Plasma MMP-9 Levels as the Future Risk of Conversion to Dementia in ApoE4-Positive MCI Patients: Investigation Based on the Alzheimer's Disease Neuroimaging Initiative Database.

BACKGROUND: Matrix metalloproteinase 9 (MMP-9) has been reported to be correlated with declines in hippocampal volume and cognitive function in ApoE4-positive MCI patients. OBJECTIVES: The present study was aimed to investigate the effects of plasma matrix MMP-9 on the conversion risk between mild cognitive impairment (MCI) patients with and without ApoE4. DESIGN AND SETTING: Retrospective observational study using the data extracted from the Alzheimer's Disease Neuroimaging Initiative database. PARTICIPANTS: We included 211 ApoE4-positive MCI subjects (ApoE4+ MCI) and 184 ApoE4-negative MCI subjects (ApoE4- MCI). MEASUREMENTS: We obtained demographic and data including plasma MMP-9 levels at baseline and longitudinal changes in Clinical Dementia Rating (CDR) up to 15 years. We compared conversion rates between ApoE4+ MCI and ApoE4- MCI by the Log-rank test and calculated the hazard ratio (HR) for covariates including age, sex, educational attainment, drinking and smoking histories, medications, and plasma MMP-9 levels using a multiple Cox regression analysis of ApoE4+ MCI and ApoE4- MCI. RESULTS: No significant differences were observed in baseline plasma MMP-9 levels between ApoE4+ MCI and ApoE4- MCI. High plasma MMP-9 levels increased the conversion risk significantly more than low plasma MMP-9 levels (HR, 2.46 [95% CI, 1.31-4.48]) and middle plasma MMP-9 levels (HR, 1.67 [95% CI, 1.04-2.65]) in ApoE4+ MCI, but not in ApoE4- MCI. CONCLUSION: Plasma MMP-9 would be the risk of the future conversion to dementia in ApoE4+ MCI.

Fast x-ray detector system with simultaneous measurement of timing and energy for a single photon.

We developed a fast X-ray detector system for nuclear resonant scattering (NRS) experiments. Our system employs silicon avalanche photo-diode (Si-APD) as a fast X-ray sensor. The system is able to acquire both timing and energy of a single X-ray photon simultaneously in a high rate condition, 106 counts per second for one Si-APD. The performance of the system was investigated in SPring-8, a synchrotron radiation facility in Japan. Good time resolution of 120 ps (FWHM) was achieved with a slight tail distribution in the time spectrum by a level of 10-9 at 1 ns apart from the peak. Using this system, we successfully observed the NRS from the 26.27-keV level of mercury-201, which has a half-life of 630(50) ps. We also demonstrated the reduction of background events caused by radioactive decays in a radioactive sample by discriminating photon energy.

High-resolution copy number variation analysis of schizophrenia in Japan.

Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10-9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.

Spectrum of clinical and genetic features of patients with inherited platelet disorder with suspected predisposition to hematological malignancies: a nationwide survey in Japan.

BACKGROUND: Inherited thrombocytopenia (IT) contains several forms of familial thrombocytopenia and some of them have propensity to hematological malignancies. The etiological and genetic features of this heterogeneous syndrome have not yet been elucidated. PATIENTS AND METHODS: We conducted a nationwide survey to collect clinical information and samples from patients with familial thrombocytopenia and/or hematological malignancies in order to obtain a comprehensive understanding of IT. RESULTS: Among the 43 pedigrees with clinical samples, RUNX1 mutations were identified in 8 pedigrees (18.6%). While MYH9 and ANKRD26 mutations were identified in 2 and 1 pedigrees, respectively, no gene mutations were detected in the remaining 32 pedigrees from a panel of previously reported pathogenetic mutations. Clinical data were comparable between FPD/AML and non-FPD/AML probands. CONCLUSIONS: Our study clarified that it is unexpectedly difficult to diagnose FPD/AML based on clinical information alone, and thus, genetic testing is strongly recommended. Our survey also identified some pedigrees with a strong family history of myelodysplastic syndromes of unknown origin. Additionally, there were 14 pedigrees in which three or more members were affected by immune thrombocytopenia (ITP), and a computer-aided simulation suggested that such a distribution almost never happens by coincidence, which implicates a genetic predisposition to ITP.

