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A case with non-small cell lung cancer exhibited extreme hyperglycemia after lorlatinib treatment, whose adverse effects on hyperglycemia is little known. But, the lorlatinib could be continued by intensifying diabetes treatment, indicating the importance of glucose monitoring during lorlatinib administration, and of adequate intensification of treatment for such hyperglycemia.

Purpose The HORSE-BC study previously demonstrated that 2nd-line endocrine therapy (ET) for metastatic breast cancer (MBC) patients with acquired endocrine resistance still provided a clinically meaningful benefit. Herein, we investigated health-related quality of life (HR-QOL) in HORSE-BC. Methods MBC patients with acquired endocrine resistance who were scheduled for 2nd-line ET were recruited. HR-QOL was assessed at baseline and 1 and 3 months after initiation of 2nd-line ET. To investigate the minimally important difference (MID) in the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES), we evaluated the means and standard deviations (SDs) for the distribution-based method, and differences in the change in HR-QOL for the anchor-based method. We also investigated the association between FACT-ES total scores and clinical benefit. Results Overall, 56 patients were enrolled. Of these, 47 were analyzed. When defined as 1/3 SD estimates based on the distribution method, the calculated MID was 5.9. The MIDs of the FACT-ES total scores based on the anchor method were 7.7 for decline and 4.1 for improvement. The proportions of MID decline were 6.1% and 14.7% lower in patients who experienced clinical benefits than in those who did not at 1 month and 3 months, respectively. The respective ratios of MID improvement in patients who experienced clinical benefits were 18.3% and 3.2% higher, respectively; mean change in FACT-ES total score from baseline was improved in patients who experienced clinical benefits. Conclusion Maintaining HR-QOL as determined by FACT-ES may be associated with clinical benefits in patients with acquired endocrine-resistant MBC treated with ET.

Kazuki Furuhashi,1,2 Tomoyuki Fujisawa,1 Dai Hashimoto,3 Yousuke Kamiya,1 Hideki Yasui,1 Masato Karayama,1 Yuzo Suzuki,1 Hironao Hozumi,1 Noriyuki Enomoto,1 Yutaro Nakamura,1 Naoki Inui,1,4 Takafumi Suda1 1Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan; 2Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan; 3Department of Respiratory Medicine, Seirei Hamamatsu General Hospital, Hamamatsu, Japan; 4Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, JapanCorrespondence: Kazuki FuruhashiSecond Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, JapanTel +81 53 435 2870Fax +81 53 435 2096Email k.furu@hama-med.ac.jpIntroduction: Fluticasone furoate (FF)/vilanterol (VI) dry powder inhaler (DPI) is the only once-daily maintenance inhaled corticosteroid (ICS)/long-acting β2 adrenergic agonist (LABA) combination for asthma. We aimed to compare the clinical effects of once-daily FF/VI and twice-daily budesonide (BUD)/formoterol (FM) DPI in patients with controlled stable asthma.Methods: We performed a randomized crossover trial in which stable asthmatic patients controlled on ICS/LABA received 8 weeks of FF/VI (100/25 μg 1 puff once-daily) or BUD/FM (160/4.5 μg 2 puffs twice-daily) DPI treatment. After a 4–8-week washout period, patients received another crossover treatment for 8 weeks. We assessed pulmonary function, the 5-item version asthma control questionnaire (ACQ5), the asthma control test (ACT), and fractional exhaled nitric oxide (FeNO) at baseline and after 8 weeks of treatment (week 8). As the primary outcome was change in force expiratory volume in 1 s (FEV1) between baseline and week 8, we evaluated the incidence of asthma exacerbation and adherence barrier questionnaire (Ask-12) at week 8.Results: Twenty-three patients were initially enrolled in this study; however, one patient had to be excluded. The FF/VI DPI treatment group showed a similar magnitude of change in FEV1 between baseline and week 8 as the BUD/FM DPI treatment group. In addition, there were no significant differences in pulmonary function tests, ACQ5 scores, ACT scores, and FeNO between baseline and week 8 in both groups. Although the incidence of exacerbation did not differ between groups, the Ask-12 score in the FF/VI DPI group was significantly lower than that in the BUD/FM DPI group.Conclusions: The present study indicates that once-daily FF/VI DPI is not inferior to twice-daily BUD/FM DPI in clinical effect and more likely to improve inconvenience and forgetfulness in inhalation adherence barriers for stable asthma control therapy. Once-daily FF/VI DPI may be an effective alternative for asthma maintenance treatment.Keywords: fluticasone furoate/vilanterol, budesonide/formoterol, stable asthma, randomized crossover trial, inhalation adherence barriers

