Effetto dell’ivabradina nelle fasi iniziali e nella progressione dell’aterosclerosi

Effect of ivabradine in the initial steps and in the progression of the atherosclerosis Purpose: Ivabradine reduces heart rate (HR) by selectively inhibiting the If current in the sinus node. A sub-group of the BEAUTifUL study showed that ivabradine reduces the incidence of myocardial infarction in coronary artery disease (CAD) patients with HR ≥ 70bpm, suggesting a protective effect on the arterial wall. The SIGNifY study is currently testing this hypothesis in more than 19000 CAD patients. In dyslipidaemic mice, ivabradine improves vascular function and reduces aortic plaques area. It has been suggested that ivabradine may exert a protective activity by decreasing low/oscillatory shear stress, which is proinflammatory in the endothelium. This study aims to determine if HR reduction with ivabradine induces an atheroprotective gene expression profile in the endothelium of dyslipidaemic mice before plaque formation. Methods: 6 week-old ApoE deficient mice (n=6), fed a chow diet, were treated with ivabradine (30 mg/Kg/day, in drinking water) for 2 or 4 weeks. Two control groups (n=6) received no ivabradine. Ivabradine reduced HR by 17.4% and 22.9% in mice treated for 2 weeks and 4 weeks respectively. At the end of treatment, endothelium-enriched RNA was isolated from the aortic arch. Gene expression was analyzed by Agilent Whole Mouse Gene Expression Microarray (60k probes). Pathway analysis was performed using DAVID tools. Principal components analysis showed that most of the variability in gene expression can be attributed to ivabradine treatment and was independent of treatment duration. Differentially expressed genes were selected as having a ≥ 1.5-fold expression difference between treated and untreated groups with a p-value ≤ 0.01 at unpaired t-test. Results: Treatment induced changes in the expression of 930 transcripts. Shear stress-modulated pathways such as MAPK signalling and steroid biosynthesis process (both inhibited by treatment) were among the most significantly affected pathways (p-value = 0.0065 and 0.0009, respectively). We found up-regulation of anti-inflammatory genes and down-regulation of pro-apoptotic and pro-inflammatory genes, the majority of which were NF-kappa B and/or Ang II-regulated genes. Among them, the receptor for oxidized lipoprotein (Olr1) was strongly downregulated (3.2 fold). Conclusions: In dyslipidaemic mice, short term treatment with ivabradine induces an atheroprotective gene expression profile in the endothelium. Since many of the affected genes are shear stress regulated, our data suggest that shear stress frequency modulation could be part of the molecular mechanisms by which ivabradine protects the endothelium

Selective transcriptional regulation by Myc: Experimental design and computational analysis of high-throughput sequencing data

AbstractThe gene expression programs regulated by the Myc transcription factor were evaluated by integrated genome-wide profiling of Myc binding sites, chromatin marks and RNA expression in several biological models. Our results indicate that Myc directly drives selective transcriptional regulation, which in certain physiological conditions may indirectly lead to RNA amplification. Here, we illustrate in detail the experimental design concerning the high-throughput sequencing data associated with our study (Sabò et al., Nature. (2014) 511:488–492) and the R scripts used for their computational analysis

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

Despite considerable efforts carried out to develop stem/progenitor cell-based technologies aiming at replacing and restoring the cardiac tissue following severe damages, thus far no strategies based on adult stem cell transplantation have been demonstrated to efficiently generate new cardiac muscle cells. Intriguingly, dedifferentiation, and proliferation of pre-existing cardiomyocytes and not stem cell differentiation represent the preponderant cellular mechanism by which lower vertebrates spontaneously regenerate the injured heart. Mammals can also regenerate their heart up to the early neonatal period, even in this case by activating the proliferation of endogenous cardiomyocytes. However, the mammalian cardiac regenerative potential is dramatically reduced soon after birth, when most cardiomyocytes exit from the cell cycle, undergo further maturation, and continue to grow in size. Although a slow rate of cardiomyocyte turnover has also been documented in adult mammals, both in mice and humans, this is not enough to sustain a robust regenerative process. Nevertheless, these remarkable findings opened the door to a branch of novel regenerative approaches aiming at reactivating the endogenous cardiac regenerative potential by triggering a partial dedifferentiation process and cell cycle re-entry in endogenous cardiomyocytes. Several adaptations from intrauterine to extrauterine life starting at birth and continuing in the immediate neonatal period concur to the loss of the mammalian cardiac regenerative ability. A wide range of systemic and microenvironmental factors or cell-intrinsic molecular players proved to regulate cardiomyocyte proliferation and their manipulation has been explored as a therapeutic strategy to boost cardiac function after injuries. We here review the scientific knowledge gained thus far in this novel and flourishing field of research, elucidating the key biological and molecular mechanisms whose modulation may represent a viable approach for regenerating the human damaged myocardium

