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Biomedical subjects

Y Sasai

Publications and source records attributed to Y Sasai.

At least 19 recordsLinked to original sources
PubMed1999

Distinct genetic involvement of the TP53 gene in therapy-related leukemia and myelodysplasia with chromosomal losses of Nos 5 and/or 7 and its possible relationship to replication error phenotype.

We examined chromosomes and molecular aberrations in 21 patients with therapy-related leukemias (t-AML) or myelodysplastic syndromes (t-MDS). All patients showed abnormal karyotypes, and chromosomal losses of No. 5 and/or No. 7 (-5/5q- and/or -7/7q-) were identified in 12 patients. Among these 12, six patients (50%) harbored a TP53 mutation, and two of five examined showed microsatellite instability, suggesting replication error (RER+) phenotype. Meanwhile, among the other nine patients without -5/5q- and/or -7/7q-, none harbored a TP53 mutation, and none of five examined showed RER+ phenotype. Thus, TP53 mutations and RER+ phenotype were preferentially associated with specific chromosomal losses in t-AML/MDS. We then screened for mutational events in representative DNA mismatch repair genes; exons 5-7 and 12-15 of the hMSH2 gene and exon 9 of hMLH1. Notably, two unrelated patients showing RER+ phenotype had an identical missense alteration at codon 419 of hMSH2 in their marrow cells and fibroblasts, which were not found in 120 DNA samples from healthy volunteers or patients with other hematological disorders. Consequently, this study revealed a possible relationship of RER+ phenotype accompanying an hMSH2 alteration to the development of therapy-related AML/MDS in association with TP53 mutations and specific chromosomal losses, and suggests that some patients may be predisposed to myelodysplasia after chemotherapy for their primary tumor.

Adult↗
PubMed1999

[Syngeneic peripheral blood stem cell transplantation for chronic myelogenous leukemia associated with Klinefelter's syndrome].

We report on a patient with Klinefelter's syndrome who underwent successful syngeneic peripheral blood stem cell transplantation (PBSCT) for chronic myelogenous leukemia (CML). A-46-year-old man was given a diagnosis of chronic phase CML in May 1994 on the basis of findings of leukocytosis (54,000/microliter) and bone marrow chromosomal abnormalities [47, XXY, t(9; 22; 14) (q34; q11; q24)]. Hydroxyurea and interferon alpha were administered. In August 1996, a syngeneic transplant was performed following myeloablative therapy, using peripheral blood stem cells collected from the patient's identical twin brother, who had been pretreated with rhG-CSF. Following transplantation (4.0 x 10(6) CD34+ cells/kg) and the subsequent administration of rhG-CSF, the patient rapidly achieved normal tri-lineage hematopoiesis. A post-transplant chromosomal analysis of the patient's bone marrow cells detected the 47, XXY karyotype. Although the major BCR-ABL gene had been detected in bone marrow by RT-PCR methods prior to the syngeneic PBSCT (August 1996), it was not detected after PBSCT (January 1997). In March 1998, interphase fluorescence in situ hibridization (FISH) procedures disclosed XXY signal patterns in peripheral blood lymphocyte samples from the patient and donor, at frequencies of 96% and 97%, respectively. Both the patient and donor had high levels of serum FSH and LH and low levels of serum testosterone.

Diseases in Twins↗
PubMed1998

A novel homeobox gene, dharma, can induce the organizer in a non-cell-autonomous manner.

The formation of Spemann organizer is one of the most important steps in dorsoventral axis determination in vertebrate development. However, whether the organizer forms autonomously or is induced non-cell-autonomously is controversial. In this report we have isolated a novel zebrafish homeobox gene, dharma, capable of inducing the organizer ectopically. The expression of dharma was first detected in several blastomeres at one side of the margin soon after the mid-blastula transition and continued in the dorsal side of the yolk syncytial layer (YSL) under the embryonic shield, the zebrafish organizer, until the onset of gastrulation. Furthermore, dharma expressed in the YSL induced the organizer in a non-cell-autonomous manner. These results provided the first identification of a zygotic gene to be implicated in the formation of an organizer-inducing center.

Amino Acid Sequence↗
PubMed1998

Significance of chromosomal alterations and mutations of the N-RAS and TP53 genes in relation to leukemogenesis of acute myeloid leukemia.

