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The FDA-approved oral multi-kinase inhibitor, sorafenib (BAY 43-9006, Nexavar), is the first approved systemic therapy for patients with unresectable hepatocellular carcinoma (HCC). Although it has been shown to significantly improve the overall survival of patients with HCC, drug resistance limits the response rate to this therapeutic. Here, we report that acquired sorafenib resistance is associated with overexpression of the deacetylase, SIRT7, and a high level of ERK phosphorylation. Further, we identify that the hyperactivation of ERK is controlled by SIRT7-mediated deacetylation of DDX3X. The inhibition of SIRT7 combined with sorafenib resulted in a marked reduction of cell viability in vitro and of tumor growth in vivo. It seems plausible that SIRT7 is responsible for the acquired sorafenib resistance and its inhibition is most likely beneficial together in conjunction with sorafenib by suppressing ERK signaling.HighlightsSorafenib resistance in HCC is associated with SIRT7 and ERK hyperactivation.Suppression of SIRT7 combined with sorafenib restores sensitivity to sorafenib.SIRT7 controls sorafenib resistance through ERK activation by mediating DDX3X deacetylation.

Caspases play essential roles in apoptotic processes, which is necessary for cellular homeostasis. However, over-activation of caspases and subsequent excessive apoptosis is considered a main cause of Parkinson's disease and liver diseases. Here, we found that the insect-derived peptide, CopA3, which has shown antiapoptotic effects in many apoptosis models, directly binds to caspases. The resulting complexes do not dissociate during denaturing polyacrylamide gel electrophoresis, as evidenced by a distinct shift in the migration of caspase reflecting an increase in their molecular weight. Surface plasmon resonance and experiment using cysteine-substituted mutants of CopA3 collectively revealed that binding of CopA3 to caspases is dependent on an internal cysteine residue. Notably, CopA3 binding significantly inhibited proteolytic activation of downstream caspases by upstream caspases. In summary, the demonstration that CopA3 directly binds to caspases and inhibits their activating cleavage suggests a possible therapeutic approach for treating human diseases resulting from uncontrolled apoptosis.

Cancers can now be diagnosed and treated early, and the number of cancer survivors is increasing.1 In addition to survival, management of chronic diseases among cancer survivors has emerged as a major concern, because survivors experience numerous sequelae and age-related conditions.2 Psoriasis is a chronic inflammatory skin disorder that affects approximately 2-4% of the general population worldwide, and a recent population-based study found that the risk of cancer was higher in psoriasis patients compared to controls.3 Conversely, one report found that the risk of psoriasis in breast cancer patients was higher than in those who were generally healthy.4 However, the incidence of psoriasis in survivors of various types of cancer has received little attention.

A sufficient β-cell mass is crucial for preventing diabetes, and perinatal β-cell proliferation is important in determining the adult β-cell mass. However, it is not yet known how perinatal β-cell proliferation is regulated. Here, we report that serotonin regulates β-cell proliferation through serotonin receptor 2B (HTR2B) in an autocrine/paracrine manner during the perinatal period. In β-cell–specific Tph1 knockout (Tph1 βKO) mice, perinatal β-cell proliferation was reduced along with the loss of serotonin production in β-cells. Adult Tph1 βKO mice exhibited glucose intolerance with decreased β-cell mass. Disruption of Htr2b in β-cells also resulted in decreased perinatal β-cell proliferation and glucose intolerance in adulthood. Growth hormone (GH) was found to induce serotonin production in β-cells through activation of STAT5 during the perinatal period. Thus, our results indicate that GH-GH receptor-STAT5-serotonin-HTR2B signaling plays a critical role in determining the β-cell mass by regulating perinatal β-cell proliferation, and defects in this pathway affect metabolic phenotypes in adults.

Purpose Fine-needle aspiration biopsy (FNAB) can be used to diagnose thyroid cancer and other tumors. Although FNAB without negative pressure (FNAB-P) reduces the risk of blood contamination, FNAB with negative pressure (FNAB+P) increases the sensitivity of the biopsy results. Therefore, we performed a randomized study of FNAB with or without negative pressure to identify the better diagnostic method. Methods Between March 2016 and February 2017, 172 consecutive patients were enrolled to investigate >0.5 cm nodules with indeterminate or suspicious malignant features. Patients were randomly assigned to the FNAB+P group (a 50 mL syringe was used to provide negative pressure) or to the FNAB-P group (passive collection of blood in the needle's hub). The 2 methods' diagnostic adequacy and quality were evaluated using an objective scoring system. The study's protocol was registered with the World Health Organization Clinical Research Information Service (http://cris.nih.go.kr/cris, KCT0001857). Results The patients were randomly assigned to the FNAB+P group (n = 86) or the FNAB-P group (n = 86). There were no significant intergroup differences in nodule position, size, age, consistency, calcification, BRAF mutation, or pathology. Evaluation of diagnostic adequacy parameters revealed no significant differences in background blood/clot (P = 0.728), amount of cellular material (P = 0.052), degree of cellular degeneration (P = 0.622), degree of cellular trauma (P = 0.979), or retention of appropriate architecture (P = 0.487). Furthermore, there was no significant intergroup difference in the diagnostic quality (P = 0.634). Conclusion This prospective randomized study failed to detect significant differences in the diagnostic adequacy and quality of FNAB with or without negative pressure. Therefore, the examiner may select whichever FNAB method they prefer.

