The Experts below are selected from a list of 19599 Experts worldwide ranked by ideXlab platform
Giora Z Feuerstein - One of the best experts on this subject based on the ideXlab platform.
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multimodal biomarker investigation on efficacy and mechanism of action for the mammalian target of rapamycin inhibitor temsirolimus in a preclinical mammary carcinoma oncomouse model a translational medicine study in support for early clinical develo
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Xinkang Wang, Yutian Zhan, Lei Zhao, John Alvarez, Inder Chaudhary, Binbing S Zhou, Robert T Abraham, Giora Z FeuersteinAbstract:The mammalian target of rapamycin (mTOR) has proven to be a valid therapeutic target in a number of human cancers, and it is a candidate for clinical trials in human breast cancer. We report on a biomarker-based translational medicine approach to assess the efficacy and mechanism of action for the mTOR inhibitor temsirolimus (CCI-779) in a mammary carcinoma OncoMouse model [polyomavirus middle T antigen (PyMT)]. The mTOR signaling pathway biomarkers were assessed using a reverse-phase protein array. Pharmacokinetics studies were conducted in both the tumor and plasma compartments. Pharmacodynamic biomarkers for compound-target engagement of tumor phospho-S6 proteins were assayed by Western blot. Temsirolimus (intravenously once a week for 2 weeks) was administeRed in both early and advanced stages of tumors. Biomarkers for temsirolimus effects on tumor progression were assessed by three-dimensional ultrasound imaging in combination with immunohistochemistry to assess vascular density (Texas Red-dextran and CD31 immunostaining) and macrophage burden (F4/80 antigen). Tumor growth was significantly arrested in temsirolimus (25 ± 14% from 8 to 10 weeks, p p p p p
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multimodal biomarker investigation on efficacy and mechanism of action for the mammalian target of rapamycin inhibitor temsirolimus in a preclinical mammary carcinoma oncomouse model a translational medicine study in support for early clinical develo
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Xinkang Wang, Yutian Zhan, Lei Zhao, John Alvarez, Inder Chaudhary, Binbing S Zhou, Robert T Abraham, Giora Z FeuersteinAbstract:The mammalian target of rapamycin (mTOR) has proven to be a valid therapeutic target in a number of human cancers, and it is a candidate for clinical trials in human breast cancer. We report on a biomarker-based translational medicine approach to assess the efficacy and mechanism of action for the mTOR inhibitor temsirolimus (CCI-779) in a mammary carcinoma OncoMouse model [polyomavirus middle T antigen (PyMT)]. The mTOR signaling pathway biomarkers were assessed using a reverse-phase protein array. Pharmacokinetics studies were conducted in both the tumor and plasma compartments. Pharmacodynamic biomarkers for compound-target engagement of tumor phospho-S6 proteins were assayed by Western blot. Temsirolimus (intravenously once a week for 2 weeks) was administeRed in both early and advanced stages of tumors. Biomarkers for temsirolimus effects on tumor progression were assessed by three-dimensional ultrasound imaging in combination with immunohistochemistry to assess vascular density (Texas Red-dextran and CD31 immunostaining) and macrophage burden (F4/80 antigen). Tumor growth was significantly arrested in temsirolimus (25 ± 14% from 8 to 10 weeks, p < 0.05, and 26 ± 17% from 11 to 13 weeks, p < 0.01), compaRed with 493 ± 160 and 376 ± 50% increases, respectively, in vehicle-treated groups. Temsirolimus Reduced tumor vascular density, 36 to 48 and 58 to 60%, p < 0.05, by the Texas Red-dextran method or CD31-positive vessel count, respectively. Temsirolimus Reduced tumor macrophage burden by 46% at 13 weeks (p < 0.05). Temsirolimus inhibited (p < 0.05) the phosphoproteins S6 pS235/236 and S6 pS240/244 up to 81 and 87%, respectively. We conclude that the multimodal biomarkers of temsirolimus efficacy and mechanism of action (phosphoproteins) strongly suggest that it might translate to therapeutic efficacy in human tumors that bear congruency to features present in the mammary carcinoma of PyMT tumors.
