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1. Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized I-SPY2 Trial-Efficacy and Biomarker Discovery.

Author

Albain, Kathy, Yau, Christina, Petricoin, Emanuel, Wolf, Denise, Lang, Julie, Chien, A, Haddad, Tufia, Forero-Torres, Andres, Wallace, Anne, Kaplan, Henry, Pusztai, Lajos, Euhus, David, Nanda, Rita, Elias, Anthony, Clark, Amy, Godellas, Constantine, Boughey, Judy, Isaacs, Claudine, Tripathy, Debu, Lu, Janice, Yung, Rachel, Gallagher, Rosa, Wulfkuhle, Julia, Brown-Swigart, Lamorna, Krings, Gregor, Chen, Yunn, Potter, David, Stringer-Reasor, Erica, Blair, Sarah, Asare, Smita, Wilson, Amy, Hirst, Gillian, Singhrao, Ruby, Buxton, Meredith, Clennell, Julia, Sanil, Ashish, Berry, Scott, Asare, Adam, Matthews, Jeffrey, DeMichele, Angela, Hylton, Nola, Melisko, Michelle, Perlmutter, Jane, Rugo, Hope, Symmans, W, Vant Veer, Laura, Yee, Douglas, Berry, Donald, and Esserman, Laura

Subjects
Female, Humans, Antineoplastic Combined Chemotherapy Protocols, Bayes Theorem, Breast Neoplasms, Neoadjuvant Therapy, Paclitaxel, Receptor, ErbB-2, Receptor, TIE-2, Recombinant Fusion Proteins, Trastuzumab
Abstract

PURPOSE: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. PATIENTS AND METHODS: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy graduates if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. RESULTS: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%-99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. CONCLUSIONS: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.

Published
2024

4. Hexyl-(cuban-1-yl-methyl)-biguanide (HCB) inhibits hormone therapy resistant breast cancer cells, in part by Inhibiting CYP3A4 arachidonic acid epoxygenase activity.

Author

Guo, Zhijun, Lei, Jianxun, Hong, Kwon Ho, Norris, Beverly, Flory, Craig M, Jayaraman, Swaathi, McDermott, Connor, Ambrose, Elizabeth, Sevrioukova, Irina, Poulos, Tom, Denisov, Ilia, Sliga, Stephen, Schumacher, Robert J, Georg, Gunda I, Hawse, John R, Goetz, Matthew P, and Potter, David A

Subjects
Oncology and Carcinogenesis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Published
2021

6. Kinetic studies of ether low temperature combustion mechanisms using laser photolysis and modelling

Author

Potter, David George, Seakins, P. W., and Tomlin, Alison

Subjects
660
Abstract

The laser flash photolysis – laser-induced fluorescence technique has been used to study the reaction kinetics of several potential biofuel ethers under low temperature combustion conditions, in order to extend the understanding of the reactions that occur in novel combustion engines. Biofuels offer a potentially carbon-neutral energy source that could contribute to climate change mitigation, and commercial interest has been given to the ether family of compounds, which display desirable fuel characteristics such as high energy densities and favourable ignition properties. Chapter 3 presents a study of the reaction between the OH radical and trimethyl orthoformate (TMOF), diethyl- (DEE), di-n-butyl- (DBE), methyl tert-butyl- (MTBE), and dimethyl ether (DME), from 298 – 744 K in 13 – 190 Torr of nitrogen. This constitutes the first temperature-dependent study of OH + trimethyl orthoformate, and a significant extension of the temperature range of previous studies on the OH + di-n-butyl ether and OH + diethyl ether reactions. The temperature dependences of the rate coefficients for OH + ether (all in units of cm3 molecule–1 s–1) can be parameterised by: kOH+TMOF(298–744 K) = (8.0 ± 12.2) × 10–13 [(T/298)(2.6±1.2) + (T/298)(–8.1±4.6)] × e(2.7±3.9)/RT, kOH+DEE(298–727 K) = (1.28 ± 0.21) × 10–11 × e(–0.11±0.59)/RT, kOH+DBE(298–732 K) = (3.05 ± 7.13) × 10–12 (T/298)1.3±1.6 × e(6.4±5.8)/RT, kOH+MTBE(298–680 K) = (9.8 ± 21.6) × 10–13 (T/298)2.7±1.5 × e(2.5±5.6)/RT, and kOH+DME(298–656 K) = (1.22 ± 2.83) × 10–15 (T/298)6.9±0.5 × e(19.1±3.8)/RT. Chapter 4 presents a technique for determining R + O2 rate coefficients and OH yields by the observation of OH regeneration from chemical activation. This technique was verified using the CH3OCH2 + O2 reaction in the dimethyl ether system via comparison with previous measurements, and analyses using numerical integration software determined the optimum experimental conditions for the method. Potentially, this technique can be used to obtain rate parameters important for the combustion modelling of a wide range of potential fuel molecules. Rate coefficients for the system are reported at 291 – 483 K, in 4.1 – 32.6 Torr of nitrogen, and the mean room temperature rate coefficient was determined to be kCH3OCH2+O2 = (0.94 ± 0.04) × 10–11 cm3 molecule–1 s–1, across all pressures explored. Chapter 5 employed the technique described in Chapter 4 to present novel measurements of the C2H5OC2H4 + O2 reaction rate coefficient integral to the low temperature combustion of diethyl ether under experimental conditions of 298 – 464 K, in 5.2 – 28.4 Torr of nitrogen. The mean 298 K rate coefficient was determined to be kC2H5OC2H4+O2 = (3.10 ± 0.55) × 10–11 cm3 molecule–1 s–1. OH yields and rate coefficients were compared to ab initio calculations of the diethyl ether low temperature oxidation surface at the CCSD(T)/Jun-cc-pVTZ//M06-2X/Jun-cc-pVTZ level, using master equation methods. The transition state barrier to the OH product was required to be lowered by ~7 kcal mol–1 in order to achieve good agreement between experimental data and theoretical calculations. Chapter 6 reports some initial observations of subsequent OH regeneration following the R + O2 reaction at higher temperatures (~500 K and above), and some interesting unwanted chemistry occurring under high temperature and high O2 conditions. The main recommendations for future work are further explorations of the source of this extraneous chemistry, and development of the data interpretation under such conditions. The investigation of a wide range of fuels’ R + O2 reactions using the method presented in Chapter 4 should also be carried out to improve estimated rates in combustion models.

Published
2019

7. Erratum: Author Correction: Surgical Standards for Management of the Axilla in Breast Cancer Clinical Trials with Pathological Complete Response Endpoint.

Author

Boughey, Judy C, Alvarado, Michael D, Lancaster, Rachael B, Symmans, W Fraser, Mukhtar, Rita, Wong, Jasmine M, Ewing, Cheryl A, Potter, David A, Tuttle, Todd M, Hieken, Tina J, Carter, Jodi M, Jakub, James W, Kaplan, Henry G, Buchanan, Claire L, Jaskowiak, Nora T, Sattar, Husain A, Mueller, Jeffrey, Nanda, Rita, Isaacs, Claudine J, Pohlmann, Paula R, Lynce, Filipa, Tousimis, Eleni A, Zeck, Jay C, Lee, M Catherine, Lang, Julie E, Mhawech-Fauceglia, Paulette, Rao, Roshni, Taback, Bret, Goodellas, Constantine, Chen, Margaret, Kalinsky, Kevin M, Hibshoosh, Hanina, Killelea, Brigid, Sanft, Tara, Hirst, Gillian L, Asare, Smita, Matthews, Jeffrey B, Perlmutter, Jane, Esserman, Laura J, and I-SPY2 Investigators

Subjects
I-SPY2 Investigators
Abstract

[This corrects the article DOI: 10.1038/s41523-018-0074-6.].

