European compliance benchmark

The International Legal Research Group -European Compliance Benchmark is acooperation between The European Law Students' Association (ELSA) and K&L Gates. K&L Gates has provided ELSA with research questionsthat24 member and observer groups in our network successfullyinvestigatedin the framework of their respective national legislation. The topic of this LRG centered around the world of Corporate Compliance, as it is one of the hottest legal topicscurrently. What is meant by this is the degree to which companies abide by the regulations set for corporate governance and prevention of criminal measures in a commercial context. The questions of the LRG focused on outlining the relevant rules as well as assessing what the ramifications are for breaking them

CD271 activation prevents low to high-risk progression of cutaneous squamous cell carcinoma and improves therapy outcomes

Background: Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent form of skin cancer, showing a rapid increasing incidence worldwide. Although most cSCC can be cured by surgery, a sizeable number of cases are diagnosed at advanced stages, with local invasion and distant metastatic lesions. In the skin, neurotrophins (NTs) and their receptors (CD271 and Trk) form a complex network regulating epidermal homeostasis. Recently, several works suggested a significant implication of NT receptors in cancer. However, CD271 functions in epithelial tumors are controversial and its precise role in cSCC is still to be defined. Methods: Spheroids from cSCC patients with low-risk (In situ or Well-Differentiated cSCC) or high-risk tumors (Moderately/Poorly Differentiated cSCC), were established to explore histological features, proliferation, invasion abilities, and molecular pathways modulated in response to CD271 overexpression or activation in vitro. The effect of CD271 activities on the response to therapeutics was also investigated. The impact on the metastatic process and inflammation was explored in vivo and in vitro, by using zebrafish xenograft and 2D/3D models. Results: Our data proved that CD271 is upregulated in Well-Differentiated tumors as compared to the more aggressive Moderately/Poorly Differentiated cSCC, both in vivo and in vitro. We demonstrated that CD271 activities reduce proliferation and malignancy marker expression in patient-derived cSCC spheroids at each tumor grade, by increasing neoplastic cell differentiation. CD271 overexpression significantly increases cSCC spheroid mass density, while it reduces their weight and diameter, and promotes a major fold-enrichment in differentiation and keratinization genes. Moreover, both CD271 overexpression and activation decrease cSCC cell invasiveness in vitro. A significant inhibition of the metastatic process by CD271 was observed in a newly established zebrafish cSCC model. We found that the recruitment of leucocytes by CD271-overexpressing cells directly correlates with tumor killing and this finding was further highlighted by monocyte infiltration in a THP-1-SCC13 3D model. Finally, CD271 activity synergizes with Trk receptor inhibition, by reducing spheroid viability, and significantly improves the outcome of photodynamic therapy (PTD) or chemotherapy in spheroids and zebrafish. Conclusion: Our study provides evidence that CD271 could prevent the switch between low to high-risk cSCC tumors. Because CD271 contributes to maintaining active differentiative paths and favors the response to therapies, it might be a promising target for future pharmaceutical development

PHOTOGRAMMETRY FOR ARCHAEOLOGICAL 3D SURVEYING: THE CASE-STUDY OF PONTE ROTTO ALONG THE ANCIENT APPIA (BENEVENTO, ITALY)

The paper describes the results of photogrammetric survey of Ponte Rotto (literally, Broken Bridge), a Roman bridge on the ancient Appia way close to Benevento (southern Italy). The photogrammetric survey was carried out by means of a DJI Phantom 4 with a 12 Mpixel camera. One nadir and two side flights allowed obtaining 273 images and placing 6 Ground Control Points. A 3D model with a 8 millions points cloud was constructed (average error < 4 cm and Ground Simple Distance < 7 mm). The extrapolated ortho-photos were used for quantitative evaluation of lithotypes and damage diagnosis performed by Fitzner and Heinrichs method

β-Glucuronidase Pattern Predicted From Gut Metagenomes Indicates Potentially Diversified Pharmacomicrobiomics