Xinkang Wang - One of the best experts on this subject based on the ideXlab platform.
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multimodal biomarker investigation on efficacy and mechanism of action for the mammalian target of rapamycin inhibitor temsirolimus in a preclinical mammary carcinoma oncomouse model a translational medicine study in support for early clinical develo
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Xinkang Wang, Yutian Zhan, Lei Zhao, John Alvarez, Inder Chaudhary, Binbing S Zhou, Robert T Abraham, Giora Z FeuersteinAbstract:The mammalian target of rapamycin (mTOR) has proven to be a valid therapeutic target in a number of human cancers, and it is a candidate for clinical trials in human breast cancer. We report on a biomarker-based translational medicine approach to assess the efficacy and mechanism of action for the mTOR inhibitor temsirolimus (CCI-779) in a mammary carcinoma OncoMouse model [polyomavirus middle T antigen (PyMT)]. The mTOR signaling pathway biomarkers were assessed using a reverse-phase protein array. Pharmacokinetics studies were conducted in both the tumor and plasma compartments. Pharmacodynamic biomarkers for compound-target engagement of tumor phospho-S6 proteins were assayed by Western blot. Temsirolimus (intravenously once a week for 2 weeks) was administeRed in both early and advanced stages of tumors. Biomarkers for temsirolimus effects on tumor progression were assessed by three-dimensional ultrasound imaging in combination with immunohistochemistry to assess vascular density (Texas Red-dextran and CD31 immunostaining) and macrophage burden (F4/80 antigen). Tumor growth was significantly arrested in temsirolimus (25 ± 14% from 8 to 10 weeks, p p p p p
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multimodal biomarker investigation on efficacy and mechanism of action for the mammalian target of rapamycin inhibitor temsirolimus in a preclinical mammary carcinoma oncomouse model a translational medicine study in support for early clinical develo
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Xinkang Wang, Yutian Zhan, Lei Zhao, John Alvarez, Inder Chaudhary, Binbing S Zhou, Robert T Abraham, Giora Z FeuersteinAbstract:The mammalian target of rapamycin (mTOR) has proven to be a valid therapeutic target in a number of human cancers, and it is a candidate for clinical trials in human breast cancer. We report on a biomarker-based translational medicine approach to assess the efficacy and mechanism of action for the mTOR inhibitor temsirolimus (CCI-779) in a mammary carcinoma OncoMouse model [polyomavirus middle T antigen (PyMT)]. The mTOR signaling pathway biomarkers were assessed using a reverse-phase protein array. Pharmacokinetics studies were conducted in both the tumor and plasma compartments. Pharmacodynamic biomarkers for compound-target engagement of tumor phospho-S6 proteins were assayed by Western blot. Temsirolimus (intravenously once a week for 2 weeks) was administeRed in both early and advanced stages of tumors. Biomarkers for temsirolimus effects on tumor progression were assessed by three-dimensional ultrasound imaging in combination with immunohistochemistry to assess vascular density (Texas Red-dextran and CD31 immunostaining) and macrophage burden (F4/80 antigen). Tumor growth was significantly arrested in temsirolimus (25 ± 14% from 8 to 10 weeks, p < 0.05, and 26 ± 17% from 11 to 13 weeks, p < 0.01), compaRed with 493 ± 160 and 376 ± 50% increases, respectively, in vehicle-treated groups. Temsirolimus Reduced tumor vascular density, 36 to 48 and 58 to 60%, p < 0.05, by the Texas Red-dextran method or CD31-positive vessel count, respectively. Temsirolimus Reduced tumor macrophage burden by 46% at 13 weeks (p < 0.05). Temsirolimus inhibited (p < 0.05) the phosphoproteins S6 pS235/236 and S6 pS240/244 up to 81 and 87%, respectively. We conclude that the multimodal biomarkers of temsirolimus efficacy and mechanism of action (phosphoproteins) strongly suggest that it might translate to therapeutic efficacy in human tumors that bear congruency to features present in the mammary carcinoma of PyMT tumors.