PURPOSE: To examine whether depression, anxiety disorder and their co-occurrence would increase the risk of mortality in patients with breast cancer, and whether antidepressant treatment would reduce the same. PATIENTS AND METHODS: Data were retrieved from the database of the Korean National Health Insurance Service. Of 145,251 patients diagnosed with breast cancer between 2007 and 2014, 20,870 patients diagnosed with depression or anxiety disorder one year before breast cancer diagnosis were excluded. Thus, data of 124,381 patients were included in this study. RESULTS: Anxiety disorder was more prevalent than depression in patients with breast cancer, and similar factors were associated with both depression and anxiety disorder. Overall, female sex, older age, residence in metropolitan areas, lower income, higher comorbidity, carcinoma in situ, and the receipt of any type of cancer therapies were associated with an increased risk of depression or anxiety disorder. Depression and anxiety disorder were associated with an increased risk of mortality (Hazard Ratio (HR) = 1.26, 95% CI=1.18–1.36; HR=1.14, 95% CI=1.08–1.22, respectively) and their co-occurrence further increased the risk (HR=1.38, 95% CI=1.24–1.54). Antidepressant treatment was related to a reduced risk of mortality. Compared to patients with no depression, among those with depression, the risk of mortality was 2.18 times higher (95% CI=1.69–2.81) in patients who did not receive antidepressant treatment and 1.25 times higher (95% CI =1.17–1.32) in those who received antidepressant treatment. CONCLUSION: The current findings suggest that psychiatric comorbidities are markers of increased mortality risk in patients with breast cancer. This underscores the need for screening and treating depression and anxiety disorders to improve survival in breast cancer. Citation Format: Kim YS, Shim E-J, Lee JW, Cho J, Jung HK, Kim NH, Lee JE, Min J, Noh WC, Park S-H. Association of depression and anxiety disorder with the risk of mortality in breast cancer: A national health insurance service study in South Korea [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-21.

Serotonin is known to be present in pancreatic β-cells and to play several physiological roles, including insulin secretion, β-cell proliferation, and paracrine inhibition of α-cells. However, the serotonin production of different cell lines and islets has not been compared based on age, sex, and diabetes related conditions. Here, we directly compared the serotonin concentrations in βTC and MIN6 cell lines, as well as in islets from mice using ultra-performance liquid chromatography tandem mass spectrometry. The average serotonin concentration was 5–10 ng/mg protein in the islets of male and non-pregnant female mice. The serotonin level was higher in females than males at 8 weeks, although there was no difference at 1 year. Furthermore, we observed serotonin by immunofluorescence staining in the pancreatic tissues of mice and human. Serotonin was detected by immunofluorescence staining in a portion of β-cells from islets of old female mice, but not of male or young female mice. A similar pattern was observed in human pancreas as well. In humans, serotonin production in β-cells was associated with a diabetes-free condition. Thus, serotonin production in β-cells was associated with old age, female sex, and diabetes-free condition.

SUMMARYNoroviruses (NoVs) are major causal agents of acute gastroenteritis in humans. NoV GII.4 is the predominant genotype globally. However, uncommon and minor types of NoVs are consistently detected and some have been shown to dominate over GII.4. Therefore, the prevalence of dominant and uncommon NoVs makes the identification of these viruses important for the prediction and prevention of pandemics. In this study, the full-genome sequence of a NoV (strain JW) detected in Korea was extensively characterized. The full-length genome was 7510 nucleotides long, and phylogenetic analysis based on the whole-genome sequences, including open reading frame (ORF)1, ORF2, and ORF3, indicated that it belonged to the GII.21 genotype. Strain JW showed maximum identity with strain YO284; however, comparison of the amino acid sequence of ORF2, which functions as an antigen, showed substitutions in several amino acids. GII.21 is not a prevalent epidemiological agent of acute gastroenteritis in humans, but it is consistently found in gastroenteritis patients from several countries. The present study provides the first full-genome sequence analysis of NoV GII.21 isolated from a patient in Korea. Our findings provide not only valuable genome information but also data for epidemiology studies, epidemic prevention, and vaccine development strategies.

Loss of functional β-cell mass is an essential feature of type 2 diabetes, and maintaining mature β-cell identity is important for preserving a functional β-cell mass. However, it is unclear how β-cells achieve and maintain their mature identity. Here we demonstrate a novel function of protein arginine methyltransferase 1 (PRMT1) in maintaining mature β-cell identity. Prmt1 knockout in fetal and adult β-cells induced diabetes, which was aggravated by high-fat diet–induced metabolic stress. Deletion of Prmt1 in adult β-cells resulted in the immediate loss of histone H4 arginine 3 asymmetric dimethylation (H4R3me2a) and the subsequent loss of β-cell identity. The expression levels of genes involved in mature β-cell function and identity were robustly downregulated as soon as Prmt1 deletion was induced in adult β-cells. Chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin sequencing analyses revealed that PRMT1-dependent H4R3me2a increases chromatin accessibility at the binding sites for CCCTC-binding factor (CTCF) and β-cell transcription factors. In addition, PRMT1-dependent open chromatin regions may show an association with the risk of diabetes in humans. Together, our results indicate that PRMT1 plays an essential role in maintaining β-cell identity by regulating chromatin accessibility.

