Publications by authors named "Takashi Suzuki"

1,160 Publications

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Subtype-specific collaborative transcription factor networks are promoted by OCT4 in the progression of prostate cancer.

Nat Commun 2021 06 18;12(1):3766. Epub 2021 Jun 18.

Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.

Interactive networks of transcription factors (TFs) have critical roles in epigenetic and gene regulation for cancer progression. It is required to clarify underlying mechanisms for transcriptional activation through concerted efforts of TFs. Here, we show the essential role of disease phase-specific TF collaboration changes in advanced prostate cancer (PC). Investigation of the transcriptome in castration-resistant PC (CRPC) revealed OCT4 as a key TF in the disease pathology. OCT4 confers epigenetic changes by promoting complex formation with FOXA1 and androgen receptor (AR), the central signals for the progression to CRPC. Meanwhile, OCT4 facilitates a distinctive complex formation with nuclear respiratory factor 1 (NRF1) to gain chemo-resistance in the absence of AR. Mechanistically, we reveal that OCT4 increases large droplet formations with AR/FOXA1 as well as NRF1 in vitro. Disruption of TF collaborations using a nucleoside analogue, ribavirin, inhibited treatment-resistant PC tumor growth. Thus, our findings highlight the formation of TF collaborations as a potent therapeutic target in advanced cancer.
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http://dx.doi.org/10.1038/s41467-021-23974-4DOI Listing
June 2021

Freezing Resistance and Behavior of Winter Buds and Canes of Wine Grapes Cultivated in Northern Japan.

Cryobiology 2021 Jun 15. Epub 2021 Jun 15.

Research Faculty and Graduate School of Agriculture, Hokkaido University, Sapporo, Hokkaido 060-8589, Japan. Electronic address:

In high-latitude regions, the cold hardiness of buds and canes of grapevine is important for budburst time and yield in the next season. The freezing resistance of buds and canes sampled from six wine grapes currently cultivated in Hokkaido, Japan, all of them grown from autumn to winter, was investigated. A significant difference between the cultivars in their freezing resistance was detected in the buds harvested in winter. In addition, outstanding differences in the low temperature exotherms (LTE) related to the supercooling ability of tissue cells happened in the winter buds, and there is a close relationship between freezing resistance and LTE detected in the winter buds. This suggests that the supercooling ability of tissue cells in winter buds is strongly related to the freezing resistance. However, detailed electron microscopy exposed that the differences in freezing resistance among cultivars appeared in freezing behavior of leaf primordium rather than apical meristem. This indicated that as the water mobility from the bud apical meristem to the spaces around the cane phloem progressed, the slightly dehydrated cells improved the supercooling ability and increased the freezing resistance.
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http://dx.doi.org/10.1016/j.cryobiol.2021.06.004DOI Listing
June 2021

Live Imaging of Virus-Infected Cells by Using a Sialidase Fluorogenic Probe.

Methods Mol Biol 2021 ;2274:141-154

Department of Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.

Visualization of virus-infected cells is usually performed by immunostaining with an antiviral antibody. On the other hand, we established an easy method for fluorescence (FL) imaging of cells infected with influenza A and B viruses and some paramyxoviruses without the need for cell fixation and an antiviral antibody. These viruses and the cells they have infected express the viral surface enzyme "neuraminidase" or "hemagglutinin-neuraminidase" that shows sialidase activity. Sialidase activity is fluorescently visualized by using a sialidase fluorogenic probe developed in our previous study. The probe enables histochemical FL imaging of the virus-infected cells and is applicable to virus isolation and detection of an influenza virus resistant to antiinfluenza drugs of sialidase inhibitors.
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http://dx.doi.org/10.1007/978-1-0716-1258-3_13DOI Listing
June 2021

Pathology of Aldosterone Biosynthesis and its Action.

Tohoku J Exp Med 2021 ;254(1):1-15

Department of Pathology, Tohoku University, Graduate School of Medicine.

Aldosterone plays pivotal roles in renin-angiotensin-aldosterone system in order to maintain the equilibrium of liquid volume and electrolyte metabolism. Aldosterone action is mediated by both mineralocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Its excessive actions directly induced tissue injuries in its target organs such as myocardial and vascular fibrosis in addition to chronic kidney diseases. Excessive aldosterone actions were also reported to be involved in unbalanced electrolyte metabolism in inflammatory bowel disease and development of pulmonary diseases. Hyperaldosteronism is tentatively classified into primary and secondary types. Primary aldosteronism is more frequent and has been well known to result in secondary hypertension with subsequent cardiovascular damages. Primary aldosteronism is also further classified into distinctive subtypes and among those, aldosterone-producing adenoma is the most frequent one accounting for the great majority of unilateral primary aldosteronism cases. In bilateral hyperaldosteronism, aldosterone-producing diffuse hyperplasia and aldosterone-producing micronodules or nodules are the major subtypes. All these aldosterone-producing lesions were reported to harbor somatic mutations including KCNJ5, CACNA1D, ATP1A1 and ATP2B3, which were all related to excessive aldosterone production. Among those mutations above, somatic mutation of KCNJ5 is the most frequent in aldosterone-producing adenoma and mostly composed of clear cells harboring abundant aldosterone synthase expression. In contrast, CACNA1D-mutated aldosterone-producing micronodules or aldosterone-producing nodules were frequently detected not only in primary aldosteronism patients but also in the zona glomerulosa of normal adrenal glands, which could eventually lead to an autonomous aldosterone production resulting in normotensive or overt primary aldosteronism, but their details have remained unknown.
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http://dx.doi.org/10.1620/tjem.254.1DOI Listing
January 2021

Targeting epigenetic and post-transcriptional gene regulation by PSF impairs hormone therapy-refractory cancer growth.

