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Akiko Hori

Publications and source records attributed to Akiko Hori.

At least 19 recordsLinked to original sources
PubMed2006

DNA recombination-initiation plays a role in the extremely biased inheritance of yeast [rho-] mitochondrial DNA that contains the replication origin ori5.

Hypersuppressiveness, as observed in Saccharomyces cerevisiae, is an extremely biased inheritance of a small mitochondrial DNA (mtDNA) fragment that contains a replication origin (HS [rho(-)] mtDNA). Our previous studies showed that concatemers (linear head-to-tail multimers) are obligatory intermediates for mtDNA partitioning and are primarily formed by rolling-circle replication mediated by Mhr1, a protein required for homologous mtDNA recombination. In this study, we found that Mhr1 is required for the hypersuppressiveness of HS [ori5] [rho(-)] mtDNA harboring ori5, one of the replication origins of normal ([rho(+)]) mtDNA. In addition, we detected an Ntg1-stimulated double-strand break at the ori5 locus. Purified Ntg1, a base excision repair enzyme, introduced a double-stranded break by itself into HS [ori5] [rho(-)] mtDNA at ori5 isolated from yeast cells. Both hypersuppressiveness and concatemer formation of HS [ori5] [rho(-)] mtDNA are simultaneously suppressed by the ntg1 null mutation. These results support a model in which, like homologous recombination, rolling-circle HS [ori5] [rho(-)] mtDNA replication is initiated by double-stranded breakage in ori5, followed by Mhr1-mediated homologous pairing of the processed nascent DNA ends with circular mtDNA. The hypersuppressiveness of HS [ori5] [rho(-)] mtDNA depends on a replication advantage furnished by the higher density of ori5 sequences and on a segregation advantage furnished by the higher genome copy number on transmitted concatemers.

Alloxan↗
PubMed2006

Successful engraftment of mismatched unrelated cord blood transplantation following reduced intensity preparative regimen using fludarabine and busulfan.

We conducted a pilot study to evaluate the feasibility of reduced-intensity cord blood transplantation (RI-CBT) using a non-total body irradiation (TBI) regimen in adult patients with advanced hematologic malignancies. Seventeen patients with a median age of 58 years (range, 38-74) underwent RI-CBT at Tsukuba Memorial Hospital between April 2004 and November 2005. Preparative regimens were fludarabine 30 mg/m(2) for 6 days, and busulfan 4 mg/kg for 2 days. Tacrolimus was used for prophylaxis of graft-vs-host disease (GVHD). Median numbers of infused total nucleated were 2.6 x 10(7)/kg (range, 2.0-3.3). HLA disparity was found in 2/6 antigens (n=16) and 1/6 antigens (n=1). Underlying diseases progressed despite preparative regimens in four patients. Of the remaining 13 patients, nine patients achieved engraftment at a median of day 18 (range, 17-28). Six of the nine patients with engraftment achieved complete donor-type chimerism by day 100. Six patients were alive in remission at median follow-up of 13.1 months (range, 1.0-19.0). This study demonstrated the feasibility of RI-CBT using a non-TBI regimen in adults. When disease progression is controlled by the preparative regimen, RI-CBT carries a clinically significant graft-vs-tumor effect. Further studies are required to identify patients who benefit from this regimen.

Adult↗
PubMed2006

Hepatic injury following reduced intensity unrelated cord blood transplantation for adult patients with hematological diseases.

Liver injury is a common complication in allogeneic hematopoietic stem cell transplantation. Its major causes comprise graft-versus-host disease (GVHD), infection, and toxicities of preparative regimens and immunosuppressants; however, we have little information on liver injuries after reduced intensity cord blood transplantation (RICBT). We reviewed medical records of 104 recipients who underwent RICBT between March 2002 and May 2004 at Toranomon Hospital. Preparative regimen and GVHD prophylaxis comprised fludarabine/melphalan/total body irradiation and cyclosporine or tacrolimus. We assessed the etiology of liver injuries based on the clinical presentation, laboratory results, comorbid events, and imaging studies in 85 patients who achieved primary engraftment. The severity of liver dysfunction was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hyperbilirubinemia was graded according to a report by Hogan et al (Blood. 2004;103:78-84). Moderate to very severe liver injuries were observed in 36 patients. Their causes included cholestatic liver disease (CLD) related to GVHD or sepsis (n = 15), GVHD (n = 7), cholangitis lenta (n = 5), and others (n = 9). Median onsets of CLD, GVHD, and cholangitis lenta were days 37, 40, and 22, respectively. Frequencies of grade 3-4 alanine aminotransferase elevation were comparable across the 3 types of hepatic injuries. Serum gamma-glutamil transpeptidase was not elevated in any patients with cholangitis lenta, whereas 27% and 40% of patients with CLD and GVHD, respectively, developed grade 3-4 gamma-glutamil transpeptidase elevation. Multivariate analysis identified 2 risk factors for hyperbilirubinemia; grade II-IV acute GVHD (relative risk, 2.23; 95% confidential interval, 1.11-4.47; P = .024) and blood stream infection (relative risk, 3.77; 95% confidential interval, 1.91-7.44; P = .00013). In conclusion, the present study has demonstrated that the hepatic injuries are significant problems after RICBT, and that GVHD and blood stream infection contribute to their pathogenesis.

