912 results on '"J. Axelrod"'
Search Results
2. Dynamics of a buffer-gas-loaded, deep optical trap for molecules
- Author
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Ashwin Singh, Lothar Maisenbacher, Ziguang Lin, Jeremy J. Axelrod, Cristian D. Panda, and Holger Müller
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Physics ,QC1-999 - Abstract
We describe an approach to optically trapping small, chemically stable molecules at cryogenic temperatures by buffer-gas loading a deep optical dipole trap. The ∼10K trap depth will be produced by a tightly focused, 1064-nm cavity capable of reaching intensities of hundreds of GW/cm^{2}. Molecules will be directly buffer-gas loaded into the trap using a helium buffer gas at 1.5K. The very far-off-resonant, quasielectrostatic trapping mechanism is insensitive to a molecule's internal state, energy level structure, and its electric and magnetic dipole moment. Here, we theoretically investigate the trapping and loading dynamics, as well as the heating and loss rates, and conclude that 10^{4}–10^{6} molecules are likely to be trapped. Our trap would open new possibilities in molecular spectroscopy, studies of cold chemical reactions, and precision measurement, amongst other fields of physics. more...
- Published
- 2023
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Catalog
3. Integrating neuroplasticity and evolution
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Caleb J. Axelrod, Swanne P. Gordon, and Bruce A. Carlson
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General Agricultural and Biological Sciences ,General Biochemistry, Genetics and Molecular Biology - Published
- 2023
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4. Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL
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Kallesh D. Jayappa, Craig A. Portell, Vicki L. Gordon, Brian J. Capaldo, Stefan Bekiranov, Mark J. Axelrod, L. Kyle Brett, Julia D. Wulfkuhle, Rosa I. Gallagher, Emanuel F. Petricoin, Timothy P. Bender, Michael E. Williams, and Michael J. Weber more...
- Subjects
Specialties of internal medicine ,RC581-951 - Abstract
Abstract: De novo resistance and rapid recurrence often characterize responses of B-cell malignancies to ibrutinib (IBR), indicating a need to develop drug combinations that block compensatory survival signaling and give deeper, more durable responses. To identify such combinations, we previously performed a combinatorial drug screen and identified the Bcl-2 inhibitor venetoclax (VEN) as a promising partner for combination with IBR in mantle cell lymphoma (MCL). We have opened a multi-institutional clinical trial to test this combination. However, analysis of primary samples from patients with MCL as well as chronic lymphocytic leukemia (CLL) revealed unexpected heterogeneous de novo resistance even to the IBR+VEN combination. In the current study, we demonstrate that resistance to the combination can be generated by microenvironmental agonists: interleukin-10 (IL-10), CD40L and, most potently, cytosine guanine dinucleotide–oligodeoxynucleotides (CpG-ODNs), which is a surrogate for unmethylated DNA and a specific agonist for Toll-like receptor 9 (TLR9) signaling. Incubation with these agonists caused robust activation of NF-κB signaling, especially alternative NF-κB, which led to enhanced expression of the antiapoptotic proteins Mcl-1, Bcl-xL, and survivin, thus decreasing dependence on Bcl-2. Inhibitors of NF-κB signaling blocked overexpression of these antiapoptotic proteins and overcame resistance. Inhibitors of Mcl-1, Bcl-xL, or survivin also overcame this resistance, and showed synergistic benefit with the IBR+VEN combination. We conclude that microenvironmental factors, particularly the TLR9 agonist, can generate de novo resistance to the IBR+VEN combination in CLL and MCL cells. This signaling pathway presents targets for overcoming drug resistance induced by extrinsic microenvironmental factors in diverse B-cell malignancies. more...
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- 2017
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5. Overcoming resolution loss due to thermal magnetic field fluctuations from phase plates in transmission electron microscopy
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Jeremy J. Axelrod, Petar N. Petrov, Jessie T. Zhang, Jonathan Remis, Bart Buijsse, Robert M. Glaeser, and Holger Mȕller
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Instrumentation ,Article ,Atomic and Molecular Physics, and Optics ,Electronic, Optical and Magnetic Materials - Abstract
We identify thermal magnetic field fluctuations, caused by thermal electron motion (“Johnson noise”) in electrically conductive materials, as a potential resolution limit in transmission electron microscopy with a phase plate. Specifically, resolution loss can occur if the electron diffraction pattern is magnified to extend phase contrast to lower spatial frequencies, and if conductive materials are placed too close to the electron beam. While our initial implementation of a laser phase plate (LPP) was significantly affected by these factors, a redesign eliminated the problem and brought the performance close to the expected level. The resolution now appears to be limited by residual Johnson noise arising from the electron beam liner tube in the region of the LPP, together with the chromatic aberration of the relay optics. These two factors can be addressed during future development of the LPP. more...
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- 2023
- Full Text
- View/download PDF
6. Interspecific and intraspecific comparisons reveal the importance of evolutionary context in sunfish brain form divergence
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Frederic Laberge, Beren W. Robinson, and Caleb J. Axelrod
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0106 biological sciences ,0301 basic medicine ,Ecotype ,Brain ,Pelagic zone ,Context (language use) ,Interspecific competition ,Biology ,Biological Evolution ,010603 evolutionary biology ,01 natural sciences ,Intraspecific competition ,Perciformes ,Divergence ,03 medical and health sciences ,030104 developmental biology ,Jaw ,Habitat ,Evolutionary biology ,Animals ,Parallel evolution ,Ecosystem ,Ecology, Evolution, Behavior and Systematics - Abstract
Habitats can select for specialized phenotypic characteristics in animals. However, the consistency of evolutionary responses to particular environmental conditions remains difficult to predict. One trait of great ecological importance is brain form, which is expected to vary between habitats that differ in their cognitive requirements. Here, we compared divergence in brain form and oral jaw size across a common littoral-pelagic ecological axis in two sunfishes at both the intraspecific and interspecific levels. Brain form differed between habitats at every level of comparison; however, divergence was inconsistent, despite consistent differences in oral jaw size. Pumpkinseed and bluegill species differed in cerebellum, optic tectum and olfactory bulb size. These differences are consistent with a historical ecological divergence because they did not manifest between littoral and pelagic ecotypes within either species, suggesting constraints on changes to these regions over short evolutionary time scales. There were also differences in brain form between conspecific ecotypes, but they were inconsistent between species. Littoral pumpkinseed had larger brains than their pelagic counterpart, and littoral bluegill had smaller telencephalons than their pelagic counterpart. Inconsistent brain form divergence between conspecific ecotypes of pumpkinseed and bluegill sharing a common littoral-pelagic habitat axis suggests that contemporary ecological conditions and historic evolutionary context interact to influence evolutionary changes in brain form in fishes. more...
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- 2021
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7. Evolutionary divergence in phenotypic plasticity shapes brain size variation between coexisting sunfish ecotypes
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Caleb J. Axelrod, Beren W. Robinson, and Frédéric Laberge
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Ecotype ,Fishes ,Animals ,Organ Size ,Adaptation, Physiological ,Ecology, Evolution, Behavior and Systematics ,Perciformes - Abstract
Mechanisms that generate brain size variation and the consequences of such variation on ecological performance are poorly understood in most natural animal populations. We use a reciprocal-transplant common garden experiment and foraging performance trials to test for brain size plasticity and the functional consequences of brain size variation in Pumpkinseed sunfish (Lepomis gibbosus) ecotypes that have diverged between nearshore littoral and offshore pelagic lake habitats. Different age-classes of wild-caught juveniles from both habitats were exposed for 6 months to treatments that mimicked littoral and pelagic foraging. Plastic responses in oral jaw size suggested that treatments mimicked natural habitat-specific foraging conditions. Plastic brain size responses to foraging manipulations differed between ecotypes, as only pelagic sourced fish showed brain size plasticity. Only pelagic juveniles under 1 year-old expressed this plastic response, suggesting that plastic brain size responses decline with age and so may be irreversible. Finally, larger brain size was associated with enhanced foraging performance on live benthic but not pelagic prey, providing the first experimental evidence of a relationship between brain size and prey-specific foraging performance in fishes. The recent post-glacial origin of these ecotypes suggests that brain size plasticity can rapidly evolve and diverge in fish under contrasting ecological conditions. more...
