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Analytic treatment interruptions (ATIs) are currently the standard for assessing the impact of experimental interventions aimed at inducing sustained antiretroviral therapy (ART)-free remission in trials related to HIV cure. ATIs are associated with substantial risk to both study participants and their sexual partner(s). Two documented HIV transmissions occurring in the context of ATIs have been recently reported, but recommendations for mitigating the risk of such events during ATIs are limited. We outline a practical approach to risk mitigation during ATI studies and describe strategies we are utilising in an upcoming clinical trial that may be applicable to other centres.

Background: DNA damage accumulation has been linked to the cancer phenotype. The purpose of this study was to compare the levels of DNA base 8-hydroxy-2'-deoxyguanosine (8-OHdG) and C-reactive protein (CRP) inflammatory markers in healthy controls and pancreatic cancer patients from a hospital-based case-control study. Materials and Methods: Fifty-five pancreatic cancer patients and 55 healthy controls were enrolled from a pool of patients referred to the Endoscopic Ultrasound (EUS) center. Analysis of DNA content of peripheral blood cells was conducted for 8-OHdG with the 32P-postlabelling assay. Serum CRP levels were measured by high-sensitivity assays and demographic data for comparison were collected from individual medical records. Results: The group of cases showed significant increased median (IQR) 8-OHdG DNA adducts/106 nucleotides and CRP compared to the controls (208.8 (138.0-340.8) vs 121.8 (57.7-194.8) RAL value; P < 0.001) and (3.5 (1.5-8.6) vs 0.5 (0.2-1.5) mg/L P < 0.001). A number of conditional regression models confirmed associations of pancreatic cancer with oxidative DNA damage in peripheral leukocytes.Conclusions: Our findings suggest the importance of leukocyte 8-OHdG adducts as an indicator for systemic oxidative DNA damage in pancreatic cancer patients. In addition to increase in the CRP inflammatory marker, this supports the impact of inflammation in the occurrence of pancreatic cancer as well as inflammatory responses during cancer development.

Background: Bulky DNA adducts are markers of exposure to genotoxic aromatic compounds, which reflect the ability of an individual to metabolically activate carcinogens and to repair DNA damage. Polycyclic aromatic hydrocarbons (PAHs) represent a major class of carcinogens that are capable of forming such adducts. Factors that have been reported to be related to DNA adduct levels include smoking, diet, body mass index (BMI), genetic polymorphisms, the season of collection of biologic material, and air pollutants. Methods: We pooled 11 studies (3,600 subjects) in which bulky DNA adducts were measured in human white blood cells with similar 32P-postlabeling techniques and for which a similar set of variables was available, including individual data on age, gender, ethnicity, batch, smoking habits, BMI, and season of blood collection, and a limited set of gene variants. Results: Lowest DNA adduct levels (P = 0.006) were observed in the spring (median = 0.50 adducts per 108 nucleotides), followed by summer (0.64), autumn (0.70), and winter (0.85). The same pattern emerged in multivariate analysis but only among never smokers (P = 0.02). Adduct levels were significantly lower (P = 0.001) in northern Europe (the Netherlands and Denmark; mean = 0.60, median = 0.40) than in southern Europe (Italy, Spain, France, and Greece; mean = 0.79, median = 0.60). Conclusions: In this large pooled analysis, we have found only weak associations between bulky DNA adducts and exposure variables. Seasonality (with higher adducts levels in winter) and air pollution may partly explain some of the interarea differences (north vs. south Europe), but most inter-area and interindividual variations in adduct levels still remain unexplained. Impact: Our study describes the largest pooled analysis of bulky DNA adducts so far, showing that interindividual variation is still largely unexplained, though seasonality seems to play a role. Cancer Epidemiol Biomarkers Prev; 19(12); 3174–81. ©2010 AACR.

