Publications by authors named "Kensuke Suzuki"

147 Publications

Letter to the Editor Regarding a New Technical Principle of Carotid Artery Stenting With Lesion Crossing Using a 0.035-inch Guidewire and 6-4-French Tapering-Type Catheter for Severe Stenosis.

Cardiovasc Intervent Radiol 2021 Jul 13. Epub 2021 Jul 13.

Department of Neurosurgery, Dokkyo Medical University Saitama Medical Center, 2-1-50 Minamikoshigaya, Koshigaya-shi, Saitama, 343-8555, Japan.

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http://dx.doi.org/10.1007/s00270-021-02919-wDOI Listing
July 2021

Treg and IL-1 receptor type 2-expressing CD4 T cell-deleted CD4 T cell fraction prevents the progression of age-related hearing loss in a mouse model.

J Neuroimmunol 2021 Aug 8;357:577628. Epub 2021 Jun 8.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Hirakata, Osaka, Japan.

We investigated the association between cellular immunity and age-related hearing loss (ARHL) development using three CD4 T cell fractions, namely, naturally occurring regulatory T cells (Treg), interleukin 1 receptor type 2-expressing T cells (I1R2), and non-Treg non-I1R2 (nTnI) cells, which comprised Treg and I1R2-deleted CD4 T cells. Inoculation of the nTnI fraction into a ARHL murine model, not only prevented the development of ARHL and the degeneration of spiral ganglion neurons, but also suppressed serum nitric oxide, a source of oxidative stress. Further investigations on CD4 T cell fractions could provide novel insights into the prevention of aging, including presbycusis.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577628DOI Listing
August 2021

Photoredox-Catalyzed C-F Bond Allylation of Perfluoroalkylarenes at the Benzylic Position.

J Am Chem Soc 2021 Jun 2;143(25):9308-9313. Epub 2021 Jun 2.

Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.

Site-selective and direct C-F bond transformation of perfluoroalkylarenes was achieved with allylic stannanes via an iridium photoredox catalyst system. The present defluoroallylation proceeds exclusively at the benzylic position through perfluoroalkyl radicals generated by a single-electron transfer from an excited photoredox catalyst to perfluoroalkylarenes. A variety of perfluoroalkyl groups are applicable: linear perfluoroalkyl-substituted arenes such as Ar-CF and Ar-CF and heptafluoroisopropylarenes (Ar-CF(CF)) underwent site-selective defluoroallylation. DFT calculation studies revealed that the generated BuSnF traps F to prevent a retroreaction from the unstable perfluoroalkyl radical intermediate, and the radical intermediate favorably reacts with allylic stannanes. The synthesis of a bis(trifluoromethyl)methylene unit containing compound, which is an analog that is useful as a pharmaceutical agent for the prophylaxis or treatment of diabetes and inflammatory diseases, demonstrated the utility of this reaction.
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http://dx.doi.org/10.1021/jacs.1c03760DOI Listing
June 2021

Target Coil Embolization Using the Combined Transarterial and Transvenous Balloon-assisted Technique for Traumatic Direct Carotid Cavernous Fistula.

NMC Case Rep J 2021 Apr 2;8(1):13-19. Epub 2021 Apr 2.

Department of Neurosurgery, Dokkyo Medical University Saitama Medical Center, Koshigaya, Saitama, Japan.

Herein, we describe a case of traumatic direct carotid cavernous fistula (DCCF) treated with target coil embolization using the combined transarterial and transvenous balloon-assisted technique. The patient was a 59-year-old woman who had been involved in a vehicular accident. She was admitted to the hospital due to chemosis and exophthalmos. Cerebral angiography revealed a shunt from the internal carotid artery (ICA) to the cavernous sinus (CS), which indicated DCCF. Thus, target coil embolization using the combined transarterial and transvenous balloon-assisted technique was performed. Angiography was performed 1 week after surgery to confirm the disappearance of DCCF. No recurrence was observed during the 1-year follow-up after treatment. Thus, target coil embolization using the combined transarterial and transvenous balloon-assisted technique is safe and effective for the treatment of traumatic DCCF.
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http://dx.doi.org/10.2176/nmccrj.cr.2020-0045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116922PMC
April 2021

Targeted Transvenous Embolization of Cavernous Sinus Dural Arteriovenous Fistula With Liquid Materials Using a Dual-Lumen Balloon Microcatheter.

Cureus 2021 Mar 11;13(3):e13821. Epub 2021 Mar 11.

Neurosurgery, Dokkyo Medical University Saitama Medical Center, Koshigaya, JPN.

We describe a challenging transvenous embolization technique involving a dual-lumen balloon microcatheter (DLBM) and liquid materials for cavernous sinus dural arteriovenous fistula (CSDAVF). DLBM contributed to identifying the shunt point and preventing liquid material leakage to normal venous drainage without treatment-related complications. In a transvenous embolization using liquid materials for CSDAVF complications such as cranial nerve palsy and embolic agent migration into the internal carotid artery due to numerous anastomoses must be considered. The use of angiography during DLBM inflation to characterize the shunt point and DLBM to prevent liquid material leakage to the normal venous drainage might decrease the mass effect due to liquid materials, thereby minimizing the causes of newly occurring cranial nerve palsy. This technique may be helpful for the treatment of CSDAVF in practice, but there is generally a risk in using liquid materials in the cavernous sinus; therefore, further consideration is needed in the future.
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http://dx.doi.org/10.7759/cureus.13821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035909PMC
March 2021

LIN28B induces a differentiation program through CDX2 in colon cancer.

