Publications by authors named "Ryosuke Suzuki"

123 Publications

Seroprevalence of Flavivirus Neutralizing Antibodies in Thailand by High-Throughput Neutralization Assay: Endemic Circulation of Zika Virus before 2012.

mSphere 2021 Jul 14:e0033921. Epub 2021 Jul 14.

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

Thailand is a hyperendemic country for flavivirus infections in Southeast Asia. Although the reporting system for flavivirus surveillance in Thailand is well established, syndromic surveillance tends to underestimate the true epidemiological status of flaviviruses due to the majority of infections being asymptomatic. To accurately understand the prevalence of flaviviruses in endemic regions, we performed neutralization tests against multiple flaviviruses using 147 serum samples from healthy donors collected from four distinct regions in Thailand. Single-round infectious particles (SRIP) for six flaviviruses, dengue virus types 1 to 4 (DENV-1 to -4), Japanese encephalitis virus (JEV), and Zika virus (ZIKV), were used as antigens for developing a safe, high-throughput neutralization assay. Titers of neutralizing antibodies (NAbs) against the six flaviviruses revealed that DENV-1 and DENV-2, followed by ZIKV were the predominant circulating flaviviruses in a total of four regions, whereas the prevalence of NAbs against JEV varied among regions. Although the seroprevalence of ZIKV was low relative to that of DENV-1 and DENV-2, the findings strongly suggested that ZIKV has been circulating at a sustained level in Thailand since before 2012. These findings not only demonstrated the application of an SRIP-neutralization test in a serological study, but also elucidated the circulation and distribution trends of different flaviviruses in Thailand. Neutralization tests are the most reliable assay for flavivirus antibody detection; however, these assays are not suitable for high-throughput processing due to their time-consuming and labor-intensive nature. In this study, we developed single-round infectious particles (SRIPs) with a luciferase gene for dengue virus types 1 to 4, Japanese encephalitis virus, and Zika virus for use in a safe, high-throughput neutralization assay. We performed neutralization tests against multiple flaviviruses using 147 serum samples that were collected from healthy donors residing in four distinct regions of Thailand in 2011 to 2012. The assay was useful for surveys of flavivirus seroprevalence. The data revealed that dengue virus type 1 (DENV-1) and DENV-2 were the predominant circulating flaviviruses in Thailand and that Zika virus has been circulating at a sustained level in Thailand since before 2012.
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http://dx.doi.org/10.1128/mSphere.00339-21DOI Listing
July 2021

Deep learning image reconstruction algorithm for pancreatic protocol dual-energy computed tomography: image quality and quantification of iodine concentration.

Eur Radiol 2021 Jun 15. Epub 2021 Jun 15.

Department of Radiology, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan.

Objectives: To evaluate the image quality and iodine concentration (IC) measurements in pancreatic protocol dual-energy computed tomography (DECT) reconstructed using deep learning image reconstruction (DLIR) and compare them with those of images reconstructed using hybrid iterative reconstruction (IR).

Methods: The local institutional review board approved this prospective study. Written informed consent was obtained from all participants. Thirty consecutive participants with pancreatic cancer (PC) underwent pancreatic protocol DECT for initial evaluation. DECT data were reconstructed at 70 keV using 40% adaptive statistical iterative reconstruction-Veo (hybrid-IR) and DLIR at medium and high levels (DLIR-M and DLIR-H, respectively). The diagnostic acceptability and conspicuity of PC were qualitatively assessed using a 5-point scale. IC values of the abdominal aorta, pancreas, PC, liver, and portal vein; standard deviation (SD); and coefficient of variation (CV) were calculated. Qualitative and quantitative parameters were compared between the hybrid-IR, DLIR-M, and DLIR-H groups.

Results: The diagnostic acceptability and conspicuity of PC were significantly better in the DLIR-M group compared with those in the other groups (p < .001-.001). The IC values of the anatomical structures were almost comparable between the three groups (p = .001-.9). The SD of IC values was significantly lower in the DLIR-H group (p < .001) and resulted in the lowest CV (p < .001-.002) compared with those in the hybrid-IR and DLIR-M groups.

Conclusions: DLIR could significantly improve image quality and reduce the variability of IC values than could hybrid-IR.

Key Points: Image quality and conspicuity of pancreatic cancer were the best in DLIR-M. DLIR significantly reduced background noise and improved SNR and CNR. The variability of iodine concentration was reduced in DLIR.
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http://dx.doi.org/10.1007/s00330-021-08121-3DOI Listing
June 2021

Identification of natural compounds extracted from crude drugs as novel inhibitors of hepatitis C virus.

Biochem Biophys Res Commun 2021 Aug 12;567:1-8. Epub 2021 Jun 12.

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

Natural product-derived crude drugs are expected to yield an abundance of new drugs to treat infectious diseases. Hepatitis C virus (HCV) is an oncogenic virus that significantly impacts public health. In this study, we sought to identify anti-HCV compounds in extracts of natural products. A total of 110 natural compounds extracted from several herbal medicine plants were examined for antiviral activity against HCV. Using a Huh7-mCherry-NLS-IPS reporter system for HCV infection, we first performed a rapid screening for anti-HCV compounds extracted from crude drugs. The compounds threo-2,3-bis(4-hydroxy-3-methoxyphenyl)-3-butoxypropan-1-ol (#106) and medioresinol (#110), which were extracted from Crataegus cuneate, exhibited anti-HCV activity and significantly inhibited HCV production in a dose-dependent manner. Analyses using HCV pseudoparticle and subgenomic replicon systems indicated that compounds #106 and #110 specifically inhibit HCV RNA replication but not viral entry or translation. Interestingly, compound #106 also inhibited the replication and production of hepatitis A virus. Our findings suggest that C. cuneate is a new source for novel anti-hepatitis virus drug development.
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http://dx.doi.org/10.1016/j.bbrc.2021.06.022DOI Listing
August 2021

Optimized Bolus Threshold for Dual-Energy CT Angiography with Monoenergetic Images: A Randomized Clinical Trial.

Radiology 2021 Jun 15:210102. Epub 2021 Jun 15.

From the Departments of Radiology (Y.N., F.N., N.K., M.M.) and Frontier Science for Imaging (F.H.), Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; Department of Radiology Services (R.S., T.M.) and Innovative and Clinical Research Promotion Center (T.I.), Gifu University Hospital, Gifu, Japan; and Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass (A.R.K.).

