Cardioprotective Effects of Sodium Glucose Cotransporter 2 Inhibition in Angiotensin II-Dependent Hypertension Are Mediated by the Local Reduction of Sympathetic Activity and Inflammation.

The cardioprotective effects of sodium glucose cotrasponter 2 (SGLT2) inhibitors seem to be independent from the effects on glycemic control, through little-known mechanisms. In this study, we investigate whether the cardioprotective effects of empagliflozin, a SGLT2 inhibitor, may be associated with myocardial sympathetic activity and inflammatory cell infiltration in an experimental model of angiotensin II-dependent hypertension. Angiotensin II (Ang II), Ang II plus Empagliflozin, physiological saline, or physiological saline plus empagliflozin were administered to Sprague Dawley rats for two weeks. Blood pressure was measured by plethysmographic method. Myocardial hypertrophy and fibrosis were analysed by histomorphometry, and inflammatory cell infiltration and tyrosine hydroxylase expression, implemented as a marker of sympathetic activity, were evaluated by immunohistochemistry. Ang II increased blood pressure, myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase expression, as compared to the control group. Empagliflozin administration prevented the development of myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase overexpression in Ang II-treated rats, without affecting blood glucose and the Ang II-dependent increase in blood pressure. These data demonstrate that the cardioprotective effects of SGLT2 inhibition in Ang II-dependent hypertension may result from the myocardial reduction of sympathetic activity and inflammation and are independent of the modulation of blood pressure and blood glucose levels.

RNA-seq profiling reveals different pathways between remodeled vessels and myocardium in hypertrophic cardiomyopathy.

OBJECTIVE: Coronary microvascular dysfunction (CMD) is a key pathophysiological feature of hypertrophic cardiomyopathy (HCM), contributing to myocardial ischemia and representing a critical determinant of patients' adverse outcome. The molecular mechanisms underlying the morphological and functional changes of CMD are still unknown. Aim of this study was to obtain insights on the molecular pathways associated with microvessel remodeling in HCM. METHODS: Interventricular septum myectomies from patients with obstructive HCM (n = 20) and donors' hearts (CTRL, discarded for technical reasons, n = 7) were collected. Remodeled intramyocardial arterioles and cardiomyocytes were microdissected by laser capture and next-generation sequencing was used to delineate the transcriptome profile. RESULTS: We identified 720 exclusive differentially expressed genes (DEGs) in cardiomyocytes and 1315 exclusive DEGs in remodeled arterioles of HCM. Performing gene ontology and pathway enrichment analyses, we identified selectively altered pathways between remodeled arterioles and cardiomyocytes in HCM patients and controls. CONCLUSIONS: We demonstrate the existence of distinctive pathways between remodeled arterioles and cardiomyocytes in HCM patients and controls at the transcriptome level.

3D-Arterial analysis software and CEUS in the assessment of severity and vulnerability of carotid atherosclerotic plaque: a comparison with CTA and histopathology.

PURPOSE: Our purpose is to assess Multiparametric Ultrasound (MPUS) efficacy for evaluation of carotid plaque vulnerability and carotid stenosis degree in comparison with Computed Tomography angiography (CTA) and histology. MATERIAL AND METHODS: 3D-Arterial Analysis is a 3D ultrasound software that automatically provides the degree of carotid stenosis and a colorimetric map of carotid plaque vulnerability. We enrolled 106 patients who were candidates for carotid endarterectomy. Prior to undergoing surgery, all carotid artery plaques were evaluated with Color-Doppler-US (CDUS), Contrast-Enhanced Ultrasound (CEUS), and 3D Arterial analysis (3DAA) US along with Computerized Tomographic Angiography (CTA) to assess the carotid artery stenosis degree. Post-surgery, the carotid specimens were fixed with 10% neutral buffered formalin solution, embedded in paraffin and used for light microscopic examination to assess plaque vulnerability morphological features. RESULTS: The results of the CTA examinations revealed 91 patients with severe carotid stenoses with a resultant diagnostic accuracy of 82.3% for CDUS, 94.5% for CEUS, 98.4% for 3DAA, respectively. The histopathological examination showed 71 vulnerable plaques with diagnostic accuracy values of 85.8% for CDUS, 93.4% for CEUS, 90.3% for 3DAA, 92% for CTA, respectively. CONCLUSIONS: The combination of CEUS and 3D Arterial Analysis may provide a powerful new clinical tool to identify and stratify "at-risk" patients with atherosclerotic carotid artery disease, identifying vulnerable plaques. These applications may also help in the postoperative assessment of treatment options to manage cardiovascular risks.