- Published
- 2022
8. Author response for 'Evolutionary divergence in phenotypic plasticity shapes brain size variation between coexisting sunfish ecotypes'
- Author
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null Caleb J. Axelrod, null Beren W. Robinson, and null Frédéric Laberge
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- 2022
- Full Text
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9. Overcoming resolution-loss mechanisms in laser phase plate cryo-electron microscopy
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Jeremy J. Axelrod, Petar N. Petrov, Jonathan Remis, Robert M. Glaeser, and Holger Mueller
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Biophysics - Published
- 2023
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10. Laser Phase Plate: Advancing Beyond Proof-of-Concept
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J J Axelrod, J Dioquino, P Petrov, J Remis, S Sandhaus, J Silber, J Whinnery, R M Glaeser, and H Müller
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Instrumentation - Published
- 2022
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11. Laser phase plate for transmission electron microscopy
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Osip Schwartz, Holger Müller, Carter Turnbaugh, Jeremy J. Axelrod, Sara L. Campbell, and Robert M. Glaeser
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0303 health sciences ,Materials science ,business.industry ,Phase-contrast imaging ,Phase (waves) ,Cell Biology ,Electron ,Laser ,Biochemistry ,law.invention ,03 medical and health sciences ,Amorphous carbon ,Transmission electron microscopy ,law ,Microscopy ,Optoelectronics ,business ,Molecular Biology ,Electron scattering ,030304 developmental biology ,Biotechnology - Abstract
Transmission electron microscopy (TEM) of rapidly frozen biological specimens, or cryo-EM, would benefit from the development of a phase plate for in-focus phase contrast imaging. Several types of phase plates have been investigated, but rapid electrostatic charging of all such devices has hindered these efforts. Here, we demonstrate electron phase manipulation with a high-intensity continuous-wave laser beam, and use it as a phase plate for TEM. We demonstrate the laser phase plate by imaging an amorphous carbon film. The laser phase plate provides a stable and tunable phase shift without electrostatic charging or unwanted electron scattering. These results suggest the possibility for dose-efficient imaging of unstained biological macromolecules and cells. more...
- Published
- 2019
- Full Text
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12. Light scattering in TIRF microscopy: A theoretical study of the limits to surface selectivity
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Jeremy J. Axelrod and Daniel Axelrod
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Physics ,Total internal reflection ,business.industry ,Scattering ,Biophysics ,Physics::Optics ,Articles ,Optical field ,Models, Theoretical ,Polarization (waves) ,Light scattering ,Refractometry ,Optics ,Microscopy, Fluorescence ,Humans ,Exponential decay ,business ,Refractive index ,Excitation - Abstract
In TIRF microscopy, the sample resides near a surface in an evanescent optical field that, ideally, decreases in intensity with distance from the surface in a pure exponential fashion. In practice, multiple surfaces and imperfections in the optical system and refractive index (RI) inhomogeneities in the sample (often living cells) produce propagating scattered light that degrades the exponential purity. RI inhomogeneities cannot easily be avoided. How severe is the consequent optical degradation? Starting from Maxwell's equations, we derive a first-order perturbative approximation of the electric field strength of light scattered by sample RI inhomogeneities of several types under coherent evanescent field illumination. The approximation provides an expression for the scattering field of any arbitrary RI inhomogeneity pattern. The scattering is not all propagating; some is evanescent and remains near the scattering centers. The results presented here are only a first-order approximation, and they ignore multiple scattering and reflections off the total internal reflection (TIR) surface. For simplicity, we assume that the RI variations in the z direction are insignificant within the depth of the evanescent field and consider only scattering of excitation light, not fluorescence emission light. The general conclusion of most significance from this study is that TIR scattering from a sample with RI variations typical of those on a cell culture alters the effective thickness of the illumination to only ∼50% greater than it would be without scattering. The qualitative surface selectivity of TIR fluorescence is largely retained even in the presence of scattering. Quantitatively, however, scattering will cause a deviation from the incident exponential decay at shorter distances, adding a slower decaying background. Calculations that assume a pure exponential decay will be approximations, and scattering should be taken into account. TIR scattering is only slightly dependent on polarization but is strongly reduced for the highest accessible incidence angles. more...
- Published
- 2021
13. Selective abrogation of S6K2 maps lipid homeostasis as a survival vulnerability in MAPKi-resistant NRASMUT melanoma
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Qin Liu, Aaron R. Goldman, Mark J. Axelrod, Zayas-Bazan D, Lipchick B, Zachary T. Schug, Subhasree Basu, Hsin-Yi Chen, Patricia Reyes-Uribe, Michael J. Weber, Jessie Villanueva, Yiling Lu, GB Mills, Adam N. Guterres, Andrew V. Kossenkov, Maureen E. Murphy, Xiangfan Yin, and David W. Speicher more...
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Lipid peroxidation ,MAPK/ERK pathway ,Programmed cell death ,chemistry.chemical_compound ,Kinase ,Chemistry ,Effector ,Ribosomal protein s6 ,Cancer research ,P70-S6 Kinase 1 ,Lipid metabolism - Abstract
SUMMARYAlthough oncogenic NRAS activates MAPK signaling, inhibition of the MAPK pathway is not therapeutically efficacious in NRAS-mutant tumors. Here we report that silencing the ribosomal protein S6 kinase 2 (S6K2), while preserving the activity of S6K1, perturbs lipid metabolism, enhances fatty acid unsaturation, triggers lipid peroxidation and induces cell death selectively in NRAS-mutant melanoma cells that are resistant to MAPK inhibition. S6K2 depletion stimulates SREBP1 activity in an S6K1-dependent manner and relieves suppression of PPARα, triggering apoptosis and ferroptosis. Combining PPARα agonists and polyunsaturated fatty acids phenocopies the effects of S6K2 abrogation, blocking tumor growth. Collectively, our study establishes S6K2 and its effector subnetwork as promising targets for NRAS-mutant melanoma that are resistant to global MAPK pathway inhibitors. more...
- Published
- 2021
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14. Author response for 'Interspecific and intraspecific comparisons reveal the importance of evolutionary context in sunfish brain form divergence'
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null Caleb J. Axelrod, null Frédéric Laberge, and null Beren W. Robinson
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- 2020
- Full Text
- View/download PDF
15. Author response for 'Interspecific and intraspecific comparisons reveal the importance of evolutionary context in sunfish brain form divergence'
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Caleb J. Axelrod, Beren W. Robinson, and Frederic Laberge
- Subjects
Evolutionary biology ,Context (language use) ,Interspecific competition ,Biology ,Intraspecific competition ,Divergence - Published
- 2020
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16. Observation of the relativistic reversal of the ponderomotive potential
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Robert M. Glaeser, Osip Schwartz, Carter Turnbaugh, Holger Müller, Jeremy J. Axelrod, and Sara L. Campbell
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Physics ,Diffraction ,General Physics ,Quantum Physics ,General Physics and Astronomy ,FOS: Physical sciences ,Electron ,Kinetic energy ,Polarization (waves) ,01 natural sciences ,Electromagnetic radiation ,Charged particle ,Mathematical Sciences ,Article ,Standing wave ,Engineering ,0103 physical sciences ,Physical Sciences ,Atomic physics ,010306 general physics ,Wave function ,Quantum Physics (quant-ph) ,Physics - Optics ,Optics (physics.optics) - Abstract
The secular dynamics of a non-relativistic charged particle in an electromagnetic wave can be described by the ponderomotive potential. Although ponderomotive electron-laser interactions at relativistic velocities are important for emerging technologies from laser-based particle accelerators to laser-enhanced electron microscopy, the effects of special relativity on the interaction have only been studied theoretically. Here, we use a transmission electron microscope to measure the position-dependent phase shift imparted to a relativistic electron wave function when it traverses a standing laser wave. The kinetic energy of the electrons is varied between $80\,\mathrm{keV}$ and $300\,\mathrm{keV}$, and the laser standing wave has a continuous-wave intensity of $175\,\mathrm{GW/cm}^2$. In contrast to the non-relativistic case, we demonstrate that the phase shift depends on both the electron velocity and the wave polarization, confirming the predictions of a quasiclassical theory of the interaction. Remarkably, if the electron's speed is greater than $1/\sqrt{2}$ of the speed of light, the phase shift at the electric field nodes of the wave can exceed that at the antinodes. In this case there exists a polarization such that the phase shifts at the nodes and antinodes are equal, and the electron does not experience Kapitza-Dirac diffraction. Our results thus provide new capabilities for coherent electron beam manipulation. more...
- Published
- 2020
17. Isolating the effects of ontogenetic niche shift on brain size development using pumpkinseed sunfish ecotypes
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Frederic Laberge, Beren W. Robinson, and Caleb J. Axelrod
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0106 biological sciences ,0301 basic medicine ,Ecological niche ,Ecotype ,Ecology (disciplines) ,Ontogeny ,Foraging ,Niche ,Brain ,Organ Size ,Biology ,010603 evolutionary biology ,01 natural sciences ,Perciformes ,03 medical and health sciences ,030104 developmental biology ,Evolutionary biology ,Brain size ,Juvenile ,Animals ,Ecology, Evolution, Behavior and Systematics ,Ecosystem ,Developmental Biology - Abstract
A functional relationship between relative brain size and cognitive performance has been hypothesized. However, the influence of ontogenetic niche shifts on cognitive performance is not well understood. Increases in body size can affect niche use but distinguishing nonecologically relevant brain development from effects associated with ecology is difficult. If survival is enhanced by functional changes in ecocognitive performance over ontogeny, then brain size development should track ontogenetic shifts in ecology. We control for nonecologically relevant brain size development by comparing brain growth between two ecotypes of Pumpkinseed sunfish whose ecologies diverge over ontogeny from a shared juvenile niche. Brain size differs between ecotypes from their birth year onwards even though their foraging ecology appears to diverge at age 3. This finding suggests that the eco-cognitive requirements of adult niches shape early life brain growth more than the requirements of juvenile ecology. more...