Yuzo Suzuki,1 Naoki Inui,1 Masato Karayama,1 Shiro Imokawa,2 Takashi Yamada,3 Koushi Yokomura,4 Kazuhiro Asada,5 Hideki Kusagaya,6 Yusuke Kaida,7 Hiroyuki Matsuda,8 Naoki Koshimizu,9 Mikio Toyoshima,10 Masafumi Masuda,11 Hiroshi Hayakawa,12 Hironao Hozumi,1 Kazuki Furuhashi,1 Noriyuki Enomoto,1 Tomoyuki Fujisawa,1 Yutaro Nakamura,1 Takafumi Suda11Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan; 2Department of Respiratory Medicine, Iwata City Hospital, Iwata, Japan; 3Department of Respiratory Medicine, Shizuoka City Shizuoka Hospital, Shizuoka, Japan; 4Department of Respiratory Medicine, Seirei-Mikatahara Hospital, Hamamatsu, Japan; 5Department of Respiratory Medicine, Shizuoka General Hospital, Shizuoka, Japan; 6Department of Respiratory Medicine, Shizuoka Saiseikai Hospital, Shizuoka, Japan; 7Department of Respiratory Medicine, JA Shizuoka Kohseiren Enshu Hospital, Hamamatsu, Japan; 8Department of Respiratory Medicine, Shizuoka Red Cross Hospital, Shizuoka, Japan; 9Department of Respiratory Medicine, Fujieda City Hospital, Fujieda, Japan; 10Department of Respiratory Medicine, Hamamatsu Rosai Hospital, Hamamatsu, Japan; 11Department of Respiratory Medicine, Shizuoka City Shimizu Hospital, Shizuoka, Japan; 12Department of Respiratory Medicine, Tenryu Hospital, National Hospital Organization, Hamamatsu, JapanCorrespondence: Yuzo SuzukiSecond Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama Higashi-ku, Hamamatsu, Shizuoka 431-3192, JapanTel +81 53 435 2263Fax +81 53 435 2354Email yuzosuzu@hama-med.ac.jpBackground: Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor, has been shown to improve survival in non-small cell lung cancer (NSCLC). The possible involvement of PD-1 axis in the pathogenesis of inflammatory lung disease, such as chronic obstructive pulmonary disease (COPD) has also been reported. However, effects of PD-1 blockade on the respiratory system remain unknown.Objectives: This prospective study aimed to investigate whether inhibition of the PD-1 axis altered lung inflammation and pulmonary function in NSCLC patients with and without COPD.Method: This was a prospective multi-center study. Measurements of fractioned exhaled nitric oxide (FeNO) and pulmonary function were performed before and after 4 cycles of nivolumab therapy.Results: A total of 137 patients with NSCLC were initially enrolled, and subsequently 95 patients (41 COPD and 54 non-COPD) receiving 4 cycles of nivolumab administration were included. After anti-PD-1 therapy, FeNO levels were significantly elevated together with increase in peripheral eosinophils. Interestingly, significant FeNO elevation was only found in COPD patients without increased peripheral eosinophils, but this was not the case in non-COPD patients. Additionally, COPD patients exhibited significant increases in FVC and FEV1 but no changes in dyspnea scales, and acute exacerbation did not occur during the therapy.Conclusion: Our observations suggest that anti-PD-1 therapy changed FeNO levels and pulmonary function in NSCLC patients. This therapy does not worsen COPD in terms of symptoms, pulmonary function, or acute exacerbation.Keywords: immune checkpoint inhibitor, programmed death 1, PD-1, non-small cell lung cancer, NSCLC, chronic obstructive pulmonary disease, COPD

Masato Karayama,1 Naoki Inui,1,2 Hideki Yasui,1 Masato Kono,1 Hironao Hozumi,1 Yuzo Suzuki,1 Kazuki Furuhashi,1 Dai Hashimoto,1 Noriyuki Enomoto,1 Tomoyuki Fujisawa,1 Yutaro Nakamura,1 Hiroshi Watanabe,2 Takafumi Suda11Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan; 2Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu 431-3192, JapanPurpose: The diagnosis and severity of chronic obstructive pulmonary disease (COPD) are defined by airflow limitation using spirometry. However, COPD has diverse clinical features, and several phenotypes based on non-spirometric data have been investigated. To identify novel phenotypes of COPD using radiologic data obtained by three-dimensional computed tomography (3D-CT).Patients and methods: The inner luminal area and wall thickness of third- to sixth-generation bronchi and the percentage of the low-attenuation area (less than −950 HU) of the lungs were measured using 3D-CT in patients with COPD. Using the radiologic data, hierarchical clustering was performed. Respiratory reactance and resistance were measured to evaluate functional differences among the clusters.Results: Four clusters were identified among 167 patients with COPD: Cluster I, mild emphysema with severe airway changes, severe airflow limitation, and high exacerbation risk; Cluster II, mild emphysema with moderate airway changes, mild airflow limitation, and mild dyspnea; Cluster III, severe emphysema with moderate airway changes, severe airflow limitation, and increased dyspnea; and Cluster IV, moderate emphysema with mild airway changes, mild airflow limitation, low exacerbation risk, and mild dyspnea. Cluster I had the highest respiratory resistance among the four clusters. Clusters I and III had higher respiratory reactance than Clusters II and IV.Conclusions: The 3D-CT-based radiologic phenotypes were associated with the clinical features of COPD. Measurement of respiratory resistance and reactance may help to identify phenotypic differences.Keywords: airway, chronic obstructive pulmonary disease, clustering analysis, emphysema, phenotype, three-dimensional computed tomography