In Vitro and In Vivo Effects of the Urokinase Plasminogen Activator Inhibitor WX-340 on Anaplastic Thyroid Cancer Cell Lines.

Increased expression of the urokinase-type plasminogen activator (uPA) system is associated with tumor invasion, neo-angiogenesis, and metastatic spread, and has been shown to positively correlate with a poor prognosis in several cancer types, including thyroid carcinomas. In recent years, several uPA inhibitors were found to have anticancer effects in preclinical studies and in some phase II clinical trials, which prompted us to evaluate uPA as a potential therapeutic target for the treatment of patients affected by the most aggressive form of thyroid cancer, the anaplastic thyroid carcinoma (ATC). In this study, we evaluated the in vitro and in vivo effects of WX-340, a highly specific and selective uPA inhibitor, on two ATC-derived cell lines, CAL-62 and BHT-101. The results obtained indicated that WX-340 was able to reduce cell adhesion and invasiveness in a dose-dependent manner in both cell lines. In addition, WX-340 increased uPA receptor (uPAR) protein levels without affecting its plasma membrane concentration. However, this compound was unable to significantly reduce ATC growth in a xenograft model, indicating that uPA inhibition alone may not have the expected therapeutic effects.

Metastasis of lung carcinoid in the thyroid gland after 18 years: it is never too late. A case report and review of the literature.

Metastasis to the thyroid gland is a rare event. To date, only 11 cases of metastasis from neuroendocrine tumors (NETs) originating in the lung have been reported. We present a case of a patient in his 40s harboring two nodules in the thyroid gland that were diagnosed as well-differentiated NET (G1). Eighteen years before the patient underwent a lung lobectomy of the right upper lobe for a bronchial typical carcinoid with metastasis in one lymph node. Normal blood levels of calcitonin virtually ruled out the diagnosis of medullary thyroid carcinoma (MTC) and supported the diagnosis of a possible thyroid metastasis of the previous bronchial NET. Mutational analysis performed on both primary and metastasis tumor tissue did not show any mutation in the 409 genes analyzed.

Adipose tissue remodelling in obese subjects is a determinant of presence and severity of fatty liver disease.

AIMS: Experimental data suggest that visceral adipose tissue (VAT) dysfunction contributes to non-alcoholic fatty liver disease (NAFLD) development in obesity, however, data on humans are limited. Aims of this study were to investigate the relationship between NAFLD and VAT morphofunctional impairment and to determine whether the extent of VAT remodelling is associated with liver damage and metabolic alterations in obesity. METHODS: We analysed data from 40 obese individuals candidate to bariatric surgery in whom paired intraoperative liver and omental biopsies were performed for diagnosing NAFLD and VAT inflammation by immunohistochemistry and mRNA expression studies. RESULTS: Within our study population, NAFLD was significantly associated with greater VAT CD68+ macrophages infiltration (P = .04), fibrosis (P = .04) and impaired microvascular density (P = .03) as well as increased expression of markers of local hypoxia, apoptosis and inflammation (UNC5B, CASP7, HIF1-α, IL-8, MIP2, WISP-1, all P < .01). The degree of VAT inflammation correlated with the severity of hepatic injury (steatosis, inflammation, fibrosis; all P < .01) and impaired gluco-metabolic profile. CONCLUSIONS: In obese patients, NAFLD is associated in a dose-dependent manner with signs of VAT remodelling, which reflect more severe clinical metabolic impairment. Our study depicts morphological alterations and novel mediators of VAT dysfunction, adding knowledge for future therapeutic approaches to NAFLD and its metabolic complications.

Liquid Biopsy for Cancer Cachexia: Focus on Muscle-Derived microRNAs.

