SPATIAL SOUND SYSTEM TO AID INTERACTIVITY IN A HUMAN CENTRED DESIGN EVALUATION OF AN AIRCRAFT CABIN ENVIRONMENT

There is a lot of research towards the concept of 3D sound in virtual reality environments. With the incipient growth in the significance of designing more realistic and immersive experiences for a Human Centred Design (HCD) approach, sound perception is believed to add an interactive element in maximizing the human perspective. In this context, the concept of an audio-visual interaction model between a passenger and a crew member in an immersive aircraft cabin environment is studied and presented in this paper. The study focuses on the design and usability of spatial sources as an interactive component in a regional aircraft cabin design for Human in the Loop evaluation. Sound sources are placed among the virtual manikins acting as passengers with the aim of building a realistic virtual environment for the user enacting the role of a crew member. The crew member, while walking throughthe cabin can orient and identify the position of the sound source inside the immersive Cabin environment. We review the 3D sound approaches and cues for sound spatialization in a virtual environment and propose that audio-visual interactivity aids the immersive Human centred design analysis

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Not Just Arterial Damage: Increased Incidence of Venous Thromboembolic Events in Cardiovascular Patients With Elevated Plasma Levels of Apolipoprotein CIII

Background Apolipoprotein CIII (apo CIII ) is a crucial player in triglyceride-rich lipoprotein metabolism, but may also act pleiotropically, provoking inflammatory responses and stimulating coagulation. Elevated apo CIII plasma levels have been associated with increased activity of coagulation factors. Since these features of prothrombotic diathesis are linked with venous thromboembolism ( VTE ), we hypothesized that apo CIII plays a role in VTE . Methods and Results We recorded nonfatal VTE events in 1020 patients (age 63.3\ub111.4 years; 29.1% women) with or without coronary artery disease (79.1% with coronary artery disease and 20.9% without coronary artery disease) during a long follow-up. Complete plasma lipid and apolipoproteins were available for all patients. Forty-five patients (4.4%) experienced nonfatal VTE events during a median follow-up period of 144 months. Apo CIII plasma concentration at enrollment was higher in patients with VTE compared with patients without VTE (12.2 [95% CI, 11.10-13.5] mg/dL vs 10.6 [95% CI, 10.4-10.9] mg/dL, respectively; P=0.011). Patients with apo CIII levels above the median value (10.6 mg/dL) exhibited an increased risk of VTE (incidence rate, 6.0 [95% CI , 4.0-8.0] vs 1.8 [95% CI, 0.7-2.9] VTE events/1000 person-years; unadjusted hazard ratio [ HR ], 3.42 [95% CI , 1.73-6.75]; P<0.001). This association was confirmed after adjustment for sex, age, coronary artery disease diagnosis, body mass index, hypertension, and anticoagulant treatment at enrollment ( HR , 2.66; 95% CI , 1.31-5.37 [ P=0.007]), with inclusion of lipid parameters in the Cox model (HR, 3.74; 95% CI , 1.24-11.33 [ P=0.019]), and even with exclusion of patients who died at follow-up ( HR, 3.92; 95% CI , 1.68-9.14 [ P=0.002]) or patients taking anticoagulants ( HR , 3.39; 95% CI , 1.72-6.69 [ P<0.001]). Conclusions Our results suggest that high plasma apo CIII concentrations may predict an increased risk of VTE in patients with cardiovascular disease

One-carbon genetic variants and the role of MTHFD1 1958G>A in liver and colon cancer risk according to global DNA methylation

Several polymorphic gene variants within one-carbon metabolism, an essential pathway for nucleotide synthesis and methylation reactions, are related to cancer risk. An aberrant DNA methylation is a common feature in cancer but whether the link between one-carbon metabolism variants and cancer occurs through an altered DNA methylation is yet unclear. Aims of the study were to evaluate the frequency of one-carbon metabolism gene variants in hepatocellular-carcinoma, cholangiocarcinoma and colon cancer, and their relationship to cancer risk together with global DNA methylation status. Genotyping for BHMT 716A>G, DHFR 19bp ins/del, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, TCII 776C>G and TS 2rpt-3rpt was performed in 102 cancer patients and 363 cancer-free subjects. Methylcytosine (mCyt) content was measured by LC/MS/MS in peripheral blood mononuclear cells (PBMCs) DNA. The MTHFD1 1958AA genotype was significantly less frequent among cancer patients as compared to controls (p = 0.007) and related to 63% reduction of overall cancer risk (p = 0.003) and 75% of colon cancer risk (p = 0.006). When considering PBMCs mCyt content, carriers of the MTHFD1 1958GG genotype showed a lower DNA methylation as compared to carriers of the A allele (p = 0.048). No differences were highlighted by evaluating a possible relationship between the other polymorphisms analyzed with cancer risk and DNA methylation. The MTHFD1 1958AA genotype is linked to a significantly reduced cancer risk. The 1958GG genotype is associated to PBMCs DNA hypomethylation as compared to the A allele carriership that may exert a protective effect for cancer risk by preserving from DNA hypomethylation

