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Article ; Online: Virus-like particle vaccine displaying an external, membrane adjacent MUC16 epitope elicits ovarian cancer-reactive antibodies.

Tu, Hsin-Fang / Wong, Margaret / Tseng, Ssu-Hsueh / Ingavat, Nattha / Olczak, Pola / Notarte, Kin Israel / Hung, Chien-Fu / Roden, Richard B S

Journal of ovarian research

2024 Volume 17, Issue 1, Page(s) 19

Abstract: Background: MUC16 is a heavily glycosylated cell surface mucin cleaved in the tumor microenvironment to shed CA125. CA125 is a serum biomarker expressed by > 95% of non-mucinous advanced stage epithelial ovarian cancers. MUC16/CA125 contributes to the ... ...

Abstract	Background: MUC16 is a heavily glycosylated cell surface mucin cleaved in the tumor microenvironment to shed CA125. CA125 is a serum biomarker expressed by > 95% of non-mucinous advanced stage epithelial ovarian cancers. MUC16/CA125 contributes to the evasion of anti-tumor immunity, peritoneal spread and promotes carcinogenesis; consequently, it has been targeted with antibody-based passive and active immunotherapy. However, vaccination against this self-antigen likely requires breaking B cell tolerance and may trigger autoimmune disease. Display of self-antigens on virus-like particles (VLPs), including those produced with human papillomavirus (HPV) L1, can efficiently break B cell tolerance. Results: A 20 aa juxta-membrane peptide of the murine MUC16 (mMUC16) or human MUC16 (hMUC16) ectodomain was displayed either via genetic insertion into an immunodominant loop of HPV16 L1-VLPs between residues 136/137, or by chemical coupling using malemide to cysteine sulfhydryl groups on their surface. Female mice were vaccinated intramuscularly three times with either DNA expressing L1-MUC16 fusions via electroporation, or with alum-formulated VLP chemically-coupled to MUC16 peptides. Both regimens were well tolerated, and elicited MUC16-specific serum IgG, although titers were higher in mice vaccinated with MUC16-coupled VLP on alum as compared to L1-MUC16 DNA vaccination. Antibody responses to mMUC16-targeted vaccination cross-reacted with hMUC16 peptide, and vice versa; both were reactive with the surface of CA125+ OVCAR3 cells, but not SKOV3 that lack detectable CA125 expression. Interestingly, vaccination of mice with mMUC16 peptide mixed with VLP and alum elicited mMUC16-specific IgG, implying VLPs provide robust T help and that coupling may not be required to break tolerance to this epitope. Conclusion: Vaccination with VLP displaying the 20 aa juxta-membrane MUC16 ectodomain, which includes the membrane proximal cleavage site, is likely to be well tolerated and induce IgG targeting ovarian cancer cells, even after CA125 is shed.
MeSH term(s)	Humans ; Female ; Animals ; Mice ; Ovarian Neoplasms/genetics ; Vaccines, Virus-Like Particle ; Epitopes ; Apoptosis ; Cell Line, Tumor ; Peptides ; Immunoglobulin G ; DNA ; CA-125 Antigen/genetics ; Tumor Microenvironment ; Membrane Proteins/genetics ; Alum Compounds
Chemical Substances	aluminum sulfate (34S289N54E) ; Vaccines, Virus-Like Particle ; Epitopes ; Peptides ; Immunoglobulin G ; DNA (9007-49-2) ; CA-125 Antigen ; MUC16 protein, human ; Membrane Proteins ; Alum Compounds
Language	English
Publishing date	2024-01-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2455679-8
ISSN	1757-2215 ; 1757-2215
ISSN (online)	1757-2215
ISSN	1757-2215
DOI	10.1186/s13048-023-01325-9
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Article ; Online: In situ vaccination via tissue-targeted cDC1 expansion enhances the immunogenicity of chemoradiation and immunotherapy.

