Collaborative Research Activities of the Arase and Van Allen Probes.

This paper presents the highlights of joint observations of the inner magnetosphere by the Arase spacecraft, the Van Allen Probes spacecraft, and ground-based experiments integrated into spacecraft programs. The concurrent operation of the two missions in 2017-2019 facilitated the separation of the spatial and temporal structures of dynamic phenomena occurring in the inner magnetosphere. Because the orbital inclination angle of Arase is larger than that of Van Allen Probes, Arase collected observations at higher L -shells up to L ∼ 10 . After March 2017, similar variations in plasma and waves were detected by Van Allen Probes and Arase. We describe plasma wave observations at longitudinally separated locations in space and geomagnetically-conjugate locations in space and on the ground. The results of instrument intercalibrations between the two missions are also presented. Arase continued its normal operation after the scientific operation of Van Allen Probes completed in October 2019. The combined Van Allen Probes (2012-2019) and Arase (2017-present) observations will cover a full solar cycle. This will be the first comprehensive long-term observation of the inner magnetosphere and radiation belts.

Penetration of MeV electrons into the mesosphere accompanying pulsating aurorae.

Pulsating aurorae (PsA) are caused by the intermittent precipitations of magnetospheric electrons (energies of a few keV to a few tens of keV) through wave-particle interactions, thereby depositing most of their energy at altitudes ~ 100 km. However, the maximum energy of precipitated electrons and its impacts on the atmosphere are unknown. Herein, we report unique observations by the European Incoherent Scatter (EISCAT) radar showing electron precipitations ranging from a few hundred keV to a few MeV during a PsA associated with a weak geomagnetic storm. Simultaneously, the Arase spacecraft has observed intense whistler-mode chorus waves at the conjugate location along magnetic field lines. A computer simulation based on the EISCAT observations shows immediate catalytic ozone depletion at the mesospheric altitudes. Since PsA occurs frequently, often in daily basis, and extends its impact over large MLT areas, we anticipate that the PsA possesses a significant forcing to the mesospheric ozone chemistry in high latitudes through high energy electron precipitations. Therefore, the generation of PsA results in the depletion of mesospheric ozone through high-energy electron precipitations caused by whistler-mode chorus waves, which are similar to the well-known effect due to solar energetic protons triggered by solar flares.

Multiple time-scale beats in aurora: precise orchestration via magnetospheric chorus waves.

The brightness of aurorae in Earth's polar region often beats with periods ranging from sub-second to a few tens of a second. Past observations showed that the beat of the aurora is composed of a superposition of two independent periodicities that co-exist hierarchically. However, the origin of such multiple time-scale beats in aurora remains poorly understood due to a lack of measurements with sufficiently high temporal resolution. By coordinating experiments using ultrafast auroral imagers deployed in the Arctic with the newly-launched magnetospheric satellite Arase, we succeeded in identifying an excellent agreement between the beats in aurorae and intensity modulations of natural electromagnetic waves in space called "chorus". In particular, sub-second scintillations of aurorae are precisely controlled by fine-scale chirping rhythms in chorus. The observation of this striking correlation demonstrates that resonant interaction between energetic electrons and chorus waves in magnetospheres orchestrates the complex behavior of aurora on Earth and other magnetized planets.

Prognostic value of quality-of-life scores in patients with breast cancer undergoing preoperative chemotherapy.

Background: Recently, evaluation of quality of life (QOL) has been recognized as a significant outcome measure in the treatment of several cancers. In this study, the Anti-Cancer Drugs-Breast (ACD-B) QOL score was used to assess disease-specific survival in women with breast cancer undergoing preoperative chemotherapy (POC). Methods: QOL-ACD-B scores were evaluated before and after POC. The cut-off value of QOL-ACD-B contributing to events such as relapse or death was calculated by receiver operating characteristic (ROC) curve analysis. Results: In 300 women with breast cancer treated with POC, QOL was significantly reduced (P < 0·001). A high QOL-ACD-B score before POC was an independent factor in the multivariable analysis of overall survival (hazard ratio 0·26, 95 per cent c.i. 0·04 to 0·96). Conclusion: Evaluation by QOL-ACD-B before POC may be useful to predict the prognosis of patients with breast cancer undergoing POC.