SummaryObjective Although the presence of oncocytic change in less than 75% of a tumour is not considered to indicate oncocytic variants of papillary thyroid carcinoma (PTC), we frequently observe partial oncocytic change, especially in obese PTC patients. Thus, we sought to investigate the relationship between the presence of oncocytic change of PTC and its prognosis. Design, setting and participants We retrospectively studied 142 patients with PTC who had undergone surgery between 2000 and 2005, and re-evaluated their PTC slides to record the proportion of oncocytic change in 10% increments from 0% to 100%. Major outcome measure We analysed the relationship between the proportion of oncocytic change and clinicopathological prognostic factors. Results Oncocytic change was found in 45·8% (65/142) of PTC patients. The proportion of patients with oncocytic change was higher in obese patients than in lean patients and showed a significant correlation with the BMI (r = 0·195, P = 0·020). The PTC patients with oncocytic change showed a higher recurrence rate than PTC patients without oncocytic change (30·8% vs 11·7%, respectively; P = 0·005). The presence of oncocytic change in PTC patients was associated with a shorter disease-free survival in a Kaplan–Meier analysis after a mean follow-up of 8·9 years. Conclusion The patients with PTC with oncocytic change presented with a higher recurrence rate and were more likely to be obese. These findings suggest that presence of oncocytic change is a poor prognostic factor in PTC patients, even if the oncocytic change involves less than 75% of a tumour.

Allogeneic stem cell transplantation from HLA-matched siblings (MSD-SCT) for elderly patients with severe aplastic anemia (SAA) is not a widely accepted first-line treatment. Recently, fludarabine, lower-dose cyclophosphamide and antithymocyte globulin conditioning (Flu/lower-dose Cy/ATG) with lower toxicities has been investigated. To determine whether this regimen can overcome the negative effects of age, we analyzed 117 adult patients with SAA who received MSD-SCT using Flu/lower-dose Cy/ATG, and compared outcomes between 63 younger age group (YAG; ⩽40 years) and 54 older age group (OAG; >40 years) patients. No primary graft failure was observed. Neutrophil engraftment was significantly faster in the YAG compared with the OAG (12 vs 13 days; P=0.04). The incidences of acute grade II-IV (9.5% vs 9.3% at day 100; P=0.42) and chronic GVHD (8.1% vs 9.5% at 5 years; P=0.80), secondary graft failure (20.8% vs 7.9% at 5 years; P=0.11) and transplant-related mortality (5.4% and 11.1% at 5 years; P=0.91) were not significantly different between the YAG and OAG. In addition, failure-free (73.7% vs 81.0% at 5 years; P=0.73) and overall survival rates (93.7% vs 88.9% at 5 years; P=0.20) were comparable. Our results suggest that MSD-SCT using Flu/lower-dose Cy/ATG may be a feasible first-line treatment even in older patients with SAA.

The aim of this study was to evaluate the impact of pretransplant transfusion of packed red cells (PRCs) on outcome after allogeneic stem cell transplantation (SCT) in severe aplastic anemia (SAA). A total of 221 adult SAA patients receiving allogeneic SCT were analyzed. The patients were divided into two groups according to the amount of pretransplant transfusion before SCT: the low transfusion group (⩽32 PRC units, n=164) and the high transfusion group (>32 PRC units, n=57). The incidence of engraftment failure was not different between the two groups. The incidence of acute GvHD (grades II-IV) was higher in the high transfusion group than in the low transfusion group (P=0.04), and the incidences of chronic extensive GVHD were not significantly different (P=0.136). The high transfusion group had higher 5-year transplant-related mortality (TRM) (24.8% vs 6.8%, P

Background Chamaecyparis obtusa (C. obtusa) is a tropical tree species found in Japan and the southern region of South Korea. Although the biological activities of essential oil extracted from C. obtusa (EOCO) are not yet fully understood, essential oil has been shown to have antibacterial activities and anti-inflammatory effects. Objectives We investigated the effect of essential oil extracted from Chamaecyparis obtusa on the development of collagen-induced arthritis (CIA), a well-characterised preclinical model of human RA. Methods DBA1/J mice were injected intraperitoneally with EOCO dissolved in dimethyl sulfoxide (DMSO) 3 times a week for 5 weeks after type II collagen (CII) immunisation. Arthritis severity was evaluated by clinical and histological parameters. Serum anti-CII antibody levels were assayed by ELISA. Iinterleukin-17 (IL-17) expressions in the joints were determined by immunohistochemistry. Effect of EOCO on Th17 cells and natural killer (NK) cells was analysed using flow cytometry. Results EOCO markedly reduced the clinical and histological severity of CIA. Serum anti-CII antibody levels and the expression of IL-17 in the joints were significantly lower in mice treated with EOCO than those treated with DMSO alone. EOCO inhibited the differentiation of Th17 cells in total splenocytes, not in isolated CD4+ T cells, from mice. EOCO increased the production of granzyme B and perforin in NK cells. Conclusions Our data demonstrate a protective effect of EOCO on the development of CIA through the inhibition of Th17 cell differentiation. This effect may be related with NK cell activity enhanced by EOCO. References [1] Hong EJ, Na KJ, Choi IG, Choi KC, Jeung EB. Antibacterial and antifungal effects of essential oils from coniferous trees. Biol Pharm Bull2004;27:863–6. [2] An BS, Kang JH, Yang H, Jung EM, Kang HS, Choi IG, et al. Anti-inflammatory effects of essentia oils from Chamaecyparis obtusa via the cyclooxygenase-2 pathway in rats. Mol Med Rep2013;8:255–9. Acknowledgements This study was carried out with the support of ‘Forest Science and Technology Projects (Project No. S111114L020100)’ provided by Korea Forest Service. Disclosure of Interest None declared