Questo contributo cerca, nell’analisi di un consistente corpus di parlato dialogico dell’italiano, una risposta alla problematicità della generalizzazione dei dati e, allo stesso tempo, una conferma della possibile identificazione di peculiarità prevalentemente ricorrenti nello stile conversazionale di parlanti donne. La risposta che le autrici propongono, pur nella consapevolezza della natura probabilistica dei dati raccolti, è contenuta nella esplorazione quantitativa, ma soprattutto qualitativa, dei dati relativi ai marcatori presenti nei dialoghi maschili vs. femminili, così come nella osservazione della quantità di materiale linguistico impiegato dai parlanti di entrambi i sessi nello svolgimento degli stessi compiti linguistici.

Background: Left Atrial Appendage (LAA) is the main source of left atrial thrombi causing embolic strokes in patients with Non Valvular Atrial Fibrillation (NVAF). Since many patients carry contraindications to Oral Anticoagulation (OAC), percutaneous devices for closure of LAA have been introduced, to avoid peripheral thromboembolism in absence of OAC. Methods: From March 2012 to March 2014 we enrolled patients which had permanent and persistent NVAF and high thromboembolic risk with absolute contraindication to OAC. They were subjected to insertion of Boston Scientific Watchman device in LAA under transesophageal and fluoroscopic guide, with continuous heparin administration to maintain constant activated clotting time (ACT) of 300-350 sec and under general anesthesia. Patients were discharged with indication to double antiplatelet therapy with Aspirin and Clopidogrel for 6 months and Aspirin thereafter, avoiding Warfarin at all. Follow-up Transesophageal Echocardiography (TEE) was performed 2 months, six months and 12 months after implantation. Results: We enrolled 21 patients, aging 49 to 80 yrs. (mean 67.61± 8.2), with high thromboembolic risk (CHADsVasc 3.23 ± 1.33), and with different contraindications to OAC, in most cases due to severe bleeding risk and difficulty in keeping stable INR values (HASBLED 3 ± 1.09). The mean size of the device implanted was 24.75 ± 2.56 mm, the mean total procedure time was 67.78 ± 18 min, the mean fluoroscopy time was 16.81 ± 2.53 min. In all cases LAA was successfully occluded at first TEE, performed within 2 months from the procedure, while we noticed a trend towards development of non-pathological leaks in the next control TEEs, with patients always free from embolic events at mean follow-up of 13.09 ± 6.04 months. Moreover, we noticed a trend towards reduction of left atrial spontaneous echo contrast after LAA closure. Conclusion: Percutaneous LAA closure followed by administration of DAPT appears to be safe and effective at mid-term follow-up in patients with absolute contraindications to OAC. Long term safety and efficacy will be demonstrated with longer follow-up and with more patients enrolled.

Bulky DNA adducts are biomarkers of exposure to aromatic compounds and of the ability of the individual to metabolically activate carcinogens and to repair DNA damage. Their ability to predict cancer onset is uncertain. We have performed a pooled analysis of three prospective studies on cancer risk in which bulky DNA adducts have been measured in blood samples collected from healthy subjects (N = 1947; average follow-up 51-137 months). In addition, we have performed a meta-analysis by identifying all articles on the same subject published up to the end of 2006, including case-control studies. In the pooled analysis, a weakly statistically significant increase in the risk of lung cancer was apparent (14% per unit standard deviation change in adduct levels, 95% confidence interval 1-28%; using the weighted mean difference method, 0.15 SD, units higher adducts in cases than in controls). The association was evident only in current smokers and was absent in former smokers. Also the meta-analysis, which included both lung and bladder cancers, showed a statistically significant association in current smokers, whereas the results in never smokers were equivocal; in former smokers, no association was detected. The results of our pooled and meta-analyses suggest that bulky DNA adducts are associated with lung cancer arising in current smokers after a follow-up of several years. European Union (FOOD-CT-2005-513943) (WP4-8) to Environmental Cancer Risk, nutrition and individual susceptibility Network of Excellence (EC CONTRACT Food-CT-2005-513943).

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