MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Ménétrier-like gastropathy.

We performed whole exome sequencing in individuals from a family with autosomal dominant gastropathy resembling Ménétrier disease, a premalignant gastric disorder with epithelial hyperplasia and enhanced EGFR signalling. Ménétrier disease is believed to be an acquired disorder, but its aetiology is unknown. In affected members, we found a missense p.V742G variant in MIB2, a gene regulating NOTCH signalling that has not been previously linked to human diseases. The variant segregated with the disease in the pedigree, affected a highly conserved amino acid residue, and was predicted to be deleterious although it was found with a low frequency in control individuals. The purified protein carrying the p.V742G variant showed reduced ubiquitination activity in vitro and white blood cells from affected individuals exhibited significant reductions of HES1 and NOTCH3 expression reflecting alteration of NOTCH signalling. Because mutations of MIB1, the homolog of MIB2, have been found in patients with left ventricle non-compaction (LVNC), we investigated members of our family with Ménétrier-like disease for this cardiac abnormality. Asymptomatic left ventricular hypertrabeculation, the mildest end of the LVNC spectrum, was detected in two members carrying the MIB2 variant. Finally, we identified an additional MIB2 variant (p.V984L) affecting protein stability in an unrelated isolated case with LVNC. Expression of both MIB2 variants affected NOTCH signalling, proliferation and apoptosis in primary rat cardiomyocytes.In conclusion, we report the first example of left ventricular hypertrabeculation/LVNC with germline MIB2 variants resulting in altered NOTCH signalling that might be associated with a gastropathy clinically overlapping with Ménétrier disease.

Clinicopathological factors associated with BRAF-V600E mutation in colorectal serrated adenomas.

Serrated adenomas are genetically heterogeneous, and the histological classification into sessile serrated (SSA) adenoma and traditional serrated adenoma (TSA) does not reflect the molecular landscape. The objective of this study was to assess clinical or pathological factors associated with BRAF-V600E mutation in serrated adenomas. Systematic review and meta-analysis was performed by searching electronic databases from January 2011 to January 2019 for studies assessing the association of BRAF-V600E mutation with clinical or pathological features of serrated adenomas. Odds ratio (OR) was calculated for each factor; a P-value <0.05 was considered significant. Forty studies assessing 3511 serrated adenomas (2375 SSAs and 1136 TSAs) were included. BRAF-V600E mutation was significantly associated with proximal localisation (OR = 2.71; P < 0.00001) and CIMP-H status (OR = 4.81; P < 0.0001) in both SSA and TSA, with polyp size <10 mm (OR = 0.41; P = 0.02) in TSA, and with endoscopic pit pattern II-O (OR = 13.11; P < 0.00001) and expression of MUC5A5 (OR = 4.43; P = 0.003) and MUC6 (OR = 2.28; P < 0.05) in SSA. Conversely, BRAF mutation was not associated with age <70 years (OR = 1.63; P = 0.34), age <60 years (OR = 0.86; P = 0.79), female sex (OR = 0.77; P = 0.12), flat morphology (OR = 1.52; P = 0.16), presence of any dysplasia (OR = 1.01; P = 0.59), serrated dysplasia (OR = 1.23; P = 0.72) and invasive cancer (OR = 0.67; P = 0.32), nuclear ß-catenin expression (OR = 0.73; P = 0.21) and p53 overexpression (OR = 1.24; P = 0.82). In conclusion, BRAF-V600E mutation is associated with proximal localisation and CIMP-H status in both SSA and TSA, with size <10 mm only in TSA, and with expression of MUC5A5 and MUC6 and endoscopic pit pattern II-O at least in SSA. In serrated adenomas, BRAF-V600E mutation does not seem to be associated with age and sex, with the prevalence of dysplasia and cancer and with the morphology of the dysplastic component.

Chronic Diarrhea in Common Variable Immunodeficiency: a Case Series and Review of the Literature.

