The long non-coding RNA TAZ-AS202 promotes lung cancer progression via regulation of the E2F1 transcription factor and activation of Ephrin signaling.

Long non-coding RNAs (lncRNAs) are transcripts without coding potential that are pervasively expressed from the genome and have been increasingly reported to play crucial roles in all aspects of cell biology. They have been also heavily implicated in cancer development and progression, with both oncogenic and tumor suppressor functions. In this work, we identified and characterized a novel lncRNA, TAZ-AS202, expressed from the TAZ genomic locus and exerting pro-oncogenic functions in non-small cell lung cancer. TAZ-AS202 expression is under the control of YAP/TAZ-containing transcriptional complexes. We demonstrated that TAZ-AS202 is overexpressed in lung cancer tissue, compared with surrounding lung epithelium. In lung cancer cell lines TAZ-AS202 promotes cell migration and cell invasion. TAZ-AS202 regulates the expression of a set of genes belonging to cancer-associated pathways, including WNT and EPH-Ephrin signaling. The molecular mechanism underlying TAZ-AS202 function does not involve change of TAZ expression or activity, but increases the protein level of the transcription factor E2F1, which in turn regulates the expression of a large set of target genes, including the EPHB2 receptor. Notably, the silencing of both E2F1 and EPHB2 recapitulates TAZ-AS202 silencing cellular phenotype, indicating that they are essential mediators of its activity. Overall, this work unveiled a new regulatory mechanism that, by increasing E2F1 protein, modifies the non-small cell lung cancer cells transcriptional program, leading to enhanced aggressiveness features. The TAZ-AS202/E2F1/EPHB2 axis may be the target for new therapeutic strategies.

Serum uric acid is associated with non-dipping circadian pattern in young patients (30-40 years old) with newly diagnosed essential hypertension.

BACKGROUND: We aimed at evaluating the relationship between the circadian blood pressure rhythm and UA level in young patients (30-40 years old) with newly diagnosed essential hypertension. METHODS: The study included 62 essential hypertensive patients and 29 healthy controls (20 men, 35 ± 3 years) divided into two groups according to 24-hour ABPM results: 30 dippers and 32 nondippers. RESULTS: Nondippers showed significantly higher both serum UA levels compared to dippers and controls (6.1 ± 0.7, 5.2 ± 0.9 and 4.1 ± 0.9 mg/dL, p < 0.001, respectively); and high sensitivity C-reactive protein (hsCRP) (4.1 ± 2.2 mg/L, 3.3 ± 1.9 mg/L, and 1.4 ± 0.9 mg/L, p < 0.001, respectively). After adjusting for age, sex, body mass index, smoking, creatinine levels, hsCRP and comorbidity, multivariate logistic regression analysis revealed an independent association between serum UA levels and nondipper pattern (OR 2.44, 95%CIs 1.4-4.1, p = 0.002). CONCLUSION: Serum UA is independently associated with nondipper circadian pattern in young patients with newly diagnosed essential hypertension.

Exercise training improves cardiopulmonary and endothelial function in women with breast cancer: findings from the Diana-5 dietary intervention study.

To investigate whether exercise training (ET) improves cardiopulmonary and endothelial function in women with breast cancer (BC). Fifty-one female patients (aged between 39 and 72 years) with a history of primary invasive BC within the previous 5 years and enrolled in the Mediterranean diet-based DIANA (diet and androgens)-5 Trial were subdivided into 2 groups: an ET group (n = 25) followed a formal ET program of moderate intensity (3 session/week on a bicycle at 60-70 % VO2peak for 3 months, followed by one session/week until 1-year follow-up), while a control group (n = 26) did not perform any formal ET. At baseline and at 1-year follow-up, all patients underwent cardiopulmonary exercise stress test (CPET) and measurements of vascular endothelial function by peripheral artery tonometry (Reactive Hyperemia Index, RHI). There were no significant differences between the groups in baseline anthropometrical, BC characteristics, and metabolic profile. No differences in baseline CPET and RHI parameters were found. Peak oxygen consumption (VO2peak) significantly increased in ET group (from 12.4 ± 2.9 to 14.3 ± 3.3 mL/kg/min, p < 0.001) compared to the control group (from 12.8 ± 2.5 to 12.6 ± 2.8 mL/kg/min, p = 0.55; p < 0.001 between groups). Compared to the control group (from 2.0 ± 0.4 to 1.9 ± 0.4, p = 0.62), the ET group showed a significant improvement of RHI after 1 year (from 2.1 ± 0.7 to 2.5 ± 0.8, p < 0.001). Changes in VO2peak were correlated with changes in RHI (ΔVO2peak vs. ΔRHI: r = 0.47, p = 0.017). In BC survivors, ET program improves cardiopulmonary functional capacity and vascular endothelial function after 12 months. Whether these changes may favorably modulate some of the pathophysiological mechanisms implied in cancer evolution should be investigated.

