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A study of single grains of lead halide perovskite reveals the presence of both excitons and free charge carriers. The nature of charge carriers in methylammonium lead iodide perovskites (MAPbI 3 ) at room temperature is still a matter of considerable debate 1 , 2 , 3 . Here, we demonstrate that within single grains of MAPbI 3 , strong spatial heterogeneities on the nanometre length scale are present and associated with simultaneous free-carrier and exciton populations. These heterogeneous populations, hidden in ensemble measurements, have a signature of spatially resolved relaxation dynamics for above-bandgap photoexcitation. Using spectrally resolved transient absorption microscopy, we directly observe both red- and blueshifts of the band-edge absorption across individual grains due to a dynamic Stark shift and screening of excitonic transitions by hot carriers. These observations help address a long-standing debate on the identity of the charge carriers, showing that both excitons and free carriers coexist, but are spatially segregated on the length scale of hundreds of nanometres.

RUNX3, runt-domain transcription factor, is a master regulator of gene expression in major developmental pathways. It acts as a tumor suppressor in many cancers but is oncogenic in certain tumors. We observed upregulation of RUNX3 mRNA and protein expression in nasal-type extranodal natural killer (NK)/T-cell lymphoma (NKTL) patient samples and NKTL cell lines compared to normal NK cells. RUNX3 silenced NKTL cells showed increased apoptosis and reduced cell proliferation. Potential binding sites for MYC were identified in the RUNX3 enhancer region. Chromatin immunoprecipitation–quantitative PCR revealed binding activity between MYC and RUNX3. Co-transfection of the MYC expression vector with RUNX3 enhancer reporter plasmid resulted in activation of RUNX3 enhancer indicating that MYC positively regulates RUNX3 transcription in NKTL cell lines. Treatment with a small-molecule MYC inhibitor (JQ1) caused significant downregulation of MYC and RUNX3, leading to apoptosis in NKTL cells. The growth inhibition resulting from depletion of MYC by JQ1 was rescued by ectopic MYC expression. In summary, our study identified RUNX3 overexpression in NKTL with functional oncogenic properties. We further delineate that MYC may be an important upstream driver of RUNX3 upregulation and since MYC is upregulated in NKTL, further study on the employment of MYC inhibition as a therapeutic strategy is warranted.

RUNX1/AML1 is among the most commonly mutated genes in human leukemia. Haploinsufficiency of RUNX1 causes familial platelet disorder with predisposition to myeloid malignancies (FPD/MM). However, the molecular mechanism of FPD/MM remains unknown. Here we show that murine Runx1 +/− hematopoietic cells are hypersensitive to granulocyte colony-stimulating factor (G-CSF), leading to enhanced expansion and mobilization of stem/progenitor cells and myeloid differentiation block. Upon G-CSF stimulation, Runx1 +/− cells exhibited a more pronounced phosphorylation of STAT3 as compared with Runx1 +/+ cells, which may be due to reduced expression of Pias3, a key negative regulator of STAT3 signaling, and reduced physical sequestration of STAT3 by RUNX1. Most importantly, blood cells from a FPD patient with RUNX1 mutation exhibited similar G-CSF hypersensitivity. Taken together, Runx1 haploinsufficiency appears to predispose FPD patients to MM by expanding the pool of stem/progenitor cells and blocking myeloid differentiation in response to G-CSF.

ObjectivesSeveral lines of evidence suggest that brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of fibromyalgia (FM) and studies have found that FM patients have altered serum and plasma BDNF levels. However, it is not known whether polymorphisms of the BDNF gene are associated with FM. In this study, we explored the association between polymorphisms of the BDNF gene with FM susceptibility and the severity of symptoms.MethodsThe study enrolled 409 patients with FM and 423 controls from 10 medical centres that participated in the Korean nationwide FM survey study. Alleles at 10 positions in the BDNF gene were genotyped: rs2883187 (C>T), rs7103873 (G>C), rs7103411(C>T), rs10835210 (C>A), rs11030104 (A>G), rs12273539 (C>T), rs11030102(C>G), rs11030101 (A>T), rs6265 (G>A), and rs7124442(C>T).ResultsThe allele and genotype frequencies of BDNF rs11030104 differed significantly between the FM patients and controls (p=0.031). The GG genotype of rs11030104 had a protective role against FM (p=0.016) and the G allele of rs11030104 was negatively associated with the presence of FM compared with the A allele (p=0.013). In comparison, although the allele and genotype frequencies of BDNF rs12273539 did not differ between the FM patients and controls, the TT genotype of BDNF rs12273539 was associated with susceptibility to FM (p=0.038). Haplotype analyses suggested that some BDNF haplotypes have a protective role against FM. Finally, we found that that some genotypes and haplotypes of the BDNF gene contribute to the specific symptoms of FM.ConclusionsThis study is the first to evaluate the associations of BDNF gene polymorphisms with FM. Our results suggest that some BDNF single-nucleotide polymorphisms and haplotypes are associated with susceptibility to, and contribute to the symptoms of, FM.Disclosure of InterestNone declared