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by reduced immunoglobulin serum levels and absent or impaired antibody production. Clinical manifestations, including infections, inflammatory and autoimmune diseases, and malignancies, also involve various segments of the gastrointestinal tract. Chronic diarrhea is one of the most common gastrointestinal symptoms and may cause a wide spectrum of potentially life-threatening conditions as malabsorption and protein-energy malnutrition. We describe three female CVID adult patients presenting with chronic diarrhea, weight loss, and protein-energy malnutrition due to different underlying conditions. Our review of the literature explores the various gastrointestinal involvements in CVID and points out several histopathological findings proper of the disease, thus highlighting the relevance of the endoscopic and histological assessment in CVID patients presenting with chronic diarrhea.

Small bowel carcinomas in celiac or Crohn's disease: distinctive histophenotypic, molecular and histogenetic patterns.

Non-familial small bowel carcinomas are relatively rare and have a poor prognosis. Two small bowel carcinoma subsets may arise in distinct immune-inflammatory diseases (celiac disease and Crohn's disease) and have been recently suggested to differ in prognosis, celiac disease-associated carcinoma cases showing a better outcome, possibly due to their higher DNA microsatellite instability and tumor-infiltrating T lymphocytes. In this study, we investigated the histological structure (glandular vs diffuse/poorly cohesive, mixed or solid), cell phenotype (intestinal vs gastric/pancreatobiliary duct type) and Wnt signaling activation (ß-catenin and/or SOX-9 nuclear expression) in a series of 26 celiac disease-associated small bowel carcinoma, 25 Crohn's disease-associated small bowel carcinoma and 25 sporadic small bowel carcinoma cases, searching for new prognostic parameters. In addition, non-tumor mucosa of celiac and Crohn's disease patients was investigated for epithelial precursor changes (hyperplastic, metaplastic or dysplastic) to help clarify carcinoma histogenesis. When compared with non-glandular structure and non-intestinal phenotype, both glandular structure and intestinal phenotype were associated with a more favorable outcome at univariable or stage- and microsatellite instability/tumor-infiltrating lymphocyte-inclusive multivariable analysis. The prognostic power of histological structure was independent of the clinical groups while the non-intestinal phenotype, associated with poor outcome, was dominant among Crohn's disease-associated carcinoma. Both nuclear ß-catenin and SOX-9 were preferably expressed among celiac disease-associated carcinomas; however, they were devoid, per se, of prognostic value. We obtained findings supporting an origin of celiac disease-associated carcinoma in SOX-9-positive immature hyperplastic crypts, partly through flat ß-catenin-positive dysplasia, and of Crohn's disease-associated carcinoma in a metaplastic (gastric and/or pancreatobiliary-type) mucosa, often through dysplastic polypoid growths of metaplastic phenotype. In conclusion, despite their common origin in a chronically inflamed mucosa, celiac disease-associated and Crohn's disease-associated small bowel carcinomas differ substantially in histological structure, phenotype, microsatellite instability/tumor-infiltrating lymphocyte status, Wnt pathway activation, mucosal precursor lesions and prognosis.

Autosomal dominant Ménétrier-like disease.

BACKGROUND: Familial occurrence of Ménétrier disease is rare and has been reported only in few instances. METHODS: Affected patients from a large pedigree were evaluated at the clinical, endoscopic, and pathological levels. RESULTS: Affected members presented with gastropathy of variable severity but without protein loss. Endoscopy and pathology findings were consistent with Ménétrier disease; however, gastric transforming growth factor α (TGF-α) immunohistochemistry and real-time polymerase chain reaction showed no increase in TGF-α expression. CONCLUSIONS: We describe a unique, 4-generation pedigree with autosomal dominant gastropathy exhibiting the typical clinical, endoscopic, and pathological findings of Ménétrier-like disease, though in the absence of protein loss and with no increase in the levels of gastric TGF-α. Members of this family may be affected by a novel and previously unrecognised hereditary form of gastric hyperplasia.

Maternal C-reactive protein and developmental programming of atherosclerosis.