Cardiotoxicity of Anticancer Drugs: Molecular Mechanisms and Strategies for Cardioprotection

Chemotherapy and targeted therapies have significantly improved the prognosis of oncology patients. However, these antineoplastic treatments may also induce adverse cardiovascular effects, which may lead to acute or delayed onset of cardiac dysfunction. These common cardiovascular complications, commonly referred to as cardiotoxicity, not only may require the modification, suspension, or withdrawal of life-saving antineoplastic therapies, with the risk of reducing their efficacy, but can also strongly impact the quality of life and overall survival, regardless of the oncological prognosis. The onset of cardiotoxicity may depend on the class, dose, route, and duration of administration of anticancer drugs, as well as on individual risk factors. Importantly, the cardiotoxic side effects may be reversible, if cardiac function is restored upon discontinuation of the therapy, or irreversible, characterized by injury and loss of cardiac muscle cells. Subclinical myocardial dysfunction induced by anticancer therapies may also subsequently evolve in symptomatic congestive heart failure. Hence, there is an urgent need for cardioprotective therapies to reduce the clinical and subclinical cardiotoxicity onset and progression and to limit the acute or chronic manifestation of cardiac damages. In this review, we summarize the knowledge regarding the cellular and molecular mechanisms contributing to the onset of cardiotoxicity associated with common classes of chemotherapy and targeted therapy drugs. Furthermore, we describe and discuss current and potential strategies to cope with the cardiotoxic side effects as well as cardioprotective preventive approaches that may be useful to flank anticancer therapies

Adrenal Ganglioneuroma with Multifocal Retroperitoneal Extension: A Challenging Diagnosis

A ganglioneuroma (GN) is the rarest and most benign of the neuroblastic tumors and originates from neural crest cells wherever sympathetic nervous tissue exists, such as in the retroperitoneum and adrenal gland. The diagnosis can be very challenging, given the rarity and asymptomatic presentation of this neoplasia, and can be achieved only by means of histological evaluation. Although benign, a few cases of metastatic GNs have been reported in the literature. The prognosis, however, seems to be excellent after surgical resection. We describe a rare case of multifocal retroperitoneal GN, diagnosed incidentally in a 46-year-old woman, with para-aortic and adrenal localizations. After intraoperative pathological diagnosis was made, complete excision of all the visible masses was performed. The postoperative period was uneventful and she was recurrence free 3 months after surgery. To our knowledge, this is the first case report of a multifocal retroperitoneal GN. Among the broad differential diagnoses of adrenal incidentalomas, an adrenal location of neuroblastic tumors should not be forgotten

INSPEcT: a computational tool to infer mRNA synthesis, processing and degradation dynamics from RNA- and 4sU-seq time course experiments.

Abstract Motivation: Cellular mRNA levels originate from the combined action of multiple regulatory processes, which can be recapitulated by the rates of pre-mRNA synthesis, pre-mRNA processing and mRNA degradation. Recent experimental and computational advances set the basis to study these intertwined levels of regulation. Nevertheless, software for the comprehensive quantification of RNA dynamics is still lacking. Results: INSPEcT is an R package for the integrative analysis of RNA- and 4sU-seq data to study the dynamics of transcriptional regulation. INSPEcT provides gene-level quantification of these rates, and a modeling framework to identify which of these regulatory processes are most likely to explain the observed mRNA and pre-mRNA concentrations. Software performance is tested on a synthetic dataset, instrumental to guide the choice of the modeling parameters and the experimental design. Availability and implementation: INSPEcT is submitted to Bioconductor and is currently available as Supplementary Additional File S1. Contact: [email protected] Supplementary Information: Supplementary data are available at Bioinformatics online

Comunidad de paseriformes nidificantes de la Península Valdés (Patagonia, Argentina)