Adolescent↗
PubMed2006

Molecular tracing of Japan-indigenous hepatitis E viruses.

The ancestor(s) of apparently Japan-indigenous strains of Hepatitis E virus (HEV) was probably of foreign origin, but it remains unclear when and from where it made inroads. In this study, 24 genotype 3 and 24 genotype 4 HEV strains recovered in Japan each showed a significant cluster, clearly distinct from those of foreign strains, in the phylogenetic tree constructed from an 821 nt RNA polymerase gene fragment. The evolutionary rate, approximately 0.8 x 10(-3) nucleotide substitutions per site per year, enabled tracing of the demographic history of HEV and suggested that the ancestors of Japan-indigenous HEV had made inroads around 1900, when several kinds of Yorkshire pig were imported from the UK to Japan. Interestingly, the evolutionary growth of genotype 3 in Japan has been slow since the 1920s, whereas genotype 4 has spread rapidly since the 1980s. In conclusion, these data suggest that the indigenization and spread of HEV in Japan were associated with the popularization of eating pork.

Animals↗
PubMed2005

A prospective trial to evaluate the safety and efficacy of pravastatin for the treatment of refractory chronic graft-versus-host disease.

This prospective study evaluates the safety and efficacy of pravastatin for the treatment of chronic graft-versus-host disease (GVHD). We included 18 patients with refractory chronic GVHD. Oral pravastatin was started at 10 mg/day, and the dose was increased up to 40 mg/day in 4 weeks. This maximum dose was administered over 8 weeks. There were no severe adverse events caused by pravastatin. A clinical response was observed in the skin score in two patients, mouth score in five patients, eye score in two patients, liver score in three patients, platelet count score in one patient, and weight loss in two patients. The overall response rate was 28%. Immunophenotypic analyses showed that T-helper (Th)1 cells were dominant in all but one patient before treatment and that the Th1/Th2 ratio tended to be lower in the responders than in the nonresponders. A randomized controlled trial is warranted to evaluate the efficacy of pravastatin against chronic GVHD.

Chronic Disease↗
PubMed2005

Coordination assemblies from a Pd(II)-cornered square complex.

The [enPd(II)]2+ (en = ethylenediamine) unit has emerged as a versatile building block in molecular self-assembly. In particular, the 90 degrees coordination angle of the metal has been judiciously used in the design of new discrete two- and three-dimensional structures. Our last 15 years of work with the Pd(II)-cornered unit is summarized in this Account, from the spontaneous formation of a Pd4 square metal complex to a family of architectures such as cages, bowls, boxes, tubes, catenanes, and spheres.

Journal Article↗
PubMed2005

Outcomes of patients with acute leukaemia who relapsed after reduced-intensity stem cell transplantation from HLA-identical or one antigen-mismatched related donors.

The characteristics of relapse following reduced-intensity stem-cell transplantation (RIST) remain to be clarified. We reviewed the medical records of 19 patients with acute leukaemia [acute myeloid leukaemia (AML), 16; acute lymphoblastic leukaemia (ALL), 3] who relapsed after RIST from related donors using purine-analogue-based regimens. Their median age was 55 years (range, 29-65 years). Median interval between RIST and relapse was 4.9 months (range, 1.8-24.9 months). Three chose not to receive interventions. The remaining 16 patients received withdrawal of immunosuppression (n = 3), chemotherapy (n = 2), donor lymphocyte infusion (n = 10) and second transplantation (n = 7), alone (n = 9) or in combination (n = 7). Four are alive with a median follow-up of 27.6 months (range, 16.0-28.9 months); three in remission and one in relapse. The 2-year overall survival after relapse was 28.9%. Causes of death in 15 patients included progressive disease (n = 7), graft-versus-host disease (n = 5) and infections (n = 3). Cumulative incidences of relapse-related and non-relapse-related deaths at 2 years after relapse were 37% and 32% respectively. Two prognostic factors were identified on univariate analysis: age [P = 0.017; hazard ratio (HR), 1.16; 95% confidence interval (CI), 1.03-1.32], and ALL as underlying disease (P = 0.011; HR, 10.4; 95% CI, 1.73-62.4). Some AML patients who relapse after RIST achieve durable remission with allogeneic immunotherapy-based interventions; however they carry a significant risk of non-relapse mortality.

