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Somatic mutations are accumulated in normal human tissues with aging and exposure to carcinogens. If we can accurately count any passenger mutations in any single DNA molecule, since their quantity is much larger than driver mutations, we can sensitively detect mutation accumulation in polyclonal normal tissues. Duplex sequencing, which tags both DNA strands in one DNA molecule, enables accurate count of such mutations, but requires a very large number of sequencing reads for each single sample of human-genome size. Here, we reduced the genome size to 1/90 using the Bam HI restriction enzyme and established a cost-effective pipeline. The enzymatically cleaved and optimal sequencing (EcoSeq) method was able to count somatic mutations in a single DNA molecule with a sensitivity of as low as 3 × 10 −8 per base pair (bp), as assessed by measuring artificially prepared mutations. Taking advantages of EcoSeq, we analyzed normal peripheral blood cells of pediatric sarcoma patients who received chemotherapy ( n = 10) and those who did not ( n = 10). The former had a mutation frequency of 31.2 ± 13.4 × 10 −8 per base pair while the latter had 9.0 ± 4.5 × 10 −8 per base pair ( P < 0.001). The increase in mutation frequency was confirmed by analysis of the same patients before and after chemotherapy, and increased mutation frequencies persisted 46 to 64 mo after chemotherapy, indicating that the mutation accumulation constitutes a risk of secondary leukemia. EcoSeq has the potential to reveal accumulation of somatic mutations and exposure to environmental factors in any DNA samples and will contribute to cancer risk estimation.

Background The preoperative predictors of quality of life (QOL) in patients who undergo lung resection for lung cancer are poorly known. Here, we investigated these predictors in such patients using two QOL measures. Methods In this single‐institutional prospective cohort study, we administered the EQ‐5D‐5 levels (EQ‐5D‐5L) from January 2015, and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire with 30 items from April 2015 to April 2018 preoperatively (Pre) and at one month postoperatively (M1), and one year postoperatively (Y1). General health status was measured by the EQ‐5D visual analogue scale (VAS) and EORTC global health status/QOL (GHS) scores. Multivariable linear regression analyses were used to explore the preoperative predictors of QOL at Y1. Results A total of 223 patients were included in the study. The EQ‐5D VAS and EORTC GHS scores, at Pre, M1, and Y1, were 80 ± 15, 77 ± 15, and 84 ± 11; and 74 ± 19, 65 ± 20, and 78 ± 17, respectively. In the multivariable analyses, the albumin level, preoperative VAS score, and preoperative pain/discomfort and anxiety/depression were identified as predictors by the EQ‐5D VAS score. The preoperative EORTC GHS score, absence of diabetes mellitus, preoperative cognitive function score, and preoperative symptom score of pain were identified as predictors by the EORTC GHS score. Conclusions The EQ‐5D VAS and EORTC GHS scores traced similar trajectories of QOL. In both QOL measures, preoperative pain was found as a common predictor. These predictors may help improve patient/survivor care in the future., We investigated the preoperative predictors of QOL in surgical patients with lung cancer. General health status/QOL was measured by EQ‐5D VAS and EORTC GHS scores. Multivariable linear regression analyses were used. Although each QOL measure detected some preoperative predictors, preoperative pain was a common predictor in both, one year after surgery. Predictors detected in this study were possible targets for patient/survivor care.