Exercise training improves heart rate recovery in women with breast cancer.

PURPOSE: To determine whether exercise training improves autonomic function in women with breast cancer (BC). METHODS: Fifty-one patients (aged between 39 and 72 years) with a history of primary invasive BC within the previous 5 years and enrolled in the Mediterranean diet-based DIANA (Diet and Androgens)-5 Trial were subdivided in two groups: a ET group (n = 25) followed a formal ET program of moderate intensity (3 session/week on a bicycle at 60-70% VO2peak for 3 months, followed by one session/week until 1-year follow-up), while a control group (n = 26) did not perform any formal ET. At baseline and after 1-year, all patients underwent cardiopulmonary exercise stress test (CPET). Heart rate recovery (HRR) was calculated as the difference between heart rate at peak exercise and heart rate at first minute of the cool-down period. RESULTS: There were no significant differences between groups in baseline anthropometrical, BC characteristics, metabolic profile, CPET parameters and HRR. Compared to controls, at 1-year follow-up ET group showed a significant improvement in VO2peak (from 12.6 ± 3.0 to 14.5 ± 3.3 ml/kg/min, p < 0.001; p < 0.001 between groups); and in HRR (from 17.6 ± 6.4 to 23.0 ± 8.3 beats/min, p < 0.001; p < 0.001 between groups). In ET group the changes in HRR directly correlated with changes in VO2peak (r = 0.58, p = 0.002). CONCLUSIONS: Moderate intensity exercise training in BC survivors is associated with improvement of autonomic function. Whether the improvement of sympatho-vagal balance may favorably modulate some of the pathophysiological mechanisms implied in cancer evolution need further investigation.

[Anti remodeling therapy: new strategies and future perspective in post-ischemic heart failure. Part II]. / Terapie antiremodeling: nuove strategie e prospettive future nell'insufficienza cardiaca cronica post ischemica: Parte II.

In recent years, the remarkable progress achieved in terms of survival after myocardial infarction have led to an increased incidence of chronic heart failure in survivors. This phenomenon is due to the still incomplete knowledge we possess about the complex pathophysiological mechanisms that regulate the response of cardiac tissue to ischemic injury. These involve various cell types such as fibroblasts, cells of the immune system, endothelial cells, cardiomyocytes and stem cells, as well as a myriad of mediators belonging to the system of cytokines and not only. In parallel with the latest findings on post-infarct remodeling, new potential therapeutic targets are arising to halt the progression of disease. After the evaluation of the results obtained from gene therapy and stem cells, in this part we evaluate micro-RNA, post-translational modification and microspheres based therapy.

Exercise training reduces high mobility group box-1 protein levels in women with breast cancer: findings from the DIANA-5 study.

PURPOSE: To determine whether exercise training might exert anti-inflammatory effect by reducing HMGB1 levels in women with breast cancer (BC). METHODS: We analyzed monocentric data from the DIANA (DIET AND ANDROGENS)-5 PROJECT. Study population consisted of 94 patients randomized into two groups: 61 patients (53 +/- 8 yrs, training group) were assigned to a structured exercise training intervention (3 times/week for the first 3 months, and once /week for the following 9 months); whereas 33 patients (52 +/- 7 yrs, control group) followed only the general indications to adhere to the life-style intervention suggestions of the DIANA protocol. At study entry and after 12 months, all patients underwent cardiopulmonary exercise testing, biochemical as- sessment [HMGB1, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6)]; and lipid and glycemic profile. RESULTS: There were no significant differences between groups in baseline clinical and inflammatory profile. Among the training group, only 19/61 patients had high adherence to the exercise intervention. After stratifying the study population according to the level of adhesion to the exer- cise intervention, 1-year HMGB1 levels were lower among patients more adherent to exercise (p for trend = 0.001). Further adjusting for age, body mass index and baseline values, 1-year HMGB1 levels remained significantly and inversely associated to the level of adhesion to the exercise intervention (B = -0.97, SE = 0.43, p = 0.01). CONCLUSIONS: Moderate intensity exercise training in BC survivors is associated with reduced HMGB1 levels that are proportional to the level of adhesion to the exercise intervention, independently from other classical inflammatory molecules, suggesting an exercise-induced anti-inflammatory effect mediated by HMGB1.

Effects of exercise training started within 2 weeks after acute myocardial infarction on myocardial perfusion and left ventricular function: a gated SPECT imaging study.

BACKGROUND: Several studies suggested that exercise training might improve myocardial perfusion by inducing coronary vascular adaptations or enhancing collateralization. However, these findings were obtained in patients with chronic coronary artery disease using thallium-201 myocardial perfusion scintigraphy. We evaluated whether a long-term exercise-based cardiac rehabilitation (CR) started early (9 ± 3 days) after ST elevation acute myocardial infarction (STEMI) improves myocardial perfusion and left ventricular (LV) function, evaluated by gated single-photon emission computed tomography (SPECT) imaging. DESIGN: Randomized controlled study. METHODS: Fifty patients with recent STEMI were randomized into two groups: 24 enrolled in a 6-month exercise-based CR programme (group T) and 26 discharged with generic instructions for maintaining physical activity and correct lifestyle (group C). All patients underwent cardiopulmonary exercise test and gated SPECT within 3 weeks after STEMI and at 6-month follow up. RESULTS: At follow up, group T showed a significant reduction of stress-induced ischaemia (p < 0.01) and an improvement in resting and post-stress wall motion (both p < 0.005) and resting (p < 0.05) and post-stress wall thickness (p < 0.005) score indexes. At follow up, group T showed an improvement in peak oxygen consumption (p < 0.0001), O(2) pulse (p < 0.05), and in the slope of increase in ventilation over carbon dioxide output (p < 0.001). No changes in myocardial perfusion parameters, LV function, and cardiopulmonary indexes were observed in group C at follow up. CONCLUSIONS: Six months of exercise training early after STEMI reduces stress-induced ischaemia and improves LV wall motion and thickness. Exercise-induced changes in myocardial perfusion and function were associated with the absence of unfavourable LV remodelling and with the improvement of cardiovascular functional capacity.

Vulnerable personality and Takotsubo cardiomyopathy consequent to emotional stressful events: a clinical case report.

INTRODUCTION: Although the onset of Takotsubo cardiomyopathy (TTC) can be triggered by an acute, intense emotional stress, the exact pathogenic mechanisms still remain undefined. PRESENTATION: A 58-year-old female was sent by ambulance to the Emergency Department (ED) for chest pain and ST elevations on ECG. Her chest pain began 3 hours before on admission after a domestic argument. Transthoracic echocardiogram showed severe systolic dysfunction with an ejection fraction of 20%. Cardiac catheterization revealed no significant coronary artery disease. The left ventriculogram showed apical ballooning with hyperdynamic proximal segments. A diagnosis of Takotsubo Cardiomyophaty (TTC) was made according to the Mayo Clinic 2008 criteria. The patient evolved with improvement of her condition and, therefore, was discharged from the hospital. Follow-up echocardiogram seven days later showed normal LV size and function with ejection fraction (EF) of 43%. Paykel Life Stress Event Scale identified as emotional trigger a domestic argument occurred 3 hours before symptom onset. History showed a major life stress event, death of a loved one, six months before symptoms. The patient underwent psychological assessment after hospital discharge by Emotional Regulation Questionnaire and BDI showing high suppression/ low reappraisal profile and moderate depression. CONCLUSION: This case highlights the hypothesis of a possible link between cognitive emotional processing and vulnerability to Takotsubo syndrome.

[Obesity and ischemic heart disease. Is there a link between wellness' diseases?]. / Obesità e cardiopatia ischemica. Esiste un legame tra le malattie del benessere?

Obesity, the most common nutritional disorder in Western countries, is usually associated to cardiovascular diseases. However, the precise molecular pathways underlying this close association remain poorly understood. Nowadays, the adipose tissue is considered as an endocrine organ able to produce substances called adipo(cyto)kines that have different effects on lipid metabolism, closely involved in metabolic syndrome, and cardiovascular risk. The increased cardiovascular risk can be related also to peculiar dysfunction in the endocrine activity of adipose tissue observed in obesity responsible of vascular impairment (including endothelial dysfunction), prothrombotic tendency, and low-grade chronic inflammation. The present review aims at providing an up-dated overview on the adipocyte-derived molecules potentially involved in cardiovascular pathophysiology.