Publications by authors named "Yu Matsumoto"

94 Publications

Vascular Bursts Act as a Versatile Tumor Vessel Permeation Route for Blood-Borne Particles and Cells.

Small 2021 Sep 15:e2103751. Epub 2021 Sep 15.

Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Dynamic bursting in tumor vasculature has recently sparked interest as a novel particle transportation route for drug delivery. These bursts facilitate the transport of sub-100 nm nanoparticles into tumors, though their contribution on the access of other blood-borne particles remains unknown. To evaluate the versatility of this phenomenon, the in vivo kinetics of a variety of intravenously injected particles and their penetration in tumor xenografts and allografts are compared. Dextran, polymeric micelles, liposomes, and polymeric vesicles with diameters ranging from 32 to 302 nm are found to colocalize in virtually all vascular bursts. By mathematical modeling, the burst vent size is estimated to be 625 nm or larger, indicating the dynamic and stochastic formation of large permeation routes in tumor vasculature. Furthermore, some burst vents are found to be µm-sized, allowing the transport of 1 µm microspheres. Moreover, antibody drugs and platelets are capable of utilizing vascular burst transportation, demonstrating the application of this phenomenon to other types of therapeutics and cellular components. These findings indicate the vast potential of vascular bursts, extending the biological and therapeutic significance of this phenomenon to a wide range of blood-borne particles and cells.
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http://dx.doi.org/10.1002/smll.202103751DOI Listing
September 2021

Smoldering adult T-cell leukemia complicated with pneumocystis pneumonia: A case report.

Respir Med Case Rep 2021 28;33:101404. Epub 2021 Mar 28.

Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.

Adult T-cell leukemia (ATL) is a tumor of CD4-positive T cells that accompanies an infection by human T-cell lymphotropic virus (HTLV-I). ATL is classified into four types-acute, lymphomatous, chronic, and smoldering. Opportunistic infections are known to occur in patients with acute or lymphomatous type ATL; however, whether patients with chronic or smoldering ATL also have a high risk of opportunistic infections is not yet known. Herein, we report a case of pneumocystis pneumonia in a patient with smoldering ATL. He was a 64-year-old man with primary complaints of cough and dyspnea on exertion. A chest radiograph showed infiltration shadows in the left lung field. He was prescribed antibiotics for pneumonia; however, his symptoms worsened, and he developed hypoxemia. White-blood cell count was 13000/μL, and 7% of atypical lymphocytes were found in the smears of peripheral blood cells. His serum β-D glucan concentration was increased to 85.9 pg/mL, and his serum tested positive for anti-HTLV-1 antibody. Chest-computed tomography revealed diffuse ground-glass opacities in the bilateral lung fields. Pneumocystis-polymerase chain reaction performed on bronchoalveolar lavage fluid confirmed pneumocystis, but atypical lymphocytes were not detected via transbronchial lung biopsy. Therefore, he was diagnosed with pneumocystis pneumonia associated with smoldering ATL. Sulfamethoxazole-trimethoprim and corticosteroid therapies were administered to treat the pneumocystis pneumonia, and his symptoms and lung shadows improved rapidly. Thus, opportunistic infections, including pneumocystis pneumonia, may be caused by smoldering ATL. In the case of atypical lymphocyte detection in peripheral-blood smears, clinicians should consider the possibility of ATL.
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http://dx.doi.org/10.1016/j.rmcr.2021.101404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348172PMC
March 2021

A Case of Pulmonary Alveolar Proteinosis with Severe Respiratory Failure Improved by Segmental Lung Lavage with Fiberoptic Bronchoscopy under General Anesthesia.

Intern Med 2021 Aug 6. Epub 2021 Aug 6.

Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan.

Pulmonary alveolar proteinosis (PAP) is a rare disorder in which lipoproteinaceous materials accumulate in the alveolar compartments. A 72-year-old man was diagnosed with autoimmune PAP with severe respiratory failure. We decided to perform segmental lung lavage (SLL) with fiberoptic bronchoscopy under general anesthesia. If improvement was not significant, whole-lung lavage (WLL) would be done. SLL improved the respiratory failure and computed tomography findings. This case showed improvement in not only the area where lavage was done but also the non-lavaged area. SLL with fiberoptic bronchoscopy under general anesthesia might be an appropriate treatment option for patients with severe PAP.
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http://dx.doi.org/10.2169/internalmedicine.7432-21DOI Listing
August 2021

Anesthesia and surgery induce a functional decrease in excitatory synaptic transmission in prefrontal cortex neurons, and intraoperative administration of dexmedetomidine does not elicit the synaptic dysfunction.

Biochem Biophys Res Commun 2021 Oct 29;572:27-34. Epub 2021 Jul 29.