application/pdf, 本研究の目的は、香川県警察、奈良県警察、高知県警察、愛媛県警察、岩手県警察と共同で、効果的な万引きへの対応と対策に関するアンケート調査を行い、業種別の効果的な万引きへの対応と対策について検討することであった。香川県、奈良県、高知県、愛媛県、岩手県の411店舗に調査を実施した。調査の結果、印象的な万引きの事例やうまく防げた事例などにおいて、業種ごとに特徴がみられた。また、万引きの実態と対応、実際に行っている対策や店舗の万引き対策への意識において、業種ごとに特徴がみられた。

Targeting bromodomains (BRDs) of the bromo-and-extra-terminal (BET) family offers opportunities for therapeutic intervention in cancer and other diseases. Here, we profile the interactomes of BRD2, BRD3, BRD4, and BRDT following treatment with the pan-BET BRD inhibitor JQ1, revealing broad rewiring of the interaction landscape, with three distinct classes of behavior for the 603 unique interactors identified. A group of proteins associate in a JQ1-sensitive manner with BET BRDs through canonical and new binding modes, while two classes of extra-terminal (ET)-domain binding motifs mediate acetylation-independent interactions. Last, we identify an unexpected increase in several interactions following JQ1 treatment that define negative functions for BRD3 in the regulation of rRNA synthesis and potentially RNAPII-dependent gene expression that result in decreased cell proliferation. Together, our data highlight the contributions of BET protein modules to their interactomes allowing for a better understanding of pharmacological rewiring in response to JQ1.

Background: Specific IgE (sIgE) is often used to predict oral food challenge (OFC) outcomes in food allergy, but interpretation of the results may vary depending on the assay method employed and the patient population tested. The aim of this study was to use two commercial assay systems to determine egg-sIgE values predictive of allergy within the most common populations treated at pediatric clinics. Methods: In a multicenter prospective study, 433 children with suspected or confirmed egg allergy underwent oral challenge (OFC) using cooked egg (CE) and raw egg (RE) powders to diagnose either true allergy in 1-year-old (group A, n = 220) or tolerance in 2- to 6-year-old (group B, n = 213). Egg white (EW)- and ovomucoid (OM)-sIgE values were measured using the ImmunoCAP(®) sIgE (ImmunoCAP) and the IMMULITE(®) 2000 3 gAllergy(™) (3gAllergy) systems. Children were recruited from six primary care clinics and 18 hospitals in Japan. Results: Receiver-operating characteristic (ROC) curve analysis yielded similar areas under the curve (AUC) for the two assays (0.7-0.8). The optimal cutoff values and the probability curves (PCs) of the sIgE by the two assays to predict CE and RE OFC outcomes were determined for both groups. Values for 3gAllergy were higher than for ImmunoCAP; however, correlation of sIgE and predicted probability calculated by PCs were strong between the two methods. Conclusions: Cutoff values and PCs for egg-sIgE established using both ImmunoCAP and 3gAllergy may be useful for predicting egg allergy in early childhood patient populations.

Naoki Inui,1,2 Sayomi Matsushima,1 Shinpei Kato,1 Hideki Yasui,1 Masato Kohno,1 Tomoyuki Fujisawa,1 Noriyuki Enomoto,1 Yutaro Nakamura,1 Mikio Toyoshima,3 Takafumi Suda1 1Second Division, Department ofInternal Medicine, 2Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Handayama, Hamamatsu, Japan; 3Department ofRespiratory Medicine, Hamamatsu Rosai Hospital, Shougen-cho, Hamamatsu, JapanAbstract: The forced oscillation technique (FOT) can measure respiratory mechanics and has attracted attention in chronic obstructive pulmonary disease (COPD). We aimed to evaluate the effects of only indacaterol and tiotropium monotherapies on airflow limitation and respiratory impedance. Pulmonary function tests, COPD assessment test (CAT), and multifrequency FOT with MostGraph-01 were performed at the beginning and after 8weeks of treatment with indacaterol or tiotropium. The resistance index, resistance at 5Hz (R5), resistance at 20Hz (R20), reactance index, reactance at 5Hz (X5), resonant frequency (Fres), and low-frequency reactance area (ALX) were determined at whole-breath, inspiratory, and expiratory phases. Eighty-two patients (mean age: 73years; mean forced expiratory volume in 1second (FEV1): 61.6%±19.0% predicted) were randomized to indacaterol or tiotropium treatment. Both bronchodilators improved airflow limitation, with mean trough improvements in FEV1 of 165mL and 80mL in the indacaterol and tiotropium groups, respectively. The CAT score decreased in the indacaterol group (P