Cancer Res 2021 May 11. Epub 2021 May 11.

Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology

RNA-binding protein PSF functions as an epigenetic modifier by interacting with long non-coding RNAs and the co-repressor complex. PSF also promotes RNA splicing events to enhance oncogenic signals. In this study, we conducted an in vitro chemical array screen and identified multiple small molecules that interact with PSF. Several molecules inhibited RNA binding by PSF and decreased prostate cancer cell viability. Among these molecules and its derivatives was a promising molecule, No.10-3 (7,8-dihydroxy-4-(4-methoxyphenyl)chromen-2-one), that was the most effective at blocking PSF RNA binding ability and suppressing treatment-resistant prostate and breast cancer cell proliferation. Exposure to No. 10-3 inhibited PSF target gene expression at the mRNA level. Treatment with No. 10-3 reversed epigenetically repressed PSF downstream targets, such as cell cycle inhibitors, at the transcriptional level. Chromatin immunoprecipitation-sequencing (ChIP-seq) in prostate cancer cells revealed that No. 10-3 enhances histone acetylation to induce expression of apoptosis as well as cell cycle inhibitors. Furthermore, No. 10-3 exhibited anti-tumor efficacy in a hormone therapy-resistant prostate cancer xenograft mouse model, suppressing treatment-resistant tumor growth. Taken together, this study highlights the feasibility of targeting PSF-mediated epigenetic and RNA splicing activities for the treatment of aggressive cancers.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3819DOI Listing
May 2021

Functional inhibition of cancer stemness-related protein DPP4 rescues tyrosine kinase inhibitor resistance in renal cell carcinoma.

Oncogene 2021 Jun 10;40(22):3899-3913. Epub 2021 May 10.

Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.

Tyrosine kinase inhibitors (TKIs) are used as targeted drugs for advanced renal cell carcinoma (RCC), although most cases eventually progress by acquiring resistance. Cancer stemness plays critical roles in tumor aggressiveness and therapeutic resistance, and dipeptidyl peptidase IV (DPP4) has been recently identified as a cancer stemness-related protein. A question arises whether DPP4 contributes to TKI efficacy in RCC. We established patient-derived RCC spheroids and showed that DPP4 expression is associated with stemness-related gene expression. TKI sunitinib resistance was rescued by DPP4 inhibition using sitagliptin or specific siRNAs in RCC cells and tumors. DPP4 expression can be inducible by retinoic acid and repressed by ALDH1A inhibition. Among type 2 diabetes patients with clinical RCC tumors, higher TKI efficacy is observed in those bearing DPP4 tumors treated with DPP4 inhibitors. This study provides new insights into TKI resistance and drug repositioning of DPP4 inhibitor as a promising strategy for advanced RCC.
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http://dx.doi.org/10.1038/s41388-021-01822-5DOI Listing
June 2021

Mass conservative reaction-diffusion systems describing cell polarity.

Math Methods Appl Sci 2021 May 18;44(7):5974-5988. Epub 2021 Jan 18.

Center for Mathematical Modeling and Data Science Osaka University Osaka Japan.

A reaction-diffusion system with mass conservation modeling cell polarity is considered. A range of the parameters is found where the -limit set of the solution is spatially homogeneous, containing constant stationary solution as well as possible nontrivial spatially homogeneous orbit.
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http://dx.doi.org/10.1002/mma.7162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048841PMC
May 2021

Formation of Ni(II)-phenoxyl radical complexes by O: a mechanistic insight into the reaction of Ni(II)-phenol complexes with O.

Dalton Trans 2021 Apr;50(15):5161-5170

Graduate School of Science and Engineering, Ibaraki University, Mito 310-8512, Japan.

A reaction of Ni(ClO4)2·6H2O with a tripodal ligand having two di(tert-butyl)phenol moieties, H2tbuL, and 1 equivalent of triethylamine in CH2Cl2/CH3OH (1 : 1, v/v) under N2 gave a NiII-(phenol)(phenolate) complex, [Ni(HtbuL)(CH3OH)2]ClO4. The formation of the NiII-phenoxyl radical complex by O2 was observed in the reaction of this complex in the solid state. On the other hand, the NiII-phenoxyl radical complex [Ni(Me2NL)(CH3OH)2]ClO4 was obtained by the reaction of H2Me2NL having a p-(dimethylamino)phenol moiety with Ni(ClO4)2·6H2O in a similar procedure under O2, through the oxidation of the NiII-(phenol)(phenolate) complex. However, a direct redox reaction of the NiII ion could not be detected in the phenoxyl radical formation. The results of the reaction kinetics, XAS and X-ray structure analyses suggested that the O2 oxidation from the NiII-(phenol)(phenolate) complex to the NiII-phenoxyl radical complex occurs via the proton transfer-electron transfer (PT-ET) type mechanism of the phenol moiety weakly coordinated to the nickel ion.
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http://dx.doi.org/10.1039/d1dt00105aDOI Listing
April 2021

The medial tangent of the proximal tibia is a suitable extra-articular landmark in determining the tibial anteroposterior axis.

BMC Musculoskelet Disord 2021 Apr 12;22(1):346. Epub 2021 Apr 12.

Department of Orthopaedic Surgery, Nihon University School of Medicine, 30-1 Oyaguchi Kami-cho, Itabashi-ku, Tokyo, 173-8610, Japan.

Background: Tibial rotational alignment in total knee arthroplasty (TKA) is generally determined based on intra-articular structure, and can be difficult to ascertain in some cases. The aim of this study was to investigate whether the medial tangent angle of the tibia (MTAT) could be useful in determining the anteroposterior axis of the tibia.