Peripheral blood lymphocyte subset repertoires are biased and reflect clinical features in patients with dermatomyositis.

OBJECTIVE: Dermatomyositis (DM) is an idiopathic inflammatory myopathy which often involves the lungs. DM is likely to be associated with aberrant T- and B-cell activation in the pathogenesis because of the proven effectiveness of T- and B-cell-targeted treatments. Assuming that the aberrant activation is reflected by biases in the lymphocyte subset repertoires, we aimed to elucidate these biases, especially in relation to clinical features of DM. METHOD: Based on the immunophenotyping standardized by the Human Immunology Project Consortium, untreated 13 DM patients, including seven patients with interstitial lung disease (ILD), and 18 age-matched healthy donors (HDs) were examined for proportions of peripheral blood lymphocyte subsets. Six DM patients were examined before and after successful induction of remission. RESULTS: Naïve CD4+ T cells and naïve B cells were more abundant, while there were fewer naïve CD8+ T cells, central memory CD8+ T cells, effector memory CD4+ T cells, Th1 cells, Tfh cells, and memory B cells in DM patients than in HDs. When the patients were subgrouped according to the presence of ILD, the lymphocyte subset repertoires in the patients with ILD contributed to the statistical differences in all the biased lymphocyte subset proportions. After treatment, transitional B cells vanished and there was an increase in memory B cells. CONCLUSION: The lymphocyte subset repertoires in the DM patients were biased, and were associated with the presence of ILD and disease activity of DM.

Correction to: Circulating tumor cell clusters-associated gene plakoglobin is a significant prognostic predictor in patients with breast cancer.

[This corrects the article DOI: 10.1186/s40364-017-0099-2.].

Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein for patients with chronic hepatitis B and C: a comparative study.

We compared Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+ -M2BP) levels between patients with chronic hepatitis B (n=249) and chronic hepatitis C (n=386) based on the degree of liver fibrosis. We examined WFA+ -M2BP levels in patients with F4 (cirrhosis), F3 or more (advanced fibrosis) and F2 or more (significant fibrosis) in the two groups. We further examined the relationship between five fibrosis markers and the degree of fibrosis. The WFA+ -M2BP values ranged from 0.25 cut-off index (COI) to 12.9 COI in patients with hepatitis B and 0.34-20.0 COI in patients with hepatitis C (P<.0001). The median WFA+ -M2BP values in F4 in the two groups were 2.83 COI in patients with hepatitis B and 5.03 COI in patients with hepatitis C (P=.0046). The median WFA+ -M2BP values in F3 or more in the two groups were 1.79 COI in patients with hepatitis B and 3.79 COI in patients with hepatitis C (P<.0001). The median WFA+ -M2BP values in F2 or more in the two groups were 1.49 COI in the hepatitis B cohort and 3.19 COI in the hepatitis C group (P<.0001). Among five liver fibrosis markers, WFA+ -M2BP had the highest correlation coefficient (rs =.629) in terms of correlation with the degree of fibrosis in the patients with hepatitis C and had the second highest rs value (.415) in the hepatitis B group. Although WFA+ -M2BP could be a useful indicator of liver fibrosis, WFA+ -M2BP levels in the two groups significantly differed even in the same degree of fibrosis. Individual cut-off values in each aetiology for the degree of fibrosis should be determined.

Tumour-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to neoadjuvant chemotherapy of aggressive breast cancer.