Background Sjogren’s syndrome (SS) is a systemic autoimmune disease that affects exocrine glands and lymphoid organs. B cell hyperactivity and imbalance between T helper 17 (Th17) cells and regulatory T (Treg) cells are involved in pathogenesis of SS. Metformin, a commonly used anti-diabetic drug, is found to have immunomodulatory effect via AMP-activated protein kinase enhanced inhibition of mTOR-STAT3 signalling. Objectives We examined the therapeutic effect of metformin on SS by using animal model of SS, non-obese diabetic (NOD) mice. Methods Metformin (50 mg/kg) or vehicle (saline) was given per oral every day from 11 weeks after birth until 20 weeks. Salivary flow rate (SFR) was addressed on every 2 or 3 weeks between 11 weeks and 20 weeks. Histologic analyses of salivary gland and spleen were performed on week 20. Expression of Inflammatory cytokine was determined by immunohistochemistry analysis and real-time PCR. Flow cytometry was performed with peripheral blood to examine Th17 and Treg cells and germinal centre (GC) B cell populations. Serum immunoglobulin level was measured by enzyme-linked immunosorbent assay. Splenic cells of NOD mice were treated with metformin or vehicle in vitro and cultured for 3 days. Results SFRs of metformin-treated mice recovered, whereas SFRs of those treated with vehicle declined. Histologic examination of salivary gland showed decreased infiltration of lymphocytes and reduced expression of IL-6 and TNF-alpha in metformin-treated mice. Relative expression of IL-6, TNF-alpha, and IL-17 mRNA in salivary gland and spleen also declined in metformin-treated mice. Flow cytometric analysis revealed decreased Th1 and Th17 cells and increased Treg cells in peripheral blood of mice treated with metformin. In addition, GC B cells and immunoglobulin levels were reduced in peripheral blood of mice treated with metformin. Decreased Tfh cells and increased Tfr cells were observed from in vitro cultures of splenic cells treated with metformin. Conclusions Metformin controls B cell differentiation and keeps balance between Th17 and Treg cells in NOD mice, in addition to reducing lymphocytic infiltration and inflammatory cytokine expression in salivary gland. Metformin has potential therapeutic effects on SS. References [1] Lee SY, Moon SJ, Kim EK, Seo HB, Yang EJ, Son HJ, et al. Metformin Suppresses Systemic Autoimmunity in Roquinsan/san Mice through Inhibiting B Cell Differentiation into Plasma Cells via Regulation of AMPK/mTOR/STAT3. J Immunol2017;198–2661–70. [2] Pontarini E, Lucchesi D, Bombardieri M. Current views on the pathogenesis of Sjgren’s syndrome. Curr Opin Rheumatol2017. Disclosure of Interest None declared

To investigate the prognostic significance of computed tomography (CT) attenuation and 2-[Data were collected retrospectively from 66 patients with pancreatic adenocarcinoma who had undergone pretreatment combined FDG positron-emission tomography (PET)/CT imaging and subsequent curative or palliative treatment. Metabolic parameters of primary tumour including total lesion glycolysis (TLG) and heterogeneity factor were measured. Volume, CT attenuation (attenuation), and FDG uptake of SAT and VAT were derived from PET/CT acquisitions. Survival analysis using Cox proportional hazard modelling was performed to assess the relationship between both attenuation and FDG uptake of fat tissue and OS.During follow-up, 33 patients (50%) died and the median OS was 12 months. There were significant positive correlations between attenuation and mean standardised uptake values of both SAT (p0.001, r=0.697) and VAT (p0.001, r=0.742). Attenuation and FDG uptake of adipose tissue were significantly associated with heterogeneity factor and T stage. Patients with high FDG uptake and attenuation of SAT and VAT had significantly worse OS than those with low values. On multivariate analysis, attenuation of SAT (p=0.047) and VAT (p=0.021), and FDG uptake of VAT (p=0.005) were correlated significantly with OS after adjusting for age, sex, body mass index, TNM stage, and TLG.CT attenuation of SAT and VAT, and FDG uptake of VAT significantly correlated with OS in patients with pancreatic adenocarcinoma, independent of TNM staging and TLG.

Primary thyroid cancers including papillary, follicular, poorly differentiated, and anaplastic carcinomas show substantial differences in biological and clinical behaviors. Even in the same pathological type, there is wide variability in the clinical course of disease progression. The molecular carcinogenesis of thyroid cancer has advanced tremendously in the last decade. However, specific inhibition of oncogenic pathways did not provide a significant survival benefit in advanced progressive thyroid cancer that is resistant to radioactive iodine therapy. Accumulating evidence clearly shows that cellular energy metabolism, which is controlled by oncogenes and other tumor-related factors, is a critical factor determining the clinical phenotypes of cancer. However, the role and nature of energy metabolism in thyroid cancer remain unclear. In this article, we discuss the role of cellular energy metabolism, particularly mitochondrial energy metabolism, in thyroid cancer. Determining the molecular nature of metabolic remodeling in thyroid cancer may provide new biomarkers and therapeutic targets that may be useful in the management of refractory thyroid cancers.

We investigated obstetric outcomes and comorbidities during pregnancy in females with preexisting lupus nephritis (LN) and identified predictors for renal flare. In cases of renal flare during pregnancy, we assessed the long-term post-delivery renal outcome. We performed a retrospective analysis of 183 systemic lupus erythematosus (SLE) pregnancies including blood chemistry, urinalysis, urinary protein, and disease activity recorded at prepregnancy, during pregnancy, and at one month, six months, and one year post-delivery. Pregnancies with preexisting LN had a greater frequency of adverse obstetric outcomes and maternal comorbidity. Renal flares occurred in 50.7% of pregnancies with preexisting LN, 89.2% of which were reactivations. Renal flare among pregnancies with SLE was predicted based on preexisting lupus nephritis (OR 17.73; 95% CI, 5.770–54.484), an active disease prior to pregnancy (OR 2.743; 95% CI, 1.074–7.004), and prepregnancy eGFR 2 (OR 11.151; 95% CI, 3.292–37.768). Persistent LN one year after delivery was observed in 33.3% of pregnancies. The median follow-up time after delivery was 5.9 (3.1–9.7) years and chronic kidney disease (CKD) occurred in 21.4% of pregnancies with renal flare. In patients with renal flare, failing to achieve a ≥ 50% reduction in urine protein levels within six months, longer total duration of renal flare, and acute kidney injury at renal flare was associated with CKD development. Females with preexisting LN should achieve remission before pregnancy. When patients experience renal flares during pregnancy, it is important to reduce the proteinuria level by >50% within six months and to achieve early remission for excellent long-term renal outcomes.

