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Article ; Online: Microcystin-LR-induced epithelial-mesenchymal transition-like cells acquire resistance to multi-toxins.

Takumi, Shota / Tomioka, Masaru / Yunoki, Yasunari / Eto, Risa / Komatsu, Yumiko / Shiozaki, Kazuhiro / Komatsu, Masaharu

Toxicon : official journal of the International Society on Toxinology

2023 Volume 238, Page(s) 107592

Abstract: The protein phosphatase inhibitor microcystin-LR (MC-LR), a hepatocyte-selective cyanotoxin, induces phenotypic changes in HEK293 OATP1B3-expressing (HEK293-OATP1B3) cells, which include cytoskeletal reorganization (HEK293-OATP1B3-AD) and anoikis ... ...

Abstract	The protein phosphatase inhibitor microcystin-LR (MC-LR), a hepatocyte-selective cyanotoxin, induces phenotypic changes in HEK293 OATP1B3-expressing (HEK293-OATP1B3) cells, which include cytoskeletal reorganization (HEK293-OATP1B3-AD) and anoikis resistance (HEK293-OATP1B3-FL) transformed cells, respectively. These cells acquire resistance to MC-LR and partial epithelial-mesenchymal transition (EMT) characteristics. In cancer cells, EMT is generally involved in multi-drug resistance. Here, we focused on the multi-drug resistance of HEK293-OATP1B3-AD and HEK293-OATP1B3-FL cells. The MTT assay and immunoblotting were conducted to examine the responses of HEK293-OATP1B3, HEK293-OATP1B3-AD, and HEK293-OATP1B3-FL cells to multiple toxins and drugs that function as substrates for OATP1B3, including MC-LR, nodularin (Nod), okadaic acid (OA), and cisplatin (CDDP). HEK293-OATP1B3-AD and HEK293-OATP1B3-FL cells were more resistant to MC-LR, Nod, and OA than HEK293-OATP1B3 cells. Conversely, the three cell types were equivalently sensitive to CDDP. By using protein phosphatase assay, the reduction of the inhibitory effect of MC-LR and Nod on phosphatase activity might be one reason for the resistance to MC-LR and Nod in HEK293-OATP1B3-AD and HEK293-OATP1B3-FL cells. Furthermore, the parental HEK293-OATP1B3 cells showed enhanced p53 phosphorylation and stabilization after MC-LR exposure, while p53 phosphorylation was attenuated in HEK293-OATP1B3-AD and HEK293-OATP1B3-FL cells. Moreover, in HEK293-OATP1B3-AD and HEK293-OATP1B3-FL cells, AKT phosphorylation was higher than that of the parental HEK293-OATP1B3 cell line. These results suggest that the multi-toxin resistance observed in HEK293-OATP1B3-AD and HEK293-OATP1B3-FL cells is associated with AKT activation and p53 inactivation.
MeSH term(s)	Humans ; Organic Anion Transporters, Sodium-Independent/metabolism ; Organic Anion Transporters, Sodium-Independent/pharmacology ; Solute Carrier Organic Anion Transporter Family Member 1B3/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Tumor Suppressor Protein p53/metabolism ; HEK293 Cells ; Microcystins/metabolism ; Okadaic Acid/toxicity ; Epithelial-Mesenchymal Transition ; Phosphoprotein Phosphatases ; Marine Toxins
Chemical Substances	cyanoginosin LR (EQ8332842Y) ; Organic Anion Transporters, Sodium-Independent ; Solute Carrier Organic Anion Transporter Family Member 1B3 ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Tumor Suppressor Protein p53 ; Microcystins ; Okadaic Acid (1W21G5Q4N2) ; Phosphoprotein Phosphatases (EC 3.1.3.16) ; Marine Toxins
Language	English
Publishing date	2023-12-30
Publishing country	England
Document type	Journal Article
ZDB-ID	204479-1
ISSN	1879-3150 ; 0041-0101
ISSN (online)	1879-3150
ISSN	0041-0101
DOI	10.1016/j.toxicon.2023.107592
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Article: Coccomyxa subellipsoidea

Seki, Toshiro / Ohshima, Shino / Komatsu, Satoko / Yamada, Soga / Kashiwagi, Hirofumi / Goto, Yumiko / Tsuda, Banri / Kanno, Akiko / Yasuda, Atsushi / Kuno, Hitoshi / Tsuji, Noriko M / Shiina, Takashi / Kametani, Yoshie

Microorganisms

2024 Volume 12, Issue 4

Abstract: Coccomyxa ... ...