Published
2019

8. Surgical Standards for Management of the Axilla in Breast Cancer Clinical Trials with Pathological Complete Response Endpoint.

Author

Boughey, Judy C, Alvarado, Michael D, Lancaster, Rachael B, Fraser Symmans, W, Mukhtar, Rita, Wong, Jasmine M, Ewing, Cheryl A, Potter, David A, Tuttle, Todd M, Hieken, Tina J, Carter, Jodi M, Jakub, James W, Kaplan, Henry G, Buchanan, Claire L, Jaskowiak, Nora T, Sattar, Husain A, Mueller, Jeffrey, Nanda, Rita, Isaacs, Claudine J, Pohlmann, Paula R, Lynce, Filipa, Tousimis, Eleni A, Zeck, Jay C, Lee, M Catherine, Lang, Julie E, Mhawech-Fauceglia, Paulette, Rao, Roshni, Taback, Bret, Chen, Margaret, Kalinsky, Kevin M, Hibshoosh, Hanina, Killelea, Brigid, Sanft, Tara, Hirst, Gillian L, Asare, Smita, Matthews, Jeffrey B, Perlmutter, Jane, Esserman, Laura J, and and I-SPY 2 Investigators

Subjects
and I-SPY 2 Investigators, Clinical Trials and Supportive Activities, Clinical Research, Patient Safety, Cancer
Abstract

Advances in the surgical management of the axilla in patients treated with neoadjuvant chemotherapy, especially those with node positive disease at diagnosis, have led to changes in practice and more judicious use of axillary lymph node dissection that may minimize morbidity from surgery. However, there is still significant confusion about how to optimally manage the axilla, resulting in variation among practices. From the viewpoint of drug development, assessment of response to neoadjuvant chemotherapy remains paramount and appropriate assessment of residual disease-the primary endpoint of many drug therapy trials in the neoadjuvant setting-is critical. Therefore decreasing the variability, especially in a multicenter clinical trial setting, and establishing a minimum standard to ensure consistency in clinical trial data, without mandating axillary lymph node dissection, for all patients is necessary. The key elements which include proper staging and identification of nodal involvement at diagnosis, and appropriately targeted management of the axilla at the time of surgical resection are presented. The following protocols have been adopted as standard procedure by the I-SPY2 trial for management of axilla in patients with node positive disease, and present a framework for prospective clinical trials and practice.

