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Shin Kaneko

Publications and source records attributed to Shin Kaneko.

8 recordsLinked to original sources
PubMed2005

An in vivo assay for retrovirally transduced human peripheral T lymphocytes using nonobese diabetic/severe combined immunodeficiency mice.

OBJECTIVE: Availability of a mouse model to analyze human peripheral lymphocytes genetically modified with retroviral vectors would be useful in T-cell-directed gene transfer studies. To address this issue, we assessed the ability of nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice to maintain such cells in their peripheral blood. MATERIALS AND METHODS: Human peripheral lymphocytes stimulated with recombinant human interleukin-2 (rhIL-2) and anti-CD3 and CD28 antibodies were transduced with the enhanced green fluorescent protein (EGFP) gene using the retroviral vector GCsap(MSCV) and then transplanted into NOD/SCID mice at 1 x 10(8) cells per mouse. RESULTS: Transplanted human peripheral lymphocytes survived and expressed EGFP in the mice over the 6- to 8-week posttransplant period without any signs of graft-vs-host disease. Of importance was that these cells remained at the G(0)/G(1) stage and again proliferated in response to cytokines when cultured in vitro. Interestingly, the mice in which the transduced T lymphocytes remained at the resting stage clearly elucidated the superiority of the murine stem cell virus (MSCV) LTR to maintain the transgene expression by nonproliferating T lymphocytes over the Moloney murine leukemia virus (MoMLV)- and myeloproliferative sarcoma virus (MPSV)-derived LTRs, which was obscure in in vitro culture where the transduced lymphocytes was being stimulated with rhIL-2. CONCLUSIONS: The mouse model and GCsap(MSCV) vector described herein comprise a simple and reliable in vivo assay system for studies of gene and cell therapies employing human peripheral lymphocytes.

Animals↗
PubMed2005

Characterization of a myeloma patient with a life-threatening hemorrhagic diathesis: presence of a lambda dimer protein inhibiting shear-induced platelet aggregation by binding to the A1 domain of von Willebrand factor.

We have identified a patient with IgD lambda-type multiple myeloma who was characterized by a severe bleeding tendency, especially after puncture of arterial vessels. Both the bleeding time (>25 min) and activated partial thromboplastin time (APTT) were prolonged. To clarify the underlying pathogenesis, we purified the APTT-prolonging activity from the patient's serum. The purified protein was a highly negatively-charged homodimer of the lambda light chain. The lambda dimer protein (M-protein) inhibited ristocetinand high shear-induced platelet aggregation, dependent on platelet glycoprotein Ibalpha (GPIbalpha), but not epinephrine-, collagen-, ADP-, thrombin-, or botrocetin-induced platelet aggregation. The lambda dimer protein inhibited the binding of platelets to immobilized or ristocetin-treated von Willebrand factor (VWF). Furthermore, a 39/34 kD fragment of VWF encompassing the A1 domain specifically bound to the immobilized lambda dimer protein in the presence of ristocetin, suggesting that the lambda dimer protein directly binds to the A1 domain of VWF. To help elucidate the binding site within the A1 domain, binding of ristocetin-treated VWF to the immobilized lambda dimer protein was assayed in the presence of various anti-A1 domain monoclonal antibodies. Based on these data, we conclude that the lambda dimer protein binds to the region of the A1 domain composed of helices alpha3 and alpha4 and thus interferes with VWF-GPIbalpha interaction. The existence of a protein that inhibits high shear-induced platelet aggregation in acquired von Willebrand disease (VWD) has only rarely been reported. The results suggest that the hemostatic function in arteries with high shear force is profoundly disrupted if the binding of GPIbalpha to VWF is abrogated, supporting the relevance of shear-induced VWF interaction with GPIbalpha in the initiation of the hemostatic process.

Adenosine Diphosphate↗
PubMed2004

Clinicopathological features and prognostic factors of Japanese patients with "peripheral T-cell lymphoma, unspecified" diagnosed according to the WHO classification.

Clinicopathological features of 36 patients, male: 58.3%; median: 68 years, with "peripheral T-cell lymphoma, unspecified" diagnosed by the WHO criteria were reviewed. Majority (69.4%) had stage IV disease with frequent involvements into bone marrow, spleen, liver, and skin. According to the IPI, 72.2% were categorized as high or high-intermediate risk group. CR and PR were achieved in 12 and 10 out of 31 patients treated by CHOP-based chemotherapy, respectively. One- and two-year overall survivals were 60.6 and 25.0%, respectively. Performance status, serum LDH, and B symptom were significant prognostic factors. Survival of CD4-/CD8+ cases, corresponding to cytotoxic T-cell lymphoma, was significantly worse than that of CD4+/CD8-.

Adult↗
PubMed2004

Association of pyoderma gangrenosum and sterile osteomyelitis in a patient having myelodysplastic syndrome with der(1;7)(q10;q10).

