Tumor Shrinkage in Response to Vitamin K2 in Hepatocellular Carcinoma with Multiple Lung Metastases: A Case Report

Introduction: Advanced or metastatic hepatocellular carcinoma (HCC) can be lethal because of the limited therapeutic approach such as sorafenib. Recently, Vitamin K2 (VK2) has been increasingly recognized to have anti-cancer effects for HCC in vitro and vivo. However, the direct anti-cancer effect of VK2 to HCC has not been established yet in human.Presentation of Case: We presented here a 88-year-HCC patient displayed a tumor shrinkage in response to VK2 in multiple lung metastases, indicating the possibility of VK2 as an anti-cancer agent in human. Menatetrenone, a VK2 analogue, was introduced for multiple lung metastases as a palliative treatment, and thereafter multiple lung metastases, except one lung lesion, displayed tumor shrinkage and disappeared within five months after VK2 intake. The residual one lesion continued to grow up during the intake of VK2, suggesting that the residual tumor was insensitive to VK2 represented by tumor heterogeneity. Consequently, after a radiation therapy for the residual lesion, the elevated tumor markers of all were finally decreased into normal levels, and he is still alive for 18 months after VK2 intake without elevated tumor marker levels and toxic adverse effects.Conclusion:VK2 may be a therapeutic option for advanced and metastatic HCCs without any toxic adverse

Focused deposition of nanoparticles on polymer film with an improved TSI-nanoparticle sampler (Model 3089)

A two-dimensional array of spots of deposited nanoparticles as small as 7 × 7 m was fabricated on a polymer film using a modified commercial nanometer aerosol sampler (NAS; TSI-model 3089) coupled with a surface-discharge microplasma aerosol charger (SMAC). The charged aerosol particles were electrostatically focused by a metal mesh (electrically grounded) on the polymer film (insulator) and electrode (3 kV). The effect of mesh geometry on the concentration ratio (focusing ratio × collection efficiency) was evaluated using monodisperse polystyrene latex particles with diameters of 48, 100, and 300 nm. The electrostatic focusing effect was also analyzed by a numerical simulation of the electrostatic field. The two-dimensional patterning of nanoparticles is an effective method in concentrating particles for the subsequent observation and chemical analysis of aerosol particles. In our experiments, the SMAC-NAS system achieved a net concentration ratio of more than 20 times for 48-and 100-nm particles, which would significantly shorten the aerosol-sampling time. The particle deposition patterns formed on a transparent polymer film may provide samples for analyzing the transmittance, luminescence, and other optical characteristics of deposited nanoparticles. © 2015 American Association for Aerosol Research.Embargo Period 12 month

In vitro modeling of hepatocellular carcinoma molecular subtypes for anti-cancer drug assessment

Tractable experimental model that accounts for inter-tumor molecular heterogeneity is a key element of anti-cancer drug development. Hepatocellular carcinoma is known to exhibit highly heterogeneous molecular aberrations across the tumors, including somatic genetic and epigenetic alterations. Previous studies showed that molecular tumor subtypes determined by transcriptome, as a comprehensive functional readout, are reproducibly observed across global patient populations irrespective of geographic and etiological variations. Here we demonstrate that transcriptomic hepatocellular carcinoma subtypes, S1 and S2, determined by our previous transcriptome meta-analysis of multiple clinical hepatocellular carcinoma cohorts, are presented in a panel of hepatoma cell lines widely used by the research community. Interestingly, cell line that resembles gene expression pattern of S3 subtype, representing less aggressive tumors, was not identified in the panel. MYC pathway-activated S2-like cell lines showed higher sensitivity to a small molecule BET bromodomain inhibitor, (+)-JQ1, which has anti-MYC activity. These results support the use of hepatoma cell lines as models to evaluate molecular subtype-specific drug response, which is expected to lead to development of tailored, precision care of the patients with hepatocellular carcinoma

Molecular liver cancer prevention in cirrhosis by organ transcriptome analysis and lysophosphatidic acid pathway inhibition

Cirrhosis is a milieu that develops hepatocellular carcinoma (HCC), the second most lethal cancer worldwide. HCC prediction and prevention in cirrhosis are key unmet medical needs. Here we have established an HCC risk gene signature applicable to all major HCC etiologies: hepatitis B/C, alcohol, and non-alcoholic steatohepatitis. A transcriptome meta-analysis of >500 human cirrhotics revealed global regulatory gene modules driving HCC risk and the lysophosphatidic acid pathway as a central chemoprevention target. Pharmacological inhibition of the pathway in vivo reduced tumors and reversed the gene signature, which was verified in organotypic ex vivo culture of patient-derived fibrotic liver tissues. These results demonstrate the utility of clinical organ transcriptome to enable a strategy, namely, reverse-engineering precision cancer prevention

インスリン テイコウセイ カラ ミタ sirolimus-eluting stent ト paclitaxel-eluting stent ノ ナイマク ゾウショク ノ ケントウ

(目的)虚血性心疾患の治療において経皮的冠動脈形成術は有用な治療であるが再狭窄が問題である.これに対し,近年薬剤溶出性ステント(Drug eluting stent:DES)が臨床応用され再狭窄は減少してきているが依然として認めている.現在数種類のDES が臨床使用されているが,病態によりどのDES を選択するか明確な指標はない.主に使用されているシロリムス溶出性ステント(sirolimus-eluting stent:SES)とパクリタキセル溶出性ステント(paclitaxel-eluting stent:PES)では塗布されている薬剤の作用機序が異なる.以前我々はDES 留置後においてもインスリン抵抗性が内膜増殖に関与していると報告してきた.本研究の目的は作用機序の異なるこれら2 つのDES において,内膜増殖とインスリン抵抗性の関与を比較検討することである.(方法)2007 年5 月から2009 年12 月までにPCI を施行しDES を留置した212 例をSES 留置例とPES 留置例それぞれで,インスリン抵抗性を認める群(P 群)と認めない群(N 群)に分けて再狭窄を検討した.(結果)再狭窄はSES 留置例,PES 留置例ともにP 群とN 群とで有意差を認めなかった.QCA 解析をするとPES 留置例では,最小血管径(minimum lumen diameter:MLD),%狭窄率(% stenosis),晩期損失径(late lumen loss)に有意差を認めなかったが,SES 留置例では最小血管径で2.18±0.77, 2.61±0.53(p=0.028),晩期損失径で0.36±0.56, 0.13±0.22 mm( p=0.048)と有意差を認め,%狭窄率では20.36±24.44,12.2±6.86(p=0.098)とP 群で狭窄率が高い傾向を認めた.(結語)PES 留置後は慢性期の内膜増殖にインスリン抵抗性の影響を受けないが,SES 留置後はインスリン抵抗性が内膜増殖に関与している.Percutaneous coronary intervention(PCI) has been widely adopted as an effective treatmentstrategy for patients with ischemic heart disease. However,the rate of coronary artery restenosis is still high. Drugelutingstent( DES) have been implanted in clinical practiceand reduced the incidence of restenosis. Nevertheless, restenosisof coronary artery still occurs in DES patients. Twotypes of DES, sirolimus-eluting stent:SES and paclitaxelelutingstent:PES are widely applied. Previously we reportedthat insulin resistance is one of the factors for stentrestenosis. The aim of this study is to investigate the diferenceof intimal hyperplasia in insulin resistant patients withthe two types of DES implantation.METHODS:We studied the 320 patients who underwentPCI to a new lesion using DES between May 2007 andDecember 2009.We divided these patients by presence ofinsulin resistance into Group P (positive:n=120) andGroup N( negative:n=92). Furthermore, we divided thesepatients into implantation of SES and PES. We measuredthe minimal lumen diameter( MLD) and late loss by quantitativecoronary angiography( QCA).RESULTS:In SES implantation Group and PES implantationGroup, the rate of restenosis was no difference betweenGroup P and Group N. In PES implantation Group,MLD and Late Loss had no difference. However in SES implantationGroup, MLD was significantly lower ( 2.18±0.77vs 2.61±0.53 mm, p<0.05) and Late Loss was significantlyhigher in Group P compared with Group N (0.36±0.56 vs0.13±0.22 mm, p<0.05).CONCLUSION:We suggest that in patients who wereimplanted the two types of DES, insulin resistance was relatedto intimal hyperplasia. Especially SES patients withpositive insulin resistance prone to show more intimal hyperplasia

