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1. The James Webb Space Telescope Mission

Author: Gardner, Jonathan P., Mather, John C., Abbott, Randy, Abell, James S., Abernathy, Mark, Abney, Faith E., Abraham, John G., Abraham, Roberto, Abul-Huda, Yasin M., Acton, Scott, Adams, Cynthia K., Adams, Evan, Adler, David S., Adriaensen, Maarten, Aguilar, Jonathan Albert, Ahmed, Mansoor, Ahmed, Nasif S., Ahmed, Tanjira, Albat, Rüdeger, Albert, Loïc, Alberts, Stacey, Aldridge, David, Allen, Mary Marsha, Allen, Shaune S., Altenburg, Martin, Altunc, Serhat, Alvarez, Jose Lorenzo, Álvarez-Márquez, Javier, de Oliveira, Catarina Alves, Ambrose, Leslie L., Anandakrishnan, Satya M., Andersen, Gregory C., Anderson, Harry James, Anderson, Jay, Anderson, Kristen, Anderson, Sara M., Aprea, Julio, Archer, Benita J., Arenberg, Jonathan W., Argyriou, Ioannis, Arribas, Santiago, Artigau, Étienne, Arvai, Amanda Rose, Atcheson, Paul, Atkinson, Charles B., Averbukh, Jesse, Aymergen, Cagatay, Bacinski, John J., Baggett, Wayne E., Bagnasco, Giorgio, Baker, Lynn L., Balzano, Vicki Ann, Banks, Kimberly A., Baran, David A., Barker, Elizabeth A., Barrett, Larry K., Barringer, Bruce O., Barto, Allison, Bast, William, Baudoz, Pierre, Baum, Stefi, Beatty, Thomas G., Beaulieu, Mathilde, Bechtold, Kathryn, Beck, Tracy, Beddard, Megan M., Beichman, Charles, Bellagama, Larry, Bely, Pierre, Berger, Timothy W., Bergeron, Louis E., Darveau-Bernier, Antoine, Bertch, Maria D., Beskow, Charlotte, Betz, Laura E., Biagetti, Carl P., Birkmann, Stephan, Bjorklund, Kurt F., Blackwood, James D., Blazek, Ronald Paul, Blossfeld, Stephen, Bluth, Marcel, Boccaletti, Anthony, Boegner Jr., Martin E., Bohlin, Ralph C., Boia, John Joseph, Böker, Torsten, Bonaventura, N., Bond, Nicholas A., Bosley, Kari Ann, Boucarut, Rene A., Bouchet, Patrice, Bouwman, Jeroen, Bower, Gary, Bowers, Ariel S., Bowers, Charles W., Boyce, Leslye A., Boyer, Christine T., Boyer, Martha L., Boyer, Michael, Boyer, Robert, Bradley, Larry D., Brady, Gregory R., Brandl, Bernhard R., Brannen, Judith L., Breda, David, Bremmer, Harold G., Brennan, David, Bresnahan, Pamela A., Bright, Stacey N., Broiles, Brian J., Bromenschenkel, Asa, Brooks, Brian H., Brooks, Keira J., Brown, Bob, Brown, Bruce, Brown, Thomas M., Bruce, Barry W., Bryson, Jonathan G., Bujanda, Edwin D., Bullock, Blake M., Bunker, A. J., Bureo, Rafael, Burt, Irving J., Bush, James Aaron, Bushouse, Howard A., Bussman, Marie C., Cabaud, Olivier, Cale, Steven, Calhoon, Charles D., Calvani, Humberto, Canipe, Alicia M., Caputo, Francis M., Cara, Mihai, Carey, Larkin, Case, Michael Eli, Cesari, Thaddeus, Cetorelli, Lee D., Chance, Don R., Chandler, Lynn, Chaney, Dave, Chapman, George N., Charlot, S., Chayer, Pierre, Cheezum, Jeffrey I., Chen, Bin, Chen, Christine H., Cherinka, Brian, Chichester, Sarah C., Chilton, Zachary S., Chittiraibalan, Dharini, Clampin, Mark, Clark, Charles R., Clark, Kerry W., Clark, Stephanie M., Claybrooks, Edward E., Cleveland, Keith A., Cohen, Andrew L., Cohen, Lester M., Colón, Knicole D., Coleman, Benee L., Colina, Luis, Comber, Brian J., Comeau, Thomas M., Comer, Thomas, Reis, Alain Conde, Connolly, Dennis C., Conroy, Kyle E., Contos, Adam R., Contreras, James, Cook, Neil J., Cooper, James L., Cooper, Rachel Aviva, Correia, Michael F., Correnti, Matteo, Cossou, Christophe, Costanza, Brian F., Coulais, Alain, Cox, Colin R., Coyle, Ray T., Cracraft, Misty M., Noriega-Crespo, Alberto, Crew, Keith A., Curtis, Gary J., Cusveller, Bianca, Maciel, Cleyciane Da Costa, Dailey, Christopher T., Daugeron, Frédéric, Davidson, Greg S., Davies, James E., Davis, Katherine Anne, Davis, Michael S., Day, Ratna, de Chambure, Daniel, de Jong, Pauline, De Marchi, Guido, Dean, Bruce H., Decker, John E., Delisa, Amy S., Dell, Lawrence C., Dellagatta, Gail, Dembinska, Franciszka, Demosthenes, Sandor, Dencheva, Nadezhda M., Deneu, Philippe, DePriest, William W., Deschenes, Jeremy, Dethienne, Nathalie, Detre, Örs Hunor, Diaz, Rosa Izela, Dicken, Daniel, DiFelice, Audrey S., Dillman, Matthew, Disharoon, Maureen O., van Dishoeck, Ewine F., Dixon, William V., Doggett, Jesse B., Dominguez, Keisha L., Donaldson, Thomas S., Doria-Warner, Cristina M., Santos, Tony Dos, Doty, Heather, Douglas Jr., Robert E., Doyon, René, Dressler, Alan, Driggers, Jennifer, Driggers, Phillip A., Dunn, Jamie L., DuPrie, Kimberly C., Dupuis, Jean, Durning, John, Dutta, Sanghamitra B., Earl, Nicholas M., Eccleston, Paul, Ecobichon, Pascal, Egami, Eiichi, Ehrenwinkler, Ralf, Eisenhamer, Jonathan D., Eisenhower, Michael, Eisenstein, Daniel J., Hamel, Zaky El, Elie, Michelle L., Elliott, James, Elliott, Kyle Wesley, Engesser, Michael, Espinoza, Néstor, Etienne, Odessa, Etxaluze, Mireya, Evans, Leah, Fabreguettes, Luce, Falcolini, Massimo, Falini, Patrick R., Fatig, Curtis, Feeney, Matthew, Feinberg, Lee D., Fels, Raymond, Ferdous, Nazma, Ferguson, Henry C., Ferrarese, Laura, Ferreira, Marie-Héléne, Ferruit, Pierre, Ferry, Malcolm, Filippazzo, Joseph Charles, Firre, Daniel, Fix, Mees, Flagey, Nicolas, Flanagan, Kathryn A., Fleming, Scott W., Florian, Michael, Flynn, James R., Foiadelli, Luca, Fontaine, Mark R., Fontanella, Erin Marie, Forshay, Peter Randolph, Fortner, Elizabeth A., Fox, Ori D., Framarini, Alexandro P., Francisco, John I., Franck, Randy, Franx, Marijn, Franz, David E., Friedman, Scott D., Friend, Katheryn E., Frost, James R., Fu, Henry, Fullerton, Alexander W., Gaillard, Lionel, Galkin, Sergey, Gallagher, Ben, Galyer, Anthony D., Marín, Macarena García, Gardner, Lisa E., Garland, Dennis, Garrett, Bruce Albert, Gasman, Danny, Gáspár, András, Gastaud, René, Gaudreau, Daniel, Gauthier, Peter Timothy, Geers, Vincent, Geithner, Paul H., Gennaro, Mario, Gerber, John, Gereau, John C., Giampaoli, Robert, Giardino, Giovanna, Gibbons, Paul C., Gilbert, Karolina, Gilman, Larry, Girard, Julien H., Giuliano, Mark E., Gkountis, Konstantinos, Glasse, Alistair, Glassmire, Kirk Zachary, Glauser, Adrian Michael, Glazer, Stuart D., Goldberg, Joshua, Golimowski, David A., Gonzaga, Shireen P., Gordon, Karl D., Gordon, Shawn J., Goudfrooij, Paul, Gough, Michael J., Graham, Adrian J., Grau, Christopher M., Green, Joel David, Greene, Gretchen R., Greene, Thomas P., Greenfield, Perry E., Greenhouse, Matthew A., Greve, Thomas R., Greville, Edgar M., Grimaldi, Stefano, Groe, Frank E., Groebner, Andrew, Grumm, David M., Grundy, Timothy, Güdel, Manuel, Guillard, Pierre, Guldalian, John, Gunn, Christopher A., Gurule, Anthony, Gutman, Irvin Meyer, Guy, Paul D., Guyot, Benjamin, Hack, Warren J., Haderlein, Peter, Hagan, James B., Hagedorn, Andria, Hainline, Kevin, Haley, Craig, Hami, Maryam, Hamilton, Forrest Clifford, Hammann, Jeffrey, Hammel, Heidi B., Hanley, Christopher J., Hansen, Carl August, Hardy, Bruce, Harnisch, Bernd, Harr, Michael Hunter, Harris, Pamela, Hart, Jessica Ann, Hartig, George F., Hasan, Hashima, Hashim, Kathleen Marie, Hashimoto, Ryan, Haskins, Sujee J., Hawkins, Robert Edward, Hayden, Brian, Hayden, William L., Healy, Mike, Hecht, Karen, Heeg, Vince J., Hejal, Reem, Helm, Kristopher A., Hengemihle, Nicholas J., Henning, Thomas, Henry, Alaina, Henry, Ronald L., Henshaw, Katherine, Hernandez, Scarlin, Herrington, Donald C., Heske, Astrid, Hesman, Brigette Emily, Hickey, David L., Hilbert, Bryan N., Hines, Dean C., Hinz, Michael R., Hirsch, Michael, Hitcho, Robert S., Hodapp, Klaus, Hodge, Philip E., Hoffman, Melissa, Holfeltz, Sherie T., Holler, Bryan Jason, Hoppa, Jennifer Rose, Horner, Scott, Howard, Joseph M., Howard, Richard J., Huber, Jean M., Hunkeler, Joseph S., Hunter, Alexander, Hunter, David Gavin, Hurd, Spencer W., Hurst, Brendan J., Hutchings, John B., Hylan, Jason E., Ignat, Luminita Ilinca, Illingworth, Garth, Irish, Sandra M., Isaacs III, John C., Jackson Jr., Wallace C., Jaffe, Daniel T., Jahic, Jasmin, Jahromi, Amir, Jakobsen, Peter, James, Bryan, James, John C., James, LeAndrea Rae, Jamieson, William Brian, Jandra, Raymond D., Jayawardhana, Ray, Jedrzejewski, Robert, Jeffers, Basil S., Jensen, Peter, Joanne, Egges, Johns, Alan T., Johnson, Carl A., Johnson, Eric L., Johnson, Patricia, Johnson, Phillip Stephen, Johnson, Thomas K., Johnson, Timothy W., Johnstone, Doug, Jollet, Delphine, Jones, Danny P., Jones, Gregory S., Jones, Olivia C., Jones, Ronald A., Jones, Vicki, Jordan, Ian J., Jordan, Margaret E., Jue, Reginald, Jurkowski, Mark H., Justis, Grant, Justtanont, Kay, Kaleida, Catherine C., Kalirai, Jason S., Kalmanson, Phillip Cabrales, Kaltenegger, Lisa, Kammerer, Jens, Kan, Samuel K., Kanarek, Graham Childs, Kao, Shaw-Hong, Karakla, Diane M., Karl, Hermann, Kassin, Susan A., Kauffman, David D., Kavanagh, Patrick, Kelley, Leigh L., Kelly, Douglas M., Kendrew, Sarah, Kennedy, Herbert V., Kenny, Deborah A., Keski-Kuha, Ritva A., Keyes, Charles D., Khan, Ali, Kidwell, Richard C., Kimble, Randy A., King, James S., King, Richard C., Kinzel, Wayne M., Kirk, Jeffrey R., Kirkpatrick, Marc E., Klaassen, Pamela, Klingemann, Lana, Klintworth, Paul U., Knapp, Bryan Adam, Knight, Scott, Knollenberg, Perry J., Knutsen, Daniel Mark, Koehler, Robert, Koekemoer, Anton M., Kofler, Earl T., Kontson, Vicki L., Kovacs, Aiden Rose, Kozhurina-Platais, Vera, Krause, Oliver, Kriss, Gerard A., Krist, John, Kristoffersen, Monica R., Krogel, Claudia, Krueger, Anthony P., Kulp, Bernard A., Kumari, Nimisha, Kwan, Sandy W., Kyprianou, Mark, Labador, Aurora Gadiano, Labiano, Álvaro, Lafrenière, David, Lagage, Pierre-Olivier, Laidler, Victoria G., Laine, Benoit, Laird, Simon, Lajoie, Charles-Philippe, Lallo, Matthew D., Lam, May Yen, LaMassa, Stephanie Marie, Lambros, Scott D., Lampenfield, Richard Joseph, Lander, Matthew Ed, Langston, James