- Published
- 2020
18. High-Power Near-Concentric Fabry-Perot Cavity for Phase Contrast Electron Microscopy
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Robert M. Glaeser, Jonathan P Remis, Holger Mueller, Jeske Y. Dioquino, Jeremy J. Axelrod, Petar N. Petrov, Zanlin Yu, Sara L. Campbell, Osip Schwartz, Yifan Cheng, and Carter Turnbaugh
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Materials science ,Physics - Instrumentation and Detectors ,FOS: Physical sciences ,Electron ,01 natural sciences ,Signal ,010305 fluids & plasmas ,law.invention ,ARTICLES ,Optics ,Engineering ,law ,0103 physical sciences ,Instrumentation ,Applied Physics ,010302 applied physics ,Quantum Physics ,business.industry ,Instrumentation and Detectors (physics.ins-det) ,Laser ,Transmission electron microscopy ,Optical cavity ,Equipment and Techniques for Lasers, Lasers, Pump-Probe and Resonance Ionization Lasers ,Physical Sciences ,Chemical Sciences ,Continuous wave ,Electron microscope ,business ,Quantum Physics (quant-ph) ,Fabry–Pérot interferometer - Abstract
Transmission electron microscopy (TEM) of vitrified biological macromolecules (cryo-EM) is limited by the weak phase contrast signal that is available from such samples. Using a phase plate would thus substantially improve the signal-to-noise ratio. We have previously demonstrated the use of a high-power Fabry-Perot cavity as a phase plate for TEM. We now report improvements to our laser cavity that allow us to achieve record continuous-wave intensities of over 450 GW/cm$^{2}$, sufficient to produce the optimal 90{\deg} phase shift for 300 keV electrons. In addition, we have performed the first cryo-EM reconstruction using a laser phase plate, demonstrating that the stability of this laser phase plate is sufficient for use during standard cryo-EM data collection. more...
- Published
- 2020
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19. Cascade reactions leading to the mechanism of action of vinaxanthone and xanthofulvin, natural products that drive nerve repair
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Abram J. Axelrod, Ruben Abagyan, Anders M. Eliasen, Matthew R. Chin, and Dionicio Siegel
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0301 basic medicine ,Chemistry ,Regeneration (biology) ,Organic Chemistry ,Allosteric regulation ,Biochemistry ,Chemical synthesis ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Mechanism of action ,Semaphorin ,Biological target ,Drug Discovery ,Succinate receptor 1 ,medicine ,medicine.symptom ,030217 neurology & neurosurgery ,Function (biology) - Abstract
The natural products vinaxanthone and xanthofulvin promote regeneration in animal models of spinal cord injury and corneal transplant. However, inhibition of the initially described biological target of these compounds, semaphorin 3A, does not fully account for the recovery demonstrated in vivo following administration of the natural products. Through chemical synthesis substantial quantities of both natural products have been accessed with early reaction development paving the way for synthesizing both compounds. The success of a model system, first disclosed herein, translated to the syntheses of both natural products. Following from this we also report for the first time the discovery of a new target of the natural products, the succinate receptor 1 (SUCNR1). Both natural products function as positive allosteric modulators of SUCNR1. As the first known allosteric modulators of SUCNR1, the compounds represent powerful new tools to understand the pharmacology of SUCNR1 and its control of growth and cellular defense. more...
- Published
- 2018
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20. Total chemical synthesis of human thyroid-stimulating hormone (hTSH) β-subunit: Application of arginine-tagged acetamidomethyl (AcmR) protecting groups
- Author
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John A. Brailsford, Jennifer L. Stockdill, Eric V. Johnston, Abram J. Axelrod, Paul A. Vadola, Samuel J. Danishefsky, and Michael T. Peterson
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Glycosylation ,Arginine ,010405 organic chemistry ,Organic Chemistry ,Disaccharide ,Chitobiose ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Chemical synthesis ,Article ,Glycopeptide ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Protein biosynthesis ,Hormone - Abstract
The β-subunit of human thyroid stimulating hormone (hTSH) has been synthesized as a single glycoform bearing a chitobiose disaccharide at the native glycosylation site. Key to the successful completion of this synthesis was the introduction of an arginine-tagged acetamidomethyl group, which served to greatly facilitate handling of a glycopeptide fragment with poor aqueous solubility. This general solution to the challenge of working with intractable peptides is expected to find wide use in protein synthesis. more...
- Published
- 2018
- Full Text
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21. Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL
- Author
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Stefan Bekiranov, Timothy P. Bender, Julia Wulfkuhle, Emanuel F. Petricoin, Michael J. Weber, Mark J. Axelrod, Vicki L. Gordon, Kallesh Danappa Jayappa, Michael E. Williams, Rosa I. Gallagher, Brian J. Capaldo, L. Kyle Brett, and Craig A. Portell more...
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0301 basic medicine ,Agonist ,medicine.drug_class ,Venetoclax ,Chronic lymphocytic leukemia ,Hematology ,Drug resistance ,Pharmacology ,Biology ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,Survivin ,medicine ,Mantle cell lymphoma ,Signal transduction - Abstract
De novo resistance and rapid recurrence often characterize responses of B-cell malignancies to ibrutinib (IBR), indicating a need to develop drug combinations that block compensatory survival signaling and give deeper, more durable responses. To identify such combinations, we previously performed a combinatorial drug screen and identified the Bcl-2 inhibitor venetoclax (VEN) as a promising partner for combination with IBR in Mantle Cell Lymphoma (MCL). We have opened a multi-institutional clinical trial to test this combination. However, analysis of primary samples from patients with MCL as well as chronic lymphocytic leukemia (CLL) revealed unexpected heterogeneous de novo resistance even to the IBR+VEN combination. In the current study, we demonstrate that resistance to the combination can be generated by microenvironmental agonists: IL-10, CD40L and, most potently, CpG-oligodeoxynucleotides (CpG-ODN), which is a surrogate for unmethylated DNA and a specific agonist for TLR9 signaling. Incubation with these agonists caused robust activation of NF-κB signaling, especially alternative NF-κB, which led to enhanced expression of the anti-apoptotic proteins Mcl-1, Bcl-xL, and survivin, thus decreasing dependence on Bcl-2. Inhibitors of NF-κB signaling blocked overexpression of these anti-apoptotic proteins and overcame resistance. Inhibitors of Mcl-1, Bcl-xL, or survivin also overcame this resistance, and showed synergistic benefit with the IBR+VEN combination. We conclude that microenvironmental factors, particularly the TLR9 agonist, can generate de novo resistance to the IBR+VEN combination in CLL and MCL cells. This signaling pathway presents targets for overcoming drug resistance induced by extrinsic microenvironmental factors in diverse B-cell malignancies. more...
- Published
- 2017
- Full Text
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22. Antitumor effect of insulin-like growth factor-1 receptor inhibition in head and neck squamous cell carcinoma
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Abel P. David, Stephen S. Schoeff, Mark J. Jameson, Patrick O. McGarey, Lane Donaldson, Ashraf Khalil, Rolando E. Mendez, Henry F. Frierson, Julia Wulfkuhle, Mark J. Axelrod, Christine E. Lehman, Edward B. Stelow, Linnea E. Taniguchi, Matthew A. Hubbard, Stefan Bekiranov, Daniel Gioeli, Emanuel F. Petricoin, and Michael I. Dougherty more...
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0301 basic medicine ,medicine.drug_class ,medicine.medical_treatment ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,Insulin-like growth factor ,0302 clinical medicine ,Tumor Cells, Cultured ,Medicine ,Humans ,Viability assay ,Insulin-Like Growth Factor I ,Clonogenic assay ,Insulin-like growth factor 1 receptor ,Neoplasm Staging ,business.industry ,Squamous Cell Carcinoma of Head and Neck ,Triazines ,Imidazoles ,medicine.disease ,Head and neck squamous-cell carcinoma ,body regions ,stomatognathic diseases ,030104 developmental biology ,Treatment Outcome ,Otorhinolaryngology ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Pyrazines ,Cancer research ,Pyrazoles ,Mouth Neoplasms ,Signal transduction ,business ,Tyrosine kinase - Abstract
Objectives The insulin-like growth factor-1 receptor (IGF1R) has been implicated in therapeutic resistance in head and neck squamous cell carcinoma (HNSCC), and small molecule tyrosine kinase inhibitors (TKIs) of IGF1R activity may have anticancer activity. Therefore, the relationship between survival and IGF1R expression was assessed for oral cavity (OC) cancer, and the antitumor effects of two IGF1R-TKIs, OSI-906 and BMS-754807, were evaluated in HNSCC cell lines in vitro. Methods Clinical outcome data and tissue microarray immunohistochemistry were used to generate IGF1R expression-specific survival curves. Immunoblot, alamarBlue proliferation assay, trypan blue exclusion viability test, clonogenic assay, flow cytometry, and reverse phase protein array (RPPA) were used to evaluate in vitro responses to IGF1R-TKIs. Results For patients with stage III/IV OCSCC, higher IGF1R expression was associated with poorer overall 5-year survival (P = 0.029). Both BMS-754807 and OSI-906 caused dose-dependent inhibition of IGF1R and Akt phosphorylation and inhibited proliferation; BMS-754807 was more potent than OSI-906. Both drugs reduced HNSCC cell viability; only OSI-906 was able to eliminate all viable cells at 10 μM. The two drugs similarly inhibited clonogenic cell survival. At 1 μM, only BMS-754807 caused a fourfold increase in the basal apoptotic rate. RPPA demonstrated broad effects of both drugs on canonical IGF1R signaling pathways and also inhibition of human epidermal growth factor receptor-3 (HER3), Src, paxillin, and ezrin phosphorylation. Conclusion OSI-906 and BMS-754807 inhibit IGF1R activity in HNSCC cell lines with reduction in prosurvival and proliferative signaling and with concomitant antiproliferative and proapoptotic effects. Such antagonists may have utility as adjuvants to existing therapies for HNSCC. Level of evidence NA Laryngoscope, 130:1470-1478, 2020. more...
