ORCID Profile
0000-0002-6522-7308
Current Organisations
Iran University of Science and Technology
,
University of British Columbia
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Publisher: The American Association of Immunologists
Date: 15-05-2012
Abstract: The innate immune response is a first line of defense against invading pathogens however, the magnitude of this response must be tightly regulated, as hyper- or suboptimal responses can be detrimental to the host. Systemic inflammation resulting from bacterial infection can lead to sepsis, which remains a serious problem with high mortality rates. Lyn tyrosine kinase plays a key role in adaptive immunity, although its role in innate immunity remains unclear. In this study, we show that Lyn gain-of-function (Lynup/up) mice display enhanced sensitivity to endotoxin and succumb to upregulated proinflammatory cytokine production at a dose well tolerated by control animals. Endotoxin sensitivity in Lynup/up mice depends on dendritic cells (DCs) and NK cells and occurs though a mechanism involving increased maturation and activation of the DC compartment, leading to elevated production of IFN-γ by NK cells. We further show that modulation of endotoxin-induced signal transduction in DCs by Lyn involves the phosphatases Src homology 2 domain-containing phosphatase-1 and SHIP-1. Collectively, we demonstrate that Lyn regulates DC physiology such that alterations in Lyn-dependent signaling have profound effects on the nature and magnitude of inflammatory responses. Our studies highlight how perturbations in signaling pathways controlling DC/NK cell-regulated responses to microbial products can profoundly affect the magnitude of innate immune responses.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546765
Abstract: Supplementary Figure S2 compares the immune cell content in peripheral blood and spleens from immunocompetent, immunocompromised and G-CSFR-/- mice harboring MT or MTG-CSF-/- tumors.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-02-2003
DOI: 10.1126/STKE.2003.169.PE6
Abstract: Suppressor of cytokine signaling (SOCS) family proteins were initially identified as inhibiting cytokine signaling pathways through a negative feedback loop involving the inhibition of Janus kinase activity. More recent data suggest that SOCS proteins may also modulate signaling mediated through receptor tyrosine kinases. Krebs and Hilton discuss research implicating SOCS-1 and SOCS-3 as inhibitors of insulin receptor-mediated and insulin-like growth factor-1 receptor-mediated signaling pathways, as well as the increasing evidence that SOCS proteins may act in part by participating in a ubiquitin ligase complex to promote the degradation of target proteins.
Publisher: The American Association of Immunologists
Date: 15-11-2014
Abstract: The Lyn tyrosine kinase governs the development and function of various immune cells, and its dysregulation has been linked to malignancy and autoimmunity. Using models of chemically induced colitis and enteric infection, we show that Lyn plays a critical role in regulating the intestinal microbiota and inflammatory responses as well as protection from enteric pathogens. Lyn−/− mice were highly susceptible to dextran sulfate sodium (DSS) colitis, characterized by significant wasting, rectal bleeding, colonic pathology, and enhanced barrier permeability. Increased DSS susceptibility in Lyn−/− mice required the presence of T but not B cells and correlated with dysbiosis and increased IFN-γ+ and/or IL-17+ colonic T cells. This dysbiosis was characterized by an expansion of segmented filamentous bacteria, associated with altered intestinal production of IL-22 and IgA, and was transmissible to wild-type mice, resulting in increased susceptibility to DSS. Lyn deficiency also resulted in an inability to control infection by the enteric pathogens Salmonella enterica serovar Typhimurium and Citrobacter rodentium. Lyn−/− mice exhibited profound cecal inflammation, bacterial dissemination, and morbidity following S. Typhimurium challenge and greater colonic inflammation throughout the course of C. rodentium infection. These results identify Lyn as a key regulator of the mucosal immune system, governing pathophysiology in multiple models of intestinal disease.