The Valdes Peninsula is a high-natural value area, located on the east coast of Argentine Patagonia. The aim of the reported research was to analyze the community of breeding passerine birds of the inland areas, with the purpose to identify the species that characterize each community, determining the main environmental typologies frequented, in order to study the relationships between bird richness and abundance, and environmental structure. During the breeding season 2011, 107 point counts were performed. 869 birds belonging to 23 passerine species were contacted and analyzed through a cluster analysis using the Indicator Value method. Results revealed the existence of two different communities: one that essentially refers to the grassy steppe where the characteristic species are Shortbilled Pipit (Anthus furcatus) and Common Miner (Geositta cunicularia), and the other one, which occupies the shrub-steppe consisting of more characteristic species, starting from the Rufous-collared Sparrow (Zonotrichia capensis), the most widespread species. These results update previous results on the community of passerines living in the study area and provide some useful insights for management purposes.La Península de Valdes es un area de gran riqueza natural, localizada en la costa Este de la Pa- tagonia Argentina. El propósito de este trabajo fue analizar la comunidad de aves Passeriformes de las areas internas de la región, con el proposito de identificar las especies que caracterizan cada comuni- dad, determinando las principales tipologias ambientales frecuentadas, para poder estudiar las rela- ciones entre la riqueza y abundancia de aves y la estructura del ambiente. Se realizaron 107 puntos de conteo durante la temporada reproductiva de 2011, en donde se detectaron 869 aves pertenecientes a 23 especies de Passeriformes. Para los análisis se usó el método de agrupamiento por el método del Indicator Value. Los resultados evidencian la existencia de dos diferentes comunidades: una asociada exclusivamente a la estepa herbácea y caracterizada por las especies Cachirla uña corta (Anthus furca- tus) y Minero común (Geositta cunicularia); mientras que la otra, asociada a la estepa arbustiva, es car- acterizada por diferentes especies típicas, como el Chingolo (Zonotrichia capensis), que es la especie de mayor distribución. Estos resultados constituyen una actualización al conocimiento de la fauna de la Península de Valdés, los cuales pueden ser útiles para el manejo y conservación de la avifauna de la región.Fil: Pruscini, Fabio. Università Di Urbino; ItaliaFil: Morelli, Federico. Università Di Urbino; ItaliaFil: Sisti, Davide. Università Di Urbino; ItaliaFil: Perna, Paolo. Universita Degli Di Camerino. Scuola Di Scienze Ambientale; ItaliaFil: Catorci, Andrea. Universita Degli Di Camerino. Scuola Di Scienze Ambientale; ItaliaFil: Bertellotti, Nestor Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Nacional Patagónico; ArgentinaFil: Rocchi, Marco Bruno Luigi. Università Di Urbino; ItaliaFil: Santolini, Ricardo. Università Di Urbino; Itali

Minimal Extrathyroidal Extension in Predicting 1-Year Outcomes: A Longitudinal Multicenter Study of Low-to-Intermediate-Risk Papillary Thyroid Carcinoma (ITCO#4)

Background: The role of minimal extrathyroidal extension (mETE) as a risk factor for persistent papillary thyroid carcinoma (PTC) is still debated. The aim of this study was to assess the clinical impact of mETE as a predictor of worse initial treatment response in PTC patients and to verify the impact of radioiodine therapy after surgery in patients with mETE. Methods: We reviewed all records in the Italian Thyroid Cancer Observatory (ITCO) database and selected 2237 consecutive patients with PTC who satisfied the inclusion criteria (PTC with no lymph node metastases and at least 1 year of follow-up). For each case, we considered initial surgery, histological variant of PTC, tumor diameter, recurrence risk class according to the American Thyroid Association (ATA) risk stratification system, use of radioiodine therapy, and initial therapy response, as suggested by ATA guidelines. Results: At 1-year follow-up, 1831 patients (81.8%) had an excellent response, 296 (13.2%) had an indeterminate response, 55 (2.5%) had a biochemical incomplete response, and 55 (2.5%) had a structural incomplete response. Statistical analysis suggested that mETE (odds ratio [OR] 1.16, p=0.65), tumor size >2 cm (OR 1.45, p=0.34), aggressive PTC histology (OR 0.55, p=0.15), and age at diagnosis (OR 0.90, p=0.32) were not significant risk factors for a worse initial therapy response. When evaluating the combination of mETE, tumor size, and aggressive PTC histology, the presence of mETE with a >2 cm tumor was significantly associated with a worse outcome (OR 5.27, 95% CI, p=0.014). The role of radioiodine ablation in patients with mETE was also evaluated. When considering radioiodine treatment, propensity score-based matching was performed, and no significant differences were found between treated and non-treated patients (p=0.24). Conclusions: This study failed to show the prognostic value of mETE in predicting initial therapy response in a large cohort of PTC patients without lymph node metastases. The study suggests that the combination of tumor diameter and mETE can be used as a reliable prognostic factor for persistence and could be easily applied in clinical practice to manage PTC patients with low-to-intermediate risk of recurrent/persistent disease

Management of Germ Cell Tumors During the Outbreak of the Novel Coronavirus Disease-19 Pandemic:A Survey of International Expertise Centers

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs). MATERIALS AND METHODS: To depict the state-of-the-art management of GCTs during the COVID-19 pandemic, a survey including 26 questions was circulated by e-mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network-Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options. RESULTS: Fifty-three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID-19-positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony-stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences. CONCLUSION: Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID-19 pandemic. IMPLICATIONS FOR PRACTICE: Despite the chaos, disruptions, and fears fomented by the COVID-19 illness, oncology care teams in Italy, other European countries, and Canada are delivering the enormous promise of curative management strategies for patients with testicular cancer and other germ cell tumors. At the same time, these teams are applying safe and innovative solutions and sharing best practices to minimize frequency and intensity of patient contacts with thinly stretched health care capacity