JCI Insight 2021 May 10;6(9). Epub 2021 May 10.

Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Disease, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA.

Most colorectal cancers (CRCs) are moderately differentiated or well differentiated, a status that is preserved even in metastatic tumors. However, the molecular mechanisms underlying CRC differentiation remain to be elucidated. Herein, we unravel a potentially novel posttranscriptional regulatory mechanism via a LIN28B/CDX2 signaling axis that plays a critical role in mediating CRC differentiation. Owing to a large number of mRNA targets, the mRNA-binding protein LIN28B has diverse functions in development, metabolism, tissue regeneration, and tumorigenesis. Our RNA-binding protein IP (RIP) assay revealed that LIN28B directly binds CDX2 mRNA, which is a pivotal homeobox transcription factor in normal intestinal epithelial cell identity and differentiation. Furthermore, LIN28B overexpression resulted in enhanced CDX2 expression to promote differentiation in subcutaneous xenograft tumors generated from CRC cells and metastatic tumor colonization through mesenchymal-epithelial transition in CRC liver metastasis mouse models. A ChIP sequence for CDX2 identified α-methylacyl-CoA racemase (AMACR) as a potentially novel transcriptional target of CDX2 in the context of LIN28B overexpression. We also found that AMACR enhanced intestinal alkaline phosphatase activity, which is known as a key component of intestinal differentiation, through the upregulation of butyric acid. Overall, we demonstrated that LIN28B promotes CRC differentiation through the CDX2/AMACR axis.
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http://dx.doi.org/10.1172/jci.insight.140382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262288PMC
May 2021

Public perceptions, individual characteristics, and preventive behaviors for COVID-19 in six countries: a cross-sectional study.

Environ Health Prev Med 2021 Mar 3;26(1):29. Epub 2021 Mar 3.

Department of Business Management, Meijo University, 1-501 Shiogamaguchi, Tempaku-ku, Nagoya, 468-8502, Japan.

Background: Public perceptions and personal characteristics are heterogeneous between countries and subgroups, which may have different impacts on health-protective behaviors during the coronavirus disease 2019 (COVID-19) pandemic. To assess whether self-reported perceptions of COVID-19 and personal characteristics are associated with protective behaviors among general adults and to compare patterns in six different countries.

Methods: This cross-sectional study uses the secondary data collected through an online survey between 15 and 23 April 2020 across six countries (China, Italy, Japan, Korea, the UK, and the USA). A total of 5945 adults aged 18 years or older were eligible for our analysis. A logistic regression model was used to estimate odds ratios (OR) and 95% confidence intervals (95%CI) of three recommended behaviors (wearing a mask, handwashing, and avoiding social gatherings).

Results: In most countries except for China, the participants who perceived wearing a mask as being extremely effective to curtail the pandemic were more likely to wear a mask (OR, 95%CI: Italy: 4.14, 2.08-8.02; Japan: 3.59, 1.75-7.30; Korea: 7.89, 1.91-31.63: UK: 9.23, 5.14-17.31; USA: 4.81, 2.61-8.92). Those who perceived that handwashing was extremely effective had higher ORs of this preventive behavior (OR, 95%CI: Italy: 16.39, 3.56-70.18; Japan: 12.24, 4.03-37.35; Korea: 12.41, 2.02-76.39; UK: 18.04, 2.60-152.78; USA: 10.56, 2.21-44.32). The participants who perceived avoiding social gathering as being extremely effective to curtail the pandemic were more likely to take this type of preventive behavior (OR, 95%CI: China: 3.79, 1.28-10.23; Korea: 6.18, 1.77-20.60; UK: 4.45, 1.63-11.63; USA: 4.34, 1.84-9.95). The associations between personal characteristics, living environment, psychological status, and preventive behaviors varied across different countries. Individuals who changed their behavior because of recommendations from doctors/public health officials were more likely to take preventive behaviors in many countries.

Conclusions: These findings suggest that higher perceived effectiveness may be a common factor to encourage preventive behaviors in response to the COVID-19 pandemic. These results may provide a better understanding of the homogeneity and heterogeneity of factors related to preventive behaviors and improve public health policies in various countries and groups.
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http://dx.doi.org/10.1186/s12199-021-00952-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928175PMC
March 2021

PTHrP Drives Pancreatic Cancer Growth and Metastasis and Reveals a New Therapeutic Vulnerability.

Cancer Discov 2021 Jul 15;11(7):1774-1791. Epub 2021 Feb 15.

Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.

Pancreatic cancer metastasis is a leading cause of cancer-related deaths, yet very little is understood regarding the underlying biology. As a result, targeted therapies to inhibit metastasis are lacking. Here, we report that the parathyroid hormone-related protein (PTHrP encoded by ) is frequently amplified as part of the amplicon in patients with pancreatic cancer. PTHrP upregulation drives the growth of both primary and metastatic tumors in mice and is highly enriched in pancreatic ductal adenocarcinoma metastases. Loss of PTHrP-either genetically or pharmacologically-dramatically reduces tumor burden, eliminates metastasis, and enhances overall survival. These effects are mediated in part through a reduction in epithelial-to-mesenchymal transition, which reduces the ability of tumor cells to initiate metastatic cascade. , which encodes osteopontin, is revealed to be a downstream effector of PTHrP. Our results establish a new paradigm in pancreatic cancer whereby PTHrP is a driver of disease progression and emerges as a novel therapeutic vulnerability. SIGNIFICANCE: Pancreatic cancer often presents with metastases, yet no strategies exist to pharmacologically inhibit this process. Herein, we establish the oncogenic and prometastatic roles of , a novel amplified gene in pancreatic ductal adenocarcinoma. We demonstrate that blocking PTHrP activity reduces primary tumor growth, prevents metastasis, and prolongs survival in mice..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292165PMC
July 2021

Inactivation of the PD-1-Dependent Immunoregulation in Mice Exacerbates Contact Hypersensitivity Resembling Immune-Related Adverse Events.

