Publications by authors named "Hiroyuki Arai"

614 Publications

A cell-free assay implicates a role of sphingomyelin and cholesterol in STING phosphorylation.

Sci Rep 2021 Jun 7;11(1):11996. Epub 2021 Jun 7.

Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.

Stimulator of interferon genes (STING) is essential for the type I interferon response induced by microbial DNA from virus or self-DNA from mitochondria/nuclei. In response to emergence of such DNAs in the cytosol, STING translocates from the endoplasmic reticulum to the Golgi, and activates TANK-binding kinase 1 (TBK1) at the trans-Golgi network (TGN). Activated TBK1 then phosphorylates STING at Ser365, generating an interferon regulatory factor 3-docking site on STING. How this reaction proceeds specifically at the TGN remains poorly understood. Here we report a cell-free reaction in which endogenous STING is phosphorylated by TBK1. The reaction utilizes microsomal membrane fraction prepared from TBK1-knockout cells and recombinant TBK1. We observed agonist-, TBK1-, "ER-to-Golgi" traffic-, and palmitoylation-dependent phosphorylation of STING at Ser365, mirroring the nature of STING phosphorylation in vivo. Treating the microsomal membrane fraction with sphingomyelinase or methyl-β-cyclodextrin, an agent to extract cholesterol from membranes, suppressed the phosphorylation of STING by TBK1. Given the enrichment of sphingomyelin and cholesterol in the TGN, these results may provide the molecular basis underlying the specific phosphorylation reaction of STING at the TGN.
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http://dx.doi.org/10.1038/s41598-021-91562-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184970PMC
June 2021

12/15-Lipoxygenase Regulates IL-33-Induced Eosinophilic Airway Inflammation in Mice.

Front Immunol 2021 19;12:687192. Epub 2021 May 19.

Laboratory of Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Dysregulated fatty acid metabolism is clinically associated with eosinophilic allergic diseases, including severe asthma and chronic rhinosinusitis. This study aimed to demonstrate the role of 12/15-lipoxygenase (12/15-LOX) in interleukin (IL)-33-induced eosinophilic airway inflammation; to this end, we used 12/15-LOX-deficient mice, which displayed augmented IL-33-induced lung inflammation, characterized by an increased number of infiltrated eosinophils and group 2 innate lymphoid cells (ILC2s) in the airway. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics revealed that the levels of a series of 12/15-LOX-derived metabolites were significantly decreased, and application of 14(S)-hydroxy docosahexaenoic acid (HDoHE), a major 12/15-LOX-derived product, suppressed IL-33-mediated eosinophilic inflammation in 12/15-LOX-deficient mice. Using bioactive lipid screening, we found that 14(S)-HDoHE and 10(S),17(S)-diHDoHE markedly attenuated ILC2 proliferation and cytokine production at micromolar concentration . In addition, maresin 1 (MaR1) and resolvin D1 (RvD1), 12/15-LOX-derived specialized proresolving mediators (SPMs), inhibited cytokine production of ILC2s at nanomolar concentration. These findings demonstrate the protective role of endogenous 12/15-LOX-derived lipid mediators in controlling ILC2-mediated eosinophilic airway inflammation and related diseases. Thus, 12/15-LOX-derived lipid mediators may represent a potential therapeutic strategy for ameliorating airway inflammation-associated conditions.
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http://dx.doi.org/10.3389/fimmu.2021.687192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170304PMC
May 2021

extract enhances learning and memory in senescence-accelerated mouse-prone 8 (SAMP8) mice.

Food Funct 2021 May;12(9):3992-4004

Department of Environmental Physiology, Faculty of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan.

Learning and memory impairment may result from age-related decline in synaptic plasticity-related proteins in the hippocampus. Therefore, exploration of functional foods capable of ameliorating memory and cognition decline is an interesting endeavor in neuroscience research. We report the effects of Anredera cordifolia (AC) extract on learning and memory deficits in a senescence-accelerated mouse-prone 8 (SAMP8) mouse model, which demonstrate age-related memory deficits and related pathological changes in the brain. After 8 weeks of oral administration of AC extract, the mice were trained in the Novel Object Recognition (NOR) task, and after 7 more weeks, in the Morris Water Maze (MWM) task. Following the completion of behavioral testing, the blood biochemistry parameters, the hippocampal levels of brain-derived neurotropic factor (BDNF), PSD95, and NR2A, and the p-cAMP-response element binding (p-CREB)/CREB ratio were measured. The AC-treated group spent more time exploring the novel objects in the NOR task, and showed faster acquisition and better retention in the MWM task than the negative control (CN) group. In addition, AC enhanced the levels of the aforementioned neuronal plasticity-related proteins, and did not affect the blood biochemistry parameters. Therefore, our data suggest that the AC extract may improve learning and memory without causing any noticeable side effects in the body.
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http://dx.doi.org/10.1039/d0fo03272gDOI Listing
May 2021

Fibroblast heterogeneity and tertiary lymphoid tissues in the kidney.

Immunol Rev 2021 May 5. Epub 2021 May 5.

Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Fibroblasts reside in various organs and support tissue structure and homeostasis under physiological conditions. Phenotypic alterations of fibroblasts underlie the development of diverse pathological conditions, including organ fibrosis. Recent advances in single-cell biology have revealed that fibroblasts comprise heterogeneous subpopulations with distinct phenotypes, which exert both beneficial and detrimental effects on the host organs in a context-dependent manner. In the kidney, phenotypic alterations of resident fibroblasts provoke common pathological conditions of chronic kidney disease (CKD), such as renal anemia and peritubular capillary loss. Additionally, in aged injured kidneys, fibroblasts provide functional and structural supports for tertiary lymphoid tissues (TLTs), which serve as the ectopic site of acquired immune reactions in various clinical contexts. TLTs are closely associated with aging and CKD progression, and the developmental stages of TLTs reflect the severity of renal injury. In this review, we describe the current understanding of fibroblast heterogeneity both under physiological and pathological conditions, with special emphasis on fibroblast contribution to TLT formation in the kidney. Dissecting the heterogeneous characteristics of fibroblasts will provide a promising therapeutic option for fibroblast-related pathological conditions, including TLT formation.
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http://dx.doi.org/10.1111/imr.12969DOI Listing
May 2021

Designation Products: Boron Neutron Capture Therapy for Head and Neck Carcinoma.

