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Article ; Online: Tsyn-Seq: a T-cell Synapse-Based Antigen Identification Platform.

2024 Volume 12, Issue 5, Page(s) 530–543

Abstract: Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes ... ...

Abstract	Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell-APC aggregates were detected by dual-reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 antigen derived from human papillomavirus type 16 (HPV16), Tsyn-seq successfully enriched the correct cognate antigen from a cDNA library derived from an HPV16-positive cervical cancer cell line. Tsyn-seq provides a method for rapidly identifying antigens recognized by TCRs of interest from a tumor cDNA library. See related Spotlight by Makani and Joglekar, p. 515.
MeSH term(s)	Humans ; Receptors, Antigen, T-Cell/immunology ; Receptors, Antigen, T-Cell/genetics ; T-Lymphocytes/immunology ; High-Throughput Nucleotide Sequencing ; Papillomavirus E7 Proteins/immunology ; Papillomavirus E7 Proteins/genetics ; Gene Library ; Antigen-Presenting Cells/immunology ; NFATC Transcription Factors/metabolism ; NFATC Transcription Factors/immunology ; Cell Line, Tumor ; NF-kappa B/metabolism ; Immunological Synapses/immunology ; Human papillomavirus 16/immunology ; Human papillomavirus 16/genetics ; Female
Chemical Substances	Receptors, Antigen, T-Cell ; Papillomavirus E7 Proteins ; NFATC Transcription Factors ; oncogene protein E7, Human papillomavirus type 16 ; NF-kappa B
Language	English
Publishing date	2024-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-23-0467
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Article ; Online: Utility of cerebrospinal fluid liquid biopsy in distinguishing CNS lymphoma from cerebrospinal infectious/demyelinating diseases.

Iriyama, Chisako / Murate, Kenichiro / Iba, Sachiko / Okamoto, Akinao / Goto, Naoe / Yamamoto, Hideyuki / Kato, Toshiharu / Mihara, Keichiro / Miyama, Takahiko / Hattori, Keiko / Kajiya, Ryoko / Okamoto, Masataka / Mizutani, Yasuaki / Yamada, Seiji / Tsukamoto, Tetsuya / Hirose, Yuichi / Mutoh, Tatsuro / Watanabe, Hirohisa / Tomita, Akihiro

Cancer medicine

2023 Volume 12, Issue 16, Page(s) 16972–16984

Abstract: Background: Distinguishing between central nervous system lymphoma (CNSL) and CNS infectious and/or demyelinating diseases, although clinically important, is sometimes difficult even using imaging strategies and conventional cerebrospinal fluid (CSF) ... ...

Abstract	Background: Distinguishing between central nervous system lymphoma (CNSL) and CNS infectious and/or demyelinating diseases, although clinically important, is sometimes difficult even using imaging strategies and conventional cerebrospinal fluid (CSF) analyses. To determine whether detection of genetic mutations enables differentiation between these diseases and the early detection of CNSL, we performed mutational analysis using CSF liquid biopsy technique. Methods: In this study, we extracted cell-free DNA from the CSF (CSF-cfDNA) of CNSL (N = 10), CNS infectious disease (N = 10), and demyelinating disease (N = 10) patients, and performed quantitative mutational analysis by droplet-digital PCR. Conventional analyses were also performed using peripheral blood and CSF to confirm the characteristics of each disease. Results: Blood hemoglobin and albumin levels were significantly lower in CNSL than CNS infectious and demyelinating diseases, CSF cell counts were significantly higher in infectious diseases than CNSL and demyelinating diseases, and CSF-cfDNA concentrations were significantly higher in infectious diseases than CNSL and demyelinating diseases. Mutation analysis using CSF-cfDNA detected MYD88 Conclusions: These results suggest that mutation analysis using CSF-cfDNA might be useful for differentiating CNSL from CNS infectious/demyelinating diseases and for early detection of CNSL, even in cases where brain biopsy is difficult to perform.
MeSH term(s)	Humans ; Myeloid Differentiation Factor 88 ; Central Nervous System Neoplasms/diagnosis ; Central Nervous System Neoplasms/genetics ; Central Nervous System Neoplasms/cerebrospinal fluid ; Lymphoma, Non-Hodgkin ; Liquid Biopsy ; Cell-Free Nucleic Acids ; Communicable Diseases ; Demyelinating Diseases
Chemical Substances	Myeloid Differentiation Factor 88 ; Cell-Free Nucleic Acids
Language	English
Publishing date	2023-07-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2659751-2
ISSN	2045-7634 ; 2045-7634
ISSN (online)	2045-7634
ISSN	2045-7634
DOI	10.1002/cam4.6329
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Article ; Online: Acute fulminant intravascular hemolysis induced by Clostridium perfringens in a symptomatic multiple myeloma patient under immuno-chemotherapy.

Yamamoto, Hideyuki / Mizutani, Yuki / Iriyama, Chisako / Goto, Naoe / Okamoto, Akinao / Kato, Toshiharu / Shintani, Chiyo / Yamamoto, Naoki / Miyama, Takahiko / Mihara, Keichiro / Okamoto, Masataka / Tomita, Akihiro

Annals of hematology

2022 Volume 101, Issue 12, Page(s) 2813–2815

MeSH term(s)	Humans ; Clostridium perfringens ; Hemolysis ; Multiple Myeloma/complications ; Multiple Myeloma/drug therapy ; Sepsis ; Immunotherapy ; Clostridium Infections/complications
Language	English
Publishing date	2022-11-01
Publishing country	Germany
Document type	Letter
ZDB-ID	1064950-5
ISSN	1432-0584 ; 0939-5555 ; 0945-8077
ISSN (online)	1432-0584
ISSN	0939-5555 ; 0945-8077
DOI	10.1007/s00277-022-05010-7
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Article: Next-Generation Immune Repertoire Sequencing as a Clue to Elucidate the Landscape of Immune Modulation by Host-Gut Microbiome Interactions.

Ichinohe, Tatsuo / Miyama, Takahiko / Kawase, Takakazu / Honjo, Yasuko / Kitaura, Kazutaka / Sato, Hiroyuki / Shin-I, Tadasu / Suzuki, Ryuji

Frontiers in immunology

2018 Volume 9, Page(s) 668

Abstract: The human immune system is a fine network consisted of the innumerable numbers of functional cells that balance the immunity and tolerance against various endogenous and environmental challenges. Although advances in modern immunology have revealed a ... ...

Abstract	The human immune system is a fine network consisted of the innumerable numbers of functional cells that balance the immunity and tolerance against various endogenous and environmental challenges. Although advances in modern immunology have revealed a role of many unique immune cell subsets, technologies that enable us to capture the whole landscape of immune responses against specific antigens have been not available to date. Acquired immunity against various microorganisms including host microbiome is principally founded on T cell and B cell populations, each of which expresses antigen-specific receptors that define a unique clonotype. Over the past several years, high-throughput next-generation sequencing has been developed as a powerful tool to profile T- and B-cell receptor repertoires in a given individual at the single-cell level. Sophisticated immuno-bioinformatic analyses by use of this innovative methodology have been already implemented in clinical development of antibody engineering, vaccine design, and cellular immunotherapy. In this article, we aim to discuss the possible application of high-throughput immune receptor sequencing in the field of nutritional and intestinal immunology. Although there are still unsolved caveats, this emerging technology combined with single-cell transcriptomics/proteomics provides a critical tool to unveil the previously unrecognized principle of host-microbiome immune homeostasis. Accumulation of such knowledge will lead to the development of effective ways for personalized immune modulation through deeper understanding of the mechanisms by which the intestinal environment affects our immune ecosystem.
MeSH term(s)	Adaptive Immunity ; Animals ; Gastrointestinal Microbiome/immunology ; High-Throughput Nucleotide Sequencing ; Homeostasis ; Humans
Language	English
Publishing date	2018-04-03
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2018.00668
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Article ; Online: Allogeneic hematopoietic cell transplantation using fludarabine plus myeloablative busulfan and melphalan confers promising survival in high-risk hematopoietic neoplasms: a single-center retrospective analysis.

Edahiro, Taro / Kawase, Takakazu / Nagoshi, Hisao / Fujino, Keita / Toishigawa, Kayo / Miyama, Takahiko / Mino, Tatsuji / Yoshida, Tetsumi / Morioka, Takehiko / Hirata, Yuji / Noma, Mitsunori / Fujii, Teruhisa / Nishizawa, Masatoshi / Fukushima, Noriyasu / Ichinohe, Tatsuo

Hematology (Amsterdam, Netherlands)

2020 Volume 26, Issue 1, Page(s) 186–198

Abstract: Objectives: Optimal selection of pretransplant conditioning is crucially vital for improving survival and quality-of-life of patients who receive allogeneic hematopoietic cell transplantation (allo-HCT), particularly in those with high-risk diseases. In ...

Abstract	Objectives: Optimal selection of pretransplant conditioning is crucially vital for improving survival and quality-of-life of patients who receive allogeneic hematopoietic cell transplantation (allo-HCT), particularly in those with high-risk diseases. In this study, we evaluated the efficacy and safety of recently-developed reduced-toxicity myeloablative regimen that combines fludarabine, intravenous busulfan, and melphalan (FBM). Methods: We conducted a single-center retrospective analysis of 39 patients (23 with myeloid neoplasms and 16 with lymphoid neoplasms), with a median age of 50 (range, 17-68) years, who underwent their first allo-HCT using the FBM regimen. Graft types were bone marrow in 11, peripheral blood in 11, and cord blood in 17 patients. Cyclosporine- or tacrolimus-based graft-versus-host disease (GVHD) prophylaxis was administered. The primary end point of the study was the overall survival rate at 2-year after transplantation. Results: After a median follow-up of 910 days for the surviving patients, 2-year overall survival was 62% for the entire cohort; 73% in the low-to-intermediate-risk group and 44% in the high-to-very high-risk group classified by the refined CIBMTR Disease Risk Index. Cumulative incidences of engraftment, grade II-IV acute GVHD, chronic GVHD, relapse, and non-relapse mortality were 95%, 56%, 56%, 31%, and 17%, respectively. Conclusion: These results suggest that our FBM regimen can be applied to allo-HCT using various graft types and yields acceptable outcomes with relatively low non-relapse mortality in both myeloid and lymphoid neoplasms. Also, we observed a promising survival in the group of patients with high-risk diseases, warranting more accumulation of patients and longer follow-up.
MeSH term(s)	Adolescent ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Busulfan/administration & dosage ; Combined Modality Therapy ; Female ; Graft vs Host Disease/diagnosis ; Graft vs Host Disease/etiology ; Hematologic Neoplasms/diagnosis ; Hematologic Neoplasms/mortality ; Hematologic Neoplasms/therapy ; Hematopoietic Stem Cell Transplantation/adverse effects ; Hematopoietic Stem Cell Transplantation/methods ; Humans ; Male ; Melphalan/administration & dosage ; Middle Aged ; Myeloablative Agonists/administration & dosage ; Recurrence ; Remission Induction ; Retrospective Studies ; Survival Analysis ; Transplantation Conditioning/adverse effects ; Transplantation Conditioning/methods ; Transplantation, Homologous ; Treatment Outcome ; Vidarabine/administration & dosage ; Vidarabine/analogs & derivatives ; Young Adult
Chemical Substances	Myeloablative Agonists ; Vidarabine (FA2DM6879K) ; Busulfan (G1LN9045DK) ; fludarabine (P2K93U8740) ; Melphalan (Q41OR9510P)
Language	English
Publishing date	2020-10-15
Publishing country	England
Document type	Journal Article
ZDB-ID	1341428-8
ISSN	1607-8454 ; 1024-5332 ; 1024-5340
ISSN (online)	1607-8454
ISSN	1024-5332 ; 1024-5340
DOI	10.1080/16078454.2021.1881228
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Zs.A 4538: Show issues

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Article ; Online: Nivolumab-induced severe pancytopenia in a patient with lung adenocarcinoma.

Tokumo, Kentaro / Masuda, Takeshi / Miyama, Takahiko / Miura, Shinichiro / Yamaguchi, Kakuhiro / Sakamoto, Shinjiro / Horimasu, Yasushi / Nakashima, Taku / Miyamoto, Shintaro / Yoshida, Takashi / Iwamoto, Hiroshi / Fujitaka, Kazunori / Hamada, Hironobu / Hattori, Noboru

Lung cancer (Amsterdam, Netherlands)

2018 Volume 119, Page(s) 21–24

Abstract: Severe leukopenia, thrombocytopenia, and bi-cytopenia due to nivolumab have been reported. In this report, we present the first case of nivolumab-induced severe pancytopenia in a patient with lung adenocarcinoma. A 56-year-old Japanese man with lung ... ...

Abstract	Severe leukopenia, thrombocytopenia, and bi-cytopenia due to nivolumab have been reported. In this report, we present the first case of nivolumab-induced severe pancytopenia in a patient with lung adenocarcinoma. A 56-year-old Japanese man with lung adenocarcinoma received nivolumab therapy as second-line treatment. After 3 cycles of this therapy, although computed tomography (CT) showed a reduced tumor size, laboratory findings revealed pancytopenia and a bone marrow biopsy showed a severely hypoplastic marrow. The pancytopenia was diagnosed as an adverse effect of nivolumab; filgrastim (75 μg/day), steroid-pulse therapy (intravenous methylprednisolone: 500 mg/day), and subsequently intravenous prednisolone (50 mg/day) were administered. Furthermore, intravenous administration of immunoglobulins was also performed. However, these treatments were ineffective. He was further diagnosed with fungal pneumonia and a catheter-related bloodstream infection. Anti-bacterial chemotherapy was administered. Two months after hospitalization, the neutrophil count improved to 1000/μL, but multiple red blood cell and platelet transfusions were needed. Therefore, further chemotherapy for lung adenocarcinoma could not be initiated, and the patient died due to progression of lung cancer 118 days after the onset of pancytopenia. The possibility of severe pancytopenia as an immune-related adverse event should be considered as a mandatory prerequisite for nivolumab therapy.
MeSH term(s)	Adenocarcinoma/diagnosis ; Adenocarcinoma/drug therapy ; Adenocarcinoma/pathology ; Antineoplastic Agents, Immunological/adverse effects ; Antineoplastic Agents, Immunological/therapeutic use ; Bone Marrow/pathology ; Drug-Related Side Effects and Adverse Reactions/diagnosis ; Drug-Related Side Effects and Adverse Reactions/pathology ; Fatal Outcome ; Humans ; Lung Neoplasms/diagnosis ; Lung Neoplasms/drug therapy ; Lung Neoplasms/pathology ; Male ; Middle Aged ; Nivolumab/adverse effects ; Nivolumab/therapeutic use ; Pancytopenia/diagnosis ; Pancytopenia/etiology ; Pancytopenia/pathology ; Remission Induction
Chemical Substances	Antineoplastic Agents, Immunological ; Nivolumab (31YO63LBSN)
Language	English
Publishing date	2018-03-02
Publishing country	Ireland
Document type	Case Reports ; Journal Article
ZDB-ID	632771-0
ISSN	1872-8332 ; 0169-5002
ISSN (online)	1872-8332
ISSN	0169-5002
DOI	10.1016/j.lungcan.2018.02.018
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Zs.A 2135: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Mucus-degrading Bacteroides link carbapenems to aggravated graft-versus-host disease

Hayase, Eiko / Hayase, Tomo / Jamal, Mohamed A. / Miyama, Takahiko / Chang, Chia-Chi / Ortega, Miriam R. / Ahmed, Saira S. / Karmouch, Jennifer L. / Sanchez, Christopher A. / Brown, Alexandria N. / El-Himri, Rawan K. / Flores, Ivonne I. / McDaniel, Lauren K. / Phạm, Dũng / Halsey, Taylor / Frenk, Annette C. / Chapa, Valerie A. / Heckel, Brooke E. / Jin, Yimei /

Cell. 2022 Sept. 29, v. 185, no. 20 p.3705-3719.e14

2022

Abstract: The intestinal microbiota is an important modulator of graft-versus-host disease (GVHD), which often complicates allogeneic hematopoietic stem cell transplantation (allo-HSCT). Broad-spectrum antibiotics such as carbapenems increase the risk for ... ...

Abstract	The intestinal microbiota is an important modulator of graft-versus-host disease (GVHD), which often complicates allogeneic hematopoietic stem cell transplantation (allo-HSCT). Broad-spectrum antibiotics such as carbapenems increase the risk for intestinal GVHD, but mechanisms are not well understood. In this study, we found that treatment with meropenem, a commonly used carbapenem, aggravates colonic GVHD in mice via the expansion of Bacteroides thetaiotaomicron (BT). BT has a broad ability to degrade dietary polysaccharides and host mucin glycans. BT in meropenem-treated allogeneic mice demonstrated upregulated expression of enzymes involved in the degradation of mucin glycans. These mice also had thinning of the colonic mucus layer and decreased levels of xylose in colonic luminal contents. Interestingly, oral xylose supplementation significantly prevented thinning of the colonic mucus layer in meropenem-treated mice. Specific nutritional supplementation strategies, including xylose supplementation, may combat antibiotic-mediated microbiome injury to reduce the risk for intestinal GVHD in allo-HSCT patients.
Keywords	Bacteroides thetaiotaomicron ; cell transplantation ; dietary supplements ; hematopoietic stem cells ; intestinal microorganisms ; intestines ; meropenem ; microbiome ; mucins ; mucus ; polysaccharides ; risk ; risk reduction ; xylose ; mucus-degrading bacteria ; Bacteroides ; allogeneic hematopoietic stem cell transplantation ; graft-versus-host disease ; broad-spectrum antibiotics ; carbapenem ; mucus layer ; intestinal microbiome
Language	English
Dates of publication	2022-0929
Size	p. 3705-3719.e14.
Publishing place	Elsevier Inc.
Document type	Article ; Online
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2022.09.007
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Article ; Online: Highly functional T-cell receptor repertoires are abundant in stem memory T cells and highly shared among individuals.

Miyama, Takahiko / Kawase, Takakazu / Kitaura, Kazutaka / Chishaki, Ren / Shibata, Masashi / Oshima, Kumi / Hamana, Hiroshi / Kishi, Hiroyuki / Muraguchi, Atsushi / Kuzushima, Kiyotaka / Saji, Hiroh / Shin-I, Tadasu / Suzuki, Ryuji / Ichinohe, Tatsuo

Scientific reports

2017 Volume 7, Issue 1, Page(s) 3663

Abstract: To expand our knowledge of the ontogeny of the T-cell receptor (TCR) repertoire of antigen-specific T-cell subsets, we combined next-generation deep sequencing and single-cell multiplex clonotype analysis to evaluate the diversity and frequency of paired ...

Abstract	To expand our knowledge of the ontogeny of the T-cell receptor (TCR) repertoire of antigen-specific T-cell subsets, we combined next-generation deep sequencing and single-cell multiplex clonotype analysis to evaluate the diversity and frequency of paired TCRs, their functions and whether clonotypic TCRs are shared among different individuals. Using an HLA-A02-restricted cytomegalovirus (CMV) pp65-derived immunogenic peptide, we found that the more dominant pp65-specific TCR clonotypes in the blood of healthy donors have higher binding affinities for the CMV peptide and arise from clonotypes that are highly shared among individuals. Interestingly, these highly shared HLA-A02-restricted CMV-specific TCRs were detected in a CMV-seronegative individual as well as in HLA-A*02-negative donors albeit at lower frequency. More intriguingly, these shared TCR clonotypes were abundant in the stem memory T-cell subset, and TCR diversity of the stem memory T-cell repertoire was significantly lower than in the central memory and effector memory T-cell repertoires. These results suggest that the stem memory T-cell subset may serve as a reservoir of highly shared and highly functional memory T-cells.
MeSH term(s)	Biomarkers ; Cell Line ; Gene Expression ; Genetic Variation ; HLA Antigens/genetics ; HLA Antigens/immunology ; High-Throughput Nucleotide Sequencing ; Humans ; Immunity, Cellular ; Immunologic Memory ; Immunophenotyping ; Lymphocyte Activation/immunology ; Phosphoproteins/immunology ; Precursor Cells, T-Lymphoid/immunology ; Precursor Cells, T-Lymphoid/metabolism ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; T-Cell Antigen Receptor Specificity ; Transduction, Genetic ; Viral Matrix Proteins/immunology
Chemical Substances	Biomarkers ; HLA Antigens ; Phosphoproteins ; Receptors, Antigen, T-Cell ; Viral Matrix Proteins ; cytomegalovirus matrix protein 65kDa
Language	English
Publishing date	2017-06-16
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/s41598-017-03855-x
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Article ; Online: Mucus-degrading Bacteroides link carbapenems to aggravated graft-versus-host disease.

Hayase, Eiko / Hayase, Tomo / Jamal, Mohamed A / Miyama, Takahiko / Chang, Chia-Chi / Ortega, Miriam R / Ahmed, Saira S / Karmouch, Jennifer L / Sanchez, Christopher A / Brown, Alexandria N / El-Himri, Rawan K / Flores, Ivonne I / McDaniel, Lauren K / Pham, Dung / Halsey, Taylor / Frenk, Annette C / Chapa, Valerie A / Heckel, Brooke E / Jin, Yimei /

Cell

2022 Volume 185, Issue 20, Page(s) 3705–3719.e14

Abstract	The intestinal microbiota is an important modulator of graft-versus-host disease (GVHD), which often complicates allogeneic hematopoietic stem cell transplantation (allo-HSCT). Broad-spectrum antibiotics such as carbapenems increase the risk for intestinal GVHD, but mechanisms are not well understood. In this study, we found that treatment with meropenem, a commonly used carbapenem, aggravates colonic GVHD in mice via the expansion of Bacteroides thetaiotaomicron (BT). BT has a broad ability to degrade dietary polysaccharides and host mucin glycans. BT in meropenem-treated allogeneic mice demonstrated upregulated expression of enzymes involved in the degradation of mucin glycans. These mice also had thinning of the colonic mucus layer and decreased levels of xylose in colonic luminal contents. Interestingly, oral xylose supplementation significantly prevented thinning of the colonic mucus layer in meropenem-treated mice. Specific nutritional supplementation strategies, including xylose supplementation, may combat antibiotic-mediated microbiome injury to reduce the risk for intestinal GVHD in allo-HSCT patients.
MeSH term(s)	Animals ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Bacteroides ; Carbapenems/pharmacology ; Carbapenems/therapeutic use ; Graft vs Host Disease/drug therapy ; Graft vs Host Disease/etiology ; Hematopoietic Stem Cell Transplantation ; Meropenem ; Mice ; Mucins/metabolism ; Mucus/metabolism ; Polysaccharides/metabolism ; Xylose
Chemical Substances	Anti-Bacterial Agents ; Carbapenems ; Mucins ; Polysaccharides ; Xylose (A1TA934AKO) ; Meropenem (FV9J3JU8B1)
Language	English
Publishing date	2022-09-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2022.09.007
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Article ; Online: Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency.

Ikeda, Kenichiro / Ueda, Takeshi / Yamasaki, Norimasa / Nakata, Yuichiro / Sera, Yasuyuki / Nagamachi, Akiko / Miyama, Takahiko / Kobayashi, Hiroshi / Takubo, Keiyo / Kanai, Akinori / Oda, Hideaki / Wolff, Linda / Honda, Zen-Ichiro / Ichinohe, Tatsuo / Matsubara, Akio / Suda, Toshio / Inaba, Toshiya / Honda, Hiroaki

Scientific reports

2016 Volume 6, Page(s) 29454

Abstract: Polycomb repressive complex 2 (PRC2) participates in transcriptional repression through methylation of histone H3K27. The WD-repeat protein embryonic ectoderm development (EED) is a non-catalytic but an essential component of PRC2 and its mutations were ... ...

Abstract	Polycomb repressive complex 2 (PRC2) participates in transcriptional repression through methylation of histone H3K27. The WD-repeat protein embryonic ectoderm development (EED) is a non-catalytic but an essential component of PRC2 and its mutations were identified in hematopoietic malignancies. To clarify the role(s) of EED in adult hematopoiesis and leukemogenesis, we generated Eed conditional knockout (Eed(Δ/Δ)) mice. Eed(Δ/Δ) mice died in a short period with rapid decrease of hematopoietic cells. Hematopoietic stem/progenitor cells (HSPCs) were markedly decreased with impaired bone marrow (BM) repopulation ability. Cell cycle analysis of HSPCs demonstrated increased S-phase fraction coupled with suppressed G0/G1 entry. Genes encoding cell adhesion molecules are significantly enriched in Eed(Δ/Δ) HSPCs, and consistently, Eed(Δ/Δ) HSPCs exhibited increased attachment to a major extracellular matrix component, fibronectin. Thus, EED deficiency increases proliferation on one side but promotes quiescence possibly by enhanced adhesion to the hematopoietic niche on the other, and these conflicting events would lead to abnormal differentiation and functional defect of Eed(Δ/Δ) HSPCs. In addition, Eed haploinsufficiency induced hematopoietic dysplasia, and Eed heterozygous mice were susceptible to malignant transformation and developed leukemia in cooperation with Evi1 overexpression. Our results demonstrated differentiation stage-specific and dose-dependent roles of EED in normal hematopoiesis and leukemogenesis.
Language	English
Publishing date	2016-07-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep29454
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