増殖型癌融解ウイルスの卵巣癌治療への応用

金沢大学附属病院hTERTプロモーターをアデノウイルス5型E1遺伝子上流に組み込み、テロメレース陽性細胞でのみ増殖可能なアデノウイルス(tumor-or telomerase-specific replication-component adenovirus, TRAD)を作成した。卵巣癌細胞株SKOV3を用いてin vitroでの抗腫瘍効果を抗癌剤との併用効果も含めて検討するとともに、ヌードマウスに10^7個のSKOV3細胞を腹腔内投与して作成した腹膜播種モデルでも同様の検討を行った。また抗癌剤耐性株を樹立し、これらにおけるTRADの効果も確認した。in vitroではTRADの増殖ならびに殺細胞効果はテロメレース陽性の癌細胞株でのみ認められた。この効果はシスプラチン(4μM)との併用により増強した。ヌードマウス腹膜播種モデルでは低濃度シスプラチン(0.5mg/kg)処理巣独では効果がなかったが、TRADとの併用により約80%の播種性病変の減少が認められた(P<0.001)また生存率の向上も認められた(P<0.05)。この際、TRADは播病巣に局在し、明確な有害事象も認められなかった。またCDDP耐性株においてTRADの殺細胞効果に変化はなく、交差耐性は認められなかった。またウイルス局在を可視化するためにGFPを発現する組換え体TRAD-GFPも作成した。TRAD-GFPは癌細胞特異的に感染増殖し癌細胞の所在を視覚化するマーカーとして有用であったばかりでなく、GFPによるcellsortingを行うことで癌細胞を選択的に収集し遺伝子解析を行うといった臨床応用にむけた知見が得られた。研究課題/領域番号:18791146, 研究期間(年度):2006 – 2007出典：「増殖型癌融解ウイルスの卵巣癌治療への応用」研究成果報告書　課題番号18791146（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-18791146/)を加工して作

Function of Ostia in Airflow Patterns within Nasal Cavity Model with Maxillary Sinus

The variation of ostium geometry in human nose is highly debatable. The ways it affects the airflow pattern within the main nasal cavity and maxillary sinus itself remains unclear. Further studies on this matter are valuable particularly in the medical field. Therefore, the purpose of this study is to investigate the effect of ostium number, position and diameter (3~15mm) on the airflow behavior within the nasal cavity and maxillary sinus. As the results, within the maxillary sinus, the streamlines change with variation of the ostium. In case of the mass flow rate, the flow entering the sinus increases as the ostium size widened and with the presence of multiple ostia. To conclude, ostium variations especially in size and number do effects the airflow pattern particularly within the sinus itself.