Publisher: Informa UK Limited
Date: 08-2007
DOI: 10.1128/MCB.00802-07
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.C.6551242.V1
Abstract: While immunotherapies such as immune checkpoint blockade and adoptive T-cell therapy improve survival for a subset of human malignancies, many patients fail to respond. Phagocytes including dendritic cells (DC), monocytes, and macrophages (MF) orchestrate innate and adaptive immune responses against tumors. However, tumor-derived factors may limit immunotherapy effectiveness by altering phagocyte signal transduction, development, and activity. Using Cytometry by Time-of-Flight, we found that tumor-derived GCSF altered myeloid cell distribution both locally and systemically. We distinguished a large number of GCSF-induced immune cell subset and signal transduction pathway perturbations in tumor-bearing mice, including a prominent increase in immature neutrophil/myeloid-derived suppressor cell (Neut/MDSC) subsets and tumor-resident PD-L1 sup + /sup Neut/MDSCs. GCSF expression was also linked to distinct tumor-associated MF populations, decreased conventional DCs, and splenomegaly characterized by increased splenic progenitors with diminished DC differentiation potential. GCSF-dependent dysregulation of DC development was recapitulated in bone marrow cultures i in vitro /i , using medium derived from GCSF-expressing tumor cell cultures. Importantly, tumor-derived GCSF impaired T-cell adoptive cell therapy effectiveness and was associated with increased tumor volume and diminished survival of mice with mammary cancer. Treatment with neutralizing anti-GCSF antibodies reduced colonic and circulatory Neut/MDSCs, normalized colonic immune cell composition and diminished tumor burden in a spontaneous model of mouse colon cancer. Analysis of human colorectal cancer patient gene expression data revealed a significant correlation between survival and low GCSF and Neut/MDSC gene expression. Our data suggest that normalizing GCSF bioactivity may improve immunotherapy in cancers associated with GCSF overexpression. Significance: Tumor-derived GCSF leads to systemic immune population changes. GCSF blockade restores immune populations, improves immunotherapy, and reduces tumor size, paralleling human colorectal cancer data. GCSF inhibition may synergize with current immunotherapies to treat GCSF-secreting tumors. /
Publisher: Proceedings of the National Academy of Sciences
Date: 19-10-2004
Abstract: SOCS7 is a member of the suppressor of cytokine signaling (SOCS) family of proteins (SOCS1-SOCS7 and CIS). SOCS proteins are composed of an N-terminal domain of variable length, a central Src homology 2 domain, and a C-terminal SOCS box. Biochemical and genetic studies have revealed that SOCS1, SOCS2, SOCS3, and CIS play an important role in the termination of cytokine and growth factor signaling. However, the biological actions of other SOCS proteins are less well defined. To investigate the physiological role of SOCS7, we have used gene targeting to generate mice that lack expression of the Socs7 gene. Socs7 -/- mice were born in expected numbers, were fertile, and did not exhibit defects in hematopoiesis or circulating glucose or insulin concentrations. However, Socs7 -/- mice were 7-10% smaller than their wild-type littermates, and within 15 weeks of age ≈50% of the Socs7 -/- mice died as a result of hydrocephalus that was characterized by cranial distortion, dilation of the ventricular system, reduced thickness of the cerebral cortex, and disorganization of the subcommissural organ. In situ hybridization studies revealed prominent expression of Socs7 in the brain, suggestive of an important functional role of SOCS7 in this organ.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546750.V1
Abstract: Flow cytometry antibodies
Publisher: The Company of Biologists
Date: 15-08-2000
Abstract: Cytokines regulate cellular behavior by interacting with receptors on the plasma membrane of target cells and activating intracellular signal transduction cascades such as the JAK-STAT pathway. Suppressors of cytokine signaling (SOCS) proteins negatively regulate cytokine signaling. The SOCS family consists of eight proteins: SOCS1-SOCS7 and CIS, each of which contains a central Src-homology 2 (SH2) domain and a C-terminal SOCS box. The expression of CIS, SOCS1, SOCS2 and SOCS3 is induced in response to stimulation by a wide variety of cytokines, and overexpression of these proteins in cell lines results in inhibition of cytokine signaling. Thus, SOCS roteins appear to form part of a classical negative feedback loop. The analysis of mice lacking SOCS1 has revealed that it is critical in the negative regulation of IFNγ signaling and in the differentiation of T cells. Additionally, the analysis of mouse embryos lacking SOCS3 suggests that SOCS3 negatively regulates fetal liver erythropoiesis, probably through its ability to modulate erythropoietin (Epo) signaling. Thus, the use of gene targeting has confirmed that SOCS proteins regulate cytokine signaling in a physiological setting.
