Direct evidence of substorm-related impulsive injections of electrons at Mercury.

Mercury's magnetosphere is known to involve fundamental processes releasing particles and energy like at Earth due to the solar wind interaction. The resulting cycle is however much faster and involves acceleration, transport, loss, and recycling of plasma. Direct experimental evidence for the roles of electrons during this cycle is however missing. Here we show that in-situ plasma observations obtained during BepiColombo's first Mercury flyby reveal a compressed magnetosphere hosts of quasi-periodic fluctuations, including the original observation of dynamic phenomena in the post-midnight, southern magnetosphere. The energy-time dispersed electron enhancements support the occurrence of substorm-related, multiple, impulsive injections of electrons that ultimately precipitate onto its surface and induce X-ray fluorescence. These observations reveal that electron injections and subsequent energy-dependent drift now observed throughout Solar System is a universal mechanism that generates aurorae despite the differences in structure and dynamics of the planetary magnetospheres.

Comparison of autologous hematopoietic cell transplantation and chemotherapy as postremission treatment in non-M3 acute myeloid leukemia in first complete remission.

UNLABELLED: Randomized trials of acute myeloid leukemia (AML) in first complete remission (CR1) showed that autologous hematopoietic cell transplantation (auto-HCT) improves relapse-free survival (RFS) but not overall survival (OS), compared with chemotherapy. Using a database of 2518 adult patients with AML in CR1, we conducted a 5-month landmark analysis and found that auto-HCT improves 3-year RFS but not OS compared with chemotherapy. INTRODUCTION: A number of randomized trials in patients with AML in CR1 have been conducted and they showed that auto-HCT improves RFS but not OS, compared with chemotherapy. However, because these trials have had compliance problems, the value of auto-HCT still has not been clearly established. PATIENTS AND METHODS: Using a database of 2518 adult patients with AML in CR1, we retrospectively analyzed the outcome of auto-HCT and compared it with intensive nonmyeloablative chemotherapy using landmark analyses. RESULTS: In 103 auto-HCT recipients, OS and RFS at 3 years from treatment were 65% and 57%, respectively. Multivariate analysis showed that unfavorable risk cytogenetics and entry into CR1 after 2 courses of induction treatment predicted a poor outcome. Because the median time interval between CR1 and auto-HCT was 153 days, landmark analyses at 5 months after CR1 were performed to compare 1290 patients who received chemotherapy alone (median age, 52 years; range, 16-70) with 103 who received auto-HCT (median age, 48 years; range, 16-67). Auto-HCT improves 3-year RFS (58% vs. 37%; P < .001) but not OS compared with chemotherapy alone. Among patients with unfavorable risk cytogenetics or those who required 2 courses to reach CR1, there was no significant difference in RFS between the 2 groups. CONCLUSION: Auto-HCT can be considered as a postremission therapy for AML patients with favorable or intermediate risk cytogenetics who achieve CR1 after a single course of induction treatment.

A novel feedback mechanism by Ephrin-B1/B2 in T-cell activation involves a concentration-dependent switch from costimulation to inhibition.

Bidirectional signals via Eph receptors/ephrins have been recognized as major forms of contact-dependent cell communications such as cell attraction and repulsion. T cells express EphBs, and their ligands, the ephrin-Bs, have been known as costimulatory molecules for T-cell proliferation. Recently, another remarkable feature of ephrin-As has emerged in the form of a concentration-dependent transition from promotion to inhibition in axon growth. Here we examined whether this modification plays a role in ephrin-B costimulation in murine primary T cells. Low doses of ephrin-B1 and ephrin-B2 costimulated T-cell proliferation induced by anti-CD3, but high concentrations strongly inhibited it. In contrast, ephrin-B3 showed a steadily increasing stimulatory effect. This modulation was virtually preserved in T cells from mice simultaneously lacking four genes, EphB1, EphB2, EphB3, and EphB6. High concentrations of ephrin-B1/B2, but not ephrin-B3, inhibited the anti-CD3-induced phosphorylation of Lck and its downstream signals such as Erk and Akt. Additionally, high doses of any ephrin-Bs could phosphorylate EphB4. However, only ephrin-B1/B2 but not ephrin-B3 recruited SHP1, a phosphatase to suppress the phosphorylation of Lck. These data suggest that EphB4 signaling could engage in negative feedback to TCR signals. T-cell activation may be finely adjusted by the combination and concentration of ephrin-Bs expressed in the immunological microenvironment.