Kazuyuki Itoh - One of the best experts on this subject based on the ideXlab platform.
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a role of lim kinase 1 cofilin pathway in regulating endocytic trafficking of egf receptor in human breast cancer cells
Histochemistry and Cell Biology, 2006Co-Authors: Yukio Nishimura, Ora Bernard, Kiyoko Yoshioka, Biborka Bereczky, Kazuyuki ItohAbstract:We have previously shown that overexpression of LIM kinase1 (LIMK1) resulted in a marked retardation of the internalization of the receptor-mediated endocytic tracer, Texas Red-labeled epidermal growth factor (EGF) in low-invasive human breast cancer cell MCF-7. We thereby postulate that LIMK1 signaling plays an important role in the regulation of ligand-induced endocytosis of EGF receptor (EGFR) in tumor cells by reorganizing and influencing actin-filament dynamics. In the present study, we further assessed the effect of wild-type LIMK1, a kinase-deficient dominant negative mutant of LIMK1 (DN-LIMK1) and an active, unphosphorylatable cofilin mutant (S3A cofilin) on internalization of EGF-EGFR in MDA-MB-231, a highly invasive human breast cancer cell line. We demonstrate here that a marked delay in the receptor-mediated internalization of Texas Red-labeled EGF was observed in the wild-type LIMK1 transfectants, and that most of the internalized EGF staining were accumulated within transferrin receptor-positive early endosomes even after 30 min internalization. In contrast, the expression of dominant-negative LIMK1 mutant rescued the efficient endocytosis of Texas Red-EGF, and large amounts of Texas Red-EGF staining already reached LIMPII-positive late endosomes/lysosomal vacuoles after 15 min internalization. We further analyzed the effect of S3A cofilin mutant on EGFR trafficking, and found an efficient delivery of Texas Red-EGF into late endosomes/lysosomes at 15–30 min after internalization. Taken together, our novel findings presented in this paper implicate that LIMK1 signaling indeed plays a pivotal role in the regulation of EGFR trafficking through the endocytic pathway in invasive tumor cells.
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lim kinase 1 evidence for a role in the regulation of intracellular vesicle trafficking of lysosomes and endosomes in human breast cancer cells
European Journal of Cell Biology, 2004Co-Authors: Yukio Nishimura, Ora Bernard, Kiyoko Yoshioka, Masaru Himeno, Kazuyuki ItohAbstract:LIM kinase (LIMK) plays a critical role in stimulus-induced remodeling of the actin cytoskeleton by linking signals from the Rho family GTPases to changes in cofilin activity. Recent studies have shown an important role for LIMK1 signaling in tumor cell invasion through regulating actin dynamics. In this study, we investigate the role of LIMK1 in intracellular vesicle trafficking of lysosomes/endosomes. We analyzed by confocal immunofluorescence microscopy the cellular distribution of lysosomal proteins and the endocytosis of an endocytic tracer, epidermal growth factor (EGF), in LIMK1-transfected cells. We found in these cells an abnormal dispersed translocation of lysosomes stained for LIMPII and cathepsin D throughout the cytoplasm. The small punctate structures that stained for these lysosomal proteins were Redistributed to the periphery of the cell. Computational 3D-image analysis of confocal immunofluorescence micrographs further demonstrated that these vesicles did not colocalize with the transferrin receptor, an early endosomal marker. Furthermore, LIMPII-positive lysosomes did not colocalize with early endosomes labeled with endocytosed Texas Red-transferrin. These results indicate that there is no mixing between dispersed lysosomes and early endosomes in the LIMK1-transfected cells. Moreover, LIMK1 overexpression resulted in a marked retardation in the receptor-mediated internalization of Texas Red-labeled EGF in comparison with mock-transfected cells. At 30 min after internalization, most of the Texas Red-EGF staining overlapped with LIMPII-positive late endosomes/lysosomes in mock-transfected cells, whereas in LIMK1 transfectants only a small fraction of internalized EGF colocalized with LIMPII-positive structures in the perinuclear region. Taken together, the findings presented in this paper suggest that LIMK1 has a role in regulating vesicle trafficking of lysosomes and endosomes in invasive tumor cells.