: β-glucuronidases (GUS) of intestinal bacteria remove glucuronic acid from glucoronides, reversing phase II metabolism of the liver and affecting the level of active deconjugated metabolites deriving from drugs or xenobiotics. Two hundred seventy-nine non-redundant GUS sequences are known in the gut microbiota, classified in seven structural categories (NL, L1, L2, mL1, mL2, mL1,2, and NC) with different biocatalytic properties. In the present study, the intestinal metagenome of 60 healthy subjects from five geographically different cohorts was assembled, binned, and mined to determine qualitative and quantitative differences in GUS profile, potentially affecting response to drugs and xenobiotics. Each metagenome harbored 4-70 different GUS, altogether accounting for 218. The amount of intestinal bacteria with at least one GUS gene was highly variable, from 0.7 to 82.2%, 25.7% on average. No significant difference among cohorts could be identified, except for the Ethiopia (ETH) cohort where GUS-encoding bacteria were significantly less abundant. The structural categories were differently distributed among the metagenomes, but without any statistical significance related to the cohorts. GUS profiles were generally dominated by the category NL, followed by mL1, L2, and L1. The GUS categories most involved in the hydrolysis of small molecules, including drugs, are L1 and mL1. Bacteria contributing to these categories belonged to Bacteroides ovatus, Bacteroides dorei, Bacteroides fragilis, Escherichia coli, Eubacterium eligens, Faecalibacterium prausnitzii, Parabacteroides merdae, and Ruminococcus gnavus. Bacteria harboring L1 GUS were generally scarcely abundant (&lt;1.3%), except in three metagenomes, where they reached up to 24.3% for the contribution of E. coli and F. prausnitzii. Bacteria harboring mL1 GUS were significantly more abundant (mean = 4.6%), with Bacteroides representing a major contributor. Albeit mL1 enzymes are less active than L1 ones, Bacteroides likely plays a pivotal role in the deglucuronidation, due to its remarkable abundance in the microbiomes. The observed broad interindividual heterogeneity of GUS profiles, particularly of the L1 and mL1 categories, likely represent a major driver of pharmacomicrobiomics variability, affecting drug response and toxicity. Different geographical origins, genetic, nutritional, and lifestyle features of the hosts seemed not to be relevant in the definition of glucuronidase activity, albeit they influenced the richness of the GUS profile

A new method for the study of biophysical and morphological parameters in 3D cell cultures: Evaluation in LoVo spheroids treated with crizotinib.

Three-dimensional (3D) culture systems like tumor spheroids represent useful in vitro models for drug screening and more broadly for cancer biology research, but the generation of uniform populations of spheroids remains challenging. The possibility to properly characterize spheroid properties would increase the reliability of these models. To address this issue different analysis were combined: i) a new device and relative analytical method for the accurate, simultaneous, and rapid measurement of mass density, weight, and size of spheroids, ii) confocal imaging, and iii) protein quantification, in a clinically relevant 3D model. The LoVo colon cancer cell line forming spheroids, treated with crizotinib (CZB) an ATP-competitive small-molecule inhibitor of the receptor tyrosine kinases, was employed to study and assess the correlation between biophysical and morphological parameters in both live and fixed cells. The new fluidic-based measurements allowed a robust phenotypical characterization of the spheroids structure, offering insights on the spheroids bulk and an accurate measurement of the tumor density. This analysis helps overcome the technical limits of the imaging that hardly penetrates the thickness of 3D structures. Accordingly, we were able to document that CZB treatment has an impact on mass density, which represents a key marker characterizing cancer cell treatment. Spheroid culture is the ultimate technology in drug discovery and the adoption of such precise measurement of the tumor characteristics can represent a key step forward for the accurate testing of treatment's potential in 3D in vitro models