Cancer cachexia displays a complex nature in which systemic inflammation, impaired energy metabolism, loss of muscle and adipose tissues result in unintentional body weight loss. Cachectic patients have a poor prognosis and the presence of cachexia reduces the tolerability of chemo/radio-therapy treatments and it is frequently the primary cause of death in advanced cancer patients. Early detection of this condition could make treatments more effective. However, early diagnostic biomarkers of cachexia are currently lacking. In recent years, although solid biopsy still remains the "gold standard" for diagnosis of cancer, liquid biopsy is gaining increasing interest as a source of easily accessible potential biomarkers. Moreover, the growing interest in circulating microRNAs (miRNAs), has made these molecules attractive for the diagnosis of several diseases, including cancer. Some muscle-derived circulating miRNA might play a pivotal role in the onset/progression of cancer cachexia. This topic is of great interest since circulating miRNAs might be easily detectable by means of liquid biopsies and might allow an early diagnosis of this syndrome. We here summarize the current knowledge on circulating muscular miRNAs involved in muscle atrophy, since they might represent easily accessible and promising biomarkers of cachexia.

Angiotensin Type 2 and Mas Receptor Activation Prevents Myocardial Fibrosis and Hypertrophy through the Reduction of Inflammatory Cell Infiltration and Local Sympathetic Activity in Angiotensin II-Dependent Hypertension.

Compound 21 (C21), an AT2 receptor agonist, and Angiotensin 1-7 (Ang 1-7), through Mas receptor, play an important role in the modulation of the protective arm of the renin-angiotensin system. The aim of this study was to investigate in an experimental model of angiotensin II-dependent hypertension whether the activation of the potentially protective arm of the renin-angiotensin system, through AT2 or Mas receptor stimulation, counteracts the onset of myocardial fibrosis and hypertrophy, and whether these effects are mediated by inflammatory mechanism and/or sympathetic activation. Sprague Dawley rats (n = 67) were treated for 1 (n = 25) and 4 (n = 42) weeks and divided in the following groups: (a) Angiotensin II (Ang II, 200 ng/kg/min, osmotic minipumps, sub cutis); (b) Ang II+Compound 21 (C21, 0.3 mg/kg/day, intraperitoneal); (c) Ang II+Ang 1-7 (576 µg/kg/day, intraperitoneal); (d) Ang II+Losartan (50 mg/kg/day, per os); (e) control group (physiological saline, sub cutis). Systolic blood pressure was measured by tail cuff method and, at the end of the experimental period, the rats were euthanized and the heart was excised to evaluate myocardial fibrosis, hypertrophy, inflammatory cell infiltration and tyrosine hydroxylase expression, used as marker of sympathetic activity. Ang II caused a significant increase of blood pressure, myocardial interstitial and perivascular fibrosis and myocardial hypertrophy, as compared to control groups. C21 or Ang 1-7 administration did not modify the increase in blood pressure in Ang II treated rats, but both prevented the development of myocardial fibrosis and hypertrophy. Treatment with losartan blocked the onset of hypertension and myocardial fibrosis and hypertrophy in Ang II treated rats. Activation of AT2 receptors or Mas receptors prevents the onset of myocardial fibrosis and hypertrophy in Ang II-dependent hypertension through the reduction of myocardial inflammatory cell infiltration and tyrosine hydroxylase expression. Unlike what happens in case of treatment with losartan, the antifibrotic and antihypertrophic effects that follow the activation of the AT2 or Mas receptors are independent on the modulation of blood pressure.

Renal Anti-Fibrotic Effect of Sodium Glucose Cotransporter 2 Inhibition in Angiotensin II-Dependent Hypertension.