Publisher: Informa UK Limited
Date: 07-2002
Publisher: Oxford University Press (OUP)
Date: 09-2001
DOI: 10.1634/STEMCELLS.19-5-378
Abstract: Cytokines regulate the growth and differentiation of cells by binding to cell-surface receptors and activating intracellular signal transduction cascades such as the JAK-STAT pathway. Cytokine signaling is negatively regulated with respect to both magnitude and duration, and it is now clear that the suppressor of cytokine signaling (SOCS) family of proteins (SOCS1-SOCS7 and CIS) contributes significantly to this process. Transcripts encoding CIS, SOCS1, SOCS2, and SOCS3 are upregulated in response to cytokine stimulation, and the corresponding SOCS proteins inhibit cytokine-induced signaling pathways. SOCS proteins therefore form part of a classical negative feedback circuit. SOCS family members modulate signaling by several mechanisms, which include inactivation of the Janus kinases (JAKs), blocking access of the signal transducers and activators of transcription (STATs) to receptor binding sites, and ubiquitination of signaling proteins and their subsequent targeting to the proteasome. Gene targeting has been used to generate mice lacking socs1, socs2, or socs3, in order to elucidate the physiological function of these SOCS family members. The analysis of socs1(-/-) mice has revealed that SOCS1 plays a key role in the negative regulation of interferon-gamma signaling and in T cell differentiation. Socs2(-/-) mice are 30%-40% larger than wild-type mice, demonstrating that SOCS2 is a critical regulator of postnatal growth. Additionally, the study of embryos lacking socs3 has revealed that SOCS3 is an important regulator of fetal liver hematopoiesis. The biological role of other SOCS proteins remains to be determined.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546768
Abstract: Supplementary Figure S1 shows the characterization of MT and MTG-CSF-/- cell lines and tumors, including surface protein expression, tumor volume/weight, and immune cell subset content. Composition of immune cells in blood and spleen of MT and MTG-CSF-/- mice is also shown.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546759.V1
Abstract: Supplementary Figure S3 shows deep phenotyping of Neut/MDSCs and B cells in the bone marrow of mice bearing MT or MTG-CSF-/- tumors, using FlowSOM applied in tSNE maps.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546756.V1
Abstract: Supplementary Figure S4 shows that G-CSF and G-CSFR signaling inhibit DC development and activation, in DCs derived in a OP9-DLL1 co-culture system.