Department of Neurophysiology, Hyogo College of Medicine, Nishinomiya, Japan. Electronic address:

Postoperative delirium (POD), a syndrome of confusion and inattention, frequently occurs after anesthesia and surgery. The prefrontal cortex (PFC) plays key roles in executive functions and cognitive controls. However, the neuropathogenesis of POD in the PFC remains largely unknown. We investigated whether anesthesia and surgery induced neurofunctional changes in the mouse PFC. After laparotomy was performed under isoflurane anesthesia, PFC neuronal activities were compared at the synaptic level using whole-cell patch-clamp recordings. A battery of behavioral tests measuring natural and learned behaviors, and effects of intraoperative dexmedetomidine were also examined. In the anesthesia/surgery group showing changes in natural and learned behaviors, the frequency of excitatory synaptic responses in PFC pyramidal neurons was decreased after the surgery without any changes in the response kinetics. On the other hand, neuronal intrinsic properties and inhibitory synaptic responses were not changed. In the anesthesia/surgery group administered intraoperative dexmedetomidine, the excitatory synaptic transmission and the behaviors were not altered. These results suggest that anesthesia and surgery induce a functional reduction selectively in the PFC excitatory synaptic transmission, and intraoperative dexmedetomidine inhibits the plastic change in the PFC excitatory synaptic input.
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http://dx.doi.org/10.1016/j.bbrc.2021.07.065DOI Listing
October 2021

Brown Rice Inhibits Development of Nonalcoholic Fatty Liver Disease in Obese Zucker (fa/fa) Rats by Increasing Lipid Oxidation Via Activation of Retinoic Acid Synthesis.

J Nutr 2021 Sep;151(9):2705-2713

Department of Agricultural Chemistry, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan.

Background: White rice and its unrefined form, brown rice, contain numerous compounds that are beneficial to human health. However, the starch content of rice can contribute to obesity, a main risk factor for nonalcoholic fatty liver disease (NAFLD).

Objectives: We investigated the effect of rice consumption on NAFLD and its underlying molecular mechanism.

Methods: We randomly divided 7-week-old male obese Zucker (fa/fa) rats, an animal model of NAFLD, into 3 groups (n = 10 each) fed 1 of 3 diets for 10 weeks: a control diet (Cont; AIN-93G diet; 53% cornstarch), a white rice diet (WR; AIN-93G diet with cornstarch replaced with white rice powder), or a brown rice diet (BR; AIN-93G diet with cornstarch replaced with brown rice powder). Liver fat accumulation and gene expression related to lipid and vitamin A metabolisms, including retinoic acid (RA) signaling, were analyzed.

Results: Hepatic lipid values were significantly decreased in the BR group compared with the Cont group, by 0.4-fold (P < 0.05). The expression of genes related to hepatic fatty acid oxidation, such as carnitine palmitoyltransferase 2, was approximately 2.1-fold higher in the BR group than the Cont group (P < 0.05). The expression of peroxisomal acyl-coenzyme A oxidase 1 and acyl-CoA dehydrogenase medium chain was also significantly increased, by 1.6-fold, in the BR group compared with the Cont group (P < 0.05). The expression of VLDL-secretion-related genes, such as microsomal triglyceride transfer protein, was also significantly higher in the BR group (2.4-fold; P < 0.05). Furthermore, aldehyde dehydrogenase 1 family member A1, an RA synthase gene, was 2-fold higher in the BR group than the Cont group (P < 0.05).

Conclusions: Brown rice prevented development of NAFLD in obese Zucker (fa/fa) rats. The beneficial effects of pregelatinized rice on NAFLD could be manifested as increased fatty acid oxidation and VLDL secretion, which are regulated by RA signaling.
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http://dx.doi.org/10.1093/jn/nxab188DOI Listing
September 2021

MIG12 is involved in the LXR activation-mediated induction of the polymerization of mammalian acetyl-CoA carboxylase.

Biochem Biophys Res Commun 2021 Aug 19;567:138-142. Epub 2021 Jun 19.

Department of Agricultural Chemistry, Faculty of Applied Biosciences, Tokyo University of Agriculture, Tokyo, Japan. Electronic address:

Liver X receptors (LXR) α and β are a family of nuclear receptors that regulate lipogenesis by controlling the expression of the genes involved in the synthesis of fatty acids. MID1IP1, which encodes MIG12, is a target gene of LXR. MIG12 induces fatty acid synthesis by stimulating the polymerization-mediated activation of acetyl-CoA carboxylase (ACC). Here, we show that LXR's activation stimulates ACC polymerization in HepG2 cells by increasing the expression of MIG12. A knockdown of MID1IP1 abrogated the stimulation completely. The mutations of MIG12's leucine-zipper domain reduced the interaction between MIG12 and ACC, thus decreasing the MIG12's capacity to stimulate ACC polymerization. These results indicate that LXR's activation stimulates lipogenesis not only through the induction of the genes encoding lipogenic enzymes but also through MIG12's stimulation of ACC polymerization.
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http://dx.doi.org/10.1016/j.bbrc.2021.06.040DOI Listing
August 2021

Alteration of Vestibular Function in Pediatric Cochlear Implant Recipients.

Front Neurol 2021 28;12:661302. Epub 2021 May 28.

