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• Serum angiotensin-converting enzyme (ACE) levels are decreased by ACE inhibitors. • Three-fourths of Japanese patients with sarcoidosis have normal ACE values (<25.0 IU/L). • The possibility of sarcoidosis cannot be ruled out with the current standard value. • The sensitivity to detect sarcoidosis increases using the cut-off value of 17.7 IU/L. • Careful interpretation of this biomarker is needed. In clinical practice, we frequently experience patients with sarcoidosis who show relatively high but normal values of angiotensin-converting enzyme (ACE). The objective of this study was to reconsider the cut-off value of ACE. We studied 79 Japanese patients who were diagnosed as having sarcoidosis at our hospital. We excluded patients who had taken steroids or ACE inhibitors and patients with renal impairment. We respectively evaluated ACE values and performed receiver operating characteristic (ROC) analysis from a comparison with data for 299 normal Japanese subjects who showed ACE values in the current Japanese standard normal range (7.0–25.0 IU/L). Patients with sarcoidosis had higher ACE values than those in normal subjects (ACE: 20.3 IU/L [IQR, 16.0–24.4] vs. 15.4 IU/L [IQR, 12.8–18.5]; p < 0.001). However, 62 patients (78.5%) had normal ACE levels (cut-off value <25.0 IU/L), and the sensitivity of ACE level for detecting sarcoidosis was only 21.5%. From ROC analysis, a cut-off value of 17.7 IU/L (AUC: 0.727, 95% CI: 0.660–0.794, p < 0.001) was the best cut-off value for detecting sarcoidosis and sensitivity increased to 67.0%. The possibility of sarcoidosis cannot be ruled out by using the current Japanese standard value even in patients who have normal ACE levels. Careful interpretation of this biomarker is needed. [ABSTRACT FROM AUTHOR]

A G2000 glass scintillator (G2000-SC) was used to determine the carbon profile and range of a 290-MeV/n carbon beam used in heavy-ion therapy because it was sensitive enough to detect single-ion hits at hundreds of mega electron Volts. An electron-multiplying charge-coupled device camera was used to detect the ion luminescence generated during the irradiation of G2000-SC with the beam. The resulting image showed that the position of the Bragg peak can be determined. The beam passes through the 112-mm-thick water phantom and stops 5.73 ± 0.03 mm from the incident side to the G2000-SC. Additionally, the location of the Bragg peak was simulated when irradiating G2000-SC with the beam using the Monte Carlo code particle and heavy ion transport system (PHITS). Simulation results show that the incident beam stops at 5.60 mm after entering G2000-SC. The beam stop location obtained from images and the PHITS code is defined at 80% distal fall-off from the Bragg peak position. Consequently, G2000-SC provided effective profile measurements of therapeutic carbon beams. • A G2000 glass scintillator was used to determine the carbon profile at a flux of 109 ions/cm2/s with an energy of 290 MeV/n. • The PHITS simulations were in agreement with the measurements concerning the location of the Bragg Peak. • Bragg peak was possible to be read out using PL measurement from the G2000 glass scintillator post carbon beam irradiation. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to investigate the association between respiratory function and electrocardiogram (ECG) characteristics in patients with chronic obstructive pulmonary disease (COPD), and to identify the ECG results that indicate possible COPD. Methods The association between respiratory function and ECG results was retrospectively analyzed in 45 patients with COPD and 100 patients without COPD (controls). Results Multiple logistic regression analysis revealed that QRS amplitude in lead І was a significant predictor of COPD (partial regression coefficient = −4.208, p = 0.002). Receiver operating characteristic curve analysis showed that a QRS amplitude less than 0.54 mV in lead І indicated possible COPD (sensitivity: 71%, specificity: 76%, area under the curve: 0.78 [95% confidence interval: 0.69–0.86], p < 0.001). Conclusion Low voltage in lead І (QRS less than 0.54 mV) is an important criterion in detecting COPD. [ABSTRACT FROM AUTHOR]

