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1.
Cell ; 184(8): 2167-2182.e22, 2021 04 15.
Article in English | MEDLINE | ID: mdl-33811809

ABSTRACT

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1ß, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.


Subject(s)
COVID-19/complications , Cardiotonic Agents/therapeutic use , Cell Cycle Proteins/antagonists & inhibitors , Heart Diseases/drug therapy , Quinazolinones/therapeutic use , Transcription Factors/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Animals , Cell Cycle Proteins/metabolism , Cell Line , Cytokines/metabolism , Female , Heart Diseases/etiology , Human Embryonic Stem Cells , Humans , Inflammation/complications , Inflammation/drug therapy , Mice , Mice, Inbred C57BL , Transcription Factors/metabolism , COVID-19 Drug Treatment
2.
Annu Rev Immunol ; 29: 235-71, 2011.
Article in English | MEDLINE | ID: mdl-21219185

ABSTRACT

The immune system can identify and destroy nascent tumor cells in a process termed cancer immunosurveillance, which functions as an important defense against cancer. Recently, data obtained from numerous investigations in mouse models of cancer and in humans with cancer offer compelling evidence that particular innate and adaptive immune cell types, effector molecules, and pathways can sometimes collectively function as extrinsic tumor-suppressor mechanisms. However, the immune system can also promote tumor progression. Together, the dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. In this review, we discuss the current experimental and human clinical data supporting a cancer immunoediting process that provide the fundamental basis for further study of immunity to cancer and for the rational design of immunotherapies against cancer.


Subject(s)
Neoplasms/immunology , Adaptive Immunity , Animals , Humans , Immunity, Innate , Immunologic Surveillance , Neoplasms/physiopathology , Neoplasms/therapy
3.
Nat Immunol ; 21(8): 835-847, 2020 08.
Article in English | MEDLINE | ID: mdl-32690952

ABSTRACT

Natural killer (NK) cells belong to the innate immune system and contribute to protecting the host through killing of infected, foreign, stressed or transformed cells. Additionally, via cellular cross-talk, NK cells orchestrate antitumor immune responses. Hence, significant efforts have been undertaken to exploit the therapeutic properties of NK cells in cancer. Current strategies in preclinical and clinical development include adoptive transfer therapies, direct stimulation, recruitment of NK cells into the tumor microenvironment (TME), blockade of inhibitory receptors that limit NK cell functions, and therapeutic modulation of the TME to enhance antitumor NK cell function. In this Review, we introduce the NK cell-cancer cycle to highlight recent advances in NK cell biology and to discuss the progress and problems of NK cell-based cancer immunotherapies.


Subject(s)
Immunotherapy/methods , Killer Cells, Natural/immunology , Neoplasms/immunology , Neoplasms/therapy , Animals , Humans , Tumor Microenvironment/immunology
4.
Nat Immunol ; 21(10): 1205-1218, 2020 10.
Article in English | MEDLINE | ID: mdl-32839608

ABSTRACT

Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases. NKG7 expressed by CD4+ and CD8+ T cells played key roles in promoting inflammation during visceral leishmaniasis and malaria-two important parasitic diseases. Additionally, NKG7 expressed by natural killer cells was critical for controlling cancer initiation, growth and metastasis. NKG7 function in natural killer and CD8+ T cells was linked with their ability to regulate the translocation of CD107a to the cell surface and kill cellular targets, while NKG7 also had a major impact on CD4+ T cell activation following infection. Thus, we report a novel therapeutic target expressed on a range of immune cells with functions in different immune responses.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Inflammation/immunology , Killer Cells, Natural/immunology , Leishmania donovani/physiology , Leishmaniasis, Visceral/immunology , Malaria/immunology , Membrane Proteins/metabolism , Plasmodium/physiology , Animals , Cells, Cultured , Cytotoxicity, Immunologic , Disease Models, Animal , Exocytosis , Humans , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Secretory Vesicles/metabolism
5.
Nat Immunol ; 20(6): 701-710, 2019 06.
Article in English | MEDLINE | ID: mdl-31110314

