Pier Luigi Cocco

Independent expression of serological markers of thyroid autoimmunity and hepatitis virus C infection in the general population: Results of a community-based study in northwestern Sardinia

To assess the relationship between serological markers of thyroid autoimmunity and chronic hepatitis C, we surveyed the general population of two villages in the region of Sardinia, Italy, where infection with hepatitis viruses is endemic and the prevalence of autoimmune diseases is elevated. A total of 1310 subjects aged 6–88 years (65% of the total resident population) participated in the survey, and 1233 (94%; 444 males and 789 females) agreed to provide a blood sample. Autoantibodies to thyroid peroxidase (anti-TPO) were measured by radioimmunoassay; antibodies to HCV (anti-HCV) by a third generation enzyme immunoassay and borderline positive results confirmed by recombinant immunoblot assay. For both anti-HCV and anti-TPO the ageand gender-standardized prevalence rates (SPR) were calculated and the significance of the association between the two antibodies tested by Yates corrected χ2 test. The overall SPR for anti-HCV was 50.7×10−3 (86/1,233), similar between men [49.1×10−3 (22/444)] and women [52.3×10−3 (64/789)]. The overall SPR for anti-TPO was 136.9×10−3 (204/1,233), and that among women [201×10−3 (174/789)] was almost 3-fold that among men [71.6×10−3 (30/444)]. A concurrent anti-HCV and anti-TPO positivity was found in a small minority of subjects [8/1,233 (0.65%)], all women aged 57–81 years. The SPR for the two concurrent events was 3.3×10−3, which was not significantly different (Yates corrected χ2 test = 0.65) from that expected under the assumption of unrelated events. To explore whether HCV infection is a risk factor for anti-TPO positivity, we designed a casecontrol study with anti-TPO positive subjects as the cases, and anti-TPO negative subjects as the controls. The age- and gender-adjusted odd ratio (OR) was 0.4 (95% CI 0.2,0.7), indicating a negative association. In conclusion, no evidence for epidemiological association of circulating thyroid autoantibodies and antibodies to HCV was found. Our findings do not therefore support a pathogenetic link between HCV infection and thyroid autoimmunity.

Exposure to ultraviolet radiation and risk of malignant lymphoma and multiple myeloma—a multicentre European case–control study

BACKGROUND Three recent studies have reported a decreased risk of non-Hodgkin lymphoma (NHL) for high ultraviolet (UV) radiation exposure. METHODS We conducted a multicentre case-control study during 1998-2004 in France, Germany, Ireland, Italy and Spain, comprising 1518 cases of NHL, 268 cases of Hodgkin lymphoma, 242 cases of multiple myeloma and 2124 population or hospital controls. We collected information on sensitivity to sun and personal exposure to UV radiation in childhood and adulthood via interview, and assessed occupational exposure to UV radiation from the occupational history. RESULTS The risk of Hodgkin and NHL was increased for increasing skin sensitivity to the sun [odds ratio (OR) for no suntan vs very brown 2.35, 95% CI 0.94-5.87 and 1.39, 95% CI 1.03-1.87, respectively]. The risk of diffuse large B-cell lymphoma was reduced for increasing adult personal (OR for highest vs lowest quartile of exposure in free days 0.62, 95% CI 0.44-0.87) and for occupational exposure to UV radiation (OR for highest vs lowest exposure tertile 0.63, 95% CI 0.37-1.04). The risk of multiple myeloma was increased for personal exposure to UV radiation during adulthood (OR for highest vs lowest quartile of exposure in free days 1.49, 95% CI 0.88-2.50). A protective effect was observed for use of sun lamps for diffuse large B-cell lymphoma (OR for 25+ times vs never 0.63, 95% CI 0.38-1.03). CONCLUSIONS The hypothesis of a protective effect of UV radiation on lymphoma is supported by our results. The underlying mechanisms might differ from those operating in skin carcinogenesis. The increased risk of multiple myeloma is worth replication.