BACKGROUND: Clinical trials have shown that empagliflozin (Empa), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, promotes nephroprotective effects in diabetic patients. The mechanisms underlying nephroprotection are not completely known and it is not known whether the renal beneficial action is present even in non-diabetic kidney disease. The aim of this study was to evaluate the effect of Empa administration on the development of renal fibrosis in an experimental model of angiotensin II (Ang II)-dependent hypertension. METHODS: Sprague Dawley rats (n = 31) were divided into 4 experimental groups. Ang II (200 ng/kg/min, osmotic minipumps, s.c., n = 9) or Ang II + Empa (10 mg/kg/day, per os, n = 10) were administered for 2 weeks. Control rats were treated with placebo (physiological saline, n = 6), and another group was treated with placebo plus Empa (n = 6) for the same period. Blood pressure (plethysmographic method) was measured at the beginning and at the end of the experimental protocol. After 2 weeks, the rats were euthanized and the kidneys were excised for histomorphometric evaluation of glomerular and tubulo-interstitial fibrosis and for the immunohistochemical evaluation of inflammatory infiltrates (monocytes/macrophages) and types I and IV collagen expression. RESULTS: The administration of Ang II resulted in an increase in blood pressure (p < 0.01), glomerular (p < 0.05) and tubulo-interstitial (p < 0.01) fibrosis, renal inflammatory infiltrates (p < 0.01) and type I (p < 0.01) and type IV collagen expression (p < 0.05) compared to the control group. Treatment with Empa did not significantly modify the increase in blood pressure due to Ang II, but prevented the development of renal glomerular and tubulo-interstitial fibrosis, and the increase in inflammatory infiltrates and types I and IV collagen expression in Ang II-treated rats (p < 0.01). CONCLUSIONS: These data demonstrate that the treatment with Empa prevents the development of renal fibrosis in Ang II-dependent hypertension. In Ang II-dependent hypertension, the anti-fibrotic effect due to SGLT2 inhibition is caused by the reduction of inflammatory infiltrates and it is independent on the modulation of blood pressure increase.

Osteopontin in vitreous and idiopathic epiretinal membranes.

PURPOSE: To investigate osteopontin (OPN) expression in vitreous and in related idiopathic epiretinal membranes (ERMs), with respect to VEGF-A, IL8, MIP1α, IL6, and IL33, and correlate OPN expression with disease staging. METHODS: Fifteen (15) vitreous and allied ERMs were collected at the time of therapeutic vitreoretinal surgery. Additional 5 vitreous and 10 ERMs (historical collection) were used. Biochemical and molecular analysis of OPN was performed in clear vitreous, vitreal pelleted cells, and ERMs. Double-immunofluorescence analysis (OPN - GFAP and OPN - αSMA) was performed on paraffin and whole-mounted ERMs. Vitreal OPN levels were correlated to those of VEGF-A, IL8, MIP1α, IL6, and IL33. RESULTS: High OPN levels were observed in vitreal samples, and OPN transcripts were amplified in vitreal cells and related ERMs. OPN immunoreactivity was found in ERMs, mainly in GFAP-bearing (Muller cells) and to a less extend in αSMA-expressing (myofibroblasts) cells. OPN levels were highest at early stages of ERM formation and positively correlated to VEGF-A and MIP1α. CONCLUSIONS: High OPN levels in vitreous, OPN transcripts in vitreal cells/ERMs, OPN immunoreactivity in activated Müller cells and contractile myofibroblasts, as well as the correlation with VEGF-A and MIP1α fulfill the potential involvement of OPN in both inflammation and tissue remodeling that takes part in vitreoretinal interface disorders. The highest OPN levels at early stages of ERM formation would prospect OPN as a potential biomarker for disease severity.

Reduced Biliverdin Reductase-A Expression in Visceral Adipose Tissue is Associated with Adipocyte Dysfunction and NAFLD in Human Obesity.

Biliverdin reductase A (BVR-A) is an enzyme involved in the regulation of insulin signalling. Knockout (KO) mice for hepatic BVR-A, on a high-fat diet, develop more severe glucose impairment and hepato-steatosis than the wild type, whereas loss of adipocyte BVR-A is associated with increased visceral adipose tissue (VAT) inflammation and adipocyte size. However, BVR-A expression in human VAT has not been investigated. We evaluated BVR-A mRNA expression levels by real-time PCR in the intra-operative omental biopsy of 38 obese subjects and investigated the association with metabolic impairment, VAT dysfunction, and biopsy-proven non-alcoholic fatty liver disease (NAFLD). Individuals with lower VAT BVR-A mRNA levels had significantly greater VAT IL-8 and Caspase 3 expression than those with higher BVR-A. Lower VAT BVR-A mRNA levels were associated with an increased adipocytes' size. An association between lower VAT BVR-A expression and higher plasma gamma-glutamyl transpeptidase was also observed. Reduced VAT BVR-A was associated with NAFLD with an odds ratio of 1.38 (95% confidence interval: 1.02-1.9; χ2 test) and with AUROC = 0.89 (p = 0.002, 95% CI = 0.76-1.0). In conclusion, reduced BVR-A expression in omental adipose tissue is associated with VAT dysfunction and NAFLD, suggesting a possible involvement of BVR-A in the regulation of VAT homeostasis in presence of obesity.