テロメレース酵素活性サブユニット(hTERT)遺伝子プロモーターのクローニングと不死化細胞や癌細胞における転写活性化に必要なコアプロモーター領域の同定

取得学位 : 博士（医学）, 学位授与番号 : 医博乙第1549号 , 学位授与年月日 : 平成14年3月6日, 学位授与大学 : 金沢大

Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers

がん進展制御研究所　Telomerase activation is a critical step for human carcinogenesis through the maintenance of telomeres, but the activation mechanism during carcinogenesis remains unclear. Transcriptional regulation of the human telomerase reverse transcriptase (hTERT) gene is the major mechanism for cancer-specific activation of telomerase, and a number of factors have been identified to directly or indirectly regulate the hTERT promoter, including cellular transcriptional activators (c-Myc, Sp1, HIF-1, AP2, ER, Ets, etc.) as well as the repressors, most of which comprise tumor suppressor gene products, such as p53, WT1, and Menin. Nevertheless, none of them can clearly account for the cancer specificity of hTERT expression. The chromatin structure via the DNA methylation or modulation of nucleosome histones has recently been suggested to be important for regulation of the hTERT promoter. DNA unmethylation or histone methylation around the transcription start site of the hTERT promoter triggers the recruitment of histone acetyltransferase (HAT) activity, allowing hTERT transcription. These facts prompted us to apply these regulatory mechanisms to cancer diagnostics and therapeutics. Telomerase-specific replicative adenovirus (Telomelysin, OBP-301), in which E1A and E1B genes are driven by the hTERT promoter, has been developed as an oncolytic virus that replicates specifically in cancer cells and causes cell death via viral toxicity. Direct administration of Telomelysin was proved to effectively eradicate solid tumors in vivo, without apparent adverse effects. Clinical trials using Telomelysin for cancer patients with progressive stages are currently ongoing. Furthermore, we incorporated green fluorescent protein gene (GFP) into Telomelysin (TelomeScan, OBP-401). Administration of TelomeScan into the primary tumor enabled the visualization of cancer cells under the cooled charged-coupled device (CCD) camera, not only in primary tumors but also the metastatic foci. This technology can be applied to intraoperative imaging of metastatic lymphnodes. Thus, we found novel tools for cancer diagnostics and therapeutics by utilizing the hTERT promoter. © 2008 Japanese Cancer Association

Use of Balloon Enteroscopy in Preoperative Diagnosis of Neurofibromatosis-Associated Gastrointestinal Stromal Tumours of the Small Bowel: A Case Report

Neurofibromatosis type I (NF1) is one of the most common inheritable disorders and is associated with an increased risk of gastrointestinal stromal tumours (GISTs). However, the predominant location of these lesions in the small bowel makes them difficult to diagnose. We report the successful use of balloon enteroscopy in conjunction with conventional methods for clinical diagnosis of jejunal GISTs in a 70-year-old man with NF1 who presented with melaena. The importance of screening NF1 patients for GISTs and the complementary role of balloon enteroscopy with capsule endoscopy in such diagnoses is discussed

Concomitant activation of AKT with extracellular-regulated kinase 1/2 occurs independently of PTEN or PIK3CA mutations in endometrial cancer and may be associated with favorable prognosiss

がん進展制御研究所　Deregulated signaling via the phosphatidylinositol 3-kinase (PI3K) pathway is common in many types of cancer, but its clinicopathological significance in endometrial cancer remains unclear. In the present study, we examined the status of the PI3K signaling pathway, especially in relation to PTEN and PIK3CA status, in endometrioid-type endometrial cancer. The immunohistochemical analysis revealed a high level of phosphorylated (p)-AKT expression, which is a hallmark of activated PI3K signaling, in approximately 60% of endometrial cancers. There was no correlation between p-AKT expression and clinicopathological characteristics, such as International Federation of Gynecology and Obstetrics stage, tumor grade, and myometrial invasion. Unexpectedly, a high level of p-AKT expression occurred independently of the presence of PTEN or PIK3CA mutations. Furthermore, p-AKT expression did not correlate with the expression of potential downstream targets, including p-mTOR and p-FOXO1/3a. In turn, p-AKT expression was strongly associated with extracellular-regulated kinase 1/2 expression (P = 0.0031), which is representative of the activated RAS-MAP kinase pathway. Kaplan-Meier analysis suggested that low p-AKT expression was associated with low rates of relapse-free survival, although the difference was not statistically significant, indicating that AKT activation does not confer worse prognosis. The present study demonstrates the presence of complex signaling pathways that might mask the conventional tumorigenic PTEN-PI3K-AKT-mTOR pathway, and strongly suggests a close association between the extracellular-regulated kinase and PI3K pathways in this tumor type. © 2007 Japanese Cancer Association

Activation of ERK1/2 occurs independently of KRAS or BRAF status in endometrial cancer and is associated with favorable prognosis