ABSTRACT

Cachexia represents a leading cause of morbidity and mortality in various cancers, chronic inflammation and infections. Understanding of the mechanisms that drive cachexia has remained limited, especially for infection-associated cachexia (IAC). In the present paper we describe a model of reversible cachexia in mice with chronic viral infection and identify an essential role for CD8+ T cells in IAC. Cytokines linked to cancer-associated cachexia did not contribute to IAC. Instead, virus-specific CD8+ T cells caused morphologic and molecular changes in the adipose tissue, which led to depletion of lipid stores. These changes occurred at a time point that preceded the peak of the CD8+ T cell response and required T cell-intrinsic type I interferon signaling and antigen-specific priming. Our results link systemic antiviral immune responses to adipose-tissue remodeling and reveal an underappreciated role of CD8+ T cells in IAC.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cachexia/etiology , Virus Diseases/complications , Virus Diseases/immunology , Adipose Tissue/diagnostic imaging , Adipose Tissue/immunology , Adipose Tissue/metabolism , Adipose Tissue/virology , Animals , CD8-Positive T-Lymphocytes/metabolism , Cachexia/diagnostic imaging , Cachexia/metabolism , Cachexia/pathology , Chronic Disease , Cytokines/blood , Cytokines/metabolism , Female , Interferon Type I/metabolism , Lipid Metabolism , Lipolysis , Lymphocyte Activation/immunology , Lymphocytic choriomeningitis virus , Magnetic Resonance Imaging/methods , Male , Mice , Signal Transduction , Virus Diseases/virology
9.
Nat Immunol ; 18(9): 1004-1015, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28759001

ABSTRACT

Avoiding destruction by immune cells is a hallmark of cancer, yet how tumors ultimately evade control by natural killer (NK) cells remains incompletely defined. Using global transcriptomic and flow-cytometry analyses and genetically engineered mouse models, we identified the cytokine-TGF-ß-signaling-dependent conversion of NK cells (CD49a-CD49b+Eomes+) into intermediate type 1 innate lymphoid cell (intILC1) (CD49a+CD49b+Eomes+) populations and ILC1 (CD49a+CD49b-Eomesint) populations in the tumor microenvironment. Strikingly, intILC1s and ILC1s were unable to control local tumor growth and metastasis, whereas NK cells favored tumor immunosurveillance. Experiments with an antibody that neutralizes the cytokine TNF suggested that escape from the innate immune system was partially mediated by TNF-producing ILC1s. Our findings provide new insight into the plasticity of group 1 ILCs in the tumor microenvironment and suggest that the TGF-ß-driven conversion of NK cells into ILC1s is a previously unknown mechanism by which tumors escape surveillance by the innate immune system.


Subject(s)
Cellular Reprogramming/immunology , Fibrosarcoma/immunology , Gastrointestinal Neoplasms/immunology , Gastrointestinal Stromal Tumors/immunology , Immunity, Innate/immunology , Killer Cells, Natural/immunology , Neoplasms, Experimental/immunology , Tumor Escape/immunology , Animals , Case-Control Studies , Cell Line, Tumor , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Gene Expression Profiling , Humans , Killer Cells, Natural/cytology , Lymphocytes/cytology , Lymphocytes/immunology , Mice , Sequence Analysis, RNA , Signal Transduction , Transforming Growth Factor beta/immunology
10.
Immunity ; 52(6): 895-897, 2020 06 16.
Article in English | MEDLINE | ID: mdl-32553176

ABSTRACT

The regulatory mechanisms controlling natural killer (NK) cells in the tumor microenvironment remain unknown. In this issue, Ni. et al. provide evidence that the transcription factor HIF-1α acts as a key negative regulator of NK cell metabolic fitness in the tumor microenvironment that critically impedes NK cell anti-tumor immune responses.


