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1.  Effects of exercise and horticultural intervention on the brain and mental health in older adults with depressive symptoms and memory problems: study protocol for a randomized controlled trial [UMIN000018547] 
Trials  2015;16:499.
Background
Depressive symptoms and memory problems are significant risk factors for dementia. Exercise can reduce depressive symptoms and improve cognitive function in older people. In addition, the benefits of horticultural activity on physical and mental well-being have been demonstrated in people with dementia. Although evidence of such non-pharmacological interventions is mounting, no studies have examined whether physical exercise and horticultural activity exert a positive impact on brain and mental health (e.g., depressive symptoms) in non-demented older adults at high risk of cognitive impairment and depression. Therefore, we propose a randomized controlled trial to assess the efficacy and efficiency of physical exercise and horticultural activity in improving brain and mental health in community-dwelling older adults with memory problems and depressive symptoms.
Methods/Design
The 20-week randomized controlled trial will include 90 community-dwelling adults aged 65 years or older with memory problems and depressive symptoms. Participants will be randomized to one of three experiments: exercise, horticultural activity, or educational control group, using a 1:1:1 allocation ratio. The combined exercise program and horticultural activity program will consist of 20 weekly 90-minute sessions. Participants in the exercise group will practice aerobic exercise, muscle strength training, postural balance retraining, and dual-task training. The horticultural activity program will include crop-related activities, such as field cultivation, growing, and harvesting. Participants in the educational control group will attend two 90-minute educational classes during the 6-month trial period. Depressive symptoms and memory performance will be measured by the Geriatric Depression Scale-15, and the Logical Memory subtests of the Wechsler Memory Scale-Revised will be used to measure depressive symptoms and memory performance as primary outcomes, at baseline (prior to randomization), immediately following intervention (6 months from baseline), and 6 months after intervention. Hippocampal volume will be measured at baseline and immediately after intervention, using magnetic resonance imaging. Secondary outcomes will comprise cognitive function, including language, attention/executive performance, and processing speed; brain-derived neurotrophic-factor serum levels; and health-related quality of life.
Discussion
This intervention study will determine the clinical importance and efficacy of physical exercise and horticultural activity as non-pharmacological interventions in community-dwelling older adults at high risk of poor brain and mental health.
Trial registration
UMIN000018547; registered 7 August 2015.
doi:10.1186/s13063-015-1032-3
PMCID: PMC4634591  PMID: 26537979
Cognition; Depression; Exercise; Hippocampal volume; Horticulture
2.  Set-Shifting Ability Is Associated with Gray Matter Volume in Older People with Mild Cognitive Impairment 
Background/Aims
An understanding of the association between gray matter volume and executive functioning could provide strategies to reduce dementia risk in older people with mild cognitive impairment (MCI).
Methods
In a cross-sectional analysis, we assessed executive functioning in 83 older people with MCI using three standard neuropsychological tests: set shifting (difference between Trail Making Test Parts B and A), working memory (difference between Digit Span forward and backward from the Wechsler Adult Intelligence Scale-IV), and selective attention/response inhibition (difference between the second and third conditions of the color- and picture-word Stroop test). Gray matter volume was computed from brain MRIs and SIENAX from FSL software.
Results
Gray matter volume was significantly associated with set-shifting performance after accounting for age, gender, body mass index, education, and global cognition (standardized β = −0.376, p = 0.001), but not with working memory or selective attention/response inhibition.
Conclusion
The executive function of set-shifting ability was correlated with gray matter volume in older people with MCI.
doi:10.1159/000438721
PMCID: PMC4662337  PMID: 26628898
Gray matter; Executive functioning; Mild cognitive impairment
3.  Impact of physical frailty on disability in community-dwelling older adults: a prospective cohort study 
BMJ Open  2015;5(9):e008462.
Objective
To examine the relationship between physical frailty and risk of disability, and to identify the component(s) of frailty with the most impact on disability in community-dwelling older adults.
Design
Prospective cohort study.
Setting
A Japanese community.
Participants
4341 older adults aged ≥65 living in the community participated in a baseline assessment from 2011 to 2012 and were followed for 2 years.
Main outcome measures
Care-needs certification in the national long-term care insurance (LTCI) system of Japan, type of physical frailty (robust, prefrail, frail) and subitems (slowness, weakness, exhaustion, low activity, weight loss), adjusted for several potential confounders such as demographic characteristics, analysed with Kaplan-Meier survival curves for incidence of disability by frailty phenotype.
Results
During the 2-year follow-up period, 168 participants (3.9%) began using the LTCI system for incidence of disability. Participants classified as frail (HR 4.65, 95% CI 2.63 to 8.22) or prefrail (2.52, 1.56 to 4.07) at the baseline assessment had an increased risk of disability incidence compared with robust participants. Analyses for subitems of frailty showed that slowness (2.32, 1.62 to 3.33), weakness (1.90, 1.35 to 2.68) and weight loss (1.61, 1.13 to 2.31) were related to increased risk of disability incidence. In stratified analyses, participants who were classified as frail and who had lower cognitive function had the highest percentage (30.3%) of disability incidence during the 2 years after baseline assessment.
Conclusions
Physical frailty, even being prefrail, had a strong impact on the risk of future disability. Some components of frailty, such as slowness, weakness and weight loss, are strongly associated with incident disability in community-dwelling older adults.
doi:10.1136/bmjopen-2015-008462
PMCID: PMC4563225  PMID: 26338685
Frailty; Disability; Slowness
4.  Neuroblastoma - Undifferentiated Subtype, Prognostic Significance of Prominent Nucleolar Formation and MYC/MYCN Protein Expression: A Report from the Children’s Oncology Group 
Cancer  2013;119(20):3718-3726.
