65 results on '"Cosulich, A"'
Search Results
2. Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12C with Demonstrable CNS Penetration.
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Kettle, Jason G., Bagal, Sharan K., Barratt, Derek, Bodnarchuk, Michael S., Boyd, Scott, Braybrooke, Erin, Breed, Jason, Cassar, Doyle J., Cosulich, Sabina, Davies, Michael, Davies, Nichola L., Deng, Chao, Eatherton, Andrew, Evans, Laura, Feron, Lyman J., Fillery, Shaun, Gleave, Emma S., Goldberg, Frederick W., Cortés González, Miguel A., and Guerot, Carine
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- 2023
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3. Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C.
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Kettle, Jason G., Bagal, Sharan K., Bickerton, Sue, Bodnarchuk, Michael S., Boyd, Scott, Breed, Jason, Carbajo, Rodrigo J., Cassar, Doyle J., Chakraborty, Atanu, Cosulich, Sabina, Cumming, Iain, Davies, Michael, Davies, Nichola L., Eatherton, Andrew, Evans, Laura, Feron, Lyman, Fillery, Shaun, Gleave, Emma S., Goldberg, Frederick W., and Hanson, Lyndsey
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- 2022
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4. Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methyl-pyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs.
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Johannes, Jeffrey W., Balazs, Amber, Barratt, Derek, Bista, Michal, Chuba, Matthew D., Cosulich, Sabina, Critchlow, Susan E., Degorce, Sébastien L., Di Fruscia, Paolo, Edmondson, Scott D., Embrey, Kevin, Fawell, Stephen, Ghosh, Avipsa, Gill, Sonja J., Gunnarsson, Anders, Hande, Sudhir M., Heightman, Tom D., Hemsley, Paul, Illuzzi, Giuditta, and Lane, Jordan
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- 2021
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5. Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (AZD5305): A PARP1–DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs
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Johannes, Jeffrey W., Balazs, Amber, Barratt, Derek, Bista, Michal, Chuba, Matthew D., Cosulich, Sabina, Critchlow, Susan E., Degorce, Sébastien L., Di Fruscia, Paolo, Edmondson, Scott D., Embrey, Kevin, Fawell, Stephen, Ghosh, Avipsa, Gill, Sonja J., Gunnarsson, Anders, Hande, Sudhir M., Heightman, Tom D., Hemsley, Paul, Illuzzi, Giuditta, Lane, Jordan, Larner, Carrie, Leo, Elisabetta, Liu, Lina, Madin, Andrew, Martin, Scott, McWilliams, Lisa, O’Connor, Mark J., Orme, Jonathan P., Pachl, Fiona, Packer, Martin J., Pei, Xiaohui, Pike, Andrew, Schimpl, Marianne, She, Hongyao, Staniszewska, Anna D., Talbot, Verity, Underwood, Elizabeth, Varnes, Jeffrey G., Xue, Lin, Yao, Tieguang, Zhang, Ke, Zhang, Andrew X., and Zheng, Xiaolan
- Abstract
Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1–DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25(AZD5305), a potent and selective PARP1 inhibitor and PARP1–DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.
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- 2021
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6. Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C
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Kettle, Jason G., Bagal, Sharan K., Bickerton, Sue, Bodnarchuk, Michael S., Breed, Jason, Carbajo, Rodrigo J., Cassar, Doyle J., Chakraborty, Atanu, Cosulich, Sabina, Cumming, Iain, Davies, Michael, Eatherton, Andrew, Evans, Laura, Feron, Lyman, Fillery, Shaun, Gleave, Emma S., Goldberg, Frederick W., Harlfinger, Stephanie, Hanson, Lyndsey, Howard, Martin, Howells, Rachel, Jackson, Anne, Kemmitt, Paul, Kingston, Jennifer K., Lamont, Scott, Lewis, Hilary J., Li, Songlei, Liu, Libin, Ogg, Derek, Phillips, Christopher, Polanski, Radek, Robb, Graeme, Robinson, David, Ross, Sarah, Smith, James M., Tonge, Michael, Whiteley, Rebecca, Yang, Junsheng, Zhang, Longfei, and Zhao, Xiliang
- Abstract
Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12Cmutant represents an “Achilles heel” and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine–quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12Cinhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.
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- 2020
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7. Discovery of (R)-8-(1-(3,5-Difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (AZD8186): A Potent andSelective Inhibitor of PI3Kβ and PI3Kδ for the Treatmentof PTEN-Deficient Cancers.
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Barlaam, Bernard, Cosulich, Sabina, Degorce, Sébastien, Fitzek, Martina, Green, Stephen, Hancox, Urs, Lambert-van der Brempt, Christine, Lohmann, Jean-Jacques, Maudet, Mickaël, Morgentin, Rémy, Pasquet, Marie-Jeanne, Péru, Aurélien, Plé, Patrick, Saleh, Twana, Vautier, Michel, Walker, Mike, Ward, Lara, and Warin, Nicolas
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- 2015
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8. Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12Cwith Demonstrable CNS Penetration
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Kettle, Jason G., Bagal, Sharan K., Barratt, Derek, Bodnarchuk, Michael S., Boyd, Scott, Braybrooke, Erin, Breed, Jason, Cassar, Doyle J., Cosulich, Sabina, Davies, Michael, Davies, Nichola L., Deng, Chao, Eatherton, Andrew, Evans, Laura, Feron, Lyman J., Fillery, Shaun, Gleave, Emma S., Goldberg, Frederick W., Cortés González, Miguel A., Guerot, Carine, Haider, Afreen, Harlfinger, Stephanie, Howells, Rachel, Jackson, Anne, Johnström, Peter, Kemmitt, Paul D., Koers, Alex, Kondrashov, Mikhail, Lamont, Gillian M., Lamont, Scott, Lewis, Hilary J., Liu, Libin, Mylrea, Megan, Nash, Samuel, Niedbala, Michael J., Peter, Alison, Phillips, Christopher, Pike, Kurt, Raubo, Piotr, Robb, Graeme R., Ross, Sarah, Sanders, Matthew G., Schou, Magnus, Simpson, Iain, and Steward, Oliver
- Abstract
The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12Cwith an anticipated low clearance and high oral bioavailability profile in humans.
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- 2023
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9. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor
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Rodrik-Outmezguine, Vanessa S., Okaniwa, Masanori, Yao, Zhan, Novotny, Chris J., McWhirter, Claire, Banaji, Arpitha, Won, Helen, Wong, Wai, Berger, Mike, de Stanchina, Elisa, Barratt, Derek G., Cosulich, Sabina, Klinowska, Teresa, Rosen, Neal, and Shokat, Kevan M.
- Abstract
Inhibitors of the mTOR kinase are in clinical trials for the treatment of cancer; here, mutations in mTOR that can lead to drug resistance are investigated and the results are used to design a new class of mTOR inhibitors that can overcome this resistance.
