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  • 1
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    Online Resource
    A Novel Topical Fluorescent Probe for Detection of Glioblastoma
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 14 ( 2021-07-15), p. 3936-3947
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 14 ( 2021-07-15), p. 3936-3947
    Abstract: Five-aminolevulinic acid (5-ALA) is widely used as an intraoperative fluorescent probe for radical resection of high-grade glioma, and thus aids in extending progression-free survival of patients. However, there exist some cases where 5-ALA fails to fluoresce. In some other cases, it may undergo fluorescence quenching but cannot be orally readministered during surgery. This study aimed to develop a novel hydroxymethyl rhodamine green (HMRG)-based fluorescence labeling system that can be repeatedly administered as a topical spray during surgery for the detection of glioblastoma. Experimental Design: We performed a three-stage probe screening using tumor lysates and fresh tumor tissues with our probe library consisting of a variety of HMRG probes with different dipeptides. We then performed proteome and transcript expression analyses to detect candidate enzymes responsible for cleaving the probe. Moreover, in vitro and ex vivo studies using U87 glioblastoma cell line were conducted to validate the findings. Results: The probe screening identified proline-arginine–HMRG (PR-HMRG) as the optimal probe that distinguished tumors from peritumoral tissues. Proteome analysis identified calpain-1 (CAPN1) to be responsible for cleaving the probe. CAPN1 was highly expressed in tumor tissues which reacted to the PR-HMRG probe. Knockdown of this enzyme suppressed fluorescence intensity in U87 glioblastoma cells. In situ assay using a mouse U87 xenograft model demonstrated marked contrast of fluorescence with the probe between the tumor and peritumoral tissues. Conclusions: The novel fluorescent probe PR-HMRG is effective in detecting glioblastoma when applied topically. Further investigations are warranted to assess the efficacy and safety of its clinical use.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-4518
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 2
    Online Resource
    Online Resource
    DDIS-02. DEVELOPMENT OF NOVEL SPRAY-TYPE FLUORESCENT PROBES FOR GLIOBLASTOMA DETECTION
    Oxford University Press (OUP) ; 2019
    In:  Neuro-Oncology Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi65-vi65
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi65-vi65
    Abstract: PURPOSE: ALA is commonly used as an intraoperative tool in malignant glioma surgery, which has been proven effective for radical tumor resection and extended progression-free survival. However, there are some limitations in its use, such as false positivity, false negativity, and inability of re-administration. We aim to develop a novel fluorescent labeling system which can be repeatedly administered by spray during surgery, using hydroxymethyl rhodamine green (HMRG) as fluorescent scaffold originally designed at our university for cancer detection. [Methods]Primary probe screening was performed using the homogenized glioblastoma (GBM) samples with the fluorescent probe library comprised of more than 320 kinds of HMRG fluorescent scaffold combined with various types of dipeptides. Second probe screening was performed using fresh GBM specimens and the selected probes in primary screening. To identify the responsible enzymes, diced electrophoresis gel (DEG) assay was performed. This method utilizes the combination of two dimensional electrophoresis (isoelectric point and molecular weight) and a multiwell-plate-based fluorometric assay to find protein spots with the specified activities. [Results] The prominent probes were selected based upon the above two-step screenings. We identified two enzymes by proteome analysis and experiments using inhibitors, which was further confirmed with real-time PCR and western blotting. [Discussion] This screening methodology is innovative in that it is based on selecting probes from the probe library that respond to clinical samples rather than creating probes from the responsible enzymes. Practical fluorescent probes can be established even for low-grade gliomas, which would be a breakthrough for rapid intraoperative diagnosis in glioma surgery. [Conclusion] HMRG-based aminopeptidase fluorescent probes may be effective for GBM detection.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noz175.262
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2094060-9
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  • 3
    Online Resource
    Online Resource
    DDDR-02. CDK4/6 INHIBITION WITH ABEMACICLIB SENSITIZES INTRACRANIAL TUMORS TO CHECKPOINT BLOCKADE IN PRE-CLINICAL MODELS OF BRAIN METASTASIS
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii98-vii98
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii98-vii98