application/pdf, 本研究の目的は、中四国地方の店舗の万引きに関する知識および意識と防犯対策について検討することであった。中四国の事業所114店舗を対象としたアンケート調査を実施した。まず、対象店舗を認知件数をもとに、万引きの無い店舗、少ない店舗、多い店舗に分類し、認知件数によって万引きに関する知識および意識と防犯対策が異なるのかについて検討を行った。その結果、万引きの多い店舗ほど万引きに関する知識および意識が高く、防犯対策も行っていることが明らかとなった。次に、万引きに関する知識および意識と防犯対策の関連について検討を行った。その結果、万引きに関する知識のある店舗は万引きに関する意識が高く、防犯対策を実施していることが明らかとなった。

Aims Atherosclerosis is a chronic inflammatory disease occurring within theartery wall. A crucial step in atherogenesis is the infiltration and retention ofmonocytes into the subendothelial space of large arteries induced bychemokines and growth factors. Angiopoietin-1 (Ang-1) regulatesangiogenesis and reduces vascular permeability and has also been reported topromote monocyte migration in vitro. We investigated the role of Ang-1 inatherosclerosis-prone apolipoprotein-E (ApoE) knockout mouse.Methods and Results Apo-E knockout (Apo-E-/-) mice fed a Western ornormal chow diet received a single i.v. injection of adenovirus encoding Ang-1or control vector. Adenovirus-mediated systemic expression of Ang-1 induceda significant increase in early atherosclerotic lesion size andmonocyte/macrophage accumulation compared with control animals receivingempty vector. Ang-1 significantly increased plasma MCP-1 and VEGF levelsas measured by ELISA. FACS analysis showed that Ang-1 selectivelyincreased inflammatory Gr1+ monocytes in the circulation, while the cellsurfaceexpression of CD11b, which mediates monocyte emigration, wassignificantly reduced.Conclusions Ang-1 specifically increases circulating Gr1+ inflammatorymonocytes and increases monocyte/macrophage retention in atheroscleroticplaques, thereby contributing to development of atherosclerosis.

application/pdf, 本研究の目的は、店舗での効果的な万引き対策推進のために、店舗関係者を対象として、店舗向け万引き防止対策講習会と店舗向け万引き防止対策動画の効果について検討することであった。店舗向け万引き防止対策講習会に参加した162名と店舗向け万引き防止対策動画を視聴した42名を対象としてアンケート調査を行った。講習会参加者と動画視聴者では、講習会参加者のほうが全体の評価と対策の実感が高いことが明らかとなった。全体の評価と対策の実感との関連では、講習会参加者、動画視聴者ともに、正の関連が認められたことから、全体の評価と対策の実感がつながっていることが明らかとなった。

Yasuo Sekine, Ryoko Yanagibori, Kiminori Suzuki, Sonomi Sugiyama, Haruko Yamaji, Michiko Ishibashi, Takehiko Fujisawa Chiba Foundation for Health Promotion and Disease Prevention, Chiba, Japan Background and objective: Patients with chronic obstructive pulmonary disease (COPD) are at risk for lung cancer; the diseases have common etiologies, including cigarette smoking. We aimed to clarify the effectiveness of COPD detection using a regional mass-screening program for lung cancer. Materials and methods: A total of 7,067 residents of Togane, Chiba, Japan received lung cancer screening between May and July, 2011. We defined four groups of possible COPD candidates: group A (n=358), positive smoking history, positive chronic respiratory symptoms; group B (n=766), positive smoking history, positive lifestyle-related disease; group C (n=75), passive smoking history, positive chronic respiratory symptoms; and group D (n=301), passive smoking history, positive lifestyle-related disease. Candidates underwent on-site pulmonary function testing (PFT). Results: The criteria for COPD candidates were fulfilled in 1,686 of 7,067 individuals (23.9%); 1,500 participants underwent PFT (89%), and 171 (11.4%) were diagnosed with COPD. The overall COPD detection rate was 2.4%. The frequency of COPD was significantly higher in groups A and B than in groups C and D (P=0.048); however, the distribution of COPD grades was similar among the groups (P=0.372). Multiple logistic regression analysis identified male sex, age 60 years or greater, and positive smoking history as risk factors for COPD. Conclusion: COPD screening using a community-based lung cancer-screening program may be effective for disease detection. Individuals who are 60 years of age or older with a positive smoking history should undergo PFT to detect COPD. Keywords: chronic obstructive pulmonary disease, lung neoplasms, mass screening, respiratory function tests

