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Duchenne muscular dystrophy (DMD) is the most frequent X chromosome-linked disease caused by mutations in the gene encoding for dystrophin, leading to progressive and unstoppable degeneration of skeletal muscle tissues. Despite recent advances in the understanding of the molecular processes involved in the pathogenesis of DMD, there is still no cure. In this study, we aim at investigating the potential involvement of the transsulfuration pathway (TSP), and its by-end product namely hydrogen sulfide (H2S), in primary human myoblasts isolated from DMD donors and skeletal muscles of dystrophic (mdx) mice. In myoblasts of DMD donors, we demonstrate that the expression of key genes regulating the H2S production and TSP activity, including cystathionine γ lyase (CSE), cystathionine beta-synthase (CBS), 3 mercaptopyruvate sulfurtransferase (3-MST), cysteine dioxygenase (CDO), cysteine sulfonic acid decarboxylase (CSAD), glutathione synthase (GS) and γ -glutamylcysteine synthetase (γ-GCS) is reduced. Starting from these findings, using Nuclear Magnetic Resonance (NMR) and quantitative Polymerase Chain Reaction (qPCR) we show that the levels of TSP-related metabolites such as methionine, glycine, glutathione, glutamate and taurine, as well as the expression levels of the aforementioned TSP related genes, are significantly reduced in skeletal muscles of mdx mice compared to healthy controls, at both an early (7 weeks) and overt (17 weeks) stage of the disease. Importantly, the treatment with sodium hydrosulfide (NaHS), a commonly used H2S donor, fully recovers the impaired locomotor activity in both 7 and 17 old mdx mice. This is an effect attributable to the reduced expression of pro-inflammatory markers and restoration of autophagy in skeletal muscle tissues. In conclusion, our study uncovers a defective TSP pathway activity in DMD and highlights the role of H2S-donors for novel and safe adjuvant therapy to treat symptoms of DMD.

Anti Yo antibodies (AYA) are the antibodies most frequently identified with Paraneoplastic Cerebellar Degeneration (PCD). They are detected above all in PCD associated with breast and gynecologic malignancies. Here, we report a third case of PCD with cerebellar contrast enhancement findings at MRI. In fact, AYA cross anti cerebellar cortex immune reaction leads mainly to hyperintensity signals in T2-weighted-MRI sequences, followed by cerebellar atrophy. As such, meningeal contrast enhancement could lead to a diagnostic pitfall as it can be considered a carcinomatosis - above all in serum antibody negative cases as well as when a metastatic tumour is found. Our patient had no tumoral cells in the cerebrospinal fluid and her neurological syndrome remained stable after immunoglobulin treatment. AYA serum finding was diriment for PCD diagnosis.

Nuclear factor erythroid 2–related factor2 (Nrf2) is a redox-sensitive transcription factor. Its activation by low dietary intake of ligands leads to antioxidant effects (eustress), while pro-oxidant effects (oxidative distress) may be associated with high doses. NADPH oxidases (NOXs) and the mitochondrial electron transport chain are the main sources of intracellular ROS, but their involvement in the biphasic/hormetic activity elicited by Nrf2 ligands is not fully understood. In this study, we investigated the involvement of NOX expression and mitochondrial function in the hormetic properties of omega-3 typically present in fish oil (FO) and conjugated linoleic acid (CLA) in the mouse liver. Four-week administration of FO, at both low and high doses (L-FO and H-FO) improves Nrf2-activated cyto-protection (by phase 2 enzymes), while a significant increase in respiration efficiency occurs in the liver mitochondria of H-FO BALB/c mice. Eustress conditions elicited by low dose CLA (L-CLA) are associated with increased activity of phase 2 enzymes, and with higher NOX1-2, mitochondrial defences, mitochondrial uncoupling protein 2 (UCP2), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression, compared with controls. Steatogenic effects (lipid accumulation and alteration of lipid metabolism) elicited by high CLA (H-CLA) elicited that are associated with oxidative distress, increased mitochondrial complex I/III activity and reduced levels of phase 2 enzymes, in comparison with L-CLA-treated mice. Our results confirm the steatogenic activity of H-CLA and first demonstrate the role of NOX1 and NOX2 in the eustress conditions elicited by L-CLA. Notably, the negative association of the Nrf2/PGC-1α axis with the different CLA doses provides new insight into the mechanisms underlying the hormetic effect triggered by this Nrf2 ligand.

Background In silico experiments, with the aid of computer simulation, speed up the process of in vitro or in vivo experiments. Cancer therapy design is often based on signalling pathway. MicroRNAs (miRNA) are small non-coding RNA molecules. In several kinds of diseases, including cancer, hepatitis and cardiovascular diseases, they are often deregulated, acting as oncogenes or tumor suppressors. miRNA therapeutics is based on two main kinds of molecules injection: miRNA mimics, which consists of injection of molecules that mimic the targeted miRNA, and antagomiR, which consists of injection of molecules inhibiting the targeted miRNA. Nowadays, the research is focused on miRNA therapeutics. This paper addresses cancer related signalling pathways to investigate miRNA therapeutics. Results In order to prove our approach, we present two different case studies: non-small cell lung cancer and melanoma. KEGG signalling pathways are modelled by a digital circuit. A logic value of 1 is linked to the expression of the corresponding gene. A logic value of 0 is linked to the absence (not expressed) gene. All possible relationships provided by a signalling pathway are modelled by logic gates. Mutations, derived according to the literature, are introduced and modelled as well. The modelling approach and analysis are widely discussed within the paper. MiRNA therapeutics is investigated by the digital circuit analysis. The most effective miRNA and combination of miRNAs, in terms of reduction of pathogenic conditions, are obtained. A discussion of obtained results in comparison with literature data is provided. Results are confirmed by existing data. Conclusions The proposed study is based on drug discovery and miRNA therapeutics and uses a digital circuit simulation of a cancer pathway. Using this simulation, the most effective combination of drugs and miRNAs for mutated cancer therapy design are obtained and these results were validated by the literature. The proposed modelling and analysis approach can be applied to each human disease, starting from the corresponding signalling pathway.