Publisher: Proceedings of the National Academy of Sciences
Date: 19-09-2006
Abstract: We have generated mice from a N -ethyl- N -nitrosourea mutagenesis screen that carry a mutation in the translation initiation codon of Gata-1 , termed Plt13 , which is equivalent to mutations found in patients with acute megakaryoblastic leukemia and Down syndrome. The Gata-1 locus is present on the X chromosome in humans and in mice. Male mice hemizygous for the mutation ( Gata-1 Plt13 /Y) failed to produce red blood cells and died during embryogenesis at a similar stage to Gata-1 -null animals. Female mice that carry the Plt13 mutation are mosaic because of random inactivation of the X chromosome. Adult Gata-1 Plt13 /+ females were not anemic, but they were thrombocytopenic and accumulated abnormal megakaryocytes without a concomitant increase in megakaryocyte progenitor cells. Gata-1 Plt13 /+ mice contained large numbers of blast-like colony-forming cells, particularly in the fetal liver, but also in adult spleen and bone marrow, from which continuous mast cells lines were readily derived. Although the equivalent mutation to Gata-1 Plt13 in humans results in production of GATA-1s, a short protein isoform initiated from a start codon downstream of the mutated initiation codon, Gata-1s was not detected in Gata-1 Plt13 /+ mice.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2003
DOI: 10.1038/NI931
Publisher: Elsevier BV
Date: 11-1994
Publisher: Elsevier BV
Date: 2007
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546768.V1
Abstract: Supplementary Figure S1 shows the characterization of MT and MTG-CSF-/- cell lines and tumors, including surface protein expression, tumor volume/weight, and immune cell subset content. Composition of immune cells in blood and spleen of MT and MTG-CSF-/- mice is also shown.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546753
Abstract: CyTOF panels
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546750
Abstract: Flow cytometry antibodies
Publisher: Elsevier BV
Date: 04-2006
Publisher: American Association for Cancer Research (AACR)
Date: 10-2013
DOI: 10.1158/0008-5472.CAN-13-0842
Abstract: Cancer is associated with immune dysfunction characterized by the presence of proinflammatory and immunosuppressive cells and factors that contribute to tumor growth and progression. Here we show that mammary tumor growth is associated with defects in hematopoiesis, leading to myeloproliferative-like disease (leukemoid reaction), anemia, and disruption of the bone marrow stem rogenitor compartment. The defects we characterized included impaired erythropoiesis, leukocytosis, loss of early progenitor cells in the bone marrow, and splenic extramedullary hematopoiesis. We established an in vitro model to dissect interactions between mammary cancers and the hematopoietic system. Investigations in this model revealed that granulocyte colony-stimulating factor (G-CSF) produced by mammary tumors can synergize with FLT3L and granulocyte macrophage CSF (GM-CSF) to expand myeloid progenitors and their progeny in culture. Mammary tumor growth was associated with histone methylation changes within lineage-negative c-Kit-positive hematopoietic cells within the bone marrow of tumor-bearing mice. Similarly, parallel histone methylation patterns occurred in cultured bone marrow cells exposed to mammary tumor-conditioned cell culture media. Notably, changes in histone methylation in these cell populations correlated with dysregulated expression of genes controlling hematopoietic lineage commitment and differentiation, including Hox family genes and members of the Polycomb repressive complex 2 (PRC2) chromatin-remodeling complex. Together, our results show that mammary tumor-secreted factors induce profound perturbations in hematopoiesis and expression of key hematopoietic regulatory genes. Cancer Res 73(19) 5892–904. ©2013 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546759
Abstract: Supplementary Figure S3 shows deep phenotyping of Neut/MDSCs and B cells in the bone marrow of mice bearing MT or MTG-CSF-/- tumors, using FlowSOM applied in tSNE maps.
Publisher: Elsevier BV
Date: 12-1996
Publisher: Wiley
Date: 20-07-2006
Publisher: Springer Science and Business Media LLC
Date: 1999
Abstract: Murine B cell lines such as WEHI-231, BAL17 and M12.4.1 are frequently used as model systems to study signal transduction, cell cycle regulation, and apoptosis. Dissection of these processes often involves expressing exogenous genes in these cells. Electroporation is an inefficient method to express genes in B cell lines and requires several weeks to isolate and analyze clones, followed by an additional one to two weeks to grow sufficient cells for biochemical experiments (e.g. immunoprecipitations). In this report, we describe an optimized procedure for retroviral-mediated gene transfer into murine B cell lines that allows one to obtain a pure population of cells expressing an exogenous gene within 4 days. Two days post-infection, between 10% (BAL17 and M12.4.1 cells) and 70% (WEHI-231 cells) of the cells express the exogenous gene. Culturing the cells for an additional 48 hours with puromycin kills all the non-infected cells and yields a pure population of cells that express the exogenous gene. Sufficient cells for biochemical experiments can be obtained by expanding the cell culture for an additional 5 to 7 days. This rapid and efficient retroviral-mediated gene transfer procedure can greatly expedite the study of signal transduction and other processes in B cells.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546756
Abstract: Supplementary Figure S4 shows that G-CSF and G-CSFR signaling inhibit DC development and activation, in DCs derived in a OP9-DLL1 co-culture system.