Abstract	Coccomyxa subellipsoidea
Language	English
Publishing date	2024-04-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720891-6
ISSN	2076-2607
ISSN	2076-2607
DOI	10.3390/microorganisms12040741
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Article: Feline restrictive orbital myofibroblastic sarcoma treated with toceranib phosphate (Palladia) as adjuvant chemotherapy: A case study of one cat.

Komatsu, Hiroyuki / Ueshima, Asuka / Kobayashi, Yoshitaka / Shimoyama, Yumiko / Takiyama, Naoaki / Rimpo, Kenji

Clinical case reports

2023 Volume 11, Issue 6, Page(s) e7582

Abstract: Key clinical message: This is the first case report of treatment with toceranib phosphate as postsurgical adjuvant chemotherapy for advanced FROMS. This reported case highlights the need for further studies on the efficacy of toceranib phosphate as ... ...

Abstract	Key clinical message: This is the first case report of treatment with toceranib phosphate as postsurgical adjuvant chemotherapy for advanced FROMS. This reported case highlights the need for further studies on the efficacy of toceranib phosphate as adjuvant chemotherapy for FROMS. Abstract: Feline restrictive orbital myofibroblastic sarcoma (FROMS) is a rare aggressive tumor in cats. We explored the effectiveness of using toceranib phosphate as postsurgical adjuvant chemotherapy for advanced FROMS in a 7-year-old cat. Despite treatment, the cat died 4 months after surgery. This report highlights the need for further studies on the efficacy of toceranib phosphate as adjuvant chemotherapy for FROMS.
Language	English
Publishing date	2023-06-17
Publishing country	England
Document type	Case Reports
ZDB-ID	2740234-4
ISSN	2050-0904
ISSN	2050-0904
DOI	10.1002/ccr3.7582
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Article ; Online: Reverse genetics approaches of Borna disease virus: applications in development of viral vectors and preventive vaccines.

Komatsu, Yumiko / Tomonaga, Keizo

Current opinion in virology

2020 Volume 44, Page(s) 42–48

Abstract: The plasmid-based reverse genetics system, which involves generation of recombinant viruses from cloned cDNA, has accelerated the understanding of clinical and virological aspects of different viruses. Borna disease virus (BoDV) is a nonsegmented, ... ...

Abstract	The plasmid-based reverse genetics system, which involves generation of recombinant viruses from cloned cDNA, has accelerated the understanding of clinical and virological aspects of different viruses. Borna disease virus (BoDV) is a nonsegmented, negative-strand RNA virus that causes persistent intranuclear infection in various vertebrate species. Since its first report, reverse genetics approaches with modified strategies have greatly improved rescue efficiency of recombinant BoDV and enhanced the understanding of function of each viral protein and mechanism of intranuclear persistency. Here, we summarize different reverse genetics approaches of BoDV and recent developments in the use of reverse genetics for generation of viral vectors for gene therapy and virus-like particles for potential preventive vaccines.
MeSH term(s)	Animals ; Borna Disease/prevention & control ; Borna disease virus/genetics ; Borna disease virus/pathogenicity ; Genetic Vectors ; Genome, Viral ; Plasmids/genetics ; Plasmids/immunology ; RNA, Viral/genetics ; Reverse Genetics/methods ; Vaccines, Virus-Like Particle/genetics ; Vaccines, Virus-Like Particle/immunology ; Viral Proteins/genetics ; Viral Vaccines/genetics ; Viral Vaccines/immunology ; Virus Replication
Chemical Substances	RNA, Viral ; Vaccines, Virus-Like Particle ; Viral Proteins ; Viral Vaccines
Language	English
Publishing date	2020-07-10
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2611378-8
ISSN	1879-6265 ; 1879-6257
ISSN (online)	1879-6265
ISSN	1879-6257
DOI	10.1016/j.coviro.2020.05.011
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Article ; Online: The Borna Disease Virus 2 (BoDV-2) Nucleoprotein Is a Conspecific Protein That Enhances BoDV-1 RNA-Dependent RNA Polymerase Activity.