Oxidative stress is a key mediator of autoimmune/neurodegenerative disorders. The antioxidant/anti-inflammatory effect of a synthetic conjugated linoleic acid (CLA) mixture in MRL/MpJ-Fas lpr mice (MRL/lpr), an animal model of neuropsychiatric lupus, was previously associated with the improvement of nuclear factor-E2-related factor 2 (Nrf2) defenses in the spleen and liver. However, little is known about the neuroprotective ability of a CLA mixture. This study investigated the age-dependent progression of oxidative stress and the hyperactivation of redox-sensitive compensatory pathways (macroautophagy, Nrf2) in old/diseased MRL/lpr mice brains and examines the effect produced by dietary CLA supplementation. Disrupted redox homeostasis was evidenced in the blood, liver, and brain of 21- to 22-week-old MRL/lpr (Old) mice compared with 8- to 10-week-old MRL/lpr (Young) animals. This alteration was associated with significant hyperactivation of compensatory mechanisms (macroautophagy, Nrf2, and astrocyte activation) in the brains of Old mice. Five-week daily supplementation with CLA (650 mg/kg-1 body weight) of 16-week-old (CLA+Old) mice diminished all the pathological hallmarks at a level comparable to Young mice or healthy controls (BALB/c). Such data demonstrated that MRL/lpr mice can serve as a valuable model for the evaluation of the effectiveness of neuroprotective drugs. Notably, the preventive effect provided by CLA supplementation against age-associated neuronal damage and hyperactivation of compensatory mechanisms suggests that the activation of an adaptive response is at least in part accountable for its neuroprotective ability.

Dietary supplementation with pure cis9, trans11 isomer of Conjugated Linoleic Acid –known as Rumenic Acid (RA)– improves cytoprotective defenses downstream through the activation of nuclear factor-E2-related factor-2(Nrf2). This capability, when Rumenic Acid is consumed in the form of foods, is still unknown. The ability of standard (St) or cow milk naturally-enriched in RA (En) to activate Nrf2 pathway and its impact on dextran sodium sulfate (DSS)-induced colitis was comparatively evaluated. Activity of Nrf2 pathway was investigated in colonic tissue of BALB/c mice, receiving 4-week supplement with skimmed milk (SK), St or St reinforced with pure RA (RSt) providing increasing RA dose (0, 124 or 404 mg RA/kg-1 b.w, respectively). Next, the anti-oxidant/ anti-inflammatory effect produced by St or En treatment (383 mg RA/kg-1 b.w.) was explored. Finally, macroscopic and histomorphologic features of colitis were evaluated in animals challenged with 5% (w/v) DSS, at the end of St or En treatment. Significant activation of Nrf2 pathway is associated with RSt and En intake (P

Laryngeal neuroendocrine carcinomas (LNECs) are rare and highly heterogeneous malignancies presenting a wide range of pathological and clinical manifestations. Herein, we retrospectively characterize ten patients diagnosticated with LNEC, five of which were defined as well-moderately differentiated neuroendocrine carcinomas, and five that were defined as poorly differentiated neuroendocrine carcinomas, according to the latest WHO classification. Clinical features were analyzed and compared between the two subgroups together with a microRNA study which evidenced a peculiar signature likely related to poorly differentiated larynx neuroendocrine carcinomas. These findings may offer new useful insights for clinicians to improve diagnosis efficiency, therapy response, and patients’ outcome for this aggressive neoplasm.

Spindle cell larynx carcinoma (SpCC) represents around 3% of laryngeal cancers. It is originated by a single cancer stem cell undergoing epithelial to mesenchymal transition. This explains the aggressiveness, the peculiar resistance to conventional therapy and the frequent relapses. We focused on this particular cancer subset characteristics in patients, in early and advanced stages primarily aiming to define and highlight the differences with Laryngeal Squamous Cell Carcinoma (LSCC) focusing on clinical features, treatments, follow-up and survival in a patient's cohort composed by comparable cases from two subgroups.