Purpose
To investigate biological/clinicopathological characteristics of neuroblastoma, undifferentiated subtype (NBUD).
Patients and Methods
157 NBUD cases filed at the Children’s Oncology Group Neuroblastoma Pathology Reference Laboratory were studied, and survival rates of the patients were analyzed with known prognostic factors. Immunostainings for MYCN and MYC protein were performed on 68 tumors.
Results
NBUD cases had a poor prognosis (48.4±5.0% 3-year event-free survival [EFS]; 56.5±5.0% overall survival), and were often associated with high Mitosis-Karyorrhexis Index (MKI, 65%), prominent nucleoli (PN, 83%), ≥18months of age (75%), MYCN amplification (MYCN-A, 83%), diploid pattern (63%), and 1pLOH (loss of heterozygosity, 72%). However, these prognostic indicators, except for MYCN status, had no significant impact on survival. Surprisingly, EFS for patients with MYCN-A tumors (53.4±5.6%) was significantly better (P=0.0248) than for patients with MYCN-Non-Amplified (MYCN-NA) tumors (31.7±11.7%), with MYCN-NA and PN (+) tumors having the worst prognosis (9.3+8.8%, p=0.0045). Immunohistochemically, MYCN expression was found in 42/48 MYCN-A tumors. In contrast, MYC expression was almost exclusively found in the MYCN-NA tumors (9/20) especially when they had PN (8/11). Those patients with only MYC-positive tumors had the worst EFS (N=8, 12.5±11.7%) compared with only MYCN-positive (N=39, 49.9±17.7%) and both negative tumors (N=15, 70.0±17.1%) (P=0.0029). High MKI was often found in only MYCN-positive (30/38) but rarely in only MYC-positive (2/8) tumors.
Conclusions
NBUD represents a unique subtype of neuroblastoma associated with a poor prognosis. In this subtype, MYC protein expression may be a new prognostic factor indicating more aggressive clinical behavior than MYCN amplification and subsequent MYCN protein expression.
doi:10.1002/cncr.28251
PMCID: PMC4554323  PMID: 23901000
Neuroblastoma; undifferentiated subtype; MYCN Amplification; MYC/MYCN expression; prognostic factors; MYC gene expression
5.  Lifestyle-Related Factors Contributing to Decline in Knee Extension Strength among Elderly Women: A Cross-Sectional and Longitudinal Cohort Study 
PLoS ONE  2015;10(7):e0132523.
This cross-sectional and 4-year longitudinal cohort study aimed to clarify how various lifestyle-related variables affect knee extension strength in elderly Japanese women. The participants were community-dwelling women (n = 575) living in the Itabashi Ward of Tokyo, Japan aged 75–85 years at baseline (in 2008) who returned for a follow-up examination 4 years later (in 2012). Maximum isometric knee extension strength in the dominant leg was measured during comprehensive medical check-ups at baseline and follow-up. Interviews with participants included questions on their history of 11 diseases and lifestyle-related factors such as physical activity as well as dietary, smoking, and drinking habits. Cross-sectional and longitudinal analyses yielded inconsistent results regarding the associations between lifestyle-related factors and knee extension strength. While going out more frequently and regular physical exercise positively affected baseline knee extension strength, they did not affect knee extension strength in the longitudinal analysis. The longitudinal analysis revealed that more frequent intake of soy products or green and yellow vegetables at baseline decreased age-related knee extension strength decline. The inconsistent results from the cross-sectional and longitudinal analyses indicate that conducting both types of analyses is crucial for researching this type of subject. The present study demonstrates that the age-related decline in muscle strength is lower in those who frequently eat soy products or green and yellow vegetables. Thus, recommending higher intake of soy products, and green and yellow vegetables for the elderly might help maintain their muscle health.
doi:10.1371/journal.pone.0132523
PMCID: PMC4503692  PMID: 26177292
6.  Validation of a Prognostic Multi-gene Signature in High-risk Neuroblastoma using the High Throughput Digital NanoString nCounter™ System 
Molecular oncology  2014;8(3):669-678.
Microarray-based molecular signatures have not been widely integrated into neuroblastoma diagnostic classification systems due to the complexities of the assay and requirement for high-quality RNA. New digital technologies that accurately quantify gene expression using RNA isolated from formalin-fixed paraffin embedded (FFPE) tissues are now available. In this study, we describe the first use of a high-throughput digital system to assay the expression of genes in an “ultra-high risk” microarray classifier in FFPE high-risk neuroblastoma tumors. Customized probes corresponding to the 42 genes in a published multi-gene neuroblastoma signature were hybridized to RNA isolated from 107 FFPE high-risk neuroblastoma samples using the NanoString nCounter™ Analysis System. For classification of each patient, the Pearson’s correlation coefficient was calculated between the standardized nCounter™ data and the molecular signature from the microarray data. We demonstrate that the nCounter™ 42-gene panel sub-stratified the high-risk cohort into two subsets with statistically significantly different overall survival (p=0.0027) and event-free survival (p=0.028). In contrast, none of the established prognostic risk markers (age, stage, tumor histology, MYCN status, and ploidy) were significantly associated with survival. We conclude that the nCounter™ System can reproducibly quantify expression levels of signature genes in FFPE tumor samples. Validation of this microarray signature in our high-risk patient cohort using a completely different technology emphasizes the prognostic relevance of this classifier. Prospective studies testing the prognostic value of molecular signatures in high-risk neuroblastoma patients using FFPE tumor samples and the nCounter™ System are warranted.
doi:10.1016/j.molonc.2014.01.010
PMCID: PMC4004665  PMID: 24560446
High-risk neuroblastoma; gene signature; molecular classifier; NanoString; nCounter
7.  MYCN-dependent Expression of Sulfatase-2 Regulates Neuroblastoma Cell Survival 
Cancer research  2014;74(21):5999-6009.
