Regulatory frameworks are evolving to require water management on a watershed or catchment basis,... more Regulatory frameworks are evolving to require water management on a watershed or catchment basis, which implies an integrated groundwater-surface water approach.. However, there is currently no way - short of custom programming - to link surface water models (e.g. MIKE 11) to groundwater models (e.g. MODFLOW). MIKE 11 is a widely-used one-dimensional channel flow model for problems ranging from advanced
In the past several decades large amounts of money have gone into agricultural credit programmes ... more In the past several decades large amounts of money have gone into agricultural credit programmes in low-income countries. The results of these efforts have often been disappointing: Serious loan-recovery problems persist, the rich get most of the cheap loans, low interest rates ...
The successes of targeted therapeutics against EGFR and ALK in non-small cell lung cancer (NSCLC)... more The successes of targeted therapeutics against EGFR and ALK in non-small cell lung cancer (NSCLC) have demonstrated the substantial survival gains made possible by precision therapy. However, the majority of patients do not have tumors with genetic alterations responsive to these therapies, and therefore identification of new targets is needed. Our laboratory previously identified MER receptor tyrosine kinase as one such potential target. We now report our findings targeting MER with a clinically translatable agent--Mer590, a monoclonal antibody specific for MER. Mer590 rapidly and robustly reduced surface and total MER levels in multiple cell lines. Treatment reduced surface MER levels by 87%, and this effect was maximal within four hours. Total MER levels were also dramatically reduced, and this persisted for at least seven days. Mechanistically, MER down-regulation was mediated by receptor internalization and degradation, leading to inhibition of downstream signaling through STAT...
Mer and Flt3 receptor tyrosine kinases have been implicated as therapeutic targets in acute myelo... more Mer and Flt3 receptor tyrosine kinases have been implicated as therapeutic targets in acute myeloid leukemia (AML). In this manuscript we describe UNC1666, a novel ATP-competitive small molecule tyrosine kinase inhibitor, which potently diminishes Mer and Flt3 phosphorylation in AML. Treatment with UNC1666 mediated biochemical and functional effects in AML cell lines expressing Mer or Flt3 internal tandem duplication (ITD), including decreased phosphorylation of Mer, Flt3 and downstream effectors Stat, Akt and Erk, induction of apoptosis in up to 98% of cells, and reduction of colony formation by greater than 90%, compared to treatment with vehicle. These effects were dose-dependent, with inhibition of downstream signaling and functional effects correlating with the degree of Mer or Flt3 kinase inhibition. Treatment of primary AML patient samples expressing Mer and/or Flt3-ITD with UNC1666 also inhibited Mer and Flt3 intracellular signaling, induced apoptosis, and inhibited colony f...
The TYRO3, AXL (also known as UFO) and MERTK (TAM) family of receptor tyrosine kinases (RTKs) are... more The TYRO3, AXL (also known as UFO) and MERTK (TAM) family of receptor tyrosine kinases (RTKs) are aberrantly expressed in multiple haematological and epithelial malignancies. Rather than functioning as oncogenic drivers, their induction in tumour cells predominately promotes survival, chemoresistance and motility. The unique mode of maximal activation of this RTK family requires an extracellular lipid–protein complex. For example, the protein ligand, growth arrest-specific protein 6 (GAS6), binds to phosphatidylserine (PtdSer) that is externalized on apoptotic cell membranes, which activates MERTK on macrophages. This triggers engulfment of apoptotic material and subsequent anti-inflammatory macrophage polarization. In tumours, autocrine and paracrine ligands and apoptotic cells are abundant, which provide a survival signal to the tumour cell and favour an anti-inflammatory, immunosuppressive microenvironment. Thus, TAM kinase inhibition could stimulate antitumour immunity, reduce tumour cell survival, enhance chemosensitivity and diminish metastatic potential.
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although survival r... more Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although survival rates have improved, patients with certain biologic subtypes still have suboptimal outcomes. Current chemotherapeutic regimens are associated with short- and long-term toxicities and novel, less toxic therapeutic strategies are needed. Mer receptor tyrosine kinase is ectopically expressed in ALL patient samples and cell lines. Inhibition of Mer expression reduces prosurvival signaling, increases chemosensitivity, and delays development of leukemia in vivo, suggesting that Mer tyrosine kinase inhibitors are excellent candidates for targeted therapies. Brain and spinal tumors are the second most common malignancies in childhood. Multiple chemotherapy approaches and radiotherapies have been attempted, yet overall survival remains dismal. Mer is also abnormally expressed in atypical teratoid/rhabdoid tumors (AT/RT), providing a rationale for targeting Mer as a therapeutic strategy. We have pr...