- Published
- 2019
23. Education in Global Health Radiology
- Author
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Brett R. Murdock, Rose Ndumia, Mai Elezaby, Rebecca Stein-Wexler, David J. Axelrod, Gillian Battino, and Melissa P. Culp
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medicine.medical_specialty ,Multidisciplinary approach ,General partnership ,Political science ,Best practice ,education ,Global health ,medicine ,Context (language use) ,Radiology ,Open communication ,Curriculum ,Social responsibility - Abstract
Radiologists and radiology professionals have noted the gaps in diagnostic and interventional imaging access worldwide as documented by the World Health Organization. Since global health focuses on issues that transcend national boundaries, emphasizes solutions that often require global cooperation, and is multidisciplinary, then the concept of radiology education in global health should consider this broader context of international partnership and collaboration. There are several models in place for education in the global health setting with emphasis on radiology. This chapter discusses faculty exchanges, scholarly collaboration, partnership, formal education, online education as a tool, integration of global health concepts into radiology curricula, and socially responsible collaboration. Regardless of the type of model used, educational goals and objectives should be based on initial assessment data and address the appropriate needs. Curricula should be established in partnership with all stakeholders and with consideration for ethical best practices, continuous evaluation and improvement of the program, and open communication among stakeholders. more...
- Published
- 2019
- Full Text
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24. Laser phase plate for transmission electron microscopy
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Osip, Schwartz, Jeremy J, Axelrod, Sara L, Campbell, Carter, Turnbaugh, Robert M, Glaeser, and Holger, Müller
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Light ,Microscopy, Electron, Transmission ,Lasers ,Static Electricity ,Electrons - Abstract
Transmission electron microscopy (TEM) of rapidly frozen biological specimens, or cryo-EM, would benefit from the development of a phase plate for in-focus phase contrast imaging. Several types of phase plates have been investigated, but rapid electrostatic charging of all such devices has hindered these efforts. Here, we demonstrate electron phase manipulation with a high-intensity continuous-wave laser beam, and use it as a phase plate for TEM. We demonstrate the laser phase plate by imaging an amorphous carbon film. The laser phase plate provides a stable and tunable phase shift without electrostatic charging or unwanted electron scattering. These results suggest the possibility for dose-efficient imaging of unstained biological macromolecules and cells. more...
- Published
- 2018
25. Intraspecific brain size variation between coexisting sunfish ecotypes
- Author
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Beren W. Robinson, Frederic Laberge, and Caleb J. Axelrod
- Subjects
0106 biological sciences ,0301 basic medicine ,Foraging ,Population ,Adaptation, Biological ,Biology ,010603 evolutionary biology ,01 natural sciences ,General Biochemistry, Genetics and Molecular Biology ,Intraspecific competition ,Neuroscience and Cognition ,03 medical and health sciences ,Littoral zone ,Animals ,education ,Ecosystem ,General Environmental Science ,Ecotype ,education.field_of_study ,General Immunology and Microbiology ,Ecology ,Brain ,Pelagic zone ,General Medicine ,Organ Size ,Perciformes ,030104 developmental biology ,Habitat ,Brain size ,General Agricultural and Biological Sciences - Abstract
Variation in spatial complexity and foraging requirements between habitats can impose different cognitive demands on animals that may influence brain size. However, the relationship between ecologically related cognitive performance and brain size is not well established. We test whether variation in relative brain size and brain region size is associated with habitat use within a population of pumpkinseed sunfish composed of different ecotypes that inhabit either the structurally complex shoreline littoral habitat or simpler open-water pelagic habitat. Sunfish using the littoral habitat have on average 8.3% larger brains than those using the pelagic habitat. We found little difference in the proportional sizes of five brain regions between ecotypes. The results suggest that cognitive demands on sunfish may be reduced in the pelagic habitat given no habitat-specific differences in body condition. They also suggest that either a short divergence time or physiological processes may constrain changes to concerted, global modifications of brain size between sunfish ecotypes. more...
- Published
- 2018
26. A Chemical Strategy for Protease Substrate Profiling
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Daniel A. Bachovchin, Abram J. Axelrod, Ronald C. Hendrickson, Paolo Cifani, Matthew M. Miele, Sahana D. Rao, Andrew R. Griswold, and Alex Kentsis
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Dipeptidases ,Inflammasomes ,Pyridines ,medicine.medical_treatment ,Clinical Biochemistry ,Biotin ,NLR Proteins ,Biology ,01 natural sciences ,Biochemistry ,Article ,Substrate Specificity ,Cleave ,Drug Discovery ,medicine ,Humans ,Proline ,Dipeptidyl-Peptidases and Tripeptidyl-Peptidases ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Pharmacology ,Gel electrophoresis ,chemistry.chemical_classification ,Protease ,Mass spectrometry based proteomics ,Molecular Structure ,010405 organic chemistry ,Inflammasome ,0104 chemical sciences ,Enzyme ,chemistry ,Protease substrate ,Molecular Medicine ,Apoptosis Regulatory Proteins ,medicine.drug ,Peptide Hydrolases - Abstract
The dipeptidyl peptidases (DPPs) regulate hormones, cytokines, and neuropeptides by cleaving dipeptides after proline from their amino termini. Due to technical challenges, many DPP substrates remain unknown. Here, we introduce a simple method, termed CHOPS (chemical enrichment of protease substrates), for the discovery of protease substrates. CHOPS exploits a 2-pyridinecarboxaldehyde (2PCA)-biotin probe, which selectively biotinylates protein N-termini except those with proline in the second position. CHOPS can, in theory, discover substrates for any protease, but is particularly well suited to discover canonical DPP substrates, as cleaved but not intact DPP substrates can be identified by gel electrophoresis or mass spectrometry. Using CHOPS, we show that DPP8 and DPP9, enzymes that control the Nlrp1 inflammasome through an unknown mechanism, do not directly cleave Nlrp1. We further show that DPP9 robustly cleaves short peptides but not full-length proteins. More generally, this work delineates a practical technology for identifying protease substrates, which we anticipate will complement available "N-terminomic" approaches. more...
- Published
- 2018
27. A laser-based phase plate for phase contrast transmission electron microscopy
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Osip Schwartz, S.L. Campbell, H. Muller, Carter Turnbaugh, Robert M. Glaeser, and Jeremy J. Axelrod
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0301 basic medicine ,Materials science ,Physics::Instrumentation and Detectors ,business.industry ,Phase (waves) ,Physics::Optics ,Ponderomotive force ,Laser ,law.invention ,Intensity (physics) ,03 medical and health sciences ,Phase plate ,030104 developmental biology ,Optics ,law ,Transmission electron microscopy ,Cathode ray ,Spatial frequency ,business - Abstract
In the first demonstration of a laser-based phase plate for transmission electron microscopy, a continuous-wave laser in a resonant cavity reaches a record 60 GW/cm2 average intensity and phase shifts the electron beam via the ponderomotive force. more...
- Published
- 2018
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28. Small Volumes in Biology
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Ronald W. Holz, Daniel Axelrod, Nancy L. Thompson, and Jeremy J. Axelrod
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Computational biology ,Biology ,Instrumentation - Published
- 2019
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29. Synergistic apoptosis in head and neck squamous cell carcinoma cells by co-inhibition of insulin-like growth factor-1 receptor signaling and compensatory signaling pathways
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Mark R. Conaway, Stephanie Leimgruber, Elizabeth R. Sharlow, Mark J. Jameson, Ashraf Khalil, Rolando E. Mendez, Michael J. Weber, Brian J. Capaldo, Mark J. Axelrod, and Daniel Gioeli
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medicine.medical_specialty ,business.industry ,Kinase ,medicine.medical_treatment ,medicine.disease ,Head and neck squamous-cell carcinoma ,Dasatinib ,chemistry.chemical_compound ,Insulin-like growth factor ,Endocrinology ,Otorhinolaryngology ,chemistry ,Apoptosis ,Internal medicine ,Cancer research ,Medicine ,Signal transduction ,Growth inhibition ,business ,Protein kinase B ,medicine.drug - Abstract
Background. In head and neck squamous cell carcinoma (HNSCC), resistance to single-agent targeted therapy may be overcome by co-targeting of compensatory signaling pathways. Methods. A targeted drug screen with 120 combinations was used on 9 HNSCC cell lines. Results. Multiple novel drug combinations demonstrated synergistic growth inhibition. Combining the insulin-like growth factor-1 receptor (IGF-1R) inhibitor, BMS754807, with either the human epidermal growth factor receptor (HER)-family inhibitor, BMS599626, or the Src-family kinase inhibitor, dasatinib, resulted in substantial synergy and growth inhibition. Depending on the cell line, these combinations induced syner- gistic or additive apoptosis; when synergistic apoptosis was observed, AKT phosphorylation was inhibited to a greater extent than either drug alone. Conversely, when additive apoptosis occurred, AKT phosphoryla- tion was not reduced by the drug combination. Conclusion. Combined IGF-1R/HER family and IGF-1R/Src family inhibi- tion may have therapeutic potential in HNSCC. AKT may be a node of convergence between IGF-1R signaling and pathways that compensate for IGF-1R inhibition. V C 2014 Wiley Periodicals, Inc. Head Neck 00: 000- 000, 2014 more...
