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Article: [A Case of Intestinal Fistula Associated with Small Intestinal Metastasis from Small Cell Lung Carcinoma].

Furuyama, Takaki / Asano, Sakiko / Kondo, Ito / Hinokida, Makoto / Tatsutomi, Yusuke / Nakazawa, Kunihiko / Ushirokoji, Yoshio

Gan to kagaku ryoho. Cancer & chemotherapy

2024 Volume 50, Issue 13, Page(s) 1543–1545

Abstract: A 53-year-old man who complained of dyspnea and prolonged cough visited to our hospital. Computed tomography (CT)revealed massive tumors of right lung and small intestine. CT-guided fine-needle aspiration(FNA)on lung lesion was performed and the lung ... ...

Abstract	A 53-year-old man who complained of dyspnea and prolonged cough visited to our hospital. Computed tomography (CT)revealed massive tumors of right lung and small intestine. CT-guided fine-needle aspiration(FNA)on lung lesion was performed and the lung tumor was diagnosed as small cell carcinoma. We subsequently performed surgical resection for the tumor of small intestine, but part of tumor lesion remained due to pelvic wall invasion. The resected tumor was diagnosed as metastasis from lung carcinoma by histopathological examination. After surgery the patient was treated with atezolizumab and carboplatin-etoposide chemotherapy, but the remnant metastasis caused intestinal fistula. Treatment was continued carefully with fistula management using pouches. Although the fistula was closed during chemotherapy response, it recurred after discontinuation of treatment due to severe adverse events. The patient died 325 days after the surgery.
MeSH term(s)	Male ; Humans ; Middle Aged ; Small Cell Lung Carcinoma/drug therapy ; Small Cell Lung Carcinoma/surgery ; Neoplasm Recurrence, Local ; Lung Neoplasms/drug therapy ; Lung Neoplasms/surgery ; Lung Neoplasms/pathology ; Intestine, Small/surgery ; Intestine, Small/pathology ; Intestinal Fistula/etiology ; Intestinal Fistula/surgery
Language	Japanese
Publishing date	2024-02-01
Publishing country	Japan
Document type	Case Reports ; English Abstract ; Journal Article
ZDB-ID	604842-0
ISSN	0385-0684
ISSN	0385-0684
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Article ; Online: Human STAT1 gain of function with chronic mucocutaneous candidiasis: A comprehensive review for strengthening the connection between bedside observations and laboratory research.

Asano, Takaki / Noma, Kosuke / Mizoguchi, Yoko / Karakawa, Shuhei / Okada, Satoshi

Immunological reviews

2023 Volume 322, Issue 1, Page(s) 81–97

Abstract: Germline human heterozygous STAT1 gain-of-function (GOF) variants were first discovered a common cause of chronic mucocutaneous candidiasis (CMC) in 2011. Since then, numerous STAT1 GOF variants have been identified. A variety of clinical phenotypes, ... ...

Abstract	Germline human heterozygous STAT1 gain-of-function (GOF) variants were first discovered a common cause of chronic mucocutaneous candidiasis (CMC) in 2011. Since then, numerous STAT1 GOF variants have been identified. A variety of clinical phenotypes, including fungal, viral, and bacterial infections, endocrine disorders, autoimmunity, malignancy, and aneurysms, have recently been revealed for STAT1 GOF variants, which has led to the expansion of the clinical spectrum associated with STAT1 GOF. Among this broad range of complications, it has been determined that invasive infections, aneurysms, and malignancies are poor prognostic factors for STAT1 GOF. The effectiveness of JAK inhibitors as a therapeutic option has been established, although further investigation of their long-term utility and side effects is needed. In contrast to the advancements in treatment options, the precise molecular mechanism underlying STAT1 GOF remains undetermined. Two primary hypotheses for this mechanism involve impaired STAT1 dephosphorylation and increased STAT1 protein levels, both of which are still controversial. A precise understanding of the molecular mechanism is essential for not only advancing diagnostics but also developing therapeutic interventions. Here, we provide a comprehensive review of STAT1 GOF with the aim of establishing a stronger connection between bedside observations and laboratory research.
MeSH term(s)	Humans ; Candidiasis, Chronic Mucocutaneous/diagnosis ; Candidiasis, Chronic Mucocutaneous/genetics ; Candidiasis, Chronic Mucocutaneous/therapy ; Gain of Function Mutation ; STAT1 Transcription Factor/genetics ; STAT1 Transcription Factor/metabolism ; Research ; Aneurysm
Chemical Substances	STAT1 Transcription Factor ; STAT1 protein, human
Language	English
Publishing date	2023-12-12
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/imr.13300
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Article ; Online: Novel NF-kappa B Inhibitor Alpha Gain-of-Function Variant in an Infant with Lymphocytosis and Recurrent Serratia Bacteremia.