ObjectivesAlthough polymorphisms of the catechol-O-methyl transferase (COMT) gene have been implicated in altered pain sensitivity, results concerning the association between COMT gene polymorphisms and FM are equivocal. We assessed the associations between COMT single-nucleotide polymorphisms (SNP) and FM risk and symptom severity.MethodsIn total, 409 FM patients and 423 controls were enrolled. Alleles and genotypes at five positions [rs6269 (A>G), rs4633 (C>T), rs4818 (C>G), rs4680 (C>G) and rs165599 (A>G)] in the COMT gene were genotyped from peripheral blood DNA.ResultsAlleles and genotypes of the rs4818 COMT gene polymorphism were significantly associated with increased susceptibility to FM. The rs4818 GG genotype was more strongly associated with FM compared to the CC genotype (OR =1.680, 95% CI: 1.057, 2.672, P=0.027). Although allele and genotype frequencies did not differ among groups, the rs4633 CT genotype was not associated with the presence of FM following adjustment for age and sex (OR =0.745; 95% CI: 0.558, 0.995; P=0.046). However, no association was observed between clinical measures and individual COMT SNPs. In haplotype analysis, there was a significant association between ACG haplotype and FM susceptibility sex (OR =2.960, 95% CI: 1.447, 6.056, P=0.003) and the number of tender points (P=0.046).ConclusionsThis large-scale study suggests that polymorphisms of the COMT gene may be associated with FM risk and pain sensitivity in Korean FM patients. However, our results differed to those of previous studies, suggesting ethnic variation in COMT gene polymorphisms in FM.Disclosure of InterestNone declared

ObjectivesResearchers continue to gather evidence that transient receptor potential vanilloid (TRPV) channels contribute towards pain signaling pathways. However, it is unknown whether polymorphisms of the TRPV gene are associated with fibromyalgia (FM). For the first time, we investigated the association between the polymorphisms of the TRPV2 and TRPV3 genes with FM susceptibility and the severity of the symptoms.MethodsA total of 409 patients with FM and 423 controls were enrolled from 10 medical centers that participated in the Korean nationwide FM survey. The alleles and genotypes at three positions [rs3813768 (C>G), rs8121 (C>T), and rs1129235 (C>A)] in the TRPV2 gene, and two positions [rs7216486 (G>A) and rs395357 (C>T)] in the TRPV3 gene, were genotyped.ResultsThe frequencies of the alleles and genotypes of individual TRPV2 and TRPV3 genes were not significantly associated with FM susceptibility. However, the GTA haplotype of TRPV2 showed a defense against FM susceptibility (P=0.035). In addition, polymorphisms of TRPV3 were associated with symptom severity in FM patients. The single nucleotide polymorphism (SNP) rs395357 of TRPV3 was associated with the scores of the Brief Fatigue Inventory (BFI) (P=0.017) in FM patients. Furthermore, haplotypes of TRPV3 were associated with the BFI and the SF-36 mental health summary scores (P=0.036, respectively)ConclusionsThis study was the first to evaluate the associations of TRPV gene polymorphisms with FM. Our results suggest that certain TRPV2 haplotypes may have a protective role against FM, and also that some genotypes and haplotypes of TRPV3 contribute towards the symptoms of FM.Disclosure of InterestNone declared