Lam, Brandon / Kung, Yu Jui / Lin, John / Tseng, Ssu-Hsueh / Tu, Hsin-Fang / Huang, Claire / Lee, Brandon / Velarde, Esteban / Tsai, Ya Chea / Villasmil, Rafael / Park, Sung Taek / Xing, Deyin / Hung, Chien-Fu / Wu, T-C

The Journal of clinical investigation

2024 Volume 134, Issue 1

Abstract: Even with the prolific clinical use of next-generation cancer therapeutics, many tumors remain unresponsive or become refractory to therapy, creating a medical need. In cancer, DCs are indispensable for T cell activation, so there is a restriction on ... ...

Abstract	Even with the prolific clinical use of next-generation cancer therapeutics, many tumors remain unresponsive or become refractory to therapy, creating a medical need. In cancer, DCs are indispensable for T cell activation, so there is a restriction on cytotoxic T cell immunity if DCs are not present in sufficient numbers in the tumor and draining lymph nodes to take up and present relevant cancer antigens. To address this bottleneck, we developed a therapeutic based on albumin fused with FMS-related tyrosine kinase 3 ligand (Alb-Flt3L) that demonstrated superior pharmacokinetic properties compared with Flt3L, including significantly longer half-life, accumulation in tumors and lymph nodes, and cross-presenting-DC expansion following a single injection. We demonstrated that Alb-Flt3L, in combination with standard-of-care chemotherapy and radiation therapy, serves as an in situ vaccination strategy capable of engendering polyclonal tumor neoantigen-specific immunity spontaneously. In addition, Alb-Flt3L-mediated tumor control synergized with immune checkpoint blockade delivered as anti-PD-L1. The mechanism of action of Alb-Flt3L treatment revealed a dependency on Batf3, type I IFNs, and plasmacytoid DCs. Finally, the ability of Alb-Flt3L to expand human DCs was explored in humanized mice. We observed significant expansion of human cross-presenting-DC subsets, supporting the notion that Alb-Flt3L could be used clinically to modulate human DC populations in future cancer therapeutic regimens.
MeSH term(s)	Mice ; Humans ; Animals ; Dendritic Cells ; Membrane Proteins/metabolism ; Neoplasms ; Antigens ; Immunotherapy ; Vaccination
Chemical Substances	Membrane Proteins ; Antigens
Language	English
Publishing date	2024-01-02
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/JCI171621
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Article ; Online: Development and anticancer properties of Up284, a spirocyclic candidate ADRM1/RPN13 inhibitor.

Anchoori, Ravi K / Anchoori, Vidyasagar / Lam, Brandon / Tseng, Ssu-Hsueh / Das, Samarjit / Velasquez, Fernanda Carrizo / Karanam, Balasubramanyam / Poddatoori, Deepika / Patnam, Ramesh / Rudek, Michelle A / Chang, Yung-Nien / Roden, Richard B S

PloS one

2023 Volume 18, Issue 6, Page(s) e0285221

Abstract: Bortezomib has been successful for treatment of multiple myeloma, but not against solid tumors, and toxicities of neuropathy, thrombocytopenia and the emergence of resistance have triggered efforts to find alternative proteasome inhibitors. Bis- ... ...