Primary cilia are microtubule-based, dynamic organelles characterized by continuous assembly and disassembly. The intraflagellar transport (IFT) machinery, including IFT88 in cilia, is involved in the maintenance of bidirectional motility along the axonemes, which is required for ciliogenesis and functional competence. Cancer cells are frequently associated with loss of primary cilia and IFT functions. However, there is little information on the role of IFT88 or primary cilia in the metabolic remodeling of cancer cells. Therefore, we investigated the cellular and metabolic effects of the loss-of-function (LOF) mutations of IFT88/primary cilia in thyroid cancer cells. IFT88-deficient 8505C thyroid cancer cells were generated using the CRISPR/Cas9 system, and RNA-sequencing analysis was performed. LOF of the IFT88 gene resulted in a marked defect in ciliogenesis and mitochondrial oxidative function. Gene expression patterns in IFT88-deficient thyroid cancer cells favored glycolysis and lipid biosynthesis. However, LOF of IFT88/primary cilia did not promote thyroid cancer cell proliferation, migration, and invasion. The results suggest that IFT88/primary cilia play a role in metabolic reprogramming in thyroid cancer cells.

Method: This study sample was consisted of 3610 Korean adults aged 50 years and older which were based on data obtained from the 2009 to 2011 Korean National Health and Nutrition Examination Survey (KNHANES) IV and V. Self-rated health status was measured using the visual analogue scale of the EuroQol 5-dimension (EQ-VAS). The complex sample general linear regression model for EQ-VAS was performed to determine the association with medical and socioeconomic status.

The signaling pathway involving the R-spondins and its cognate receptor, GPR48/LGR4, is crucial in development and carcinogenesis. However, the functional implications of the R-spondin-GPR48/LGR4 pathway in thyroid remain to be identified. The aim of this study was to investigate the role of R-spondin-GPR48/LGR4 signaling in papillary thyroid carcinomas. We retrospectively reviewed a total of 214 patients who underwent total thyroidectomy and cervical lymph node dissection for papillary thyroid carcinoma. The role of GPR48/LGR4 in proliferation and migration was examined in thyroid cancer cell lines. R-spondin 2, and GPR48/LGR4 were expressed at significantly higher levels in thyroid cancer than in normal controls. Elevated GPR48/LGR4 expression was significantly associated with tumor size (P=0.049), lymph node metastasis (P=0.004), recurrence (P=0.037), and the BRAFV600E mutation (P=0.003). Moreover, high GPR48/LGR4 expression was an independent risk factor for lymph node metastasis (P=0.027) and the BRAFV600E mutation (P=0.009). in vitro assays demonstrated that elevated expression of GPR48/LGR4 promoted proliferation and migration of thyroid cancer cells, whereas downregulation of GPR48/LGR4 decreased proliferation and migration by inhibition of the β-catenin pathway. Moreover, treatment of thyroid cancer cells with exogenous R-spondin 2 induced activation of the β-catenin pathway through GPR48/LGR4. The R-spondin 2-GPR48/LGR4 signaling axis also induced the phosphorylation of ERK, as well as phosphorylation of LRP6 and serine 9 of GSK3β. Our findings demonstrate that upregulation of the R-spondin 2-GPR48/LGR4 pathway contributes to tumor aggressiveness in papillary thyroid carcinoma by promoting ERK phosphorylation, suggesting that this pathway represents a novel therapeutic target for treatment of differentiated thyroid cancer.

We report the FDG PET/CT findings of seminoma in a 21-year-old woman with androgen insensitivity syndrome. PET images showed focal FDG uptake in the left pelvic sidewall, and a hypodense lesion with calcifications was noted in the corresponding CT images. Another smaller hypodense lesion with calcifications was noted in the right pelvic sidewall, but faint FDG uptake. Laparoscopic surgery was performed, and both lesions were pathologically confirmed as seminomas.

Background Osteoarthritis (OA) is a chronic joint disease with complex etiologies characterized by synovial inflammation, subchondral bone remodeling, and the formation of osteophytes, which leads to cartilage deterioration. Periodontitis (PD) is also a chronic inflammatory disease characterized by loss of periodontal ligament and alveolar bone. Recently, the association between OA and metabolic diseases has been proposed, and the association between several systemic diseases such as rheumatoid arthritis, metabolic syndrome and periodontitis has been also revealed. Objectives The aim of this study was to investigate the association between OA and PD in South Korea using data from the Korea National Health and Nutrition Examination Survey (KNHANES) during 2010–2014. Methods Cross-sectional data of 7,969 adults who completed the KHANES, and participated in both a periodontal examination and a knee imaging were analyzed. OA of knee was defined when a participant had knee arthralgia and showed radiographic change of Kellgren-Lawrence (KL) grade over 1. OA patients were grouped into mild (KL grade 1–2) and severe (KL grade 3–4) OA. The periodontal status was assessed by the Community Periodontal Index. Binary logistic regression analysis was performed according to the OA and PD status, severity of OA, and subgroups (age, gender) adjusting for the socio-demographics, oral health behaviors and status, smoking, and drinking. Results Of the 7,969 participants, 1408 (17.7%) had OA and 2987 (37.5%) had PD. OA and PD showed no significant association in overall analysis. However, in subgroup analysis, female patients with severe OA were more likely to have PD (adjusted odd ratio (OR) 1.377, P=0.0316); likewise, OR for severe OA in female patient with PD was 1.367. (P=0.0.54) Conclusions Severe OA and PD were associated with each other especially in female in the Korean population. Further prospective and experimental studies are necessary to identify the impact and mechanisms of association between severe OA and PD in female. References Zhuo Q, Yang W, Chen J, Wang Y. Metabolic syndrome meets osteoarthritis. Nature reviews Rheumatology 2012; 8(12): 729–37. Kwon YE, Ha JE, Paik DI, Jin BH, Bae KH. The relationship between periodontitis and metabolic syndrome among a Korean nationally representative sample of adults. Journal of clinical periodontology 2011; 38(9): 781–6. Disclosure of Interest None declared