Correlating the morphological features of tetralogy of Fallot and the Eisenmenger malformation.

We studied a series of 43 autopsied cases of tetralogy of Fallot, assessing the mode of insertion of the outlet septum relative to the limbs of the septomarginal trabeculation, and compared the findings in retrospective fashion with our previous observations of a group of hearts with the so-called Eisenmenger malformation. In the majority of hearts with tetralogy of Fallot, the outlet septum inserted frontally relative to the septomarginal trabeculation, but in a minority of cases the outlet septum inserted in lateral fashion, as had been observed in all our hearts studied with the Eisenmenger malformation. The different modes of insertion were found to correlate, first, with the axis of anatomical aortic rightward rotation, coincident with the commissure between the right coronary and the left coronary leaflets of the aortic valve. The different modes of insertion of the outlet septum also correlated with the level of attachment of the arterial valvar leaflets on its subpulmonary and subaortic surfaces; concomitantly, correlation was found between the length of the subpulmonary infundibulum and the length of the muscular outlet septum itself. In the majority of hearts showing tetralogy of Fallot, the elongated infundibulum was also uniformly narrow, but in a minority the infundibulum was well expanded, obstructed only at its mouth, but widening at the valvar level. In all the hearts with the Eisenmenger malformation, in contrast, the unobstructed infundibulum was well expanded. The morphological findings of the present study show unequivocally that tetralogy of Fallot and Eisenmenger malformation are two phenotypically different congenital cardiac anomalies.

Different regulation of miR-29a-3p in glomeruli and tubules in an experimental model of angiotensin II-dependent hypertension: potential role in renal fibrosis.

The aim of this study was to evaluate the role of the angiotensin II (Ang II) induced-differential miRNA expression in renal glomerular and tubulo-interstitial fibrosis in an experimental model of Ang II-dependent hypertension. To clarify this issue, Sprague Dawley rats were treated with Ang II (200 ng/kg per minute, n = 15) or physiological saline (n = 14) for 4 weeks. Systolic blood pressure and albuminuria were measured every 2 weeks. At the end of the experimental period, renal glomerular and tubulo-interstitial fibrosis was evaluated by histomorphometric analysis, after Sirius-Red and Masson's trichrome staining. Ang II increased systolic blood pressure (P < 0.0001), albuminuria (P < 0.01) and both glomerular and tubulo-interstitial fibrosis (P < 0.01). Using laser capture microdissection and miRNA microarray analysis this study showed that miR-29a-3p was down-regulated in renal tubules and up-regulated in glomeruli. Real-time polymerase chain reaction (PCR) experiments confirmed in Ang II-treated rats a down-regulation of miR-29a-3p in tubules (P < 0.01), while no significant changes were observed in glomeruli. Matrix metalloproteinase-2 (MMP-2) was identified as putative miR-29a-3p target (by TargetScan, miRanda, Tarbase software) and functionally confirmed by luciferase activity assay. These data demonstrate that the effects of Ang II on miR-29a-3p expression in renal tubules is different from the one exerted in the glomeruli and that miR-29a-3p targets MMP-2. These results suggest that the development of renal fibrosis at glomerular and tubulo-interstitial level depends on different molecular mechanisms.

The Eisenmenger malformation: a morphologic study.

We studied 11 autopsied cases of the Eisenmenger malformation, comparing the findings with 11 hearts with intact ventricular septal structures, and nine hearts having perimembranous ventricular septal defects in the absence of aortic overriding. We found variable lengths for the subpulmonary infundibulum in the hearts with Eisenmenger defects. It was well developed in three hearts, of intermediate length in seven, and very short in one of the specimens. The muscular outlet septum was also of variable length compared with the free-standing subpulmonary infundibular sleeve. Except for one, all hearts had fibrous continuity between the aortic and tricuspid valvar leaflets, such that the ventricular septal defect was then perimembranous. In the remaining case, there was a completely subaortic muscular infundibulum, with the ventricular septal defect showing only muscular borders. The medial papillary muscle was absent in the majority of cases, but was well formed in three hearts, all with relatively short muscular outlet septums. We identified mild, intermediate, and severe degrees of rightward rotation of the aortic valve, and these findings correlated with the extent of aortic valvar overriding. In nine of the 11 hearts, the ventriculo-arterial connections were concordant, but there was double-outlet from the right ventricle in the other two specimens. Based on our anatomic and morphometric observations, we conclude that the hearts we have defined as having Eisenmenger defects show marked individual variation in their specific phenotypic anatomy.

