Emerging roles of telomeric chromatin alterations in cancer

Telomeres, the nucleoprotein structures that cap the ends of eukaryotic chromosomes, play important and multiple roles in tumorigenesis. Functional telomeres need the establishment of a protective chromatin structure based on the interplay between the specific complex named shelterin and a tight nucleosomal organization. Telomere shortening in duplicating somatic cells leads eventually to the destabilization of the telomere capping structure and to the activation of a DNA damage response (DDR) signaling. The final outcome of this process is cell replicative senescence, which constitute a protective barrier against unlimited proliferation. Cells that can bypass senescence checkpoint continue to divide until a second replicative checkpoint, crisis, characterized by chromosome fusions and rearrangements leading to massive cell death by apoptosis. During crisis telomere dysfunctions can either inhibit cell replication or favor tumorigenesis by the accumulation of chromosomal rearrangements and neoplastic mutations. The acquirement of a telomere maintenance mechanism allows fixing the aberrant phenotype, and gives the neoplastic cell unlimited replicative potential, one of the main hallmarks of cancer. Despite the crucial role that telomeres play in cancer development, little is known about the epigenetic alterations of telomeric chromatin that affect telomere protection and are associated with tumorigenesis. Here we discuss the current knowledge on the role of telomeric chromatin in neoplastic transformation, with a particular focus on H3.3 mutations in alternative lengthening of telomeres (ALT) cancers and sirtuin deacetylases dysfunctions

Coastal Dynamic and Evolution: Case Studies from Different Sites around theWorld

In recent decades, coastal areas have experienced a progressive increase in erosion and flooding processes as a consequence of the combined effect of natural factors and strong human pressures. These processes are particularly evident on low-lying areas and are expected to be exacerbated by the ongoing climate change, which will impact the littorals both in the short term, by affecting the duration and frequency of storms, and in the long term, by inducing variation in the sea-level position. In this context, this Special Issue is devoted to collecting geomorphological studies on coastal dynamic and evolution by means of multidisciplinary research methodologies and investigations, which represent a very useful set of information for supporting the integrated management of coastal zone. The volume includes 14 papers addressing three main topics (i) shoreline characterization, dynamic and evaluation; (ii) coastal hazard evaluation and impact assessment of marine events; and (iii) relevance of sediment collection and analysis for beach nourishment. Case studies from Russia, Italy, California (USA), Morocco, Spain, Indonesia, Ireland and Colombia are shown in the Special Issue, giving to the reader a wide overview of coastal settings and methodological approaches

Feasibility of Podcasts and City by City Analysis for Upside.FM

The objective of the project is to conduct a feasibility study for Upside, with regard to their underlying business model. We then hope to make recommendations for other cities and complementary products that can fit under the Upside umbrella

High plasma levels of endothelin-1 enhance the predictive value of preclinical atherosclerosis for future cerebrovascular and cardiovascular events: a 20-year prospective study

BACKGROUND AND PURPOSE: Clinical and experimental evidence suggests that endothelin-1 (Et-1) plays a role in cardiac and vascular disease. In the present study, we investigated the prognostic significance of Et-1 for cerebrovascular and cardiovascular outcome, in a 20-year follow-up. METHODS: We studied 82 originally healthy individuals, referred to our Unit of Cardiovascular Prevention, to evaluate the presence of asymptomatic carotid lesions. We subdivided these individuals into two groups, according to the plasma values of Et-1 (respectively ≤ or >2.7 pg/ml). Traditional cardiovascular risk factors were investigated, and by carotid ultrasound examination, we distinguished between normal individuals and those with intima-media thickening or asymptomatic carotid plaque. RESULTS: Major cardiac and cerebral events (all-cause death, myocardial infarction, revascularization procedures, fatal and nonfatal stroke) were registered in 41 individuals and significantly more in those with high vs. low Et-1 levels (95 vs. 5%; P < 0.0001). Furthermore, by logistic multivariate regression analysis, we found that among all evaluated baseline clinical and laboratory variables, hypertension [odds ratio (OR): 20.4 (3.3-127), P = 0.001], high Et-1 concentrations [OR: 1.4 (1.0-1.8), P = 0.02] and the presence of intima-media thickness or asymptomatic carotid plaque [OR: 3.7 (1.14-12.1), P = 0.02] were independent predictors of future events. Finally, integrating technical and laboratory data, high levels of Et-1 have defined a high risk of major cardiac and cerebral event and stroke at follow-up, which increased in relation to the progression of carotid atherosclerosis (P < 0.05). CONCLUSION: Et-1 plasmatic levels significantly influence the cardiovascular and cerebrovascular risk profile, beyond traditional cardiovascular risk factors and preclinical carotid atherosclerosis

Mitochondrial DNA Variations in Colombian Creole Sheep Confirm an Iberian Origin and Shed Light on the Dynamics of Introduction Events of African Genotypes

The genetic origins and diversity of Creole sheep from five regions of Colombia were investigated based on mitochondrial DNA (mtDNA) variations across 89 sequences from five breeds: one wool Creole sheep (CL) and four hair Creole sheep, including Ethiopian (OPCE), Sudan (OPCS), Pelibuey (OPCP) and Wayúu (OPCW). A global comparison was done using 62 haplotypes from Iberian, African, Indian, Caribbean, Mexican, Caucasian and European sheep based on sequences retrieved from GenBank. This study aimed to identify the maternal origin of Colombian Creole sheep and their genetic relationships at a global level. The results showed 31 different haplotypes from Colombian Creole sheep, which can be assigned to maternal lineage B, the most common lineage found in European sheep breeds and the only one found in several Iberian breed (e.g., Churra, Spanish Merino) that most likely participated in the Creole formation. Additional analyses showed that wool and hair sheep retained a broad genetic identity despite being geographically separated. The global-level phylogenetic analysis revealed that Colombian Creole sheep belong to a distinct and defined genetic lineage that is likely the result of a founder effect with ecotypes of Iberian descent and the subsequent introduction of foreign breeds. This is consistent with historical reports on the presence of sheep in South America and, particularly, Colombia