Oncologist 2021 Apr 29. Epub 2021 Apr 29.

Center for Regulatory Science, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.

The Japanese Ministry of Health, Labour and Welfare approved a drug called borofalan ( B), a treatment system, and a dose calculation program for boron neutron capture therapy (BNCT) in March 2020. The application pertaining to the products submitted to the Pharmaceuticals and Medical Devices Agency was supported by a Japanese, open-label, uncontrolled trial (Study 002) in patients with unresectable, locally recurrent head and neck squamous cell carcinoma after chemoradiotherapy or radiotherapy, or in those with unresectable locally advanced or locally recurrent (LA/LR) head and neck nonsquamous cell carcinoma. The drug was administered as a single intravenous dose using infusion rates of 200 mg/kg per hour for the first 2 hours after the start of administration and 100 mg/kg per hour during irradiation. Neutron irradiation was performed using the devices at a single dose of 12 Gy-equivalent for oral, pharyngeal, or laryngeal mucosa for up to 60 minutes from 2 hours after the start of drug administration. The primary endpoint was the overall response rate (ORR). The results of Study 002 showed that the ORR based on an assessment of the Independent Central Review Committee per RECIST version 1.1 was 71.4% (90% confidence interval [CI], 51.3%-86.8%). The lower limit of the 90% CI exceeded the prespecified threshold for ORR. When BNCT is applied to patients with unresectable LA/LR head and neck cancer, precautions should be taken, and patients should be monitored for possible onset of dysphagia, brain abscess, skin disorder, crystal urine, cataract, and/or carotid hemorrhage. IMPLICATIONS FOR PRACTICE: Borofalan ( B), a treatment system and a dose calculation program for boron neutron capture therapy (BNCT), demonstrated significant efficacy in an open-label, uncontrolled trial in which overall response rate was the primary endpoint for patients with unresectable locally advanced or locally recurrent head and neck cancer. Although no information about survival benefits was obtained, BNCT will become an effective treatment option that is expected to manage local lesions that are intractable with any standard therapy. In addition, BNCT is expected to maintain quality of life of the intended patient population, on account of its high tumor selectivity and low invasiveness.
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http://dx.doi.org/10.1002/onco.13805DOI Listing
April 2021

Germ line polymorphisms of genes involved in pluripotency transcription factors predict efficacy of cetuximab in metastatic colorectal cancer.

Eur J Cancer 2021 Jun 23;150:133-142. Epub 2021 Apr 23.

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA. Electronic address:

Background: Cancer stem cells (CSCs) are primarily maintained by a network of pluripotency transcription factors (PTFs). Given a close relationship of CSC regulation with epidermal growth factor receptor and vascular endothelial growth factor signalling, we investigated whether single-nucleotide polymorphisms (SNPs) in PTF genes are related to the efficacy of cetuximab and/or bevacizumab in patients with metastatic colorectal cancer (mCRC).

Patients And Methods: Genomic and clinical data from three independent clinical trial cohorts were tested: cetuximab cohort (FOLFIRI/cetuximab arm in FIRE-3, n = 129), bevacizumab cohort 1 (FOLFIRI/bevacizumab arm in FIRE-3, n = 107) and bevacizumab cohort 2 (FOLFIRI/bevacizumab arm in TRIBE, n = 215). Genomic DNA extracted from blood samples was genotyped, and ten SNPs were tested for association with clinical outcomes.

Results: In the cetuximab cohort, four SNPs were significantly associated with progression-free survival in univariate analysis: NANOG rs11055767 (any A allele vs C/C, hazard ratio [HR] = 0.62, 95% confidence interval [CI] = 0.42-0.94, p = 0.02), NANOG rs10744044 (any A allele vs G/G, HR = 0.59, 95% CI = 0.39-0.90, p = 0.01), NANOGP8 rs2168958 (any C allele vs A/A, HR = 2.12, 95% CI = 1.36-3.29, p < 0.001) and NANOGP8 rs2279066 (any C allele vs T/T, HR = 1.80, 95% CI = 1.06-1.68, p = 0.03). Multivariate analysis confirmed the significant associations for NANOGP8 rs2168958 and NANOGP8 rs2279066. In either bevacizumab cohort, no significant associations were observed in univariate analysis.

Conclusions: Germ line polymorphisms in the PTF genes could be predictive markers for cetuximab in mCRC.
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http://dx.doi.org/10.1016/j.ejca.2021.03.048DOI Listing
June 2021

RNA-Binding Protein Polymorphisms as Novel Biomarkers to Predict Outcomes of Metastatic Colorectal Cancer: A Meta-analysis from TRIBE, FIRE-3, and MAVERICC.

Mol Cancer Ther 2021 Jun 30;20(6):1153-1160. Epub 2021 Mar 30.

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.

RNA-binding proteins (RBPs) regulate many posttranscriptional cellular activities. Accumulating evidence suggests associations between RBPs with colonic tumorigenesis and chemosensitivity. We investigated the prognostic and predictive values of SNPs of genes encoding RBPs in metastatic colorectal cancer (mCRC), using clinical and genomic data from three randomized clinical trials of standard first-line chemotherapy for mCRC (TRIBE, FIRE-3, and MAVERICC). Genomic DNA extracted from blood samples was genotyped using an OncoArray. We tested 30 candidate SNPs of 10 major RBP-related genes with additive models. Prognostic values were estimated by meta-analysis approach. Treatment-by-SNP interactions were tested to estimate predictive values for targeted drugs and cytotoxic backbone chemotherapies. This study included 884 patients. The meta-analysis revealed prognostic values of rs314277 [HR, 1.26; 95% confidence interval (CI), 1.06-1.49, = 0.005, FDR-adjusted = 0.072 for overall survival (OS)] and rs314276 (HR, 1.25; 95% CI, 1.08-1.44, = 0.002, FDR-adjusted = 0.062 for OS). Although some SNPs showed potentially predictive values, these associations were not confirmed after FDR adjustment. In conclusion, the results of this study are warranting additional studies to provide the evidence that RBP-related SNPs may be associated with the prognosis of patients with mCRC treated with standard first-line chemotherapies. In addition, further studies are warranted to study the predictive value.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0649DOI Listing
June 2021

The Landscape of Alterations in DNA Damage Response Pathways in Colorectal Cancer.

