Publications by authors named "Yusuke Ito"

131 Publications

Linagliptin, A Xanthine-Based Dipeptidyl Peptidase-4 Inhibitor, Ameliorates Experimental Autoimmune Myocarditis.

JACC Basic Transl Sci 2021 Jun 9;6(6):527-542. Epub 2021 Jun 9.

Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.

This study sought to show the mechanism of how to ameliorate experimental autoimmune myocarditis (EAM) by administering dipeptidyl peptidase (DPP)-4 inhibitor linagliptin. The number of RAR-related orphan nuclear receptor gamma-positive Th17 cells infiltrated to the EAM myocardium was significantly attenuated by linagliptin treatment. Tandem mass spectrometry-based analysis demonstrated that DPP-4 binds to cathepsin G in EAM hearts, thereby protecting cathepsin G activity through inhibiting SerpinA3N activity. Linagliptin suppresses oxidative stress in EAM hearts as well. Thus, we found that DPP-4 plays a detrimental role in the progression of EAM by interacting with cathepsin G, which, in turn, suppresses SerpinA3N activity.
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http://dx.doi.org/10.1016/j.jacbts.2021.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246030PMC
June 2021

Impact of Rehabilitation Dose on Nutritional Status at Discharge from a Convalescent Rehabilitation Ward in Malnourished Patients with Hip Fracture.

Healthcare (Basel) 2021 Jun 12;9(6). Epub 2021 Jun 12.

Department of Rehabilitation Medicine, Mie University Graduate School of Medicine, Mie 514-8507, Japan.

The object of this study is to determine the impact of the rehabilitation dose on the nutritional status at discharge from a convalescent rehabilitation ward in malnourished patients with hip fracture. This retrospective case-control study involved malnourished patients with hip fracture aged 65 years or older who had been admitted to a convalescent rehabilitation ward and whose data were registered in the Japan Rehabilitation Nutrition Database. The primary outcome was nutritional status at discharge. Patients were classified according to whether nutritional status was improved or not at discharge, according to the Mini Nutritional Assessment-Short Form (MNA-SF) score. The association between improved nutritional status and rehabilitation dose was assessed by a logistic regression analysis. Data were available for 145 patients (27 men, 118 women; mean age 85.1 ± 7.9 years). Daily rehabilitation dose was 109.5 (median 94.6-116.2) min and the MNA-SF score at admission was 5 (median 4-6). Nutritional status was improved in 97 patients and not improved in 48. Logistic regression analysis showed the following factors to be independently associated with nutritional status at discharge: Functional Independence Measure score (OR 1.042, 95% CI 1.016-1.068), energy intake (OR 1.002 CI 1.000-1.004), daily rehabilitation dose (OR 1.023, 95% CI 1.002-1.045), and length of hospital stay (OR 1.026, 95% CI 1.003-1.049). The daily rehabilitation dose in malnourished patients with hip fracture may positively impact nutritional status at discharge.
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http://dx.doi.org/10.3390/healthcare9060722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231257PMC
June 2021

A Case of Huge Cutaneous Verrucous Carcinoma of the Neck.

Cureus 2021 May 22;13(5):e15162. Epub 2021 May 22.

Department of Otorhinolaryngology and Head and Neck Surgery, Kameda Medical Center, Chiba, JPN.

Verrucous carcinoma (VC) is a rare subtype of squamous cell carcinoma. VC commonly occurs in the mucosa, but rarely occurs in the skin. The treatment for VC is surgical removal of the tumor. Because lymph node metastasis of VC is rare, the indications for prophylactic neck dissection for cutaneous VC of the neck are controversial. Here, we present the case of a 68-year-old man with a huge cutaneous VC of the neck and the long-term clinical course. The tumor occupied the entire right cervical skin, with suspected lymph node metastasis in the affected neck. Tumor resection and neck lymph node dissection were performed. Pathological examination revealed cutaneous VC with invasion to the adjacent tissues and no lymph node metastasis. Cutaneous VC of the neck is likely to grow locally without regional lymph node metastasis regardless of the long-term course and the size of the tumor.
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http://dx.doi.org/10.7759/cureus.15162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216570PMC
May 2021

[A Case of Lymphoepithelioma-Like Carcinoma of the Ureter].

Hinyokika Kiyo 2021 May;67(5):205-209

The Department of Urology, Yokohama City University.

Lymphoepithelioma-like carcinoma (LELC) of the ureter is very rare and only 14 previous cases have been reported. Here, we report a case of LELC of the ureter. A 76-year-old woman was admitted to our hospital complaining of gross hematuria. Left ureteral cancer was suspected by the imaging examination, and laparoscopic left total nephroureterectomy was performed. Histopathological examination showed pure type of LELC in the ureter. She is alive without disease recurrence at fifteen months after surgery.
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http://dx.doi.org/10.14989/ActaUrolJap_67_5_205DOI Listing
May 2021

Mefloquine, a Potent Anti-severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Drug as an Entry Inhibitor .

Front Microbiol 2021 30;12:651403. Epub 2021 Apr 30.

Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.