- Published
- 2015
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30. A Close Look at a Ketosynthase from a Trans-Acyltransferase Modular Polyketide Synthase
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Darren C. Gay, Glen Gay, Abram J. Axelrod, Matthew Jenner, Christoph Kohlhaas, Annette Kampa, Neil J. Oldham, Jörn Piel, and Adrian T. Keatinge-Clay
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Models, Molecular ,Protein Conformation ,Stereochemistry ,Molecular Sequence Data ,Mutant ,Crystallography, X-Ray ,Mass Spectrometry ,Article ,Substrate Specificity ,Polyketide ,Protein structure ,Structural Biology ,Catalytic Domain ,Polyketide synthase ,Serine ,Transferase ,Amino Acid Sequence ,Cysteine ,Molecular Biology ,Peptide sequence ,biology ,Amino Acid Substitution ,Biochemistry ,Acyltransferase ,Mutation ,biology.protein ,Polyketide Synthases ,Linker - Abstract
SummaryThe recently discovered trans-acyltransferase modular polyketide synthases catalyze the biosynthesis of a wide range of bioactive natural products in bacteria. Here we report the structure of the second ketosynthase from the bacillaene trans-acyltransferase polyketide synthase. This 1.95 Å resolution structure provides the highest resolution view available of a modular polyketide synthase ketosynthase and reveals a flanking subdomain that is homologous to an ordered linker in cis-acyltransferase modular polyketide synthases. The structure of the cysteine-to-serine mutant of the ketosynthase acylated by its natural substrate provides high-resolution details of how a native polyketide intermediate is bound and helps explain the basis of ketosynthase substrate specificity. The substrate range of the ketosynthase was further investigated by mass spectrometry. more...
- Published
- 2014
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31. Combinatorial drug screening identifies synergistic co-targeting of Bruton’s tyrosine kinase and the proteasome in mantle cell lymphoma
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Elyse Lopez, M L Wang, Richard J. Ford, Archito T. Tamayo, Mark J. Axelrod, Michael J. Weber, Laura Kyle Brett, Liang Zhang, Vicki L. Gordon, Michael E. Williams, Zhishuo Ou, and L V Pham
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Drug ,Proteasome Endopeptidase Complex ,Cancer Research ,media_common.quotation_subject ,Lymphoma, Mantle-Cell ,Drug synergism ,Cell Line, Tumor ,hemic and lymphatic diseases ,Protein-Tyrosine Kinases ,Agammaglobulinaemia Tyrosine Kinase ,medicine ,Humans ,Bruton's tyrosine kinase ,Proteasome endopeptidase complex ,Protein Kinase Inhibitors ,Letter to the Editor ,media_common ,biology ,Drug Synergism ,Hematology ,medicine.disease ,3. Good health ,Oncology ,Proteasome ,Cancer research ,biology.protein ,Mantle cell lymphoma ,Drug Screening Assays, Antitumor ,Proteasome Inhibitors ,Tyrosine kinase - Abstract
Combinatorial drug screening identifies synergistic co-targeting of Bruton’s tyrosine kinase and the proteasome in mantle cell lymphoma
- Published
- 2013
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32. Combinatorial drug screening identifies compensatory pathway interactions and adaptive resistance mechanisms
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Daniel J. Neitzke, Daniel Gioeli, Adel Tarcsafalvi, Mark J. Axelrod, Michael J. Weber, Vicki L. Gordon, and Mark R. Conaway
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Drug ,Cell signaling ,medicine.medical_treatment ,media_common.quotation_subject ,Feedback inhibition ,Blotting, Western ,Antineoplastic Agents ,Apoptosis ,Pharmacology ,Biology ,Lapatinib ,Drug Substitution ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Targeted therapies ,Cell Line, Tumor ,Neoplasms ,medicine ,Humans ,Immunoprecipitation ,Receptor ,Crosstalk ,030304 developmental biology ,media_common ,0303 health sciences ,Drug Synergism ,Flow Cytometry ,3. Good health ,High-Throughput Screening Assays ,Compensatory signaling ,Pathway interactions ,Crosstalk (biology) ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Signal transduction ,Drug Screening Assays, Antitumor ,medicine.drug ,Research Paper ,Signal Transduction - Abstract
// Mark Axelrod 1 , Vicki L. Gordon 1 , Mark Conaway 2 , Adel Tarcsafalvi 1,3 , Daniel J. Neitzke 1,4 , Daniel Gioeli 1 , and Michael J. Weber 1 1 Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, USA 2 Department of Public Health Sciences, University of Virginia, Charlottesville, USA 3 Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, USA 4 Medical Scientist Training Program, Medical University of South Carolina, Charleston, USA Correspondence: Michael J. Weber, email: // Keywords : Targeted therapies, Compensatory signaling, Pathway interactions, Crosstalk, Feedback inhibition Received : March 15, 2013 Accepted : April 9, 2013 Published : April 10, 2013 Abstract Constitutively activated signaling molecules are often the primary drivers of malignancy, and are favored targets for therapeutic intervention. However, the effectiveness of targeted inhibition of cell signaling can be blunted by compensatory signaling which generates adaptive resistance mechanisms and reduces therapeutic responses. Therefore, it is important to identify and target these compensatory pathways with combinations of targeted agents to achieve durable clinical benefit. In this report, we demonstrate the use of high-throughput combinatorial drug screening as a discovery tool to identify compensatory pathways that generate resistance to the cytotoxic effects of targeted therapy. We screened 420 drug combinations in 14 different cell lines representing three cancer lineages, and assessed the ability of each combination to cause synergistic cytotoxicity. Drug substitution studies were used to validate the functionally important drug targets. Of the 84 combinations that caused robust synergy in multiple cell lines, none were synergistic in more than half of the lines tested, and we observed no pattern of lineage specificity in the observed synergies. This reflects the plasticity of cell signaling networks, even among cell lines of the same tissue of origin. Mechanistic analysis of one novel synergistic combination identified in the screen, the multi-kinase inhibitor Ro31-8220 and lapatinib, demonstrated compensatory crosstalk between the p70S6 kinase and EGF receptor pathways. In addition, we identified BAD as a node of convergence between these two pathways that may be playing a role in the enhanced apoptosis observed upon combination treatment. more...
- Published
- 2013
33. Synthetic Lethal Screening with Small-Molecule Inhibitors Provides a Pathway to Rational Combination Therapies for Melanoma
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Michael J. Weber, Brian J. Capaldo, Mark J. Axelrod, Karin Jensen, Aaron J. Mackey, Devin G. Roller, and Daniel Gioeli
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Niacinamide ,Sorafenib ,MAPK/ERK pathway ,Cancer Research ,Diclofenac ,Skin Neoplasms ,Cell ,Phospholipases A2, Cytosolic ,Antineoplastic Agents ,Pharmacology ,Biology ,Article ,Small Molecule Libraries ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Extracellular Signal-Regulated MAP Kinases ,Melanoma ,Cell Death ,Genome, Human ,Phenylurea Compounds ,MEK inhibitor ,Drug Synergism ,Small molecule ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Oncology ,biology.protein ,Cyclooxygenase ,Signal transduction ,Signal Transduction ,Genetic screen ,medicine.drug - Abstract
Recent data show that extracellular signals are transmitted through a network of proteins rather than hierarchical signaling pathways, suggesting that the inhibition of a single component of a canonical pathway is insufficient for the treatment of cancer. The biologic outcome of signaling through a network is inherently more robust and resistant to inhibition of a single network component. In this study, we conducted a functional chemical genetic screen to identify novel interactions between signaling inhibitors that would not be predicted on the basis of our current understanding of signaling networks. We screened over 300 drug combinations in nine melanoma cell lines and have identified pairs of compounds that show synergistic cytotoxicity. The synergistic cytotoxicities identified did not correlate with the known RAS and BRAF mutational status of the melanoma cell lines. Among the most robust results was synergy between sorafenib, a multikinase inhibitor with activity against RAF, and diclofenac, a nonsteroidal anti-inflammatory drug (NSAID). Drug substitution experiments using the NSAIDs celecoxib and ibuprofen or the MAP–ERK kinase inhibitor PD325901 and the RAF inhibitor RAF265 suggest that inhibition of COX and mitogen-activated protein kinase signaling are targets for the synergistic cytotoxicity of sorafenib and diclofenac. Cotreatment with sorafenib and diclofenac interrupts a positive feedback signaling loop involving extracellular signal–regulated kinase, cellular phospholipase A2, and COX. Genome-wide expression profiling shows synergy-specific downregulation of survival-related genes. This study has uncovered novel functional drug combinations and suggests that the underlying signaling networks that control responses to targeted agents can vary substantially, depending on unexplored components of the cell genotype. Mol Cancer Ther; 11(11); 2505–15. ©2012 AACR. more...