Gunderman, Lauren M / Asano, Takaki / Casanova, Jean-Laurent / Boisson, Bertrand / Khojah, Amer

Journal of clinical immunology

2023 Volume 43, Issue 6, Page(s) 1122–1126

MeSH term(s)	Humans ; Infant ; Serratia ; NF-kappa B ; Lymphocytosis/diagnosis ; Lymphocytosis/genetics ; Gain of Function Mutation ; NF-KappaB Inhibitor alpha ; Bacteremia/diagnosis ; Bacteremia/drug therapy ; Tumor Necrosis Factor-alpha
Chemical Substances	NF-kappa B ; NF-KappaB Inhibitor alpha (139874-52-5) ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2023-04-10
Publishing country	Netherlands
Document type	Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	779361-3
ISSN	1573-2592 ; 0271-9142
ISSN (online)	1573-2592
ISSN	0271-9142
DOI	10.1007/s10875-023-01481-z
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Article ; Online: Inborn errors of immunity with loss- and gain-of-function germline mutations in STAT1.

Asano, Takaki / Utsumi, Takanori / Kagawa, Reiko / Karakawa, Shuhei / Okada, Satoshi

Clinical and experimental immunology

2022 Volume 212, Issue 2, Page(s) 96–106

MeSH term(s)	Humans ; Candidiasis, Chronic Mucocutaneous/genetics ; Gain of Function Mutation ; Germ-Line Mutation ; Mutation ; STAT1 Transcription Factor/metabolism
Chemical Substances	STAT1 protein, human ; STAT1 Transcription Factor
Language	English
Publishing date	2022-11-24
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	218531-3
ISSN	1365-2249 ; 0009-9104 ; 0964-2536
ISSN (online)	1365-2249
ISSN	0009-9104 ; 0964-2536
DOI	10.1093/cei/uxac106
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Article ; Online: Collagen-Derived Dipeptides and Amino Acids Have Immunomodulatory Effects in M1-Differentiated RAW264.7 Cells and PBMC.

Tominaga, Takaki / Huang, Jiapeng / Wang, Shuo / Noguchi, Miwa / Tong, Yishan / Asano-Oritani, Momoko / Suzuki, Katsuhiko

International journal of molecular sciences

2023 Volume 24, Issue 8

Abstract: A number of food components, such as polyphenols and phytonutrients, have immunomodulatory effects. Collagen has various bioactivities, such as antioxidative effects, the promotion of wound healing, and relieving symptoms of bone/joint disease. Collagen ... ...