Hutton, Larson, Kirsten, Larson, Melora, LaVerghetta, Robert Joseph, Law, David R., Lawrence, Jon F., Lee, David W., Lee, Janice, Lee, Yat-Ning Paul, Leisenring, Jarron, Leveille, Michael Dunlap, Levenson, Nancy A., Levi, Joshua S., Levine, Marie B., Lewis, Dan, Lewis, Jake, Lewis, Nikole, Libralato, Mattia, Lidon, Norbert, Liebrecht, Paula Louisa, Lightsey, Paul, Lilly, Simon, Lim, Frederick C., Lim, Pey Lian, Ling, Sai-Kwong, Link, Lisa J., Link, Miranda Nicole, Lipinski, Jamie L., Liu, XiaoLi, Lo, Amy S., Lobmeyer, Lynette, Logue, Ryan M., Long, Chris A., Long, Douglas R., Long, Ilana D., Long, Knox S., López-Caniego, Marcos, Lotz, Jennifer M., Love-Pruitt, Jennifer M., Lubskiy, Michael, Luers, Edward B., Luetgens, Robert A., Luevano, Annetta J., Lui, Sarah Marie G. Flores, Lund III, James M., Lundquist, Ray A., Lunine, Jonathan, Lützgendorf, Nora, Lynch, Richard J., MacDonald, Alex J., MacDonald, Kenneth, Macias, Matthew J., Macklis, Keith I., Maghami, Peiman, Maharaja, Rishabh Y., Maiolino, Roberto, Makrygiannis, Konstantinos G., Malla, Sunita Giri, Malumuth, Eliot M., Manjavacas, Elena, Marini, Andrea, Marrione, Amanda, Marston, Anthony, Martel, André R, Martin, Didier, Martin, Peter G., Martinez, Kristin L., Maschmann, Marc, Masci, Gregory L., Masetti, Margaret E., Maszkiewicz, Michael, Matthews, Gary, Matuskey, Jacob E., McBrayer, Glen A., McCarthy, Donald W., McCaughrean, Mark J., McClare, Leslie A., McClare, Michael D., McCloskey, John C., McClurg, Taylore D., McCoy, Martin, McElwain, Michael W., McGregor, Roy D., McGuffey, Douglas B., McKay, Andrew G., McKenzie, William K., McLean, Brian, McMaster, Matthew, McNeil, Warren, De Meester, Wim, Mehalick, Kimberly L., Meixner, Margaret, Meléndez, Marcio, Menzel, Michael P., Menzel, Michael T., Merz, Matthew, Mesterharm, David D., Meyer, Michael R., Meyett, Michele L., Meza, Luis E., Midwinter, Calvin, Milam, Stefanie N., Miller, Jay Todd, Miller, William C., Miskey, Cherie L., Misselt, Karl, Mitchell, Eileen P., Mohan, Martin, Montoya, Emily E., Moran, Michael J., Morishita, Takahiro, Moro-Martín, Amaya, Morrison, Debra L., Morrison, Jane, Morse, Ernie C., Moschos, Michael, Moseley, S. H., Mosier, Gary E., Mosner, Peter, Mountain, Matt, Muckenthaler, Jason S., Mueller, Donald G., Mueller, Migo, Muhiem, Daniella, Mühlmann, Prisca, Mullally, Susan Elizabeth, Mullen, Stephanie M., Munger, Alan J, Murphy, Jess, Murray, Katherine T., Muzerolle, James C., Mycroft, Matthew, Myers, Andrew, Myers, Carey R., Myers, Fred Richard R., Myers, Richard, Myrick, Kaila, Nagle IV, Adrian F., Nayak, Omnarayani, Naylor, Bret, Neff, Susan G., Nelan, Edmund P., Nella, John, Nguyen, Duy Tuong, Nguyen, Michael N., Nickson, Bryony, Nidhiry, John Joseph, Niedner, Malcolm B., Nieto-Santisteban, Maria, Nikolov, Nikolay K., Nishisaka, Mary Ann, Nota, Antonella, O'Mara, Robyn C., Oboryshko, Michael, O'Brien, Marcus B., Ochs, William R., Offenberg, Joel D., Ogle, Patrick Michael, Ohl, Raymond G., Olmsted, Joseph Hamden, Osborne, Shannon Barbara, O'Shaughnessy, Brian Patrick, Östlin, Göran, O'Sullivan, Brian, Otor, O. Justin, Ottens, Richard, Ouellette, Nathalie N. -Q., Outlaw, Daria J., Owens, Beverly A., Pacifici, Camilla, Page, James Christophe, Paranilam, James G., Park, Sang, Parrish, Keith A., Paschal, Laura, Patapis, Polychronis, Patel, Jignasha, Patrick, Keith, Pattishall Jr., Robert A., Paul, Douglas William, Paul, Shirley J., Pauly, Tyler Andrew, Pavlovsky, Cheryl M., Peña-Guerrero, Maria, Pedder, Andrew H., Peek, Matthew Weldon, Pelham, Patricia A., Penanen, Konstantin, Perriello, Beth A., Perrin, Marshall D., Perrine, Richard F., Perrygo, Chuck, Peslier, Muriel, Petach, Michael, Peterson, Karla A., Pfarr, Tom, Pierson, James M., Pietraszkiewicz, Martin, Pilchen, Guy, Pipher, Judy L., Pirzkal, Norbert, Pitman, Joseph T., Player, Danielle M., Plesha, Rachel, Plitzke, Anja, Pohner, John A., Poletis, Karyn Konstantin, Pollizzi, Joseph A., Polster, Ethan, Pontius, James T., Pontoppidan, Klaus, Porges, Susana C., Potter, Gregg D., Prescott, Stephen, Proffitt, Charles R., Pueyo, Laurent, Neira, Irma Aracely Quispe, Radich, Armando, Rager, Reiko T., Rameau, Julien, Ramey, Deborah D., Alarcon, Rafael Ramos, Rampini, Riccardo, Rapp, Robert, Rashford, Robert A., Rauscher, Bernard J., Ravindranath, Swara, Rawle, Timothy, Rawlings, Tynika N., Ray, Tom, Regan, Michael W., Rehm, Brian, Rehm, Kenneth D., Reid, Neill, Reis, Carl A., Renk, Florian, Reoch, Tom B., Ressler, Michael, Rest, Armin W., Reynolds, Paul J., Richon, Joel G., Richon, Karen V., Ridgaway, Michael, Riedel, Adric Richard, Rieke, George H., Rieke, Marcia, Rifelli, Richard E., Rigby, Jane R., Riggs, Catherine S., Ringel, Nancy J., Ritchie, Christine E., Rix, Hans-Walter, Robberto, Massimo, Robinson, Michael S., Robinson, Orion, Rock, Frank W., Rodriguez, David R., del Pino, Bruno Rodríguez, Roellig, Thomas, Rohrbach, Scott O., Roman, Anthony J., Romelfanger, Frederick J., Romo Jr., Felipe P., Rosales, Jose J., Rose, Perry, Roteliuk, Anthony F., Roth, Marc N., Rothwell, Braden Quinn, Rouzaud, Sylvain, Rowe, Jason, Rowlands, Neil, Roy, Arpita, Royer, Pierre, Rui, Chunlei, Rumler, Peter, Rumpl, William, Russ, Melissa L., Ryan, Michael B., Ryan, Richard M., Saad, Karl, Sabata, Modhumita, Sabatino, Rick, Sabbi, Elena, Sabelhaus, Phillip A., Sabia, Stephen, Sahu, Kailash C., Saif, Babak N., Salvignol, Jean-Christophe, Samara-Ratna, Piyal, Samuelson, Bridget S., Sanders, Felicia A., Sappington, Bradley, Sargent, B. A., Sauer, Arne, Savadkin, Bruce J., Sawicki, Marcin, Schappell, Tina M., Scheffer, Caroline, Scheithauer, Silvia, Scherer, Ron, Schiff, Conrad, Schlawin, Everett, Schmeitzky, Olivier, Schmitz, Tyler S., Schmude, Donald J., Schneider, Analyn, Schreiber, Jürgen, Schroeven-Deceuninck, Hilde, Schultz, John J., Schwab, Ryan, Schwartz, Curtis H., Scoccimarro, Dario, Scott, John F., Scott, Michelle B., Seaton, Bonita L., Seely, Bruce S., Seery, Bernard, Seidleck, Mark, Sembach, Kenneth, Shanahan, Clare Elizabeth, Shaughnessy, Bryan, Shaw, Richard A., Shay, Christopher Michael, Sheehan, Even, Sheth, Kartik, Shih, Hsin-Yi, Shivaei, Irene, Siegel, Noah, Sienkiewicz, Matthew G., Simmons, Debra D., Simon, Bernard P., Sirianni, Marco, Sivaramakrishnan, Anand, Slade, Jeffrey E., Sloan, G. C., Slocum, Christine E., Slowinski, Steven E., Smith, Corbett T., Smith, Eric P., Smith, Erin C., Smith, Koby, Smith, Robert, Smith, Stephanie J., Smolik, John L., Soderblom, David R., Sohn, Sangmo Tony, Sokol, Jeff, Sonneborn, George, Sontag, Christopher D., Sooy, Peter R., Soummer, Remi, Southwood, Dana M., Spain, Kay, Sparmo, Joseph, Speer, David T., Spencer, Richard, Sprofera, Joseph D., Stallcup, Scott S., Stanley, Marcia K., Stansberry, John A., Stark, Christopher C., Starr, Carl W., Stassi, Diane Y., Steck, Jane A., Steeley, Christine D., Stephens, Matthew A., Stephenson, Ralph J., Stewart, Alphonso C., Stiavelli, Massimo, Stockman Jr., Hervey, Strada, Paolo, Straughn, Amber N., Streetman, Scott, Strickland, David Kendal, Strobele, Jingping F., Stuhlinger, Martin, Stys, Jeffrey Edward, Such, Miguel, Sukhatme, Kalyani, Sullivan, Joseph F., Sullivan, Pamela C., Sumner, Sandra M., Sun, Fengwu, Sunnquist, Benjamin Dale, Swade, Daryl Allen, Swam, Michael S., Swenton, Diane F., Swoish, Robby A., Litten, Oi In Tam, Tamas, Laszlo, Tao, Andrew, Taylor, David K., Taylor, Joanna M., Plate, Maurice te, Van Tea, Mason, Teague, Kelly K., Telfer, Randal C., Temim, Tea, Texter, Scott C., Thatte, Deepashri G., Thompson, Christopher Lee, Thompson, Linda M., Thomson, Shaun R., Thronson, Harley, Tierney, C. M., Tikkanen, Tuomo, Tinnin, Lee, Tippet, William Thomas, Todd, Connor William, Tran, Hien D., Trauger, John, Trejo, Edwin Gregorio, Truong, Justin Hoang Vinh, Tsukamoto, Christine L., Tufail, Yasir, Tumlinson, Jason, Tustain, Samuel, Tyra, Harrison, Ubeda, Leonardo, Underwood, Kelli, Uzzo, Michael A., Vaclavik, Steven, Valenduc, Frida, Valenti, Jeff A., Van Campen, Julie, van de Wetering, Inge, Van Der Marel, Roeland P., van Haarlem, Remy, Vandenbussche, Bart, Vanterpool, Dona D., Vernoy, Michael R., Costas, Maria Begoña Vila, Volk, Kevin, Voorzaat, Piet, Voyton, Mark F., Vydra, Ekaterina, Waddy, Darryl J., Waelkens, Christoffel, Wahlgren, Glenn Michael, Walker Jr., Frederick E., Wander, Michel, Warfield, Christine K., Warner, Gerald, Wasiak, Francis C., Wasiak, Matthew F., Wehner, James, Weiler, Kevin R., Weilert, Mark, Weiss, Stanley B., Wells, Martyn, Welty, Alan D., Wheate, Lauren, Wheeler, Thomas P., White, Christy L., Whitehouse, Paul, Whiteleather, Jennifer Margaret, Whitman, William Russell, Williams, Christina C., Willmer, Christopher N. A., Willott, Chris J., Willoughby, Scott P., Wilson, Andrew, Wilson, Debra, Wilson, Donna V., Windhorst, Rogier, Wislowski, Emily Christine, Wolfe, David J., Wolfe, Michael A., Wolff, Schuyler, Wondel, Amancio, Woo, Cindy, Woods, Robert T., Worden, Elaine, Workman, William, Wright, Gillian S., Wu, Carl, Wu, Chi-Rai, Wun, Dakin D., Wymer, Kristen B., Yadetie, Thomas, Yan, Isabelle C., Yang, Keith C., Yates, Kayla L., Yeager, Christopher R., Yerger, Ethan John, Young, Erick T., Young, Gary, Yu, Gene, Yu, Susan, Zak, Dean S., Zeidler, Peter, Zepp, Robert, Zhou, Julia, Zincke, Christian A., Zonak, Stephanie, and Zondag, Elisabeth
Subjects: Astrophysics - Instrumentation and Methods for Astrophysics
Abstract: Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit., Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figures
Published: 2023
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2. Filipino Students’ Reading Abilities: A Note on the Challenges and Potential Areas for Improvement

