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Article ; Online: Lack of shared neoantigens in prevalent mutations in cancer.

Ragone, Concetta / Cavalluzzo, Beatrice / Mauriello, Angela / Tagliamonte, Maria / Buonaguro, Luigi

2024 Volume 22, Issue 1, Page(s) 344

Abstract: Tumors are mostly characterized by genetic instability, as result of mutations in surveillance mechanisms, such as DNA damage checkpoint, DNA repair machinery and mitotic checkpoint. Defect in one or more of these mechanisms causes additive accumulation ... ...

Abstract	Tumors are mostly characterized by genetic instability, as result of mutations in surveillance mechanisms, such as DNA damage checkpoint, DNA repair machinery and mitotic checkpoint. Defect in one or more of these mechanisms causes additive accumulation of mutations. Some of these mutations are drivers of transformation and are positively selected during the evolution of the cancer, giving a growth advantage on the cancer cells. If such mutations would result in mutated neoantigens, these could be actionable targets for cancer vaccines and/or adoptive cell therapies. However, the results of the present analysis show, for the first time, that the most prevalent mutations identified in human cancers do not express mutated neoantigens. The hypothesis is that this is the result of the selection operated by the immune system in the very early stages of tumor development. At that stage, the tumor cells characterized by mutations giving rise to highly antigenic non-self-mutated neoantigens would be efficiently targeted and eliminated. Consequently, the outgrowing tumor cells cannot be controlled by the immune system, with an ultimate growth advantage to form large tumors embedded in an immunosuppressive tumor microenvironment (TME). The outcome of such a negative selection operated by the immune system is that the development of off-the-shelf vaccines, based on shared mutated neoantigens, does not seem to be at hand. This finding represents the first demonstration of the key role of the immune system on shaping the tumor antigen presentation and the implication in the development of antitumor immunological strategies.
MeSH term(s)	Humans ; Neoplasms/genetics ; Neoplasms/therapy ; Antigens, Neoplasm/genetics ; Cancer Vaccines/genetics ; Mutation/genetics ; Cell Cycle Checkpoints ; Immunotherapy ; Tumor Microenvironment
Chemical Substances	Antigens, Neoplasm ; Cancer Vaccines
Language	English
Publishing date	2024-04-10
Publishing country	England
Document type	Journal Article
ZDB-ID	2118570-0
ISSN	1479-5876 ; 1479-5876
ISSN (online)	1479-5876
ISSN	1479-5876
DOI	10.1186/s12967-024-05110-0
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Article ; Online: Molecular mimicry and cancer vaccine development.

Tagliamonte, Maria / Cavalluzzo, Beatrice / Mauriello, Angela / Ragone, Concetta / Buonaguro, Franco M / Tornesello, Maria Lina / Buonaguro, Luigi

Molecular cancer

2023 Volume 22, Issue 1, Page(s) 75

Abstract: Background: The development of cancer immunotherapeutic strategies relies on the identification and validation of optimal target tumor antigens, which should be tumor-specific as well as able to elicit a swift and potent anti-tumor immune response. The ... ...

Abstract	Background: The development of cancer immunotherapeutic strategies relies on the identification and validation of optimal target tumor antigens, which should be tumor-specific as well as able to elicit a swift and potent anti-tumor immune response. The vast majority of such strategies are based on tumor associated antigens (TAAs) which are shared wild type cellular self-epitopes highly expressed on tumor cells. Indeed, TAAs can be used to develop off-the-shelf cancer vaccines appropriate to all patients affected by the same malignancy. However, given that they may be also presented by HLAs on the surface of non-malignant cells, they may be possibly affected by immunological tolerance or elicit autoimmune responses. Main body: In order to overcome such limitations, analogue peptides with improved antigenicity and immunogenicity able to elicit a cross-reactive T cell response are needed. To this aim, non-self-antigens derived from microorganisms (MoAs) may be of great benefit.
MeSH term(s)	Humans ; Cancer Vaccines ; Molecular Mimicry ; Neoplasms/drug therapy ; Antigens, Neoplasm ; T-Lymphocytes
Chemical Substances	Cancer Vaccines ; Antigens, Neoplasm
Language	English
Publishing date	2023-04-26
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2091373-4
ISSN	1476-4598 ; 1476-4598
ISSN (online)	1476-4598
ISSN	1476-4598
DOI	10.1186/s12943-023-01776-0
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Article ; Online: Microorganisms-derived antigens for preventive anti-cancer vaccines.

