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  • 1
    Abstract: As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non-BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.
    Type of Publication: Journal article published
    PubMed ID: 29227286
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  • 2
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; AGENTS ; human ; KINASE ; DISEASE ; LONG-TERM ; GENE ; GENES ; PROTEIN ; DRUG ; PATIENT ; ACTIVATION ; primary ; TRANSPLANTATION ; INDUCTION ; T-CELLS ; BINDING ; protein kinase ; TARGET ; CELL-DEATH ; INDUCED APOPTOSIS ; MODULATION ; LYMPHOCYTES ; CROHNS-DISEASE ; INFLAMMATORY-BOWEL-DISEASE ; 6- MERCAPTOPURINE ; CD28 ; COLITIS IN-VIVO ; GTPASE
    Abstract: Azathioprine and its metabolite 6-mercaptopurine (6-MP) are immunosuppressive drugs that are used in organ transplantation and autoimmune and chronic inflammatory diseases such as Crohn disease. However, their molecular mechanism of action is unknown. In the present study, we have identified a unique and unexpected role for azathioprine and its metabolites in the control of T cell apoptosis by modulation of Rac1 activation upon CD28 costimulation. We found that azathioprine and its metabolites induced apoptosis of T cells from patients with Crohn disease and control patients. Apoptosis induction required costimulation with CD28 and was mediated by specific blockade of Rac1 activation through binding of azathioprine- generated 6-thioguanine triphosphate (6-Thio-GTP) to Rac1 instead of GTP. The activation of Rac1 target genes such as mitogen-activated protein kinase kinase (MEK), NF-kappaB, and bcl-x(L), was suppressed by azathioprine, leading to a mitochondrial pathway of apoptosis. Azathioprine thus converts a costimulatory signal into an apoptotic signal by modulating Rac1 activity. These findings explain the immunosuppressive effects of azathioprine and suggest that 6-Thio-GTP derivates may be useful as potent immunosuppressive agents in autoimmune diseases and organ transplantation
    Type of Publication: Journal article published
    PubMed ID: 12697733
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  • 3
    Keywords: CANCER ; CELLS ; EXPRESSION ; proliferation ; SURVIVAL ; tumor ; CELL ; Germany ; human ; IN-VIVO ; THERAPY ; VIVO ; COMMON ; DISEASE ; incidence ; LONG-TERM ; SITE ; SITES ; GENE ; GENES ; GENOME ; transcription ; gene therapy ; PATIENT ; T cell ; T cells ; T-CELL ; T-CELLS ; RETROVIRUSES ; VECTORS ; VECTOR ; HUMAN GENOME ; REGION ; REGIONS ; PROGENITOR CELLS ; SELECTION ; TARGETS ; CD34(+) CELLS ; GENE-THERAPY ; mutagenesis ; retroviral vector ; RETROVIRAL VECTORS ; LOCATION ; insertional mutagenesis ; INTEGRATION ; THERAPIES ; bias ; SEVERE COMBINED IMMUNODEFICIENCY ; progenitor ; USA ; in vivo ; FATE ; progenitor cell ; TRANSDUCED CELLS ; LOCI ; host ; RETROVIRAL INTEGRATION ; SITE SELECTION ; MEDICINE ; VECTOR INTEGRATION ; PROGENITOR-CELL ; in vivo selection ; INSERTION ; SCID-X1
    Abstract: Recent reports have challenged the notion that retroviruses and retroviral vectors integrate randomly into the host genome. These reports pointed to a strong bias toward integration in and near gene coding regions and, for gammaretroviral vectors, around transcription start sites. Here, we report the results obtained from a large-scale mapping of 572 retroviral integration sites (RlSs) isolated from cells of 9 patients with X-linked SCID (SCID-X1) treated with a retrovirus-based gene therapy protocol. Our data showed that two-thirds of insertions occurred in or very near to genes, of which more than half were highly expressed in CD34(+) progenitor cells. Strikingly, one-fourth of all integrations were clustered as common integration sites (CISs). The highly significant incidence of CISs in circulating T cells and the nature of their locations indicate that insertion in many gene loci has an influence on cell engraftment, survival, and proliferation. Beyond the observed cases of insertional mutagenesis in 3 patients, these data help to elucidate the relationship between vector insertion and long-term in vivo selection of transduced cells in human patients with SCID-X1
    Type of Publication: Journal article published