Publisher: Elsevier BV
Date: 11-1994
Abstract: Intracellular signaling pathways are to a large extent regulated by reversible protein phosphorylation of pathway components. To fully investigate the regulation of these pathways, it is often necessary to identify the sites of protein phosphorylation induced on in idual components. The low abundance of many of these molecules and the potentially low stoichiometry of phosphorylation means that conventional analytical techniques are incapable of identifying specific sites of modification inducible in vivo. The most common technique used is two-dimensional (2D) phosphopeptide mapping (electrophoresis, thin-layer chromatography) of peptides derived by proteolysis of a phosphoprotein. The number of spots detected is commonly interpreted as the number of sites of phosphorylation. Here we have achieved positive identification of phosphorylation sites by capillary high-performance liquid chromatography, with on-line mass spectrometric detection, of phosphopeptides recovered from 2D phosphopeptide maps. We demonstrate that the chemical composition of phosphopeptides is not altered during the 2D mapping procedure. By detailed analysis of the sites of phosphorylation induced in vitro on CD3-zeta by p56lck we demonstrate that interpretation of the sites of phosphorylation based on 2D phosphopeptide mapping alone is difficult. To minimize over- or misinterpretation of 2D phosphopeptide maps we therefore postulate rules that should be applied generally in cases in which protein phosphorylation sites are being evaluated by 2D phosphopeptide patterns alone.
Publisher: World Scientific Pub Co Pte Lt
Date: 08-2014
DOI: 10.1142/S0217595914500213
Abstract: One of the most important steps in designing a cellular manufacturing system is cell formation which includes grouping the machines in cells and the parts as part families, so that the costs are minimized. Several aspects of the problem should be taken into account in cell formation more specifically, machines and their reliability are among the most important issues that should be modelled correctly. Another important facet of a cellular manufacturing system is material handling cost consisting of inter-cellular and intra-cellular movement costs. In addition, setup cost may play a significant role in decision-making in many real world problems of cell formation. Obviously, cell formation cannot be completed without considering the demands for parts. Considering all these aspects of the problem in this research, a generalized model for solving cell formation problem is proposed. Exact methods, e.g., B& B, are cumbersome in solving such complex models for large-size problems. Therefore, in this paper, a modified version of simulated annealing algorithm is designed and numerical ex les are provided to show that the proposed method is efficient and effective.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546753.V1
Abstract: CyTOF panels
Publisher: SAGE Publications
Date: 11-2004
Abstract: This article examines whether optimism and health-related hardiness contribute to health and well-being among older women. Positive psychological characteristics, including optimism and health-related hardiness, are correlated with good self-rated health, but these variables are all affected by socioeconomic status, social support, physical illness and access to services. Using data from 9501 Australian women aged 73 to 78, we show that optimism and health-related hardiness explain a significant proportion of variance in all subscales of the SF-36, and in stress, even after these confounders are taken into account. The data, although cross-sectional, suggest that positive personal characteristics may contribute to well-being.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.C.6551242