Heparan sulfate proteoglycans (HSPGs) play a critical role in the interaction of tumor cells and their microenvironment. HSPG activity is dictated by sulfation patterns controlled by sulfotransferases, which add sulfate groups, and sulfatases (Sulfs), which remove 6-O-sulfates. Here we report altered expression of these enzymes in human neuroblastoma cells with higher levels of Sulf-2 expression a specific feature of MYCN-amplified cells (MYCN-A cells) that represent a particularly aggressive subclass. Sulf-2 overexpression in neuroblastoma cells lacking MYCN amplification (MYCN-NA cells) increased their in vitro survival. Mechanistic investigations revealed evidence of a link between Sulf-2 expression and MYCN pathogenicity in vitro and in vivo. Analysis of Sulf-2 protein expression in 65 human neuroblastoma tumors demonstrated a higher level of Sulf-2 expression in MYCN-A tumors than in MYCN-NA tumors. In two different patient cohorts, we confirmed the association in expression patterns of Sulf-2 and MYCN and determined that Sulf-2 overexpression predicted poor outcomes in a non-independent manner with MYCN. Our findings define Sulf-2 as a novel positive regulator of neuroblastoma pathogenicity that contributes to MYCN oncogenicity.
doi:10.1158/0008-5472.CAN-13-2513
PMCID: PMC4216758  PMID: 25164011
neuroblastoma; MYCN; Sulfatase-2; heparan sulfate
8.  Imatinib use immediately before stem cell transplantation in children with Philadelphia chromosome-positive acute lymphoblastic leukemia: Results from Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Study Ph+ALL04 
Cancer Medicine  2015;4(5):682-689.
Incorporation of imatinib into chemotherapeutic regimens has improved the prognosis of children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). We investigated a role of imatinib immediately before hematopoietic stem cell transplantation (HSCT). Children with Ph+ALL were enrolled on JPLSG Ph+ALL 04 Study within 1 week of initiation of treatment for ALL. Treatment regimen consisted of Induction phase, Consolidation phase, Reinduction phase, 2 weeks of imatinib monotherapy phase, and HSCT phase (Etoposide+CY+TBI conditioning). Minimal residual disease (MRD), the amount of BCR–ABL transcripts, was measured with the real-time PCR method. The study was registered in UMIN-CTR: UMIN ID C000000290. Forty-two patients were registered and 36 patients (86%) achieved complete remission (CR). Eight of 17 patients (47%) who had detectable MRD at the beginning of imatinib monotherapy phase showed disappearance or decrease in MRD after imatinib treatment. Consequently, 26 patients received HSCT in the first CR and all the patients had engraftment and no patients died because of complications of HSCT. The 4-year event-free survival rates and overall survival rates among all the 42 patients were 54.1 ± 7.8% and 78.1 ± 6.5%, respectively. Four of six patients who did achieve CR and three of six who relapsed before HSCT were salvaged with imatinib-containing chemotherapy and subsequently treated with HSCT. The survival rate was excellent in this study although all patients received HSCT. A longer use of imatinib concurrently with chemotherapy should eliminate HSCT in a subset of patients with a rapid clearance of the disease.
doi:10.1002/cam4.383
PMCID: PMC4430261  PMID: 25641907
Ph+ALL; children; imatinib; HSCT; MRD
9.  Cognitive Functioning and Walking Speed in Older Adults as Predictors of Limitations in Self-Reported Instrumental Activity of Daily Living: Prospective Findings from the Obu Study of Health Promotion for the Elderly 
Our aim was to determine whether baseline measures of cognitive functioning, walking speed, and depressive status are independent predictors of limitations in instrumental activities of daily living (IADL) in older adults. The cross-sectional study involved 1329 community-dwelling adults, aged 75 years or older. At baseline, the Mini-Mental State Examination (MMSE), Symbol Digit Substitution Test (SDST), Geriatric Depressive Scale (GDS), and a word list memory task were completed, and self-reported IADLs and walking speed were recorded. The longitudinal study involved 948 participants without baseline IADL limitation, which was assessed at baseline and 15-month follow up, using the three Kihon Checklist subitems. In cross-sectional analyses, participants with IADL limitation demonstrated greater GDS scores, slower walking speeds, and lower MMSE, word list memory task, and SDST (only for women) scores relative to those without IADL limitation. In the longitudinal analyses, baseline walking speed (men: OR 0.98; women: OR 0.97, p < 0.05) and word list memory task scores (men: OR 0.84; women: OR 0.83, p < 0.05) in both sexes and SDST scores in women (OR 0.96, p = 0.04) were independent predictors of subsequent IADL limitation. Walking speed, memory, and processing speed may be independent predictors of IADL limitation in older adults.