We examined chromosomes and mutations of the N-RAS and TP53 genes in 73 patients with acute myeloid leukemia (AML). Twenty-six patients showed a reciprocal chromosomal translocation or an inversion, and 34 patients showed only unbalanced aberrations. Balanced aberrations were predominantly detected in the AML patients who did not have myelodysplasia, preceding myelodysplastic syndrome, and a history of chemotherapy or radiation therapy. In contrast, unbalanced aberrations were more frequently seen in the patients with AML with trilineage myelodysplasia, AML transformed from MDS, and therapy-related AML. Twenty-two mutations of the N-RAS and TP53 genes were detected, and these mutations were frequently associated with unbalanced chromosomal aberrations. Furthermore, the spectrum of mutations was suggestive of an exposure to alkylating chemicals.

Acute Disease↗
PubMed1998

SoxD: an essential mediator of induction of anterior neural tissues in Xenopus embryos.

Vertebrate neurogenesis is initiated by the organizer factors that inhibit antineuralizing activities of bone morphogenetic proteins (BMPs) in the ectoderm. Here, we report a candidate mediator of neuralization, SoxD. Expression of SoxD starts at late blastula stages widely in the prospective ectoderm and becomes restricted to the dorsal ectoderm by mid-gastrula stages. SoxD expression is enhanced by the neural inducer Chordin and is suppressed by BMP4 and its downstream genes. Microinjection of SoxD mRNA causes ectopic formation of neural tissues in vivo and induces neural and neuronal markers in the isolated animal cap. Injection of a dominant-negative form of SoxD mRNA can block neuralization of ectoderm caused by attenuation of BMP signals and can strongly suppress formation of anterior neural tissues in vivo. These data show that SoxD functions as an essential mediator of downstream signaling of neural induction.

Amino Acid Sequence↗
PubMed1998

Rare alteration of genomic structure or expression of the DPC4 gene in myelogenous leukemias.

We examined homozygous deletion, point mutation and expression of DPC4 gene, a recently isolated candidate pancreatic tumor suppressor gene, in 53 patients with myelogenous leukemias and 5 cell lines. The patients consisted of 34 cases of chronic myelogenous leukemia including 22 in the chronic phase, 3 in the accelerated phase, and 9 in blastic crisis, and 19 with acute myelogenous leukemia including 9 at the initial presentation and 10 at relapse. Polymerase chain reaction (PCR)-based deletion analysis for DPC4 exon 8 and PCR-single strand conformation polymorphism study for the entire coding region were carried out. Homozygous deletion or subtle mutation was not detected in any of the samples examined. However, 3 patients with various clinical phases showed a decrease of DPC4 expression. These results suggest that DPC4 alteration is not a crucial event in the development or the progression of myelogenous leukemias.

DNA-Binding Proteins↗
PubMed1998

Xenopus Zic-related-1 and Sox-2, two factors induced by chordin, have distinct activities in the initiation of neural induction.

In a differential screen for downstream genes of the neural inducers, we identified two extremely early neural genes induced by Chordin and suppressed by BMP-4: Zic-related-1 (Zic-r1), a zinc finger factor related to the Drosophila pair-rule gene odd-paired, and Sox-2, a Sry-related HMG factor. Expression of the two genes is first detected widely in the prospective neuroectoderm at the beginning of gastrulation, following the onset of Chordin expression and preceding that of Neurogenin (Xngnr-1). Zic-r1 mRNA injection activates the proneural gene Xngnr-1, and initiates neural and neuronal differentiation in isolated animal caps and in vivo. In contrast, Sox-2 alone is not sufficient to cause neural differentiation, but can work synergistically with FGF signaling to initiate neural induction. Thus, Zic-r1 acts in the pathway bridging the neural inducer with the downstream proneural genes, while Sox-2 makes the ectoderm responsive to extracellular signals, demonstrating that the early phase of neural induction involves simultaneous activation of multiple functions.

Animals↗
PubMed1998

[Clinical study on the inhibitory effect of a 5-HT3 antagonist, granisetron, for nausea and vomiting induced by chemotherapy (CHOP, VEPA, high-dose ETP) for non-Hodgkin's lymphoma].

The antiemetic effect of granisetron on nausea and vomiting induced by cancer chemotherapy (CHOP, VEPA, VEPA-B, massive dose of ETP) was studied in fifty patients with non-Hodgkin's lymphoma. There was almost no difference in the inhibitory effect by regimen, with the rates of perfect inhibition of nausea and vomiting standing at 55.6% to 60%. Nausea and vomiting was perfectly controlled in 60% of 35 patients receiving CHOP therapy. As a part of this study, a comparison was made of perfect inhibitory effect on nausea and vomiting by potency of chemotherapy under the potency scale of 750 mg/m2 of CPA as 1, revealing no significant difference in the rates of complete inhibition as 71.4% for a drug potency of less than 0.8 vs 52.4% for 0.8 or above (p = 0.26). However, it was clear that the higher the dose of chemotherapy, the lower the rate of complete inhibition. The results confirmed the high efficacy and safety of granisetron in the treatment of nausea and vomiting induced by cancer chemotherapy.