Front Immunol 2020 27;11:618711. Epub 2021 Jan 27.

Department of Immunology, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan.

Blockade of PD-1, an indispensable physiological immunoregulatory mechanism, enhances immune activities and is widely used in the immunotherapy of cancer. This treatment often accompanies inflammatory complication called immune-related adverse events (irAE), most frequently in the skin. To analyze how skin inflammation develops by the blockade of PD-1-dependent immunoregulation, we studied the exacerbation of oxazolone-induced contact hypersensitivity by PD-L1 blockade. The inactivation of PD-1 signaling enhanced swelling of the skin with massive CD8 T cell infiltration. Among PD-1-expressing cells, T cells were the predominant targets of anti-PD-L1 mAb treatment since PD-L1 blockade did not affect skin inflammation in RAG2 mice. PD-L1 blockade during immunization with oxazolone significantly promoted the development of hapten-reactive T cells in the draining lymph nodes. The enhancement of local CD8 T cell-dominant immune responses by PD-L1 blockade was correlated with the upregulation of CXCL9 and CXCL10. Challenges with a low dose of oxazolone did not demonstrate any significant dermatitis; however, the influence of PD-L1 blockade on T cell immunity was strong enough to cause the emergence of notable dermatitis in this suboptimal dosing, suggesting its relevance to dermal irAE development. In the low-dose setting, the blockade of CXCR3, receptor of CXCL9/10, prevented the induction of T cell-dominant inflammation by anti-PD-L1 mAb. This experimental approach reproduced CD8 T cell-dominant form of cutaneous inflammation by the blockade of PD-L1 that has been observed in dermal irAE in human patients.
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http://dx.doi.org/10.3389/fimmu.2020.618711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873368PMC
June 2021

Sequential therapy of crizotinib followed by alectinib for non-small cell lung cancer harbouring anaplastic lymphoma kinase rearrangement (WJOG9516L): A multicenter retrospective cohort study.

Eur J Cancer 2021 Mar 22;145:183-193. Epub 2021 Jan 22.

Respiratory Division, Department of Internal Medicine, Itami City Hospital, 1-100 Koyaike, Itami City, Hyogo, 664-8540, Japan.

Background: The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited.

Methods: We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group.

Results: Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001).

Conclusion: The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.
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http://dx.doi.org/10.1016/j.ejca.2020.12.026DOI Listing
March 2021

(o-Phenylenediamino)borylstannanes: Efficient Reagents for Borylation of Various Alkyl Radical Precursors.

Chemistry 2021 Feb 21;27(12):3891. Epub 2021 Jan 21.

Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1, Yamadaoka, Suita, Osaka, 565-0871, Japan.

Invited for the cover of this issue are Kensuke Suzuki, Yoshihiro Nishimoto and Makoto Yasuda from Osaka University. The image depicts a circus trapeze act, with different elements of the picture representing components of the borylation reaction reported in this work. Read the full text of the article at 10.1002/chem.202004692.
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http://dx.doi.org/10.1002/chem.202005326DOI Listing
February 2021

Rab11-FIP1 mediates epithelial-mesenchymal transition and invasion in esophageal cancer.

EMBO Rep 2021 02 6;22(2):e48351. Epub 2021 Jan 6.

Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA.

Esophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer worldwide. The most commonly mutated gene in ESCC is TP53. Using a combinatorial genetic and carcinogenic approach, we generate a novel mouse model of ESCC expressing either mutant or null p53 and show that mutant p53 exhibits enhanced tumorigenic properties and displays a distinct genomic profile. Through RNA-seq analysis, we identify several endocytic recycling genes, including Rab Coupling Protein (Rab11-FIP1), which are significantly downregulated in mutant p53 tumor cells. In 3-dimensional (3D) organoid models, genetic knockdown of Rab11-FIP1 results in increased organoid size. Loss of Rab11-FIP1 increases tumor cell invasion in part through mutant p53 but also in an independent manner. Furthermore, loss of Rab11-FIP1 in human ESCC cell lines decreases E-cadherin expression and increases mesenchymal lineage-specific markers, suggesting induction of epithelial-mesenchymal transition (EMT). Rab11-FIP1 regulates EMT through direct inhibition of Zeb1, a key EMT transcriptional factor. Our novel findings reveal that Rab11-FIP1 regulates organoid formation, tumor cell invasion, and EMT.
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http://dx.doi.org/10.15252/embr.201948351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857540PMC
February 2021

The multiple functions and subpopulations of eosinophils in tissues under steady-state and pathological conditions.

Allergol Int 2021 Jan 24;70(1):9-18. Epub 2020 Nov 24.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Osaka, Japan.