doi:10.3390/ijerph120303002
PMCID: PMC4377948  PMID: 25768239
instrumental activities of daily living; memory; processing speed; walking speed
10.  Age-Dependent Prognostic Effect by Mitosis-Karyorrhexis Index in Neuroblastoma: A Report from the Children’s Oncology Group 
Prognostic effects of Mitosis-Karyorrhexis Index (MKI) used in the International Neuroblastoma Pathology Classification (INPC) are age-dependent. A total of 4,282 neuroblastomas reviewed at the Children’s Oncology Group Neuroblastoma Pathology Reference Laboratory (8/1/2001–3/31/2012) included 2,365 low-MKI (L-MKI), 1,068 intermediate-MKI (I-MKI), and 849 high-MKI (H-MKI) tumors. Cox proportional hazards models were fit to determine age cut-offs at which the relative risk of event/death was maximized in each MKI class. Backward-selected Cox models were fit to determine the prognostic strength of the age cut-offs for survival in the presence of other prognostic factors. The age cut-offs used in the INPC for L-MKI tumors (<60 months, n = 2,710, 84.0% ± 1.0% event-free survival [EFS], 93.8 ± 0.7% overall survival [OS] vs ≥60 months, n = 195, 49.8% ± 4.6% EFS, 71.7% ± 4.1% OS; P < 0.0001) and I-MKI tumors (<18 months, n = 568, 83.8% ± 2% EFS, 93.7% ± 1.3% OS vs ≥18 months, n = 500, 51.4% ± 2.9% EFS, 66.7% ± 2.7% OS; P < 0.0001) were within the effective range for distinguishing prognostic groups. As for H-MKI tumors (no cut-off age in the INPC, 51.0% ± 2.2% EFS, 64.4% ± 2.1% OS), a new cut-off of 3–4 months was suggested (<4 months, n = 38, 82.3% ± 8.4% EFS, 81.8% ± 8.5% OS vs ≥4 months, n = 811, 49.6% ± 2.2% EFS, 63.7% ± 2.1% OS, P = 0.0034 and 0.0437, respectively). Multivariate analyses revealed that cut-offs of 60 and 18 months for L-MKI and I-MKI tumors, respectively, were independently prognostic. However, the cut-off of 4 months for H-MKI tumors did not reach statistical significance in the presence of other factors. The age cut-offs for MKI classes (60 months for L-MKI, 18 months for I-MKI, no cut-off for H-MKI) in the current INPC are reasonable and effective for distinguishing prognostic groups with increased risk of event/death for older patients.
doi:10.2350/14-06-1505-OA.1
PMCID: PMC4340697  PMID: 25207821
age cut-off; International Neuroblastoma Pathology Classification; mitosis-karyorrhexis index; neuroblastoma; prognosis
11.  Self-reported Exhaustion is Associated with Small Life Space in Older Adults with Mild Cognitive Impairment 
Journal of Physical Therapy Science  2014;26(12):1979-1983.
[Purpose] Older adults experience exhaustion-induced health problems, such as poor physical function and low physical activity levels. The associations between self-reported exhaustion and physical function and activity are not clear in older adults with mild cognitive impairment (MCI). The aim of this study was to investigate the relationships between self-reported exhaustion and physical function and activity in older adults with mild cognitive impairment. [Subjects] A total of 356 older adults with mild cognitive impairment (mean age = 71.6 ± 0.3 years, 50.8% women) were included in this study. [Methods] Self-reported exhaustion was identified by one item from the Study of Osteoporotic Fractures index. Gait speed, gait endurance, and life space were also assessed. [Results] Sixty-two participants reported having exhaustion, giving a 17.4% prevalence of self-reported exhaustion among these individuals. Logistic regression analysis showed that the Life-Space Assessment score was the only parameter significantly independently associated with exhaustion status (adjusted odds ratio 0.97, 95% confidence interval 0.95–0.99). [Conclusion] These results suggest that self-reported exhaustion is associated with life space. Future research is needed to identify ways for older people with MCI to improve their exhaustion status.
doi:10.1589/jpts.26.1979
PMCID: PMC4273072  PMID: 25540512
Mild cognitive impairment; Self-reported exhaustion; Life space
12.  Phase I Trial of Fenretinide Delivered Orally in a Novel Organized Lipid Complex in Patients with Relapsed/Refractory Neuroblastoma: A Report from the New Approaches to Neuroblastoma Therapy (NANT) Consortium 
Pediatric blood & cancer  2013;60(11):1801-1808.
Background
A phase I study was conducted to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of fenretinide (4-HPR) delivered in an oral powderized lipid complex (LXS) in patients with relapsed/refractory neuroblastoma.
Procedure
4-HPR/LXS powder (352 - 2210 mg/m2/day) was administered on Days 0 – 6, in 21-day courses, by standard 3+3 design.
Results
Thirty-two patients (median age = 8 years, range 3 – 27 years) enrolled with thirty evaluable for dose escalation. Prior therapies included stem cell transplantation/support (n = 26), 13-cis-retinoic acid (n = 22), 125/131I-MIBG (n = 13), and anti-GD2 antibody (n = 6). 170+ courses were delivered. Course 1 DLTs were a Grade 3 (n = 1) alkaline phosphatase at 352 mg/m2/day. Other major toxicities were Grade 4 (n = 1) alkaline phosphatases on Courses 5 and 6 at 774 mg/m2/day, and Grade 3 (n = 1) ALT/AST elevation on Course 2 at 1700 mg/m2/day. Of twenty-nine response-evaluable patients, six had stable disease (SD)(4 – 26 courses); four with marrow- or bone disease-only had complete responses (CR)(10 - 46 courses). 4-HPR plasma levels were several fold higher (P<0.05) than previously reported using capsular fenretinide. The Day 6 mean peak 4-HPR plasma level at 1700 mg/m2/day was 21 μM. An MTD was not reached.
Conclusions
4-HPR/LXS oral powder obtained higher plasma levels, with minimal toxicity and evidence of anti-tumor activity, than a previous capsule formulation. A recommended phase II schedule of 4-HPR/LXS powder is 1500 mg/m2/day, TID, on Days 0 – 6, of a 21-day course.
doi:10.1002/pbc.24643
PMCID: PMC4066886  PMID: 23813912
fenretinide; neuroblastoma; pediatric; powder; Lym-X-Sorb™
13.  The lost intrinsic fragmentation of MAT1 protein during granulopoiesis promotes the growth and metastasis of leukemic myeloblasts 
Stem cells (Dayton, Ohio)  2013;31(9):1942-1953.