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- 2016
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10. Diverse Heterocyclic Scaffolds as Allosteric Inhibitors of AKT.
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Kettle, Jason G., Brown, Simon, Crafter, Claire, Davies, Barry R., Dudley, Phillippa, Fairley, Gary, Faulder, Paul, Fillery, Shaun, Greenwood, Hannah, Hawkins, Janet, James, Michael, Johnson, Keith, Lane, Clare D., Pass, Martin, Pink, Jennifer H., Plant, Helen, and Cosulich, Sabina C.
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- 2012
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11. Differential Branch Pulmonary Artery Regurgitant Fraction Is a Function of Differential Pulmonary Arterial Anatomy and Pulmonary Vascular Resistance.
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Harris, Matthew A., Whitehead, Kevin K., Gillespie, Matthew J., Liu, Timothy Y., Cosulich, Michael T., Shin, David C., Goldmuntz, Elizabeth, Weinberg, Paul M., and Fogel, Mark A.
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PULMONARY artery diseases ,VASCULAR resistance ,CARDIAC magnetic resonance imaging ,ARTERIAL stenosis ,RETROSPECTIVE studies ,CATHETERIZATION ,TETRALOGY of Fallot ,RIGHT heart ventricle - Abstract
Objectives: We sought to investigate whether differential branch pulmonary artery (BPA) regurgitation correlates with differences in BPA anatomy and physiology. Background: Patients with repaired conotruncal anomalies such as Tetralogy of Fallot frequently have residual BPA stenosis or BPA size differences. Previous reports have demonstrated an increased left pulmonary artery (LPA) regurgitant fraction (RF) in these patients. Methods: We retrospectively reviewed 76 consecutive cardiac magnetic resonance (CMR) studies for BPA size and phase-contrast magnetic resonance data, including 13 consecutive patients who underwent both CMR and catheterization. Results: Thirty of the 76 patients had either BPA stenosis or significant size discrepancy. Whereas previous studies had shown an increased RF in the LPA, patients with BPA stenosis or size discrepancy showed no significant difference between right and left BPA RF (30% vs. 30%, p = 0.985). However, there was a significantly increased RF of the larger versus smaller BPA (39% vs. 21%, p < 0.001), resulting in an insignificant deviation from normal fractional flow distribution (RPA 63% vs. LPA 37%; normal net fractional flow distribution RPA 55% vs. LPA 45%). Retrospective review of patients who underwent both CMR and catheterization provides support for the preceding findings and validates differential BPA RF as strongly correlating with differential pulmonary vascular resistance (PVR) (r = 0.8364, p < 0.001). Conclusions: BPA RF is a function of the relative PVR and the presence of BPA stenosis or size discrepancy. Contrary to prior reports, the LPA RF is only elevated in patients with relatively equal sized BPAs. In the setting of BPA stenosis or size discrepancy the larger BPA has a relatively increased RF and PVR. Therefore, the differential RF is an important tool for screening patients with unilateral stenosis for contralateral increases in PVR that cannot be identified with net flows alone. This can affect the indication and timing for BPA intervention. [Copyright &y& Elsevier]
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- 2011
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12. Pre-Fontan cardiac magnetic resonance predicts post-Fontan length of stay and avoids ionizing radiation.
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Harris, Matthew A., Cosulich, Michael T., Gillespie, Matthew J., Whitehead, Kevin K., Liu, Timothy I., Weinberg, Paul M., and Fogel, Mark A.
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LEFT heart ventricle ,CARDIAC surgery patients ,CARDIAC magnetic resonance imaging ,RIGHT heart ventricle ,PULMONARY artery diseases ,MEDICAL records ,PHYSIOLOGICAL effects of ionizing radiation ,THERAPEUTICS - Abstract
Objective: Patients frequently undergo cardiac catheterization before the Fontan operation because of the limited echocardiographic windows in the region of the superior cavopulmonary connection and branch pulmonary arteries. Patients with obstruction to pulmonary blood flow are at increased risk for prolonged length of hospital stay after the Fontan operation. Cardiac magnetic resonance has unlimited imaging windows and can quantify both the branch pulmonary artery size and net flow distribution and thereby serve as a method for identifying patients at increased risk for prolonged length of stay. Methods: We retrospectively reviewed 24 cardiac magnetic resonance studies of patients (mean age, 3.1 ± 1.0 years) referred before the Fontan operation. Cardiac magnetic resonance measured the cross-sectional area and flow to each branch pulmonary artery. Post-Fontan hospital course data were acquired from the medical record. Results: Prolonged length of stay after the Fontan operation is observed among patients with one branch that is less than 25% of the total cross-sectional area (18.0 ± 5.5 vs 8.2 ± 3.8 days, P = .01) or with less than 40% flow to one branch (12.5 ± 6.9 vs 7.6 ± 1.5 days, P = .04). There is moderate correlation between the total branch pulmonary area and length of stay (r = −0.75). Conclusions: Cardiac magnetic resonance noninvasively assesses the branch pulmonary area size and flow before the Fontan operation. These data predict which patients are more likely to experience a prolonged hospital course. [Copyright &y& Elsevier]
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- 2009
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13. Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C
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Kettle, Jason G., Bagal, Sharan K., Bickerton, Sue, Bodnarchuk, Michael S., Boyd, Scott, Breed, Jason, Carbajo, Rodrigo J., Cassar, Doyle J., Chakraborty, Atanu, Cosulich, Sabina, Cumming, Iain, Davies, Michael, Davies, Nichola L., Eatherton, Andrew, Evans, Laura, Feron, Lyman, Fillery, Shaun, Gleave, Emma S., Goldberg, Frederick W., Hanson, Lyndsey, Harlfinger, Stephanie, Howard, Martin, Howells, Rachel, Jackson, Anne, Kemmitt, Paul, Lamont, Gillian, Lamont, Scott, Lewis, Hilary J., Liu, Libin, Niedbala, Michael J., Phillips, Christopher, Polanski, Radek, Raubo, Piotr, Robb, Graeme, Robinson, David M., Ross, Sarah, Sanders, Matthew G., Tonge, Michael, Whiteley, Rebecca, Wilkinson, Stephen, Yang, Junsheng, and Zhang, Wenman
- Abstract
KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21, AZD4625, a clinical development candidate for the treatment of KRASG12Cpositive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure–activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12Cwith an anticipated low clearance and high oral bioavailability profile in humans.
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- 2022
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14. postcards from Russel.
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Canarutto, Sarah Cosulich
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- 2007
15. Role of cytokines in non-genotoxic hepatocarcinogenesis: cause or effect?
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Roberts, R. A., James, N. H., Cosulich, S., Hasmall, S. C., and Orphanides, G.
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- 2001
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16. Azurin immobilisation on thiol covered Au(111)
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*, O. Cavalleri, , Natale, C., Stroppolo, M. E., *, A. Relini, , Cosulich, E., Thea, S., and Novi, M.