Pharmacokinetics-based optimal dose prediction of donor source-dependent response to mycophenolate mofetil in unrelated hematopoietic cell transplantation.

Mycophenolate mofetil (MMF) has been widely used for prophylaxis against graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-SCT). However, no clear advantage over methotrexate has been reported, other than reduced incidence of mucositis. We speculated that the wide inter-individual variation of plasma mycophenolic acid (MPA) levels veiled the benefits of MMF. Data from 36 unrelated allogeneic bone marrow (allo-BMT) and cord blood transplantation (CBT) were analyzed retrospectively based on MPA area under the curve (AUC(0-24h)). In allo-BMT, high AUC(0-24h) (>30 µg h/ml) resulted in no incidence of grade II-IV acute/extensive chronic GVHD and tended to show higher overall and disease-free survival, lower relapse rates, and non-relapse mortality. In CBT, AUC(0-24h) less than 30 µg h/ml was sufficient for low incidence of acute/chronic GVHD and high survival. Strong correlation between AUC(0-24h) and C(2h), plasma MPA concentration at 2 h after administration was observed. Single point assessment of C(2h) was shown to provide a useful surrogate of AUC(0-24h) to predict GVHD incidence. The results of this study suggest that individualized MMF dosing in a donor source-dependent fashion may be important for maximizing the benefit of MMF in allo-SCT.

Histiocytic sarcoma with two immunohistopathologically distinct populations.

This report is a case of histiocytic sarcoma (HS), in which tumor cells consist of two immunohistopathologically distinct populations (A) oval CD68+lysozyme+CD163- cells and (B) abundant cytoplasm or spindle-shaped CD68+lysozyme-CD163+ cells. Cervical lymph node was infiltrated mainly by population (A), where chemotherapy was quite effective. On the other hand, vast majority of infiltrated tumor cells in the hilar lymph node belonged to population (B), in which the cells were resistant to chemo-radiotherapy. Considering the poor prognosis of HS, the expression of CD163 could be a marker for resistance to chemo-radiotherapy. It is also notable that CD163-negative stage of HS may exist and still be reactive for the treatment.

Role for vitamin D receptor in the neuronal control of the hematopoietic stem cell niche.

Hematopoietic stem/progenitor cells (HSPCs) are released from the bone marrow to the circulation by the cytokine, granulocyte colony-stimulating factor, via sympathetic nervous system (SNS)-mediated osteoblast suppression. Because the orientation of HSPCs in their osteoblastic niche is reported to be guided by [Ca(2+)], we speculated on a cooperation between the calcium-regulating hormones and SNS in the regulation of HSPC trafficking. Here, we present the severe impairment of granulocyte colony-stimulating factor-induced osteoblast suppression and subsequent HSPC mobilization in vitamin D receptor (VDR)-deficient mice. In osteoblasts, functional VDR possessing, at least in part, a transcriptional activity, was specifically induced by ß2-adrenergic receptor (AR) agonists. While ß2-AR agonists transiently increased mRNA expression of Vdr and its downstream gene, Rankl, 1α,25-dihydroxyvitamin-D(3) sustained the ß2-AR-induced Rankl expression at high level by stabilizing VDR protein. These data suggest that VDR is essential for durable ß2-AR signaling in the stem cell niche. Our study demonstrates not only a novel function of VDR as a critical modulator of HSPC trafficking, but also the presence of a SNS-mediated, bone-remodeling mechanism through VDR. VDR contributes to brain-bone-blood integration in an unanticipated way distinct from other classical calcium-regulating hormones.

Therapy-related, mixed phenotype acute leukemia with t(1;21)(p36;q22) and RUNX1 rearrangement.