Background The bolus-tracking technique from single-energy CT has been applied to dual-energy CT (DECT) without optimization or validation. Further optimization is imperative because of a paucity of literature and differences in the attenuation profile of virtual monoenergetic images (VMIs). Purpose To determine the optimal trigger threshold with bolus-tracking technique for DECT angiography (DECTA) in a phantom study and assess the feasibility of an optimized threshold for bolus-tracking technique in DECTA at 40 keV with a 50% reduced iodine dose in human participants. Materials and Methods A phantom study with rapid kilovoltage-switching DECT was performed to determine the optimal threshold for each kiloelectron-volt VMI. In a prospective study, consecutive participants who underwent whole-body CT angiography (CTA) from August 2018 to July 2019 were randomized into three groups: single-energy CTA (SECTA) with standard iodine dose (600 mg of iodine per kilogram), DECTA with 50% reduced iodine dose (300 mg of iodine per kilogram) by using a conventional threshold, and DECTA with 300 mg of iodine per kilogram by using an optimized threshold. A trigger threshold of 100 HU at 120 kVp was used as a reference for comparison. Injected iodine doses and aortic CT numbers were compared among the three groups using Kruskal-Wallis test. Results Ninety-six participants (mean age ± standard deviation, 72 years ± 9; 80 men) were evaluated (32 participants in each group). The optimized threshold for VMIs at 40 keV was 30 HU. The median iodine dose was lower in the optimized DECTA group (13 g) compared with conventional DECTA (19 g) and SECTA (26 g) groups ( < .017 for each comparison). The median aortic CT numbers were higher in the order corresponding to conventional DECTA (655-769 HU), optimized DECTA (543-610 HU), and SECTA (343-359 HU) groups ( < .001). Conclusion The optimized trigger threshold of 30 HU for bolus-tracking technique during dual-energy CT angiography at 40 keV achieved lower iodine load while maintaining aortic enhancement. ©RSNA, 2021 See also the editorial by Malayeri in this issue.
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http://dx.doi.org/10.1148/radiol.2021210102DOI Listing
June 2021

[A Case of Pelvic Unicentric Castleman Disease Treated by Preoperative Transcatheter Arterial Embolization and Tumor Complete Resection with Combined Lower Abdominal and Posterior Approach].

Hinyokika Kiyo 2021 Apr;67(4):157-162

The Department of Urology, Kyoto University Hospital.

A 22-year-old woman was referred to our hospital for further examination of an incidentally discovered hypervascular pelvic tumor with a maximum diameter of 10 cm. Although Castleman disease was suspected based on the imaging findings and pathologic findings of the needle biopsy, a definitive diagnosis was not made. Preoperative transcatheter arterial embolization was performed to decrease intraoperative bleeding, and tumor resection was performed on the following day. As for posterior approach prior to anterior approach, the patient was placed in a prone position, and the dorsal aspect of tumor was approached through the dissection of gluteal muscles. Then, dilated branches of the internal iliac vein was found on the tumor capsule, which were safely ligated under direct vision with favorable visual field. Then, the patient was placed in a supine position, the tumor was completely resected by anterior approach without transfusion. Histopathological diagnosis was Castleman disease hyaline vascular type. The patient was discharged without complication and has been free from recurrence for 6 months after surgery.
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http://dx.doi.org/10.14989/ActaUrolJap_67_4_157DOI Listing
April 2021

Abnormal cleavage is involved in the self-correction of bovine preimplantation embryos.

Biochem Biophys Res Commun 2021 Jul 25;562:76-82. Epub 2021 May 25.

Department of Biological Production, Tokyo University of Agriculture and Technology, Tokyo, 183-8509, Japan. Electronic address:

Chromosome instability leading to aneuploidy during early cleavage is well known in humans and cattle. Partial compaction (PC), which occurs only in some blastomeres, is suggested as a self-correction mechanism through which human embryos avoid aneuploid mosaicism. Partially compacted embryos show abnormal cleavages more frequently during early development; however, the mechanism by which blastomeres are excluded has not been elucidated. Here, we confirmed PC in approximately half of the tested bovine embryos, similar to that in human embryos. DNA sequencing of single-cell and intact embryos revealed that the morulae that excluded some blastomeres had euploidy, but many of the excluded blastomeres had aneuploidy. Time-lapse imaging of zygotes without the zona pellucida revealed that the excluded blastomeres underwent reverse and direct cleavages, which are abnormal cleavages, more frequently than the blastomeres involved in compaction. These results suggest the potential role of abnormal cleavage in the self-correction mechanism during the development of mammalian preimplantation embryos.
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http://dx.doi.org/10.1016/j.bbrc.2021.05.028DOI Listing
July 2021

Practical Arachnoid Anatomy for the Technical Consideration of Galen Complex Dissection: Cadaveric and Clinical Evaluation.

World Neurosurg 2021 Jul 19;151:e372-e378. Epub 2021 Apr 19.

Department of Neurosurgery, Yokohama City University, Yokohama, Japan.

Background: The occipital transtentorial approach (OTA) is a very useful but challenging approach to expose the pineal region because the deep-seated arachnoid membranes usually fold and extend over the great vein of Galen (GVG), leading to dense and poor visibility. In addition, the practical aspects of arachnoid anatomy are not well understood. We aimed to develop a safe surgical procedure for the OTA according to the practical aspects of arachnoid anatomy.

Methods: The procedure is shown through an illustrative video of surgery and cadaver. Five cadavers were analyzed for their arachnoid structures and the surgical procedures via the OTA, in strict compliance with legal and ethical requirements.

Results: All cadavers showed a 2-layered arachnoid structure-one belonging to the occipital lobe, and the other to the cerebellum. According to our cadaveric analysis, the arachnoid attachment of the tentorial apex can be peeled bluntly, with an average distance of 10.2 mm. For our clinical presentation, a pineal tumor with hydrocephalus was detected in a 14-year-old boy. While using the OTA and expanding the deep surgical field, we detached the membrane from the tentorial apex and bluntly peeled it to reveal the deep veins. Finally, gross total removal of the tumor was achieved.

