Virginia Boccardi

Oncogene‐induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions

In normal human somatic cells, telomere dysfunction causes cellular senescence, a stable proliferative arrest with tumour suppressing properties. Whether telomere dysfunction‐induced senescence (TDIS) suppresses cancer growth in humans, however, is unknown. Here, we demonstrate that multiple and distinct human cancer precursor lesions, but not corresponding malignant cancers, are comprised of cells that display hallmarks of TDIS. Furthermore, we demonstrate that oncogenic signalling, frequently associated with initiating cancer growth in humans, dramatically affected telomere structure and function by causing telomeric replication stress, rapid and stochastic telomere attrition, and consequently telomere dysfunction in cells that lack hTERT activity. DNA replication stress induced by drugs also resulted in telomere dysfunction and cellular senescence in normal human cells, demonstrating that telomeric repeats indeed are hypersensitive to DNA replication stress. Our data reveal that TDIS, accelerated by oncogene‐induced DNA replication stress, is a biological response of cells in human cancer precursor lesions and provide strong evidence that TDIS is a critical tumour suppressing mechanism in humans.

Relationships Between Daily Acute Glucose Fluctuations and Cognitive Performance Among Aged Type 2 Diabetic Patients

OBJECTIVE The mean amplitude of glycemic excursions (MAGE) is a significant determinant of overall metabolic control as well as increased risk for diabetes complications. Older individuals with type 2 diabetes are more likely to have moderate cognitive deficits and structural changes in brain tissue. Considering that poor metabolic control is considered a deranging factor for cognitive performance in diabetic patients, we evaluated whether the contributions of MAGE to cognitive status in older patients with type 2 diabetes were independent from the main markers of glycemic control, such as sustained chronic hyperglycemia (A1C), postprandial glycemia (PPG), and fasting plasma glucose (FPG). RESEARCH DESIGN AND METHODS In 121 older patients with type 2 diabetes, 48-h continuous subcutaneous glucose monitoring (CSGM) were assessed. MAGE and PPG were evaluated during CSGM. The relationship of MAGE to performance on cognitive tests was assessed, with adjustment for age, glycemic control markers, and other determinants of cognitive status. The cognitive tests were a composite score of executive and attention functioning and the Mini Mental Status Examination (MMSE). RESULTS MAGE was significantly correlated with MMSE (r = 0.83; P < 0.001) and with cognition composite score (r = 0.68; P < 0.001). Moreover, MAGE was associated with the MMSE (P < 0.001) and cognition composite score (P < 0.001) independently of age, sex, BMI, waist-to-hip (WHR) ratio, drug intake, physical activity, mean arterial blood pressure, FPG, PPG, and A1C. CONCLUSIONS MAGE during a daily period was associated with an impairment of cognitive functioning independent of A1C, FPG, and PPG. The present data suggest that interventional trials in older patients with type 2 diabetes should target not only A1C, PPG, and FPG but also daily acute glucose swings.

Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors

OBJECTIVE Blood glucose fluctuations have been found to be relevant to the progression of atherosclerosis in patients with type 2 diabetes and to be more detrimental for the development of atherosclerosis than the sustained hyperglycemia. We aim at evaluating the effect of blunted daily acute glucose fluctuations by DPP-IV inhibitors on intima-media thickness (IMT), a surrogate marker for early atherosclerosis. METHODS Data from a 12-week prospective, randomized, open-label parallel group trial with a blinded-endopoint study on 90 patients with DMT2, assessing the role of Dipeptidyl Peptidase-4 inhibition in lowering oxidative stress and inflammation by reducing daily acute glucose fluctuations (MAGE), were included in the present analysis. RESULTS Administration of both sitagliptin and vildagliptin treatment resulted in a significant decline in IMT. Indeed, vs baseline data Vildagliptin vs Sitagliptin resulted in a greater IMT reduction. After 3 months therapy changes in IMT significantly correlated with changes in MAGE but not with change in HbA1c in the whole population. Only change in MAGE and LDL plasma levels resulted to be independent predictors of the reduced carotid intima-media thickness after adjusting for conventional cardiovascular risk factors in patients with type 2 diabetes. Significant correlations between change in MAGE, change in IMT and change in fasting and interprandial inflammation score and nitrotyrosine plasma levels were found. CONCLUSION Reduction of glucose excursion due to DPP-IV inhibitors administration, may prevent atherosclerosis progression in patients with type 2 diabetes probably through the reduction of daily inflammation and oxidative stress.

Mediterranean diet, telomere maintenance and health status among elderly.

Leukocyte telomere length (LTL) and rate of telomere shortening are known biomarkers of aging while, numerous studies showed that Mediterranean diet (MD) may boost longevity. We studied association between telomere length, telomerase activity and different adherence to MD and its effects on healthy status. The study was conducted in 217 elderly subjects stratified according Mediterranean diet score (MDS) in low adherence (MDS≤3), medium adherence (MDS 4–5) and high adherence (MDS≥6) groups. LTL was measured by quantitative polymerase chain reaction and telomerase activity by a PCR-ELISA protocol. High adherence group showed longer LTL (p = 0.003) and higher telomerase activity (p = 0.013) compared to others. Linear regression analysis including age, gender, smoking habit and MDS showed that MDS was independently associated with LTL (p = 0.024) and telomerase activity levels (p = 0.006). Telomerase activity was independently associated with LTL (p = 0.007) and negatively modulated by inflammation and oxidative stress. Indeed, telomerase levels were associated with healthy status independently of multiple covariates (p = 0.048). These results support a novel role of MD in promoting health-span suggesting that telomere maintenance, rather than LTL variability is the major determinant of healthy status among elderly.

Higher circulating levels of IGF-1 are associated with longer leukocyte telomere length in healthy subjects

Mutations that inhibit the insulin-like growth factor-1 (IGF-1) extend the lifespan of worms, flies and mice. However, it appears that relatively low circulating levels of IGF-1 in humans are associated with aging-related diseases and diminished longevity. As leukocyte telomere length (LTL) is ostensibly a biomarker of human aging, we examined the relationship between LTL and blood IGF-1 in a healthy cohort. Our sample comprised 476 healthy, unrelated Caucasians (208 men and 268 women), aged 16-104 years, living in the West Coast of Southern Italy. We measured LTL by Southern blots and IGF-1 by enzyme-linked immunoassay. Both IGF-1 and LTL diminished with age (IGF-1, r=-0.601, P<0.001; LTL, r=-0.706, P<0.001). Age-adjusted LTL was positively associated with IGF-1 level throughout the age range of the cohort (r=0.270, P<0.001). IGF-1 accounted for about 10% of the inter-individual variation in LTL over and above the effect of age. Our findings suggest that both circulating IGF-1 and LTL are indices of healthy aging in humans. Further research will be necessary to establish whether LTL will ultimately be used in clinical settings as an index of healthy aging.

Surgery or Peroral Esophageal Myotomy for Achalasia: A Systematic Review and Meta-Analysis.

AbstractTo date very few studies with small sample size have compared peroral esophageal myotomy (POEM) with the current surgical standard of care, laparoscopic Heller myotomy (LHM), in terms of efficacy and safety, and no recommendations have been proposed.To investigate the efficacy and safety of POEM compared with LHM, for the treatment of achalasia.The databases of Pubmed, Medline, Cochrane, and Ovid were systematically searched between January 1, 2005 and January 31, 2015, with the medical subject headings (MeSH) and keywords “achalasia,” “POEM,” “per oral endoscopic myotomy,” and “peroral endoscopic myotomy,” “laparoscopic Heller myotomy” (LHM), “Heller myotomy.”All types of study designs including adult patients with diagnosis of achalasia were selected. Studies that did not report the comparison between endoscopic and surgical treatment, experimental studies in animal models, single case reports, technical reports, reviews, abstracts, and editorials were excluded.The total number of included patients was 486 (196 in POEM group and 290 in LHM group).There were no differences between POEM and LHM in reduction in Eckardt score (MD = −0.659, 95% CI: −1.70 to 0.38, P = 0.217), operative time (MD = −0.354, 95% CI: −1.12 to 0.41, P = 0.36), postoperative pain scores (MD = −1.86, 95% CI: −5.17 to 1.44, P = 0.268), analgesic requirements (MD = −0.74, 95% CI: −2.65 to 1.16, P = 0.445), and complications (OR = 1.11, 95% CI: 0.5–2.44, P = 0.796). Length of hospital stay was significantly lower for POEM (MD = −0.629, 95% CI: −1.256 to −0.002, P = 0.049). There was a trend toward significant reduction in symptomatic gastroesophageal reflux rate in favors of LHM compared to POEM group (OR = 1.81, 95% CI: 1.11–2.95, P = 0.017).All included studied were not randomized. Furthermore all selected studies did not report the results of follow-up longer than 1 year and most of them included patients who were both treatment naive and underwent previous endoscopic or surgical interventions for achalasia.POEM represents a safe and efficacy procedure comparable to the safety profile of LHM for achalasia at a short-term follow-up. Long-term clinical trials are urgently needed.

A new pleiotropic effect of statins in elderly: modulation of telomerase activity

Recent evidence suggests a link between statins and telomere biology. Whether statin treatment may modulate telomerase activity and affect telomere erosion rate is unknown. We aimed at investigating the potential impact of statin therapy on peripheral blood mononuclear cells telomerase activity, its implication on LTL variability, and its association with telomere shortening rates along with aging. The cross‐sectional study was conducted in 230 subjects (age range: 30‐86 y) stratified according to statins treatment. LTL was measured by quantitative polymerase chain reaction and telomerase activity by a PCR‐ELISA protocol. Subjects on statin treatment showed higher telomerase activity (P<0.0001) and longer LTL (P= 0.028) levels compared to the nonstatin group. Statin therapy was associated with higher telomerase activity independently of multiple covariates, including age, gender, smoking habits, lipid, systemic inflammation, glucose, and blood pressure levels (P=0.019). Indeed, subjects on statin treatment showed significant lower telomere erosion along with aging. Every 1 y increment in age, LTL decreases by 0.058 Kb in no statin and 0.033 Kb in statin groups, respectively, as well as the major difference in telomere attrition between groups was found after the age of 65 yr (P<0.0001). In summary, statins, modulating telomerase activity, affect telomere erosion along with aging.—Boccardi, V., Barbieri, M., Rizzo, M. R., Marfella, R., Esposito, A., Marano, L., Paolisso, G., A new pleiotropic effect of statins in elderly: modulation of telomerase activity FASEB J. 27, 3879–3885 (2013). www.fasebj.org