Eosinophils not only play a critical role in the pathogenesis of eosinophil-associated diseases, but they also have multiple important biological functions, including the maintenance of homeostasis, host defense against infections, immune regulation through canonical Th1/Th2 balance modulation, and anti-inflammatory and anti-tumorigenic activities. Recent studies have elucidated some emerging roles of eosinophils in steady-state conditions; for example, eosinophils contribute to adipose tissue metabolism and metabolic health through alternatively activated macrophages and the maintenance of plasma cells in intestinal tissue and bone marrow. Moreover, eosinophils exert tissue damage through eosinophil-derived cytotoxic mediators that are involved in eosinophilic airway inflammation, leading to diseases including asthma and chronic rhinosinusitis with nasal polyps characterized by fibrin deposition through excessive response by eosinophils-induced. Thus, eosinophils possessing these various effects reflect the heterogenous features of these cells, which suggests the existence of distinct different subpopulations of eosinophils between steady-state and pathological conditions. Indeed, a recent study demonstrated that instead of dividing eosinophils by classical morphological changes into normodense and hypodense eosinophils, murine eosinophils from lung tissue can be phenotypically divided into two distinct subtypes: resident eosinophils and inducible eosinophils gated by Siglec-F CD62L CD101 and Siglec-F CD62L CD101, respectively. However, it is difficult to explain every function of eosinophils by rEos and iEos, and the relationship between the functions and subpopulations of eosinophils remains controversial. Here, we overview the multiple roles of eosinophils in the tissue and their biological behavior in steady-state and pathological conditions. We also discuss eosinophil subpopulations.
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http://dx.doi.org/10.1016/j.alit.2020.11.001DOI Listing
January 2021

Combination therapy with lenvatinib and radiation significantly inhibits thyroid cancer growth by uptake of tyrosine kinase inhibitor.

Exp Cell Res 2021 01 21;398(1):112390. Epub 2020 Nov 21.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan.

Although surgical treatment cures >90% of differentiated thyroid cancer (DTC) patients, the remaining patients, including advanced DTC cases, have poor clinical outcomes. These patients with inoperable disease have only two choices of radioactive iodine therapy and tyrosine kinase inhibitors such as lenvatinib, which have a high incidence of treatment-related adverse events and can only prolong progression free survival by approximately 5-15 months. In this study, we investigated the antitumor effects of combination therapy with lenvatinib and radiation (CTLR) for DTC. CTLR synergistically inhibited cell replication and colony formation in vitro and tumor growth in nude mice without apparent toxicities and suppressed the expression of proliferation marker (Ki-67). CTLR also induced apoptosis and G2/M phase cell cycle arrest. Moreover, quantitative analysis of the intracellular uptake of lenvatinib using liquid chromatography and mass spectrometry demonstrated that intracellular uptake of lenvatinib was significantly increased 48 h following irradiation. These data suggest that increased membrane permeability caused by irradiation increases the intracellular concentration of levatinib, contributing to the synergistic effect. This mechanism-based potential of combination therapy suggests a powerful new therapeutic strategy for advanced thyroid cancer with fewer side effects and might be a milestone for developing a regimen in clinical practice.
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http://dx.doi.org/10.1016/j.yexcr.2020.112390DOI Listing
January 2021

(o-Phenylenediamino)borylstannanes: Efficient Reagents for Borylation of Various Alkyl Radical Precursors.

Chemistry 2021 Feb 29;27(12):3968-3973. Epub 2020 Dec 29.

Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1, Yamadaoka, Suita, Osaka, 565-0871, Japan.

(o-Phenylenediamino)borylstannanes were newly synthesized to achieve radical boryl substitutions of a variety of alkyl radical precursors. Dehalogenative, deaminative, decharcogenative, and decarboxylative borylations proceeded in the presence of a radical initiator to give the corresponding organic boron compounds. Radical clock experiments and computational studies have provided insights into the mechanism of the homolytic substitution (S 2) of the borylstannanes with alkyl radical intermediates. DFT calculation disclosed that the phenylenediamino structure lowered the LUMO level including the vacant p-orbital on the boron atom to enhance the reactivity to alkyl radicals in S 2. Moreover, C(sp )-H borylation of THF was accomplished using the triplet state of xanthone.
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http://dx.doi.org/10.1002/chem.202004692DOI Listing
February 2021

Stent-assisted coil embolization for an unruptured vertebral artery-posterior inferior cerebellar artery aneurysm with retrograde access via type 1 persistent primitive proatlantal artery: A case report.

Interv Neuroradiol 2021 Jun 11;27(3):397-401. Epub 2020 Nov 11.

Department of Neurosurgery, Dokkyo Medical University Saitama Medical Center, Saitama, Japan.

Vertebral artery (VA)-posterior inferior cerebellar artery (PICA) aneurysms are rare lesions that are difficult to treat with both endovascular and surgical techniques. Tight angulation of the PICA from VA may make access to the PICA difficult from ipsilateral VA if adjunctive techniques are needed. Recently, the safety and efficacy of retrograde access have been reported. We report a case of endovascular treatment for a VA-PICA aneurysm with a stent-assisted technique using retrograde access via contralateral persistent primitive proatlantal artery (PPA).The patient was a 76-year-old woman with an unruptured VA-PICA aneurysm on the dominant VA side. Coil embolization with a stent-assisted technique using retrograde access seemed appropriate. However, the origin of the left VA was not confirmed. Left common carotid artery angiography demonstrated that the PPA (type 1) branching from external carotid artery joined the VA V4 segment.Retrograde access via the PPA for stenting was performed. A microcatheter for stenting was retrogradely advanced to the right PICA at ease. After deploying the stent, coil insertion was completed from the right VA, and the final angiogram showed adequate occlusion of the aneurysm with preservation of the PICA.Thus, PPA may be an approach route in the treatment of VA-PICA aneurysms with unconfirmed contralateral VA orifice and apparent PPA on angiography, when retrograde access is needed.
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http://dx.doi.org/10.1177/1591019920973848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190938PMC
June 2021

Predictors of Clopidogrel Hyper-Responsiveness in Neuro-Interventional Procedures.