DNA Methylation and Hydroxymethylation in Primary Colon Cancer and Synchronous Hepatic Metastasis

Colon cancer is one of the most frequent solid tumor and simultaneous diagnosis of primary colon cancer and liver metastases occurs in about one fourth of cases. The current knowledge on epigenetic signatures, especially those related to hydroxymethylation in primary cancer tissue, synchronous metastasis, and blood circulating cells is lacking. This study aimed to investigate both methylcytosine (mCyt) and hydroxymethylcytosine (hmCyt) status in the DNA of individual patients from colon cancer tissue, synchronous liver metastases, and in cancer-free colon and liver tissues and leukocytes. Patients undergoing curative surgery (n= 16) were enrolled and their laboratory and clinical history data collected. The contents of mCyt and hmCyt were determined by a liquid chromatography/mass spectrometry (LC/MS/MS) method in DNA extracted from primary colon cancer, synchronous hepatic metastatic tissues and homologous cancer-free tissues, i.e., colon and liver tissues as well as leukocytes. The mCyt and hmCyt levels were compared between cancerous and cancer-free tissues, and correlations between leukocytes and colon/liver tissues for both the mCyt and hmCyt levels were evaluated. The mCyt levels were similar in primary colon cancer and liver metastasis tissues (4.69 \ub1 0.37% vs. 4.77 \ub1 0.38%, respectively,p= 0.535), and both primary and metastatic tissues were hypomethylated compared to cancer-free colon (4.98 \ub1 0.26%). The difference in the mCyt content between cancerous and cancer-free colon tissues was significantly lower in primary colon cancer (p= 0.004), but not in liver metastasis (p= 0.148). The hmCyt content was similar in primary colon cancer compared to liver metastasis (0.035%, C.I. 0.024-0.052% versus 0.035%, C.I. 0.021-0.058%, respectively,p =0.905) and markedly depleted compared to the cancer-free colon (0.081%, C.I. 0.055-0.119%) with a statistically significant difference (p< 0.05) for both comparisons. The mCyt levels showed a borderline correlation between leukocytes and colon cancer tissue (Pearson's correlation coefficient = 0.51,p= 0.052) while no correlations were detected for the hmCyt levels. In conclusion, primary colon cancer and synchronous liver metastasis tissues showed a similar epigenetic status but were significantly hypomethylated and hypohydroxymethylated as compared to homologous cancer-free colon tissues

The RFC1 80G>A, among Common One-Carbon Polymorphisms, Relates to Survival Rate According to DNA Global Methylation in Primary Liver Cancers

Polymorphisms within one-carbon metabolism genes have been largely studied in relation to cancer risk for the function of this pathway in nucleotide synthesis and DNA methylation. Aims of this study were to explore the possible link among several common functional gene polymorphisms within one-carbon metabolism and survival rate in primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma, and to assess the additional effect of global DNA methylation on survival rate and mortality risk. Forty-seven primary liver cancer patients were genotyped for ten polymorphisms: DHFR 19bp ins/del, TS 2rpt-3rpt, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, BHMT 716 A>G, TC II 776C>G. Methylation was determined in peripheral blood mononuclear cells (PBMCs) DNA as methylcytosine (mCyt) content using LC/MS/MS. Among the polymorphisms analysed, the RFC1 80G>A (rs1051266) influenced the survival rate in primary liver cancers. The RFC1 80AA was associated to a significantly reduced survival rate (22.2%) as compared to both GG and GA genotypes (61.5% and 76% respectively, p = 0.005). When the cancer patients were stratified according to the mCyt median value as high (>5.34%) or low ( 645.34%), the concomitant presence of AA genotype and low mCyt level led to a significantly worse survival rate as compared to the G allele carriership (pA polymorphism influenced the survival rate, and the presence of RFC1 80AA genotype with low global methylation in PBMCs DNA was associated with poorer prognosis and higher mortality risk, therefore highlighting novel molecular signatures potentially helpful to define prognostic markers for primary liver cancers