BACKGROUND: Tumour-infiltrating lymphocytes (TILs) can be used to monitor the immune response, and are important in predicting treatment responses and outcomes for various types of cancer. Recently, specific TIL subsets have been reported to be clinically useful in predicting treatment responses. The CD8+/FOXP3+ TIL ratio (CFR) may be a more sensitive indicator for monitoring immune function. This study investigated the clinical significance and value of CFR as a biomarker to predict treatment responses to neoadjuvant chemotherapy for breast cancer. METHODS: Patients with resectable early-stage breast cancer treated with neoadjuvant chemotherapy at Osaka City University Hospital, Japan, between 2007 and 2013 were included. Oestrogen receptor, progesterone receptor, human epidermal growth factor receptor (HER) 2, Ki-67, CD8 and FOXP3 status were assessed by immunohistochemistry, and correlated with pathological complete response (pCR). RESULTS: A total of 177 patients were included, of whom 90 had a high CFR and 87 a low CFR. Triple-negative breast cancer (TNBC) was more common in the high-CFR group than in the low-CFR group (46 versus 23 per cent; P = 0·002), as was HER2-enriched breast cancer (HER2BC) (27 versus 14 per cent; P = 0·033). Among these patients, the pCR rate was significantly higher in the high-CFR group than in the low-CFR group (TNBC: P = 0·022; HER2BC: P < 0·001). In multivariable analysis high-CFR status was an independent predictor of a favourable prognosis: hazard ratio 0·24 (95 per cent c.i. 0·05 to 0·72; P = 0·015) for TNBC and 0·10 (0·10 to 0·90; P = 0·041) for HER2BC. CONCLUSION: The CFR may be a useful biomarker to predict treatment response to neoadjuvant therapy in aggressive breast cancer subtypes, such as TNBC and HER2BC.

Coping strategies and risk of cardiovascular disease incidence and mortality: the Japan Public Health Center-based prospective Study.

AIMS: Coping strategies may be significantly associated with health outcomes. This is the first study to investigate the association between baseline coping strategies and cardiovascular disease (CVD) incidence and mortality in a general population cohort. METHODS AND RESULTS: The Japan Public Health Center-based prospective Study asked questions on coping in its third follow-up survey (2000-04). Analyses on CVD incidence and mortality included 57 017 subjects aged 50-79 without a history of CVD and who provided complete answers on approach- and avoidance-oriented coping behaviours and strategies. Cox regression models, adjusted for confounders, were used to determine hazard ratios (HRs) according to coping style. Mean follow-up time was 7.9 years for incidence and 8.0 years for mortality.The premorbid use of an approach-oriented coping strategy was inversely associated with incidence of stroke (HR = 0.85; 95% CI, 0.73-1.00) and CVD mortality (HR = 0.74; 95% CI, 0.55-0.99). Stroke subtype analyses revealed an inverse association between the approach-oriented coping strategy and incidence of ischaemic stroke (HR = 0.79; 95% CI, 0.64-0.98) and a positive association between the combined coping strategy and incidence of intra-parenchymal haemorrhage (HR = 2.03; 95% CI, 1.01-4.10). Utilizing an avoidance coping strategy was associated with increased mortality from ischaemic heart disease (IHD) only in hypertensive individuals (HR = 3.46; 95% CI, 1.07-11.18). The coping behaviours fantasizing and positive reappraisal were associated with increased risk of CVD incidence (HR = 1.24; 95% CI, 1.03-1.50) and reduced risk of IHD mortality (HR = 0.63; 95% CI, 0.40-0.99), respectively. CONCLUSION: An approach-oriented coping strategy, i.e. proactively dealing with sources of stress, may be associated with significantly reduced stroke incidence and CVD mortality in a Japanese population-based cohort.

c-Kit expression as a prognostic molecular marker in patients with basal-like breast cancer.

BACKGROUND: As patients with basal-like breast cancer (BLBC) have a poor prognosis and there is no specifically tailored therapy, molecular biological characterization of BLBC is necessary. c-Kit is a transmembrane receptor tyrosine kinase known to play important roles in various solid cancers. This study classified BLBCs from patients with breast carcinoma, and addressed the significance of c-Kit expression in these tumours. METHODS: Primary breast tumours were stained with antibodies against oestrogen receptor, progesterone receptor, human epidermal growth factor receptor (HER) 2, epidermal growth factor receptor (EGFR), cytokeratin 5/6 and c-Kit. The association between c-Kit, BLBC and survival was analysed. RESULTS: A total of 667 patients with breast cancer were followed up for a median of 39 (range 6-72) months. Some 190 tumours (28·5 per cent) were classified as triple-negative for breast cancer (negative for oestrogen receptor, progesterone receptor and HER2) and 149 (78·4 per cent) had characteristics of BLBC (positive for cytokeratin 5/6 and/or EGFR). c-Kit expression was detected in 111 (16·6 per cent) of 667 tumours. c-Kit-positive tumours were more commonly found among patients with BLBC (42 of 149, 28·2 per cent; P < 0·001) and in patients with nodal metastasis (47 of 216, 21·8 per cent; P = 0·014) than in those without. In patients with BLBC, the prognosis was significantly worse in those with c-Kit expression (P < 0·001). Multivariable logistic regression analysis revealed c-Kit as an independent negative prognostic factor for cancer-specific survival in patients with BLBC (hazard ratio 2·29, 95 per cent confidence interval 1·11 to 4·72). CONCLUSION: c-Kit might be a prognostic marker and possible molecular target for therapy in patients with BLBC.