Department of Otolaryngology and Head and Neck Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Vestibular dysfunction is a complication of cochlear implantation (CI). Reports on the evaluation of vestibular function before and after CI are limited, especially in children. We investigated the effect of CI on vestibular function in pediatric patients. We routinely evaluated vestibular function before but not immediately after CI. Therefore, patients who underwent sequential bilateral CI were enrolled in this study. Seventy-three children who underwent sequential CI from 2003 to 2020 at our hospital were included. Since the vestibular function of the first implanted ear was evaluated before the second surgery for the contralateral ear, post-CI evaluation timing differed among the cases. The evaluation included a caloric test, a cervical vestibular-evoked myogenic potential (cVEMP) test, and a damped rotation test. The objective variables included the results of these tests, and the explanatory variables included the age at surgery, cause of hearing loss, electrode type, and surgical approach used. The associations of these tests were analyzed. cVEMP was the most affected after CI (36.1%), followed by the caloric test (23.6%), and damped rotation test (7.8%). Cochleostomy was significantly more harmful than a round window (RW) approach or an extended RW approach based on the results of the caloric test ( = 0.035) and damped rotation test ( = 0.029). Perimodiolar electrodes affected the caloric test results greater than straight electrodes ( = 0.041). There were no significant associations among these tests' results. Minimally invasive surgery in children using a round window approach or an extended round window approach with straight electrodes is desirable to preserve vestibular function after CI.
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http://dx.doi.org/10.3389/fneur.2021.661302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193854PMC
May 2021

Intraoperative guidance using ICG fluorescence imaging system for safe and precise laparoscopic liver resection.

Minerva Surg 2021 Jun 23;76(3):211-219. Epub 2021 Apr 23.

Division of General and Gastroenterological Surgery (Omori), Department of Surgery, Toho University Faculty of Medicine, Tokyo, Japan.

Background: Laparoscopic liver resection (LLR) has been spread as minimally invasive surgery for liver disease. Advances in surgical technique and devices enabled us to perform various procedures of LLR. Indocyanine green (ICG) fluorescence imaging has been suggested as useful tool to identify liver tumors, anatomical territory of liver parenchyma, and cholangiography in open liver surgery. Due to recent development, this technology can be applied in LLR. we describe safe and effective using of the ICG fluorescence imaging during LLR.

Methods: From September 2013 to August 2019, 34 patients were performed LLR using a total of 46 procedures by ICG fluorescence imaging system for purposes including identification of anatomic domain of the liver in 12 LLRs, detection of liver tumors in 30 nodules, or intraoperative cholangiography in 4 LLRs.

Results: During the detection of liver tumors, 25 nodules in 30 malignant to benign tumors were positively detected (83.3%). Although there has been no publication regarding information on ICG fluorescence imaging of low grade malignant or benign tumors, we found positive emission in focal nodular hyperplasia, an angiomyolipoma, and an intraductal papillary neoplasm of the bile duct. The identification of anatomic domain in the liver was successful in all 12 LLRs with negative and positive staining techniques. In the intraoperative cholangiography, all 4 tests were successfully performed. One of 4 patients were found to have biliary leakage which was repaired intraoperatively.

Conclusions: The ICG fluorescence imaging could be useful in safe and precise performance of LLR.
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http://dx.doi.org/10.23736/S2724-5691.21.08597-7DOI Listing
June 2021

Efficacy of pH-Sensitive Nanomedicines in Tumors with Different c-MYC Expression Depends on the Intratumoral Activation Profile.

ACS Nano 2021 03 24;15(3):5545-5559. Epub 2021 Feb 24.

Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.

Effective inhibition of the protein derived from cellular myelocytomatosis oncogene (c-Myc) is one of the most sought-after goals in cancer therapy. While several c-Myc inhibitors have demonstrated therapeutic potential, inhibiting c-Myc has proven challenging, since c-Myc is essential for normal tissues and tumors may present heterogeneous c-Myc levels demanding contrasting therapeutic strategies. Herein, we developed tumor-targeted nanomedicines capable of treating both tumors with high and low c-Myc levels by adjusting their ability to spatiotemporally control drug action. These nanomedicines loaded homologues of the bromodomain and extraterminal (BET) motif inhibitor JQ1 as epigenetic c-Myc inhibitors through pH-cleavable bonds engineered for fast or slow drug release at intratumoral pH. In tumors with high c-Myc expression, the fast-releasing (FR) nanomedicines suppressed tumor growth more effectively than the slow-releasing (SR) ones, whereas, in the low c-Myc tumors, the efficacy of the nanomedicines was the opposite. By studying the tumor distribution and intratumoral activation of the nanomedicines, we found that, despite SR nanomedicines achieved higher accumulation than the FR counterparts in both c-Myc high and low tumors, the antitumor activity profiles corresponded with the availability of activated drugs inside the tumors. These results indicate the potential of engineered nanomedicines for c-Myc inhibition and spur the idea of precision pH-sensitive nanomedicine based on cancer biomarker levels.
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http://dx.doi.org/10.1021/acsnano.1c00364DOI Listing
March 2021

D-dimer can be a diagnostic marker for cisplatin-related aortic thrombosis: A case report.

Medicine (Baltimore) 2021 Feb;100(7):e24695

Department of Respiratory Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan.

Rationale: Cisplatin is one of the key drugs that is frequently used for treating various types of malignancies. Although renal and digestive toxicities are well-known cisplatin-related toxicities, attention should also be paid to acute aortic thrombosis, a relatively rare but potentially fatal disorder caused by cisplatin. Additionally, D-dimer is mainly measured to detect venous thromboembolism or disseminated intravascular coagulation, whereas its usefulness for detecting aortic thrombosis remains unclear. Here, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein acute aortic thrombosis was diagnosed based on elevated D-dimer levels.

Patient Concerns: A 65-year-old man with stage IV squamous cell lung cancer presented with elevated D-dimer levels during treatment with second-line chemotherapy with cisplatin and S-1. Contrast-enhanced computed tomography (CT) revealed an intramural thrombus, which had not been previously identified, extending from the abdominal aorta to the common iliac artery.