    Abstract: Although immune checkpoint inhibitors (ICI) have become a useful tool in the management of central nervous system (CNS) metastases, only a subset of patients experience durable clinical responses and prognosis continues to remain poor. In particular, the role of ICI for CNS metastases from breast cancer has also not been adequately explored. CDK4/6 inhibition has been shown to sensitize extracranial tumors to ICI, and we previously reported intracranial efficacy of combination CDK4/6 inhibition with abemaciclib and anti-PD-1 in preclinical models of melanoma brain metastasis. We have now investigated this combination strategy further in a mouse model of triple negative breast cancer brain metastasis. 4T1 mammary carcinoma cells were first injected into the mammary fat pad and then intracranially 3 days later. While single agent anti-PD-1 antibody or abemaciclib were both ineffective at reducing tumor growth, we found a significant reduction in intracranial and extracranial tumor burden when abemaciclib was combined with anti-PD-1. Immunofluorescence for CD8 and CD3 revealed a significant increase in tumor-infiltrating CD8+ T cells with abemaciclib monotherapy as well as combination therapy in intracranial 4T1 tumors. We observed a similar increase in intracranial tumor-infiltrating CD8+ T cells in two melanoma brain metastasis models, YUMM1.7 and B16-F10, following combination therapy. We conclude that combination with abemaciclib can improve intracranial efficacy of ICI by driving CD8+ T cell infiltration into intracranial tumors. Future work will focus on investigating additional treatment-induced changes in the tumor immune microenvironment and dissecting the effect of CDK4/6 inhibition on T cell activation and function.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.367
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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  • 4
    Online Resource
    Online Resource
    EPCO-01. MOLECULAR PROFILING OF SPINAL CORD EPENDYMOMA
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi1-vi1
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi1-vi1
    Abstract: Ependymomas are currently classified into 9 subgroups by DNA methylation profiles. Although spinal cord ependymoma (SP-EPN) is distinct from other tumors, diversity within SP-EPN is still unclear. Here, we used transcriptomic and epigenomic profiles to investigate the diversity among Japanese SP-EPN cases. MATERIALS AND METHODS We analyzed 57 SP-EPN patients (32 males and 25 females, aged from 18 to 78 years, median: 52), including two cases of neurofibromatosis type 2, five cases of grade 3 (WHO grade). We obtained transcriptome (RNA-seq) and DNA methylation (Infinium Methylation EPIC array) data from fresh frozen specimens of SP-EPN resected at the University of Tokyo Hospital and our collaborative groups. RESULTS Three cases had a previous intracranial ependymoma operation. Hierarchical clustering of the DNA methylation data showed that these three cases of intracranial origin as a different cluster from spinal origin. The 45 grade 2 spinal ependymoma showed a relatively homogenous methylation pattern. However, the methylation status of HOX gene cluster regions is compatible with the segment of origin, which reflects the cells of origins are derived after the determination of segment identity. RNA sequencing of 57 cases revealed two subgroups within grade 2. Gene ontology analysis of differentially expressed genes suggested the difference in metabolic state such as rRNA translation and mitochondrial respiration between the two expression subgroups. CONCLUSION Epigenetic analysis indicated the accurate body segment origin of SP-EPN. We observed that metabolic states could divide grade 2 spinal cord ependymoma into 2 subgroups and will present the relationship to clinicopathological information.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab196.000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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  • 5
    Online Resource
    Online Resource
    SURG-10. DEVELOPMENT OF NOVEL TOPICAL FLUORESCENT PROBE FOR INTRAOPERATIVE RAPID DETECTION OF GLIOMA
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi197-vi197
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi197-vi197
    Abstract: Fluorescence imaging is an important surgical adjunct in malignant glioma surgery. 5-aminolevulinic acid (5-ALA) has been proven effective for radical tumor resection and extended progression-free survival in a phase III randomized trial and therefore integrated into surgery for malignant glioma. Importantly, however, some limitations still exist in its use, which include false positivity and false negativity as well as inability of re-administration. In this study, we aimed to develop a novel, spray-type fluorescent probe using hydroxymethyl rhodamine green (HMRG) as a fluorescent scaffold. METHODS We have previously established a fluorescent probe library comprised of more than 320 kinds of HMRG probes. They have HMRG as a fluorescent scaffold with various types of dipeptides attached to it. Primary probe screening was performed using the homogenized tumor samples from patients with glioblastoma operated at our institution. Secondary screening followed using the selected probes and fresh tumor samples obtained from patients with glioblastoma operated from 2016 until 2018. Diced electrophoresis gel (DEG) assay, two-dimensional gel electrophoresis followed by a multi-well plate-based fluorometric assay, was performed to