Prevention of diabetic nephropathy by compound 21, selective agonist of angiotensin type 2 receptors, in Zucker diabetic fatty rats.

The aim of this study was to evaluate the effect of compound 21 (C21), a selective AT2 receptor agonist, on diabetic nephropathy and the potential additive effect of C21, when associated with losartan treatment, on the development of albuminuria and renal fibrosis in Zucker diabetic fatty (ZDF) rats. The experiments lasted 15 wk (from 5 to 20 wk of age) and were performed in 40 ZDF rats and 12 control lean rats. ZDF rats were divided into 4 groups: 1) 9 rats were treated with losartan; 2) 10 rats were treated with C21; 3) 9 rats were treated with losartan plus C21; and 4) 12 rats were maintained without any treatment. ZDF rats showed an increase in blood glucose level, albuminuria, renal fibrosis, macrophage infiltration, and TNF-α expression and a reduction of glomerular nephrin expression compared with control lean rats. C21 treatment reduced renal glomerular, tubulointerstitial, and perivascular fibrosis, and macrophage infiltration and TNF-α expression in ZDF rats. C21 treatment caused a decrease in albuminuria in ZDF rats up to 11 wk of age. Losartan decreased macrophage infiltration, TNF-α expression, and renal glomerular and perivascular fibrosis, restored glomerular nephrin expression, but did not affect tubulointerstitial fibrosis. Losartan treatment caused a decrease in albuminuria in ZDF rats up to 15 wk of age. At the end of the protocol, only the combination of C21 plus losartan significantly reduced albuminuria in ZDF rats. These data demonstrate that C21 has beneficial effects on diabetic nephropathy, suggesting the combination of C21 and losartan as a novel pharmacological tool to slow the progression of nephropathy in type II diabetes.

Sodium Glucose Cotransporter-2 Inhibitors in Non-Diabetic Kidney Disease: Evidence in Experimental Models.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of glucose-lowering agents widely used for the treatment of type 2 diabetes mellitus. A number of clinical trials in type 2 diabetic patients with different degrees of renal impairment have clearly demonstrated that SGLT2 inhibitors reduce the progression rate of diabetic kidney disease. Furthermore, recent studies have shown that SGLT2 inhibitors also exert a protective effect in the case of non-diabetic kidney disease. Consequently, it has been hypothesized that the nephroprotective activity of these drugs could exceed the canonical impact on glycemic control and that the resulting beneficial effects could be the consequence of their pleiotropic properties (proven reduction of inflammation, fibrosis, oxidative stress and sympathetic nervous activity) both at systemic and tissue levels, suggesting that the efficacy of these drugs could also be extended to non-diabetic nephropathies. This review focuses on the nephroprotective effects of SGLT2 inhibitors in different experimental models of non-diabetic kidney disease. The different glucose-independent mechanisms potentially implemented by SGLT2 inhibitors to ultimately protect the non-diabetic kidney are described in detail, and conflicting results, when present, are discussed.

Merkel Cell Polyomavirus in the Context of Oral Squamous Cell Carcinoma and Oral Potentially Malignant Disorders.

Despite recent advances in prevention, detection and treatment, oral squamous cell carcinoma (OSCC) remains a global health concern, strongly associated with environmental and lifestyle risk factors and infection with oncogenic viruses. Merkel Cell Polyomavirus (MCPyV), well known to be the causative agent of Merkel Cell Carcinoma (MCC) has been found in OSCC, suggesting its potential role as a co-factor in the development of oral cavity cancers. To improve our understanding about MCPyV in oral cavities, the detection and analysis of MCPyV DNA, transcripts and miRNA were performed on OSCCs and oral potentially malignant disorders (OPMDs). In addition, the cellular miR-375, known to be deregulated in tumors, was examined. MCPyV DNA was found in 3 out of 11 OSCC and 4 out of 12 OPMD samples, with a viral mean value of 1.49 × 102 copies/mL. Viral integration was not observed and LTAg and VP1 transcripts were detected. Viral miRNAs were not detected whereas the cellular miR-375 was found over expressed in all MCPyV positive oral specimens. Our results reported evidence of MCPyV replication in both OSCC and OPMD suggesting the oral cavity as a site of replicative MCPyV infection, therefore underscoring an active role of this virus in the occurrence of oral lesions.