    PubMed ID: 17671652
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  • 4
    Keywords: RECEPTOR ; CELLS ; CELL ; Germany ; GENE ; PROTEIN ; PROTEINS ; TISSUE ; MICE ; TUMOR-NECROSIS-FACTOR ; DNA ; MACROPHAGES ; MECHANISM ; CONTRAST ; DENDRITIC CELLS ; KERATINOCYTES ; mechanisms ; SKIN ; T cell ; T cells ; T-CELL ; T-CELLS ; SUPPRESSION ; treatment ; cytokines ; TARGET ; MUTANT ; inactivation ; DNA-BINDING ; BETA ; MOUSE MODEL ; TARGETS ; side effects ; REPRESSION ; DIMERIZATION ; chemokine ; TNF-ALPHA ; NEUTROPHILS ; CYTOKINE ; molecular ; PERSISTENT ; RECOMBINANT ; INFILTRATION ; MOLECULAR-MECHANISM ; RE ; keratinocyte ; allergy ; IMMUNE SUPPRESSION ; chemokines ; INFLAMMATORY CYTOKINES ; MOLECULAR-MECHANISMS ; PHASE ; USA ; corticosteroids ; GLUCOCORTICOIDS ; RESISTANT ; SKIN INFLAMMATION ; CONTACT ; MEDICINE ; INFLAMMATORY RESPONSE ; EPIDERMAL LANGERHANS CELLS ; HYPERSENSITIVITY REACTIONS ; INFLAMMATORY PROTEIN-2
    Abstract: Glucocorticoids (GCs) are widely used in the treatment of allergic skin conditions despite having numerous side effects. Here we use Cre/loxP-engineered tissue- and cell-specific and function-selective GC receptor (GR) mutant mice to identify responsive cell types and molecular mechanisms underlying the and inflammatory activity of GCs in contact hypersensitivity (CHS). CHS was repressed by GCs only at the challenge phase, i.e., during reexposure to the hapten. Inactivation of the GR gene in keratinocytes or T cells of mutant mice did not attenuate the effects of GCs, but its ablation in macrophages and neutrophils abolished downregulation of the inflammatory response. Moreover, mice expressing a DNA binding-defective GR were also resistant to GC treatment. The persistent infiltration of macrophages and neutrophils in these mice is explained by an impaired repression of inflammatory cytokines and chemokines such as IL-1 beta, monocyte chemoattractant protein-1, macrophage inflammatory protein-2, and IFN-gamma-inducible protein 10. In contrast TNF-alpha repression remained intact. Consequently, injection of recombinant proteins of these cytokines and chemokines partially reversed suppression of CHS by GCs. These studies provide evidence that in contact allergy, therapeutic action of corticosteroids is in macrophages and neutrophils and that dimerization GR is required
    Type of Publication: Journal article published
    PubMed ID: 17446934
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  • 5
    Keywords: CELLS ; EXPRESSION ; SURVIVAL ; CELL ; human ; IN-VIVO ; EXPOSURE ; MORTALITY ; MICE ; ACTIVATION ; RESPONSES ; INFECTION ; MECHANISM ; DENDRITIC CELLS ; IMMUNE-RESPONSES ; virus ; NO ; HEALTH ; HUMANS ; antigen presentation ; INDIVIDUALS ; immune response ; IMMUNE-RESPONSE ; INFLAMMATORY RESPONSES ; SUPPRESSOR ; elderly ; USA ; ENGLAND ; EXPANSION ; NATURAL-KILLER ; PUBLIC-HEALTH ; MEDICINE ; IFN-GAMMA PRODUCTION ; outcome ; response ; ALPHA-GALACTOSYLCERAMIDE ; Crosstalk ; INNATE IMMUNE-RESPONSE ; KILLER T-CELLS ; MURINE CYTOMEGALOVIRUS ; Myeloid cell ; myeloid cells ; myeloid-derived suppressor cells ; SUPPRESSOR-CELLS ; TUMOR IMMUNOSURVEILLANCE
    Abstract: infection with influenza A virus (IAV) presents a substantial threat to public health worldwide, with young, elderly, and immunodeficient individuals being particularly susceptible. Inflammatory responses play an important role in the fatal outcome of IAV infection, but the mechanism remains unclear. We demonstrate here that the absence of invariant NKT (iNKT) cells in mice during IAV infection resulted in the expansion of myeloid-derived suppressor cells (MDSCs), which suppressed IAV-specific immune responses through the expression of both arginase and NOS, resulting in high IAV titer and increased mortality. Adoptive transfer of iNKT cells abolished the suppressive activity of MDSCs, restored IAV-specific immune responses, reduced IAV titer, and increased survival rate. The crosstalk between iNKT and MDSCs was CD1d- and CD40-dependent. Furthermore, IAV infection and exposure to TLR agonists relieved the suppressive activity of MDSCs. Finally, we extended these results to humans by demonstrating the presence of myeloid cells with suppressive activity in the PBLs of individuals infected with IAV and showed that their suppressive activity is substantially reduced by iNKT cell activation. These findings identify what we believe to be a novel immunomodulatory role of iNKT cells, which we suggest could be harnessed to abolish the immunosuppressive activity of MDSCs during IAV infection