Summary: Background: KL-6 is a high-molecular-weight glycoprotein classified as human Mucin-1 (MUC1). KL-6 has been reported to be a sensitive biomarker for interstitial lung diseases (ILDs) in the Japanese population. It is also known that polymorphisms in the MUC1 gene affect serum levels of KL-6. This study was conducted to evaluate serum levels of KL-6 and MUC1 polymorphisms in both German and Japanese populations. Methods: Serum levels of KL-6 were measured in 267 patients with ILDs (152 German and 115 Japanese) and 186 healthy subjects (HS) (76 German and 110 Japanese). In addition, rs4072037 single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction. The optimal cutoff values for discriminating patients with ILDs from HS was determined by receiver operating characteristic analysis based on ethnicity and rs4072037 genotypes. Results: The serum KL-6 levels in patients with ILDs were significantly higher compared with HS in both the German and the Japanese cohorts (both p <0.001). The discriminating cutoff value of serum KL-6 in the German cohort was significantly higher than the value in the Japanese cohort. The difference in the serum levels of KL-6 was significantly associated with the rs4072037 genotype distribution. Conclusions: Even in the German cohort, the serum KL6 levels were significantly higher in patients with ILDs than HS. Because of differences in the genotype distribution of rs4072037, the KL-6 cutoff value for the German cohort that discriminated patients with ILDs from HS was significantly higher than the value in the Japanese cohort. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To evaluate the effect of bakumondoto, Kampo medicine, on cough in patients with chronic obstructive pulmonary disease (COPD). Design: A 16-week, randomized, open-labeled, cross-over design. Setting: Outpatient clinics at one university hospital and two general hospitals in Japan from May 2007 to March 2009. Participants: Twenty-four elderly patients (14 men and 9 women aged over 65) with COPD. Intervention: Treatment with or without bakumondoto for 8 weeks in a cross-over design. Measurements: The primary outcome measurements were the frequency and intensity of cough assessed by a visual analogue scale (VAS) and a daily cough diary. Secondary outcome measurements were quality of life (QOL) assessed using St. George''s Respiratory Questionnaire (SGRQ) and lung functions measured using spirometry. Results: Treatment with bakumondoto significantly improved cough severity during the first treatment period (week 0 vs. week 8, p =0.004) and showed a trend to decrease during the second treatment period (week 8 vs. week16, p =0.129) assessed by the VAS. Neither QOL nor lung function was affected by the treatment with bakumondoto. Conclusion: Bakumondoto may be effective in suppressing cough in elderly patients with COPD. To further confirm the efficacy, a larger and placebo-controlled study with objective cough assessment is necessary. [Copyright &y& Elsevier]

Background: Suppressor of cytokine signaling (SOCS) proteins are inhibitors of cytokine signaling. Our previous study suggested that SOCS1 regulates collagen synthesis by lung fibroblasts, suggesting a role of SOCS1 in the pathophysiology of pulmonary fibrosis. Objectives: We sought to investigate the role of SOCS1 in pulmonary inflammation and fibrosis in vivo. Methods: SOCS1-haplodeficient mice treated with bleomycin (BLM) were evaluated for pulmonary inflammation and fibrosis compared with wild-type mice. The human study group was composed of 18 patients with interstitial lung disease. Lung specimens obtained by means of open lung biopsy were investigated to determine whether the severity of fibrosis was associated with decreased SOCS1 expression. Finally, we further analyzed the effect of exogenous SOCS1 on BLM-induced lung injury based on adenoviral SOCS1 gene transfer to the lung. Results: SOCS1-haplodeficient mice treated with BLM showed markedly enhanced pulmonary inflammation and fibrosis compared with wild-type mice. Using human lung specimens, we found that SOCS1 mRNA levels inversely correlated with duration of the disease. SOCS1 expression was significantly less in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) compared with that in non-IPF patients. Moreover, SOCS1 expression was significantly less in severe fibrotic lesions (lower lobe) than in less fibrotic lesions (upper lobe). Adenoviral SOCS1 gene transfer to murine lungs significantly decreased lymphocytic inflammation, pulmonary fibrosis, and mortality because of BLM-induced lung injury. Exogenous SOCS1 inhibited expression of various cytokines, including TNF-α, which might play a key role. Conclusions: These results suggest that SOCS1 might act as a suppressor for pulmonary fibrosis. SOCS1 might be a target of IPF treatment. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to determine whether moderate-intensity exercise training reduces oxidative stress in patients with type 2 diabetes mellitus over 12 months. The patients were divided into 3 groups: aerobic training combined with the use of a fitness center (group A, n = 43), aerobic training only (group B, n = 44), or controls (group C, n = 16). The subjects in groups A and B were instructed to exercise at 50% of peak oxygen uptake for more than 30 minutes on at least 3 days per week over a 12 month period. In addition, the subjects in group A were instructed to use a fitness center and were taught how to perform aerobic training in the indicated manner by certified fitness instructors. We measured the levels of urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) as a parameter of oxidative stress. Serum glycated albumin levels were reduced significantly after 6 and 12 months in groups A and B and after 12 months in group C. Urinary 8-OHdG levels decreased after 12 months in groups A and B, but remained unchanged in group C. There was a significant positive linear association between percentage changes in urinary 8-OHdG and glycated albumin levels over the 12 months. In conclusion, aerobic exercise training improved glycemic control and reduced oxidative stress in patients with type 2 diabetes mellitus. Furthermore, improvement in glycemic control was associated with a reduction in oxidative stress. [Copyright &y& Elsevier]