Buonaguro, Luigi / Cavalluzzo, Beatrice / Mauriello, Angela / Ragone, Concetta / Tornesello, Anna Lucia / Buonaguro, Franco M / Tornesello, Maria Lina / Tagliamonte, Maria

Molecular aspects of medicine

2023 Volume 92, Page(s) 101192

Abstract: Cancer prevention is one of the aim with the highest priority in order to reduce the burden of cancer diagnosis and treatment on individuals as well as on healthcare systems. To this aim, vaccines represent the most efficient primary cancer prevention ... ...

Abstract	Cancer prevention is one of the aim with the highest priority in order to reduce the burden of cancer diagnosis and treatment on individuals as well as on healthcare systems. To this aim, vaccines represent the most efficient primary cancer prevention strategy. Indeed, anti-cancer immunological memory elicited by preventive vaccines might promptly expand and prevent tumor from progressing. Antigens derived from microorganisms (MoAs), represent the obvious target for developing highly effective preventive vaccines for virus-induced cancers. In this respect, the drastic reduction in cancer incidence following HBV and HPV preventive vaccines are the paradigmatic example of such evidence. More recently, experimental evidences suggest that MoAs may represent a "natural" anti-cancer preventive vaccination or can be exploited for developing vaccines to prevent cancers presenting highly homologous tumor-associated antigens (TAAs) (e.g. molecular mimicry). The present review describes the different preventive anti-cancer vaccines based on antigens derived from pathogens at the different stages of development.
MeSH term(s)	Humans ; Cancer Vaccines/therapeutic use ; Neoplasms/prevention & control ; Vaccination
Chemical Substances	Cancer Vaccines
Language	English
Publishing date	2023-06-07
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	197640-0
ISSN	1872-9452 ; 0098-2997
ISSN (online)	1872-9452
ISSN	0098-2997
DOI	10.1016/j.mam.2023.101192
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Zs.A 1189: Show issues

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Article ; Online: Cross-reactive CD8

Cavalluzzo, Beatrice / Viuff, Marie Christine / Tvingsholm, Siri Amanda / Ragone, Concetta / Manolio, Carmen / Mauriello, Angela / Buonaguro, Franco M / Tornesello, Maria Lina / Izzo, Francesco / Morabito, Alessandro / Hadrup, Sine Reker / Tagliamonte, Maria / Buonaguro, Luigi

Journal of experimental & clinical cancer research : CR

2024 Volume 43, Issue 1, Page(s) 87

Abstract: Background: We have recently shown extensive sequence and conformational homology between tumor-associated antigens (TAAs) and antigens derived from microorganisms (MoAs). The present study aimed to assess the breadth of T-cell recognition specific to ... ...

