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Article: Personalized immunotherapy in cancer precision medicine.

Kiyotani, Kazuma / Toyoshima, Yujiro / Nakamura, Yusuke

2021

Abstract: With the significant advances in cancer genomics using next-generation sequencing technologies, genomic and molecular profiling-based precision medicine is used as a part of routine clinical test for guiding and selecting the most appropriate treatments ... ...

Abstract	With the significant advances in cancer genomics using next-generation sequencing technologies, genomic and molecular profiling-based precision medicine is used as a part of routine clinical test for guiding and selecting the most appropriate treatments for individual cancer patients. Although many molecular-targeted therapies for a number of actionable genomic alterations have been developed, the clinical application of such information is still limited to a small proportion of cancer patients. In this review, we summarize the current status of personalized drug selection based on genomic and molecular profiling and highlight the challenges how we can further utilize the individual genomic information. Cancer immunotherapies, including immune checkpoint inhibitors, would be one of the potential approaches to apply the results of genomic sequencing most effectively. Highly cancer-specific antigens derived from somatic mutations, the so-called neoantigens, occurring in individual cancers have been in focus recently. Cancer immunotherapies, which target neoantigens, could lead to a precise treatment for cancer patients, despite the challenge in accurately predicting neoantigens that can induce cytotoxic T cells in individual patients. Precise prediction of neoantigens should accelerate the development of personalized immunotherapy including cancer vaccines and T-cell receptor-engineered T-cell therapy for a broader range of cancer patients.
Language	English
Publishing date	2021-08-09
Publishing country	China
Document type	Journal Article ; Review
ZDB-ID	2676322-9
ISSN	2095-3941
ISSN	2095-3941
DOI	10.20892/j.issn.2095-3941.2021.0032
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Article ; Online: Immunogenomics in personalized cancer treatments.

Kiyotani, Kazuma / Toyoshima, Yujiro / Nakamura, Yusuke

Journal of human genetics

2021 Volume 66, Issue 9, Page(s) 901–907

Abstract: Recent advances in next-generation sequencing technologies have led to significant improvements in cancer genomic research and cancer treatment. Through the use of comprehensive cancer genome data, precision medicine has become more of a reality; albeit, ...

Abstract	Recent advances in next-generation sequencing technologies have led to significant improvements in cancer genomic research and cancer treatment. Through the use of comprehensive cancer genome data, precision medicine has become more of a reality; albeit, at present, only ~10-15% of patients can benefit from current genomic testing practices. Improvements in cancer genome analyses have contributed to a better understanding of antitumor immunity and have provided solutions for targeting highly cancer-specific neoantigens generated from somatic mutations in individual patients. Since then, numerous studies have demonstrated the importance of neoantigens and neoantigen-reactive T cells in the tumor microenvironment and how their presence influences the beneficial responses associated with various cancer immunotherapies, including immune checkpoint inhibitor therapy. Indeed, cancer immunotherapies that explicitly target neoantigens specific to individual cancer patients would lead to the ultimate form of cancer precision medicine. For this to be realized, several issues would need to be overcome, including the accurate prediction and selection of neoantigens that can induce cytotoxic T cells in individual patients. The precise prediction of target neoantigens will likely accelerate the development of personalized immunotherapy including cancer vaccines and T-cell receptor-engineered T-cell therapy for patients with cancer.
MeSH term(s)	Genetic Therapy ; Genomics ; Humans ; Immunotherapy ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; Precision Medicine ; Tumor Microenvironment
Language	English
Publishing date	2021-06-30
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1425192-9
ISSN	1435-232X ; 1434-5161
ISSN (online)	1435-232X
ISSN	1434-5161
DOI	10.1038/s10038-021-00950-w
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Article ; Online: Personalized immunotherapy in cancer precision medicine