Neutrophilic dermatoses such as Sweet's disease and pyoderma gangrenosum (PG) are occasionally associated with myelodysplastic syndrome (MDS). We present here a 67-yr-old male having PG and sterile osteomyelitis in association with underlying MDS (refractory anemia) and Crohn's disease. To establish the diagnosis of MDS, sternal bone marrow puncture was performed, which showed chromosomal abnormality containing der(1;7)(q10;q10). After the puncture, he suffered from gradually progressive skin ulceration, flare, and bone pain. Magnetic resonance imaging (MRI) of the sternum showed severe inflammation in the sternum and the overlying subcutaneous tissue. All of the cultures obtained from the wound were negative for both bacteria and fungus. Biopsy was performed from the antero-sternal skin lesion, which showed epidermal ulceration with prominent infiltration of neutrophils. He was thus diagnosed as having PG and sterile osteomyelitis, and was treated with prednisolone, which completely resolved the symptoms. We consider that the bone marrow aspiration in the present patient provoked PG and sterile osteomyelitis. As was previously reported by others, certain chromosomal abnormalities in MDS may be related with the development of neutrophilic dermatoses.

Aged↗
PubMed2002

Erythroid expansion mediated by the Gfi-1B zinc finger protein: role in normal hematopoiesis.

In the search for genes expressed in hematopoietic stem cells, we identified that the expression of Gfi-1B (growth factor independence-1B) is highly restricted to hematopoietic stem cells, erythroblasts, and megakaryocytes. Gfi-1 and Gfi-1B are zinc finger proteins that share highly conserved SNAG and 6 zinc finger domains. Gfi-1 has been characterized as an oncogene involved in lymphoid malignancies in mice. In contrast, role of Gfi-1B in hematopoiesis has not been well characterized. In this study, we analyzed its function in human hematopoiesis. Enforced expression of Gfi-1B in human CD34(+) hematopoietic progenitors induced a drastic expansion of erythroblasts in an erythropoietin-independent manner. Expression of Gfi-1B did not promote erythroid commitment, but enhanced proliferation of immature erythroblasts. Erythroblasts expanded by exogenous Gfi-1B, however, failed to differentiate beyond proerythroblast stage and showed massive apoptosis. These biologic effects of Gfi-1B were mediated through its zinc finger domain, but not by the SNAG or non-zinc finger domain. Proliferation of erythroblasts was associated with sustained expression of GATA-2 but not of GATA-1, indicating a potential link between Gfi-1B and GATA family regulators. Importantly, the function of Gfi-1B to modulate transcription was dependent on promoter context. In addition, activation of transcription of an artificial promoter was mediated through its zinc finger domain. These findings establish Gfi-1B as a novel erythroid regulator and reveal its specific involvement in the regulation of erythroid cell growth through modulating erythroid-specific gene expression.

Animals↗
PubMed2002

Reciprocal roles for CCAAT/enhancer binding protein (C/EBP) and PU.1 transcription factors in Langerhans cell commitment.

Myeloid progenitor cells give rise to a variety of progenies including dendritic cells. However, the mechanism controlling the diversification of myeloid progenitors into each progeny is largely unknown. PU.1 and CCAAT/enhancing binding protein (C/EBP) family transcription factors have been characterized as key regulators for the development and function of the myeloid system. However, the roles of C/EBP transcription factors have not been fully identified because of functional redundancy among family members. Using high titer--retroviral infection, we demonstrate that a dominant-negative C/EBP completely blocked the granulocyte--macrophage commitment of human myeloid progenitors. Alternatively, Langerhans cell (LC) commitment was markedly facilitated in the absence of tumor necrosis factor (TNF)alpha, a strong inducer of LC development, whereas expression of wild-type C/EBP in myeloid progenitors promoted granulocytic differentiation, and completely inhibited TNFalpha-dependent LC development. On the other hand, expression of wild-type PU.1 in myeloid progenitors triggered LC development in the absence of TNFalpha, and its instructive effect was canceled by coexpressed C/EBP. Our findings establish reciprocal roles for C/EBP and PU.1 in LC development, and provide new insight into the molecular mechanism of LC development, which has not yet been well characterized.

CCAAT-Enhancer-Binding Proteins↗
PubMed2002

Clonal identification and characterization of self-renewing pluripotent stem cells in the developing liver.

Using flow cytometry and single cell-based assays, we prospectively identified hepatic stem cells with multilineage differentiation potential and self-renewing capability. These cells could be clonally propagated in culture where they continuously produced hepatocytes and cholangiocytes as descendants while maintaining primitive stem cells. When cells that expanded in vitro were transplanted into recipient animals, they morphologically and functionally differentiated into hepatocytes and cholangiocytes with reconstitution of hepatocyte and bile duct structures. Furthermore, these cells differentiated into pancreatic ductal and acinar cells or intestinal epithelial cells when transplanted into pancreas or duodenal wall. These data indicate that self-renewing pluripotent stem cells persist in the developing mouse liver and that such cells can be induced to become cells of other organs of endodermal origin under appropriate microenvironment. Manipulation of hepatic stem cells may provide new insight into therapies for diseases of the digestive system.

Animals↗