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1.  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.
PMCID: PMC4273072  PMID: 25540512
Mild cognitive impairment; Self-reported exhaustion; Life space
2.  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.
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.
4-HPR/LXS powder (352 - 2210 mg/m2/day) was administered on Days 0 – 6, in 21-day courses, by standard 3+3 design.
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.
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.
PMCID: PMC4066886  PMID: 23813912
fenretinide; neuroblastoma; pediatric; powder; Lym-X-Sorb™
3.  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.
PMCID: PMC3795903  PMID: 23765726
C-terminal fragmentation of MAT1; retinoid signaling; CAK-coordinated cell cycle and transcription; TFIIH kinase; myeloid leukemia
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.
PMCID: PMC3740971  PMID: 23633489
Interleukin-6; STAT3; drug resistance; neuroblastoma; tumor microenvironment
5.  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.
PMCID: PMC4137159  PMID: 24874261
Acquisition of typing skill; Priming; Japanese language; Typewriting; Fan effect; Chunking; Mora
6.  Cognitive function and gait speed under normal and dual-task walking among older adults with mild cognitive impairment 
BMC Neurology  2014;14:67.
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.
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.
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).
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.
PMCID: PMC3994221  PMID: 24694100
7.  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.
PMCID: PMC3947577  PMID: 23045288
Osteosarcoma-initiating cells; self-renewal; tumorigenicity; lineage differentiation; osteosarcoma-forming cells; osteogenic differentiation
8.  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.
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).
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.
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.
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.
PMCID: PMC3397468  PMID: 22744966
neuroblastoma; International Neuroblastoma Pathology Classification; MYCN; genotype-phenotype correlation; prognosis; immunohistochemistry
9.  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.
PMCID: PMC3906735  PMID: 17409416
suppression of anoikis; E-cadherin; ErbB4; EWS-FLI1; Ewing tumor
10.  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.
PMCID: PMC3995061  PMID: 24782766
brain-derived neurotrophic factor; cognition; biomarker; dementia; aged
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.
PMCID: PMC3815584  PMID: 22389450
Galectin-3; galectin-3 binding protein; neuroblastoma; interleukin-6; microenvironment
12.  Cognitive Activities and Instrumental Activity of Daily Living in Older Adults with Mild Cognitive Impairment 
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).
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.
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.
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.
PMCID: PMC3843918  PMID: 24348501
Cognitive impairment; Dementia; Alzheimer's disease; Cognitive reserve

13.  Clinical Significance of Tumor-Associated Inflammatory Cells in Metastatic Neuroblastoma 
Journal of Clinical Oncology  2012;30(28):3525-3532.
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.
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.
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.
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.
PMCID: PMC3675667  PMID: 22927533
14.  Six-Minute Walking Distance Correlated with Memory and Brain Volume in Older Adults with Mild Cognitive Impairment: A Voxel-Based Morphometry Study 
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).
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.
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.
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.
PMCID: PMC3776400  PMID: 24052797
Exercise capacity; Logical memory; Visual memory; Brain atrophy; Fitness; Walking; Cognitive impairment
15.  Poor balance and lower gray matter volume predict falls in older adults with mild cognitive impairment 
BMC Neurology  2013;13:102.
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.
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.
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.
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.
PMCID: PMC3750260  PMID: 23915144
16.  Ewing tumors that do not over-express BMI-1 are a distinct molecular subclass with variant biology: A report from the Children’s Oncology Group 
Ewing sarcoma family tumors (ESFT) are aggressive tumors of putative stem cell origin for which prognostic biomarkers and novel treatments are needed. In several human cancers high expression of the polycomb protein BMI-1 is associated with poor outcome. We have assessed the potential clinical significance of BMI-1 expression level in ESFT.
Experimental Design
BMI-1 expression was assessed in 130 tumors by immunostaining and associations with clinical features and outcome determined. The molecular signatures of BMI-1-low and BMI-1-high tumors were compared using microarrays and differentially activated canonical pathways identified by gene specific enrichment analysis. Automated quantitative analysis (AQUA) of phospho-proteins was used to assess relative levels of pathway activation. Sensitivity to IGF1-R inhibition was determined using MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assays.