がん進展制御研究所The extracellular-regulated kinase (ERK) signaling pathway plays important roles in regulating the malignant potential of cancer cells in vitro. However, the effect of ERK signaling on the prognosis of human tumors is not clearly understood. The present study examined the expression of phosphorylated ERK1/2 (p-ERK1/2) as a hallmark of ERK activation, in relation to KRAS and BRAF mutations, in 63 endometrial cancer specimens with endometrioid-subtype, in order to clarify the prognostic value of p-ERK1/2 expression. Immmunohistochemical analysis revealed that 40 tumors (63%) expressed p-ERK1/2, with varying levels of expression. Total ERK1/2 expression was also evaluated in a subset of tumors; most cases expressed ERK1/2 constitutively but no correlation was observed with p-ERK expression, indicating that p-ERK1/2 staining was not due to ERK overexpression but to hyperactivation of ERK1/2. There was no statistically significant correlation between p-ERK1/2 expression and clinicopathological features, including patient age, International Federation of Gynecology and Obstetrics stage, pathological grade, myometrial invasion and lymph node metastasis. Sequencing analysis indicated that 23% of patients had a mutation in exon 1 of KRAS, whereas none of the patients had a mutation in exons 11 or 15 of BRAF, which are reportedly hot spots for mutation in many tumor types. There was no significant correlation between KRAS or BRAF status and p-ERK1/2 expression. Unexpectedly, patients with low p-ERK1/2 expression had significantly lower relapse-free survival (P = 0.041) and overall survival (P = 0.020). Multivariate Cox regression analysis indicated that p-ERK1/2 expression was an independent prognostic indicator for overall survival (P = 0.047). These findings suggest that ERK activation occurs in a KRAS - and BRAF-independent manner in endometrial cancer, and is associated with favorable prognosis. © 2007 Japanese Cancer Association

Tamoxifen-induced ovarian hyperstimulation during premenopausal hormonal therapy for breast cancer in Japanese women

Purpose: Tamoxifen is an anti-estrogenic drug that is widely used for endocrine-dependent breast cancer as adjuvant hormonal therapy, and its use has been reported to be frequently associated with high levels of serum estradiol. Since the population of premenopausal women receiving tamoxifen therapy is growing in Japan, we retrospectively analyzed the incidence of ovarian hyperstimulation by tamoxifen therapy in Japanese women. Methods: Eleven patients who received surgical therapy for endocrine-dependent breast cancer and showed high values of serum estradiol during post-operative tamoxifen therapy were recruited in this study and evaluated by examining the serum concentration of follicular stimulating hormone (FSH) and follicular development. Results: The mean age, serum concentrations of estradiol and FSH, and follicular diameter were 41.3 years old, 1015.8 pg/mL, 11.8 mIU/mL, and 3.47 cm, respectively. In 6 cases, multiple follicular development was observed, while the other cases showed single follicular development with a mean serum estradiol level of 848.6 pg/mL and follicular diameter of 4.46 cm. There was no significant difference in age or FSH concentration between the two groups. The mean periods from the start of the single administration of tamoxifen to the initial detection of a high estradiol concentration was 716.5 days. Conclusions: These findings indicate that tamoxifen could stimulate the ovarian function even after 2-year treatment. Since single and multiple follicular developments with large sizes were observed, dual mechanisms through the inhibition of both negative and positive feedback to the hypothalamic-pituitary-axis can be proposed to explain the adverse effects of tamoxifen on ovarian function. © 2015, Yamazaki et al

Limiting global warming to 1.5ºC will lower increases in inequalities of four hazard indicators of climate change

Clarifying characteristics of hazards and risks of climate change at 2 °C and 1.5 °C global warming is important for understanding the implications of the Paris Agreement. We perform and analyze large ensembles of 2 °C and 1.5 °C warming simulations. In the 2 °C runs, we find substantial increases in extreme hot days, heavy rainfalls, high streamflow and labor capacity reduction related to heat stress. For example, about half of the world's population is projected to experience a present day 1-in-10 year hot day event every other year at 2 °C warming. The regions with relatively large increases of these four hazard indicators coincide with countries characterized by small CO2 emissions, low-income and high vulnerability. Limiting global warming to 1.5 °C, compared to 2 °C, is projected to lower increases in the four hazard indicators especially in those regions.ISSN:1748-9326ISSN:1748-931