Diagnoses: We diagnosed the patient as having acute aortic thrombosis caused by cisplatin.

Interventions: The patient received intravenous administration of unfractionated heparin for 9 days followed by oral warfarin.

Outcomes: One month after initiating treatment, the patient's D-dimer levels decreased to the normal range, and contrast-enhanced CT revealed that the thrombi had nearly completely disappeared without any sequelae or organ damage.

Lessons: Our findings revealed that cisplatin can cause acute aortic thrombosis and that regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.
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http://dx.doi.org/10.1097/MD.0000000000024695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899838PMC
February 2021

Methionine controls insulin/mammalian target of rapamycin complex 1 activity by modulating tuberous sclerosis complex 2 stability.

Biochem Biophys Res Commun 2021 02 20;541:84-89. Epub 2021 Jan 20.

Department of Agricultural Chemistry, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo, 156-8502, Japan. Electronic address:

Tuberous sclerosis complex 2 (TSC2) is a tumor-suppressor protein that is partially regulated by insulin, energy, oxygen, and growth factors. Mutations in the TSC2 gene and loss of TSC2 promote cell growth by the mammalian target of rapamycin complex 1 (mTORC1) activation. Furthermore, S-adenosylmethionine (SAM) sensor upstream of mTORC1 indirectly inhibits mTORC1 activity via the methionine metabolite SAM. Here, we investigated the effects of methionine on insulin/TSC2/mTORC1 activity. Our results showed that methionine affected TSC2 stability and abolished TSC2 localization to the lysosome. Moreover, activation of insulin signaling contributed to TSC2 degradation in a methionine deprivation-dependent manner. Thus, methionine and insulin crosstalk occurred via TSC2.
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http://dx.doi.org/10.1016/j.bbrc.2021.01.033DOI Listing
February 2021

Manipulating dynamic tumor vessel permeability to enhance polymeric micelle accumulation.

J Control Release 2021 01 2;329:63-75. Epub 2020 Dec 2.

Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Selectively delivering anticancer drugs to solid tumors while avoiding their accumulation in healthy tissues is a major goal in polymeric micelle research. We have recently discovered that the extravasation and permeation of polymeric micelles occur in a dynamic manner characterized by vascular bursts followed by a brief and vigorous outward flow of fluid (called "nano-eruptions"). Nano-eruptions allow delivery of polymeric micelle-associated drugs, though delivery can be heterogeneous both among tumors and within an individual tumor, leading to suboptimal intratumoral distribution. Manipulation of nano-eruptions is expected to improve the efficiency of drug delivery systems (DDSs). By using compounds that affect the intratumoral environment, i.e. a TGF-β inhibitor and chloroquine, the possibility of manipulating nano-eruptions to improve delivery efficiency was investigated. Both compounds were tested in a mouse xenograft model of GFP-labeled pancreatic tumor cells by tracing nano-eruption events and extravasation of size-modulated polymeric micelles in real-time through intravital confocal laser scanning microscopy. The TGF-β inhibitor increased the number of dynamic vents, extended duration time, and generated dynamic vents with a wide range of sizes. Chloroquine did not affect the frequency of nano-eruptions, but it increased tumor vessel diameter, maximum nano-eruption area, and maximum radial increase. Both the TGF-β inhibitor and chloroquine augmented nano-eruptions to diffuse polymeric micelles through tumor stroma, and these medications had a greater effect on the polymeric micelles with larger size, i.e. 70-nm, than on the smaller polymeric micelles having a 30-nm diameter. The results indicate that TGF-β inhibition and chloroquine refashion the intratumoral distribution of DDSs by different mechanisms.
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http://dx.doi.org/10.1016/j.jconrel.2020.11.063DOI Listing
January 2021

Stability of tuberous sclerosis complex 2 is controlled by methylation at R1457 and R1459.

Sci Rep 2020 12 3;10(1):21160. Epub 2020 Dec 3.

Laboratory of Nutritional Biochemistry, Department of Agricultural Chemistry, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo, 156-8502, Japan.

Mutations in genes that encode components of tuberous sclerosis complex 2 (TSC2) are associated with tuberous sclerosis complex disease. TSC2 interacts with tuberous sclerosis complex 1 to form a complex that negatively regulates cell growth and proliferation via the inactivation of mechanistic target of rapamycin complex 1. The activity of TSC2 is mainly regulated via posttranslational modifications such as phosphorylation. However, the control of TSC2 activity is not entirely achieved by phosphorylation. In this study, we show that TSC2 is methylated at R1457 and R1459 by protein arginine methyltransferase 1 (PRMT1). Methylation of these two residues can affect the phosphorylation status through protein kinase B (Akt) of TSC2 at T1462 and is essential for TSC2 stability. Taken together, these findings indicate that novel posttranslational modifications are important for the regulation of TSC2 stability through PRMT1-mediated methylation.
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http://dx.doi.org/10.1038/s41598-020-78274-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713242PMC
December 2020

Classification of the Chorda Tympani: An Endoscopic Study.

Otol Neurotol 2021 03;42(3):e355-e362

Department of Otolaryngology and Head and Neck Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Objectives: To determine the ability of preoperative computed tomography (CT) to predict the variable surgical anatomy of the chorda tympani nerve (CTN) based on endoscopic tympanotomy.

Study Design: Retrospective case review.

Setting: Tertiary referral center.