Binbing S Zhou - One of the best experts on this subject based on the ideXlab platform.
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multimodal biomarker investigation on efficacy and mechanism of action for the mammalian target of rapamycin inhibitor temsirolimus in a preclinical mammary carcinoma oncomouse model a translational medicine study in support for early clinical develo
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Xinkang Wang, Yutian Zhan, Lei Zhao, John Alvarez, Inder Chaudhary, Binbing S Zhou, Robert T Abraham, Giora Z FeuersteinAbstract:The mammalian target of rapamycin (mTOR) has proven to be a valid therapeutic target in a number of human cancers, and it is a candidate for clinical trials in human breast cancer. We report on a biomarker-based translational medicine approach to assess the efficacy and mechanism of action for the mTOR inhibitor temsirolimus (CCI-779) in a mammary carcinoma OncoMouse model [polyomavirus middle T antigen (PyMT)]. The mTOR signaling pathway biomarkers were assessed using a reverse-phase protein array. Pharmacokinetics studies were conducted in both the tumor and plasma compartments. Pharmacodynamic biomarkers for compound-target engagement of tumor phospho-S6 proteins were assayed by Western blot. Temsirolimus (intravenously once a week for 2 weeks) was administeRed in both early and advanced stages of tumors. Biomarkers for temsirolimus effects on tumor progression were assessed by three-dimensional ultrasound imaging in combination with immunohistochemistry to assess vascular density (Texas Red-dextran and CD31 immunostaining) and macrophage burden (F4/80 antigen). Tumor growth was significantly arrested in temsirolimus (25 ± 14% from 8 to 10 weeks, p p p p p
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multimodal biomarker investigation on efficacy and mechanism of action for the mammalian target of rapamycin inhibitor temsirolimus in a preclinical mammary carcinoma oncomouse model a translational medicine study in support for early clinical develo
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Xinkang Wang, Yutian Zhan, Lei Zhao, John Alvarez, Inder Chaudhary, Binbing S Zhou, Robert T Abraham, Giora Z FeuersteinAbstract:The mammalian target of rapamycin (mTOR) has proven to be a valid therapeutic target in a number of human cancers, and it is a candidate for clinical trials in human breast cancer. We report on a biomarker-based translational medicine approach to assess the efficacy and mechanism of action for the mTOR inhibitor temsirolimus (CCI-779) in a mammary carcinoma OncoMouse model [polyomavirus middle T antigen (PyMT)]. The mTOR signaling pathway biomarkers were assessed using a reverse-phase protein array. Pharmacokinetics studies were conducted in both the tumor and plasma compartments. Pharmacodynamic biomarkers for compound-target engagement of tumor phospho-S6 proteins were assayed by Western blot. Temsirolimus (intravenously once a week for 2 weeks) was administeRed in both early and advanced stages of tumors. Biomarkers for temsirolimus effects on tumor progression were assessed by three-dimensional ultrasound imaging in combination with immunohistochemistry to assess vascular density (Texas Red-dextran and CD31 immunostaining) and macrophage burden (F4/80 antigen). Tumor growth was significantly arrested in temsirolimus (25 ± 14% from 8 to 10 weeks, p < 0.05, and 26 ± 17% from 11 to 13 weeks, p < 0.01), compaRed with 493 ± 160 and 376 ± 50% increases, respectively, in vehicle-treated groups. Temsirolimus Reduced tumor vascular density, 36 to 48 and 58 to 60%, p < 0.05, by the Texas Red-dextran method or CD31-positive vessel count, respectively. Temsirolimus Reduced tumor macrophage burden by 46% at 13 weeks (p < 0.05). Temsirolimus inhibited (p < 0.05) the phosphoproteins S6 pS235/236 and S6 pS240/244 up to 81 and 87%, respectively. We conclude that the multimodal biomarkers of temsirolimus efficacy and mechanism of action (phosphoproteins) strongly suggest that it might translate to therapeutic efficacy in human tumors that bear congruency to features present in the mammary carcinoma of PyMT tumors.