Endobronchial‐invasive lung cancers are generally diagnosed at advanced stages and may require emergency treatment for airway obstruction. Stent implantation is a common intervention for such obstructed airways but certain subsets of patients cannot receive adequate treatment without respiratory support. Veno‐venous extracorporeal membrane oxygenation (ECMO) is a salvage therapy for respiratory failure but its usefulness in managing patients with advanced lung cancer remains unclear given the poor prognosis. In recent years, molecular targeted agents for patients with driver mutations offer rapid responses and may be administered even while under critical care. In this report, we describe the case of 39‐year‐old female who presented to our emergency department with severe respiratory distress. A computed tomography scan revealed a large mediastinal tumor invading the tracheal carina causing severe stenosis of the left main bronchus and right main pulmonary artery. ECMO support was required as the respiratory condition remained unstable despite high pressure ventilation. Under ECMO support, the patient underwent bronchial stent implantation and was successfully weaned off ECMO. The tumor was histologically diagnosed as pulmonary adenocarcinoma with anaplastic lymphoma kinase gene rearrangement. Treatment with a tyrosine kinase inhibitor, alectinib, induced a marked tumor reduction within a short period. The patient recovered well and is now in remission one year later. This case indicates that intensive respiratory support with ECMO may become a bridge through the critical period for selected patients with respiratory failure secondary to advanced lung cancer. Key points Significant findings of this study ECMO was important to maintain oxygenation during airway intervention for acute respiratory failure due to critical lung adenocarcinoma with ALK gene rearrangement. What this study adds With the development of targeted therapies and the improvement in therapeutic bronchoscopy, intensive respiratory support with ECMO may be helpful especially in selected lung cancer patients with oncogenic driver mutations., Respiratory support with extracorporeal membrane oxygenation (ECMO) in managing patients with advanced lung cancer remains unclear given the poor prognosis. Targeted agents for patients with driver mutations offer rapid responses and may be administered even while under critical care. In some patients with critical lung cancer, ECMO may become a bridge through the critical period with respect to effective anti‐cancer therapies.

Aim: Depending upon the degree of DNA degradation of formalin-fixed and paraffin-embedded tissue samples, accuracy of measurement by Infinium MethylationEPIC BeadChip assay (Illumina, CA, USA) was assessed. Materials & methods: DNA quality of six formalin-fixed and paraffin-embedded lung tissue samples with different formalin fixation periods was assessed by Illumina quality control, DNA copy number and DNA integrity number value. Infinium data from restored bisulfite treated DNA were compared with datum from a fresh-frozen sample. Results: The correlation coefficient decreased from 0.993 to 0.970 depending upon DNA degradation, even if the Illumina quality control was met. Exclusion of specific probes improved the correlation regardless of tissue. Conclusion: Poor DNA quality can be assessed as an amplifiable DNA copy number and DNA integrity number value. Probe filtering has the potential to improve assay accuracy.

Background Indium is a metal used as a compound called indium-tin oxide for liquid crystal display. Its inhalation causes lung toxicity, resulting in a new occupational lung disease called indium lung. Although the carcinogenicity of indium has been reported in an animal model, its carcinogenicity in humans is unknown. Case presentation This is the first reported case of a primary lung cancer originating from indium lung. In this report, we describe a 46-year-old man with interstitial pneumonia-type indium lung diagnosed 16 years ago. The initial symptom was left chest pain, and computed tomography showed a mass adjacent to the aorta with left pleural effusion. Specimens collected using video-assisted thoracoscopy revealed an adenocarcinoma with a high expression of programmed cell death-ligand 1 (cT4N0M1a stage IVA). Although the lesions showed a remarkable aggressive nature, the patient benefited from pembrolizumab, a monoclonal antibody against programmed cell death 1, which was used as second-line therapy for 2 years. Conclusions It is important for clinicians to be aware of lung cancer development in indium-exposed workers or in patients with indium lung, as this could have an aggressive behavior. Treatment with immune checkpoint inhibitors is an option even in patients with interstitial pneumonia-type indium lung.