Author: Mark Vergel Idulog, Ronald Gadiano, Edmon Toledo, Melanie Hermosada, Hazel Casaldon, Marianne Mariposa, Christie Geron, Elena Dequito, Jeromea Genanda, Mark Anthony Malipot, Jupeth Toriano Pentang, and Ronalyn Bautista
Subjects: filipino learners, literacy program, non-reader, philippine education, reading comprehension, Education (General), L7-991
Abstract: The reading abilities of Filipino students have been a challenge for educators and policymakers alike. Despite government efforts to improve literacy rates in the Philippines, recent studies have shown that many students need help with reading comprehension, vocabulary development, and critical thinking skills. This research note examines the current state of reading abilities among Filipino students and potential areas for improvement. The poor reading abilities can be attributed to several factors, including a lack of resources and socioeconomic factors. However, there are identified potential areas for improvement, such as promoting early literacy programs, investing in teacher training, and developing reading materials that are culturally relevant and engaging for Filipino students. These findings have important implications for education policies and practices in the Philippines and for educators and researchers seeking to improve reading abilities among Filipino students.
Published: 2023
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3. Filipino Students’ Reading Abilities: A Note on the Challenges and Potential Areas for Improvement

Author: Idulog, Mark Vergel, primary, Gadiano, Ronald, additional, Toledo, Edmon, additional, Hermosada, Melanie, additional, Casaldon, Hazel, additional, Mariposa, Marianne, additional, Geron, Christie, additional, Dequito, Elena, additional, Genanda, Jeromea, additional, Malipot, Mark Anthony, additional, Pentang, Jupeth, additional, and Bautista, Ronalyn, additional
Published: 2023
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4. The James Webb Space Telescope Mission