Coronavirus disease 2019 (COVID-19) has caused serious public health, social, and economic damage worldwide and effective drugs that prevent or cure COVID-19 are urgently needed. Approved drugs including Hydroxychloroquine, Remdesivir or Interferon were reported to inhibit the infection or propagation of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), however, their clinical efficacies have not yet been well demonstrated. To identify drugs with higher antiviral potency, we screened approved anti-parasitic/anti-protozoal drugs and identified an anti-malarial drug, Mefloquine, which showed the highest anti-SARS-CoV-2 activity among the tested compounds. Mefloquine showed higher anti-SARS-CoV-2 activity than Hydroxychloroquine in VeroE6/TMPRSS2 and Calu-3 cells, with IC = 1.28 μM, IC = 2.31 μM, and IC = 4.39 μM in VeroE6/TMPRSS2 cells. Mefloquine inhibited viral entry after viral attachment to the target cell. Combined treatment with Mefloquine and Nelfinavir, a replication inhibitor, showed synergistic antiviral activity. Our mathematical modeling based on the drug concentration in the lung predicted that Mefloquine administration at a standard treatment dosage could decline viral dynamics in patients, reduce cumulative viral load to 7% and shorten the time until virus elimination by 6.1 days. These data cumulatively underscore Mefloquine as an anti-SARS-CoV-2 entry inhibitor.
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http://dx.doi.org/10.3389/fmicb.2021.651403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119653PMC
April 2021

Diabetes is associated with greater leg pain and worse patient-reported outcomes at 1 year after lumbar spine surgery.

Sci Rep 2021 Apr 14;11(1):8142. Epub 2021 Apr 14.

Department of Orthopaedic Surgery and Spinal Surgery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Although patients with diabetes reportedly have more back pain and worse patient-reported outcomes than those without diabetes after lumbar spine surgery, the impact of diabetes on postoperative recovery in pain or numbness in other regions is not well characterized. In this study, the authors aimed to elucidate the impact of diabetes on postoperative recovery in pain/numbness in four areas (back, buttock, leg, and sole) after lumbar spine surgery. The authors retrospectively reviewed 993 patients (152 with diabetes and 841 without) who underwent decompression and/or fixation within three levels of the lumbar spine at eight hospitals during April 2017-June 2018. Preoperative Numerical Rating Scale (NRS) scores in all four areas, Oswestry Disability Index (ODI), and Euro quality of life 5-dimension (EQ-5D) were comparable between the groups. The diabetic group showed worse ODI/EQ-5D and greater NRS scores for leg pain 1 year after surgery than the non-diabetic group. Although other postoperative NRS scores tended to be higher in the diabetic group, the between-group differences were not significant. Diabetic neuropathy caused by microvascular changes may induce irreversible nerve damage especially in leg area. Providers can use this information when counseling patients with diabetes about the expected outcomes of spine surgery.
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http://dx.doi.org/10.1038/s41598-021-87615-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046758PMC
April 2021

Potential anti-COVID-19 agents, cepharanthine and nelfinavir, and their usage for combination treatment.

iScience 2021 Apr 26;24(4):102367. Epub 2021 Mar 26.

Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.

Antiviral treatments targeting the coronavirus disease 2019 are urgently required. We screened a panel of already approved drugs in a cell culture model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and identified two new agents having higher antiviral potentials than the drug candidates such as remdesivir and chroloquine in VeroE6/TMPRSS2 cells: the anti-inflammatory drug cepharanthine and human immunodeficiency virus protease inhibitor nelfinavir. Cepharanthine inhibited SARS-CoV-2 entry through the blocking of viral binding to target cells, while nelfinavir suppressed viral replication partly by protease inhibition. Consistent with their different modes of action, synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation was highlighted. Mathematical modeling antiviral activity coupled with the calculated total drug concentrations in the lung predicts that nelfinavir will shorten the period until viral clearance by 4.9 days and the combining cepharanthine/nelfinavir enhanced their predicted efficacy. These results warrant further evaluation of the potential anti-SARS-CoV-2 activity of cepharanthine and nelfinavir.
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http://dx.doi.org/10.1016/j.isci.2021.102367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997640PMC
April 2021

Salicylamide Enhances Melanin Synthesis in B16F1 Melanoma Cells.

Biomol Ther (Seoul) 2021 Jul;29(4):445-451

Division of Animal Science, College of Agriculture, Tamagawa University, Tokyo 194-8610, Japan.

Salicylamide, a non-steroidal anti-inflammatory drug (NSAID), is used as an analgesic and antipyretic agent. We have previously shown that several NSAIDs have anti-melanogenic properties in B16F1 melanoma cells. In contrast, we have found that salicylamide enhances melanin contents in B16F1 melanoma cells; however, the underlying mechanism is not known. Therefore, we investigated the mechanism through which salicylamide stimulates melanogenesis. Interestingly, salicylamide enhanced diphenolase activity in a cell-free assay. Western blotting and real-time RT-PCR revealed that salicylamide increased tyrosinase expression via transcriptional activation of the gene. Together, our results indicate that salicylamide could be used as an anti-hypopigmentation agent for skin and/or hair.
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http://dx.doi.org/10.4062/biomolther.2020.222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255140PMC
July 2021

Edoxaban, a direct oral factor Xa inhibitor, ameliorates coagulation, microvascular thrombus formation, and acute liver injury in a lipopolysaccharide-induced coagulopathy model in rats.

J Thromb Thrombolysis 2021 Jul 3;52(1):9-17. Epub 2021 Feb 3.

Pharmacovigilance Department, Daiichi Sankyo Co., Ltd., Tokyo, 103-8426, Japan.