J Stroke Cerebrovasc Dis 2021 Jan 9;30(1):105420. Epub 2020 Nov 9.

Department of Neurosurgery, Dokkyo Medical University Saitama Medical Center, Japan. Electronic address:

Background: Hyper-responsiveness to clopidogrel abnormally inhibits platelet aggregation and increases hemorrhagic complications. The present study investigated clinical factors related to clopidogrel hyper-responsiveness in neuro-interventional procedures.

Methods: Two hundred twenty-four patients receiving clopidogrel for coil embolization to treat unruptured cerebral aneurysm or carotid artery stenting to treat carotid artery stenosis at the internal carotid artery origin were retrospectively reviewed for their P2Y12 reactivity unit (PRU) values and clinical characteristics. Hyper-responsiveness to clopidogrel was defined as a PRU of <95.

Results: The mean PRU was 218.2 ± 77.8. Hyper-responsiveness to clopidogrel was observed in 12 patients (5.4%). Hyper-responsiveness was observed in younger patients, patients with a lower concentration of hemoglobin A1c, and patients with a higher low-density lipoprotein cholesterol (LDL-C) concentration compared with non-hyper-responsive patients (P = 0.01, P < 0.01, P < 0.01, respectively). On analysis of concomitant drugs, the patients in the hyper-responsive group were less frequently administered calcium channel blockers (CCBs) compared with the non-hyper-responsive group (P = 0.01). No significant differences in the usage of proton pump inhibitors or statins were observed. A LDL-C concentration of >120 mg/dL and no usage of CCBs were significant independent predictors of hyper-responsiveness to clopidogrel with a multivariate analysis (OR; 6.16, 95% CI, 1.57-26.64, P = 0.01, OR; 0.09, 95% CI, 0.01-0.82, P = 0.03, respectively).

Conclusion: The present study shows that a higher LDL-C concentration and no usage of CCBs are independent predictors of clopidogrel hyper-responsiveness. These results are useful to predict perioperative hemorrhagic complications. Considering dose reduction of clopidogrel or alternative drugs in high risk cases is necessary to prevent perioperative hemorrhagic complications.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105420DOI Listing
January 2021

Transvenous embolisation via an occluded inferior petrosal sinus for cavernous sinus dural arteriovenous fistulas.

Neurol Neurochir Pol 2020 7;54(6):585-588. Epub 2020 Oct 7.

Department of Neurosurgery, Dokkyo Medical University Saitama Medical Center, Japan.

Aim Of The Study: We retrospectively searched for cases of transvenous embolisation for cavernous sinus dural arteriovenous fistulas.

Materials And Methods: Twenty-five cases underwent transvenous embolisation via the inferior petrosal sinus (IPS). IPS was probed using a standard 0.035-inch guidewire for microcatheter navigation, which was successful in all cases.

Results: IPS was occluded in 17 cases (68%). Only one case experienced a complication, where the approach was changed to the contralateral side because of internal jugular vein injury. The relationship between the external auditory canal and the IPS route was reviewed in 18 cases using digital angiography (lateral view). The guidewire passed across, above, or below the external auditory canal in 10 (56%), six (33%), and two (11%) cases, respectively.

Clinical Implications: No previous reports have analysed the relationship between the external auditory canal and the IPS route. We present a safe and successful technique for approaching the cavernous sinus via the IPS.
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http://dx.doi.org/10.5603/PJNNS.a2020.0071DOI Listing
January 2021

Efficacy and safety of S-1 monotherapy in previously treated elderly patients (aged ≥75 years) with non-small cell lung cancer: A retrospective analysis.

Thorac Cancer 2020 10 26;11(10):2867-2876. Epub 2020 Aug 26.

Division of Respiratory Medicine, Gunma Prefectural Cancer Center, Ota, Japan.

Background: S-1 monotherapy is effective and feasible for previously treated patients with advanced non-small cell lung cancer (NSCLC). However, it is not clear whether its effectiveness and tolerability in elderly patients are equivalent to those in younger patients. Hence, this study aimed to evaluate the efficacy and feasibility of S-1 monotherapy in elderly patients with NSCLC who had previously received other treatments.

Methods: We included 96 elderly patients (aged ≥75 years) with advanced NSCLC treated with S-1 alone as a subsequent-line treatment at 12 medical facilities between January 2005 and March 2018 in this study. The baseline characteristics of the patients, response to S-1 monotherapy, and adverse events (AEs) were investigated, retrospectively.

Results: A total of 68 male and 28 female patients (median age, 78 [range: 75-86] years) were analyzed. In elderly patients who were treated with S-1 monotherapy as a subsequent-line treatment, the objective response rate, disease control rate, median progression-free survival (PFS), and overall survival (OS) were 8.3%, 43.8%, 3.4 months, and 9.6 months, respectively. Observed AEs included anorexia, anemia, nausea, fatigue, reduced platelet count, and skin hyperpigmentation. Treatment-related death was observed in one patient because of pneumonitis. In patients who experienced no progressive disease, subsequent-line S-1 alone was associated with longer PFS and OS.

Conclusions: S-1 monotherapy is effective and feasible as a subsequent-line treatment in elderly patients who were previously treated for NSCLC, and it produces results. S-1 monotherapy could be one of the treatment choices for elderly patients with previously treated NSCLC.
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http://dx.doi.org/10.1111/1759-7714.13622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529563PMC
October 2020

[Spontaneous Retroclival Subdural Hematoma Diagnosed Using Magnetic Resonance Imaging in an Adult Patient:A Case Report].