Author: Gardner, Jonathan P., primary, Mather, John C., additional, Abbott, Randy, additional, Abell, James S., additional, Abernathy, Mark, additional, Abney, Faith E., additional, Abraham, John G., additional, Abraham, Roberto, additional, Abul-Huda, Yasin M., additional, Acton, Scott, additional, Adams, Cynthia K., additional, Adams, Evan, additional, Adler, David S., additional, Adriaensen, Maarten, additional, Aguilar, Jonathan Albert, additional, Ahmed, Mansoor, additional, Ahmed, Nasif S., additional, Ahmed, Tanjira, additional, Albat, Rüdeger, additional, Albert, Loïc, additional, Alberts, Stacey, additional, Aldridge, David, additional, Allen, Mary Marsha, additional, Allen, Shaune S., additional, Altenburg, Martin, additional, Altunc, Serhat, additional, Alvarez, Jose Lorenzo, additional, Álvarez-Márquez, Javier, additional, de Oliveira, Catarina Alves, additional, Ambrose, Leslie L., additional, Anandakrishnan, Satya M., additional, Andersen, Gregory C., additional, Anderson, Harry James, additional, Anderson, Jay, additional, Anderson, Kristen, additional, Anderson, Sara M., additional, Aprea, Julio, additional, Archer, Benita J., additional, Arenberg, Jonathan W., additional, Argyriou, Ioannis, additional, Arribas, Santiago, additional, Artigau, Étienne, additional, Arvai, Amanda Rose, additional, Atcheson, Paul, additional, Atkinson, Charles B., additional, Averbukh, Jesse, additional, Aymergen, Cagatay, additional, Bacinski, John J., additional, Baggett, Wayne E., additional, Bagnasco, Giorgio, additional, Baker, Lynn L., additional, Balzano, Vicki Ann, additional, Banks, Kimberly A., additional, Baran, David A., additional, Barker, Elizabeth A., additional, Barrett, Larry K., additional, Barringer, Bruce O., additional, Barto, Allison, additional, Bast, William, additional, Baudoz, Pierre, additional, Baum, Stefi, additional, Beatty, Thomas G., additional, Beaulieu, Mathilde, additional, Bechtold, Kathryn, additional, Beck, Tracy, additional, Beddard, Megan M., additional, Beichman, Charles, additional, Bellagama, Larry, additional, Bely, Pierre, additional, Berger, Timothy W., additional, Bergeron, Louis E., additional, Bernier, Antoine-Darveau, additional, Bertch, Maria D., additional, Beskow, Charlotte, additional, Betz, Laura E., additional, Biagetti, Carl P., additional, Birkmann, Stephan, additional, Bjorklund, Kurt F., additional, Blackwood, James D., additional, Blazek, Ronald Paul, additional, Blossfeld, Stephen, additional, Bluth, Marcel, additional, Boccaletti, Anthony, additional, Boegner Jr, Martin E., additional, Bohlin, Ralph C., additional, Boia, John Joseph, additional, Böker, Torsten, additional, Bonaventura, N., additional, Bond, Nicholas A., additional, Bosley, Kari Ann, additional, Boucarut, Rene A., additional, Bouchet, Patrice, additional, Bouwman, Jeroen, additional, Bower, Gary, additional, Bowers, Ariel S., additional, Bowers, Charles W., additional, Boyce, Leslye A., additional, Boyer, Christine T., additional, Boyer, Martha L., additional, Boyer, Michael, additional, Boyer, Robert, additional, Bradley, Larry D., additional, Brady, Gregory R., additional, Brandl, Bernhard R., additional, Brannen, Judith L., additional, Breda, David, additional, Bremmer, Harold G., additional, Brennan, David, additional, Bresnahan, Pamela A., additional, Bright, Stacey N., additional, Broiles, Brian J., additional, Bromenschenkel, Asa, additional, Brooks, Brian H., additional, Brooks, Keira J., additional, Brown, Bob, additional, Brown, Bruce, additional, Brown, Thomas M., additional, Bruce, Barry W., additional, Bryson, Jonathan G., additional, Bujanda, Edwin D., additional, Bullock, Blake M., additional, Bunker, A. J., additional, Bureo, Rafael, additional, Burt, Irving J., additional, Bush, James Aaron, additional, Bushouse, Howard A., additional, Bussman, Marie C., additional, Cabaud, Olivier, additional, Cale, Steven, additional, Calhoon, Charles D., additional, Calvani, Humberto, additional, Canipe, Alicia M., additional, Caputo, Francis M., additional, Cara, Mihai, additional, Carey, Larkin, additional, Case, Michael Eli, additional, Cesari, Thaddeus, additional, Cetorelli, Lee D., additional, Chance, Don R., additional, Chandler, Lynn, additional, Chaney, Dave, additional, Chapman, George N., additional, Charlot, S., additional, Chayer, Pierre, additional, Cheezum, Jeffrey I., additional, Chen, Bin, additional, Chen, Christine H., additional, Cherinka, Brian, additional, Chichester, Sarah C., additional, Chilton, Zachary S., additional, Chittiraibalan, Dharini, additional, Clampin, Mark, additional, Clark, Charles R., additional, Clark, Kerry W., additional, Clark, Stephanie M., additional, Claybrooks, Edward E., additional, Cleveland, Keith A., additional, Cohen, Andrew L., additional, Cohen, Lester M., additional, Colón, Knicole D., additional, Coleman, Benee L., additional, Colina, Luis, additional, Comber, Brian J., additional, Comeau, Thomas M., additional, Comer, Thomas, additional, Reis, Alain Conde, additional, Connolly, Dennis C., additional, Conroy, Kyle E., additional, Contos, Adam R., additional, Contreras, James, additional, Cook, Neil J., additional, Cooper, James L., additional, Cooper, Rachel Aviva, additional, Correia, Michael F., additional, Correnti, Matteo, additional, Cossou, Christophe, additional, Costanza, Brian F., additional, Coulais, Alain, additional, Cox, Colin R., additional, Coyle, Ray T., additional, Cracraft, Misty M., additional, Crew, Keith A., additional, Curtis, Gary J., additional, Cusveller, Bianca, additional, Maciel, Cleyciane Da Costa, additional, Dailey, Christopher T., additional, Daugeron, Frédéric, additional, Davidson, Greg S., additional, Davies, James E., additional, Davis, Katherine Anne, additional, Davis, Michael S., additional, Day, Ratna, additional, de Chambure, Daniel, additional, de Jong, Pauline, additional, De Marchi, Guido, additional, Dean, Bruce H., additional, Decker, John E., additional, Delisa, Amy S., additional, Dell, Lawrence C., additional, Dellagatta, Gail, additional, Dembinska, Franciszka, additional, Demosthenes, Sandor, additional, Dencheva, Nadezhda M., additional, Deneu, Philippe, additional, DePriest, William W., additional, Deschenes, Jeremy, additional, Dethienne, Nathalie, additional, Detre, Örs Hunor, additional, Diaz, Rosa Izela, additional, Dicken, Daniel, additional, DiFelice, Audrey S., additional, Dillman, Matthew, additional, Disharoon, Maureen O., additional, Dixon, William V., additional, Doggett, Jesse B., additional, Dominguez, Keisha L., additional, Donaldson, Thomas S., additional, Doria-Warner, Cristina M., additional, Santos, Tony Dos, additional, Doty, Heather, additional, Douglas, Jr, Robert E., additional, Doyon, René, additional, Dressler, Alan, additional, Driggers, Jennifer, additional, Driggers, Phillip A., additional, Dunn, Jamie L., additional, DuPrie, Kimberly C., additional, Dupuis, Jean, additional, Durning, John, additional, Dutta, Sanghamitra B., additional, Earl, Nicholas M., additional, Eccleston, Paul, additional, Ecobichon, Pascal, additional, Egami, Eiichi, additional, Ehrenwinkler, Ralf, additional, Eisenhamer, Jonathan D., additional, Eisenhower, Michael, additional, Eisenstein, Daniel J., additional, El Hamel, Zaky, additional, Elie, Michelle L., additional, Elliott, James, additional, Elliott, Kyle Wesley, additional, Engesser, Michael, additional, Espinoza, Néstor, additional, Etienne, Odessa, additional, Etxaluze, Mireya, additional, Evans, Leah, additional, Fabreguettes, Luce, additional, Falcolini, Massimo, additional, Falini, Patrick R., additional, Fatig, Curtis, additional, Feeney, Matthew, additional, Feinberg, Lee D., additional, Fels, Raymond, additional, Ferdous, Nazma, additional, Ferguson, Henry C., additional, Ferrarese, Laura, additional, Ferreira, Marie-Héléne, additional, Ferruit, Pierre, additional, Ferry, Malcolm, additional, Filippazzo, Joseph Charles, additional, Firre, Daniel, additional, Fix, Mees, additional, Flagey, Nicolas, additional, Flanagan, Kathryn A., additional, Fleming, Scott W., additional, Florian, Michael, additional, Flynn, James R., additional, Foiadelli, Luca, additional, Fontaine, Mark R., additional, Fontanella, Erin Marie, additional, Forshay, Peter Randolph, additional, Fortner, Elizabeth A., additional, Fox, Ori D., additional, Framarini, Alexandro P., additional, Francisco, John I., additional, Franck, Randy, additional, Franx, Marijn, additional, Franz, David E., additional, Friedman, Scott D., additional, Friend, Katheryn E., additional, Frost, James R., additional, Fu, Henry, additional, Fullerton, Alexander W., additional, Gaillard, Lionel, additional, Galkin, Sergey, additional, Gallagher, Ben, additional, Galyer, Anthony D., additional, García Marín, Macarena, additional, Gardner, Lisa E., additional, Garland, Dennis, additional, Garrett, Bruce Albert, additional, Gasman, Danny, additional, Gáspár, András, additional, Gastaud, René, additional, Gaudreau, Daniel, additional, Gauthier, Peter Timothy, additional, Geers, Vincent, additional, Geithner, Paul H., additional, Gennaro, Mario, additional, Gerber, John, additional, Gereau, John C., additional, Giampaoli, Robert, additional, Giardino, Giovanna, additional, Gibbons, Paul C., additional, Gilbert, Karoline, additional, Gilman, Larry, additional, Girard, Julien H., additional, Giuliano, Mark E., additional, Gkountis, Konstantinos, additional, Glasse, Alistair, additional, Glassmire, Kirk Zachary, additional, Glauser, Adrian Michael, additional, Glazer, Stuart D., additional, Goldberg, Joshua, additional, Golimowski, David A., additional, Gonzaga, Shireen P., additional, Gordon, Karl D., additional, Gordon, Shawn J., additional, Goudfrooij, Paul, additional, Gough, Michael J., additional, Graham, Adrian J., additional, Grau, Christopher M., additional, Green, Joel David, additional, Greene, Gretchen R., additional, Greene, Thomas P., additional, Greenfield, Perry E., additional, Greenhouse, Matthew A., additional, Greve, Thomas R., additional, Greville, Edgar M., additional, Grimaldi, Stefano, additional, Groe, Frank E., additional, Groebner, Andrew, additional, Grumm, David M., additional, Grundy, Timothy, additional, Güdel, Manuel, additional, Guillard, Pierre, additional, Guldalian, John, additional, Gunn, Christopher A., additional, Gurule, Anthony, additional, Gutman, Irvin Meyer, additional, Guy, Paul D., additional, Guyot, Benjamin, additional, Hack, Warren J., additional, Haderlein, Peter, additional, Hagan, James B., additional, Hagedorn, Andria, additional, Hainline, Kevin, additional, Haley, Craig, additional, Hami, Maryam, additional, Hamilton, Forrest Clifford, additional, Hammann, Jeffrey, additional, Hammel, Heidi B., additional, Hanley, Christopher J., additional, Hansen, Carl August, additional, Hardy, Bruce, additional, Harnisch, Bernd, additional, Harr, Michael Hunter, additional, Harris, Pamela, additional, Hart, Jessica Ann, additional, Hartig, George F., additional, Hasan, Hashima, additional, Hashim, Kathleen Marie, additional, Hashimoto, Ryan, additional, Haskins, Sujee J., additional, Hawkins, Robert Edward, additional, Hayden, Brian, additional, Hayden, William L., additional, Healy, Mike, additional, Hecht, Karen, additional, Heeg, Vince J., additional, Hejal, Reem, additional, Helm, Kristopher A., additional, Hengemihle, Nicholas J., additional, Henning, Thomas, additional, Henry, Alaina, additional, Henry, Ronald L., additional, Henshaw, Katherine, additional, Hernandez, Scarlin, additional, Herrington, Donald C., additional, Heske, Astrid, additional, Hesman, Brigette Emily, additional, Hickey, David L., additional, Hilbert, Bryan N., additional, Hines, Dean C., additional, Hinz, Michael R., additional, Hirsch, Michael, additional, Hitcho, Robert S., additional, Hodapp, Klaus, additional, Hodge, Philip E., additional, Hoffman, Melissa, additional, Holfeltz, Sherie T., additional, Holler, Bryan Jason, additional, Hoppa, Jennifer Rose, additional, Horner, Scott, additional, Howard, Joseph M., additional, Howard, Richard J., additional, Huber, Jean M., additional, Hunkeler, Joseph S., additional, Hunter, Alexander, additional, Hunter, David Gavin, additional, Hurd, Spencer W., additional, Hurst, Brendan J., additional, Hutchings, John B., additional, Hylan, Jason E., additional, Ignat, Luminita Ilinca, additional, Illingworth, Garth, additional, Irish, Sandra M., additional, Isaacs III, John C., additional, Jackson Jr, Wallace C., additional, Jaffe, Daniel T., additional, Jahic, Jasmin, additional, Jahromi, Amir, additional, Jakobsen, Peter, additional, James, Bryan, additional, James, John C., additional, James, LeAndrea Rae, additional, Jamieson, William Brian, additional, Jandra, Raymond D., additional, Jayawardhana, Ray, additional, Jedrzejewski, Robert, additional, Jeffers, Basil S., additional, Jensen, Peter, additional, Joanne, Egges, additional, Johns, Alan T., additional, Johnson, Carl A., additional, Johnson, Eric L., additional, Johnson, Patricia, additional, Johnson, Phillip Stephen, additional, Johnson, Thomas K., additional, Johnson, Timothy W., additional, Johnstone, Doug, additional, Jollet, Delphine, additional, Jones, Danny P., additional, Jones, Gregory S., additional, Jones, Olivia C., additional, Jones, Ronald A., additional, Jones, Vicki, additional, Jordan, Ian J., additional, Jordan, Margaret E., additional, Jue, Reginald, additional, Jurkowski, Mark H., additional, Justis, Grant, additional, Justtanont, Kay, additional, Kaleida, Catherine C., additional, Kalirai, Jason S., additional, Kalmanson, Phillip Cabrales, additional, Kaltenegger, Lisa, additional, Kammerer, Jens, additional, Kan, Samuel K., additional, Kanarek, Graham Childs, additional, Kao, Shaw-Hong, additional, Karakla, Diane M., additional, Karl, Hermann, additional, Kassin, Susan A., additional, Kauffman, David D., additional, Kavanagh, Patrick, additional, Kelley, Leigh L., additional, Kelly, Douglas M., additional, Kendrew, Sarah, additional, Kennedy, Herbert V., additional, Kenny, Deborah A., additional, Keski-Kuha, Ritva A., additional, Keyes, Charles D., additional, Khan, Ali, additional, Kidwell, Richard C., additional, Kimble, Randy A., additional, King, James S., additional, King, Richard C., additional, Kinzel, Wayne M., additional, Kirk, Jeffrey R., additional, Kirkpatrick, Marc E., additional, Klaassen, Pamela, additional, Klingemann, Lana, additional, Klintworth, Paul U., additional, Knapp, Bryan Adam, additional, Knight, Scott, additional, Knollenberg, Perry J., additional, Knutsen, Daniel Mark, additional, Koehler, Robert, additional, Koekemoer, Anton M., additional, Kofler, Earl T., additional, Kontson, Vicki L., additional, Kovacs, Aiden Rose, additional, Kozhurina-Platais, Vera, additional, Krause, Oliver, additional, Kriss, Gerard A., additional, Krist, John, additional, Kristoffersen, Monica R., additional, Krogel, Claudia, additional, Krueger, Anthony P., additional, Kulp, Bernard A., additional, Kumari, Nimisha, additional, Kwan, Sandy W., additional, Kyprianou, Mark, additional, Labador, Aurora Gadiano, additional, Labiano, Álvaro, additional, Lafrenière, David, additional, Lagage, Pierre-Olivier, additional, Laidler, Victoria G., additional, Laine, Benoit, additional, Laird, Simon, additional, Lajoie, Charles-Philippe, additional, Lallo, Matthew D., additional, Lam, May Yen, additional, LaMassa, Stephanie Marie, additional, Lambros, Scott D., additional, Lampenfield, Richard