Subject(s)
Neoplasms , Transcription Factors , Humans , Killer Cells, Natural , Sequence Analysis, RNA , Tumor Microenvironment
11.
Immunity ; 53(3): 564-580.e9, 2020 09 15.
Article in English | MEDLINE | ID: mdl-32750334

ABSTRACT

Tumor immune escape limits durable responses to T cell therapy. Here, we examined how regulation and function of gene products that provide the target epitopes for CD8+ T cell anti-tumor immunity influence therapeutic efficacy and resistance. We used a CRISPR-Cas9-based method (CRISPitope) in syngeneic melanoma models to fuse the same model CD8+ T cell epitope to the C-termini of different endogenous gene products. Targeting melanosomal proteins or oncogenic CDK4R24C (Cyclin-dependent kinase 4) by adoptive cell transfer (ACT) of the same epitope-specific CD8+ T cells revealed diverse genetic and non-genetic immune escape mechanisms. ACT directed against melanosomal proteins, but not CDK4R24C, promoted melanoma dedifferentiation, and increased myeloid cell infiltration. CDK4R24C antigen persistence was associated with an interferon-high and T-cell-rich tumor microenvironment, allowing for immune checkpoint inhibition as salvage therapy. Thus, the choice of target antigen determines the phenotype and immune contexture of recurrent melanomas, with implications to the design of cancer immunotherapies.


Subject(s)
Adoptive Transfer/methods , CD8-Positive T-Lymphocytes/transplantation , Epitopes, T-Lymphocyte/immunology , Melanoma/immunology , Melanoma/therapy , Tumor Escape/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Cell- and Tissue-Based Therapy/methods , Epitopes, T-Lymphocyte/genetics , Gene Knockout Techniques , Immune Checkpoint Inhibitors/pharmacology , Mice , Mice, Inbred C57BL , Myeloid Cells/cytology , Myeloid Cells/immunology , Tumor Microenvironment/immunology
12.
Immunity ; 53(4): 824-839.e10, 2020 10 13.
Article in English | MEDLINE | ID: mdl-33053331

ABSTRACT

CD8+ T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8+ T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8+ T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226neg CD8+ T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8+ tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in Cd226-/- mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8+ T cell function and limits the efficacy of cancer immunotherapy.


Subject(s)
Antigens, Differentiation, T-Lymphocyte/immunology , CD8-Positive T-Lymphocytes/immunology , Neoplasms/immunology , T-Box Domain Proteins/immunology , Animals , Humans , Immune Checkpoint Inhibitors/immunology , Immunotherapy/methods , Mice , Mice, Inbred C57BL , Neoplasms/therapy , Programmed Cell Death 1 Receptor/immunology , Receptors, Antigen, T-Cell/immunology , Signal Transduction/immunology , Transcriptome/immunology , Tumor Microenvironment/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 9/immunology
13.
Immunity ; 53(4): 805-823.e15, 2020 10 13.
Article in English | MEDLINE | ID: mdl-33053330

ABSTRACT

The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8+ TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226hi TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226+CD8+ T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.


Subject(s)
Antigens, Differentiation, T-Lymphocyte/immunology , CD8-Positive T-Lymphocytes/immunology , Receptors, Virus/immunology , Animals , Cell Line , Cell Line, Tumor , HEK293 Cells , Humans , Immune Checkpoint Inhibitors/immunology , Immunotherapy/methods , Jurkat Cells , Lymphocytes, Tumor-Infiltrating/immunology , Male , Melanoma/immunology , Mice , Mice, Inbred C57BL
14.
Nat Immunol ; 17(9): 1025-36, 2016 08 19.
Article in English | MEDLINE | ID: mdl-27540992

ABSTRACT

Alteration in the expression of cell-surface proteins is a common consequence of malignant transformation. Natural killer (NK) cells use an array of germline-encoded activating and inhibitory receptors that scan for altered protein-expression patterns, but tumor evasion of detection by the immune system is now recognized as one of the hallmarks of cancer. NK cells display rapid and potent immunity to metastasis or hematological cancers, and major efforts are now being undertaken to fully exploit NK cell anti-tumor properties in the clinic. Diverse approaches encompass the development of large-scale NK cell-expansion protocols for adoptive transfer, the establishment of a microenvironment favorable to NK cell activity, the redirection of NK cell activity against tumor cells and the release of inhibitory signals that limit NK cell function. In this Review we detail recent advances in NK cell-based immunotherapies and discuss the advantages and limitations of these strategies.


