, Karnofsky Performance Status, graft type, and donor type. Pre-HCT whole-blood samples from cases and matched controls were obtained from the Center for International Blood and Marrow Transplant Research repository. We comprehensively identified differentially methylated regions (DMRs) by comparing the methylation patterns among matched cases and controls. Our findings show that cases displayed more hyper-DMRs pretransplantation compared with controls, even after adjusting for pre-HCT use of hypomethylating agents. Hyper-DMRs specific to cases were mapped to the transcription start site of 218 unique genes enriched in 5 different signaling pathways that may serve as regions of interest and factors to consider as prognostic determinants of post-HCT relapse in MDS patients. Interestingly, although patients selected for this cohort were wild-type for the TP53 gene, cases showed significantly greater levels of methylation at TP53 compared with controls. These findings indicate that previously identified prognostic genes for MDS, such as TP53, may affect disease relapse not only through genetic mutation, but also through epigenetic methylation mechanisms.

Chronic endometritis in women with endometriosis-associated infertility

The article highlights modern ideas about the role of the endometrium in the genesis of reproductive failures. A crucial place of chronic endometritis in the structure of the endometrial infertility factor in endometriosis is noted. Given the frequent association of chronic endometritis and endometriosis, common features of these diseases have been identified. The characteristic of endometrial microbiota in infertility, chronic endometritis and endometriosis is given. An extremely important area of scientific research is precisely the interaction between the microbiota of the endometrium and its immunity, and not just the confirmation of the presence of microorganisms in the endometrium. The modern aspects of the etiology and pathogenesis of chronic endometritis and endometriosis are described. The main pathogenetic determinants of chronic endometritis are the failure of adaptation mechanisms to the constant effects of microbes and, as a consequence, the decrease and inferiority of the immune response and the development of autoimmune reactions. The modern paradigm for the development and progression of endometriosis involves the presence of bacterial contamination of the endometrium and the abdominal cavity, which in turn becomes a trigger for genetically-epigenetic modifications of cells, launching different cascades that underlie reproductive function disorders. The pathogenetically significant relationship between chronic endometritis and endometriosis is highlighted. It was revealed that chronic endometritis can be both a cause and a consequence of endometriosis. Disorders of the endometrial receptivity in chronic endometritis associated with endometriosis, their importance in the implementation of endometrial infertility are described. The important role of the microbiome in the formation of reproductive disorders is noted.

Epigenomic Signatures in Myelodysplastic Syndrome Patients As Predictors of Donor Compatibility and Transplant Outcome

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders for which allogeneic hematopoietic stem cell transplantation (HCT) is currently the only curative treatment. Epigenetic lesions are considered a major pathogenetic determinant in many cancers, including MDS, and combination epigenetic therapies have emerged. In this study, we hypothesize that interplay between key epigenomic signatures in the MDS patient undergoing HCT and their donor epigenomic profile serve as a prognostic factor of post-HCT MDS relapse risk. Reduced representation bisulfite sequencing (RRBS) was chosen to identify genome-wide epigenetic alterations as a cost-efficient method for building large data resources that reduces sequence redundancy and selects only CpG-rich regions of the genome for sequencing. A unique cohort of 188 samples from the Center for International Blood and Marrow Transplant Research (CIBMTR) biorepository was sequenced through RRBS. This cohort was composed of 94 pre-transplant samples from MDS patients that received peripheral blood stem cell grafts and were selected as case/controls for post-HCT relapse/non-relapse matched on patient, disease and transplant characteristics. The remaining 94 samples were from the patients' healthy allogeneic donors. Only patient samples that were wild-type for previously-identified MDS-prognostic TP53, RAS pathway and JAK2 mutations were included in this cohort to promote discovery of novel factors. We developed methylPrep, a Python application, to filter the low methylation calls and group shared sites by donors, relapsed patients and non-relapsed patients. We comprehensively identified differentially methylated regions (DMRs) by comparing the methylation patterns in healthy donors and MDS patients that relapsed or did not relapse. The healthy donor group displayed higher global methylation levels (GML) than the patient group as a whole, and the relapsed patient showed higher GML than the non-relapsed patient, though these differences were not statistically significant, and we continue to investigate whether hypo-methylating agents play a role. We selected high DMRs (50-bp interval), with at least 25% difference in methylation calls, using Fisher's exact test, where the threshold q-value equals 0.05, and uncovered 367 significant hyper-DMRs and 38 significant hypo-DMRs in donors compared to patients genome-wide. For disease relapsed versus non-relapsed MDS patients, we identified 121 hyper-DMRs and 64 hypo-DMRs, and the distribution of DMRs was highly varied. Furthermore, we compared epigenome compatibility between donors and patients who did or did not relapse after transplantation and discovered a distinct difference in DMR patterns from chromosome to chromosome and through region annotation. Interestingly, a higher number of DMRs were located in promoter regions between donors and non-relapsed patients versus donors and disease-relapsed patients. Identified DMRs, especially those located in promoter regions, may be involved in regulation of gene expression. These promoter DMRs may serve as candidate indicators or sites for potential diagnosis and therapy selection for MDS patients and may aid in the prediction of transplant outcomes and matching of the best donor for the MDS patient. Continued investigation will enable validation and assessment of the impact and mode of action for these distinct methylation signatures and global methylation patterns in MDS associated with HCT outcomes. Figure Disclosures Nazha: Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Novartis: Speakers Bureau; Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Abbvie: Consultancy.