We describe here a new case of therapy-related acute leukemia with t(1;21)(p36;q22). A 25-year-old man was admitted because of anemia and thrombocytopenia. Four years before, he had received combination chemotherapy including etoposide for seminoma. Bone marrow was hypercellular, with 49% myeloperoxidase (MPO) staining-negative blasts. Chromosome analysis showed 46,XY,t(1;21)(p36.3;q22)[11]/49,sl,+8,+16,+20[9]. Fluorescence in situ hybridization demonstrated that RUNX1 signals at 21q22 were split onto the der(1)t(1;21) and der(21)t(1;21). Immunophenotypic analyses revealed that blasts were positive for CD19, CD79a, and cytCD22, as well as MPO, CD13, and CD33, fulfilling the diagnostic criteria of mixed phenotype acute leukemia, B/myeloid. The patient died of disease progression after 10 months. Thus, acute leukemia with t(1;21) and RUNX1 rearrangement could be associated with B/myeloid mixed phenotype as well as previous topoisomerase II inhibitor therapy and poor prognoses.

Prognostic factors and outcomes of adult patients with acute myeloid leukemia after first relapse.

BACKGROUND: Patients with acute myeloid leukemia who are treated with conventional chemotherapy still have a substantial risk of relapse; the prognostic factors and optimal treatments after relapse have not been fully established. We, therefore, retrospectively analyzed data from patients with acute myeloid leukemia who had achieved first complete remission to assess their prognosis after first relapse. DESIGN AND METHODS: Clinical data were collected from 70 institutions across the country on adult patients who were diagnosed with acute myeloid leukemia and who had achieved a first complete remission after one or two courses of induction chemotherapy. RESULTS: Among the 1,535 patients who were treated with chemotherapy alone, 1,015 relapsed. Half of them subsequently achieved a second complete remission. The overall survival was 30% at 3 years after relapse. Multivariate analysis showed that achievement of second complete remission, salvage allogeneic hematopoietic cell transplantation, and a relapse-free interval of 1 year or longer were independent prognostic factors. The outcome after allogeneic transplantation in second complete remission was comparable to that after transplantation in first complete remission. Patients with acute myeloid leukemia and cytogenetic risk factors other than inv(16) or t(8;21) had a significantly worse outcome when they did not undergo salvage transplantation even when they achieved second complete remission. CONCLUSIONS: We found that both the achievement of second complete remission and the application of salvage transplantation were crucial for improving the prognosis of patients with acute myeloid leukemia in first relapse. Our results indicate that the optimal treatment strategy after first relapse may differ according to the cytogenetic risk.

Therapy-related myelodysplastic/myeloproliferative neoplasms with del(5q) and t(1;11)(p32;q23) lacking MLL rearrangement.

A 69-year-old man was admitted because of macrocytic anemia and peripheral monocytosis: hemoglobin 75 g/L and white blood cells 16.0x10(9) /L with 22% monocytes. Five years prior, he had received CHOP regimen and radiotherapy for diffuse large B-cell lymphoma. Bone marrow was hypercellular with trilineage dysplasia and 2.4% blasts. Chromosome analysis showed 46,XY,t(1;11)(p32;q23),del(5)(q13q35),+8,inv(9)(p11q13),-15,-21,+mar1. These findings indicated a diagnosis of therapy-related myelodysplastic/myeloproliferative neoplasms (t-MDS/MPN). Fluorescence in situ hybridization revealed that the breakpoint at 11q23 was centromeric to the MLL gene. Taken together with the previously reported cases, trilineage dysplasia and del(5q) without MLL rearrangement suggests that alkylating agents may have a crucial role in the pathogenesis of t-MDS/MPN, which is a rare but recognizable entity.

A novel unbalanced whole-arm translocation der(3;10)(q10;q10) in acute monocytic leukemia.

We describe here a novel unbalanced whole-arm translocation der(3;10)(q10;q10) in a 58-year-old man with acute monocytic leukemia. Bone marrow was massively infiltrated with 22.2% monoblasts, 55.4% promonocytes, and 5.6% monocytes. These monocytic cells were positive for myeloperoxidase and alpha-naphthyl butyrate esterase staining. Surface marker analysis revealed that they were positive for CD4, CD13, CD33, CD56, and HLA-DR but negative for CD14 and CD34. Chromosome analysis of the bone marrow cells showed 46,XY,+3,der(3;10)(q10;q10)[18]/46,XY[2]. Spectral karyotyping confirmed der(3;10)(q10;q10) as a sole structural abnormality. By acquisition of a normal chromosome 3 but not a chromosome 10, the der(3;10)(q10;q10) resulted in trisomy 3q and monosomy 10p. The +3,der(3;10)(q10;q10) is thought to play a crucial role in the pathogenesis of acute monocytic leukemia because of the gain of 3q or the loss of 10p.