- Abstract
Azurin is a blue single copper protein involved in the respiratory chain of denitrifying bacteria. The structural gene for azurin from Pseudomonas aeruginosa was cloned in an Escherichia coli recombinant strain. The protein overexpressed in the bacterial periplasmic space was subsequently purified. Two strategies were followed to anchor azurin to gold surfaces. First, the protein was immobilised on bare gold. Azurin adsorbs on gold via its disulfide group. Scanning tunnelling microscopy (STM) inspection of the azurinAu(111) interface revealed the formation of a closely packed protein monolayer and allowed individual azurin molecules to be resolved. In order to uncouple the protein layer from the metal, the gold surfaces were then covered with self-assembled monolayers of 11-mercaptoundecanoic acid. The changes in the sample morphology due to the protein adsorption have been investigated by atomic force microscopy (AFM). A fairly uniform distribution of protein molecules covers the surface. Owing to the tip broadening effect, an average protein diameter of about 20 nm was measured. An upper limit of 1 nN for the non-disruptive imaging force in the contact mode was found.
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- 2000
17. A dominant negative form of IKK2 prevents suppression of apoptosis by the peroxisome proliferator nafenopin
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Cosulich, Sabina C., James, Neil H., Needham, Maurice R.C., Newham, Peter P., Bundell, Ken R., and Roberts, Ruth A.
- Abstract
Peroxisome proliferators (PPs) are a class of non-genotoxic chemicals that cause rodent liver enlargement and hepatocarcinogenesis. In primary rat hepatocyte cultures, PPs suppress spontaneous apoptosis and that induced by a number of pro-apoptotic stimuli such as transforming growth factor-β1. Tumour necrosis factor α (TNF-α) and the transcription factor NFκB have been implicated in the mode of action of PPs. TNF-α signalling to NFκB is thought to be responsible for many of the effects elicited by this cytokine. NFκB regulates gene expression in immunity, stress responses and the inhibition of apoptosis. Activation of NFκB requires the successive action of NFκB-inducing kinase and the phosphorylation of NFκB inhibitory proteins (IκB) by an IκB kinase (IKK) complex. The IKK2 subunit of IκB kinase is thought to be essential for NFκB activation and prevention of apoptosis. To determine whether IKK2 plays a role in the suppression of apoptosis by PPs, we expressed a dominant negative form of IKK2 (IKK2dn) in primary rat hepatocyte cultures. Infection with an adenovirus construct expressing IKK2dn caused apoptosis in control primary rat hepatocytes in the absence of exogenous TNF-α. Moreover, IKK2dn-induced apoptosis could not be rescued by addition of TNF-α or the peroxisome proliferator nafenopin. These results demonstrate a requirement for intracellular signalling pathways mediated by IKK2 in the suppression of apoptosis by the PP class of hepatocarcinogens.
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- 2000
18. A dominant negative form of IKK2 prevents suppression of apoptosis by the peroxisome proliferator nafenopin.
- Author
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Cosulich, S C, James, N H, Needham, M R, Newham, P P, Bundell, K R, and Roberts, R A
- Abstract
Peroxisome proliferators (PPs) are a class of non-genotoxic chemicals that cause rodent liver enlargement and hepatocarcinogenesis. In primary rat hepatocyte cultures, PPs suppress spontaneous apoptosis and that induced by a number of pro-apoptotic stimuli such as transforming growth factor-beta(1). Tumour necrosis factor alpha (TNF-alpha) and the transcription factor NFkappaB have been implicated in the mode of action of PPs. TNF-alpha signalling to NFkappaB is thought to be responsible for many of the effects elicited by this cytokine. NFkappaB regulates gene expression in immunity, stress responses and the inhibition of apoptosis. Activation of NFkappaB requires the successive action of NFkappaB-inducing kinase and the phosphorylation of NFkappaB inhibitory proteins (IkappaB) by an IkappaB kinase (IKK) complex. The IKK2 subunit of IkappaB kinase is thought to be essential for NFkappaB activation and prevention of apoptosis. To determine whether IKK2 plays a role in the suppression of apoptosis by PPs, we expressed a dominant negative form of IKK2 (IKK2dn) in primary rat hepatocyte cultures. Infection with an adenovirus construct expressing IKK2dn caused apoptosis in control primary rat hepatocytes in the absence of exogenous TNF-alpha. Moreover, IKK2dn-induced apoptosis could not be rescued by addition of TNF-alpha or the peroxisome proliferator nafenopin. These results demonstrate a requirement for intracellular signalling pathways mediated by IKK2 in the suppression of apoptosis by the PP class of hepatocarcinogens.
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- 2000
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19. Performance evaluation of hyperbranched aramids as potential supports for protein immobilization
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Cosulich, M.E., Russo, S., Pasquale, S., and Mariani, A.
- Abstract
Several adducts of α-amylase and hyperbranched aramids have been evaluated in terms of their bioactivity performance. Twelve samples of hyperbranched aromatic polyamides, originated from either two AB2-type monomers or from five systems formed by reactant pairs (A2+B3or A3+B3or A2+B4) have been synthesized under different reaction conditions and used as protein supports. Through the addition of a suitable coupling agent, the enzyme fixation step has been carried out by joining the carboxylic groups on or near the outer surface of the aramids to the amino groups of the aminoacids present in α-amylase.
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- 2000
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20. Biochemical and immunochemical characterization of hop-hornbeam (Ostrya Carpinifolia Scop.) pollen
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Patriarca, Stefania, Voltolini, Susanna, Navone, Riccardo, Martini, Stefania, Montanari, Carlo, Negrini, A., and Cosulich, Elisabetta
- Abstract
In the last few years Ostrya carpinifoliapollen is consideredas an important cause of respiratoryallergy in Mediterranean areas. The concentration ofthe pollen was measured over a period of fifteen yearsfrom 1981 to 1996 in an area around Genoa; the resultsof this study have clearly indicated an increasingtrend that correlate with persons sensitization. In this study we sought to define the immunochemical andbiochemical properties of hop-hornbean pollen. Soluble proteins extracted from Ostryacarpinifoliapollen and from the taxonomicallyrelated species Corylus Avellana, were analyzedby polyacrylamide gel electrophoresis (SDS-PAGE), byhorizontal isoelectrofocusing (IEF) and by twodimensions electrophoresis (2D-PAGE). Allergenicproteins were identified with sera of sensibilizedpatients and cross-reactivity was evaluated byimmunoblotting techniques. The electrophoreticanalysis showed a partial identity between theproteins from Ostryaand Corylusextracts. The immunoblotting assay, developed withhuman IgE from subjects allergic to hop-hornbeampollen, displayed the major IgE reactivity for acomponent with a molecular weight of 17 kDa expressedin both Ostryaand Corylusextracts. This reactivity is consistent with the presence ofBet v 1 that is described as the major pollen allergenin the Betulaceae and Corylaceae families. Sera fromsubjects allergic to Ostryawere then preadsorbed with recombinant Bet v 1 immobilized in the Pharmacia CAP System; a significant reduction ofthe IgE binding activity was observed after thetreatment. We therefore suggest that Bet v 1 couldbe one of the allergenic proteins present in theOstryapollen possibly being responsible forcross-reactivity with other members of taxonomicallyrelated families.