OBJECTIVE: Maternal hypercholesterolemia during pregnancy enhances the susceptibility to atherosclerosis in their offspring by oxidation-dependent mechanisms. The present study investigated whether maternal C-reactive protein (CRP) level, which is an indicator of inflammation and cardiovascular risk, or smoking, which enhances oxidative stress, predict the in utero programming of atherosclerosis. STUDY DESIGN: Subsets of patients from the Fate of Early Lesions in Childhood study (156 normocholesterolemic children) were examined at autopsy, classified by maternal cholesterol levels during pregnancy. Maternal CRP level was correlated with maternal cholesterol and aortic atherosclerosis of children. RESULTS: CRP level was elevated in hypercholesterolemic mothers and showed significant correlation with atherogenesis in children in univariate and multivariate analysis. However, many hypercholesterolemic mothers did not have elevated CRP levels. Smoking only correlated in univariate analysis. CONCLUSION: CRP level during pregnancy is a predictor of increased atherogenesis in children of hypercholesterolemic mothers, albeit a weaker one than maternal cholesterol. In the presence of hypercholesterolemia, maternal smoking does not further enhance atherogenic programming.

Effects of a pomegranate fruit extract rich in punicalagin on oxidation-sensitive genes and eNOS activity at sites of perturbed shear stress and atherogenesis.

BACKGROUND: Atherosclerosis is enhanced in arterial segments exposed to disturbed flow. Perturbed shear stress increases the expression of oxidation-sensitive responsive genes (such as ELK-1 and p-CREB). Polyphenolic antioxidants contained in the juice derived from the pomegranate contribute to the reduction of oxidative stress and atherogenesis during disturbed shear stress. AIM OF THE STUDY: To evaluate the effects of intervention with the Pomegranate Fruit Extract (PFE) rich in polyphones (punicalagin, which is a potent antioxidant) on ELK-1, p-CREB, and endothelial nitric oxide synthase (eNOS) expression induced by high shear stress in vitro and in vivo. RESULTS: At the doses used in the study, both the PFE and the regular pomegranate juice concentrate reduced the activation of ELK-1 and p-CREB and increased eNOS expression (which was decreased by perturbed shear stress) in cultured human endothelial cells and in atherosclerosis-prone areas of hypercholesterolemic mice. PFE and pomegranate juice increased cyclic GMP levels while there was no significant effect of both compounds on the conversion of L-arginine to L-citrulline. Administration of these compounds to hypercholesterolemic mice significantly reduced the progression of atherosclerosis and isoprostane levels and increased nitrates. This protective effect was relevant with PFE. Vasomotor reactivity was improved and EC(25) values in response to Ach and NONOate were significantly increased in treated mice in comparison to controls. CONCLUSION: This study indicates that the proatherogenic effects induced by perturbed shear stress can be also reversed by chronic administration of PFE.

Epigenetic Hallmarks of Fetal Early Atherosclerotic Lesions in Humans.

