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Article ; Online: T

Khant, Zaw Aung / Hirai, Toshinori / Kadota, Yoshihito / Masuda, Rie / Yano, Takanori / Azuma, Minako / Suzuki, Yukiko / Tashiro, Kuniyuki

Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine

2017 Volume 16, Issue 1, Page(s) 84–86

Abstract: We report a 34-year-old male who manifested T ...

Abstract	We report a 34-year-old male who manifested T
MeSH term(s)	Adult ; Cerebral Cortex/drug effects ; Cerebral Cortex/pathology ; Contrast Media/adverse effects ; Gadolinium ; Gadolinium DTPA/adverse effects ; Humans ; Image Enhancement/methods ; Magnetic Resonance Imaging/methods ; Male ; Retrospective Studies
Chemical Substances	Contrast Media ; Gadolinium (AU0V1LM3JT) ; Gadolinium DTPA (K2I13DR72L)
Language	English
Publishing date	2017-01-10
Publishing country	Japan
Document type	Case Reports ; Journal Article
ZDB-ID	2217833-8
ISSN	1880-2206 ; 1347-3182
ISSN (online)	1880-2206
ISSN	1347-3182
DOI	10.2463/mrms.mp.2016-0054
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Article ; Online: Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia.

Suske, Tobias / Sorger, Helena / Manhart, Gabriele / Ruge, Frank / Prutsch, Nicole / Zimmerman, Mark W / Eder, Thomas / Abdallah, Diaaeldin I / Maurer, Barbara / Wagner, Christina / Schönefeldt, Susann / Spirk, Katrin / Pichler, Alexander / Pemovska, Tea / Schweicker, Carmen / Pölöske, Daniel / Hubanic, Emina / Jungherz, Dennis / Müller, Tony Andreas /

Aung, Myint Myat Khine / Orlova, Anna / Pham, Ha Thi Thanh / Zimmel, Kerstin / Krausgruber, Thomas / Bock, Christoph / Müller, Mathias / Dahlhoff, Maik / Boersma, Auke / Rülicke, Thomas / Fleck, Roman / de Araujo, Elvin Dominic / Gunning, Patrick Thomas / Aittokallio, Tero / Mustjoki, Satu / Sanda, Takaomi / Hartmann, Sylvia / Grebien, Florian / Hoermann, Gregor / Haferlach, Torsten / Staber, Philipp Bernhard / Neubauer, Heidi Anne / Look, Alfred Thomas / Herling, Marco / Moriggl, Richard

The Journal of clinical investigation

2024 Volume 134, Issue 8

Abstract: T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations ... driver in T cell development and immature T cell cancer onset and compared it with STAT5A hyperactive ... variants in transgenic mice. Enhanced STAT5 activity caused disrupted T cell development and promoted ...

Abstract	T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector functions such as STAT5A and STAT5B hyperactivation are poorly understood. Here, we studied the most frequent and clinically challenging STAT5BN642H driver in T cell development and immature T cell cancer onset and compared it with STAT5A hyperactive variants in transgenic mice. Enhanced STAT5 activity caused disrupted T cell development and promoted an early T cell progenitor-ALL phenotype, with upregulation of genes involved in T cell receptor (TCR) signaling, even in absence of surface TCR. Importantly, TCR pathway genes were overexpressed in human T-ALL and mature T cell cancers and activation of TCR pathway kinases was STAT5 dependent. We confirmed STAT5 binding to these genes using ChIP-Seq analysis in human T-ALL cells, which were sensitive to pharmacologic inhibition by dual STAT3/5 degraders or ZAP70 tyrosine kinase blockers in vitro and in vivo. We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H.
MeSH term(s)	Animals ; Humans ; Mice ; Mice, Transgenic ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Protein-Tyrosine Kinases ; Receptors, Antigen, T-Cell/genetics ; Signal Transduction ; STAT5 Transcription Factor/genetics
Chemical Substances	Protein-Tyrosine Kinases (EC 2.7.10.1) ; Receptors, Antigen, T-Cell ; STAT5 Transcription Factor ; STAT5B protein, human ; STAT5A protein, human
Language	English
Publishing date	2024-04-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI168536
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Article: WASP facilitates tumor mechanosensitivity in T lymphocytes.