Methods: This study was performed on 103 lower limbs in 53 patients who underwent primary total hip arthroplasty. The selection criteria for our study were based on the assumption that knees in patients undergoing THA exhibit fewer degenerative changes than knees in patients undergoing TKA. Using computed tomography images, the MTAT, comprising the medial tangent of the proximal tibia and the anteroposterior (AP) axis of the tibia, was measured on three horizontal planes: at the distal edge of the tibial tubercle (A), at 5 cm distally (B), and at 10 cm further distally (C). The tibial medial surface was grouped into three classes according to shape: valley type, flat type, and hill type. The percentage at which these shapes were observed in each group was also calculated. Measurement reliability was calculated using the intraclass correlation coefficient.

Results: The angles were 45.2° (interquartile range: IR 43.0-47.7) at A, 42.7° (IR 38.7-45.9) at B, and 42.4° (IR 38.2-45.9) at C. Intra-rater reliability and inter-rater reliability was 0.982 and 0.974 at A, 0.810 and 0.411 at B, and 0.940 and 0.811 at C, respectively. Regarding the tibial medial surface, the valley type was observed in all cases at A, and the hill type was observed in the highest percentage of cases at B and C.

Conclusions: The MTAT was approximately 45° at level A, and reproducibility was the highest among the three groups. The two points forming the valley on the tibial medial surface were bony ridges. Therefore, the medial tangent of the tibia at level A could be easily determined. Because the distal edge of the tibial tubercle exists at the surgical area and the extra-articular area, it can be a suitable intraoperative, extra-articular landmark in determining the tibial AP axis, even for revision TKA.
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http://dx.doi.org/10.1186/s12891-021-04206-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042940PMC
April 2021

Heterogeneous Nuclear Ribonucleoprotein K Is Involved in the Estrogen-Signaling Pathway in Breast Cancer.

Int J Mol Sci 2021 Mar 4;22(5). Epub 2021 Mar 4.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.

Heterogeneous nuclear ribonucleoprotein K (hnRNPK) transcripts are abundant in estrogen receptor (ER)- or progesterone receptor (PR)-positive breast cancer. However, the biological functions of hnRNPK in the ER-mediated signaling pathway have remained largely unknown. Therefore, this study analyzes the functions of hnRNPK expression in the ER-mediated signaling pathway in breast cancer. We initially evaluated hnRNPK expression upon treatment with estradiol (E2) and ICI 182,780 in the ERα-positive breast carcinoma cell line MCF-7. The results revealed that E2 increased hnRNPK; however, hnRNPK expression was decreased with ICI 182,780 treatment, indicating estrogen dependency. We further evaluated the effects of hnRNPK knockdown in the ER-mediated signaling pathway in MCF-7 cells using small interfering RNAs. The results revealed that hnRNPK knockdown decreased ERα expression and ERα target gene pS2 by E2 treatment. As hnRNPK interacts with several other proteins, we explored the interaction between hnRNPK and ERα, which was demonstrated using immunoprecipitation and proximity ligation assay. Subsequently, we immunolocalized hnRNPK in patients with breast cancer, which revealed that hnRNPK immunoreactivity was significantly higher in ERα-positive carcinoma cells and significantly lower in Ki67-positive or proliferative carcinoma cells. These results indicated that hnRNPK directly interacted with ERα and was involved in the ER-mediated signaling pathway in breast carcinoma. Furthermore, hnRNPK expression could be an additional target of endocrine therapy in patients with ERα-positive breast cancer.
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http://dx.doi.org/10.3390/ijms22052581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962001PMC
March 2021

The Function of Sialidase Revealed by Sialidase Activity Imaging Probe.

Int J Mol Sci 2021 Mar 20;22(6). Epub 2021 Mar 20.

Department of Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.

Sialidase cleaves sialic acid residues from glycans such as glycoproteins and glycolipids. In the brain, desorption of the sialic acid by sialidase is essential for synaptic plasticity, learning and memory and synaptic transmission. BTP3-Neu5Ac has been developed for sensitive imaging of sialidase enzyme activity in mammalian tissues. Sialidase activity in the rat hippocampus detected with BTP3-Neu5Ac increases rapidly by neuronal depolarization. It is presumed that an increased sialidase activity in conjunction with neural excitation is involved in the formation of the neural circuit for memory. Since sialidase inhibits the exocytosis of the excitatory neurotransmitter glutamate, the increased sialidase activity by neural excitation might play a role in the negative feedback mechanism against the glutamate release. Mammalian tissues other than the brain have also been stained with BTP3-Neu5Ac. On the basis of information on the sialidase activity imaging in the pancreas, it was found that sialidase inhibitor can be used as an anti-diabetic drug that can avoid hypoglycemia, a serious side effect of insulin secretagogues. In this review, we discuss the role of sialidase in the brain as well as in the pancreas and skin, as revealed by using a sialidase activity imaging probe. We also present the detection of influenza virus with BTP3-Neu5Ac and modification of BTP3-Neu5Ac.
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http://dx.doi.org/10.3390/ijms22063187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003999PMC
March 2021

In Silico Drug Repurposing by Structural Alteration after Induced Fit: Discovery of a Candidate Agent for Recovery of Nucleotide Excision Repair in Xeroderma Pigmentosum Group D Mutant (R683W).

Biomedicines 2021 Mar 3;9(3). Epub 2021 Mar 3.

Division of Dermatology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.

