Pathway-Based Analysis of a Melanoma Genome-Wide Association Study: Analysis of Genes Related to Tumour-Immunosuppression

Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (pemp = 0.002), as well as the subgroups related to the generation of tolerogenic dendritic cells (pemp = 0.006) and secretion of suppressive factors (pemp = 0.0004), thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges

Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele

Simulation of SIP-server with hysteretic input and loss-based overload control scheme

This paper presents the simulation model of the Loss-Based Overload Control mechanism, proposed by the IETF for overload control in networks of SIP-servers. The model is designed to analyze the performance characteristics of SIP-server including a return time of the system from overload mode and buffer occupancy. The results of mathematical modeling in non-stationary case were used as the base of simulation. Numerical example illustrating the effect of Round Trip Time for the overload control mechanism is presented. © 2014 IEEE

Analytical modeling of rate-based overload control with token bucket traffic shaping on client side

Providing multimedia services to users assumes perfect quality of transfer and modern processing equipment that involves need of development of new methods of the analysis and forecasting of functioning of a communication network. In the paper we investigate the problem of the overload that occurs on a SIP (Session Initiation Protocol) server. SIP overload mitigation is based on RBOC (Rate-based overload control) schema, which was designed by IETF SIP overload control workgroup. The aim of RBOC schema is to restrict signaling message flow rate from the client side towards the server side. Hysteretic overload control algorithm is used to define trigger point for sending control information by the server to the client. Token bucket algorithm is applied to restrict the number of the tokens that the server grants the client. Simulation model for estimation main performance metrics is developed. Traffic with different type of distribution is used for investigation the behavior of the system with tandem servers. The optimization problem for maximization of processor utilization of SIP server on the dependence of threshold values and the number of token is formulated. © ECMS Valeri M. Mladenov, Petia Georgieva, Grisha Spasov, Galidiya Petrova (Editors)

Simulation of SIP-server with hysteretic input and loss-based overload control scheme

This paper presents the simulation model of the Loss-Based Overload Control mechanism, proposed by the IETF for overload control in networks of SIP-servers. The model is designed to analyze the performance characteristics of SIP-server including a return time of the system from overload mode and buffer occupancy. The results of mathematical modeling in non-stationary case were used as the base of simulation. Numerical example illustrating the effect of Round Trip Time for the overload control mechanism is presented. © 2014 IEEE

Analytical modeling of rate-based overload control with token bucket traffic shaping on client side

Providing multimedia services to users assumes perfect quality of transfer and modern processing equipment that involves need of development of new methods of the analysis and forecasting of functioning of a communication network. In the paper we investigate the problem of the overload that occurs on a SIP (Session Initiation Protocol) server. SIP overload mitigation is based on RBOC (Rate-based overload control) schema, which was designed by IETF SIP overload control workgroup. The aim of RBOC schema is to restrict signaling message flow rate from the client side towards the server side. Hysteretic overload control algorithm is used to define trigger point for sending control information by the server to the client. Token bucket algorithm is applied to restrict the number of the tokens that the server grants the client. Simulation model for estimation main performance metrics is developed. Traffic with different type of distribution is used for investigation the behavior of the system with tandem servers. The optimization problem for maximization of processor utilization of SIP server on the dependence of threshold values and the number of token is formulated. © ECMS Valeri M. Mladenov, Petia Georgieva, Grisha Spasov, Galidiya Petrova (Editors)

Conceptual approaches to the organization and activity of tourist clusters

У монографії висвітлюються теоретичні та практичні аспекти створення та функціонування туристичних кластерів. Аналізується світовий досвід туристичної і кластерної політики різних регіонів світу для різних видів туризму. Надаються пропозиції щодо впровадження світового досвіду кластеризації туристичної діяльності в Україні. Видання має стати у пригоді працівникам сфери туризму, рекреації, гостинності, студентам та аспірантам вищих навчальних закладів.The monograph highlights the theoretical and practical aspects of the creation and operation of tourism clusters. The world experience of tourism and cluster policy of different regions of the world for different types of tourism is analyzed. Proposals for the implementation of world experience in clustering tourism in Ukraine are provided. The publication should be useful for employees in the field of tourism, recreation, hospitality, students and graduate students

State regulation of tourism sphere of Ukraine in the context of the processes of European integration

У монографії висвітлюється місце України на світовому туристичному ринку, аналізується туристична політика як основа державного регулювання, досліджуються механізми державного регулювання туризму в країнах ЄС, вивчається міжнародний досвід застосування основних підходів регулювання у сфері туризму, пропонуються напрями вдосконалення макроекономічного регулювання розвитку сфери туризму в Україні, проводиться порівняльна характеристика нормативно-правової бази країн ЄС і України у сфері туризму, виявляються і аналізуються джерела фінансування туристичної сфери України, наводяться механізми створення туристичних кластерів як об’єктів стратегічного регулювання розвитку туристичної галузі, досліджуються існуючі та перспективні кластери туристичної сфери країни. Видання має стати у пригоді працівникам сфери туризму, рекреації, гостинності, студентам та аспірантам вищих навчальних закладів.The monograph covers the place of Ukraine on the world tourism market, analyzes tourism policy as a basis of state regulation, examines the mechanisms of state regulation of tourism in the EU countries, examines the international experience of applying the main regulatory approaches in the field of tourism, proposes directions for improving the macroeconomic regulation of tourism development in Ukraine, comparative Characteristics of the legal and regulatory framework of the EU and Ukraine in the field of tourism, identified and analyzed sources of f the investment of the tourist sphere of Ukraine, the mechanisms of creation of tourist clusters as objects of strategic regulation of tourism industry development, the existing and prospective clusters of the tourist sphere of the country are explored. The publication should be useful for tourism, recreation, hospitality, students and post-graduate students of higher educational institutions

Assessment of tourist and recreational potential of the region

У монографії надаються методи визначення потенціалу українських регіональних ринків організованого туризму, визначається методика інтегральної оцінки туристично-рекреаційних потенціалів регіонів України. Оціюється природно-ресурсний і культурно-історичний потенціали регіону для подальшого розвитку туристично-рекреаційної діяльності. Визначається місце регіону в означених потенціалах країни. Видання має стати у пригоді працівникам у сфері туризму, рекреації, гостинності, студентам та аспірантам вищих навчальних закладів.В монографии предоставляются методы определения потенциала украинских региональных рынков организованного туризма, определяется методика интегральной оценки туристско-рекреационных потенциалов регионов Украины. Руки определяется природно-ресурсный и культурно-исторический потенциалы региона для дальнейшего развития туристско-рекреационной деятельности. Определяется место региона в указанных потенциалах страны. Издание должно пригодиться работникам в сфере туризма, рекреации, гостеприимства, студентам и аспирантам высших учебных заведений.This monograph provides methods for determining the capacity of Ukrainian regional markets of organized tourism, is determined by the method of integral estimation of tourist-recreational potential of regions of Ukraine. Hand is determined by natural resources and cultural-historical potential of the region for further development of tourism and recreational activities. Is determined by the location of the region in the identified potentials of the country. The publication should be useful to workers in the field of tourism, recreation, hospitality, and post-graduate students of higher educational institutions