Patients: We identified 192 ears of 162 patients who underwent transcanal endoscopic ear surgery from August 2013 to June 2018. Patients with middle ear malformations, revision surgeries, myringoplasty, and cholesteatoma involving the CTN were excluded.

Interventions: An intraoperative endoscopic image depicting the chorda tympani was selected for each patient and classified into one of five types. Preoperative CT images were analyzed to match the pictorial classification.

Main Outcome Measures: The visible tympanic segment of the chorda tympani was classified into the following five types: external auditory canal (EAC), detached, attached long, attached short, and ultrashort.

Results: A total of 128 ears from 101 patients ranging in age from 2 to 81 years were enrolled. The EAC, detached, attached long, attached short, and ultrashort types of CTN were found in 7 (5.5%), 6 (4.7%), 84 (65.6%), 18 (14.0%), and 13 (10.2%) patients, respectively. The presence of the EAC type could be predicted by preoperative CT while the other four types could be predicted by binning into two groups, with a sensitivity of 0.61 and specificity of 0.72.

Conclusion: The variable anatomy of the chorda tympani nerve can be classified into five major groups based on endoscopic tympanotomy.
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http://dx.doi.org/10.1097/MAO.0000000000002998DOI Listing
March 2021

AMP-activated protein kinase regulates β-catenin protein synthesis by phosphorylating serine/arginine-rich splicing factor 9.

Biochem Biophys Res Commun 2021 01 25;534:347-352. Epub 2020 Nov 25.

Department of Agricultural Chemistry, Faculty of Applied Biosciences, Tokyo University of Agriculture, setagaya-ku, Tokyo, 156-8502, Japan. Electronic address:

β-catenin is a multi-functional protein with a central role in regulating embryonic development and tissue homeostasis. The abnormal accumulation of β-catenin, due to disrupted β-catenin degradation or unregulated β-catenin synthesis, causes the development of cancer. A recent study showed that the overexpression of proto-oncogene serine/arginine-rich splicing factor 9 (SRSF9) promotes β-catenin accumulation via binding β-catenin mRNA and enhancing its translation in a manner that is dependent on the mechanistic target of rapamycin (mTOR). However, the regulation of the interaction between SRSF9 and mRNA of β-catenin remains unclear. Here, we show that AMP-activated protein kinase (AMPK) phosphorylates SRSF9 at the RNA-interacting SWQDLKD motif that plays a major role in determining substrate specificity. The phosphorylation by AMPK inhibits the binding of SRSF9 to β-catenin mRNA and suppresses β-catenin protein synthesis caused by SRSF9 overexpression without changing the β-catenin mRNA levels. Our findings suggest that AMPK activators are potential therapeutic targets for SRSF9-derived overproduction of β-catenin in cancer cells.
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http://dx.doi.org/10.1016/j.bbrc.2020.11.079DOI Listing
January 2021

Niclosamide activates the AMP-activated protein kinase complex containing the β2 subunit independently of AMP.

Biochem Biophys Res Commun 2020 12 29;533(4):758-763. Epub 2020 Sep 29.

Department of Agricultural Chemistry, Faculty of Applied Biosciences, Tokyo University of Agriculture, Setagaya-ku, Tokyo, 156-8502, Japan.

AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by suppressing anabolic processes and activating catabolic processes. AMPK activators are an important therapeutic target for metabolic syndrome due to favorable physiological effects of AMPK activation on metabolism. Recent studies show that niclosamide, an FDA-approved anthelmintic drug that exerts an uncoupling effect on the mitochondria of the parasite, improves blood glucose levels and reduces hepatic steatosis in mice via AMPK activation. Niclosamide is thought to activate AMPK by increasing AMP/ATP ratio through mitochondrial uncoupling, but details of its action remain unclear. In this study, we found that niclosamide also activates the AMPK complex, which contains the AMP-insensitive γ subunit. Further, niclosamide shows greater AMPK activation for the AMPK complex containing β2 subunit, but not the β1 subunit. This effect was inhibited by substituting the Ser108 residue of the β2 subunit to alanine. Niclosamide displays a novel AMPK activation mechanism independent of the increase in AMP/ATP ratio.
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http://dx.doi.org/10.1016/j.bbrc.2020.09.071DOI Listing
December 2020

Anti-nociceptive and anxiolytic effects of systemic flupirtine and its direct inhibitory actions on in vivo neuronal mechanical sensory responses in the adult rat anterior cingulate cortex.

Biochem Biophys Res Commun 2020 10 14;531(4):528-534. Epub 2020 Aug 14.

Department of Neurophysiology, Hyogo College of Medicine, Nishinomiya, 663-8501, Japan. Electronic address:

Flupirtine is a non-opioid centrally acting analgesic that has been in clinical use, and is reported to act on neuronal ion channels and neurotransmitter receptors. However, its action on emotional aspects of pain is still unknown. In this study, we examined whether flupirtine has anxiolytic action and assayed its direct actions on the anterior cingulate cortex (ACC) at the single neuronal and synaptic levels. Anti-nociceptive and anxiolytic effects of flupirtine were evaluated by von Frey test and elevated plus-maze (EPM) in adult rats. The effects of flupirtine on firings and synaptic currents in the rat ACC were examined using in vivo extracellular and brain slice patch-clamp recording techniques, respectively. Systemic administration of flupirtine increased paw withdrawal threshold, and reduced anxiety-like behavior in the EPM. ACC neurons fired spontaneously. Mechanical stimulation of the contralateral hind paw with the von Frey filaments increased firing from the basal spontaneous activity. Intravenous administration of flupirtine reduced both spontaneous and stimulus-evoked firing frequency in the ACC. Flupirtine microinjected into the ACC also inhibited the spontaneous and evoked-responses. In brain slices, flupirtine did not induce any detectable outward currents, but it prolonged the decay time of GABAergic inhibitory synaptic responses. These results suggest that flupirtine directly augments GABAergic synaptic currents and suppresses evoked mechanical nociceptive responses in the ACC. This direct action in the ACC may reduce emotional aspect of pain and induce anxiolytic action.
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http://dx.doi.org/10.1016/j.bbrc.2020.07.129DOI Listing
October 2020

AMP-activated protein kinase regulates alternative pre-mRNA splicing by phosphorylation of SRSF1.

Biochem J 2020 06;477(12):2237-2248

Department of Agricultural Chemistry, Faculty of Applied Biosciences, Tokyo University of Agriculture, Tokyo, Japan.

AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by inhibiting anabolic processes and activating catabolic processes. Recent studies have demonstrated that metformin, which is an AMPK activator, modifies alternative precursor mRNA (pre-mRNA) splicing. However, no direct substrate of AMPK for alternative pre-mRNA splicing has been reported. In the present study, we identified the splicing factor serine/arginine-rich splicing factor 1 (SRSF1) as a novel AMPK substrate. AMPK directly phosphorylated SRSF1 at Ser133 in an RNA recognition motif. Ser133 phosphorylation suppressed the interaction between SRSF1 and specific RNA sequences without altering the subcellular localization of SRSF1. Moreover, AMPK regulated the SRSF1-mediated alternative pre-mRNA splicing of Ron, which is a macrophage-stimulating protein receptor, by suppressing its interaction with exon 12 of Ron pre-mRNA. The findings of this study revealed that the AMPK-dependent phosphorylation of SRSF1 at Ser133 inhibited the ability of SRSF1 to bind RNA and regulated alternative pre-mRNA splicing.
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http://dx.doi.org/10.1042/BCJ20190894DOI Listing
June 2020

Activation of peroxisome proliferator-activated receptor gamma/small heterodimer partner pathway prevents high fat diet-induced obesity and hepatic steatosis in Sprague-Dawley rats fed soybean meal.

J Nutr Biochem 2020 01 15;75:108250. Epub 2019 Oct 15.

Department of Applied Biology and Chemistry, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan. Electronic address:

Soybeans are a complete nutritional resource and soybean proteins are known to affect lipid metabolism via multiple mechanisms. Soybean meal (SBM) is produced after extraction of soybean oil and in this study, we investigated the ability whether the SBM could prevent high fat diet-induced obesity and understand the underlying mechanisms. Male Sprague-Dawley rats, aged 5 weeks, were randomly divided into three groups (n=8 each) and fed one of three diets for 28 days: Cont (AIN-93G), HFD (high fat diet with 40% of calories derived from fat) and HFD+SBM (HFD with 30% SBM). White adipose tissue weight as well as plasma and hepatic triglycerides were significantly decreased in HFD+SBM rats. Expression of hepatic SREBP-1 and its target genes was significantly decreased in HFD+SBM rats. Meanwhile, expression of SHP gene expression was significantly increased in HFD+SBM, and there was a negative correlation between SHP and SREBP-1 expression. Together these results suggest that hepatic SREBP-1 gene expression is negatively regulated by SHP. Expression of PPARG, the transcriptional factor that regulates SHP expression, was increased in HFD+SBM rats. Furthermore, expression of genes controlled by PPARG/SHP, such as those involved in hepatic gluconeogenesis, was also significantly decreased in HFD+SBM rats. Therefore, in addition to the previous findings of SBM on obesity here we show an additional mechanism which by changing the expression of genes involved in lipid metabolism via the PPARG/SHP pathway in the liver.
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http://dx.doi.org/10.1016/j.jnutbio.2019.108250DOI Listing
January 2020

One-Pot Synthesis of PEG-Poly(amino acid) Block Copolymers Assembling Polymeric Micelles with PEG-Detachable Functionality.

ACS Biomater Sci Eng 2019 Nov 5;5(11):5727-5733. Epub 2019 Feb 5.

Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.

Block copolymers composed of poly(ethylene glycol) (PEG) and poly(amino acids) (PAA) segments have shown exceptional features for developing biocompatible nanostructures. While the conventional methods for synthesizing PEG-PAA provide excellent control of the degree of polymerization and polydispersity, these protocols involve several steps, which increase the time and costs, and reduce the number of possible block copolymer designs. In this study, we developed a one-pot synthetic method for PEG-PAA block copolymers by doing sequential ring-opening polymerizations (ROP) of ethylene oxide (EO) and the -carboxyanhydrides (NCAs) of amino acids promoted by the organic base 1,1,3,3-tetramethylguanidine (TMG) as the catalyst. The procedure was effectively used to synthesize PEG-poly(benzyl-l-glutamate) (PEG-PBLG) and PEG-poly(l-Lysine) (PEG-PLL) with narrow molecular weight distribution, comparable to that of block copolymers synthesized by the conventional method initiating the ROP of NCA by amine-terminated PEG. The resulting block copolymers present an ester bond between the PEG and the PAA segments, which can be gradually hydrolyzed in physiological conditions, being advantageous for improving the biocompatibility. Besides, we confirmed that the one-pot PEG-PBLG self-assembled into micelles in aqueous conditions, which showed comparable blood circulation and biodistribution to the micelles prepared from conventional PEG-PBLG. These results indicate the high potential of our one-pot synthetic approach for preparing hydrolyzable PEG-PAAs for constructing supramolecular assemblies.
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http://dx.doi.org/10.1021/acsbiomaterials.8b01549DOI Listing
November 2019

A Novel Technique for Imaging and Analysis of Hair Cells in the Organ of Corti Using Modified Sca/eS and Machine Learning.

