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Krister Wennerberg - One of the best experts on this subject based on the ideXlab platform.

  • Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
    Molecular Cancer, 2016
    Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister Wennerberg
    Abstract:

    Background Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines. Method The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed Readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses. Results Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability Readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity Readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability Readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor dactolisib, showed synthetic lethality in several mTOR-addicted cell lines. Conclusions Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.

  • Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
    Molecular cancer, 2016
    Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister Wennerberg
    Abstract:

    Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines. The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed Readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses. Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability Readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity Readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability Readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor dactolisib, showed synthetic lethality in several mTOR-addicted cell lines. Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.

Benjamin D'anjou - One of the best experts on this subject based on the ideXlab platform.

  • Repetitive Quantum Nondemolition Measurement and Soft Decoding of a Silicon Spin Qubit
    Physical Review B, 2020
    Co-Authors: Xiao Xue, Benjamin D'anjou, T. F. Watson, Daniel R. Ward, Donald E. Savage, Max G. Lagally, Mark Friesen, Mark A. Eriksson, Lieven M. K. Vandersypen
    Abstract:

    Quantum error correction is of crucial importance for fault-tolerant quantum computers. As an essential step toward the implementation of quantum error-correcting codes, quantum nondemolition measurements are needed to efficiently detect the state of a logical qubit without destroying it. Here we implement quantum nondemolition measurements in a Si/SiGe two-qubit system, with one qubit serving as the logical qubit and the other serving as the ancilla. Making use of a two-qubit controlled-rotation gate, the state of the logical qubit is mapped onto the ancilla, followed by a destructive Readout of the ancilla. Repeating this procedure enhances the logical Readout fidelity from 75.5±0.3% to 94.5±0.2% after 15 ancilla Readouts. In addition, we compare the conventional thresholding method with an improved signal processing method called soft decoding that makes use of analog information in the Readout signal to better estimate the state of the logical qubit. We demonstrate that soft decoding leads to a significant reduction in the required number of repetitions when the Readout errors become limited by Gaussian noise, for instance, in the case of Readouts with a low signal-to-noise ratio. These results pave the way for the implementation of quantum error correction with spin qubits in silicon.

  • Optimal post-processing for a generic single-shot qubit Readout
    Physical Review A, 2014
    Co-Authors: Benjamin D'anjou, William A. Coish
    Abstract:

    We analyze three different post-processing methods applied to a single-shot qubit Readout: the average-signal (boxcar filter), peak-signal, and maximum-likelihood methods. In contrast to previous work, we account for a stochastic turn-on time $t_i$ associated with the leading edge of a pulse signaling one of the qubit states. This model is relevant to spin-qubit Readouts based on spin-to-charge conversion and would be generically reached in the limit of large signal-to-noise ratio $r$ for several other physical systems, including fluorescence-based Readouts of ion-trap qubits and nitrogen-vacancy center spins. We derive analytical closed-form expressions for the conditional probability distributions associated with the peak-signal and boxcar filters. For the boxcar filter, we find an asymptotic scaling of the single-shot error rate $\varepsilon \sim \ln r/\sqrt{r}$ when $t_i$ is stochastic, in contrast to the result $\varepsilon \sim \ln r/ r$ for deterministic $t_i$. Consequently, the peak-signal method outperforms the boxcar filter significantly when $t_i$ is stochastic, but is only marginally better for deterministic $t_i$ (a result that is consistent with the widespread use of the boxcar filter for fluorescence-based Readouts and the peak-signal for spin-to-charge conversion). We generalize the theoretically optimal maximum-likelihood method to stochastic $t_i$ and show numerically that a stochastic turn-on time $t_i$ will always result in a larger single-shot error rate. Based on this observation, we propose a general strategy to improve the quality of single-shot Readouts by forcing $t_i$ to be deterministic.

Lieven M. K. Vandersypen - One of the best experts on this subject based on the ideXlab platform.

  • Repetitive Quantum Nondemolition Measurement and Soft Decoding of a Silicon Spin Qubit
    Physical Review B, 2020
    Co-Authors: Xiao Xue, Benjamin D'anjou, T. F. Watson, Daniel R. Ward, Donald E. Savage, Max G. Lagally, Mark Friesen, Mark A. Eriksson, Lieven M. K. Vandersypen
    Abstract:

    Quantum error correction is of crucial importance for fault-tolerant quantum computers. As an essential step toward the implementation of quantum error-correcting codes, quantum nondemolition measurements are needed to efficiently detect the state of a logical qubit without destroying it. Here we implement quantum nondemolition measurements in a Si/SiGe two-qubit system, with one qubit serving as the logical qubit and the other serving as the ancilla. Making use of a two-qubit controlled-rotation gate, the state of the logical qubit is mapped onto the ancilla, followed by a destructive Readout of the ancilla. Repeating this procedure enhances the logical Readout fidelity from 75.5±0.3% to 94.5±0.2% after 15 ancilla Readouts. In addition, we compare the conventional thresholding method with an improved signal processing method called soft decoding that makes use of analog information in the Readout signal to better estimate the state of the logical qubit. We demonstrate that soft decoding leads to a significant reduction in the required number of repetitions when the Readout errors become limited by Gaussian noise, for instance, in the case of Readouts with a low signal-to-noise ratio. These results pave the way for the implementation of quantum error correction with spin qubits in silicon.

Prson Gautam - One of the best experts on this subject based on the ideXlab platform.

  • Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
    Molecular Cancer, 2016
    Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister Wennerberg
    Abstract:

    Background Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines. Method The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed Readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses. Results Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability Readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity Readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability Readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor dactolisib, showed synthetic lethality in several mTOR-addicted cell lines. Conclusions Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.

  • Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
    Molecular cancer, 2016
    Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister Wennerberg
    Abstract:

    Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines. The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed Readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses. Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability Readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity Readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability Readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor dactolisib, showed synthetic lethality in several mTOR-addicted cell lines. Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.

Xiao Xue - One of the best experts on this subject based on the ideXlab platform.

  • Repetitive Quantum Nondemolition Measurement and Soft Decoding of a Silicon Spin Qubit
    Physical Review B, 2020
    Co-Authors: Xiao Xue, Benjamin D'anjou, T. F. Watson, Daniel R. Ward, Donald E. Savage, Max G. Lagally, Mark Friesen, Mark A. Eriksson, Lieven M. K. Vandersypen
    Abstract:

    Quantum error correction is of crucial importance for fault-tolerant quantum computers. As an essential step toward the implementation of quantum error-correcting codes, quantum nondemolition measurements are needed to efficiently detect the state of a logical qubit without destroying it. Here we implement quantum nondemolition measurements in a Si/SiGe two-qubit system, with one qubit serving as the logical qubit and the other serving as the ancilla. Making use of a two-qubit controlled-rotation gate, the state of the logical qubit is mapped onto the ancilla, followed by a destructive Readout of the ancilla. Repeating this procedure enhances the logical Readout fidelity from 75.5±0.3% to 94.5±0.2% after 15 ancilla Readouts. In addition, we compare the conventional thresholding method with an improved signal processing method called soft decoding that makes use of analog information in the Readout signal to better estimate the state of the logical qubit. We demonstrate that soft decoding leads to a significant reduction in the required number of repetitions when the Readout errors become limited by Gaussian noise, for instance, in the case of Readouts with a low signal-to-noise ratio. These results pave the way for the implementation of quantum error correction with spin qubits in silicon.