ALBERT

Description: Introduction: Adult T cell leukemia-lymphoma (ATL) is clinically divided into aggressive (acute and lymphoma) and indolent (chronic and smoldering) subtypes. Recent studies revealed that ATL has a wide variety of gene alternations (Nat Genet. 2015; 47:1304, Nature. 2016; 534:402). Consistent with the notion that human leukocyte antigen (HLA) play a critical role for immune response, reduced expression of HLA has been shown to associate with poor prognosis in various types of malignancies (Oncogene. 2008; 27:5869). However, it is extremely difficult to assess the impact of somatic mutations of HLA genes in cancer cells because of its highly polymorphic nature. Taking advantage of computational tools using whole-exome sequencing data, somatic mutations of HLA class I genes were previously reported in about 3% of various types of cancers (Nat Biotechnol. 2015; 33:1152). To date, HLA typing has been performed through partial sequencing data of polymorphic exons, resulting in the loss of critical information on the entire region of HLA genes. In this context, using a next generation sequence (NGS)-based HLA DNA typing method, we analyzed the entire region of HLA genes in ATL cells and its impact on clinical outcomes. Methods: The present study was approved by the Investigational Review Board of University of the Ryukyus and Tokai University. Peripheral blood mononuclear cells collected from 25 ATL patients (Pts) (20 with acute type and 5 with chronic type) were analyzed. Cell adhesion molecular 1 (CADM1)-positive ATL cells and CADM1-negative non-ATL cells were separated by a magnetic-activated cell-sorting protocol, and genomic DNAs in each fraction were distinctively extracted. The PCR products of the eight HLA loci (HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1) were obtained using the previously designed long ranged PCR primers (Tissue Antigens. 2012; 80:305) that cover the entire HLA gene sequences from the enhancer-promoter region to the 3'UTR region. The full-length level HLA genotypes were determined by mapping of sequence reads obtained by the Ion Torrent system to HLA allele reference sequences in the international ImMunoGeneTics project (IMGT)-HLA database. Somatic mutations and loss of heterozygosity (LOH) generated in ATL cells were identified by detail comparison of sequence data between the ATL and non-ATL cells. Survival curves were estimated using the Kaplan-Meier method and compared by the log-rank test. Results: We found a total of 20 somatic mutations in ATL cells among 9 Pts, including 15 single nucleotide variations (SNVs) and 5 insertions/deletions (indels) (Table 1). Of the 15 SNVs, 3 were nonsense mutations in exon 2/3 of HLA-A/B, 7 were nonsynonymous mutations in exon 1/4/5 of HLA-A/B/C, and 2 were mutations at splice sites in intron 2 of HLA-B/C. The mutations of splice sites in intron 2 and all the 5 indels caused frameshift generating premature stop codons. In contrast to the exons, there were only 3 mutations found in introns. Of 8 Pts harboring LOH, two Pts showed LOH in HLA-A gene, 4 Pts in HLA-A, -C, and -B genes, one Pt in HLA-DRB1, -DQA1, -DQB1, -DPA1 and -DPB1 genes, and one Pt in all the HLA-genes from HLA-A to HLA-DPB1. All the somatic mutations altering the structure of the HLA proteins (St-mt) and/or LOH were found in Pts with acute type ATL, while no St-mt or LOH were detected in Pts with chronic type ATL. Pts with St-mt/LOH (n = 9) significantly worsened in 3 years overall survival rate as compared to that in Pts without St-mt/LOH (n = 16) (11 % vs. 32 %, P = 0.016) (Fig. 1A). Among Pts with acute type ATL, Pts with St-mutations/LOH (n = 9) also showed a trend to worsen in the survival rate as compared to those in Pts without St-mutation /LOH (n = 11) (11 % vs. 30 %, P=0.064) (Fig. 1B). Conclusion: NGS-based HLA gene analyses at full-length level revealed that St-mt/LOH were frequently occurred predominantly in HLA class I loci in tumor cells from Pts with aggressive ATL. Importantly, St-mt/LOH in HLA genes were associated with aggressive phenotypes and poor prognosis, suggesting the possibility that ATL cells would develop immune escape mechanisms through a variety of acquired abnormalities in HLA gene. Since allogeneic stem cell transplantation is an essential therapeutic option for aggressive ATL, comprehensive knowledges on HLA gene abnormalities provide considerable advantage to optimize therapeutic modalities. Disclosures Fukushima: Daiichi-Sankyo: Research Funding.