Abstract	A number of food components, such as polyphenols and phytonutrients, have immunomodulatory effects. Collagen has various bioactivities, such as antioxidative effects, the promotion of wound healing, and relieving symptoms of bone/joint disease. Collagen is digested into dipeptides and amino acids in the gastrointestinal tract and subsequently absorbed. However, the difference in immunomodulatory effects between collagen-derived dipeptides and amino acids is unknown. To investigate such differences, we incubated M1 macrophages or peripheral blood mononuclear cells (PBMC) with collagen-derived dipeptides (hydroxyproline-glycine (Hyp-Gly) and proline-hydroxyproline (Pro-Hyp)) and amino acids (proline (Pro), hydroxyproline (Hyp), and glycine (Gly)). We first investigated the dose dependency of Hyp-Gly on cytokine secretion. Hyp-Gly modulates cytokine secretion from M1 macrophages at 100 µM, but not at 10 µM and 1 µM. We then compared immunomodulatory effects between dipeptides and mixtures of amino acids on M1 macrophages and PBMC. There was, however, no difference in cytokine secretion between dipeptides and their respective amino acids. We conclude that collagen-derived dipeptides and amino acids have immunomodulatory effects on M1-differentiated RAW264.7 cells and PBMC and that there is no difference in the immunomodulatory effects between dipeptides and amino acids.
MeSH term(s)	Dipeptides/pharmacology ; Dipeptides/chemistry ; Hydroxyproline/metabolism ; Amino Acids/pharmacology ; Leukocytes, Mononuclear/metabolism ; Collagen/metabolism ; Proline/pharmacology ; Proline/chemistry ; Glycine ; Cytokines
Chemical Substances	Dipeptides ; Hydroxyproline (RMB44WO89X) ; Amino Acids ; Collagen (9007-34-5) ; Proline (9DLQ4CIU6V) ; Glycine (TE7660XO1C) ; Cytokines
Language	English
Publishing date	2023-04-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24086925
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Article ; Online: Isolated congenital asplenia: An overlooked cause of thrombocytosis.

Borsani, Oscar / Asano, Takaki / Boisson, Bertrand / Fraticelli, Sara / Braschi-Amirfarzan, Marta / Pietra, Daniela / Casetti, Ilaria Carola / Vanni, Daniele / Trotti, Chiara / Borghesi, Alessandro / Casanova, Jean-Laurent / Arcaini, Luca / Rumi, Elisa

American journal of hematology

2022 Volume 97, Issue 8, Page(s) 1110–1115

MeSH term(s)	Humans ; Primary Immunodeficiency Diseases ; Spleen/abnormalities ; Thrombocytosis/etiology
Language	English
Publishing date	2022-03-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	196767-8
ISSN	1096-8652 ; 0361-8609
ISSN (online)	1096-8652
ISSN	0361-8609
DOI	10.1002/ajh.26522
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Article: Isolated chronic mucocutaneous candidiasis due to a novel duplication variant of IL17RC.

Research square

2023

Abstract: Purpose: Inborn errors of the IL-17A/F-responsive pathway lead to chronic mucocutaneous candidiasis (CMC) as a predominant clinical phenotype, without other significant clinical manifestations apart from mucocutaneous staphylococcal diseases. Amongst ... ...

Abstract	Purpose: Inborn errors of the IL-17A/F-responsive pathway lead to chronic mucocutaneous candidiasis (CMC) as a predominant clinical phenotype, without other significant clinical manifestations apart from mucocutaneous staphylococcal diseases. Amongst inborn errors affecting IL-17-dependent immunity, autosomal recessive (AR) IL-17RC deficiency is a rare disease with only three kindreds described to date. The lack of an Methods: Flow cytometry, qPCR, RNA-sequencing, and immunoblotting were conducted, and an Results: The patient presented with oral and mucocutaneous candidiasis without staphylococcal diseases since the age of three months. Genetic analysis showed that the novel duplication variant (Chr3: 9,971,476-9,971,606 dup (+ 131bp)) involving exon 13 of Conclusions: The clinical and cellular phenotype of the current case of AR IL-17RC deficiency supports a previous report on this rare disorder. Our newly established evaluation system will be useful for diagnosis of AR IL-17RC deficiency, providing accurate validation of unknown
Language	English
Publishing date	2023-08-01
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3062583/v1
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Article ; Online: Fatal COVID-19 Infection in Two Children with STAT1 Gain-of-Function.

Staines-Boone, Aidé Tamara / Vignesh, Pandiarajan / Tsumura, Miyuki / de la Garza Fernández, Germán / Tyagi, Reva / Rawat, Amit / Das, Jhumki / Tomomasa, Dan / Asano, Takaki / Hijikata, Atsushi / Salazar-Gálvez, Yuridia / Kanegane, Hirokazu / Okada, Satoshi / Reyes, Saul O Lugo

Journal of clinical immunology

2023 Volume 44, Issue 1, Page(s) 20

Abstract: While SARS-CoV-2 infection causes a mild disease in most children, SARS-CoV-2 infection may be lethal in a few of them. In the defense against SARS-CoV-2, type I interferons are key players, and several studies have identified a defective or neutralized ... ...