Pathogenetic determinants of endometrial dysfunction in patients with myoma

Introduction. Among the patients with infertility associated with small forms of uterine fibroids (subserous and intra mural), there are a high incidence of inflammatory changes in the cervix, chronic salpingo-opharitis, hydrosalpinx, adhesive process in pelvic organs, chronic endocervicitis and endometrial dysfunction were identified more frequently.&#x0D; The aim of the study was to investigate the clinical and morphological features of endometrial dysfunction in patients with infertility associated with uterine myoma. Material and methods. The study included 165 patients: 70 patients with primary infertility, 65 women with secondary infertility and 30 patients in the control group. All patients were examined and treated in The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott. Laparoscopic and hysteroscopic examination followed by endometrial biopsy was performed on the 19-24th day of the menstrual cycle. Immunohistochemical method was used to study the expression of ER, PR receptors, proinflammatory markers (CD8+, CD20+, CD4+, CD138+), endothelial marker (CD34+) and p16ink4a oncoprotein expression. Estimation of ER and PR expression was carried out by semi-quantitative method of H-Score, other markers, by computer image analysis system “Morphology 5.0” (VideoTest, Russia). Statistical processing of the results was performed using statistical packages (Stata 13).&#x0D; Results. In group of patients with infertility associated with small forms of subserous and intramural uterine myomas, pathognomonic signs of endometrial dysfunction were: high frequency of chronic endometritis, pathological activation of neoangiogenesis, positive expression of inhibitor of cyclin-dependent kinase p16ink4a, reduction of ER and PR expression in the stromal endometrial component, change in receptor affinity of sex steroid hormones.

Kidney involvement in systemic sclerosis: From pathogenesis to treatment.

Among all possible systemic sclerosis internal organ complications, kidney involvement is frequently neglected or underestimated, except for the life-threatening scleroderma renal crisis. Fortunately, this severe clinical presentation is nowadays better controlled with available treatments, in particular angiotensin-converting enzyme inhibitors, and this has led to a reduction in its short- and longer-term mortality. Pathogenetic determinants are not well understood and many different other kidney involvements are possible in systemic sclerosis, including proteinuria, albuminuria, reduction of renal filtration, autoantibodies-related glomerulonephritis, and drug-related side effects. Different serological and radiological methods of evaluations are nowadays available, some representing promising diagnostic tool and prognostic outcome measure. Except for angiotensin-converting enzyme inhibitors in scleroderma renal crisis, no other treatment is currently recommended for treatment of kidney involvement in systemic sclerosis. For this reason, further studies are necessary to investigate its prognostic impact, in particular in combination with other systemic sclerosis-related internal organ manifestations. This review summarizes current available literature on kidney involvement in systemic sclerosis.

Podoplanin promotes progression of malignant pleural mesothelioma by regulating motility and focus formation.