Conclusions: A 2-layered arachnoid structure interposes the GVG from above and below the tentorium. The arachnoid membrane below the tentorium can be peeled off bluntly from the GVG to the attachment bundle limited by the penetrating veins. This detachment technique is useful for safe enlargement of the surgical field for the OTA.
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http://dx.doi.org/10.1016/j.wneu.2021.04.041DOI Listing
July 2021

Flavonoid-triazolyl hybrids as potential anti-hepatitis C virus agents: Synthesis and biological evaluation.

Eur J Med Chem 2021 Jun 31;218:113395. Epub 2021 Mar 31.

Key Laboratory of Computational Chemistry Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China. Electronic address:

A series of flavonoid-triazolyl hybrids were synthesized and evaluated as novel inhibitors of hepatitis C virus (HCV). The results of anti-HCV activity assays showed that most of the synthesized derivatives at a concentration of 100 μg/mL inhibited the generation of progeny virus. Among these derivatives, 10m and 10r exhibited the most potent anti-HCV activity and inhibited the production of HCV in a dose-dependent manner. Interestingly, 10m and 10r had no significant inhibitory effect on viral translation or replication. Additional action mechanism studies revealed that the most potent compounds, 10m and 10r, significantly inhibited viral entry to 34.0% and 52.0%, respectively, at 10 μM. These results suggest further effective application of 10m and 10r as potential HCV preventive agents.
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http://dx.doi.org/10.1016/j.ejmech.2021.113395DOI Listing
June 2021

Self-ordered nanospike porous alumina fabricated under a new regime by an anodizing process in alkaline media.

Sci Rep 2021 Mar 31;11(1):7240. Epub 2021 Mar 31.

Division of Materials Science and Engineering, Faculty of Engineering, Hokkaido University, N13-W8, Kita-ku, Sapporo, Hokkaido, 060-8628, Japan.

High-aspect ratio ordered nanomaterial arrays exhibit several unique physicochemical and optical properties. Porous anodic aluminum oxide (AAO) is one of the most typical ordered porous structures and can be easily fabricated by applying an electrochemical anodizing process to Al. However, the dimensional and structural controllability of conventional porous AAOs is limited to a narrow range because there are only a few electrolytes that work in this process. Here, we provide a novel anodizing method using an alkaline electrolyte, sodium tetraborate (NaBO), for the fabrication of a high-aspect ratio, self-ordered nanospike porous AAO structure. This self-ordered porous AAO structure possesses a wide range of the interpore distance under a new anodizing regime, and highly ordered porous AAO structures can be fabricated using pre-nanotexturing of Al. The vertical pore walls of porous AAOs have unique nanospikes measuring several tens of nanometers in periodicity, and we demonstrate that AAO can be used as a template for the fabrication of nanomaterials with a large surface area. We also reveal that stable anodizing without the occurrence of oxide burning and the subsequent formation of uniform self-ordered AAO structures can be achieved on complicated three-dimensional substrates.
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http://dx.doi.org/10.1038/s41598-021-86696-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012646PMC
March 2021

Morphokinetic analysis of pronuclei using time-lapse cinematography in bovine zygotes.

Theriogenology 2021 May 2;166:55-63. Epub 2021 Mar 2.

Department of Biological Production, Tokyo University of Agriculture and Technology, Tokyo, 183-8538, Japan. Electronic address:

The morphokinetics of pronuclei (PN) are considered crucial factors affecting embryogenesis in mammals. Whereas, since bovine zygotes contain a large number of cytosolic lipid droplets, detailed observation of PN has not been performed. In this study, we visualized PN using time-lapse cinematography (TLC) with light microscopy for the first time in delipidated bovine zygotes. The proportions of 0 PN, 1PN, 2PN, and multi-PN in delipidated bovine zygotes were 10.1%, 6.5%, 72.7%, and 10.8%, respectively. Abnormal fertilization, including 1 PN and multi-PN, was observed in 15.6% of blastocysts. The times from IVF to PN appearance, PN fading, and first cleavage in 2 PN bovine zygotes that developed into blastocysts were 10.4, 25.5, and 27.6 h, respectively, which were similar to PN morphokinetics in humans. The 2 PN zygotes showed that the prolonged time from IVF to the appearance of PN and from the fading of PN to the first cleavage negatively affected blastocyst formation. The time from appearance to fading of PN in multi-PN zygotes that developed into blastocysts was longer than that in multi-PN zygotes that did not develop into blastocysts. Besides, among zygotes that developed into blastocysts, the time from appearance to fading of PN in multi-PN zygotes was longer than that in 2 PN and 1 PN zygotes. These results suggest that PN morphokinetic abnormalities are associated with subsequent embryonic development. Observation of PN in bovine zygotes by using non-invasive visible light TLC by delipidation could be a powerful tool to clarify the relationship between PN morphokinetics and developmental competence.
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http://dx.doi.org/10.1016/j.theriogenology.2021.02.021DOI Listing
May 2021

Split Nano Luciferase-based Assay to Measure Assembly of Japanese Encephalitis Virus.

Bio Protoc 2020 May 5;10(9):e3606. Epub 2020 May 5.

Department of Biochemistry and Molecular Biology, Faculty of Agriculture and Life Science, Hirosaki University, 3 Bunkyo-cho, Hirosaki-shi, Aomori, Japan.

Cells infected with flavivirus release various forms of infectious and non-infectious particles as products and by-products. Comprehensive profiling of the released particles by density gradient centrifugation is informative for understanding viral particle assembly. However, it is difficult to detect low-abundance minor particles in such analyses. We developed a method for viral particle analysis that integrates a high-sensitivity split luciferase system and density gradient centrifugation. This protocol enables high-resolution profiling of particles produced by cells expressing Japanese encephalitis virus factors.
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http://dx.doi.org/10.21769/BioProtoc.3606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842715PMC
May 2020

Identification of Two Critical Neutralizing Epitopes in the Receptor Binding Domain of Hepatitis B Virus preS1.

J Virol 2020 Dec 9. Epub 2020 Dec 9.