Background A disintegrin and metalloproteinase (ADAM) with thrombospondin type 1 motif, 12 (ADAMTS12) is a degradative enzyme that interacts with the degradable fragments of cartilage oligomeric matrix protein, which is a prominent noncollagenous matrix component in articular cartilage. ADAMTS12 has been observed in the cartilage, synovial fluid and serum of arthritis patients, and may play an important role in the pathogenesis of arthritis. Objectives In this study, we investigated whether the genetic polymorphisms of ADAMTS12 are associated with rheumatoid arthritis (RA) in a Korean population. Methods To observe the association between ADAMTS12 and RA, we genotyped three single nucleotide polymorphisms (SNPs) (rs1364044, intron C/T; rs10461703, intron C/T; rs25754, missense Thr1495Ile) of ADAMTS12 using a direct sequencing method in 303 RA patients and 495 control subjects. Multiple logistic regression models were performed to analyze the genetic data. SNPStats and SNPAnalyzer Pro programs were used to estimate odds ratios, 95% confidence intervals, and p values. Bonferroni’s correction (pc) was conducted to obtain a defined result. Results Of the three SNPs, the genotype frequency of rs10461703 was associated with the development of RA (pc=0.0024 in the co-dominant model; pc=0.0009 in the dominant model; pc=0.0006 in the log-additive model). The allele frequency of rs10461703 also showed a significant difference between RA and controls (pc<0.0001). The C allele frequency of rs10461703 was lower in the RA group (36.6%) than in the control group (45.7%), whereas the T allele frequency of rs10461703 in the RA group (63.4%) was higher than that in the control group (54.3%). The other two SNPs (rs1364044 and rs25754) were not associated with the development of RA. However, we did not find any association between the three tested SNPs and RA patients according to clinical features including erythrocyte sedimentation rate, C-reactive protein level, rheumatoid factor (+ and -) and bone erosion (+ and -). Table 1. Genotype and allele frequencies of ADAMTS12 SNPs in RA and control subjects SNPGenotype/AlleleRAControlModelOR95% CIPPc Freq.%Freq.%LCLUCL rs1364044C/C9833.218739.8Co-dominant 10.800.571.140.391.00 C/T14147.820443.4Co-dominant 20.780.501.23 T/T5619.07916.8Dominant0.800.581.110.170.51 Recessive0.880.591.320.541.00 Over-dominant0.870.641.190.401.00 Log-additive0.870.701.080.210.63 C33757.157861.5 T25342.936238.51.200.971.480.090.27 rs10461703T/T12241.514529.3Co-dominant 11.71.212.400.00080.0024 T/C12943.924850.1Co-dominant 22.141.363.37 C/C4314.610220.6Dominant1.821.322.500.00030.0009 Recessive1.571.052.370.0270.08 Over-dominant1.320.971.790.0750.23 Log-additive1.511.211.880.00020.0006 T37363.453854.3 C21536.645245.70.690.560.85<0.0001<0.0001 Conclusions Our results suggest that ADAMTS12 may be a susceptibility gene for RA development in the Korean population. Disclosure of Interest None Declared

Abstract The characteristics of protein-losing enteropathy were evaluated in patients with systemic lupus erythematosus. Among the patients with systemic lupus erythematosus (n = 380) in a tertiary hospital, we reviewed the records of seven patients with generalized edema, hypoalbuminemia without proteinuria and positive results on 99mTc-labelled human serum albumin scintigrams. Patient characteristics and laboratory findings were compared between these seven patients and patients with lupus enteritis (n = 15) or idiopathic protein-losing enteropathy (n = 11). Compared with the lupus enteritis patients, the erythrocyte sedimentation rate and serum total cholesterol levels were significantly increased in patients with systemic lupus erythematosus–related protein-losing enteropathy. Compared with idiopathic protein-losing enteropathy patients, the level of serum total cholesterol was significantly increased, but the level of serum albumin was decreased in patients with systemic lupus erythematosus–related protein-losing enteropathy. Among patients with systemic lupus erythematosus–related protein-losing enteropathy, four patients had high serum total cholesterol levels (≥248 mg/dL) and achieved complete remission after receiving high doses of steroid treatment. However, three patients who had low serum total cholesterol levels (≤219 mg/dL) responded poorly to the steroid-only treatment, and could achieve complete remission only after 3 months of cyclophosphamide pulse treatment with concurrent corticosteroid therapy. The levels of serum total cholesterol are intriguing feature in systemic lupus erythematosus–associated protein-losing enteropathy patients.