application/pdf, 本研究では、2011年に作成し、配布した店舗向け万引き防止のための店作りマニュアルの課題を明らかにし、店舗調査と保安員調査の結果をもとに万引きを未然に防止するための新たな店内声かけマニュアルを作成した。その後、実際の店舗で実験的に試行し、その効果について検証を行った。その結果、未然防止のための店内声かけの有効性が示唆された。こうした取り組みも含めて、これまでの取り組みのあり方から、エビデンスに基づく万引き防止の社会的実践サイクルについて考察した。

application/pdf, 本研究の目的は、効果的な万引き対策の実践のために、店内保安員を対象として、万引き対策への意識と万引きに対する態度について検討することであった。店内保安員20名を対象としてアンケート調査を行った。店内保安員歴は万引き対策への意識と万引きに対する態度とは無関係であり、捕捉人数の多さは対策のさらなる推進と個室に持ち込まれた際の声かけと関係していた。店舗と比較すると、店内保安員は、個室に持ち込まれた際には声かけを躊躇していることが示された。また、万引き対策をさらに推進させるべきと考える意識の高さが捕捉において重要な要因であり、万引き犯への恐怖は捕捉を思いとどまらせる要因となっていることが示された。

Multilocus sequence data provide far greater power to resolve species limits than the single locus data typically used for broad surveys of clades. However, current statistical methods based on a multispecies coalescent framework are computationally demanding, because of the number of possible delimitations that must be compared and time-consuming likelihood calculations. New methods are therefore needed to open up the power of multilocus approaches to larger systematic surveys. Here, we present a rapid and scalable method that introduces two new innovations. First, the method reduces the complexity of likelihood calculations by decomposing the tree into rooted triplets. The distribution of topologies for a triplet across multiple loci has a uniform trinomial distribution when the 3 individuals belong to the same species, but a skewed distribution if they belong to separate species with a form that is specified by the multispecies coalescent. A Bayesian model comparison framework was developed and the best delimitation found by comparing the product of posterior probabilities of all triplets. The second innovation is a new dynamic programming algorithm for finding the optimum delimitation from all those compatible with a guide tree by successively analyzing subtrees defined by each node. This algorithm removes the need for heuristic searches used by current methods, and guarantees that the best solution is found and potentially could be used in other systematic applications. We assessed the performance of the method with simulated, published and newly generated data. Analyses of simulated data demonstrate that the combined method has favourable statistical properties and scalability with increasing sample sizes. Analyses of empirical data from both eukaryotes and prokaryotes demonstrate its potential for delimiting species in real cases.

Background Endothelial dysfunction is central to the pathogenesis of coronary artery disease, but the role of local and circulating endothelial progenitor cells in maintaining vascular health is poorly understood. We hypothesised that impaired local and circulating vascular repair mechanisms predispose to endothelial dysfunction and the premature onset of coronary artery disease.\ud Methods and results Patients with premature coronary artery disease (n = 16) and healthy age- and sex-matched controls (n = 16) underwent venous occlusion plethysmography with intra-arterial infusion of acetylcholine and sodium nitroprusside. Numbers of circulating endothelial progenitor cells were directly quantified in whole blood by flow cytometry. Endothelial cells were isolated from the blood vessel wall and from peripheral blood mononuclear cells, and expanded in vitro for phenotypic and functional characterisation and analysis of microRNA expression levels. A dose-dependent increase in forearm blood flow (p

© 2015 The Author(s). The BioMart Community Portal (www.biomart.org) is a community-driven effort to provide a unified interface to biomedical databases that are distributed worldwide. The portal provides access to numerous database projects supported by 30 scientific organizations. It includes over 800 different biological datasets spanning genomics, proteomics, model organisms, cancer data, ontology information and more. All resources available through the portal are independently administered and funded by their host organizations. The BioMart data federation technology provides a unified interface to all the available data. The latest version of the portal comes with many new databases that have been created by our ever-growing community. It also comes with better support and extensibility for data analysis and visualization tools. A new addition to our toolbox, the enrichment analysis tool is now accessible through graphical and web service interface. The BioMart community portal averages over one million requests per day. Building on this level of service and the wealth of information that has become available, the BioMart Community Portal has introduced a new, more scalable and cheaper alternative to the large data stores maintained by specialized organizations.