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- 2000
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21. Role of MAP kinase signalling pathways in the mode of action of peroxisome proliferators
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Cosulich, Sabina, James, Neil, and Roberts, Ruth
- Abstract
Peroxisome proliferators (PPs) are a class of non-genotoxic chemicals that cause rodent liver enlargement and hepatocarcinogenesis. In primary rat hepatocytes, PPs cause cell proliferation, suppression of apoptosis and peroxisome proliferation. We have investigated the role of different families of mitogen-activated protein (MAP) kinases in the mode of action of PPs. Addition of 50 μM nafenopin to primary rat hepatocyte cultures caused weak activation of extracellular signal regulated kinases and p38 MAP kinase. However, incubation of primary hepatocytes with the p38 MAP kinase inhibitor SB203580 or the MAP kinase kinase (MEK) inhibitor PD098059 prevented the induction of DNA synthesis and the suppression of transforming growth factor β1-induced apoptosis by the PP nafenopin. In contrast, in the presence of these MAP kinase inhibitors, nafenopin still induced palmitoyl CoA oxidation, a measure of peroxisome proliferation. We have shown previously that PPs such as nafenopin require tumour necrosis factor α (TNF-α) to exert their effects on cellular proliferation and apoptosis. Here we show that treatment of primary rat hepatocyte cultures with nafenopin causes an increase in bioactive TNF-α and that this process requires p38 MAP kinase activity.
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- 2000
22. Role of MAP kinase signalling pathways in the mode of action of peroxisome proliferators.
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Cosulich, S, James, N, and Roberts, R
- Abstract
Peroxisome proliferators (PPs) are a class of non-genotoxic chemicals that cause rodent liver enlargement and hepatocarcinogenesis. In primary rat hepatocytes, PPs cause cell proliferation, suppression of apoptosis and peroxisome proliferation. We have investigated the role of different families of mitogen-activated protein (MAP) kinases in the mode of action of PPs. Addition of 50 microM nafenopin to primary rat hepatocyte cultures caused weak activation of extracellular signal regulated kinases and p38 MAP kinase. However, incubation of primary hepatocytes with the p38 MAP kinase inhibitor SB203580 or the MAP kinase kinase (MEK) inhibitor PD098059 prevented the induction of DNA synthesis and the suppression of transforming growth factor beta(1)-induced apoptosis by the PP nafenopin. In contrast, in the presence of these MAP kinase inhibitors, nafenopin still induced palmitoyl CoA oxidation, a measure of peroxisome proliferation. We have shown previously that PPs such as nafenopin require tumour necrosis factor alpha (TNF-alpha) to exert their effects on cellular proliferation and apoptosis. Here we show that treatment of primary rat hepatocyte cultures with nafenopin causes an increase in bioactive TNF-alpha and that this process requires p38 MAP kinase activity.
- Published
- 2000
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23. Apoptosis or plasma cell differentiation of CD38-positive B-chronic lymphocytic leukemia cells induced by cross-linking of surface IgM or IgD
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Zupo, Simona, Massara, Rosanna, Dono, Mariella, Rossi, Edoardo, Malavasi, Fabio, Cosulich, M. Elisabetta, and Ferrarini, Manlio
- Abstract
Previously, we demonstrated that B-chronic lymphocytic leukemia (B-CLL) cells could be divided into 2 groups depending on the expression of CD38 by the malignant cells. The 2 groups differed in their signal-transducing capacities initiated by cross-linking of surface IgM; only in CD38-positive cells was an efficient signal delivered, invariably resulting in cell apoptosis. In this study, we investigated the effect of surface IgD cross-linking in 10 patients with CD38-positive B-CLL. Exposure of the malignant cells to goat antihuman δ-chain antibodies (Gaδ-ab) caused [Ca++]i mobilization and tyrosine kinase phosphorylation in a manner not different from that observed after goat antihuman μ-chain antibody (Gaμ-ab) treatment in vitro. However, Gaδ-ab-treated cells failed to undergo apoptosis and instead displayed prolonged survival in culture and differentiated into plasma cells when rIL2 was concomitantly present. Cross-linking of surface IgD failed to induce proliferation of the malignant cells in vitro. Moreover, treatment with Gaδ-ab did not prevent apoptosis of B-CLL cells induced by Gaμ-ab. Collectively, these experiments demonstrated that IgM and IgD expressed by the same cell may deliver opposite signals under particular circumstances and provide some clues for the understanding of the pathophysiology of B-CLL.
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- 2000
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24. Late apoptotic effects of taxanes on K562 erythroleukemia cells: Apoptosis is delayed upstream of caspase-3 activation
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Gangemi, Rosaria M.R., Santamaria, Barbara, Bargellesi, Antonio, Cosulich, Elisabetta, and Fabbi, Marina
- Abstract
The efficacy of taxanes on human leukemia cells is the object of intensive in vitro investigation concerning the influence of cell-type-specific characteristics on cytotoxic response to drugs. The present study dissects the response to taxanes of HL60 acute myelomonocytic leukemia and of K562 chronic myelogenous leukemia, in parallel over a 72-hr time-span. The kinetics of cytotoxicity following pulsed and continuous exposure to either taxol or taxotere showed a delayed response of K562 cells independently of dose and type of exposure. In K562 cells, apoptosis became evident at 48 hr and prominent at 72 hr of treatment. These events were mirrored by delayed kinetics of caspase-3 activation. Comparable microtubule targeting was demonstrated in HL60 and in K562 cell lines, as bcl-2 and raf-1 were phosphorylated following treatment with taxanes. These observations indicate that early activation processes were responsible for apoptosis, but that the delay was determined by other factors. In addition, cell-free-system experiments excluded the presence of excess nuclear and/or cytoplasmic inhibitory factors and demonstrated that K562 cells possess a fully competent caspase system which can be readily activated. Processing of caspase-3 pro-enzyme was in fact increased by addition of cytochrome c. These results extend to taxol and taxotere the notion that drug-induced apoptosis is delayed upstream of caspase-3 activation in K562 cells, that such kinetics is independent of drug concentration and exposure time, and that it is linked to intrinsic cellular characteristics mapping between bcl-2 phosphorylation and cytochrome c release. Int. J. Cancer 85:527533, 2000. © 2000 Wiley-Liss, Inc.
