The Experts below are selected from a list of 24 Experts worldwide ranked by ideXlab platform

Jay L. Zweier - One of the best experts on this subject based on the ideXlab platform.

  • Myocardial Postischemic Injury Is Reduced by PolyADPribose Polymerase-1 Gene Disruption
    Molecular Medicine, 2000
    Co-Authors: Andrew A. Pieper, Thorsten Walles, Guo Wei, Emily E. Clements, Ajay Verma, Solomon H. Snyder, Jay L. Zweier
    Abstract:

    Background PolyADPribose polymerase (PARP) is activated by DNA strand breaks to catalyze the addition of ADPribose groups to nuclear proteins, especially PARP-1. Excessive polyADPribosylation leads to cell death through depletion of NAD^+ and ATP. Materials and Methods In vivo PARP activation in heart tissue slices was assayed through conversion of [^33P]NAD^+ into PolyADPribose (PAR) following ischemia-reperfusion (I/R) and also monitored by immunohistochemical staining for PAR. Cardiac contractility, nitric oxide (NO), reactive oxygen species (ROS), NAD^+ and ATP levels were examined in wild type (WT) and in PARP-1 gene-deleted (PARP-1^−/−) isolated, perfused mouse hearts. Myocardial infarct size was assessed following coronary artery occlusion in rats treated with PARP inhibitors. Results Ischemia-reperfusion (I/R) augmented formation of nitric oxide, oxygen free radicals and PARP activity. I/R induced decreases in cardiac contractility and NAD^+ levels were attenuated in PARP-1^−/− mouse hearts. PARP inhibitors reduced myocardial infarct size in rats. Residual polyADPribosylation in PARP-1^−/− hearts may reflect alternative forms of PARP. Conclusions PolyADPribosylation from PARP-1 and other sources of enzymatic PAR synthesis is associated with cardiac damage following myocardial ischemia. PARP inhibitors may have therapeutic utility in myocardial disease.

  • Molecular Medicine © 2000 The Picower Institute Press Original Articles Myocardial Postischemic Injury Is Reduced by
    1999
    Co-Authors: Polyadpribose Polymerase, Gene Disruption, Andrew A. Pieper, Thorsten Walles, Guo Wei, Emily E. Clements, Ajay Verma, Solomon H. Snyder, Jay L. Zweier
    Abstract:

    Background: PolyADPribose polymerase (PARP) is activated by DNA strand breaks to catalyze the addition of ADPribose groups to nuclear proteins, especially PARP-1. Excessive polyADPribosylation leads to cell death through depletion of NAD � and ATP. Materials and Methods: In vivo PARP activation in heart tissue slices was assayed through conversion of [ 33 P]NAD � into PolyADPribose (PAR) following ischemia-reperfusion (I/R) and also monitored by immunohistochemical staining for PAR. Cardiac contractility, nitric oxide (NO), reactive oxygen species (ROS), NAD � and ATP levels were examined in wild type (WT) and in PARP-1 gene-deleted (PARP-1-/-) isolated, perfused mouse hearts. Myocardial infarc

William D Figg - One of the best experts on this subject based on the ideXlab platform.

  • CECs and IL-8 have prognostic and predictive utility in patients with recurrent platinum-sensitive ovarian cancer: biomarker correlates from the randomized phase 2 trial of olaparib and cediranib compared with olaparib in recurrent platinum-sensitive ovarian cancer
    Frontiers Media S.A., 2015
    Co-Authors: Jung-min Elee, Jane B. Trepel, Peter Echoyke, Liang Ecao, Tristan M Sissung, Nicole Ehouston, Minshu Eyu, William D Figg, Ismail Eturkbey, Seth M. Steinberg
    Abstract:

    Objective: Olaparib (O), a PARP inhibitor, and cediranib (C), a VEGFR1-3 inhibitor together had greater activity than O alone in women with recurrent platinum-sensitive ovarian cancer (OvCa). The objective of this study is to identify potential lead biomarker candidates for response to O+C in the setting of a multi-institutional phase II study of O with and without C in recurrent platinum-sensitive OvCa. Methods: A self-selected group of patients participated in a prospectively planned exploratory biomarker substudy of the randomized phase II study of O v. O+C. Whole blood for peripheral blood mononuclear cell (PBMC) and plasma isolation was collected prior to and on day 3 of treatment. Quantitation of circulating endothelial cells (CEC), IL-6, IL-8, VEGF, and soluble VEGFR-2 plasma concentrations, and PolyADPribose (PAR) incorporation were performed. SNP analysis of XRCC1 280H, R194W, and Q399R was done. Dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) was performed at baseline and day 3 of treatment. Parameter changes were compared between the two arms using an exact Wilcoxon rank sum test. Kaplan-Meier and log-rank tests were used to examine survival outcome. Results: 13 patients elected to participate in the translational substudy, 7 patients on O and 6 patients on O+C. Patients on O+C had a greater decrease in IL-8 concentration and larger CEC fold-increase compared with those on O alone (p=0.026, p=0.032). The fold increase in CEC on day 3 was associated with duration of PFS (R2=0.77, 95% CI 0.55-0.97, p

  • phase i ib study of olaparib and carboplatin in brca1 or brca2 mutation associated breast or ovarian cancer with biomarker analyses
    Journal of the National Cancer Institute, 2014
    Co-Authors: Jungmin Lee, Tristan M Sissung, William D Figg, John L Hays, Christina M Annunziata, Anne M Noonan, Lori M Minasian, Jo Anne Zujewski, Nicolas Gordon, Nilofer S Azad
    Abstract:

    DNA repair is essential for cells to survive damage caused by ambient environmental toxins, chemotherapy, and other treatments (1,2). Homologous recombination (HR) is a predominantly error-free mechanism to repair double-strand DNA break (DSB). Key components of DSB repair are the tumor-suppressor proteins BRCA1 and BRCA2. Dysfunctional HR leads to activation of the base excision repair pathway, a single-strand DNA break repair pathway requiring PolyADPribose polymerase (PARP) (3). Increased PARP-1 expression and/or activity in tumor cells has been demonstrated in many tumor types (4–6). Active base excision repair stalls replication to allow single-strand DNA break repair. The absence of single-strand DNA break repair causes DNA helix strain at transcription forks and leads to DSBs requiring HR and, therefore, BRCA1 and BRCA2 (7). Development of DSBs in the absence of HR activates nonhomologous end joining, a poor-fidelity DSB repair pathway. PARP inhibition has been shown to induce phosphorylation of DNA-dependent protein kinase and permit error-prone nonhomologous end joining in HR-deficient cells (8). Thus, HR dysfunction sensitizes cells to PARP inhibition, leading to further chromosomal instability, cell cycle arrest, and apoptosis (9). Germline HR deficiency improves the therapeutic window for PARP inhibition (10–12). The interrelationship between DNA repair pathways led to the development of PARP inhibitors (PARPis) as therapeutic agents. Olaparib, an oral PARP1/2 inhibitor, is tolerated at single-agent continuous doses up to 400mg twice daily (capsules) (13). It has been active as monotherapy in tumors with defective HR, specifically germline BRCA1 or BRCA2 mutations (gBRCAm). Clinical activity with prolonged disease stabilization and tumor burden reduction has been reported in gBRCAm-associated breast and/or ovarian cancer (gBRCAm BrCa/OvCa) (14–18). Phase II studies have confirmed the activity of olaparib monotherapy with response rates of 41% in gBRCAm patients with advanced BrCa (17) and 31% to 40% in those with OvCa (13,15). The optimal application of PARPis in treatment of gBRCAm BrCa/OvCa has not yet been determined. gBRCAm carriers with OvCa have increased susceptibility to platinums (19) and often receive multiple lines of platinum-based chemotherapy and can have longer overall survival than nonmutation carriers (20,21). It has been demonstrated preclinically that concomitant use of olaparib increases cytotoxic activity of cisplatin in cisplatin-resistant OvCa cell lines (22), and an intermittent schedule of olaparib with carboplatin yields antitumor activity in a BRCA2-mutated human ovarian cancer xenograft model (23). Thus, we hypothesized addition of olaparib to carboplatin as a stress to the DNA repair machinery would improve clinical benefit of carboplatin and could be safely given to women with gBRCAm-associated cancers. We conducted a phase I/Ib study to evaluate the safety, tolerability, and activity of olaparib administered with carboplatin. Our translational aim was to discover potential predictive biomarkers of response to the carboplatin/PARPi combination.