Adult↗
PubMed1998

[t(3;5) (q21;q31) chromosomal abnormality in a patient with acute myelogenous leukemia with trilineage myelodysplasia].

A 60-year-old woman was admitted in June 1993, because of anemia and purpura and given a diagnosis of acute myelogenous leukemia with trilineage dysplasia. She entered partial remission (PR) after three courses of low-dose Ara-C and G-CSF, but never reached complete remission (CR) in spite of additional chemotherapy. In October 1994, the number of leukocytes, myeloblasts, and erythroblasts in the patient's peripheral blood increased, and her clinical condition deteriorated. The disease was resistant to other therapy. The patient had pneumonia and died of septic shock in December 1994. A chromosomal analysis performed on admission showed 46,XX,t(3;5) (q21;q31) [9/9]. As an additional chromosomal abnormality, deletion of the X chromosome was observed in January, 1994. Analysis of the p53 gene by the polymerase chain reaction-single strand conformation polymorphism method showed one base transposition, from TAT to TGT (Tyr to Cys), at codon 220 of exon 6. Karyotype evolution and p53 gene mutation were observed during the disease course and may have been related to progression of the disease.

Chromosomes, Human, Pair 3↗
PubMed1998

[Clinical evaluation of cefozopran for infections associated with hematological malignancies].

Cefozopran (CZOP) was used as an initial antibacterial therapy for infections in patients with hematological malignancies. CZOP was given at a daily dose of 4 g by drip intravenously to patients who were febrile over 38 degrees C and were suspected as having bacterial infections. As underlying diseases, 8 patients had acute lymphoblastic leukemia (ALL), 9 acute myeloblastic leukemia (AML), 2 aplastic anemia (AA), 2 adult T cell leukemia/lymphoma (ATLL), 28 non Hodgkin lymphoma (NHL), and 2 multiple myeloma (MM). Bacterial infections diagnosed were sepsis in 7 patients, suspected sepsis in 32, bronchitis in 6, pneumonia in 5 and acute peritonitis in 1. Clinical responses among 51 evaluable cases were excellent in 14, good in 15, fair in 3, poor in 19 and the overall response rate was 57%. The overall response rates for AML, ALL, AA, ATLL, NHL and MM were 56%, 63%, 100%, 50%, 50%, and 100%, respectively. Those for sepsis, suspected sepsis, bronchitis, pneumonia and acute peritonitis were 14%, 63%, 100%, 40%, and 0%, respectively. This therapy was effective in 53% (9/17) of patients whose granulocyte count remained below 500/microliter throughout the course of CZOP therapy. Six bacterial and one fungal strains were isolated from blood and sputum of six patients including five sepsis cases; two bacteria were eradicated and bacterial change was observed in one case. As side adverse effects, 10 patients had liver dysfunction, 1 anemia, 2 proteinemia, 1 indirect bilirubinemia, 2 thrombocytopenia, and 1 eosinophilia. We tried to establish a scoring system for the severities of patients with their infections, underlying diseases, treatments for the underlying disease, and granulocyte counts in order to evaluate the efficacy of CZOP more precisely. This scoring system was consisted of three grades; severe, moderate, and mild. CZOP was effective on mild and moderate grades. These results indicate that the initial antibacterial therapy by CZOP is useful for the treatment of mild and moderate grade infections complicated with hematological malignancies.

Acute Disease↗
PubMed1998

[Clinical evaluation of panipenem/betamipron as a second line chemotherapy in severe infections associated with hematological disorders].

Thirty three patients with severe infections associated with hematological disorders were treated with panipenem/betamipron as a second line chemotherapy. Of these, 30 patients were evaluated for effectiveness. An excellent response was obtained in 14 patients (46.7%) and a good response in 5 (16.7%), and the overall efficacy rate was 63.3%. Efficacy rates were 3/6 in patients with sepsis, 68.4% (13/19) in patients with fever of undetermined origin, 2/4 in patients with pneumonia. In patients whose peripheral granulocyte count was below 100/microliter at the start of chemotherapy, the efficacy rate was 3/7. Side effects were observed in 5 of 33 patients (15.2%). These results show that PAPM/BP is useful as a second line chemotherapy for the treatment of severe infections in patients with hematological disorders.