Aims Endothelial dysfunction is a hallmark of preeclampsia. Desensitization of the phosphoinositide 3-kinase (PI3K)/ Akt pathway underlies endothelial dysfunction and haeme oxygenase-1 (HO-1) is decreased in preeclampsia. To identify therapeutic targets, we sought to assess whether these two regulators act to suppress soluble endoglin (sEng), an antagonist of transforming growth factor-β (TGF-β) signalling, which is known to be elevated in preeclampsia. Methods and resultsVascular endothelial growth factor-A (VEGF-A), fibroblast growth factor (FGF-2), angiopoietin-1 (Ang-1), and insulin, which all activate the PI3K/Akt pathway, inhibited the release of sEng from endothelial cells. Inhibition of the PI3K/Akt pathway, by overexpression of phosphatase and tensin homolog (PTEN) or a dominant-negative isoform of Akt (Aktdn) induced sEng release from endothelial cells and prevented the inhibitory effect of VEGF-A. Conversely, overexpression of a constitutively active Akt (Akt myr) inhibited PTEN and cytokine-induced sEng release. Systemic delivery of Akt myr to mice significantly reduced circulating sEng, whereas Aktdn promoted sEng release. Phosphorylation of Akt was reduced in preeclamptic placenta and this correlated with the elevated level of circulating sEng. Knock-down of Akt using siRNA prevented HO-1-mediated inhibition of sEng release and reduced HO-1 expression. Furthermore, HO-1 null mice have reduced phosphorylated Akt in their organs and overexpression of Akt myr failed to suppress the elevated levels of sEng detected in HO-1 null mice, indicating that HO-1 is required for the Akt-mediated inhibition of sEng. ConclusionThe loss of PI3K/Akt and/or HO-1 activity promotes sEng release and positive manipulation of these pathways offers a strategy to circumvent endothelial dysfunction.

Plasmons, which are collective charge oscillations, offer the potential to use optical signals in nano-scale electric circuits. Recently, plasmonics using graphene have attracted interest, particularly because of the tunable plasmon frequency through the carrier density $n$. However, the $n$ dependence of the plasmon velocity is weak ($\propto n^{1/4}$) and it is difficult to tune the frequency over orders of magnitude. Here, we demonstrate that the velocity of plasmons in graphene can be changed over two orders of magnitude by applying a magnetic field $B$ and by the presence/absence of a gate; at high $B$, edge magnetoplasmons (EMPs), which are plasmons localized at the sample edge, are formed and their velocity depends on $B$ and the gate screening effect. The wide range tunability of the velocity and the observed low-loss plasmon transport encourage designing graphene nanostructures for plasmonics applications., submitted

Usually, dust generated during the copper smelting process by the Teniente Converter and the Flash Smelting Furnaces in Chile, contains high concentrations of copper, zinc, arsenic, antimony and other metals. In general, the dust is recirculated to the smelting process or it is directed to hydrometallurgical process for recovery and stabilization. However, in recent years the generation of dust has increased because of the degradation of the quality of the concentrate. In addition, the environmental regulations have become stricter. It is therefore desirable to understand the behavior of those elements, when the smelting process operates with recirculation of dust. In this study, the effect of dust recirculation to smelting process on the distribution among the matte, slag and gas phases was evaluated, as a function of matte grade, amount of recirculated dust, oxygen enrichment and temperature. It was found that the concentration in thematte of the impurities such as arsenic, antimony and bismuth, increased slightly with recirculation of dust. On the other hand, the concentration of lead and zinc depend of the direct recirculation of dust to the process. Additionally, it was found that high concentrations of arsenic and antimony in the dust may lead to the formation and precipitation of copper arsenates and other metals (speiss), which may generates important operational problems. Usualmente, el polvo generado durante el proceso de fusión de concentrado de cobre por el Convertidor Teniente y el Horno Flash en Chile, contienen altos contenidos de cobre, zinc, arsénico y antimonio, entre otros metales. En general, el polvo se recircula al proceso de fusión o se envía a procesos hidrometalúrgicos para recuperación y estabilización. Sin embargo, en los años recientes, la generación de polvo ha aumentado debido a la baja en la calidad del concentrado. Adicionalmente, las normas ambientales se han vuelto más estrictas. Por lo tanto, es deseable entender el comportamiento de estos elementos cuando el proceso opera con recirculación de polvos. En este estudio, el efecto de la recirculación de polvo al proceso de fusión de cobre en la distribución entre la mata, escoria y gas fue evaluado como una función del grado de la mata, cantidad de polvo recirculado, enriquecimiento de oxígeno y temperatura. Se encontró que la concentración en el eje, de metales tales como, arsénico, antimonio y bismuto aumentaron levemente con el polvo recirculado. Por otro lado, la concentración de plomo y zinc depende fuertemente de la recirculación directa de polvo al proceso. Adicionalmente, se encontró que altos niveles de arsénico y antimonio en el polvo, pueden provocar formación y precipitación de arseniatos de cobre y otros metales (speiss), los cuales pueden provocar problemas operacionales de importancia.