THE IMPACT OF ONE-CARBON METABOLISM POLYMORPHIC VARIANTS ON CANCER RISK AND SURVIVAL RATE IN PRIMARY LIVER AND COLON NEOPLASMS ACCORDING TO GLOBAL DNA METHYLATION AND HYDROXYMETHYLATION STATUS: ROLE OF EPIGENETIC MODULATION FROM THE RESULTS OF A CLINICAL STUDY

Il metabolismo delle unit\ue0 monocarboniose (o mono carbonioso) rappresenta un pathway complesso coinvolto sia nella sintesi dei nucleotidi che nelle reazioni di metilazione biologica inclusa quella del DNA, il principale meccanismo epigenetico negli esseri umani. Uno stato di aberrante metilazione del DNA \ue8 una caratteristica comune nel tumore. Numerose varianti polimorfiche di geni all\u2019interno del metabolismo mono-carbonioso sono state correlate al rischio di cancro, ma se il legame tra queste varianti geniche e il rischio/tempo di sopravvivenza legati al cancro possa realizzarsi attraverso un\u2019alterata metilazione del DNA \ue8 una ipotesi fino ad ora scarsamente studiata e ancora non chiarita. Oltre alla metilazione, l\u2019idrossimetilazione del DNA \ue8 stata recentemente descritta come un nuovo, potenzialmente utile marker epigenetico. I tumori primitivi del fegato, in particolare l\u2019epatocarcinoma (HCC) e il colangiocarcinoma (CC), e il cancro del colon, nonostante l\u2019alta incidenza, sono stati scarsamente caratterizzati dal punto di vista epigenetico. Gli scopi del presente progetto sono stati definire il possibile ruolo della metilazione ed idrossimetilazione del DNA nel tumore ed in particolare: 1. Determinare se le varianti polimorfiche dei geni del metabolismo mono-carbonioso possano influenzare il rischio di tumore primitivo del fegato e di tumore del colon attraverso la metilazione del DNA, definita come livelli di metilcitosina (mCyt) misurata nel DNA delle cellule periferiche mononucleate del sangue (PBMCs). 2. Verificare se lo stato di metilazione del DNA misurato nei PBMCs dei soggetti affetti da HCC, CC e tumore del colon possa correlare con l\u2019andamento clinico e il tempo di sopravvivenza, definendo pertanto un possibile marcatore epigenetico di malattia. 3. Caratterizzare ulteriormente lo status epigenetico di HCC e CC valutando il contenuto globale di mCyt e hmCyt nel DNA del tessuto neoplastico e nel tessuto omologo non neoplastico. Materiali e metodi: La genotipizzazione di BHMT 716A>G, DHFR 19bp ins/del, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, TCII 776C>G e TS 2rpt-3rpt \ue8 stata eseguita in 102 pazienti neoplastici e 363 soggetti liberi da tumore. La metilcitosina e l\u2019idrossimetilcitosina sono state misurate attraverso un metodo LC/MS/MS nel DNA dei PBMCs di tutti i soggetti e nel tessuto neoplastico e nel tessuto omologo non neoplastico di 47 patienti affetti da tumore primitivo del fegato sottoposti a intervento chirurgico. Risultati: 1. Il genotipo MTHFD1 1958AA era significativamente meno frequente nei soggetti neoplastici rispetto ai controlli (p=0.007) e la sua presenza si associava ad una riduzione del 63% di rischio generale di tumore (OR=0.37, p=0.003) e del 75% di rischio di tumore del colon (OR=0.25, p=0.006). Il genotipo MTHFD1 1958GG era significativamente pi\uf9 frequente tra i pazienti neoplastici (p=0.007) ed era associato ad un pi\uf9 basso livello di metilazione del DNA se comparato ai soggetti portatori dell\u2019allele A (p=0.048). 2. La variante polimorfica RFC1 80AA era associata ad una sopravvivenza significativamente ridotta nei pazienti con tumore primitivo del fegato, rispetto ai portatori dei genotipi GG e GA (p=0.005) in un periodo di follow-up di 60 mesi. Quando i livelli di mCyt sono stati stratificati come alti (> 5.34%) o bassi ( 64 5.34%), in accordo con il valore medio di mCyt, la concomitante presenza del genotipo AA e di bassa mCyt comportava una peggiore prognosi, nel confronto con i soggetti portatori dell\u2019allele G, sia con alti che con bassi valori di mCyt (p<0.0001); non vi erano differenze di sopravvivenza tra i portatori dell\u2019allele G e i soggetti AA con alti livelli di mCyt (p=0.919). Inoltre, un pi\uf9 alto rischio di mortalit\ue0 era associato con la concomitante presenza del genotipo AA e di bassi livelli di mCyt se comparato ai soggetti portatori dell\u2019allele G (OR=8.35, p=0.001). 