Published
2018

9. Implementing stakeholder engagement to explore alternative models of consent: An example from the PREP-IT trials

Author

Slobogean, Gerard P., Bhandari, Mohit, Sprague, Sheila, D'Alleyrand, Jean-Claude, Harris, Anthony D., Mullins, Daniel C., Thabane, Lehana, Wells, Jeffrey, Wood, Amber, Della Rocca, Gregory J., Hebden, Joan, Jeray, Kyle J., Marchand, Lucas, O'Hara, Lyndsay M., Zura, Robert, Gardner, Michael J., Blasman, Jenna, Davies, Jonah, Liang, Stephen, Taljaard, Monica, Devereaux, P.J., Guyatt, Gordon H., Heels-Ansdell, Diane, Marvel, Debra, Palmer, Jana, Friedrich, Jeff, O'Hara, Nathan N., Grissom, Ms Frances, Gitajn, I. Leah, Morshed, Saam, O'Toole, Robert V., Petrisor, Bradley A., Camara, Megan, Mossuto, Franca, Joshi, Manjari G., Fowler, Justin, Rivera, Jessica, Talbot, Max, Dodds, Shannon, Garibaldi, Alisha, Li, Silvia, Nguyen, Uyen, Pogorzelski, David, Rojas, Alejandra, Scott, Taryn, Del Fabbro, Gina, Szasz, Olivia Paige, McKay, Paula, Howe, Andrea, Rudnicki, Joshua, Demyanovich, Haley, Little, Kelly, Mullins, C. Daniel, Medeiros, Michelle, Kettering, Eric, Hale, Diamond, Petrisor, Brad A., Johal, Herman, Ristevski, Bill, Williams, Dale, Denkers, Matthew, Rajaratnam, Krishan, Al-Asiri, Jamal, Leonard, Jordan, Marcano-Fernández, Francesc A., Gallant, Jodi, Persico, Federico, Gjorgjievski, Marko, George, Annie, Natoli, Roman M., Gaski, Greg E., McKinley, Todd O., Virkus, Walter W., Sorkin, Anthony T., Szatkowski, Jan P., Baele, Joseph R., Mullis, Brian H., Hill, Lauren C., Hudgins, Andrea, Osborn, Patrick, Pierrie, Sarah, Martinez, Eric, Kimmel, Joseph, Adams, John D., Beckish, Michael L., Bray, Christopher C., Brown, Timothy R., Cross, Andrew W., Dew, Timothy, Faucher, Gregory K., Gurich, Richard W., Jr., Lazarus, David E., Millon, S. John, Palmer, M. Jason, Porter, Scott E., Schaller, Thomas M., Sridhar, Michael S., Sanders, John L., Rudisill, L. Edwin, Jr., Garitty, Michael J., Poole, Andrew S., Sims, Michael L., Walker, Clark M., Carlisle, Robert M., II, Hofer, Erin Adams, Huggins, Brandon S., Hunter, Michael D., Marshall, William A., Ray, Shea Bielby, Smith, Cory D., Altman, Kyle M., Bedard, Julia C., Loeffler, Markus F., Pichiotino, Erin R., Cole, Austin A., Maltz, Ethan J., Parker, Wesley, Ramsey, T. Bennett, Burnikel, Alex, Colello, Michael, Stewart, Russell, Wise, Jeremy, Moody, M. Christian, Tanner, Stephanie L., Snider, Rebecca G., Townsend, Christine E., Pham, Kayla H., Martin, Abigail, Robertson, Emily, Miclau, Theodore, Kandemir, Utku, Marmor, Meir, Matityahu, Amir, McClellan, R. Trigg, Meinberg, Eric, Shearer, David, Toogood, Paul, Ding, Anthony, Donohoe, Erin, Murali, Jothi, Belaye, Tigist, Berhaneselase, Eleni, Paul, Alexandra, Garg, Kartik, Gary, Joshua L., Warner, Stephen J., Munz, John W., Choo, Andrew M., Achor, Timothy S., “Chip” Routt, Milton L., Rao, Mayank, Pechero, Guillermo, Miller, Adam, Hagen, Jennifer E., Patrick, Matthew, Vlasak, Richard, Krupko, Thomas, Sadasivan, Kalia, Koenig, Chris, Bailey, Daniel, Wentworth, Daniel, Van, Chi, Schwartz, Justin, Dehghan, Niloofar, Jones, Clifford B., Tracy Watson, J., McKee, Michael, Karim, Ammar, Talerico, Michael, Sietsema, Debra L., Williams, Alyse, Dykes, Tayler, Obremskey, William T., Jahangir, Amir Alex, Sethi, Manish, Boyce, Robert, Stinner, Daniel J., Mitchell, Phillip, Trochez, Karen, Rodriguez, Andres, Gajari, Vamshi, Rodriguez, Elsa, Pritchett, Charles, Boulton, Christina, Lowe, Jason, Wild, Jason, Ruth, John T., Taylor, Michel, Seach, Andrea, Saeed, Sabina, Culbert, Hunter, Cruz, Alejandro, Knapp, Thomas, Hurkett, Colin, Lowney, Maya, Prayson, Michael, Venkatarayappa, Indresh, Horne, Brandon, Jerele, Jennifer, Clark, Linda, Marcano-Fernández, Francesc, Jornet-Gibert, Montsant, Martínez-Carreres, Laia, Martí-Garín, David, Serrano-Sanz, Jorge, Sánchez-Fernández, Joel, Sanz-Molero, Matsuyama, Carballo, Alejandro, Pelfort, Xavier, Acerboni-Flores, Francesc, Alavedra-Massana, Anna, Anglada-Torres, Neus, Berenguer, Alexandre, Cámara-Cabrera, Jaume, Caparros-García, Ariadna, Fillat-Gomà, Ferran, Fuentes-López, Ruben, Garcia-Rodriguez, Ramona, Gimeno-Calavia, Nuria, Graells-Alonso, Guillem, Martínez-Álvarez, Marta, Martínez-Grau, Patricia, Pellejero-García, Raúl, Ràfols-Perramon, Ona, Peñalver, Juan Manuel, Domènech, Mònica Salomó, Soler-Cano, Albert, Velasco-Barrera, Aldo, Yela-Verdú, Christian, Bueno-Ruiz, Mercedes, Sánchez-Palomino, Estrella, Guerra-Farfan, Ernesto, Tomas-Hernandez, Jordi, Teixidor-Serra, Jordi, Molero-Garcia, Vicente, Selga-Marsa, Jordi, Porcel-Vasquez, Juan Antonio, Andres-Peiro, Jose Vicente, Minguell-Monyart, Joan, Garcia-Sanchez, Yaiza, Nuñez-Camarena, Jorge, Tauste-Rubio, Eladia, Gonzalez-Amigo, Marta, Romeo, Nicholas M., Vallier, Heather A., Breslin, Mary A., Fraifogl, Joanne, Wilson, Eleanor S., Wadenpfuhl, Leanne K., Halliday, Paul G., Viskontas, Darius G., Apostle, Kelly L., Boyer, Dory S., Moola, Farhad O., Perey, Bertrand H., Stone, Trevor B., Lemke, H. Michael, Zomar, Mauri, Spicer, Ella, Fan, Chen “Brenda”, Payne, Kyrsten, Phelps, Kevin, Bosse, Michael, Karunakar, Madhav, Kempton, Laurence, Sims, Stephen, Hsu, Joseph, Seymour, Rachel, Churchill, Christine, Bartel, Claire, Mayberry, Robert Miles, Brownrigg, Maggie, Girardi, Cara, Mayfield, Ada, Hymes, Robert A., Schwartzbach, Cary C., Schulman, Jeff E., Malekzadeh, A. Stephen, Holzman, Michael A., Ramsey, Lolita, Ahn, James S., Panjshiri, Farhanaz, Das, Sharmistha, English, Antoinisha D., Haaser, Sharon M., Cuff, Jaslynn A.N., Pilson, Holly, Carroll, Eben A., Halvorson, Jason J., Babcock, Sharon, Goodman, J. Brett, Holden, Martha B., Bullard, Debra, Williams, Wendy, Higgins, Thomas F., Haller, Justin M., Rothberg, David L., Marchand, Lucas S., Neese, Ashley, Russell, Mark, Olsen, Zachary M., Coe, Marcus, Dwyer, Kevin, Mullin, Devin S., Reilly, Clifford A., DePalo, Peter, Hall, Amy E., Heng, Marilyn, Harris, Mitchel B., Smith, R. Malcolm, Lhowe, David W., Esposito, John G., Bansal, Mira, Bergin, Patrick F., Russell, George V., Graves, Matthew L., Morellato, John, Champion, Heather K., Johnson, Leslie N., McGee, Sheketha L., Bhanat, Eldrin L., Mehta, Samir, Donegan, Derek, Ahn, Jaimo, Horan, Annamarie, Dooley, Mary, Kuczinski, Ashley, Iwu, Ashley, Potter, David, VanDemark, Robert, III, Pfaff, Branden, Hollinsworth, Troy, Weaver, Michael J., von Keudell, Arvind G., McTague, Michael F., Allen, Elizabeth M., Jaeblon, Todd, Beer, Robert, Demyanovich, Haley K., Gage, Mark J., Reilly, Rachel M., Sparrow, Cindy, Pechero, Guillermo, Jr., Holden, Martha, Wells, Jeff, Eglseder, Andrew, Johnson, Aaron, Langhammer, Christopher, Lebrun, Christopher, Manson, Theodore, Nascone, Jason, Paryavi, Ebrahim, Pensy, Raymond, Pollak, Andrew, Sciadini, Marcus, Degani, Yasmin, and Joseph, Katherine

Published
2021
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10. Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria.

Author

Guo, Zhijun, Sevrioukova, Irina, Denisov, Ilia, Zhang, Xia, Chiu, Ting-Lan, Thomas, Dafydd, Hanse, Eric, Cuellar, Rebecca, Grinkova, Yelena, Langenfeld, Vanessa, Swedien, Daniel, Stamschror, Justin, Alvarez, Juan, Luna, Fernando, Galván, Adela, Bae, Young, Wulfkuhle, Julia, Gallagher, Rosa, Petricoin, Emanuel, Norris, Beverly, Flory, Craig, Schumacher, Robert, OSullivan, M, Cao, Qing, Chu, Haitao, Lipscomb, John, Atkins, William, Gupta, Kalpna, Kelekar, Ameeta, Blair, Ian, Capdevila, Jorge, Falck, John, Sligar, Stephen, Poulos, Thomas, Georg, Gunda, Ambrose, Elizabeth, and Potter, David

Subjects
CYP3A4, autophagy, biguanide, breast cancer, cytochrome P450, electron transport chain, epoxyeicosatrienoic acid, hexyl-benzyl-biguanide, metformin, mitochondria, AMP-Activated Protein Kinases, Animals, Biguanides, Breast Neoplasms, Catalytic Domain, Cell Respiration, Cytochrome P-450 CYP3A, Estrogen Receptor alpha, Female, Gene Expression Regulation, Neoplastic, Gene Silencing, Heme, Humans, MCF-7 Cells, Membrane Potential, Mitochondrial, Mice, Mitochondria, Models, Molecular, Protein Transport
Abstract

The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPKα. CYP3A4 knockdown activated AMPKα, promoted autophagy, and prevented mammary tumor formation. The diabetes drug metformin inhibited CYP3A4-mediated EET biosynthesis and depleted cancer cell-intrinsic EETs. Metformin bound to the active-site heme of CYP3A4 in a co-crystal structure, establishing CYP3A4 as a biguanide target. Structure-based design led to discovery of N1-hexyl-N5-benzyl-biguanide (HBB), which bound to the CYP3A4 heme with higher affinity than metformin. HBB potently and specifically inhibited CYP3A4 AA epoxygenase activity. HBB also inhibited growth of established ER+ mammary tumors and suppressed intratumoral mTOR. CYP3A4 AA epoxygenase inhibition by biguanides thus demonstrates convergence between eicosanoid activity in mitochondria and biguanide action in cancer, opening a new avenue for cancer drug discovery.