Experiments on the direction-resolved full-counting statistics of single-electron tunneling allow testing the fundamentally important Fluctuation Theorem (FT). At the same time, the FT provides a frame for analyzing such data. Here we consider tunneling through a double quantum dot system which is coupled capacitively to a quantum point contact (QPC) detector. Fluctuations of the environment, including the shot noise of the QPC, lead to an enhancement of the effective temperature in the FT. We provide a quantitative explanation of this effect; in addition we discuss the influence of the finite detector bandwidth on the measurements., Prepared for "Perspectives of Mesoscopic Physics - Dedicated to Prof. Yoseph Imry's 70th Birthday"

International audience

26th International Conference on The Physics of Semiconductors, UK

We study the non-equilibrium regime of the Kondo effect in a quantum dot laterally coupled to a narrow wire. We observe a split Kondo resonance when a finite bias voltage is imposed across the wire. The splitting is attributed to the creation of a double-step Fermi distribution function in the wire. Kondo correlations are strongly suppressed when the voltage across the wire exceeds the Kondo temperature. A perpendicular magnetic field enables us to selectively control the coupling between the dot and the two Fermi seas in the wire. Already at fields of order 0.1 T only the Kondo resonance associated with the strongly coupled reservoir survives.

We define a mesoscopic ring in a 2-dimensional electron gas (2DEG) interrupted by two tunnel barriers, enabling us to apply a well-defined potential difference between the two halves of the ring. The electron interference in the ring is modified using a perpendicular magnetic field and a bias voltage. We observe clear Aharonov-Bohm oscillations up to the quantum Hall regime as a function of both parameters. The electron travel time between the barriers is found to increase with the applied magnetic field. Introducing a scattering model, we develop a new method to measure the non-equilibrium electron dephasing time, which becomes very short at high voltages and magnetic fields. The relevance of electron-electron interactions is discussed., Comment: 4 pages, 4 figures

Quantum dots are small conductive regions in a semiconductor, containing a variable number of electrons (N=1 to 1000) that occupy well defined discrete quantum states. They are often referred to as artificial atoms with the unique property that they can be connected to current and voltage contacts. This allows one to use transport measurements to probe the discrete energy spectra. To continue the analogy with atoms, two quantum dots can be connected to form an 'artificial molecule'. Depending on the strength of the inter-dot coupling, the two dots can have an ionic binding (i.e. electrons are localized on the individual dots) or a covalent binding (i.e. electrons are delocalized over both dots). The covalent binding leads to a bonding and an anti-bonding state with an energy splitting proportional to the tunnel coupling. In the dc current response to microwave excitation we observe a transition from an ionic bonding to a covalent bonding, when we vary the inter-dot coupling strength. This demonstrates controllable quantum coherence in single electron devices., Comment: 5 pages, accepted by Nature

Glucose tolerance is reported to be impaired in the elderly, and this is said to be mainly due to a decrease in insulin sensitivity (insulin resistance). Insulin resistance is known to be associated with atherosclerosis and coronary artery disease. To clarify whether or not age-dependent changes in glucose tolerance and insulin sensitivity are risk factors for coronary artery disease, as they are in the case of the insulin resistance syndrome, we studied age-dependent changes in glucose tolerance, insulin sensitivity, blood pressure, and serum lipids in a large number of subjects who underwent annual health check-ups, and then studied the relationships between coronary artery disease and aging, insulin sensitivity, and other risk factors in subjects who underwent coronary angiography. Aging was associated with an increased prevalence of noninsulin-dependent diabetes mellitus and impaired glucose tolerance; even in subjects with normal glucose tolerance, plasma glucose levels during an oral glucose tolerance test were significantly higher in the elderly. Insulin sensitivity, as assessed by the ratio of the sum of the plasma glucose divided by the sum of the serum insulin during the test (sigma PG/sigma IRI), was significantly lower in subjects over 60 years old than in younger subjects. Age-dependent impairment of insulin sensitivity and glucose tolerance was associated with increased blood pressure and serum cholesterol levels, but not with changes in boy mass index or serum triglyceride levels. As an independent variable, aging, but not insulin sensitivity, was related to the severity of coronary artery disease. These data suggest that aging is associated with glucose intolerance, insulin resistance, and an increased risk of coronary artery disease, but that the effect of aging on coronary artery disease cannot be explained by insulin resistance alone. Other factors, such as glucose intolerance and increased blood pressure, in addition to insulin resistance, appear to be responsible of the increased risk for coronary artery disease in the elderly.

