The Experts below are selected from a list of 141 Experts worldwide ranked by ideXlab platform

Rosalie M Luiten - One of the best experts on this subject based on the ideXlab platform.

  • Effective Melanoma Immunotherapy in Mice by the Skin- Depigmenting Agent Monobenzone and the Adjuvants
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Jan D. Bos, Nico J, Rosalie M Luiten
    Abstract:

    Background: Presently melanoma still lacks adequate treatment options for metastatic disease. While melanoma is exceptionally challenging to standard regimens, it is suited for treatment with immunotherapy based on its immunogenicity. Since treatment-related skin depigmentation is considered a favourable prognostic sign during melanoma intervention, we here aimed at the reverse approach of directly inducing vitiligo as a shortcut to effective anti-melanoma immunity. Methodology and Principal Findings: We developed an effective and simple to use form of immunotherapy by combining the topical skin-bleaching agent Monobenzone with immune-stimulatory imiquimod cream and cytosine-guanine oligodeoxynucleotides (CpG) injections (MIC therapy). This powerful new approach promptly induced a melanoma antigenspecific immune response, which abolished subcutaneous B16.F10 melanoma growth in up to 85 % of C57BL/6 mice. Importantly, this regimen induced over 100 days of tumor-free survival in up to 60 % of the mice, and forcefully suppressed tumor growth upon re-challenge either 65- or 165 days after MIC treatment cessation. Conclusions: MIC therapy is effective in eradicating melanoma, by vigilantly incorporating NK-, B- and T cells in its therapeutic effect. Based on these results, the MIC regimen presents a high-yield, low-cost and simple therapy, readil

  • Statistics of in vivo peripheral blood NK cell counts.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    Exp.: experiment. CI: CpG, imiquimod.nt: not tested. MIC: Monobenzone, imiquimod & CpG.ns: not significant (considered if p>0.05). For Exp. 4 see Fig. 4A.*: Unpaired t-test.1:Day after tumor inoculation on which PBL were tested.

  • Statistics of in vivo tumor experiments inoculating 1×10e5 melanoma cells and starting treatment when all tumors were at least 2×2 mm.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    ns: not significant (considered if p>0.05).nt: not tested.1:Day of tumor size comparison (last day on which experimental animals were all alive).*: Unpaired t-test.**: Logrank test for survival.Exp.: experiment.TFS: tumor-free survival.CI: CpG, imiquimod.MIC: Monobenzone, imiquimod & CpG.

  • MIC treatment of subcutaneous B16.F10 melanoma induced melanoma-reactive CD8+ T cells and -NK cells in vivo.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    Splenocytes were tested for their ex vivo activation upon co-culture with B16.F10 melanoma or EL4 thymoma control cells (n = 5 mice per group). A, Left panel: CD8+ T cells from Monobenzone- and MIC-treated mice showed significant TNF-α production upon co-culture with melanoma cells (black bars; p

  • Statistics of in vivo tumor experiments.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    ns: not significant (considered if p>0.05). Exp.: experiment.nt: not tested. TFS: tumor-free survival.*: Unpaired t-test. CI: CpG & imiquimod.**: Logrank test for survival (endpoint tumor size max 200 mm2). MIC: Monobenzone, imiquimod & CpG.1:Day of tumor size comparison (last day on which experimental animals were all alive).For Exp. 2 see Fig. 1A/B, for Exp. 3 see Fig. 3C (upper panel), for Exp. 4 see Fig. 3A/B and C (lower panel),

Jasper G Van Den Boorn - One of the best experts on this subject based on the ideXlab platform.

  • Effective Melanoma Immunotherapy in Mice by the Skin- Depigmenting Agent Monobenzone and the Adjuvants
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Jan D. Bos, Nico J, Rosalie M Luiten
    Abstract:

    Background: Presently melanoma still lacks adequate treatment options for metastatic disease. While melanoma is exceptionally challenging to standard regimens, it is suited for treatment with immunotherapy based on its immunogenicity. Since treatment-related skin depigmentation is considered a favourable prognostic sign during melanoma intervention, we here aimed at the reverse approach of directly inducing vitiligo as a shortcut to effective anti-melanoma immunity. Methodology and Principal Findings: We developed an effective and simple to use form of immunotherapy by combining the topical skin-bleaching agent Monobenzone with immune-stimulatory imiquimod cream and cytosine-guanine oligodeoxynucleotides (CpG) injections (MIC therapy). This powerful new approach promptly induced a melanoma antigenspecific immune response, which abolished subcutaneous B16.F10 melanoma growth in up to 85 % of C57BL/6 mice. Importantly, this regimen induced over 100 days of tumor-free survival in up to 60 % of the mice, and forcefully suppressed tumor growth upon re-challenge either 65- or 165 days after MIC treatment cessation. Conclusions: MIC therapy is effective in eradicating melanoma, by vigilantly incorporating NK-, B- and T cells in its therapeutic effect. Based on these results, the MIC regimen presents a high-yield, low-cost and simple therapy, readil

  • Statistics of in vivo peripheral blood NK cell counts.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    Exp.: experiment. CI: CpG, imiquimod.nt: not tested. MIC: Monobenzone, imiquimod & CpG.ns: not significant (considered if p>0.05). For Exp. 4 see Fig. 4A.*: Unpaired t-test.1:Day after tumor inoculation on which PBL were tested.