Censored (Tobit) regression is used to estimate the effects of race, location of residence, and s... more Censored (Tobit) regression is used to estimate the effects of race, location of residence, and sex of the household head on formal debt held by South African households. The magnitude of the effects suggests that lenders discriminate and that formal financial markets could be improved even without technical innovation.
Well head protection areas (WHPAs) are a common planning tool for reducing the risk of contaminat... more Well head protection areas (WHPAs) are a common planning tool for reducing the risk of contamination to drinking water supply wells. Typical WHPA delineation involves steady-state groundwater flow modeling with deterministic backward particle tracking. However, WHPAs based solely on steady-state groundwater models ignore or simplify processes outside of the saturated groundwater zone and neglect important dynamic and transient effects. The
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 29, 2014
Purpose: Although tyrosine kinase inhibitors (TKI) can be effective therapies for leukemia, they ... more Purpose: Although tyrosine kinase inhibitors (TKI) can be effective therapies for leukemia, they fail to fully eliminate leukemic cells and achieve durable remissions for many patients with advanced BCR-ABL+ leukemias or acute myeloid leukemias (AML). Through a large-scale synthetic lethal RNAi screen, we identified pyruvate dehydrogenase, the limiting enzyme for pyruvate entry into the mitochondrial tricarboxylic acid cycle, as critical for the survival of chronic myeloid leukemia cells upon BCR-ABL inhibition. Here we examined the role of mitochondrial metabolism in the survival of Ph+ leukemia and AML upon TK inhibition. Experimental Design: Ph+ cancer cell lines, AML cell lines, leukemia xenografts, cord blood, patient samples were examined. Results: We showed that the mitochondrial ATP-synthase inhibitor oligomycin-A greatly sensitized leukemia cells to TKI in vitro. Surprisingly, oligomycin-A sensitized leukemia cells to BCR-ABL inhibition at concentrations 100-1000-fold below...
Natural killer (NK) cell tumors are a rare and heterogeneous group of disorders. Immature NK cell... more Natural killer (NK) cell tumors are a rare and heterogeneous group of disorders. Immature NK cell tumors are less common, and are less recognized and defined than mature NK cell tumors. There is insufficient experience of diagnosis and treatment with immature NK cell tumors, especially in pediatric patients. Here we describe a pediatric patient with precursor NK cell leukemia and review the literature of the previously reported cases in children to further help characterize the diagnosis, treatment, and outcome.
Regulatory frameworks are evolving to require water management on a watershed or catchment basis,... more Regulatory frameworks are evolving to require water management on a watershed or catchment basis, which implies an integrated groundwater-surface water approach.. However, there is currently no way - short of custom programming - to link surface water models (e.g. MIKE 11) to groundwater models (e.g. MODFLOW). MIKE 11 is a widely-used one-dimensional channel flow model for problems ranging from advanced
In the past several decades large amounts of money have gone into agricultural credit programmes ... more In the past several decades large amounts of money have gone into agricultural credit programmes in low-income countries. The results of these efforts have often been disappointing: Serious loan-recovery problems persist, the rich get most of the cheap loans, low interest rates ...
The successes of targeted therapeutics against EGFR and ALK in non-small cell lung cancer (NSCLC)... more The successes of targeted therapeutics against EGFR and ALK in non-small cell lung cancer (NSCLC) have demonstrated the substantial survival gains made possible by precision therapy. However, the majority of patients do not have tumors with genetic alterations responsive to these therapies, and therefore identification of new targets is needed. Our laboratory previously identified MER receptor tyrosine kinase as one such potential target. We now report our findings targeting MER with a clinically translatable agent--Mer590, a monoclonal antibody specific for MER. Mer590 rapidly and robustly reduced surface and total MER levels in multiple cell lines. Treatment reduced surface MER levels by 87%, and this effect was maximal within four hours. Total MER levels were also dramatically reduced, and this persisted for at least seven days. Mechanistically, MER down-regulation was mediated by receptor internalization and degradation, leading to inhibition of downstream signaling through STAT...
Mer and Flt3 receptor tyrosine kinases have been implicated as therapeutic targets in acute myelo... more Mer and Flt3 receptor tyrosine kinases have been implicated as therapeutic targets in acute myeloid leukemia (AML). In this manuscript we describe UNC1666, a novel ATP-competitive small molecule tyrosine kinase inhibitor, which potently diminishes Mer and Flt3 phosphorylation in AML. Treatment with UNC1666 mediated biochemical and functional effects in AML cell lines expressing Mer or Flt3 internal tandem duplication (ITD), including decreased phosphorylation of Mer, Flt3 and downstream effectors Stat, Akt and Erk, induction of apoptosis in up to 98% of cells, and reduction of colony formation by greater than 90%, compared to treatment with vehicle. These effects were dose-dependent, with inhibition of downstream signaling and functional effects correlating with the degree of Mer or Flt3 kinase inhibition. Treatment of primary AML patient samples expressing Mer and/or Flt3-ITD with UNC1666 also inhibited Mer and Flt3 intracellular signaling, induced apoptosis, and inhibited colony f...
The TYRO3, AXL (also known as UFO) and MERTK (TAM) family of receptor tyrosine kinases (RTKs) are... more The TYRO3, AXL (also known as UFO) and MERTK (TAM) family of receptor tyrosine kinases (RTKs) are aberrantly expressed in multiple haematological and epithelial malignancies. Rather than functioning as oncogenic drivers, their induction in tumour cells predominately promotes survival, chemoresistance and motility. The unique mode of maximal activation of this RTK family requires an extracellular lipid–protein complex. For example, the protein ligand, growth arrest-specific protein 6 (GAS6), binds to phosphatidylserine (PtdSer) that is externalized on apoptotic cell membranes, which activates MERTK on macrophages. This triggers engulfment of apoptotic material and subsequent anti-inflammatory macrophage polarization. In tumours, autocrine and paracrine ligands and apoptotic cells are abundant, which provide a survival signal to the tumour cell and favour an anti-inflammatory, immunosuppressive microenvironment. Thus, TAM kinase inhibition could stimulate antitumour immunity, reduce tumour cell survival, enhance chemosensitivity and diminish metastatic potential.
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although survival r... more Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although survival rates have improved, patients with certain biologic subtypes still have suboptimal outcomes. Current chemotherapeutic regimens are associated with short- and long-term toxicities and novel, less toxic therapeutic strategies are needed. Mer receptor tyrosine kinase is ectopically expressed in ALL patient samples and cell lines. Inhibition of Mer expression reduces prosurvival signaling, increases chemosensitivity, and delays development of leukemia in vivo, suggesting that Mer tyrosine kinase inhibitors are excellent candidates for targeted therapies. Brain and spinal tumors are the second most common malignancies in childhood. Multiple chemotherapy approaches and radiotherapies have been attempted, yet overall survival remains dismal. Mer is also abnormally expressed in atypical teratoid/rhabdoid tumors (AT/RT), providing a rationale for targeting Mer as a therapeutic strategy. We have pr...
Censored (Tobit) regression is used to estimate the effects of race, location of residence, and s... more Censored (Tobit) regression is used to estimate the effects of race, location of residence, and sex of the household head on formal debt held by South African households. The magnitude of the effects suggests that lenders discriminate and that formal financial markets could be improved even without technical innovation.
Well head protection areas (WHPAs) are a common planning tool for reducing the risk of contaminat... more Well head protection areas (WHPAs) are a common planning tool for reducing the risk of contamination to drinking water supply wells. Typical WHPA delineation involves steady-state groundwater flow modeling with deterministic backward particle tracking. However, WHPAs based solely on steady-state groundwater models ignore or simplify processes outside of the saturated groundwater zone and neglect important dynamic and transient effects. The
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 29, 2014
Purpose: Although tyrosine kinase inhibitors (TKI) can be effective therapies for leukemia, they ... more Purpose: Although tyrosine kinase inhibitors (TKI) can be effective therapies for leukemia, they fail to fully eliminate leukemic cells and achieve durable remissions for many patients with advanced BCR-ABL+ leukemias or acute myeloid leukemias (AML). Through a large-scale synthetic lethal RNAi screen, we identified pyruvate dehydrogenase, the limiting enzyme for pyruvate entry into the mitochondrial tricarboxylic acid cycle, as critical for the survival of chronic myeloid leukemia cells upon BCR-ABL inhibition. Here we examined the role of mitochondrial metabolism in the survival of Ph+ leukemia and AML upon TK inhibition. Experimental Design: Ph+ cancer cell lines, AML cell lines, leukemia xenografts, cord blood, patient samples were examined. Results: We showed that the mitochondrial ATP-synthase inhibitor oligomycin-A greatly sensitized leukemia cells to TKI in vitro. Surprisingly, oligomycin-A sensitized leukemia cells to BCR-ABL inhibition at concentrations 100-1000-fold below...
Natural killer (NK) cell tumors are a rare and heterogeneous group of disorders. Immature NK cell... more Natural killer (NK) cell tumors are a rare and heterogeneous group of disorders. Immature NK cell tumors are less common, and are less recognized and defined than mature NK cell tumors. There is insufficient experience of diagnosis and treatment with immature NK cell tumors, especially in pediatric patients. Here we describe a pediatric patient with precursor NK cell leukemia and review the literature of the previously reported cases in children to further help characterize the diagnosis, treatment, and outcome.
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Papers by Douglas Graham