Xeroderma pigmentosum complementation group D (XPD) is a UV-sensitive syndrome and a rare incurable genetic disease which is caused by the genetic mutation of the excision repair cross-complementation group 2 gene (). Patients who harbor only XPD R683W mutant protein develop severe photosensitivity and progressive neurological symptoms. Cultured cells derived from patients with XPD (XPD R683W cells) demonstrate a reduced nucleotide excision repair (NER) ability. We hope to ameliorate clinical symptoms if we can identify candidate agents that would aid recovery of the cells' NER ability. To investigate such candidates, we created in silico methods of drug repurposing (in silico DR), a strategy that utilizes the recovery of ATP-binding in the XPD R683W protein after the induced fit. We chose 4E1RCat and aprepitant as the candidates for our in silico DR, and evaluated them by using the UV-induced unscheduled DNA synthesis (UDS) assay to verify the recovery of NER in XPD R683W cells. UDS values of the cells improved about 1.4-1.7 times after 4E1RCat treatment compared with solvent-only controls; aprepitant showed no positive effect. In this study, therefore, we succeeded in finding the candidate agent 4E1RCat for XPD R683W. We also demonstrated that our in silico DR method is a cost-effective approach for drug candidate discovery.
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http://dx.doi.org/10.3390/biomedicines9030249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999925PMC
March 2021

Isoforms of IDH in breast carcinoma: IDH2 as a potent prognostic factor associated with proliferation in estrogen-receptor positive cases.

Breast Cancer 2021 Jul 12;28(4):915-926. Epub 2021 Mar 12.

Department of Pathology and Histotechnology, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.

Background: Isocitrate dehydrogenase (IDH) is an important enzyme that oxidatively decarboxylates isocitrate to α-ketoglutarate, and three isoforms (IDH1-3) have been identified. Overexpression and/or downregulation of IDH isoforms was reported in several human malignancies, suggesting importance of IDH in oncogenesis. However, significance of IDH isoforms remains largely unclear in the breast carcinoma.

Methods: We immunolocalized IDH1, IDH2 and IDH3α in 226 breast carcinomas and evaluated their clinical significance. Subsequently, we examined effects of IDH2 on proliferation in breast carcinoma cells.

Results: Immunoreactivity of IDH1-3α was detected in 53%, 38% and 41% of breast carcinomas, and the non-neoplastic epithelium was IDH1-positive, IDH2-negative and IDH3α-positive. IDH1 immunoreactivity was inversely associated with pathological T factor (pT) and Ki-67 in the breast carcinoma, while IDH3α immunoreactivity was not significantly associated with clinicopathological factors. IDH2 status was positively correlated with stage, pT, histological grade, HER2, Ki-67 and microvessel density. Moreover, IDH2 status was significantly associated with worse prognosis of the patients, and it turned out an independent prognostic factor for estrogen-receptor (ER) positive patients. These findings were more evident in the IDH1-negative / IDH2-positive/IDH3α-negative subgroup which is the opposite immunohistochemical IDH phenotype of normal mammary epithelium. In vitro studies demonstrated that RNA interference of IDH2 significantly decreased proliferation activity of T47D and SKBR-3 cells.

Conclusion: These results suggest that IDH2 is associated with an aggressive phenotype of breast carcinoma through increasing cell proliferation, different from IDH1 and IDH3α, and immunohistochemical IDH2 status is a potent prognostic factor especially in ER-positive breast cancer patients.
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http://dx.doi.org/10.1007/s12282-021-01228-xDOI Listing
July 2021

Prognostic impact of CEA/CA19-9 at the time of recurrence in patients with gastric cancer.

Surg Today 2021 Mar 7. Epub 2021 Mar 7.

Department of Clinical Oncology, Toho University Graduate School of Medicine, Ota-ku, Tokyo, Japan.

Purpose: We evaluated the clinical impact of the carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) values at the time of recurrence in gastric cancer patients.

Methods: Among 790 patients with R0 resected gastric cancer without neoadjuvant therapy between 2004 and 2017, 89 recurrence cases were retrospectively evaluated. The clinical impact of CEA and CA19-9 values on recurrence sites and post-recurrent prognosis were evaluated using univariate and multivariate analyses.

Results: The positive rates of CEA and CA19-9 at recurrence were significantly higher than the preoperative positive rates (CEA, 56% vs 24%; CA19-9, 37% vs 15%). Although CA19-9-positive patients at recurrence exhibited a poor survival, the difference was not significant. The positive rates of CEA at liver or lymph node recurrence were significantly higher than the preoperative positive rates. The positive rate of CA19-9 at peritoneal recurrence was significantly higher than the preoperative positive rate. CA19-9-positive patients at recurrence exhibited worse prognosis than CA19-9-negative patients, although the difference was not significant. At lymph node recurrence, CA19-9-positive patients exhibited a significantly worse survival than CA19-9-negative patients.

Conclusion: In recurrent gastric cancer, the positive status of CA19-9 at recurrence might have a negative prognostic impact after recurrence; particularly, in patients with lymph node recurrence.
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http://dx.doi.org/10.1007/s00595-021-02248-yDOI Listing
March 2021

Stromal CCL5 Promotes Breast Cancer Progression by Interacting with CCR3 in Tumor Cells.

Int J Mol Sci 2021 Feb 15;22(4). Epub 2021 Feb 15.

Department of Pathology and Histotechnology, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan.