- Published
- 2000
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25. Apoptosis or plasma cell differentiation of CD38-positive B-chronic lymphocytic leukemia cells induced by cross-linking of surface IgM or IgD
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Zupo, Simona, Massara, Rosanna, Dono, Mariella, Rossi, Edoardo, Malavasi, Fabio, Cosulich, M. Elisabetta, and Ferrarini, Manlio
- Abstract
Previously, we demonstrated that B-chronic lymphocytic leukemia (B-CLL) cells could be divided into 2 groups depending on the expression of CD38 by the malignant cells. The 2 groups differed in their signal-transducing capacities initiated by cross-linking of surface IgM; only in CD38-positive cells was an efficient signal delivered, invariably resulting in cell apoptosis. In this study, we investigated the effect of surface IgD cross-linking in 10 patients with CD38-positive B-CLL. Exposure of the malignant cells to goat antihuman δ-chain antibodies (Gaδ-ab) caused [Ca++]i mobilization and tyrosine kinase phosphorylation in a manner not different from that observed after goat antihuman μ-chain antibody (Gaμ-ab) treatment in vitro. However, Gaδ-ab-treated cells failed to undergo apoptosis and instead displayed prolonged survival in culture and differentiated into plasma cells when rIL2 was concomitantly present. Cross-linking of surface IgD failed to induce proliferation of the malignant cells in vitro. Moreover, treatment with Gaδ-ab did not prevent apoptosis of B-CLL cells induced by Gaμ-ab. Collectively, these experiments demonstrated that IgM and IgD expressed by the same cell may deliver opposite signals under particular circumstances and provide some clues for the understanding of the pathophysiology of B-CLL.
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- 2000
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26. Hyperbranched aramids by direct polyamidation of two reactant systems: Synthesis and properties
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Russo, Saverio, Boulares, Alya, Da Rin, Andrea, Mariani, Alberto, and Cosulich, Maria Elisabetta
- Abstract
Some A2+ B3and A3+ B3reagent pairs have been used for the direct polyamidation reaction leading, besides the network formation, to hyperbranched aramid structures. Depending on the chosen experimental conditions, variable amounts of a sol fraction having close similarities with the hyperbranched aramid structures derived from the polyamidation of AB2monomers, have indeed been obtained. Solubility of the sol fraction in various organic solvents, as well as its thermal properties and its capability of enzyme fixation, have been determined for the various systems under investigation. Future developments are envisaged.
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- 1999
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27. Suppression of apoptosis and induction of DNA synthesis in vitro by the phthalate plasticizers monoethylhexylphthalate (MEHP) and diisononylphthalate (DINP): a comparison of rat and human hepatocytes in vitro
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Hasmall, Susan C., James, Neil H., Macdonald, Neil, West, Douglas, Chevalier, Stephan, Cosulich, Sabina C., and Roberts, Ruth A.
- Abstract
Abstract: Diethylhexylphthalate (DEHP) and diisononylphthalate (DINP) are plasticizers with many important commercial, industrial and medical applications. However, both DEHP and DINP are rodent peroxisome proliferators (PPs), a class of compounds that cause rodent liver tumours associated with peroxisome proliferation, induction of hepatic DNA synthesis and the suppression of apoptosis. Despite these effects in the rodent, humans appear to be nonresponsive to the adverse effects of PPs. Previously, we have shown that the fibrate hypolipidaemic peroxisome proliferator, nafenopin, induced DNA synthesis and suppressed apoptosis in rat but not in human hepatocytes. In this work, we have examined species differences in the response of rat and human hepatocytes to DEHP and DINP in vitro. In rat hepatocytes in vitro, both DINP and MEHP (a principle metabolite of DEHP and the proximal peroxisome proliferator) caused a concentration-dependent induction of DNA synthesis and suppression of both spontaneous and transforming growth factor β1 (TGFβ1)-induced apoptosis. Similarly, both MEHP and DINP caused a concentration-dependent induction of peroxisomal β-oxidation although the response to DINP was less robust. In contrast to the pleiotropic response noted in rat hepatocytes, neither DINP nor MEHP caused an induction of β-oxidation, stimulation of DNA synthesis and suppression of apoptosis in human hepatocytes cultured from three separate donors. These data provide evidence for species differences in the hepatic response to the phthalates DEHP and DINP, confirming that human hepatocytes appear to be refractory to the hepatocarcinogenic effects of PPs first noted in rodents.
- Published
- 1999
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28. Bcl-2 regulates amplification of caspase activation by cytochrome c
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Cosulich, Sabina C., Savory, Peter J., and Clarke, Paul R.
- Abstract
Caspases, a family of specific proteases, have central roles in apoptosis [1]. Caspase activation in response to diverse apoptotic stimuli involves the relocalisation of cytochrome c from mitochondria to the cytoplasm where it stimulates the proteolytic processing of caspase precursors. Cytochrome c release is controlled by members of the Bcl-2 family of apoptosis regulators [2,3]. The anti-apoptotic members Bcl-2 and Bcl-xLmay also control caspase activation independently of cytochrome c relocalisation or may inhibit a positive feedback mechanism [4–7]. Here, we investigate the role of Bcl-2 family proteins in the regulation of caspase activation using a model cell-free system. We found that Bcl-2 and Bcl-xLset a threshold in the amount of cytochrome c required to activate caspases, even in soluble extracts lacking mitochondria. Addition of dATP (which stimulates the procaspase-processing factor Apaf-1 [8,9]) overcame inhibition of caspase activation by Bcl-2, but did not prevent the control of cytochrome c release from mitochondria by Bcl-2. Cytochrome c release was accelerated by active caspase-3 and this positive feedback was negatively regulated by Bcl-2. These results provide evidence for a mechanism to amplify caspase activation that is suppressed at several distinct steps by Bcl-2, even after cytochrome c is released from mitochondria.
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- 1999
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29. Systemic administration of autologous, alloactivated helper-enriched lymphocytes to patients with metastatic melanoma of the lung
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Balsari, Andrea, Marolda, Raffaele, Gambacorti-Passerini, Carlo, Sciorelli, Gianalfredo, Tona, Gabriella, Cosulich, Elisabetta, Taramelli, Donatella, Fossati, Giuseppe, Parmiani, Giorgio, and Cascinelli, Natale
- Abstract
A phase I study was carried out to test the feasibility and toxicity of infusing large numbers of autologous, alloactivated helper lymphocytes into patients with metastatic melanoma. Patient peripheral blood lymphocytes (Pt-PBL) obtained by lymphopheresis and expressing the helper phenotype BT5/9 were separated and stimulated for 48 or 72 h with a pool of PBL from four to six healthy donors. Patients were then infused with such activated lymphocytes over a 2–3 h period. A total of 4 phereses and infusions (2/week for 2 weeks) were carried out for each cycle in each patient. Of the five patients treated, two received a second round of infusions. Infusion of autologous PBL stimulated in vitro for 48 h caused chills, fever, headache, and increased blood pressure. All symptoms disappeared in 2–3 h and were easily controlled by appropriate therapy. When lymphocytes were given after 72 h of allostimulation, no or very mild toxicity was observed. Serum chemistry, coagulation, autoimmunity, and urine analysis showed no gross abnormalities during therapy or follow-up of the patients. Immunological parameters (OKT4/OKT8 ratio, NK activity and cytotoxic T cell activity to autologous melanoma) were evaluated before starting the therapy, during its course and during the 3 to 6 months follow-up. The OKT4/OKT8 ratio increased significantly but transiently soon after the first course of infusions in one of the two patients tested. NK activity increased after 75–100 days in the three patients tested and in one of them it was high even after 180 days. No correlation between NK activity and prognosis was apparent. Cytotoxicity to autologous tumor was assessed in two patients, only one of whom exhibited an increased activity from 75 to 180 days, which was associated with a prognosis better than that of the negative patient. Five patients were treated: two had progressive disease, two had stable disease for 5 and 6 months, respectively. In the first of these patients, a new cycle of lymphocyte infusions was carried out which caused a measurable reduction of lung tumor nodules whose growth, however, resumed 4 months later. This patient died 14 months after the onset of therapy. The fifth patient had a partial regression of pulmonary and intracranial metastases after therapy, but eventually died 3 months later. These results indicate that infusion of a high numbers of autologous, allostimulated helper PBL is a feasible and safe procedure, which could therefore be used in future studies of adoptive immunotherapy of cancer.
