PubMed Health⌕ Search

Biomedical subjects

Takahiro Ueda

Publications and source records attributed to Takahiro Ueda.

At least 19 recordsLinked to original sources
PubMed2026

Case Report: Immune-driven clonal selection underlying lineage switch from B-Precursor acute lymphoblastic leukemia to acute myeloid leukemia following inotuzumab ozogamicin.

Lineage switch (LS), defined as a change in leukemic lineage during the disease course, is a rare but clinically significant event in acute leukemia and is typically associated with poor prognosis. Although LS has been increasingly reported following targeted immunotherapies, the clonal mechanisms underlying this phenomenon remain incompletely understood, particularly in cases without KMT2A rearrangement. We report a case of LS from B-precursor acute lymphoblastic leukemia (BCP-ALL) to acute myeloid leukemia (AML) following treatment with the CD22-targeted antibody-drug conjugate inotuzumab ozogamicin. To elucidate the clonal architecture underlying LS, targeted next-generation sequencing was performed on bone marrow samples obtained at multiple time points throughout the disease course. Genomic analysis demonstrated that the lymphoid and myeloid disease phases shared ancestral genetic alterations but displayed distinct mutational profiles. At the time of LS, TP53 and SMC1A mutations newly emerged, whereas only a subset of mutations detected at ALL relapse was retained. These findings suggest that the AML phase most likely resulted from the selective expansion of a genetically distinct subclone derived from a common progenitor, rather than the direct transdifferentiation of the dominant ALL clone, consistent with immunotherapy-driven clonal selection. Longitudinal genomic profiling revealed stepwise clonal evolution during disease progression, supporting a model of immunotherapy-driven clonal selection leading to LS. This case provides molecular evidence suggesting that immune-targeted therapy can promote expansion of minor pre-existing subclones with alternative lineage potential within a common progenitor even in non-KMT2A-rearranged leukemia. Our findings highlight the importance of comprehensive genomic monitoring during immunotherapy to identify therapy-resistant subclones and better understand mechanisms of lineage plasticity in acute leukemia.

Humans↗
PubMed2006

Grand canonical Monte Carlo simulations of the 129Xe NMR line shapes of xenon adsorbed in (+/-)-[Co(en)3]Cl3.

The 129Xe NMR line shapes of xenon adsorbed in the nanochannels of the (+/-)-[Co(en)3]Cl3 ionic crystal have been calculated by grand canonical Monte Carlo (GCMC) simulations. The results of our GCMC simulations illustrate their utility in predicting 129Xe NMR chemical shifts in systems containing a transition metal. In particular, the nanochannels of (+/-)-[Co(en)3]Cl3 provide a simple, yet interesting, model system that serves as a building block toward understanding xenon chemical shifts in more complex porous materials containing transition metals. Using only the Xe-C and Xe-H potentials and shielding response functions derived from the Xe@CH4 van der Waals complex to model the interior of the channel, the GCMC simulations correctly predict the 129Xe NMR line shapes observed experimentally (Ueda, T.; Eguchi, T.; Nakamura, N.; Wasylishen, R. E. J. Phys. Chem. B 2003, 107, 180-185). At low xenon loading, the simulated 129Xe NMR line shape is axially symmetric with chemical-shift tensor components delta(parallel) = 379 ppm and delta(perpendicular) = 274 ppm. Although the simulated isotropic chemical shift, delta(iso) = 309 ppm, is overestimated, the anisotropy of the chemical-shift tensor is correctly predicted. The simulations provide an explanation for the observed trend in the 129Xe NMR line shapes as a function of the overhead xenon pressure: delta(perpendicular) increased from 274 to 292 ppm, while delta(parallel) changed by only 3 ppm over the entire xenon loading range. The overestimation of the isotropic chemical shifts is explained based upon the results of quantum mechanical 129Xe shielding calculations of xenon interacting with an isolated (+/-)-[Co(en)3]Cl3 molecule. The xenon chemical shift is shown to be reduced by about 12% going from the Xe@[Co(en)3]Cl3 van der Waals complex to the Xe@C2H6 fragment.

Journal Article↗
PubMed2006

Phenotypic heterogeneity in the XPB DNA helicase gene (ERCC3): xeroderma pigmentosum without and with Cockayne syndrome.