Inflammation and oxidative stress play an important role in the pathogenesis of depressive disorders and Nuclear erythroid related factor 2 (Nrf2), a regulator of RedOx homeostasis and inflammation, is a promising target for depression prevention/treatment. As fish oil (FO) and Conjugated Linoleic Acid (CLA) are known Nrf2 inducer, their protective ability was comparatively evaluated in a murine model of depression (MRL/MpJ-Faslpr ). Oxidative stress, fatty acids content and critical factors reflecting brain functioning - namely brain-derived neurotrophic factor (BDNF), synaptic markers and cholinergic signaling - were preliminarily evaluated in frontal cortex of 8-weeks (Young) and in 22-weeks old animals (Old), which were used as model of depression. These markers were measured in Old mice at the end of a 5-week pre-treatment with FO or CLA (728 or 650 mg kg-1, respectively). Old mice exhibited disrupted Redox homeostasis, compensatory Nrf2 hyperactivation, lower Docosaheaxaenoic acid (DHA), lower BDNF and synaptic function proteins compared to Young mice. FO and CLA treatment relieved almost all the pathophysiological hallmarks at a level comparable to Young mice. Presented data provide the first evidence for the comparable efficacy of FO or CLA supplementation in preventing depression signs in Old MRL/lpr mice, likely through their ability of improving Nrf2-mediated antioxidant defenses.

A pectin coated dehydrated apple snack containing ≥9 log colony forming units/20 g portion of the probiotic Lactobacillus paracasei IMPC2.1, was developed. The strain was incorporated into the apple slices using vacuum impregnation (IP1) or soaking/stirring (IP2); apple slices were then coated with citrus pectin and dehydrated at 4 °C for 14 days. Microbial application led to colonization of the apple surface, as seen using scanning electron microscope images, and all probiotic products showed comparable radical scavenging activity and total phenol content. IP2 led to better bacterial survival during 30 days storage at 4 °C and color parameters comparable to the fresh apple. The simulated gastro-intestinal (GI) digestion suggested the ability of the strain to survive the digestive process. This inclusion/coating/dehydration process led to a probiotic snack, which could successfully deliver bacterial cells in a viable form to the GI tract.

Summary Aims The purpose of this study was to evaluate the effects of three different water temperatures on physiological responses (dehydration, sweat rate, urine output, rectal temperature and plasma electrolytes) of competitive athletes during a “simulated” race of 5 km in an indoor swimming pool. Methods Nine male competitive master swimmers swam 5 km with the water at temperatures of 23, 27 and 32 C. Immediately before (Pre) and after (Post) each trial, samples of blood and urine were collected, body weight was recorded and rectal temperature was measured. The dehydration percentage and sweat rate were the highest at 32 C and the lowest at 23 C (23 C: −0.9 ± 0.5; 27 C: −1.3 ± 0.6; 32 C: −2.2 ± 0.7% and 23 C: 0.48 ± 0.28; 27 C: 0.76 ± 0.36; 32 C: 1.25 ± 0.37 l/h). The Post urine volume output was not significantly different in the three trials (23 C: 122.6 ± 62.4; 27 C: 78.2 ± 24.9; 32 C 81.4 ± 37.0 mL). The 27 and 32 C water increased the rectal temperature (Pre: 37.0 ± 0.3; Post: 37.9 ± 0.5 C–Pre: 36.9 ± 0.4; Post: 38.0 ± 0.4 C, respectively). Results This study shows that dehydration, sweat rate and body temperatures simultaneously increase with the rise of water temperature during the shortest open water swimming event distance (5 km) performed at race intensity.

Inflammatory cells play key roles in restenosis upon vascular surgical procedures such as bypass grafts, angioplasty and stent deployment but the molecular mechanisms by which these cells affect restenosis remain unclear. The p110δ isoform of phosphoinositide 3-kinase (PI3K) is mainly expressed in white blood cells. Here, we have investigated whether p110δ PI3K is involved in the pathogenesis of restenosis in a mouse model of carotid injury, which mimics the damage following arterial grafts. We used mice in which p110δ kinase activity has been disabled by a knockin (KI) point mutation in its ATP-binding site (p110δD910A/D910A PI3K mice). Wild-type (WT) and p110δD910A/D910A mice were subjected to longitudinal carotid injury. At 14 and 30 days after carotid injury, mice with inactive p110δ showed strongly decreased infiltration of inflammatory cells (including T lymphocytes and macrophages) and vascular smooth muscle cells (VSMCs), compared with WT mice. Likewise, PI-3065, a p110δ-selective PI3K inhibitor, almost completely prevented restenosis after artery injury. Our data showed that p110δ PI3K plays a main role in promoting neointimal thickening and inflammatory processes during vascular stenosis, with its inhibition providing significant reduction in restenosis following carotid injury. p110δ-selective inhibitors, recently approved for the treatment of human B-cell malignancies, therefore, present a new therapeutic opportunity to prevent the restenosis upon artery injury.

Introduction The need for performing axillary lymph-node dissection in early breast cancer when the sentinel lymph node (SLN) is positive has been questioned in recent years. The purpose of this study was to identify a low-risk subgroup of early breast cancer patients in whom surgical axillary staging could be avoided, and to assess the probability of having a positive lymph-node (LN). Methods We evaluated the cohort of 612 consecutive women affected by early breast cancer. We considered age, tumor size, histological grade, vascular invasion, lymphatic invasion and cancer subtype (Luminal A, Luminal B HER-2+, Luminal B HER-2−, HER-2+, and Triple Negative) as variables for univariate and multivariate analyses to assess probability of there being a positive SLN o nonsentinel lymph node (NSLN). Chi-square, Fisher's Exact test and Student's t tests were used to investigate the relationship between variables; whereas logit models were used to estimate and quantify the strength of the relationship among some covariates and SLN or the number of metastases. Results A significant positive effect of vascular invasion and lymphatic invasion (odds ratios are 4 and 6), and a negative effect of TN (odds ratios is 10) were noted. With respect to positive NSLN, size alone has a significant (positive) effect on tumor presence, but focusing on the number of metastases, also age has a (negative) significant effect. Conclusion This work shows correlation between subtypes and the probability of having positive SLN. Patients not expressing vascular invasion, lymphatic invasion and, moreover, a triple-negative tumor subtype may be good candidates for breast conservative surgery without axillary surgical staging.