  • Statistics of in vivo tumor experiments inoculating 1×10e5 melanoma cells and starting treatment when all tumors were at least 2×2 mm.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    ns: not significant (considered if p>0.05).nt: not tested.1:Day of tumor size comparison (last day on which experimental animals were all alive).*: Unpaired t-test.**: Logrank test for survival.Exp.: experiment.TFS: tumor-free survival.CI: CpG, imiquimod.MIC: Monobenzone, imiquimod & CpG.

  • MIC treatment of subcutaneous B16.F10 melanoma induced melanoma-reactive CD8+ T cells and -NK cells in vivo.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    Splenocytes were tested for their ex vivo activation upon co-culture with B16.F10 melanoma or EL4 thymoma control cells (n = 5 mice per group). A, Left panel: CD8+ T cells from Monobenzone- and MIC-treated mice showed significant TNF-α production upon co-culture with melanoma cells (black bars; p

  • Statistics of in vivo tumor experiments.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    ns: not significant (considered if p>0.05). Exp.: experiment.nt: not tested. TFS: tumor-free survival.*: Unpaired t-test. CI: CpG & imiquimod.**: Logrank test for survival (endpoint tumor size max 200 mm2). MIC: Monobenzone, imiquimod & CpG.1:Day of tumor size comparison (last day on which experimental animals were all alive).For Exp. 2 see Fig. 1A/B, for Exp. 3 see Fig. 3C (upper panel), for Exp. 4 see Fig. 3A/B and C (lower panel),

Cornelis J M Melief - One of the best experts on this subject based on the ideXlab platform.

  • Effective Melanoma Immunotherapy in Mice by the Skin- Depigmenting Agent Monobenzone and the Adjuvants
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Jan D. Bos, Nico J, Rosalie M Luiten
    Abstract:

    Background: Presently melanoma still lacks adequate treatment options for metastatic disease. While melanoma is exceptionally challenging to standard regimens, it is suited for treatment with immunotherapy based on its immunogenicity. Since treatment-related skin depigmentation is considered a favourable prognostic sign during melanoma intervention, we here aimed at the reverse approach of directly inducing vitiligo as a shortcut to effective anti-melanoma immunity. Methodology and Principal Findings: We developed an effective and simple to use form of immunotherapy by combining the topical skin-bleaching agent Monobenzone with immune-stimulatory imiquimod cream and cytosine-guanine oligodeoxynucleotides (CpG) injections (MIC therapy). This powerful new approach promptly induced a melanoma antigenspecific immune response, which abolished subcutaneous B16.F10 melanoma growth in up to 85 % of C57BL/6 mice. Importantly, this regimen induced over 100 days of tumor-free survival in up to 60 % of the mice, and forcefully suppressed tumor growth upon re-challenge either 65- or 165 days after MIC treatment cessation. Conclusions: MIC therapy is effective in eradicating melanoma, by vigilantly incorporating NK-, B- and T cells in its therapeutic effect. Based on these results, the MIC regimen presents a high-yield, low-cost and simple therapy, readil

  • Statistics of in vivo peripheral blood NK cell counts.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    Exp.: experiment. CI: CpG, imiquimod.nt: not tested. MIC: Monobenzone, imiquimod & CpG.ns: not significant (considered if p>0.05). For Exp. 4 see Fig. 4A.*: Unpaired t-test.1:Day after tumor inoculation on which PBL were tested.

  • Statistics of in vivo tumor experiments inoculating 1×10e5 melanoma cells and starting treatment when all tumors were at least 2×2 mm.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    ns: not significant (considered if p>0.05).nt: not tested.1:Day of tumor size comparison (last day on which experimental animals were all alive).*: Unpaired t-test.**: Logrank test for survival.Exp.: experiment.TFS: tumor-free survival.CI: CpG, imiquimod.MIC: Monobenzone, imiquimod & CpG.