To clarify the trajectory and profile of quality of life (QOL) in lung cancer patients undergoing surgery during hospitalization. Among prospectively enrolled 279 patients between 2015 and 2018, we used the EQ-5D-5 levels (EQ-5D-5L), which consist of a descriptive system of five dimensions and a visual analog scale (VAS) (from 0 to 100). The five dimensions are mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, which are rated according to a 5-grade evaluation. QOL assessments were performed preoperatively (Pre) and on postoperative day 1/3/5/7 (D1/D3/D5/D7). To observe the trajectory of QOL, the EQ-5D VAS was used. To define the profile of QOL, we applied univariate linear regression analysis to predict EQ-5D VAS based on the five dimensions of EQ-5D as explanatory variables and to determine the rank of absolute values of the standardized coefficient of each dimension that represented strength of the effect on the EQ-5D VAS. The means of VAS scores were as follows: Pre/D1/D3/D5/D7 = 79/45/58/64/71. Younger age, fewer comorbidities, and surgical indications decreased the VAS at D1. More comorbidities, advanced cancer stage, postoperative adverse events, and chest tube placements hampered restoration of the VAS. Regarding QOL profiles, anxiety/depression was the highest rank preoperatively while usual activity, but not pain/discomfort, was the highest postoperatively. This is the first study to visualize the trajectory of QOL in surgical patients with lung cancer during hospitalization. This information may help improve perioperative patient care.

A 34-year-old man was diagnosed with thymoma, which was evaluated preoperatively as stage II or III, with myasthenia gravis (MG). The size of the tumor was 70 × 44 × 80 mm. No invasion to neighboring organs was observed. Prednisolone was prescribed for stabilization of MG. However, a myasthenic crisis (MC) occurred, and intensive care, including emergent endobronchial intubation followed by artificial ventilation, pulse steroid therapy, high-dose intravenous immunoglobulin, and tacrolimus hydrate, was initiated. A chest computed tomography on day 6 revealed tumor reduction to 50 × 30 × 60 mm. An extended total thymectomy by median sternotomy was performed, and artificial ventilation was continued after that. Scheduled artificial ventilation and steroid therapy together can, therefore, enable complete resection of thymoma in patients undergoing treatment for MC. While ventilation helps avert a respiratory failure, the steroid therapy temporarily reduces the tumor size, making resection easier.

Nitrosoallene-mediated endo-dig cyclization reactions producing (hetero)cyclic exo-unsaturated oximes (enoximes) are described. The intramolecular 1,4-type addition to in situ generated nitrosoallenes afforded α-substituted cyclic enoximes with exo-methylene units, which are the favored conformation for further cyclizations. The strong electron-withdrawing ability of the nitroso group facilitated the construction of five-to-seven-membered ring systems via C-O, C-N, C-S, and C-C bond formations, including a quaternary carbon center, at low temperatures.

application/pdf, Cellular Signalling. 2017, 39, P.108-117

Cry46Ab is a Cry toxin derived from Bacillus thuringiensis TK-E6. Cry46Ab is not significantly homologous to other mosquitocidal Cry or Cyt toxins and is classified as an aerolysin-type pore-forming toxin based on structural similarity. In this study, the potency of Cry46Ab was assessed for its potential application to mosquito control. A synthetic Cry46Ab gene, cry46Ab-S1, was designed to produce recombinant Cry46Ab as a glutathione-S-transferase fusion in Escherichia coli. Recombinant Cry46Ab showed apparent toxicity to Culex pipiens larvae, with a 50% lethal dose of 1.02 μg/ml. In an artificial lipid bilayer, Cry46Ab activated by trypsin caused typical current transitions between open and closed states, suggesting it functions as a pore-forming toxin similar to other Cry and Cyt toxins. The single-channel conductance was 103.3 ± 4.1 pS in 150 mM KCl. Co-administration of recombinant Cry46Ab with other mosquitocidal Cry toxins, especially the combination of Cry4Aa and Cry46Ab, resulted in significant synergistic toxicity against C. pipiens larvae. Co-administration of multiple toxins exhibiting different modes of action is believed to prevent the onset of resistance in insects. Our data, taken in consideration with the differences in its structure, suggest that Cry46Ab could be useful in not only reducing resistance levels but also improving the insecticidal activity of Bt-based bio-insecticides.