- Published
- 1986
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30. Regulation of apoptosis by BH3 domains in a cell-free system
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Cosulich, Sabina C, Worrall, Vivienne, Hedge, Philip J, Green, Stephen, and Clarke, Paul R
- Abstract
Background:The Bcl-2 family of proteins plays a key role in the regulation of apoptosis. Some family members prevent apoptosis induced by a variety of stimuli, whereas others promote apoptosis. Competitive dimerisation between family members is thought to regulate their function. Homologous domains within individual proteins are necessary for interactions with other family members and for activity, although the specific mechanisms might differ between the pro-apoptotic and anti-apoptotic proteins.
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- 1997
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31. CD38 expression distinguishes two groups of B-cell chronic lymphocytic leukemias with different responses to anti-IgM antibodies and propensity to apoptosis
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Zupo, S, Isnardi, L, Megna, M, Massara, R, Malavasi, F, Dono, M, Cosulich, E, and Ferrarini, M
- Abstract
The expression of CD38 by B cells chronic lymphocytic leukemia (B-CLL) was studied in 20 untreated patients. The cells expressed abundant CD38 (relative fluorescence intensity range, 6 to 15) in 6 cases (group I patients), whereas CD38 expression was low to absent (relative fluorescence intensity range, 0 to 3) in the remaining cases (group II patients). Exposure of the cells from group I patients to goat antihuman mu chain antibodies (Ga mu-ab) resulted in the elevation of intracellular free Ca2+ concentration([Ca2+]i) followed by apoptosis. In contrast, exposure of group II cells to Ga mu-ab was not followed by increased levels of [Ca2+]i, programmed cell death or cell proliferation. No differences in the expression of surface IgM were noted in the two groups of B-CLL cells. Normal peripheral blood B cells, which expressed low to absent CD38, were capable of mobilizing [Ca2+]i and of proliferating after exposure to Ga mu-ab. The collected data suggest that, although group I B-CLL cells were able to transduce the signals delivered by IgM crosslinking, this pathway was severely impaired in group II B-CLL cells. However, unlike that observed in normal circulating B cells, stimulation of group I cells with Ga mu-ab resulted in apoptosis rather than proliferation. CD38 did not appear to be directly involved in [Ca2+]i mobilization induced by Ga mu-ab in group I B-CLL cells because their exposure to anti-CD38 monoclonal antibodies failed to cause [Ca2+]i mobilization or to block the [Ca2+]i response induced by Ga mu-ab. These data indicate that CD38 expression identified a particular subset of B-CLL cells with defined functional properties, including the propensity to undergo apoptosis.
- Published
- 1996
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32. Isolation and Identification of Piperacillin Amide as an Impurity in Piperacillin
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Siegel, Marshall M., Mills, Richard, Gehrlein, Lane, Gore, William E., Morton, George, Chang, T., Cosulich, Donna, Medwid, Jeffrey, and Mirando, P.
- Abstract
Piperacillin amide (IV) was successfully identified as the predominant impurity in commercial lots of piperacillin monohydrate (III). The impurity was isolated viaa preparative liquid chromatographic scheme utilizing Florisil as the adsorbent and a mobile phase of water-acetonitrile (4:96, v/v). The isolated component had nearly the same reverse-phase HPLC properties as piperacillin and was chemically and thermally unstable. This labile impurity was spectroscopically identified by field desorption (FD), fast atom bombardment (FAB) with collision activation decomposition (CAD), and desorption chemical ionization (DCI) mass spectrometries, and NMR and IR spectrometries. Identity was confirmed on comparison of the chromatographic and spectrometric data of the impurity with an independently synthesized sample of piperacillin amide.
- Published
- 1984
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33. Cleavage and inactivation of DNA-dependent protein kinase catalytic subunit during apoptosis in Xenopus egg extracts.
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Le Romancer, M, Cosulich, S C, Jackson, S P, and Clarke, P R
- Abstract
DNA-dependent protein kinase (DNA-PK) consists of a 460 kDa subunit that contains the catalytic domain (DNA-PKcs) complexed with two polypeptides of 70 kDa and 80 kDa (Ku70 and Ku80) which comprise the Ku autoantigen. DNA-PKcs requires association with DNA via Ku for catalytic activation and is implicated in double strand break repair, V(D)J recombination and transcription. We have utilised a cell-free system of concentrated Xenopus laevis egg extracts to investigate the regulation and possible functions of DNA-PK. Recently, we have shown that this system can reproduce events of apoptosis, including activation of an apoptotic protease that cleaves poly(ADP-ribose) polymerase. Here, we report that DNA-PK is rapidly inactivated with the onset of apoptosis in this system. Loss of activity is concomitant with cleavage of the catalytic subunit, whereas the Ku subunits are stable. Cleavage and inactivation of DNA-PKcs is prevented by prior addition of the anti-apoptotic protein Bcl-2 or inhibition of an apoptotic protease that has characteristics of the CPP-32/Ced-3 family of cysteine proteases that cleave poly(ADP-ribose) polymerase. These results suggest that cleavage and inactivation of DNA-PKcs prevents this factor from functioning in DNA repair, recombination or transcriptional regulation during apoptosis.
- Published
- 1996
34. Autoimmune thyroid disease: purification and phenotypic analysis of intrathyroid T cells
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Canonica, G., Caria, M., Torre, G., Risso, A., Cosulich, M., and Bagnasco, M.