  • MIC treatment of subcutaneous B16.F10 melanoma induced melanoma-reactive CD8+ T cells and -NK cells in vivo.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    Splenocytes were tested for their ex vivo activation upon co-culture with B16.F10 melanoma or EL4 thymoma control cells (n = 5 mice per group). A, Left panel: CD8+ T cells from Monobenzone- and MIC-treated mice showed significant TNF-α production upon co-culture with melanoma cells (black bars; p

  • Statistics of in vivo tumor experiments.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    ns: not significant (considered if p>0.05). Exp.: experiment.nt: not tested. TFS: tumor-free survival.*: Unpaired t-test. CI: CpG & imiquimod.**: Logrank test for survival (endpoint tumor size max 200 mm2). MIC: Monobenzone, imiquimod & CpG.1:Day of tumor size comparison (last day on which experimental animals were all alive).For Exp. 2 see Fig. 1A/B, for Exp. 3 see Fig. 3C (upper panel), for Exp. 4 see Fig. 3A/B and C (lower panel),

Esther P. M. Tjin - One of the best experts on this subject based on the ideXlab platform.

  • anti melanoma immunity and local regression of cutaneous metastases in melanoma patients treated with Monobenzone and imiquimod a phase 2 a trial
    OncoImmunology, 2018
    Co-Authors: Esther P. M. Tjin, H E Teulings, Karina J Willemsen, Stephanie Van Der Kleij, Sylvia Ter Meulen, Helen E Kemp, Gabrielle Krebbers, Carel J M Van Noesel, Cornelis L M C Franken
    Abstract:

    Vitiligo development in melanoma patients during immunotherapy is a favorable prognostic sign and indicates breakage of tolerance against melanocytic/melanoma antigens. We investigated a novel immunotherapeutic approach of the skin-depigmenting compound Monobenzone synergizing with imiquimod in inducing antimelanoma immunity and melanoma regression. Stage III-IV melanoma patients with non-resectable cutaneous melanoma metastases were treated with Monobenzone and imiquimod (MI) therapy applied locally to cutaneous metastases and adjacent skin during 12 weeks, or longer. Twenty-one of 25 enrolled patients were evaluable for clinical assessment at 12 weeks. MI therapy was well-tolerated. Partial regression of cutaneous metastases was observed in 8 patients and stable disease in 1 patient, reaching the statistical endpoint of treatment efficacy. Continued treatment induced clinical response in 11 patients, including complete responses in three patients. Seven patients developed vitiligo-like depigmentation on areas of skin that were not treated with MI therapy, indicating a systemic effect of MI therapy. Melanoma-specific antibody responses were induced in 7 of 17 patients tested and melanoma-specific CD8+T-cell responses in 11 of 15 patients tested. These systemic immune responses were significantly increased during therapy as compared to baseline in responding patients. This study shows that MI therapy induces local and systemic anti-melanoma immunity and local regression of cutaneous metastases in 38% of patients, or 52% during prolonged therapy. This study provides proof-of-concept of MI therapy, a low-cost, broadly applicable and well-tolerated treatment for cutaneous melanoma metastases, attractive for further clinical investigation.

  • Effective Melanoma Immunotherapy in Mice by the Skin- Depigmenting Agent Monobenzone and the Adjuvants
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Jan D. Bos, Nico J, Rosalie M Luiten
    Abstract:

    Background: Presently melanoma still lacks adequate treatment options for metastatic disease. While melanoma is exceptionally challenging to standard regimens, it is suited for treatment with immunotherapy based on its immunogenicity. Since treatment-related skin depigmentation is considered a favourable prognostic sign during melanoma intervention, we here aimed at the reverse approach of directly inducing vitiligo as a shortcut to effective anti-melanoma immunity. Methodology and Principal Findings: We developed an effective and simple to use form of immunotherapy by combining the topical skin-bleaching agent Monobenzone with immune-stimulatory imiquimod cream and cytosine-guanine oligodeoxynucleotides (CpG) injections (MIC therapy). This powerful new approach promptly induced a melanoma antigenspecific immune response, which abolished subcutaneous B16.F10 melanoma growth in up to 85 % of C57BL/6 mice. Importantly, this regimen induced over 100 days of tumor-free survival in up to 60 % of the mice, and forcefully suppressed tumor growth upon re-challenge either 65- or 165 days after MIC treatment cessation. Conclusions: MIC therapy is effective in eradicating melanoma, by vigilantly incorporating NK-, B- and T cells in its therapeutic effect. Based on these results, the MIC regimen presents a high-yield, low-cost and simple therapy, readil

  • Statistics of in vivo peripheral blood NK cell counts.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    Exp.: experiment. CI: CpG, imiquimod.nt: not tested. MIC: Monobenzone, imiquimod & CpG.ns: not significant (considered if p>0.05). For Exp. 4 see Fig. 4A.*: Unpaired t-test.1:Day after tumor inoculation on which PBL were tested.