Chemokines secreted from stromal cells have important roles for interactions with carcinoma cells and regulating tumor progression. C-C motif chemokine ligand (CCL) 5 is expressed in various types of stromal cells and associated with tumor progression, interacting with C-C chemokine receptor (CCR) 1, 3 and 5 expressed in tumor cells. However, the expression on CCL5 and its receptors have so far not been well-examined in human breast carcinoma tissues. We therefore immunolocalized CCL5, as well as CCR1, 3 and 5, in 111 human breast carcinoma tissues and correlated them with clinicopathological characteristics. Stromal CCL5 immunoreactivity was significantly correlated with the aggressive phenotype of breast carcinomas. Importantly, this tendency was observed especially in the CCR3-positive group. Furthermore, the risk of recurrence was significantly higher in the patients with breast carcinomas positive for CCL5 and CCR3 but negative for CCR1 and CCR5, as compared with other patients. In summary, the CCL5-CCR3 axis might contribute to a worse prognosis in breast cancer patients, and these findings will contribute to a better understanding of the significance of the CCL5/CCRs axis in breast carcinoma microenvironment.
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http://dx.doi.org/10.3390/ijms22041918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919043PMC
February 2021

Glial insulin regulates cooperative or antagonistic Golden goal/Flamingo interactions during photoreceptor axon guidance.

Elife 2021 Mar 5;10. Epub 2021 Mar 5.

Graduate School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan.

Transmembrane protein Golden goal (Gogo) interacts with atypical cadherin Flamingo (Fmi) to direct R8 photoreceptor axons in the visual system. However, the precise mechanisms underlying Gogo regulation during columnar- and layer-specific R8 axon targeting are unknown. Our studies demonstrated that the insulin secreted from surface and cortex glia switches the phosphorylation status of Gogo, thereby regulating its two distinct functions. Non-phosphorylated Gogo mediates the initial recognition of the glial protrusion in the center of the medulla column, whereas phosphorylated Gogo suppresses radial filopodia extension by counteracting Flamingo to maintain a one axon-to-one column ratio. Later, Gogo expression ceases during the midpupal stage, thus allowing R8 filopodia to extend vertically into the M3 layer. These results demonstrate that the long- and short-range signaling between the glia and R8 axon growth cones regulates growth cone dynamics in a stepwise manner, and thus shapes the entire organization of the visual system.
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http://dx.doi.org/10.7554/eLife.66718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987344PMC
March 2021

A Simple, Low-Cost Technique for Difficult-to-Close Laparoscopic Port Sites.

Am Surg 2021 Feb 10:3134821995080. Epub 2021 Feb 10.

Department of Gastroenterological Surgery, 12756Dokkyo Medical University, Tochigi, Japan.

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http://dx.doi.org/10.1177/0003134821995080DOI Listing
February 2021

Enhancement of elastin expression by transdermal administration of sialidase isozyme Neu2.

Sci Rep 2021 Feb 8;11(1):3302. Epub 2021 Feb 8.

Department of Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan.

Reduction of elastin in the skin causes various skin diseases as well as wrinkles and sagging with aging. Sialidase is a hydrolase that cleaves a sialic acid residue from sialoglycoconjugate. Cleavage of sialic acid from microfibrils by the sialidase isozyme Neu1 facilitates elastic fiber assembly. In the present study, we showed that a lower layer of the dermis and muscle showed relatively intense sialidase activity. The sialidase activity in the skin decreased with aging. Choline and geranate (CAGE), one of the ionic liquids, can deliver the sialidase subcutaneously while maintaining the enzymatic activity. The elastin level in the dermis was increased by applying sialidase from Arthrobacter ureafaciens (AUSA) with CAGE on the skin for 5 days in rats and senescence-accelerated mice prone 1 and 8. Sialidase activity in the dermis was considered to be mainly due to Neu2 based on the expression level of sialidase isozyme mRNA. Transdermal administration of Neu2 with CAGE also increased the level of elastin in the dermis. Therefore, not only Neu1 but also Neu2 would be involved in elastic fiber assembly. Transdermal administration of sialidase is expected to be useful for improvement of wrinkles and skin disorders due to the loss of elastic fibers.
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http://dx.doi.org/10.1038/s41598-021-82820-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870814PMC
February 2021

In Vitro and In Vivo Evaluation of Three Newly Isolated Bacteriophage Candidates, phiEF7H, phiEF14H1, phiEF19G, for Treatment of Endophthalmitis.

Microorganisms 2021 Jan 20;9(2). Epub 2021 Jan 20.

Department of Ophthalmology and Visual Science, Kochi Medical School, Kochi University, Kochi 783-8505, Japan.

Post-operative endophthalmitis caused by spp. progresses rapidly and often results in substantial and irreversible vision loss. Therefore, novel alternative treatments that are effective against enterococcal endophthalmitis are required. Bacteriophage therapy has the potential to be an optional therapy for infectious diseases. Therefore, we investigated the therapeutic potential of three newly isolated enterococcal phages, phiEF7H, phiEF14H1, and phiEF19G, in -induced endophthalmitis. These phages could lyse the broad-range , including strains derived from endophthalmitis and vancomycin-resistant in vitro, as determined by the streak test. Morphological and genomic analyses revealed that these phages were classified into the genus . The whole genomes of these phages contained 143,399, 143,280, and 143,400 bp, respectively. Endophthalmitis was induced in mice by injection of three strains of derived from post-operative endophthalmitis or vancomycin-resistant strains into the vitreous body. The number of viable bacteria and infiltration of neutrophils in the eye were both decreased by intravitreous injection of phiEF7H, phiEF14H1, and phiEF19G 6 h after injection of all strains. Thus, these results suggest that these newly isolated phages may serve as promising candidates for phage therapy against endophthalmitis.
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http://dx.doi.org/10.3390/microorganisms9020212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909552PMC
January 2021

Relation of Dietary Fatty Acids and Vitamin D to the Prevalence of Meibomian Gland Dysfunction in Japanese Adults: The Hirado-Takushima Study.

