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Biomedical subjects

Yuki Yuza

Publications and source records attributed to Yuki Yuza.

10 recordsLinked to original sources
PubMed2006

Sensitive mutation detection in heterogeneous cancer specimens by massively parallel picoliter reactor sequencing.

The sensitivity of conventional DNA sequencing in tumor biopsies is limited by stromal contamination and by genetic heterogeneity within the cancer. Here, we show that microreactor-based pyrosequencing can detect rare cancer-associated sequence variations by independent and parallel sampling of multiple representatives of a given DNA fragment. This technology can thereby facilitate accurate molecular diagnosis of heterogeneous cancer specimens and enable patient selection for targeted cancer therapies.

Base Sequence↗
PubMed2006

Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors.

The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC). Dramatic and durable responses have occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In contrast, these inhibitors have shown limited efficacy in glioblastoma, where a distinct EGFR mutation, the variant III (vIII) in-frame deletion of exons 2-7, is commonly found. In this study, we determined that EGFRvIII mutation was present in 5% (3/56) of analyzed human lung squamous cell carcinoma (SCC) but was not present in human lung adenocarcinoma (0/123). We analyzed the role of the EGFRvIII mutation in lung tumorigenesis and its response to tyrosine kinase inhibition. Tissue-specific expression of EGFRvIII in the murine lung led to the development of NSCLC. Most importantly, these lung tumors depend on EGFRvIII expression for maintenance. Treatment with an irreversible EGFR inhibitor, HKI-272, dramatically reduced the size of these EGFRvIII-driven murine tumors in 1 week. Similarly, Ba/F3 cells transformed with the EGFRvIII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272. These findings suggest a therapeutic strategy for cancers harboring the EGFRvIII mutation.

Animals↗
PubMed2006

A common signaling cascade may underlie "addiction" to the Src, BCR-ABL, and EGF receptor oncogenes.

"Oncogene addiction" describes an unexplained dependency of cancer cells on a particular cellular pathway for survival or proliferation. We report that differential attenuation rates of prosurvival and proapoptotic signals in oncogene-dependent cells contribute to cell death following oncogene inactivation. Src-, BCR-ABL-, and EGF receptor-dependent cells exhibit a similar profile of signal attenuation following oncogene inactivation characterized by rapid diminution of phospho-ERK, -Akt, and -STAT3/5, and a delayed accumulation of the proapoptotic effector phospho-p38 MAPK. These findings implicate a transient imbalance in survival and apoptotic oncogenic outputs in the apoptotic response to oncogene inactivation. Moreover, these observations implicate a common profile of signal attenuation for multiple oncogenes and suggest that "addiction" associated with apoptosis reflects an active rather than a passive process.

Animals↗
PubMed2006

Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.

BACKGROUND: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. METHODS AND FINDINGS: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. CONCLUSIONS: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.

Animals↗
PubMed2005

An alternative inhibitor overcomes resistance caused by a mutation of the epidermal growth factor receptor.

Mutations of the epidermal growth factor receptor (EGFR) gene have been identified in non-small cell lung cancer specimens from patients responding to anilinoquinazoline EGFR inhibitors. However, clinical resistance to EGFR inhibitor therapy is commonly observed. Previously, we showed that such resistance can be caused by a second mutation of the EGFR gene, leading to a T790M amino acid change in the EGFR tyrosine kinase domain and also found that CL-387,785, a specific and irreversible anilinoquinazoline EGFR inhibitor, was able to overcome this resistance on the biochemical level. Here, we present the successful establishment of a stable Ba/F3 cell line model system for the study of oncogenic EGFR signaling and the functional consequences of the EGFR T790M resistance mutation. We show the ability of gefitinib to induce growth arrest and apoptosis in cells transfected with wild-type or L858R EGFR, whereas the T790M mutation leads to high-level functional resistance against gefitinib and erlotinib. In addition, CL-387,785 is able to overcome resistance caused by the T790M mutation on a functional level, correlating with effective inhibition of downstream signaling pathways. Similar data was also obtained with the use of the gefitinib-resistant H1975 lung cancer cell line. The systems established by us should prove useful for the large-scale screening of alternative EGFR inhibitor compounds against the T790M or other EGFR mutations. These data also support the notion that clinical investigations of compounds similar to CL-387,785 may be useful as a treatment strategy for patients with resistance to EGFR inhibitor therapy caused by the T790M mutation.