Malignant pleural mesothelioma (MPM) is characterized by dissemination and aggressive growth in the thoracic cavity. Podoplanin (PDPN) is an established diagnostic marker for MPM, but the function of PDPN in MPM is not fully understood. The purpose of this study was to determine the pathogenetic function of PDPN in MPM. Forty‐seven of 52 tumors (90%) from Japanese patients with MPM and 3/6 (50%) MPM cell lines tested positive for PDPN. Knocking down PDPN in PDPN‐high expressing MPM cells resulted in decreased cell motility. In contrast, overexpression of PDPN in PDPN‐low expressing MPM cells enhanced cell motility. PDPN stimulated motility was mediated by activation of the RhoA/ROCK pathway. Moreover, knocking down PDPN with short hairpin (sh) RNA in PDPN‐high expressing MPM cells resulted in decreased development of a thoracic tumor in mice with severe combined immune deficiency (SCID). In sharp contrast, transfection of PDPN in PDPN‐low expressing MPM cells resulted in an increase in the number of Ki‐67‐positive proliferating tumor cells and it promoted progression of a thoracic tumor in SCID mice. Interestingly, PDPN promoted focus formation in vitro, and a low level of E‐cadherin expression and YAP1 activation was observed in PDPN‐high MPM tumors. These findings indicate that PDPN is a diagnostic marker as well as a pathogenetic regulator that promotes MPM progression by increasing cell motility and inducing focus formation. Therefore, PDPN might be a pathogenetic determinant of MPM dissemination and aggressive growth and may thus be an ideal therapeutic target.

Pathogenetic determinants in Kawasaki disease: the haematological point of view.

Kawasaki disease is a multisystemic vasculitis that can result in coronary artery lesions. It predominantly affects young children and is characterized by prolonged fever, diffuse mucosal inflammation, indurative oedema of the hands and feet, a polymorphous skin rash and non‐suppurative lymphadenopathy. Coronary artery involvement is the most important complication of Kawasaki disease and may cause significant coronary stenosis resulting in ischemic heart disease. The introduction of intravenous immunoglobulin decreases the incidence of coronary artery lesions to less than 5%. The etiopathogenesis of this disease remains unclear. Several lines of evidence suggest that an interplay between a microbial infection and a genetic predisposition could take place in the development of the disease. In this review, we summarize the state of the art of pathogenetic mechanisms of Kawasaki disease underscoring the relevance of haematological features as a novel field of investigation.

Phospholipase A2 of Microbiota as Pathogenetic Determinant to Induce Inflammatory States in Ulcerative Colitis: Therapeutic Implications of Phospholipase A2 Inhibitors

Background: Attack by commensal microbiota is one component of induction of inflammatory episodes in ulcerative colitis (UC). In UC, the mucus layer is intrinsically devoid of phosphatidylcholine (PC) resulting in low hydrophobicity which facilitates bacterial invasion. Colonic ectophospholipase-carrying bacterial strains are likely candidates to further thinning the PC mucus barrier and to precipitate inflammatory episodes. Objective: To evaluate the effect of phospholipase A₂ (PLA₂) inhibitors on inflammation in a genetic UC mouse model. Methods: As PLA₂ inhibitor, we applied the bile acid-phospholipid conjugate ursodeoxycholate-lysophosphatidylethanolamide (UDCA-LPE) or as control 5% Tween 80 by oral gavage to intestine-specific kindlin 2 knockout mice. Results: Luminal UDCA-LPE reduced the PLA₂ activity in stool by 36 ± 8%. Concomitantly no inflammatory phenotype was observed when compared to kindlin 2^(–/–) mice not treated with UDCA-LPE. The improvement was documented in regard to stool consistency, calprotectin levels in stool, and macroscopic/endoscopic as well as histologic features of the mucosa. The pattern of colonic microbiota distribution obtained in the UC phenotype mice was reversed by UDCA-LPE to the control mice pattern. Conclusion: The inhibition of the bacterial ectophospholipase A₂ activity improves mucosal inflammation in a genetic mouse model of UC. It is assumed that the remaining mucus PC shield is better preserved when luminal PLA₂ is suppressed.