Importance: Although increasingly strong evidence suggests a role of maternal total cholesterol and low-density lipoprotein cholesterol (LDLC) levels during pregnancy as a risk factor for atherosclerotic disease in the offspring, the underlying mechanisms need to be clarified for future clinical applications. Objective: To test whether epigenetic signatures characterize early fetal atherogenesis associated with maternal hypercholesterolemia and to provide a quantitative estimate of the contribution of maternal cholesterol level to fetal lesion size. Design, Setting, and Participants: This autopsy study analyzed 78 human fetal aorta autopsy samples from the Division of Human Pathology, Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy. Maternal levels of total cholesterol, LDLC, high-density lipoprotein cholesterol (HDLC), triglycerides, and glucose and body mass index (BMI) were determined during hospitalization owing to spontaneous fetal death. Data were collected and immediately processed and analyzed to prevent degradation from January 1, 2011, through November 30, 2016. Main Outcomes and Measurements: Results of DNA methylation and messenger RNA levels of the following genes involved in cholesterol metabolism were assessed: superoxide dismutase 2 (SOD2), low-density lipoprotein receptor (LDLR), sterol regulatory element binding protein 2 (SREBP2), liver X receptor α (LXRα), and adenosine triphosphate-binding cassette transporter 1 (ABCA1). Results: Among the 78 fetal samples included in the analysis (59% male; mean [SD] fetal age, 25 [3] weeks), maternal cholesterol level explained a significant proportion of the fetal aortic lesion variance in multivariate analysis (61%; P = .001) independently by the effect of levels of HDLC, triglycerides, and glucose and BMI. Moreover, maternal total cholesterol and LDLC levels were positively associated with methylation of SREBP2 in fetal aortas (Pearson correlation, 0.488 and 0.503, respectively), whereas in univariate analysis, they were inversely correlated with SREBP2 messenger RNA levels in fetal aortas (Pearson correlation, -0.534 and -0.671, respectively). Epivariations of genes controlling cholesterol metabolism in cholesterol-treated human aortic endothelial cells were also observed. Conclusions and Relevance: The present study provides a stringent quantitative estimate of the magnitude of the association of maternal cholesterol levels during pregnancy with fetal aortic lesions and reveals the epigenetic response of fetal aortic SREBP2 to maternal cholesterol level. The role of maternal cholesterol level during pregnancy and epigenetic signature in offspring in cardiovascular primary prevention warrants further long-term causal relationship studies.

Novel toll-like receptor 9 agonist induces epidermal growth factor receptor (EGFR) inhibition and synergistic antitumor activity with EGFR inhibitors.

PURPOSE: Immunostimulating Toll-like receptor 9 (TLR9) agonists cause antitumor activity interfering also with cancer proliferation and angiogenesis by mechanisms still incompletely understood. We hypothesized that modified TLR9 agonists could impair epidermal growth factor receptor (EGFR) signaling and, by this means, greatly enhance EGFR inhibitors effect, acting on both the receptor targeting and the immunologic arm. EXPERIMENTAL DESIGN: We used a novel second-generation, modified, immunomodulatory TLR9 agonist (IMO), alone and in combination with the anti-EGFR monoclonal antibody cetuximab or tyrosine kinase inhibitor gefitinib, on the growth of GEO and cetuximab-resistant derivatives GEO-CR colon cancer xenografts. We have also evaluated the expression of several proteins critical for cell proliferation, apoptosis, and angiogenesis, including EGFR, mitogen-activated protein kinase, Akt, bcl-2, cyclooxygenase-2, vascular endothelial growth factor, and nuclear factor-kappaB. RESULTS: IMO inhibited GEO growth and signaling by EGFR and the other proteins critical for cell proliferation and angiogenesis. IMO plus the anti-EGFR antibody cetuximab synergistically inhibited tumor growth, signaling proteins, and microvessel formation. EGFR signaling inhibition by IMO is relevant because IMO cooperated also with EGFR tyrosine kinase inhibitor gefitinib in GEO tumors, while it was inactive against GEO-CR xenografts. On the other hand, IMO boosted the non-EGFR-dependent cetuximab activity, causing a cooperative antitumor effect in GEO-CR cells. Finally, combination of IMO, cetuximab and chemotherapeutic irinotecan eradicated the tumors in 90% of mice. CONCLUSION: IMO interferes with EGFR-related signaling and angiogenesis and has a synergistic antitumor effect with EGFR inhibitors, especially with cetuximab, boosting both the EGFR dependent and independent activity of this agent. Moreover, this therapeutic strategy could be translated in patients affected by colorectal cancer.

Distinct metaplastic and inflammatory phenotypes in autoimmune and adenocarcinoma-associated chronic atrophic gastritis.