Razionale ed obiettivi del Progetto Sentieri

SENTIERI Project (Mortality study of residents in italian polluted sites) studied mortality of residents in the sites of national interest for environmental remediation (Italian polluted sites - IPSs). IPSs are in proximity of either active or dismissed industrial areas, near dumping sites of industrial and hazardous waste or incinerators. SENTIERI Project described and evaluated the mortality of the populations residing in IPSs and it specifically focused on causes of death for which environmental exposure is suspected or ascertained to play an etiologic role. The epidemiological evidence of the causal association was classified a priori into one of these three categories: Sufficient (S), Limited (L) and Inadequate (I). The study results will allow the priorities setting in remediation intervention, so as to prevent adverse health effects from environmental exposure. At the time of 2001 Census, about 10%of Italian population resided in the 44 IPSs included in SENTIERI; the mortality analysis was carried out for the years 1995-2002 for 63 causes of death. The study results for the 44 IPSs are here commented and read on the basis the a priori evaluation of the epidemiological evidence in terms of strength of the causal association, and taking into account the limits of a gepographic study design and its implied complexities. The producers and results of the evidence evaluation have been presented in a 2010 Supplement of Epidemiologia & Prevenzione devoted to SENTIERIIl Progetto SENTIERI (Studio Epidemiologico Nazionale dei Territori e degli Insediamenti Esposti a Rischio da Inquinamento) riguarda l\u27analisi della mortalit? delle popolazioni residenti in prossimit? di una serie di grandi centri industriali attivi o dismessi, o di aree oggetto di smaltimento di rifiuti industriali e/o pericolosi, che presentano un quadro di contaminazione ambientale e di rischio sanitario tale da avere determinato il riconoscimento di "siti di interesse nazionale per le bonifiche"(SIN). Il Progetto SENTIERI concorre alla descrizione e valutazione dello stato di salute delle popolazioni residenti nei SIN, in particolare per le cause di morte per le quali le esposizioni ambientali svolgano un ruolo eziologico certo o sospetto; i risultati dello studio contribuiranno a individuare le priorit? negli interventi di risanamento finalizzati alla prevenzione degli effetti sulla salute delle esposizioni ambientali. Le procedure e i risultati della valutazione della evidenza sono pubblicati nel Supplemento interamente dedicato a SENTIERI, pubblicato nel 2010 da Epidemiologia & Prevenzione. La popolazione residente al Censimento 2001 nei 44 SIN inclusi in SENTIERI costituisce approssimativamente il 10%della popolazione italiana. L\u27analisi della mortalit? nei 44 SIN riguarda 63 cause di morte e gruppi di cause per il periodo 1995-2002. Il commento e l\u27interpretazione dei risultati della mortalit? nei 44 SIN ? stato completato considerando limiti e complessit? del disegno geografico. E\u27 comunque possibile affermare che l\u27interpretazione dei risultati ? principalmente determinata dalla valutazione a priori dell\u27evidenza epidemiologica della forza delle associazioni considerate

Multicentre Mortality study of polluted site of national concern in Italy - Sentieri Project

About 250,000 sites in European Environment Agency-EEA member countries are defined as requiring clean up (http://themes.eea.europa.eu/). Thousands of these sites are located in Italy (Ministerial Decrees n. 486, 2001, and successive Decrees); 57 of them are "of national concern" because of a major impact of environmental pollution and the complexity of required remediation. SENTIERI examines sources of environmental pollution in Italian polluted sites (IPS) and describes health status of resident populations using mortality data. In particular, it examines forty four sites fulfilling admissibility criteria, 298 municipalities, 5,534,492 inhabitants, about 10% of the total Italian population at 2001 census

Valutazioni globali del carico di mortalit? nei siti di interesse nazionale per le bonifiche