BMI-1 is over-expressed by the vast majority of ESFT. However, in 20% of cases BMI-1 levels are low to undetectable. Significantly, although clinical presentation and outcome were similar between BMI-1-high and BMI-1-low tumors, whole genome expression array analysis showed marked differences in their respective gene expression profiles. Gene specific enrichment analysis identified that several cancer-associated canonical biologic pathways, including IGF1, mTOR and WNT are significantly down-regulated in BMI-1-low compared to BMI-1-high tumors. Consistent with these in vivo data, the response to IGF1-R inhibition in vitro was diminished in BMI-1-low compared to BMI-1-high ESFT cells.
ESFT that do not over-express BMI-1 represent a novel subclass with a distinct molecular profile and altered activation of and dependence on cancer-associated biologic pathways.
PMCID: PMC3711406  PMID: 21047978
17.  Demonstration of novel gain-of-function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype 
Integrin αIIbβ3 is indispensable for normal hemostasis, but its role for thrombopoiesis is still controversial. Recently, αIIb and β3 mutations have been identified in patients with congenital macrothrombocytopenia. We analyzed three unrelated Japanese families with congenital macrothrombocytopenia. Expression and activation state of αIIbβ3 in platelets was examined by flow cytometry and immunoblotting. Sequence of whole coding region and exon–intron boundaries of ITGA2B and ITGB3 genes was performed. The effects of mutations on αIIbβ3 activation state and phosphorylation of FAK were analyzed in transfected cells. We newly identified three mutations: two mutations in highly conserved Gly-Phe-Phe-Lys-Arg sequence in juxtamembrane region of αIIb, p.Gly991Cys and p.Phe993del, and one donor site mutation of intron 13 of ITGB3 leading to 40 amino acids deletion, p.(Asp621_Glu660del), in the membrane proximal β-tail domain of β3. One patient, who showed Glanzmann thrombasthenia-like marked reduction in surface αIIbβ3 expression (3–11% of normal control), was a compound heterozygote with ITGA2B p.Gly991Cys and a novel nonsense mutation, ITGA2B p.Arg422*. All three mutations, ITGA2B p.Gly991Cys, ITGA2B p.Phe993del, and ITGB3 p.(Asp621_Glu660del), led to highly activated conformation of αIIbβ3 and spontaneous tyrosine phosphorylation of FAK in transfected cells. These results suggest that gain-of-function mutations around membrane region of αIIbβ3 lead to abnormal platelet number and morphology with impaired surface αIIbβ3 expression.
PMCID: PMC3865572  PMID: 24498605
Congenital macrothrombocytopenia; gain-of-function mutations; glanzmann thrombasthenia; integrin αIIbβ3; platelets
18.  Outcome After Surgery Alone or With Restricted Use of Chemotherapy for Patients With Low-Risk Neuroblastoma: Results of Children's Oncology Group Study P9641 
Journal of Clinical Oncology  2012;30(15):1842-1848.
The primary objective of Children's Oncology Group study P9641 was to demonstrate that surgery alone would achieve 3-year overall survival (OS) ≥ 95% for patients with asymptomatic International Neuroblastoma Staging System stages 2a and 2b neuroblastoma (NBL). Secondary objectives focused on other low-risk patients with NBL and on those who required chemotherapy according to protocol-defined criteria.
Patients and Methods
Patients underwent maximally safe resection of tumor. Chemotherapy was reserved for patients with, or at risk for, symptomatic disease, with less than 50% tumor resection at diagnosis, or with unresectable progressive disease after surgery alone.