Epstein-Barr virus infection and risk of lymphoma: Immunoblot analysis of antibody responses against EBV-related proteins in a large series of lymphoma subjects and matched controls

Epstein‐Barr Virus (EBV) is consistently associated with distinct lymphoproliferative malignancies and aberrant EBV antibody patterns are found in most EBV cancer patients. We evaluate the detection of an abnormal reactive serological pattern to EBV (ab_EBV) infection and the risk of lymphoma in a multicentric case–control study. Serum samples were collected at study entry from 1,085 incident lymphoma cases from Spain, France, Germany, Czech Republic, Italy and 1,153 age, sex and country matched controls. EBV immunoglobulin G (IgG) serostatus was evaluated through a peptide‐based ELISA combining immunodominant epitopes of EBNA1 (BKRF1) and VCA‐p18 (BFRF3). Further, immunoblot analysis was performed to evaluate distinct antibody diversity patterns to EBV early antigens (EA), besides EBNA1, VCA‐p18, VCA‐p40 (BdRF1) and Zebra (BZLF1). Patients with chronic active EBV infection and aberrant EBV activity were characterized as having an abnormal reactive pattern (ab_EBV). Ab_EBV was observed in 20.9% of 2,238 included subjects with an increased proportion of cases presenting ab_EBV as compared to the control population (23.9% vs. 18.0% p = 0.001). Ab_EBV positivity was a risk factor for all lymphomas combined (odds ratio [OR] = 1.42, 95% confidence interval [CI]=1.15–1.74), and specifically for chronic lymphocytic leukaemia (OR = 2.96, 95%CI = 2.22–3.95). Lower levels of ab_EBV were observed for follicular lymphoma (OR = 0.38, 95%CI = 0.15–0.98). EBV may be involved in a larger subset of lymphomas among clinically immunocompetent subjects than previously thought, probably explained by an underlying loss of immune control of EBV latent infection. Ab_EBV is a useful tool to explore EBV imbalances preceeding or paralleling possible EBV associated oncogenic events.

Altered cholesterol ester cycle in skin fibroblasts from patients with Alzheimer's disease.

Intracellular cholesterol metabolism was reported to modulate amyloid-beta (Abeta) generation in Alzheimers disease (AD). Results presented herein demonstrated that, like brain cells, cultured skin fibroblasts from AD patients contained more cholesterol esters than fibroblasts from healthy subjects. Particularly, Oil Red-O, Nile Red, and filipin staining highlighted higher levels of neutral lipids which responded to inhibitors of acyl-coenzyme A:cholesterol acyl-transferase (ACAT-1), associated with an increase in free cholesterol. ACAT-1 mRNA levels increased significantly in AD fibroblasts, whereas those of sterol regulatory element binding protein-2, neutral cholesterol ester hydrolase, and ATP-binding cassette transporter member 1 were markedly down-regulated. Instead, mRNA levels of low-density lipoprotein receptor, hydroxy-methyl-glutaryl-coenzyme A reductase, caveolin-1, and amyloid-beta protein precursor (AbetaPP) were virtually unchanged. Notably, mRNA levels of both beta-site AbetaPP-cleaving enzyme 1 (BACE1) and neprilysin were significantly down-regulated. An increase in Abeta(40) and Abeta(42) immunostaining and a decrease in BACE1 active form were also found in AD versus control fibroblasts. Altogether, these findings support the hypothesis that the derangement of cholesterol homeostasis is a systemic alteration involving central but also peripheral cells of AD patients, and point to cholesterol ester levels in AD fibroblasts as an additional metabolic hallmark useful in the laboratory and clinical practice.

Accumulation of neutral lipids in peripheral blood mononuclear cells as a distinctive trait of Alzheimer patients and asymptomatic subjects at risk of disease

BackgroundAlzheimers disease is the most common progressive neurodegenerative disease. In recent years, numerous progresses in the discovery of novel Alzheimers disease molecular biomarkers in brain as well as in biological fluids have been made. Among them, those involving lipid metabolism are emerging as potential candidates. In particular, an accumulation of neutral lipids was recently found by us in skin fibroblasts from Alzheimers disease patients. Therefore, with the aim to assess whether peripheral alterations in cholesterol homeostasis might be relevant in Alzheimers disease development and progression, in the present study we analyzed lipid metabolism in plasma and peripheral blood mononuclear cells from Alzheimers disease patients and from their first-degree relatives.MethodsBlood samples were obtained from 93 patients with probable Alzheimers disease and from 91 of their first-degree relatives. As controls we utilized 57, cognitively normal, over-65 year-old volunteers and 113 blood donors aged 21-66 years, respectively. Data are reported as mean ± standard error. Statistical calculations were performed using the statistical analysis software Origin 8.0 version. Data analysis was done using the Student t-test and the Pearson test.ResultsData reported here show high neutral lipid levels and increased ACAT-1 protein in about 85% of peripheral blood mononuclear cells freshly isolated (ex vivo) from patients with probable sporadic Alzheimers disease compared to about 7% of cognitively normal age-matched controls. A significant reduction in high density lipoprotein-cholesterol levels in plasma from Alzheimers disease blood samples was also observed. Additionally, correlation analyses reveal a negative correlation between high density lipoprotein-cholesterol and cognitive capacity, as determined by Mini Mental State Examination, as well as between high density lipoprotein-cholesterol and neutral lipid accumulation. We observed great variability in the neutral lipid-peripheral blood mononuclear cells data and in plasma lipid analysis of the subjects enrolled as Alzheimers disease-first-degree relatives. However, about 30% of them tend to display a peripheral metabolic cholesterol pattern similar to that exhibited by Alzheimers disease patients.ConclusionWe suggest that neutral lipid-peripheral blood mononuclear cells and plasma high density lipoprotein-cholesterol determinations might be of interest to outline a distinctive metabolic profile applying to both Alzheimers disease patients and asymptomatic subjects at higher risk of disease.

