Geldanamycinによる悪性グリオーマ増殖抑制に関する基礎的研究

金沢大学附属病院目的:Geldanamycin (GA)は、benzoquinone ansamycinの一種の抗生物質であり、種々の腫瘍の増殖を抑制する。我々はグリオーマ細胞の増殖に対するGAの細胞周期特異的な影響についてin vitroで検討を行った。方法:血清の除去と添加により細胞周期を同調させた(early G1 or G1/S transition)ヒトグリオーマ細胞T98G細胞を実験に用いた。このグリオーマ細胞にGAを作用させ、増殖と細胞周期の変化を検討した。さらに、細胞内のシグナル伝達に関与するタンパクであるAktおよびmitochondrial apoptotic pathwayに関与するタンパクの発現も検討した。結果:1、GAをG1/S transition期の細胞に投与すると、細胞は球形の形態を示し、作用後12時間でM期に同調し(M arrest)、M arrestは48時間持続した。2、GAをearly G1期の細胞に投与すると、細胞はG1期にとどまり、SまたはG2/M期への進行を示さなかった。また、ほとんどの細胞は細胞の形態の変化を示さなかった(G1 arrest)。3、sub-G1期の細胞数は、G1/S期にGAを作用させた細胞では、early G1期に作用させた細胞より有為に多かった。4、GA作用後のPhosphorylated Aktの発現の減少は、early G1またはG1/S transition群でそれぞれ、48、24時間後より認められた。5、caspase-9,3 and 7のcleavageは、early G1、G1/S transitiongroupsでそれぞれ36、24時間後より認められた。PARPの減少とcleaved PARPの発現もearly G1 groupにて遅れて認められた。結論:GAは、グリオーマ細胞において細胞周期特異的な増殖抑制効果を示した。これらの効果は、mitochondrial apoptotic pathwayを介しており、GA-induced apoptosisはAkt活性の減少によるものと考えられた。研究課題/領域番号:14770706, 研究期間(年度):2002-2003出典：「Geldanamycinによる悪性グリオーマ増殖抑制に関する基礎的研究」研究成果報告書　課題番号14770706（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-14770706/)を加工して作

VEGFおよびAng2遺伝子抑制による動脈硬化内膜増殖抑制に関する研究

金沢大学医薬保健研究域医学系研究課題/領域番号:12770748, 研究期間(年度):2000出典：「VEGFおよびAng2遺伝子抑制による動脈硬化内膜増殖抑制に関する研究」研究成果報告書　課題番号 12770748（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-12770748/)を加工して作

アンジオスタチン遺伝子導入による悪性神経膠種における血管新生抑制に関する研究

金沢大学医薬保健研究域医学系脳腫瘍での血管新生を抑制することによって、脳腫瘍の増殖を抑制し、脳腫瘍の新たな治療法を確立することを目的として本研究を計画した.本研究において、脳腫瘍細胞でいかなる血管新生因子が発現しているかを明らかにすることが、研究の基礎として必須である.そこで我々は、新たに固定されたチロシンキナーゼ受容体であるTie2とそのリガンドである血管新生因子angiopoietin1(Ang1)、angiopoietin2(Ang2)の脳腫瘍細胞での発現を検討した.その結果、Mrnaレベルでは、Ang1は、悪性度の高いグリオーマ細胞や血管の豊富な髄膜腫に、また、Ang2は血管の豊富な髄膜腫や血管芽細胞腫に強く発現していた.さらに、これら血管新生因子の受容体であるTie2はAng2と同様に血管の豊富な髄膜腫や血管芽細胞腫に強く発現していることが明らかになった.これら遺伝子レベルでの検討に加えて、タンパクレベルでの検討を追加し、Mrnaの発現とほぼ一致した結果が得られた.これらのことより、脳腫瘍の血管新生にはAng1、Ang2が深く関与していることが示唆された.また腫瘍細胞により、二種類の血管新生因子の発現様式が異なることより、腫瘍特異的な血管新生因子の発現が予想された.研究課題/領域番号:10770676, 研究期間(年度):1998 – 1999出典：「アンジオスタチン遺伝子導入による悪性神経膠種における血管新生抑制に関する研究」研究成果報告書　課題番号10770676（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-10770676/)を加工して作

低酸素による血管細胞増殖誘導の分子機構 : 血管内皮増殖因子(VEGF)のオ-トクリン/パラクリン作用

取得学位 : 博士（医学）, 学位授与番号 : 医博甲第1139号, 学位授与年月日：平成6年3月25日,学位授与年：199

Simple classification of carotid bifurcation: is it possible to predict twisted carotid artery during carotid endarterectomy?

