Biomedical subjects

Michiyuki Hakozaki

Publications and source records attributed to Michiyuki Hakozaki.

6 recordsLinked to original sources

PubMed2026

Combination of EZH2 and MEK inhibitors as an effective therapy for neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.

BACKGROUND: Neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with poor outcomes and limited therapeutic options. Although mitogen-activated protein kinase kinase (MEK) inhibitors are active in benign plexiform neurofibromas, their efficacy in MPNST treatment is modest. Enhancer of zeste homolog 2 (EZH2) inhibitors are preclinically efficacious in MPNST treatment, but their mechanisms of action remain unclear. We evaluated the therapeutic potential and molecular mechanism of combined EZH2 and MEK inhibitors in NF1-associated MPNST. METHODS: Five human NF1-associated MPNST cell lines were exposed to EZH2 and/or MEK inhibitors. Cell growth and apoptosis were quantified over time. Therapeutic efficacy was tested in a subcutaneous xenograft model. Proliferation and apoptosis in tumors were assessed using standard histologic markers, and intracellular localization of phosphorylated extracellular signal-regulated kinase (pERK) was examined using fluorescent immunohistochemistry. RESULTS: Monotherapy with EZH2 or MEK inhibitors reduced proliferation and increased apoptosis across all MPNST lines. Combination therapy produced greater tumor cell growth suppression and marked increases in apoptosis. In vivo, the combination significantly delayed tumor progression compared with monotherapy, with concomitant reductions in proliferative indices and increases in apoptotic indices. EZH2 inhibitor limited nuclear pERK entry. CONCLUSIONS: Dual EZH2 and MEK inhibitors yield additive antitumor activity in NF1-associated MPNST. Although the molecular mechanism could not be elucidated, our findings suggest that EZH2 inhibitors exhibited a polycomb repressive complex 2-independent, noncanonical mechanism characterized by pERK nuclear translocation restriction, providing a strong rationale for clinical evaluation of this combination in NF1-associated MPNST.

EZH2 inhibitor↗

PubMed2007

Etodolac, a selective cyclooxygenase-2 inhibitor, induces apoptosis by activating caspases in human malignant rhabdoid tumor cells (FRTK-1).

Malignant rhabdoid tumor (MRT) is a rare and highly aggressive tumor presenting in the kidney and soft tissue in childhood. However, effective treatment for MRT has not been established. We investigated the antitumor effect of etodolac, a selective cyclooxygenase-2 inhibitor, on MRT cells in vitro using the MRT cell line FRTK-1. Etodolac induced apoptosis of FRTK-1 cells through activation of caspase-8, -9 and -3. Moreover, several caspase inhibitors completely or partially inhibited etodolac-induced apoptosis. Our data indicated that etodolac had an antitumor effect on MRT cells and holds promise as a novel therapeutic strategy for MRT.

Amino Acid Chloromethyl Ketones↗

PubMed2006

Acute calcific tendinitis of the thumb in a child: a case report.

Acute calcific tendinitis is rare in hand and digit, especially in children. We describe a rare case of acute calcific tendinitis of the thumb [extensor pollicis longus (EPL) tendon] in a 10-year-old boy. Plain radiographs showed a calcium deposit in the EPL tendon. Conservative therapy completely resolved all symptoms in 1 week. The calcium deposit shown on plain radiographs became smaller and completely disappeared within 6 weeks.

Calcinosis↗

PubMed2006

Ewing's sarcoma in the spinal nerve root: a case report and review of the literature.

Ewing's sarcoma (ES) is a highly malignant tumor composed of uniform small round cells. Recently, a single biologic entity, Ewing's sarcoma family of tumors (ESFT) has been accepted. The entity includes ES, extraskeletal Ewing's sarcoma (EES) and primitive neuroectodermal tumor (PNET). ESFT cells have immunoreactivity for CD99, an antigen determined by the MIC2 gene. Most ESFT has the (11;22) (q24;q12) translocation. The translocation results in the fusion of the EWS gene with the transcription factor gene FLI1 which has been considered a hallmark of ESFT. We present an extremely unusual case with ESFT in a spinal nerve root mimicking a neurogenic dumbbell tumor. A male aged 20 years noticed pain in his right buttock. Magnetic resonance imaging (MRI) revealed a mass in the right L5/S intervertebral foramen and the lesions in the sacrum. Surgery was performed with a presumptive diagnosis of a nerve sheath tumor. At surgery, the tumor was located in the right L5 nerve root sleeve. The sacral lesions were observed closely. At one month after surgery, radiologically multiple lesions were detected in the pelvic bones. Microscopically the lesions from the root and ilium were composed of small round cells immunoreactive for CD99. Reverse transcription-polymerase chain reaction detected transcripts resulting from the fusion of the EWS gene with FLI1 genes in the iliac lesion. Immunoreactivity for CD99 and detection of the EWS-FLI1 hybrid transcripts are important for the correct diagnosis of ESFT arising in an unusual location.

Adult↗

PubMed2006

Establishment and characterization of a new cell line, FRTK-1, derived from human malignant rhabdoid tumor of the kidney, with overexpression of epidermal growth factor receptor and cyclooxygenase-2.

A new human malignant rhabdoid tumor (MRT) cell line (designated FRTK-1) was established from MRT of the kidney of an 18-month-old boy. The cell line is maintained for over 24 months with more than 100 passages. FRTK-1 cells in vitro showed 2 different growth patterns, adherent and non-adherent patterns. The FRTK-1 cells showed the same morphological and immunophenotypical characteristics as primary tumor cells of kidney. Cytogenetic and molecular analyses revealed a non-sense mutation in the hSNF5/INI1 gene and loss of expression of hSNF5/INI1 gene product protein. Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) were expressed in the FRTK-1 cells. Until now, there has been no report of MRT cell lines with expression of COX-2. Therefore, FRTK-1 cell line might be useful for investigating biological behavior and developing new molecular targeting antitumor drugs for MRT with expression of EGFR or COX-2.

Adolescent↗

PubMedDate not supplied

Establishment and characterization of a new cell line, FPS-1, derived from human undifferentiated pleomorphic sarcoma, overexpressing epidermal growth factor receptor and cyclooxygenase-2.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is among the most common soft tissue sarcomas in adults. In order to improve its aggressive course or prognosis and establish new therapeutic methods, molecular genetic and biological characterizations of UPS are required. MATERIALS AND METHODS: A new human UPS cell line (FPS-1) was established from UPS of the upper arm of a 79-year-old man. The cell line has been maintained for over 14 months with more than 60 passages. FPS-1 cells were characterized using molecular biological methods. RESULTS: FPS-1 cells showed the same morphological and immunophenotypical characteristics as the primary tumor. Cytogenetic and molecular analyses revealed a nonsense mutation in exon 6 of the p53 gene. Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) were expressed in FPS-1 cells. CONCLUSION: FPS-1 cells might be useful for investigating biological behavior and developing new molecular targeting antitumor drugs for UPS with EGFR or COX-2 expression.

Aged↗