Joseph, additional, Lander, Matthew Ed, additional, Langston, James Hutton, additional, Larson, Kirsten, additional, Larson, Melora, additional, LaVerghetta, Robert Joseph, additional, Law, David R., additional, Lawrence, Jon F., additional, Lee, David W., additional, Lee, Janice, additional, Lee, Yat-Ning Paul, additional, Leisenring, Jarron, additional, Leveille, Michael Dunlap, additional, Levenson, Nancy A., additional, Levi, Joshua S., additional, Levine, Marie B., additional, Lewis, Dan, additional, Lewis, Jake, additional, Lewis, Nikole, additional, Libralato, Mattia, additional, Lidon, Norbert, additional, Liebrecht, Paula Louisa, additional, Lightsey, Paul, additional, Lilly, Simon, additional, Lim, Frederick C., additional, Lim, Pey Lian, additional, Ling, Sai-Kwong, additional, Link, Lisa J., additional, Link, Miranda Nicole, additional, Lipinski, Jamie L., additional, Liu, XiaoLi, additional, Lo, Amy S., additional, Lobmeyer, Lynette, additional, Logue, Ryan M., additional, Long, Chris A., additional, Long, Douglas R., additional, Long, Ilana D., additional, Long, Knox S., additional, López-Caniego, Marcos, additional, Lotz, Jennifer M., additional, Love-Pruitt, Jennifer M., additional, Lubskiy, Michael, additional, Luers, Edward B., additional, Luetgens, Robert A., additional, Luevano, Annetta J., additional, G. Flores Lui, Sarah Marie, additional, Lund III, James M., additional, Lundquist, Ray A., additional, Lunine, Jonathan, additional, Lützgendorf, Nora, additional, Lynch, Richard J., additional, MacDonald, Alex J., additional, MacDonald, Kenneth, additional, Macias, Matthew J., additional, Macklis, Keith I., additional, Maghami, Peiman, additional, Maharaja, Rishabh Y., additional, Maiolino, Roberto, additional, Makrygiannis, Konstantinos G., additional, Malla, Sunita Giri, additional, Malumuth, Eliot M., additional, Manjavacas, Elena, additional, Marini, Andrea, additional, Marrione, Amanda, additional, Marston, Anthony, additional, Martel, André R, additional, Martin, Didier, additional, Martin, Peter G., additional, Martinez, Kristin L., additional, Maschmann, Marc, additional, Masci, Gregory L., additional, Masetti, Margaret E., additional, Maszkiewicz, Michael, additional, Matthews, Gary, additional, Matuskey, Jacob E., additional, McBrayer, Glen A., additional, McCarthy, Donald W., additional, McCaughrean, Mark J., additional, McClare, Leslie A., additional, McClare, Michael D., additional, McCloskey, John C., additional, McClurg, Taylore D., additional, McCoy, Martin, additional, McElwain, Michael W., additional, McGregor, Roy D., additional, McGuffey, Douglas B., additional, McKay, Andrew G., additional, McKenzie, William K., additional, McLean, Brian, additional, McMaster, Matthew, additional, McNeil, Warren, additional, De Meester, Wim, additional, Mehalick, Kimberly L., additional, Meixner, Margaret, additional, Meléndez, Marcio, additional, Menzel, Michael P., additional, Menzel, Michael T., additional, Merz, Matthew, additional, Mesterharm, David D., additional, Meyer, Michael R., additional, Meyett, Michele L., additional, Meza, Luis E., additional, Midwinter, Calvin, additional, Milam, Stefanie N., additional, Miller, Jay Todd, additional, Miller, William C., additional, Miskey, Cherie L., additional, Misselt, Karl, additional, Mitchell, Eileen P., additional, Mohan, Martin, additional, Montoya, Emily E., additional, Moran, Michael J., additional, Morishita, Takahiro, additional, Moro-Martín, Amaya, additional, Morrison, Debra L., additional, Morrison, Jane, additional, Morse, Ernie C., additional, Moschos, Michael, additional, Moseley, S. H., additional, Mosier, Gary E., additional, Mosner, Peter, additional, Mountain, Matt, additional, Muckenthaler, Jason S., additional, Mueller, Donald G., additional, Mueller, Migo, additional, Muhiem, Daniella, additional, Mühlmann, Prisca, additional, Mullally, Susan Elizabeth, additional, Mullen, Stephanie M., additional, Munger, Alan J, additional, Murphy, Jess, additional, Murray, Katherine T., additional, Muzerolle, James C., additional, Mycroft, Matthew, additional, Myers, Andrew, additional, Myers, Carey R., additional, R. Myers, Fred Richard, additional, Myers, Richard, additional, Myrick, Kaila, additional, Nagle, IV, Adrian F., additional, Nayak, Omnarayani, additional, Naylor, Bret, additional, Neff, Susan G., additional, Nelan, Edmund P., additional, Nella, John, additional, Nguyen, Duy Tuong, additional, Nguyen, Michael N., additional, Nickson, Bryony, additional, Nidhiry, John Joseph, additional, Niedner, Malcolm B., additional, Nieto-Santisteban, Maria, additional, Nikolov, Nikolay K., additional, Nishisaka, Mary Ann, additional, Noriega-Crespo, Alberto, additional, Nota, Antonella, additional, O’Mara, Robyn C., additional, Oboryshko, Michael, additional, O’Brien, Marcus B., additional, Ochs, William R., additional, Offenberg, Joel D., additional, Ogle, Patrick Michael, additional, Ohl, Raymond G., additional, Olmsted, Joseph Hamden, additional, Osborne, Shannon Barbara, additional, O’Shaughnessy, Brian Patrick, additional, Östlin, Göran, additional, O’Sullivan, Brian, additional, Otor, O. Justin, additional, Ottens, Richard, additional, Ouellette, Nathalie N.-Q., additional, Outlaw, Daria J., additional, Owens, Beverly A., additional, Pacifici, Camilla, additional, Page, James Christophe, additional, Paranilam, James G., additional, Park, Sang, additional, Parrish, Keith A., additional, Paschal, Laura, additional, Patapis, Polychronis, additional, Patel, Jignasha, additional, Patrick, Keith, additional, Pattishall Jr, Robert A., additional, Paul, Douglas William, additional, Paul, Shirley J., additional, Pauly, Tyler Andrew, additional, Pavlovsky, Cheryl M., additional, Peña-Guerrero, Maria, additional, Pedder, Andrew H., additional, Peek, Matthew Weldon, additional, Pelham, Patricia A., additional, Penanen, Konstantin, additional, Perriello, Beth A., additional, Perrin, Marshall D., additional, Perrine, Richard F., additional, Perrygo, Chuck, additional, Peslier, Muriel, additional, Petach, Michael, additional, Peterson, Karla A., additional, Pfarr, Tom, additional, Pierson, James M., additional, Pietraszkiewicz, Martin, additional, Pilchen, Guy, additional, Pipher, Judy L., additional, Pirzkal, Norbert, additional, Pitman, Joseph T., additional, Player, Danielle M., additional, Plesha, Rachel, additional, Plitzke, Anja, additional, Pohner, John A., additional, Poletis, Karyn Konstantin, additional, Pollizzi, Joseph A., additional, Polster, Ethan, additional, Pontius, James T., additional, Pontoppidan, Klaus, additional, Porges, Susana C., additional, Potter, Gregg D., additional, Prescott, Stephen, additional, Proffitt, Charles R., additional, Pueyo, Laurent, additional, Quispe Neira, Irma Aracely, additional, Radich, Armando, additional, Rager, Reiko T., additional, Rameau, Julien, additional, Ramey, Deborah D., additional, Alarcon, Rafael Ramos, additional, Rampini, Riccardo, additional, Rapp, Robert, additional, Rashford, Robert A., additional, Rauscher, Bernard J., additional, Ravindranath, Swara, additional, Rawle, Timothy, additional, Rawlings, Tynika N., additional, Ray, Tom, additional, Regan, Michael W., additional, Rehm, Brian, additional, Rehm, Kenneth D., additional, Reid, Neill, additional, Reis, Carl A., additional, Renk, Florian, additional, Reoch, Tom B., additional, Ressler, Michael, additional, Rest, Armin W., additional, Reynolds, Paul J., additional, Richon, Joel G., additional, Richon, Karen V., additional, Ridgaway, Michael, additional, Riedel, Adric Richard, additional, Rieke, George H., additional, Rieke, Marcia J., additional, Rifelli, Richard E., additional, Rigby, Jane R., additional, Riggs, Catherine S., additional, Ringel, Nancy J., additional, Ritchie, Christine E., additional, Rix, Hans-Walter, additional, Robberto, Massimo, additional, Robinson, Gregory L., additional, Robinson, Michael S., additional, Robinson, Orion, additional, Rock, Frank W., additional, Rodriguez, David R., additional, del Pino, Bruno Rodríguez, additional, Roellig, Thomas, additional, Rohrbach, Scott O., additional, Roman, Anthony J., additional, Romelfanger, Frederick J., additional, Romo Jr, Felipe P., additional, Rosales, Jose J., additional, Rose, Perry, additional, Roteliuk, Anthony F., additional, Roth, Marc N., additional, Rothwell, Braden Quinn, additional, Rouzaud, Sylvain, additional, Rowe, Jason, additional, Rowlands, Neil, additional, Roy, Arpita, additional, Royer, Pierre, additional, Rui, Chunlei, additional, Rumler, Peter, additional, Rumpl, William, additional, Russ, Melissa L., additional, Ryan, Michael B., additional, Ryan, Richard M., additional, Saad, Karl, additional, Sabata, Modhumita, additional, Sabatino, Rick, additional, Sabbi, Elena, additional, Sabelhaus, Phillip A., additional, Sabia, Stephen, additional, Sahu, Kailash C., additional, Saif, Babak N., additional, Salvignol, Jean-Christophe, additional, Samara-Ratna, Piyal, additional, Samuelson, Bridget S., additional, Sanders, Felicia A., additional, Sappington, Bradley, additional, Sargent, B. A., additional, Sauer, Arne, additional, Savadkin, Bruce J., additional, Sawicki, Marcin, additional, Schappell, Tina M., additional, Scheffer, Caroline, additional, Scheithauer, Silvia, additional, Scherer, Ron, additional, Schiff, Conrad, additional, Schlawin, Everett, additional, Schmeitzky, Olivier, additional, Schmitz, Tyler S., additional, Schmude, Donald J., additional, Schneider, Analyn, additional, Schreiber, Jürgen, additional, Schroeven-Deceuninck, Hilde, additional, Schultz, John J., additional, Schwab, Ryan, additional, Schwartz, Curtis H., additional, Scoccimarro, Dario, additional, Scott, John F., additional, Scott, Michelle B., additional, Seaton, Bonita L., additional, Seely, Bruce S., additional, Seery, Bernard, additional, Seidleck, Mark, additional, Sembach, Kenneth, additional, Shanahan, Clare Elizabeth, additional, Shaughnessy, Bryan, additional, Shaw, Richard A., additional, Shay, Christopher Michael, additional, Sheehan, Even, additional, Sheth, Kartik, additional, Shih, Hsin-Yi, additional, Shivaei, Irene, additional, Siegel, Noah, additional, Sienkiewicz, Matthew G., additional, Simmons, Debra D., additional, Simon, Bernard P., additional, Sirianni, Marco, additional, Sivaramakrishnan, Anand, additional, Slade, Jeffrey E., additional, Sloan, G. C., additional, Slocum, Christine E., additional, Slowinski, Steven E., additional, Smith, Corbett T., additional, Smith, Eric P., additional, Smith, Erin C., additional, Smith, Koby, additional, Smith, Robert, additional, Smith, Stephanie J., additional, Smolik, John L., additional, Soderblom, David R., additional, Sohn, Sangmo Tony, additional, Sokol, Jeff, additional, Sonneborn, George, additional, Sontag, Christopher D., additional, Sooy, Peter R., additional, Soummer, Remi, additional, Southwood, Dana M., additional, Spain, Kay, additional, Sparmo, Joseph, additional, Speer, David T., additional, Spencer, Richard, additional, Sprofera, Joseph D., additional, Stallcup, Scott S., additional, Stanley, Marcia K., additional, Stansberry, John A., additional, Stark, Christopher C., additional, Starr, Carl W., additional, Stassi, Diane Y., additional, Steck, Jane A., additional, Steeley, Christine D., additional, Stephens, Matthew A., additional, Stephenson, Ralph J., additional, Stewart, Alphonso C., additional, Stiavelli, Massimo, additional, Jr, Hervey Stockman, additional, Strada, Paolo, additional, Straughn, Amber N., additional, Streetman, Scott, additional, Strickland, David Kendal, additional, Strobele, Jingping F., additional, Stuhlinger, Martin, additional, Stys, Jeffrey Edward, additional, Such, Miguel, additional, Sukhatme, Kalyani, additional, Sullivan, Joseph F., additional, Sullivan, Pamela C., additional, Sumner, Sandra M., additional, Sun, Fengwu, additional, Sunnquist, Benjamin Dale, additional, Swade, Daryl Allen, additional, Swam, Michael S., additional, Swenton, Diane F., additional, Swoish, Robby A., additional, Tam Litten, Oi In, additional, Tamas, Laszlo, additional, Tao, Andrew, additional, Taylor, David K., additional, Taylor, Joanna M., additional, Plate, Maurice te, additional, Van Tea, Mason, additional, Teague, Kelly K., additional, Telfer, Randal C., additional, Temim, Tea, additional, Texter, Scott C., additional, Thatte, Deepashri G., additional, Thompson, Christopher Lee, additional, Thompson, Linda M., additional, Thomson, Shaun R., additional, Thronson, Harley, additional, Tierney, C. M., additional, Tikkanen, Tuomo, additional, Tinnin, Lee, additional, Tippet, William Thomas, additional, Todd, Connor William, additional, Tran, Hien D., additional, Trauger, John, additional, Trejo, Edwin Gregorio, additional, Vinh Truong, Justin Hoang, additional, Tsukamoto, Christine L., additional, Tufail, Yasir, additional, Tumlinson, Jason, additional, Tustain, Samuel, additional, Tyra, Harrison, additional, Ubeda, Leonardo, additional, Underwood, Kelli, additional, Uzzo, Michael A., additional, Vaclavik, Steven, additional, Valenduc, Frida, additional, Valenti, Jeff A., additional, Van Campen, Julie, additional, van de Wetering, Inge, additional, Van Der Marel, Roeland P., additional, van Haarlem, Remy, additional, Vandenbussche, Bart, additional, van Dishoeck, Ewine F., additional, Vanterpool, Dona D., additional, Vernoy, Michael R., additional, Vila Costas, Maria Begoña, additional, Volk, Kevin, additional, Voorzaat, Piet, additional, Voyton, Mark F., additional, Vydra, Ekaterina, additional, Waddy, Darryl J., additional, Waelkens, Christoffel, additional, Wahlgren, Glenn Michael, additional, Walker Jr, Frederick E., additional, Wander, Michel, additional, Warfield, Christine K., additional, Warner, Gerald, additional, Wasiak, Francis C., additional, Wasiak, Matthew F., additional, Wehner, James, additional, Weiler, Kevin R., additional, Weilert, Mark, additional, Weiss, Stanley B., additional, Wells, Martyn, additional, Welty, Alan D., additional, Wheate, Lauren, additional, Wheeler, Thomas P., additional, White, Christy L., additional, Whitehouse, Paul, additional, Whiteleather, Jennifer Margaret, additional, Whitman, William Russell, additional, Williams, Christina C., additional, Willmer, Christopher N. A., additional, Willott, Chris J., additional, Willoughby, Scott P., additional, Wilson, Andrew, additional, Wilson, Debra, additional, Wilson, Donna V., additional, Windhorst, Rogier, additional, Wislowski, Emily Christine, additional, Wolfe, David J., additional, Wolfe, Michael A., additional, Wolff, Schuyler, additional, Wondel, Amancio, additional, Woo, Cindy, additional, Woods, Robert T., additional, Worden, Elaine, additional, Workman, William, additional, Wright, Gillian S., additional, Wu, Carl, additional, Wu, Chi-Rai, additional, Wun, Dakin D., additional, Wymer, Kristen B., additional, Yadetie, Thomas, additional, Yan, Isabelle C., additional, Yang, Keith C., additional, Yates, Kayla L., additional, Yeager, Christopher R., additional, Yerger, Ethan John, additional, Young, Erick T., additional, Young, Gary, additional, Yu, Gene, additional, Yu, Susan, additional, Zak, Dean S., additional, Zeidler, Peter, additional, Zepp, Robert, additional, Zhou, Julia, additional, Zincke, Christian A., additional, Zonak, Stephanie, additional, and Zondag, Elisabeth, additional
Published: 2023
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5. Local enema treatment to inhibit FOLH1/GCPII as a novel therapy for inflammatory bowel disease