Progressive osteosclerosis and visceral calcification after cord blood transplantation.

A 26-year-old woman, who successfully underwent umbilical cord blood transplantation for aplastic anemia 4 years previously, had suffered from hepatosplenic microabscesses caused by unidentifiable grocott stain-positive spores from immediately after the transplantation. At 51 months post-transplant, we attempted bone marrow biopsy from her posterior iliac crest, but failed to penetrate the cortical bone. X-ray of her spine and pelvis showed marked and diffuse osteosclerosis. Retrospective analysis of computed tomography revealed the gradual replacement of sternal, vertebral, and pelvic bone marrow with calcified tissues in addition to the dispersed calcification of the liver, spleen, and kidneys over the last 2 years. The bone mineral density of the lumbar spine had increased but not that of the femoral neck. Biomedical parameters for bone remodeling demonstrated enhanced bone formation as well as bone resorption and secondary hyperparathyroidism. Based on the past reports, we suggest that chronic fungal infection, which caused visceral calcification, induced the production of humoral factors for osteoblastic activation.

Duplication of isodicentric chromosome 21, idic(21)(p11.2), leading to pentasomy 21q in acute myeloid leukemia with multilineage dysplasia.

Isodicentric chromosome 21, idic(21)(p11.2), is a rare but recurrent cytogenetic aberration in acute lymphoblastic leukemia. We describe here a novel case of acute myeloid leukemia (AML) with double idic(21)(p11.2). A 35-year-old man was diagnosed as having de novo AML with multilineage dysplasia because of 30% myeloperoxidase-positive blasts and trilineage dysplasia in the bone marrow. Surface marker analysis revealed that the blasts were positive for CD7, CD13, CD33, CD34, and HLA-DR. Chromosome analysis and spectral karyotyping showed 47,XY,+21,idic(21)(p11.2)x2, leading to pentasomy 21q. Fluorescence in situ hybridization demonstrated two RUNX1 signals on the idic(21)(p11.2), resulting in a total of five RUNX1 signals in metaphase spreads and interphase nuclei. These results suggest that the idic(21)(p11.2) could be implicated also in the pathogenesis of AML through amplification of genes including RUNX1 located on 21q.

Inhibition of G(1) to S phase progression by a novel zinc finger protein P58(TFL) at P-bodies.

We recently reported the translocation of the immunoglobulin (Ig) light chain kappa locus gene with a possible tumor suppressor gene, TFL, in transformed follicular lymphoma. However, the functional significance in cell transformation remains to be elucidated. Here, we first identified two gene products, P58(TFL) and P36(TFL), derived by alternative splicing. The expression was prominent in normal human lymphocytes but defective in some leukemia/lymphoma cell lines. Overexpression of either protein in a mouse pro-B cell line, Ba/F3, and a human leukemia cell line, Jurkat, inhibited G(1) to S phase progression through suppression of retinoblastoma protein (Rb) phosphorylation. The dominant gene product, P58(TFL), colocalized with mRNA-processing body markers, eukaryotic translation initiation factor 2C and DCP1 decapping-enzyme homolog A, but not with a stress granule maker, T-cell intracellular antigen 1, in the cytoplasm. Taken together with the unique CCCH-type zinc finger motif, the present study suggests that P58(TFL) could play an important role in the regulation of cell growth through posttranscriptional modification of cell cycle regulators, at least partially, upstream of Rb.

[Defibrotide therapy for patients with sinusoidal obstruction syndrome after hematopoietic stem cell transplantation].