Kazuma Kiyotani / Yujiro Toyoshima / Yusuke Nakamura

Cancer Biology & Medicine, Vol 18, Iss 4, Pp 955-

2021 Volume 965

Abstract	With the significant advances in cancer genomics using next-generation sequencing technologies, genomic and molecular profiling-based precision medicine is used as a part of routine clinical test for guiding and selecting the most appropriate treatments for individual cancer patients. Although many molecular-targeted therapies for a number of actionable genomic alterations have been developed, the clinical application of such information is still limited to a small proportion of cancer patients. In this review, we summarize the current status of personalized drug selection based on genomic and molecular profiling and highlight the challenges how we can further utilize the individual genomic information. Cancer immunotherapies, including immune checkpoint inhibitors, would be one of the potential approaches to apply the results of genomic sequencing most effectively. Highly cancer-specific antigens derived from somatic mutations, the so-called neoantigens, occurring in individual cancers have been in focus recently. Cancer immunotherapies, which target neoantigens, could lead to a precise treatment for cancer patients, despite the challenge in accurately predicting neoantigens that can induce cytotoxic T cells in individual patients. Precise prediction of neoantigens should accelerate the development of personalized immunotherapy including cancer vaccines and T-cell receptor-engineered T-cell therapy for a broader range of cancer patients.
Keywords	personalized medicine ; cancer precision medicine ; neoantigen ; personalized immunotherapy ; immune checkpoint blockade ; cancer vaccine ; adoptive t cell therapy ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
Subject code	616
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	China Anti-Cancer Association
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Bioinformatic prediction of potential T cell epitopes for SARS-Cov-2.

Kiyotani, Kazuma / Toyoshima, Yujiro / Nemoto, Kensaku / Nakamura, Yusuke

Journal of human genetics

2020 Volume 65, Issue 7, Page(s) 569–575

Abstract: To control and prevent the current COVID-19 pandemic, the development of novel vaccines is an emergent issue. In addition, we need to develop tools that can measure/monitor T-cell and B-cell responses to know how our immune system is responding to this ... ...

Abstract	To control and prevent the current COVID-19 pandemic, the development of novel vaccines is an emergent issue. In addition, we need to develop tools that can measure/monitor T-cell and B-cell responses to know how our immune system is responding to this deleterious virus. However, little information is currently available about the immune target epitopes of novel coronavirus (SARS-CoV-2) to induce host immune responses. Through a comprehensive bioinformatic screening of potential epitopes derived from the SARS-CoV-2 sequences for HLAs commonly present in the Japanese population, we identified 2013 and 1399 possible peptide epitopes that are likely to have the high affinity (<0.5%- and 2%-rank, respectively) to HLA class I and II molecules, respectively, that may induce CD8
MeSH term(s)	Asian Continental Ancestry Group/genetics ; Base Sequence ; Betacoronavirus/immunology ; COVID-19 Vaccines ; Coronavirus/genetics ; Coronavirus Infections/immunology ; Coronavirus Infections/prevention & control ; Epitopes, T-Lymphocyte/chemistry ; Epitopes, T-Lymphocyte/genetics ; Epitopes, T-Lymphocyte/immunology ; Histocompatibility Antigens Class I/chemistry ; Histocompatibility Antigens Class I/genetics ; Histocompatibility Antigens Class I/immunology ; Histocompatibility Antigens Class II/chemistry ; Histocompatibility Antigens Class II/genetics ; Histocompatibility Antigens Class II/immunology ; Humans ; Mutation ; Open Reading Frames ; SARS Virus/immunology ; SARS-CoV-2 ; Viral Vaccines/immunology
Chemical Substances	COVID-19 Vaccines ; Epitopes, T-Lymphocyte ; Histocompatibility Antigens Class I ; Histocompatibility Antigens Class II ; Viral Vaccines
Keywords	covid19
Language	English
Publishing date	2020-05-06
Publishing country	England
Document type	Journal Article
ZDB-ID	1425192-9
ISSN	1435-232X ; 1434-5161
ISSN (online)	1435-232X
ISSN	1434-5161
DOI	10.1038/s10038-020-0771-5
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Article ; Online: SARS-CoV-2 genomic variations associated with mortality rate of COVID-19.

Toyoshima, Yujiro / Nemoto, Kensaku / Matsumoto, Saki / Nakamura, Yusuke / Kiyotani, Kazuma

Journal of human genetics

2020 Volume 65, Issue 12, Page(s) 1075–1082

Abstract: The coronavirus disease 2019 (COVID-19) outbreak, caused by SARS-CoV-2, has rapidly expanded to a global pandemic. However, numbers of infected cases, deaths, and mortality rates related to COVID-19 vary from country to country. Although many studies ... ...