BACKGROUND: Autoimmune gastritis (AIG) and adenocarcinoma-associated chronic atrophic gastritis (CAG) are both associated with oxyntic atrophy, but AIG patients demonstrate an increased risk of carcinoid tumors rather than the elevated risk of adenocarcinoma observed with CAG. We therefore sought to compare the characteristics of the metaplastic mucosa in AIG and CAG patients. METHODS: We examined markers for metaplasia (spasmolytic polypeptide expressing metaplasia (SPEM) and intestinal metaplasia) as well as proliferation (Ki67) and immune cell populations (neutrophils, macrophages, and eosinophils) in gastric sections from 16 female patients with autoimmune thyroiditis and AIG and 17 patients with CAG associated with gastric adenocarcinoma. RESULTS: Both AIG and CAG patients demonstrated prominent SPEM and intestinal metaplasia. However, AIG patients displayed significantly lower numbers of infiltrating macrophages and significantly reduced mucosal cell proliferation as compared to CAG patients. CONCLUSIONS: These findings indicate that, while both AIG and CAG patients display prominent oxyntic atrophy and metaplasia, the AIG patients do not show proliferative metaplastic lineages that would predispose to adenocarcinoma.

Small Bowel Carcinomas in Coeliac or Crohn's Disease: Clinico-pathological, Molecular, and Prognostic Features. A Study From the Small Bowel Cancer Italian Consortium.

BACKGROUND AND AIMS: An increased risk of small bowel carcinoma [SBC] has been reported in coeliac disease [CD] and Crohn's disease [CrD]. We explored clinico-pathological, molecular, and prognostic features of CD-associated SBC [CD-SBC] and CrD-associated SBC [CrD-SBC] in comparison with sporadic SBC [spo-SBC]. METHODS: A total of 76 patients undergoing surgical resection for non-familial SBC [26 CD-SBC, 25 CrD-SBC, 25 spo-SBC] were retrospectively enrolled to investigate patients' survival and histological and molecular features including microsatellite instability [MSI] and KRAS/NRAS, BRAF, PIK3CA, TP53, HER2 gene alterations. RESULTS: CD-SBC showed a significantly better sex-, age-, and stage-adjusted overall and cancer-specific survival than CrD-SBC, whereas no significant difference was found between spo-SBC and either CD-SBC or CrD-SBC. CD-SBC exhibited a significantly higher rate of MSI and median tumour-infiltrating lymphocytes [TIL] than CrD-SBC and spo-SBC. Among the whole SBC series, both MSI─which was the result of MLH1 promoter methylation in all but one cases─and high TIL density were associated with improved survival at univariable and stage-inclusive multivariable analysis. However, only TILs retained prognostic power when clinical subgroups were added to the multivariable model. KRAS mutation and HER2 amplification were detected in 30% and 7% of cases, respectively, without prognostic implications. CONCLUSIONS: In comparison with CrD-SBC, CD-SBC patients harbour MSI and high TILs more frequently and show better outcome. This seems mainly due to their higher TIL density, which at multivariable analysis showed an independent prognostic value. MSI/TIL status, KRAS mutations and HER2 amplification might help in stratifying patients for targeted anti-cancer therapy.

PET/MR Versus PET/CT Imaging: Impact on the Clinical Management of Small-Bowel Crohn's Disease.

BACKGROUND AND AIMS: The aim of this study was to compare the accuracy and clinical impact of hybrid positron emission tomography [PET]/magnetic resonance-enterography [MR-E] and PET/computed tomography-enterography [CT-E] in patients with Crohn's disease [CD]. METHODS: A total of 35 patients with symptomatic small-bowel CD who were scheduled to undergo operation were evaluated before operation by same-day PET/CT-E and PET/MR-E. PET/MR-E was also compared with MR-E alone. Imaging accuracy for detecting pathological sites and discriminating between fibrotic and inflammatory strictures was assessed. Treatment was adjusted according to imaging findings and change in medical/surgical strategy was also evaluated. RESULTS: PET/CT-E, PET/MR-E, and MR-E were equally accurate in detecting CD sites. PET/MR-E was more accurate in assessing extra-luminal disease [p = 0.002], which was associated with higher need for stoma [p = 0.022] and distant localisation [p = 0.002]. When the latter was observed, laparoscopy was started with hand-assisted device, reducing operative time [p = 0.022]. PET/MR-E was also more accurate in detecting a fibrotic component compared with PET/CT-E [p = 0.043] and with MR-E [p = 0.024]. Fibrosis was more frequently classified as inflammation with MR-E compared with PET/MR-E [p = 0.019]. Out of 8 patients with predominantly inflammatory CD who received medical treatment, 6 [75%] remained surgery free. Overall, 29 patients received surgery. At median follow-up of 9 [6-22] months, no recurrences occurred in either the medical or the surgical group. CONCLUSIONS: Preoperative PET/MR-E imaging is highly accurate for assessing CD lesions before operation and contributed to clinical management of patients with small-bowel CD more often than PET/CT-E.