Clin Cancer Res 2021 Jun 25;27(11):3234-3242. Epub 2021 Mar 25.

Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

Purpose: Defective DNA damage response (DDR) is a hallmark of cancer leading to genomic instability and is associated with chemosensitivity. Although the mismatch repair system has been extensively studied, the clinical implications of other mechanisms associated with DDR alterations in patients with colorectal cancer remain unclear. This study aimed to understand DDR pathways alterations and their association with common clinical features in patients with colorectal cancer.

Experimental Design: Next-generation sequencing and whole-transcriptome sequencing were conducted using formalin-fixed paraffin-embedded samples submitted to a commercial Clinical Laboratory Improvement Amendments-certified laboratory. Samples with pathogenic or presumed pathogenic mutations in 29 specific DDR-related genes were considered as DDR-mutant (DDR-MT) and the remaining samples as DDR-wild type (DDR-WT).

Results: Of 9,321 patients with colorectal cancer, 1,290 (13.8%) were DDR-MT. The frequency of DDR-MT was significantly higher in microsatellite instability-high (MSI-H) cases than in microsatellite stable cases (76.4% vs. 9.5%). The DDR-MT genotype was higher in the right-sided, -wild, -mutant, and CMS1 subgroups. However, these associations were primarily confounded by the distribution of MSI status. Compared with the DDR-WT tumors, the DDR-MT tumors had a higher mutational burden and gene expression levels in the immune-related pathway, which were independent of MSI status.

Conclusions: We characterized a distinct subgroup of patients with colorectal cancer with tumors harboring mutations in the DDR-related genes. These patients more commonly had MSI-H tumors and exhibited an activated immune signature regardless of their tumor's MSI status. These findings warrant further investigations to develop personalized treatment strategies in this significant subgroup of patients with colorectal cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3635DOI Listing
June 2021

Impact of Body Weight Loss on Survival in Patients with Advanced Gastric Cancer Receiving Second-Line Treatment.

Nutr Cancer 2021 Mar 23:1-14. Epub 2021 Mar 23.

Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

Limited information is available regarding the impact of body weight loss (BWL) in patients with advanced gastric cancer (AGC) who receive second-line chemotherapy. We retrospectively reviewed data for consecutive AGC patients who received second-line treatment with taxane-based chemotherapy at our institution between January 2014 and September 2018. We calculated variables, including percent BWL per month during chemotherapy (%BWL/m), and analyzed the correlations between BWL and other clinicopathological parameters with survival. Forty-four AGC patients were registered (median age, 67.5 years; females,  = 16 [36.3%]; severe ascites,  = 12 [27.3%]). The median overall survival was significantly shorter among patients with a %BWL/m of 1% or more, compared with patients with less weight loss (6.3 mo, vs. 12.3 mo,  = 0.038). The %BWL/m (≥1% vs. <1%) was significantly correlated with survival in a univariate analysis (HR = 2.11,  = 0.04), and the survival period was shorter for patients with severe ascites (HR = 1.92; 95% CI, 0.90-3.90) and if their %BWL/m was 1% or more (HR = 2.01; 95% CI, 0.98-4.10) in a multivariate analysis. In conclusion, BWL during second-line chemotherapy was associated with a poor prognosis among patients with AGC.
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http://dx.doi.org/10.1080/01635581.2021.1902542DOI Listing
March 2021

PMDA's Vision for Horizon Scanning of Emerging Technologies Potentially Relevant to the Development of New Medical Products: The Regulatory Challenge.

Clin Pharmacol Ther 2021 02 18;109(2):295-298. Epub 2020 Aug 18.

Center for Regulatory Science, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.

A key goal of regulatory agencies for medical products is to make innovative products available to patients and the medical community in a timely manner in order to improve the quality of public health and health care. Thus, regulators must respond quickly to emerging technologies. It is a horizon scanning method, based on which the Japanese regulatory agency will have the expertise prior to review of forthcoming products of evolving technologies.
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http://dx.doi.org/10.1002/cpt.1986DOI Listing
February 2021

Homeostatic regulation of STING by retrograde membrane traffic to the ER.

Nat Commun 2021 01 4;12(1):61. Epub 2021 Jan 4.

Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.

Coat protein complex I (COP-I) mediates the retrograde transport from the Golgi apparatus to the endoplasmic reticulum (ER). Mutation of the COPA gene, encoding one of the COP-I subunits (α-COP), causes an immune dysregulatory disease known as COPA syndrome. The molecular mechanism by which the impaired retrograde transport results in autoinflammation remains poorly understood. Here we report that STING, an innate immunity protein, is a cargo of the retrograde membrane transport. In the presence of the disease-causative α-COP variants, STING cannot be retrieved back to the ER from the Golgi. The forced Golgi residency of STING results in the cGAS-independent and palmitoylation-dependent activation of the STING downstream signaling pathway. Surf4, a protein that circulates between the ER/ ER-Golgi intermediate compartment/ Golgi, binds STING and α-COP, and mediates the retrograde transport of STING to the ER. The STING/Surf4/α-COP complex is disrupted in the presence of the disease-causative α-COP variant. We also find that the STING ligand cGAMP impairs the formation of the STING/Surf4/α-COP complex. Our results suggest a homeostatic regulation of STING at the resting state by retrograde membrane traffic and provide insights into the pathogenesis of COPA syndrome.
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http://dx.doi.org/10.1038/s41467-020-20234-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782846PMC
January 2021

Elucidation of Gut Microbiota-Associated Lipids Using LC-MS/MS and 16S rRNA Sequence Analyses.

iScience 2020 Dec 23;23(12):101841. Epub 2020 Nov 23.

RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.