Adult↗
PubMed1997

Ectodermal patterning in vertebrate embryos.

Recent molecular insights on how the ectodermal layer is patterned in vertebrates are reviewed. Studies on the induction of the central nervous system (CNS) by Spemann's Organizer led to the isolation of noggin and chordin. These secretory proteins function by binding to, and inhibiting, ventral BMPs, in particular BMP-4. Neural induction can be considered as the dorsalization of ectoderm, in which low levels of BMP-signaling result in CNS formation. At high levels of BMP signaling the ectoderm adopts a ventral fate and skin is formed. In Xenopus the forming neural plate already has extensive dorsal-ventral (D-V) patterning, and neural induction and D-V patterning may share common molecular mechanisms. At later stages sonic hedgehog (shh) plays a principal role in D-V patterning, particularly in the neural tube of the amniote embryo. A great many transcription factor markers are available and mouse knockouts provide evidence of their involvement in the regional specification of the neural tube. Recent evidence indicating that differentiation of posterior CNS is promoted by FGF, Wnt-3a, and retinoic acid is reviewed from the point of view of the classical experiments of Nieuwkoop that defined an activation and a transformation step during neural induction.

Animals↗
PubMed1997

Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia.

We recently reported an internal tandem duplication of the human flt3 receptor gene (FLT3) as a somatic mutation in 17% of acute myelogenous leukemia (AML). The present study revealed the duplication at the juxtamembrane and the first tyrosine kinase domains of FLT3 in seven of 92 (8%) patients with myelodysplastic syndrome (MDS) and AML with trilineage myelodysplasia (AML/TMDS), the diseases which may represent neoplastic changes of pluripotent stem cells. A tandem duplication of exon 11 of FLT3 was harbored by two of 58 (3%) patients with MDS and five of 34 (15%) with overt leukemia, including MDS-derived leukemia, AML/TMDS and therapy-related leukemia. Although the duplicated regions varied within exon 11 in each case, they occurred in-frame, and altered mRNA expressions were demonstrated by reverse-transcription polymerase chain reaction. Two cases of MDS with a FLT3 duplication transformed to overt leukemia within a few months. Longitudinal analyses in two other patients with leukemia revealed that the duplication was a late genetic event during the disease course; one of whom showed two independent duplications of FLT3 at the terminal therapy-resistant phase. Of seven patients with the FLT3 duplication, six had abnormal karyotypes, and four harbored a point mutation of the N-RAS and/or TP53 genes. Patients with FLT3 mutations have poor prognoses. This study uncovered the fact that the accumulation of genetic events, including FLT3 duplication, correlates with leukemic transformation from antecedent myelodysplasia and with subsequent disease progression.

Aged↗
PubMed1996

Endoderm induction by the organizer-secreted factors chordin and noggin in Xenopus animal caps.

Spemann's organizer has potent neural inducing and mesoderm dorsalizing activities in the Xenopus gastrula. A third activity, the organizer's ability to induce a secondary gut, has been difficult to analyze experimentally due to the lack of early gene markers. Here we introduce endodermin, a pan-endodermal gene marker, and use it to demonstrate that chordin (Chd), a protein secreted by the organizer region, is able to induce endodermal differentiation in Xenopus. The ability of chd, as well as that of noggin, to induce endoderm in animal cap explants is repressed by the ventralizing factor BMP-4. When FGF signaling is blocked by a dominant-negative FGF receptor in chd-injected animal caps, neural induction is inhibited and most of the explant is induced to become endoderm. The results suggest that proteins secreted by the organizer, acting together with known peptide growth factors, regulate differentiation of the endodermal germ layer.

Amino Acid Sequence↗
PubMed1996

Dorsoventral patterning in Xenopus: inhibition of ventral signals by direct binding of chordin to BMP-4.

Chordin (Chd) is an abundant protein secreted by Spemann organizer tissue during gastrulation. Chd antagonizes signaling by mature bone morphogenetic proteins (BMPs) by blocking binding to their receptors. Recombinant Xenopus Chd binds to BMP-4 with high affinity (KD, 3 x 10(-10) M), binding specifically to BMPs but not to activin or TGF-beta1. Chd protein is able to dorsalize mesoderm and to neuralize ectoderm in Xenopus gastrula explants at 1 nM. We propose that the noncell-autonomous effects of Spemann's organizer on dorsoventral patterning are executed in part by diffusible signals that directly bind to and neutralize ventral BMPs during gastrulation.

Activins↗