Defects in the xeroderma pigmentosum type B (XPB) gene (ERCC3), a DNA helicase involved in nucleotide excision repair (NER) and an essential subunit of the basal transcription factor, TFIIH, have been described in only three families. We report three new XPB families: one has two sisters with relatively mild xeroderma pigmentosum (XP) symptoms not previously associated with XPB mutations and two have severe XP/Cockayne syndrome (CS) complex symptoms. All XP-B cells had reduced NER and post-ultraviolet (UV) cell viability. Surprisingly, cells from the milder XP sisters had the same missense mutation (c.296T>C, p.F99S) that was previously reported in two mild XP/CS complex brothers. These cells had higher levels of XPB protein than the severely affected XP/CS complex patients. An XPB expression vector with the p.F99S mutation partially complemented the NER defect in XP-B cells. The three severely affected XP/CS complex families all have the same splice acceptor site mutation (c.2218-6C>A, p.Q739insX42) in one allele. This resulted in alteration of 41 amino acids at the C terminus, producing partial NER complementation. This limited number of mutations probably reflects the very restricted range of alterations of this vital protein that are compatible with life. We found new mutations in the second allele yielding markedly truncated proteins in all five XP or XP/CS complex families: c.1273C>T, p.R425X; c.471+1G>A, p.K157insTSDSX; c.807-808delTT, p.F270X; c.1421-1422insA, p.D474EfsX475; and c.1633C>T, p.Q545X. The remarkable phenotypic heterogeneity of XPB is associated with partially active missense mutations in milder patients while severe XP/CS complex patients have nonsense mutations in both alleles with low levels of altered XPB proteins.

Abnormalities, Multiple↗
PubMed2005

Reduced XPC DNA repair gene mRNA levels in clinically normal parents of xeroderma pigmentosum patients.

Xeroderma pigmentosum group C (XP-C) is a rare autosomal recessive disorder. Patients with two mutant alleles of the XPC DNA repair gene have sun sensitivity and a 1000-fold increase in skin cancers. Clinically normal parents of XP-C patients have one mutant allele and one normal allele. As a step toward evaluating cancer risk in these XPC heterozygotes we characterized cells from 16 XP families. We identified 15 causative mutations (5 frameshift, 6 nonsense and 4 splicing) in the XPC gene in cells from 16 XP probands. All had premature termination codons (PTC) and absence of normal XPC protein on western blotting. The cell lines from 26 parents were heterozygous for the same mutations. We employed a real-time quantitative reverse transcriptase-PCR assay as a rapid and sensitive method to measure XPC mRNA levels. The mean XPC mRNA levels in the cell lines from the XP-C probands were 24% (P<10(-7)) of that in 10 normal controls. This reduced XPC mRNA level in cells from XP-C patients was caused by the PTC that induces nonsense-mediated mRNA decay. The mean XPC mRNA levels in cell lines from the heterozygous XP-C carriers were intermediate (59%, P=10(-4)) between the values for the XP patients and the normal controls. This study demonstrates reduced XPC mRNA levels in XP-C patients and heterozygotes. Thus, XPC mRNA levels may be evaluated as a marker of cancer susceptibility in carriers of mutations in the XPC gene.

Adolescent↗
PubMed2005

Side population cells derived from adult human liver generate hepatocyte-like cells in vitro.

We sought to determine whether hepatic side population (SP) cells derived from adult human liver possess the potential of a novel candidate hepatic stem cell. Human cadaveric donor liver was subjected to collagenase perfusion and hepatocytes were separated from nonparenchymal cells by differential centrifugation. SP cells were isolated from the nonparenchymal portion after Hoechst 33342 staining. Since CD45 is a panleukocyte antigen, CD45-negative SP cells were separated from the vast majority of CD45-positive SP cells (90%), and hepatic growth medium was used to culture both groups. Both CD45-negative and CD45-positive hepatic SP cells generated colonies in the hepatic growth medium in 2-3 weeks. The colonies yielded large cells morphologically consistent with human hepatocytes, demonstrating granule-rich cytoplasm, dense, often double nuclei, and intracellular lipofuscin pigment. The cultured cells from both sources were positive for markers of human hepatocytes: HepPar, cytokeratin 8 (CK8), and human albumin. Reverse transcriptase-polymerase chain reaction (RT-PCR) performed on both groups demonstrated positivity for additional liver markers including human albumin, CK18, alpha-1 anti-trypsin, and the human cytochrome P450 enzyme CYP2B6. Double immunostaining (CD45 and HepPar) and RT-PCR confirmed that the hepatocyte-like cells derived from the CD45-negative SP cells acquired HepPar positivity but had no detectable CD45 antigen expression. In contrast, the cultured cells derived from the CD45-positive SP cells also acquired HepPar positivity, but only a minimal fraction expressed the CD45 antigen. We conclude that hepatic SP cells derived from the nonparenchymal portion of human liver are a potential source of human hepatocytes irrespective of their CD45 status, and further animal studies will be required to assess their regenerative potential.