Hashimoto thyroiditis (HT) and Graves' disease (GD) share some immunological features. Determining the genetic basis that distinguishes HT from GD is key for a better understanding of the differences between these two related diseases.The aim of this study was to identify a non-HLA susceptibility locus that is specific to either HT or GD.We performed a two-stage genome-wide comparison between HT and GD in Japan. During the discovery stage, we performed a logistic regression analysis adjusting for sex using 727 413 single nucleotide polymorphisms (SNPs) for 265 HT and 261 GD patients. During the replication stage, 35 SNPs were analyzed for 181 HT and 286 GD cases. A combined meta-analysis was performed using the results from these two stages. An SNP showing a genome-wide significant level was further analyzed using 1363 healthy controls to determine the specificity of susceptibility.A genome-wide direct comparison between HT and GD revealed an SNP at the VAV3 locus with genome-wide significant association signals (rs7537605: P(combined) = 3.90 × 10(-8); odds ratio(combined) = 1.77; 95% confidence interval = 1.44-2.17). An association analysis using healthy controls showed that rs7537605 is significantly associated with HT (P = 1.24 × 10(-5); odds ratio = 1.60; 95% confidence interval = 1.30-1.97) but not with GD (P = .50), suggesting that the variant specifically affects susceptibility to HT.A genome-wide direct comparison between HT and GD revealed an HT-specific variant within VAV3 in the Japanese. Considering physiological roles of VAV3, such as a guanine nucleotide exchange factor, our finding provides new insight into the molecular mechanism of HT.

We here describe a case involving a 67-yearold female patient who was referred to our hospital due to severe anemia (hemoglobin, 5.0 g/dL), thrombocytopenia (platelet count, 0.6 × 104/μL), and a mediastinal shadow with calcification noted on X-ray. On admission, an anterior mediastinal tumor was detected, and bone marrow biopsy revealed few megakaryocytes and severely reduced numbers of erythroid cells. The diagnosis was thymoma with pure red cell aplasia (PRCA) and acquired amegakaryocytic thrombocytopenia (AAMT). On Day 8 of admission, the patient received immunosuppressive therapy together with cyclosporine for the 2 severe hematologic diseases, which were stabilized within 2 months. Subsequently, total thymectomy was performed. The diagnosis of the tumor invading the left lung was invasive thymoma, Masaoka- Koga stage III. The histological diagnosis was World Health Organization type AB. Thymoma accompanied with PRCA and AAMT is very rare, and, based on our case, immunotherapeutic therapy for the hematologic disorders should precede surgical intervention.

Objective To assess the long-term efficacy and safety of infliximab (IFX) treatment for refractory uveitis associated with Behcet's disease (BD) and to identify predictors of long-term IFX therapy outcomes. Methods We retrospectively studied 44 consecutive BD patients with uveitis who were started on IFX therapy and analyzed the efficacy and safety of IFX and the treatment continuation rate. To determine predictors of IFX responsiveness, we analyzed the clinical characteristics of the patients who received regular maintenance therapy and those who required treatment intensification. The serum cytokine levels prior to IFX were measured through the Bio-Plex human cytokine assays. Results IFX significantly reduced the frequency of ocular attacks and improved the visual acuity of patients with BD-related uveitis. However, approximately half of the patients required dose escalations, necessitating a shortening of the intervals between IFX infusions due to loss of efficacy during the 5-year treatment. The frequency of ocular attacks was significantly higher in patients with complete BD than in patients with incomplete BD. A multiplex cytokine analysis revealed that patients with BD-related uveitis exhibited increased serum IL-2, IL-6, IL-8, and MCP-1 levels. Moreover, among BD patients, the serum IL-2 and IL-6 levels were particularly high in those who maintained remission and received regular IFX treatments. Conclusion We confirmed the long-term efficacy and tolerability of IFX in patients with BD-related uveitis. Our results indicate that complete BD may be less responsive to IFX and that the pretreatment serum cytokine profiles may be useful for predicting the long-term IFX therapy outcomes.