Summary: Pulse wave velocity (PWV) is a good indicator of arterial stiffness and an important predictor of cardiovascular events. Recent studies have revealed that PWV increases in patients with obstructive sleep apnea–hypopnea syndrome (OSAHS) and it also correlates with its severity. However, the therapeutic effect of continuous positive airway pressure (CPAP) on PWV remains undetermined. To clarify this point, we started CPAP treatment on 17 OSAHS patients. Brachial-ankle PWV was measured before starting CPAP, and at 2 months and 4 months after the start of CPAP. Before the CPAP treatment, mean brachial-ankle PWV of the patients was 15.6±0.6m/s, and mean Epworth sleepiness scale (ESS) score was 8.6±1.0. Brachial-ankle PWV was found to positively correlate with heart rate, systolic and diastolic blood pressures, mean blood pressure, and arousal index. During the study period, the CPAP treatment did not have a significant effect on heart rate, blood pressures and serum total cholesterol levels. However, it significantly improved ESS score at 4 months after the start of CPAP (P=0.001), while it effectively decreased brachial-ankle PWV at 2 months and at 4 months after the start of CPAP (P=0.010 and P=0.027, respectively). The CPAP treatment was shown to decrease brachial-ankle PWV without affecting blood pressures in OSAHS patients. Although the precise mechanism for this effect is unclear, our finding suggests a close relationship between OSAHS and arterial stiffness, while also reemphasizing the clinical importance of CPAP treatment. [Copyright &y& Elsevier]

Background: Periostin, an extracellular matrix protein, contributes to subepithelial thickening in asthmatic airways, and its serum levels reflect airway eosinophilic inflammation. However, the relationship between periostin and the development of airflow limitation, a functional consequence of airway remodeling, remains unknown. Objective: We aimed to determine the relationship between serum periostin levels and pulmonary function decline in asthmatic patients on inhaled corticosteroid (ICS) treatment. Methods: Two hundred twenty-four asthmatic patients (average age, 62.3 years) treated with ICS for at least 4 years were enrolled. Annual changes in FEV1, from at least 1 year after the initiation of ICS treatment to the time of enrollment or later (average, 16.2 measurements over 8 years per individual), were assessed. At enrollment, clinical indices, biomarkers that included serum periostin, and periostin gene polymorphisms were examined. Associations between clinical indices or biomarkers and a decline in FEV1 of 30 mL or greater per year were analyzed. Results: High serum periostin levels (≥95 ng/mL) at enrollment, the highest treatment step, higher ICS daily doses, a history of admission due to asthma exacerbation, comorbid or a history of sinusitis, and ex-smoking were associated with a decline in FEV1 of 30 mL or greater per year. Multivariate analysis showed that high serum periostin, the highest treatment step, and ex-smoking were independent risk factors for the decline. Polymorphisms of periostin gene were related to higher serum periostin levels (rs3829365) and a decline in FEV1 of 30 mL or greater per year (rs9603226). Conclusions: Serum periostin appears to be a useful biomarker for the development of airflow limitation in asthmatic patients on ICS. [Copyright &y& Elsevier]