Kanda, Takehiro / Horie, Masayuki / Komatsu, Yumiko / Tomonaga, Keizo

Journal of virology

2021 Volume 95, Issue 21, Page(s) e0093621

Abstract: An RNA virus-based episomal vector (REVec) based on Borna disease virus 1 (BoDV-1) is a promising viral vector that achieves stable and long-term gene expression in transduced cells. However, the onerous procedure of reverse genetics used to generate an ... ...

Abstract	An RNA virus-based episomal vector (REVec) based on Borna disease virus 1 (BoDV-1) is a promising viral vector that achieves stable and long-term gene expression in transduced cells. However, the onerous procedure of reverse genetics used to generate an REVec is one of the challenges that must be overcome to make REVec technologies practical for use. In this study, to resolve the problems posed by reverse genetics, we focused on BoDV-2, a conspecific virus of BoDV-1 in the
MeSH term(s)	Amino Acid Sequence ; Animals ; Borna Disease/virology ; Borna disease virus/enzymology ; Borna disease virus/metabolism ; Cell Nucleus/virology ; Chlorocebus aethiops ; Genetic Vectors/metabolism ; HEK293 Cells ; Humans ; Nucleoproteins/metabolism ; Plasmids/metabolism ; RNA, Viral/metabolism ; RNA-Dependent RNA Polymerase/metabolism ; Reverse Genetics/methods ; Vero Cells ; Viral Proteins/metabolism ; Virus Replication ; Viruses, Unclassified/metabolism
Chemical Substances	Nucleoproteins ; RNA, Viral ; Viral Proteins ; RNA-Dependent RNA Polymerase (EC 2.7.7.48)
Language	English
Publishing date	2021-08-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00936-21
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Article ; Online: Feline restrictive orbital myofibroblastic sarcoma treated with toceranib phosphate (Palladia) as adjuvant chemotherapy

Hiroyuki Komatsu / Asuka Ueshima / Yoshitaka Kobayashi / Yumiko Shimoyama / Naoaki Takiyama / Kenji Rimpo

Clinical Case Reports, Vol 11, Iss 6, Pp n/a-n/a (2023)

A case study of one cat

2023

Abstract: Key Clinical Message This is the first case report of treatment with toceranib phosphate as postsurgical adjuvant chemotherapy for advanced FROMS. This reported case highlights the need for further studies on the efficacy of toceranib phosphate as ... ...

Abstract	Key Clinical Message This is the first case report of treatment with toceranib phosphate as postsurgical adjuvant chemotherapy for advanced FROMS. This reported case highlights the need for further studies on the efficacy of toceranib phosphate as adjuvant chemotherapy for FROMS. Abstract Feline restrictive orbital myofibroblastic sarcoma (FROMS) is a rare aggressive tumor in cats. We explored the effectiveness of using toceranib phosphate as postsurgical adjuvant chemotherapy for advanced FROMS in a 7‐year‐old cat. Despite treatment, the cat died 4 months after surgery. This report highlights the need for further studies on the efficacy of toceranib phosphate as adjuvant chemotherapy for FROMS.
Keywords	adjuvant chemotherapy ; feline orbital tumor ; feline restrictive orbital myofibroblastic sarcoma ; toceranib phosphate ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
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Article ; Online: In vivo biodistribution analysis of transmission competent and defective RNA virus-based episomal vector.

Komatsu, Yumiko / Tanaka, Chiaki / Komorizono, Ryo / Tomonaga, Keizo

Scientific reports

2020 Volume 10, Issue 1, Page(s) 5890

Abstract: RNA virus-based episomal vector (REVec) is an emerging viral vector system that mediates long-term stable gene expression in variety of cell types in vitro. However, little is known about its tissue tropism and persistence of gene expression in vivo. ... ...