Abstract	While SARS-CoV-2 infection causes a mild disease in most children, SARS-CoV-2 infection may be lethal in a few of them. In the defense against SARS-CoV-2, type I interferons are key players, and several studies have identified a defective or neutralized interferon response as the cause of overwhelming viral infection. However, inappropriate, untimely, or excessive interferon production may also be detrimental to the host. Here, we describe two patients with STAT1 gain-of-function (GOF), a known type I interferonopathy, who died of COVID-19. Whole-exome sequencing and interferon-gamma-activated sequence (GAS) and interferon-sensitive responsive element (ISRE) reporter assay were performed to identify and characterize STAT1 variants. Patient 1 developed hemophagocytic lymphohistiocytosis (HLH) in the context of COVID-19 infection and died in less than a week at the age of 4 years. Patient 2 developed a high fever, cough, and hypoxemia and succumbed to COVID-19 pneumonia at the age of 5 years. Two heterozygous missense variants, p.E563Q and p.K344E, in STAT1 were identified. Functional validation by reporter assay and immunoblot confirmed that both variants are gain-of-function (GOF). GOF variants transiently expressing cells exhibited enhanced upregulation of downstream genes, including ISG15, MX1, and OAS1, in response to IFN-α stimulation. A catastrophic course with HLH or acute respiratory failure is thought to be associated with inappropriate immunoregulatory mechanisms to handle SARS-CoV-2 in STAT1 GOF. While most patients with inborn errors of immunity who developed COVID-19 seem to handle it well, these cases suggest that patients with STAT1-GOF might be at risk of developing fatal complications due to SARS-CoV-2.
MeSH term(s)	Child ; Child, Preschool ; Humans ; COVID-19/genetics ; Gain of Function Mutation ; Interferon Type I ; Interferon-alpha/genetics ; SARS-CoV-2/metabolism ; STAT1 Transcription Factor/genetics ; STAT1 Transcription Factor/metabolism
Chemical Substances	Interferon Type I ; Interferon-alpha ; STAT1 protein, human ; STAT1 Transcription Factor
Language	English
Publishing date	2023-12-22
Publishing country	Netherlands
Document type	Case Reports ; Journal Article
ZDB-ID	779361-3
ISSN	1573-2592 ; 0271-9142
ISSN (online)	1573-2592
ISSN	0271-9142
DOI	10.1007/s10875-023-01634-0
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Article ; Online: Isolated Chronic Mucocutaneous Candidiasis due to a Novel Duplication Variant of IL17RC.

Journal of clinical immunology

2023 Volume 44, Issue 1, Page(s) 18

Abstract	Purpose: Inborn errors of the IL-17A/F-responsive pathway lead to chronic mucocutaneous candidiasis (CMC) as a predominant clinical phenotype, without other significant clinical manifestations apart from mucocutaneous staphylococcal diseases. Among inborn errors affecting IL-17-dependent immunity, autosomal recessive (AR) IL-17RC deficiency is a rare disease with only three kindreds described to date. The lack of an in vitro functional evaluation system of IL17RC variants renders its diagnosis difficult. We sought to characterize a 7-year-old Japanese girl with CMC carrying a novel homozygous duplication variant of IL17RC and establish a simple in vitro system to evaluate the impact of this variant. Methods: Flow cytometry, qPCR, RNA-sequencing, and immunoblotting were conducted, and an IL17RC-knockout cell line was established for functional evaluation. Results: The patient presented with oral and mucocutaneous candidiasis without staphylococcal diseases since the age of 3 months. Genetic analysis showed that the novel duplication variant (Chr3: 9,971,476-9,971,606 dup (+131bp)) involving exon 13 of IL17RC results in a premature stop codon (p.D457Afs16 or p.D457Afs17). Our functional evaluation system revealed this duplication to be loss-of-function and enabled discrimination between loss-of-function and neutral IL17RC variants. The lack of response to IL-17A by the patient's SV40-immortalized fibroblasts was restored by introducing WT-IL17RC, suggesting that the genotype identified is responsible for her clinical phenotype. Conclusions: The clinical and cellular phenotype of the current case of AR IL-17RC deficiency supports a previous report on this rare disorder. Our newly established evaluation system will be useful for the diagnosis of AR IL-17RC deficiency, providing accurate validation of unknown IL17RC variants.
MeSH term(s)	Female ; Humans ; Infant ; Child ; Candidiasis, Chronic Mucocutaneous/diagnosis ; Candidiasis, Chronic Mucocutaneous/genetics ; Interleukin-17/genetics ; Candidiasis/genetics ; Fibroblasts/metabolism ; Base Sequence
Chemical Substances	Interleukin-17
Language	English
Publishing date	2023-12-22
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	779361-3
ISSN	1573-2592 ; 0271-9142
ISSN (online)	1573-2592
ISSN	0271-9142
DOI	10.1007/s10875-023-01601-9
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Article ; Online: Human STAT1 Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy.