Mandal, Srishti / Melo, Mariane / Gordiichuk, Pavlo / Acharya, Sayanti / Poh, Yeh-Chuin / Li, Na / Aung, Aereas / Dane, Eric L / Irvine, Darrell J / Kumari, Sudha

bioRxiv : the preprint server for biology

2023

Abstract: Cytotoxic T lymphocytes (CTLs) carry out immunosurveillance by scanning target cells of diverse ... physical properties for the presence of antigens. While the recognition of cognate antigen by the T cell receptor is ... of target cells plays an important role in antigen-triggered T cell responses. However, the molecular ...

Abstract	Cytotoxic T lymphocytes (CTLs) carry out immunosurveillance by scanning target cells of diverse physical properties for the presence of antigens. While the recognition of cognate antigen by the T cell receptor is the primary signal for CTL activation, it has become increasingly clear that the mechanical stiffness of target cells plays an important role in antigen-triggered T cell responses. However, the molecular machinery within CTLs that transduces the mechanical information of tumor cells remains unclear. We find that CTL's mechanosensitive ability requires the activity of the actin-organizing protein Wiskott-Aldrich Syndrome Protein (WASP). WASP activation is modulated by the mechanical properties of antigen-presenting contexts across a wide range of target cell stiffnesses and activated WASP then mediates mechanosensitive activation of early TCR signaling markers in the CTL. Our results provide a molecular link between antigen mechanosensing and CTL immune response and suggest that CTL-intrinsic cytoskeletal organizing principles enable the processing of mechanical information from diverse target cells.
Language	English
Publishing date	2023-10-04
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.02.560434
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Article: The Relationship Between CTLA-4 (-318 C/T) Polymorphism and Urothelial Cancer Carcinogenesis in Japanese Patients.

Damayanti, Putri / Hlaing, Sa Tin Myo / Zin Aung, Khine / Tsukino, Hiromasa / Hinoura, Takuji / Kuroda, Yoshiki

Cureus

2023 Volume 15, Issue 10, Page(s) e48068

Abstract: ... The Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) gene is suspected to be a susceptibility gene in urothelial carcinoma. The aim ... of this study is to investigate polymorphism in the CTLA-4 gene (CTLA-4 -318 C/T) and whether it is associated ... In this case-control study, DNA was extracted from peripheral blood cells, and the CTLA-4 -318C/T genotypes were detected ...

Abstract	Background Urothelial cancer is one of the most common types of urinary system cancer and there are several factors that can influence its growth. One of the most prominent factors among these is genetics. The Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) gene is suspected to be a susceptibility gene in urothelial carcinoma. The aim of this study is to investigate polymorphism in the CTLA-4 gene (CTLA-4 -318 C/T) and whether it is associated with urothelial cancer. Methods The study population consisted of 253 cases and 272 controls. In this case-control study, DNA was extracted from peripheral blood cells, and the CTLA-4 -318C/T genotypes were detected using polymerase chain reaction-restriction fragment length polymorphism. Results C/T (adjusted OR (aOR) 3.37; 95%CI: 1.98-5.74) genotype, C/T + T/T (aOR 3.25; 95%CI: 1.96-5.39) genotype, and T allele (aOR 2.94 95%CI: 1.87-4.62) all indicated they are significant risk factors for urothelial cancer, with the effects of polymorphism being higher in the nonsmoker group than in the smoker group. Furthermore, the association between polymorphism and urothelial cancer carcinogenesis was similar among men and women. Conclusions This is the first study examining the association between CTLA-4 -318C/T polymorphism and urothelial carcinoma in Japanese patients. A significant association between CTLA-4 -318C/T polymorphism and urothelial cancer among Japanese patients was detected in this study. This supports the development of research on polymorphisms in urothelial cancer and is an important root of immunoreactions in cancer. We believe this study will be beneficial to clarify the relationship between CTLA-4 polymorphism and urothelial cancer.
Language	English
Publishing date	2023-10-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2747273-5
ISSN	2168-8184
ISSN	2168-8184
DOI	10.7759/cureus.48068
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Article ; Online: Universal redirection of CAR T cells against solid tumours via membrane-inserted ligands for the CAR.