Subject(s)
Immunotherapy/methods , Killer Cells, Natural/immunology , Neoplasms/therapy , Adjuvants, Immunologic/therapeutic use , Animals , Antigens, Neoplasm/immunology , Cytokines/metabolism , Cytotoxicity, Immunologic , Forecasting , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Humans , Immunity, Innate , Immunophenotyping , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Interleukin-15/physiology , Killer Cells, Natural/transplantation , Mice , Neoplasms/immunology , Neoplasms/pathology , Receptors, Natural Killer Cell/immunology , Recombinant Fusion Proteins/immunology , T-Box Domain Proteins/physiology , Tumor Escape , Tumor Microenvironment/immunology
15.
Nat Immunol ; 17(7): 816-24, 2016 07.
Article in English | MEDLINE | ID: mdl-27213690

ABSTRACT

The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish(-/-) mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. Our data uncover a potent intracellular checkpoint in NK cell-mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function.


Subject(s)
Immunotherapy/methods , Killer Cells, Natural/immunology , Neoplasms/therapy , Suppressor of Cytokine Signaling Proteins/metabolism , Animals , Cell Proliferation/genetics , Cytotoxicity, Immunologic/genetics , Immunologic Surveillance , Interferon-gamma/metabolism , Interleukin-15/metabolism , Janus Kinase 1/metabolism , Lymphocyte Activation/genetics , Melanoma, Experimental , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Targeted Therapy , Neoplasms/immunology , Signal Transduction/genetics , Suppressor of Cytokine Signaling Proteins/genetics
16.
Nat Immunol ; 15(5): 431-8, 2014 May.
Article in English | MEDLINE | ID: mdl-24658051

ABSTRACT

CD96, CD226 (DNAM-1) and TIGIT belong to an emerging family of receptors that interact with nectin and nectin-like proteins. CD226 activates natural killer (NK) cell-mediated cytotoxicity, whereas TIGIT reportedly counterbalances CD226. In contrast, the role of CD96, which shares the ligand CD155 with CD226 and TIGIT, has remained unclear. In this study we found that CD96 competed with CD226 for CD155 binding and limited NK cell function by direct inhibition. As a result, Cd96(-/-) mice displayed hyperinflammatory responses to the bacterial product lipopolysaccharide (LPS) and resistance to carcinogenesis and experimental lung metastases. Our data provide the first description, to our knowledge, of the ability of CD96 to negatively control cytokine responses by NK cells. Blocking CD96 may have applications in pathologies in which NK cells are important.


Subject(s)
Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , Killer Cells, Natural/immunology , Receptors, Immunologic/metabolism , Animals , Antigens, CD/genetics , Antigens, Differentiation, T-Lymphocyte/genetics , Cell Adhesion Molecules/metabolism , Cells, Cultured , Cytotoxicity, Immunologic/genetics , Lipopolysaccharides/immunology , Lung Neoplasms/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Nectins , Neoplasm Metastasis , Neoplasms, Experimental/immunology , Pneumonia/immunology , Protein Binding/genetics , Receptors, Virus/metabolism
17.
Immunity ; 47(4): 789-802.e9, 2017 10 17.
Article in English | MEDLINE | ID: mdl-29045907