Author: Date, Abhijit A., Rais, Rana, Babu, Taarika, Ortiz, Jairo, Kanvinde, Pranjali, Thomas, Ajit G., Zimmermann, Sarah C., Gadiano, Alexandra J., Halpert, Gilad, Slusher, Barbara S., and Ensign, Laura M.
Published: 2017
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6. Filipino Students’ Reading Abilities: A Note on the Challenges and Potential Areas for Improvement

Author: Idulog, Mark Vergel, Gadiano, Ronald, Toledo, Edmon, Hermosada, Melanie, Casaldon, Hazel, Mariposa, Marianne, Geron, Christie, Dequito, Elena, Genanda, Jeromea, Malipot, Mark Anthony, Pentang, Jupeth Toriano, Bautista, Ronalyn, Idulog, Mark Vergel, Gadiano, Ronald, Toledo, Edmon, Hermosada, Melanie, Casaldon, Hazel, Mariposa, Marianne, Geron, Christie, Dequito, Elena, Genanda, Jeromea, Malipot, Mark Anthony, Pentang, Jupeth Toriano, and Bautista, Ronalyn
Abstract: The reading abilities of Filipino students have been a challenge for educators and policymakers alike. Despite government efforts to improve literacy rates in the Philippines, recent studies have shown that many students need help with reading comprehension, vocabulary development, and critical thinking skills. This research note examines the current state of reading abilities among Filipino students and potential areas for improvement. The poor reading abilities can be attributed to several factors, including a lack of resources and socioeconomic factors. However, there are identified potential areas for improvement, such as promoting early literacy programs, investing in teacher training, and developing reading materials that are culturally relevant and engaging for Filipino students. These findings have important implications for education policies and practices in the Philippines and for educators and researchers seeking to improve reading abilities among Filipino students.
Published: 2023

7. Effectiveness of Madre de Cacao leaves extract Gliricidia sepium, Guava leaves extract Psidium guajava & Natural Vinegar Dilute acetic acid in eradicating mosquito wrigglers Culicidae diptera

Author: John Michael Sasan, Stephanie T. Gamboa, Jermaine L. Gadiano, Anthony John C. Edoloverio, and Clint MJ O. Camangyan
Subjects: Q1-390, gliricidia sepium, acetic acid, culicidae diptera, Science (General), fungi, food and beverages, Education (General), L7-991, biopesticide
Abstract: Given the high cost, health, and environmental dangers associated with currently available synthetic pesticides, finding and developing economical, safe, and effective alternatives is critical. The goal of this research is to develop an organic mosquito repellent that will assist to reduce the number of mosquitos in the environment. The experiment lasted a total of 24 hours. Each treatment included three replicates with six larvae grouped in Parallel Group Design, and each treatment had varied doses of Madre de Cacao leaf extract, guava leaf extract, and natural vinegar. The level of efficiency of Madre de Cacao leaves extract, Guava leaves extract, and natural vinegar as a larvicide was determined using the Mean. At the 0.05 level of significance, the One-Way Analysis of Variance (ANOVA) was performed to assess the significant difference in the degree of efficacy of Madre de Cacao leaf extract, guava leaf extract, and natural vinegar at various doses. The presence of bioactive substances such as alkaloids, saponins, tannins, flavonoids, and coumarins on mosquitoes suggests that Madre de cacao leaf extract, guava leaf extract, and natural vinegar might be a possible natural larvicide and an alternative to commercial mosquito pesticide. To minimize the undesirable side effects of conventional pesticides, the researchers recommend using Madre de cacao leaf extract as a natural larvicide on home insects, especially in locations where the plant grows abundantly and in moist areas where mosquitoes are widespread. Other portions of the Madre de Cacao and Guava should be used instead of the leaves, according to further study.
Published: 2022

8. Kannawidan ti Panagtalon: The Case of Ilokano Corn and Tobacco Farmers

Author: Janelyne Guzman, Ranec Azarias, Maui Chanelle Pasion, Danara Chloe Nastor, and Leslie Yvonne Gadiano
Abstract: Farmers cultivate lands, and they supply people’s needs particularly the food they eat. Before the emergence of modern technology, farmers relied on indigenous knowledge that was translated into their farming practices. Also, reviewed literature revealed a dearth of studies on the beliefs, practices, and rituals of tobacco and corn farmers. In such context, this study aimed to explore such indigenous knowledge in tobacco and corn farming among farmers in Santiago, Ilocos Sur. In this study, the researchers used ethnomethodology, and interviewed 14 farmers. The cool and warm analyses of the interview transcripts identified the kannawidantipanagatalon which is translated as heritage of farming. This Ilokano phrase is used to describe the beliefs, practices, and rituals that were handed down to corn and tobacco farmers from their forefathers. Pammatitikabos (belief in full moon) and pammatitilinned (belief in new moon) are their identified beliefs; panagusarti sabot (using coconut shell) as dipper, panagusarti (use of) dingwen (animal), arado (using plow) and palpal (a farming equipment that is being used to break large soil particles), ken (and) panagusarti kayo ngaasad (using dibbler) are their farming practices. In addition, panag-atang (offering foods to drive away bad spirits with a prayer) is their identified farming ritual. Clearly, tobacco and corn farming are still guided by their beliefs, practices, and rituals that they find useful in making a profitable farming activity. As such, the identified indigenous knowledge remains intact despite the advent of modern farming.
Published: 2022

9. Kannawidan ti Panagtalon: The Case of Ilokano Corn and Tobacco Farmers

Author: Guzman, Janelyne, primary, Azarias, Ranec, additional, Pasion, Maui Chanelle, additional, Nastor, Danara Chloe, additional, and Gadiano, Leslie Yvonne, additional
Published: 2022
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10. Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats

Author: Tunstall, Brendan J., Ho, Chelsea P., Cao, Jianjing, Vendruscolo, Janaína C.M., Schmeichel, Brooke E., Slack, Rachel D., Tanda, Gianluigi, Gadiano, Alexandra J., Rais, Rana, Slusher, Barbara S., Koob, George F., Newman, Amy H., and Vendruscolo, Leandro F.
Published: 2018
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11. Effectiveness of Madre de Cacao leaves extract Gliricidia sepium, Guava leaves extract Psidium guajava & Natural Vinegar Dilute acetic acid in eradicating mosquito wrigglers Culicidae diptera

Author: Sasan, John Michael, Gamboa, Stephanie T., Gadiano, Jermaine L., Edoloverio, Anthony John C., Camangyan, Clint MJ O., Sasan, John Michael, Gamboa, Stephanie T., Gadiano, Jermaine L., Edoloverio, Anthony John C., and Camangyan, Clint MJ O.
Abstract: Given the high cost, health, and environmental dangers associated with currently available synthetic pesticides, finding and developing economical, safe, and effective alternatives is critical. The goal of this research is to develop an organic mosquito repellent that will assist to reduce the number of mosquitos in the environment. The experiment lasted a total of 24 hours. Each treatment included three replicates with six larvae grouped in Parallel Group Design, and each treatment had varied doses of Madre de Cacao leaf extract, guava leaf extract, and natural vinegar. The level of efficiency of Madre de Cacao leaves extract, Guava leaves extract, and natural vinegar as a larvicide was determined using the Mean. At the 0.05 level of significance, the One-Way Analysis of Variance (ANOVA) was performed to assess the significant difference in the degree of efficacy of Madre de Cacao leaf extract, guava leaf extract, and natural vinegar at various doses. The presence of bioactive substances such as alkaloids, saponins, tannins, flavonoids, and coumarins on mosquitoes suggests that Madre de cacao leaf extract, guava leaf extract, and natural vinegar might be a possible natural larvicide and an alternative to commercial mosquito pesticide. To minimize the undesirable side effects of conventional pesticides, the researchers recommend using Madre de cacao leaf extract as a natural larvicide on home insects, especially in locations where the plant grows abundantly and in moist areas where mosquitoes are widespread. Other portions of the Madre de Cacao and Guava should be used instead of the leaves, according to further study.
Published: 2022