J Clin Med 2021 Jan 18;10(2). Epub 2021 Jan 18.

Lid and Meibomian Gland Working Group (LIME), 626-11 Minami-Nakano, Minumaku, Saitama, Saitama 337-0042, Japan.

Intervention studies have shown that n-3 polyunsaturated fatty acid (PUFA) supplementation is effective for the treatment of meibomian gland dysfunction (MGD). Ointment containing an analog of vitamin D has also been found to improve symptoms and signs of MGD. We have now evaluated the relation of MGD prevalence to dietary intake of fatty acids (FAs) and vitamin D among a Japanese population. Subjects comprised 300 adults aged 20 to 92 years residing on Takushima Island. MGD was diagnosed on the basis of subjective symptoms, lid margin abnormalities, and meibomian gland obstruction. Dietary FA and vitamin D intake was estimated with a brief-type self-administered diet history questionnaire. MGD prevalence was 35.3%. Multivariate adjusted odds ratios (95% confidence intervals) between extreme quintiles of intake for MGD prevalence were 0.40 (0.16-0.97) for total fat, 0.40 (0.17-0.97) for saturated FAs, 0.40 (0.17-0.97) for oleic acid, 0.52 (0.23-1.18) for n-3 PUFAs, 0.63 (0.27-1.49) for n-6 PUFAs, 1.32 (0.59-2.95) for the n-6/n-3 PUFA ratio, and 0.38 (0.17-0.87) for vitamin D. Total fat, saturated FA, oleic acid, and vitamin D intake may thus be negatively associated with MGD prevalence in the Japanese.
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http://dx.doi.org/10.3390/jcm10020350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831319PMC
January 2021

Impact of the COVID-19 pandemic on a trauma center of a university hospital in Japan.

J Orthop Sci 2020 Dec 29. Epub 2020 Dec 29.

Trauma and Reconstruction Center, Teikyo University Hospital, 2-11-1, Kaga, Itabashi-Ku, Tokyo, 173-8606, Japan.

Background: The Coronavirus disease 2019 pandemic caused the Japanese government to declare a State of Emergency on April 7, 2020. The aim of this study is to provide an overview of the effects of the pandemic on surgical cases at a university hospital trauma center.

Methods: An observational study was performed at a trauma center in a tertiary hospital in Tokyo, Japan. The number of surgeries was compared between two periods: a historical control period (Tuesday April 9 to Monday May 27, 2019) and the period of the Japan State of Emergency due to COVID-19 (Tuesday April 7-Monday May 25, 2020). Information on patient age, gender, and surgical diagnosis, site, and procedure was collected for cases operated on in each period. The number of trauma surgeries was compared between the two periods. Data from the two periods were compared statistically.

Results: The total number of surgical cases was 151 in the control period and 83 in the COVID-19 period (including no cases with COVID-19), a decrease of 45.0%. There were significantly more surgeries for patients with hip fractures in the COVID-19 period (9 vs. 19, P < 0.001 by Fisher exact test).

Conclusions: During the State of Emergency in Japan, the number of operations for trauma patients at the trauma center decreased, but surgeries for hip fracture increased.
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http://dx.doi.org/10.1016/j.jos.2020.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834403PMC
December 2020

L-type amino acid transporter 1 is associated with chemoresistance in breast cancer via the promotion of amino acid metabolism.

Sci Rep 2021 01 12;11(1):589. Epub 2021 Jan 12.

Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.

F-FDG PET/CT has been used as an indicator of chemotherapy effects, but cancer cells can remain even when no FDG uptake is detected, indicating the importance of exploring other metabolomic pathways. Therefore, we explored the amino acid metabolism, including L-type amino acid transporter-1 (LAT1), in breast cancer tissues and clarified the role of LAT1 in therapeutic resistance and clinical outcomes of patients. We evaluated LAT1 expression before and after neoadjuvant chemotherapy and examined the correlation of glucose uptake using FDG-PET with the pathological response of patients. It revealed that LAT1 levels correlated with proliferation after chemotherapy, and amino acid and glucose metabolism were closely correlated. In addition, LAT1 was considered to be involved in treatment resistance and sensitivity only in luminal type breast cancer. Results of in vitro analyses revealed that LAT1 promoted amino acid uptake, which contributed to energy production by supplying amino acids to the TCA cycle. However, in MCF-7 cells treated with chemotherapeutic agents, oncometabolites and branched-chain amino acids also played a pivotal role in energy production and drug resistance, despite decreased glucose metabolism. In conclusion, LAT1 was involved in drug resistance and could be a novel therapeutic target against chemotherapy resistance in luminal type breast cancer.
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http://dx.doi.org/10.1038/s41598-020-80668-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803739PMC
January 2021

Randomized Phase II Study to Comparing Docetaxel/Nedaplatin versus Docetaxel for 5-Fluorouracil/Cisplatin Resistant Esophageal Squamous Cell Carcinoma.

Ann Thorac Cardiovasc Surg 2021 Jan 6. Epub 2021 Jan 6.

Department of Surgery, School of Medicine, Toho University, Tokyo, Japan.

Purpose: To compare efficacy and safety of dual docetaxel/nedaplatin treatment versus docetaxel alone as second-line chemotherapy for advanced esophageal cancer.

Methods: In all, 36 patients with metastatic and/or recurrent esophagus squamous cell carcinoma resistant to first-line chemotherapy (fluorouracil/cisplatin) were recruited from 2011 to 2018 and randomized into two groups. Treatment response and survival were compared between the docetaxel/nedaplatin (60/80 mg/m/day) group and docetaxel (70 mg/m/day) group. Treatment was repeated every 3 weeks until tumor progression. Patients were followed up until March 2019 or death.