Department of Virology II, National Institute of Infectious Diseases

Hepatitis B virus (HBV) infection is a major public health problem. Human hepatocytes are infected with HBV via binding between the preS1 region in the large envelope protein of HBV and sodium taurocholate cotransporting polypeptide. Although several monoclonal antibodies (MAbs) that recognize the receptor binding domain in preS1 and neutralize HBV infection have been isolated, details of neutralizing epitopes are not understood. In this study, we generated 13 MAbs targeting the preS1 receptor binding domain from preS1-specific memory B cells derived from DNA immunized mice. The MAbs were classified into three groups according to the epitope regions, designated epitopes I-III. A virus neutralization assay revealed that MAbs recognizing epitopes I and III neutralized HBV infection, suggesting that these domains are critical epitopes for viral neutralization. In addition, a neutralization assay against multiple genotypes of HBV revealed that epitope I is a semi-pangenotypic neutralizing epitope, whereas epitope III is a genotype-specific epitope. We also showed that neutralizing MAbs against preS1 could neutralize HBV bearing vaccine-induced escape mutation. These findings provide insight into novel immunoprophylaxis for the prevention and treatment of HBV infection. The HBV preS1 2-47 aa region (preS1/2-47) is essential for virus binding with sodium taurocholate cotransporting polypeptide. Several MAbs targeting preS1/2-47 have been reported to neutralize HBV infection; however, which region in preS1/2-47 contains the critical neutralizing epitope for HBV infection is unclear. Here, we generated several MAbs targeting preS1/2-47 and found that MAbs recognizing the N- or C-terminus of preS1/2-47 remarkably neutralized HBV infection. We further confirmed the neutralizing activity of anti-preS1 MAbs against HBV with vaccine escape mutation. These data clarified the relationship between the antibody epitope and the virus neutralizing activity and also suggested the potential ability of a vaccine antigen containing the preS1 region to overcome the weakness of current HB vaccines comprising the small S protein.
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http://dx.doi.org/10.1128/JVI.01680-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092832PMC
December 2020

Sphingomyelin Is Essential for the Structure and Function of the Double-Membrane Vesicles in Hepatitis C Virus RNA Replication Factories.

J Virol 2020 11 9;94(23). Epub 2020 Nov 9.

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

Some plus-stranded RNA viruses generate double-membrane vesicles (DMVs), one type of the membrane replication factories, as replication sites. Little is known about the lipid components involved in the biogenesis of these vesicles. Sphingomyelin (SM) is required for hepatitis C virus (HCV) replication, but the mechanism of SM involvement remains poorly understood. SM biosynthesis starts in the endoplasmic reticulum (ER) and gives rise to ceramide, which is transported from the ER to the Golgi by the action of ceramide transfer protein (CERT), where it can be converted to SM. In this study, inhibition of SM biosynthesis, either by using small-molecule inhibitors or by knockout (KO) of CERT, suppressed HCV replication in a genotype-independent manner. This reduction in HCV replication was rescued by exogenous SM or ectopic expression of the CERT protein, but not by ectopic expression of nonfunctional CERT mutants. Observing low numbers of DMVs in stable replicon cells treated with a SM biosynthesis inhibitor or in CERT-KO cells transfected with either HCV replicon or with constructs that drive HCV protein production in a replication-independent system indicated the significant importance of SM to DMVs. The degradation of SM of the -isolated DMVs affected their morphology and increased the vulnerability of HCV RNA and proteins to RNase and protease treatment, respectively. Poliovirus, known to induce DMVs, showed decreased replication in CERT-KO cells, while dengue virus, known to induce invaginated vesicles, did not. In conclusion, these findings indicated that SM is an essential constituent of DMVs generated by some plus-stranded RNA viruses. Previous reports assumed that sphingomyelin (SM) is essential for HCV replication, but the mechanism was unclear. In this study, we showed for the first time that SM and ceramide transfer protein (CERT), which is in the SM biosynthesis pathway, are essential for the biosynthesis of double-membrane vesicles (DMVs), the sites of viral replication. Low numbers of DMVs were observed in CERT-KO cells transfected with replicon RNA or with constructs that drive HCV protein production in a replication-independent system. HCV replication was rescued by ectopic expression of the CERT protein, but not by CERT mutants, that abolishes the binding of CERT to vesicle-associated membrane protein-associated protein (VAP) or phosphatidylinositol 4-phosphate (PI4P), indicating new roles for VAP and PI4P in HCV replication. The biosynthesis of DMVs has great importance to replication by a variety of plus-stranded RNA viruses. Understanding of this process is expected to facilitate the development of diagnosis and antivirus.
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http://dx.doi.org/10.1128/JVI.01080-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654263PMC
November 2020

A Simple and High-Throughput ELISA-Based Neutralization Assay for the Determination of Anti-Flavivirus Neutralizing Antibodies.

Vaccines (Basel) 2020 Jun 10;8(2). Epub 2020 Jun 10.

Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto 1-12-4, Nagasaki 852-8523, Japan.

Mosquito-borne flavivirus infections, including dengue virus and Zika virus, are major public health threats globally. While the plaque reduction neutralization test (PRNT) is considered the gold standard for determining neutralizing antibody levels to flaviviruses, the assay is time-consuming and laborious. This study, therefore, aimed to develop an enzyme-linked immunosorbent assay (ELISA)-based microneutralization test (EMNT) for the detection of neutralizing antibodies to mosquito-borne flaviviruses. The inhibition of viral growth due to neutralizing antibodies was determined colorimetrically by using EMNT. Given the significance of Fcγ-receptors (FcγR) in antibody-mediated neutralization and antibody-dependent enhancement (ADE) of flavivirus infection, non-FcγR and FcγR-expressing cell lines were used in the EMNT to allow the detection of the sum of neutralizing and immune-enhancing antibody activity as the neutralizing titer. Using anti-flavivirus monoclonal antibodies and clinical samples, the utility of EMNT was evaluated by comparing the end-point titers of the EMNT and the PRNT. The correlation between EMNT and PRNT titers was strong, indicating that EMNT was robust and reproducible. The new EMNT assay combines the biological functional assessment of virus neutralization activity and the technical advantages of ELISA and, is simple, reliable, practical, and could be automated for high-throughput implementation in flavivirus surveillance studies and vaccine trials.
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http://dx.doi.org/10.3390/vaccines8020297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350015PMC
June 2020

N-Terminal PreS1 Sequence Regulates Efficient Infection of Cell-Culture-Generated Hepatitis B Virus.

Hepatology 2021 02 31;73(2):520-532. Epub 2020 Oct 31.