Background There have been several studies which demonstrated the impact of birth on the risk of certain diseases such as asthma or cardiovascular diseases. However, rheumatic diseases have not yet been thoroughly investigated in terms of association with birth month. Objectives In this study, we sought to determine whether birth month or season could affect the risk of rheumatologic diseases. Methods The birth month patterns of patients with rheumatic diseases were compared with to those of general population. We utilized the claims data of Health Insurance Review and Assessment Service (HIRA) which covers nearly 90% of total population in Korea. The associations between birth month/season and 32 diseases were investigated using logistic regression. Results Our dataset included 17,247,458 (male 8,224,670; female 9,022,788) individuals from HIRA database from January, 1997 to August, 2015. Among 27 rheumatic diseases, 8 diseases including Crohn9s disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), systemic lupus erythematosus, polymyalgia rheumatica (PMR), ankylosing spondylitis (AS), multiple sclerosis, gout, fibromyalgia (FMS) were significantly associated with birth month (P Conclusions We found significant impacts of birth month/season on various rheumatic diseases. Seasonal variation of infective agents, sun exposure or food ingestion during gestation or early infancy may explain the association between birth month/season and certain disease development. Disclosure of Interest None declared

Emerging molecular studies have identified a subgroup of patients with unfavorable core-binding factor-positive (CBF)-AML who should be treated by intensified post-remission treatments. We analyzed 264 adults with CBF-AML from 2002 to 2011, and focused on 206 patients who achieved CR after standard '3+7' induction chemotherapy. Patients who achieved CR with an available donor were treated with allogeneic hematopoietic SCT (allo-HSCT, n=115) and the rest were treated with autologous (auto) HSCT (n=72) or chemotherapy alone (n=19). OS was not significantly different between CBFβ/MYH11 (n=62) and RUNX1/RUNX1T1 (n=144), and auto-HSCT showed favorable OS compared with allo-HSCT or chemotherapy alone. Cytogenetic analysis identified that inv(16) without trisomy had a favorable OS and t(8;21) with additional chromosomes had an unfavorable OS, but multivariate analysis revealed those were NS. Patients with c-kit mutation showed inferior OS. For transplanted patients, residual post-transplant CBF-minimal residual disease quantitative PCR with higher WT1 expression at D+60 showed the worst OS with a higher incidence of relapse. Conclusively, we found that unfavorable CBF-AML can be defined with risk stratification using cytogenetic and molecular studies, and a careful risk-adapted treatment approach using frontline transplantation with novel therapies should be evaluated for this particular risk subgroup.

Few studies are available that compare PBSC and BM from unrelated donors, especially in adult high-risk ALL. To determine which graft source is superior in adult high-risk ALL, we analyzed the long-term outcomes of 106 consecutive transplants from 8/8-matched or 7/8-matched unrelated donors (38 PBSC vs 68 BM). All patients received a uniform strategy of pre-transplant therapy, myeloablative conditioning and GVHD prophylaxis. At 5 years, PBSC transplants showed higher incidence of chronic GVHD than did BM transplants (74.3% vs 46.7%, P=0.001). PBSC transplants showed outcomes comparable to those of BM transplants for relapse (23.7% vs 28.1%), non-relapse mortality (18.4% vs 25.0%), disease-free survival (57.9% vs 46.9%) and OS (57.9% vs 50.0%). In a separate comparison of outcomes between the two graft sources according to the presence of a Ph chromosome, no significant advantage of PBSC over BM was found in both subgroups of patients. Our data suggest that the outcomes of unrelated donor transplantation are similar between PBSC and BM in adult high-risk ALL. Whether PBSC should be the preferred graft source for a specific subgroup of adult ALL needs to be further investigated.

Objective The objective of this paper is to identify the risk factors for development of symptomatic osteonecrosis (ON) and predictors of total hip replacement (THR) among systemic lupus erythematosus (SLE) patients in Korea. Methods The medical records of 1051 patients with SLE were reviewed, and 73 patients with symptomatic ON were identified. Among them, 64 patients were eligible for the analysis. Sixty-four age- and sex-matched SLE patients without apparent ON were included as disease controls. The risk factors for development of symptomatic ON were identified by logistic regression analyses. The predictors of THR were determined by Cox proportional hazards regression analyses. Results Among 64 patients with ON, 59 had ON of the hip and 36 underwent THR. Independent risk factors for development of symptomatic ON included Cushingoid body habitus (OR 21.792 (95% confidence interval (CI) 2.594–183.083)), use of cyclophosphamide (OR 2.779 (95% CI 1.106–6.981)) and azathioprine (OR 2.662 (95% CI 1.143–6.200)). In the Cox proportional hazards model, only advanced radiological stage of ON (Association for Research on Osseous Circulation (ARCO) stage) was a statistically significant predictor of THR. In subgroup analysis with stage I–III ON, multivariate Cox regression analysis showed neuropsychiatric SLE (NPSLE) (HR 6.295 (95% CI 2.178–18.192)) and cumulative prednisolone dose in the first six months after ON diagnosis > 0.9 g (HR 3.238 (95% CI 1.095–9.58)) to be independent predictors. Conclusions Advanced ARCO stage at the onset of ON is an independent risk factor for THR in SLE patients with ON. In ARCO stage I–III ON, patients with NPSLE and those receiving > 0.9 g prednisolone during the first six months after the ON diagnosis are likely to require THR.