Animals↗
PubMed2005

The MYO1F, unconventional myosin type 1F, gene is fused to MLL in infant acute monocytic leukemia with a complex translocation involving chromosomes 7, 11, 19 and 22.

We analysed a complex translocation involving chromosomes 7, 11, 19 and 22 in infant acute monocytic leukemia, and identified that the MLL gene on 11q23 was fused to the unconventional myosin type 1F, MYO1F, gene on 19p13.2-13.3. MYO1F consists of at least 28 exons and was predicted to encode a 1098-amino-acid with an N-terminal head domain containing both ATP-binding and actin-binding sequences, a neck domain with a single IQ motif, and a tail with TH1, TH2 and SH3 domains. Northern blot analysis of RNAs prepared from multiple tissues showed that the expression of approximately 4-kb transcripts appeared constant in most tissues examined. However, MYO1F was expressed in only three of 22 leukemic cell lines. The MLL-MYO1F fusion protein contains almost the entire MYO1F, however, C-terminal MYO1F has neither the transactivation domain nor the dimerization domain found in various MLL fusion partners. Further analysis of this novel type of MLL fusion protein would provide new insights into leukemogenesis. MYO1F is the fourth partner gene of MLL on 19p13. At the cytogenetic level, it may be difficult to distinguish MLL-ENL, MLL-ELL, MLL-EEN and MLL-MYO1F fusions created by t(11;19)(q23;p13), and it is likely that cases of t(11;19) lacking a known fusion gene may result in this gene fusion.

Amino Acid Sequence↗
PubMed2005

Successful treatment of Diamond-Blackfan anemia with metoclopramide.

Diamond-Blackfan anemia (DBA) is a congenital anemia characterized by a low reticulocyte count, the absence or severe reduction of hemoglobin-containing cells in the bone marrow, and normal megakaryocytic and granulocytic differentiation. Although the anemia may initially respond to corticosteroid therapy, many patients require lifelong red blood cell (RBC) transfusion, leading to infectious complications and iron overload. Metoclopramide has recently been used to treat DBA. Treatment with metoclopramide induces the release of prolactin from the pituitary and stimulates erythropoiesis. For these reasons, we used metoclopramide to treat a 20-year-old man with DBA refractory to low and high doses of corticosteroids, cyclosporin A, and tacrolimus (FK506). The hemoglobin and hematocrit slowly increased, and he has remained asymptomatic and transfusion-independent for 8 months. Metoclopramide therapy should be considered in patients with refractory DBA before treatment-related complications develop.

Adult↗
PubMed2003

Gene and protein expression profiling during differentiation of neuroblastoma cells triggered by 13-cis retinoic acid.

PURPOSE: The precise changes in RNA and protein expression that accompany neuroblastoma differentiation remain unknown. The authors used microarray technologies to screen molecules associated with the differentiation of neuroblastoma (NB) cells induced by 13-cis retinoic acid. METHODS: The authors quantified the expression of 2,061 RNA transcripts related to oncogenesis and of 380 proteins expressed in SK-N-SH and CHP-134 NB cell lines in the presence or absence of 13-cis retinoic acid. RESULTS: Hierarchical clustering captured gene expression altered during neuroblastoma differentiation induced by 13-cis retinoic acid. Several genes were further abstracted based on P values below 0.0017 or protein chips observed in both NB cell lines. The altered expressions of gene products revealed by both DNA and protein chips were in agreement. The expressions of N-myc, cyclin D3, and Wnt10B were downregulated, whereas those of retinoblastoma (RB) and related genes (p107, RB2/p130, p300/CBP, E2F-1, DP-1) as well as others were upregulated. CONCLUSIONS: These results suggest that microarray technology can screen for genes that are important in neuroblastoma differentiation.

Antineoplastic Agents↗