Infection increases the risk of thrombosis through the activation of inflammation and coagulation. Edoxaban, a direct oral factor Xa inhibitor, is used for the prevention and treatment of thrombotic diseases. The aim of this study was to determine the effects of edoxaban on microvascular thrombus formation in a rat model of lipopolysaccharide (LPS)-induced coagulopathy. Rats were intravenously injected with 7.5 mg/kg of LPS (Escherichia coli 055:B5). Immediately after LPS injection, the rats were treated with subcutaneous injection of edoxaban. At 2 and 6 h after the injection of LPS, biomarkers of coagulation and organ damages and inflammatory cytokines were measured. Microvascular thrombus formation in organs was evaluated using I-fibrinogen (human) or by the pathological analysis. Mortality was examined 24 h after LPS injection. After the injection of LPS, D-dimer and thrombin-antithrombin complex increased and platelet numbers decreased, indicating the activation of coagulation. Microvascular thrombi were found in the liver. Markers of liver injury (aspartate aminotransferase and alanine aminotransferase) also increased. Treatment with edoxaban attenuated the changes in the coagulation markers and microvascular thrombus formation in the liver. Edoxaban suppressed the increase in the liver injury markers and reduced the mortality. Edoxaban did not affect the levels of inflammatory cytokines. In conclusions, edoxaban significantly inhibited the activation of coagulation, the formation of microvascular thrombus in the liver and the liver damage, and reduced mortality in rats injected with LPS. These results suggest that the FXa inhibition by edoxaban might be a beneficial therapy for the management of infection-associated thrombosis.
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http://dx.doi.org/10.1007/s11239-021-02381-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856452PMC
July 2021

Correlation of urinary loss rate after catheter removal and long-term urinary continence after robot-assisted laparoscopic radical prostatectomy.

Int J Urol 2021 04 28;28(4):440-443. Epub 2021 Jan 28.

Department of Urology, Yokohama City University Hospital, Yokohama, Kanagawa, Japan.

Objectives: To assess the correlation of urine loss rate after catheter removal with long-term continence after robot-assisted radical prostatectomy.

Methods: We enrolled 163 patients on whom robot-assisted radical prostatectomy was carried out and whose urine loss rate we were able to evaluate after catheter removal. Urinary incontinence was evaluated from immediately after removal of the catheter to the date of discharge, and at 1, 3, 6 and 12 months after surgery. Urine loss rate was defined as the urine loss volume divided by the total urine volume.

Results: The continence rates of patients with ≤1% urine loss rate on the day of catheter removal were 100% at 6 and 12 months after surgery. A multivariate analysis proved that ≤10% urine loss rate on the day of catheter removal was a significant predictor of continence at 3 months after surgery. Furthermore, the continence rate at 12 months of patients who did not achieve ≤10% urine loss rate on the day of catheter removal was 79.5%. Among them, the continence rate at 12 months of patients who achieved ≥15% urine loss rate improvement from the day of catheter removal to the next day was 95.2%; the factor differed significantly between the continence and incontinence groups at 12 months after surgery.

Conclusions: The urine loss rate on the day of catheter removal is significantly related to the acquisition of urinary continence. Furthermore, our findings suggest that long-term urinary continence can be expected, even in the event of poor urine loss rate on the day of catheter removal, if it improves on the next day.
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http://dx.doi.org/10.1111/iju.14488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049105PMC
April 2021

Single-Domain and Atomically Flat Surface of κ-GaO Thin Films on FZ-Grown ε-GaFeO Substrates via Step-Flow Growth Mode.

ACS Omega 2020 Nov 4;5(45):29585-29592. Epub 2020 Nov 4.

Faculty of Electrical Engineering and Electronics, Kyoto Institute of Technology, Matsugasaki Sakyo-ku, Kyoto 606-8585, Japan.

Herein, single-domain κ-GaO thin films were grown on FZ-grown ε-GaFeO substrates via a step-flow growth mode. The ε-GaFeO possessing the same crystal structure and similar lattice parameters as those of the orthorhombic κ-GaO facilitated the growth of κ-GaO thin films, as observed by the X-ray diffraction (XRD) analysis. Furthermore, the surface morphologies of the κ-GaO thin films exhibited a step-terrace and atomically flat structure. XRD φ-scan and transmission electron microscopy with selected area electron diffraction revealed that there is no occurrence of in-plane rotational domains in the κ-GaO thin films on ε-GaFeO substrates and that the κ-GaO thin film comprised a single domain. TEM analysis revealed that there were no clear dislocations in the observation area. Moreover, high-resolution TEM observation showed that the atomic arrangements of the film and the substrate were continuous without the presence of an intermediate layer along the growth direction and were well-aligned in the in-plane direction.
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http://dx.doi.org/10.1021/acsomega.0c04634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676342PMC
November 2020

PPARα agonist and metformin co-treatment ameliorates NASH in mice induced by a choline-deficient, amino acid-defined diet with 45% fat.

Sci Rep 2020 11 11;10(1):19578. Epub 2020 Nov 11.

Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan.