Abstract	Background: We have recently shown extensive sequence and conformational homology between tumor-associated antigens (TAAs) and antigens derived from microorganisms (MoAs). The present study aimed to assess the breadth of T-cell recognition specific to MoAs and the corresponding TAAs in healthy subjects (HS) and patients with cancer (CP). Method: A library of > 100 peptide-MHC (pMHC) combinations was used to generate DNA-barcode labelled multimers. Homologous peptides were selected from the Cancer Antigenic Peptide Database, as well as Bacteroidetes/Firmicutes-derived peptides. They were incubated with CD8 + T cells from the peripheral blood of HLA-A02:01 healthy individuals (n = 10) and cancer patients (n = 16). T cell recognition was identified using tetramer-staining analysis. Cytotoxicity assay was performed using as target cells TAP-deficient T2 cells loaded with MoA or the paired TuA. Results:* A total of 66 unique pMHC recognized by CD8+ T cells across all groups were identified. Of these, 21 epitopes from microbiota were identified as novel immunological targets. Reactivity against selected TAAs was observed for both HS and CP. pMHC tetramer staining confirmed CD8+ T cell populations cross-reacting with CTA SSX2 and paired microbiota epitopes. Moreover, PBMCs activated with the MoA where shown to release IFNγ as well as to exert cytotoxic activity against cells presenting the paired TuA. Conclusions: Several predicted microbiota-derived MoAs are recognized by T cells in HS and CP. Reactivity against TAAs was observed also in HS, primed by the homologous bacterial antigens. CD8+ T cells cross-reacting with MAGE-A1 and paired microbiota epitopes were identified in three subjects. Therefore, the microbiota can elicit an extensive repertoire of natural memory T cells to TAAs, possibly able to control tumor growth ("natural anti-cancer vaccination"). In addition, non-self MoAs can be included in preventive/therapeutic off-the-shelf cancer vaccines with more potent anti-tumor efficacy than those based on TAAs.
MeSH term(s)	Humans ; Epitopes, T-Lymphocyte ; CD8-Positive T-Lymphocytes ; Antigens, Neoplasm ; Neoplasms ; Peptides/chemistry
Chemical Substances	Epitopes, T-Lymphocyte ; Antigens, Neoplasm ; Peptides
Language	English
Publishing date	2024-03-20
Publishing country	England
Document type	Journal Article
ZDB-ID	803138-1
ISSN	1756-9966 ; 0392-9078
ISSN (online)	1756-9966
ISSN	0392-9078
DOI	10.1186/s13046-024-03004-z
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Zs.A 2065: Show issues

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Article: Human Endogenous Retrovirus Reactivation: Implications for Cancer Immunotherapy.

Petrizzo, Annacarmen / Ragone, Concetta / Cavalluzzo, Beatrice / Mauriello, Angela / Manolio, Carmen / Tagliamonte, Maria / Buonaguro, Luigi

Cancers

2021 Volume 13, Issue 9

Abstract: Human endogenous retroviruses (HERVs) derive from ancestral exogenous retroviruses whose genetic material has been integrated in our germline DNA. Several lines of evidence indicate that cancer immunotherapy may benefit from HERV reactivation, which can ... ...

Abstract	Human endogenous retroviruses (HERVs) derive from ancestral exogenous retroviruses whose genetic material has been integrated in our germline DNA. Several lines of evidence indicate that cancer immunotherapy may benefit from HERV reactivation, which can be induced either by drugs or by cellular changes occurring in tumor cells. Indeed, several studies indicate that HERV proviral DNA can be transcribed either to double-stranded RNA (dsRNA) that is sensed as a "danger signal" by pattern recognition receptors (PRRs), leading to a viral mimicry state, or to mRNA that is translated into proteins that may contribute to the landscape of tumor-specific antigens (TSAs). Alternatively, HERV reactivation is associated with the expression of long noncoding RNAs (lncRNAs). In this review, we will highlight recent findings on HERV reactivation in cancer and its implications for cancer immunotherapy.
Language	English
Publishing date	2021-04-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13091999
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Article ; Online: Molecular mimicry between tumor associated antigens and microbiota-derived epitopes.

Ragone, Concetta / Manolio, Carmen / Mauriello, Angela / Cavalluzzo, Beatrice / Buonaguro, Franco M / Tornesello, Maria Lina / Tagliamonte, Maria / Buonaguro, Luigi

Journal of translational medicine

2022 Volume 20, Issue 1, Page(s) 316

Abstract: Background: The gut microbiota profile is unique for each individual and are composed by different bacteria species according to individual birth-to-infant transitions. In the last years, the local and systemic effects of microbiota on cancer onset, ... ...

Abstract	Background: The gut microbiota profile is unique for each individual and are composed by different bacteria species according to individual birth-to-infant transitions. In the last years, the local and systemic effects of microbiota on cancer onset, progression and response to treatments, such as immunotherapies, has been extensively described. Here we offer a new perspective, proposing a role for the microbiota based on the molecular mimicry of tumor associated antigens by microbiome-associated antigens. Methods: In the present study we looked for homology between published TAAs and non-self microbiota-derived epitopes. Blast search for sequence homology was combined with extensive bioinformatics analyses. Results: Several evidences for homology between TAAs and microbiota-derived antigens have been found. Strikingly, three cases of 100% homology between the paired sequences has been identified. The predicted average affinity to HLA molecules of microbiota-derived antigens is very high (< 100 nM). The structural conformation of the microbiota-derived epitopes is, in general, highly similar to the corresponding TAA. In some cases, it is identical and contact areas with both HLA and TCR chains are indistinguishable. Moreover, the spatial conformation of TCR-facing residues can be identical in paired TAA and microbiota-derived epitopes, with exactly the same values of planar as well as dihedral angles. Conclusions: The data reported in the present study show for the first time the high homology in the linear sequence as well as in structure and conformation between TAAs and peptides derived from microbiota species of the Firmicutes and the Bacteroidetes phyla, which together account for 90% of gut microbiota. Cross-reacting CD8
MeSH term(s)	Antigens, Neoplasm ; Epitopes ; Epitopes, T-Lymphocyte ; Humans ; Microbiota ; Molecular Mimicry ; Neoplasms ; Receptors, Antigen, T-Cell/genetics
Chemical Substances	Antigens, Neoplasm ; Epitopes ; Epitopes, T-Lymphocyte ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2022-07-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2118570-0
ISSN	1479-5876 ; 1479-5876
ISSN (online)	1479-5876
ISSN	1479-5876
DOI	10.1186/s12967-022-03512-6
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Article ; Online: Sorafenib-Loaded PLGA Carriers for Enhanced Drug Delivery and Cellular Uptake in Liver Cancer Cells.

Caputo, Tania Mariastella / Cusano, Angela Maria / Principe, Sofia / Cicatiello, Paola / Celetti, Giorgia / Aliberti, Anna / Micco, Alberto / Ruvo, Menotti / Tagliamonte, Maria / Ragone, Concetta / Minopoli, Michele / Carriero, Maria Vincenza / Buonaguro, Luigi / Cusano, Andrea

International journal of nanomedicine

2023 Volume 18, Page(s) 4121–4142

Abstract: Introduction: Currently, conventional treatments of hepatocellular carcinoma (HCC) are not selective enough for tumor tissue and lead to multidrug resistance and drug toxicity. Although sorafenib (SOR) is the standard first-line systemic therapy ... ...