T-cell receptor Vß skewing frequently occurs in refractory cytopenia of childhood and is associated with an expansion of effector cytotoxic T cells: a prospective study by EWOG-MDS.

Immunosuppressive therapy (IST), consisting of antithymocyte globulin and cyclosporine A, is effective in refractory cytopenia of childhood (RCC), suggesting that, similar to low-grade myelodysplastic syndromes in adult patients, T lymphocytes are involved in suppressing hematopoiesis in a subset of RCC patients. However, the potential role of a T-cell-mediated pathophysiology in RCC remains poorly explored. In a cohort of 92 RCC patients, we prospectively assessed the frequency of T-cell receptor (TCR) ß-chain variable (Vß) domain skewing in bone marrow and peripheral blood by heteroduplex PCR, and analyzed T-cell subsets in peripheral blood by flow cytometry. TCRVß skewing was present in 40% of RCC patients. TCRVß skewing did not correlate with bone marrow cellularity, karyotype, transfusion history, HLA-DR15 or the presence of a PNH clone. In 28 patients treated with IST, TCRVß skewing was not clearly related with treatment response. However, TCRVß skewing did correlate with a disturbed CD4(+)/CD8(+) T-cell ratio, a reduction in naive CD8(+) T cells, an expansion of effector CD8(+) T cells and an increase in activated CD8(+) T cells (defined as HLA-DR(+), CD57(+) or CD56(+)). These data suggest that T lymphocytes contribute to RCC pathogenesis in a proportion of patients, and provide a rationale for treatment with IST in selected patients with RCC.

Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia.

Relapse of chronic myeloid leukemia (CML) is triggered by stem cells with a reconstituting capacity similar to that of hematopoietic stem cells (HSCs) and CML stem cells are a source of resistance in drug therapy with tyrosine kinase inhibitors (TKIs). Ecotropic viral integration site 1 (EVI1), a key transcription factor in HSC regulation, is known to predict poor outcomes in myeloid malignancies, however, incapability of prospective isolation of EVI1-high leukemic cells precludes the functional evaluation of intraindividual EVI1-high cells. Introduction of CML into Evi1-internal ribosomal entry site (IRES)-green fluorescent protein (GFP) knock-in mice, a versatile HSC-reporter strain, enables us to separate Evi1-high CML cells from the individual. Evi1-IRES-GFP allele models of CML in chronic phase (CML-CP), by retroviral overexpression of BCR-ABL and by crossing BCR-ABL transgenic mice, revealed that Evi1 is predominantly enriched in the stem cell fraction and associated with an enhanced proliferative as well as a leukemia-initiating capacity and that Evi1-high CML-CP cells exhibit resistance to TKIs. Overexpressing BCR-ABL and NUP98-HOXA9 in Evi1-IRES-GFP knock-in mice to model CML in blast crisis (CML-BC), in which Evi1-high cells turned to be a major population as opposed to a minor population in CML-CP models, showed that Evi1-high CML-BC cells have a greater potential to recapitulate the disease and appear resistant to TKIs. Furthermore, given that Evi1 heterozygosity ameliorates CML-CP and CML-BC development and that the combination of Evi1 and BCR-ABL causes acute myeloid leukemia resembling CML-BC, Evi1 could regulate CML development as a potent driver. In addition, in human CML-CP cases, we show that EVI1 is highly expressed in stem cell-enriched CD34+CD38-CD90+ fraction at single-cell level. This is the first report to clarify directly that Evi1-high leukemic cells themselves possess the superior potential to Evi1-low cells in oncogenic self-renewal, which highlights the role of Evi1 as a valuable and a functional marker of CML stem cells.

EVI1 oncogene promotes KRAS pathway through suppression of microRNA-96 in pancreatic carcinogenesis.