    Type of Publication: Journal article published
    PubMed ID: 19033672
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  • 6
    Keywords: PEPTIDE ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; SURVIVAL ; tumor ; CELL ; MODEL ; THERAPY ; tumor growth ; LONG-TERM ; MOLECULES ; TUMORS ; ACCUMULATION ; MICE ; ACTIVATION ; CARCINOGENESIS ; TOLERANCE ; MOLECULE ; antibodies ; MOUSE ; TRANSGENIC MICE ; IMMUNOTHERAPY ; MOUSE MODEL ; ADAPTIVE IMMUNITY ; IL-2 ; INTERLEUKIN-2 ; AGENT ; RECOMBINANT ; RE ; TUMOR-GROWTH ; THERAPIES ; CD40 LIGAND ; USA ; host ; MEDICINE ; ANTITUMOR RESPONSES ; LIGATION ; T-CELL HELP
    Abstract: Current anticancer therapy is a delicate balance between elimination of malignant cells and harmful side effects for the host. In this study, we used a tumor-homing peptide to engineer anti-CD40 agonist antibodies and recombinant IL-2 such that they were selectively delivered into spontaneously arising tumors in a transgenic mouse model of islet cell carcinogenesis. Intravenous injection of these agents, either separately or together, led to accumulation in the vicinity of tumor neovessels without toxic side effects. Although both molecules are critical for adaptive immunity, the most profound effects were seen in endothelial cells. Combined, local anti-CD40 and IL-2 therapy reduced tumor vascularity and significantly delayed tumor growth in mice. Remarkably, tumor-bearing mice remained disease-free long-term when targeted anti-CD40 and IL-2 were combined with transfers of preactivated antitumor immune cells. In this therapeutic setting, triggering of CD40 on endothelial cells induced an inflammatory response of the vessel wall and facilitated effector cell accumulation in the tumor parenchyma while IL-2 promoted antigen-specific immune cell persistence. We believe this is a novel and highly effective anticancer approach, whereby tumor stroma is "conditioned" for enhanced immune cell entry and survival, facilitating immune-mediated tumor destruction and leading to a sustained antitumor response
    Type of Publication: Journal article published
    PubMed ID: 18398504
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  • 7
    Keywords: brain ; ANGIOGENESIS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; tumor ; CELL ; human ; IN-VIVO ; MODEL ; VITRO ; VIVO ; COMMON ; GENE ; TUMORS ; MICE ; LIGAND ; NEOPLASIA ; NUDE-MICE ; CELL-LINE ; MELANOMA ; SUBUNITS ; ARCHITECTURE ; INHIBITORS ; mRNA ; USA ; angiopoietin ; angiopoietin-2 ; TIE2 ; CHRONIC GRANULOMATOUS-DISEASE ; gene array ; HEMANGIOMAS ; MIDDLE-T-ONCOGENE ; NEUTROPHIL CYTOCHROME-B
    Abstract: Hemangiomas are the most common type of tumor in infants. As they are endothelial cell-derived neoplasias, their growth can be regulated by the autocrine-acting Tie2 ligand angiopoietin 2 (Ang2). Using an experimental model of human hemangiomas, in which polyoma middle T-transformed brain endothelial (bEnd) cells are grafted subcutaneously into nude mice, we compared hemangioma growth originating from bEnd cells derived from wild-type, Ang2(+/-), and Ang2(-/-) mice. Surprisingly, Ang2-deficient bEnd cells formed endothelial tumors that grew rapidly and were devoid of the typical cavernous architecture of slow-growing Ang2-expressing hemangiomas, while Ang2(+/-) cells were greatly impaired in their in vivo growth. Gene array analysis identified a strong downregulation of NADPH oxidase 4 (Nox4) in Ang2(+/-) cells. Correspondingly, lentiviral silencing of Nox4 in an Ang2-sufficient bEnd cell line decreased Ang2 mRNA levels and greatly impaired hemangioma growth in vivo. Using a structure-based approach, we identified fulvenes as what we believe to be a novel class of Nox inhibitors. We therefore produced and began the initial characterization of fulvenes as potential Nox inhibitors, finding that fulvene-5 efficiently inhibited Nox activity in vitro and potently inhibited hemangioma growth in vivo. In conclusion, the present study establishes Nox4 as a critical regulator of hemangioma growth and identifies fulvenes as a potential class of candidate inhibitor to therapeutically interfere with Nox function