Langerhans (LC) cells require incubation with protein antigen for several days before the cells effectively stimulate proliferation of cloned, H-2 restricted, antigen-specific T h cells. In contrast, splenic antigen-presenting cells are immediately effective. LC are immediately competent, however, if an immunogenic peptide rather than the intact protein is the immunogen, indicating that resident or unchallenged LC have the required class II MHC and can provide the signals necessary for T-cell proliferation but may lack the capacity to internalize or cleave protein antigens. We propose that delayed antigen presentation by LC may be intrinsic and advantageous for promoting early systemic immunity. LC stimulate cloned T h1 and T h2 cells equally well, suggesting that LC may not limit or bias the type of immunity that occurs with cutaneous antigenic challenge. [ABSTRACT FROM AUTHOR]

Recombinant human soluble thrombomodulin (rTM) is a newly developed anti-coagulant approved for treatment of disseminated intravascular coagulation (DIC) in Japan. rTM exerts anti-inflammatory and cytoprotective functions via its lectin-like and epidermal growth factor-like domains, respectively. In this study, we retrospectively reviewed the treatment of 21 consecutive patients with coagulopathy, complicated by acute promyelocytic leukemia (APL), with all-trans retinoic acid (ATRA) with or without combination with rTM. Surprisingly, none of the 14 rTM-treated patients developed retinoic acid (RA)-related differentiation syndrome (DS). The co-culture of vascular endothelial cell-derived EA.hy926 and APL-derived NB4 cells in the presence of RA increased production of tumor necrosis factor alpha (TNF-α) in culture media, in parallel with activation of p38 mitogen-activated protein kinase and increased levels of intracellular adhesion molecule 1 (ICAM1) in EA.hy926 cells. This was also associated with increased levels of the phosphorylated forms of VE-cadherin and enhanced vascular permeability of EA.hy926 monolayers. Importantly, addition of rTM to this co-culture system inhibited the RA-induced phosphorylation of p38 and VE-cadherin and decreased ICAM1 and vascular permeability in EA.hy926 cells, without a decrease inthe levels of TNF-α. Taken together, use of rTM may be a promising treatment strategy to prevent DS in APL patients who receive ATRA. [ABSTRACT FROM AUTHOR]

Thrombomodulin (TM) exerts anti-inflammatory functions. We previously found that recombinant human soluble TM alleviated murine graft-versus-host disease (GVHD). Nevertheless, it is unclear how TM mediates its anti-inflammatory functions in GVHD. Here, we identified G-protein coupled receptor 15 (GPR15) expressed on T cells as a receptor/sensor of TM. The fifth region of epidermal growth factor–like domain of TM (TME5) bound GPR15 in vitro. TME5 prolonged survival of mice undergoing acute GVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TME5 increased regulatory T cells (Tregs) but decreased Th 1 proportions in targeted organs. TME5 suppressed allo-reaction in vitro in association with an increase in the number of induced Tregs. However, the anti-inflammatory function of TME5 was abolished when GPR15 knockout T cells were used as donor T cells. We further found that TME5 suppressed production of IL-6 in T cells, which probably facilitated differentiation of Tregs. Moreover, TME5 reduced activation of bone marrow–derived dendritic cells (BMDCs) and hampered function of BMDCs in inducing allo-reaction in vivo and in vitro. Our findings suggested that inducing Tregs as well as blocking activation of DCs in vivo by using TME5 is a potential therapeutic option for preventing GVHD in allo-HSCT. [ABSTRACT FROM AUTHOR]