Abstract: While immunotherapies such as immune checkpoint blockade and adoptive T-cell therapy improve survival for a subset of human malignancies, many patients fail to respond. Phagocytes including dendritic cells (DC), monocytes, and macrophages (MF) orchestrate innate and adaptive immune responses against tumors. However, tumor-derived factors may limit immunotherapy effectiveness by altering phagocyte signal transduction, development, and activity. Using Cytometry by Time-of-Flight, we found that tumor-derived GCSF altered myeloid cell distribution both locally and systemically. We distinguished a large number of GCSF-induced immune cell subset and signal transduction pathway perturbations in tumor-bearing mice, including a prominent increase in immature neutrophil/myeloid-derived suppressor cell (Neut/MDSC) subsets and tumor-resident PD-L1 sup + /sup Neut/MDSCs. GCSF expression was also linked to distinct tumor-associated MF populations, decreased conventional DCs, and splenomegaly characterized by increased splenic progenitors with diminished DC differentiation potential. GCSF-dependent dysregulation of DC development was recapitulated in bone marrow cultures i in vitro /i , using medium derived from GCSF-expressing tumor cell cultures. Importantly, tumor-derived GCSF impaired T-cell adoptive cell therapy effectiveness and was associated with increased tumor volume and diminished survival of mice with mammary cancer. Treatment with neutralizing anti-GCSF antibodies reduced colonic and circulatory Neut/MDSCs, normalized colonic immune cell composition and diminished tumor burden in a spontaneous model of mouse colon cancer. Analysis of human colorectal cancer patient gene expression data revealed a significant correlation between survival and low GCSF and Neut/MDSC gene expression. Our data suggest that normalizing GCSF bioactivity may improve immunotherapy in cancers associated with GCSF overexpression. Significance: Tumor-derived GCSF leads to systemic immune population changes. GCSF blockade restores immune populations, improves immunotherapy, and reduces tumor size, paralleling human colorectal cancer data. GCSF inhibition may synergize with current immunotherapies to treat GCSF-secreting tumors. /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546765.V1
Abstract: Supplementary Figure S2 compares the immune cell content in peripheral blood and spleens from immunocompetent, immunocompromised and G-CSFR-/- mice harboring MT or MTG-CSF-/- tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 09-03-2023
DOI: 10.1158/2767-9764.CRC-22-0278
Abstract: While immunotherapies such as immune checkpoint blockade and adoptive T-cell therapy improve survival for a subset of human malignancies, many patients fail to respond. Phagocytes including dendritic cells (DC), monocytes, and macrophages (MF) orchestrate innate and adaptive immune responses against tumors. However, tumor-derived factors may limit immunotherapy effectiveness by altering phagocyte signal transduction, development, and activity. Using Cytometry by Time-of-Flight, we found that tumor-derived GCSF altered myeloid cell distribution both locally and systemically. We distinguished a large number of GCSF-induced immune cell subset and signal transduction pathway perturbations in tumor-bearing mice, including a prominent increase in immature neutrophil/myeloid-derived suppressor cell (Neut/MDSC) subsets and tumor-resident PD-L1+ Neut/MDSCs. GCSF expression was also linked to distinct tumor-associated MF populations, decreased conventional DCs, and splenomegaly characterized by increased splenic progenitors with diminished DC differentiation potential. GCSF-dependent dysregulation of DC development was recapitulated in bone marrow cultures in vitro, using medium derived from GCSF-expressing tumor cell cultures. Importantly, tumor-derived GCSF impaired T-cell adoptive cell therapy effectiveness and was associated with increased tumor volume and diminished survival of mice with mammary cancer. Treatment with neutralizing anti-GCSF antibodies reduced colonic and circulatory Neut/MDSCs, normalized colonic immune cell composition and diminished tumor burden in a spontaneous model of mouse colon cancer. Analysis of human colorectal cancer patient gene expression data revealed a significant correlation between survival and low GCSF and Neut/MDSC gene expression. Our data suggest that normalizing GCSF bioactivity may improve immunotherapy in cancers associated with GCSF overexpression. Tumor-derived GCSF leads to systemic immune population changes. GCSF blockade restores immune populations, improves immunotherapy, and reduces tumor size, paralleling human colorectal cancer data. GCSF inhibition may synergize with current immunotherapies to treat GCSF-secreting tumors.
Location: Iran (Islamic Republic of)
Location: Australia
No related grants have been discovered for Danielle Krebs.