No Shinkei Geka 2020 Aug;48(8):725-731

Department of Neurosurgery, Dokkyo Medical University Saitama Medical Center.

Spontaneous retroclival subdural hematoma is rare among adults. To the best of our knowledge, only six cases have been reported. A 73-year-old man presented with sudden severe headache, diplopia, and dysarthria, with no history of trauma. Head CT revealed a retrociliary hematoma. No obvious causes of bleeding, such as cerebral aneurysms or malformations, were detected. Conservative treatment was provided to the patient. MRI showed an intraventricular hemorrhage and a space between the basilar artery and hematoma three days after onset. The hematoma almost disappeared on day 7. MRI, particularly T2-weighted sagittal MRI, is effective in localizing hematomas and confirming intraventricular hemorrhages.
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http://dx.doi.org/10.11477/mf.1436204261DOI Listing
August 2020

High HMGA2 expression without gene rearrangement in meningiomas.

Neuropathology 2020 Dec 18;40(6):540-545. Epub 2020 Aug 18.

Department of Neurosurgery, Dokkyo Medical University Saitama Medical Center, Koshigaya-shi, Saitama, Japan.

High mobility group AT-hook 2 (HMGA2) is a non-histone transcriptional regulator protein. Aberrant expression of the HMGA2 gene (HMGA2) and structural rearrangement at the chromosomal region 12q14 with HMGA2 involvement have been reported in several mesenchymal tumors. We analyzed truncated and full-length HMGA2 expression in 55 cases of meningioma, the most common brain tumor of mesenchymal origin. Fluorescence in situ hybridization and 3'-rapid amplification of cDNA ends were used to investigate the possibility of gene rearrangements. Moreover, the relationship between HMGA2 expression and clinicopathological features was assessed. Compared with normal brain tissues, 95% of the meningioma tissues exhibited increased HMGA2 expression. In 14 cases, the expression of truncated HMGA2 was more than two-fold higher than that of paired full-length HMGA2. Chromosomal translocation involving the chromosomal region 12q14 was undetectable. No significant correlation was found between the Ki-67 labeling index and HMGA2 expression and between the HMGA2 expression and the clinicopathological features. The majority of the meningioma cases displayed increased HMGA2 expression, which was not attributed to the chromosomal rearrangement at the corresponding region. Similar to that in the other mesenchymal tumors, increased HMGA2 expression was not associated with tumor cell proliferation in meningiomas.
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http://dx.doi.org/10.1111/neup.12670DOI Listing
December 2020

Antioxidant nanomedicine with cytoplasmic distribution in neuronal cells shows superior neurovascular protection properties.

Brain Res 2020 09 3;1743:146922. Epub 2020 Jun 3.

Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki, Japan; Department of Neurosurgery, Graduate School of Comprehensive Human Science, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki, Japan.

This study investigated whether nitroxide radical (4-amino-TEMPOL)-containing nanoparticles (RNPs; antioxidant nanomedicine) can prevent neurovascular unit impairment caused by reactive oxygen species (ROS) after cerebral ischemia-reperfusion. C57BL/6J mice underwent transient middle cerebral artery occlusion (tMCAO). The mice were randomly divided and administered intra-arterial RNPs injection (9 mg/kg, 7 μM/kg), edaravone (3 mg/kg, 17 μM/kg), or phosphate-buffered saline (control group). Survival rate and neurological score were evaluated 24 h post-injection. RNPs distribution was determined using immunofluorescence staining and blood-brain barrier (BBB) disruption using Evans blue extravasation assay. Effect of RNPs and edaravone on microglia polarization into microglia M1 and M2 was evaluated. We also determined multiple ROS-scavenging activities in brain homogenates of RNPs- and edaravone-treated animals using an electron spin resonance-based spin-trapping method. Compared with edaravone, RNPs significantly improved the survival rate and neurological deficit, inhibited BBB disruption and supported polarization of microglia into M2 microglia. RNPs were localized in endothelial cells, the perivascular space, neuronal cell cytoplasm, astrocytes, and microglia. Scavenging capacities of hydroxyl, alkoxyl, and peroxyl radicals were significantly higher in the RNPs-treated group. RNPs show promising results as a future neuroprotective nanomedicine approach for cerebral ischemia-reperfusion injury.
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http://dx.doi.org/10.1016/j.brainres.2020.146922DOI Listing
September 2020

Efficacy and safety of immune checkpoint inhibitor monotherapy in pretreated elderly patients with non-small cell lung cancer.

Cancer Chemother Pharmacol 2020 04 19;85(4):761-771. Epub 2020 Mar 19.

Department of Respiratory Medicine, Comprehensive Cancer Center, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.

Purpose: Immune checkpoint inhibitors (ICIs) are an effective subsequent-line treatment for patients with advanced non-small cell lung cancer (NSCLC). However, it remains unclear whether the efficacy and safety of subsequent-line ICI monotherapy in elderly patients (aged ≥ 75 years) are similar to that in non-elderly patients. Therefore, we aimed to investigate the efficacy and safety of ICI monotherapy in pretreated elderly patients with NSCLC.

Methods: Between January 2016 and February 2018, 131 elderly patients with advanced NSCLC who received subsequent-line ICI monotherapy at 13 Japanese institutions were enrolled in this study. Baseline characteristics, the efficacy of ICI treatment, and adverse events were evaluated.