Background: Autoimmune thyroid disease (AITD) includes Graves disease (GD) and Hashimoto thyroiditis (HT), which partially share immunological features. Determining the genetic basis that distinguishes GD and HT is a key to understanding the differences between these 2 related diseases. Aim: The aims of this study were to identify HLA antigens that can explain the immunopathological difference between GD and HT and to elucidate epistatic interactions between protective and susceptible HLA alleles, which can delineate the distinct function of HLA in AITD etiology. Design: We genotyped 991 patients with AITD (547 patients with GD and 444 patients with HT) and 481 control subjects at the HLA-A, HLA-C, HLA-B, DRB1, DQB1, and DPB1 loci. A direct comparison of HLA antigen frequencies between GD and HT was performed. We further analyzed an epistatic interaction between the susceptible and protective HLA alleles in the development of GD and HT. Results: We identified 4 and 2 susceptible HLA molecules primarily associated with GD and HT, respectively, HLA-B*35:01, HLA-B*46:01, HLA-DRB1*14:03, and HLA-DPB1*05:01 for GD and HLA-A*02:07 and HLA-DRB4 for HT. In a direct comparison between GD and HT, we identified GD-specific susceptible class II molecules, HLA-DP5 (HLA-DPB1*05:01; Pc = 1.0 × 10−9) and HLA-DR14 (HLA-DRB*14:03; Pc = .0018). In contrast, HLA components on 3 common haplotypes in Japanese showed significant protective effects against the development of GD and HT (HLA-A*24:02-C*12:02-B*52:01-DRB1*15:02-DQB1*06:01-DPB1*09:01 and HLA-A*24:02-C*07:02-B*07:02-DRB1*01:01-DQB1*05:01-DPB1*04:02 haplotypes for GD and HLA-A*33:03-C*14:03-B*44:03-DRB1*13:02-DQB1*06:04-DPB1*04:01 haplotype for GD and HT). Interestingly, the representative protective HLA, HLA-DR13 (HLA-DRB1*13:02), was epistatic to susceptible HLA-DP5 in controlling the development of GD. Conclusion: We show that HLA exerts a dual function, susceptibility and resistance, in controlling the development of GD and HT. We also show that the protective HLA allele is partially epistatic to the susceptible HLA allele in GD.

We report the case of an 83-year-old woman who presented with an abnormal pulmonary nodule suspected to be lung cancer in the left S3 segment. Bronchoscopy showed that the left main bronchus branched off into the B1+2, B3 plus lingular bronchus, and lower bronchus. Video-assisted thoracic surgery was performed, and the nodule was pathologically diagnosed as a primary lung cancer. Subsequently, left upper lobectomy was performed, and an abnormal bronchus was observed behind the main pulmonary artery. Intraoperative bronchoscopy indicated that the bronchus was the displaced B1+2. The B3 plus lingular bronchus existed at the common place of the upper bronchus. The displaced B1+2 and the other upper bronchus were transected separately. No other abnormalities were observed in the pulmonary arteries, veins, or bronchi. Preoperative examination is the best way to detect this bronchial abnormality;identification with intraoperative bronchoscopy can play a crucial role in determining the perioperative strategy.

We have developed a comprehensive software suite for bioinformatics research of cDNAs; it is aimed at rapid characterization of the features of genes and the proteins they code. Methods implemented include the detection of translation initiation and termination signals, statistical analysis of codon usage, comparative study of amino acid composition, comparative modeling of the structures of product proteins, prediction of alternative splice forms, and metabolic pathway reconstruction. The software package is freely available under the GNU General Public License at http://www.g-language.org/data/cdna/ .

Previous studies have suggested that the human leukocyte antigen (HLA) is involved in the etiology of Crohn’s disease (CD); however, few reports are available on the association between HLA class I antigens and CD in Japan. In this study, we performed association analysis of HLA class I antigens in CD using 208 Japanese patients and 384 healthy controls. We identified novel positive associations between CD and HLA-A*02:01 (odds ratio (OR)=1.64, P=0.016) and HLA-A*02:07 (OR=2.31, P=0.0067) and confirmed previously reported positive associations between CD and HLA-Cw*14:02 (OR=2.18, P=0.0021) and HLA-B*51:01 (OR=1.70, P=0.033). We also identified novel negative associations between CD and HLA-A*24:02 (OR=0.60, P=0.0047) and HLA-B*07:02 (OR=0.38, P=0.0041). Although the associations were not significant after full Bonferroni correction, we suggested that HLA class I genes have dual functions, susceptibility and resistance in controlling the development of CD.