Imaging of gastrointestinal absorption and biodistribution of an orally administered probe using positron emission tomography in humans.

The purpose of this study was to establish a method for imaging the process of gastrointestinal (GI) absorption and subsequent biodistribution in the human body after oral drug administration, using positron emission tomography (PET) with 2-[(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG). First, we developed a method to deliver the radiotracer safely into the stomach using soft gelatin capsules to avoid any significant exposure to the pharyngoesophageal region. Second, we performed pharmacokinetic (PK) analyses on time-radioactivity profiles in GI tissues and blood to calculate the gastric emptying and intestinal elimination rate constants and to estimate the fluid volume in the lumen of the small intestine from PET image analysis. This is the first study involving oral administration of a PET probe in humans, and the results demonstrate the high potential of PET technology to investigate the GI absorption and PK profiles of drugs in humans.

Significance of E-cadherin expression in triple-negative breast cancer.

PURPOSE: Triple-negative breast cancer (TNBC), a subtype of breast cancer that is oestrogen receptor (ER) negative, progesterone receptor (PR) negative, and human epidermal growth factor receptor 2 (HER2) negative, has a poor prognosis. Although a correlation between E-cadherin expression level and outcome has been demonstrated among all types of breast cancer, little is known about the significance of E-cadherin expression levels in TNBC. METHODS: A total of 574 patients who had undergone a resection of a primary breast cancer except for invasive lobular carcinomas were enrolled in this study. Expressions of ER, PR, HER2, and E-cadherin were assessed by immunohistochemistry. We examined the association between TNBC and other clinicopathological variables and evaluated the significance of the E-cadherin expression. RESULTS: Among the 574 breast cancer cases, 123 (21.4%) revealed a triple-negative phenotype. Patients with TNBC experienced more frequent lymph node metastasis (P=0.024) and a poorer prognosis (P<0.001) in comparison with non-TNBC patients. Triple-negative breast cancer was an independent prognostic factor. Reduced levels of E-cadherin were observed in 238 (41.5%) of the 574 breast cancer cases. E-cadherin reduction was significantly frequent in cases of TNBC (P<0.001) and lymph node metastasis (P=0.032). Furthermore, in the 123 TNBC cases, the prognosis of patients with an E-cadherin-negative expression was significantly worse than that of E-cadherin-positive patients (P=0.0265), especially for those in clinical stage II (P=0.002). A multivariate logistic regression analysis showed a reduction of the E-cadherin expression to be an independent prognostic factor (P=0.046). CONCLUSION: E-cadherin expression may be a useful prognostic marker for classifying subgroups of TNBC.

Relationship between the isoniazid-resistant mutation katGS315T and the prevalence of MDR-/XDR-TB in Osaka, Japan.