Abstract	RNA virus-based episomal vector (REVec) is an emerging viral vector system that mediates long-term stable gene expression in variety of cell types in vitro. However, little is known about its tissue tropism and persistence of gene expression in vivo. Here, to evaluate the feasibility of REVec for in vivo gene delivery, we conducted biodistribution analysis of transmission competent REVec and transmission defective ΔG-REVec in Lewis rats. Following intracranial administration of REVec, transgene expression was detected in various tissues. In contrast, transgene expression was only observed in the brain after ΔG-REVec administration. Low levels of vector shedding in the feces and blood and of neutralizing antibody in the serum were detected after REVec injection. In the brain, microglia, astrocytes and neurons were susceptible to REVec-mediated transduction. However, the animals administered with REVec, but not with ΔG-REVec showed a significant decrease in body weight compared to mock treated animals. Additionally, CD8 T cell infiltration was observed in the brain of these animals. In summary, we demonstrated that REVec promotes long-term transgene expression in vivo without causing high vector shedding or neutralizing antibody production; however, suggests the need to attenuate vector associated pathogenicity in the future.
MeSH term(s)	Animals ; Animals, Genetically Modified ; Antibodies, Neutralizing/blood ; Antibodies, Viral/blood ; Astrocytes/metabolism ; Brain/metabolism ; Feasibility Studies ; Feces/virology ; Female ; Gene Expression ; Genetic Vectors/administration & dosage ; Genetic Vectors/genetics ; Genetic Vectors/isolation & purification ; Genetic Vectors/pharmacokinetics ; Microglia/metabolism ; Neurons/metabolism ; Plasmids/genetics ; RNA Viruses/genetics ; RNA Viruses/immunology ; RNA Viruses/isolation & purification ; Rats ; Rats, Inbred Lew ; Tissue Distribution ; Transduction, Genetic ; Transgenes/genetics ; Virus Replication ; Virus Shedding
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral
Language	English
Publishing date	2020-04-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-62630-7
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Article ; Online: Production of high-titer transmission-defective RNA virus-based episomal vector using tangential flow filtration.

Komatsu, Yumiko / Kakuya, Yoji / Tomonaga, Keizo

Microbiology and immunology

2020 Volume 64, Issue 9, Page(s) 602–609

Abstract: In recent years, viral vector based in vivo gene delivery strategies have achieved a significant success in the treatment of genetic diseases. RNA virus-based episomal vector lacking viral glycoprotein gene (ΔG-REVec) is a nontransmissive gene delivery ... ...

Abstract	In recent years, viral vector based in vivo gene delivery strategies have achieved a significant success in the treatment of genetic diseases. RNA virus-based episomal vector lacking viral glycoprotein gene (ΔG-REVec) is a nontransmissive gene delivery system that enables long-term gene expression in a variety of cell types in vitro, yet in vivo gene delivery has not been successful due to the difficulty in producing high titer vector. The present study showed that tangential flow filtration (TFF) can be effectively employed to increase the titer of ΔG-REVec. Concentration and diafiltration of ΔG-REVec using TFF significantly increased its titer without loss of infectious activity. Importantly, intracranial administration of high titer vector enabled persistent transgene expression in rodent brain.
MeSH term(s)	Animals ; Brain/virology ; Cell Line ; Chlorocebus aethiops ; Female ; Filtration/methods ; Gene Expression ; Gene Transfer Techniques ; Genetic Vectors/administration & dosage ; Genetic Vectors/isolation & purification ; HEK293 Cells ; Humans ; Plasmids/genetics ; Plasmids/isolation & purification ; Pregnancy ; RNA Viruses/genetics ; RNA Viruses/isolation & purification ; Rats ; Rats, Inbred Lew ; Transgenes ; Vero Cells ; Viral Load
Language	English
Publishing date	2020-08-27
Publishing country	Australia
Document type	Journal Article
ZDB-ID	224792-6
ISSN	1348-0421 ; 0385-5600
ISSN (online)	1348-0421
ISSN	0385-5600
DOI	10.1111/1348-0421.12831
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Article ; Online: EGFR-TKI rechallenge in patients with EGFR-mutated non-small-cell lung cancer who progressed after first-line osimertinib treatment: A multicenter retrospective observational study.

Araki, Taisuke / Kanda, Shintaro / Obara, Miho / Agatsuma, Toshihiko / Kakizaki, Yumiko / Hama, Mineyuki / Yamamoto, Hiroshi / Takada, Munetake / Yamamoto, Manabu / Matsuo, Akemi / Kondo, Daichi / Komatsu, Masamichi / Sonehara, Kei / Tateishi, Kazunari / Hanaoka, Masayuki / Koizumi, Tomonobu

Respiratory investigation

2024 Volume 62, Issue 2, Page(s) 262–268

Abstract: Background: Rechallenge therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is known to confer some clinical benefit for patients with metastatic EGFR-mutated non-small cell lung cancer (NSCLC). However, little is known ... ...