- Published
- 2012
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34. Abstract 2381: Loss of S6K2 perturbs redox balance and fatty acid metabolism, leading to oxidative cell death
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Mark J. Axelrod, Patricia Reyes-Uribe, Andrew V. Kossenkov, Michael J. Weber, Gordon B. Mills, Minu Samanta, Hsin-Yi Chen, Qin Liu, Yiling Lu, Xiangfan Yin, and Jessie Villanueva
- Subjects
Lipid peroxidation ,MAPK/ERK pathway ,Cancer Research ,chemistry.chemical_compound ,Programmed cell death ,Oncology ,chemistry ,Apoptosis ,Cancer research ,Lipid metabolism ,P70-S6 Kinase 1 ,mTORC1 ,PI3K/AKT/mTOR pathway - Abstract
Oncogenes often upregulate nutrient sensing and utilizing pathways, leading to altered metabolism in tumor cells. RAS-driven tumors typify cancers undergoing marked metabolic reprogramming. In melanoma, RAS signaling is often deregulated; while activating mutations in NRAS are present in >25% of tumors, RAS-driven tumors account for almost 50% of cases. However, there are no effective therapies for this type of tumors. Although oncogenic NRAS activates the MAPK pathway, inhibition of this pathway alone has limited antitumor efficacy and most NRAS-mutant tumors are resistant to MAPK inhibitor (MAPKi) monotherapy. We discovered that NRAS-mutant melanomas resistant to MAPKi are highly dependent on the ribosomal protein S6 kinase 2 (S6K2). We demonstrate that loss of S6K2, a signaling effector of the mTORC1 nutrient-sensing pathway, triggers cell death selectively in NRAS-mutant melanoma resistant to MAPKi. Acute depletion of S6K2 enhanced ROS production, lipid synthesis and accumulation of intracellular unsaturated fatty acids. ROS susceptible (poly)-unsaturated fatty acids sensitized cells to ROS, resulting in lipid peroxidation and oxidative cell death. We further determined that S6K2 depletion was coupled to increased expression of markers of apoptosis and ferroptosis, suggesting that S6K2 blockade could trigger multiple forms of cell death, including apoptotic and a ferroptotic-like cell death. Notably, co-inhibition of S6K1 (a S6K isoform that is co-regulated by mTORC1) together with S6K2 diminished the effects of S6K2 blockade, suggesting that selective inhibition of S6K2 is required to induce cell death. Indeed, while silencing of S6K2 triggered lipid peroxidation and oxidative cell death and S6K1 silencing had negligible effects, concomitant depletion of S6K1 and S6K2 attenuated lipid peroxidation and cell death. Mimicking the effects of S6K2 loss by combining an ROS-inducing agent with unsaturated fatty acids or treating tumor cells with lipid peroxidation inducers restrained NRAS-mutant melanoma growth in vitro and in vivo. Taken together, our studies have identified a critical vulnerability of NRAS-mutant melanoma by uncoupling S6K1 and S6K2 to trigger metabolic dysfunction and tumor cell death. This strategy is remarkably distinct from using PI3K/mTOR inhibitors, which concurrently suppress S6K1 and S6K2 and are often cytostatic. We propose that this paradigm could be exploited to develop therapeutic approaches targeting NRAS-mutant tumors and overcome resistance to MAPKi in the context of oncogenic NRAS. Citation Format: Hsin-Yi Chen, Minu Samanta, Patricia Reyes-Uribe, Andrew V. Kossenkov, Xiangfan Yin, Yiling Lu, Mark Axelrod, Michael J. Weber, Qin Liu, Gordon B. Mills, Jessie Villanueva. Loss of S6K2 perturbs redox balance and fatty acid metabolism, leading to oxidative cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2381. more...
- Published
- 2018
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35. SP-0677: Radiation, Senescence and salivary glands
- Author
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J. Axelrod
- Subjects
Senescence ,Oncology ,Radiology, Nuclear Medicine and imaging ,Hematology ,Biology ,Cell biology - Published
- 2018
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36. Laser-Based Zernike Plate for Phase Contrast Transmission Electron Microscopy
- Author
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Osip Schwartz, Jeremy J. Axelrod, Robert M. Glaeser, and Holger Müller
- Subjects
0301 basic medicine ,Materials science ,business.industry ,Zernike polynomials ,Phase contrast microscopy ,Biophysics ,Laser ,law.invention ,03 medical and health sciences ,symbols.namesake ,030104 developmental biology ,Optics ,law ,Transmission electron microscopy ,symbols ,business - Published
- 2018
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37. Treatment of Posttraumatic Aortic Pseudoaneurysms Using Detachable Hydrogel-Coated Coils
- Author
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Craig R. Greben, Avi Setton, Hearns W. Charles, David J. Axelrod, Eric J. Gandras, and Matthew Bank
- Subjects
Adult ,Male ,medicine.medical_specialty ,business.industry ,Wounds, Penetrating ,Abdominal Injuries ,Critical Care and Intensive Care Medicine ,Embolization, Therapeutic ,Surgery ,Humans ,Medicine ,Radiology ,business ,Aortic Aneurysm, Abdominal - Published
- 2009
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38. Bronchobiliary Fistula Successfully Treated with n-Butyl Cyanoacrylate via a Bronchial Approach
- Author
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Matthew J. McKinley, Avi Setton, David J. Axelrod, Craig R. Greben, Hearns W. Charles, Eric J. Gandras, and S. Yedida Goldman
- Subjects
medicine.medical_specialty ,Biliary Fistula ,Conservative management ,medicine.medical_treatment ,Percutaneous transhepatic cholangiography ,Fatal Outcome ,medicine ,Humans ,Bronchobiliary fistula ,Radiology, Nuclear Medicine and imaging ,Cyanoacrylates ,Cholangiopancreatography, Endoscopic Retrograde ,Endoscopic retrograde cholangiopancreatography ,medicine.diagnostic_test ,business.industry ,N-butyl-cyanoacrylate ,Liver Neoplasms ,Enbucrilate ,Middle Aged ,Embolization, Therapeutic ,Surgery ,Sputum ,Female ,Bronchial Fistula ,Radiology ,medicine.symptom ,Colorectal Neoplasms ,Cardiology and Cardiovascular Medicine ,business ,Airway - Abstract
A bronchobiliary fistula is an abnormal communication between the biliary tree and the airway that can result in debilitating amounts of bilioptysis, or bile-stained sputum. The authors present an approach for the conservative management of a bronchobiliary fistula in a patient who failed traditional conservative therapy and refused surgical intervention. more...
- Published
- 2007
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39. Hematologic Disorders*
- Author
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Madeleine Becker, David J. Axelrod, Keira Chism, Tal E. Weinberger, Dimitri Markov, Lex Denysenko, Christine Marchionni, Olu Oyesanmi, Howard Field, and Elisabeth J. Shakin Kunkel
- Published
- 2015
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40. Investigating hospital administrators' experience of workplace mistreatment
- Author
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Lawrence J. Axelrod and Karen Harlos
- Subjects
Psychology ,Humanities ,General Psychology - Abstract
La presente etude porte sur la nature et les repercussions des mauvais traitements dans les milieux de travail, a l'exception du harcelement sexuel et des contacts physiques, que subissent les administrateurs d'hopitaux. L'analyse factorielle montre que les comportements qui caracterisent les mauvais traitements comprennent trois dimensions: la violence verbale, l'obstruction au travail et la negligence psychologique. La violence verbale est consideree comme une forme de mauvais traitement interpersonnel tandis que l'obstruction et la negligence sont considerees comme des formes de mauvais traitement organisationnel. Les administrateurs ont rapporte subir des mauvais traitements de nature organisationnelle plus frequemment que des mauvais traitements interpersonnels. Nous avons ensuite examine les liens entre les mauvais traitements, le soutien offert dans le milieu, le bien-etre psychologique des employes, le degre d'identification envers l'organisation, la satisfaction au travail et l'intention de quitter son emploi. Comme nous l'avions predit, les milieux de travail positifs agissent sur les mauvais traitements dans les milieux de travail, le degre d'identification et la satisfaction au travail mais, curieusement, ils n'interviennent pas dans l'intention de quitter l'organisation. Nous discutons de l'impact d'un milieu de travail sain et productif sur les administrateurs d'hopitaux. more...