We explored the beneficial effects of GW7647, a peroxisome proliferator activated receptor α (PPARα) agonist, and metformin, an anti-diabetic drug on an advanced nonalcoholic steatohepatitis (NASH) model in rodents and investigated the possible mechanisms involved. Mice were fed control chow or a choline-deficient L-amino acid-defined diet containing 45% fat (HF-CDAA). The mice fed HF-CDAA diets for 16 weeks were divided into four groups: the no treatment (HF-CDAA), HF-CDAA containing 1000 mg/kg metformin, HF-CDAA containing 10 mg/kg GW7647, and HF-CDAA with both metformin and GW7647 groups. Metformin alone slightly deteriorated the aspartate and alanine aminotransferase (AST/ALT) values, whereas co-treatment with GW7647 and metformin greatly suppressed liver injury and fibrosis via activation of the AMP-activated protein kinase (AMPK) pathway. Further study revealed that co-treatment decreased the expression of inflammatory-, fibrogenesis-, and endoplasmic reticulum (ER) stress-related genes and increased the oxidized nicotinamide adenine dinucleotide (NAD)/reduced nicotinamide adenine dinucleotide (NADH) ratio, suggesting the superiority of co-treatment due to restoration of mitochondrial function. The additive benefits of a PPARα agonist and metformin in a HF-CDAA diet-induced advanced NASH model was firstly demonstrated, possibly through restoration of mitochondrial function and AMPK activation, which finally resulted in suppression of hepatic inflammation, ER stress, then, fibrosis.
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http://dx.doi.org/10.1038/s41598-020-75805-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658250PMC
November 2020

Quantifying antiviral effects against simian/human immunodeficiency virus induced by host immune response.

J Theor Biol 2021 01 18;509:110493. Epub 2020 Sep 18.

Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 819-0395, Japan; MIRAI, JST, Saitama 332-0012, Japan; Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto 606-8501, Japan; NEXT-Ganken Program, Japanese Foundation for Cancer Research (JFCR), Tokyo 135-8550, Japan; Science Groove Inc., Fukuoka 810-0041, Japan. Electronic address:

Chimeric simian and human immunodeficiency viruses (SHIVs) are appropriate animal models for the human immunodeficiency virus (HIV) because HIV has quite a narrow host range. Additionally, SHIVs that encode the HIV-1 Env protein and are infectious to macaques have many strains that show different pathogenesis, such as the highly pathogenic SHIV-KS661 and the less pathogenic SHIV-#64. Therefore, we used SHIVs to understand different aspects of AIDS pathogenesis. In a previous study, we established a mathematical model of in vivo early SHIV infection dynamics, which revealed the expected uninfected and infected dynamics in Rhesus macaques. In concrete, the number of uninfected CD4 T cells in SHIV-KS661-infected Rhesus macaques decreased more significantly and rapidly than that of SHIV-#64 Rhesus macaques, and these Rhesus macaques did not any induce host immune response. In contrast, the number of uninfected CD4 T cells in SHIV-#64-infected Rhesus macaques is maintained, and host immune response developed. Although we considered that the peak viral load might determine whether systemic CD4 T cell depletion occurs or host immune responses develop, we could not investigate this because our model quantified only SHIV infection prior to the development of the pathogenicity or host immune responses. Therefore, we developed a new mathematical model to investigate why SHIV-#64 and SHIV-KS661 showed different long-term viral dynamics. We fitted our new model considering antibody responses to our experimental datasets that included antibody titers, CD4 T cells, and viral load data. We performed a maximum likelihood estimation using a non-linear mixed effect model. From the results, we derived the basic reproduction numbers of SHIV-#64 and SHIV-KS661 from intravenous infection (IV) and SHIV-KS661 from intrarectal infection (IR), as well as the antiviral effects of antibodies against SHIV-#64(IV) and SHIV-KS661(IR). We found significant differences between the basic reproduction number of SHIV-#64(IV) or -KS661(IR) and that of SHIV-KS661(IV). We found no clear difference between the antiviral effects of SHIV-#64(IV) and SHIV-KS661(IR), and revealed that an antiviral effect more than 90% of that of maximum antibody responses was induced from initial antibody responses (i.e., antibody response just after its inducement). In conclusion, we found that the basic reproduction number, rather than SHIV strains determines whether systemic CD4 T cell depletion develops, and the subsequent antibody responses occurs.
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http://dx.doi.org/10.1016/j.jtbi.2020.110493DOI Listing
January 2021

Fluoroquinolones for BK viral complication after transplantation: Meta-analysis.

Transpl Infect Dis 2020 Dec 10;22(6):e13433. Epub 2020 Aug 10.

Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo City, Japan.

Objectives: BK polyomavirus (BKV) causes two distinct complications after transplantation, hemorrhagic cystitis (BKV-HC) after hematopoietic stem cell transplantation (HSCT), and BKV-associated nephropathy (BKVAN) after kidney transplantation (KT). Although fluoroquinolones show efficacy against BKV proliferation in vitro, the clinical effect remains uncertain; thus, we performed meta-analysis to assess its efficacy in the prophylaxis.

Methods: Articles published before March 2020 were searched from PubMed, the Cochrane Library, ISRCTN registry, and ClinicalTrials.gov. Primary outcomes were BKV-HC after HSCT and BKVAN after KT. Secondary outcomes were BK viremia, viruria after KT, and fluoroquinolone-related adverse events.

