Measurement of Proteasome Activity in Peripheral Blood Mononuclear Cells as an Indicator of Susceptibility to Bortezomib-Induced Severe Neurological Adverse Events in Patients with Multiple Myeloma.

Aims: To explore the biomarker for predicting the occurrence of adverse events in myeloma patients treated by intravenous bortezomib, we measured proteasome activity in peripheral blood mononuclear cells.

Methods: Samples were obtained from 34 bortezomib-naïve patients. Proteasome activity was measured at pre- and postchemotherapy phase by using a synthetic substrate.

In vivo regulation of erythropoiesis by chemically inducible dimerization of the erythropoietin receptor intracellular domain.

Erythropoietin (Epo) and its receptor (EpoR) are required for the regulation of erythropoiesis. Epo binds to the EpoR homodimer on the surface of erythroid progenitors and erythroblasts, and positions the intracellular domains of the homodimer to be in close proximity with each other. This conformational change is sufficient for the initiation of Epo-EpoR signal transduction.

Suitable drug combination with bortezomib for multiple myeloma under stroma-free conditions and in contact with fibronectin or bone marrow stromal cells.

Several clinical trials have demonstrated the effectiveness of bortezomib in combination with various anti-myeloma agents; however, no definitive information is available regarding drugs best suited for use in combination with bortezomib. Using isobologram analysis, we investigated the combined effects of bortezomib with four key anti-myeloma drugs (melphalan, cyclophosphamide, doxorubicin and lenalidomide), which represent components of major bortezomib-based regimens with corticosteroids, in three myeloma cell lines (U266, RPMI8226 and KMS-12BM) under various conditions. Melphalan showed the best performance with bortezomib under all culture conditions tested (liquid culture, on fibronectin-coated plates, and co-culture with bone marrow stromal cells), whereas cyclophosphamide was antagonistic with bortezomib especially in the presence of stromal cells.

Bortezomib therapy-related lung disease in Japanese patients with multiple myeloma: incidence, mortality and clinical characterization.

Because of the potentially high mortality rate (6.5%) associated with bortezomib-induced lung disease (BILD) in Japanese patients with relapsed or refractory multiple myeloma, we evaluated the incidence, mortality and clinical features of BILD in a Japanese population. This study was conducted under the Risk Minimization Action Plan (RMAP), which was collaboratively developed by the pharmaceutical industry and public health authority.

Phase I/II study of bortezomib-melphalan-prednisolone for previously untreated Japanese patients with multiple myeloma.

This phase I/II study was conducted to evaluate the safety and efficacy of bortezomib-melphalan-prednisolone in Japanese patients with previously untreated multiple myeloma who are ineligible for hematopoietic stem cell transplantation. One hundred and one patients were enrolled, and 99 patients received up to nine 6-week cycles of bortezomib (0.7/1.

Disruption of the Hbs1l-Myb locus causes hereditary persistence of fetal hemoglobin in a mouse model.

The human β-globin locus is comprised of embryonic, fetal, and adult globin genes, each of which is expressed at distinct stages of pre- and postnatal development. Functional defects in globin proteins or expression results in mild to severe anemia, such as in sickle-cell disease or β-thalassemia, but the clinical symptoms of both disorders are ameliorated by persistent expression of the fetal globin genes. Recent genome-wide association studies (GWAS) identified the intergenic region between the HBS1L and MYB loci as a candidate modifier of fetal hemoglobin expression in adults.

Phase I/II study of decitabine in patients with myelodysplastic syndrome: a multi-center study in Japan.

The management of myelodysplastic syndrome (MDS) remains challenging. We performed a phase I/II study to evaluate the safety and efficacy of decitabine in patients with MDS in Japan. Patients with MDS with red cell transfusion dependence or 5-30% blasts in marrow and with an International Prognostic Scoring System score of intermediate-1 or higher were eligible.

Adherence to the standard dose of imatinib, rather than dose adjustment based on its plasma concentration, is critical to achieve a deep molecular response in patients with chronic myeloid leukemia.

The correlation between imatinib (IM) trough plasma concentration (Cmin) and clinical response was assessed in patients with chronic-phase chronic myeloid leukemia. The Cmin correlated with neither the achievement of complete cytogenetic response (977 vs. 993 ng/ml, P = 0.

[Successful treatment with rituximab in a patient with refractory thrombotic thrombocytopenic purpura refractory to plasma exchange].

We report a patient with refractory idiopathic thrombotic thrombocytopenic purpura (TTP) who was successfully treated with rituximab. A 50-year-old woman was referred to our hospital with progressive psychoneurotic symptoms, hemolytic anemia and thrombocytopenia. The diagnosis of TTP was confirmed by the absence of ADAMTS13 activity with the presence of circulating ADAMTS13 inhibitor.

Detection of the STAT5B-RARA fusion transcript in acute promyelocytic leukemia with the normal chromosome 17 on G-banding.

Acute promyelocytic leukemia (APL) is characterized by chromosomal rearrangements of 17q21, leading to fusion of the gene-encoding retinoic acid receptor alpha (RARA) with a number of alternative partner genes. Signal transducer and activator of transcription 5 beta (STAT5B) is one of the alternative partners. We report a rare case of APL with STAT5B-RARA fusion transcript and the normal chromosome 17 on G-banding.

Quinupristin/dalfopristin and voriconazole controlled Staphylococcus epidermidis pneumonia and chronic necrotizing aspergillosis in a patient with severe lung degradation consequent to multiple treatments for Hodgkin's lymphoma.