コウド インスリン テイコウセイ ジョウタイ ニ オケル ヤクザイ ヨウシュツセイ ステント リュウチ ゴ サイキョウサク ノ ヨソク インシ ノ ケントウ

目的:虚血性心疾患に対する経皮的冠動脈形成術(Percutaneous coronary intervention:PCI)は有用な治療法として確立されている.薬剤溶出性ステント(Drug-eluting stent:DES)により,大きな問題であった再狭窄は減少したが,完全には克服されていない.最近糖尿病の前段階としてインスリン抵抗性が注目されており,再狭窄に影響を及ぼすことが示唆されている.今回我々はHomeostasis Model Assessment 指数(HOMA-IR)を用いてインスリン抵抗性の程度とDES 留置後の再狭窄の関連を検討した.方法:2007 年5 月から2010 年10 月までに待機的にPCI を施行しDES を留置した248 例について,HOMAIRより高度インスリン抵抗性を有する群(H 群:n=75)と中等度インスリン抵抗性を有する群(M 群:n=64)およびインスリン抵抗性を有さない群(L 群:n=109)に分類し,定量的冠動脈造影を用いて再狭窄率および再狭窄関連因子について検討した.結果:再狭窄率はH 群で有意に高かった(p=0.0005).慢性期最小血管径はH 群で他の2 群と比較して有意に小さかった(H:1.62±1.02 mm,M:2.42±0.48 mm,L:2.17±0.70 mm, p=0.0086).さらに%狭窄率はH 群で他の2 群と比較して有意に大きく(H:40.1±34.7%,M::14.7±10.4%,L:22.7±21.6%, p=0.0092),晩期損失径もH 群で他の2 群と比較して有意に大きかった(H:0.87±0.90 mm,M:0.19±0.17 mm,L:0.41±0.62 mm, p=0.0097).結論:高度インスリン抵抗性は,DES 留置後再狭窄の危険因子となりえると考えられた.INTRODUCTION: Percutaneous coronary intervention (PCI) has beenwidely adopted as an effective treatment strategy for patientswith ischemic heart disease;especially, restenosis issuppressed after drug-eluting stent (DES) implantation.However, coronary artery restenosis after DES implantationstill appear now and then. The aim of this study was toclarify the factors associated with coronary artery restenosisafter DES implantation and evaluate the homeostasismodel assessment of insulin resistance (HOMA-IR) indexas a predictor of restenosis.METHODS: We reserched the clinical records of 248 patients who hadbeen subjected to elective PCI and DES implantation betweenMay 2007 and December 2010. We divided these patientsby the value of HOMA-IR into three groups(GroupH;HOMA-IR≧5 . 0 , Group M;2 . 5≦HOMA-IRHOMA-IR), and examined the relationshipbetween coronary artery restenosis and HOMA-IR.RESULTS: The rate of restenosis was significantly higher in GroupH (26.7 %) than in the other two groups (M;7.8 % andL;8.3%, p=0.0005 %). Follow up MLD was significantlylower in Group H (H;1.62±1.02 mm v.s. M;2.42±0.48 mm v.s. L;2.17±0.70 mm, p=0.0086). Furthermore, %stenosis and late lumen loss was significantly higher inGroup H (H;40.1±34.7%, M;14.7±10.4%, L;22.7±21.6%, p=0.0092, and H;0.87±0.9 mm v.s. M;0.19±0.17 mmv.s. L;0.41±0.62 mm, P=0.0097). Logistic analysis showedthat the only independent predictor of restenosis was HOMA-IR over 5.0( OR 2.87;p=0.004).CONCLUSION: The results suggested that severe insulin resistance wasa predictor of restenosis after drug-eluting stent implantation;furthermore, that improvement of insulin resistancemay contribute to prevent coronary restenosis after drugelutingstent implantation