Potential Sea Level Rise Inundation in the Mediterranean: From Susceptibility Assessment to Risk Scenarios for Policy Action

Coastal ecosystems and anthropic activities are prone to be affected by the negative impact of marine-related processes induced by climate change, such as erosion, flooding and permanent inundation. Studies aiming at defining potential risk scenarios represent a valuable tool for the identification of the most suitable coastal adaptation measures. After outlining sea level rise implications at the Mediterranean scale, this paper deals with inundation risk scenarios for the years 2050 and 2100 for the north-eastern sector of the Island of Gozo (Malta), central Mediterranean Sea. The analysis, carried out by applying an index-based procedure, firstly required the evaluation of the susceptibility to inundation of the investigated coastal stretch under different sea level projections. Then, the spatial combination of inundation susceptibility with the exposure and vulnerability of the area allowed identification of the most critical sectors in terms of coastal risk. The results of the analysis showed that, under the worst-case climate scenarios, 5.5% and 8.1% of the investigated coastal sector are prone to very high inundation risk (Class R4) in 2050 and 2100, respectively. In particular, the bays of Ramla and Marsalforn, which are characterized by significant economic and touristic activities, were found to be the sites where the expected impacts of future sea level rise will be higher if no management strategy and adaptation action are taken in the near future

Looking for the best immune-checkpoint inhibitor in pre-treated NSCLC patients: An indirect comparison between nivolumab, pembrolizumab and atezolizumab

Immune-checkpoint inhibitors represent the new standard of care in patients with advanced NSCLC who progressed after first-line treatment. This work aim to assess any difference in both efficacy and safety profiles among Nivolumab, Pembrolizumab and Atezolizumab in pre-treated NSCLC patients. Randomized clinical trials comparing immune-checkpoint inhibitor versus docetaxel in pre-treated patients with advanced NSCLC were included and direct comparison meta-analysis of selected trials have been performed. Subsequently the summary estimates of Nivolumab, Pembrolizumab and Atezolizumab emerging from the direct meta-analysis were selected to provide the pooled estimates of hazard ratio (HR) and relative risk (RR) for the indirect comparisons among these agents. A total of 5 studies met the selection criteria and were included in the meta-analysis. Indirect comparisons for efficacy outcomes showed the RR for ORR nivolumab versus atezolizumab 1.66 (95% CI 1.07â2.58), pembrolizumab versus atezolizumab 1.94 (95% CI 1.30â2.90). No significant differences in both PFS and OS have been observed. Indirect comparisons for safety showed the RR for G3-5 AEs nivolumab versus pembrolizumab 0.41 (95% CI 0.29â0.60), nivolumab versus atezolizumab 0.50 (95% CI 0.35â0.72). No significant differences in both pneumonitis and discontinuation rate have been observed. The results of this work revealed that nivolumab and pembrolizumab are associated with a significant increase of ORR as compared to atezolizumab and nivolumab is associated with a significant lower incidence of G3-5 AEs as compared to the other drugs. These evidences could support the oncologists to select the best drug for each patient

Space Flight Effects on Antioxidant Molecules in Dry Tardigrades: The TARDIKISS Experiment

The TARDIKISS (Tardigrades in Space) experiment was part of the Biokon in Space (BIOKIS) payload, a set of multidisciplinary experiments performed during the DAMA (Dark Matter) mission organized by Italian Space Agency and Italian Air Force in 2011. This mission supported the execution of experiments in short duration (16 days) taking the advantage of the microgravity environment on board of the Space Shuttle Endeavour (its last mission STS-134) docked to the International Space Station. TARDIKISS was composed of three sample sets: one flight sample and two ground control samples. These samples provided the biological material used to test as space stressors, including microgravity, affected animal survivability, life cycle, DNA integrity, and pathways of molecules working as antioxidants. In this paper we compared the molecular pathways of some antioxidant molecules, thiobarbituric acid reactive substances, and fatty acid composition between flight and control samples in two tardigrade species, namely, Paramacrobiotus richtersi and Ramazzottius oberhaeuseri. In both species, the activities of ROS scavenging enzymes, the total content of glutathione, and the fatty acids composition between flight and control samples showed few significant differences. TARDIKISS experiment, together with a previous space experiment (TARSE), further confirms that both desiccated and hydrated tardigrades represent useful animal tool for space research

Dose reduction and discontinuation of standard-dose regorafenib associated with adverse drug events in cancer patients: a systematic review and meta-analysis

Regorafenib (REG) is an oral multikinase inhibitor used in colorectal cancer, gastrointestinal stromal tumour and hepatocellular carcinoma. Several adverse events (AEs) are commonly reported during REG administration, and strategies for managing AEs in everyday clinical practice include supportive care, dose modifications and, when necessary, treatment withdrawal. We performed a systematic review and meta-analysis to assess the schedule treatment modifications of REG associated with AEs across randomized controlled clinical trials (RCTs