3. Livelli di mCyt 655.59% nei PBMCs erano associati ad una significativa migliore aspettativa di vita se comparati a valori di mCyt < 5.59% (p=0.034) in un follow-up di 48 mesi nei pazienti affetti da tumore primitivo del fegato. Il contenuto di mCyt nel tessuto neoplastico di HCC era notevolmente pi\uf9 basso che nel tessuto di CC (rispettivamente 3.97% vs 5.26%, p<0.0001). Nell\u2019HCC sono stati osservati livelli di mCyt significativamente ridotti nel tessuto neoplastico rispetto al tessuto non neoplastico (3.97% vs. 4.82% mCyt, p<0.0001), ma questa differenza non era presente nel tessuto epatico dei pazienti affetti da CC. L\u2019idrossimetilazione era significativamente ridotta nel tessuto neoplastico degli HCC vs il tessuto epatico non neoplastico (0.044 vs. 0.128, p<0.0001), cos\uec come nel tessuto neoplastico del CC confrontato sia con il tessuto epatico non neoplastico, sia con la colecisti (rispettivamente 0.030 vs. 0.124, p=0.026; 0.030 vs. 0.123, p=0.006). Conclusioni: i nostri risultati suggeriscono una possibile associazione tra le varianti polimorfiche dei geni del metabolismo mono-carbonioso e la metilazione del DNA. Questa associazione suggerisce che la metilazione del DNA potrebbe rappresentare il legame importante tra varianti geniche polimorfiche e il tumore primitivo del fegato e il tumore del colon, sia in termini di rischio che di aspettativa di vita. Questo riscontro potrebbe collocare la metilazione del DNA nei PBMCs come possibile biomarcatore per questi tipi di tumore. Inoltre, considerato che la metilazione del DNA \ue8 un fenomeno potenzialmente reversibile che dipende dal metabolismo mono-carbonioso per il rifornimento di gruppi metilici, si possono immaginare possibili strategie indirizzate ad ottimizzare l\u2019apporto di questi componenti allo scopo di mantenere la metilazione del DNA all\u2019interno di valori adeguati per la prevenzione di malattia. I risultati di questo studio dimostrano, inoltre, che un significativo ridotto grado di metilazione del DNA caratterizza il tessuto neoplastico dell\u2019HCC rispetto al CC, mentre bassi livelli di idrossimetilazione caratterizzano sia il tessuto neoplastico dell\u2019HCC che del CC in confronto al tessuto non neoplastico. Ulteriori conferme dei presenti dati saranno opportune e necessarie per verificare l\u2019utilit\ue0 e l\u2019affidabilit\ue0 nella pratica clinica dei biomarcatori genetici-epigenetici come indici prognostici per i pazienti affetti da tumore primitivo del fegato e da tumore del colon.One-carbon metabolism is a complex pathway involved both in nucleotide synthesis and in biological methylation reactions including that of DNA methylation, the main epigenetic mechanism in humans. An aberrant DNA methylation is a common feature in cancer disease. Several polymorphic gene variants within one-carbon metabolism have been related to cancer risk, but whether the link between one-carbon metabolism variants and cancer risk/survival rate may occur through an altered DNA methylation is still poorly investigated and yet unclear. In addition to DNA methylation, hydroxymethylation of DNA has been recently described as a novel, potentially useful epigenetic mark. Primary liver cancers, i.e. hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) as well as colon cancer are highly prevalent but epigenetically poorly characterized, so far. The main aims of the present project were to define a possible role for DNA methylation in cancer, and specifically: 1. to determine whether polymorphic variants of one- carbon metabolism genes may influence the risk of human primary liver cancers and colon cancer through DNA methylation, defined as methylcytosine (mCyt) levels measured in peripheral blood mononuclear cells (PBMCs) DNA; 2. to verify whether DNA methylation status measured in PBMCs of subjects affected by HCC, CC and colon cancer may correlate with