For all 915 eligible patients, 5-year event-free survival (EFS) and OS were 89% ± 1% and 97% ± 1%, respectively. For patients with asymptomatic stage 2a or 2b disease, 5-year EFS and OS were 87% ± 2% and 96% ± 1%, respectively. Among patients with stage 2b disease, EFS and OS were significantly lower for those with unfavorable histology or diploid tumors, and OS was significantly lower for those ≥ 18 months old. For patients with stage 1 and 4s NBL, 5-year OS rates were 99% ± 1% and 91% ± 1%, respectively. Patients who required chemotherapy at diagnosis achieved 5-year OS of 98% ± 1%. Of all patients observed after surgery, 11.1% experienced recurrence or progression of disease.
Excellent survival rates can be achieved in asymptomatic low-risk patients with stages 2a and 2b NBL after surgery alone. Immediate use of chemotherapy may be restricted to a minority of patients with low-risk NBL. Patients with stage 2b disease who are older or have diploid or unfavorable histology tumors fare less well. Future studies will seek to refine risk classification.
PMCID: PMC3383182  PMID: 22529259
19.  A Randomized Controlled Trial of Multicomponent Exercise in Older Adults with Mild Cognitive Impairment 
PLoS ONE  2013;8(4):e61483.
To examine the effect of multicomponent exercise program on memory function in older adults with mild cognitive impairment (MCI), and identify biomarkers associated with improvement of cognitive functions.
Methodology/Principal Findings
Subjects were 100 older adults (mean age, 75 years) with MCI. The subjects were classified to an amnestic MCI group (n = 50) with neuroimaging measures, and other MCI group (n = 50) before the randomization. Subjects in each group were randomized to either a multicomponent exercise or an education control group using a ratio of 1∶1. The exercise group exercised for 90 min/d, 2 d/wk, 40 times for 6 months. The exercise program was conducted under multitask conditions to stimulate attention and memory. The control group attended two education classes. A repeated-measures ANOVA revealed that no group × time interactions on the cognitive tests and brain atrophy in MCI patients. A sub-analysis of amnestic MCI patients for group × time interactions revealed that the exercise group exhibited significantly better Mini-Mental State Examination (p = .04) and logical memory scores (p = .04), and reducing whole brain cortical atrophy (p<.05) compared to the control group. Low total cholesterol levels before the intervention were associated with an improvement of logical memory scores (p<.05), and a higher level of brain-derived neurotrophic factor was significantly related to improved ADAS-cog scores (p<.05).
The results suggested that an exercise intervention is beneficial for improving logical memory and maintaining general cognitive function and reducing whole brain cortical atrophy in older adults with amnestic MCI. Low total cholesterol and higher brain-derived neurotrophic factor may predict improvement of cognitive functions in older adults with MCI. Further studies are required to determine the positive effects of exercise on cognitive function in older adults with MCI.
Trial Registration
UMIN-CTR UMIN000003662 ctr.cgi?function = brows&action = brows&type = summary&recptno = R000004436&language = J.
PMCID: PMC3621765  PMID: 23585901
20.  Cognitive function affects trainability for physical performance in exercise intervention among older adults with mild cognitive impairment 
Although much evidence supports the hypothesis that cognitive function and physical function are interrelated, it is unclear whether cognitive decline with mild cognitive impairment influences trainability of physical performance in exercise intervention. The purpose of this study was to examine the association between cognitive function at baseline and change in physical performance after exercise intervention in older adults with mild cognitive impairment.
Forty-four older adults diagnosed with mild cognitive impairment based on the Peterson criteria (mean age 74.8 years) consented to and completed a 6-month twice weekly exercise intervention. The Timed Up and Go (TUG) test was used as a measure of physical performance. The Mini-Mental State Examination (MMSE), Trail Making Test Part B, Geriatric Depression Scale, baseline muscle strength of knee extension, and attendance rate of intervention, were measured as factors for predicting trainability.
In the correlation analysis, the change in TUG showed modest correlations with attendance rate in the exercise program (r = −0.354, P = 0.027) and MMSE at baseline (r = −0.321, P = 0.034). A multiple regression analysis revealed that change in TUG was independently associated with attendance rate (β = −0.322, P = 0.026) and MMSE score (β = −0.295, P = 0.041), controlling for age and gender.