Inder Chaudhary - One of the best experts on this subject based on the ideXlab platform.
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multimodal biomarker investigation on efficacy and mechanism of action for the mammalian target of rapamycin inhibitor temsirolimus in a preclinical mammary carcinoma oncomouse model a translational medicine study in support for early clinical develo
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Xinkang Wang, Yutian Zhan, Lei Zhao, John Alvarez, Inder Chaudhary, Binbing S Zhou, Robert T Abraham, Giora Z FeuersteinAbstract:The mammalian target of rapamycin (mTOR) has proven to be a valid therapeutic target in a number of human cancers, and it is a candidate for clinical trials in human breast cancer. We report on a biomarker-based translational medicine approach to assess the efficacy and mechanism of action for the mTOR inhibitor temsirolimus (CCI-779) in a mammary carcinoma OncoMouse model [polyomavirus middle T antigen (PyMT)]. The mTOR signaling pathway biomarkers were assessed using a reverse-phase protein array. Pharmacokinetics studies were conducted in both the tumor and plasma compartments. Pharmacodynamic biomarkers for compound-target engagement of tumor phospho-S6 proteins were assayed by Western blot. Temsirolimus (intravenously once a week for 2 weeks) was administeRed in both early and advanced stages of tumors. Biomarkers for temsirolimus effects on tumor progression were assessed by three-dimensional ultrasound imaging in combination with immunohistochemistry to assess vascular density (Texas Red-dextran and CD31 immunostaining) and macrophage burden (F4/80 antigen). Tumor growth was significantly arrested in temsirolimus (25 ± 14% from 8 to 10 weeks, p p p p p
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multimodal biomarker investigation on efficacy and mechanism of action for the mammalian target of rapamycin inhibitor temsirolimus in a preclinical mammary carcinoma oncomouse model a translational medicine study in support for early clinical develo
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Xinkang Wang, Yutian Zhan, Lei Zhao, John Alvarez, Inder Chaudhary, Binbing S Zhou, Robert T Abraham, Giora Z FeuersteinAbstract:The mammalian target of rapamycin (mTOR) has proven to be a valid therapeutic target in a number of human cancers, and it is a candidate for clinical trials in human breast cancer. We report on a biomarker-based translational medicine approach to assess the efficacy and mechanism of action for the mTOR inhibitor temsirolimus (CCI-779) in a mammary carcinoma OncoMouse model [polyomavirus middle T antigen (PyMT)]. The mTOR signaling pathway biomarkers were assessed using a reverse-phase protein array. Pharmacokinetics studies were conducted in both the tumor and plasma compartments. Pharmacodynamic biomarkers for compound-target engagement of tumor phospho-S6 proteins were assayed by Western blot. Temsirolimus (intravenously once a week for 2 weeks) was administeRed in both early and advanced stages of tumors. Biomarkers for temsirolimus effects on tumor progression were assessed by three-dimensional ultrasound imaging in combination with immunohistochemistry to assess vascular density (Texas Red-dextran and CD31 immunostaining) and macrophage burden (F4/80 antigen). Tumor growth was significantly arrested in temsirolimus (25 ± 14% from 8 to 10 weeks, p < 0.05, and 26 ± 17% from 11 to 13 weeks, p < 0.01), compaRed with 493 ± 160 and 376 ± 50% increases, respectively, in vehicle-treated groups. Temsirolimus Reduced tumor vascular density, 36 to 48 and 58 to 60%, p < 0.05, by the Texas Red-dextran method or CD31-positive vessel count, respectively. Temsirolimus Reduced tumor macrophage burden by 46% at 13 weeks (p < 0.05). Temsirolimus inhibited (p < 0.05) the phosphoproteins S6 pS235/236 and S6 pS240/244 up to 81 and 87%, respectively. We conclude that the multimodal biomarkers of temsirolimus efficacy and mechanism of action (phosphoproteins) strongly suggest that it might translate to therapeutic efficacy in human tumors that bear congruency to features present in the mammary carcinoma of PyMT tumors.