Expression of epidermal growth factor receptor correlates with disease relapse and progression to androgen-independence in human prostate cancer.

PURPOSE: The transforming growth factor alpha-epidermal growth factor receptor (EGFR) autocrine pathway has been implicated in prostate cancer cell growth. Amplification and/or overexpression of c-erbB-2, a receptor closely related to the EGFR, has been recently involved in prostate cancer progression. We investigated EGFR and c-erbB-2 expression in primary androgen-dependent and in advanced androgen-independent prostate cancer and their potential role as markers of disease progression. EXPERIMENTAL DESIGN: EGFR and c-erbB-2 expression were evaluated by immunohistochemistry in a consecutive series of 74 prostate cancer patients with the following characteristics: 29 patients (group 1) treated with radical prostatectomy; 29 patients (group 2) treated with luteinizing hormone-releasing hormone analogues and antiandrogen therapy followed by radical prostatectomy; and 16 patients with hormone-refractory metastatic disease. In all patients we evaluated: association between EGFR and/or c-erbB-2 expression and clinicopathological parameters; and disease-free survival according to EGFR and c-erbB-2 expression in univariate analysis (Kaplan-Meier product-limit method) and in multivariate analysis (Cox proportional hazards regression model). RESULTS: EGFR expression was found in 12 of 29 (41.4%) group 1 patients, in 22 of 29 (75.9%) group 2 patients (P < 0.0005), and in 16 of 16 (100%) metastatic patients (P < 0.005), whereas c-erbB-2 expression was found in 11 of 29 (37.9%) group 1, in 10 of 29 (34.5%) group 2 patients, and in 9 of 16 (56.3%) metastatic patients. A significant association was found between EGFR expression and a high Gleason score (P < 0.01) and between EGFR expression and higher serum prostate-specific antigen values (P < 0.02) in all groups of patients. Among the 58 patients treated with radical prostatectomy, 23 of 34 EGFR-positive patients (67.6%) relapsed, whereas only 2 of 24 EGFR-negative patients (8.3%) relapsed (P < 0.00004). c-erbB-2 expression did not significantly correlate with disease relapse (P = 0.07). In a Cox multivariate analysis, the only parameter with an independent prognostic effect on disease-free survival was EGFR expression (relative hazard, 11.23; P = 0.0014). CONCLUSIONS: EGFR expression increases during the natural history of prostate cancer. Correlation with disease progression and hormone-refractory disease suggests that EGFR-targeted drugs could be of therapeutic relevance in prostate cancer.

Fetal ontogeny and tumor expression of the early thymic antigen UN1.