Abstract	Bortezomib has been successful for treatment of multiple myeloma, but not against solid tumors, and toxicities of neuropathy, thrombocytopenia and the emergence of resistance have triggered efforts to find alternative proteasome inhibitors. Bis-benzylidine piperidones such as RA190 covalently bind ADRM1/RPN13, a ubiquitin receptor that supports recognition of polyubiquitinated substrates of the proteasome and their subsequent deububiqutination and degradation. While these candidate RPN13 inhibitors (iRPN13) show promising anticancer activity in mouse models of cancer, they have suboptimal drug-like properties. Here we describe Up284, a novel candidate iRPN13 possessing a central spiro-carbon ring in place of RA190's problematic piperidone core. Cell lines derived from diverse cancer types (ovarian, triple negative breast, colon, cervical and prostate cancers, multiple myeloma and glioblastoma) were sensitive to Up284, including several lines resistant to bortezomib or cisplatin. Up284 and cisplatin showed synergistic cytotoxicity in vitro. Up284-induced cytotoxicity was associated with mitochondrial dysfunction, elevated levels of reactive oxygen species, accumulation of very high molecular weight polyubiquitinated protein aggregates, an unfolded protein response and the early onset of apoptosis. Up284 and RA190, but not bortezomib, enhanced antigen presentation in vitro. Up284 cleared from plasma in a few hours and accumulated in major organs by 24 h. A single dose of Up284, when administered to mice intra peritoneally or orally, inhibited proteasome function in both muscle and tumor for >48 h. Up284 was well tolerated by mice in repeat dose studies. Up284 demonstrated therapeutic activity in xenograft, syngeneic and genetically-engineered murine models of ovarian cancer.
MeSH term(s)	Humans ; Male ; Female ; Animals ; Mice ; Multiple Myeloma ; Cisplatin ; Proteasome Endopeptidase Complex ; Ovarian Neoplasms ; Bortezomib/pharmacology ; Intracellular Signaling Peptides and Proteins
Chemical Substances	Cisplatin (Q20Q21Q62J) ; RA190 ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Bortezomib (69G8BD63PP) ; ADRM1 protein, human ; Intracellular Signaling Peptides and Proteins
Language	English
Publishing date	2023-06-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0285221
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Article ; Online: Control of Spontaneous HPV16 E6/E7 Expressing Oral Cancer in HLA-A2 (AAD) Transgenic Mice with Therapeutic HPV DNA Vaccine.

Tseng, Ssu-Hsueh / Liu, Li / Peng, Shiwen / Kim, Jinhwi / Ferrall, Louise / Hung, Chien-Fu / Wu, T -C

Journal of biomedical science

2021 Volume 28, Issue 1, Page(s) 63

Abstract: Background: Human Papillomavirus type 16 (HPV16) has been associated with a subset of head and neck cancers. Two HPV encoded oncogenic proteins, E6 and E7, are important for the malignant progression of HPV-associated cancers. A spontaneous HPV16 E6/E7- ... ...

Abstract	Background: Human Papillomavirus type 16 (HPV16) has been associated with a subset of head and neck cancers. Two HPV encoded oncogenic proteins, E6 and E7, are important for the malignant progression of HPV-associated cancers. A spontaneous HPV16 E6/E7-expressing oral tumor model in human HLA-A2 (AAD) transgenic mice will be important for the development of therapeutic HPV vaccines for the control of HPV-associated head and neck cancers. Methods: In the current studies, we characterized the HLA-A2 restricted HPV16 E7-specific CD8 + T cell mediated immune responses in the HLA-A2 (AAD) transgenic mice using a therapeutic naked DNA vaccine encoding calreticulin (CRT) linked to a mutated E7(N53S). We also employed oncogenic DNA plasmids that encoded HPV16E6/E7/Luc, NRas Results: We found that CRT/E7(N53S) DNA vaccine primarily generated human HPV16 E7 peptide (aa11-20) specific CD8 + T cells, as compared to the wild-type CRT/E7 vaccine, which primarily generated murine H-2D Conclusions: Taken together, the data indicated that the combination of HPV16 E6/E7-expressing DNA, NRas
MeSH term(s)	Animals ; HLA-A2 Antigen/genetics ; Mice ; Mice, Transgenic ; Mouth Neoplasms/genetics ; Mouth Neoplasms/prevention & control ; Oncogene Proteins, Viral/metabolism ; Papillomavirus Infections/prevention & control ; Papillomavirus Vaccines/therapeutic use ; Repressor Proteins/metabolism
Chemical Substances	E6 protein, Human papillomavirus type 16 ; HLA-A2 Antigen ; Oncogene Proteins, Viral ; Papillomavirus Vaccines ; Repressor Proteins
Language	English
Publishing date	2021-09-13
Publishing country	England
Document type	Journal Article
ZDB-ID	1193378-1
ISSN	1423-0127 ; 1021-7770
ISSN (online)	1423-0127
ISSN	1021-7770
DOI	10.1186/s12929-021-00759-x
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Article ; Online: Bioinformatics and in vitro experimental analyses identify the selective therapeutic potential of interferon gamma and apigenin against cervical squamous cell carcinoma and adenocarcinoma.