MAT1, an assembly factor and targeting subunit of both cyclin-dependent kinase-activating kinase (CAK) and general transcription factor IIH (TFIIH) kinase, regulates cell cycle and transcription. Previous studies show that expression of intact MAT1 protein is associated with expansion of human hematopoietic stem cells (HSC), whereas intrinsically programmed or retinoic acid (RA)-induced MAT1 fragmentation accompanies granulocytic differentiation of HSC or leukemic myeloblasts. Here we determined that, in humanized mouse microenvironment, MAT1 overexpression resisted intrinsic MAT1 fragmentation to sustain hematopoietic CD34+ cell expansion while preventing granulopoiesis. Conversely, we mimicked MAT1 fragmentation in vitro and in a mouse model by overexpressing a fragmented 81-aa MAT1 polypeptide (pM9) that retains the domain for assembling CAK but cannot affix CAK to TFIIH-core. Our results showed that pM9 formed ΔCAK by competing with MAT1 for CAK assembly to mimic MAT1 fragmentation-depletion of CAK. This resulting ΔCAK acted as a dominant negative to inhibit the growth and metastasis of different leukemic myeloblasts, with or without RA-resistance, by concurrently suppressing CAK and TFIIH kinase activities to inhibit cell cycle and gene transcription. These findings suggest that the intrinsically programmed MAT1 expression and fragmentation regulate granulopoiesis by inversely coordinating CAK and TFIIH activities, whereas pM9 shares a mechanistic resemblance with MAT1 fragmentation in suppressing myeloid leukemogenesis.
doi:10.1002/stem.1444
PMCID: PMC3795903  PMID: 23765726
C-terminal fragmentation of MAT1; retinoid signaling; CAK-coordinated cell cycle and transcription; TFIIH kinase; myeloid leukemia
14.  CRITICAL ROLE OF STAT3 IN IL-6-MEDIATED DRUG RESISTANCE IN HUMAN NEUROBLASTOMA 
Cancer research  2013;73(13):3852-3864.
Drug resistance is a major cause of treatment failure in cancer. Here we have evaluated the role of STAT3 in environment-mediated drug resistance (EMDR) in human neuroblastoma. We determined that STAT3 was not constitutively active in most neuroblastoma cell lines but was rapidly activated upon treatment with interleukin-6 (IL-6) alone and in combination with the soluble IL-6 receptor (sIL-6R). Treatment of neuroblastoma cells with IL-6 protected them from drug-induced apoptosis in a STAT3-dependent manner because the protective effect of IL-6 was abrogated in the presence of a STAT3 inhibitor and upon STAT3 knockdown. STAT3 was necessary for the upregulation of several survival factors such as survivin (BIRC5) and Bcl-xL (BCL2L1) when cells were exposed to IL-6. Importantly, IL-6-mediated STAT3 activation was enhanced by sIL-6R produced by human monocytes, pointing to an important function of monocytes in promoting IL-6-mediated EMDR. Our data also point to the presence of reciprocal activation of STAT3 between tumor cells and bone marrow stromal cells including not only monocytes but also Treg cells and non-myeloid stromal cells. Thus, the data identify an IL-6/sIL-6R/STAT3 interactive pathway between neuroblastoma cells and their microenvironment that contributes to drug resistance.
doi:10.1158/0008-5472.CAN-12-2353
PMCID: PMC3740971  PMID: 23633489
Interleukin-6; STAT3; drug resistance; neuroblastoma; tumor microenvironment
15.  Acquisition process of typing skill using hierarchical materials in the Japanese language 
In the present study, using a new keyboard layout with only eight keys, we conducted typing training for unskilled typists. In this task, Japanese college students received training in typing words consisting of a pair of hiragana characters with four keystrokes, using the alphabetic input method, while keeping the association between the keys and typists’ finger movements; the task was constructed so that chunking was readily available. We manipulated the association between the hiragana characters and alphabet letters (hierarchical materials: overlapped and nonoverlapped mappings). Our alphabet letter materials corresponded to the regular order within each hiragana word (within the four letters, the first and third referred to consonants, and the second and fourth referred to vowels). Only the interkeystroke intervals involved in the initiation of typing vowel letters showed an overlapping effect, which revealed that the effect was markedly large only during the early period of skill development (the effect for the overlapped mapping being larger than that for the nonoverlapped mapping), but that it had diminished by the time of late training. Conversely, the response time and the third interkeystroke interval, which are both involved in the latency of typing a consonant letter, did not reveal an overlapped effect, suggesting that chunking might be useful with hiragana characters rather than hiragana words. These results are discussed in terms of the fan effect and skill acquisition. Furthermore, we discuss whether there is a need for further research on unskilled and skilled Japanese typists.
doi:10.3758/s13414-014-0693-4
PMCID: PMC4137159  PMID: 24874261
Acquisition of typing skill; Priming; Japanese language; Typewriting; Fan effect; Chunking; Mora
16.  Cognitive function and gait speed under normal and dual-task walking among older adults with mild cognitive impairment 
BMC Neurology  2014;14:67.
Background
Gait ability and cognitive function are interrelated during both normal walking (NW) and dual-task walking (DTW), and gait ability is thus adversely affected by cognitive impairment in both situations. However, this association is insufficiently understood in people with mild cognitive impairment (MCI). Here, we conducted a study with MCI participants, to examine whether the association depends on walking conditions and MCI subtypes.