Results: Ninety-eight men and 33 women (median age 77 [range 75-87] years) were enrolled. Among those who received subsequent-line ICI monotherapy, the overall response, disease control rates, median progression-free survival (PFS), and overall survival (OS) were 27.4%, 61.8%, 4.5 months, and 16.0 months, respectively. Adverse events such as anorexia, fatigue, pneumonitis, and hypothyroidism were observed. There were two treatment-related deaths due to pneumonitis and thrombocytopenia. Subsequent-line ICI monotherapy in patients with good performance status (PS), receiving steroids for immune-related adverse events (irAEs), and exhibiting partial response (PR) was associated with improved PFS, as well as OS in patients with good PS and PR.

Conclusions: Subsequent-line ICI monotherapy in elderly patients, with previously treated NSCLC, was effective, safe and showed outcomes equivalent to those in non-elderly patients. Immunotherapy provides a survival benefit for elderly patients, who exhibit its efficacy and a favorable general condition.
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http://dx.doi.org/10.1007/s00280-020-04055-7DOI Listing
April 2020

Reduced Local Response to Corticosteroids in Eosinophilic Chronic Rhinosinusitis with Asthma.

Biomolecules 2020 02 18;10(2). Epub 2020 Feb 18.

Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Hirakata, Osaka 573-1010, Japan.

Eosinophilic chronic rhinosinusitis (ECRS), a subgroup of chronic rhinosinusitis with nasal polyps, is recognized as a refractory eosinophilic disorder characterized by both upper and lower airway inflammation. In some severe cases, disease control is poor, likely due to local steroid insensitivity. In this study, we focused on protein phosphatase 2A (PP2A), a key factor regulating glucocorticoid receptor (GR) nuclear translocation, and examined its association with local responses to corticosteroids in eosinophilic airway inflammation. Our results indicated reduced responses to corticosteroids in nasal epithelial cells from ECRS patients with asthma, which were also associated with decreased PP2A mRNA expression. Eosinophil peroxidase stimulates elevated PP2A phosphorylation levels, reducing PP2A protein expression and activity. In addition, mRNA levels of inflammatory mediators (TSLP, IL-25, IL-33, CCL4, CCL5, CCL11, and CCL26) associated with eosinophilic airway inflammation in epithelial cells were increased in nasal polyps (eosinophil-rich areas) compared with those in uncinate process tissues (eosinophil-poor areas) from the same patients. PP2A reduction by siRNA reduced GR nuclear translocation, whereas PP2A overexpression by plasmid transfection, or PP2A activation by formoterol, enhanced GR nuclear translocation. Collectively, our findings indicate that PP2A may represent a promising therapeutic target in refractory eosinophilic airway inflammation characterized by local steroid insensitivity.
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http://dx.doi.org/10.3390/biom10020326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072408PMC
February 2020

ASK1 promotes uterine inflammation leading to pathological preterm birth.

Sci Rep 2020 02 5;10(1):1887. Epub 2020 Feb 5.

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

It is widely accepted that enhanced uterine inflammation associated with microbial infection is a main causative factor for preterm birth. However, little is known about the molecular basis by which inflammation is associated with preterm birth. Here, we demonstrate that apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein 3-kinase family, facilitates inflammation-induced preterm birth and that inhibition of ASK1 activity is sufficient to suppress preterm birth. ASK1-deficient pregnant mice exhibited reduced incidence of lipopolysaccharide (LPS)-induced preterm birth. ASK1 was required for the induction of LPS-induced inflammatory responses related to preterm birth, including pro-inflammatory cytokine production in the uterus and peritoneal cavities. In addition, selective suppression of uterine ASK1 activity through a chemical genetic approach reduced the incidence of LPS-induced preterm birth. Moreover, translational studies with human choriodecidua demonstrated that ASK1 was required for LPS-induced activation of JNK and p38 and pro-inflammatory cytokine production. Our findings suggest that ASK1 activation is responsible for the induction of inflammation that leads to preterm birth and that the blockade of ASK1 signaling might be a promising therapeutic target for preventing preterm birth.
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http://dx.doi.org/10.1038/s41598-020-58653-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002619PMC
February 2020

Rare clinical presentations of pleomorphic xanthoastrocytoma with a high proliferative index: Two case reports.

Medicine (Baltimore) 2020 Jan;99(3):e18880

Introduction: Pleomorphic xanthoastrocytomas (PXA) are rare, typically benign, slow-growing tumors that commonly occur in the cerebral hemispheres. We describe two cases of clinically aggressive PXA with uncommon locations; one was in the tectal plate, and the other had simultaneous multicentric lesions.

Patient Concerns: The both cases presented with severe headache with no significant past medical history.

Diagnosis: PXA World Health Organization grade II were histopathologically diagnosed from surgically resected specimens, and immunohistochemical and sequence analysis revealed a high Ki-67 proliferative index and BRAF V600E mutation in both the cases.

Interventions: The first case presented with multicentric lesions and underwent partial resection, whereas the second case presented with a tectal plate tumor that was managed by gross total surgical resection. Strong 5-aminolevulinic acid (5-ALA)-induced fluorescence was observed in both the lesions. Postoperative radiotherapy plus concomitant and adjuvant temozolomide was administered to both the patients.

Outcomes: Despite completing adjuvant chemo-radiotherapy, both the patients had local tumor recurrence at 2 and 5 months after the operation, respectively.