Acute Disease↗
PubMed2005

Feasibility of early tapering of cyclosporine following reduced-intensity stem cell transplantation for advanced hematologic or solid malignancies.

Although some researchers have reported that early tapering of cyclosporine is feasible and beneficial to augment graft-versus-leukemia effects after conventional stem-cell transplantation, there is little information on the feasibility of this strategy following reduced-intensity stem cell transplantation (RIST). We summarized outcomes of 17 patients who underwent early tapering of cyclosporine following RIST from HLA-identical siblings.

Adult↗
PubMed2004

Reduced-intensity allogeneic hematopoietic stem-cell transplantation as an immunotherapy for metastatic colorectal cancer.

BACKGROUND: Allogeneic stem-cell transplantation (allo-SCT) can induce curative graft-versus-leukemia reactions for hematologic malignancies through allogeneic immunity. Because the gastrointestinal tract is a target of graft-versus-host disease (GvHD), colorectal cancer might be a candidate for allo-SCT. METHODS: Four patients with metastatic colorectal cancer underwent reduced-intensity stem-cell transplantation (RIST) in the National Cancer Center Hospital between July 2002 and February 2003. Three patients received transplants from an human leukocyte antigen (HLA)-identical related donor, and the remaining patient received selected CD34-positive cells from a two-loci HLA-mismatched donor. The basis of preparative regimen was busulfan 4 mg/kg for 2 days and fludarabine 25 mg/kg for 6 days. RESULTS: All the patients tolerated the preparative regimen and achieved engraftment without significant toxicities. All developed acute or chronic GvHD. Although serum levels of CA19-9 and carcinoembryonic antigen were transiently elevated after RIST in all the patients, the levels subsequently decreased below the levels from before RIST in all but one patient. Three had measurable lesions before RIST, one achieved partial response, and the others stable disease, which was durable for 120 and 60 days. Three patients died; the causes of death were progressive disease, GvHD, and accident. Postmortem examination was obtained for two patients; in one patient, the peritoneal metastatic lesions macroscopically disappeared, and in the other patient, the supraclavicular lymph node disappeared while the other measurable lesions remained stable. CONCLUSIONS: All the patients showed some evidence suggesting the presence of a graft-versus-tumor effect for colorectal cancer, which should be confirmed in a future prospective trial.

Adult↗
PubMed2004

Recovery in the fetal pancreatic islet following fetal administration of streptozotocin in the rat in vivo and in vitro.

In our previous study, after direct administration of streptozotocin (STZ; 400 microg/g) to fetuses on day 19 of gestation, the B-cell volume in fetal pancreatic islets showed a marked decrease, but gradually recovered with electron microscopic confirmation of B-cell regeneration. However, STZ at this dose often caused fetal death. In this study, therefore, we determined whether B-cells are newly generated after treatment with STZ at a smaller dose in vivo and in vitro. For in vivo experiment, fetuses were administered STZ at 40 microg/g on day 19 of gestation. The B-cell volume in pancreatic islets decreased markedly 3 hr after the administration of STZ, but it began to increase after 6 hr. The fetal plasma insulin concentration decreased from 6 to 12 hr after the administration, but recovered after 48 hr. The cell division index in fetal pancreatic islets of the STZ-treated group began to be significantly larger after 6 hr. For in vitro experiment, fetal pancreases on day 18 of gestation were pretreated with 10 mM STZ for 6 hr and cultured for 98 hr. B-cells were completely destroyed with STZ treatment; however, as these pancreases were cultured in a medium free of STZ, B-cells began to appear and insulin secretion was detected after 48 hr. After 72 hr, the cell division index was significantly greater. These results suggest that the fetal pancreas treated with STZ has the ability to regenerate B-cells both in vivo and in vitro.

Animals↗
PubMed2004

Development of early neutropenic fever, with or without bacterial infection, is still a significant complication after reduced-intensity stem cell transplantation.