Methods
We classified 389 elderly adults into amnestic MCI (n = 191) and non-amnestic MCI (n = 198), assessed their cognitive functions, and administered gait experiments under NW and DTW conditions. Gait ability was defined as gait speed. Five aspects of cognitive function were assessed: processing speed, executive function, working memory, verbal memory, and visual memory.
Results
Regression analysis adjusted for covariates showed a significant association between cognitive functions and gait speed. Processing speed and executive function correlated with gait speed during both NW and DTW (p < .05). Gait speed during DTW was also significantly associated with working memory (p < .001). Visual memory was associated during NW and DTW, particularly for amnestic MCI participants (p < .05).
Conclusions
Our findings support the idea that the association between gait speed and cognitive function depends on walking condition and MCI subtypes. Additional studies are necessary to determine the neural basis for the disruption in gait control in older adults with MCI.
doi:10.1186/1471-2377-14-67
PMCID: PMC3994221  PMID: 24694100
17.  Human osteosarcoma CD49f−CD133+ cells: impaired in osteogenic fate while gain of tumorigenicity 
Oncogene  2012;32(36):4252-4263.
The biological relationships among self-renewal, tumorigenicity, and lineage differentiation of human osteosarcoma-initiating cells (OSIC) remain elusive, making it difficult to identify and distinguish OSIC from osteosarcoma-forming cells (OSFC) for developing OSIC-targeted therapies. Using a new inverse lineage tracking strategy coupled with serial human-to-mouse xenotransplantation, we identified a subpopulation of osteosarcoma cells with OSIC-like properties and sought to distinguish them from their progeny, OSFC. We found that serial transplantation of cells from different osteosarcoma cell lines and primary osteosarcoma tissues progressively increased the CD49f+ subpopulation composing the bulk of the osteosarcoma mass. These CD49f+ cells displayed characteristics of OSFC: limited in vivo tumorigenicity, weak lineage differentiation, more differentiated osteogenic feature, and greater chemo-sensitivity. By contrast, their parental CD49f−CD133+ cells had an inhibited osteogenic fate, together with OSIC-like properties of self-renewal, strong tumorigenicity, and differentiation to CD49f+ progeny. Hence, the CD49f−CD133+ phenotype appears to identify OSIC-like cells that possess strong tumorigenicity correlated with an impaired osteogenic fate and the ability to initiate tumor growth through generation of CD49f+ progeny. These findings advance our understanding of OSIC-like properties and, for the first time, provide a much-needed distinction between OSIC and OSFC in this cancer.
doi:10.1038/onc.2012.438
PMCID: PMC3947577  PMID: 23045288
Osteosarcoma-initiating cells; self-renewal; tumorigenicity; lineage differentiation; osteosarcoma-forming cells; osteogenic differentiation
18.  Peripheral Neuroblastic Tumors with Genotype-Phenotype Discordance: A Report from the Children’s Oncology Groupand the International Neuroblastoma Pathology Committee 
Pediatric blood & cancer  2012;60(3):363-370.
Background
Of 4,706 peripheral neuroblastic tumors (pNTs) registered on the Children’s Cancer Group and Children’s Oncology Group Neuroblastoma Study between 1989 and 2010, 51 cases (1.1%) had genotype-phenotype discordance characterized by MYCN amplification (indicating poor prognosis) and Favorable Histology (indicating better prognosis).
Procedure
To distinguish prognostic subgroups in the genotype-phenotype discordant pNTs, two subgroups, “conventional” and “bull’s eye”, were identified based on the nuclear morphology. The “conventional” tumors (35 cases) included: Neuroblastoma, Poorly differentiated subtype (NB-PD, 26 cases) with “salt-and-pepper” nuclei; Neuroblastoma, Differentiating subtype (4 cases); Ganglioneuroblastoma, Intermixed (3 cases); and Ganglioneuroma, Maturing subtype (2 cases). The “bull’s eye” tumors included NB-PD with prominent nucleoli (16 cases). Clinicopathologic characteristics of these two subgroups were analyzed. N-myc protein expression was tested immunohistochemically on available tumors.
Results
No significant difference was found between these two subgroups in the distribution of prognostic factors such as age at diagnosis, clinical stage, histopathology category/subtype, mitosis-karyorrhexis index, ploidy, 1p LOH, and unbalanced 11qLOH. However, prognosis of the patients with “conventional” tumors (5-year EFS 85.7±12.2%; OS 89.3±10.3%) was significantly better than those with “bull’s eye” tumors (EFS 31.3±13.0%; OS 42.9±16.2%) (P=0.0010 and 0.0008, respectively). Immunohistochemically all (11/11) tested “conventional” tumors were negative, and 10/11 tested “bull’s eye” tumors were positive for N-myc protein expression.
Conclusions
Based on the presence or absence of prominent nucleoli (the putative site of RNA synthesis/accumulation leading to N-myc protein expression), two prognostic subgroups, “conventional” with a better prognosis and “bull’s eye” with a poor prognosis, were distinguished among the genotype-phenotype discordant pNTs.
doi:10.1002/pbc.24238
PMCID: PMC3397468  PMID: 22744966
neuroblastoma; International Neuroblastoma Pathology Classification; MYCN; genotype-phenotype correlation; prognosis; immunohistochemistry
19.  E-Cadherin Cell-Cell Adhesion in Ewing Tumor Cells Mediates Suppression of Anoikis through Activation of the ErbB4 Tyrosine Kinase 
Cancer research  2007;67(7):3094-3105.