Published
2017

11. Prolonged survival in patients with breast cancer and a history of brain metastases: results of a preplanned subgroup analysis from the randomized phase III BEACON trial

Author

Cortés, Javier, Rugo, Hope S, Awada, Ahmad, Twelves, Chris, Perez, Edith A, Im, Seock–Ah, Gómez-Pardo, Patricia, Schwartzberg, Lee S, Diéras, Veronique, Yardley, Denise A, Potter, David A, Mailliez, Audrey, Moreno-Aspitia, Alvaro, Ahn, Jin-Seok, Zhao, Carol, Hoch, Ute, Tagliaferri, Mary, Hannah, Alison L, and O’Shaughnessy, Joyce

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Cancer, Neurosciences, Clinical Trials and Supportive Activities, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Brain metastases, Etirinotecan pegol, NKTR-102, Chemotherapy, Metastatic breast cancer, Clinical Sciences, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeConventional chemotherapy has limited activity in patients with breast cancer and brain metastases (BCBM). Etirinotecan pegol (EP), a novel long-acting topoisomerase-1 inhibitor, was designed using advanced polymer technology to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels.MethodsThe phase 3 BEACON trial enrolled 852 women with heavily pretreated locally recurrent or metastatic breast cancer between 2011 and 2013. BEACON compared EP with treatment of physician's choice (TPC; eribulin, vinorelbine, gemcitabine, nab-paclitaxel, paclitaxel, ixabepilone, or docetaxel) in patients previously treated with anthracycline, taxane, and capecitabine, including those with treated, stable brain metastases. The primary endpoint, overall survival (OS), was assessed in a pre-defined subgroup of BCBM patients; an exploratory post hoc analysis adjusting for the diagnosis-specific graded prognostic assessment (GPA) index was also conducted.ResultsIn the trial, 67 BCBM patients were randomized (EP, n = 36; TPC, n = 31). Treatment subgroups were balanced for baseline characteristics and GPA indices. EP was associated with a significant reduction in the risk of death (HR 0.51; P

Published
2017

12. Managing work flow in high enrolling trials: The development and implementation of a sampling strategy in the PREPARE trial

Author

Slobogean, Gerard P., Sprague, Sheila, Wells, Jeffrey, Bhandari, Mohit, D'Alleyrand, Jean-Claude, Harris, Anthony D., Mullins, Daniel C., Thabane, Lehana, Wood, Amber, Della Rocca, Gregory J., Hebden, Joan, Jeray, Kyle J., Marchand, Lucas, O'Hara, Lyndsay M., Zura, Robert, Gardner, Michael J., Blasman, Jenna, Davies, Jonah, Liang, Stephen, Taljaard, Monica, Devereaux, P.J., Guyatt, Gordon H., Heels-Ansdell, Diane, Marvel, Debra, Palmer, Jana, Friedrich, Jeff, O'Hara, Nathan N., Grissom, Ms. Frances, Gitajn, I. Leah, Morshed, Saam, O'Toole, Robert V., Petrisor, Bradley A., Camara, Megan, Mossuto, Franca, Joshi, Manjari G., Fowler, Justin, Rivera, Jessica, Talbot, Max, Dodds, Shannon, Garibaldi, Alisha, Li, Silvia, Nguyen, Uyen, Pogorzelski, David, Rojas, Alejandra, Scott, Taryn, Del Fabbro, Gina, Szasz, Olivia Paige, McKay, Paula, Howe, Andrea, Rudnicki, Joshua, Demyanovich, Haley, Little, Kelly, Mullins, C. Daniel, Medeiros, Michelle, Kettering, Eric, Hale, Diamond, Eglseder, Andrew, Johnson, Aaron, Langhammer, Christopher, Lebrun, Christopher, Manson, Theodore, Nascone, Jason, Paryavi, Ebrahim, Pensy, Raymond, Pollak, Andrew, Sciadini, Marcus, Degani, Yasmin, Demyanovich, Haley K., Joseph, Katherine, Petrisor, Brad A., Johal, Herman, Ristevski, Bill, Williams, Dale, Denkers, Matthew, Rajaratnam, Krishan, Al-Asiri, Jamal, Leonard, Jordan, Marcano-Fernández, Francesc A., Gallant, Jodi, Persico, Federico, Gjorgjievski, Marko, George, Annie, Natoli, Roman M., Gaski, Greg E., McKinley, Todd O., Virkus, Walter W., Sorkin, Anthony T., Szatkowski, Jan P., Baele, Joseph R., Mullis, Brian H., Hill, Lauren C., Hudgins, Andrea, Osborn, Patrick, Pierrie, Sarah, Martinez, Eric, Kimmel, Joseph, Adams, John D., Beckish, Michael L., Bray, Christopher C., Brown, Timothy R., Cross, Andrew W., Dew, Timothy, Faucher, Gregory K., Gurich, Richard W., Jr., Lazarus, David E., Millon, S. John, Palmer, M. Jason, Porter, Scott E., Schaller, Thomas M., Sridhar, Michael S., Sanders, John L., Rudisill, L. Edwin, Jr., Garitty, Michael J., Poole, Andrew S., Sims, Michael L., Walker, Clark M., Carlisle, Robert M., II, Hofer, Erin Adams, Huggins, Brandon S., Hunter, Michael D., Marshall, William A., Ray, Shea Bielby, Smith, Cory D., Altman, Kyle M., Bedard, Julia C., Loeffler, Markus F., Pichiotino, Erin R., Cole, Austin A., Maltz, Ethan J., Parker, Wesley, Ramsey, T. Bennett, Burnikel, Alex, Colello, Michael, Stewart, Russell, Wise, Jeremy, Moody, M. Christian, Tanner, Stephanie L., Snider, Rebecca G., Townsend, Christine E., Pham, Kayla H., Martin, Abigail, Robertson, Emily, Miclau, Theodore, Kandemir, Utku, Marmor, Meir, Matityahu, Amir, McClellan, R. Trigg, Meinberg, Eric, Shearer, David, Toogood, Paul, Ding, Anthony, Donohue, Erin, Belaye, Tigist, Berhaneselase, Eleni, Paul, Alexandra, Garg, Kartik, Gary, Joshua L., Warner, Stephen J., Munz, John W., Choo, Andrew M., Achor, Timothy S., “Chip” Routt, Milton L., Rao, Mayank, Pechero, Guillermo, Miller, Adam, Hagen, Jennifer E., Patrick, Matthew, Vlasak, Richard, Krupko, Thomas, Sadasivan, Kalia, Koenig, Chris, Bailey, Daniel, Wentworth, Daniel, Van, Chi, Schwartz, Justin, Dehghan, Niloofar, Jones, Clifford B., Watson, J Tracy, McKee, Michael, Karim, Ammar, Talerico, Michael, Sietsema, Debra L., Williams, Alyse, Dykes, Tayler, Obremskey, William T., Jahangir, Amir Alex, Sethi, Manish, Boyce, Robert, Stinner, Daniel J., Mitchell, Phillip, Trochez, Karen, Rodriguez, Andres, Gajari, Vamshi, Rodriguez, Elsa, Pritchett, Charles, Boulton, Christina, Lowe, Jason, Wild, Jason, Ruth, John T., Taylor, Michel, Seach, Andrea, Saeed, Sabina, Culbert, Hunter, Cruz, Alejandro, Knapp, Thomas, Hurkett, Colin, Lowney, Maya, Prayson, Michael, Venkatarayappa, Indresh, Horne, Brandon, Jerele, Jennifer, Clark, Linda, Marcano-Fernández, Francesc, Jornet-Gibert, Montsant, Martínez-Carreres, Laia, Martí-Garín, David, Serrano-Sanz, Jorge, Sánchez-Fernández, Joel, Sanz-Molero, Matsuyama, Carballo, Alejandro, Pelfort, Xavier, Acerboni-Flores, Francesc, Alavedra-Massana, Anna, Anglada-Torres, Neus, Berenguer, Alexandre, Cámara-Cabrera, Jaume, Caparros-García, Ariadna, Fillat-Gomà, Ferran, Fuentes-López, Ruben, Garcia-Rodriguez, Ramona, Gimeno-Calavia, Nuria, Graells-Alonso, Guillem, Martínez-Álvarez, Marta, Martínez-Grau, Patricia, Pellejero-García, Raúl, Ràfols-Perramon, Ona, Peñalver, Juan Manuel, Domènech, Mònica Salomó, Soler-Cano, Albert, Velasco-Barrera, Aldo, Yela-Verdú, Christian, Bueno-Ruiz, Mercedes, Sánchez-Palomino, Estrella, Guerra, Ernesto, García, Yaiza, Romeo, Nicholas M., Vallier, Heather A., Breslin, Mary A., Fraifogl, Joanne, Wilson, Eleanor S., Wadenpfuhl, Leanne K., Halliday, Paul G., Viskontas, Darius G., Apostle, Kelly L., Boyer, Dory S., Moola, Farhad O., Perey, Bertrand H., Stone, Trevor B., Lemke, H. Michael, Zomar, Mauri, Spicer, Ella, Fan, Chen “Brenda”, Payne, Kyrsten, Phelps, Kevin, Bosse, Michael, Karunakar, Madhav, Kempton, Laurence, Sims, Stephen, Hsu, Joseph, Seymour, Rachel, Churchill, Christine, Bartel, Claire, Mayberry, Robert Miles, Brownrigg, Maggie, Girardi, Cara, Mayfield, Ada, Hymes, Robert A., Schwartzbach, Cary C., Schulman, Jeff E., Malekzadeh, A. Stephen, Holzman, Michael A., Ramsey, Lolita, Ahn, James S., Panjshiri, Farhanaz, Das, Sharmistha, English, Antoinisha D., Haaser, Sharon M., Cuff, Jaslynn A.N., Pilson, Holly, Carroll, Eben A., Halvorson, Jason J., Babcock, Sharon, Goodman, J. Brett, Holden, Martha B., Bullard, Debra, Williams, Wendy, Higgins, Thomas F., Haller, Justin M., Rothberg, David L., Neese, Ashley, Russell, Mark, Coe, Marcus, Dwyer, Kevin, Mullin, Devin S., Reilly, Clifford A., DePalo, Peter, Hall, Amy E., Heng, Marilyn, Harris, Mitchel B., Smith, R. Malcolm, Lhowe, David W., Esposito, John G., Bansal, Mira, Bergin, Patrick F., Russell, George V., Graves, Matthew L., Morellato, John, Champion, Heather K., Johnson, Leslie N., McGee, Sheketha L., Bhanat, Eldrin L., Mehta, Samir, Donegan, Derek, Ahn, Jaimo, Horan, Annamarie, Dooley, Mary, Kuczinski, Ashley, Iwu, Ashley, Potter, David, VanDemark, Robert, III, Pfaff, Branden, Hollinsworth, Troy, Weaver, Michael J., von Keudell, Arvind G., McTague, Michael F., Allen, Elizabeth M., Jaeblon, Todd, Beer, Robert, Gage, Mark J., Reilly, Rachel M., Sparrow, Cindy, and McGee, Sheketha