Host-microbiota interactions create a unique metabolic milieu that modulates intestinal environments. Integration of 16S ribosomal RNA (rRNA) sequences and mass spectrometry (MS)-based lipidomics has a great potential to reveal the relationship between bacterial composition and the complex metabolic network in the gut. In this study, we conducted untargeted lipidomics followed by a feature-based molecular MS/MS spectral networking to characterize gut bacteria-dependent lipid subclasses in mice. An estimated 24.8% of lipid molecules in feces were microbiota-dependent, as judged by > 10-fold decrease in antibiotic-treated mice. Among these, there was a series of unique and microbiota-related lipid structures, including acyl alpha-hydroxyl fatty acid (AAHFA) that was newly identified in this study Based on the integrated analysis of 985 lipid profiles and 16S rRNA sequence data providing 2,494 operational taxonomic units, we could successfully predict the bacterial species responsible for the biosynthesis of these unique lipids, including AAHFA.
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http://dx.doi.org/10.1016/j.isci.2020.101841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721639PMC
December 2020

Inferior mesenteric arteriovenous fistula during treatment with bevacizumab in colorectal cancer patient: A case report.

World J Gastrointest Oncol 2020 Nov;12(11):1364-1371

Department of Clinical Oncology, St. Marianna University School of Medicine, Kanagawa 216-8511, Japan.

Background: Fistula formation is a severe adverse event related to antiangiogenetic agents such as bevacizumab and inferior mesenteric arteriovenous fistula (IMAVF) is a result of acquired factor, especially colon surgery. However, IMAVF occurs very rarely and there are few reports in patients during chemotherapy. We report a case of a patient who developed IMAVF during treatment with bevacizumab in metastatic colorectal cancer (mCRC) after colon surgery.

Case Summary: An 81-year-old man was diagnosed with descending colon cancer and underwent left hemicolectomy without any complications. He was definitely diagnosed with high-risk stage 2 and received tegafur-uracil plus leucovorin as adjuvant chemotherapy. Three years and 6 mo after the operation, the cancer relapsed with peritoneal dissemination. The patient underwent CyberKnife radiosurgery targeting the recurrent tumor and received chemotherapy with S-1 plus bevacizumab. At 1 year after chemotherapy, he complained of severe diarrhea, which is suspected drug-induced colitis. As diarrhea worsened despite the termination of treatment, he underwent colonoscopy and computed tomography (CT) scans that revealed edematous change from sigmoid to rectosigmoid colon. CT scans also revealed an aneurysm adjacent to the inferior mesenteric vein and multidetector CT angiography showed the IMAVF. Elective angiography confirmed the diagnosis of an IMAVF and it was successfully treated by arterial embolization. The patient resumed chemotherapy with only S-1 6 mo after embolization.

Conclusion: Clinicians should keep in mind the probability of severe diarrhea arose from IMAVF in mCRC patients treated with bevacizumab.
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http://dx.doi.org/10.4251/wjgo.v12.i11.1364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667451PMC
November 2020

Prospective assessment of plate-haptic rotationally asymmetric multifocal toric intraocular lens with near addition of + 1.5 diopters.

BMC Ophthalmol 2020 Nov 18;20(1):454. Epub 2020 Nov 18.

Department of Ophthalmology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8575, Japan.

Background: To prospectively evaluate surgical results following implantation of rotationally asymmetric, plate-haptic, refractive segmented multifocal toric intraocular lenses (IOLs) with near addition of + 1.5 diopters (D) (Lentis Comfort LS-313 MF15T, Oculentis GmbH).

Methods: In 59 eyes of 41 patients, ocular examinations were conducted before and 1 day, 1 week, 1, 3, and 6 months after surgery. Uncorrected (UDVA) and corrected (CDVA) distance visual acuity, uncorrected (UIVA) and distance-corrected (DCIVA) intermediate visual acuity at 70 cm, and uncorrected (UNVA) and distance-corrected (DCNVA) near visual acuity at 30 cm were tested. A defocus curve was drawn, and the degree of disturbing photic phenomena were questioned.

Results: The IOL showed excellent rotational stability; the average absolute rotation was 1.66 ± 1.17 degrees from 1 day 1 to 6 months postoperatively, and 98.1 and 100% of eyes yielded rotation of less than 5 and 10 degrees, respectively. Postoperative distance and intermediate visual acuity were highly satisfactory; UDVA, CDVA, UIVA, and DCIVA were about 20/20, 20/16, 20/25, 20/25, respectively. Near visual acuity was suboptimal; UNVA and DCNVA were at approximately 20/60. The defocus curve analysis showed that 20/25 and 20/40 uncorrected visual acuity was attained at as close as 60 and 40 cm, respectively. Contrast sensitivity was within a normal range, and subjective photic phenomena were minimum.

Conclusions: The refractive segmented, rotationally asymmetric multifocal toric IOLs with + 1.5 D near addition showed superb rotational stability and highly satisfactory distance and intermediate vision. Contrast sensitivity was high and incidence of photic symptoms was very low.

Trial Registration: This study was registered at JAPIC Clinical Trials Information, ID: JapicCTI-183,877, https://www.clinicaltrials.jp/cti-user/trial/Search.jsp (February 5, 2018).
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http://dx.doi.org/10.1186/s12886-020-01731-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672890PMC
November 2020

Immunogenic cell death pathway polymorphisms for predicting oxaliplatin efficacy in metastatic colorectal cancer.

J Immunother Cancer 2020 11;8(2)

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Background: Immunogenic cell death (ICD) is a tumor cell death involving both innate and adaptive immune responses. Given published findings that oxaliplatin, but not irinotecan, drives ICD, we investigated whether single nucleotide polymorphisms (SNPs) in the ICD pathway are associated with the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer (mCRC).

Methods: Two randomized clinical trials data were analyzed: discovery cohort, FOLFOX/bevacizumab arm (MAVERICC); validation cohort, FOLFOXIRI/bevacizumab arm (TRIBE); and two control cohorts, FOLFIRI/bevacizumab arms (both trials). Genomic DNA extracted from blood samples was genotyped. Ten SNPs in the ICD pathway were tested for associations with clinical outcomes.