Redox alterations of platelets and erythrocytes represent progression marker and pathogenetic determinants in Kawasaki disease

Background Kawasaki disease (KD) is a rare generalized systemic vasculitis of unknown etiology in which the main complication is the development of coronary artery abnormalities. Considering that an inflammation-associated systemic pro-oxidant status could play a critical pathogenetic role in KD progression [1], we evaluated some peripheral blood redox-associated parameters, including redox and aging features associated with red blood cells (RBCs) and platelets (PLT) integrity as possible pathogenetic determinants or progression markers in KD disease.

Detection of the criteria of prognostication of efficency of chronic acquired toxoplasmosis treatment

The great number of treatment schemes of toxoplasmosis predetermines the question for clinician how to choose the most effective therapy regimen. Aim. Detection of the criteria of prognostication of efficiency of the treatment patients with the chronic acquired toxoplasmosis (CAT) in an acute phase before and after the complex therapy. Methods. For attaining the set aim we examined 143 patients (92 women and 51 men) 18-75 years old with CAT in an acute phase. For evaluation of efficiency of the complex antiparasitic pathogenetic therapy and the character of dynamics of the studying indicators there was carried out the repeat examination of 143 patients in 1-2 and 5-6 month after the end of treatment. Results. An efficiency of considered treatment regimens depends on an initial pathogenetic determinant specific for each of them and its calculation allows prognosticate and individualize the treatment of patients. Conclusions. The immunological parameters, data of clinical blood analysis and biochemical indicators of the liver function and also the clinical-anamnestic indicators have the predictor properties that allows use it for prognosis of efficiency of CAT treatment. An efficiency of the different treatment regimens of toxoplasmosis can be prognosticated on the base of initial values of parameters of homeostasis of patient’s organism. An efficiency of elaborated algorithms of prognosis of efficiency of the different regimens of CAT therapy was 86,7-90% at the reliability ≥95%, that allows recommend it for clinical use. The use of prognostic algorithms allows individualize the treatment of patients with CAT.

Autophagy as a pathogenic mechanism and drug target in lymphoproliferative disorders

Autophagy represents a key mechanism of cytoprotection that can be activated by a variety of extracellular and intracellular stresses and allows the cell to sequester cytoplasmic components and damaged organelles, delivering them to lysosomes for degradation and recycling. However, the autophagy process has also been associated with the death of the cell. It has been demonstrated to be constitutive in some instances and inducible in others, and the idea that it could represent a pathogenetic determinant as well as a possible prognostic tool and a therapeutic target in a plethora of human diseases has recently been considered. Among these, cancer represents a major one. In this review, we recapitulate the critical implications of autophagy in the pathogenesis, progression, and treatment of lymphoproliferative disorders. Leukemias and lymphomas, in fact, represent paradigmatic human diseases in which advances have recently been made in this respect.

Autoantibodies to Estrogen Receptor α in Systemic Sclerosis (SSc) as Pathogenetic Determinants and Markers of Progression

Systemic sclerosis (SSc) is a multisystem autoimmune disease of unknown etiology characterized by inflammation, autoantibody production, and fibrosis. It predominantly affects women, this suggesting that female sex hormones such as estrogens may play a role in disease pathogenesis. However, up to date, the role of estrogens in SSc has been scarcely explored. The activity of estrogens is mediated either by transcription activity of the intracellular estrogen receptors (ER), ERα and ERβ, or by membrane-associated ER. Since the presence of autoantibodies to ERα and their role as estrogen agonists interfering with T lymphocyte homeostasis were demonstrated in other autoimmune diseases, we wanted to ascertain whether anti-ERα antibodies were detectable in sera from patients with SSc. We detected anti-ERα antibody serum immunoreactivity in 42% of patients with SSc (30 out of 71 analyzed). Importantly, a significant association was found between anti-ERα antibody values and key clinical parameters of disease activity and severity. Fittingly, anti-ERα antibody levels were also significantly associated with alterations of immunological features of SSc patients, including increased T cell apoptotic susceptibility and changes in T regulatory cells (Treg) homeostasis. In particular, the percentage of activated Treg (CD4+CD45RA− FoxP3brightCD25bright) was significantly higher in anti-ERα antibody positive patients than in anti-ERα antibody negative patients. Taken together our data clearly indicate that anti-ERα antibodies, probably via the involvement of membrane-associated ER, can represent: i) promising markers for SSc progression but, also, ii) functional modulators of the SSc patients’ immune system.