We report here a 34-year-old woman with complicated severe opportunistic pulmonary infection, who was treated with the newly developed antibiotics quinupristin/dalfopristin (QPR/DPR) and voriconazole. She had received repeated chemotherapy, irradiation of the left lung, autologous and allogeneic bone marrow transplantation (BMT), and segmentectomy of the base of the left lung as treatments for Hodgkin's lymphoma. Although she had been in complete remission (CR), the structure of the left lung was severely degraded.

Transgene insertion in proximity to the c-myb gene disrupts erythroid-megakaryocytic lineage bifurcation.

The nuclear proto-oncogene c-myb plays crucial roles in the growth, survival, and differentiation of hematopoietic cells. We established three lines of erythropoietin receptor-transgenic mice and found that one of them exhibited anemia, thrombocythemia, and splenomegaly. These abnormalities were independent of the function of the transgenic erythropoietin receptor and were observed exclusively in mice harboring the transgene homozygously, suggesting transgenic disruption of a certain gene.

Therapy-related acute myeloid leukemia 6 years after clonal detection of inv(11)(q21q23) and MLL gene rearrangement.

Results of recent studies with animal models suggest that expression of MLL fusion proteins promotes acute leukemogenesis. However, the most potent MLL fusion proteins are not sufficient for the development of acute myeloid leukemia (AML). The clinical data on the pathogenesis of this type of leukemia are limited.

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.

T-cell acute lymphoblastic leukemia with add(1)(p36) and del(12)(p11) following acute myelocytic leukemia with partial deletion of 9p.

We describe the case of a 40-year-old man whose disease was initially diagnosed as acute myelocytic leukemia. The patient achieved remission with chemotherapy, but relapsed shortly afterwards with an acute T-cell lymphoblastic leukemia. He died of intracranial bleeding.

Association of non-alcoholic steatohepatitis (NASH) with chronic neutrophilic leukemia.

A 54-yr-old female having chronic neutrophilic leukemia (CNL) associated with severe liver injury is presented. Physical examination on admission showed severe jaundice, hepatosplenomegaly, massive ascites, and pretibial edema. Complete blood count showed a hemoglobin level of 9.

Rapidly progressive Lennert's lymphoma terminating in fulminant hepatic failure.

A 65-year-old male with rapidly progressive Lennert's lymphoma terminating in fulminant hepatic failure is presented. Staging radiological studies revealed that he had cervical and mediastinal lymph node swellings and multiple nodular lesions in the spleen. Lymph node biopsy specimens showed the proliferation of epithelioid cells interspersed with large blastic lymphocytes.

Successful treatment of a patient with subcutaneous panniculitis-like T-cell lymphoma with high-dose chemotherapy and total body irradiation.

A 24-yr-old man was referred for fever, right cheek swelling, subcutaneous tumor and liver dysfunction. Physical examination showed an elastic hard subcutaneous tumor on the right cheek, left axillary lymph node swelling and multiple small subcutaneous tumors in the trunk. Laboratory examinations showed elevated levels of transaminase, soluble interleukin-2 receptor and ferritin.

Nodal CD8 positive cytotoxic T-cell lymphoma: a distinct clinicopathological entity.

We studied 11 cases of nodal cytotoxic T-cell lymphoma, which express the CD8+ phenotype and cytotoxic molecules (T-cell intracellular antigen-1, granzyme B and perforin), to characterize the clinicopathologic spectrum of these neoplasms. The 11 cases consisted of four men and seven women, aged 5 to 82 years (mean, 53 years). All cases were nodal, and eight of 11 had extranodal involvement, the most common being in bone marrow (eight cases) and liver (six cases).

Erythroid-specific expression of the erythropoietin receptor rescued its null mutant mice from lethality.

Erythropoietin (Epo) and its receptor (EpoR) are indispensable to erythropoiesis. Although roles besides angiogenesis, such as neuroprotection and heart development, have been reported for the Epo-EpoR system, the precise contribution of Epo-EpoR to these nonhematopoietic tissues requires clarification. Exploiting a GATA-1 minigene cassette with hematopoietic regulatory domains, we established 2 lines of transgene-rescued EpoR-null mutant mice expressing EpoR exclusively in the hematopoietic lineage.

A patient with acquired pure red cell aplasia showing a positive antiglobulin test and the presence of inhibitor against erythroid precursors.

A 66-year-old Japanese man developed severe anemia and erythroid hypoplasia in bone marrow without any significant underlying disease. The results of an antiglobulin test were strongly positive, and serum erythropoietin (Epo) was high. The patient was diagnosed as having acquired pure red cell aplasia (PRCA) and was treated with steroids.

GATA suppresses erythropoietin gene expression through GATA site in mouse erythropoietin gene promoter.

The promoter and enhancer elements of the mouse erythropoietin (mEpo) gene, which have high homology with those of the human erythropoietin (hEpo) gene, were fused with luciferase. The construct was transfected into erythropoietin-producing hepatoma cell line (Hep3B) cells by lipofectin with lacZ as an internal standard. The wild type (TGATA) showed a 39.

L-arginine rescues decreased erythropoietin gene expression by stimulating GATA-2 with L-NMMA.

Background: NG-monomethyl-L-arginine (L-NMMA) decreases the expression of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) and increases the expression of GATA-2 mRNA and levels of GATA-2 binding activity, thereby inhibiting erythropoietin (Epo) promoter activity and causing a decrease in the expression of Epo protein. In the present study, we examined the effect of L-arginine on Epo gene expression in Hep3B cells and BDF1 mice.

Methods: Hep3B cells were incubated with and without different concentrations of L-NMMA and/or l-arginine.