Abstract	The coronavirus disease 2019 (COVID-19) outbreak, caused by SARS-CoV-2, has rapidly expanded to a global pandemic. However, numbers of infected cases, deaths, and mortality rates related to COVID-19 vary from country to country. Although many studies were conducted, the reasons of these differences have not been clarified. In this study, we comprehensively investigated 12,343 SARS-CoV-2 genome sequences isolated from patients/individuals in six geographic areas and identified a total of 1234 mutations by comparing with the reference SARS-CoV-2 sequence. Through a hierarchical clustering based on the mutant frequencies, we classified the 28 countries into three clusters showing different fatality rates of COVID-19. In correlation analyses, we identified that ORF1ab 4715L and S protein 614G variants, which are in a strong linkage disequilibrium, showed significant positive correlations with fatality rates (r = 0.41, P = 0.029 and r = 0.43, P = 0.022, respectively). We found that BCG-vaccination status significantly associated with the fatality rates as well as number of infected cases. In BCG-vaccinated countries, the frequency of the S 614G variant had a trend of association with the higher fatality rate. We also found that the frequency of several HLA alleles, including HLA-A*11:01, were significantly associated with the fatality rates, although these factors were associated with number of infected cases and not an independent factor to affect fatality rate in each country. Our findings suggest that SARS-CoV-2 mutations as well as BCG-vaccination status and a host genetic factor, HLA genotypes might affect the susceptibility to SARS-CoV-2 infection or severity of COVID-19.
MeSH term(s)	Age Factors ; BCG Vaccine/genetics ; BCG Vaccine/therapeutic use ; Betacoronavirus/classification ; Betacoronavirus/genetics ; Betacoronavirus/immunology ; Betacoronavirus/isolation & purification ; COVID-19 ; Coronavirus Infections/genetics ; Coronavirus Infections/immunology ; Coronavirus Infections/mortality ; Coronavirus Infections/virology ; Epitopes/genetics ; Genome, Viral ; Global Health ; HLA-A Antigens/genetics ; HLA-A Antigens/immunology ; HLA-B Antigens/genetics ; HLA-B Antigens/immunology ; Humans ; Mutation ; Pandemics ; Pneumonia, Viral/genetics ; Pneumonia, Viral/immunology ; Pneumonia, Viral/mortality ; Pneumonia, Viral/virology ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/genetics
Chemical Substances	BCG Vaccine ; Epitopes ; HLA-A Antigens ; HLA-B Antigens ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Keywords	covid19
Language	English
Publishing date	2020-07-22
Publishing country	England
Document type	Journal Article
ZDB-ID	1425192-9
ISSN	1435-232X ; 1434-5161
ISSN (online)	1435-232X
ISSN	1434-5161
DOI	10.1038/s10038-020-0808-9
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Article: [Clinical Features in Surgical Cases of Female Spontaneous Pneumothorax;Comparison with Male Patients].

Toyoshima, Yujiro / Otani, Yoshimi / Okada, Naoki / Shomura, Hiroki

Kyobu geka. The Japanese journal of thoracic surgery

2018 Volume 71, Issue 6, Page(s) 403–406

Abstract: We assessed the clinical features in surgery cases of female spontaneous pneumothorax by comparing them with male patients. One hundred six patients ( female/male:16/90)who had undergone surgery for spontaneous pneumothorax between January 2003 and ... ...

Abstract	We assessed the clinical features in surgery cases of female spontaneous pneumothorax by comparing them with male patients. One hundred six patients ( female/male:16/90)who had undergone surgery for spontaneous pneumothorax between January 2003 and August 2013 was retrospectively studied. Patient background, pneumothorax classification and treatment were assessed. No significant difference was found in patient background and treatment. In pneumothorax classification, the frequency of secondary pneumothorax in females was significantly greater than that in males (p<0.001). Additionally, in females, the number of bulla identified during surgery was significantly fewer and the number of recurrences before surgery was more frequent than that in males.
MeSH term(s)	Blister/diagnosis ; Female ; Humans ; Male ; Pleural Diseases/diagnosis ; Pneumothorax/classification ; Pneumothorax/etiology ; Pneumothorax/surgery ; Recurrence ; Retrospective Studies ; Sex Factors
Language	Japanese
Publishing date	2018-06-19
Publishing country	Japan
Document type	Comparative Study ; Journal Article
ZDB-ID	603899-2
ISSN	0021-5252
ISSN	0021-5252
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Article ; Online: SARS-CoV-2 genomic variations associated with mortality rate of COVID-19

Toyoshima, Yujiro / Nemoto, Kensaku / Matsumoto, Saki / Nakamura, Yusuke / Kiyotani, Kazuma

Journal of Human Genetics ; ISSN 1434-5161 1435-232X

2020

Keywords	Genetics(clinical) ; Genetics ; covid19
Language	English
Publisher	Springer Science and Business Media LLC
Publishing country	us
Document type	Article ; Online
DOI	10.1038/s10038-020-0808-9
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum.