T lymphocytes from patients with systemic lupus erythematosus are resistant to induction of autophagy

Autophagy, the cytoprotection mechanism that takes place under metabolic impairment, has been implicated in the pathogenesis of autoimmunity. Here, we investigated the spontaneous and induced autophagic behavior of T lymphocytes from patients with systemic lupus erythematosus (SLE) compared with that of T lymphocytes from healthy donors by measuring the autophagy marker microtubule-associated protein 1 light chain 3 (LC3)-II. No significant differences in spontaneous autophagy were found between T lymphocytes from patients with SLE and from healthy donors, apart from CD4(+) naive T cells from patients with SLE in which constitutively higher levels of autophagy (P<0.001) were detected. At variance, whereas treatment of T lymphocytes from healthy donors with serum IgG from patients with SLE resulted in a 2-fold increase in LC3-II levels (P<0.001), T lymphocytes from SLE patients were resistant to autophagic induction and also displayed an up-regulation of genes negatively regulating autophagy, e.g., α-synuclein. These findings could open new perspectives in the search for pathogenetic determinants of SLE progression and in the development of therapeutic strategies aimed to recover T-cell compartment homeostasis by restoring autophagic susceptibility.

Diet-Derived Phytochemicals: From Cancer Chemoprevention to Cardio-Oncological Prevention

Cardiovascular diseases and cancer are the leading causes of death in most countries. These diseases share many common risk factors as well as pathogenetic determinants, and their incidence is related to age in an exponential manner. Furthermore, it has become apparent that several treatments used in therapy or even in prevention of cancer can impair the structural and functional integrity of the cardiovascular system, giving rise to an interdisciplinary field: cardio-oncology. However, tumors and cardiovascular diseases also share common protective factors: they can be prevented either by avoiding exposure to recognized risk factors, and/or by favoring the intake of protective compounds and by modulating the host defense machinery. These latter approaches are generally known as chemoprevention. A great variety of dietary and pharmacological agents have been shown to be potentially capable of preventing cancer in preclinical models, most of which are of plant origin. Phytochemicals, in particular diet-derived compounds, have therefore been proposed and applied in clinical trials as cancer chemopreventive agents. There is now increasing evidence that some phytochemicals can be also protective for the heart, having the potential to reduce cancer, cardiovascular disease and even anticancer drug-induced cardiotoxicity. We introduce the concept that these compounds induce pre-conditioning, a low level cellular stress that induces strong protective mechanisms conferring resistance to toxins such as cancer chemotherapeutics. Cancer cells and cardiomyocytes have fundamental differences in their metabolism and sensitivity to preconditioning, autophagy and apoptosis, so that dosage of the prevention compounds is important. Here we discuss the mechanisms responsible for the cardiotoxicity of anticancer drugs, the possibility to prevent them and provide examples of diet-derived phytochemicals and other biological substances that could be exploited for protecting the cardiovascular system according to a joint cardio-oncological preventative approach.

Can a chronic dental infection be considered a cause of cardiovascular disease? A review of the literature

Cardiovascular diseases (CVD) have a complex etiology determined by risk factors, which are in turn associated to a strong genetic component and to environmental factors. In the biological background for the development of CVD, low-grade chronic inflammation plays a role as a pathogenetic determinant of atherosclerosis. Dental infections have been associated with CVD. Periodontal disease is a chronic infection of the supporting tissues of the tooth that can lead to teeth loss. In recent years, a number of reports have demonstrated the possible relationship between periodontal disease and CVD. Apical periodontitis, on the other hand, is the late consequence of an endodontic infection, which is caused by the persistence of coronal caries and involves the root canal system of the tooth. Most of the time, it is a chronic infection. Some studies have found a correlation between a "composite status" of oral health (eg. caries, tooth loss, periodontal disease) and CVD, but only a few of them have addressed the association between apical periodontitis and CVD. This "state of the art" paper represents the first stage of an incoming study on the relationship between chronic endodontic infection and CVD.