Mechanistic insight into WEB-2170-induced apoptosis in human acute myelogenous leukemia cells: The crucial role of PTEN

OBJECTIVE This study aimed to investigate the mechanisms of action of WEB-2170, an inverse agonist of platelet-activating factor receptor, capable of inducing apoptosis in human acute myelogenous leukemia (AML) cells. MATERIAL AND METHODS Gene expression profiling followed by cytofluorimetric, morphologic, and biologic analyses were used to monitor WEB-2170 effects in AML cell lines (ie, NB4, KG1, NB4-MR4, THP1, and U937) and blasts from patients with different AML (M0-M5) subtypes. PTEN silencing with small interfering RNA was also performed. RESULTS We have demonstrated that drug-mediated cytostasis/apoptosis in NB4 cells is characterized by upregulation of cyclin G2, p21/WAF1, NIX, TNF-alpha, and PTEN expression, and downregulation of cyclin D2 and BCL2 expression. We observed an increase in PTEN protein accompanied by a decrease in phospho-extracellular signal-regulated kinase 2 (ERK2) and phospho-AKT, and by forkhead box O3a (FOXO3a) cytoplasmic-nuclear translocation; the mitochondrial cytochrome C release and PARP cleavage marked the late apoptotic steps. We have found that WEB-2170 triggered apoptosis in NB4, KG1, and NB4-MR4 cells where PTEN was expressed, but not in THP1 and U937 cells where PTEN was absent. Finally, we show that PTEN silencing in NB4 cells by PTEN-specific small interfering RNA resulted in a significant reduction of drug-induced apoptosis. CONCLUSION We demonstrated that WEB-2170 is a powerful antileukemic agent with interesting translational opportunities to treat AML and described mechanisms of drug-induced intrinsic and extrinsic apoptosis both in AML cell lines and blasts from AML patients by addressing PTEN as the master regulator of the whole process.

Classic Kaposi's sarcoma in southern Sardinia, Italy

The first examination of classical Kaposis sarcoma incidence in southern Sardinia (Italy) in 1998–2002 found the highest rate recorded in the island of 2.49 per 100 000 per year (standardised).

Occupation and Risk of Non-Hodgkin Lymphoma and Its Subtypes: A Pooled Analysis from the InterLymph Consortium.

