microRNA pattern in tumoral lung tissues from former- and non-smokers: a possible footprint for environmental and genetic risk factors evaluation.

For the last decade the interest of microRNA as a possible early biomarker for lung-cancer has increased. Less attention has been focused in using microRNA as a biomarker to study the contribution of environmental exposure to air pollutants in non-smokers lung cancer patients. The aim of this thesis is the identification of environmental related microRNA pattern in collected tissues from a total of 64 formal- and non- smoker patients recruited in a three-year observational study. The identified patterns may be used as early predictors of lung cancer, as well as environmental-related footprints. Through microRNA-chip array analysis of lung tissue, it was studied the expression of 2549 microRNAs. A differential analysis between healthy and tumoral tissue showed the presence of 273 microRNA differentially regulated, 222 were down-regulated and 51 up-regulated. Differential analysis was also applied to identify environmental pollution related microRNAs and finding microRNA deregulation in Passive Smoking at home (n=8), Passive smoking at work (n=1), Vehicle traffic at home (n=53), home distance from Etna Volcano (n=21), and home Type radon risk (n=19) exposures. A second biomarker, Benzo(a)Pyrene-DNA adducts levels in blood, was also studied to understand its correlation to the above-mentioned environmental factors. The specificity of this biomarker was minor than microRNA pattern biomarker, but it was strongly correlated to vehicle traffic pollution. The analysis of the microRNA environmental signatures indicates the contribution of environmental factors to the analysed lung cancers in the following decreasing rank: (a) vehicle traffic, (b) passive smoke, (c) radon, and (d) volcano ashes. These results provide evidence that microRNA analysis can be used to investigate the contribution of environmental factors in human lung cancer occurring in non-smoker

Prediction of Titanium Implant Success by Analysis of microRNA Expression in Peri-Implant Tissue. A 5-Year Follow-Up Study

The aim of the present study is to evaluate the expression of microRNA (miRNA) in peri-implant soft tissue and to correlate epigenetic information with the clinical outcomes of the implants up to the five-year follow-up. Seven patients have been rehabilitated with fixed screw-retained bridges each supported by implants. Peri-implant bone resorption and soft tissue health parameters have been recorded over time with a five-year follow-up. Mini-invasive samples of soft peri-implant tissue have been taken three months after implant insertion. miRNA have been extracted from cells of the soft tissue samples to evaluate gene-expression at the implant sites by microarray analysis. The epigenomic data obtained by microarray technology has been statistically analyzed by dedicated software and compared with measured clinical parameters. Specific miRNA expression profiles predictive of specific clinical outcomes were found. In particular, some specific miRNA signatures appeared to be \u201cprotective\u201d from bone resorption despite the presence of plaque accumulation. miRNA may be predictors of dental implant clinical outcomes and may be used as biomarkers for diagnostic and prognostic purposes in the field of implant dentistry

Two calix[4]pyrroles as potential therapeutics for castration-resistant prostate cancer

Macrocyclic compounds meso-(p-acetamidophenyl)-calix[4]pyrrole and meso-(m-acetamidophenyl)-calix[4]pyrrole have previously been reported to exhibit cytotoxic properties towards lung cancer cells. Here, we report pre-clinical in vitro and in vivo studies showing that these calixpyrrole derivatives can inhibit cell growth in both PC3 and DU145 prostatic cancer cell lines. We explored the impact of these compounds on programmed cell death, as well as their ability to inhibit cellular invasion. In this study we have demonstrated the safety of these macrocyclic compounds by cytotoxicity tests on ex-vivo human peripheral blood mononuclear cells (PBMCs), and by in vivo subcutaneous administration. Preliminary in vivo tests demonstrated no hepato-, no nephro- and no genotoxicity in Balb/c mice compared to controls treated with cisplatin. These findings suggest these calixpyrroles might be novel therapeutic tools for the treatment of prostate cancer and of particular interest for the treatment of androgen-independent castration-resistant prostate cancer

Fraisinib: a calixpyrrole derivative reducing A549 cell-derived NSCLC tumor in vivo acts as a ligand of the glycine-tRNA synthase, a new molecular target in oncology

Background and purpose: Lung cancer is the leading cause of death in both men and women, constituting a major public health problem worldwide. Non-small-cell lung cancer accounts for 85%–90% of all lung cancers. We propose a compound that successfully fights tumor growth in vivo by targeting the enzyme GARS1.Experimental approach: We present an in-depth investigation of the mechanism through which Fraisinib [meso-(p-acetamidophenyl)-calix(4)pyrrole] affects the human lung adenocarcinoma A549 cell line. In a xenografted model of non-small-cell lung cancer, Fraisinib was found to reduce tumor mass volume without affecting the vital parameters or body weight of mice. Through a computational approach, we uncovered that glycyl-tRNA synthetase is its molecular target. Differential proteomics analysis further confirmed that pathways regulated by Fraisinib are consistent with glycyl-tRNA synthetase inhibition.Key results: Fraisinib displays a strong anti-tumoral potential coupled with limited toxicity in mice. Glycyl-tRNA synthetase has been identified and validated as a protein target of this compound. By inhibiting GARS1, Fraisinib modulates different key biological processes involved in tumoral growth, aggressiveness, and invasiveness.Conclusion and implications: The overall results indicate that Fraisinib is a powerful inhibitor of non-small-cell lung cancer growth by exerting its action on the enzyme GARS1 while displaying marginal toxicity in animal models. Together with the proven ability of this compound to cross the blood–brain barrier, we can assess that Fraisinib can kill two birds with one stone: targeting the primary tumor and its metastases “in one shot.” Taken together, we suggest that inhibiting GARS1 expression and/or GARS1 enzymatic activity may be innovative molecular targets for cancer treatment