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

Background And Aims: An efficient cell-culture system for hepatitis B virus (HBV) is indispensable for research on viral characteristics and antiviral reagents. Currently, for the HBV infection assay in cell culture, viruses derived from HBV genome-integrated cell lines of HepG2.2.15 or HepAD-38 are commonly used. However, these viruses are not suitable for the evaluation of polymorphism-dependent viral characteristics or resistant mutations against antiviral reagents. HBV obtained by the transient transfection of the ordinary HBV molecular clone has limited infection efficiencies in cell culture.

Approach And Results: We found that an 11-amino-acid deletion (d11) in the preS1 region enhances the infectivity of cell-culture-generated HBV (HBVcc) to sodium taurocholate cotransporting polypeptide-transduced HepG2 (HepG2/NTCP) cells. Infection of HBVcc derived from a d11-introduced genotype C strain (GTC-d11) was ~10-fold more efficient than infection of wild-type GTC (GTC-wt), and the number of infected cells was comparable between GTC-d11- and HepG2.2.15-derived viruses when inoculated with the same genome equivalents. A time-dependent increase in pregenomic RNA and efficient synthesis of covalently closed circular DNA were detected after infection with the GTC-d11 virus. The involvement of d11 in the HBV large surface protein in the enhanced infectivity was confirmed by an HBV reporter virus and hepatitis D virus infection system. The binding step of the GTC-d11 virus onto the cell surface was responsible for this efficient infection.

Conclusions: This system provides a powerful tool for studying the infection and propagation of HBV in cell culture and also for developing the antiviral strategy against HBV infection.
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http://dx.doi.org/10.1002/hep.31308DOI Listing
February 2021

Comparative characterization of flavivirus production in two cell lines: Human hepatoma-derived Huh7.5.1-8 and African green monkey kidney-derived Vero.

PLoS One 2020 24;15(4):e0232274. Epub 2020 Apr 24.

Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan.

The Flaviviridae is a family of enveloped viruses with a positive-sense single-stranded RNA genome. It contains many viruses that threaten human health, such as Japanese encephalitis virus (JEV) and yellow fever virus (YFV) of the genus Flavivirus as well as hepatitis C virus of the genus Hepacivirus. Cell culture systems highly permissive for the Flaviviridae viruses are very useful for their isolation, propagation, and diagnosis, an understanding of their biology, and the development of vaccines and antiviral agents. Previously, we isolated a human hepatoma HuH-7-derived cell clone, Huh7.5.1-8, which is highly permissive to hepatitis C virus infection. Here, we have characterized flavivirus infection in the Huh7.5.1-8 cell line by comparing with that in the African green monkey kidney-derived Vero cell line, which is permissive for a wide spectrum of viruses. Upon infection with JEV, Huh7.5.1-8 cells produced a higher amount of virus particles early in infection and were more susceptible to virus-induced cell death than Vero cells. Similar outcomes were obtained when the cells were infected with another flavivirus, YFV (17D-204 strain). Quantification of cellular and extracellular viral RNA revealed that high JEV production in Huh7.5.1-8 cells can be attributed to rapid viral replication kinetics and efficient virus release early in infection. In a plaque assay, Huh7.5.1-8 cells developed JEV plaques more rapidly than Vero cells. Although this was not the case with YFV plaques, Huh7.5.1-8 cells developed higher numbers of YFV plaques than Vero cells. Sequence analysis of cDNA encoding an antiviral RNA helicase, RIG-I, showed that Huh7.5.1-8 cells expressed not only a full-length RIG-I mRNA with a known dominant-negative missense mutation but also variants without the mutation. However, the latter mRNAs lacked exon 5/6-12, indicating functional loss of RIG-I in the cells. These characteristics of the Huh7.5.1-8 cell line are helpful for flavivirus detection, titration, and propagation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232274PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182267PMC
July 2020

Atypical oncologic failure after laparoscopic and robot-assisted radical cystectomy at a single institution.

Int J Clin Oncol 2020 Jul 18;25(7):1385-1392. Epub 2020 Apr 18.

Department of Urology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan.

Background: The incidence of atypical oncologic failure in patients with bladder cancer, including peritoneal carcinomatosis, and recurrences at the port site and soft tissue after laparoscopic and robot-assisted radical cystectomy are not well characterized.

Methods: We retrospectively reviewed the records of 52, 51, and 12 patients who underwent open, laparoscopic, and robot-assisted radical cystectomy, respectively, for bladder cancer from 2007 to 2018 at our institution. We identified techniques associated with atypical oncologic failure.

Results: The median follow-up period was 29 months. Among the 115 patients, 29 (25%) experienced oncological recurrences, and 7 (6%), 12 (10%), and 23 (20%) had atypical, local, and distant recurrences, respectively. The laparoscopic and robot-assisted radical cystectomy groups had significantly higher incidences of total atypical oncologic failure than the open radical cystectomy group (p = 0.013), including six, one, and two patients with peritoneal carcinomatosis, port site carcinomatosis, and soft tissue involvement, respectively. All 7 patients with atypical oncologic failure died of cancer; the median time from surgery to death was 9.3 months. All these patients were cT ≧ 3 and had grade 3 disease. In three patients (43%), the pathological tissue contained variants other than urothelial carcinoma. Five (71%) were among the initial twenty patients. Four patients (57%) had histories of intraoperative urine spillage or bladder perforation during transurethral resection.

Conclusions: Patients with cT ≧ 3 stage, with pathological variants other than urothelial carcinoma, and those undergoing procedures that lead to extravesical dissemination should avoid laparoscopic radical cystectomy when the procedures are first introduced.
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http://dx.doi.org/10.1007/s10147-020-01677-yDOI Listing
July 2020

Surgical outcomes and learning curve of totally intracorporeal ileal conduit urinary diversion following laparoscopic radical cystectomy at a single institution.

Asian J Endosc Surg 2020 Oct 28;13(4):532-538. Epub 2020 Feb 28.

Department of Urology, Kobe City Medical Centre General Hospital, Kobe, Japan.

Introduction: Constant evaluation of the outcomes of laparoscopic intracorporeal urinary diversion is not yet established. This study aimed to describe surgical outcomes and learning curve of intracorporeal ileal conduit (ICIC) following laparoscopic radical cystectomy (LRC) at a single institution.

Methods: From June 2012 to February 2018, 38 patients with bladder cancer underwent LRC with ileal conduit at our institution. Surgical outcomes were compared between ICIC (n = 30) and extracorporeal ileal conduit (ECIC) (n = 8). The learning curve during ICIC with regard to the operative time and complication rate was compared.