General cognitive function was associated with improvements in physical performance after exercise intervention in subjects with mild cognitive impairment. Further research is needed to examine the effects of exercise programs designed to address cognitive obstacles in older adults with mild cognitive impairment.
PMCID: PMC3564456  PMID: 23390362
exercise; mobility; rehabilitation; Timed Up and Go test
21.  Effects of multicomponent exercise on cognitive function in older adults with amnestic mild cognitive impairment: a randomized controlled trial 
BMC Neurology  2012;12:128.
To examine the effects of a multicomponent exercise program on the cognitive function of older adults with amnestic mild cognitive impairment (aMCI).
Design: Twelve months, randomized controlled trial; Setting: Community center in Japan; Participants: Fifty older adults (27 men) with aMCI ranging in age from 65 to 93 years (mean age, 75 years); Intervention: Subjects were randomized into either a multicomponent exercise (n = 25) or an education control group (n = 25). Subjects in the multicomponent exercise group exercised under the supervision of physiotherapists for 90 min/d, 2 d/wk, for a total of 80 times over 12 months. The exercises included aerobic exercises, muscle strength training, and postural balance retraining, and were conducted using multiple conditions to stimulate cognitive functions. Subjects in the control group attended three education classes regarding health during the 12-month period. Measurements were administered before, after the 6-month, and after the 12-month intervention period; Measurements: The performance measures included the mini-mental state examination, logical memory subtest of the Wechsler memory scale-revised, digit symbol coding test, letter and categorical verbal fluency test, and the Stroop color word test.
The mean adherence to the exercise program was 79.2%. Improvements of cognitive function following multicomponent exercise were superior at treatment end (group × time interactions for the mini-mental state examination (P = 0.04), logical memory of immediate recall (P = 0.03), and letter verbal fluency test (P = 0.02)). The logical memory of delayed recall, digit symbol coding, and Stroop color word test showed main effects of time, although there were no group × time interactions.
This study indicates that exercise improves or supports, at least partly, cognitive performance in older adults with aMCI.
PMCID: PMC3534485  PMID: 23113898
Aerobic exercise; MCI; Elderly; Alzheimer’s disease; Prevention
22.  Effects of Exercise Intervention on Vascular Risk Factors in Older Adults with Mild Cognitive Impairment: A Randomized Controlled Trial 
The purpose of this study is to clarify the effects of exercise intervention on vascular risk factors in older adults with mild cognitive impairment (MCI).
Community-dwelling older adults who met the definition of MCI using the Petersen criteria (n = 100; mean age = 75.3 years) were randomly allocated to the exercise (n = 50) or education control group (n = 50). Participants in the exercise group exercised under the supervision of physiotherapists for 90 min/day, 2 days/week, 80 times for 12 months. Anthropometric profiles, blood markers, blood pressure, and physical fitness (the 6-min walking test) were measured. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and TC/HDL-C risk ratio measurements were taken from blood samples.
The exercise group showed significantly reduced TC and TC/HDL-C risk ratio after training compared with baseline levels (p < 0.001, p = 0.004). However, no significant reduction was found for the control group (p = 0.09, p = 0.09). Physical fitness also significantly improved after exercise intervention compared with the control group (p < 0.0001).
Exercise intervention was associated with positive changes in important vascular risk factors related to cognitive decline and vascular disease in older adults with MCI.
PMCID: PMC3507268  PMID: 23189083
Cholesterol; Rehabilitation; Cognitive impairment; Metabolic profiles; Dementia; Vascular risk factors; Physical activity
23.  Li-Fraumeni syndrome with simultaneous osteosarcoma and liver cancer: Increased expression of a CD44 variant isoform after chemotherapy 
BMC Cancer  2012;12:444.
Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome that is commonly associated with a germline mutation in the tumor suppressor gene p53. Loss of p53 results in increased expression of CD44, a cancer stem cell (CSC) marker, which is involved in the scavenging of reactive oxygen species (ROS). Here, we report a change in the expression of a CD44 variant isoform (CD44v8-10) in an 8-year-old female LFS patient with osteosarcoma and atypical liver cancer after chemotherapy.