- Published
- 2005
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41. Hemoglobin conformation couples erythrocyte S -nitrosothiol content to O 2 gradients
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Anne Eischeid, Benjamin Gaston, Joseph Doherty, Mark J. Axelrod, Allan Doctor, Ruth Platt, Thomas S. Maxey, Jaclyn Kline, Andrew J. Gow, Matthew J. Gurka, Mary Lynn Sheram, and Timothy J. McMahon
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Erythrocytes ,Protein Conformation ,Allosteric regulation ,Nitric oxide ,Hemoglobins ,Mice ,chemistry.chemical_compound ,Sepsis ,Animals ,Humans ,Lung ,Deoxygenation ,Fluorescent Dyes ,S-Nitrosothiols ,chemistry.chemical_classification ,Carbon Monoxide ,Respiratory Distress Syndrome ,Multidisciplinary ,Reproducibility of Results ,Biological Sciences ,Systemic Inflammatory Response Syndrome ,Oxygen ,chemistry ,Biochemistry ,Luminescent Measurements ,Thiol ,Biophysics ,Room air distribution ,Biological Assay ,Hemoglobin ,Copper ,Carbon monoxide - Abstract
It is proposed that the bond between nitric oxide (NO) and the Hb thiol Cys-β 93 (SNOHb) is favored when hemoglobin (Hb) is in the relaxed (R, oxygenated) conformation, and that deoxygenation to tense (T) state destabilizes the SNOHb bond, allowing transfer of NO from Hb to form other (vasoactive) S -nitrosothiols (SNOs). However, it has not previously been possible to measure SNOHb without extensive Hb preparation, altering its allostery and SNO distribution. Here, we have validated an assay for SNOHb that uses carbon monoxide (CO) and cuprous chloride (CuCl)-saturated Cys. This assay is specific for SNOs and sensitive to 2–5 pmol. Uniquely, it measures the total SNO content of unmodified erythrocytes (RBCs) (SNO RBC ), preserving Hb allostery. In room air, the ratio of SNO RBC to Hb in intact RBCs is stable over time, but there is a logarithmic loss of SNO RBC with oxyHb desaturation (slope, 0.043). This decay is accelerated by extraerythrocytic thiol (slope, 0.089; P < 0.001). SNO RBC stability is uncoupled from O 2 tension when Hb is locked in the R state by CO pretreatment. Also, SNO RBC is increased ≈20-fold in human septic shock ( P = 0.002) and the O 2 -dependent vasoactivity of RBCs is affected profoundly by SNO content in a murine lung bioassay. These data demonstrate that SNO content and O 2 saturation are tightly coupled in intact RBCs and that this coupling is likely to be of pathophysiological significance. more...
- Published
- 2005
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42. The Pineal Gland and Its Endocrine Role
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J. Axelrod and J. Axelrod
- Subjects
- Pineal gland--Congresses, Melatonin--Physiological effect--Congresses, Pineal body--Congresses, Melatonin--Congresses
- Abstract
The pineal gland has been a subject of interest and speculation for more than 2000 years. Greek anatomists were impressed by the ob servation that the pineal gland is an unpaired structure and they believed that it regulated the flow of thoughts. The philosopher Descartes proposed an important role for this organ in brain function. At the beginning of the 20th century experiments by several investi gators indicated that the pineal influenced sexual function and skin pigmentation and was also responsive to light signals. With the iso lation of melatonin from bovine pineal glands by Lerner and cowork ers in 1958 the modern era of pineal research was initiated. Within a few years the pathway for the biosynthesis of melatonin in the pineal was elucidated. Soon thereafter it was shown that the formation of melatonin was influenced by environmental lighting. Ana tomists found that the pineal was innervated by sympathetic nerves and that the gland had photoreceptor elements. It was also shown that the gonads were influenced by light via the pineal gland. Research on the pineal gland became of increasing interest to anatomists, bioche mists, pharmacologists and endocrinologists. With the expanding know ledge concerning the function of the pineal gland contributed by the wide variety of disciplines, it was thought that a study workshop would be timely. more...
- Published
- 2013
43. Abstract 5587: Novel monoclonal antibodies block N-glycosylation Sites of the MUC16 ectodomain in ovarian carcinoma
- Author
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Samuel J. Danishefsky, Amy Wang, Dharmarao Thapi, Nestor Rosales, David Spriggs, Marina Stasenko, Alberto Fernández-Tejada, Xiujun Yan, Abraham J. Axelrod, and Sahityasri Thapi
- Subjects
Cancer Research ,Cell signaling ,animal structures ,Glycosylation ,medicine.drug_class ,Chemistry ,Monoclonal antibody ,Cell biology ,chemistry.chemical_compound ,Oncology ,N-linked glycosylation ,Growth factor receptor ,Ectodomain ,Cell surface receptor ,Ca125 antigen ,medicine - Abstract
The MUC16 gene encodes the CA125 antigen that imparts a negative survival impact on patients with high-grade serous ovarian cancer. Short elements from the C-terminal region of MUC16 transform 3T3 cells. Introduction of the 114 amino acid C-terminal portion of MUC16 promotes invasive growth in xenograft models. This effect is dependent on N-glycosylation sites of MUC16 and interactions present on the cell surface. Mechanisms by which the ectodomain promotes MUC16 oncogenic behaviors, the function of N-glycosylation and the implicated cell surface receptors are not fully delineated. To unravel the complex MUC16 cancer biology, in this study we investigated the glycosylation-based mechanisms and potential partners involved in MUC16 oncogenic effects, and show that site-specific glycosylation of MUC16 plays a key role in mucin-related transformation by mediating complex cell surface interactions. These effects are mediated through MGAT5-dependent N-glycosylation of two proximal N- glycosylation sites within the 58 amino acid retained MUC16 ectodomain acting in combination with Galectin-3 and growth factor receptors. Neither N- nor O-glycosylation sites in the more distally located MUC16 regions can functionally substitute for those two sites. The tumor-enhancing properties of MUC16 depend on co-localization of MUC16, Galectin-3, and growth factors receptors on lipid rafts. Loss of either Galectin-3 expression or the glycosylation enzyme MGAT5 completely abrogates MUC16 tumor promotion. Using synthetic glycopeptides, we have developed novel monoclonal antibodies (mAbs) directed at the crucial ectodomain N-glycosylation sites to inhibit the glycosylation- dependent effects of MUC16 on metastasis and invasion. These novel antibodies were characterized in vitro and in vivo studies using various ovarian cancer cell lines. All of the antibodies against the N- glycosylation sites closest to the cell membrane of MUC16 block Galectin-3-mediated polymerization to cell surface signaling molecules and inhibit the tumor-promoting effects of MUC16. The implications are broad: both for the biological understanding of cancer mucin biology and for potential therapeutic strategies. Citation Format: Dharmarao Thapi, Alberto Fernandez-Tejada, Abraham J. Axelrod, Nestor Rosales, Xiujun Yan, Marina Stasenko, Sahityasri Thapi, Amy Wang, Samuel J. Danishefsky, David R. Spriggs. Novel monoclonal antibodies block N-glycosylation Sites of the MUC16 ectodomain in ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5587. doi:10.1158/1538-7445.AM2017-5587 more...
- Published
- 2017
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44. Near-concentric Fabry-Pérot cavity for continuous-wave laser control of electron waves
- Author
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Osip Schwartz, Holger Müller, Philipp Haslinger, D. R. Tuthill, Colin Ophus, Jeremy J. Axelrod, and Robert M. Glaeser
- Subjects
0301 basic medicine ,Communications Technologies ,Materials science ,Zernike polynomials ,business.industry ,Phase (waves) ,Physics::Optics ,Optics ,Optical Physics ,Electron ,Laser ,Atomic and Molecular Physics, and Optics ,law.invention ,03 medical and health sciences ,symbols.namesake ,030104 developmental biology ,law ,symbols ,Continuous wave ,High harmonic generation ,Laser power scaling ,Electrical and Electronic Engineering ,business ,Beam (structure) - Abstract
Manipulating free-space electron wave functions with laser fields can bring about new electron-optical elements for transmission electron microscopy (TEM). In particular, a Zernike phase plate would enable high-contrast TEM imaging of soft matter, leading to new opportunities in structural biology and materials science. A Zernike phase plate can be implemented using a tight, intense continuous laser focus that shifts the phase of the electron wave by the ponderomotive potential. Here, we use a near-concentric cavity to focus 7.5 kW of continuous-wave circulating laser power at 1064 nm into a 7 µm mode waist, achieving a record continuous laser intensity of 40 GW/cm2. Such parameters are sufficient to impart a phase shift of 1 rad to a 10 keV electron beam, or 0.16 rad to a 300 keV beam. Our numerical simulations confirm that the standing-wave phase shift profile imprinted on the electron wave by the intra-cavity field can serve as a nearly ideal Zernike phase plate. more...