Results: No significant differences in patient characteristics between the ICIC and ECIC groups were found. Comparison of outcomes between the ICIC and ECIC groups were as follows: median total operative time, 688 vs 713 minutes; urinary diversion time, 213 vs 192 minutes; and estimated blood loss, 450 vs 420 mL, respectively. The median time to walking and oral intake were similar in both groups. Rates of high-grade complications associated with urinary diversion (Clavien-Dindo grade ≥ III) were 3% in ICIC and 25% in ECIC. Although 25% of ECIC patients developed wound dehiscence (Clavien-Dindo grade IIIb), no patient in the ICIC group had postoperative wound infection. For the learning curve of ICIC (n = 30), urinary diversion time decreased significantly (27 minutes decrease per 10 cases, P = .02). Clavien-Dindo grade ≥ II complication did not occur after 20 cases.

Conclusions: LRC with ICIC could be performed safely with low incidence of severe wound infection compared with ECIC. The incidence and severity of complications also decreased with time.
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http://dx.doi.org/10.1111/ases.12793DOI Listing
October 2020

The machinery for endocytosis of epidermal growth factor receptor coordinates the transport of incoming hepatitis B virus to the endosomal network.

J Biol Chem 2020 01 12;295(3):800-807. Epub 2019 Dec 12.

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

Sodium taurocholate cotransporting polypeptide (NTCP) is expressed at the surface of human hepatocytes and functions as an entry receptor of hepatitis B virus (HBV). Recently, we have reported that epidermal growth factor receptor (EGFR) is involved in NTCP-mediated viral internalization during the cell entry process. Here, we analyzed which function of EGFR is essential for mediating HBV internalization. In contrast to the reported crucial function of EGFR-downstream signaling for the entry of hepatitis C virus (HCV), blockade of EGFR-downstream signaling proteins, including mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and signal transducer and activator of transcription (STAT), had no or only minor effects on HBV infection. Instead, deficiency of EGFR endocytosis resulting from either a deleterious mutation in EGFR or genetic knockdown of endocytosis adaptor molecules abrogated internalization of HBV via NTCP and prevented viral infection. EGFR activation triggered a time-dependent relocalization of HBV preS1 to the early and late endosomes and to lysosomes in concert with EGFR transport. Suppression of EGFR ubiquitination by site-directed mutagenesis or by knocking down two EGFR-sorting molecules, signal-transducing adaptor molecule (STAM) and lysosomal protein transmembrane 4β (LAPTM4B), suggested that EGFR transport to the late endosome is critical for efficient HBV infection. Cumulatively, these results support the idea that the EGFR endocytosis/sorting machinery drives the translocation of NTCP-bound HBV from the cell surface to the endosomal network, which eventually enables productive viral infection.
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http://dx.doi.org/10.1074/jbc.AC119.010366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970923PMC
January 2020

A Superhydrophilic Aluminum Surface with Fast Water Evaporation Based on Anodic Alumina Bundle Structures via Anodizing in Pyrophosphoric Acid.

Materials (Basel) 2019 Oct 25;12(21). Epub 2019 Oct 25.

Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Katahira 2-1-1, Aoba-ku, Sendai, Miyagi 980-8577, Japan.

A superhydrophilic aluminum surface with fast water evaporation based on nanostructured aluminum oxide was fabricated via anodizing in pyrophosphoric acid. Anodizing aluminum in pyrophosphoric acid caused the successive formation of a barrier oxide film, a porous oxide film, pyramidal bundle structures with alumina nanofibers, and completely bent nanofibers. During the water contact angle measurements at 1 s after the water droplet was placed on the anodized surface, the contact angle rapidly decreased to less than 10°, and superhydrophilic behavior with the lowest contact angle measuring 2.0° was exhibited on the surface covered with the pyramidal bundle structures. As the measurement time of the contact angle decreased to 200-33 ms after the water placement, although the contact angle slightly increased in the initial stage due to the formation of porous alumina, at 33 ms after the water placement, the contact angle was 9.8°, indicating that superhydrophilicity with fast water evaporation was successfully obtained on the surface covered with the pyramidal bundle structures. We found that the shape of the pyramidal bundle structures was maintained in water without separation by in situ high-speed atomic force microscopy measurements.
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http://dx.doi.org/10.3390/ma12213497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862615PMC
October 2019

[Clinical Effect of Nivolumab on Advanced Renal Cell Carcinoma with Peritoneal Metastasis].

Hinyokika Kiyo 2019 Oct;65(10):413-419

The Department of Urology, Kyoto University Hospital.

Peritoneal dissemination or metastasis is a relatively rare presentation of renal cell carcinoma. We report four cases of advanced renal cell carcinoma with peritoneal metastases treated with nivolumab. Three cases showed an objective response in the metastatic lesions including peritoneal sites. After nivolumab administration, the computed tomography scan showed a transient enlargement of peritoneal lesions in two cases, which could be considered as pseudoprogression. Temporal changes of neutrophil-tolymphocyte ratio, C-reactive protein, and eosinophil ratio during the clinical course reflected the treatment effect of nivolumab in these patients, indicating that these could be potential biomarkers of the response. To our knowledge, this is the first case series showing therapeutic activity of nivolumab against peritoneal metastases in patients with renal cell carcinoma.
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http://dx.doi.org/10.14989/ActaUrolJap_65_10_413DOI Listing
October 2019

Comparison of the Clinical Features of Hepatitis A in People Living with HIV between Pandemics in 1999-2000 and 2017-2018 in the Metropolitan Area of Japan.

Jpn J Infect Dis 2020 Mar 31;73(2):89-95. Epub 2019 Oct 31.

Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo.