UN1 antigen (Ag), a 100-120 kDa sialoglycoprotein, was initially identified on immature thymocytes (CD3(dim)), a small subpopulation of CD4(+) peripheral blood T-lymphocytes, on leukemic T-cell lines and in fetal thymus. Biochemical analysis of the Ag has identified molecular features that are characteristic of cell-membrane-associated mucin-like glycoproteins. To investigate the biological role and the potential usefulness of the Ag, we have more extensively studied the pattern of UN1 Ag expression in a panel of fetal tissues, at different gestational ages, and on adult normal and tumor specimens. In the fetal samples examined by immunohistochemistry, including intestine, liver, lung and adrenal gland, we found that UN1 Ag is widely expressed during early stages of fetal development and down-regulated during ontogenesis. Very poor or not detectable expression of UN1 Ag was found at late gestational age. Immunohistochemical, Western blot and flow cytometric analysis of a panel of normal adult tissues and benign lesions failed to find Ag expression, whereas UN1 Ag was highly detectable in a variety of cancer specimens from breast, lung, gastrointestinal, gynaecological malignancies and melanomas. Based on these data UN1 Ag, for the wide expression on fetal tissues, the down-regulation during ontogeny and the re-expression in cancer cells, may be considered a novel oncofetal Ag of interest for biological investigation and clinical applications.

Glycoxidation of low-density lipoprotein increases TUNEL positivity and CPP32 activation in human coronary cells.

Apoptosis of arterial cells induced by oxidized low-density lipoprotein (oxLDL) is thought to contribute to the progression of vascular dysfunction and atherogenesis. It is well established that diabetes mellitus is accompanied by both glycosylation and oxidation of LDL (glc-oxLDL), but the biological effects of these modified lipoproteins are poorly understood. We demonstrate here for the first time that glc-oxLDL increases TUNEL positivity and caspase-3 activation (by Western blot and immunocytochemistry) of human coronary smooth muscle cells. Overall, these effects induced by glc-oxLDL were greater than those achieved with oxLDL. Thus, glc-oxLDL activated downstream apoptotic signaling. This may influence the evolution of atherogenesis and vascular complications in diabetes.

Differential expression of UN1, early thymocyte-associated sialoglycoprotein, in breast normal tissue, benign disease and carcinomas.

BACKGROUND: The UNI antigen (Ag) is a 120 kDa sialoglycoprotein which has been primarily found in human undifferentiated CD3dim thymocytes and leukemic T-cell lines, but subsequently also detected in solid tumors. We studied the expression of this Ag in a panel of normal and pathological breast tissues. MATERIALS AND METHODS: Analysis of UN1 Ag expression on tissue specimens was performed by immunohistochemistry and Western blotting. RESULTS: No Ag expression was found in 14 sections of normal tissue and 10 sections of benign nonproliferative lesions. Progressively increasing levels of UN1 Ag expression were found in fibroadenomas (24 positive out of 27 cases), proliferative lesions (9 cases), in situ (17 cases) and invasive carcinomas (56 cases). Finally, the highest expression was observed in 10 metastatic lesions. CONCLUSION: These data suggest that UN1 Ag is a promising marker of potential value for immunophenotyping studies and therapeutic applications in breast diseases.

Disseminated Cryptococcus neoformans infection and Crohn's disease in an immunocompetent patient.

Cryptococcus neoformans is a human pathogen ubiquitously present in the environment. It primarily affects immunocompromised patients, but individuals with no underlying disease or immunodeficiency can also be affected. We herein describe the case of a patient found to have Crohn's disease and disseminated cryptococcosis simultaneously. She had no predisposing underlying cause for impaired immunity. Our patient showed signs that would have make it hard to discriminate between an inflammatory bowel disease and an infection if bowel only would have been involved. The patient underwent surgical intervention; medical therapy was effective against Cryptococcus. She is at now being followed-up for Crohn's disease. When dealing with patient affected with inflammatory bowel diseases, careful history taking, objective and instrumental examination are demandable in order not to overlook associated conditions or infectious diseases. Diagnosis and therapy of cryptococcosis infection in patient with Crohn's disease are herein discussed.

External iliac artery pseudoaneurysm complicating renal transplantation.

