Copy number loss of (src homology 2 domain containing)-transforming protein 2 (SHC2) gene: discordant loss in monozygotic twins and frequent loss in patients with multiple system atrophy

<p>Abstract</p> <p>Background</p> <p>Multiple system atrophy (MSA) is a sporadic disease. Its pathogenesis may involve multiple genetic and nongenetic factors, but its etiology remains largely unknown. We hypothesized that the genome of a patient with MSA would demonstrate copy number variations (CNVs) in the genes or genomic regions of interest. To identify genomic alterations increasing the risk for MSA, we examined a pair of monozygotic (MZ) twins discordant for the MSA phenotype and 32 patients with MSA.</p> <p>Results</p> <p>By whole-genome CNV analysis using a combination of CNV beadchip and comparative genomic hybridization (CGH)-based CNV microarrays followed by region-targeting, high-density, custom-made oligonucleotide tiling microarray analysis, we identified disease-specific copy number loss of the (Src homology 2 domain containing)-transforming protein 2 (<it>SHC2</it>) gene in the distal 350-kb subtelomeric region of 19p13.3 in the affected MZ twin and 10 of the 31 patients with MSA but not in 2 independent control populations (<it>p </it>= 1.04 × 10^-8, odds ratio = 89.8, Pearson's chi-square test).</p> <p>Conclusions</p> <p>Copy number loss of <it>SHC2 </it>strongly indicates a causal link to MSA. CNV analysis of phenotypically discordant MZ twins is a powerful tool for identifying disease-predisposing loci. Our results would enable the identification of novel diagnostic measure, therapeutic targets and better understanding of the etiology of MSA.</p

Kelvin-Helmholtz instabilities with Godunov SPH

Numerical simulations for the non-linear development of Kelvin-Helmholtz instability in two different density layers have been performed with the particle-based method (Godunov SPH) developed by Inutsuka (2002). The Godunov SPH can describe the Kelvin-Helmholtz instability even with a high density contrast, while the standard SPH shows the absence of the instability across a density gradient (Agertz et al. 2007). The interaction of a dense blob with a hot ambient medium has been performed also. The Godunov SPH describes the formation and evolution of the fingers due to the combinations of Rayleigh-Taylor, Richtmyer-Meshkov, and Kelvin-Helmholtz instabilities. The blob test result coincides well with the results of the grid-based codes. An inaccurate handling of a density gradient in the standard SPH has been pointed out as the direct reason of the absence of the instabilities. An unphysical force happens at the density gradient even in a pressure equilibrium, and repulses particles from the initial density discontinuity. Therefore, the initial perturbation damps, and a gap forms at the discontinuity. The unphysical force has been studied in terms of the consistency of a numerical scheme. Contrary to the standard SPH, the momentum equation of the Godunov SPH doesnt use the particle approximation, and has been derived from the kernel convolution or a new Lagrangian function. The new Lagrangian function used in the Godunov SPH is more analogous to the real Lagrangian function for continuum. The momentum equation of the Godunov SPH has much better linear consistency, so the unphysical force is greatly reduced compared to the standard SPH in a high density contrast.Comment: 11 pages, 7 figures, Accepted for publication in MNRA

Diagnosis of Gastric Cancer in Early Stage — The Clinical Ob­servation of Operated Cases