Okada, Satoshi / Asano, Takaki / Moriya, Kunihiko / Boisson-Dupuis, Stephanie / Kobayashi, Masao / Casanova, Jean-Laurent / Puel, Anne

Journal of clinical immunology

2020 Volume 40, Issue 8, Page(s) 1065–1081

Abstract: Heterozygous gain-of-function (GOF) mutations in STAT1 in patients with chronic mucocutaneous candidiasis (CMC) and hypothyroidism were discovered in 2011. CMC is the recurrent or persistent mucocutaneous infection by Candida fungi, and hypothyroidism ... ...

Abstract	Heterozygous gain-of-function (GOF) mutations in STAT1 in patients with chronic mucocutaneous candidiasis (CMC) and hypothyroidism were discovered in 2011. CMC is the recurrent or persistent mucocutaneous infection by Candida fungi, and hypothyroidism results from autoimmune thyroiditis. Patients with these diseases develop other infectious diseases, including viral, bacterial, and fungal diseases, and other autoimmune manifestations, including enterocolitis, immune cytopenia, endocrinopathies, and systemic lupus erythematosus. STAT1-GOF mutations are highly penetrant with a median age at onset of 1 year and often underlie an autosomal dominant trait. As many as 105 mutations at 72 residues, including 65 recurrent mutations, have already been reported in more than 400 patients worldwide. The GOF mechanism involves impaired dephosphorylation of STAT1 in the nucleus. Patient cells show enhanced STAT1-dependent responses to type I and II interferons (IFNs) and IL-27. This impairs Th17 cell development, which accounts for CMC. The pathogenesis of autoimmunity likely involves enhanced type I IFN responses, as in other type I interferonopathies. The pathogenesis of other infections, especially those caused by intramacrophagic bacteria and fungi, which are otherwise seen in patients with diminished type II IFN immunity, has remained mysterious. The cumulative survival rates of patients with and without severe disease (invasive infection, cancer, and/or symptomatic aneurysm) at 60 years of age are 31% and 87%, respectively. Severe autoimmunity also worsens the prognosis. The treatment of patients with STAT1-GOF mutations who suffer from severe infectious and autoimmune manifestations relies on hematopoietic stem cell transplantation and/or oral JAK inhibitors.
MeSH term(s)	Adolescent ; Adult ; Age of Onset ; Alleles ; Autoimmunity ; Candidiasis, Chronic Mucocutaneous/diagnosis ; Candidiasis, Chronic Mucocutaneous/etiology ; Candidiasis, Chronic Mucocutaneous/metabolism ; Candidiasis, Chronic Mucocutaneous/therapy ; Child ; Child, Preschool ; Disease Management ; Gain of Function Mutation ; Genetic Association Studies ; Genetic Predisposition to Disease ; Heterozygote ; Humans ; Infant ; Interferon Type I/metabolism ; Middle Aged ; Phenotype ; STAT1 Transcription Factor/genetics ; Young Adult
Chemical Substances	Interferon Type I ; STAT1 Transcription Factor ; STAT1 protein, human
Language	English
Publishing date	2020-08-27
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	779361-3
ISSN	1573-2592 ; 0271-9142
ISSN (online)	1573-2592
ISSN	0271-9142
DOI	10.1007/s10875-020-00847-x
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