Adult↗
PubMed2005

A novel XPA gene mutation and its functional analysis in a Japanese patient with xeroderma pigmentosum group A.

Most Japanese patients with xeroderma pigmentosum group A (XPA) have the homozygous intron 3 splicing mutations (AlwNI mutation). Here, we report a Japanese XPA patient, XP79KO, a compound heterozygote with a newly identified T to G transversion at splice donor site in intron 1 in one allele, and with the AlwNI mutation in another allele in the XPA gene. The mutation in intron 1 creates two new abnormal splice sites that resulted in two types of aberrant mRNA. These abnormal splicings cause frameshifts that make stop codons downstream. No XPA protein was detected in XP79KO fibroblasts.

Child↗
PubMed2005

Brain white matter changes during treatment of a child for acute lymphoblastic leukemia.

A 13-year old boy with acute lymphoblastic leukemia had bilateral paresis of the upper extremities and aphasia 1 week after high dose methotrexate and triple intrathecal therapy (methotrexate, cytarabin, hydrocortisone). The stroke-like neurological symptoms disappeared on the third day. T2-weighted magnetic resonance imaging showed hyperintensities of white matter on the second day. Despite resolution of the neurological symptoms, magnetic resonance images were still abnormal 3 years after the attack. Methotrexate has been considered to be responsible for ischemic damage to oligodendroglial cells, resulting in demyelination. The changes are occasionally prolonged without persistent neurologic symptoms.

Adolescent↗
PubMed2005

Clinical aspects of infant leukemia--experiences of a single institution of Japan: high level of serum immunoglobulin M in infant leukemia.

The prognosis and clinical and biological characteristics of infant leukemia differ from those of leukemia in children 1 year or older. We reviewed the charts of patients younger than 1 year in whom leukemia was diagnosed from January 1981 through December 2003 at our institution. Fourteen infants had leukemia, 6 had acute lymphoblastic leukemia (ALL), and 8 had acute myeloid leukemia (AML). The age of patients at diagnosis ranged from 2 to 11 months. Five of 8 AML patients presented with cutaneous manifestations, such as erythema and nodules, at diagnosis. Central nervous system (CNS) involvement was seen in 1 AML patient at diagnosis. Hyperleukocytosis of more than 50 x 10(9)/L was seen in 4 of 6 ALL patients and in 4 of 8 AML patients at diagnosis. All ALL patients showed a morphological diagnosis of L1 using the French-America-British classification system. For patients with AML, the morphological diagnoses were M0 for 1 patient, M2 for 1 patient, M4 for 2 patients (1 with eosinophilia), M5b for 2 patients, and M7 for 2 patients. One patient showing M7 morphology had Down syndrome. Surface markers were examined in 5 of 6 ALL patients and all AML patients. Five ALL patients showed a B-cell precursor immunophenotype. Two of 5 patients with ALL had CD10-positive leukemic cells and 3 of 5 patients with ALL had CD10-negative leukemic cells. All AML patients were positive for CD13 or CD33 or both. Three of 5 patients with ALL showed abnormal chromosomes related to 11q. Six of 7 patients with AML showed abnormal karyotypes. MLL gene rearrangements were seen in 3 (2 ALL, 1 AML) of 5 (2 ALL, 3 AML) patients. Serum immunoglobulin M levels were increased in 9 of 14 patients. Complete remission (CR) was achieved in all infants with ALL. Three patients relapsed and then died of the original disease. One of these 3 patients died after cord blood transplantation. Three ALL patients are alive without leukemia. CR was achieved in 6 of 8 AML patients. Four of 6 patients are alive without leukemia. Infant leukemia patients in our institution had some special features. CNS involvement at diagnosis was seen in only 1 patient and serum IgM levels were higher than those in children whose leukemia was diagnosed at 1 to 10 years of age.

Chromosome Aberrations↗
PubMed2004

Cloning and functional analysis of the rhesus macaque ABCG2 gene. Forced expression confers an SP phenotype among hematopoietic stem cell progeny in vivo.