Framingham Risk Score ト ドウミャク コウカ リスク ニ ツイテノ ケントウ

背景:冠動脈疾患において以前よりフラミンガムリスクスコア(Framingham Risk Score:FRS)は10 年以内の虚血性心疾患発症を予測することが知られている.また近年,冠動脈マルチスライスCT(MultisliceConputed Tomography:MSCT)により求められる冠動脈カルシウムスコア(Coronary Artery CalciumScore:CACS)や種々の炎症マーカーが冠動脈疾患予測因子として報告されている.目的:年齢,性別,総コレステロール値,High Density Lipoprotein Cholesterol (HDL-C)コレステロール値,収縮期血圧,喫煙の有無から簡易に求めることのできるFRS を算出し,FRS と冠動脈疾患各動脈硬化リスク因子について検討した.対象:2009 年6 月から2011 年9 月までに当院に虚血性心疾患精査目的に受診しMSCT および,冠動脈造影を施行した連続347 例(男性229 例,女性108 例)についてFRS を計測し15 以上の高リスク群(H 群)と15未満の低リスク群(L 群)に分類した.冠動脈造影における有病率と冠動脈疾患予測因子であるCT にて計測されるCACS,及び血液検査における炎症マーカーについて比較検討した.結果:対象はH 群149 例,L 群198 例に分けられた.冠動脈造影における冠動脈疾患有病率はH 群53.6%,L 群41.4%とH 群において有意に高値であった(P=0.023).CACS においてもH 群687.1±759.1,L 群489.8±725.6 とH 群において有意に高値であった(P=0.015).血液検査におけるマーカーにおいては高感度CRP(H 群 vs L 群:0.29±0.70 vs 0.17±0.29 mg/dl P=0.046)と酸化Low Density Lipoprotein Cholesterol(LDL)(H 群 vs L 群:110.2±47.0 vs 96.8±35.6 U/L P=0.007)において有意差を認めた.結語:FRS は簡便に計測でき,各種冠動脈疾患予測因子とも関連しており冠動脈疾患予測の一助となりうる可能性があると考えた.Background: The Framingham risk score (FRS) is widely used inclinical practice to identify subjects at high risk for developingischemic heart disease. However, FRS may not accuratelyidentify subjects at risk. Recently, coronary arterycalcium score (CACS) detected by multi-slice computedtomography (MSCT) and several atherosclerosis riskmarkers has been known to predict ischemic heart diseases.Subjects: The aim of this study is to clarify the relation betweenFRS and several coronary risk factors. We researched theclinical records of 347 patients who had been subjected toMSCT and coronary angiography( CAG) between Jun 2009and September 2011. We subdivided these patients by thevalue of FRS into a group H (n=149;FRS &#8805; 15) and agroup L( n=198;FRS<15), and examined the relationshipbetween FRS and the other coronary risk factors.Results: The prevalence of coronary heart disease by CAG wassignificantly higher in group H (53.6 %) than in group L(41.4%, p=0.023). CACS was significantly higher in groupH than in group L( 687.0±759.1 vs 489.8±725.6, p=0.015).In group H the level of high-sensitive CRP and MDL-LDLwere significantly higher than those in group L(0.29±0.70vs 0.17±0.29 p=0.046 and 110.18±47.0 vs 96.82±35.6 P=0.007).Conclusion: We suggest that the FRS is easy to calculate and usefulto predict ischemic heart disease compared with the othercoronary risk markers