Yang, Pei-Ming / Chou, Chia-Jung / Tseng, Ssu-Hsueh / Hung, Chien-Fu

Oncotarget

2017 Volume 8, Issue 28, Page(s) 46145–46162

Abstract: The clinical management and treatment of cervical cancer, one of the most commonly diagnosed cancers and a leading cause of cancer-related female death, remains a huge challenge for researchers and health professionals. Cervical cancer can be categorized ...

Abstract	The clinical management and treatment of cervical cancer, one of the most commonly diagnosed cancers and a leading cause of cancer-related female death, remains a huge challenge for researchers and health professionals. Cervical cancer can be categorized into two major subtypes: common squamous cell carcinoma (SCC) and adenocarcinoma (AC). Although it is a relatively rare histological subtype of cervical cancer, there has been a steady increase in the incidences of AC. Therefore, new strategies to treat cervical cancer are urgently needed. In this study, the potential uses of IFNγ-based therapy for cervical cancer were evaluated using bioinformatics approaches. Gene expression profiling identified that cell cycle dysregulation was a major hallmark of cervical cancer including SCC and AC subtypes, and was associated with poor clinical outcomes for cervical cancer patients. In silico and in vitro experimental analyses demonstrated that IFNγ treatment could reverse the cervical cancer hallmark and induce cell cycle arrest and apoptosis. Furthermore, we demonstrated that apigenin could enhance the anticancer activity of IFNγ in a HeLa cervical AC cell line by targeting cyclin-dependent kinase 1. Taken together, the present study suggests the selective therapeutic potential of IFNγ alone or in combination with apigenin for managing cervical SCC and AC.
Language	English
Publishing date	2017-07-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.17574
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Article ; Online: Localization of Salmonella and albumin-IL-2 to the tumor microenvironment augments anticancer T cell immunity.

Kung, Yu-Jui / Lam, Brandon / Tseng, Ssu-Hsueh / MacDonald, Alana / Tu, Hsin-Fang / Wang, Suyang / Lin, John / Tsai, Ya Chea / Wu, T C / Hung, Chien-Fu

Journal of biomedical science

2022 Volume 29, Issue 1, Page(s) 57

Abstract: Background: For centuries, microbial-based agents have been investigated as a therapeutic modality for the treatment of cancer. In theory, these methods would be cheap to produce, broadly applicable in a wide array of cancer types, and could synergize ... ...

Abstract	Background: For centuries, microbial-based agents have been investigated as a therapeutic modality for the treatment of cancer. In theory, these methods would be cheap to produce, broadly applicable in a wide array of cancer types, and could synergize with other cancer treatment strategies. We aimed to assess the efficacy of combining microbial-based therapy using Salmonella SL7207 with interleukin-2 (IL-2), a potent immunostimulatory agent, in the treatment of murine colon carcinoma. Methods: Female BALB/c mice were implanted subcutaneously with CT26 tumors, a model of colon carcinoma. Mice bearing tumors were selected and administered Albumin-IL-2 (Alb-IL2), a fusion protein, for further analysis of anticancer effect. Results: We demonstrated that Salmonella SL7207, a genetically modified strain of Salmonella enterica serovar Typhimurium, preferentially accumulates in the tumor microenvironment, potentiating it to stimulate localized innate immunity. We delivered IL-2 as a fusion protein, Alb-IL2, which we demonstrate to have preferential accumulation properties, bringing it to the tumor and secondary lymphoid organs. Treatment of tumor-bearing mice with Salmonella + Alb-IL2 leads to superior tumor control and enhanced overall survival compared to controls. When assessing immunological factors contributing to our observed tumor control, significantly enhanced T cell population with superior effector function was observed in mice treated with Salmonella + Alb-IL2. We confirmed that these T cells were indispensable to the observed tumor control through antibody-mediated T cell depletion experiments. Conclusions: These findings highlight the ability of Salmonella + Alb-IL2 to serve as a novel therapeutic approach to induce T cell-mediated antitumor immunity and exert long-term tumor control in a murine model of cancer.
MeSH term(s)	Albumins ; Animals ; Carcinoma ; Colonic Neoplasms ; Female ; Interleukin-2 ; Mice ; Salmonella ; Tumor Microenvironment
Chemical Substances	Albumins ; Interleukin-2
Language	English
Publishing date	2022-08-12
Publishing country	England
Document type	Journal Article
ZDB-ID	1193378-1
ISSN	1423-0127 ; 1021-7770
ISSN (online)	1423-0127
ISSN	1021-7770
DOI	10.1186/s12929-022-00841-y
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Article ; Online: Albumin and interferon-β fusion protein serves as an effective vaccine adjuvant to enhance antigen-specific CD8+ T cell-mediated antitumor immunity.