1. An attempt has been made to find the diagnostic criteria for early gastric cancer. It is most important to detect the evidences or suspected features of the malignant growth in incipient stage in order to attain the radical cure by surgical operation. 2. Twelve patients with early gastric cancer (groups A and B) were selected out of 476 patients who had undergone gastrectomy during the past three years in the Okayama Saiseikai General Hospital. The other 6 patients in the &#34;precancerous group&#34; (group C) were also studied, who had abnormal epithelial proliferation in the resected stomach membrane during the same period. 3. The processes of discovery of early cancer have been described. Fairly precise diagnosis can be made in the mucosal carcinoma, but it is not in the ulcer-carcinoma. It was generally difficult to estimate the degree of the malignancy and the extension of the growth preoperatively. 4. The details of the diagnostic aids are as follows. i. Negative occult blood of stool does not always mean the definite diagnostic aid. ii. The malignant gastric change may occur even in non-anacidity. Further investigations should be followed up on gastric ulcer patients if malignant alteration is under the consideration. iii. Minor roentgenological findings, such as the absence or irregularity of mucosal folds, rigid and/or overlapped contour, localized absence or decrease of the peristaltic waves and absence or bow-shaped deformity of the angulus, are of important significance. Such changes should be minutely sought for by X-ray film examination. iv. On gastroscopy and gastrocamera photography, such changes as erosion or irregular granular thickening of the membrane with abnormal reddening and edematous appearance, irregularity of ulcer edge, uneven swelling on ulcer margin with reddening and unsharpness of the edge of adherent coat on ulcer floor, must be noted in the early gastric cancer. v. It is not safe to leave a patient having stomach ulceration under a mere conservative management because it is often quite difficult to dissolve the question of malignancy of the lesion with all sorts of examinations. vi. So far as clinical examinations have indicated malignancy, histological examination must be carried out immediately at the time of operation, even when malignant lesion is absent in inspection and palpation on the exposure of the stomach. vii. On the gross observation of the resected stomach, a particular attention must be paid to erosion, depression or atrophy, irregular granular thickening and abnormal reddening on the restricted areas of the mucosal surface.</p

Peripheral Blood as a Preferable Source of Stem Cells for Salvage Transplantation in Patients with Graft Failure after Cord Blood Transplantation: A Retrospective Analysis of the Registry Data of the Japanese Society for Hematopoietic Cell Transplantation

To compare the different stem cell sources used in salvage transplantation for graft failure (GF) after cord blood transplantation (CBT), we retrospectively analyzed data of 220 patients who developed GF after undergoing CBT between January 2001 and December 2007 and underwent a second hematopoietic stem cell transplantation (HSCT) within 3 months. The donor sources for salvage HSCT were cord blood (n = 180), peripheral blood stem cells (PBSCs; n = 24), and bone marrow (BM; n = 16). The cumulative incidence of neutrophil engraftment on day 30 after the second HSCT was 39% with CB, 71% with PBSCs, and 75% with BM. Multivariate analysis revealed that PBSC and BM grafts were associated with a significantly higher engraftment rate than CB (hazard ratio [HR], 7.77; P < .001 and HR, 2.81; P = .016, respectively). Although the incidence of grade II-IV acute graft-versus-host disease was significantly higher in the PBSC group than in the CB group (HR, 2.83; P = .011), the incidence of 1-year nonrelapse mortality was lower in the PBSC group than in the CB group (HR, 0.43; P = .019), and 1-year overall survival was superior in the PBSC group compared with the CB group (HR, 0.45; P = .036). Our results suggest that PBSC is the preferable source of stem cells in salvage HSCT for GF after CBT

An examination of the Apo-1/Fas promoter Mva I polymorphism in Japanese patients with multiple sclerosis

BACKGROUND: The Apo-1/Fas (CD95) molecule is an apoptosis-signaling cell surface receptor belonging to the tumor necrosis factor (TNF) receptor family. Both Fas and Fas ligand (FasL) are expressed in activated mature T cells, and prolonged cell activation induces susceptibility to Fas-mediated apoptosis. The Apo-1/Fas gene is located in a chromosomal region that shows linkage in multiple sclerosis (MS) genome screens, and studies indicate that there is aberrant expression of the Apo-1/Fas molecule in MS. METHODS: Mva I polymorphism on the Apo-1/Fas promoter gene was detected by PCR-RFLP from the DNA of 114 Japanese patients with conventional MS and 121 healthy controls. We investigated the association of the Mva I polymorphism in Japanese MS patients using a case-control association study design. RESULTS: We found no evidence that the polymorphism contributes to susceptibility to MS. Furthermore, there was no association between Apo-1/Fas gene polymorphisms and clinical course (relapsing-remitting course or secondary-progressive course). No significant association was observed between Apo-1/Fas gene polymorphisms and the age at disease onset. CONCLUSIONS: Overall, our findings suggest that Apo-1/Fas promoter gene polymorphisms are not conclusively related to susceptibility to MS or the clinical characteristics of Japanese patients with MS

Human NK cell development in hIL-7 and hIL-15 knockin NOD/SCID/IL2rgKO mice.