We describe three cases of lymph proliferative diseases characterized by the presence of lymphoma cells expressing the KSHV/HHV-8 antigen with or without EBV expression. The patients were HIV seronegative without serous effusions. One case was diagnosed as KSHV-germinotropic lymphoproliferative disorder due to the presence of atypical plasmablasts involving germinal centers. These plasmablasts were positive for MUM1 and vIL6, co-expressed EBV and LNA-1 of HHV-8/KSHV, and showed a polyclonal pattern of Ig gene rearrangements on PCR. The disease was localized and the prognosis was good. In two other cases, a diagnosis of KSHV/HHV-8-related diffuse large cell B-lymphoma morphology was made. The lymphoma cells were anaplastic or frankly pleomorphic, expressed KSHV but not EBV, and were positive for CD20, MUM1, PAX-5, and vIL6. In both cases the prognosis was poor. On the basis of the features observed, we raise three considerations: (1) KSHV-related lymphoproliferative disorders represent a distinctive and heterogeneous group of diseases with variable clinico-pathologic findings and immunophenotypes (BCL6-/MUM1+/CD138- and BCL6+/MUM1+/CD138- or BCL6-/MUM1+/CD138+). (2) Although the pathogenic mechanism of HHV8 in lymphomagenesis is unclear, the presence the viral DNA in lymph nodes of HIV- patients is not a simply opportunistic infection, but is directly implicated in the pathogenesis of KSHV-related diseases; the activation of IL-6 receptor signalling may play an important role in most cases. (3) The different prognoses among different diseases with KSHV etiology may be related to the fact that the pathogenic potential appears to be constrained by a competent immune system.

Background: We describe 2 cases of vulvar pseudotumour due to lymphatic obstruction with chronic lymphoedema of unknown cause that presented as a solitary mass that mimicked aggressive angiomyxoma. Material and Methods: Both patients presented with a vulvar mass without medical history of trauma, surgery in the anogenital region or skin diseases. One patient was overweight (BMI = 26). Both surgically resected vulvar specimens were represented by a polypoid mass with a soft and a gelatinous cut surface. Results: Histologically, the presence of an abundant oedematous stroma with spindle-shaped cells and numerous thin-walled small-to-medium vessels may be confused with an aggressive angiomyxoma. The diagnostic key was represented by the massive oedema, rather than myxoid stroma, with the presence of dilated, tortuous lymphatic channels (some surrounded by clusters of lymphocytes) in the dermis. Conclusion: The recognition of these lesions is important because they may be the cause of problems in differential diagnosis and therapeutic management. In fact, such lesions can be mistaken from both the clinical and histological perspective as a primitive tumour of the vulva-like aggressive angiomyxoma. However, these lesions are not true neoplasms and are likely due to lymphatic obstruction with lymphoedema. A simple surgical excision with vulvoplasty is curative.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders which have a severe life-long effect on behavior and social functioning, and which are associated with metabolic abnormalities. Their diagnosis is on the basis of behavioral and developmental signs usually detected before three years of age, and there is no reliable biological marker. The objective of this study was to establish the volatile urinary metabolomic profiles of 24 autistic children and 21 healthy children (control group) to investigate volatile organic compounds (VOCs) as potential biomarkers for ASDs. Solid-phase microextraction (SPME) using DVB/CAR/PDMS sorbent coupled with gas chromatography-mass spectrometry was used to obtain the metabolomic information patterns. Urine samples were analyzed under both acid and alkaline pH, to profile a range of urinary components with different physicochemical properties. Multivariate statistics techniques were applied to bioanalytical data to visualize clusters of cases and to detect the VOCs able to differentiate autistic patients from healthy children. In particular, orthogonal projections to latent structures discriminant analysis (OPLS-DA) achieved very good separation between autistic and control groups under both acidic and alkaline pH, identifying discriminating metabolites. Among these, 3-methyl- cyclopentanone, 3-methyl-butanal, 2-methyl-butanal, and hexane under acid conditions, and 2-methyl-pyrazine, 2,3-dimethyl-pyrazine, and isoxazolo under alkaline pH had statistically higher levels in urine samples from autistic children than from the control group. Further investigation with a higher number of patients should be performed to outline the metabolic origins of these variables, define a possible association with ASDs, and verify the usefulness of these variables for early-stage diagnosis. [Figure not available: see fulltext.] © 2014 Springer-Verlag Berlin Heidelberg.