When a ${\mathrm{C}}_{60}$ film is irradiated with a $3\phantom{\rule{0.3em}{0ex}}\mathrm{keV}$ electron beam, a cross-linked ${\mathrm{C}}_{60}$ polymer is formed and exhibits metallic electron-transport $(I\text{\ensuremath{-}}V)$ properties in air at room temperature [J. Onoe et al., Appl. Phys. Lett. 82, 595 (2003)]. To elucidate the origin of the metallic $I\text{\ensuremath{-}}V$ characteristics of the cross-linked polymer, we examined the valence photoelectron spectra of the polymer using in situ high-resolution ultraviolet photoelectron spectroscopy (UPS) and found that the spectrum for the cross-linked ${\mathrm{C}}_{60}$ polymer came across the Fermi level $({E}_{F})$. To understand the UPS results for the ${\mathrm{C}}_{60}$ polymer, we performed first-principles calculations of the band structure for three kinds of optimized three-dimensional unit cells of one-dimensional (1D) cross-linked ${\mathrm{C}}_{60}$ polymers with a cross-linkage consisting of both six- and seven-membered rings and of five- and eight-membered rings (P58). It was found that one quasi-1D P58 cross-linked ${\mathrm{C}}_{60}$ polymer shows semimetallic properties, which provides one possible explanation of both previous (metallic $I\text{\ensuremath{-}}V$ characteristics) and present (valence photoelectron spectra) experimental results.

Fullerene polymers made of C 60 are systematically investigated by means of a first-principles pseudopotential approach within the local density approximation of the density functional theory. We assume 10 different structures of fullerene polymers. The first three are C 6o polymer networks cross-linked by [2+2] cycloadditional four-membered rings, and the other seven are composed of peanut-shaped fused C 60 polymer chains cross-linked by either seven-membered rings or eight-membered rings. Owing to the overlap of wave functions as well as the hybrid networks of sp 2 -like (3-fold coordinated) and sp 3 -like (4-fold coordinated) carbon atoms, the electronic structure is considerably different from each other. We find that the resulting electronic structure is either semiconductor or semimetal depending on the spatial dimensionality of materials.

Background DNAM-1 (CD226) is well known as a genetic risk factor of many autoimmune diseases such as systemic sclerosis (SSc). More recently, Avouac et al. have reported that mice deficient for DNAM-1 are protected from bleomycin-induced dermal fibrosis. In human, however, the roles of DNAM-1 in SSc are still unknown. Objectives To evaluate cell surface expression of DNAM-1 on peripheral blood lymphocytes from SSc patients and to identify the roles of DNAM-1 in the pathogenesis of SSc. Methods The expression of DNAM-1 was analyzed by flow cytometry (FCM) on surface of CD4+ T cells, CD8+ T cells and CD19+ B cells from 41 SSc patients (median age, 59 years; female, 37) and 23 healthy controls (HCs). We evaluated the relationship between DNAM-1 expression level on CD8+ T cells and clinical manifestations of SSc. Intracellular and extracellular cytokine production in CD8+ T cells with or without DNAM-1 was measured by FCM (intracellular staining and multiplex bead array, respectively) after stimulation with PMA/Ionomycin. The cytotoxic capacity of CD8+ T cells against human umbilical vein endothelial cells (HUVECs) was assessed in the presence or absence of anti-DNAM-1 neutralizing antibody in SSc patients and HCs. Results The proportion of DNAM-1 high CD8+ T cells was increased in SSc patients (median, 52.5%) compared to HCs (29.7%, P=0.0002). We found no significant difference between SSc patients and HCs in CD4+ T cells and CD19+ B cells. The expression of DNAM-1 on CD8+ T cells was higher in patients with diffuse cutaneous subtype than those with limited cutaneous subtype (P=0.0009) and was higher in those with interstitial pneumonia than those without (P=0.0016). The percentage of DNAM-1 high CD8+ T cells was significantly correlated with modified Rodnan skin thickness score (r =0.4295, P=0.0071). The production of IL-13 was significantly increased in DNAM-1 positive CD8+ T cells compared with DNAM-1 negative ones and the neutralization of DNAM-1 impaired the IL-13 production from CD8+ T cells. The cytotoxic ability of CD8+ T cells was significantly elevated in SSc patients and positively correlated with the percentage of DNAM-1 high CD8+ T cells. The cytotoxicity against HUVECs was partially inhibited in the presence of anti-DNAM-1 neutralizing antibody. Conclusions These findings indicate that DNAM-1 high CD8+ T cells are involved in the pathogenesis of SSc via the production of profibrotic IL-13 and endothelial cell injury. References Avouac J, Elhai M, Tomcik M, et al. Critical role of the adhesion receptor DNAX accessory molecule-1 (DNAM-1) in the development of inflammation-driven dermal fibrosis in a mouse model of systemic sclerosis. Ann Rheum Dis. 2013;72:1089-98. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3217