Description: Introduction Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma, of which approximately 95% are diffuse large B-cell lymphomas (DLBCLs). Despite the substantial development of intensive chemotherapy during the past two decades, overall clinical outcome of PCNSL has been poorly improved especially in elderly and so has been our knowledge about the molecular pathogenesis of PCNSL, in terms of driver alterations that are relevant to the development of PCNSL. Method To delineate the genetic basis of PCNSL pathogenesis, we performed a comprehensive genetic study. We first analyzed paired tumor/normal DNA from 35 PCNSL cases by whole-exome sequencing (WES). Significantly mutated genes identified by WES and previously known mutational targets in PCNSL and systemic DLBCL were further screened for mutations using SureSelect-based targeted deep sequencing (Agilent) in an extended cohort of PCNSL cases (N = 90). Copy number alterations (CNAs) have been also investigated using SNP array-karyotyping (N =54). We also analyzed WES and SNP array data of systemic DLBCL cases (N = 49) generated by the Cancer Genome Atlas Network (TCGA) to unravel the genetic difference between PCNSL and systemic DLBCL. Results The mean number of nonsynonymous mutations identified by WES was 183 per sample, which was comparable to the figure in systemic DLBCL and characterized by frequent somatic hypermutations (SHMs) involving non-Ig genes. A higher representation of C〉T transition involving CpG dinucleotides and hotspot mutations within the WRCY motif targeted by SHM further suggested the involvement of activation-induced cytidine deaminase (AID) in the pathogenesis of PCNSL. We found 12 genes significantly mutated in PCNSL (q 〈 0.1), including MYD88, PIM1, HLA-A, TMEM30A, B2M, PRDM1, UBE2A, HIST1H1C, as well as several previously unreported mutational targets in systemic DLBCL or PCNSL, such as SETD1B, GRB2, ITPKB, EIF4A2. Copy number analysis identified recurrent genomic segments affected by focal deletions (N = 27) and amplifications (N = 10), most of which included driver genes targeted by recurrent somatic mutations or known targets of focal CNAs such as CDKN2A and FHIT. Subsequent targeted sequencing finally identified a total of 107 significantly mutated genes, of which 43 were thought to be targeted by SHM according to their mutational signature and genomic distribution. Most cases with PCNSL (98%) had mutations and CNAs involving genes that are relevant to constitutive NF-KB/Toll-like receptor (TLR)/BCR activity, including those in MYD88 (80%), CD79B/A (60%), CARD11 (18%), TNFAIP3 (26%), GRB2 (24%) and ITPKB (23%). Genetic alterations implicated in escape from immunosurveillance were also frequently identified in as many as 76% of cases. Mutations of HLA-B (64%), HLA-A (36%), HLA-C (28%), B2M (14%) and CD58 (12%) were commonly detected in addition to CNAs in 6p21.32 (HLA class II), 1p13.1 (CD58) and 15q15.2 (B2M), suggesting the importance of immune escape in the pathogenesis of PCNSL. SHMs were also seen in most cases (98%), which affected not only known targets of AID including PIM1, IGLL5 and BTG2 but also previously unreported genes involved in cell proliferation, apoptosis, or B cell development. The pattern of frequently mutated genes in PNCSL was more uniform compared with that in systemic DLBCL, and similar to that found in the activated B cell subtype of DLBCL (ABC-DLBCL), which was in accordance with the previous report of immunophenotypic analysis of PCNSL. On the other hand, mutations of HLA class I genes (HLA-B, HLA-A) were more frequently mutated in PCNSL compared with ABC-type DLBCL. Conclusion WES, SNP array karyotyping and follow-up targeted sequencing of a large cohort of PCNSL cases revealed the genetic landscape of PCNSL, which were more homogeneous than that of systemic DLBCL, and thought to be involved in activation of constitutive NF-KB/TLR/BCR signaling, escape from immunosurveillance, as well as highly frequent SHMs. Disclosures No relevant conflicts of interest to declare.

Description: Key Points HLA-DPB1 alleles diverged into 2 major groups according to highly conserved DNA sequences Ex3-3′UTR. Two evolutionarily different HLA-DPB1 gene regions complementarily affect aGVHD in HLA-DPB1 mismatch UR-HCT.

Description: In this paper, we analyze incident response management work using free-formed information that is important for incident response communication. We develop a standard operating procedure for the work and study a support method based on a language processing technology to prevent missing or overlapping necessary tasks and optimize management of progress and integration management of related tasks. A prototype system was developed and evaluated in a workshop held by a local government, or in an exercise. As a result, it is confirmed that the use of language processing technology can make incident response management work efficient.

Description: The common situational awareness among the disaster-response organizations and the appropriate action based on the information sharing are the key factor for the effective and efficient disaster response. Supported by the Cross-ministerial Strategic Innovation Promotion Program (SIP), we have developed the Shared Information Platform for Disaster Management (SIP4D) which facilitate the “cross-ministerial information sharing” by intermediating the various governmental organizations. Also, as the empirical research for utilize the shared disaster-information by SIP4D, we have developed the Medical Activity Support System for Disaster Management, the Reservoir Disaster Prevention Support System, and the Disaster Management Information Service Platform. In this paper, we introduce the overview of our R&D project, and report the implementation plans of our systems in the society.