Bio Protoc 2019 Aug 20;9(16):e3342. Epub 2019 Aug 20.

Department of Otolaryngology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Here, we describe a sorbitol-based optical clearing method, called modified Sca/eS that can be used to image all hair cells (HCs) in the mouse cochlea. This modification of Sca/eS is defined by three steps: decalcification, de-lipidation, and refractive index matching, which can all be completed within 72 h. Furthermore, we established automated analysis programs that perform machine learning-based pattern recognition. These programs generate 1) a linearized image of HCs, 2) the coordinates of HCs, 3) a holocochleogram, and 4) clusters of HC loss. In summary, a novel approach that integrates modified Sca/eS and programs based on machine learning facilitates quantitative and comprehensive analysis of the physiological and pathological properties of all HCs.
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http://dx.doi.org/10.21769/BioProtoc.3342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854069PMC
August 2019

Platinum-doublet chemotherapy followed by pembrolizumab therapy for lung cancer with lymphangitis carcinomatosa mimicking interstitial pneumonitis: A case report.

Medicine (Baltimore) 2019 Aug;98(33):e16834

Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.

Rationale: Pembrolizumab, an immune-checkpoint inhibitor (ICI), has been shown to be effective for treatment-naive patients with non-small cell lung cancer (NSCLC) and high expression of programmed death-ligand 1 (PD-L1). Therefore, treatment regimens containing pembrolizumab have become a standard therapy for these patients. However, the use of pembrolizumab is limited owing to the side effects of ICIs.

Patient Concerns And Diagnoses: The patient was a 65-year-old man with a left lung mass surrounded by interstitial shadow. The tumor was diagnosed as adenocarcinoma, cT4N3M0, stage IIIC, and the tumor cells showed high PD-L1 expression. It was unclear whether the interstitial shadow was interstitial lung disease (ILD) or lymphangitis carcinomatosa.

Interventions And Outcomes: The patient received carboplatin and nab-paclitaxel, a less risky regimen for ILD, as the first-line therapy. Administration of 2 cycles of this regimen markedly improved both the tumor diameter and interstitial shadow. The interstitial shadow was clinically diagnosed as lymphangitis carcinomatosa and not ILD. Subsequently, the patient was treated with pembrolizumab, and the tumor showed much further shrinkage with no deterioration of the interstitial shadow. To date, the patient is alive with no complaints and no disease progression, and has continued pembrolizumab treatment for a total of 12 months.

Lessons: In patients at a high risk of ICI-related side effects, platinum-doublet chemotherapy may be permitted as the first-line therapy for NSCLC with high PD-L1 expression. However, if the risk associated with ICIs is resolved, early switching from chemotherapy to pembrolizumab might be desirable, even if the chemotherapy is effective.
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http://dx.doi.org/10.1097/MD.0000000000016834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831270PMC
August 2019

Polymeric Micelles Loading Proteins through Concurrent Ion Complexation and pH-Cleavable Covalent Bonding for In Vivo Delivery.

Macromol Biosci 2020 01 16;20(1):e1900161. Epub 2019 Jul 16.

Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Protein drugs have great potential as targeted therapies, yet their application suffers from several drawbacks, such as instability, short half-life, and adverse immune responses. Thus, protein delivery approaches based on stimuli-responsive nanocarriers can provide effective strategies for selectively enhancing the availability and activation of proteins in targeted tissues. Herein, polymeric micelles with the ability of encapsulating proteins are developed via concurrent ion complexation and pH-cleavable covalent bonding between proteins and block copolymers directed to pH-triggered release of the protein payload. Carboxydimethylmaleic anhydride (CDM) is selected as the pH-sensitive moiety, since the CDMamide bond is stable at physiological pH (pH 7.4), while it cleaves at pH 6.5, that is, the pathophysiological pH of tumors and inflammatory tissues. By using poly(ethylene glycol)-poly(l-lysine) block copolymers having 45% CDM addition, different proteins with various sizes and isoelectric points are loaded successfully. By using myoglobin-loaded micelles (myo/m) as a model, the stability of the micelles in physiological conditions and the dissociation and release of functional myoglobin at pH 6.5 are successfully confirmed. Moreover, myo/m shows extended half-life in blood compared to free myoglobin and micelles assembled solely by polyion complex, indicating the potential of this system for in vivo delivery of proteins.
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http://dx.doi.org/10.1002/mabi.201900161DOI Listing
January 2020

Endobronchial Diffuse Large B-cell Lymphoma.

Arch Bronconeumol (Engl Ed) 2020 Apr 23;56(4):251. Epub 2019 May 23.

Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.

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http://dx.doi.org/10.1016/j.arbres.2019.04.007DOI Listing
April 2020

Lambda Sign: Sarcoidosis.