Conclusion: The progressive clinical courses in our cases suggest that additional postoperative therapy should be considered during the treatment of PXA with a high Ki67 index, and that temozolomide with radiotherapy, followed by temozolomide maintenance therapy, may not prevent recurrence in such tumors. Importantly, our experience implies that unlike other subtypes of low grade gliomas, 5-ALA fluorescence is useful for intraoperative visualization of PXA.
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http://dx.doi.org/10.1097/MD.0000000000018880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220053PMC
January 2020

Increased CD69 expression on activated eosinophils in eosinophilic chronic rhinosinusitis correlates with clinical findings.

Allergol Int 2020 Apr 10;69(2):232-238. Epub 2020 Jan 10.

Department of Otorhinolaryngology, Head & Neck Surgery, Kansai Medical University, Osaka, Japan.

Background: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis associated with asthma. CD69 is an important marker of activation for eosinophils. But, whether a correlation exist between the CD69 expression on eosinophils and clinical findings is unclear.

Methods: We performed quantitative PCR and/or flow cytometry using tissue and purified eosinophils from the blood and nasal polyps of 12 patients with ECRS and from 8 patients without ECRS (controls). We assessed clinical findings including nasal polyp (NP) scores, sinus CT findings, and pulmonary function test results, and examined their possible association with the CD69 expression. We also performed CD69 cross-linking experiments in mouse eosinophils to investigate the functional role of CD69.

Results: Levels of cytokine mRNAs (IL-4, -5, -10, and -13) were significantly higher in purified NP eosinophils and tissues from patients with ECRS than the levels of those in controls. The expressions of major basic protein (MBP), eosinophilic cationic protein (ECP), eosinophilic-derived neurotoxin (EDN), eosinophil peroxidase (EPX) in cytotoxic granules, and CD69 mRNA were significantly higher in purified eosinophils from NPs than in those from blood. We also found a correlation between expression of CD69 and clinical findings. Moreover, we found EPX release from mouse eosinophils following CD69 cross-linking.

Conclusions: These data suggest that increased CD69 expression by eosinophils is not only a biomarker for nasal obstruction and pulmonary dysfunction, but also a potential therapeutic target for patients with ECRS and asthma.
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http://dx.doi.org/10.1016/j.alit.2019.11.002DOI Listing
April 2020

Multiple Biological Aspects of Eosinophils in Host Defense, Eosinophil-Associated Diseases, Immunoregulation, and Homeostasis: Is Their Role Beneficial, Detrimental, Regulator, or Bystander?

Biol Pharm Bull 2020 ;43(1):20-30

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University.

Eosinophils are innate immune leukocytes and play important roles as terminal effector cells owing to their mediators, such as tissue-destructive cationic proteins, cytokines, chemokines, and lipid mediators. Historically, they are not only considered an important player in host defense against parasitic, viral, fungal, and bacterial infections but also implicated in the pathogenesis of eosinophil-associated diseases, such as allergic rhinitis, asthma, eosinophilic chronic rhinosinusitis, esophagitis, atopic dermatitis, myopathies, and hypereosinophilic syndrome. Moreover, recent studies have shown that eosinophils have an immune regulatory and homeostatic function. Interestingly, there is emerging evidence that eosinophils are accumulated through adoptive T-helper 2 (Th2) and innate Th2 responses, mechanisms of the classical allergen-specific immunoglobulin E (IgE)-mediated response, and group 2 innate lymphoid cell-derived interleukin-5, respectively. Furthermore, in agreement with current concepts of eosinophil subtypes, it has been shown that resident and phenotypically distinct eosinophils, i.e., resident and recruited inflammatory eosinophils, exist in inflamed sites, and each has different functions. Thus, the classical and novel studies suggest that eosinophils have multiple functions, and their roles may be altered by the environment. In this article, we review multiple biological aspects of eosinophils (novel and classical roles), including their beneficial and detrimental effects, immunoregulation, and homeostatic function.
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http://dx.doi.org/10.1248/bpb.b19-00892DOI Listing
November 2020

Increased Twist and ZEB2 expression in a cutaneous metastasis of high-grade glioma.

Neuropathology 2020 Apr 21;40(2):196-201. Epub 2019 Dec 21.

Department of Neurosurgery, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan.

Extra-central nervous system metastasis of gliomas is extremely rare, and the biological mechanism underlying it remains poorly understood. Epithelial-to-mesenchymal transition (EMT) has received attention as one of the important processes of cancer metastasis. Here we describe the case of a 32-year-old man with cutaneous metastasis of high-grade glioma, together with the analysis of EMT-related molecules. Our patient presented with a high-grade glioma in the right frontal lobe. Cutaneous metastasis under the surgical scar developed 17 months after complete resection of the intracranial tumor. Histopathology of both the original and metastatic tumors revealed hypercellularity; the tumors predominantly comprised glial tumor cells with poor cellular processes. Immunohistochemical analysis demonstrated intense expression of nestin, focal expression of glial fibrillary acid protein, and absence of expression of oligodendrocyte transcription factor 2, endothelial membrane antigen, or neurofilament. Genetic analyses could not provide definitive diagnostic information of glioma subtypes. Immunohistochemical analysis for EMT-related biomarkers demonstrated increased Twist, zinc finger E-box-binding homeobox 2 (ZEB2), matrix metalloproteinase 2 (MMP2), and MMP9 expressions in tumor cells of the metastatic lesion compared with those of the primary lesion. Slug, E-cadherin, and N-cadherin expression were absent in both primary and metastatic lesions; however, ZEB1 expression was present in both. Our results suggest that Twist, ZEB2, MMP2, and MMP9 facilitate cutaneous metastasis of gliomas.
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http://dx.doi.org/10.1111/neup.12621DOI Listing
April 2020