Higuchi, Yujiro / Ando, Masahiro / Kojima, Fumikazu / Yuan, Junhui / Hashiguchi, Akihiro / Yoshimura, Akiko / Hiramatsu, Yu / Nozuma, Satoshi / Fukumura, Shinobu / Yahikozawa, Hiroyuki / Abe, Erika / Toyoshima, Itaru / Sugawara, Masashiro / Okamoto, Yuji / Matsuura, Eiji / Takashima, Hiroshi

Journal of neurology

2023 Volume 271, Issue 1, Page(s) 419–430

Abstract: Background and objective: Biallelic mutations in the COA7 gene have been associated with spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3), and a notable clinical diversity has been observed. We aim to identify the genetic and phenotypic ... ...

Abstract	Background and objective: Biallelic mutations in the COA7 gene have been associated with spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3), and a notable clinical diversity has been observed. We aim to identify the genetic and phenotypic spectrum of COA7-related disorders. Methods: We conducted comprehensive genetic analyses on the COA7 gene within a large group of Japanese patients clinically diagnosed with inherited peripheral neuropathy or cerebellar ataxia. Results: In addition to our original report, which involved four patients until 2018, we identified biallelic variants of the COA7 gene in another three unrelated patients, and the variants were c.17A > G (p.D6G), c.115C > T (p.R39W), and c.449G > A (p.C150Y; novel). Patient 1 presented with an infantile-onset generalized dystonia without cerebellar ataxia. Despite experiencing an initial transient positive response to levodopa and deep brain stimulation, he became bedridden by the age of 19. Patient 2 presented with cerebellar ataxia, neuropathy, as well as parkinsonism, and showed a slight improvement upon levodopa administration. Dopamine transporter SPECT showed decreased uptake in the bilateral putamen in both patients. Patient 3 exhibited severe muscle weakness, respiratory failure, and feeding difficulties. A haplotype analysis of the mutation hotspot in Japan, c.17A > G (p.D6G), uncovered a common haplotype block. Conclusion: COA7-related disorders typically encompass a spectrum of conditions characterized by a variety of major (cerebellar ataxia and axonal polyneuropathy) and minor (leukoencephalopathy, dystonia, and parkinsonism) symptoms, but may also display a dystonia-predominant phenotype. We propose that COA7 should be considered as a new causative gene for infancy-onset generalized dystonia, and COA7 gene screening is recommended for patients with unexplained dysfunctions of the central and peripheral nervous systems.
MeSH term(s)	Humans ; Male ; Cerebellar Ataxia/genetics ; Dystonia ; Dystonic Disorders/complications ; Dystonic Disorders/diagnostic imaging ; Dystonic Disorders/genetics ; Levodopa ; Mutation/genetics ; Parkinsonian Disorders/complications ; Parkinsonian Disorders/diagnostic imaging ; Parkinsonian Disorders/genetics ; Phenotype ; Young Adult
Chemical Substances	Levodopa (46627O600J) ; COA7 protein, human
Language	English
Publishing date	2023-09-26
Publishing country	Germany
Document type	Journal Article
ZDB-ID	187050-6
ISSN	1432-1459 ; 0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
ISSN (online)	1432-1459
ISSN	0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
DOI	10.1007/s00415-023-11998-3
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Article: Bioinformatic prediction of potential T cell epitopes for SARS-Cov-2