Tseng, Ssu-Hsueh / Cheng, Max A / Farmer, Emily / Ferrall, Louise / Kung, Yu Jui / Lam, Brandon / Lim, Ling / Wu, T-C / Hung, Chien-Fu

Journal for immunotherapy of cancer

2022 Volume 10, Issue 4

Abstract: Background: Type I interferons (IFN) promote dendritic cells maturation and subsequently enhance generation of antigen-specific CD8 +T cell for the control of tumor. Using type I interferons as an adjuvant to vaccination could prove to be a potent ... ...

Abstract	Background: Type I interferons (IFN) promote dendritic cells maturation and subsequently enhance generation of antigen-specific CD8 +T cell for the control of tumor. Using type I interferons as an adjuvant to vaccination could prove to be a potent strategy. However, type I interferons have a short half-life. Albumin linked to a protein will prolong the half-life of the linked protein. Methods: In this study, we explored the fusion of albumin to IFNβ (Alb-IFNβ) for its functional activity both in vitro and in vivo. We determined the half-life of Alb-IFNβ following treatment in the serum, tumor, and tumor draining lymph nodes in both wild type and FcRn knockout mice. We characterized the ability of Alb-IFNβ to enhance antigen-specific CD8+ T cells using ovalbumin (OVA) or human papillomavirus (HPV) E7 long peptides. Next, we evaluated the therapeutic antitumor effect of coadministration of AlbIFNβ with antigenic peptides against HPVE7 expressing tumor and the treatment's ability to generate HPVE7 antigen specific CD8+ T cells. The contribution of the antitumor effect by lymphocytes was also examined by an antibody depletion experiment. The ability of Alb-IFNβ to serve as an adjuvant was tested using clinical grade therapeutic protein-based HPV vaccine, TACIN. Results: Alb-IFNβ retains biological function and does not alter the biological activity of IFNβ. In addition, Alb-IFNβ extends half-life of IFNβ in serum, lymph nodes and tumor. The coadministration of Alb-IFNβ with OVA or HPVE7 antigenic peptides enhances antigen-specific CD8 +T cell immunity, and in a TC-1 tumor model results in a significant therapeutic antitumor effect. We found that CD8 +T cells and dendritic cells, but not CD4 +T cells, are important for the observed antitumor therapeutic effect mediated by Alb-IFNβ. Finally, Alb-IFNβ served as a potent adjuvant for TA-CIN for the treatment of HPV antigen expressing tumors. Conclusions: Overall, Alb-IFNβ serves as a potent adjuvant for enhancement of strong antigen-specific CD8 +T cell antitumor immunity, reduction of tumor burden, and increase in overall survival. Alb-IFNβ potentially can serve as an innovative adjuvant for the development of vaccines for the control of infectious disease and cancer.
MeSH term(s)	Adjuvants, Vaccine ; Albumins/metabolism ; Albumins/pharmacology ; Animals ; CD8-Positive T-Lymphocytes ; Cancer Vaccines ; Humans ; Interferon-beta ; Mice ; Neoplasms ; Papillomavirus E7 Proteins ; Papillomavirus Infections ; Recombinant Fusion Proteins/therapeutic use
Chemical Substances	Adjuvants, Vaccine ; Albumins ; Cancer Vaccines ; Papillomavirus E7 Proteins ; Recombinant Fusion Proteins ; Interferon-beta (77238-31-4)
Language	English
Publishing date	2022-04-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2021-004342
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Article ; Online: NKG2D-Fc fusion protein promotes antitumor immunity through the depletion of immunosuppressive cells.