Objectives: Meningiomas are slow-growing intracranial/intraspinal tumors, with a wide range of histopathologic variants. The more aggressive atypical and malignant types can disseminate via the venous system, lymphatic, system, or cerebrospinal fluid, with the lung and pleura being the most common sites of extracranial metastases. A case of metastatic meningioma with high expression of CD90 was spotted during a review of flow cytometry data for lung malignancies. Therefore, we have analyzed CD90 expression in a series of meningioma metastases with their corresponding primary tumors and in a series of 92 primary meningioma tumors. Methods: In addition to flow cytometry and immunohistochemical analysis of the case, a series of meningiomas and relative metastases has been evaluated for CD90 immunohistochemical expression. Furthermore, an immunohistochemical analysis has been conducted in a tissue microarray, including typical and atypical meningiomas. Results: CD90 had high expression in three of four cases of metastases and in their corresponding primary atypical meningioma. In addition, CD90 was significantly expressed in atypical rather than in typical meningiomas ( P = .003). However, the correlation of CD90 with patient survival reveals only a trend of statistical association with extracranial metastases. Conclusions: CD90 is a biomarker overexpressed in atypical meningioma, with a potential role in metastatic switch of this tumor.

We describe a case of an unusual lymphoproliferative disease in a 60-year-old man. He presented at Hospital “Cardarelli” in March 2004 with fever, fatigue and weight loss. Physical examination and ...

Background: The association between lymphomas and Kaposi’s sarcoma has been described since 1920. The simultaneous presence of the 2 pathologic entities within the same lymph node is a rare and interesting occurrence. In the few cases described, the presence of human herpesvirus 8 (HHV8) and Epstein-Barr virus (EBV) in the different neoplastic areas was investigated only by immunohistochemistry and in situ hybridization studies. Methods: Two cases of concurrent non-Hodgkin lymphoma and Kaposi’s sarcoma in the same lymph node are described: a diffuse large B cell lymphoma in an AIDS patient and a T cell-rich large B cell lymphoma in a HIV-negative patient, complete with the clinical, immunohistological and molecular features, the latter ones defined after isolation of the different neoplastic areas by laser capture microdissection. Results: Polymerase chain reaction assays revealed HHV8 DNA sequences only in the microdissected Kaposi’s sarcoma areas and EBV DNA sequences only in the lymphomatous areas in both cases, confirming the HHV8 infection only in the neoplastic sarcomatous cells and evidencing the EBV infection only in the lymphomatous cells. Conclusion: This study represents a further confirmation of the supposed different etiopathogenic mechanisms of the 2 neoplasias, suggesting a coincidental occurrence even when localized in the same lymph node, independently from HIV infection.

Oncocytic mucoepidermoid carcinoma of the salivary gland is rare. We report a 48-year-old man who presented with a slowly growing right parotid mass. A preoperative fine needle aspiration showed exclusively oncocytic cells and cellular debris. A first diagnosis of Warthin tumor or myoepithelioma was made. The patient underwent a superficial parotidectomy, and her postoperative course was uneventful. Histologically, the tumor was composed of solid nests and cystic gland containing clear mucoid material, lined predominantly with oncocytes and few mucous goblet cells. A final diagnosis of oncocytic variant of mucoepidermoid low-grade carcinoma was made. The recognition of this variant is important, because may be easy confused with most frequent benign tumor with oncocytic cells; in this case a complete surgical excision and long-term clinical follow-up are an adequate management.

Basal cell carcinoma (BCC) is currently the most common cutaneous cancer found in humans. Although it generally shows a relatively benign course (BCC1), some cases of BCCs show "aggressive" behavior, rapidly infiltrating deeper structures, or metastasizing (BCC2). Until now, the traditional histological diagnostic criteria have failed to discriminate unequivocally between BCC1 and BCC2. Therefore, there is still a need to find reliable prognostic indicators that correlate with outcome and may detect patients at high risk for BCC recurrence, or metastasis and death. Recent studies have suggested that there is a significant correlation between tumor angiogenesis, expressed as the microvessel density within and toward a tumor, tumor aggressiveness, and the overall survival of patients with solid tumors. In this study, the authors examined the angiogenic rate in human cutaneous BCCs, to establish if it correlates with their biological behavior. Vessels were highlighted by immunocytochemical staining for FVIII-related antigen in formalin-fixed, paraffin-embedded tissues. All BCC2 samples of this series showed a significantly higher microvessel count than did BCC1. The existence of a significant discrepancy between the neovascularization in BCC1 and BCC2 suggests that the angiogenetic process may be an important step in the acquisition of the aggressive (malignant) phenotype in human. BCCs. The findings of the present study seem to establish a correlation between tumor vascularization and clinicobiological parameters of aggressiveness in BCC. Considering the emerging studies on the possible clinical use of substances interfering with the angiogenetic process, it is possible that the local therapy for BCCs could become less destructive, with consequent improvement in the quality of life of these patients, apart from the prolongation of the overall survival. From this view-point, the assay of microvessel density might be helpful in selecting patients with cutaneous BCCs at high risk for recurrence or metastasis, who could benefit ab initio from additional therapies and closer follow-up.