Despite frequent KRAS mutation, the early molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) development have not been fully elucidated. By tracking a potential regulator of another feature of PDAC precursors, acquisition of foregut or gastric epithelial gene signature, we herein report that aberrant overexpression of ecotropic viral integration site 1 (EVI1) oncoprotein, which is usually absent in normal pancreatic duct, is a widespread marker across the full spectrum of human PDAC precursors and PDAC. In pancreatic cancer cells, EVI1 depletion caused remarkable inhibition of cell growth and migration, indicating its oncogenic roles. Importantly, we found that EVI1 upregulated KRAS expression through suppression of a potent KRAS suppressor, miR-96, in pancreatic cancer cells. Collectively, the present findings suggest that EVI1 overexpression and KRAS mutation converge on activation of the KRAS pathway in early phases of pancreatic carcinogenesis and propose EVI1 and/or miR-96 as early markers and therapeutic targets in this dismal disease.

Is the 7/2(1)- isomer state of 43S spherical?

We report on the spectroscopic quadrupole moment measurement of the 7/2(1)(-) isomeric state in (16)(43)S(27) [E*=320.5(5) keV, T(1/2)=415(3) ns], using the time dependent perturbed angular distribution technique at the RIKEN RIBF facility. Our value, |Q(s)|=23(3) efm(2), is larger than that expected for a single-particle state. Shell model calculations using the modern SDPF-U interaction for this mass region reproduce remarkably well the measured |Q(s)|, and show that non-negligible correlations drive the isomeric state away from a purely spherical shape.

No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients.

BACKGROUND: Outcomes of Ewing tumor (ET) patients treated with allogeneic stem cell transplantation (allo-SCT) were compared regarding the use of reduced-intensity conditioning (RIC) and high-intensity conditioning (HIC) regimens as well as human leukocyte antigen (HLA)-matched and HLA-mismatched grafts. PATIENTS AND METHODS: We retrospectively analyzed data of 87 ET patients from the European Group for Blood and Marrow Transplantation, Pediatric Registry for Stem Cell Transplantations, Asia Pacific Blood and Marrow Transplantation and MetaEICESS registries treated with allo-SCT. Fifty patients received RIC (group A) and 37 patients received HIC (group B). Twenty-four patients received HLA-mismatched grafts and 63 received HLA-matched grafts. RESULTS: Median overall survival was 7.9 months [±1.24, 95% confidence interval (CI) 5.44-10.31] for group A and 4.4 months (±1.06, 95% CI 2.29-6.43) for group B patients (P = 1.3). Death of complications (DOC) occurred in 4 of 50 (0.08) and death of disease (DOD) in 33 of 50 (0.66) group A and in 16 of 37 (0.43) and 17 of 37 (0.46) group B patients, respectively. DOC incidence was decreased (P < 0.01) and DOD/relapse increased (P < 0.01) in group A compared with group B. HLA mismatch was not generally associated with graft-versus-Ewing tumor effect (GvETE). CONCLUSIONS: There was no improvement of survival with RIC compared with HIC due to increased DOD/relapse incidence after RIC despite less DOC incidence. This implicates general absence of a clinically relevant GvETE with current protocols.

Hematopoietic SCT activity in Asia: a report from the Asia-Pacific Blood and Marrow Transplantation Group.

The hematopoietic SCT (HSCT) activity in nine Asian countries/regions was surveyed to overview the current situation. Data of 58 113 HSCTs (allogeneic: 63% vs autologous: 37%) performed between 1986 and 2006 by 432 transplant teams were collected. The number of HSCTs has been increasing in the past two decades in most countries/regions. The increase in allogeneic HSCTs is greater than in autologous HSCTs. The proportion of unrelated donors among allogeneic HSCTs in 2006 varied widely from <1% (Iran and Vietnam) to 62% (Japan). The use of each stem cell source, that is, BM, PBSC, cord blood and others (including co-infusion of BM and PBSC), also varied widely (36, 58, 0.1 and 6% in HSCT from related donors, respectively, and 53, 11, 35 and 1% in HSCT from unrelated donors, respectively). HSCTs have been continuously increasing for all indications except for chronic myelogenous leukemia and solid tumors. Hemoglobinopathy is a common indication among non-malignant diseases in many Asian countries/regions except for China, Japan and Korea. This survey clearly shows the recent progress of HSCTs in Asia and also some differences in donor and stem cell selection and disease application among countries/regions.