Feng, Po-Hao / Lam, Brandon / Tseng, Ssu-Hsueh / Kung, Yu-Jui / Farmer, Emily / Cheng, Max A / Hung, Chien-Fu

Cancer immunology, immunotherapy : CII

2020 Volume 69, Issue 10, Page(s) 2147–2155

Abstract: A major factor impeding the success of numerous therapeutic approaches in cancer is the immunosuppressive nature of the tumor microenvironment (TME). Hence, methods capable of reverting tumor immunosuppression through depletion or reprogramming of ... ...

Abstract	A major factor impeding the success of numerous therapeutic approaches in cancer is the immunosuppressive nature of the tumor microenvironment (TME). Hence, methods capable of reverting tumor immunosuppression through depletion or reprogramming of myeloid-derived suppressive cells (MDSCs) and regulatory T cells (Tregs) are of great clinical need. Here, we explore NKG2D-Fc as a modality to modulate antitumor immunity through the depletion of immunosuppressive MDSCs and Tregs in the TME. We have generated the NKG2D-Fc fusion protein and characterized its potential to mediate tumor control and overall survival in LL2 and MC38 murine models. Upon treatment of LL2 or MC38 tumor-bearing mice with NKG2D-Fc, we observe significant tumor control and enhanced survival compared to Fc control. When characterizing MDCSs and Tregs from tumor-bearing mice, we observe clear expression of NKG2D-ligand RAE1γ and subsequent binding of NKG2D-Fc fusion protein to both MDSCs and Tregs. Examining the immune profile of mice treated with NKG2D-Fc reveals significant depletion of MDSCs and Tregs in the TME, as well as an increase in NK cells likely due to the reversed suppressive TME. In conclusion, NKG2D-Fc induces antitumor immunity and tumor control through the depletion of MDSCs and Tregs, subsequently providing a niche for the infiltration and expansion of proinflammatory cells, such as NK cells. Strategies capable of modulating the immunosuppressive state in cancer are in high clinical demand. NKG2D-Fc is a simple, single tool capable of depleting both MDSCs and Tregs and should be further investigated as a therapeutic agent for the treatment of cancer.
MeSH term(s)	Animals ; Colonic Neoplasms/immunology ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/pathology ; Cytotoxicity, Immunologic/immunology ; Female ; Immunoglobulin Fc Fragments/immunology ; Immunosuppression ; Killer Cells, Natural/immunology ; Lung Neoplasms/immunology ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Mice ; Mice, Inbred C57BL ; Myeloid-Derived Suppressor Cells/immunology ; NK Cell Lectin-Like Receptor Subfamily K/immunology ; Recombinant Fusion Proteins/immunology ; T-Lymphocytes, Regulatory/immunology ; Tumor Cells, Cultured ; Tumor Microenvironment/immunology
Chemical Substances	Immunoglobulin Fc Fragments ; KLRK1 protein, human ; NK Cell Lectin-Like Receptor Subfamily K ; Recombinant Fusion Proteins
Language	English
Publishing date	2020-05-28
Publishing country	Germany
Document type	Journal Article
ZDB-ID	195342-4
ISSN	1432-0851 ; 0340-7004
ISSN (online)	1432-0851
ISSN	0340-7004
DOI	10.1007/s00262-020-02615-7
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Article ; Online: Novel, genetically induced mouse model that recapitulates the histological morphology and immunosuppressive tumor microenvironment of metastatic peritoneal carcinomatosis.