Published
2021
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15. Abstract 44: Hexyl-benzyl-biguanide (HBB) potently and selectively inhibits CYP3A4 epoxygenase activity and inhibits EET stabilization of mitochondrial respiration in ER+HER2- breast cancer cells, inducing glycolysis and pyruvate biosynthesis

Author

Guo, Zhijun, Sevrioukova, Irina, Hanse, Eric, Zhang, Xia, Denisov, Ilia, Chiu, Ting-Lan, Cuellar, Rebecca, Torres, Christian, Wulfkuhle, Julia, Petricoin, Emanuel, Cao, Qing, Chu, Haitao, Norris, Beverly, Schumacher, Robert, Kelekar, Ameeta, Blair, Ian, Capdevila, Jorge, Falck, John, Poulos, Thomas, Sligar, Steven, Georg, Gunda, Amin, Elizabeth, and Potter, David A

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Women's Health, Breast Cancer, Cancer, Clinical Research, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Abstract: Cytochrome P450 3A4 (CYP3A4) promotes ER+HER2- breast cancer cell proliferation and survival, in part, by biosynthesis of epoxyeicosatrienoic acids (EETs). EETs are known to regulate mitochondrial function in non-transformed cells, but the roles of CYP3A4 and EETs in regulation of breast cancer bioenergetics are unknown. Hexyl-benzyl-biguanide (HBB) is useful probe of CYP3A4 epoxygenase activity and selectively inhibits EET biosynthesis (IC50 = 9 uM vs. IC50 = 50 uM for CYP2C8). HBB caused depolarization of mitochondria in MCF-7 cells, while (±)-14,15-EET provided partial protection. The soluble epoxide hydrolase (sEH) inhibitor t-AUCB ameliorated inhibition of oxygen consumption rates (OCR) by HBB (20 uM), while there was no effect on extracellular acidification rate (ECAR), indicating that the primary effect of HBB is on OCR. At 30 minutes, HBB added to MCF-7 cells transiently suppressed phosphorylation of pyruvate kinase muscle isozyme 2 (PKM2) on Tyr-105, which has been reported to favor enzymatically inactive dimer over active tetramer. Suppression of phosphorylated PKM2 correlated with subsequent PKM2 tetramer formation and increase of intracellular pyruvate and extracellular lactate at 1 hour. The (±)-14,15-EET regioisomer reduced the pro-glycolytic PKM2 tetramer at 1 hour, suggesting that HBB may promote PKM2 tetramer, in part, through reduction of EET. Prolonged exposure to HBB (20 uM) in cultured cells activated phosphorylation of PKM2 on Tyr-105, but there was increased cellular necrosis correlating with reduced mitochondrial respiration and reduction of ATP stores, indicating that loss of respiration was the dominant effect. HBB inhibited the ER+HER2- MCF-7 xenograft, similar to CYP3A4 silencing. HBB promoted phosphorylation of intratumoral PKM2 on Tyr-105, consistent with long-term exposure to HBB in cultured MCF-7 cells. Notably, MCF-7 tumor response to HBB did not correlate with phosphorylation of AMPK-alpha on Thr-172, a marker of AMPK activation. Metformin (5 mM) exhibited no effect on PKM2 or its phosphorylation in cultured MCF-7 cells. Together, these results indicate that part of the inhibitory effect of HBB on ER+HER2- breast cancer is mediated through inhibition of respiration. Significance: These results establish HBB as a useful chemical probe of respiration, with indirect effects on PKM2 regulation. HBB may also be useful as a potential therapeutic candidate for ER+HER2- breast cancer. Citation Format: Zhijun Guo, Irina Sevrioukova, Eric Hanse, Xia Zhang, Ilia Denisov, Ting-Lan Chiu, Rebecca Cuellar, Christian Torres, Julia Wulfkuhle, Emanuel Petricoin, Qing Cao, Haitao Chu, Beverly Norris, Robert Schumacher, Ameeta Kelekar, Ian Blair, Jorge Capdevila, John Falck, Thomas Poulos, Steven Sligar, Gunda Georg, Elizabeth Amin, David A. Potter. Hexyl-benzyl-biguanide (HBB) potently and selectively inhibits CYP3A4 epoxygenase activity and inhibits EET stabilization of mitochondrial respiration in ER+HER2- breast cancer cells, inducing glycolysis and pyruvate biosynthesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 44.