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

MicroRNA (miRNA) Differential Expression and Exposure to Crude-Oil- Related Compounds

This review summarizes studies on miRNA differential regulation related to exposure to crude oil and 20 different crude oil chemicals, such as hydrocarbons, sulphur, nitrogen, and metalcontaining compounds. It may be interesting to explore the possibility of using early post-transcriptional regulators as a potential novel exposure biomarker. Crude oil has been defined as a highly complex mixture of solids, liquids, and gases. Given the toxicological properties of the petroleum components, its extraction and elaboration processes represent high-risk activities for the environment and human health, especially when accidental spills occur. The effects on human health of short-term exposure to petroleum are well known, but chronic exposure effects may variate depending on the exposure type (i.e., work, clean-up activities, or nearby residence). As only two studies are focused on miRNA differential expression after crude-oil exposure, this review will also analyse the bibliography concerning different crude-oil or Petroleum-Related Compounds (PRC) exposure in Animalia L. kingdom and how it is related to differential miRNA transcript levels. Papers include in vitro, animal, and human studies across the world. A list of 10 miRNAs (miR-142-5p, miR-126-3p, miR-24-3p, miR-451a, miR-16-5p, miR-28-5p, let-7b-5p, miR-320b, miR-27a-3p and miR-346) was created based on bibliography analysis and hypothesised as a possible \u201cfootprint\u201d for crude-oil exposure. miRNA differential regulation can be considered a Big-Data related challenge, so different statistical programs and bioinformatics tools were used to have a better understanding of the biological significate of the most interesting data

Micronucleus Induction in <i>Vicia faba</i> Root Tips by Crude Oil-Polluted Soil from Ecuadorian Amazon

In the past four decades, the Amazon rainforest has emerged as a crucial zone for crude oil extraction in the South American region. In the Ecuadorian Amazon rainforest, hydrocarbon blocks (called “bloques”) cover vast zones, including agricultural and livestock farms, protected natural regions and the territories of uncontacted indigenous tribes. This study proposes a micronuclei assay on Vicia faba following a 24 h exposure to various soil samples collected from Bloque 57 in Ecuador. Sampling was conducted between the Dayuma and Aguarico zones, approximately 30 km from Nueva Loja city. The research aimed to assess the impact of different soil samples, particularly those from areas affected by crude oil spills, to induce micronuclei and mitotic index changes in V. faba roots. Results: The soil pollution caused by crude oil is not the sole factor contributing to cytotoxicity and genotoxicity in V. faba. Most samples from areas polluted by crude oil outside the small-scale farm showed no significant difference in micronuclei rate compared to negative control and Amazon unpolluted soil. Conversely, samples from the small-scale farm displayed a statistically significant genotoxic effect. Furthermore, samples collected from open-air wastewater pools demonstrated higher levels of cytotoxicity compared to the controls and those from small-scale farms. The mitotic index was lower in seedlings exposed to wastewater in open-air pools, especially for the 20 cm deep samples. This phenomenon could be linked to bitumen-like substances and oils floating on the surface, attaching to the small roots and causing suffocation

A Resveratrol Phenylacetamide Derivative Perturbs the Cytoskeleton Dynamics Interfering with the Migration Potential in Breast Cancer

Chemotherapy is commonly used for cancer treatment, however the lack of selectivity on healthy cells and the development of resistance phenomena are the major issues. A better understanding of cancer genetics helped the development of new targeted anticancer treatments, which permit drug delivery with high specificity and lower toxicity. Moreover, the multi-target drug design concept represents the current trend for future drug research and development. Starting from good results previously obtained by our research group on the resveratrol (RSV) phenylacetamide derivative 2, which displayed an interesting anti-inflammatory and anti-proliferative activity towards the breast cancer cells MCF-7 and MDA-MB-231, we identified other features, as the ability to perturb the cytoskeleton dynamics and interfere with the migration and metastatic processes. In vitro and in silico studies demonstrate that the derivative 2 is a tubulin and actin polymerization inhibitor and an actin depolymerization promotor. In addition, it interferes with the metastatic potential in both the breast cancer cells, inhibiting the in vitro cell migration and decreasing the spheroids number. These promising results demonstrate that the RSV phenylacetamide derivative 2 could be an important starting point in the discovery and development of safer and more efficacy multi-targeted agents