Sinusoidal obstruction syndrome (SOS) is one of the life-threatening complications caused by endothelial damage to the hepatic sinusoids after hematopoietic stem cell transplantation. However, a satisfactory treatment for SOS has not yet been established. Defibrotide has anti-thrombotic, anti-ischemic, anti-inflammatory, and thrombolytic properties without systemic anticoagulant effects. We treated eight post-transplant SOS patients with defibrotide. Three patients responded to the therapy and the initial response was observed within a week. In addition to the improvement of liver function, rapid recovery of response to diuretic drugs followed by the improvement of renal function was observed. All of the five patients with respiratory dysfunction died despite administration of defibrotide, suggesting that early treatment might lead to better outcomes. There were no severe adverse effects directly due to defibrotide administration. Defibrotide seems to be a promising treatment for SOS, and the initiation of a clinical study in Japan would be important.

Unbalanced whole-arm translocation der(5;19)(p10;q10) is a novel and recurrent cytogenetic aberration in myelodysplastic syndrome.

We describe here two cases of myelodysplastic syndrome (MDS) with a novel unbalanced translocation der(5;19)(p10;q10). Both patients had complex karyotypes including der(5;19) accompanied by an extra chromosome 19, resulting in deletion of the whole long arm of chromosome 5. Furthermore, these patients presented several common clinical and hematological characteristics: MDS subtypes as refractory anemia with excess of blasts (RAEB)-1 or RAEB-2, marked anemia and thrombocytopenia without neutropenia, leukoerythroblastosis, trilineage dysplasia with prominent dyserythropoiesis, CD7 expression in blasts, and association with abnormalities of chromosomes 6, 17 and 18. These findings indicate that der(5;19)(p10;q10) may play a crucial role in the pathogenesis of high-risk MDS as a rare but recurrent translocation.

Pharmacokinetics-based optimal dose-exploration of mycophenolate mofetil in allogeneic hematopoietic stem cell transplantation.

For better clinical outcomes of mycophenolate mofetil (MMF) in allogeneic hematopoietic stem cell transplantation (alloSCT), higher mycophenolic acid (MPA) plasma levels are proposed to be desirable. Here, we investigate the optimal MMF dosing strategy based on pharmacokinetic studies in 20 Japanese alloSCT patients. The first 11 patients received MMF twice daily at an escalated dose from 15 mg/kg, according to real-time pharmacokinetic monitoring of the total MPA area under the curve (AUC). In the subsequent nine patients, MMF was given at a fixed dose of 1,000 mg three-times daily. The pharmacokinetic data revealed that the dose escalation in each individual did not always increase the AUC. In contrast, the increase of dosing frequency could statistically keep higher MPA plasma levels, as reflected in higher concentration at steady state (C (ss)) or trough value (C (trough)). There was no symptomatic adverse event in both groups. These results suggest that MMF administration of every 8 h after alloSCT would be better to maintain higher MPA plasma levels than that of every 12 h even in the same daily dose. Further studies are necessary to confirm the clinical benefit of MMF to prevent graft failure, as well as severe aGVHD.

Imatinib resistance in a novel translocation der(17)t(1;17)(q25;p13) with loss of TP53 but without BCR/ABL kinase domain mutation in chronic myelogenous leukemia.

We describe here two novel translocations, t(7;14)(p22;q13) and der(17)t(1;17)(q25;p13), in a 41-year-old man with an accelerated phase (AP) of chronic myelogenous leukemia (CML). Chromosome analysis initially showed 46,XY,t(7;14)(p13;q22),t(9;22)(q34;q11.2)[20]. In 3 years, the karyotype evolved to 45,X,-Y,der(7)t(7;14)(p13;q22),t(9;22)(q34;q11.2),-14,der(17)t(1;17)(q25;p13),+der(22)t(9;22)[20], accompanied with a resistance to imatinib mesylate. The TP53 was deleted from the der(17)t(1;17)(q25;p13), but there was no mutation of TP53 in the remaining allele. Mutations in the BCR/ABL kinase domain could not be detected as well. Morphologically, dysplastic changes including pseudo-Pelger-Huët anomaly appeared in the bone marrow cells. These findings suggest that the t(7;14)(p22;q13) translocation had a crucial role in the progression to CML-AP, and that the resistance to imatinib may be due to the additional cytogenetic abnormalities, including der(17)t(1;17)(q25;p13), but not to BCR/ABL mutations.