Results: The frequency of Grade 3 or higher adverse events in the docetaxel/nedaplatin group (58.8%) was higher compared with the docetaxel group (26.3%) (P = 0.090). We found a treatment response rate of 52.9% and 36.8% and a median survival of 8.9 and 7.0 months in the docetaxel/nedaplatin-treated and docetaxel-treated group, respectively (P = 0.544).

Conclusion: No significant survival advantage was found for docetaxel/nedaplatin-treated patients, although there was an increased frequency of high-grade adverse events compared to docetaxel-treated patients. Because of the limited cohort size, a Phase III study based on our findings is not warranted to assess the clinical impact of docetaxel/nedaplatin treatment. This trial is registered with the University Hospital Medical Information Network (UMIN 000005877).
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http://dx.doi.org/10.5761/atcs.oa.20-00294DOI Listing
January 2021

Comparison and Evaluation of Prelens Tear Film Stability by Different Noninvasive in vivo Methods.

Clin Ophthalmol 2020 21;14:4459-4468. Epub 2020 Dec 21.

Department of Ophthalmology, Toho University Graduate School of Medicine, Tokyo, Japan.

Purpose: Prelens tear film stability of soft contact lens (SCL) play an important role for contact lens discomfort. In this study, we investigated the association between two types of noninvasive methods and evaluated the tear film stability with SCL using the methods.

Patients And Methods: In experiment 1, images of ring mire were recorded with a keratograph after focusing the pigment located at the front or back of the SCL. Interferometry and videokeratoscopy were used for the assessment of tear film stability in the right eye of 10 women, with two different cosmetic daily disposable SCLs: polymacon and etafilcon A with polyvinylpyrrolidone. Time to first distortion by noninvasive keratograph break up time (NIKBUT-first) was compared to noninvasive interferometry break up time (NIBUT). In experiment 2, ten normal females wore two different daily disposable SCLs: samfilcon A and narafilcon A. NIKBUT-first and NIBUT were compared between the lenses after 8 hours of SCL wearing.

Results: In experiment 1, NIBUT-first without SCL was significantly correlated to NIBUT without SCL (r=0.445, P=0.0488, Pearson's correlation coefficients). However, NIKBUT-first with SCL was not significantly correlated with NIBUT with SCL. In experiment 2, although NIKBUT-first was not significantly different between SCLs, samfilcon A had significantly longer NIBUT than narafilcon A (P=0.0315, paired -test).

Conclusion: NIKBUT-first with SCL could be related to tear film stability between the lens and the corneal surface, but not to prelens tear film stability. NIIBUT could be a suitable method to evaluate prelens tear stability.
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http://dx.doi.org/10.2147/OPTH.S288047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762444PMC
December 2020

Cellular and Mathematical Analyses of LUBAC Involvement in T Cell Receptor-Mediated NF-κB Activation Pathway.

Front Immunol 2020 23;11:601926. Epub 2020 Nov 23.

Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka, Japan.

The LUBAC ubiquitin ligase complex, composed of the HOIP, HOIL-1L, and SHARPIN subunits, stimulates the canonical nuclear factor-κB (NF-κB) activation pathways through its Met1-linked linear ubiquitination activity. Here we performed cellular and mathematical modeling analyses of the LUBAC involvement in the T cell receptor (TCR)-mediated NF-κB activation pathway, using the Jurkat human T cell line. LUBAC is indispensable for TCR-induced NF-κB and T cell activation, and transiently associates with and linearly ubiquitinates the CARMA1-BCL10-MALT1 (CBM) complex, through the catalytic HOIP subunit. In contrast, the linear ubiquitination of NEMO, a substrate of the TNF-α-induced canonical NF-κB activation pathway, was limited during the TCR pathway. Among deubiquitinases, OTULIN, but not CYLD, plays a major role in downregulating LUBAC-mediated TCR signaling. Mathematical modeling indicated that linear ubiquitination of the CBM complex accelerates the activation of IκB kinase (IKK), as compared with the activity induced by linear ubiquitination of NEMO alone. Moreover, simulations of the sequential linear ubiquitination of the CBM complex suggested that the allosteric regulation of linear (de)ubiquitination of CBM subunits is controlled by the ubiquitin-linkage lengths. These results indicated that, unlike the TNF-α-induced NF-κB activation pathway, the TCR-mediated NF-κB activation in T lymphocytes has a characteristic mechanism to induce LUBAC-mediated NF-κB activation.
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http://dx.doi.org/10.3389/fimmu.2020.601926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732508PMC
June 2021

Activity-dependent endocytosis of Wingless regulates synaptic plasticity in the Drosophila visual system.

Genes Genet Syst 2021 Feb 6;95(5):235-247. Epub 2021 Feb 6.

Graduate School of Life Science and Technology, Tokyo Institute of Technology.