Little information is available on the clinical characteristics of infectious complications that occur in the early period after reduced-intensity stem cell transplantation (RIST). We retrospectively investigated the clinical features of neutropenic fever and infectious episodes within 30 days after RIST in 76 patients who had received fluoroquinolones as part of their antibacterial prophylaxis. Preparative regimens included cladribine 0.66 mg/kg or fludarabine 180 mg/m2 plus busulfan 8 mg/kg. All but 1 patient survived 30 days after transplantation, and 75 patients (99%) became neutropenic within a median duration of 9 days. Neutropenic fever was observed in 29 patients (38%), and bacterial infection was confirmed in 15 (20%) of these, including bacteremia (n = 13), bacteremia plus pneumonia (n = 1), and urinary tract infection (n = 1). The causative organisms were gram-positive (n = 9) and gram-negative organisms (n = 7), with a mortality rate of 6%. Neither viral nor fungal infection was documented. Multivariate analysis showed that the presence of neutropenia at the initiation of preparative regimens was an independent risk factor for subsequent documented bacterial infections (P =.026; 95% confidence interval, 1.25-35.1). We conclude that neutropenic fever and bacteremia remain common complications in RIST.

Adolescent↗
PubMed2004

Allogeneic hematopoietic stem cell transplantation with a reduced-intensity conditioning regimen for treatment of metastatic renal cell carcinoma: single institution experience with a minimum 1-year follow-up.

OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of allogeneic hematopoietic stem cell transplantation with a reduced-intensity conditioning regimen (RIST) for interferon-alpha-refractory metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Of 26 patients referred to the National Cancer Center Hospital for possible RIST between June 2000 and April 2002, an HLA-identical relative was identified for 12 patients. Nine patients underwent RIST. The conditioning regimen consisted of fludarabine 180 mg/m2 or cladribine 0.66 mg/kg, plus busulfan 8 mg/kg and rabbit antithymocyte globulin 5 mg/kg. Graft-vs-host disease (GVHD) prophylaxis was cyclosporine alone. RESULTS: All patients achieved engraftment without grade III to IV nonhematologic regimen-related toxicity. All patients achieved complete donor-type chimerism without donor lymphocyte infusion by day 60. Four patients developed acute GVHD, and four developed chronic GVHD. One patient (11%) achieved partial response. As of July 2003, six patients were alive at median follow-up of 681 days. The actuarial overall survival rate was 89% at 1 year and 74% at 2 years. The overall survival rate tended to be higher in the 12 patients with a matched donor than in the other 14 patients without a matched donor (p = 0.088). CONCLUSION: Our RIST procedure is feasible without severe toxicity. The efficacy of RIST for RCC should be confirmed in phase II/III clinical trials.

Acute Disease↗
PubMed2004

Balance between acute graft-versus-host disease and graft-versus-tumor effect after reduced-intensity transplantation for metastatic renal cell carcinoma.

We describe a patient who had received reduced-intensity stem cell transplantation (RIST) for metastatic renal cell carcinoma (RCC). A 37-year-old man developed rapid progression of RCC during steroid therapy for immune-mediated thrombocytopenia and graft-versus-host disease (GVHD). After discontinuation of corticosteroid, RCC achieved long stable disease with the presence of chronic GVHD, despite low dose of prednisolone. This case suggests the impact of immunosuppression on progression of metastatic RCC after RIST.

Acute Disease↗
PubMed2003

Antithymocyte globulin affects the occurrence of acute and chronic graft-versus-host disease after a reduced-intensity conditioning regimen by modulating mixed chimerism induction and immune reconstitution.

BACKGROUND: There have been no detailed analyses of the induction of donor cell-type chimerism, the onset and incidence of acute and chronic graft-versus-host disease (GVHD), and the immune recovery kinetics after reduced-intensity stem cell transplantation (RIST). METHODS: To address these, with particular emphasis on the impact of the use of antithymocyte globulin (ATG) in RIST, we compared 39 consecutively registered patients who underwent RIST from an HLA-matched related donor and 33 patients who underwent conventional marrow-ablative transplantation. RESULTS: The incidences of grades II to IV acute and chronic GVHD tended to be less in RIST with ATG than in either RIST without ATG or conventional marrow-ablative transplantation. In a multivariate analysis, the predictive factors for acute and chronic GVHD included, respectively, ATG and grades II to IV acute GVHD. In a chimerism analysis, the achievement of complete donor chimera in T-cell lineage was delayed in RIST without ATG compared with RIST with ATG (P=0.038), which might explain the observed delayed onset of acute GVHD in RIST with ATG compared with the other two regimens. The ratio of type 1 and 2 dendritic cells did not affect the development of GVHD, whereas the number of naive CD4+ T cells did. No difference was observed in the incidence of clinically definitive infection, including cytomegalovirus, among the three cohorts, regardless of the use of ATG. CONCLUSIONS: We suggest that the conditioning regimen and immunosuppressive strategy after RIST should be carefully balanced against the risk of GVHD and of relapse of the basic disorder caused by the lack of a graft-versus-leukemia benefit.

Acute Disease↗