Background Maillard reaction products (MRPs) are known to have antioxidant, antimutagenic and anticardiogenic activities. The antioxidant capacity of MRPs is comparable to those of commonly used food antioxidants; butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and a-tocopherol. Maillard reaction (MR) could produce non-enzymatically colored or colorless products such as glucose-tyrosine, glucose-lysine, fructose-lysine, ribose-lysine, xylose-arginine, xylose-glycine and xylose-tryptophanRecently, we synthesized (E)-2,4-bis(p-hydroxyphenyl)-2-butenal using tyrosine and fructose under a typical MR condition of high temperature and pressure. Objectives Objective of this study was to assess anti-arthritis effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal and its action mechanisms.In the present study, we investigated whether (E)-2,4-bis(p-hydroxyphenyl)-2-butenal can have anti-inflammatory activity and anti-arthritic activities through inhibition of NF-kB/IKK and STAT3 pathways in cultured macrophage and synoviocytes, and collagen-induced arthritis (CIA) animal model. Methods Nitric oxide (NO) and prostaglandin E2 assay, electrophoretic mobility shift assay, luciferase assay, Western blot, real-time PCR and pull-down assay were used for mechanism studies. Anti-inflammatory effect was done in cultured RAW 264.7 cells and synoviocytes, and collagen-induced arthritis model was used for evaluation of anti-inflammation and anti-arthritis effects in vivo. Binding target of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal was identified using pull-down assay and sol-gel biochip assay, and its binding site was proposed through a docking experiment. Results (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (2.5-10 mg/ml) inhibited lipopolysaccharides (1 mg/ml)-induced pro-inflammatory responses through downregulating IkB kinase b (IKKb)/nuclear factor-kapaB (NF-kB) and signal transducer and activator of transcription 3 (STAT3) pathways in RAW 264.7 cells and synoviocytes. (E)-2,4-bis(p-hydroxyphenyl)-2-butenal not only suppressed the collagen (100 mg/0.1ml)-induced arthritic responses through inhibition of IKKb/NF-kB and STAT3 activities but also reduced the extent of bone destruction and fibrosis in joint tissue. The population of white blood cells in blood and NO generation in murine splenic T cells of collagen-induced arthritic mice were significantly reduced by (E)-2,4-bis(p-hydroxyphenyl)-2-butenal. Sol-gel biochip analysis proved that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal directly binds to IKKb, and thus inhibit its activity. A docking experiment and pull-down assay indicate that IKKb might be a potential target of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal. Conclusions These findings indicated that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal exerted its anti-inflammatory and anti-arthritic effects through inhibition of IKKb/NF-kB activity via direct binding to IKKb, and that it could be a useful agent for the treatment of arthritic diseases. References Hwang IG, Kim HY, Woo KS, Hong JT, Hwang BY, Jung JK, et al. Isolation and characterisation of an a-glucosidase inhibitory substance from fructose–tyrosine Maillard reaction products. Food Chemistry 2011;127:122–6. Disclosure of Interest None Declared

Background Fibromyalgia (FM) is a chronic pain disorder characterized by widespread pain, tenderness, and various associated symptoms including sleep disturbances, chronic fatigue, depression, and other somatic symptoms. Several longitudinal and cross-sectional studies in western countries have shown that a high body mass index (BMI) is a strong and independent risk factor for future development of FM and is associated with higher levels of FM symptoms. In addition, obese patients have more physical and emotional impairments compared with nonobese patients. Objectives The purpose of this study was to determine whether obesity and socioeconomic factors influence symptom severity in Korean patients with FM. Methods A total of 343 patients with FM were recruited from outpatient clinics at 11 medical centers across the Republic of Korea. All patients met the ACR 1990 classification criteria for FM. We interviewed these patients using a structured questionnaire that included sociodemographic data, current or past FM symptoms, and current use of relevant medications at the time of enrollment. Tender point counts and scores were assessed by thumb palpation. Patients were asked to complete a Korean version of the Fibromyalgia Impact Questionnaire (FIQ), the Brief Fatigue Inventory (BFI), the SF-36, the Beck Depression Inventory (BDI), the State-Trait Anxiety Inventory (STAI), the Self-Efficacy Scale, and the Social Support Scale. Results Based on an obesity definition of a BMI of ≥25, 76 (22.1%) of the 343 patients were obese. Obese patients were not different from nonobese patients in terms of tender points and scores, FIQ, BFI, SF-36, BDI, STAI, Self-Efficacy, and Social Support scores. After age-, gender-, and symptom duration adjustment by propensity score matching, no significant differences were also found between obese and nonobese patients. However, socioeconomic status such as employment, insurance, and education were significantly associated with symptom severity of FM. The unemployed patients had higher FIQ scores (p=0.011), higher BFI scores (p=0.013), lower physical and mental component SF-36 scores (p=0.012, p=0.005), higher BDI scores (p=0.005), and higher STAI II scores (p=0.041). Lower-income patients had higher FIQ score (p=0.040), lower physical and mental SF-36 scores (p=0.047, p=0.006), higher BDI scores (p<0.000), and lower Self-Efficacy scores (p=0.016). Finally, patients with an education of <12 years had higher tender points (p=0.034), higher BDI scores (p=0.007), and higher STAI II scores (p=0.045). Conclusions Our findings show that, contrary to Western patients, symptom severity in Korean patients with FM is associated with socioeconomic status, but not with obesity. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.2676