  • Statistics of in vivo tumor experiments inoculating 1×10e5 melanoma cells and starting treatment when all tumors were at least 2×2 mm.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    ns: not significant (considered if p>0.05).nt: not tested.1:Day of tumor size comparison (last day on which experimental animals were all alive).*: Unpaired t-test.**: Logrank test for survival.Exp.: experiment.TFS: tumor-free survival.CI: CpG, imiquimod.MIC: Monobenzone, imiquimod & CpG.

  • MIC treatment of subcutaneous B16.F10 melanoma induced melanoma-reactive CD8+ T cells and -NK cells in vivo.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    Splenocytes were tested for their ex vivo activation upon co-culture with B16.F10 melanoma or EL4 thymoma control cells (n = 5 mice per group). A, Left panel: CD8+ T cells from Monobenzone- and MIC-treated mice showed significant TNF-α production upon co-culture with melanoma cells (black bars; p

Debby Konijnenberg - One of the best experts on this subject based on the ideXlab platform.

  • Effective Melanoma Immunotherapy in Mice by the Skin- Depigmenting Agent Monobenzone and the Adjuvants
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Jan D. Bos, Nico J, Rosalie M Luiten
    Abstract:

    Background: Presently melanoma still lacks adequate treatment options for metastatic disease. While melanoma is exceptionally challenging to standard regimens, it is suited for treatment with immunotherapy based on its immunogenicity. Since treatment-related skin depigmentation is considered a favourable prognostic sign during melanoma intervention, we here aimed at the reverse approach of directly inducing vitiligo as a shortcut to effective anti-melanoma immunity. Methodology and Principal Findings: We developed an effective and simple to use form of immunotherapy by combining the topical skin-bleaching agent Monobenzone with immune-stimulatory imiquimod cream and cytosine-guanine oligodeoxynucleotides (CpG) injections (MIC therapy). This powerful new approach promptly induced a melanoma antigenspecific immune response, which abolished subcutaneous B16.F10 melanoma growth in up to 85 % of C57BL/6 mice. Importantly, this regimen induced over 100 days of tumor-free survival in up to 60 % of the mice, and forcefully suppressed tumor growth upon re-challenge either 65- or 165 days after MIC treatment cessation. Conclusions: MIC therapy is effective in eradicating melanoma, by vigilantly incorporating NK-, B- and T cells in its therapeutic effect. Based on these results, the MIC regimen presents a high-yield, low-cost and simple therapy, readil

  • Statistics of in vivo peripheral blood NK cell counts.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    Exp.: experiment. CI: CpG, imiquimod.nt: not tested. MIC: Monobenzone, imiquimod & CpG.ns: not significant (considered if p>0.05). For Exp. 4 see Fig. 4A.*: Unpaired t-test.1:Day after tumor inoculation on which PBL were tested.

  • Statistics of in vivo tumor experiments inoculating 1×10e5 melanoma cells and starting treatment when all tumors were at least 2×2 mm.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    ns: not significant (considered if p>0.05).nt: not tested.1:Day of tumor size comparison (last day on which experimental animals were all alive).*: Unpaired t-test.**: Logrank test for survival.Exp.: experiment.TFS: tumor-free survival.CI: CpG, imiquimod.MIC: Monobenzone, imiquimod & CpG.

  • MIC treatment of subcutaneous B16.F10 melanoma induced melanoma-reactive CD8+ T cells and -NK cells in vivo.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    Splenocytes were tested for their ex vivo activation upon co-culture with B16.F10 melanoma or EL4 thymoma control cells (n = 5 mice per group). A, Left panel: CD8+ T cells from Monobenzone- and MIC-treated mice showed significant TNF-α production upon co-culture with melanoma cells (black bars; p

  • Statistics of in vivo tumor experiments.
    2013
    Co-Authors: Jasper G Van Den Boorn, Cornelis J M Melief, Daisy I Picavet, Debby Konijnenberg, Esther P. M. Tjin, Nico J. Meeuwenoord, Dmitri V. Filippov, J. Wietze P. Van Der Veen, Jan D. Bos, Rosalie M Luiten
    Abstract:

    ns: not significant (considered if p>0.05). Exp.: experiment.nt: not tested. TFS: tumor-free survival.*: Unpaired t-test. CI: CpG & imiquimod.**: Logrank test for survival (endpoint tumor size max 200 mm2). MIC: Monobenzone, imiquimod & CpG.1:Day of tumor size comparison (last day on which experimental animals were all alive).For Exp. 2 see Fig. 1A/B, for Exp. 3 see Fig. 3C (upper panel), for Exp. 4 see Fig. 3A/B and C (lower panel),