Arch Bronconeumol (Engl Ed) 2020 Mar 18;56(3):174-175. Epub 2019 May 18.

Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.

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http://dx.doi.org/10.1016/j.arbres.2019.03.008DOI Listing
March 2020

Severe Metastatic Pulmonary Calcification.

Am J Med 2019 10 15;132(10):e733-e734. Epub 2019 May 15.

Department of Molecular and Internal Medicine, Institute of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.

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http://dx.doi.org/10.1016/j.amjmed.2019.04.031DOI Listing
October 2019

In vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers.

Nat Commun 2019 04 24;10(1):1894. Epub 2019 Apr 24.

Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan.

Stabilisation of fragile oligonucleotides, typically small interfering RNA (siRNA), is one of the most critical issues for oligonucleotide therapeutics. Many previous studies encapsulated oligonucleotides into ~100-nm nanoparticles. However, such nanoparticles inevitably accumulate in liver and spleen. Further, some intractable cancers, e.g., tumours in pancreas and brain, have inherent barrier characteristics preventing the penetration of such nanoparticles into tumour microenvironments. Herein, we report an alternative approach to cancer-targeted oligonucleotide delivery using a Y-shaped block catiomer (YBC) with precisely regulated chain length. Notably, the number of positive charges in YBC is adjusted to match that of negative charges in each oligonucleotide strand (i.e., 20). The YBC rendezvouses with a single oligonucleotide in the bloodstream to generate a dynamic ion-pair, termed unit polyion complex (uPIC). Owing to both significant longevity in the bloodstream and appreciably small size (~18 nm), the uPIC efficiently delivers oligonucleotides into pancreatic tumour and brain tumour models, exerting significant antitumour activity.
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http://dx.doi.org/10.1038/s41467-019-09856-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482185PMC
April 2019

PEG-OligoRNA Hybridization of mRNA for Developing Sterically Stable Lipid Nanoparticles toward In Vivo Administration.

Molecules 2019 Apr 3;24(7). Epub 2019 Apr 3.

Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

Lipid nanoparticles (LNPs) exhibit high potential as carriers of messenger RNA (mRNA). However, the arduous preparation process of mRNA-loaded LNPs remains a huge obstacle for their widespread clinical application. Herein, we tackled this issue by mRNA PEGylation through hybridization with polyethylene glycol (PEG)-conjugated RNA oligonucleotides (PEG-OligoRNAs). Importantly, mRNA translational activity was preserved even after hybridization of 20 PEG-OligoRNAs per mRNA. The straightforward mixing of the PEGylated mRNA with lipofectamine LTX, a commercial lipid-based carrier, just by pipetting in aqueous solution, allowed the successful preparation of mRNA-loaded LNPs with a diameter below 100 nm, whereas the use of non-PEGylated mRNA provided large aggregates above 100- and 1000-nm. In vivo, LNPs prepared from PEG-OligoRNA-hybridized mRNA exhibited high structural stability in biological milieu, without forming detectable aggregates in mouse blood after intravenous injection. In contrast, LNPs from non-PEGylated mRNA formed several micrometer-sized aggregates in blood, leading to rapid clearance from blood circulation and deposition of the aggregates in lung capillaries. Our strategy of mRNA PEGylation was also versatile to prevent aggregation of another type of mRNA-loaded LNP, DOTAP/Chol liposomes. Together, our approach provides a simple and robust preparation method to LNPs for in vivo application.
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http://dx.doi.org/10.3390/molecules24071303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479949PMC
April 2019

Acquired factor V inhibitor after antibiotic treatment in a patient with pneumonia: a case report.

Ann Hematol 2019 Aug 12;98(8):1989-1990. Epub 2019 Feb 12.

Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.

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http://dx.doi.org/10.1007/s00277-019-03638-6DOI Listing
August 2019

Pericardial Effusion With Tamponade in Lung Cancer Patients During Treatment With Nivolumab: A Report of Two Cases.

Front Oncol 2019 22;9. Epub 2019 Jan 22.

Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Nivolumab is an immune checkpoint inhibitor (ICI) that has shown efficacy for treating non-small cell lung cancer and has become a standard therapy for previously treated non-small cell lung cancer. Moreover, immune-related adverse events of ICI therapy are well-known. Malignant pericardial effusions occasionally arise in patients with lung cancer. There have been a few reports of pericardial effusion in non-small cell lung cancer after nivolumab administration. However, the cause of this condition is controversial; the possibilities include serositis as an immune-related adverse event or pseudo-progression. This report presents two cases of pericardial effusion with tamponade in lung cancer during treatment with nivolumab. Both patients experienced temporal increases in pericardial effusions followed by effusion regression. In one case, nivolumab administration was continued after performance of pericardiocentesis, without an increase in pericardial effusion. In the other case, temporal simultaneous increases in both the pericardial effusion and the primary tumor were detected, followed by simultaneous regression in both the effusion and the tumor. These findings support the fact that the pericardial effusions were caused by pseudo-progression. Pericardial effusion with tamponade can occur in lung cancer patients being treated with nivolumab; moreover, some of these effusions might be caused by pseudo-progression. In the case of putative pseudo-progression, continuation of nivolumab administration might be allowable with strict follow up.
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http://dx.doi.org/10.3389/fonc.2019.00004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349695PMC
January 2019
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