Case presentation
The patient visited a clinic with a chief complaint of chronic pain in a bruise on her right knee. Magnetic resonance imaging (MRI) raised the possibility of a bone malignancy. Biochemical testing also revealed significantly elevated levels of AFP, which strongly suggested the existence of a primary malignancy in the liver. MRI imaging showed the simultaneous development of osteosarcoma and liver cancer, both of which were confirmed upon biopsy. Combined therapy with surgical resection after chemotherapy was successful in this patient. Regardless of the absence of a familial history of hereditary cancer, a germline mutation in p53 was identified (a missense mutation defined as c.722 C>T, p.Ser241Phe). To better understand the cancer progression and response to treatment, immunohistochemical (IHC) analysis of biopsy specimens obtained before and after chemotherapy was performed using a specific antibody against CD44v8-10.
This case demonstrates the ectopic up-regulation of CD44v8-10 in a biopsy sample obtained after cytotoxic chemotherapy, which confers high levels of oxidative stress on cancer cells. Because the alternative splicing of CD44 is tightly regulated epigenetically, it is possible that micro-environmental stress resulting from chemotherapy caused the ectopic induction of CD44v8-10 in vivo.
PMCID: PMC3488581  PMID: 23031740
Li-Fraumeni syndrome (LFS); cancer stem cells (CSCs); CD44 variant isoforms
24.  UCHL1 S18Y variant is a risk factor for Parkinson’s disease in Japan 
BMC Neurology  2012;12:62.
A recent meta-analysis on the UCHL1 S18Y variant and Parkinson’s disease (PD) showed a significant inverse association between the Y allele and PD; the individual studies included in that meta-analysis, however, have produced conflicting results. We examined the relationship between UCHL1 S18Y single nucleotide polymorphism (SNP) and sporadic PD in Japan.
Included were 229 cases within 6 years of onset of PD, defined according to the UK PD Society Brain Bank clinical diagnostic criteria. Controls were 357 inpatients and outpatients without neurodegenerative disease. Adjustment was made for sex, age, region of residence, smoking, and caffeine intake.
Compared with subjects with the CC or CA genotype of UCHL1 S18Y SNP, those with the AA genotype had a significantly increased risk of sporadic PD: the adjusted OR was 1.57 (95 % CI: 1.06 − 2.31). Compared with subjects with the CC or CA genotype of UCHL1 S18Y and the CC or CT genotype of SNCA SNP rs356220, those with the AA genotype of UCHL1 S18Y and the TT genotype of SNP rs356220 had a significantly increased risk of sporadic PD; the interaction, however, was not significant. Our previous investigation found significant inverse relationships between smoking and caffeine intake and PD in this population. There were no significant interactions between UCHL1 S18Y and smoking or caffeine intake affecting sporadic PD.
This study reveals that the UCHL1 S18Y variant is a risk factor for sporadic PD. We could not find evidence for interactions affecting sporadic PD between UCHL1 S18Y and SNCA SNP rs356220, smoking, or caffeine intake.
PMCID: PMC3488468  PMID: 22839974
25.  Hypoglycemia associated with L-asparaginase in acute lymphoblastic leukemia treatment: a case report 
A patient with acute lymphoblastic leukemia repeatedly developed hypoglycemia during chemotherapy. Comparison of serum glucose trends between chemotherapy with and without L-asparaginase (L-Asp) demonstrated a strong association between L-Asp and hypoglycemia. Critical blood sampling during hypoglycemia indicated hyperinsulinism, suggesting that L-Asp induced hypoglycemia in the patient through inappropriate insulin secretion. Identification of hypoglycemia as an adverse effect will enable clinicians to understand and develop appropriate strategies for L-Asp use in chemotherapy regimens.
PMCID: PMC3514085  PMID: 23211036
L-asparaginase; Fasting hypoglycemia; Hyperinsulinism; Acute lymphoblastic leukemia; Fasting Glucose levels

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