    Type of Publication: Journal article published
    PubMed ID: 19620773
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  • 8
    Keywords: ACTIVATION, ANTIGEN, antigen specific, ANTIGENS, CD8(+), CD8(+) T-CELLS, CELL, CELLS, COMPARTMENT-SP
    Abstract: The progression of kidney disease to renal failure correlates with infiltration of mononuclear immune cells into the tubulointerstitium. These infiltrates contain macrophages, DCs, and T cells, but the role of each cell type in disease progression is unclear. To investigate the underlying immune mechanisms, we generated transgenic mice that selectively expressed the model antigens ovalbumin and hen egg lysozyme in glomerular podocytes (NOH mice). Coinjection of ovalbumin-specific transgenic CD8(+) CTLs and CD4(+) Th cells into NOH mice resulted in periglomerular mononuclear infiltrates and inflammation of parietal epithelial cells, similar to lesions frequently observed in human chronic glomerulonephritis. Repetitive T cell injections aggravated infiltration and caused progression to structural and functional kidney damage after 4 weeks. Mechanistic analysis revealed that DCs in renal lymph nodes constitutively cross-presented ovalbumin and activated CTLs. These CTLs released further ovalbumin for CTL activation in the lymph nodes and for simultaneous presentation to Th cells by distinct DC subsets residing in the kidney tubulointerstitium. Crosstalk between tubulointerstitial DCs and Th cells resulted in intrarenal cytokine and chemokine production and in recruitment of more CTLs, monocyte-derived DCs, and macrophages. The importance of DCs was established by the fact that DC depletion rapidly resolved established kidney immunopathology. These findings demonstrate that glomerular antigen-specific CTLs and Th cells can jointly induce renal immunopathology and identify kidney DCs as a mechanistic link between glomerular injury and the progression of kidney disease
    Type of Publication: Journal article published
    PubMed ID: 19381017
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  • 9
  • 10
    Keywords: RECEPTOR ; CELLS ; CELL ; Germany ; IN-VIVO ; LUNG ; PATHWAY ; GENE ; GENES ; PROTEIN ; HEART ; MICE ; TOLERANCE ; hormone ; inactivation ; SIGNALING PATHWAY ; PROTEIN-KINASE-C ; insulin ; signaling ; secretion ; HORMONES ; PHOSPHOLIPASE-C ; GLUCOSE-HOMEOSTASIS ; INSULIN-SECRETION ; ADENINE-NUCLEOTIDES ; ALPHA-SUBUNITS ; GLUCAGON-RELEASE ; ISOLATED RAT ISLETS ; K-ATP CHANNELS ; PANCREATIC BETA-CELLS
    Abstract: A variety of neurotransmitters, gastrointestinal hormones, and metabolic signals are known to potentiate insulin secretion through GPCRs. We show here that beta cell-specific inactivation of the genes encoding the G protein alpha-subunits G alpha(q) and G alpha(11) resulted in impaired glucose tolerance and insulin secretion in mice. Interestingly, the defects observed in G alpha(q)/G alpha(11)-deficient beta cells were not restricted to loss of muscarinic or metabolic potentiation of insulin release; the response to glucose per se was also diminished. Electrophysiological recordings revealed that glucose-induced depolarization of isolated beta cells was impaired in the absence of G alpha(q)/G alpha(11), and closure of K-ATP channels was inhibited. We provide evidence that this reduced excitability was due to a loss of beta cell-autonomous potentiation of insulin secretion through factors cosecreted with insulin. We identified as autocrine mediators involved in this process extracellular nucleotides such as uridine diphosphate acting through the G(q)/G(11)-coupled P2Y6 receptor and extracellular calcium acting through the calcium-sensing receptor. Thus, the G(q)/G(11)-mediated signaling pathway potentiates insulin secretion in response to glucose by integrating systemic as well as autocrine/paracrine mediators
    Type of Publication: Journal article published
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