Results: Three trials with 281 patients post-HSCT and 11 trials with 1882 patients post KT were included as for prophylaxis. Fluoroquinolone prophylaxis did not show effects on BKV-HC (OR 0.54, 95% CI 0.13-2.25), BKVAN (OR 0.74, 95% CI 0.35-1.55), and BK viremia (OR 0.79, 95% CI 0.49-1.28), but significantly decreased BK viruria (OR 0.64, 95% CI 0.45-0.91). Fluoroquinolone prophylaxis was associated with the higher percentage of fluoroquinolone-resistant infection among identified bacteria (OR 2.38, 95% CI 1.16-4.88), but the incidence of fluoroquinolone-resistant infection was similar (OR 1.15, 95% CI 0.71-1.86), due to the decrease of infection itself (OR 0.52, 95% CI 0.34-0.81).

Conclusions: This meta-analysis showed that fluoroquinolones did not prevent BKV-HC after HSCT or BKVAN after KT, although the effect against BKV-HC should be further investigated by randomized controlled trials. Fluoroquinolones could reduce the rate of BK viruria to some extent but may not have clinically sufficient effects.
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http://dx.doi.org/10.1111/tid.13433DOI Listing
December 2020

Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants.

Cancers (Basel) 2020 Jul 21;12(7). Epub 2020 Jul 21.

Department of Genome Sciences, British Columbia Cancer, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.

Blocking androgen receptor (AR) transcriptional activity by androgen deprivation therapy (ADT) improves the response to radiotherapy for intermediate and high risk prostate cancer. Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. Here we investigate whether blocking the transcriptional activities of full-length AR and AR-Vs with ralaniten leads to enhanced sensitivity to radiotherapy. Combination therapies using ralaniten with ionizing radiation were evaluated for effects on proliferation, colony formation, cell cycle, DNA damage, and Western blot analyses in human prostate cancer cells that express both full-length AR and AR-Vs. Ralaniten and a potent next-generation analog (EPI-7170) decreased expression of DNA repair genes whereas enzalutamide had no effect. FACS analysis revealed a dose-dependent decrease of BrdU incorporation with increased accumulation of γH2AX with a combination of ionizing radiation with ralaniten. An additive inhibitory effect on proliferation of enzalutamide-resistant cells was achieved with a combination of ralaniten compounds with ionizing radiation. Ralaniten and EPI-7170 sensitized prostate cancer cells that express full-length AR and AR-Vs to radiotherapy whereas enzalutamide had no added benefit.
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http://dx.doi.org/10.3390/cancers12071991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409302PMC
July 2020

The First Case of Concomitant Lymphadenitis and EBV-Positive Lymphoproliferative Disorder.

Mediterr J Hematol Infect Dis 2020 1;12(1):e2020035. Epub 2020 Jul 1.

Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo.

This is the first case of concurrent lymphadenitis and Epstein-Barr virus (EBV)-positive lymphoproliferative disorder (LPD) in the same lymph node with no immunocompromised history. infection is a rare opportunistic infection mainly for human immunodeficiency virus (HIV)-infected patients. Although no immunodeficiency was detected in our patient, our case indicates that the immunodeficiency in the background of EBV latency type III and the immunosuppression by malignant lymphoma itself might induce the lymphadenitis. This case highly alerts clinicians to the immunosuppressive state of EBV-positive LPD with latency type III even if any immunodeficient serological factors are not detected.
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http://dx.doi.org/10.4084/MJHID.2020.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340235PMC
July 2020

Differences in pharmacological property between combined therapy of the vasopressin V2-receptor antagonist tolvaptan plus furosemide and monotherapy of furosemide in patients with hospitalized heart failure.

J Cardiol 2020 11 19;76(5):499-505. Epub 2020 Jul 19.

Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.

Background: Tolvaptan has been shown to improve congestion in heart failure patients. The purpose of this study was to evaluate the pharmacology and clinical efficacy of combined tolvaptan and furosemide therapy.

Methods: This study included 40 patients with systemic volume overload who were hospitalized for heart failure. Patients who showed no improvement in the condition after receiving 20 mg intravenous furosemide were included and were randomly selected to receive tolvaptan as an add-on to furosemide or to receive an increased dose of furosemide. We evaluated the bioelectrical impedance analyzer parameters, the parameters of the inferior vena cava using echocardiography, vital signs, body weight, urine output, and laboratory data for 5 days.

Results: In the changes from baseline between intracellular water volume (ICW) and extracellular water volume (ECW) after additional use of tolvaptan or furosemide from Day 1 to Day 5, there were no significant differences observed between ICW and ECW over 5 days in the tolvaptan + furosemide group, although differences were found in the furosemide group from Day 2 onward. Changes in the respiratory collapse of inferior vena cava increased significantly, and systolic blood pressure decreased significantly only in the furosemide group.

Conclusions: The present study clearly demonstrates that combined therapy with tolvaptan and furosemide removed excess ICW and ECW to an equal extent, while furosemide alone primarily removed ECW, including intravascular water.
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http://dx.doi.org/10.1016/j.jjcc.2020.05.012DOI Listing
November 2020

Reaction uniformity visualized by Raman imaging in the composite electrode layers of all-solid-state lithium batteries.

Phys Chem Chem Phys 2020 Jun;22(23):13271-13276

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1, Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.