Neural activity contributes to synaptic regulation in sensory systems, which allows organisms to adjust to changing environments. However, little is known about how synaptic molecular components are regulated to achieve activity-dependent plasticity at central synapses. Previous studies have shown that following prolonged exposure to natural ambient light, the presynaptic active zone (AZ), an area associated with presynaptic neurotransmitter release in Drosophila photoreceptors, undergoes reversible remodeling. Other studies suggest that the secretory protein Wingless (Wg; an ortholog of Wnt-1) can mediate communication between synaptic cells to achieve synaptic remodeling. However, the source of Wg and the mechanism of Wg signal modulation by neuronal activity remained unclear. Here, we found that Wg secreted from glial cells regulates synaptic remodeling in photoreceptors. In addition, antibody staining revealed that Wg changes its localization depending on light conditions. Although Wg is secreted from glial cells, Wg appeared inside photoreceptor axons when flies were kept under light conditions, suggesting that an increase in neuronal activity causes Wg internalization into photoreceptors by endocytosis. Indeed, by blocking endocytosis in photoreceptors, the localization of Wg in photoreceptors disappeared. Interestingly, Wg accumulation was higher in axons with disassembled AZ structure than in axons whose AZ structure was stabilized at the single-cell level, indicating that Wg endocytosis may trigger AZ disassembly. Furthermore, when we genetically activated Wg signaling, Wg accumulation in photoreceptors decreased. Conversely, when we suppressed Wg signaling there was an increase in Wg accumulation. Through RNAi screening of Ca-binding proteins in photoreceptors, we found that Calcineurin is a key molecule that triggers Wg endocytosis. Overall, we propose that Wg signaling is regulated by a negative feedback loop driven by Wg endocytosis. The increase in neuronal activity is transmitted via calcium signaling, which leads to a decrease in Wg signaling and thereby promotes presynaptic remodeling.
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http://dx.doi.org/10.1266/ggs.20-00030DOI Listing
February 2021

Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers.

Nat Commun 2020 11 20;11(1):5911. Epub 2020 Nov 20.

Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan.

Transcriptional dysregulation, which can be caused by genetic and epigenetic alterations, is a fundamental feature of many cancers. A key cytoprotective transcriptional activator, NRF2, is often aberrantly activated in non-small cell lung cancers (NSCLCs) and supports both aggressive tumorigenesis and therapeutic resistance. Herein, we find that persistently activated NRF2 in NSCLCs generates enhancers at gene loci that are not normally regulated by transiently activated NRF2 under physiological conditions. Elevated accumulation of CEBPB in NRF2-activated NSCLCs is found to be one of the prerequisites for establishment of the unique NRF2-dependent enhancers, among which the NOTCH3 enhancer is shown to be critical for promotion of tumor-initiating activity. Enhancer remodeling mediated by NRF2-CEBPB cooperativity promotes tumor-initiating activity and drives malignancy of NRF2-activated NSCLCs via establishment of the NRF2-NOTCH3 regulatory axis.
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http://dx.doi.org/10.1038/s41467-020-19593-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679411PMC
November 2020

New Assay System Elecsys Anti-p53 to Detect Serum Anti-p53 Antibodies in Esophageal Cancer Patients and Colorectal Cancer Patients: Multi-institutional Study.

Ann Surg Oncol 2021 Jul 18;28(7):4007-4015. Epub 2020 Nov 18.

Department of Surgery, School of Medicine, Toho University, Tokyo, Japan.

Background: Several recent studies suggest that serum anti-p53 antibodies (s-p53-Abs) may be combined with other markers to detect esophageal and colorectal cancer. In this study, we assessed the sensitivity and specificity of s-p53-Abs detection of a new electrochemiluminescence immunoassay (ECLIA; Elecsys anti-p53).

Methods: Elecsys anti-p53 assay was used to analyze the level of s-p53-Abs in blood sera from patients with esophageal or colorectal cancer taken before treatment. Control blood sera from healthy volunteers, patients with benign diseases, and patients with autoimmune diseases served as a reference. In addition, squamous cell carcinoma antigen (SCC-Ag) and cytokeratin 19 fragments (CYFRA21-1) were assessed in patients with esophageal cancer, and carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 were assessed in patients with colorectal cancer.

Results: Samples from 281 patients with esophageal cancer, 232 patients with colorectal cancer, and 532 controls were included in the study. The median value of s-p53-Abs in control samples was < 0.02 μg/mL (range < 0.02-29.2 μg/mL). Assuming 98% specificity, the cut-off value was determined as 0.05 μg/mL. s-p53-Abs were detected in 20% (57/281) of patients with esophageal cancer and 18% (42/232) of patients with colorectal cancer. In combination with SCC-Ag and CEA, respectively, s-p53-Abs detected 51% (144/281) of patients with esophageal and 53% (124/232) of patients with colorectal cancer.

Conclusions: The new s-p53-Abs assay Elecsys anti-p53 was useful in detecting esophageal and colorectal cancers with high specificity. Adding s-p53-Abs to conventional markers significantly improved the overall detection rates.
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http://dx.doi.org/10.1245/s10434-020-09342-4DOI Listing
July 2021

Intact in vivo visualization of telencephalic microvasculature in medaka using optical coherence tomography.

Sci Rep 2020 11 16;10(1):19831. Epub 2020 Nov 16.

Kyoto University, Kyoto, Japan.

To date, various human disease models in small fish-such as medaka (Oryzias lapties)-have been developed for medical and pharmacological studies. Although genetic and environmental homogeneities exist, disease progressions can show large individual differences in animal models. In this study, we established an intact in vivo angiographic approach and explored vascular networks in the telencephalon of wild-type adult medaka using the spectral-domain optical coherence tomography. Our approach, which required neither surgical operations nor labeling agents, allowed to visualize blood vessels in medaka telencephala as small as about 8 µm, that is, almost the size of the blood cells of medaka. Besides, we could show the three-dimensional microvascular distribution in the medaka telencephalon. Therefore, the intact in vivo imaging via optical coherence tomography can be used to perform follow-up studies on cerebrovascular alterations in metabolic syndrome and their associations with neurodegenerative disease models in medaka.
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http://dx.doi.org/10.1038/s41598-020-76468-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669881PMC
November 2020