Kiyotani, Kazuma / Toyoshima, Yujiro / Nemoto, Kensaku / Nakamura, Yusuke

J Hum Genet

Abstract	To control and prevent the current COVID-19 pandemic, the development of novel vaccines is an emergent issue. In addition, we need to develop tools that can measure/monitor T-cell and B-cell responses to know how our immune system is responding to this deleterious virus. However, little information is currently available about the immune target epitopes of novel coronavirus (SARS-CoV-2) to induce host immune responses. Through a comprehensive bioinformatic screening of potential epitopes derived from the SARS-CoV-2 sequences for HLAs commonly present in the Japanese population, we identified 2013 and 1399 possible peptide epitopes that are likely to have the high affinity (<0.5%- and 2%-rank, respectively) to HLA class I and II molecules, respectively, that may induce CD8+ and CD4+ T-cell responses. These epitopes distributed across the structural (spike, envelope, membrane, and nucleocapsid proteins) and the nonstructural proteins (proteins corresponding to six open reading frames); however, we found several regions where high-affinity epitopes were significantly enriched. By comparing the sequences of these predicted T cell epitopes to the other coronaviruses, we identified 781 HLA-class I and 418 HLA-class II epitopes that have high homologies to SARS-CoV. To further select commonly-available epitopes that would be applicable to larger populations, we calculated population coverages based on the allele frequencies of HLA molecules, and found 2 HLA-class I epitopes covering 83.8% of the Japanese population. The findings in the current study provide us valuable information to design widely-available vaccine epitopes against SARS-CoV-2 and also provide the useful information for monitoring T-cell responses.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #185840
Database	COVID19

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Article ; Online: IFN-α/β-mediated NK2R expression is related to the malignancy of colon cancer cells.

Xiang, Huihui / Toyoshima, Yujiro / Shen, Weidong / Wang, Xiangdong / Okada, Naoki / Kii, Shuhei / Sugiyama, Ko / Nagato, Toshihiro / Kobayashi, Hiroya / Ikeo, Kazuho / Hashimoto, Shinichi / Tanino, Mishie / Taketomi, Akinobu / Kitamura, Hidemitsu

Cancer science

2022 Volume 113, Issue 8, Page(s) 2513–2525

Abstract: Neurokinin 2 receptor (NK2R), a G protein-coupled receptor for neurokinin A (NKA), a tachykinin family member, regulates various physiological functions including pain response, relaxation of smooth muscle, dilation of blood vessels, and vascular ... ...

Abstract	Neurokinin 2 receptor (NK2R), a G protein-coupled receptor for neurokinin A (NKA), a tachykinin family member, regulates various physiological functions including pain response, relaxation of smooth muscle, dilation of blood vessels, and vascular permeability. However, the precise role and regulation of NK2R expression in cancer cells have not been fully elucidated. In this study, we found that high NK2R gene expression was correlated with the poor survival of colorectal cancer patients, and Interferon (IFN-α/β) stimulation significantly enhanced NK2R gene expression level of colon cancer cells in a Janus kinas 1/2 (JAK 1/2)-dependent manner. NKA stimulation augmented viability/proliferation and phosphorylation of Extracellular-signal-regulated kinase 1/2 (ERK1/2) levels of IFN-α/β-treated colon cancer cells and NK2R blockade by using a selective antagonist reduced the proliferation in vitro. Administration of an NK2R antagonist alone or combined with polyinosinic-polycytidylic acid, a synthetic analog of double-stranded RNA, to CT26-bearing mice significantly suppressed tumorigenesis. NK2R-overexpressing CT26 cells showed enhanced tumorigenesis and metastatic colonization in both lung and liver after the inoculation into mice. These findings indicate that IFN-α/β-mediated NK2R expression is related to the malignancy of colon cancer cells, suggesting that NK2R blockade may be a promising strategy for colon cancers.
MeSH term(s)	Animals ; Carcinogenesis ; Colonic Neoplasms/genetics ; Colonic Neoplasms/pathology ; Gene Expression ; Humans ; Interferon-alpha/genetics ; Interferon-beta/genetics ; Mice ; Neurokinin A/genetics ; Receptors, Neurokinin-2/genetics ; Receptors, Neurokinin-2/metabolism
Chemical Substances	Interferon-alpha ; Receptors, Neurokinin-2 ; Interferon-beta (77238-31-4) ; Neurokinin A (86933-74-6)
Language	English
Publishing date	2022-05-31
Publishing country	England
Document type	Journal Article
ZDB-ID	2115647-5
ISSN	1349-7006 ; 1349-7006
ISSN (online)	1349-7006
ISSN	1349-7006
DOI	10.1111/cas.15397
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