Description: Tokyo Metropolitan Earthquake and Nankai Trough Earthquakes predicted to hit Japan in the near future makes it urgent that the impact of urban earthquake disasters be reduced by every means possible. To promote research to this end, the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan launched a Special Project for Reducing Vulnerability for UrbanMega Earthquake Disasters in 2012 as a five-year R&D effort embracing three academic disciplines – earth and physical sciences, structural engineering, and social sciences. This project in turn consists of three subprojects – Subproject on the earthquake hazard mechanism and risk evaluation of southern Kanto region, Subproject to develop rapid damage assessment and recovery technology of urban function, and Subproject to develop resilient society improving disaster management competence. This special issue features findings and achievements from this last subproject, whose goal is to enhance society’s resilience based on the experiences and lessons of the 1995 Great Hanshin-Awaji Earthquake Disaster that crippled Kobe, the 2011 Great East Japan Earthquake Disaster that prostrated Japan’s northeastern Pacific coast and other such disasters. Concretely speaking, by integrating the wisdom of disaster management researchers nationwide and collaborating with other subprojects, this subproject proposes disseminating disaster information technologies and training methodologies to build up disaster preparedness. This, in turn, is aided by improving disaster literacy and competence among both the general public and disaster management personnel. Focusing on the three major metropolitan areas of Tokyo, Nagoya, and Osaka, where two-thirds of Japan’s population and three-fourths of the nation’s total assets are concentrated, Web-based disaster information management and dissemination services are being proposed and examined for effectiveness through demonstration experiments and social implementation. In this issue of JDR, we are introducing 11 papers and reports from researchers involved in this subproject to present initial interim findings and progress during the first half of this five-year effort. In doing so, the authors and editors of this issue gratefully acknowledge the generous financial support of MEXT in these studies.

Description: An earthquake in metropolitan Tokyo would be a national crisis in terms of the enormous number of affected population and properties and various types of complicated damages and impact in areas where there is a concentration of capital, social, and economic functions. Moreover, the process of being affected by the disaster is so complicated that it has not been fully understood and the various possibilities of earthquake occurrence scenarios have not been fully analyzed. In addition, those understandings and analyses have not been fully utilized for disaster mitigation or preparedness.Intended to estimate complicated phenomena, this study discusses a method to analyze various phenomena by breaking down a method for estimation component pieces, making each piece work as a web service, and getting them to cooperate with one another as necessary. We also develop an earthquake-disaster estimation web application that can analyze seismic intensity, exposed population, lifelines, business establishments, goods supply and demand, and so on.Using an exposed population, the period of business disruption at business establishments, the supply and demand balance of necessities, and an amount of exposure of administrative functions as impact indices, we use our method to analyze the change in impact indices at many epicenters exhaustively plotted in the metropolitan Tokyo area. As a result, the scenario of an earthquake with a great impact is quantified in light of the earthquake susceptibility of the ground, distribution of population, business establishments, administrative functions, and so on.

Description: The concept we propose for a disaster management literacy hub (DMLH) involves systemizing and generalizing disaster management literacy (DML) and discussing how to design such a DMLH where the general public and disaster responders share materials on DML. In the early 21stcentury, measures against large-scale earthquakes should essentially include both hardware disaster mitigation measures like the construction of appropriate structures and software measures like disaster preparedness among people and organizations such as the general public, disaster responders and related organizations. We define knowledge about disaster response management and competency as DML. Our analysis of documents on the incident command system (ICS), an emergency response system under the United States Federal Emergency Management Agency (FEMA), found 56 positions of disaster responders in ICS defined by 35 actions required for four types of disaster response competency. The above analysis led us to propose that DML consist of three elements: knowledge for learning about disaster management and mitigation, skills required for effective disaster response, and basic competency and attitudes for coping with disasters. For conceptual DMLH design based on the Instructional Design (ID), we propose three types of learning:1 The general public and disaster responders learn audiovisually using training videos and materials and review tests on learn from videos.2 People who want to provide education and training at schools or in regions or municipalities with school teacher guidance/teaching plans learn how to do so.3 People learn DML by posting or searching for (collecting and arranging) materials.We discuss how to publish such learning programs, taking as a specific example a life reconstruction support system (to put disaster victims’ lives back in order) based on victims’ master database.

Description: The development and implementation of online-based disaster management information processing systems advance communication among disaster management communities. Many such communities communicate using general-purpose natural language messaging. Online disaster informationprocessing systems should process such communication for making common operational picture and managing tasks and resources. We are thus developing online disaster information management support systems that use natural language processing. In doing so, we compare conventional paper-based and online-based systems for implementing online-based systems and develop task management support systems that use natural language processing.

Description: This paper discusses the development and implementation of the web-based geo-spatial information sharing and integration system that advances the multidisciplinary researches on the processes and impacts of mega-disaster. The mega-disasters predicted in Japan, such as Tokyo Metropolitan Earthquake or Nankai Trough Earthquake Tsunami, bring huge amount of damage and loss in various sectors and various regions, and the scenarios of damage occurrence and loss propagation are very complex. Hence, in order to quantify each problem to create disaster reduction strategies, it is very important to share and integrate data and findings across many disciplines and regions. In this point of view, we are developing the Urban Resilience Geoportal as the sharing site of research findings. In this paper, we discuss the concept of such system focusing on the accumulation and sharing of multidisciplinary data, the integration of damage and loss quantification methods, the collaboration with other disaster information systems, and the utilization of data to create new findings.