- Published
- 2017
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45. p70S6 kinase is a critical node that integrates HER-family and PI3 kinase signaling networks
- Author
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Rolando E. Mendez, Stephanie Leimgruber, Mark R. Conaway, Vicki L. Gordon, Mark J. Axelrod, Daniel Gioeli, Mark J. Jameson, Elizabeth R. Sharlow, and Michael J. Weber
- Subjects
MAPK/ERK pathway ,Cell signaling ,HER-family ,Apoptosis ,Article ,03 medical and health sciences ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Signaling networks ,PI3 kinase ,Cell Line, Tumor ,Humans ,Phosphorylation ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,0303 health sciences ,biology ,TOR Serine-Threonine Kinases ,Imidazoles ,Ribosomal Protein S6 Kinases, 70-kDa ,Lapatinib ,Cell Biology ,ErbB Receptors ,030220 oncology & carcinogenesis ,Ribosomal protein s6 ,Mitogen-activated protein kinase ,biology.protein ,Cancer research ,Quinazolines ,Quinolines ,MAP kinase ,Adaptive response ,Signal transduction ,p70S6 kinase ,Fragile node ,Signal Transduction - Abstract
Therapies targeting oncogenic drivers rapidly induce compensatory adaptive responses that blunt drug effectiveness, contributing to therapeutic resistance. Adaptive responses are characteristic of robust cell signaling networks, and thus there is increasing interest in drug combinations that co-target the driver and the adaptive response. An alternative approach to co-inhibiting oncogenic and adaptive targets is to identify a critical node where the activities of these targets converge. Nodes of convergence between signaling modules represent potential therapeutic vulnerabilities because their inhibition could result in the collapse of the network, leading to enhanced cytotoxicity. In this report we demonstrate that p70S6 kinase (p70S6K) can function as a critical node linking HER-family and phosphoinositide-3-kinase (PI3K) pathway signaling. We used high-throughput combinatorial drug screening to identify adaptive survival responses to targeted therapies, and found that HER-family and PI3K represented compensatory signaling pathways. Co-targeting these pathways with drug combinations caused synergistic cytotoxicity in cases where inhibition of neither target was effective as a monotherapy. We utilized Reverse Phase Protein Arrays and determined that phosphorylation of ribosomal protein S6 was synergistically down-regulated upon HER-family and PI3K/mammalian target of rapamycin (mTOR) co-inhibition. Expression of constitutively active p70S6K protected against apoptosis induced by combined HER-family and PI3K/mTOR inhibition. Direct inhibition of p70S6K with small molecule inhibitors phenocopied HER-family and PI3K/mTOR co-inhibition. These data implicate p70S6K as a critical node in the HER-family/PI3K signaling network. The ability of direct inhibitors of p70S6K to phenocopy co-inhibition of two upstream signaling targets indicates that identification and targeting of critical nodes can overcome adaptive resistance to targeted therapies. more...
- Published
- 2014
46. CHRONIC CARE--COMMUNITY SERVICES
- Author
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M, CHERKASKY, L, BRESLOW, S J, AXELROD, and H, LUKASHOK
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Cardiovascular Diseases ,Chronic Disease ,Humans ,Home Care Services ,Long-Term Care ,Hospitals ,Social Welfare - Published
- 2014
47. Structural and functional studies of a trans-acyltransferase polyketide assembly line enzyme that catalyzes stereoselective α- and β-ketoreduction
- Author
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Shawn K, Piasecki, Jianting, Zheng, Abram J, Axelrod, Madeline E, Detelich, and Adrian T, Keatinge-Clay
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Models, Molecular ,Molecular Sequence Data ,Polyenes ,Crystallography, X-Ray ,Article ,Alcohol Oxidoreductases ,Bacterial Proteins ,Polyketides ,Pantetheine ,Amino Acid Sequence ,Peptide Synthases ,Polyketide Synthases ,Acyltransferases ,Bacillus subtilis - Abstract
While the cis-acyltransferase modular polyketide synthase assembly lines have largely been structurally dissected, enzymes from within the recently discovered trans-acyltransferase polyketide synthase assembly lines are just starting to be observed crystallographically. Here we examine the ketoreductase from the first polyketide synthase module of the bacillaene nonribosomal peptide synthetase/polyketide synthase at 2.35-Å resolution. This ketoreductase naturally reduces both α- and β-keto groups and is the only ketoreductase known to do so during the biosynthesis of a polyketide. The isolated ketoreductase not only reduced an N-acetylcysteamine-bound β-keto substrate to a D-β-hydroxy product, but also an N-acetylcysteamine- bound α-keto substrate to an L-α-hydroxy product. That the substrates must enter the active site from opposite directions to generate these stereochemistries suggests that the acyl-phosphopantetheine moiety is capable of accessing very different conformations despite being anchored to a serine residue of a docked acyl carrier protein. The features enabling stereocontrolled α-ketoreduction may not be extensive since a β-ketoreductase from a cis-acyltransferase polyketide synthase was identified that performs a completely stereoselective reduction of the same α-keto substrate to generate the D-α-hydroxy product. A sequence analysis of trans-acyltransferase ketoreductases reveals that a single residue, rather than a three-residue motif found in cis-acyltransferase ketoreductases, is predictive of the orientation of the resulting β-hydroxyl group. more...
- Published
- 2014
48. Perceptions of ecological risk from natural hazards
- Author
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Timothy L. McDaniels, Paul Slovic, and Lawrence J. Axelrod
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business.industry ,Strategy and Management ,media_common.quotation_subject ,Ecology (disciplines) ,Environmental resource management ,General Engineering ,General Social Sciences ,Natural (archaeology) ,Geography ,Natural hazard ,Perception ,Ecological risk ,Lay perceptions ,Safety, Risk, Reliability and Quality ,business ,Risk assessment ,Productivity ,media_common - Abstract
This study examines lay perceptions of ecological risk (risk to the health and productivity of natural environments) associated with natural hazards. Ratings of 30 specific characteristics influenc... more...
- Published
- 1999
- Full Text
- View/download PDF
49. Public perceptions regarding water quality and attitudes toward water conservation in the lower Fraser Basin
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Lawrence J. Axelrod, Nigel Cavanagh, and Timothy L. McDaniels
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Water conservation ,Geography ,Environmental protection ,Perception ,media_common.quotation_subject ,Water quality ,Structural basin ,Socioeconomics ,Water Science and Technology ,media_common - Abstract
This paper concerns public judgments regarding water quality, public attitudes about water conservation, and related issues in the Lower Fraser Basin of southwest British Columbia, Canada. A written survey was administered to 183 lay subjects in four communities within the Lower Fraser Basin. The results show that subjects generally perceive water quality in specific water bodies as worse than indicated in technical studies of those water bodies. Respondents also indicated a high willingness to engage in water conservation activities. Discussion and conclusions complete the paper. more...
- Published
- 1998
- Full Text
- View/download PDF
50. Initial Multicenter Experience With Double Nucleoside Therapy for Human Immunodeficiency Virus Infection During Pregnancy
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Neil S. Silverman, Elizabeth Livingston, Deborah Money, J.M. Ernest, M. M. DiVito, D. H. Watts, J. Axelrod, D. Robbins, and J. Hitti
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Pediatrics ,Human immunodeficiency virus (HIV) ,HIV Infections ,medicine.disease_cause ,Pregnancy ,Prospective Studies ,Pregnancy Complications, Infectious ,Mean corpuscular volume ,medicine.diagnostic_test ,Obstetrics ,Pregnancy Outcome ,Gestational age ,Lamivudine ,Obstetrics and Gynecology ,Treatment Outcome ,Infectious Diseases ,Drug Therapy, Combination ,Female ,Zidovudine ,Research Article ,medicine.drug ,Adult ,Canada ,medicine.medical_specialty ,Article Subject ,Anti-HIV Agents ,Anemia ,Dermatology ,lcsh:Gynecology and obstetrics ,Statistics, Nonparametric ,lcsh:Infectious and parasitic diseases ,Pharmacotherapy ,Confidence Intervals ,medicine ,Humans ,lcsh:RC109-216 ,lcsh:RG1-991 ,business.industry ,medicine.disease ,Infectious Disease Transmission, Vertical ,United States ,Surgery ,Immunology ,Liver function ,business ,Nucleoside ,Follow-Up Studies - Abstract
Objective:To study maternal and neonatal effects of combination nucleoside analog therapy administered to human immunodeficiency virus (HIV)-infected pregnant women for maternal indications.Methods:A multicenter, prospective observational study was undertaken at six perinatal centers in the United States and Canada that supported regional referral programs for the treatment of HIV-infected pregnant women. Demographic, laboratory, and pregnancy outcome data were collected for 39 women whose antiretroviral treatment regimens were expanded to include more than one nucleoside analog for maternal indications. The 40 newborns were monitored at pediatric referral centers through at least three months of age to ascertain their HIV infection status.Results:For all 39 women, zidovudine (ZDV) therapy was instituted at 13.4 ± 8.2 weeks, with a second agent (lamivudine [3TC] in 85% of cases) being added at a mean gestational age of 17.6 weeks. Duration of therapy with two agents was 20.6±10.4 weeks overall, with no women stopping medications because of side effects or toxicity. No significant changes in maternal laboratory values were seen, except for an increase in mean corpuscular volume, over the course of pregnancy. No clinically significant adverse neonatal outcomes were noted, with all but the three preterm newborns leaving hospital with their mothers. Neonatal anemia (hematocrit < 50%) was seen in 62% of newborns, with no children needing transfusion; mild elevations of liver function tests, primarily aspartate aminotransferase, were noted in 58% of newborns tested, though none were clinically jaundiced. Overall rate of neonatal HIV infection was 2.5% (95% confidence interval: 0.1–13.2%).Conclusion:Combination antiretroviral therapy during pregnancy with two nucleoside analogs was well-tolerated by mothers and newborns, with no significant short-term toxicities or side effects noted. Surveillance of exposed newborns’ hematologic and liver function appears warranted. more...
- Published
- 1998
- Full Text
- View/download PDF
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