Publications

The telomerase reverse transcriptase elongates telomeres to prevent replicative senescence. This process requires exposure of the 3'-end, which is thought to occur when two sister telomeres are generated at replication completion. Using two-dimensional agarose gel electrophoresis (2D-gels) and electron microscopy, we found that telomeric repeats are hotspots for replication fork reversal. Fork reversal generates 3' telomeric ends before replication completion. To verify whether these ends are elongated by telomerase, we probed de novo telomeric synthesis in situ and at replication intermediates by reconstituting mutant telomerase that adds a variant telomere sequence. We found variant telomeric repeats overlapping with telomeric reversed forks in 2D-gels, but not with normal forks, nontelomeric reversed forks, or telomeric reversed forks with a C-rich 3'-end. Our results define reversed telomeric forks as a substrate of telomerase during replication.

Interstitial lung disease (ILD) in systemic sclerosis (SSc) is a major cause of morbidity and mortality. Little is known about the prevalence of pleuroparenchymal fibroelastosis (PPFE),a specific entity affecting the visceral pleura and subpleural parenchyma. The main aims of this study were to estimate the prevalence of PPFE in two large cohorts of SSc patients and to assess its impact on survival and functional decline. A total of 359 SSc patients,derived from two referral centers in two different countries (UK and Italy), were included. The first available high-resolution computed tomography scan was independently evaluated by two radiologists to quantify ILD extent, lobar percentage involvement of PPFE and freestanding bronchial abnormalities.Discordant scores were adjudicated by a third scorer.PPFE extent was further classified as limited or extensive. Results were evaluated against functional decline and mortality.Cox proportional hazard analysis was used to investigate determinants of mortality. The overall prevalence of PPFE in the combined SSc population was 18%(11% with extensive PPFE), with no substantial difference between the two cohorts. PPFE was independently linked to worse survival on a multivariable analysis,including age, ILD severity, short term functional decline, pulmonary hypertension, and body mass index (HR 2.07,95% CI 1.15-3.72;p<0.001).A significant association with free-standing bronchial abnormalities was also found (p<0.0001). The present study provides a thorough assessment of PPFE prevalence, associations and clinical impact in the largest cohort of SSc subjects published to date. PPFE presence should be carefully considered, due to its prognostic implications.

Laryngeal cancer is the neoplasm with the largest male to female sex ratio in most populations. Thus, inadequate data are available on women. We analyzed several risk factors in the combined dataset from two case-control studies conducted between 1986 and 2000 in northern Italy and Switzerland. Cases were 68 women under age 79 years, with incident, histologically confirmed cancer of the larynx. Controls were 340 women, admitted to the same network of hospitals as cases, for acute, nonmalignant conditions, unrelated to tobacco and alcohol consumption. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated by logistic regression models, conditioned by age, study center and year of interview, and including terms for education, body mass index, tobacco, alcohol drinking, and nonalcohol energy intake. Laryngeal cancer was strongly associated with cigarette smoking (OR = 435.7, 95% CI: 38.2-4964.4 for smokers of >/=25 cigarettes/day) and alcohol drinking (OR = 4.3, 95% CI: 0.8-24.1 for >/=5 drinks/day). An inverse relation was found for vegetables (OR = 0.3, 95% CI: 0.1-0.9 for the highest level of consumption), fruit (OR = 0.5, 95% CI: 0.2-1.3), and olive oil (OR = 0.3, 95% CI: 0.1-0.9). Reproductive and hormonal factors were not consistently associated to laryngeal cancer risk. This investigation, based on a uniquely large number of laryngeal cancers in women, provides definite evidence that cigarette smoking is the prominent risk factor for laryngeal cancer in women, accounting for 78% of cases in this population. Alcohol and selected dietary aspects account for approximately 30% of cases, whereas menstrual and hormonal factors do not appear to have a consistent role in laryngeal carcinogenesis.

Upper aerodigestive tract cancers are strongly related to smoking, and their incidence is substantially lower in former smokers than in continuing smokers. To estimate the effect of smoking cessation on the cumulative incidence of these cancers by age 75 years (in the absence of competing causes of death), the authors combined odds ratios for males from a network of Italian hospital-based case-control studies (1984-2000) with 1993-1997 incidence data for Italian men. The studies included 961 cases with oral/pharyngeal cancer, 618 cases with esophageal cancer, and 613 cases with laryngeal cancer, plus 3,781 controls. For all upper aerodigestive tract cancers, the cumulative risks by 75 years of age were 6.3% for men who continued to smoke any type of tobacco, 3.1% and 1.2% for men who stopped smoking at around 50 and 30 years of age, respectively, and 0.8% among lifelong nonsmokers. Corresponding figures were 3.3%, 1.4%, 0.5%, and 0.2% for oral/pharyngeal cancer; 1.0%, 0.5%, 0.4%, and 0.2% for esophageal cancer; and 2.1%, 1.1%, 0.2%, and 0.2% for laryngeal cancer. In this Italian population, men who stopped smoking before age 50 years avoided more than half of the excess risk of upper aerodigestive tract cancer as men who did not, and men who stopped smoking before age 30 years avoided more than 90% of the risk.

<p>Supplementary Table 1: Main characteristics of the studies included in the analysis.</p>

<p>Genomic co-ordinates of lung specific enhancers (hg19)</p>

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER^+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.