Cardioprotective potential of oleuropein, hydroxytyrosol, oleocanthal and their combination: Unravelling complementary effects on acute myocardial infarction and metabolic syndrome.

Clinical studies have previously established the role of olive products in cardiovascular disease (CVD) prevention, whilst the identification of the responsible constituents for the beneficial effects is still pending. We sought to assess and compare the cardioprotective potential of oleuropein (OL), hydroxytyrosol (HT), oleocanthal (OC) and oleanolic Acid (OA), regarding Ischemia/Reperfusion Injury (IRI) and CVD risk factors alleviation. The scope of the study was to design a potent and safe combinatorial therapy for high-cardiovascular-risk patients on a bench-to-bedside approach. We evaluated the IRI-limiting potential of 6-weeks treatment with OL, HT, OC or OA at nutritional doses, in healthy and metabolic syndrome (MS)-burdened mice. Three combinatorial regimens were designed and the mixture with preponderant benefits (OL-HT-OC, Combo 2), including infarct sparing and antiglycemic potency, compared to the isolated compounds, was further investigated for its anti-atherosclerotic effects. In vivo experiments revealed that the combination regimen of Combo 2 presented the most favorable effects in limiting infarct size and hyperglycemia, which was selected to be further investigated in the clinical setting in Chronic Coronary Artery Syndrome (CCAS) patients. Cardiac function, inflammation markers and oxidative stress were assessed at baseline and after 4 weeks of treatment with the OL-HT-OC supplement in the clinical study. We found that OL, OC and OA significantly reduced infarct size in vivo compared to Controls. OL exhibited antihyperglycemic properties and OA attenuated hypercholesterolemia. OL-HT-OA, OL-HT-OC and OL-HT-OC-OA combination regimens were cardioprotective, whereas only OL-HT-OC mitigated hyperglycemia. Combo 2 cardioprotection was attributed to apoptosis suppression, enhanced antioxidant effects and upregulation of antioxidant enzymes. Additionally, it reduced atherosclerotic plaque extent in vivo. OL-HT-OC supplement ameliorated cardiac, vascular and endothelial function in the small-scale clinical study. Conclusively, OL-HT-OC combination therapy exerts potent cardioprotective, antihyperglycemic and anti-atherosclerotic properties in vivo, with remarkable and clinically translatable cardiovascular benefits in high-risk patients.

Increased TNF-α, IL-6 and decreased IL-1ß immunohistochemical expression by the stromal spindle-shaped cells in the central giant cell granuloma of the jaws.

OBJECTIVES: the expression of the osteoclastogenic cytokines TNF-α, IL-6 and IL-1ß were immunohistochemically evaluated in peripheral (PGCG) and central (CGCG) giant cell granulomas of the jaws in order to determine differences between these two lesions and between the two distinct tumor cell populations (multinucleated giant cells, MGCs and stromal spindle-shaped cells). STUDY DESIGN: Paraffin-embedded tissue sections from 40 PGCG and 40 CGCG were immunohistochemically stained using antibodies against TNF-α, IL-6 and IL-1ß. The percentage of positively stained cells and the staining intensity were assessed to provide a combined immunoreactivity score value. RESULTS: TNF-α, IL-6 and IL-1ß were expressed in all lesions. The CGCG compared to the PGCG showed significantly increased expression of TNF-α and IL-6 and decreased expression of IL-1ß by the spindle-shaped cells and increased expression of IL-1ß by the MGCs. The MGCs demonstrated in comparison to the stromal spindle-shaped cells significantly increased expression of all three cytokines in both PGCG and CGCG. CONCLUSIONS: The proinflammatory cytokines TNF-α, IL-6 and IL-1ß seem to be involved in the growth process of PGCG and CGCG of the jaws. A possible alteration in the synthesis or/and activity of these cytokines by the stromal spindle cells in the CGCGs may enhance osteolysis through the stimulation of osteoclast progenitor cells, given the fact that the intraosseous lesions cause bone resorption.

Circulating and Tissue Expression Profile of MicroRNAs in Primary Hyperparathyroidism Caused by Sporadic Parathyroid Adenomas.