In this study, we showed that the levels of EZH2 in bone marrow mononuclear cells (BMMNCs) isolated from individuals with chronic myeloid leukemia (CML) (n = 12) were significantly greater than those in BMMNCs isolated from healthy volunteers (n = 6) as well as individuals with Philadelphia chromosome-negative myeloproliferative neoplasms. Lentiviral transduction of the BCR/ABL gene in Ba/F3 cells increased EZH2 levels in parallel with phosphorylation of STAT5. Notably, chromatin immunoprecipitation assays showed that STAT5A bound to a promoter region of the EZH2 gene, resulting in an increase in the transcriptional activity of EZH2 in leukemia cells. Importantly, downregulation of EZH2 by short hairpin RNAs (shRNAs) inhibited the expression of XIAP and increased the miR-219 levels associated with a decrease in hypermethylation of miR-219-1 CpG islands. Moreover, overexpression of miR-219 decreased the levels of XIAP in CML cells. Since the 3′-untranslated region (3′-UTR) of XIAP contains miR219-5p-complementary binding site, miR-219 might modulate the expression of XIAP through binding of miR-219 on the 3′-UTR of XIAP. Taken together, BCR/ABL positively regulates the expression of EZH2 via STAT5 signaling. EZH2 modulates epigenetic changes at DNA methylated regions encoding miR-219 and downregulates the level of miR-219, resulting in upregulation of XIAP. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 5 (STAT5) is activated in CD34 + /CD38 − acute myelogenous leukemia (AML) cells. Inhibition of STAT5 induced apoptosis and sensitized these cells to the growth inhibition mediated by conventional chemotherapeutic agents. The present study attempted to identify molecules that are regulated by STAT5 in CD34 + /CD38 − AML cells by utilizing cDNA microarrays, comparing the gene expression profiles of control and STAT5A shRNA-transduced CD34 + /CD38 − AML cells. Interestingly, DNA methyltransferase (DNMT) 3A was downregulated after depletion of STAT5A in CD34 + /CD38 − AML cells. Reporter gene assays found that an increase in activity of DNMT3A occurred in response to activation of STAT5A in leukemia cells. On the other hand, dephosphorylation of STAT5A by AZ960 decreased this transcriptional activity. Further studies utilizing a chromatin immunoprecipitation assay identified a STAT5A-binding site on the promoter region of DNMT3A gene. Forced expression of STAT5A in leukemia cells caused hypermethylation on the promoter region of the tumor suppressor gene, PTEN, and downregulated its mRNA levels, as measured by methylation-specific and real-time polymerase chain reaction, respectively. Taken together, these data suggest that STAT5A positively regulates levels of DNMT3A, resulting in inactivation of tumor suppressor genes by epigenetic mechanisms in AML cells. [ABSTRACT FROM AUTHOR]

Abstract: Shugoshin 1 (SGOL1), a centromeric protein, plays an important role in mitosis. This study explored the levels of SGOL1 in hematological malignancies and found that SGOL1 was aberrantly expressed in various human leukemia cell lines (n =10, e.g., HL60, U937, MOLM-13, K562, EOL-1, etc.) and freshly isolated leukemia cells from individuals with acute myelogenous leukemia (AML, n =43, p <0.001) compared with bone marrow mononuclear cells isolated from healthy volunteers (n =9), as measured by real-time RT-PCR. Forced expression of SGOL1 in hematopoietic stem/progenitor cells (HSPCs) significantly increased colony numbers for CFU-M and CFU-GM compared with control vector transduced infected HSPCs, suggesting that SGOL1 might act as an oncogene in hematopoietic cells. In addition, we found that repression of SGOL1 by small interfering RNA (siRNA) slowed the proliferation of NB4, EOL-1 and U937 cells compared with the control siRNA transfected cells, in parallel with the appearance of precocious dissociation of centromeric cohesion and separation of sister chromatids in these cells. Furthermore, we found that repression of SGOL1 by siRNA accumulated EOL-1 and U937 cells in the G2/M phase of the cell cycle, in conjunction with up-regulation of the spindle checkpoint protein BubR1, followed by apoptosis via caspase pathways. Thus, SGOL1 might be a promising molecular target for treating individuals with AML. [Copyright &y& Elsevier]