Since 2017, hepatitis A virus (HAV) infection has been an epidemic among men who have sex with men (MSM) in Japan. We have come across 11 MSM patients with hepatitis A who were also infected with HIV. In 1999-2000, we came across 5 HIV-infected patients with hepatitis A. Since the conditions of current HIV-infected patients have changed owing to the recent progress in anti-HIV therapies, we compared clinical features of hepatitis A between patients in 2017-2018 and those in 1999-2000. By comparing the background characteristics of the patients, we found that the CD4/CD8 ratio was significantly higher in the 2017-2018 group. After the onset of hepatitis, peak levels of hepatic transaminases were found to be higher in the 2017-2018 group, suggesting severe hepatocellular damage. In contrast, neither the peak level of total bilirubin nor the nadir of prothrombin time was significantly different among the 2 groups. We also analyzed the HAV genome derived from some of the recently infected patients, and found that the HAV strains were almost the same among these patients; slight differences were observed from the previously identified strain. Thus, we concluded that the recovery of immunity by recent anti-HIV therapies may result in more severe hepatocellular damages and differences in clinical features.
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http://dx.doi.org/10.7883/yoken.JJID.2019.275DOI Listing
March 2020

Surfeit 4 Contributes to the Replication of Hepatitis C Virus Using Double-Membrane Vesicles.

J Virol 2020 01 6;94(2). Epub 2020 Jan 6.

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

A number of positive-strand RNA viruses, such as hepatitis C virus (HCV) and poliovirus, use double-membrane vesicles (DMVs) as replication sites. However, the role of cellular proteins in DMV formation during virus replication is poorly understood. HCV NS4B protein induces the formation of a "membranous web" structure that provides a platform for the assembly of viral replication complexes. Our previous screen of NS4B-associated host membrane proteins by dual-affinity purification, liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), and small interfering RNA (siRNA) methods revealed that the Surfeit 4 (Surf4) gene, which encodes an integral membrane protein, is involved in the replication of the JFH1 subgenomic replicon. Here, we investigated in detail the effect of Surf4 on HCV replication. Surf4 affects HCV replication in a genotype-independent manner, whereas HCV replication does not alter Surf4 expression. The influence of Surf4 on HCV replication indicates that while Surf4 regulates replication, it has no effect on entry, translation, assembly, or release. Analysis of the underlying mechanism showed that Surf4 is recruited into HCV RNA replication complexes by NS4B and is involved in the formation of DMVs and the structural integrity of RNA replication complexes. Surf4 also participates in the replication of poliovirus, which uses DMVs as replication sites, but it has no effect on the replication of dengue virus, which uses invaginated/sphere-type vesicles as replication sites. These findings clearly show that Surf4 is a novel cofactor that is involved in the replication of positive-strand RNA viruses using DMVs as RNA replication sites, which provides valuable clues for DMV formation during positive-strand RNA virus replication. Hepatitis C virus (HCV) NS4B protein induces the formation of a membranous web (MW) structure that provides a platform for the assembly of viral replication complexes. The main constituents of the MW are double-membrane vesicles (DMVs). Here, we found that the cellular protein Surf4, which maintains endoplasmic reticulum (ER)-Golgi intermediate compartments and the Golgi compartment, is recruited into HCV RNA replication complexes by NS4B and is involved in the formation of DMVs. Moreover, Surf4 participates in the replication of poliovirus, which uses DMVs as replication sites, but has no effect on the replication of dengue virus, which uses invaginated vesicles as replication sites. These results indicate that the cellular protein Surf4 is involved in the replication of positive-strand RNA viruses that use DMVs as RNA replication sites, providing new insights into DMV formation during virus replication and potential targets for the diagnosis and treatment of positive-strand RNA viruses.
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http://dx.doi.org/10.1128/JVI.00858-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955281PMC
January 2020

Integrin α3 is involved in non-enveloped hepatitis E virus infection.

Virology 2019 10 30;536:119-124. Epub 2019 Jul 30.

Department of Quality Assurance and Radiological Protection, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashi-murayama, Tokyo, 208-0011, Japan. Electronic address:

Hepatitis E virus (HEV) causes acute and fulminant hepatitis worldwide. Although enveloped (e) and non-enveloped (ne) forms of HEV have been discovered, host factors involved in infection, including receptors, remain to be elucidated. Here, we identified integrin α3 (encoded by ITGA3), a protein that binds and responds to the extracellular matrix, as an essential host factor for HEV infection. Integrin α3 expression was lower in four HEV-non-permissive cell subclones than in an HEV-permissive subclone. ITGA3 knockout cells lost HEV permissibility, suggesting that integrin α3 is critical for HEV infection. Stable expression of integrin α3 in an HEV-non-permissive subclone provided permissibility only to infection by neHEV; expression of integrin α3 lacking the ectodomain did not. Direct interaction between neHEV and the integrin α3 ectodomain was confirmed by co-precipitation using a soluble integrin α3-Fc. These results strongly suggest that integrin α3 is a key molecule for cellular attachment and entry of neHEV.
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http://dx.doi.org/10.1016/j.virol.2019.07.025DOI Listing
October 2019

Functional Correlation between Subcellular Localizations of Japanese Encephalitis Virus Capsid Protein and Virus Production.

J Virol 2019 10 12;93(19). Epub 2019 Sep 12.

Department of Biochemistry and Molecular Biology, Faculty of Agriculture and Life Science, Hirosaki University, Aomori, Japan

The flavivirus capsid protein is considered to be essential for the formation of nucleocapsid complexes with viral genomic RNA at the viral replication organelle that appears on the endoplasmic reticulum (ER), as well as for incorporation into virus particles. However, this protein is also detected at the lipid droplet (LD) and nucleolus, and physiological roles of these off-site localizations are still unclear. In this study, we made a series of alanine substitution mutants of Japanese encephalitis virus (JEV) capsid protein that cover all polar and hydrophobic amino acid residues to identify the molecular surfaces required for virus particle formation and for localization at the LD and nucleolus. Five mutants exhibited a defect in the formation of infectious particles, and two of these mutants failed to be incorporated into the subviral particles (SVP). Three mutants lost the ability to localize to the nucleolus, and only a single mutant, with mutations at α2, was unable to localize to the LD. Unlike the cytoplasmic capsid protein, the nucleolar capsid protein was resistant to detergent treatment, and the α2 mutant was hypersensitive to detergent treatment. To scrutinize the relationship between these localizations and viral particle formation, we made eight additional alanine substitution mutants and found that all the mutants that did not localize at the LD or nucleolus failed to form normal viral particles. These results support the functional correlation between LD or nucleolus localization of the flaviviral capsid protein and the formation of infectious viral particles. This study is the first to report the comprehensive mutagenesis of a flavivirus capsid protein. We assessed the requirement of each molecular surface for infectious viral particle formation as well as for LD and nucleolar localization and found functional relationships between the subcellular localization of the virus capsid protein and infectious virus particle formation. We developed a system to independently assess the packaging of viral RNA and that of the capsid protein and found a molecular surface of the capsid protein that is crucial for packaging of viral RNA but not for packaging of the capsid protein itself. We also characterized the biochemical properties of capsid protein mutants and found that the capsid protein localizes at the nucleolus in a different manner than for its localization to the LD. Our comprehensive alanine-scanning mutagenesis study will aid in the development of antiflavivirus small molecules that can target the flavivirus capsid protein.
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http://dx.doi.org/10.1128/JVI.00612-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744241PMC
October 2019

[A Case of Late Onset Nivolumab-Induced Interstitial Nephritis in a Patient with Metastatic Renal Cell Carcinoma].