Tristan M Sissung - One of the best experts on this subject based on the ideXlab platform.

  • CECs and IL-8 have prognostic and predictive utility in patients with recurrent platinum-sensitive ovarian cancer: biomarker correlates from the randomized phase 2 trial of olaparib and cediranib compared with olaparib in recurrent platinum-sensitive ovarian cancer
    Frontiers Media S.A., 2015
    Co-Authors: Jung-min Elee, Jane B. Trepel, Peter Echoyke, Liang Ecao, Tristan M Sissung, Nicole Ehouston, Minshu Eyu, William D Figg, Ismail Eturkbey, Seth M. Steinberg
    Abstract:

    Objective: Olaparib (O), a PARP inhibitor, and cediranib (C), a VEGFR1-3 inhibitor together had greater activity than O alone in women with recurrent platinum-sensitive ovarian cancer (OvCa). The objective of this study is to identify potential lead biomarker candidates for response to O+C in the setting of a multi-institutional phase II study of O with and without C in recurrent platinum-sensitive OvCa. Methods: A self-selected group of patients participated in a prospectively planned exploratory biomarker substudy of the randomized phase II study of O v. O+C. Whole blood for peripheral blood mononuclear cell (PBMC) and plasma isolation was collected prior to and on day 3 of treatment. Quantitation of circulating endothelial cells (CEC), IL-6, IL-8, VEGF, and soluble VEGFR-2 plasma concentrations, and PolyADPribose (PAR) incorporation were performed. SNP analysis of XRCC1 280H, R194W, and Q399R was done. Dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) was performed at baseline and day 3 of treatment. Parameter changes were compared between the two arms using an exact Wilcoxon rank sum test. Kaplan-Meier and log-rank tests were used to examine survival outcome. Results: 13 patients elected to participate in the translational substudy, 7 patients on O and 6 patients on O+C. Patients on O+C had a greater decrease in IL-8 concentration and larger CEC fold-increase compared with those on O alone (p=0.026, p=0.032). The fold increase in CEC on day 3 was associated with duration of PFS (R2=0.77, 95% CI 0.55-0.97, p

  • phase i ib study of olaparib and carboplatin in brca1 or brca2 mutation associated breast or ovarian cancer with biomarker analyses
    Journal of the National Cancer Institute, 2014
    Co-Authors: Jungmin Lee, Tristan M Sissung, William D Figg, John L Hays, Christina M Annunziata, Anne M Noonan, Lori M Minasian, Jo Anne Zujewski, Nicolas Gordon, Nilofer S Azad
    Abstract:

    DNA repair is essential for cells to survive damage caused by ambient environmental toxins, chemotherapy, and other treatments (1,2). Homologous recombination (HR) is a predominantly error-free mechanism to repair double-strand DNA break (DSB). Key components of DSB repair are the tumor-suppressor proteins BRCA1 and BRCA2. Dysfunctional HR leads to activation of the base excision repair pathway, a single-strand DNA break repair pathway requiring PolyADPribose polymerase (PARP) (3). Increased PARP-1 expression and/or activity in tumor cells has been demonstrated in many tumor types (4–6). Active base excision repair stalls replication to allow single-strand DNA break repair. The absence of single-strand DNA break repair causes DNA helix strain at transcription forks and leads to DSBs requiring HR and, therefore, BRCA1 and BRCA2 (7). Development of DSBs in the absence of HR activates nonhomologous end joining, a poor-fidelity DSB repair pathway. PARP inhibition has been shown to induce phosphorylation of DNA-dependent protein kinase and permit error-prone nonhomologous end joining in HR-deficient cells (8). Thus, HR dysfunction sensitizes cells to PARP inhibition, leading to further chromosomal instability, cell cycle arrest, and apoptosis (9). Germline HR deficiency improves the therapeutic window for PARP inhibition (10–12). The interrelationship between DNA repair pathways led to the development of PARP inhibitors (PARPis) as therapeutic agents. Olaparib, an oral PARP1/2 inhibitor, is tolerated at single-agent continuous doses up to 400mg twice daily (capsules) (13). It has been active as monotherapy in tumors with defective HR, specifically germline BRCA1 or BRCA2 mutations (gBRCAm). Clinical activity with prolonged disease stabilization and tumor burden reduction has been reported in gBRCAm-associated breast and/or ovarian cancer (gBRCAm BrCa/OvCa) (14–18). Phase II studies have confirmed the activity of olaparib monotherapy with response rates of 41% in gBRCAm patients with advanced BrCa (17) and 31% to 40% in those with OvCa (13,15). The optimal application of PARPis in treatment of gBRCAm BrCa/OvCa has not yet been determined. gBRCAm carriers with OvCa have increased susceptibility to platinums (19) and often receive multiple lines of platinum-based chemotherapy and can have longer overall survival than nonmutation carriers (20,21). It has been demonstrated preclinically that concomitant use of olaparib increases cytotoxic activity of cisplatin in cisplatin-resistant OvCa cell lines (22), and an intermittent schedule of olaparib with carboplatin yields antitumor activity in a BRCA2-mutated human ovarian cancer xenograft model (23). Thus, we hypothesized addition of olaparib to carboplatin as a stress to the DNA repair machinery would improve clinical benefit of carboplatin and could be safely given to women with gBRCAm-associated cancers. We conducted a phase I/Ib study to evaluate the safety, tolerability, and activity of olaparib administered with carboplatin. Our translational aim was to discover potential predictive biomarkers of response to the carboplatin/PARPi combination.

Andrew A. Pieper - One of the best experts on this subject based on the ideXlab platform.

  • Myocardial Postischemic Injury Is Reduced by PolyADPribose Polymerase-1 Gene Disruption
    Molecular Medicine, 2000
    Co-Authors: Andrew A. Pieper, Thorsten Walles, Guo Wei, Emily E. Clements, Ajay Verma, Solomon H. Snyder, Jay L. Zweier
    Abstract:

    Background PolyADPribose polymerase (PARP) is activated by DNA strand breaks to catalyze the addition of ADPribose groups to nuclear proteins, especially PARP-1. Excessive polyADPribosylation leads to cell death through depletion of NAD^+ and ATP. Materials and Methods In vivo PARP activation in heart tissue slices was assayed through conversion of [^33P]NAD^+ into PolyADPribose (PAR) following ischemia-reperfusion (I/R) and also monitored by immunohistochemical staining for PAR. Cardiac contractility, nitric oxide (NO), reactive oxygen species (ROS), NAD^+ and ATP levels were examined in wild type (WT) and in PARP-1 gene-deleted (PARP-1^−/−) isolated, perfused mouse hearts. Myocardial infarct size was assessed following coronary artery occlusion in rats treated with PARP inhibitors. Results Ischemia-reperfusion (I/R) augmented formation of nitric oxide, oxygen free radicals and PARP activity. I/R induced decreases in cardiac contractility and NAD^+ levels were attenuated in PARP-1^−/− mouse hearts. PARP inhibitors reduced myocardial infarct size in rats. Residual polyADPribosylation in PARP-1^−/− hearts may reflect alternative forms of PARP. Conclusions PolyADPribosylation from PARP-1 and other sources of enzymatic PAR synthesis is associated with cardiac damage following myocardial ischemia. PARP inhibitors may have therapeutic utility in myocardial disease.