Hematopoietic cells can be highly enriched for repopulating ability based upon the efflux of the fluorescent Hoechst 33342 dye by sorting for SP (side population) cells, a phenotype attributed to expression of ABCG2, a member of the ABC transporter superfamily. Intriguingly, murine studies suggest that forced ABCG2 expression prevents hematopoietic differentiation. We cloned the full-length rhesus ABCG2 and introduced it into a retroviral vector. ABCG2-transduced human peripheral blood progenitor cells (PBPCs) acquired the SP phenotype but showed significantly reduced growth compared with control. Two rhesus macaques received autologous PBPCs split for transduction with the ABCG2 or control vectors. Marking levels were similar between fractions with no discrepancy between bone marrow and peripheral blood marking. Analysis for the SP phenotype among bone marrow and mature blood populations confirmed ABCG2 expression at levels predicted by vector copy number long term, demonstrating no block to differentiation in the large animal. In vitro studies showed selective protection against mitoxantrone among ABCG2-transduced rhesus PBPCs. Our results confirm the existence of rhesus ABCG2, establish its importance in conferring the SP phenotype, suggest no detrimental effect of its overexpression upon differentiation in vivo, and imply a potential role for its overexpression as an in vivo selection strategy for gene therapy applications.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2004

Steroid-sensitive nephrotic syndrome associated with positive C1q immunofluorescence.

A 21-year-old woman showed heavy proteinuria and edema. A light microscopic study of a renal biopsy specimen showed diffuse mild mesangial expansion, with borderline mesangial hypercellularity. An immunofluorescence study revealed dominant positive staining (3+) of C1q in the glomerular mesangium. Stainings for C3, C4, IgG, and IgM were weak or 1+. Staining for IgA was negative. Electron-dense deposits were present in the mesangial area. There was significant fusion of foot processes. There was no serological or clinical evidence of collagen disease. She was treated with oral prednisolone (initially, 40 mg/day). The proteinuria was alleviated and the patient remains in complete remission. The histopathological studies were compatible with C1q nephropathy, although the clinical outcome differed in a number of aspects. The clinical picture in the current patient appears to represent a very rare phenotype of nephritis.

Adult↗
PubMed2004

Investigation of intermolecular interaction in molecular complex of tryptamine and benzoic acid by solid-state 2D NMR.

Solid-state NMR spectra and powder X-ray diffraction of the two-component molecular complex composed of tryptamine and benzoic acid were observed to investigate the intermolecular interaction in the molecular complex. 1D (13)C CP/MAS NMR spectrum and powder X-ray diffraction pattern of the complex was clearly different from the convolution of each spectrum of the single component. 2D (1)H-(13)C heteronuclear-correlation (HETCOR) NMR technique indicated that the intermolecular interaction between the primary amine of tryptamine and the carboxyl group of benzoic acid must be related to the complex formation.

Benzoic Acid↗
PubMed2003

Two essential splice lariat branchpoint sequences in one intron in a xeroderma pigmentosum DNA repair gene: mutations result in reduced XPC mRNA levels that correlate with cancer risk.

The lariat branch point sequence (BPS) is crucial for splicing of human nuclear pre-mRNA yet BPS mutations have infrequently been reported to cause human disease. Using an inverse RT-PCR technique we mapped two BPS to the adenosine residues at positions -4 and -24 in intron 3 of the human XPC DNA repair gene. We identified homozygous mutations in each of these BPS in two newly diagnosed Turkish families with the autosomal recessive disorder xeroderma pigmentosum (XP). Cells from two severely affected children in family A harbor a homozygous point mutation in XPC intron 3 (-9 T to A), located within the downstream BPS. Using a real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) assay, these cells expressed no detectable (<0.1%) normal XPC message. Instead they expressed an XPC mRNA isoform with deletion of exon 4 that has no DNA repair activity in a host cell reactivation (HCR) assay. In contrast, in cells from three mildly affected siblings in family B, the BPS adenosine located at the -24 position in XPC intron 3 is mutated to a G. Real-time QRT-PCR revealed 3-5% of normal XPC message. These cells from family B had a higher level of HCR than cells from the severely affected siblings in family A, who had multiple skin cancers. Mutations identified in two BPS of the XPC intron 3 resulted in alternative splicing that impaired DNA repair function, thus implicating both of these BPS as essential for normal pre-mRNA splicing. However, a small amount of normal XPC mRNA can provide partial protection against skin cancers.

Adolescent↗
PubMed2003

Generation of a chimeric mouse reconstituted with green fluorescent protein-positive bone marrow cells: a useful model for studying the behavior of bone marrow cells in regeneration in vivo.