The immune system encompasses acquired and innate immunity that matures through interaction with microenvironmental components. Cytokines serve as environmental factors that foster functional maturation of immune cells. Although NOD/SCID/IL2rgKO (NSG) humanized mice support investigation of human immunity in vivo, a species barrier between human immune cells and the mouse microenvironment limits human acquired as well as innate immune function. To study the roles of human cytokines in human acquired and innate immune cell development, we created NSG mice expressing hIL-7 and hIL-15. Although hIL-7 alone was not sufficient for supporting human NK cell development in vivo, increased frequencies of human NK cells were confirmed in multiple organs of hIL-7 and hIL-15 double knockin (hIL-7xhIL-15 KI) NSG mice engrafted with human hematopoietic stem cells. hIL-7xhIL-15 KI NSG humanized mice provide a valuable in vivo model to investigate development and function of human NK cells

Anti-Tumor Effect against Human Cancer Xenografts by a Fully Human Monoclonal Antibody to a Variant 8-Epitope of CD44R1 Expressed on Cancer Stem Cells

BACKGROUND: CD44 is a major cellular receptor for hyaluronic acids. The stem structure of CD44 encoded by ten normal exons can be enlarged by ten variant exons (v1-v10) by alternative splicing. We have succeeded in preparing MV5 fully human IgM and its class-switched GV5 IgG monoclonal antibody (mAb) recognizing the extracellular domain of a CD44R1 isoform that contains the inserted region coded by variant (v8, v9 and v10) exons and is expressed on the surface of various human epithelial cancer cells. METHODS AND PRINCIPAL FINDINGS: We demonstrated the growth inhibition of human cancer xenografts by a GV5 IgG mAb reshaped from an MV5 IgM. The epitope recognized by MV5 and GV5 was identified to a v8-coding region by the analysis of mAb binding to various recombinant CD44 proteins by enzyme-linked immunosorbent assay. GV5 showed preferential reactivity against various malignant human cells versus normal human cells assessed by flow cytometry and immunohistological analysis. When ME180 human uterine cervix carcinoma cells were subcutaneously inoculated to athymic mice with GV5, significant inhibition of tumor formation was observed. Furthermore, intraperitoneal injections of GV5markedly inhibited the growth of visible established tumors from HSC-3 human larynx carcinoma cells that had been subcutaneously transplanted one week before the first treatment with GV5. From in vitro experiments, antibody-dependent cellular cytotoxicity and internalization of CD44R1 seemed to be possible mechanisms for in vivo anti-tumor activity by GV5. CONCLUSIONS: CD44R1 is an excellent molecular target for mAb therapy of cancer, possibly superior to molecules targeted by existing therapeutic mAb, such as Trastuzumab and Cetuximab recognizing human epidermal growth factor receptor family

Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan : a study of 113 Japanese families

Autosomal dominant cerebellar ataxia (ADCA) is a genetically heterogeneous group of neurodegenerative disorders. To shed further light on the clinical and genetic spectrum of ADCA in Japan, we conducted a study to determine the frequency of a new variety of different subtypes of SCAs among ADCA patients. This current study was carried out from April 1999 to December 2006 on the basis of patients with symptoms and signs of ADCA disorders. PCR and/or direct sequencing were evaluated in a total of 113 families. Among them, 35 families were found to have the mutation associated with SCA6, 30 with SCA3, 11 with SCA1, five with SCA2, five with DRPLA, and one with SCA14. We also detected the heterozygous −16C → T single nucleotide substitution within the puratrophin-1 gene responsible for 16q22.1-linked ADCA in ten families. In this study, unusual varieties of SCA, including 27, 13, 5, 7, 8, 12, 17, and 16 were not found. Of the 113 patients, 14% had as yet unidentified ADCA mutations. The present study validates the prevalence of genetically distinct ADCA subtypes based on ethnic origin and geographical variation, and shows that 16q-linked ADCA has strong hereditary effects in patients with ADCAs in Japan