Published
2016

18. Abstract 3568: CYP3A4 epoxygenase activity mediates ER+ mammary tumor growth and angiogenesis, in part, through EET biosynthesis and is inhibited by biguanides

Author

Guo, Zhijun, Sevrioukova, Irina F, Hanse, Eric, Denisov, Ilia, Zhang, Xia, Chiu, Ting-Lan, Swedien, Daniel, Stamschror, Justin, Alvarez, Juan, Ortiz, William Marerro, Morgan, Monique, Maher, Michael, Chavez, Kathryn J, Thomas, Dafydd, Bae, Young Kyung, Henriksen, Jonathan, Norris, Beverly, Schumacher, Robert J, Wang, Henry, Bliss, Robin, Chu, Haitao, Cuellar, Rebecca, Poulos, Thomas L, Sligar, Stephen G, Atkins, William, Schmechel, Stephen, Capdevila, Jorge, Falck, John, Blair, Ian, Jones, Jeffrey P, Georg, Gunda, Gupta, Kalpna, Kelekar, Ameeta, Amin, Elizabeth, and Potter, David A

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Breast Cancer, Cancer, Women's Health, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Abstract: While cytochrome P450 enzymes (CYPs) are implicated in tumor angiogenesis through biosynthesis of epoxyeicosatrienoic acids (EETs), little is known about breast cancer cell-intrinsic CYPs that exhibit epoxygenase activity, such as CYP3A4. In an orthotopic breast cancer model, silencing of epithelial CYP3A4 suppressed angiogenesis-related escape of ER+ breast tumors from dormancy. While the diabetes drug metformin inhibits mitochondrial complex I and inhibits tumor growth, how it does so is unknown. Metformin inhibited CYP epoxygenase activity and co-crystallized in the active site of CYP3A4, hydrogen bonding with arginine 212, allowing the development of hexyl-benzyl-biguanide (HBB) as a CYP3A4 inhibitor using molecular modeling. HBB exhibited more than 10-fold greater potency than metformin for inhibition of ER+ mammary tumor growth and inhibited associated tumor angiogenesis. HBB inhibited EET biosynthesis ∼40-fold more potently than metformin and was ∼40-fold more potent for activation of AMPK phosphorylation. EETs suppressed and CYP silencing promoted AMPK phosphorylation, linking CYPs with AMPK regulation in breast cancer. HBB depolarized mitochondria, reduced oxygen consumption rates and suppressed the Warburg effect, while EETs restored the mitochondrial membrane potential. CYP3A4 silencing and HBB treatment increased reactive oxygen species (ROS) production, suggesting that CYPs suppress cancer cell death, in part, through suppression of ROS. CYP3A4 silencing sensitized breast cancer cells to hormonal therapy and chemotherapy, abrogated by EETs. Because EETs are autocrine, paracrine and endocrine, these results implicate CYPs in tumor growth, in part, through cell-cell mediation of mitochondrial homeostasis and demonstrate the potential of CYP3A4 as a therapeutic target in breast cancer. Citation Format: Zhijun Guo, Irina F. Sevrioukova, Eric Hanse, Ilia Denisov, Xia Zhang, Ting-Lan Chiu, Daniel Swedien, Justin Stamschror, Juan Alvarez, William Marerro Ortiz, Monique Morgan, Michael Maher, Kathryn J. Chavez, Dafydd Thomas, Young Kyung Bae, Jonathan Henriksen, Beverly Norris, Robert J. Schumacher, Henry Wang, Robin Bliss, Haitao Chu, Rebecca Cuellar, Thomas L. Poulos, Stephen G. Sligar, William Atkins, Stephen Schmechel, Jorge Capdevila, John Falck, Ian Blair, Jeffrey P. Jones, Gunda Georg, Kalpna Gupta, Ameeta Kelekar, Elizabeth Amin, David A. Potter. CYP3A4 epoxygenase activity mediates ER+ mammary tumor growth and angiogenesis, in part, through EET biosynthesis and is inhibited by biguanides. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3568. doi:10.1158/1538-7445.AM2015-3568

Published
2015

20. Abstract 2689: Breast cancer inhibition by a novel and potent biguanide, N1-hexyl-N5-benzyl-biguanide

Author

Guo, Zhijun, Chavez, Kathryn J, Alvarez, Juan, Zhang, Xia, Norris, Beverly, Maher, Michael, Morgan, Monique, Schumacher, Robert J, Cuellar, Rebecca, Sevrioukova, Irina F, Poulos, Thomas L, Denisov, Ilia, Sligar, Stephen G, Gupta, Kalpna, Blair, Ian A, Capdevila, Jorge, Kelekar, Ameeta, Amin, Elizabeth, Georg, Gunda, and Potter, David A

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Orphan Drug, Rare Diseases, Prevention, Breast Cancer, Women's Health, Cancer, 5.1 Pharmaceuticals, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Abstract: Metformin is a widely used biguanide diabetes drug that is associated with decreased breast cancer risk and is currently being studied for treatment and prevention of breast cancer. While metformin and biguanides buformin and phenformin exhibit inhibitory activity against breast cancer in vitro and in vivo, they lack potency (IC50=5-20 mM) and their mechanisms of action remain unclear. More potent biguanides may provide insights into biguanide anti-cancer activity and we therefore studied the novel biguanide N1-hexyl-N5-benzyl-biguanide mesylate (HBB), which potently inhibits the MCF-7 and MDA-MB-231 breast cancer lines (IC50=20 uM for both lines). HBB induces AMPK phosphorylation in both lines at 10 uM concentration, whereas similarly dosed metformin, buformin or phenformin exhibits no activity. HBB also inhibits STAT3 phosphorylation at 10 uM concentration, whereas metformin dosed at 10 uM exhibits no activity. HBB reduced the mitochondrial membrane potential of both lines, but the effect was more prominent in the MDA-MB-231 line. HBB also induced ROS within 2.5 hours of exposure in the MCF-7 and MDA-MB-231 lines and caused rapid necrosis, but not apoptosis. N-acetylcysteine provides partial protection from HBB for MDA-231 line, but not the MCF-7 line. HBB provides proof of principle that highly potent biguanides can be synthesized with at least 250-fold greater potency than metformin, which can provide insights into the cancer inhibitory mechanisms of biguanide drugs. R01 CA113570, Randy Shaver Foundation, CTSI University of Minnesota Citation Format: Zhijun Guo, Kathryn J. Chavez, Juan Alvarez, Xia Zhang, Beverly Norris, Michael Maher, Monique Morgan, Robert J. Schumacher, Rebecca Cuellar, Irina F. Sevrioukova, Thomas L. Poulos, Ilia Denisov, Stephen G. Sligar, Kalpna Gupta, Ian A. Blair, Jorge Capdevila, Ameeta Kelekar, Elizabeth Amin, Gunda Georg, David A. Potter. Breast cancer inhibition by a novel and potent biguanide, N1-hexyl-N5-benzyl-biguanide. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2689. doi:10.1158/1538-7445.AM2014-2689

Published
2014

21. Do Some Men Love Ancient Rome for the Wrong Reasons?

Author

Potter, David

Subjects
News, opinion and commentary
Abstract

ROME AND PERSIA: The Seven Hundred Year Rivalry, by Adrian Goldsworthy PAX: War and Peace in Rome’s Golden Age, by Tom Holland The Roman Empire, an enormous multiethnic state that [...]