Background: Various occupations have been associated with an elevated risk of non-Hodgkin lymphoma (NHL), but results have been inconsistent across studies. Objectives: We investigated occupational risk of NHL and of four common NHL subtypes with particular focus on occupations of a priori interest. Methods: We conducted a pooled analysis of 10,046 cases and 12,025 controls from 10 NHL studies participating in the InterLymph Consortium. We harmonized the occupational coding using the 1968 International Standard Classification of Occupations (ISCO-1968) and grouped occupations previously associated with NHL into 25 a priori groups. Odds ratios (ORs) adjusted for center, age, and sex were determined for NHL overall and for the following four subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and peripheral T-cell lymphoma (PTCL). Results: We confirmed previously reported positive associations between NHL and farming occupations [field crop/vegetable farm workers OR = 1.26; 95% confidence interval (CI): 1.05, 1.51; general farm workers OR = 1.19; 95% CI: 1.03, 1.37]; we also confirmed associations of NHL with specific occupations such as women’s hairdressers (OR = 1.34; 95% CI: 1.02, 1.74), charworkers/cleaners (OR = 1.17; 95% CI: 1.01, 1.36), spray-painters (OR = 2.07; 95% CI: 1.30, 3.29), electrical wiremen (OR = 1.24; 95% CI: 1.00, 1.54), and carpenters (OR = 1.42; 95% CI: 1.04, 1.93). We observed subtype-specific associations for DLBCL and CLL/SLL in women’s hairdressers and for DLBCL and PTCL in textile workers. Conclusions: Our pooled analysis of 10 international studies adds to evidence suggesting that farming, hairdressing, and textile industry–related exposures may contribute to NHL risk. Associations with women’s hairdresser and textile occupations may be specific for certain NHL subtypes. Citation: ‘t Mannetje A, De Roos AJ, Boffetta P, Vermeulen R, Benke G, Fritschi L, Brennan P, Foretova L, Maynadié M, Becker N, Nieters A, Staines A, Campagna M, Chiu B, Clavel J, de Sanjose S, Hartge P, Holly EA, Bracci P, Linet MS, Monnereau A, Orsi L, Purdue MP, Rothman N, Lan Q, Kane E, Seniori Costantini A, Miligi L, Spinelli JJ, Zheng T, Cocco P, Kricker A. 2016. Occupation and risk of non-Hodgkin lymphoma and its subtypes: a pooled analysis from the InterLymph Consortium. Environ Health Perspect 124:396–405; http://dx.doi.org/10.1289/ehp.1409294

Prevalence of overweight and obesity in Sardinian adolescents.

BACKGROUND: To estimate the prevalence of overweight and obesity among adolescents in Sardinia and to examine the association with several biological and geographic factors. METHODOLOGY: A cross-sectional study was performed in 3,946 unselected adolescents (2,011 boys, 1,935 girls; aged 11–15 years) attending the public secondary schools in 33 Sardinian municipalities: 28 semi-rural, 5 urban, sub-grouped according to their geographic location (mountain, hillside and plain). Oversized children were measured and their BMI defined as being above normal values according to parameters provided by the International Obesity Task Force (IOFT) by Cole et al. (BMI for age >= 95th percentile). Relative risk for overweight and obesity was calculated using Poisson regression analysis: risks associated to each covariate were reciprocally adjusted. The 95% confidence interval (CI) of the estimated risk was calculated using Wald’s formula (RR, RR = logn ß±1.96seß). MAIN FINDINGS: The overall prevalence rate found for overweight and obesity was 14.9% (95% C.I.: 13.7–16.1%) and 3.7% (95% C.I. 3.1–4.3%), respectively. Overweight rate showed no association with gender, whereas belonging to the female sex constituted a significant protection against obesity. Increasing age in the range 12-14 years was protective against both overweight and obesity in the whole sample. A similar finding however was not observed for obesity in girls or overweight in boys, when considered separately. Boys, but not girls, living in urban areas displayed a modest though significant 20% increase in overweight and a 40% decrease in obesity risk. Living in a mountainous area conveyed a 30% decrease in risk of overweight and a 50% decrease in risk of obesity, when compared to living on the plains and hillside combined. However, the small sample size of study subjects living in mountainous areas generated extremely wide 95% confidence intervals, thereby preventing the drawing of any significant conclusions. CONCLUSION: In comparison with other surveys performed by the IOFT, Sardinian adolescents show a low prevalence rate for oversize, emphasizing a marked discrepancy with the general north-south rising trend of oversize observed throughout Europe. Geographic location, aesthetic or other age related factors seem to exert a different genderspecific influence on overweight and obesity. SIGNIFICANCE: The present report is cross sectional and the consequences of overweight and obesity on individuals over time are not traceable. However, the outcome of the study suggests the need to implement suitable policies and public health programs leading to increased awareness.

Leukemia in children and youths of the Azuay province, Ecuador: 2000–2010

We mapped leukemia risk among children and youths in the Azuay province, Rio Paute river basin, Ecuador, in 2000–2010, using a Bayesian disease mapping model. We assessed the comprehensiveness of the list of leukemia cases from the Sociedad de Lucha contra el Càncer en el Ecuador (SOLCA) Hospital in Cuenca, the only referral center for oncology in the whole Rio Paute area, by comparison to the Quito cancer registry. Risk of leukemia did not vary significantly by canton within the Azuay province. However, a moderate increase in risk of borderline statistical significance was observed in the city of Cuenca and particularly among males in a heavily industrialized parish, who had an almost eight-fold excess (95% CI 3.03, 20.39, p = 0.01) of AML. Analytical studies are warranted to properly address specific etiological factor of leukemia among children and youths of the Azuay province of Ecuador.