Zhang, Angela Q / Hostetler, Alexander / Chen, Laura E / Mukkamala, Vainavi / Abraham, Wuhbet / Padilla, Lucia T / Wolff, Alexandra N / Maiorino, Laura / Backlund, Coralie M / Aung, Aereas / Melo, Mariane / Li, Na / Wu, Shengwei / Irvine, Darrell J

Nature biomedical engineering

2023 Volume 7, Issue 9, Page(s) 1113–1128

Abstract: The effectiveness of chimaeric antigen receptor (CAR) T cell therapies for solid tumours is ... expression of tumour antigens and to target antigen expression in healthy tissues. Here we show that T ... tumour regression via the proliferation and accumulation of FITC-specific CAR T cells in the tumours ...

Abstract	The effectiveness of chimaeric antigen receptor (CAR) T cell therapies for solid tumours is hindered by difficulties in the selection of an effective target antigen, owing to the heterogeneous expression of tumour antigens and to target antigen expression in healthy tissues. Here we show that T cells with a CAR specific for fluorescein isothiocyanate (FITC) can be directed against solid tumours via the intratumoural administration of a FITC-conjugated lipid-poly(ethylene)-glycol amphiphile that inserts itself into cell membranes. In syngeneic and human tumour xenografts in mice, 'amphiphile tagging' of tumour cells drove tumour regression via the proliferation and accumulation of FITC-specific CAR T cells in the tumours. In syngeneic tumours, the therapy induced the infiltration of host T cells, elicited endogenous tumour-specific T cell priming and led to activity against distal untreated tumours and to protection against tumour rechallenge. Membrane-inserting ligands for specific CARs may facilitate the development of adoptive cell therapies that work independently of antigen expression and of tissue of origin.
MeSH term(s)	Humans ; Mice ; Animals ; Fluorescein-5-isothiocyanate/metabolism ; Ligands ; Neoplasms ; T-Lymphocytes ; Immunotherapy, Adoptive
Chemical Substances	Fluorescein-5-isothiocyanate (I223NX31W9) ; Ligands
Language	English
Publishing date	2023-06-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2157-846X
ISSN (online)	2157-846X
DOI	10.1038/s41551-023-01048-8
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Article ; Online: Toll-like receptor 9 (-1237 T/C, -1486 T/C) and the risk of gastric cancer: a meta-analysis of genetic association studies.

Qyi, Yap Zi / Aung, Htar Htar / Aye, Saint-Nway / Tung, Wong Siew / Naing, Cho

BMC cancer

2023 Volume 23, Issue 1, Page(s) 1027

Abstract: ... case-control studies of toll like receptor (TLR) 9 (-1237 T/C, -1486 T/C) polymorphisms in the gastric cancer risk were ... the evidence on the association between polymorphisms of TLR 9 (-1237 T/C, -1486 T/C) and the risk ... rating (i.e., a score of ≥ 7). TLR 9 (-1486 T/C) polymorphism and the risk of gastric cancer were ...

Abstract	Background: Gastric cancer has a complex aetiology including genetic factors. Individual case-control studies of toll like receptor (TLR) 9 (-1237 T/C, -1486 T/C) polymorphisms in the gastric cancer risk were available, and they showed variation in the findings. Therefore, we performed a meta-analysis to synthesize the evidence on the association between polymorphisms of TLR 9 (-1237 T/C, -1486 T/C) and the risk of gastric cancer using data from eligible studies. Methods: This study followed the PRISMA 2020 Checklist. Studies were searched in health-related databases. The methodological quality of studies was evaluated with the use of Newcastle-Ottawa Scale criteria. The summary odds ratio (OR) and its 95% confidence interval (CI) were used to determine the strength of association between each polymorphism and the risk of gastric cancer using five genetic models. Stratification was done by ethnic groups. For the robustness of the analysis, a leave-one-out meta-analysis was performed. Results: Eight case-control studies with 3,644 participants (1914 cases, 1730 controls) were conducted across six countries. Half of the studies were conducted in China. In the NOS methodological quality assessment, only three studies received a high-quality rating (i.e., a score of ≥ 7). TLR 9 (-1486 T/C) polymorphism and the risk of gastric cancer were assessed in six studies, four of Asian ethnicity and two of non-Asian. Under the dominant model, only in the Asian ethnic group showed a marginally and significantly increased risk of gastric cancer (overall: OR = 1.22, 95%CI = 0.90-1.67, I Conclusions: The findings suggested that TLR9 (-1486 T/C) may play a role in the risk of gastric cancer specific to the Asian ethnic group. To substantiate the findings on the association between these two polymorphisms (TLR9 -1237 T/C, -1486 T/C) and the risk of gastric cancer, future well-designed case-control studies with a sufficient number of participants in multi-ethnic groups are recommended.
MeSH term(s)	Humans ; Case-Control Studies ; Genetic Association Studies ; Genetic Predisposition to Disease ; Odds Ratio ; Polymorphism, Single Nucleotide ; Risk Factors ; Stomach Neoplasms/epidemiology ; Stomach Neoplasms/genetics ; Toll-Like Receptor 9/genetics
Chemical Substances	Toll-Like Receptor 9 ; TLR9 protein, human
Language	English
Publishing date	2023-10-24
Publishing country	England
Document type	Meta-Analysis ; Journal Article
ZDB-ID	2041352-X
ISSN	1471-2407 ; 1471-2407
ISSN (online)	1471-2407
ISSN	1471-2407
DOI	10.1186/s12885-023-11509-7
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Article ; Online: T-cell receptor beta variable gene polymorphism predicts immune-related adverse events during checkpoint blockade immunotherapy.

Stephen, Bettzy / Hajjar, Joud / Sarda, Shrutii / Duose, Dzifa Yawa / Conroy, Jeffrey M / Morrison, Carl / Alshawa, Anas / Xu, Mingxuan / Zarifa, Abdulrazzak / Patel, Sapna P / Yuan, Ying / Kwiatkowski, Evan / Wang, Linghua / Rodon Ahnert, Jordi / Fu, Siqing / Meric-Bernstam, Funda / Lowman, Geoffrey M / Looney, Timothy / Naing, Aung

Journal for immunotherapy of cancer

2023 Volume 11, Issue 8

Abstract: ... therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have ...

Abstract	Background: Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past. Patients and methods: We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion Torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3). Results: Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs. Conclusion: The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs.
MeSH term(s)	Humans ; Immune Checkpoint Inhibitors ; Immunotherapy/adverse effects ; Autoimmune Diseases ; Drug-Related Side Effects and Adverse Reactions ; Receptors, Antigen, T-Cell
Chemical Substances	Immune Checkpoint Inhibitors ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-08-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2023-007236
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Article ; Online: Real-world CAR-T findings for large B-cell lymphoma from a single institution experience.

Lutfi, Forat / Tun, Aung M / Hoffmann, Marc / Ahmed, Nausheen

Annals of palliative medicine

2024

Language	English
Publishing date	2024-04-18
Publishing country	China
Document type	Journal Article
ZDB-ID	2828544-X
ISSN	2224-5839 ; 2224-5839
ISSN (online)	2224-5839
ISSN	2224-5839
DOI	10.21037/apm-23-545
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Article ; Online: T-Cell Repertoire in Combination with T-Cell Density Predicts Clinical Outcomes in Patients with Merkel Cell Carcinoma.

Farah, Maya / Reuben, Alexandre / Spassova, Ivelina / Yang, Richard K / Kubat, Linda / Nagarajan, Priyadharsini / Ning, Jing / Li, Wen / Aung, Phyu P / Curry, Jonathan L / Torres-Cabala, Carlos A / Hudgens, Courtney W / Ugurel, Selma / Schadendorf, Dirk / Gumbs, Curtis / Little, Latasha D / Futreal, Andrew / Wistuba, Ignacio I / Prieto, Victor G /

Wang, Linghua / Wong, Michael K / Wargo, Jennifer A / Becker, Jürgen C / Tetzlaff, Michael T

The Journal of investigative dermatology

2020 Volume 140, Issue 11, Page(s) 2146–2156.e4

Abstract: ... for Merkel cell carcinoma. A higher density of tumor-associated T cells correlates with improved Merkel cell carcinoma ... specific survival, but the prognostic importance of the T-cell infiltrate reactivity is unknown ... We evaluated the T-cell receptor repertoire associated with 72 primary Merkel cell carcinomas and correlated ...

Abstract	The integrity of the immune system represents a pivotal risk factor and prognostic biomarker for Merkel cell carcinoma. A higher density of tumor-associated T cells correlates with improved Merkel cell carcinoma-specific survival, but the prognostic importance of the T-cell infiltrate reactivity is unknown. We evaluated the T-cell receptor repertoire associated with 72 primary Merkel cell carcinomas and correlated metrics of the T-cell receptor repertoire with clinicopathologic characteristics and patient outcomes. We showed that a high Simpson's Dominance index (SDom) was significantly associated with fewer metastases (P = 0.01), lower stage at presentation (P = 0.02), lower final stage at last follow-up (P = 0.05), and longer time to first lymph node metastasis (P = 0.04). These correlations were mostly preserved in the Merkel cell polyomavirus-negative subgroup. Combining SDom with CD3
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Carcinoma, Merkel Cell/immunology ; Carcinoma, Merkel Cell/mortality ; Carcinoma, Merkel Cell/pathology ; Female ; Humans ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; Receptors, Antigen, T-Cell/immunology ; Skin Neoplasms/immunology ; Skin Neoplasms/mortality ; Skin Neoplasms/pathology ; T-Lymphocytes/immunology
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2020-04-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1016/j.jid.2020.02.031
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Article: High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma.

Garcha, Harsimran Kaur / Nawar, Nabanita / Sorger, Helena / Erdogan, Fettah / Aung, Myint Myat Khine / Sedighi, Abootaleb / Manaswiyoungkul, Pimyupa / Seo, Hyuk-Soo / Schönefeldt, Susann / Pölöske, Daniel / Dhe-Paganon, Sirano / Neubauer, Heidi A / Mustjoki, Satu M / Herling, Marco / de Araujo, Elvin D / Moriggl, Richard / Gunning, Patrick T

Pharmaceuticals (Basel, Switzerland)

2022 Volume 15, Issue 11

Abstract: NK/T-cell lymphoma (NKTCL) and γδ T-cell non-Hodgkin lymphomas (γδ T-NHL) are highly aggressive ... from other hematological cancers. Histone deacetylases (HDACs) have been targeted in a range of malignancies, including T ... cell lymphomas. This study represents exploratory findings of HDAC6 inhibition in NKTCL and γδ T-NHL ...

Abstract	NK/T-cell lymphoma (NKTCL) and γδ T-cell non-Hodgkin lymphomas (γδ T-NHL) are highly aggressive lymphomas that lack rationally designed therapies and rely on repurposed chemotherapeutics from other hematological cancers. Histone deacetylases (HDACs) have been targeted in a range of malignancies, including T-cell lymphomas. This study represents exploratory findings of HDAC6 inhibition in NKTCL and γδ T-NHL through a second-generation inhibitor NN-429. With nanomolar in vitro HDAC6 potency and high in vitro and in cellulo selectivity for HDAC6, NN-429 also exhibited long residence time and improved pharmacokinetic properties in contrast to older generation inhibitors. Following unique selective cytotoxicity towards γδ T-NHL and NKTCL, NN-429 demonstrated a synergistic relationship with the clinical agent etoposide and potential synergies with doxorubicin, cytarabine, and SNS-032 in these disease models, opening an avenue for combination treatment strategies.
Language	English
Publishing date	2022-10-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph15111321
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