The reaction uniformity of LiCoO2 composite positive electrodes in all-solid-state cells was compared quantitatively by investigating the Raman band shifts corresponding to the state-of-charge (SOC) of LiCoO2. The quantitative SOC analysis was conducted using the Raman imaging data of composite electrodes with smaller or larger solid electrolytes. The electrodes exhibited different reaction uniformity although the cells showed similar initial charge capacities and average SOC. In the case of larger solid electrolytes, most LiCoO2 particles showed higher or lower SOC than the average SOC, and lower battery performance. The quantitative analysis of SOC in each LiCoO2 electrode demonstrated that a variable SOC outside the average SOC resulted in larger irreversible capacity and lower rate performance. The quantitative SOC analysis newly developed in the present study is a useful technique for designing composite electrodes showing higher battery performance.
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http://dx.doi.org/10.1039/d0cp00508hDOI Listing
June 2020

Ultrafast internal modification of glass by selective absorption of a continuous-wave laser into excited electrons.

Opt Lett 2020 Jun;45(11):3171-3174

The internal modification of glass using ultrashort pulse lasers has been attracting attention in a wide range of applications. However, the remarkably low processing speed has impeded its use in the industry. In this study, we achieved ultrafast internal modification of glass by coaxially focusing a single-pulse femtosecond laser and continuous-wave (CW) laser with the wavelength that is transparent to the glass. Compared with the conventional method, the processing speed increased by a factor of 500. The observation of high-speed phenomena revealed that the CW laser was absorbed by the seed electrons that were generated by the femtosecond laser pulse. This technique may help expand the applications of femtosecond lasers in the industry.
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http://dx.doi.org/10.1364/OL.394952DOI Listing
June 2020

Simulation of ultrashort pulse laser drilling of glass considering heat accumulation.

Opt Express 2020 May;28(10):15240-15249

In accordance with the increasing demand for high-speed processing, the repetition rate of ultrashort pulse lasers has continued to increase. With the development of these lasers, there is a growing demand for the prediction of shapes processed at high repetition rates. However, the prediction of these shapes is a major challenge, because of the difficulty associated with the estimation of heat accumulation. In this study, we developed a simulation of ultrashort laser drilling in glass including heat accumulation calculation between pulses. In this simulation model, temperature is considered as an additional criterion of material removal, thus, the dependency of the repetition rate can be estimated. Two model parameters of laser absorption at high temperatures are investigated and determined by experiments under high environmental temperatures. Using the simulation model, high shape-prediction accuracy at high repetition rates was achieved and validated by comparison with experiments. This study may contribute to broadening the applications of high-repetition-rate ultrashort pulse lasers.
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http://dx.doi.org/10.1364/OE.390289DOI Listing
May 2020

Clinical significance of arterial stiffness as a factor for hospitalization of heart failure with preserved left ventricular ejection fraction: a retrospective matched case-control study.

J Cardiol 2020 08 5;76(2):171-176. Epub 2020 Apr 5.

Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.

Background: Previous studies have been conducted to identify characteristics of patients with heart failure with preserved ejection fraction (HFpEF), but the risk factors of HFpEF remain unclear. We investigated the associations between arterial stiffness and the risk of hospitalization for HFpEF patients.

Methods: For the case group, we enrolled patients with preserved EF who had been hospitalized for HF from April 2013 to March 2015 and examined the cardio-ankle vascular index (CAVI). For the control group, we enrolled outpatients with preserved EF and with hypertension, diabetes mellitus, dyslipidemia, and/or coronary artery disease but who did not present with HF symptoms and had never been diagnosed or treated for HF during the same period. The control group matched with the case group for age and sex. The association between hospitalized HFpEF and clinical variables was analyzed using conditional logistic regression models.

Results: The CAVI value was significantly higher in patients with hospitalized HFpEF compared with patients with the control [10.4 (9.8-11.0) vs. 9.2 (8.1-10.0), p < 0.001). On the multivariate conditional logistic regression analysis, high CAVI (OR 6.76, 95% CI 2.28-20.10, p < 0.001) and anemia (OR 3.91, 95% CI 1.47-10.40, p = 0.006) were independently associated with hospitalization of HFpEF patients.

Conclusions: The present study has demonstrated that the high value of CAVI was independently associated with the hospitalization of HFpEF patients.
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http://dx.doi.org/10.1016/j.jjcc.2020.02.013DOI Listing
August 2020

Development of a high-performance liquid chromatography-tandem mass spectrometric method for the determination of Methimazole in human blood matrices.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 May 27;1144:122083. Epub 2020 Mar 27.

Drug Development Department, ASKA Pharmaceutical Co., Ltd., Kawasaki, Japan.

Methimazole (MMI, 1-methyl-2-mercaptoimidazole) is widely used for the treatment of hyperthyroidisms. There are methods available for the measurement of MMI concentration in human serum or plasma from the past, but none meet the current regulatory standards for bioanalytical method validations. In this paper, we developed and validated a total MMI measurement method using liquid chromatography-tandem mass spectrometry (LC-MS/MS), a technique that conforms to current bioanalytical method validation. To form a free sulfhydryl group on MMI, sodium bisulfite was added to 50 µl of plasma or serum samples containing MMI before the derivatization step. The internal standard (MMI-D) was spiked into samples, then these samples were derivatized with 4-chloro-7-nitro-2,1,3-benzoxadiazole. After derivatization, these samples were extracted by supported liquid extraction. Then, the organic solvent was evaporated and the residue was dissolved in 50% methanol and injected into the LC-MS/MS system. A calibration curve was plotted over the concentration range 1-1000 ng/mL (r = 0.999). The intra-day and inter-day precisions were less than 10.2% and 9.8%, respectively. The intra-day and inter-day accuracies were between 89.5% and 101.1%, and 96.0% and 99.7%, respectively. The long-term stability of samples showed good precision and accuracy. The validated method was successfully applied to determine serum total MMI concentration in Graves' disease patients after oral administration of 5, 10 or 15 mg MMI. The range of circulating total MMI concentrations was found to be between 2.69 and 304.27 ng/mL in this study. It was shown that the measured serum total MMI concentrations changed in a dose-dependent manner.
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http://dx.doi.org/10.1016/j.jchromb.2020.122083DOI Listing
May 2020

Component Profiling of Soy-Sauce-Like Seasoning Produced from Different Raw Materials.