Published
2023

23. Organisations as sites of hegemonic struggle : an investigation into the micro cultural interactive processes that both produce and protect hegemony in a contemporary organisation

Author

Potter, David

Subjects
658.1
Abstract

Drawing on empirical research material from a Public Sector Service Organisation and secondary literature, this thesis explores the processes that produce, protect and facilitate the migration of hegemony in organisations. The purpose of the thesis is to contribute to the body of theory that describes and explains hegemonic processes. This thesis draws in particular on the theory of hegemony developed by Gramsci (1971) who is a common source that researchers of hegemony use. Gramsci proposed a three-dimensional model of hegemony, which contrasts with much of the Organisation and Management Studies literature in which hegemony is sometimes understood as a one-dimensional concept; as a form of socio-ideological control. This thesis seeks to make a contribution to the Organisation and Management Studies literature by synthesising the broader Gramscian conception with aspects of other applicable theories (Opler, 1945; Goffman, 1959; Blumer, 1969, Spradley, 1980; Bourdieu, 1991; and Hum phreys and Brown, 2002) and the constructs that emerge from empirical analysis, thereby developing a more encompassing explanatory model of the operation of hegemony in organisations. The findings of this research concur with Gramsci's conceptualisation of hegemony as a three-dimensional phenomenon: (1) a form of power; (2) as a dimension of social construction processes; and (3) as a theory of social change. Whilst Gramsci's model is intended to operate at the macro level of societal processes; it is not itself sufficient to explain the micro processes of hegemony. The Gramscian model will be supplemented using concepts derived from grounded theorising, informed by a literature review, on the basis of empirical research at the micro level of interaction within an organisational setting. This thesis develops and illustrates the application of a composite model through an ethnographic study which traces hegemonic practices as they impact on identities and perceived realities in the workplace. The emergent model seeks to explain, at the micro level of analysis, how hegemony is produced, migrates, and is protected within organisations.

Published
2008
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25. Higher Standards for Grade Promotion and Graduation: Unintended Effects of Reform.

Author

Potter, David C. and Wall, Mary Ellen

Abstract

Findings of a study that examined the effect of the reforms mandated by South Carolina's Educational Improvement Act of 1984 on student outcomes are presented in this paper. Specifically, the study sought to determine the impact of higher standards for grade promotion and graduation on retention rates, the proportions of students overage for their grade, different demographic groups, and student achievement between the years 1985-86 and 1989-90. Methodology involved analysis of statewide testing and demographic data and school policy reports submitted to the state department of education. Findings indicate that the stricter requirements created a high stakes testing environment. The data suggest modest gains in achievement but no improvement in the dropout rate and school holding power. In addition, student retention in grade increased, with differential effects on students with different demographic characteristics. A conclusion is that despite the modest improvement in achievement, the higher standards have had deleterious effects for some groups, particularly nonwhite males. Four figures and eight tables are included. (Contains 11 references.) (LMI)

Published
1992

26. Wnk1 Kinase Deficiency Lowers Blood Pressure in Mice: A Gene-Trap Screen to Identify Potential Targets for Therapeutic Intervention

Author

Zambrowicz, Brian P., Abuin, Alejandro, Ramirez-Solis, Ramiro, Richter, Lizabeth J., Piggott, James, BeltrandelRio, Hector, Buxton, Eric C., Edwards, Joel, Finch, Rick A., Friddle, Carl J., Gupta, Anupma, Hansen, Gwenn, Hu, Yi, Huang, Wenhu, Jaing, Crystal, Key,, Billie Wayne, Kipp, Peter, Kohlhauff, Buckley, Ma, Zhi-Qing, Markesich, Diane, Payne, Robert, Potter, David G., Qian, Ny, Shaw, Joseph, Schrick, Jeff, Shi, Zheng-Zheng, Sparks, Mary Jean, Van Sligtenhorst, Isaac, Vogel, Peter, Walke, Wade, Xu, Nianhua, Zhu, Qichao, Person, Christophe, and Sands, Arthur T.

Published
2003

30. Abstract LB102: Hexyl-(cuban-1-yl-methyl)-biguanide (HCB) suppresses N-glycosylation of immune checkpoint proteins B7-H3 and B7-H4, reverses tumor hypoxia, decreases intratumoral regulatory T cells, and increases intratumoral CD8+ T cells in the ovarian dependent ER+HER2- SSM2ucd mammary cancer allograft model

Author

Guo, Zhijun, primary, Lei, Jianxun, additional, Venkatesh, Hrishi, additional, Owen, David, additional, Bass, Adam, additional, Cannon, Christine, additional, McCarra, Joshua, additional, Koniar, Brenda, additional, Flory, Craig, additional, Norris, Beverly, additional, Schumacher, Robert J., additional, Jayaraman, Swaathi, additional, Hawse, John, additional, Antonarakis, Emmanuel S., additional, Petricoin, Emanuel F., additional, Wulfkuhle, Julia, additional, Cardiff, Robert D., additional, Ambrose, Elizabeth A., additional, Georg, Gunda I., additional, Schwertfeger, Kaylee L., additional, Farrar, Michael A., additional, Croix, Brad St., additional, Goetz, Matthew P., additional, and Potter, David A., additional

Published
2023
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33. Author Correction: Surgical Standards for Management of the Axilla in Breast Cancer Clinical Trials with Pathological Complete Response Endpoint

Author

Boughey, Judy C., Alvarado, Michael D., Lancaster, Rachael B., Symmans, W. Fraser, Mukhtar, Rita, Wong, Jasmine M., Ewing, Cheryl A., Potter, David A., Tuttle, Todd M., Hieken, Tina J., Carter, Jodi M., Jakub, James W., Kaplan, Henry G., Buchanan, Claire L., Jaskowiak, Nora T., Sattar, Husain A., Mueller, Jeffrey, Nanda, Rita, Isaacs, Claudine J., Pohlmann, Paula R., Lynce, Filipa, Tousimis, Eleni A., Zeck, Jay C., Lee, M. Catherine, Lang, Julie E., Mhawech-Fauceglia, Paulette, Rao, Roshni, Taback, Bret, Goodellas, Constantine, Chen, Margaret, Kalinsky, Kevin M., Hibshoosh, Hanina, Killelea, Brigid, Sanft, Tara, Hirst, Gillian L., Asare, Smita, Matthews, Jeffrey B., Perlmutter, Jane, Esserman, Laura J., and I-SPY2 Investigators

Published
2019
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34. NOTUM inhibition increases endocortical bone formation and bone strength

Author

Brommage, Robert, Liu, Jeff, Vogel, Peter, Mseeh, Faika, Thompson, Andrea Y., Potter, David G., Shadoan, Melanie K., Hansen, Gwenn M., Jeter-Jones, Sabrina, Cui, Jie, Bright, Dawn, Bardenhagen, Jennifer P., Doree, Deon D., Movérare-Skrtic, Sofia, Nilsson, Karin H., Henning, Petra, Lerner, Ulf H., Ohlsson, Claes, Sands, Arthur T., Tarver, James E., Powell, David R., Zambrowicz, Brian, and Liu, Qingyun