Background Recently, it has been reported that granulin (GRN) and/or progranulin (PGRN), precursor of GRN, is a soluble cofactor for TLR9 signaling [1]. We reported that serum PGRN levels are associated with SLE global activity and PGRN may have a role in the pathogenesis via increased cytokine production [2]. TLR9 is also involved in the pathological condition of dermatomyositis (DM). Moreover, DM is occasionally complicated with interstitial lung disease (ILD). However, the roles of PGRN and GRN in DM are still unknown. Objectives To determine if serum PGRN levels are elevated in DM patients, in particular, complicated with ILD and are associated with severity and prognosis. Methods The serum levels of PGRN were measured by ELISA in patients with DM (n=50; acute/subacute interstitial pneumonia (A/SIP), defined as a rapidly progressive ILD within 3 months from the onset of symptoms: n=13, chronic interstitial pneumonia (CIP): n=20, without ILD: n=17), polymyositis (PM, n=21) and normal healthy controls (NHCs, n=60). We assessed the correlation between the serum PGRN levels and the activity indexes of ILD. The sera from some of the patients were reevaluated after the disease was ameliorated by treatment (n=6). Moreover, we calculated the cumulative survival rate for 6 months in DM patients with ILD, which is classified two groups, serum PGRN levels > or =200 ng/ml and Results The serum PGRN levels were significantly higher in the DM patients (median: 100 ng/ml) than in the PM patients (60.4 ng/ml, P=0.0028) and NHCs (48.3 ng/ml, P or =200 ng/ml (60%) than that in the group with serum PGRN levels Conclusions These findings indicate that PGRN is associated with severity and prognosis of DM with ILD. PGRN may play a role in the pathogenesis of DM by affecting the TLR9 signaling and could be a useful biomarker. References Park B, Buti L, Lee S, et al. Granulin is a soluble cofactor for toll-like receptor 9 signaling. Immunity 2011;34:505-513. Tanaka A, Tsukamoto H, Mitoma H, et al. Serum progranulin levels are elevated in patients with systemic lupus erythematosus, reflecting disease activity. Arthritis Res Ther 2012;14(6):R244. Disclosure of Interest None Declared

Thermonuclear fusion process implementation has many materials problems and one of them is related to removal of impurities from plasma. In the International Thermonuclear Experimental Reactor (ITER), a divertor concept has been incorporated for this purpose. In this work, the development of a micromechanical model for FGM is presented and its application to thermal-elasto-plastic analysis is discussed for the case of W-Cu FGM for ITER divertor plates. The model allows the prediction of basic properties of 3-D FGM, computations of thermal stresses, and, in some limits, it may be used for pre-design evaluation of dynamic strain/stress distribution and inelastic behaviour. The model is found to be very useful at the first stages of graded materials design and computation of properties in the nodal points for more detailed numerical analysis.