Abstract	Introduction: Currently, conventional treatments of hepatocellular carcinoma (HCC) are not selective enough for tumor tissue and lead to multidrug resistance and drug toxicity. Although sorafenib (SOR) is the standard first-line systemic therapy approved for the clinical treatment of HCC, its poor aqueous solubility and rapid clearance result in low absorption efficiency and severely limit its use for local treatment. Methods: Herein, we present the synthesis of biodegradable polymeric Poly (D, L-Lactide-co-glycolide) (PLGA) particles loaded with SOR (PS) by emulsion-solvent evaporation process. The particles are carefully characterized focusing on particle size, surface charge, morphology, drug loading content, encapsulation efficiency, in vitro stability, drug release behaviour and tested on HepG2 cells. Additionally, PLGA particles have been coupled on side emitting optical fibers ( Results: PS have a size of 248 nm, tunable surface charge and a uniform and spherical shape without aggregation. PS shows encapsulation efficiency of 89.7% and the highest drug loading (8.9%) between the SOR-loaded PLGA formulations. Treating HepG2 cells with PS containing SOR at 7.5 µM their viability is dampened to 40%, 30% and 17% after 48, 129 and 168 hours of incubation, respectively. Conclusion: The high PS stability, their sustained release profile and the rapid cellular uptake corroborate the enhanced cytotoxicity effect on HepG2. With the prospect of developing biomedical tools to control the spatial and temporal release of drugs, we successfully demonstrated the potentiality of
MeSH term(s)	Humans ; Polylactic Acid-Polyglycolic Acid Copolymer ; Sorafenib ; Lactic Acid ; Polyglycolic Acid ; Drug Carriers ; Carcinoma, Hepatocellular/drug therapy ; Liver Neoplasms/drug therapy ; Cell Line, Tumor ; Particle Size ; Nanoparticles
Chemical Substances	Polylactic Acid-Polyglycolic Acid Copolymer (1SIA8062RS) ; Sorafenib (9ZOQ3TZI87) ; Lactic Acid (33X04XA5AT) ; Polyglycolic Acid (26009-03-0) ; Drug Carriers
Language	English
Publishing date	2023-07-26
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2364941-0
ISSN	1178-2013 ; 1176-9114
ISSN (online)	1178-2013
ISSN	1176-9114
DOI	10.2147/IJN.S415968
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Article ; Online: Identification and characterization of heteroclitic peptides in TCR-binding positions with improved HLA-binding efficacy.

Cavalluzzo, Beatrice / Ragone, Concetta / Mauriello, Angela / Petrizzo, Annacarmen / Manolio, Carmen / Caporale, Andrea / Vitagliano, Luigi / Ruvo, Menotti / Buonaguro, Luigi / Tagliamonte, Maria

Journal of translational medicine

2021 Volume 19, Issue 1, Page(s) 89

Abstract: The antigenicity as well as the immunogenicity of tumor associated antigens (TAAs) may need to be potentiated in order to break the immunological tolerance. To this aim, heteroclitic peptides were designed introducing specific substitutions in the ... ...

Abstract	The antigenicity as well as the immunogenicity of tumor associated antigens (TAAs) may need to be potentiated in order to break the immunological tolerance. To this aim, heteroclitic peptides were designed introducing specific substitutions in the residue at position 4 (p4) binding to TCR. The effect of such modifications also on the affinity to the major histocompatibility class I (MHC-I) molecule was assessed. The Trp2 antigen, specific for the mouse melanoma B16F10 cells, as well as the HPV-E7 antigen, specific for the TC1 tumor cell lines, were used as models. Affinity of such heteroclitic peptides to HLA was predicted by bioinformatics tools and the most promising ones were validated by structural conformational and HLA binding analyses. Overall, we demonstrated that TAAs modified at the TCR-binding p4 residue are predicted to have higher affinity to MHC-I molecules. Experimental evaluation confirms the stronger binding, suggesting that this strategy may be very effective for designing new vaccines with improved antigenic efficacy.
MeSH term(s)	Animals ; Antigens, Neoplasm ; HLA-A2 Antigen ; Mice ; Peptides ; Protein Binding ; Receptors, Antigen, T-Cell
Chemical Substances	Antigens, Neoplasm ; HLA-A2 Antigen ; Peptides ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2021-02-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1479-5876
ISSN (online)	1479-5876
DOI	10.1186/s12967-021-02757-x
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Article: Role of Microenvironment on the Fate of Disseminating Cancer Stem Cells.

Ingangi, Vincenzo / Minopoli, Michele / Ragone, Concetta / Motti, Maria Letizia / Carriero, Maria Vincenza

Frontiers in oncology

2019 Volume 9, Page(s) 82

Abstract: Disseminating Cancer Stem Cells (CSCs) initiate growth in specific niches of the host tissues, the cellular and molecular components of which sustain signaling pathways that support their survival, self-renewal dormancy and reactivation. In the ... ...