Aims: Acetaminophen (APAP)-induced liver injury is mainly due to the excessive formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) through the formation of a reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI), in both humans and rodents. Here, we show that the indole-derived synthetic compound has a protective effect against APAP-induced liver injury in C57Bl/6 mice model. Results: NecroX-7 decreased tert-butylhydroperoxide (t-BHP)- and APAP-induced cell death and ROS/RNS formation in HepG2 human hepatocarcinoma and primary mouse hepatocytes. In mice, NecroX-7 decreased APAP-induced phosphorylation of c-Jun N-terminal kinase (JNK) and 3-nitrotyrosine (3-NT) formation, and also protected mice from APAP-induced liver injury and lethality by binding directly to NAPQI. The binding of NecroX-7 to NAPQI did not require any of cofactors or proteins. NecroX-7 could only scavenge NAPQI when hepatocellular GSH levels were very low. Innovation: NecroX-7 is an indole-derived potent antioxidant molecule, which can be bound to some types of radicals and especially NAPQI. It is well known that the NAPQI is a major intermediate of APAP, which causes necrosis of hepatocytes in rodents and humans. Thus, blocking NAPQI formation or eliminating NAPQI are novel strategies for the treatment or prevention of APAP-induced liver injury instead of GSH replenishment. Conclusion: Our data suggest that the indole-derivative, NecroX-7, directly binds to NAPQI when hepatic GSH levels are very low and the NAPQI–NecroX-7 complex is secreted to the blood from the liver. NecroX-7 shows more preventive and similar therapeutic effects against APAP-induced liver injury when compared to the effect of N-acetylcysteine in C57Bl/6 mice. Antioxid. Redox Signal. 18, 1713–1722.

This retrospective study was performed in order to investigate the clinical characteristics and antibiotic susceptibility of viridans streptococcal bacteremia (VSB) in febrile neutropenic children in the context of the increase in incidence and antibiotic resistance of VSB.We conducted this study among neutropenic children with underlying hematology/oncology diseases who were diagnosed with VSB at a single institution from April 2009 to June 2012. Clinical and laboratory characteristics of the children as well as antibiotic susceptibility of the causative viridans streptococci were evaluated.Fifty-seven episodes of VSB were diagnosed in 50 children. Severe complications occurred in four children (7.0%), and a death of one child (1.8%) was attributable to VSB. Acute myeloid leukemia was the most common underlying disease (70.2% of all cases), and 71.9% of all cases received chemotherapy including high-dose cytarabine. VSB occurred at a median of 13 days (range 8-21 days) after the beginning of chemotherapy, and fever lasted for a median of 4 days (range 1-21 days). The C-reactive protein level significantly increased within a week after the occurrence of VSB (p0.001) and the maximum C-reactive protein level showed a positive correlation with fever duration (r = 0.362, p = 0.007). Second blood cultures were done before the use of glycopeptides in 33 children, and negative results were observed in 30 children (90.9%). Susceptibilities to cefotaxime, cefepime, and vancomycin were 58.9, 69.1, and 100%, respectively.Severe complications of VSB in neutropenic febrile children were rare. We suggest glycopeptide use according to the results of blood culture and antibiotic susceptibility tests based on the susceptibility to cefepime and the microbiologic response to empirical antibiotic treatment not including glycopeptides in this study.

The functional unit of the thyroid gland, the thyroid follicle, dynamically responds to various stimuli to maintain thyroid hormone homeostasis. However, thyroid follicles in the adult human thyroid gland have a very limited regenerative capacity following partial resection of the thyroid gland. To gain insight into follicle regeneration in the adult thyroid gland, we observed the regeneration processes of murine thyroid follicles after partial resection of the lower third of the thyroid gland in 10-week-old male C57BL/6 mice. Based on sequential observation of the partially resected thyroid lobe, we found primitive follicles forming in the area corresponding to the central zone of the intact lateral thyroid lobe. The primitive thyroid follicles were multiciliated and had coarsely vacuolated cytoplasm and large vesicular nuclei. Consistently, these primitive follicular cells did not express the differentiation markers paired box gene-8 and thyroid transcription factor-1 (clone SPT24), but were positive for forkhead box protein A2 and leucine-rich repeat-containing G-protein-coupled receptor 4/GPR48. Follicles newly generated from the primitive follicles had clear or vacuolar cytoplasm with dense, darkly stained nuclei. At day 21 after partial thyroidectomy, the tall cuboidal follicular epithelial cells had clear or vacuolar cytoplasm, and the intraluminal colloid displayed pale staining. Smaller activated follicles were found in the central zone of the lateral lobe, whereas larger mature follicles were located in the peripheral zone. Based on these observations, we propose that the follicle regeneration process in the partially resected adult murine thyroid gland associated with the appearance of primitive follicular cells may be a platform for the budding of differentiated follicles in mice.

