アンドロゲン受容体とアリル炭化水素受容体のシグナル伝達経路間クロストークに関する研究

取得学位：博士(薬学)，学位授与番号：博甲第1116号，学位授与年月日：平成21年3月23

Allelotypes of lung adenocarcinomas featuring ALK fusion demonstrate fewer onco- and suppressor gene changes

BACKGROUND: A subset of lung adenocarcinomas harboring an EML4-ALK fusion gene resulting in dominant oncogenic activity has emerged as a target for specific therapy. EML4-ALK fusion confers a characteristic histology and is detected more frequently in never or light smokers and younger patients. METHODS: To gain insights into etiology and carcinogenic mechanisms we conducted analyses to compare allelotypes of 35 ALK fusion-positive and 95 -negative tumours using single nucleotide polymorphism (SNP) arrays and especially designed software which enabled precise global genomic profiling. RESULTS: Overall aberration numbers (gains + losses) of chromosomal alterations were 8.42 and 9.56 in tumours with and without ALK fusion, respectively, the difference not being statistically significant, although patterns of gain and loss were distinct. Interestingly, among selected genomic regions, oncogene-related examples such as 1p34.3(MYCL1), 7q11.2(EGFR), 7p21.1, 8q24.21(MYC), 16p13.3, 17q12(ERBB2) and 17q25.1 showed significantly less gain. Also, changes in tumour suppressor gene-related regions, such as 9p21.3 (CDKN2A) 9p23-24.1 (PTPRD), 13q14.2 (RB1), were significantly fewer in tumours with ALK fusion. CONCLUSION: Global genomic comparison with SNP arrays showed tumours with ALK fusion to have fewer alterations in oncogenes and suppressor genes despite a similar overall aberration frequency, suggesting very strong oncogenic potency of ALK activation by gene fusion

Quinoid polycyclic aromatic hydrocarbons-mediated production of reactive oxygen species and subsequet activation of NF-κB and induction of cyclooxygenase-2

Tobacco smoke and the atmosphere consist of a wide variety of compounds with adverse health effects. Polycyclic aromatic hydrocarbons (PAHs) are principal toxic compounds. Some of PAHs containing oxygen (quinoid PAHs) generate reactive oxygen species (ROS) through enzymatic and nonenzymatic redox cycling reactions. ROS can cause severe oxidative stress leading to various diseases such as cancer and inflammation. In this study, we estimated the intracellular ROS production and nuclear factor kappa B (NF-κB) translocation in A549 cells exposed to isomers of quinoid PAHs having two to four rings. We found that both acenaphthenequinone (AcQ) and phenanthrene-9,10-quinone (PQ) enhanced ROS generation and that AcQ translocated NF-κB from the cytosol to the nucleus. In addition, AcQ induced cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production were mediated by the activation of NF-κB. Upregulation of NF-κB and COX-2 expression and PGE2 production by AcQ treatment was suppressed by the antioxidant N-acetylcysteine. These results provide that AcQ might play an important role in human lung cancer and inflammatory diseases.研究ノート (Note

Effect of 3-methylcholanthrene and benzo[a]pyrene on the differentiation of PC12 cells to neuron-like cells.

研究ノー

Rearrangement of the breakpoint cluster region in Philadelphia chromosome positive acute leukemia.

The rearrangement of breakpoint cluster region (ber) was examined in leukemic cells obtained from 3 patients initially diagnosed as having Ph+ acute leukemia, 2 with acute lymphocytic leukemia (ALL) and one with acute mixed leukemia. DNA was digested with Bgl II and BamH I. The ber rearrangement was present in the case of acute mixed leukemia (Case 1), but was absent in the 2 cases of ALL (Cases 2 and 3). These results suggest that Case 1 represented a type of blast crisis of chronic myelocytic leukemia which was unusual in the sense of the occurrence of a myeloid-lymphoid conversion and lack of an apparent chronic phase. Cases 2 and 3 appeared to be de novo Ph+ ALL.</p

Learning and memory in mice gestationally and lactationally exposed to 3-methylcholanthrene

研究ノート (Note

アルツハイマー型認知症治療薬ドネペジルによる神経幹細胞から神経細胞への分化誘導に関する研究

研究ノー

Effects of 3-methylcholanthrene on the survival of neural stem cells obtained from the hippocampus of the mice in prenatal and lactational Period.

研究ノート (Note

Aclarubicin in the treatment of elderly patients with acute nonlymphocytic leukemia.

Thirteen previously untreated patients aged 70 and above with acute nonlymphocytic leukemia were treated with aclarubicin (ACR) alone. Among 10 cases (3, acute myelocytic leukemia; 4, acute myelomonocytic leukemia; 2, acute monocytic leukemia; and one, acute erythroleukemia) in which an evaluation was possible, 5 cases (3, acute myelomonocytic leukemia; and 2, acute monocytic leukemia) obtained complete remission (CR). The CR rate was 83% in 6 patients with acute myelomonocytic leukemia or acute monocytic leukemia. The median CR duration and survival was 7.5 and 10 + months, respectively. Although side effects of the drug on digestive system such as nausea, vomiting and anorexia were observed in all patients, they were controllable by conventional treatments. The results suggest that ACR is effective for the clinical management of elderly patients with acute nonlymphocytic leukemia, especially those with acute myelomonocytic leukemia or acute monocytic leukemia.</p

Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia

Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML