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Article ; Online: Efbalropendekin Alfa enhances human natural killer cell cytotoxicity against tumor cell lines

Shehata, Hesham M / Dogra, Pranay / Gierke, Sarah / Holder, Patrick / Sanjabi, Shomyseh

2024 Volume 15, Page(s) 1341804

Abstract: IL-15 has shown preclinical activity by enhancing the functional maturation of natural killer (NK) cells. Clinical evaluation of the potential anticancer activity of most cytokines, including IL-15, has been limited by low tolerability and ... ...

Abstract	IL-15 has shown preclinical activity by enhancing the functional maturation of natural killer (NK) cells. Clinical evaluation of the potential anticancer activity of most cytokines, including IL-15, has been limited by low tolerability and rapid
MeSH term(s)	Humans ; Interleukin-15/pharmacology ; Interleukin-15/metabolism ; Antineoplastic Agents/pharmacology ; Cytokines/metabolism ; Immunologic Factors/metabolism ; Killer Cells, Natural ; Cell Line, Tumor
Chemical Substances	Interleukin-15 ; Antineoplastic Agents ; Cytokines ; Immunologic Factors
Language	English
Publishing date	2024-03-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1341804
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Article ; Online: New cytometry tools for immune monitoring during cancer immunotherapy.

Sanjabi, Shomyseh / Lear, Sean

Cytometry. Part B, Clinical cytometry

2021 Volume 100, Issue 1, Page(s) 10–18

Abstract: The success of cancer immunotherapy (CIT) in the past decade has brought renewed excitement and the need to better understand how the human immune system functions during health and disease. Advances in single cell technologies have also inspired the ... ...

Abstract	The success of cancer immunotherapy (CIT) in the past decade has brought renewed excitement and the need to better understand how the human immune system functions during health and disease. Advances in single cell technologies have also inspired the creation of a Human Cell Atlas to identify and describe every cell in the human body with the intention of elucidating how to "fix" the ones that fail normal function. For example, treatment of cancer patients with immune checkpoint blockade (ICB) antibodies can reinvigorate their T cells and produce durable clinical benefit in a subset of patients, but a number of resistance mechanisms exist that prohibit full benefit to all treated patients. Early detection of biomarkers of response and mechanisms of resistance are needed to identify the patients who can benefit most from ICB. A noninvasive approach to predict treatment outcomes early after immunotherapies is a longitudinal analysis of peripheral blood immune cells using flow cytometry. Here we review some of the advances in our understanding of how ICB antibodies can re-invigorate tumor-specific T cells and also highlight the recent advances in high complexity flow cytometry, including spectral cytometers, that allow longitudinal sampling and deep immune phenotyping in clinical settings. We encourage the scientific community to utilize advanced cytometry platforms and analyses for immune monitoring in order to optimize CIT treatments for maximum clinical benefit.
MeSH term(s)	Flow Cytometry ; Humans ; Immunotherapy ; Neoplasms/immunology ; Neoplasms/therapy
Language	English
Publishing date	2021-01-11
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2099657-3
ISSN	1552-4957 ; 1552-4949 ; 0196-4763
ISSN (online)	1552-4957
ISSN	1552-4949 ; 0196-4763
DOI	10.1002/cyto.b.21984
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Zs.A 1688: Show issues

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Article ; Online: Single cell genome sequencing of laboratory mouse microbiota improves taxonomic and functional resolution of this model microbial community.

Lyalina, Svetlana / Stepanauskas, Ramunas / Wu, Frank / Sanjabi, Shomyseh / Pollard, Katherine S

PloS one

2022 Volume 17, Issue 4, Page(s) e0261795

Abstract: Laboratory mice are widely studied as models of mammalian biology, including the microbiota. However, much of the taxonomic and functional diversity of the mouse gut microbiome is missed in current metagenomic studies, because genome databases have not ... ...

Abstract	Laboratory mice are widely studied as models of mammalian biology, including the microbiota. However, much of the taxonomic and functional diversity of the mouse gut microbiome is missed in current metagenomic studies, because genome databases have not achieved a balanced representation of the diverse members of this ecosystem. Towards solving this problem, we used flow cytometry and low-coverage sequencing to capture the genomes of 764 single cells from the stool of three laboratory mice. From these, we generated 298 high-coverage microbial genome assemblies, which we annotated for open reading frames and phylogenetic placement. These genomes increase the gene catalog and phylogenetic breadth of the mouse microbiota, adding 135 novel species with the greatest increase in diversity to the Muribaculaceae and Bacteroidaceae families. This new diversity also improves the read mapping rate, taxonomic classifier performance, and gene detection rate of mouse stool metagenomes. The novel microbial functions revealed through our single-cell genomes highlight previously invisible pathways that may be important for life in the murine gastrointestinal tract.
MeSH term(s)	Animals ; Gastrointestinal Microbiome/genetics ; Humans ; Mammals/genetics ; Metagenome ; Metagenomics ; Mice ; Microbiota/genetics ; Phylogeny
Language	English
Publishing date	2022-04-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0261795
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Article ; Online: Single cell genome sequencing of laboratory mouse microbiota improves taxonomic and functional resolution of this model microbial community

Svetlana Lyalina / Ramunas Stepanauskas / Frank Wu / Shomyseh Sanjabi / Katherine S. Pollard

PLoS ONE, Vol 17, Iss

2022 Volume 4

Abstract	Laboratory mice are widely studied as models of mammalian biology, including the microbiota. However, much of the taxonomic and functional diversity of the mouse gut microbiome is missed in current metagenomic studies, because genome databases have not achieved a balanced representation of the diverse members of this ecosystem. Towards solving this problem, we used flow cytometry and low-coverage sequencing to capture the genomes of 764 single cells from the stool of three laboratory mice. From these, we generated 298 high-coverage microbial genome assemblies, which we annotated for open reading frames and phylogenetic placement. These genomes increase the gene catalog and phylogenetic breadth of the mouse microbiota, adding 135 novel species with the greatest increase in diversity to the Muribaculaceae and Bacteroidaceae families. This new diversity also improves the read mapping rate, taxonomic classifier performance, and gene detection rate of mouse stool metagenomes. The novel microbial functions revealed through our single-cell genomes highlight previously invisible pathways that may be important for life in the murine gastrointestinal tract.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Single cell genome sequencing of laboratory mouse microbiota improves taxonomic and functional resolution of this model microbial community.

Svetlana Lyalina / Ramunas Stepanauskas / Frank Wu / Shomyseh Sanjabi / Katherine S Pollard

PLoS ONE, Vol 17, Iss 4, p e

2022 Volume 0261795

Abstract	Laboratory mice are widely studied as models of mammalian biology, including the microbiota. However, much of the taxonomic and functional diversity of the mouse gut microbiome is missed in current metagenomic studies, because genome databases have not achieved a balanced representation of the diverse members of this ecosystem. Towards solving this problem, we used flow cytometry and low-coverage sequencing to capture the genomes of 764 single cells from the stool of three laboratory mice. From these, we generated 298 high-coverage microbial genome assemblies, which we annotated for open reading frames and phylogenetic placement. These genomes increase the gene catalog and phylogenetic breadth of the mouse microbiota, adding 135 novel species with the greatest increase in diversity to the Muribaculaceae and Bacteroidaceae families. This new diversity also improves the read mapping rate, taxonomic classifier performance, and gene detection rate of mouse stool metagenomes. The novel microbial functions revealed through our single-cell genomes highlight previously invisible pathways that may be important for life in the murine gastrointestinal tract.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Complex PK-PD of an engineered IL-15/IL-15Rα-Fc fusion protein in cynomolgus monkeys: QSP modeling of lymphocyte dynamics.

Lu, Dan / Yadav, Rajbharan / Holder, Patrick / Chiang, Eugene / Sanjabi, Shomyseh / Poon, Victor / Bernett, Matthew / Varma, Rajat / Liu, Ke / Leung, Irene / Bogaert, Liz / Desjarlais, John / Shivva, Vittal / Hosseini, Iraj / Ramanujan, Saroja

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences

2023 Volume 186, Page(s) 106450

Abstract: XmAb24306 is a lymphoproliferative interleukin (IL)-15/IL-15 receptor α (IL-15Rα) Fc-fusion protein currently under clinical investigation as an immunotherapeutic agent for cancer treatment. XmAb24306 contains mutations in IL-15 that attenuate its ... ...

Abstract	XmAb24306 is a lymphoproliferative interleukin (IL)-15/IL-15 receptor α (IL-15Rα) Fc-fusion protein currently under clinical investigation as an immunotherapeutic agent for cancer treatment. XmAb24306 contains mutations in IL-15 that attenuate its affinity to the heterodimeric IL-15 receptor βγ (IL-15R). We observe substantially prolonged pharmacokinetics (PK) (half-life ∼ 2.5 to 4.5 days) in single- and repeat-dose cynomolgus monkey (cyno) studies compared to wild-type IL-15 (half-life ∼ 1 hour), leading to increased exposure and enhanced and durable expansion of NK cells, CD8+ T cells and CD4-CD8- (double negative [DN]) T cells. Drug clearance varied with dose level and time post-dose, and PK exposure decreased upon repeated dosing, which we attribute to increased target-mediated drug disposition (TMDD) resulting from drug-induced lymphocyte expansion (i.e., pharmacodynamic (PD)-enhanced TMDD). We developed a quantitative systems pharmacology (QSP) model to quantify the complex PKPD behaviors due to the interactions of XmAb24306 with multiple cell types (CD8+, CD4+, DN T cells, and NK cells) in the peripheral blood (PB) and lymphoid tissues. The model, which includes nonspecific drug clearance, binding to and TMDD by IL15R differentially expressed on lymphocyte subsets, and resultant lymphocyte margination/migration out of PB, expansion in lymphoid tissues, and redistribution to the blood, successfully describes the systemic PK and lymphocyte kinetics observed in the cyno studies. Results suggest that after 3 doses of every-two-week (Q2W) doses up to 70 days, the relative contributions of each elimination pathway to XmAb24306 clearance are: DN T cells > NK cells > CD8+ T cells > nonspecific clearance > CD4+ T cells. Modeling suggests that observed cellular expansion in blood results from the influx of cells expanded by the drug in lymphoid tissues. The model is used to predict lymphoid tissue expansion and to simulate PK-PD for different dose regimens. Thus, the model provides insight into the mechanisms underlying the observed PK-PD behavior of an engineered cytokine and can serve as a framework for the rapid integration and analysis of data that emerges from ongoing clinical studies in cancer patients as single-agent or given in combination.
MeSH term(s)	Animals ; Macaca fascicularis/metabolism ; Interleukin-15/metabolism ; Network Pharmacology ; Lymphocytes/metabolism ; Immunologic Factors ; Antineoplastic Agents ; Receptors, Interleukin-15
Chemical Substances	Interleukin-15 ; Immunologic Factors ; Antineoplastic Agents ; Receptors, Interleukin-15
Language	English
Publishing date	2023-04-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1154366-8
ISSN	1879-0720 ; 0928-0987
ISSN (online)	1879-0720
ISSN	0928-0987
DOI	10.1016/j.ejps.2023.106450
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Zs.A 3705: Show issues

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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection.

Sanjabi, Shomyseh / Oh, Soyoung A / Li, Ming O

Cold Spring Harbor perspectives in biology

2017 Volume 9, Issue 6

Abstract: Transforming growth factor β (TGF-β) is a pleiotropic cytokine involved in both suppressive and inflammatory immune responses. After 30 years of intense study, we have only begun to elucidate how TGF-β alters immunity under various conditions. Under ... ...

Abstract	Transforming growth factor β (TGF-β) is a pleiotropic cytokine involved in both suppressive and inflammatory immune responses. After 30 years of intense study, we have only begun to elucidate how TGF-β alters immunity under various conditions. Under steady-state conditions, TGF-β regulates thymic T-cell selection and maintains homeostasis of the naïve T-cell pool. TGF-β inhibits cytotoxic T lymphocyte (CTL), Th1-, and Th2-cell differentiation while promoting peripheral (p)Treg-, Th17-, Th9-, and Tfh-cell generation, and T-cell tissue residence in response to immune challenges. Similarly, TGF-β controls the proliferation, survival, activation, and differentiation of B cells, as well as the development and functions of innate cells, including natural killer (NK) cells, macrophages, dendritic cells, and granulocytes. Collectively, TGF-β plays a pivotal role in maintaining peripheral tolerance against self- and innocuous antigens, such as food, commensal bacteria, and fetal alloantigens, and in controlling immune responses to pathogens.
MeSH term(s)	Animals ; Arthritis, Rheumatoid/immunology ; Autoimmunity ; B-Lymphocytes/immunology ; Bacterial Infections/immunology ; Cell Differentiation ; Cell Lineage ; Cell Proliferation ; Cell Survival ; Dendritic Cells/immunology ; Diabetes Mellitus, Type 1/immunology ; Granulocytes/immunology ; Homeostasis ; Humans ; Immune Tolerance ; Inflammatory Bowel Diseases/immunology ; Isoantigens/immunology ; Killer Cells, Natural/immunology ; Lupus Erythematosus, Systemic/immunology ; Lymphocyte Activation ; Macrophages/immunology ; Mast Cells/immunology ; Mice ; Monocytes/immunology ; Parasitic Diseases/immunology ; T-Lymphocytes/immunology ; T-Lymphocytes, Regulatory/immunology ; Thymus Gland/immunology ; Transforming Growth Factor beta/immunology
Chemical Substances	Isoantigens ; Transforming Growth Factor beta
Language	English
Publishing date	2017-06-01
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1943-0264
ISSN (online)	1943-0264
DOI	10.1101/cshperspect.a022236
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Article ; Online: Differentiating Immune Cell Targets in Gut-Associated Lymphoid Tissue for HIV Cure.

Khan, Shahzada / Telwatte, Sushama / Trapecar, Martin / Yukl, Steven / Sanjabi, Shomyseh

AIDS research and human retroviruses

2017 Volume 33, Issue S1, Page(s) S40–S58

Abstract: The single greatest challenge to an HIV cure is the persistence of latently infected cells containing inducible, replication-competent proviral genomes, which constitute only a small fraction of total or infected cells in the body. Although resting ... ...

Abstract	The single greatest challenge to an HIV cure is the persistence of latently infected cells containing inducible, replication-competent proviral genomes, which constitute only a small fraction of total or infected cells in the body. Although resting CD4
MeSH term(s)	Anti-HIV Agents/therapeutic use ; CD4-Positive T-Lymphocytes/virology ; HIV Infections/drug therapy ; HIV Infections/immunology ; HIV Infections/virology ; HIV-1/immunology ; Humans ; Intestinal Mucosa/immunology ; Intestinal Mucosa/virology ; Lymphoid Tissue/cytology ; Lymphoid Tissue/immunology ; T-Lymphocytes, Regulatory/immunology ; Th1 Cells/immunology ; Th17 Cells/immunology ; Virus Latency/immunology ; Virus Replication/immunology
Chemical Substances	Anti-HIV Agents
Language	English
Publishing date	2017-07-31
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	639130-8
ISSN	1931-8405 ; 0889-2229
ISSN (online)	1931-8405
ISSN	0889-2229
DOI	10.1089/AID.2017.0153
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Zs.A 1928: Show issues

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Article ; Online: Single-cell analysis reveals clonally expanded tumor-associated CD57

Fehlings, Michael / Kim, Leesun / Guan, Xiangnan / Yuen, Kobe / Tafazzol, Alireza / Sanjabi, Shomyseh / Zill, Oliver A / Rishipathak, Deepali / Wallace, Andrew / Nardin, Alessandra / Ma, Siming / Milojkovic, Ana / Newell, Evan W / Mariathasan, Sanjeev / Yadav, Mahesh

Journal for immunotherapy of cancer

2022 Volume 10, Issue 8

Abstract: Background: A growing body of evidence suggests that T-cell responses against neoantigens are critical regulators of response to immune checkpoint blockade. We previously showed that circulating neoantigen-specific CD8 T cells in patients with lung ... ...

Abstract	Background: A growing body of evidence suggests that T-cell responses against neoantigens are critical regulators of response to immune checkpoint blockade. We previously showed that circulating neoantigen-specific CD8 T cells in patients with lung cancer responding to anti-Programmed death-ligand 1 (PD-L1) (atezolizumab) exhibit a unique phenotype with high expression of CD57, CD244, and KLRG1. Here, we extended our analysis on neoantigen-specific CD8 T cells to patients with metastatic urothelial cancer (mUC) and further profiled total CD8 T cells to identify blood-based predictive biomarkers of response to atezolizumab. Methods: We identified tumor neoantigens from 20 patients with mUC and profiled their peripheral CD8 T cells using highly multiplexed combinatorial tetramer staining. Another set of patients with mUC treated with atezolizumab (n=30) or chemotherapy (n=40) were selected to profile peripheral CD8 T cells by mass cytometry. Using single-cell transcriptional analysis (single-cell RNA sequencing (scRNA-seq)), together with CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) and paired T-cell receptor (TCR) sequencing, we further characterized peripheral CD8 T cells in a subset of patients (n=16). Results: High frequency of CD57 was observed in neoantigen-specific CD8 T cells in patients with mUC responding to atezolizumab. Extending these findings to bulk CD8 T cells, we found higher frequency of CD57 expressing CD8 T cells before treatment in patients responding to atezolizumab (n=20, p<0.01) but not to chemotherapy. These findings were corroborated in a validation cohort (n=30, p<0.01) and notably were independent of known biomarkers of response. scRNA-seq analysis identified a clonally expanded cluster enriched within CD57 Conclusions: Collectively, we show high frequencies of CD57 among neoantigen-specific and bulk CD8 T cells in patients responding to atezolizumab. The TCR repertoire overlap between peripheral CD57
MeSH term(s)	B7-H1 Antigen/metabolism ; CD57 Antigens/immunology ; CD8-Positive T-Lymphocytes ; Carcinoma, Transitional Cell ; Humans ; Lung Neoplasms ; Receptors, Antigen, T-Cell ; Single-Cell Analysis
Chemical Substances	B7-H1 Antigen ; CD274 protein, human ; CD57 Antigens ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2022-08-15
Publishing country	England
Document type	Journal Article ; 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-2022-004759
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Article ; Online: Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer.

Galsky, Matthew D / Guan, Xiangnan / Rishipathak, Deepali / Rapaport, Aaron S / Shehata, Hesham M / Banchereau, Romain / Yuen, Kobe / Varfolomeev, Eugene / Hu, Ruozhen / Han, Chia-Jung / Li, Haocheng / Liang, Yuxin / Vucic, Domagoj / Wang, Li / Zhu, Jun / Yu, Haocheng / Herbst, Rebecca H / Hajaj, Emma / Kiner, Evgeny /

Bamias, Aristotelis / De Santis, Maria / Davis, Ian D / Arranz, José Ángel / Kikuchi, Eiji / Bernhard, Sandrine / Williams, Patrick / Lee, Chooi / Mellman, Ira / Sanjabi, Shomyseh / Johnston, Robert / Black, Peter C / Grande, Enrique / Mariathasan, Sanjeev

Cell reports. Medicine

2024 Volume 5, Issue 2, Page(s) 101393

Abstract: In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus ... ...

Abstract	In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. In addition, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens.
MeSH term(s)	Humans ; Antibodies, Monoclonal, Humanized ; Carboplatin/therapeutic use ; Carcinoma, Transitional Cell/drug therapy ; Carcinoma, Transitional Cell/chemically induced ; Carcinoma, Transitional Cell/pathology ; Cisplatin/therapeutic use ; Deoxycytidine/therapeutic use ; Gemcitabine ; Urinary Bladder Neoplasms/drug therapy ; Urinary Bladder Neoplasms/pathology ; Urologic Neoplasms/drug therapy ; Urologic Neoplasms/chemically induced ; Urologic Neoplasms/pathology
Chemical Substances	Antibodies, Monoclonal, Humanized ; atezolizumab (52CMI0WC3Y) ; Carboplatin (BG3F62OND5) ; Cisplatin (Q20Q21Q62J) ; Deoxycytidine (0W860991D6) ; Gemcitabine
Language	English
Publishing date	2024-01-26
Publishing country	United States
Document type	Clinical Trial ; Journal Article
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2024.101393
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