Results: In total, 648 patients were included. In the discovery cohort, three SNPs were significantly associated with clinical outcomes in univariate analysis: rs1010222 with progression-free survival (G/G vs any A, HR=0.61, 95% CI 0.43-0.88), rs1050305 with overall survival (OS) (A/A vs any G, HR=1.87, 95% CI 1.04-3.35), and rs1799986 with OS (C/C vs any T, HR=1.69, 95% CI 1.07-2.70). Multivariate analysis confirmed the trend, but statistical significance was not reached. In the validation cohort, rs1050305, and rs1799986 were validated to have the significant associations with clinical outcome. No significant associations of these SNPs were observed in the two control cohorts. Treatment-by-SNP interaction test confirmed the predictive values.

Conclusions: The predictive utility of ICD-related SNPs for the efficacy of oxaliplatin-based chemotherapy was demonstrated, warranting further validation studies to be translated into personalized treatment strategies using conventional cytotoxic agents in mCRC.
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http://dx.doi.org/10.1136/jitc-2020-001714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656952PMC
November 2020

Complete Genome Sequence of the Acetic Acid Bacterium Acetobacter aceti NBRC 14818.

Microbiol Resour Announc 2020 Oct 22;9(43). Epub 2020 Oct 22.

Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

We report here the complete genome sequence of the acetic acid bacterium type strain NBRC 14818. The genome comprises a chromosome of 3,596,270 bp with 57.1% GC content and four plasmids/phages of 63,279 bp, 25,755 bp, 4,858 bp, and 2,964 bp, with an average GC content of 57.0%.
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http://dx.doi.org/10.1128/MRA.01039-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585849PMC
October 2020

The impact of ARID1A mutation on molecular characteristics in colorectal cancer.

Eur J Cancer 2020 11 17;140:119-129. Epub 2020 Oct 17.

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.

Background: ARID1A is a key subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex which regulates dynamic repositioning of nucleosomes to repair DNA damage. Only small pilot studies have evaluated the role of ARID1A mutation in colorectal cancer (CRC). The aim of the present study was to explore the potential impact of ARID1A mutation on clinicopathological and molecular characteristics in CRC.

Methods: We used integrated data sets of 7978 CRC cases (one data set from a clinical laboratory improvement amendments [CLIA]-certified laboratory and three independent published data sets). The associations of ARID1A mutation with molecular characteristics including immune profile (the status of microsatellite instability [MSI], tumour mutational burden [TMB], programmed death ligand 1 [PD-L1] and estimated infiltrating immune cells), clinicopathological features and related pathways were analysed using next-generation sequencing, RNA sequencing and immunohistochemistry.

Results: ARID1A mutant samples had more genomically unstable tumour features (MSI-high and TMB-high) and exhibited more characteristics of a T-cell-inflamed microenvironment (PD-L1 expression and high estimated infiltrating cytotoxic T lymphocytes [CTLs]) than ARID1A wild-type samples in the discovery and validation cohorts. Even ARID1A mutant samples without MSI-high status were TMB-high, had high levels of PD-L1 expression and high estimated infiltrating CTLs. ARID1A mutations were more common with right-sided primary and earlier stage tumours. ARID1A mutant tumours mainly had co-occurring gene mutations related to chromatin modifying, DNA repair, WNT signalling and epidermal growth factor receptor inhibitor resistance pathways, and ARID1A mutations strongly regulated DNA repair pathways. Key genes for chemotherapy/radiotherapy sensitivity were suppressed in ARID1A mutant samples.

Conclusions: Our findings may provide novel insights to develop individualised approaches for treatment of CRC based on ARID1A mutation status.
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http://dx.doi.org/10.1016/j.ejca.2020.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009046PMC
November 2020

Second-line chemotherapy using taxane in patients with advanced gastric cancer who presented with severe peritoneal metastasis: a multicenter retrospective study.

Int J Clin Oncol 2021 Feb 15;26(2):355-363. Epub 2020 Oct 15.

Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.

Background: Individuals with advanced gastric cancer (AGC) who present with severe peritoneal metastasis (SPM) have poor prognosis. This study aimed to evaluate efficacy and safety of second-line treatment for patients with such condition.

Methods: This retrospective study included patients receiving taxane-based second-line chemotherapy at three Japanese institutions between 2010 and 2016. Patients with AGC who present with SPM were included if they had massive ascites and/or inadequate oral intake requiring intravenous nutritional support.

Results: In this study, 43 (40%) of 108 patients had an Eastern Cooperative Oncology Group Performance Status score ≥ 2, and the median serum albumin level of the patients was 3.3 g/dL. Ramucirumab was used in combination with paclitaxel in 21 patients. The median overall survival (OS) and progression-free survival (PFS) were 5.1 and 2.8 months, respectively. Inadequate oral intake was considered a negative prognostic factor of both OS and PFS in the multivariate analysis. Three treatment-related deaths were observed, which include those attributed to febrile neutropenia, gastrointestinal perforation, and pneumonitis. Common grade ≥ 3 adverse events were neutropenia (35%), leukopenia (30%), anemia (24%), and anorexia (16%). We observed febrile neutropenia in 8% and gastrointestinal perforation in 4% of patients, and such conditions were dominantly observed in patients with inadequate oral intake.

Conclusion: Taxane-based second-line chemotherapy was effective and safe for patients with AGC who present with SPM. Attention must be provided when treating patients with inadequate oral intake as they are likely to have short prognosis and serious toxicities.
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http://dx.doi.org/10.1007/s10147-020-01802-xDOI Listing
February 2021

Changes in patient subjective happiness and satisfaction with cataract surgery.

Sci Rep 2020 10 14;10(1):17273. Epub 2020 Oct 14.

Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

The purpose of this study was to investigate the changes in patient subjective happiness and satisfaction with cataract surgery and evaluate the association between satisfaction and types of cataract. This study surveyed 247 participants (mean age, 67.9 years) and they completed questionnaires on their satisfaction with the surgery, the subjective happiness scale (SHS) and the Pittsburgh Sleep Quality Index (PSQI) before and after surgery. The SHS increased postoperatively from 4.6 ± 0.7 to 4.8 ± 0.7 (P = 0.007) and 83.4% of patients were satisfied with the surgical results and the average satisfaction score was 4.2 out of a possible 5.0. Multiple regression analysis showed that patient satisfaction was significantly associated with the postoperative SHS (β = 0.380; P < 0.001), the postoperative PSQI (β = -0.041; P = 0.035) and the presence of a posterior subcapsular cataract (PSC) (β = 0.277; P = 0.026). This study clarified that cataract surgery may improve both visual function and patient happiness and that patient satisfaction was affected by postoperative sleep quality and the disappearance of a PSC.
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http://dx.doi.org/10.1038/s41598-020-72846-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560890PMC
October 2020

Molecular Characterization of Appendiceal Goblet Cell Carcinoid.

Mol Cancer Ther 2020 12 9;19(12):2634-2640. Epub 2020 Oct 9.

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.

Goblet cell carcinoid (GCC) is a distinct subtype of appendiceal neoplasm that exhibits unique clinical and pathologic features. We aimed to reveal the molecular profiles of GCC compared with other appendiceal tumors, such as adenocarcinomas and neuroendocrine tumors. A total of 495 appendiceal tumor samples (53 GCCs, 428 adenocarcinomas, and 14 neuroendocrine tumors) were tested with next-generation sequencing (NGS) on a 592-gene panel and IHC. Microsatellite instability (MSI)/mismatch repair (MMR) status was tested with a combination of NGS, IHC, and fragment analyses. Tumor mutational burden (TMB) was evaluated by NGS, and PD-L1 expression was tested by IHC (SP142). The most prevalent mutated genes within GCCs were (24.0%), (15.4%), (9.4%), and (7.5%). Pathway-specific alterations were dominantly observed in cell cycle, MAPK, epigenetic, and TGFβ signaling pathways. GCCs as compared with adenocarcinomas exhibited significantly lower mutation rates in , and , and significantly higher mutation rates in , and GCCs as compared with neuroendocrine tumors showed significantly lower mutation rates in , and In GCCs, MSI high/MMR deficient, TMB high (≥17 mutations/Mb), and PD-L1 expression were seen in 0.0%, 0.0%, and 2.0% of tumors, respectively. No significant differences were observed in any immunotherapy-related markers examined when compared with adenocarcinomas and neuroendocrine tumors. In conclusion, GCCs had considerably distinct mutational profiles compared with appendiceal adenocarcinomas and neuroendocrine tumors. Understanding these molecular characteristics may be critical for the development of novel and more effective treatment strategies for GCC.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011958PMC
December 2020

Role of Phosphatidylethanolamine Biosynthesis in Herpes Simplex Virus 1-Infected Cells in Progeny Virus Morphogenesis in the Cytoplasm and in Viral Pathogenicity .

J Virol 2020 11 23;94(24). Epub 2020 Nov 23.

Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Glycerophospholipids are major components of cell membranes. Phosphatidylethanolamine (PE) is a glycerophospholipid that is involved in multiple cellular processes, such as membrane fusion, the cell cycle, autophagy, and apoptosis. In this study, we investigated the role of PE biosynthesis in herpes simplex virus 1 (HSV-1) infection by knocking out the host cell gene encoding phosphate cytidylyltransferase 2, ethanolamine (Pcyt2), which is a key rate-limiting enzyme in one of the two major pathways for PE biosynthesis. Pcyt2 knockout reduced HSV-1 replication and caused an accumulation of unenveloped and partially enveloped nucleocapsids in the cytoplasm of an HSV-1-infected cell culture. A similar phenotype was observed when infected cells were treated with meclizine, which is an inhibitor of Pcyt2. In addition, treatment of HSV-1-infected mice with meclizine significantly reduced HSV-1 replication in the mouse brains and improved their survival rates. These results indicated that PE biosynthesis mediated by Pcyt2 was required for efficient HSV-1 envelopment in the cytoplasm of infected cells and for viral replication and pathogenicity The results also identified the PE biosynthetic pathway as a possible novel target for antiviral therapy of HSV-associated diseases and raised an interesting possibility for meclizine repositioning for treatment of these diseases, since it is an over-the-counter drug that has been used for decades against nausea and vertigo in motion sickness. Glycerophospholipids in cell membranes and virus envelopes often affect viral entry and budding. However, the role of glycerophospholipids in membrane-associated events in viral replication in herpesvirus-infected cells has not been reported to date. In this study, we have presented data showing that cellular PE biosynthesis mediated by Pcyt2 is important for HSV-1 envelopment in the cytoplasm, as well as for viral replication and pathogenicity This is the first report showing the importance of PE biosynthesis in herpesvirus infections. Our results showed that inhibition of Pcyt2, a key cell enzyme for PE synthesis, significantly inhibited HSV-1 replication and pathogenicity in mice. This suggested that the PE biosynthetic pathway, as well as the HSV-1 virion maturation pathway, can be a target for the development of novel anti-HSV drugs.
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http://dx.doi.org/10.1128/JVI.01572-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925202PMC
November 2020

F-SMBT-1: A Selective and Reversible PET Tracer for Monoamine Oxidase-B Imaging.

J Nucl Med 2021 02 9;62(2):253-258. Epub 2020 Jul 9.

Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan.