clinical outcomes and survival rate, therefore defining a possible epigenetic marker of disease; 3. to further characterize the epigenetic layout of HCC and CC by evaluating the global DNA mCyt and hydroxymethylcytosine (hmCyt) content in neoplastic and homologous non-neoplastic tissues. Material and Methods: Genotyping for BHMT 716A>G, DHFR 19bp ins/del, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, TCII 776C>G and TS 2rpt-3rpt was performed in 102 cancer patients and 363 cancer-free subjects. Methylcytosine and hmCyt were measured by an LC/MS/MS method in PBMCs DNA of all subjects and in neoplastic and homologous non-neoplastic tissues of 47 primary liver cancer patients undergoing curative surgery. A follow-up examination was performed on all the patients 48-60 months after the surgical procedure. Results: 1. The MTHFD1 1958AA genotype was significantly less frequent among cancer patients as compared to controls (p=0.007) and related to 63% reduction of the overall cancer risk (OR=0.37, p=0.003) and 75% of risk for colon cancer (OR=0.25, p=0.006). The MTHFD1 1958GG was significantly more frequent among cancer patients (p=0.007) and associated to lower DNA methylation as compared to MTHFD1 1958 allele A carriers (p=0.048). 2. The RFC1 80AA polymorphic variant was associated in primary liver cancer with a significantly reduced survival rate as compared to GG and GA (p=0.005) at a follow-up period of 60 months. When the mCyt levels were stratified as either high (>5.34%) or low ( 645.34%) according to the mCyt median value, the combination of AA genotype and low mCyt led to a significantly worse survival as compared to the two genotype groups carrying the G allele considered as a whole (p<0.0001); no difference in survival was found between G carriers and AA in association with high mCyt (p=0.919). Moreover, a higher mortality risk was associated with the concomitant presence of the AA genotype and low mCyt, as compared to G carrier subjects (OR=8.35, p=0.001). 3. In primary liver cancer, levels of mCyt 655.59% in PBMCs were associated to a significantly higher life expectancy as compared to mCyt<5.59% (p=0.034) at a follow-up period of 48 months. Methylcytosine content in HCC neoplastic tissue was notably lower than in CC tissues (3.97% vs. 5.26% respectively, p<0.0001). Significantly reduced mCyt levels were observed in HCC neoplastic as compared to non-neoplastic tissue (3.97% vs. 4.82% mCyt, p<0.0001) but such difference was not found in liver tissue of patients affected by CC. Hydroxymethylation was significantly decreased in HCC neoplastic vs. non-neoplastic liver tissue (0.044 vs. 0.128, p<0.0001), as well as in CC neoplastic tissue vs. both non-neoplastic liver and gall bladder (0.030 vs. 0.124, p=0.026; 0.030 vs. 0.123, p=0.006, respectively). Conclusions: Our results suggest a possible association between one-carbon metabolism genes polymorphic variants and DNA methylation. This association suggests that DNA methylation may be the underlying link between polymorphic gene variants and primary liver and colon cancers, both in terms of risk and life expectancy. This finding may situate PBMCs DNA methylation as a possible biomarker for those types of cancer disease. Moreover, since DNA methylation is a reversible phenomenon that relies on one-carbon metabolism for provision of methyl groups, adequate strategies to optimize sources of such compounds to maintain DNA methylation within adequate levels for disease prevention may be considered in the framework to modulate this epigenetic mechanism. The results of this study demonstrate, furthermore, that a significantly lower degree of DNA hypomethylation characterize HCC from CC tissue, whereas DNA hypo-hydroxymethylation characterizes both HCC and CC neoplastic tissues as compared to the non-neoplastic. Further validation of the present novel data is required to assess whether this genetic-epigenetic biomarkers may indeed be a reliable and useful for clinical application as a prognostic tool for patients with primary liver and colon cancers