Metabolites 2020 Apr 1;10(4). Epub 2020 Apr 1.

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

Soy sauce is a traditional Japanese umami seasoning commonly made from soybeans, wheat, and salt water. Soy-sauce-like seasoning, made from other raw materials, such as rice and peas, has recently been developed. However, differences in the taste of soy-sauce-like seasoning, depending on the raw materials, have not been evaluated. Component profiling based on GC/MS combined with a paired comparison test were used to investigate the effect of raw materials on seasoning components and umami taste in five grain-based and four bean-based soy-sauce-like seasonings. In a principal component (PC) analysis, grain-based samples and bean-based samples were separated along the PC1 axis (explaining 48.1% of the total variance). Grain-based samples had a higher saccharide content, and bean-based samples had a higher amino acid content. Furthermore, differences in the umami intensity were also observed among sample types. This is the first detailed metabolomics study of the characteristic compounds and umami of a variety of soy-sauce-like seasonings made from different raw materials.
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http://dx.doi.org/10.3390/metabo10040137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240962PMC
April 2020

Acute rhabdomyolysis following viral infection with coxsackie A4 in a 50-day-old infant with Fukuyama congenital muscular dystrophy.

J Infect Chemother 2020 May 23;26(5):516-519. Epub 2020 Jan 23.

Department of Pediatrics, Kobe University Graduate School of Medicine, Hyogo, Japan.

Background: Fukuyama congenital muscular dystrophy (FCMD), which is characterized by generalized muscle weakness, hypotonia, and motor delay during early infancy, gradually progresses with advanced age. Although acute rhabdomyolysis following infection in patients with FCMD has occasionally been reported, no studies have investigated rhabdomyolysis following viral infection in FCMD patients during early infancy.

Case Report: We report the case of a 50-day-old girl with no apparent symptoms of muscular dystrophy who developed severe acute rhabdomyolysis caused by viral infection, resulting in quadriplegia and respiratory failure therefore requiring mechanical ventilation. Brain magnetic resonance imaging incidentally showed the typical characteristics of FCMD, and FCMD was confirmed by genetic analysis, which revealed a 3-kb retrotransposon insertion in one allele of the fukutin gene and a deep intronic splicing variant in intron 5 in another allele. The virus etiology was confirmed to be Coxsackie A4.

Conclusion: We report a severe case of acute rhabdomyolysis with the earliest onset of symptoms due to the Coxsackie A4 virus in a patient with FCMD. The present findings indicate that physicians should consider FCMD with viral infection a differential diagnosis if the patient presents with acute rhabdomyolysis following a fever.
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http://dx.doi.org/10.1016/j.jiac.2019.12.015DOI Listing
May 2020

Pyogenic sacroiliitis caused by pneumococcal serotype 16F in a child.

Pediatr Int 2019 Dec 8;61(12):1267-1268. Epub 2019 Dec 8.

Department of Infectious Disease Medicine, Hyogo Prefectural Kobe Children's Hospital, Hyogo, Japan.

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http://dx.doi.org/10.1111/ped.14034DOI Listing
December 2019

FLCN alteration drives metabolic reprogramming towards nucleotide synthesis and cyst formation in salivary gland.

Biochem Biophys Res Commun 2020 02 2;522(4):931-938. Epub 2019 Dec 2.

Department of Urology, Yokohama, 236-0004, Japan. Electronic address:

FLCN is a tumor suppressor gene which controls energy homeostasis through regulation of a variety of metabolic pathways including mitochondrial oxidative metabolism and autophagy. Birt-Hogg-Dubé (BHD) syndrome which is driven by germline alteration of the FLCN gene, predisposes patients to develop kidney cancer, cutaneous fibrofolliculomas, pulmonary cysts and less frequently, salivary gland tumors. Here, we report metabolic roles for FLCN in the salivary gland as well as their clinical relevance. Screening of salivary glands of BHD patients using ultrasonography demonstrated increased cyst formation in the salivary gland. Salivary gland tumors that developed in BHD patients exhibited an upregulated mTOR-S6R pathway as well as increased GPNMB expression, which are characteristics of FLCN-deficient cells. Salivary gland-targeted Flcn knockout mice developed cytoplasmic clear cell formation in ductal cells with increased mitochondrial biogenesis, upregulated mTOR-S6K pathway, upregulated TFE3-GPNMB axis and upregulated lipid metabolism. Proteomic and metabolite analysis using LC/MS and GC/MS revealed that Flcn inactivation in salivary gland triggers metabolic reprogramming towards the pentose phosphate pathway which consequently upregulates nucleotide synthesis and redox regulation, further supporting that Flcn controls metabolic homeostasis in salivary gland. These data uncover important roles for FLCN in salivary gland; metabolic reprogramming under FLCN deficiency might increase nucleotide production which may feed FLCN-deficient salivary gland cells to trigger tumor initiation and progression, providing mechanistic insight into salivary gland tumorigenesis as well as a foundation for development of novel therapeutics for salivary gland tumors.
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http://dx.doi.org/10.1016/j.bbrc.2019.11.184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195446PMC
February 2020

Feasibility of the new copper pipe method for evaluating half-value layer in computed tomography: A measurement and Monte Carlo simulation study.