It has been suggested that loss of heterozygosity (LOH) on the short arm of chromosome 1 is a critical event for the development of neuroblastoma, and we have previously shown frequent LOH on chromosome 14 in neuroblastoma. To pursue these observations, especially to define further the regions which are commonly deleted in the tumor, we examined for allelic losses in 27 cases of neuroblastomas by using a number of polymorphic DNA markers for chromosomes 14q and 1p. LOH was observed in 10 out of the 25 informative cases (40%) on chromosome 14q and in eight out of the 21 informative cases (38%) on 1p. The commonly deleted regions were distal to the D14S13 locus (14q32-qter) on chromosome 14 and distal to the D1S112 locus (1p36.1-pter) on chromosome 1. These results strongly suggest that tumor-suppressor genes important in the pathogenesis of human neuroblastoma are located on the distal part of both chromosomes 14q and 1p.

We performed intratumoral ethanol injection via a flexible bronchofiberscope in 13 patients with malignant tracheobronchial lesions in order to evaluate its effects on airway dilatation and hemostasis. The results obtained are described below. Immediately after intratumoral injection of ethanol, bronchofiberscopic findings revealed that the tumor turned faintly white, there was a little regression of tumor, and a promising effect was demonstrated on patients with bleeding from tumors. The injected tumor turned necrotic within several days, and histological examination revealed no viable tumor cells in necrotic tissues. The histological anti-tumor effect of ethanol was also demonstrated in experiments with nude mice. This endoscopic treatment was very effective in polypoid tumor protruding into the tracheobronchial lumen, but ineffective in the case of compressed stenosis or obstruction. In conclusion, intratumoral injection of ethanol is considered to be a promising endoscopic treatment for malignant tracheobronchial lesions.

Human peripheral blood or lymph node lymphocytes, obtained from patients with a variety of lung cancer, were incubated in vitro with mitomycin C-treated tumor monolayers in the presence of T-cell growth factor. The cytotoxicity of these lymphocytes for autologous tumor cells (autologous killer activity) was assessed by a 4-hr 51Cr-release assay. Cytotoxic activity was observed in 14 out of a total of 20 cases. Lymphocytes from patients with squamous cell carcinoma, large cell carcinoma and carcinoid exhibited positive activity levels of 11.1 +/- 1.8, 16.3 and 23.9% respectively. Nine out of 13 patients with adenocarcinoma exhibited positive activity with a mean value of 8.8 +/- 6.8%. No lymphocyte activity against small cell carcinoma was observed. Natural killer (NK) activity did not always correlate with autologous killer (AK) activity. Treatment of lymphocytes with monoclonal anti-human lymphocyte antibody revealed differences in effector cell populations concerning these two activities; AK activity was abrogated only by treatment with anti-human Lyt 3 antibody and complement, whereas NK activity was abrogated by anti-human Lyt 1, 2 and 3 and partially by anti-human Ia antibody. These results indicate that AK activity is mediated exclusively by T cells, but that NK activity is mediated by several subpopulations of lymphocytes such as T cells, null cells and others.

The Hormonal therapy resistant estrogen-receptor positive metastatic breast cancer cohort (HORSE-BC) study is a multicenter observational study evaluating the efficacy and safety of secondary endocrine therapy (ET) for postmenopausal cases of metastatic breast cancer (MBC) with poor response to primary ET. In this initial report we analyze the HORSE-BC baseline data to clarify the current status of treatment selection for MBC in Japan. Baseline data for the 50 patients enrolled in HORSE-BC were analyzed, including patient characteristics, types of secondary ET, and reasons for selecting secondary ET. Postoperative recurrence was detected in 84% of patients (42/50) and de novo stage IV breast cancer in 16% (8/50). Forty-one patients (41/50; 82%) received fulvestrant, 5 patients (10%) received selective estrogen receptor modulators (SERMs), 3 patients (6%) received ET plus a mammalian target of rapamycin (mTOR) inhibitor, and 1 patient received an aromatase inhibitor (AI) as the secondary ET. Forty-five patients selected their secondary ET based on its therapeutic effect, while 14 patients selected it based on side effects. Most patients with progression after primary ET selected fulvestrant as the secondary ET based on its therapeutic and side effects. We await the final results from the HORSE-BC study.

Bromodomains (BRDs) have emerged as compelling targets for cancer therapy. The development of selective and potent BET (bromo and extra-terminal) inhibitors and their significant activity in diverse tumor models have rapidly translated into clinical studies and have motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of BRD protein complexes complicates predictions of the consequences of their pharmacological targeting. To address this issue, we developed a promiscuous BRD inhibitor [bromosporine (BSP)] that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle, we studied the effects of BSP on leukemic cell lines known to be sensitive to BET inhibition and found, as expected, strong antiproliferative activity. Comparison of the modulation of transcriptional profiles by BSP after a short exposure to the inhibitor resulted in a BET inhibitor signature but no significant additional changes in transcription that could account for inhibition of other BRDs. Thus, nonselective targeting of BRDs identified BETs, but not other BRDs, as master regulators of context-dependent primary transcription response.