Hemolytic anemia with null PKLR mutations identified using whole exome sequencing and cured by hematopoietic stem cell transplantation combined with splenectomy

Low bone mineral density in adolescents with leukemia after hematopoietic stem cell transplantation: prolonged steroid therapy for GvHD and endocrinopathy after hematopoietic stem cell transplantation might be major concerns?

The prognosis for patients with myelodysplastic syndrome with hypomethylating treatment failure (MDS-HTF) has been known to be poor. However, the clinical outcomes and optimal treatment options for secondary AML evolving from MDS-HTF (sAML/MDS-HTF) are not well known. This retrospective analysis was conducted to evaluate the clinical outcomes and influences of treatment options on survival in 46 consecutive patients with sAML/MDS-HTF. The median OS rates were 1.4 months in the best supportive care group (n=15) and 9.4 months in the active treatment group (n=31). One-year OS rates were 13.3% and 36.8%, respectively (P=0.001). Active treatment (P

We conducted a systemic evaluation to describe the effect of minimal residual disease (MRD) kinetics on long-term allogeneic transplantation outcome by analyzing 95 adult transplants with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) who received first-line two courses of imatinib-based chemotherapy (median follow-up 5 years). MRD monitoring was centrally evaluated by real-time quantitative PCR (4.5 log sensitivity). After the first course of imatinib-based chemotherapy, 33 patients (34.7%) achieved at least major molecular response. On the basis of MRD kinetics by the end of two courses of imatinib-based chemotherapy, we stratified entire patients into four subgroups: early-stable molecular responders (EMRs, n=33), late molecular responders (LMRs, n=35), intermediate molecular responders (IMRs, n=9) and poor molecular responders (PMRs, n=18). Multivariate analysis showed that the most powerful factor affecting long-term transplantation outcome was MRD kinetics. Compared with EMRs, IMRs or PMRs had significantly higher risk of treatment failure in terms of relapse and disease-free survival (DFS). LMRs had a tendency toward a lower DFS. Quantitative monitoring of MRD kinetics during the first-line imatinib-based chemotherapy course is useful in identifying subgroups of Ph-positive ALL transplants at a high risk of relapse.

Summary. There are few reports on hepatitis B e antigen (HBeAg) titres during nucleos(t)ide analogues treatment. We investigated the changes in HBeAg levels in patients treated with entecavir and the usefulness of HBeAg quantification for predicting antiviral response. Ninety-five consecutive HBeAg-positive patients treated with entecavir for more than 48 weeks were enrolled. Serum levels of hepatitis B surface antigen (HBsAg), HBeAg and HBV DNA were assessed at 4-week intervals to week 24 and thereafter at 12-week intervals. Virologic response (Y1VR) was defined as an undetectable HBV DNA level at week 48 of therapy. During 48 weeks, HBeAg and HBV DNA level decreased significantly in a biphasic manner and HBsAg level tended to decease. Fifty-three patients (55.8%) attained Y1VR. Pretreatment HBeAg levels were significantly lower in the Y1VR group than in no Y1VR group. At week 4 and 12 of therapy, 25% and 41.4% of patients showed a decrease of HBeAg levels with >0.5 log10 and >1.0 log10 from baseline, respectively. These patients achieved more Y1VR than those with less decrease of HBeAg levels (97.7%vs 22.2% and 86.2%vs 29.3%, respectively). HBeAg level at week 12 had higher predictive values for Y1VR than HBV DNA level. Multivariate analysis revealed that a pretreatment HBeAg level of 1.0 log10 at week 12 were associated with Y1VR. These results suggest that pretreatment HBeAg level and an early decrease in HBeAg level are useful measurements for predicting one-year virologic response during entecavir treatment.

Tuberculosis (TB) is a rare infectious complication after hematopoietic stem cell transplantation (HSCT), but may be more significant in areas where the disease is endemic. Here, we present the clinical course of 2 children with acute lymphoblastic leukemia who were diagnosed with pulmonary TB after allogeneic HSCT. Both patients were treated for either probable or possible invasive fungal infection, as well as TB. One patient, diagnosed with TB 3 months after HSCT, showed remittent fever and symptoms that progressed to acute respiratory distress syndrome and death, despite 3 modifications to the anti-TB regimen. In contrast, another patient who was diagnosed with TB 8 months after transplantation, responded well to anti-TB medication and completed 1 year of treatment with resolution of lung lesions. Co-morbid opportunistic infections, profound host immunosuppression early after transplantation, and potential risk of multi-drug resistant-TB may act as major barriers to effective treatment of TB after HSCT despite appropriate anti-TB medication.

Background Protein arginine methyltransferase 1 (PRMT1) is a major enzyme responsible for the formation of methylarginine in mammalian cells. Recent studies have revealed that PRMT1 plays important roles in the development of various tissues. However, its role in pancreas development has not yet been elucidated. Methods Pancreatic progenitor cell-specific Prmt1 knock-out (Prmt1 PKO) mice were generated and characterized for their metabolic and histological phenotypes and their levels of Neurog3 gene expression and neurogenin 3 (NGN3) protein expression. Protein degradation assays were performed in mPAC cells. Results Prmt1 PKO mice showed growth retardation and a severely diabetic phenotype. The pancreatic size and β-cell mass were significantly reduced in Prmt1 PKO mice. Proliferation of progenitor cells during the secondary transition was decreased and endocrine cell differentiation was impaired. These defects in pancreas development could be attributed to the sustained expression of NGN3 in progenitor cells. Protein degradation assays in mPAC cells revealed that PRMT1 was required for the rapid degradation of NGN3. Conclusion PRMT1 critically contributes to pancreas development by destabilizing the NGN3 protein.