Studies have indicated that bone marrow contains both hematopoietic stem cells and mesenchymal stem cells that can differentiate into a variety of mesenchymal tissues, such as bone, cartilage, muscle, and adipose tissue. Therefore, bone marrow cells are thought to be very useful for cell and gene therapy for various diseases. However, the multipotentiality of these cells remains unclear. To address this issue, we established a chimeric model mouse stably reconstituted with green fluorescent protein (GFP)-marked bone marrow cells. We injected bone marrow cells from GFP-transgenic C57BL/6 mice into the tail veins of recipient wild-type C57BL/6 mice that had been irradiated with a lethal dose of 10 Gy from a cesium source. Microscopic examination and fluorescence-assisted cell sorter (FACS) analysis showed that bone marrow cells, including mesenchymal cells, were almost completely reconstituted with GFP+ cells 5 weeks after transplantation. FACS analysis with lineage-specific antibodies confirmed that the GFP+ cells could differentiate into all types of blood cells. To confirm the usefulness of this mouse model, we studied the role of circulating bone marrow-derived cells in healing of damaged intestine. We performed amputation and anastomosis of the jejunum 10 cm from the pyloric region of the stomach. On the third day after operation, a large number of GFP+ cells were infiltrated in the area of anastomosis, and these cells were positive for CD45 and F4/80 antigens. In 7 days, several cells became negative for CD45 and F4/80 and positive for alpha smooth muscle actin antigen, which is specific for smooth muscle. This finding suggested that bone marrow-derived cells had differentiated into smooth muscle. Because reconstituted bone marrow cells as opposed to injected bone marrow cells, behave naturally, this model is ideal for studying the multipotentiality of bone marrow cells in vivo.

Animals↗
PubMed2003

Unilateral renal cortical necrosis with contralateral hydronephrosis after surgery for uterus carcinoma.

Renal cortical necrosis (RCN) represents a rare cause of acute renal failure that is characterized by necrosis of the renal cortex with sparing of the medulla. Most previous RCN cases reported have been bilateral and have occurred in pregnancy. Unilateral RCN is a quite rare disorder. Here, we report a case of unilateral RCN with contralateral hydronephrosis after surgery for uterus carcinoma. In this patient it seems that hydronephrosis had been present before RCN occurrence. It is suggested that ureteric obstruction protects against RCN development.

Adenocarcinoma↗
PubMed2002

Transcription-coupled nucleotide excision repair as a determinant of cisplatin sensitivity of human cells.

The resistance of tumor cells to chemotherapeutic agents, such as cisplatin,is an important problem to be solved in cancer chemotherapy. One of the mechanisms associated with cisplatin resistance is nucleotide excision repair (NER). There are two pathways in NER, transcription-coupled NER (TC-NER) and global genome NER (GG-NER). Here, we report that TC-NER-deficient cells [xeroderma pigmentosum group A (XP-A), XP-D, XP-F, XP-G, Cockayne syndrome group A (CS-A), and CS-B] are hypersensitive to cisplatin irrespective of their GG-NER status, and that gene complementation with XPA and XPD increases resistance to cisplatin. By contrast, XP-C cells with selective defect in GG-NER but with normal TC-NER have normal resistance to cisplatin. XPC complementation had no effect on cisplatin antiproliferative activity. We propose that one of the pathways related to cisplatin response is TC-NER, not GG-NER.

Antineoplastic Agents↗
PubMed2002

The human XPC DNA repair gene: arrangement, splice site information content and influence of a single nucleotide polymorphism in a splice acceptor site on alternative splicing and function.

XPC DNA repair gene mutations result in the cancer-prone disorder xeroderma pigmentosum. The XPC gene spans 33 kb and has 16 exons (82-882 bp) and 15 introns (0.08-5.4 kb). A 1.6 kb intron was found within exon 5. Sensitive real- time quantitative reverse transcription-polymerase chain reaction methods were developed to measure full-length XPC mRNA (the predominant form) and isoforms that skipped exons 4, 7 or 12. Exon 7 was skipped in approximately 0.07% of XPC mRNAs, consistent with the high information content of the exon 7 splice acceptor and donor sites (12.3 and 10.4 bits). In contrast, exon 4 was skipped in approximately 0.7% of the XPC mRNAs, consistent with the low information content of the exon 4 splice acceptor (-0.1 bits). A new common C/A single nucleotide polymorphism in the XPC intron 11 splice acceptor site (58% C in 97 normals) decreased its information content from 7.5 to 5.1 bits. Fibroblasts homozygous for A/A had significantly higher levels (approximately 2.6-fold) of the XPC mRNA isoform that skipped exon 12 than those homozygous for C/C. This abnormally spliced XPC mRNA isoform has diminished DNA repair function and may contribute to cancer susceptibility.

Alternative Splicing↗