OBJECTIVES: To assess the etiology, management and outcome of iliac pseudoaneurysms following renal transplantation. METHODS: Eleven patients who underwent repair between 1982 and 2007 were identified. Five (Group 1) presented pseudoaneurysm at the anastomosis of the donor renal and native iliac arteries, and six (Group 2) presented iliac pseudoaneurysm following transplant nephrectomy. Intraoperative cultures and immunohistochemical examinations were obtained from all surgical cases to determine the existence of a relationship between infection or transplant rejection and pseudoaneurysm formation. RESULTS: Endovascular repair (EVR) was used to treat three patients, while eight patients underwent open repair (OR). Transplant nephrectomy was needed in all cases but one after anastomotic pseudoaneurysm repair. After pseudoaneurysm excision, arterial reconstruction was performed in all cases, with a limb salvage rate of 100%. At 30 days, no patients died in the EVR subgroup. In the OR subgroup, one patient died of sepsis (12.5%). Cultures taken from the pseudoaneurysm wall and content grew Candida albicans and E. coli in two febrile patients. Pathologic evaluation of donor renal arteries revealed evidence of chronic rejection in three patients (60%) in Group 1, and in two (33.3%) in Group 2. No patients in either Group presented late infection, failure of vascular reconstruction nor pseudoaneurysm recurrence. The follow-up ranges from 20 to 89 months. CONCLUSIONS: The etiology of pseudoaneurysms in this location is multifactorial, however, an association with chronic rejection must be considered. Though rare, the development of pseudoaneurysms at the donor renal-external iliac artery anastomosis results in high rates of transplant nephrectomy. Less invasive endovascular techniques offer a new therapeutic option in this challenging scenario notwithstanding the fact that they require further validation.

Beneficial effects of low doses of red wine consumption on perturbed shear stress-induced atherogenesis.

Moderate wine intake is associated with a reduced risk of morbidity and mortality from cardiovascular disease. Atherosclerosis is enhanced in arterial segments exposed to disturbed flow. Perturbed shear stress increases also the endothelial expression of oxidation-sensitive responsive genes (such as ELK-1 and p-JUN). This study evaluates the effects of chronic consumption of red wine on perturbed shear stress-induced atherogenesis. Results indicated that chronic treatment with red wine significantly attenuated the activation of redox-sensitive genes (ELK-1 and p-JUN) and increased endothelial nitric oxide synthase (eNOS) expression (which was decreased by perturbed shear stress) in cultured human coronary endothelial cells (EC) and in atherosclerosis-prone areas of hypercholesterolemic mice. Oral administration of red wine to hypercholesterolemic mice reduced significantly the progression of atherosclerosis. Moreover, short-term supplementation with red wine to C57BL/6J mice significantly increased upregulation of aortic eNOS and SIRT1 expression induced by physical training. These findings establish that administration of low doses of red wine can attenuate the proatherogenic effects induced by perturbed shear stress in vitro and in vivo. This evidence may have implications for the prevention of atherosclerotic lesion progression and its clinical manifestations.

The influence of pomegranate fruit extract in comparison to regular pomegranate juice and seed oil on nitric oxide and arterial function in obese Zucker rats.

Metabolic syndrome includes most widely distributed clinical conditions such as obesity, hypertension, dislipidemia, and diabetes. Pomegranate fruit extract (PFE), rich in polyphenolic antioxidants, reduces the expression of oxidation-sensitive genes at the sites of perturbed shear-stress. The aim of this study was to evaluate the effect of PFE in comparison to regular pomegranate juice (PJ) and seed oil on the biological actions of nitric oxide (NO) and the arterial function in obese Zucker rats, a model of metabolic syndrome. Our results indicated that supplementation with PFE or PJ significantly decreased the expression of vascular inflammation markers, thrombospondin (TSP), and cytokine TGFbeta1 (P<0.05), whereas seed oil supplementation had a significant effect only on TSP-1 expression (P <0.05). Plasma nitrate and nitrite (NO(x)) levels were significantly increased by PFE and PJ (P<0.05). Furthermore, the effect of PFE in increasing endothelial NO synthase (eNOS) expression was comparable to that of PJ. These data highlight possible clinical applications of PFE in metabolic syndrome.