Ability to grow under anchorage-independent conditions is one of the major hallmarks of transformed cells. Key to this is the capacity of cells to suppress anoikis, or programmed cell death induced by detachment from the extracellular matrix. To model this phenomenon in vitro, we plated Ewing tumor cells under anchorage-independent conditions by transferring them to dishes coated with agar to prevent attachment to underlying plastic. This resulted in marked up-regulation of E-cadherin and rapid formation of multicellular spheroids in suspension. Addition of calcium chelators, antibodies to E-cadherin (but not to other cadherins or β1-integrin), or expression of dominant negative E-cadherin led to massive apoptosis of spheroid cultures whereas adherent cultures were unaffected. This correlated with reduced activation of the phosphatidylinositol 3-kinase-Akt pathway but not the Ras-extracellular signal–regulated kinase 1/2 cascade. Furthermore, spheroid cultures showed profound chemoresistance to multiple cytotoxic agents compared with adherent cultures, which could be reversed by α-E-cadherin antibodies or dominant negative E-cadherin. In a screen for potential downstream effectors of spheroid cell survival, we detected E-cadherin–dependent activation of the ErbB4 receptor tyrosine kinase but not of other ErbB family members. Reduction of ErbB4 levels by RNA interference blocked Akt activation and spheroid cell survival and restored chemosensitivity to Ewing sarcoma spheroids. Our results indicate that anchorage-independent Ewing sarcoma cells suppress anoikis through a pathway involving E-cadherin cell-cell adhesion, which leads to ErbB4 activation of the phosphatidylinositol 3-kinase-Akt pathway, and that this is associated with increased resistance of cells to cytotoxic agents.
doi:10.1158/0008-5472.CAN-06-3259
PMCID: PMC3906735  PMID: 17409416
suppression of anoikis; E-cadherin; ErbB4; EWS-FLI1; Ewing tumor
20.  A Large, Cross-Sectional Observational Study of Serum BDNF, Cognitive Function, and Mild Cognitive Impairment in the Elderly 
Objective: The clinical relationship between brain-derived neurotrophic factor (BDNF) and cognitive function or mild cognitive impairment (MCI) is not well-understood. The purpose of this study was to identify the relationship between serum BDNF and cognitive function and MCI, and determine whether serum BDNF level might be a useful biomarker for assessing risk for MCI in older people.
Materials and Methods: A total of 4463 individuals aged 65 years or older (mean age 72 years) participating in the study. We measured performance in a battery of neuropsychological and cognitive function tests; serum BDNF concentration.
Results: Eight hundred twenty-seven participants (18.8%) had MCI. After adjustment for sex, age, education level, diabetes, and current smoking, serum BDNF was associated with poorer performance in the story memory, and digit symbol substitution task scores. Serum BDNF was marginally associated with the presence of MCI (odds ratio, 95% confidence interval: 1.41, 1.00–1.99) when BDNF was 1.5 SD lower than the mean value standardized for sex and age, education level, diabetes, and current smoking.
Conclusion: Low serum BDNF was associated with lower cognitive test scores and MCI. Future prospective studies should establish the discriminative value of serum BDNF for the risk of MCI.
doi:10.3389/fnagi.2014.00069
PMCID: PMC3995061  PMID: 24782766
brain-derived neurotrophic factor; cognition; biomarker; dementia; aged
21.  A GALECTIN-3-DEPENDENT PATHWAY UPREGULATES INTERLEUKIN-6 IN THE MICROENVIRONMENT OF HUMAN NEUROBLASTOMA 
Cancer research  2012;72(9):10.1158/0008-5472.CAN-11-2165.
Interleukin-6 (IL-6) is a pleiotropic cytokine with a broad range of physiological and pathological functions. Because in cancer IL-6 contributes to a microenvironment that promotes tumor cell survival, angiogenesis and inflammation, understanding the mechanism responsible for its production is important. In neuroblastoma, the second most common solid tumor in children, IL-6 is produced not by tumor cells but by stromal cells such as monocytes and bone marrow mesenchymal stem cells (BMMSC). Here we show that the production of IL-6 in BMMSC is in part stimulated by galectin-3 binding protein (Gal-3BP) secreted by neuroblastoma cells. We identified a distal region of the IL-6 promoter that contains 3 CCATT/enhancer binding protein (C/EBP) binding domains involved in the transcriptional upregulation of IL-6 by Gal-3BP.Gal-3BP interacted with Galectin-3 (Gal-3) present in BMMSC, and a Gal-3BP/Gal-3/Ras/MEK/ERK signaling pathway was responsible for the transcriptional upregulation of IL-6 in BMMSC where Gal-3 has a necessary function. In support of the role of this pathway in human neuroblastoma tumors, Gal-3BP was found to be present in tumor cells and in the adjacent extracellular matrix of 96% of 78 primary neuroblastoma tumor samples examined by immunohistochemistry. Considering the protumorigenic function of IL-6 in cancer, this tumor cell-stromal cell interactive pathway could be a target for anticancer therapy.
doi:10.1158/0008-5472.CAN-11-2165
PMCID: PMC3815584  PMID: 22389450
Galectin-3; galectin-3 binding protein; neuroblastoma; interleukin-6; microenvironment
22.  Cognitive Activities and Instrumental Activity of Daily Living in Older Adults with Mild Cognitive Impairment 
Aims
This study aimed to identify differences in the implementation of cognitive activities and instrumental activities of daily living (IADLs) between healthy individuals and subjects with mild cognitive impairment (MCI).
Methods
The study included 2,498 cognitively healthy subjects (mean age, 71.2 ± 5.1 years) and 809 MCI subjects (mean age, 71.8 ± 5.4 years). The subjects were interviewed regarding their participation in cognitive activities and the implementation of IADLs.
Results
We found a significant association between participation in any cognitive activities (p < 0.001), using a bus or a train (p < 0.001), and MCI. After adjusting for covariates, cognitive activity of any type remained significantly associated with MCI (p < 0.005) but not with the implementation of IADLs.