Reactive astrocytes play a key role in the pathogenesis of various neurodegenerative diseases. Monoamine oxidase-B (MAO-B) is one of the promising targets for the imaging of astrogliosis in the human brain. A novel selective and reversible MAO-B tracer, ()-(2-methylpyrid-5-yl)-6-[(3-F-fluoro-2-hydroxy)propoxy]quinoline (F-SMBT-1), was successfully developed via lead optimization from the first-generation tau PET tracer F-THK-5351. SMBT-1 was radiolabeled with F using the corresponding precursor. The binding affinity of radiolabeled compounds to MAO-B was assessed using saturation and competitive binding assays. The binding selectivity of F-SMBT-1 to MAO-B was evaluated by autoradiography of frozen human brain tissues. The pharmacokinetics and metabolism were assessed in normal mice after intravenous administration of F-SMBT-1. A 14-d toxicity study after the intravenous administration of F-SMBT-1 was performed using rats and mice. In vitro binding assays demonstrated a high binding affinity of F-SMBT-1 to MAO-B (dissociation constant, 3.7 nM). In contrast, it showed low binding affinity to MAO-A and protein aggregates such as amyloid-β and tau fibrils. Autoradiographic analysis showed higher amounts of F-SMBT-1 binding in the Alzheimer disease brain sections than in the control brain sections. F-SMBT-1 binding was completely displaced with the reversible MAO-B inhibitor lazabemide, demonstrating the high selectivity of F-SMBT-1 for MAO-B. Furthermore, F-SMBT-1 showed a high uptake by brain, rapid washout, and no radiolabeled metabolites in the brain of normal mice. F-SMBT-1 showed no significant binding to various receptors, ion channels, or transporters, and no toxic effects related to its administration were observed in mice and rats. F-SMBT-1 is a promising and selective MAO-B PET tracer candidate, which would be useful for quantitative monitoring of astrogliosis in the human brain.
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http://dx.doi.org/10.2967/jnumed.120.244400DOI Listing
February 2021

Voxel-Based Morphometry Reveals a Correlation Between Bone Mineral Density Loss and Reduced Cortical Gray Matter Volume in Alzheimer's Disease.

Front Aging Neurosci 2020 17;12:178. Epub 2020 Jun 17.

Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.

: Decreased bone mineral density (BMD) was associated with poorer cognitive function and increased risk of Alzheimer's disease (AD). However, objective evidence for the relationship between osteoporosis and AD in humans has not been extensively described. : We aimed to evaluate the relationships between BMD and the cortical volumes of brain regions vulnerable to AD; hippocampus, parahippocampal gyrus, precuneus, posterior cingulate, and angular gyrus, using voxel-based morphometry (VBM), to investigate the association between bone loss and AD. : A cohort of 149 consecutive elderly participants who complained of memory disturbance underwent high-resolution structural brain magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry (DXA). We used SPM12 software to conduct a voxel-based multiple regression analysis to examine the association between femoral neck BMD values and regional gray matter volume (rGMV) on structural T1-weighted MRI. : After adjusting for subject age, gender, total brain volume (TBV), and mini-mental state examination (MMSE) scores, the multiple regression analysis showed significant correlations between BMD loss and rGMV decline in the left precuneus, which is an important neural network hub vulnerable to AD. : These data suggest that the bone and brain communicate with each other, as in "bone-brain crosstalk," and that control of BMD factors could contribute to cognitive function and help prevent AD.
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http://dx.doi.org/10.3389/fnagi.2020.00178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311782PMC
June 2020

Strategic Outlook toward 2030: Japan's research for allergy and immunology - Secondary publication.

Allergol Int 2020 Oct 27;69(4):561-570. Epub 2020 Jun 27.

Division of Molecular Genetics, The Jikei University School of Medicine, Research Center for Medical Science, Tokyo, Japan. Electronic address:

Strategic Outlook toward 2030: Japan's Research for Allergy and Immunology (Strategy 2030) is the national research strategy based on Japan's Basic Law on Measures Against Allergic Diseases, a first of its kind worldwide. This strategy was established by a multi-disciplinary committee consisting of administrators of the Ministry of Health, Labour and Welfare of Japan, young and senior experts from various research societies and associations, and representatives of patient and public groups. Whereas the issues of transition, integration, and international collaboration have yet to be solved in this research realm in Japan, identification of unmet needs, digitization of information and transparent procedures, and strategic planning for complex problems (a process dubbed MIERUKA by the Toyota Way) are crucial to share and tackle the same vision and goals. The committee developed three specific actions focusing on preemptive treatment, interdisciplinarity and internationality, and life stage. The real success of Strategy 2030 is made by the spontaneous contributions of doctors, dentists, veterinarians, and other medical professionals; basic and clinical research scientists, research supporters, and pharmaceutical/medical device companies; manufacturers of food, healthcare, and home appliances; and patients, their families, and the public. The hope is to establish a stable society in which people can live long, healthy lives, as free as possible from allergic and immunological diseases, at each individual life stage. This article is based on a Japanese review first reported in Arerugi, introduces the developmental process and details of Strategy 2030.
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http://dx.doi.org/10.1016/j.alit.2020.04.006DOI Listing
October 2020

Transient and lineage-restricted requirement of Ebf3 for sternum ossification.

Development 2020 05 12;147(9). Epub 2020 May 12.

Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan

Osteoblasts arise from bone-surrounding connective tissue containing tenocytes and fibroblasts. Lineages of these cell populations and mechanisms of their differentiation are not well understood. Screening enhancer-trap lines of zebrafish allowed us to identify Ebf3 as a transcription factor marking tenocytes and connective tissue cells in skeletal muscle of embryos. Knockout of Ebf3 in mice had no effect on chondrogenesis but led to sternum ossification defects as a result of defective generation of Runx2 pre-osteoblasts. Conditional and temporal Ebf3 knockout mice revealed requirements of Ebf3 in the lateral plate mesenchyme cells (LPMs), especially in tendon/muscle connective tissue cells, and a stage-specific Ebf3 requirement at embryonic day 9.5-10.5. Upregulated expression of connective tissue markers, such as Egr1/2 and Osr1, increased number of Islet1 mesenchyme cells, and downregulation of gene expression of the Runx2 regulator Shox2 in Ebf3-deleted thoracic LPMs suggest crucial roles of Ebf3 in the onset of lateral plate mesoderm differentiation towards osteoblasts forming sternum tissues.
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http://dx.doi.org/10.1242/dev.186239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240299PMC
May 2020

Recent Developments of Systemic Chemotherapy for Gastric Cancer.

Cancers (Basel) 2020 Apr 28;12(5). Epub 2020 Apr 28.

Department of Clinical Oncology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.