J Appl Clin Med Phys 2019 Dec 25;20(12):186-192. Epub 2019 Nov 25.

Department of Radiological Technology, DAIYUKAI HEALTH SYSTEM, Ichinomiya, Japan.

This study aimed to verify the accuracy of half-value layer (HVL) measured using the new copper pipe method with the CT ionization chamber while the X-ray tube is rotating and to compare it with the conventional nonrotating method and Monte Carlo simulation method based on the actual measurement and geometry of the new copper pipe method. HVL was measured while the X-ray tube was rotating using a CT ionization chamber surrounded by copper pipe absorbers and located at the isocenter of the CT gantry. The exposure as the copper pipe thickness approached 0 mm was extrapolated from the attenuation curve to take the influence of scatter radiation into consideration. The results of the new copper pipe method were compared with those of the other two methods. Data were acquired using two different CT scanners on a single axial scan. The two one-sided test (TOST) equivalent test yielded equivalence between HVLs derived from the new copper pipe and the nonrotating methods (P < 0.05) and those derived from the new copper pipe and the simulation methods (P < 0.05) at the equivalence margins of ± 0.03 mmCu. The mean absolute difference in HVL between the new copper pipe and conventional nonrotating methods was 0.01 ± 0.02 mmCu, which corresponded to an error of effective energy of (0.86 ± 1.66)%. The new copper pipe method can ensure that HVL of CT scanner can easily be evaluated using solely the CT ionization chamber and copper pipe absorbers without requiring service engineering mode.
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http://dx.doi.org/10.1002/acm2.12780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909117PMC
December 2019

The Volume of Pediatric Blood Culture.

Pediatr Infect Dis J 2019 12;38(12):e340-e341

AMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine Hospital, Tokyo, Japan Department of Emergency and Critical Care Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan, All the authors belong to the KOKETSUKIN pediatric blood culture education group Department of General Pediatrics, Aichi Children's Health and Medicine Hospital, Aichi, Japan Department of Infectious disease, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan Division of Infectious disease, Department of Pediatrics, Kobe Children Hospital, Hyogo, Japan.

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http://dx.doi.org/10.1097/INF.0000000000002466DOI Listing
December 2019

Dynamics of pressure waves during femtosecond laser processing of glass.

Opt Express 2019 Sep;27(20):29158-29167

Although femtosecond lasers enable microfabrication of transparent materials, precise processing is difficult owing to the inevitable damage caused to the surroundings of the processed region. In the present work, we combine pump-probe imaging with a high-speed camera to capture the dynamics of pressure waves varying from pulse to pulse, before a desired shape is created by hundreds of pulses. The results demonstrate that the pressure waves change their forms and locations as the number of pulses increases. The numerical analyses explain that a tensile stress, much greater than the tensile strength, is distributed around the processed region during the travel of the pressure wave, and that repetitive pressure waves result in cracks. The identified mechanism of the damage generation will contribute to developing strategies to prevent damage and expand the range of applications of femtosecond laser processing.
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http://dx.doi.org/10.1364/OE.27.029158DOI Listing
September 2019

Identification of recombinant AtPYL2, an abscisic acid receptor, in E. coli using a substrate-derived bioactive small molecule, a biotin linker with alkyne and amino groups, and a protein cross-linker.

Bioorg Med Chem Lett 2019 11 21;29(21):126634. Epub 2019 Aug 21.

Division of Fundamental Agriscience Research, Research Faculty of Agriculture, Hokkaido University, Kita 9 Nishi 9, Kita-ku, Sapporo 060-8589, Japan; Department of Nutritional Science, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 165-8502, Japan. Electronic address:

Target protein identification of bioactive small molecules is one of the most important research in forward chemical genetics. The affinity chromatography technique to use a resin bound with a small molecule is often used for identification of a target protein of a bioactive small molecule. Here we report a new method to isolate a protein targeted with a bioactive small molecule using a biotin linker with alkyne and amino groups, protein cross-linker containing disulfide bond, and a bioactive small molecule with an azido group (azido probe). After an azido probe is associated with a target protein, the complex of a target protein and azido probe is covalently bound through the biotin linker by azide-alkyne Huisgen cycloaddition and protein cross-linker containing disulfide bond. This ternary complex is immobilized on an affinity matrix with streptavidin, and then the target protein is selectively eluted with a buffer containing a reducing agent for cleavage of disulfide bonds. This method uses a probe having an azido group, which a small functional group, and has the possibility to be a solution strategy to overcome the hindrance of a functional group introduced into the probe that reduces association a target protein. The effectiveness of the method in this study was shown using linker 1, 3'-azidoabscisic acid 3, and protein cross-linker containing a disulfide bond (DTSSP 5).
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http://dx.doi.org/10.1016/j.bmcl.2019.126634DOI Listing
November 2019