ABSTRACT

Inhibitors of the receptor tyrosine kinase c-MET are currently used in the clinic to target oncogenic signaling in tumor cells. We found that concomitant c-MET inhibition promoted adoptive T cell transfer and checkpoint immunotherapies in murine cancer models by increasing effector T cell infiltration in tumors. This therapeutic effect was independent of tumor cell-intrinsic c-MET dependence. Mechanistically, c-MET inhibition impaired the reactive mobilization and recruitment of neutrophils into tumors and draining lymph nodes in response to cytotoxic immunotherapies. In the absence of c-MET inhibition, neutrophils recruited to T cell-inflamed microenvironments rapidly acquired immunosuppressive properties, restraining T cell expansion and effector functions. In cancer patients, high serum levels of the c-MET ligand HGF correlated with increasing neutrophil counts and poor responses to checkpoint blockade therapies. Our findings reveal a role for the HGF/c-MET pathway in neutrophil recruitment and function and suggest that c-MET inhibitor co-treatment may improve responses to cancer immunotherapy in settings beyond c-MET-dependent tumors.


Subject(s)
Immunotherapy/methods , Neoplasms, Experimental/therapy , Neutrophils/immunology , Proto-Oncogene Proteins c-met/immunology , Animals , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic/immunology , Interferon-gamma/immunology , Interferon-gamma/metabolism , Kaplan-Meier Estimate , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Neoplasms, Experimental/immunology , Neoplasms, Experimental/metabolism , Neutrophils/metabolism , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/metabolism , Signal Transduction/genetics , Signal Transduction/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology
18.
EMBO J ; 40(13): e108130, 2021 07 01.
Article in English | MEDLINE | ID: mdl-34121201

ABSTRACT

While intracellular adenosine triphosphate (ATP) occupies a key position in the bioenergetic metabolism of all the cellular compartments that form the tumor microenvironment (TME), extracellular ATP operates as a potent signal transducer. The net effects of purinergic signaling on the biology of the TME depend not only on the specific receptors and cell types involved, but also on the activation status of cis- and trans-regulatory circuitries. As an additional layer of complexity, extracellular ATP is rapidly catabolized by ectonucleotidases, culminating in the accumulation of metabolites that mediate distinct biological effects. Here, we discuss the molecular and cellular mechanisms through which ATP and its degradation products influence cancer immunosurveillance, with a focus on therapeutically targetable circuitries.


Subject(s)
Adenosine Triphosphate/immunology , Adenosine Triphosphate/metabolism , Neoplasms/immunology , Neoplasms/metabolism , Animals , Humans , Signal Transduction/immunology , Tumor Microenvironment/immunology , Tumor Microenvironment/physiology
19.
Immunity ; 44(1): 103-115, 2016 Jan 19.
Article in English | MEDLINE | ID: mdl-26795246

ABSTRACT

The inhibitor of DNA binding 2 (Id2) is essential for natural killer (NK) cell development with its canonical role being to antagonize E-protein function and alternate lineage fate. Here we have identified a key role for Id2 in regulating interleukin-15 (IL-15) receptor signaling and homeostasis of NK cells by repressing multiple E-protein target genes including Socs3. Id2 deletion in mature NK cells was incompatible with their homeostasis due to impaired IL-15 receptor signaling and metabolic function and this could be rescued by strong IL-15 receptor stimulation or genetic ablation of Socs3. During NK cell maturation, we observed an inverse correlation between E-protein target genes and Id2. These results shift the current paradigm on the role of ID2, indicating that it is required not only to antagonize E-proteins during NK cell commitment, but constantly required to titrate E-protein activity to regulate NK cell fitness and responsiveness to IL-15.


Subject(s)
Cell Differentiation/immunology , Inhibitor of Differentiation Protein 2/immunology , Interleukin-15/immunology , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Animals , Cell Lineage/immunology , Cells, Cultured , Female , Flow Cytometry , Male , Mice , Mice, Mutant Strains , Receptors, Interleukin-15/immunology , Receptors, Interleukin-15/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/immunology , Transcription Factors/metabolism
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