OBJECTIVE: To determine the prevalence of katGS315T mutations in isoniazid (INH) resistant Mycobacterium tuberculosis and to elucidate the association of katGS315T mutations with the prevalence of multidrug-resistant tuberculosis (MDR-TB). DESIGN: From 2001 to 2004, 1655 isolates from all newly registered patients who visited the Osaka Prefectural Medical Centre for Respiratory and Allergic Diseases were tested for drug susceptibility. Genotyping was performed using insertion sequence (IS) 6110-restriction fragment length polymorphism (RFLP) in 1629 of 1655 (98.4%) cases. All 145 isolates of INH-resistant M. tuberculosis, including MDR strains, were tested to detect the katGS315T mutation. RESULTS: Five hundred and sixty isolates (34.4%) shared an RFLP pattern. Of the 145 INH-resistant isolates, 18/48 (37.5%) isolates belonging to the RFLP cluster had katGS315T and 23/97 (23.7%) did not have the mutation. Of the 66 MDR-TB cases, 18/29 (62.1%) isolates belonging to the RFLP cluster had katGS315T and 11/37 (29.7%) did not have the mutation. Of the 29 extensively drug-resistant (XDR) TB cases, 17/21 (80.9%) isolates belonging to the RFLP cluster had katGS315T and 3/8 (37.5%) did not have the mutation. CONCLUSION: The clustering rate by IS6110-RFLP was very high among MDR-/XDR-TB isolates with katGS315T. Our study indicates a strong correlation between the katGS315T mutation and the transmission dynamics of MDR-TB, and especially XDR-TB.

Complete regression of low-grade mucosa-associated lymphoid tissue (MALT) lymphoma in the gastric stump after eradication of Helicobacter pylori.

Recent studies have suggested that Helicobacter pylori (H. pylori)-associated gastritis may play an important role in the pathogenesis of primary gastric lymphoma. Recently, triple therapy using proton pump inhibitor, amoxicillin, and clarithromycin, has been established for the eradication therapy of H. pylori infection, and is also recommended for the treatment of the superficial type of low-grade gastric MALT (mucosa-associated lymphoid tissue ) lymphoma. MALT lymphoma of the gastric stump is rare, and total resection or chemotherapy for MALT lymphoma of the gastric stump has been previously reported. Therefore, there is no evidence that eradication therapy is effective for low-grade MALT lymphoma of the gastric stump. Our case illustrates the remarkable efficacy of eradication of H. pylori for low-grade MALT lymphoma of the gastric stump without other modalities such as surgery and systemic chemotherapy.

Effects of famotidine, mosapride and tandospirone for treatment of functional dyspepsia.

BACKGROUND: An effective therapeutic strategy for functional dyspepsia (FD) has not been well-established. AIM: We investigated and compared the therapeutic effects of famotidine, mosapride and tandospirone for the control of dyspeptic symptoms. METHODS: Fully examined FD patients of outpatient clinics at seven different medical centres were enrolled in the study. They were randomly assigned to three groups based on the type of drug administered: famotidine, mosapride and tandospirone. The effects of treatment over 4 weeks were assessed by visual analogue scales. RESULTS: All of the drugs showed beneficial effects, although famotidine was the most effective for symptom relief, which was significantly greater than tandospirone, while the effect of mosapride was similar to that of famotidine. No subtype of FD showed a better response to a particular type of drug. CONCLUSIONS: For the treatment of FD, famotidine demonstrated the best therapeutic effect, followed by mosapride, while that of tandospirone was significantly lower.

Efficacy of epidermal growth factor receptor-targeted molecular therapy in anaplastic thyroid cancer cell lines.

Anaplastic thyroid cancer is one of the most aggressive human malignancies and the outcomes of conventional therapy have been far from satisfactory. Recently, epidermal growth factor receptor (EGFR)-targeted therapy has been introduced as an alternative therapeutic strategy for highly malignant cancers. This study was undertaken to investigate the expression of EGFR in anaplastic thyroid cancer cell lines, and to explore the potential of therapies targeting EGFR as a new therapeutic approach. EGFR was universally expressed in anaplastic cancer cell lines at a variety of levels. Specific EGFR stimulation with epidermal growth factor showed significant phosphorylation of ERK1/2 and Akt, and resulted in marked growth stimulation in an anaplastic thyroid cancer cell line, which highly expressed EGFR. This EGFR-transmitted proliferation effect of the cancer cell line was completely inhibited by gefitinib, an EGFR tyrosine kinase inhibitor. Moreover, growth of xenografts inoculated in mice was inhibited in a dose-dependent manner with 25-50 mg kg(-1) of gefitinib administrated orally. Inhibition of EGFR-transmitted growth stimulation by gefitinib was clearly observed in anaplastic thyroid cancer cell lines. Our results suggested that EGFR-targeted therapy, such as gefitinib, might be worth further investigation for the treatment of anaplastic thyroid cancer.