Tseng, Ssu-Hsueh / Park, Sung-Taek / Lam, Brandon / Tsai, Ya-Chea / Cheng, Max A / Farmer, Emily / Xing, Deyin / Hung, Chien-Fu

Journal for immunotherapy of cancer

2020 Volume 8, Issue 1

Abstract: Background: Peritoneal carcinomatosis is a hallmark of advanced peritoneal tumor progression, particularly for tubal/ovarian high-grade serous carcinomas (HGSCs). Patients with peritoneal carcinomatosis have poor survival rates and are difficult to ... ...

Abstract	Background: Peritoneal carcinomatosis is a hallmark of advanced peritoneal tumor progression, particularly for tubal/ovarian high-grade serous carcinomas (HGSCs). Patients with peritoneal carcinomatosis have poor survival rates and are difficult to treat clinically due to widespread tumor dissemination in the peritoneal cavity. Methods: We developed a clinically relevant, genetically induced, peritoneal carcinomatosis model that recapitulates the histological morphology and immunosuppressive state of the tumor microenvironment of metastatic peritoneal HGSCs by intraperitoneally injecting shp53, AKT, c-Myc, luciferase and sleeping beauty transposase, followed by electroporation (EP) in the peritoneal cavity of immunocompetent mice (intraperitoneal (IP)/EP mice). Results: Similar to the spread of human ovarian cancers, IP/EP mice displayed multiple tumor nodules attached to the surface of the abdomen. Histopathological analysis indicated that these tumors were epithelial in origin. These IP/EP mice also displayed a loss of CD3 Conclusions: Overall, our tumor model recapitulates clinical peritoneal HGSC metastasis, which makes it ideal for preclinical drug screening, testing of immunotherapy-based therapeutics and studying of the tumor biology of peritoneal carcinomatosis.
MeSH term(s)	Animals ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cell Line, Tumor ; Disease Models, Animal ; Electroporation ; Female ; Humans ; Lymphocytes, Tumor-Infiltrating/immunology ; Mice ; Mice, Transgenic ; Oncogenes/genetics ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Peritoneal Neoplasms/genetics ; Peritoneal Neoplasms/secondary ; Primary Cell Culture ; Transposases/genetics ; Tumor Escape/genetics ; Tumor Microenvironment/genetics ; Tumor Microenvironment/immunology ; Tumor Suppressor Protein p53/genetics
Chemical Substances	Trp53 protein, mouse ; Tumor Suppressor Protein p53 ; Transposases (EC 2.7.7.-)
Language	English
Publishing date	2020-02-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2019-000480
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Article ; Online: Protein detection in blood with single-molecule imaging.

Mao, Chih-Ping / Wang, Shih-Chin / Su, Yu-Pin / Tseng, Ssu-Hsueh / He, Liangmei / Wu, Annie A / Roden, Richard B S / Xiao, Jie / Hung, Chien-Fu

Science advances

2021 Volume 7, Issue 33

Abstract: The ability to characterize individual biomarker protein molecules in patient blood samples could enable diagnosis of diseases at an earlier stage, when treatment is typically more effective. Single-molecule imaging offers a promising approach to ... ...

Abstract	The ability to characterize individual biomarker protein molecules in patient blood samples could enable diagnosis of diseases at an earlier stage, when treatment is typically more effective. Single-molecule imaging offers a promising approach to accomplish this goal. However, thus far, single-molecule imaging methods have not been translated into the clinical setting. The detection limit of these methods has been confined to the picomolar (10
MeSH term(s)	Biomarkers/analysis ; Humans ; Nanotechnology ; Proteins/analysis ; Single Molecule Imaging/methods
Chemical Substances	Biomarkers ; Proteins
Language	English
Publishing date	2021-08-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abg6522
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