Gastric cancer (GC) is a molecularly heterogeneous disease. Its molecular background, epidemiology, and standard of care are quite different between Eastern and Western countries. Many efforts have been made in developing more effective surgeries and adjuvant chemotherapies for resectable GC in each region. Recently, an intensive combination of cytotoxic agents has been established as a new standard of adjuvant treatment. Meanwhile, palliative chemotherapy is a uniform standard treatment for unresectable GC worldwide. Recently, one of the most remarkable advances in therapy for unresectable GC has been the approval of immune checkpoint inhibitors (ICIs). The use of ICIs as frontline treatment is currently being investigated. In addition, novel combinations of ICIs and targeted drugs are being evaluated in clinical trials. Despite these advances, the complex biology of GC has resulted in the failure of targeted therapies, with the exceptions of HER2-targeted trastuzumab and VEGFR2-targeted ramucirumab. GC harbors many redundant oncogenic pathways, and small subsets of tumors are driven by different specific pathways. Therefore, a combination strategy simultaneously inhibiting several pathways and/or stricter patient selection for better response to targeted drugs are needed to improve clinical outcomes in this field.
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http://dx.doi.org/10.3390/cancers12051100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281322PMC
April 2020

LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover.

Gut 2021 Jan 6;70(1):180-193. Epub 2020 Apr 6.

Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Objective: Non-alcoholic fatty liver disease (NAFLD) is a common prelude to cirrhosis and hepatocellular carcinoma. The genetic variant in the lysophosphatidylinositol acyltransferase 1 (, which incorporates arachidonic acid into phosphatidylinositol (PI), is associated with the entire spectrum of NAFLD. In this study, we investigated the mechanism underlying this association in mice and cultured human hepatocytes.

Design: We generated the hepatocyte-specific knockout mice to investigate the function of Lpiat1 in vivo. We also depleted in cultured human hepatic cells using CRISPR-Cas9 systems or siRNA. The effect of LPIAT1-depletion on liver fibrosis was examined in mice fed high fat diet and in liver spheroids. Lipid species were measured using liquid chromatography-electrospray ionisation mass spectrometry. Lipid metabolism was analysed using radiolabeled glycerol or fatty acids.

Results: The hepatocyte-specific knockout mice developed hepatic steatosis spontaneously, and hepatic fibrosis on high fat diet feeding. Depletion of in cultured hepatic cells and in spheroids caused triglyceride accumulation and collagen deposition. The increase in hepatocyte fat content was due to a higher triglyceride synthesis fueled by a non-canonical pathway. Indeed, reduction in the PI acyl chain remodelling caused a high PI turnover, by stimulating at the same time PI synthesis and breakdown. The degradation of PI was mediated by a phospholipase C, which produces diacylglycerol, a precursor of triglyceride.

Conclusion: We found a novel pathway fueling triglyceride synthesis in hepatocytes, by a direct metabolic flow of PI into triglycerides. Our findings provide an insight into the pathogenesis and therapeutics of NAFLD.
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http://dx.doi.org/10.1136/gutjnl-2020-320646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788230PMC
January 2021

Palmitate induces cardiomyocyte death via inositol requiring enzyme-1 (IRE1)-mediated signaling independent of X-box binding protein 1 (XBP1).

Biochem Biophys Res Commun 2020 05 19;526(1):122-127. Epub 2020 Mar 19.

Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; Japan Science and Technology Agency, Tokyo, Japan. Electronic address:

Overloading of the saturated fatty acid (SFA) palmitate induces cardiomyocyte death. The purpose of this study is to elucidate signaling pathways contributing to palmitate-induced cardiomyocyte death. Palmitate-induced cardiomyocyte death was induced in Toll-like receptor 2/4 double-knockdown cardiomyocytes to a similar extent as wild-type cardiomyocytes, while cardiomyocyte death was canceled out by triacsin C, a long-chain acyl-CoA synthetase inhibitor. These results indicated that palmitate induced cytotoxicity after entry and conversion into palmitoyl-CoA. Palmitoyl-CoA is not only degraded by mitochondrial oxidation but also taken up as a component of membrane phospholipids. Palmitate overloading causes cardiomyocyte membrane fatty acid (FA) saturation, which is associated with the activation of endoplasmic reticulum (ER) unfolded protein response (UPR) signaling. We focused on the ER UPR signaling as a possible mechanism of cell death. Palmitate loading activates the UPR signal via membrane FA saturation, but not via unfolded protein overload in the ER since the chemical chaperone 4-phenylbutyrate failed to suppress palmitate-induced ER UPR. The mammalian UPR relies on three ER stress sensors named inositol requiring enzyme-1 (IRE1), PKR-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Palmitate loading activated only IRE1 and PERK. Knockdown of PERK did not affect palmitate-induced cardiomyocyte death, while knockdown of IRE1 suppressed palmitate-induced cardiomyocyte death. However, knockdown of X-box binding protein 1 (XBP1), the downstream effector of IRE1, did not affect palmitate-induced cardiomyocyte death. These results were validated by pharmacological inhibitor experiments. In conclusion, we identified that palmitate-induced cardiomyocyte death was triggered by IRE1-mediated signaling independent of XBP1.
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http://dx.doi.org/10.1016/j.bbrc.2020.03.027DOI Listing
May 2020

Future development of artificial organs related with cutting edge emerging technology and their regulatory assessment: PMDA's perspective.

J Artif Organs 2020 Sep 28;23(3):203-206. Epub 2020 Feb 28.

Regulatory Science Center, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.

Future development of innovative artificial organs is closely related with cutting edge emerging technology. These technologies include brain machine or computer interface, organs made by three dimensional bioprinting, organs designed from induced-pluripotent stem cell for personalized tissue or organ, and xenotransplantation. To bridge the gap between scientific innovation and regulatory product review, Pharmaceuticals and Medical Devices Agency of Japan (PMDA) started the science board to discuss about the new scientific topics regarding medical products including medical device and regenerative products with external experts since 2012. Topics which PMDA raised for science board included cellular and tissue-based products from iPS cells, artificial intelligence and genome editing technology. In addition, PMDA started the horizon scanning to identify a new cutting edge technology which could potentially lead to innovative health technology or product, which has a strong impact on clinical medicine. Although the effectiveness and safety of the medical products must be reasonably assured before clinical use, PMDA introduced Sakigake review assignment (a review partner of device development) and conditional approval system to balance between pre-market and post-market evaluation.
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http://dx.doi.org/10.1007/s10047-020-01161-4DOI Listing
September 2020