A new diglycosyl megastigmane from Carallia brachiata.

A new megastigmane diglycoside was isolated from the leaves of Carallia brachiata. The structure was determined by spectroscopic methods as 3-hydroxy-5,6-epoxy-beta-ionol -3-O-beta-apiofuranosyl-(1-->6)-beta-glucopyranoside (1). Additionally, 29 known compounds consisting of two megastigmanes, one 1,2-dithiolane derivative, seven aromatic compounds, five condensed tannins, 12 flavonoids, and two glyceroglycolipids were isolated and identified.

Ice-water interface migration by temperature controlling for stretching of DNA molecules.

This report shows a new DNA stretching method using migration of an ice-water interface. DNA molecules were stretched accompanying the migration of the solid-liquid interface and immobilized in frozen area. This simple method needs no chemical modification to keep DNA in the stretched form. For full stretching of DNA molecules, one terminus of the DNA molecules were anchored on silanized substrate. The anchored DNA molecules were stretched by freezing the DNA solution. The stretched DNA molecules were observed after sublimation of the frozen solution keeping its stretched form on silanized surface which had no attractive interaction with DNA molecules except for the SH-modified terminus in solution. An infrared (IR) laser beam was introduced to a frozen DNA solution through an objective lens for local area melting of the solution. Scanning of the laser irradiation caused stretching and enclosing of DNA molecules in the frozen area followed by migration of the solid-liquid interface.

Serum CYFRA 21-1 (cytokeratin-19 fragments) is a useful tumour marker for detecting disease relapse and assessing treatment efficacy in breast cancer.

The usefulness of serum CYFRA 21-1 (cytokeratin-19 fragments) in monitoring the recurrence of breast cancer and in evaluating therapeutic effects was studied retrospectively. The sera from 173 patients with primary breast cancer or recurrent disease were measured for CYFRA 21-1, carcinoembryonic antigen (CEA), and carbohydrate antigen 15-3 (CA 15-3) levels. The positive rates of serum CYFRA 21-1 for stage IV (n=12) or recurrent disease (n=26) were 83.3 and 84.6%, respectively, while those of serum CEA were 41.7 and 26.9%, and those of serum CA 15-3 were 83.3 and 34.6%. The elevated preoperative levels of serum CYFRA 21-1 decreased to normal levels after curative operation, whereas the levels remained abnormally high after noncurative operation. There was a significantly high frequency of recurrence in patients with elevated levels of serum CYFRA 21-1 preoperatively compared to those with normal levels of the marker preoperatively. The serum CYFRA 21-1 levels were well correlated with response to chemotherapy. The positive rate of serum CYFRA 21-1 alone was higher than that of an assay combining CEA with CA 15-3, in both primary and recurrent cases (28.8 vs 18.8 and 84.6 vs 46.2%, respectively). These observations suggest that serum CYFRA 21-1 may be a reliable marker of recurrence or therapeutic efficacy.

Development of the walking support robot with the weight bearing mechanism supporting ischia--cushion for ischia and behavior of ischia during walking.

This report describes the cushion suitable for weight bearing mechanism supporting ischia and the behavior of ischia during walking. Hitachi Ltd. developed the power-assisted walking support device and the walk training machine with weight bearing mechanisms using a hip orthosis and a saddle. Because user's weight is centered on symphysis pubica, users feel sore and it is obstacle to smooth walking. Then, we propose a new weight bearing mechanism supporting ischia. Because an interface between human and robot is important, we experimented on the cushion for ischia that is the interface between human and the weight bearing mechanism supporting ischia. In the experiment, we measured seating pressure, the trajectory of the seating pressure's center, position of ischia, and force on the weight bearing arm when a user was walking while locating his hip on the cushion for ischia. The result shows that the seating cushion is suited for the interface, but it is also necessary to support separately each ischium's up down movement and rotating movement during walking.