Hinyokika Kiyo 2019 May;65(5):157-161

The Department of Urology, Graduate School of Medicine, Kyoto University.

A 43-year-old man underwent nephrectomy for right renal cell carcinoma (cT3aN0M1 (PUL), clear cell carcinoma). Thereafter, he was treated with sunitinib for lung metastases as the first-line therapy for three months. Because lung metastases progressed and new bone metastases appeared, nivolumab was started for the second-line treatment. Although the cancer progression was suppressed by multidisciplinary treatment combined with systemic immunotherapy and local radiation therapy, he developed severe acute kidney injury with cortical swelling after eighteen months of nivolumab treatment. A diagnosis of acute interstitial nephritis induced by nivolumab was made based on biopsy findings. Treatment with prednisolone (1.0 mg/kg daily) led to a rapid improvement in renal function. We must consider the possibility of immunerelated adverse events, especially nivolumab-induced acute kidney injury, even after long-term treatment.
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http://dx.doi.org/10.14989/ActaUrolJap_65_5_157DOI Listing
May 2019

[A Case of Systemic Polyarteritis Nodosa Presenting with Scrotal Pain].

Hinyokika Kiyo 2019 Apr;65(4):127-131

The Department of Urology, Kobe City Medical Center General Hospital.

A 76-year-old man with a history of hypertension was admitted with high fever and left scrotal pain. Laboratory findings revealed high serum C-reactive protein levels. The left epididymis appeared to be swollen on computed tomography. The patient was diagnosed with bacterial epididymitis and treatment with antibiotics was initiated. Despite treatment, his left scrotal pain and fever did not improve. Additionally, he developed right scrotal and posterior neck pain. For histopathological diagnosis, a left high orchiectomy was performed and the findings revealed thickened arteriolar walls with infiltration of inflammatory cells around the testis, leading to a final diagnosis of systemic polyarteritis nodosa. Treatment with steroids led to complete resolution of the patient's systemic pain and inflammation.
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http://dx.doi.org/10.14989/ActaUrolJap_65_4_127DOI Listing
April 2019

[A Case of Renal Oncocytosis with Bilateral Multiple Renal Masses].

Hinyokika Kiyo 2019 Apr;65(4):111-116

The Department of Pathology, Kobe City Medical Center General Hospital.

A 63-year-old man with microscopic hematuria underwent contrast-enhanced CT, which showed multiple bilateral renal masses. Percutaneous biopsy results indicated renal oncocytosis. The tumors remained unchanged for 3 years. Renal oncocytosis is a very rare tumor, but it is an established disease entity characterized by numerous oncocytic tumors and diffuse (sporadic) renal parenchymal epithelial oncocytic changes on an analysis histopathology. Although renal oncocytosis can be sporadic or part of Birt-Hogg-Dube syndrome (BHDS), our case did not associate with BHDS because of absence of lung cyst.
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http://dx.doi.org/10.14989/ActaUrolJap_65_4_111DOI Listing
April 2019

Fulminant type 1 diabetes mellitus induced by pembrolizumab in a patient with urothelial carcinoma: A case report.

Urol Case Rep 2019 May 15;24:100849. Epub 2019 Feb 15.

Department of Urology, Kobe City Medical Center General Hospital, 2-1-1 Minatojimaminami-cho, Chuo-ku, Kobe City, Hyogo, 650-0047, Japan.

A case of fulminant type 1 diabetes mellitus secondary to administration of pembrolizumab in a patient with urothelial carcinoma is presented. Eight days after the third infusion of pembrolizumab, the patient presented with complaints of malaise and anorexia. The patient's laboratory data showed a blood glucose level of 1092mg/dl with ketonuria and negative for glutamic acid decarboxylase antibody. As leaving ketoacidosis by insulin therapy, pembrolizumab therapy was continued without delay. After administration of another eight infusions of pembrolizumab, the patient's disease was stable without new severe side effects.
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http://dx.doi.org/10.1016/j.eucr.2019.100849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562295PMC
May 2019

Basal expression of interferon regulatory factor 1 drives intrinsic hepatocyte resistance to multiple RNA viruses.

Nat Microbiol 2019 07 15;4(7):1096-1104. Epub 2019 Apr 15.

UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.

Current models of cell-intrinsic immunity to RNA viruses centre on virus-triggered inducible antiviral responses initiated by RIG-I-like receptors or Toll-like receptors that sense pathogen-associated molecular patterns, and signal downstream through interferon regulatory factors (IRFs), transcription factors that induce synthesis of type I and type III interferons. RNA viruses have evolved sophisticated strategies to disrupt these signalling pathways and evade elimination by cells, attesting to their importance. Less attention has been paid to how IRFs maintain basal levels of protection against viruses. Here, we depleted antiviral factors linked to RIG-I-like receptor and Toll-like receptor signalling to map critical host pathways restricting positive-strand RNA virus replication in immortalized hepatocytes and identified an unexpected role for IRF1. We show that constitutively expressed IRF1 acts independently of mitochondrial antiviral signalling (MAVS) protein, IRF3 and signal transducer and activator of transcription 1 (STAT1)-dependent signalling to provide intrinsic antiviral protection in actinomycin D-treated cells. IRF1 localizes to the nucleus, where it maintains the basal transcription of a suite of antiviral genes that protect against multiple pathogenic RNA viruses, including hepatitis A and C viruses, dengue virus and Zika virus. Our findings reveal an unappreciated layer of hepatocyte-intrinsic immunity to these positive-strand RNA viruses and identify previously unrecognized antiviral effector genes.
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http://dx.doi.org/10.1038/s41564-019-0425-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588457PMC
July 2019
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