Background: The internal carotid artery (ICA) usually runs posterolaterally to the external carotid artery (ECA), but occasionally we encounter the twisted carotid bifurcation, a variant in which the ICA courses medially to the ECA during carotid endarterectomy (CEA). Prediction of this anomaly in the preoperative evaluation is mandatory, although descriptions in the literature are limited. We reviewed the clinical features of patients who underwent CEA and analyzed preoperative cerebral angiography, especially the anteroposterior (AP) view to determine whether it could be a predictive modality. Methods: In 58 consecutive CEA cases, we simply classified them into three groups; type 1 (the ICA runs laterally and the ECA runs medially), type 2 (the ICA and ECA run to overlap each other), and type 3 (the ICA runs medially and the ECA runs laterally), based on the findings of AP view of cerebral angiography. We compared the clinical features and intraoperative findings of these groups. Results: Of 58 cases, types 1–3 were 24, 30, and four cases, respectively. Twisted carotid bifurcations were recognized in seven cases (12.4 %), including three cases in type 2 and four in type 3, and all twisted cases were found on the right side. Twisted carotids and right-sided lesion were significantly frequent in type 3, but no statistical differences of coexisting diseases were recognized among the three groups. CEAs of twisted carotid bifurcations were performed successfully with correction of the carotid position in three and as it was in four cases. Conclusions: Twisted carotid bifurcations were observed during operation in 10 % in type 2 and 100 % in type 3. CEA of twisted carotid bifurcations can be performed safely with or without correction of the carotid position. AP view of cerebral angiography could be useful for preoperative evaluation. © 2016 Springer-Verlag WienEmbargo Period 12 month

Aneurysm clipping after partial endovascular embolization for ruptured cerebral aneurysms

The aim of this study was to investigate the advantages and disadvantages of a two-stage treatment for ruptured cerebral aneurysms; partial embolization in acute stage followed by clipping in chronic stage of subarachnoid hemorrhage. Between April 1997 and August 1999, twenty ruptured cerebral aneurysms were initially treated endovasculary using Guglielmi detachable coils in our institution. Among them, complete embolization could not be achieved in 6 lesions. For these lesions, subsequent clipping was added. The radiological and operative findings, and outcomes of these cases were retrospectively reviewed. In 1 case, rerupture occurred during the endovascular procedure. Rerupture was not observed in any cases in the postembolization period. In 2 cases, complications related to the clipping but not the endovascular procedure occurred. These complications included impaired visual acuity for unverified reasons, and memory disturbance due to sacrifice of a perforator arising from the anterior communicating artery. In 3 cases, coil extraction was needed during the clipping, because the loops of the coil extended into the residual neck. Complications related to coil extraction were not observed in these 3 cases. Acute partial embolization of ruptured aneurysm appears to be effective for the prevention of subsequent rerupture during the subacute period, in which treatment for vasospasm should be performed, and the clipping procedure. However, in the case of relatively large aneurysms, small arteries or other normal structures behind the aneurysm cannot be observed directly during surgery, because of the immovability of the embolized aneurysm. Further, complete clip closure is impossible when loops of coil herniate into the neck. In such situations, coil extraction with or without resection of the aneurysm might be necessary, and care must be taken not to damage parent artery and surrounding vessels

Significance of volume embolization ratio as a predictor of recanalization on endovascular treatment of cerebral aneurysms with Guglielmi detachable coils

The purposes of this study are, firstly, to define the relationship between volume embolization ratio (VER) and degree of angiographical occlusion in endovascular treatment with Guglielmi detachable coils, and secondly, to examine influences of neck and dome sizes of aneurysms on the VER and the angiographical treatment result, and thirdly, to determine the relationship between the VER and the recanalization of coiled aneurysms. Fifty-two aneurysms in 46 patients were examined. VER ranged 8.1-31.9% (mean 18.5%). The mean VERs of each categories based on angiographical treatment results were 23.1% in complete occlusion, 16.1% in neck remnant and 12.2% in incomplete occlusion, respectively. The VER correlated significantly with both neck and dome size, while the angiographical treatment result was only affected by neck size. Five aneurysms showed aneurysmal recanalization among followed-up 41 aneurysms. All recanalized aneurysms were large, and their VERs were in range of 10.4-17.6%. Measurement of VER is useful to estimate the degree of occlusion objectively and to predict the aneurysmal recanalization. A small aneurysms with a small neck is relatively easy to achieve high VER and angiographical complete occlusion, with the consequence of less recanalization. On the other hand, a large aneurysm is liable to recanalize due to low VER, even if there was little filling of contrast medium in the aneurysmal cavity

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

Ocular dominance affects magnitude of dipole moment: An MEG study

横浜栄共済病院脳卒中診療科・脳神経外科To investigate whether the ocular dominance affects laterality in the activity of the primary visual cortex, we examined the relationship between the ocular dominance and latency or dipole moment measured by checkerboard-pattern and magnetoencephalography in 11 right-handed healthy male participants. Participants with left-eye dominance showed a dipole moment of 21.5±6.1 nAm with left-eye stimulation and 16.1±3.6 nAm with right, whereas those with right-eye dominance showed a dipole moment of 18.0±5.2 and 21.5±2.7 nAm with left-eye and right-eye stimulation of the infero-medial quadrant visual field, respectively. Thus, the dipole moment was higher when the dominant eye was stimulated, which implies that ocular dominance is regulated by the ipsilateral occipital lobe. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins

Calaxin is required for cilia-driven determination of vertebrate laterality

Sasaki, K., Shiba, K., Nakamura, A. et al. Calaxin is required for cilia-driven determination of vertebrate laterality. Commun Biol 2, 226 (2019). https://doi.org/10.1038/s42003-019-0462-