identify responsible enzymes for the selected probe. Further experiments with inhibitors, real-time PCR, immunohistochemistry, and western blotting were performed for confirmation. RESULTS Proline-arginine-HMRG (PR-HMRG) was selected as a candidate probe based upon the above two-step screenings. It achieved 79.4% accuracy in receiver operating characteristic curve analysis. Calpain-1 was found to be responsible to cleave PR-HMRG probe by DEG-proteome analysis. Calpain-1 protein was expressed at significantly higher level in tumors that were fluoresced by PR-HMRG than in those that were not. CONCLUSIONS Our innovative screening method was able to find PR-HMRG as a novel fluorescent probe effective for rapid detection of glioblastoma. A preclinical study is planned to assess the efficacy and safety of the selected probe.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab196.780
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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  • 6
    Online Resource
    Online Resource
    MRI-Based Radiomics Differentiates Skull Base Chordoma and Chondrosarcoma: A Preliminary Study
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 13 ( 2022-07-03), p. 3264-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 13 ( 2022-07-03), p. 3264-
    Abstract: Chordoma and chondrosarcoma share common radiographic characteristics yet are distinct clinically. A radiomic machine learning model differentiating these tumors preoperatively would help plan surgery. MR images were acquired from 57 consecutive patients with chordoma (N = 32) or chondrosarcoma (N = 25) treated at the University of Tokyo Hospital between September 2012 and February 2020. Preoperative T1-weighted images with gadolinium enhancement (GdT1) and T2-weighted images were analyzed. Datasets from the first 47 cases were used for model creation, and those from the subsequent 10 cases were used for validation. Feature extraction was performed semi-automatically, and 2438 features were obtained per image sequence. Machine learning models with logistic regression and a support vector machine were created. The model with the highest accuracy incorporated seven features extracted from GdT1 in the logistic regression. The average area under the curve was 0.93 ± 0.06, and accuracy was 0.90 (9/10) in the validation dataset. The same validation dataset was assessed by 20 board-certified neurosurgeons. Diagnostic accuracy ranged from 0.50 to 0.80 (median 0.60, 95% confidence interval 0.60 ± 0.06%), which was inferior to that of the machine learning model (p = 0.03), although there are some limitations, such as the risk of overfitting and the lack of an extramural cohort for truly independent final validation. In summary, we created a novel MRI-based machine learning model to differentiate skull base chordoma and chondrosarcoma from multiparametric signatures.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14133264
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 7
    Online Resource
    Online Resource
    BOT-03 INVESTIGATION OF NOVEL SPRAY TYPE FLUORESCENT PROBE FOR GLIOBLASTOMA DETECTION
    Oxford University Press (OUP) ; 2019
    In:  Neuro-Oncology Advances Vol. 1, No. Supplement_2 ( 2019-12-16), p. ii12-ii12
    Details
    In: Neuro-Oncology Advances, Oxford University Press (OUP), Vol. 1, No. Supplement_2 ( 2019-12-16), p. ii12-ii12
    Abstract: 5-ALA is commonly used as an intraoperative tool in malignant glioma surgery, which has been proven effective for radical tumor resection and extended progression-free survival. However, there are some limitations in its use, such as false positivity, false negativity, and inability of re-administration. We aim to develop a novel fluorescent labeling system which can be repeatedly administered by spray during surgery, using hydroxymethyl rhodamine green (HMRG) as fluorescent scaffold originally designed at our university for cancer detection. METHODS Primary probe screening was performed using the homogenized glioblastoma (GBM) samples with the fluorescent probe library comprised of more than 320 kinds of HMRG fluorescent scaffold combined with various types of dipeptides. Second probe screening was performed using fresh GBM specimens and the selected probes in primary screening. To identify the responsible enzymes, diced electrophoresis gel (DEG) assay was performed. This method utilizes the combination of two dimensional electrophoresis (isoelectric point and molecular weight) and a multiwell-plate-based fluorometric assay to find protein spots with the specified activities. RESULTS The prominent probes were selected based upon the above two-step screenings. We identified two enzymes by proteome analysis and experiments using inhibitors, which was further confirmed with real-time PCR and western blotting. DISCUSSION This screening methodology is innovative in that it is based on selecting probes from the probe library that respond to clinical samples rather than creating probes from the responsible enzymes. Practical fluorescent probes can be established even for low-grade gliomas, which would be a breakthrough for rapid intraoperative diagnosis in glioma surgery. CONCLUSION HMRG-based aminopeptidase fluorescent probes may be effective for GBM detection.