12. Tumor-Targeted Delivery of 6-Diazo-5-oxo-<scp>l</scp>-norleucine (DON) Using Substituted Acetylated Lysine Prodrugs

Author: Kathryn M. Lemberg, Rana Rais, Ranjeet Prasad Dash, Kateřina Novotná, Jesse Alt, Pavel Majer, Barbara S. Slusher, Lukáš Tenora, Alexandra J. Gadiano, Quinn R. Kirkpatrick, Jenny Lam, and Vijayabhaskar Veeravalli
Subjects: Biodistribution, Swine, Carboxylesterase 1, Diazooxonorleucine, Antineoplastic Agents, Pharmacology, 01 natural sciences, Article, Mice, 03 medical and health sciences, chemistry.chemical_compound, Drug Delivery Systems, Cell Line, Tumor, Drug Discovery, Animals, Humans, Prodrugs, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Chemistry, Lysine, Acetylation, Prodrug, 6-Diazo-5-oxo-L-norleucine, 0104 chemical sciences, Glutamine, 010404 medicinal & biomolecular chemistry, Cell culture, Area Under Curve, Toxicity, Systemic administration, Molecular Medicine, Carboxylic Ester Hydrolases
Abstract: 6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist with robust anticancer efficacy; however, its therapeutic potential was hampered by its biodistribution and toxicity to normal tissues, specifically gastrointestinal (GI) tissues. To circumvent DON’s toxicity, we synthesized a series of tumor-targeted DON prodrugs designed to circulate inert in plasma and preferentially activate over DON in tumor. Our best prodrug 6 (isopropyl 2-(6-acetamido-2-(adamantane-1-carboxamido)hexanamido)-6-diazo-5-oxohexanoate) showed stability in plasma, liver, and intestinal homogenates yet was readily cleaved to DON in P493B lymphoma cells, exhibiting a 55-fold enhanced tumor cell-to-plasma ratio versus that of DON and resulting in a dose-dependent inhibition of cell proliferation. Using carboxylesterase 1 knockout mice that were shown to mimic human prodrug metabolism, systemic administration of 6 delivered 11-fold higher DON exposure to tumor (target tissue; AUC(0–t) = 5.1 nmol h/g) versus GI tissues (toxicity tissue; AUC(0–t) = 0.45 nmol h/g). In summary, these studies describe the discovery of a glutamine antagonist prodrug that provides selective tumor exposure.
Published: 2019

13. DPTIP, a newly identified potent brain penetrant neutral sphingomyelinase 2 inhibitor, regulates astrocyte-peripheral immune communication following brain inflammation

Author: Takashi Tsukamoto, Niyada Hin, Sarah C. Zimmermann, Amrita Datta Chaudhuri, Norman J. Haughey, Alexandra G. Gadiano, Marc Ferrer, Barbara S. Slusher, Seung Wan Yoo, Ying Wu, Camilo Rojas, Noel Southall, Xin Hu, Ondrej Stepanek, Elena Barnaeva, Juan J. Marugan, Ajit G. Thomas, and Rana Rais
Subjects: 0301 basic medicine, medicine.medical_treatment, lcsh:Medicine, Inflammation, Pharmacology, Article, Cell Line, 03 medical and health sciences, Extracellular Vesicles, Mice, Immune system, Downregulation and upregulation, In vivo, medicine, Animals, Humans, Secretion, Enzyme Inhibitors, lcsh:Science, Multidisciplinary, Chemistry, lcsh:R, Brain, Rats, Up-Regulation, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Cytokine, HEK293 Cells, Sphingomyelin Phosphodiesterase, Astrocytes, Cytokines, Encephalitis, lcsh:Q, medicine.symptom, Sphingomyelin, Astrocyte
Abstract: Brain injury and inflammation induces a local release of extracellular vesicles (EVs) from astrocytes carrying proteins, RNAs, and microRNAs into the circulation. When these vesicles reach the liver, they stimulate the secretion of cytokines that mobilize peripheral immune cell infiltration into the brain, which can cause secondary tissue damage and impair recovery. Recent studies suggest that suppression of EV biosynthesis through neutral sphingomyelinase 2 (nSMase2) inhibition may represent a new therapeutic strategy. Unfortunately, currently available nSMase2 inhibitors exhibit low potency (IC50 ≥ 1 μM), poor solubility and/or limited brain penetration. Through a high throughput screening campaign of >365,000 compounds against human nSMase2 we identified 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP), a potent (IC50 30 nM), selective, metabolically stable, and brain penetrable (AUCbrain/AUCplasma = 0.26) nSMase2 inhibitor. DPTIP dose-dependently inhibited EV release in primary astrocyte cultures. In a mouse model of brain injury conducted in GFAP-GFP mice, DPTIP potently (10 mg/kg IP) inhibited IL-1β-induced astrocyte-derived EV release (51 ± 13%; p in vitro or in vivo.
Published: 2018

14. Ghrelin agonist HM01 attenuates chemotherapy-induced neurotoxicity in rodent models

Author: Chiorazzi, A, Wozniak, K, Rais, R, Wu, Y, Gadiano, A, Farah, M, Liu, Y, Canta, A, Alberti, P, Rodriguez-Menendez, V, Meregalli, C, Fumagalli, G, Monza, L, Pozzi, E, Vornov, J, Polydefkis, M, Pietra, C, Slusher, B, Cavaletti, G, Wozniak, KM, Gadiano, AG, Farah, MH, Vornov, JJ, Slusher, BS, Chiorazzi, A, Wozniak, K, Rais, R, Wu, Y, Gadiano, A, Farah, M, Liu, Y, Canta, A, Alberti, P, Rodriguez-Menendez, V, Meregalli, C, Fumagalli, G, Monza, L, Pozzi, E, Vornov, J, Polydefkis, M, Pietra, C, Slusher, B, Cavaletti, G, Wozniak, KM, Gadiano, AG, Farah, MH, Vornov, JJ, and Slusher, BS
Abstract: Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is often dose-limiting and impacts life quality and survival of cancer patients. Ghrelin agonists have neuroprotectant effects and may have a role in treating or preventing CIPN. We evaluated the CNS-penetrant ghrelin agonist HM01 in three experimental models of CIPN at doses of 3–30 mg/kg p.o. daily monitoring orexigenic properties, nerve conduction, mechanical allodynia, and intra-epidermal nerve fiber density (IENFD). In a cisplatin-based study, rats were dosed daily for 3 days (0.5 mg/kg i.p.) + HM01. Cisplatin treatment induced mechanical hypersensitivity which was significantly reduced by HM01. In a second study, oxaliplatin was administered to mice (6 mg/kg i.p. 3 times/week for 4 weeks) resulting in significant digital nerve conduction velocity (NCV) deficits and reduction of IENFD. Concurrent HM01 dose dependently prevented the decline in NCV and attenuated the reduction in IENFD. Pharmacokinetic studies showed HM01 accumulation in the dorsal root ganglia and sciatic nerves which reached concentrations > 10 fold that of plasma. In a third model, HM01 was tested in preventive and therapeutic paradigms in a bortezomib-based rat model (0.2 mg/kg i.v., 3 times/week for 8 weeks). In the preventive setting, HM01 blocked bortezomib-induced hyperalgesia and IENFD reduction at all doses tested. In the therapeutic setting, significant effect was observed, but only at the highest dose. Altogether, the robust peripheral nervous system penetration of HM01 and its ability to improve multiple oxaliplatin-, cisplatin-, and bortezomib-induced neurotoxicities suggest that HM01 may be a useful neuroprotective adjuvant for CIPN.
Published: 2018

15. Dopamine D3R antagonist VK4-116 attenuates oxycodone self-administration and reinstatement without compromising its antinociceptive effects

Author: Ewa Galaj, Zhi Bing You, Vivek Kumar, Rana Rais, Zheng-Xiong Xi, Jianjing Cao, Guo Hua Bi, Amy Hauck Newman, Barbara S. Slusher, Eliot L. Gardner, and Alexandra J. Gadiano
Subjects: Pharmacology, business.industry, Addiction, media_common.quotation_subject, Antagonist, Extinction (psychology), 030227 psychiatry, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, Opioid, Dopamine receptor D3, Dopamine, medicine, Self-administration, business, Oxycodone, 030217 neurology & neurosurgery, medicine.drug, media_common
Abstract: Prescription opioids such as oxycodone are highly effective analgesics for clinical pain management, but their misuse and abuse have led to the current opioid epidemic in the United States. In order to ameliorate this public health crisis, the development of effective pharmacotherapies for the prevention and treatment of opioid abuse and addiction is essential and urgently required. In this study, we evaluated—in laboratory rats—the potential utility of VK4-116, a novel and highly selective dopamine D3 receptor (D3R) antagonist, for the prevention and treatment of prescription opioid use disorders. Pretreatment with VK4-116 (5–25 mg/kg, i.p.) dose-dependently inhibited the acquisition and maintenance of oxycodone self-administration. VK4-116 also lowered the break-point (BP) for oxycodone self-administration under a progressive-ratio schedule of reinforcement, shifted the oxycodone dose–response curve downward, and inhibited oxycodone extinction responding and reinstatement of oxycodone-seeking behavior. In addition, VK4-116 pretreatment dose-dependently enhanced the antinociceptive effects of oxycodone and reduced naloxone-precipitated conditioned place aversion in rats chronically treated with oxycodone. In contrast, VK4-116 had little effect on oral sucrose self-administration. Taken together, these findings indicate a central role for D3Rs in opioid reward and support further development of VK4-116 as an effective agent for mitigating the development of opioid addiction, reducing the severity of withdrawal and preventing relapse.
Published: 2018

16. Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats

Author: Jianjing Cao, Janaina C. M. Vendruscolo, Rana Rais, Alexandra J. Gadiano, Leandro F. Vendruscolo, Brooke E. Schmeichel, Rachel D. Slack, Chelsea P. Ho, Gianluigi Tanda, Brendan J. Tunstall, Amy Hauck Newman, George F. Koob, and Barbara S. Slusher
Subjects: Male, 0301 basic medicine, Drug, Time Factors, media_common.quotation_subject, Modafinil, Self Administration, Pharmacology, Article, Methamphetamine, Pharmacological treatment, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Saccharin, 0302 clinical medicine, mental disorders, Animals, Medicine, Benzhydryl Compounds, Rats, Wistar, Dopamine transporter, media_common, Analysis of Variance, Dopamine Plasma Membrane Transport Proteins, Dose-Response Relationship, Drug, Propylamines, biology, business.industry, Wakefulness-Promoting Agents, Meth, Rats, 030104 developmental biology, chemistry, Compulsive Behavior, biology.protein, Conditioning, Operant, Dopamine Antagonists, Central Nervous System Stimulants, Drug intoxication, business, Self-administration, 030217 neurology & neurosurgery, medicine.drug
Abstract: Methamphetamine (METH) is a highly addictive drug, but no pharmacological treatment is yet available for METH use disorders. Similar to METH, the wake-promoting drug (R)- modafinil (R-MOD) binds to the dopamine transporter (DAT). Unlike METH, R-MOD is not a substrate for transport by DAT and has low abuse potential. We tested the hypothesis that the atypical DAT inhibitor R-MOD and compounds that are derived from Modafinil would decrease METH intake by reducing the actions of METH at the DAT. We tested the effects of systemic injections of R-MOD and four novel Modafinil-derived ligands with increased DAT affinity (JJC8-016, JJC8-088, JJC8-089, and JJC8-091) on intravenous (i.v.) METH self-administration in rats that were allowed short access (ShA; 1 h) or long access (LgA; 6 h) to the drug. ShA rats exhibited stable METH intake over sessions, whereas LgA rats exhibited an escalation of drug intake. R-MOD decreased METH self-administration in ShA and LgA rats (in the 1(st) hour only). JJC8-091, and JJC8-016 decreased METH self-administration in both ShA and LgA rats. JJC8- 089 decreased METH self-administration in LgA rats only, whereas JJC8-088 had no effect on METH self-administration in either ShA or LgA rats. These findings support the potential of atypical DAT inhibitors for the treatment of METH use disorders and suggest several novel compounds as candidate drugs.
Published: 2018