Telomerase gene therapy: a novel approach to combat aging

Telomeres are repetitive DNA sequences located at the very ends of our chromosomes. Together with specific proteins, they form a cap like structure that prevents the cells from sensing the linear chromosome ends as ‘damaged’. Like a burning fuse, telomeres progressively shorten with every cell division and, depending on cell type, initiate either apoptosis or trigger a permanent proliferative arrest, termed cellular senescence, once a critical length is reached. It is thought that this cell division countdown timer developed as a tumour suppressing mechanism to prevent precancerous cells from proliferating indefinitely. While we currently do not know how efficient this tumour suppressing mechanism is in humans, numerous studies using mouse models have demonstrated that critically short and dysfunctional telomeres indeed present a powerful barrier to cancer growth (Artandi & DePinho, 2010). Unfortunately, this tumour suppressing mechanism also comes at a cost. As we age, telomeres in most of our tissues progressively become shorter and therefore likely contribute to the failure of our organs and tissues observed in old age. Supporting this are data demonstrating that healthy lifespan is positively correlated with longer telomeres in humans, and patients suffering from age‐related diseases and premature aging syndromes display shorter telomeres compared to healthy individuals (Zhu et al, 2011). Furthermore, cells with damaged telomeres accumulate in some tissues of aging mice and nonhuman primates, supporting the model that telomere shortening and the resulting senescence response promotes aging in mammals (Fumagalli et al, 2012; Herbig et al, 2006; Hewitt et al, 2012). Indeed, preventing the accumulation of senescent cells in aging mice significantly improves healthspan, demonstrating that cellular senescence, regardless of its induction, is a cause of aging associated disorders (Baker et al, 2011). Certain cells within our tissues have the ability to stabilize telomere lengths more efficiently than others. …

Telomerase activation: A potential key modulator for human healthspan and longevity

The elderly population is increasing progressively. Along with this increase the number of age related diseases, such as cardiovascular, neurodegenerative diseases, metabolic impairment and cancer, is also on the rise thereby negatively impacting the burden on health care systems. Telomere shortening and dysfunction results in cellular senescence, an irreversible proliferative arrest that has been suggested to promote organismal aging and disabling age-related diseases. Given that telomerase, the enzyme responsible for maintaining telomere lengths, is not expressed at levels sufficient to prevent telomere shortening in most of our cells, telomeres progressively erode with advancing age. Telomerase activation, therefore, might serve as a viable therapeutic strategy to delay the onset of cellular senescence, tissue dysfunction and organismal decline. Here we analyze the more recent findings in telomerase activation as a potential key modulator for human healthspan and longevity.

Comparison of the 6th and 7th editions of the AJCC/UICC TNM staging system for gastric cancer focusing on the “N” parameter-related survival: the monoinstitutional NodUs Italian study

BackgroundA large number of Asian population studies examined the difference between the 6th and the 7th tumor, node, metastasis (TNM) while it is still poorly validated among Caucasian populations. This is a retrospective study aimed at investigating the efficacy of the 7th edition American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system for gastric cancer focusing on the “N” parameter-related survival for prognostic assessment in gastric cancer patients of a single Western high-volume institution.MethodsFrom January 2002 to December 2009, the data of 274 patients with gastric cancer who underwent gastric surgery at the 8th General and Gastrointestinal Surgical Centre of the Second University of Naples were analyzed retrospectively. We collected data for patient demographics, tumor characteristics, surgical characteristics, and TNM stage. Particularly, the nodal status, with the number of dissected nodes and metastatic nodes, was reviewed from the pathology records. The same patient dataset was used to stage patients according to both the 6th and 7th edition criteria.ResultsAge at surgery, tumor location, histological grade, Lauren’s classification subtypes, and 6th and 7th AJCC/UICC N categories were found to have statistically significant associations with overall survival on univariate analysis. In the 6th edition staging system, the Kaplan–Meier plot did not show significant overlapped survival curves: significant differences were found between N0 and N1, P < .001; N1 and N2, P = .04; and N2 and N3, P < .001. On the contrary, in the 7th edition, among all five substages, there were similar survival curves between N categories 2 and 3a (P = .98) with a statistically significant discriminatory ability only between N1 versus N3b and N2 versus N3b (P = .02 and .04, respectively).ConclusionsBased on analysis, we found that several clinicopathological variables, especially histological grade and Lauren’s classification, were significant prognostic factors in our database. The 6th and 7th AJCC/UICC N classifications represent significantly independent prognostic factors, and the 6th AJCC/UICC N classification seems to be superior to the 7th AJCC/UICC N classification in terms of uniformity, differentiation, and monotonicity of gradients.