SENTIERI Project has assessed the overall mortality profile in all the IPSs combined, and performed IPSspecific analyses. The epidemiological evidence of the causal association between cause of death and exposure was classified into one of these three categories: Sufficient (S), Limited (L) and Inadequate (I). The procedures and results of the evidence evaluation have been presented in a 2010 Supplement of Epidemiologia & Prevenzione devoted to SENTIERI. Mortality for causes of death with a priori Sufficient or Limited evidence of association with the environmental exposure exceeds the expected figures, with a SMR of 115.8 for men (90%CI 114.4-117.2; 2 439 extra deaths) and 114.4 for women (90% CI 112.4-116.5; 1 069 extra deaths). These excesses are also observed when analysis is extended to all the causes of death (i.e. with no re-striction to the ones with a priori Sufficient or Limited evidence): for a total of 403 692 deaths (men and women combined), an excess of 9 969 deaths is observed, with an average of around 1 200 extra deaths per year. Most of these excesses are observed in IPSs located in Southern and Central Italy. The distribution of the causes of deaths shows that the excesses are not evenly distributed: cancer mortality accounts for 30%of all deaths, but is 43.2%of the excess deaths (4 309 cases of 9 969). Conversely, the percentage of excesses in non cancer causes, 19%, is lower than their share of total mortality (42%). Consistently with previous studies, the results suggest that the health status of populations living in the IPSs is worse than what regional averages show. Compared to previous studies, the analysis of the causes selected in SENTIERI, on the basis of a priori Sufficient or Limited evidence of association with the environmental exposures, provides additional information on their role, though some limitations, due to methodology and data used, should be considered .Il Progetto SENTIERI, oltre alle analisi specifiche per ogni SIN, ha valutato il profilo di mortalit? nei 44 SIN nel loro complesso. Un elemento caratterizzante di SENTIERI ? la valutazione a priori dell\u27evidenza epidemiologica di associazione tra le cause analizzate e le esposizioni; procedure e risultati della valutazione sono riportate in dettaglio in un Supplemento del 2010 di Epidemiologia & Prevenzione. In tutti i SIN la mortalit? per le cause di morte con evidenza a priori Sufficiente o Limitata per le esposizioni ambientali presenti supera l\u27atteso, con un SMR di 115.8 per gli uomini (IC 90% 114.4-117.2; 2 439 decessi in eccesso) e 114.4 per le donne (IC 90% 112.4-116.5, 1 069 decessi in eccesso). Anche nell\u27analisi di tutte le cause di morte, cio? non ristretta alle cause di morte con evidenza a priori Sufficiente o Limitata, si osserva tale sovramortalit?: il totale dei decessi, per uomini e donne, ? di 403 692, in eccesso rispetto all\u27atteso di 9 969 casi (SMR 102.5; IC 90% 102.3-102.8), con una media di oltre 1 200 casi annui. La quasi totalit? dei decessi in eccesso si osserva nei SIN del Centro-Sud. La distribuzione delle cause di morte mostra che l\u27innalzamento della mortalit? rispetto all\u27atteso nei residenti dei 44 SIN non ? uniforme per le diverse cause: la mortalit? per tumori ? il 30% di tutti i decessi ma ? il 43.2% dei decessi in eccesso (4 309 decessi per tumore su 9 969 decessi totali). Al contrario, la percentuale dell\u27eccesso per le cause non tumorali ? pari al 19%, pi? bassa del 42% sul totale dei decessi. I risultati indicano, coerentemente con studi precedenti, che lo stato di salute dei residenti nei SIN, per quanto misurato attraverso la mortalit?, ? meno favorevole rispetto al riferimento regionale. Nonostante alcune limitazioni dei dati e delle metodologie, l\u27analisi ristretta alle cause identificate in SENTIERI come maggiormente plausibili fornisce un\u27ulteriore indicazione, rispetto al passato, del ruolo delle esposizioni ambientali

Antibiotic resistance, virulence factors, phenotyping, and genotyping of E. coli isolated from the feces of healthy subjects

Escherichia coli may innocuously colonize the intestine of healthy subjects or may instigate infections in the gut or in other districts. This study investigated intestinal E. coli isolated from 20 healthy adults. Fifty-one strains were genotyped by molecular fingerprinting and analyzed for genetic and phenotypic traits, encompassing the profile of antibiotic resistance, biofilm production, the presence of surface structures (such as curli and cellulose), and their performance as recipients in conjugation experiments. A phylogroup classification and analysis of 34 virulence determinants, together with genes associated to the pks island (polyketide-peptide genotoxin colibactin) and conjugative elements, was performed. Most of the strains belonged to the phylogroups B1 and B2. The different phylogroups were separated in a principal coordinate space, considering both genetic and functional features, but not considering pulsed-field gel electrophoresis. Within the B2 and F strains, 12 shared the pattern of virulence genes with potential uropathogens. Forty-nine strains were sensitive to all the tested antibiotics. Strains similar to the potential pathogens innocuously inhabited the gut of healthy subjects. However, they may potentially act as etiologic agents of extra-intestinal infections and are susceptible to a wide range of antibiotics. Nevertheless, there is still the possibility to control infections with antibiotic therapy