- Abstract
A phenotypic analysis of T cells infiltrating the thyroid of patients with autoimmune thyroid disease (both Graves’ disease and Hashimoto’s thyroiditis) was performed. T lymphocytes were purified from mononuclear cells extracted from surgically removed tissue. The following markers were evaluated: la antigens, MLR4 antigen (expressed on activated T cells) 5/9 antigen (expressed on a subset of lymphocytes containing the whole “helper-inducer” activity in vitro), Fcy-receptors, B9 antigen (expressed by cytotoxic, or precursor of cytotoxic, T cells). We observed increased percentages of 5/9-, MLR4- and la-positive T cells with respect to peripheral blood in both HT and GD: on the contrary, in specimens from nonautoimmune thyroid diseases mononuclear infiltrate was minimal, and even T cell evaluation was not possible. In addition, B9- and Fcγ-positive T cells were increased in Hashimoto’s, but not in Graves’ thyroid tissue, thus suggesting a different role of cytotoxic effector mechanisms in the two diseases.
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- 1984
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35. Effects of fluorinated inositols on the proliferation of Swiss 3T3 fibroblasts
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Cosulich, S C, Offer, J, Smith, G A, Hesketh, R, and Metcalfe, J C
- Abstract
The six monodeoxyfluoro-myo-inositols (nFIns) have previously been synthesized as potential inhibitors of signalling pathways mediated by phosphoinositides and their derivatives. Each of the six nFIns isomers was introduced into Swiss 3T3 fibroblasts by the techniques of microinjection or scrape loading at intracellular concentrations of approx. 2-4 mM. Of the six nFIns analogues, only 3FIns and 5FIns inhibited the serum-stimulated proliferation of 3T3 fibroblasts assayed by cell counting. Proliferation was inhibited to a similar extent by 3FIns or 5FIns, irrespective of which technique was used to introduce the nFIns analogues into the cells. Proliferation of cells 35 h after serum stimulation (i.e. when the first cell cycle was completed in control cells) was inhibited by approx. 50% by both 3FIns and 5FIns, and entry into S phase in the first cell cycle was inhibited to the same extent. This indicated that the nFIns analogues were inhibiting proliferation in the G1 phase of the cell cycle. Proliferation during the second cell cycle (35-60 h after stimulation) was inhibited by 75-85%. The inhibitory nFIns analogues were not toxic to the cells, nor did they affect the cellular ATP/ADP ratio. The effectiveness of the nFIns analogues in inhibiting proliferation was directly correlated with their ability to be incorporated into phosphatidylinositol analogues, suggesting that they may act by modulating phosphoinositide signalling pathways or other functions essential for DNA synthesis.
- Published
- 1993
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36. Further results on μ-calorimeters with superconducting absorber
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Cosulich, E., Gatti, F., and Vitale, S.
- Abstract
The thermalization process of the energy released by a-particles in superconducting crystals used as absorber for µ-calorimeters is studied for an extended sample of materials at temperatures between 40 and 100 mK.
- Published
- 1993
- Full Text
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37. Functional characterization of an antigen involved in an early step of T-cell activation.
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Cosulich, M E, Rubartelli, A, Risso, A, Cozzolino, F, and Bargellesi, A
- Abstract
An activation antigen, identified by the monoclonal antibody MLR3, is described that is present on activated T lymphocytes and thymocytes but not on resting T lymphocytes. Immunoprecipitation of radiolabeled membranes from an activated T-cell line showed that the MLR3-binding molecule has a molecular size of 28-34 kDa. Immunofluorescence analysis showed that the appearance of the MLR3 antigen is an early event and precedes that of the interleukin 2 receptor both in T lymphocytes and thymocytes. The proliferative response of resting T cells to OKT3-Sepharose and interleukin 1 or accessory cells, but not the interleukin 2-dependent proliferation, was inhibited by the addition of MLR3 monoclonal antibodies. Similar results wer also obtained in an interleukin 1-dependent human thymocyte proliferation assay. In addition when MLR3-positive cells were cultured with purified interleukin 1, MLR3 surface antigen expression was not observed. Thus MLR3 monoclonal antibody appears to recognize an antigen involved in an early step of T-cell activation related to interleukin 1-dependent functions and on both T lymphocytes and thymocytes.
- Published
- 1987
- Full Text
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38. A monoclonal anti-DC1 antibody selectivity inhibits the generation of effector T cells mediating specific cytolytic activity.
- Author
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Corte, G, Moretta, A, Cosulich, M E, Ramarli, D, and Bargellesi, A
- Abstract
The products of the DC locus have been shown to be structurally different from those of the DR locus. In this paper it is shown that, unlike anti-DR antibodies, a monoclonal antibody directed against DC1 does not affect proliferation of T cells in response to alloantigens or soluble antigens or production of Ig in a pokeweed mitogen-stimulated in vitro culture. However, the anti-DC1 inhibits the generation of effector T cells mediating specific cytolytic activity, whereas no inhibitory effect can be observed on natural killer and antibody-dependent cytotoxic cell activities.
- Published
- 1982
- Full Text
- View/download PDF
39. Cleavage and inactivation of DNA-dependent protein kinase catalytic subunit during apoptosis in Xenopus egg extracts
- Author
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Romancer, Muriel Le, Cosulich, Sabina C., Jackson, Stephen P., and Clarke, Paul R.
- Abstract
DNA-dependent protein kinase (DNA-PK) consists of a 460 kDa subunit that contains the catalytic domain (DNAPKcs) complexed with two polypeptides of 70 kDa and 80 kDa (Ku70 and Ku80) which comprise the Ku autoantigen. DNA-PKcs requires association with DNA via Ku for catalytic activation and is implicated in double strand break repair, V(D)J recombination and transcription. We have utilised a cell-free system of concentrated Xenopus laevis egg extracts to investigate the regulation and possible functions of DNA-PK. Recently, we have shown that this system can reproduce events of apoptosis, including activation of an apoptotic protease that cleaves poly(ADP-ribose) polymerase. Here, we report that DNA-PK is rapidly inactivated with the onset of apoptosis in this system. Loss of activity is concomitant with cleavage of the catalytic subunit, whereas the Ku subunits are stable. Cleavage and inactivation of DNA-PKcs is prevented by prior addition of the anti-apoptotic protein Bcl-2 or inhibition of an apoptotic protease that has characteristics of the CPP-32/Ced-3 family of cysteine proteases that cleave poly(ADP-ribose) polymerase. These results suggest that cleavage and inactivation of DNA-PKcs prevents this factor from functioning in DNA repair, recombination or transcriptional regulation during apoptosis.
- Published
- 1996
- Full Text
- View/download PDF
40. SYNTHESIS OF PTEROYLGLUTAMIC ACID (LIVER L. CASEIFACTOR) AND PTEROIC ACID
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Waller, Coy W., Hutchings, Brian L., Mowat, John H., Stokstad, E. L. R., Boothe, James H., Angier, Robert B., Semb, Joseph, SubbaRow, Y., Cosulich, Donna B., Fahrenbach, M. J., Hultquist, M. E., Kuh, Erwin, Northey, E. H., Seeger, Doris R., Sickels, J. P., and Smith, James M.