The role played by the tunica albuginea in the erection mechanism seems to be very significant in promoting the constriction of sub-albugineal venous reticulum and trans-albugineal effluent veins, as well as providing an inextensible protective structure to the arteriolae and to the intracavernous nerves. The passive function exerted by the tunica albuginea is a result of its structure, which is rich in collagenic fibers, linked by elastic fiber bridges. The presence of structural disorders in the tunica albuginea of 16 patients suffering from psychogenic, arteriogenic and venogenic impotence is evaluated. The results obtained show a significant decrease in elastic fibers in the tunica albuginea of impotent patients compared to a control group of 5 patients with normal erection activity. This structural disorder could result in tunica albuginea alteration and, therefore, in erection insufficiency.

Optical transitions associated with γ-radiation-induced defects in crystalline α-quartz were investigated by photoluminescence excited by both pulsed synchrotron radiation and steady-state light. After a 10 MGy γ-dose we observed two emissions at 4.9 eV (ultraviolet band) and 2.7 eV (blue band) excitable in the range of the induced absorption band at 7.6 eV. These two luminescence bands show a different temperature dependence: the ultraviolet band becomes bright below 80 K; the blue band increases below 180 K, but drops down below 80 K. Both emissions decay in a timescale of a few ns under pulsed excitation, however the blue band could also be observed in slow recombination processes and it afterglows in about 100 s at the end of steady-state excitation. The origin of the observed luminescence bands and the comparison with optical features of oxygen-deficient centres in silica glass are discussed in the framework of different models proposed in the literature.

Endodermal cysts of the central neuraxis are benign, non-neoplastic epithelium-lined cysts arising from endodermal tissue that have been displaced early in fetal life. Intracranial endodermal cysts are rare and usually located in the posterior fossa. The present study involves a 36-year-old man with a typical epithelial cyst in the posterior fossa. Microscopically, the cyst has a simple columnar epithelium with mucus-producing cells, containing an area composed of dysplastic epithelium with evidence of an intraepithelial carcinoma. The atypical cells have a high proliferative fraction demonstrated by Ki-67 immunostain. Based on these findings, the authors view this case as evidence of a malignant transformation of a classic endodermal cyst. The clinicopathologic features and a review of the literature are discussed.

We have measured the temperature dependence, in the range 10–295 K, of the lifetimes of the ultraviolet emissions associated with twofold coordinated Si and Ge, in pure and Ge-doped silica under excitation by synchrotron radiation. The Si-related fluorescence, centered at 4.4 eV, has a single exponential decay and its lifetime decreases from 4.0 ± 0.2 to 3.5 ± 0.2 ns on increasing the temperature. The luminescence at 4.2 eV, associated with the Ge defect, decays with a single exponential dependence below 150 K and with a more complex dependence at higher temperatures, its lifetime reducing from 7.8 ± 0.2 to 3.4 ± 0.2 ns. These features give evidence of the effectiveness of the thermally activated intersystem crossing in the relaxation of the excited singlet states, which is larger in the Ge-related center.

Photochemical inhomogeneity in the reduction process of the optical activity related to Ge oxygen deficient point defects in silica, characterized by an absorption band centered at 5.15 v eV and two emission bands centered at 3.2 v eV and 4.3 v eV, have been investigated. We have made a comparative study of the stationary and time dependent photoluminescence under excitation in the UV (5 v eV) and in the vacuum-UV (7.4 v eV) ranges in natural silica samples with native and with n -irradiation bleached optical activity. Our measurements evidence that the same spectral features are observed in the native and in the irradiated samples, but for an intensity reduction in the irradiated ones. Moreover, the time decay of the photoluminescence at 4.3 v eV is the same independently from the irradiation of the sample. On the basis of these results it is suggested that the inhomogeneous distribution of defects is not changed by the irradiation.

Carcinogenicity of dioxins seems to be largely mediated by their binding to the aryl hydrocarbon receptor (AhR), a cytosolic transcriptional regulator of cell growth, differentiation, and migration. The most widely studied agonist of AhR, in the last thirty years, is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which also presents the highest binding affinity for this receptor. The activated ligand-AhR complex has been described to contribute in suppressing both humoral and cellular immune responses. Starting from the description of the main mechanisms underlying the physiological activation of AhR, the present review is aimed at evaluating a putative functional role of the intragenic AhR polymorphisms, which could greatly affect the functionality of the receptor by either inducing or contrasting its ligand-dependent activation. As consequence, this may participate in lowering or increasing the risk of cancer, particularly, in the most polluted areas.

We studied the optical absorption induced by 4.7eV pulsed laser radiation on Ge-doped a-SiO2 synthesized by a sol-gel technique. The absorption spectra in the ultraviolet spectral range were measured during and after the end of irradiation with an in situ technique, evidencing the growth of an absorption signal whose profile is characterized by two main peaks near 4.5eV and 5.7eV and whose shape depends on time. Electron spin resonance measurements performed ex situ a few hours after the end of exposure permit to complete the information acquired by optical absorption by detection of the paramagnetic Ge(1) and Ge-E' centers laser-induced in the samples., Comment: 4 pages, 3 figures

We report a case of hepatic angiomyolipoma associated to a small bowel schwannoma in a 40-years old woman. Both lesions were asyntomatic. Histologically, hepatic angiomyolipoma showed oncocytic features and scanty adipose tissue, the tumor cells expressed desmin, smooth muscle actin, S-100 protein and HMB45. The tumor cells of intramural small intestinal mass were positive for S-100 protein and GFAP and negative for CD117, CD34 and desmin. To the best of our knowledge, no case of hepatic angiomyolipoma has been previously reported in association with intestinal schwannoma.