Abstract	Disseminating Cancer Stem Cells (CSCs) initiate growth in specific niches of the host tissues, the cellular and molecular components of which sustain signaling pathways that support their survival, self-renewal dormancy and reactivation. In the metastatic niche, tumor cells may enter in a dormant state to survive and, consequently, the metastasis can remain latent for years. Despite the clinical importance of metastatic latency, little is known about what induces CSCs to enter a dormant state and what allows them to remain viable for years in this state. CSCs exhibit genetic, epigenetic and cellular adaptations that confer resistance to classical therapeutic approaches. The identification of potential CSC targets is complicated by the fact that CSCs may arise as a consequence of their relationship with the local microenvironment into the metastatic niches. Indeed, microenvironment modulates the capability of CSCs to evade the innate immune response and survive. Some new therapeutic options that include drugs targeting microenvironment components are achieving encouraging results in reducing the number of CSCs in tumors and/or overcoming their resistance in preclinical studies. This review will focus on specific CSC features with an emphasis on the role of tumor microenvironment in supporting metastatic dissemination of CSCs. In addition, it sheds light on potential microenvironment-targeted therapies aimed to counteract seeding and survival of CSCs in the metastatic niche.
Language	English
Publishing date	2019-02-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2019.00082
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Article ; Online: Tackling hepatocellular carcinoma with individual or combinatorial immunotherapy approaches.

Tagliamonte, Maria / Mauriello, Angela / Cavalluzzo, Beatrice / Ragone, Concetta / Manolio, Carmen / Petrizzo, Annacarmen / Buonaguro, Luigi

Cancer letters

2019 Volume 473, Page(s) 25–32

Abstract: Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer globally. Indeed, there is a single drug approved as first-line systemic therapy in advanced unresectable HCC, providing a very limited survival benefit. In earlier stages, 5- ... ...

Abstract	Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer globally. Indeed, there is a single drug approved as first-line systemic therapy in advanced unresectable HCC, providing a very limited survival benefit. In earlier stages, 5-year survival rates after surgical and loco-regional therapies are extremely variable depending on the stage of disease. Nevertheless, HCC is considered an immunogenic tumor arising in chronically inflamed livers. In such a scenario, immunotherapy strategies for HCC, in particular combinations including cancer vaccines, may represent a key therapeutic tool to improve clinical outcome in HCC patients. However, a lot of improvement is needed given the disappointing results obtained so far.
MeSH term(s)	Antigens, Neoplasm/genetics ; Antigens, Neoplasm/immunology ; Antineoplastic Agents, Immunological/pharmacology ; Antineoplastic Agents, Immunological/therapeutic use ; Cancer Vaccines/therapeutic use ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/immunology ; Carcinoma, Hepatocellular/mortality ; Carcinoma, Hepatocellular/therapy ; Clinical Trials as Topic ; Combined Modality Therapy/methods ; DNA Modification Methylases/antagonists & inhibitors ; Epigenesis, Genetic/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Expression Regulation, Neoplastic/immunology ; Humans ; Immunotherapy/methods ; Liver Neoplasms/genetics ; Liver Neoplasms/immunology ; Liver Neoplasms/mortality ; Liver Neoplasms/therapy ; Mutation ; Oncolytic Virotherapy/methods ; Oncolytic Viruses ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/immunology ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Radiofrequency Ablation ; Sorafenib/therapeutic use ; Survival Rate ; Treatment Outcome ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/immunology
Chemical Substances	Antigens, Neoplasm ; Antineoplastic Agents, Immunological ; Cancer Vaccines ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor ; Protein Kinase Inhibitors ; Sorafenib (9ZOQ3TZI87) ; DNA Modification Methylases (EC 2.1.1.-)
Language	English
Publishing date	2019-12-23
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2019.12.029
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