We investigated the expression profile of selected microRNAs (miRs) in serum and tissue samples from patients with sporadic parathyroid adenomas (sPAs). This was a prospective, controlled cohort study. Forty patients with sPAs who had undergone parathyroidectomy (PTX) were included. MiR extraction was performed from (i) 40 formalin-fixed paraffin-embedded samples (FFPEs) of sPAs, (ii) 10 FFPEs of normal parathyroid tissue (NPT), (iii) serum samples of the 40 patients with sPAs (t1 = baseline; t2 = 2 months post-PTX), and (vi) serum samples of 10 healthy individuals (controls; t1 = baseline and t2 = 2 months later). Ten miRs were selected based on their interaction with genes related to parathyroid tumorigenesis (miR-17-5p, miR-24-3p, miR-29b-3p, miR-31-5p, miR-135b-5p, miR-186-5p, miR-195-5p, miR-330-3p, miR-483-3p, and miR-877-5p). At tissue level, the relative expression of miR-17-5p, miR-31-5p, miR-135b-5p, miR-186-5p, and miR-330-3p was significantly decreased (fold change [FC]: 0.17, FC: 0.03, FC: 0.01, FC: 0.10, FC: 0.10, respectively; all p values <0.001), and the expression of miR-24-3p and miR-29b-3p was significantly increased (FC: 12.4, p < 0.001; FC: 18.5, p = 0.011, respectively) in sPA compared with NPT samples. The relative expression of miR-135b-5p was also significantly decreased in the serum samples of patients compared with controls (FC: 0.7, p = 0.035). No significant differences were found in the serum samples of patients before and after PTX. MiRs that regulate genes linked to parathyroid tumors such as menin 1 (miR-24-3p, miR-29b-3p), cyclin D1 (miR-17-5p), calcium sensing receptor (miR-31-5p, miR-135b-5p), cyclin-dependent kinase inhibitors (miR-186-5p), and ß-catenin (miR-330-3p) were significantly deregulated in sPAs compared with NPT samples, suggesting a role for epigenetic changes in parathyroid tumorigenesis. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Lobular breast cancer in men: case report and review of the literature.

BACKGROUND: Lobular breast cancer in men is an extremely infrequent occurrence due to the lack of lobules and acini in the male breast. Such a rare case is described here. CASE REPORT: A 74-year-old patient presented with a sizeable lesion in the right breast, which proved to be a lobular carcinoma. Genetic studies excluded Klinefelter's syndrome, though revealing an interesting genetic multiformity feature. This case represented a lobular carcinoma in a genotypically male patient under no exogenous or endogenous estrogenic influence. CONCLUSIONS: The increasing number of male lobular breast cancer cases should be explored more extensively with particular emphasis placed on causally related genetic and hormonal factors.

Prognostic role of sex steroid receptors in pancreatic adenocarcinoma.

From the available literature, it is unclear what proportion of pancreatic adenocarcinomas express estrogen receptors (ERα, ERß), progesterone receptors (PR), and androgen receptors (AR), and if any of these markers have prognostic significance. We aimed to assess (1) the expression and (2) the correlation of the aforementioned markers with clinicopathological parameters and prognosis in patients with pancreatic adenocarcinoma. During a five-year period, 60 patients with pancreatic ductal adenocarcinoma underwent surgical resection at a single institution. Immunohistochemical stains of the studied markers were quantified by Image analysis system. ERα expression was positively associated with PR expression. Moreover, ERß was inversely associated with the presence of metastases, whereas no significant associations implicated AR. As far as the prognostic significance of the studied receptors is concerned, higher ERα expression correlated with poorer survival at the univariate analysis, but the finding dissipated at the multivariate approach. No significant associations with overall survival were noted regarding the other receptors. The role of sex hormone receptors in the survival from pancreatic adenocarcinoma seems rather limited. Further prospective studies assessing those receptors should ideally be designed in order to confirm our results and possibly outline additional correlations between other steroid receptors and features of pancreatic adenocarcinoma.

Cyclin D1, p16(INK) (4A) and p27(Kip1) in pancreatic adenocarcinoma: assessing prognostic implications through quantitative image analysis.

The prognostic significance of cyclin D1, p16(INK) (4A) and p27(Kip1) expression has been documented in several human malignancies; however, their prognostic potential in pancreatic adenocarcinoma is still unclear. This study aimed to assess the correlation of the aforementioned molecules with clinicopathological parameters and prognosis. Sixty patients with pancreatic ductal adenocarcinoma underwent surgical resection at a single institution; immunohistochemical staining of the studied markers was quantified by Ιmage analysis system. Cyclin D1 overexpression was positively associated with grade, neural infiltration and vascular invasion, whereas p27 positively correlated with age. Higher cyclin D1 expression indicated poorer survival (adjusted HR = 9.75, 95%CI: 1.48-64.31, p = 0.018, increment: one unit in H-score), whereas a marginal trend toward an association between p16 positivity and improved survival was observed (adjusted HR = 0.58, 95%CI: 0.32-1.05, p = 0.072 regarding positive vs negative cases). No significant association with overall survival was noted regarding p27. In conclusion, cyclin D1 overexpression and possibly p16 loss of expression in pancreatic adenocarcinoma seem to be adverse prognostic factors, whereas p27 expression did not seem to possess such prognostic properties. Further validation of the present findings in studies encompassing larger samples seems to be needed.

Association of angiotensin-converting enzyme gene insertion/deletion polymorphism with decreased risk for basal cell carcinoma.