Peripheral ameloblastoma is a very rare tumour with histological characteristics similar to those of the centrally located ameloblastoma. It appears in the gum and in the alveolar process of the jaws. We report a case of tumour of the left maxillary region, near the canine area. Histologically it presented itself with follicles and nests of cells with a trabecular architectural pattern. High mitotic index and clear images of perineural infiltration were present. The diagnosis was peripheral ameloblastoma with malignant aspects. At 12-month follow-up no local recurrence was noted.

We investigated nanoparticles produced by laser ablation of silicon in water by the fundamental harmonic (1064 nm) of a ns pulsed Nd:YAG. The silicon oxidation is evidenced by IR absorption features characteristic of amorphous SiO2 (silica). This oxide is highly defective and manifests a luminescence activity under UV excitation: two emission bands at 2.7 eV and 4.4 eV are associated with the twofold coordinated silicon, =SiO••.

Among the primary mesenchymal tumors of the hypopharynx and larynx, lipomas are rare. Macroscopically, they often resemble a retention cyst or laryngeal nodule. Spindle cell lipomas (SCLs) are an uncommon variant of lipoma. SCLs are extremely rare in the larynx; as far as we know, only 4 cases have been previously described in the literature. We present a new case of laryngeal SCL in a 65-year-old man who presented with a 1-year history of hoarseness, choking spells, stridor, and dyspnea. Examination revealed the presence of a large polyp on the left true vocal fold that had caused stenosis of the posterior glottis. The polyp was removed endoscopically, and the patient's stridor and dyspnea resolved. Histologically, the tumor was composed of bland, CD34-positive spindle cells with an abundant fibrous and myxoid stroma interspersed with mature fatty tissue. The patient was free of local recurrence at 2 years of follow-up.

The students’ academic failure and the delay in obtaining their final degree are a significant issue for the Italian universities and their stakeholders. Based on indicators proposed by the Italian Ministry of University, the Italian universities are awarded a financial incentive if they reduce the students’ attrition and failure. In this paper we analyze the students’ careers performance using: (1) aggregate data; (2) individual data. The first compares the performances of the Italian universities using the measures and the indicators proposed by the Ministry. The second analyzes the students’ careers through an indicator based on credit earned by each student in seven academic years. The primary goal of this paper is to highlight elements that can be used by the policy makers to improve the careers of the university students.

Hepatoid carcinoma (HC) of ovary is a rare type of epithelial tumor composed mainly of epithelioid cells with abundant acidophilic cytoplasm, histologically indistinguishable from hepatocellular carcinoma. We report a previously unrecognized case of HC of ovary concurrent with a Sertoli cell tumor.A 42-year-old woman patient with a long-term history of hepatitis C presented with a mass of left ovary without evidence of hepatic tumor. After initial diagnosis of primary ovarian carcinoma (FIGO Stage I), she had experienced a first recurrence in upper abdomen. Histologically, the primary tumor was composed of epithelioid cells with "hepatoid features" in association with a sex cord stromal tumor of Sertoli-type. Immunohistochemistry hepatoid cells stained positively for hepatocyte paraffin-1, alpha-fetoprotein and alpha-1 antitrypsin; moreover, Sertoli-type cells were positive for alpha-inhibin, calretinin and CD99. A final diagnosis of HC concurrent with Sertoli-type tumor was made.The occurrence of this unreported association of HC with Sertoli-like tumor, the problems of differential diagnosis and therapeutic management of these tumors are the subject of this presentation. A diagnosis of ovarian metastasis from hepatocellular carcinoma is easy in patients with known primary tumor of liver and should be always excluded in these cases as an hepatoid variant of yolk sac tumor. Immunohistochemistry is not useful in these cases. However, a combination of clinical and pathological features is necessary for a correct diagnosis.

Epithelioid angiomyolipoma (AML) is an uncommon renal mesenchymal tumor with malignant potential and is frequently associated with tuberous sclerosis. Extrarenal AMLs are rare, and to the best of our knowledge, this is the first reported case of a primary monotypic epithelioid AML of adrenal gland in a patient without evidence of tuberous sclerosis. The patient is a 42-year old man who presented with retroperitoneal hemorrhage resulting from spontaneous rupture of adrenal mass. Histologically, the tumor showed a prominent component of epithelioid smooth muscle cells with slightly pleomorphic nuclei, sometimes with prominent nucleoli and eosinophilic cytoplasm resembling oncocytic tumors. Epithelioid cells were positive for melanoma (HMB45 and positive MelanA) and smooth muscle markers (alpha-smooth muscle-specific actin), but not for epithelial markers (cytokeratin, EMA). Differential diagnosis from renal cell carcinoma, adrenal gland carcinoma, and metastatic carcinoma is often challenging because of its epithelioid morphology. Because primary and secondary malignant tumors are much more common and aggressive neoplasms, establishing the correct diagnosis has important therapeutic and prognostic implications.