Thoracic Aorta: Anatomy and Pathology.

The aorta is the largest elastic artery in the human body and is classically divided into two anatomical segments, the thoracic and the abdominal aorta, separated by the diaphragm. The thoracic aorta includes the aortic root, the ascending aorta, the arch, and the descending aorta. The aorta's elastic properties depend on its wall structure, composed of three distinct histologic layers: intima, media, and adventitia. The different aortic segments show different embryological and anatomical features, which account for their different physiological properties and impact the occurrence and natural history of congenital and acquired diseases that develop herein. Diseases of the thoracic aorta may present either as a chronic, often asymptomatic disorder or as acute life-threatening conditions, i.e., acute aortic syndromes, and are usually associated with states that increase wall stress and alter the structure of the aortic wall. This review aims to provide an update on the disease of the thoracic aorta, focusing on the morphological substrates and clinicopathological correlations. Information on anatomy and embryology will also be provided.

Ciliated Cells in Renal Calyx mucosa: Metaplastic Change or Developmental Abnormality? Immunohistochemical Study of one Case and Review of the Literature.

Ciliated epithelial cells have been rarely observed in urothelium lined mucosa. Only extremely rare reports in the literature have described this phenomenon and no cases have been described in other sites than the male urethra. Herein, we illustrate the finding of ciliated pseudostratified columnar cells in the renal calyx mucosa adjacent to an area of urothelial invasive carcinoma in an 82 year-old man with previous history of nephrolithiasis. The ciliated cells covered a linear extension of 0.5 cm: they were positive for keratin 7 and keratin 8/18 and negative for keratin 20. Alcian blue staining was positive in some vacuoles in the apical cytoplasm of the same cells whereas PAS (Periodic Acid-Schiff) staining was negative. GATA3 resulted negative in ciliated cells except for a layer in the basal portion of the epithelium, just above the basal membrane. The actual prevalence of ciliated epithelia in the urinary tract is not well documented and the current knowledge on the subject is limited to electron scanning microscopy studies. The significance of this phenomenon remains unknown: it could be either a developmental abnormality or more probably a metaplastic change. Associated urolithiasis, which has been described in both a previous report and in the present one, could hypothetically represent a possible trigger for this unusual cell change. However, this hypothesis needs to be confirmed through further investigation.

Effects of oral immunonutrition on histological changes of inflammatory infiltration of the tumor microenvironment among patients with a new diagnosis of gastric cancer.

OBJECTIVES: We assessed the effects of oral immunonutrition (OI) on the inflammatory infiltration of the tumor microenvironment (TME) of patients undergoing surgery for gastric cancer. METHODS: We analyzed patients at the time of their first gastric cancer diagnosis. We collected surgical tissue specimens (stomach), and performed an immunohistochemical analysis to evaluate the inflammatory infiltration of the TME. Patients receiving OI were compared with patients receiving standard oral nutritional supplements and no nutritional support. RESULTS: We enrolled 12 patients with gastric cancer in the study. The median body weight loss was 5.6%. Four patients received OI, five patients received standard nutritional supplement, and three patients received no nutritional supplementation. No difference in age, body mass index (BMI), and body weight loss was observed between the three groups. The OI group showed a tendency of increased number of T-lymphocyte cluster of differentiation (CD) 8+ compared with the other groups, as well as the number of CD83+ and CD68+. The absence of F4/80+ cells was documented only in the TME of the OI group, where a linear positive correlation was present between lymphocytes CD4+ and CD8+ (R = 0.48), and between CD4+ and CD83+ (R = 0.89), although not statistically significant. In the OI group, we observed a positive correlation (not significant) between the number of lymphocytes CD8+ and macrophages CD68+ (R = 0.70; P = 0.30). A strong significant correlation was documented between CD68+ and CD40+ (R = 0.99; P = 0.01), but this correlation did not reach the significance among the patients of the other two groups (R = 0.60; P = 0.116). CONCLUSIONS: The administration of OI in patients with gastric cancer might determine changes in inflammatory patterns of the TME.