The incidence of basal cell carcinoma (BCC) is significantly reduced in individuals treated with inhibitors of angiotensin I-converting enzyme (ACE) that produces angiotensin II. The objective of this study was to investigate the possible association of a functional polymorphism in the ACE gene, which affects its transcription, with risk for BCC. In DNA samples of 92 patients with BCC and 103 healthy controls of Greek origin and comparable age and gender, we studied the ACE gene insertion/deletion (I/D) polymorphism. Fisher's exact test was used for comparison of allele and genotype frequencies between the control and patients' groups. The detected low expression I allele frequency in the group of BCC patients was significantly decreased compared to controls (15.8 vs. 31.1 %, respectively; P = 0.001). ID heterozygotes exhibited 3.06 times lower BCC risk, compared with DD homozygotes (P = 0.001; OR = 0.327, 95 % CI = 0.174-0.615). The protective role of I allele was particularly prominent in women (P = 0.007, OR = 0.299, 95 % CI = 0.125-0.716), while for men it exhibited a marginal level (P = 0.041). These findings indicate that the low expression ACE I allele carriers have a decreased risk for BCC. The protective effect of the ID genotype against BCC may be explained by a possible underlying mechanism involving the effect of produced angiotensin II levels on its receptors due to putatively different binding affinity.

Central odontogenic fibroma of the mandible: a case report.

Central odontogenic fibroma (COF) is a rare tumor that accounts for 0.1% of all odontogenic tumors. It has been defined as a benign neoplasm, which appears in the jaw. Clinically, the lesion grows slowly and leads to cortical expansion. Radiologically, the most common finding is multilocular radiolucency. In some cases, it may be associated with root resorption or displacement. Histologically, the lesion is characterized by mature collagen fibers and numerous fibroblasts. COF responds well to surgical enucleation with no tendency for malignancy or recurrence. Here, a case of central odontogenic fibroma of the mandible in a 71-year-old man is described. The lesion was an asymptomatic mass with well-defined borders covered by normal mucosa. The lesion presented as a multilocular radiolucency in relation to the root of the canine. The lesion was surgically removed and analyzed histopathologically. There were no postoperative complications.

Interactions between CYP1A1 polymorphisms and exposure to environmental tobacco smoke in the modulation of lymphocyte bulky DNA adducts and chromosomal aberrations.

CYP1A1 plays an important role in the metabolic activation of polycyclic aromatic hydrocarbons (PAH), carcinogenic components of air pollution. The influence of CYP1A1 genotype (*2A, *2B and *4) on the levels of lymphocyte bulky DNA adducts and the frequency of cells with aberrant chromosomes was assessed in 194 non-smoking subjects in whom recent exposure to environmental tobacco smoke (ETS) and airborne particulate-associated PAH were measured during two consecutive seasons (winter and summer). While CYP1A1*4 had no consistent effect on either biomarker of genetic damage, the levels of both biomarkers responded in a parallel fashion to changes in exposure/CYP1A1*2A genotype combinations during both seasons. Specifically, the levels of both biomarkers were increased in carriers of at least one CYP1A1*2A allele, as compared with CYP1A1*1 homozygotes, in subjects with ETS exposures >0.8 h/day during the previous 4 days and mean personal exposure to benzo[a]pyrene <0.9 ng/m3 during the previous 24 h (all P < 0.05). Outside these exposure limits the differential effect in CYP1A1*2A variants was lost. Although the numbers of subjects with the CYP1A1*2B polymorphism was small, the same trend appeared to be followed in this case. These effects are interpreted as resulting from differential induction of CYP1A1 expression in CYP1A1*2A and CYP1A1*2A/*2B carriers by components of ETS-polluted air at levels of exposure readily suffered by large segments of the general population and suggest that subjects with these genotypes may have increased susceptibility to the genotoxic effects of ETS.

Increased TNF-Alpha, IL-6 and decreased IL-1â immunohistochemical expression by the stromal spindle-shaped cells in the centralgiant cell granuloma of the jaws

Objectives: the exp ress ion of the osteoclastogenic cytokines TNF-Alpha, IL-6 and IL-1Beta were immunohistochemically evaluated in peripheral (PGCG) and central (CGCG) giant cell granulomas of the jaws in order to determine differences between these two lesions and between the two distinct tumor cell populations (multinucleated giant cells, MGCs and stromal spindle-shaped cells).Study Design: Paraffin-embedded tissue sections from 40 PGCG and 40 CGCG were immunohistochemically stained using antibodies against TNF-Alpha, IL-6 and IL-1Beta. The percentage of positively stained cells and the staining intensity were assessed to provide a combined immunoreactivity score value. Results: TNF-Alpha, IL-6 and IL-1Beta were expressed in all lesions. The CGCG compared to the PGCG showed significantly increased expression of TNF-Alpha and IL-6 and decreased expression of IL-1Beta by the spindle-shaped cells and increased express ion of IL-1Beta by the MGCs. The MGCs demonstrated in comparison to the stromal spindle shaped cells significantly increased expression of all three cytokines in both PGCG and CGCG. Conclusions: The proinflammatory cytokines TNF-Alpha, IL-6 and IL-1Beta seem to be involved in the growth process of PGCG and CGCG of the jaws. A possible alteration in the synthesis or/and activity of these cytokines by the stromal spindle cells in the CGCGs may enhance osteolysis through the stimulation of osteoclast progenitor cells, given the fact that the intraosseous lesions cause bone resorption (AU)