Published
2019
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38. Machine-learning Based Niche Modeling for Identification of Mayaro Virus Risk and Climatic Correlates in the Americas

Author

PMB, SOM, Michael Celone, Barbara A. Han, Sean Beeman, Alex Potter, David Pecor, Bernard Okech, Simon Pollett, PMB, SOM, Michael Celone, and Barbara A. Han, Sean Beeman, Alex Potter, David Pecor, Bernard Okech, Simon Pollett

Abstract

Machine-learning Based Niche Modeling for Identification of Mayaro Virus Risk and Climatic Correlates in the Americas Michael Celone1, Barbara A. Han2, Sean Beeman1, Alex Potter3,4, David Pecor3,4, Bernard Okech1, Simon Pollett 5,6 1 Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Department of Preventive Medicine & Biostatistics, Bethesda, Maryland; 2 Cary Institute of Ecosystem Studies, NY, USA; 3 One Health Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA; 4 Walter Reed Biosystematics Unit, Suitland, MD, USA; 5 Infectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA; 6 Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA DISCUSSION INTRODUCTION RESULTS METHODS Figure 1. Map of MAYV occurrence by location type. ADM = Administrative unit. Not shown is one occurrence location in Haiti and two locations in Mexico. Mayaro virus (MAYV) is a zoonotic Alphavirus that is endemic in several Latin American countries. Risk factors include residing near forested areas and hunting in the rainforest, highlighting the importance of sylvatic transmission and the potential for spillover events. Although a prior epidemiological alert by the Pan-American Health Organization emphasized the need for extended MAYV surveillance in the Americas, the precise areas of risk from MAYV remains unclear. The goal of the current study was to develop an ecological niche model of MAYV occurrence in the Americas in order to predict the distribution of MAYV risk throughout this region. Figure 3. Predicted ecological niche of MAYV. This map represents the predicted suitability of MAYV based on the average over the 100 sub-models, with 10 climate, vegetation, land-cover, and topographic covariates. The contents, views or opinions expressed in this publication or presentation are those, RITM0030239, Mayaro virus (MAYV) is a zoonotic Alphavirus that is endemic in several Latin American countries. Risk factors include residing near forested areas and hunting in the rainforest, highlighting the importance of sylvatic transmission and the potential for spillover events. Although a prior epidemiological alert by the Pan-American Health Organization emphasized the need for extended MAYV surveillance in the Americas, the precise areas of risk from MAYV remains unclear. The goal of the current study was to develop an ecological niche model of MAYV occurrence in the Americas in order to predict the distribution of MAYV risk throughout this region.

Published
2022

41. Abstract LB564: (±) 14,15-epoxyeicosatrienoic acid induces hallmark ER and MYC gene expression and associated ER and c-Myc nuclear translocation in ER+/HER2- breast cancer cells

Author

Lei, Jianxun, primary, Guo, Zhijun, additional, Molina-Vega, Julissa, additional, Cervantes, Paloma, additional, Jayaraman, Swaathi, additional, Hawse, John R., additional, Perez, Carlos, additional, Abrahante, Juan, additional, Tang, Xiaojia, additional, Kalari, Krishna, additional, Wang, Jinhua, additional, Falck, John R., additional, Lange, Carol, additional, Goetz, Matthew P., additional, and Potter, David, additional

Published
2022
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45. CYP3A4 Mediates Growth of Estrogen Receptor-positive Breast Cancer Cells in Part by Inducing Nuclear Translocation of Phospho-Stat3 through Biosynthesis of (±)-14,15-Epoxyeicosatrienoic Acid (EET)

Author

Mitra, Ranjana, Guo, Zhijun, Milani, Monica, Mesaros, Clementina, Rodriguez, Mariangellys, Nguyen, Julia, Luo, Xianghua, Clarke, Duncan, Lamba, Jatinder, Schuetz, Erin, Donner, David B., Puli, Narender, Falck, John R., Capdevila, Jorge, Gupta, Kalpna, Blair, Ian A., and Potter, David A.

Published
2011
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47. Abstract PD8-07: Evaluation of Tucatinib + (Paclitaxel + Pertuzumab + Trastuzumab) followed by AC in high-risk HER2 positive (HER2+) stage II/III breast cancer: Results from the I-SPY 2 TRIAL

Author

Potter, David A, primary, Roesch, Erin, additional, Yau, Christina, additional, Lu, Ruixiao, additional, Wolf, Denise, additional, Samson, Susan, additional, Stafford, Debra, additional, Albain, Kathy S, additional, Isaacs, Claudine, additional, Trivedi, Meghana, additional, Yee, Douglas, additional, Boughey, Judy, additional, Thomas, Alexandra, additional, Chien, A. Jo, additional, Hylton, Nola, additional, Li, Wen, additional, DeMichele, Angela, additional, Perlmutter, Jane, additional, Symmans, W. Fraser, additional, Hershman, Dawn L, additional, Melisko, Michelle, additional, van 't Veer, Laura J, additional, Wilson, Amy, additional, Asare, Smita M, additional, Berry, Donald A, additional, Schwab, Richard, additional, Rugo, Hope S, additional, and Esserman, Laura J, additional

Published
2022
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49. PBTE: Problem Solver or Problem Maker? Methodological Problems and Issues.

Author

Potter, David A.

Abstract

Competency-based teacher education (CBTE) cannot be defended unless a systematic large-scale research effort is directed to discovering the linkage between patterns of teacher behavior and student change. A more immediate need, however, is the development of techniques that (a) permit assessment of skills trainees possess, and (b) provide training in areas where performance is inadequate. The Teacher Behavior Research Group and the Intern Teaching Program, both in the process of developing a CBTE compenent, collaborated in a research program focused on these areas. The two groups jointly created a paradigm which allowed causal inferences to be drawn about (a) the effectiveness of training procedures, and (b) observed relationships between criterion teacher behaviors and student achievement. Results of the study indicated several inherent problems in measuring microteaching studies of teacher behavior when student achievement was the dependent variable. These problems are: (a) lesson content must be unfamiliar yet interesting to students, and it must incorporate intended teacher behaviors; (b) objectives must be limited in scope, and clearly and precisely defined: and (c) teacher behaviors must be manipulated systematically in order to obtain accurate experimental data. (JS)

Published
1975

50. Job Analysis of Teaching. Final Report.

Author

Educational Testing Service, Princeton, NJ. and Potter, David A.

Abstract

Because courts have required that selection tests be job-related, this study was undertaken to provide a practical means of performing a job analysis of teaching. Several court decisions are discussed, including Griggs v. Duke Power Company and Chance v. Board of Examiners, with respect to both Fourteenth Amendment and statutory issues. In the first phase of the job analysis, a questionnaire instrument was developed, based on the work of 48 teachers in 6 committees representing 2 school districts and 3 school levels: elementary, middle, and secondary. These committees developed lists of 14 teaching functions and 298 tasks. From this data, a 294-item questionnaire was developed, administered to 831 teachers in 19 districts in New York State, and the results were factor analyzed. Nine reliable oblique, but distinct, factors were found: busy work; administration (school); testing and evaluation; breadth of instructional goals; counseling; administration (classroom); teaching; enrichment; and extra-curricular activities. Differences in the importance of the nine factors were found to be related primarily to grade level taught. School district and years of teaching experience were also situational determinants. (The job analysis questionnaire is appended). (CTM)

Published
1980

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