Conclusions
Our study revealed that greater participation in cognitive activity was associated with lower odds of MCI. Participation in cognitive activities may reflect differences between healthy and MCI subjects. To clarify the causal relationship between cognitive activities and MCI, further studies are required.
doi:10.1159/000355553
PMCID: PMC3843918  PMID: 24348501
Cognitive impairment; Dementia; Alzheimer's disease; Cognitive reserve

23.  Clinical Significance of Tumor-Associated Inflammatory Cells in Metastatic Neuroblastoma 
Journal of Clinical Oncology  2012;30(28):3525-3532.
Purpose
Children diagnosed at age ≥ 18 months with metastatic MYCN-nonamplified neuroblastoma (NBL-NA) are at high risk for disease relapse, whereas those diagnosed at age < 18 months are nearly always cured. In this study, we investigated the hypothesis that expression of genes related to tumor-associated inflammatory cells correlates with the observed differences in survival by age at diagnosis and contributes to a prognostic signature.
Methods
Tumor-associated macrophages (TAMs) in localized and metastatic neuroblastomas (n = 71) were assessed by immunohistochemistry. Expression of 44 genes representing tumor and inflammatory cells was quantified in 133 metastatic NBL-NAs to assess age-dependent expression and to develop a logistic regression model to provide low- and high-risk scores for predicting progression-free survival (PFS). Tumors from high-risk patients enrolled onto two additional studies (n = 91) served as independent validation cohorts.
Results
Metastatic neuroblastomas had higher infiltration of TAMs than locoregional tumors, and metastatic tumors diagnosed in patients at age ≥ 18 months had higher expression of inflammation-related genes than those in patients diagnosed at age < 18 months. Expression of genes representing TAMs (CD33/CD16/IL6R/IL10/FCGR3) contributed to 25% of the accuracy of a novel 14-gene tumor classification score. PFS at 5 years for children diagnosed at age ≥ 18 months with NBL-NA with a low- versus high-risk score was 47% versus 12%, 57% versus 8%, and 50% versus 20% in three independent clinical trials, respectively.
Conclusion
These data suggest that interactions between tumor and inflammatory cells may contribute to the clinical metastatic neuroblastoma phenotype, improve prognostication, and reveal novel therapeutic targets.
doi:10.1200/JCO.2011.40.9169
PMCID: PMC3675667  PMID: 22927533
24.  Six-Minute Walking Distance Correlated with Memory and Brain Volume in Older Adults with Mild Cognitive Impairment: A Voxel-Based Morphometry Study 
Background/Aims
High fitness levels play an important role in maintaining memory function and delaying the progression of structural brain changes in older people at risk of developing dementia. However, it is unclear which specific regions of the brain volume are associated with exercise capacity. We investigated whether exercise capacity, determined by a 6-min walking distance (6MWD), is associated with measures of logical and visual memory and where gray matter regions correlate with exercise capacity in older adults with mild cognitive impairment (MCI).
Methods
Ninety-one community-dwelling older adults with MCI completed a 6-min walking test, structural magnetic resonance imaging scanning, and memory tests. The Wechsler Memory Scale-Revised Logical Memory and Rey-Osterrieth Complex Figure Tests were used to assess logical and visual memory, respectively.
Results
The logical and visual memory tests were positively correlated with the 6MWD (p < 0.01). Poor performance in the 6MWD was correlated with a reduced cerebral gray matter volume in the left middle temporal gyrus, middle occipital gyrus, and hippocampus in older adults with MCI.
Conclusions
These results suggest that a better 6MWD performance may be related to better memory function and the maintenance of gray matter volume in older adults with MCI.
doi:10.1159/000354189
PMCID: PMC3776400  PMID: 24052797
Exercise capacity; Logical memory; Visual memory; Brain atrophy; Fitness; Walking; Cognitive impairment
25.  Poor balance and lower gray matter volume predict falls in older adults with mild cognitive impairment 
BMC Neurology  2013;13:102.
Background
The risk of falling is associated with cognitive dysfunction. Older adults with mild cognitive impairment (MCI) exhibit an accelerated reduction of brain volume, and face an increased risk of falling. The current study examined the relationship between baseline physical performance, baseline gray matter volume and falls during a 12-month follow-up period among community-dwelling older adults with MCI.
Methods
Forty-two older adults with MCI (75.6 years, 43% women) underwent structural magnetic resonance imaging and baseline physical performance assessment, including knee-extension strength, one-legged standing time, and walking speed with normal pace. ‘Fallers’ were defined as people who had one or more falls during the 12-month follow-up period.
Results
Of the 42 participants, 26.2% (n = 11) experienced at least one fall during the 12-month follow-up period. Fallers exhibited slower walking speed and shorter one-legged standing time compared with non-fallers (both p < .01). One-legged standing time (sec) (standardized odds ratio [95% confidence interval]: 0.89 [0.81, 0.98], p = .02) was associated with a significantly lower rate of falls during the 12-month follow-up after adjusting for age, sex, body mass index, and history of falling in the past year at baseline. Voxel-based morphometry was used to examine differences in baseline gray matter volume between fallers and non-fallers, revealing that fallers exhibited a significantly greater reduction in the bilateral middle frontal gyrus and superior frontal gyrus.
Conclusions
Poor balance predicts falls over 12 months, and baseline lower gray matter densities in the middle frontal gyrus and superior frontal gyrus were associated with falls in older adults with MCI. Maintaining physical function, especially balance, and brain structural changes through many sorts of prevention strategies in the early stage of cognitive decline may contribute to decreasing the risk of falls in older adults with MCI.
doi:10.1186/1471-2377-13-102
PMCID: PMC3750260  PMID: 23915144

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