  • Molecular Medicine © 2000 The Picower Institute Press Original Articles Myocardial Postischemic Injury Is Reduced by
    1999
    Co-Authors: Polyadpribose Polymerase, Gene Disruption, Andrew A. Pieper, Thorsten Walles, Guo Wei, Emily E. Clements, Ajay Verma, Solomon H. Snyder, Jay L. Zweier
    Abstract:

    Background: PolyADPribose polymerase (PARP) is activated by DNA strand breaks to catalyze the addition of ADPribose groups to nuclear proteins, especially PARP-1. Excessive polyADPribosylation leads to cell death through depletion of NAD � and ATP. Materials and Methods: In vivo PARP activation in heart tissue slices was assayed through conversion of [ 33 P]NAD � into PolyADPribose (PAR) following ischemia-reperfusion (I/R) and also monitored by immunohistochemical staining for PAR. Cardiac contractility, nitric oxide (NO), reactive oxygen species (ROS), NAD � and ATP levels were examined in wild type (WT) and in PARP-1 gene-deleted (PARP-1-/-) isolated, perfused mouse hearts. Myocardial infarc

Thorsten Walles - One of the best experts on this subject based on the ideXlab platform.

  • Myocardial Postischemic Injury Is Reduced by PolyADPribose Polymerase-1 Gene Disruption
    Molecular Medicine, 2000
    Co-Authors: Andrew A. Pieper, Thorsten Walles, Guo Wei, Emily E. Clements, Ajay Verma, Solomon H. Snyder, Jay L. Zweier
    Abstract:

    Background PolyADPribose polymerase (PARP) is activated by DNA strand breaks to catalyze the addition of ADPribose groups to nuclear proteins, especially PARP-1. Excessive polyADPribosylation leads to cell death through depletion of NAD^+ and ATP. Materials and Methods In vivo PARP activation in heart tissue slices was assayed through conversion of [^33P]NAD^+ into PolyADPribose (PAR) following ischemia-reperfusion (I/R) and also monitored by immunohistochemical staining for PAR. Cardiac contractility, nitric oxide (NO), reactive oxygen species (ROS), NAD^+ and ATP levels were examined in wild type (WT) and in PARP-1 gene-deleted (PARP-1^−/−) isolated, perfused mouse hearts. Myocardial infarct size was assessed following coronary artery occlusion in rats treated with PARP inhibitors. Results Ischemia-reperfusion (I/R) augmented formation of nitric oxide, oxygen free radicals and PARP activity. I/R induced decreases in cardiac contractility and NAD^+ levels were attenuated in PARP-1^−/− mouse hearts. PARP inhibitors reduced myocardial infarct size in rats. Residual polyADPribosylation in PARP-1^−/− hearts may reflect alternative forms of PARP. Conclusions PolyADPribosylation from PARP-1 and other sources of enzymatic PAR synthesis is associated with cardiac damage following myocardial ischemia. PARP inhibitors may have therapeutic utility in myocardial disease.

  • Molecular Medicine © 2000 The Picower Institute Press Original Articles Myocardial Postischemic Injury Is Reduced by
    1999
    Co-Authors: Polyadpribose Polymerase, Gene Disruption, Andrew A. Pieper, Thorsten Walles, Guo Wei, Emily E. Clements, Ajay Verma, Solomon H. Snyder, Jay L. Zweier
    Abstract:

    Background: PolyADPribose polymerase (PARP) is activated by DNA strand breaks to catalyze the addition of ADPribose groups to nuclear proteins, especially PARP-1. Excessive polyADPribosylation leads to cell death through depletion of NAD � and ATP. Materials and Methods: In vivo PARP activation in heart tissue slices was assayed through conversion of [ 33 P]NAD � into PolyADPribose (PAR) following ischemia-reperfusion (I/R) and also monitored by immunohistochemical staining for PAR. Cardiac contractility, nitric oxide (NO), reactive oxygen species (ROS), NAD � and ATP levels were examined in wild type (WT) and in PARP-1 gene-deleted (PARP-1-/-) isolated, perfused mouse hearts. Myocardial infarc