Abstract	Background: Rechallenge therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is known to confer some clinical benefit for patients with metastatic EGFR-mutated non-small cell lung cancer (NSCLC). However, little is known about the efficacy of EGFR-TKI rechallenge after resistance to first-line (1L) osimertinib. This study aimed to assess the efficacy and safety of EGFR-TKI rechallenge therapy after resistance to 1L osimertinib in a Japanese clinical setting. Methods: Between April 2018 and August 2022, 26 patients who progressed after treatment with 1L osimertinib and received EGFR-TKI rechallenge were included in this multicenter retrospective analysis. Patients in whom 1L osimertinib was discontinued owing to toxicity and had subsequent disease progression were also included in the analysis. Results: Overall, the objective response rate for rechallenge therapy was 23.1%. The disease control rate was 53.9%, and the median progression-free survival (PFS) was 3.4 months. Patients who discontinued 1L osimertinib for toxicity had a higher response rate (42.9% vs. 15.8%) and longer PFS than those who discontinued it due to disease progression (median: 11.4 vs. 2.7 months, P = 0.001). Three patients (11.5%) developed rechallenge therapy-associated pneumonitis, two of which were grade ≥3. Conclusions: Rechallenge with EGFR-TKI after 1L osimertinib resistance showed limited clinical efficacy. However, it could be considered as a subsequent salvage therapeutic option for patients in whom 1L osimertinib was discontinued owing to toxicity.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Retrospective Studies ; ErbB Receptors/genetics ; Disease Progression ; Mutation ; Protein Kinase Inhibitors/adverse effects ; Acrylamides ; Aniline Compounds ; Indoles ; Pyrimidines
Chemical Substances	osimertinib (3C06JJ0Z2O) ; ErbB Receptors (EC 2.7.10.1) ; Protein Kinase Inhibitors ; EGFR protein, human (EC 2.7.10.1) ; Acrylamides ; Aniline Compounds ; Indoles ; Pyrimidines
Language	English
Publishing date	2024-01-20
Publishing country	Netherlands
Document type	Multicenter Study ; Observational Study ; Journal Article
ZDB-ID	2660821-2
ISSN	2212-5353 ; 2212-5345
ISSN (online)	2212-5353
ISSN	2212-5345
DOI	10.1016/j.resinv.2024.01.002
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Article ; Online: In vivo biodistribution analysis of transmission competent and defective RNA virus-based episomal vector

Yumiko Komatsu / Chiaki Tanaka / Ryo Komorizono / Keizo Tomonaga

Scientific Reports, Vol 10, Iss 1, Pp 1-

2020 Volume 12

Abstract: Abstract RNA virus-based episomal vector (REVec) is an emerging viral vector system that mediates long-term stable gene expression in variety of cell types in vitro. However, little is known about its tissue tropism and persistence of gene expression in ... ...

Abstract	Abstract RNA virus-based episomal vector (REVec) is an emerging viral vector system that mediates long-term stable gene expression in variety of cell types in vitro. However, little is known about its tissue tropism and persistence of gene expression in vivo. Here, to evaluate the feasibility of REVec for in vivo gene delivery, we conducted biodistribution analysis of transmission competent REVec and transmission defective ΔG-REVec in Lewis rats. Following intracranial administration of REVec, transgene expression was detected in various tissues. In contrast, transgene expression was only observed in the brain after ΔG-REVec administration. Low levels of vector shedding in the feces and blood and of neutralizing antibody in the serum were detected after REVec injection. In the brain, microglia, astrocytes and neurons were susceptible to REVec-mediated transduction. However, the animals administered with REVec, but not with ΔG-REVec showed a significant decrease in body weight compared to mock treated animals. Additionally, CD8 T cell infiltration was observed in the brain of these animals. In summary, we demonstrated that REVec promotes long-term transgene expression in vivo without causing high vector shedding or neutralizing antibody production; however, suggests the need to attenuate vector associated pathogenicity in the future.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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