Mucinous carcinoma of the thyroid gland is an uncommon tumour that from the histological point of view, resembles mucinous carcinoma of others sites. Although a mucinous appearance has sometimes been reported in association with cases of typical thyroid carcinoma, true mucinous carcinoma is exceptionally rare. We describe two cases of thyroid tumours with mucinous differentiation studied with immunohistochemistry. Both cases disclosed a similar histological appearance, with small nests and sheets of malignant epithelial cells associated with extensive extracellular mucin that substituted and entrapped the follicular parenchyma of the thyroid. Thyroglobulin and focally thyroid transcription factor (TTF) 1 were positive in one case. From these findings, we classified this tumour as primary mucinous thyroid carcinoma. Thyroglobulin and TTF-1 were negative in tumour cells of second case; on the contrary, positivity to the carcinoembryonic antigen and CA-125 was strong and generalized. However, successfully, the patient presented ascites associated to right ovarian mass. In this case, thyroid tumour represents the first clinical sign of an ovarian mucinous adenocarcinoma, and it has not been previously described in literature. Both patients died after few months to diagnosis. In conclusion, primary and secondary mucinous carcinoma are rare and unusual tumours of the thyroid gland that can be a cause of pitfall in differential diagnosis. In these cases, for a correct diagnosis, a complete clinical history, restricted histological criteria and immunohistochemical panel are necessary.

Nucleolar Organiser Regions (NORs) and Proliferating Cell Nuclear Antigen (PCNA) were investigated on routine paraffin embedded histologic sections of 30 oral biopsy specimens (six cases of leukoplakia with low-degree of dysplasia, nine cases of leukoplakia with moderate-degree of dysplasia, nine cases of leukoplakia with severe-degree of dysplasia, six cases of squamous microinvasive carcinomas), tested for HPV-DNA by in situ hybridisation (ISH). The absolute number of NORs per nucleus and the percentage of nuclear positivity for PCNA were found to be different in each group of pathology, with further diversity due to the presence or absence of HPV-DNA. In the major part of HPV-positive lesions, the AgNOR number and percentage of cells positive for PCNA were found to be generally lower than in corresponding negative forms. Conversely, a few cases of HPV+ lesions showed significantly higher values both of AgNOR and PCNA, if compared to the other cases of HPV+ and HPV- lesions. These data suggested that high values of AgNOR and PCNA, in moderate and high grade oral dysplasia, could represent an "alarm signal" of a worse prognosis, and then a possible indication for a strict clinical management and/or a stronger treatment of some HPV-associated preneoplastic lesions.

Gastrointestinal stromal tumors (GIST) are the most common primary mesenchymal tumors of the gastrointestinal tract (GIT). They represent a wide clinico-pathological spectrum of tumors. No single histological or clinical parameter can predict the prognosis while the response to therapy is related to the type of KIT or PDGFRA mutation. Cytogenetic and CGH studies have identified frequent gross chromosomal aberrations but the target genes of these changes are unknown. To determine whether known oncogenes take part in genomic rearrangements and to investigate the potential clinical significance of their amplifications, nine known oncogenes (CMYC, MDM2, GLI1, CDK4, HER2, EGFR1, CCND1, FGF3, EMS) were analyzed by fluorescent in situ hybridization (FISH) on a tissue microarray (TMA) containing 94 primary GIST. Clinical follow-up information was available for 57 of these patients. Amplification was found for CMYC in three of 90 (3.3%), for MDM2 in five of 94 (5.3%), for EGFR1 in five of 94 (5.3%), and for CCND1 in seven of 79 (8.9%) evaluable cases. No amplifications were seen for HER2, GLI1, CDK4, FGF3, and EMS. Amplifications of MDM2 and CCND1 were associated with clinical and histological malignancy. In conclusion, our data show that gene amplification does occur in a subset of GIST. Identification of MDM2/CCND1 amplification may represent another molecular feature that could help in the evaluation of the behavior of GISTs.

Two cases of smooth muscle tumor of the breast with high tendency to local relapses are reported. The common cytohistologic feature of these infrequent neoplasms is interfacing bundles with spindle-shaped cells showing eosinophilic cytoplasm and blunt-ended nuclei. In estimating the prognosis of these lesions, the mitotic index must be evaluated together with evidence of necrosis and hypercellularity. The present cases suggest that, in the absence of the ancillary features, a mitotic rate of 1-3 × 10 HPF might define a “grey zone” in the spectrum of lesions between leiomyomas and leiomyosarcomas: the smooth muscle tumors of indeterminate prognosis (low risk lesions).

The authors describe a case of histologically proven orbital metastasis from a hepatic carcinoma in an 85-year-old patient with rapid onset of proptosis and visual loss. The clinical diagnosis of orbital metastatic lesion was established by standardized echography and CT scan. To the best of our knowledge, this is only the third histologically proven case of hepatoma metastatic to the orbit.

We report on a primary cutaneous rhabdoid tumour in a 14-month-old child, to the best of our knowledge, the second case in the literature. The tumour showed a multipolypoid gross appearance and classical histological features. The neoplastic cells were positive for keratin and vimentin and most were positive for proliferating cell nuclear antigen. The ultrastructural examination revealed typical intracytoplasmic aggregates of intermediate filaments. The tumour showed a very aggressive course, and the child died 5 months after the diagnosis of cerebral metastasis.

A case of multicystic mesothelioma of the liver with secondary involvement of the pelvic peritoneum and the inguinal region is presented. The case is of interest because of its unusual location and peculiar biological behavior.