    Type of Medium: Online Resource
    ISSN: 2632-2498
    URL: Article
    DOI: 10.1093/noajnl/vdz039.055
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 3009682-0
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  • 8
    Online Resource
    Online Resource
    First case of human neurocoenurosis caused by Taenia serialis: A case report
    Elsevier BV ; 2020
    In:  International Journal of Infectious Diseases Vol. 92 ( 2020-03), p. 171-174
    Details
    In: International Journal of Infectious Diseases, Elsevier BV, Vol. 92 ( 2020-03), p. 171-174
    Type of Medium: Online Resource
    ISSN: 1201-9712
    URL: Article
    DOI: 10.1016/j.ijid.2020.01.004
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 2070533-5
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  • 9
    Online Resource
    Online Resource
    Multinodular and vacuolating neuronal tumor of the cerebrumの長期経過と文献的考察
    The Japanese Congress of Neurological Surgeons ; 2019
    In:  Japanese Journal of Neurosurgery Vol. 28, No. 1 ( 2019), p. 27-32
    Details
    In: Japanese Journal of Neurosurgery, The Japanese Congress of Neurological Surgeons, Vol. 28, No. 1 ( 2019), p. 27-32
    Type of Medium: Online Resource
    ISSN: 0917-950X , 2187-3100
    URL: Article
    DOI: 10.7887/jcns.28.27
    Language: English
    Publisher: The Japanese Congress of Neurological Surgeons
    Publication Date: 2019
    detail.hit.zdb_id: 2270622-7
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  • 10
    Online Resource
    Online Resource
    COMP-02. MINING-GUIDED MACHINE LEARNING ANALYSES SUPPORTS GRASPING THE LATEST TRENDS ON NEURO-ONCOLOGY
    Oxford University Press (OUP) ; 2019
    In:  Neuro-Oncology Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi61-vi61
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi61-vi61
    Abstract: The systems that can objectively predict the future trends of a particular research field are always anticipated while conducting medical research. Such systems also provide a considerable aid to researchers while determining and acquiring appropriate research budgets. This study intended to establish a novel and versatile algorithm that can predict the latest trends in neuro-oncology. Seventy-nine neuro-oncological research fields were selected using computational sorting methods, such as text-mining analyses, along with 30 journals that represent the recent trends in the neuro-oncology field. Further, the annual impact (AI) for each year with respect to each journal and field (number of articles published in the journal × the impact factor of the journal) was calculated as a novel concept. Subsequently, the AI index (AII) for the year was defined as the sum of the AIs for the aforementioned 30 journals. With respect to the aforementioned neuro-oncological research fields, the AII trends from 2008 to 2017 were subjected to machine learning predicting analyses. The prediction accuracy of the latest trends in neuro-oncology was validated using actual data obtained from previous studies. In particular, the linear prediction model achieved a relatively good accuracy. The most notable and latest predicted fields in neuro-oncology included some interesting emerging fields, such as microenvironment and anti-mitosis, as well as the already renowned fields, such as immunology and epigenetics. Furthermore, we retrospectively attempted an analysis of the fields different from neuro-oncology. Interestingly, as of 2008, the future emergence of the CRISPR-Cas9 gene editing system has been predicted using this system. Overall, the presented algorithm displays potential to be an effective and versatile tool for the prediction of future trends in a particular medical field.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noz175.245
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2094060-9
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