- Published
- 1946
- Full Text
- View/download PDF
41. FOLIC ACID Supplement*SYNTHESIS OF PTEROYLGLUTAMIC ACID (LIVER L. CASEIFACTOR) AND PTEROIC ACID—PART II
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Hultquist, M. E., Kuh, Erwin, Cosulich, Donna B., Fahrenbach, M. J., Northey, E. H., Seeger, Doris R., Sickels, J. P., Smith, James M., Angier, Robert B., Boothe, James H., Hutchings, Brian L., Mowat, John H., Semb, Joseph, Stokstad, E. L. R., SubbaRow, Y., and Waller, Coy W.
- Published
- 1946
- Full Text
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42. STRUCTURE AND SYNTHESIS OF THE PTERIDINE DEGRADATION PRODUCTS OF THE FERMENTATION L. CASEIFACTOR
- Author
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Mowat, John H., Boothe, James H., Hutchings, Brian L., Stokstad, E. L. R., Waller, Coy W., Angier, Robert B., Semb, Joseph, Cosulich, Donna B., and SubbaRow, Y.
- Published
- 1946
- Full Text
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43. The Poetical Technique of Coleridge
- Author
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Cosulich, Gilbert
- Published
- 1914
- Full Text
- View/download PDF
44. Genome-Wide Estrogen Receptor Activity in Breast Cancer
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Farcas, Anca M, Nagarajan, Sankari, Cosulich, Sabina, and Carroll, Jason S
- Abstract
The largest subtype of breast cancer is characterized by the expression and activity of the estrogen receptor alpha (ERalpha/ER). Although several effective therapies have significantly improved survival, the adaptability of cancer cells means that patients frequently stop responding or develop resistance to endocrine treatment. ER does not function in isolation and multiple associating factors have been reported to play a role in regulating the estrogen-driven transcriptional program. This review focuses on the dynamic interplay between some of these factors which co-occupy ER-bound regulatory elements, their contribution to estrogen signaling, and their possible therapeutic applications. Furthermore, the review illustrates how some ER association partners can influence and reprogram the genomic distribution of the estrogen receptor. As this dynamic ER activity enables cancer cell adaptability and impacts the clinical outcome, defining how this plasticity is determined is fundamental to our understanding of the mechanisms of disease progression.
- Published
- 2021
- Full Text
- View/download PDF
45. Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors
- Author
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Banks, Erica, Grondine, Michael, Bhavsar, Deepa, Barry, Evan, Kettle, Jason G., Reddy, Venkatesh Pilla, Brown, Crystal, Wang, Haiyun, Mettetal, Jerome T., Collins, Teresa, Adeyemi, Oladipupo, Overman, Ross, Lawson, Deborah, Harmer, Alexander R., Reimer, Corinne, Drew, Lisa, Packer, Martin J., Cosulich, Sabina, Jones, Rhys DO., Shao, Wenlin, Wilson, David, Guichard, Sylvie, Fawell, Stephen, and Anjum, Rana
- Abstract
AZD3229 demonstrates pan-KIT/PDGFRα activity in several preclinical models and is a promising agent for the treatment of GIST.
- Published
- 2020
- Full Text
- View/download PDF
46. Shower reconstruction in the CLUE experiment
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Bartoli, B., Bastieri, D., Bigongiari, C., Ciocci, M. A., Cosulich, D., Cresti, M., Dokoutchaeva, V., Kartashov, D., Liello, F., and Malakhov, N.
- Published
- 2001
- Full Text
- View/download PDF
47. Capillary Gas Chromatographic–Mass Spectrometric Analysis of 15-Deoxy-16-hydroxy-16-vinylprostaglandin E2
- Author
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Cosulich, D.B., Perkinson, N.A., and Batra, V.K.
- Abstract
A new topically active antihypertensive agent, the methyl ester of 15-deoxy-16-hydroxy-16-vinylprostaglandin E2(1), rapidly hydrolyzes in blood to the carboxylic acid 2, which also has antihypertensive activity. A capillary gas chromatographic-mass spectrometric method is described for measuring 2in human plasma or serum at expected experimental blood levels of 75–1500 pg/mL. The assay is based on selected-ion monitoring of the carboxylate anion formed from negative ion chemical ionization of the trimethylsilylpentafluorobenzyl ester of 2, using a trideuterated analogue of 2as internal standard. The method has been used to analyze samples from subjects following topical application of 1–2mg of 1. Sample preparation included isolation from 1mL of plasma or serum and purification of the ester derivative with C18cartridges, followed by a two-step trimethylsilylation.
- Published
- 1985
- Full Text
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48. Apoptosis: Does stress kill?
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Cosulich, S., Clarke, and P.
- Published
- 1996
- Full Text
- View/download PDF
49. The Structure and Synthesis of the Liver L. caseiFactor
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Angier, Robert B., Boothe, James H., Hutchings, Brian L., Mowat, John H., Semb, Joseph, Stokstad, E. L. R., SubbaRow, Y., Waller, Coy W., Cosulich, Donna B., Fahrenbach, M. J., Hultquist, M. E., Kuh, Erwin, Northey, E. H., Seeger, Doris R., Sickels, J. P., and Smith, James M.
- Published
- 1946
- Full Text
- View/download PDF
50. Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity
- Author
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Langdon, Sophie, Hughes, Adina, Taylor, Molly A., Kuczynski, Elizabeth A., Mele, Deanna A., Delpuech, Oona, Jarvis, Laura, Staniszewska, Anna, Cosulich, Sabina, Carnevalli, Larissa S., and Sinclair, Charles
- Abstract
ABSTRACTmTOR inhibition can promote or inhibit immune responses in a context dependent manner, but whether this will represent a net benefit or be contraindicated in the context of immunooncology therapies is less understood. Here, we report that the mTORC1/2 dual kinase inhibitor vistusertib (AZD2014) potentiates anti-tumour immunity in combination with anti-CTLA-4 (αCTLA-4), αPD-1 or αPD-L1 immune checkpoint blockade. Combination of vistusertib and immune checkpoint blocking antibodies led to tumour growth inhibition and improved survival of MC-38 or CT-26 pre-clinical syngeneic tumour models, whereas monotherapies were less effective. Underlying these combinatorial effects, vistusertib/immune checkpoint combinations reduced the occurrence of exhausted phenotype tumour infiltrating lymphocytes (TILs), whilst increasing frequencies of activated Th1 polarized T-cells in tumours. Vistusertib alone was shown to promote a Th1 polarizing proinflammatory cytokine profile by innate primary immune cells. Moreover, vistusertib directly enhanced activation of effector T-cell and survival, an effect that was critically dependent on inhibitor dose. Therefore, these data highlight direct, tumour-relevant immune potentiating benefits of mTOR inhibition that complement immune checkpoint blockade. Together, these data provide a clear rationale to investigate such combinations in the clinic.
- Published
- 2018
- Full Text
- View/download PDF
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