インスリン テイコウセイ カラ ミタ ヤクザイ ヨウシュツセイ ステント リュウチ ゴ ノ late catch up ゲンショウ ニ ツイテノ ケントウ

目的:虚血性心疾患の危険因子としてメタボリックシンドロームが注目されているが,その背景にはインスリン抵抗性が存在している.一方,虚血性心疾患の治療において経皮的冠動脈形成術(percutaneouscoronary intervention:PCI)は有用な治療法であるが再狭窄が課題である.近年薬剤溶出性ステント(Drugelutingstent:DES)が臨床応用され再狭窄は減少しているものの,ステント血栓症や晩期再狭窄であるlatecatch up 現象などの慢性期における新たな課題が散見されている.今回我々はインスリン抵抗性とDES 留置患者の慢性期の心血管イベントの関連を調べるためにインスリン抵抗性をHomeostasis Model Assessment 指数(HOMA-IR)を用いて検討した.方法:2004 年8 月より2008 年11 月までにPCI を施行しDES を使用した109 例についてHOMA-IR を計測しインスリン抵抗性を認める群(P 群:n=63)と認めない群(N 群:n=46)にわけ慢性期における心血管イベントについて検討した.結果:観察期間は平均で5.48±1.30 年であった.心臓死,再狭窄,心筋梗塞,脳梗塞,心不全,ステント血栓症においては両群間において有意差を認めなかった.しかしlate catch up 現象においてはP 群12.7%とN 群2.2%と有意差を認めた(p=0.048).結論:インスリン抵抗性はDES 留置後のlate catch up 現象の予測因子であった.インスリン抵抗性を改善させることにより慢性期における心血管イベントのさらなる減少が期待される.PURPOSE:Percutaneous coronary intervention( PCI) isan effective treatment for patients with ischemic heart disease;especially, restenosis is suppressed after drug-elutingstent (DES) implantation. However, several problemsstill remain. Previously, we reported neo-intimal proliferationafter DES implantation that was associated with insulinresistance. The aim of this study was to clarify whether insulinresistance was associated with Major Adverse Cardiacand Cerebrovascular Events (MACCE) after DES implantation.METHODS:We researched the clinical records of 109patients who had been subjected to elective PCI and DESimplantation between May 2007 and December 2010. Wedistributed these patients by the value of homeostasis modelassessment of insulin resistance (HOMA-IR) into aGroup P (n=63;HOMA-IR &#8805; 2.5, positive) and a Group N(n=46;HOMA-IR<2.5, negative), and examined the relationshipbetween HOMA-IR and MACCE.RESULTS:The observation period was 5.48±1.30years. There were no differences between the two groupsin the occurrence of cardiac death, restenosis, stroke, acutemyocardial infarction, heart failure and stent thrombosis.But late catch-up phenomenon in group P was significantlyhigher than in group N (12.7 % vs 2.2 % p=0.042). The logisticanalysis showed that the only independent predictorof late catch-up phenomenon was insulin resistance (OR6.55;95 % CI 0.79-54.32, p=0.049).CONCLUSION:We suggest that insulin resistance is auseful predictor of late catch-up phenomenon;furthermore,improvement of insulin resistance may contribute toprevent late catch-up phenomenon after DES implantation

Estimation of Degradation Degree in Road Infrastructure Based on Multi-Modal ABN Using Contrastive Learning

This study presents a method for distress image classification in road infrastructures introducing self-supervised learning. Self-supervised learning is an unsupervised learning method that does not require class labels. This learning method can reduce annotation efforts and allow the application of machine learning to a large number of unlabeled images. We propose a novel distress image classification method using contrastive learning, which is a type of self-supervised learning. Contrastive learning provides image domain-specific representation, constraining such that similar images are embedded nearby in the latent space. We augment the single input distress image into multiple images by image transformations and construct the latent space, in which the augmented images are embedded close to each other. This provides a domain-specific representation of the damage in road infrastructure using a large number of unlabeled distress images. Finally, the representation obtained by contrastive learning is used to improve the distress image classification performance. The obtained contrastive learning model parameters are used for the distress image classification model. We realize the successful distress image representation by utilizing unlabeled distress images, which have been difficult to use in the past. In the experiments, we use the distress images obtained from the real world to verify the effectiveness of the proposed method for various distress types and confirm the performance improvement