Pbx1 is a downstream target of Evi-1 in hematopoietic stem/progenitors and leukemic cells.

Ecotropic viral integration site-1 (Evi-1) is a nuclear transcription factor, which is essential for the proliferation/maintenance of hematopoietic stem cells (HSCs). Aberrant expression of Evi-1 has been frequently found in myeloid leukemia, and is associated with a poor patient survival. Recently, we reported candidate target genes of Evi-1 shared in HSCs and leukemic cells using gene expression profiling analysis. In this study, we identified Pbx1, a proto-oncogene in hematopoietic malignancy, as a target gene of Evi-1. Overexpression of Evi-1 increased Pbx1 expression in hematopoietic stem/progenitor cells. An analysis of the Pbx1 promoter region revealed that Evi-1 upregulates Pbx1 transcription. Furthermore, reduction of Pbx1 levels through RNAi-mediated knockdown significantly inhibited Evi-1-induced transformation. In contrast, knockdown of Pbx1 did not impair bone marrow transformation by E2A/HLF or AML1/ETO, suggesting that Pbx1 is specifically required for the maintenance of bone marrow transformation mediated by Evi-1. These results indicate that Pbx1 is a target gene of Evi-1 involved in Evi-1-mediated leukemogenesis.

Late-onset non-infectious pulmonary complications following allogeneic hematopoietic stem cell transplantation in children.

Late-onset non-infectious pulmonary complications (LONIPCs) that arise beyond 3 months after allogeneic hematopoietic SCT include bronchiolitis obliterans (BO), bronchiolitis obliterans with organizing pneumonia (BOOP) and idiopathic pneumonia syndrome (IPS). We retrospectively analyzed the incidence and outcome of LONIPCs among pediatric hematopoietic SCT recipients. We included 97 patients who survived for more than 3 months among the 114 who underwent allogeneic hematopoietic SCT between April 1997 and May 2007. Of the 97 enrolled patients, 10 (10.3%) developed LONIPCs at a median of 187 days after hematopoietic SCT (range, 123-826 days). Of the 10 patients with LONIPCs, eight had BO and two had IPS. Multivariate analysis showed that the onset of LONIPCs was associated with high-risk underlying disease and extensive chronic GVHD (hazard ratio, 5.42 (95% confidence interval, 1.36-21.7) and hazard ratio, 11.7 (95% confidence interval, 2.40-57.1), respectively). Only two patients responded to therapy with steroids and six of the 10 patients died. The 5-year OS rate was significantly lower among patients with, than without LONIPCs (28.0 vs 87.2%, P=0.000). Considering that we are lacking optimal therapies for LONIPCs, strategies aimed at the prevention of LONIPCs should be attempted.

Donor leukocyte infusion after hematopoietic stem cell transplantation in patients with juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is a clonal myeloproliferative disorder of early childhood. In all, 21 patients with JMML who received donor leukocyte infusion (DLI) after allogeneic hematopoietic stem cell transplantation (HSCT) for either mixed chimerism (MC, n=7) or relapse (n=14) were studied. Six patients had been transplanted from an HLA-matched sibling and 15 from other donors. Six of the 21 patients (MC: 3/7 patients; relapse: 3/14 patients) responded to DLI. Response rate was significantly higher in patients receiving a higher total T-cell dose (> or =1 x 10(7)/kg) and in patients with an abnormal karyotype. None of the six patients receiving DLI from a matched sibling responded. Response was observed in five of six patients who did and in one of 15 children who did not develop acute graft-versus-host disease following DLI (P=0.01). The overall outcome was poor even for the responders. Only one of the responders is alive in remission, two relapsed, and three died of complications. In conclusion, this study shows that some cases of JMML may be sensitive to DLI, this providing evidence for a graft-versus-leukemia effect in JMML. Infusion of a high number of T cells, strategies to reduce toxicity, and cytoreduction prior to DLI may improve the results.