17. Pharmacokinetics of Intranasal versus Subcutaneous Insulin in the Mouse

Author: Norman J. Haughey, Ying Wu, Jiadi Xu, Arena A. Manning, Saja H Khuder, Justin C. McArthur, Ajit G. Thomas, Barbara S. Slusher, Rana Rais, Michael T. Nedelcovych, David J. Volsky, Alexandra J. Gadiano, and Seung-Wan Yoo
Subjects: Blood Glucose, Male, 0301 basic medicine, medicine.medical_specialty, Physiology, Cognitive Neuroscience, medicine.medical_treatment, Energy metabolism, Biochemistry, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Internal medicine, Animals, Insulin, Medicine, Administration, Intranasal, business.industry, Brain, Cell Biology, General Medicine, Severe hypoglycemia, Subcutaneous insulin, Peripheral, 030104 developmental biology, Endocrinology, Blood-Brain Barrier, Plasma concentration, Nasal administration, Cognition Disorders, Energy Metabolism, business, 030217 neurology & neurosurgery
Abstract: Insulin delivery to the brain has emerged as an important therapeutic target for cognitive disorders associated with abnormal brain energy metabolism. Although insulin is transported across the blood–brain barrier, peripheral routes of administration are problematic due to systemic effects of insulin on blood glucose. Intranasal (IN) administration is being investigated as an alternative route. We conducted a head-to-head comparison of subcutaneous (SC) and IN insulin, assessing plasma and brain pharmacokinetics and blood glucose levels in the mouse. SC insulin (2.4 IU) achieved therapeutically relevant concentrations in the brain (AUCbrain = 2537 h·μIU/mL) but dramatically increased plasma insulin (AUCplasma = 520 351 h·*μIU/mL), resulting in severe hypoglycemia and in some cases death. IN administration of the same dose resulted in similar insulin levels in the brain (AUCbrain = 3442 h·μIU/mL) but substantially lower plasma concentrations (AUCplasma = 354 h·μIU/mL), amounting to a ~ 2000-fold increase in the AUCbrain:plasma ratio relative to SC. IN dosing also had no significant effect on blood glucose. When administered daily for 9 days, IN insulin increased brain glucose and energy metabolite concentrations (e.g., adenosine triphosphate and phosphocreatine) without causing overt toxicity, suggesting that IN insulin may be a safe therapeutic option for cognitively impaired patients.
Published: 2017

18. Ghrelin agonist HM01 attenuates chemotherapy-induced neurotoxicity in rodent models

Author: Alessia Chiorazzi, Ying Wu, Rana Rais, Virginia Rodriguez-Menendez, Krystyna M. Wozniak, Michael Polydefkis, Eleonora Pozzi, Annalisa Canta, Mohamed H. Farah, Guido Cavaletti, Cristina Meregalli, Alexandra J. Gadiano, Barbara S. Slusher, Paola Alberti, Laura Monza, G Fumagalli, James J. Vornov, Ying Liu, Claudio Pietra, Chiorazzi, A, Wozniak, K, Rais, R, Wu, Y, Gadiano, A, Farah, M, Liu, Y, Canta, A, Alberti, P, Rodriguez-Menendez, V, Meregalli, C, Fumagalli, G, Monza, L, Pozzi, E, Vornov, J, Polydefkis, M, Pietra, C, Slusher, B, and Cavaletti, G
Subjects: 0301 basic medicine, Agonist, Male, medicine.drug_class, Neural Conduction, Antineoplastic Agents, Pharmacology, Chemotherapy-induced neurotoxicity, Nervous System, Nerve conduction velocity, Bortezomib, 03 medical and health sciences, Eating, Mice, 0302 clinical medicine, Piperidines, Benzene Derivatives, Medicine, Animals, Cisplatin, Dose-Response Relationship, Drug, business.industry, Body Weight, Neurotoxicity, medicine.disease, Ghrelin, Animal models, chemotherapy induced peripheral neruopathy, Ghrelin agonist, Oxaliplatin, Rats, Ghrelin agonist, 030104 developmental biology, medicine.anatomical_structure, Neuroprotective Agents, Peripheral nervous system, Hyperalgesia, Female, medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is often dose-limiting and impacts life quality and survival of cancer patients. Ghrelin agonists have neuroprotectant effects and may have a role in treating or preventing CIPN. We evaluated the CNS-penetrant ghrelin agonist HM01 in three experimental models of CIPN at doses of 3–30 mg/kg p.o. daily monitoring orexigenic properties, nerve conduction, mechanical allodynia, and intra-epidermal nerve fiber density (IENFD). In a cisplatin-based study, rats were dosed daily for 3 days (0.5 mg/kg i.p.) + HM01. Cisplatin treatment induced mechanical hypersensitivity which was significantly reduced by HM01. In a second study, oxaliplatin was administered to mice (6 mg/kg i.p. 3 times/week for 4 weeks) resulting in significant digital nerve conduction velocity (NCV) deficits and reduction of IENFD. Concurrent HM01 dose dependently prevented the decline in NCV and attenuated the reduction in IENFD. Pharmacokinetic studies showed HM01 accumulation in the dorsal root ganglia and sciatic nerves which reached concentrations > 10 fold that of plasma. In a third model, HM01 was tested in preventive and therapeutic paradigms in a bortezomib-based rat model (0.2 mg/kg i.v., 3 times/week for 8 weeks). In the preventive setting, HM01 blocked bortezomib-induced hyperalgesia and IENFD reduction at all doses tested. In the therapeutic setting, significant effect was observed, but only at the highest dose. Altogether, the robust peripheral nervous system penetration of HM01 and its ability to improve multiple oxaliplatin-, cisplatin-, and bortezomib-induced neurotoxicities suggest that HM01 may be a useful neuroprotective adjuvant for CIPN.
Published: 2018

19. Local enema treatment to inhibit FOLH1 /GCPII as a novel therapy for inflammatory bowel disease

Author: Abhijit A. Date, Pranjali Kanvinde, Sarah C. Zimmermann, Barbara S. Slusher, Alexandra J. Gadiano, Ajit G. Thomas, Taarika Babu, Laura M. Ensign, Rana Rais, Jairo Ortiz, and Gilad Halpert
Subjects: Glutamate Carboxypeptidase II, Male, 0301 basic medicine, Drug, medicine.medical_specialty, Colon, media_common.quotation_subject, medicine.medical_treatment, Pharmaceutical Science, Enema, Absorption (skin), digestive system, Gastroenterology, Inflammatory bowel disease, Article, 03 medical and health sciences, Organophosphorus Compounds, 0302 clinical medicine, Internal medicine, medicine, Animals, Intestinal Mucosa, Colitis, media_common, Mice, Inbred BALB C, biology, business.industry, Inflammatory Bowel Diseases, medicine.disease, digestive system diseases, Enzyme assay, 030104 developmental biology, Trinitrobenzenesulfonic Acid, biology.protein, Tonicity, business, 030217 neurology & neurosurgery, Ex vivo
Abstract: Here we evaluate the potential for local administration of a small molecule FOLH1/GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) as a novel treatment for inflammatory bowel disease (IBD). We found that FOLH1/GCPII enzyme activity was increased in the colorectal tissues of mice with TNBS-induced colitis, and confirmed that 2-PMPA inhibited FOLH1/GCPII enzyme activity ex vivo. In order to maximize local enema delivery of 2-PMPA, we studied the effect of vehicle tonicity on the absorption of 2-PMPA in the colon. Local administration of 2-PMPA in a hypotonic enema vehicle resulted in increased colorectal tissue absorption at 30 min compared to 2-PMPA administered in an isotonic enema vehicle. Furthermore, local delivery of 2-PMPA in hypotonic enema vehicle resulted in prolonged drug concentrations for at least 24 h with minimal systemic exposure. Finally, daily treatment with the hypotonic 2-PMPA enema ameliorated macroscopic and microscopic symptoms of IBD in the TNBS-induced colitis mouse model, indicating the potential of FOLH1/GCPII inhibitors for the local treatment of IBD.
Published: 2017

20. Structure-Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter: Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability

Author: Barbara S. Slusher, Jianjing Cao, Alexandra J. Gadiano, Rana Rais, JoLynn B. Giancola, Alessandro Bonifazi, Claus J. Loland, Mark A. Coggiano, Therese Ku, Jenny Lam, Rachel D. Slack, Gianluigi Tanda, and Amy Hauck Newman
Subjects: Male, Alkylation, Halogenation, Stereochemistry, hERG, 01 natural sciences, Article, Rats, Sprague-Dawley, 03 medical and health sciences, Alicyclic compound, Mice, Structure-Activity Relationship, Drug Discovery, medicine, Potency, Structure–activity relationship, Animals, Humans, Amines, Serotonin transporter, 030304 developmental biology, Dopamine transporter, chemistry.chemical_classification, 0303 health sciences, Dopamine Plasma Membrane Transport Proteins, biology, Sulfur Compounds, Methamphetamine, 0104 chemical sciences, Rats, 010404 medicinal & biomolecular chemistry, chemistry, biology.protein, Microsomes, Liver, Molecular Medicine, Locomotion, medicine.drug
Abstract: Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in preclinical models of psychostimulant abuse. In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine, but did not exhibit psychostimulant behaviors itself. While further development of 3b is ongoing, diastereomeric separation, as well as improvements in potency and pharmacokinetics were desirable for discovering pipeline drug candidates. Thus, a series of bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines, where the piperazine-2-propanol scaffold was modified, were designed, synthesized and evaluated for binding affinities at DAT, as well as the serotonin transporter and sigma(1) receptors. Within the series, 14a showed improved DAT affinity (K(i)=23 nM) over 3b (K(i)=230 nM), moderate metabolic stability in human liver microsomes, and a hERG/DAT affinity ratio = 28. While 14a increased locomotor activity relative to vehicle, it was significantly lower than activity produced by cocaine. These results support further investigation of 14a as a potential treatment for psychostimulant use disorders.
Published: 2019

21. Investigation of Novel Primary and Secondary Pharmacophores and 3-Substitution in the Linking Chain of a Series of Highly Selective and Bitopic Dopamine D(3) Receptor Antagonists and Partial Agonists

Author: Zheng-Xiong Xi, Sophie L. Cemaj, Alexandra J. Gadiano, Anver Basha Shaik, Rana Rais, Jenny Lam, Vivek Kumar, Amy Hauck Newman, Barbara S. Slusher, Adrian M. Guerrero, and Alessandro Bonifazi
Subjects: Stereochemistry, Phenylpiperazine, 01 natural sciences, Methylenedioxy, Article, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, Dopamine receptor D3, Dopamine receptor D2, Drug Discovery, Structure–activity relationship, Humans, 030304 developmental biology, 0303 health sciences, Chemistry, Receptors, Dopamine D3, 0104 chemical sciences, Chiral column chromatography, 010404 medicinal & biomolecular chemistry, Enantiopure drug, HEK293 Cells, Dopamine Agonists, Molecular Medicine, Dopamine Antagonists, Pharmacophore
Abstract: Dopamine D(3) receptors (D(3)R) play a critical role in neuropsychiatric conditions including substance use disorders (SUD). Recently, we reported a series of N-(3-hydroxy-4-(4-phenylpiperazin-1yl)butyl)-1H-indole-2-carboxamide analogues as high affinity and selective D(3)R lead molecules for the treatment of opioid use disorders (OUD). Further optimization led to a series of analogues that replaced the 3-OH with a 3-F in the linker between the primary pharmacophore (PP) and secondary pharmacophore (SP). Among the 3-F-compounds, 9b demonstrated the highest D(3)R binding affinity (K(i) = 0.756 nM) and was 327-fold selective for D(3)R over D(2)R. In addition, modification of the PP or SP with a 3,4-(methylenedioxy)phenyl group was also examined. Further, an enantioselective synthesis as well as chiral HPLC methods were developed to give enantiopure R- and S-enantiomers of the four lead compounds. Off-target binding affinities, functional efficacies, and metabolic profiles revealed critical structural components for D(3)R selectivity as well as drug-like features required for development as pharmacotherapeutics.
Published: 2019

22. The highly selective dopamine D

Author: Chloe J, Jordan, Bree, Humburg, Myra, Rice, Guo-Hua, Bi, Zhi-Bing, You, Anver Basha, Shaik, Jianjing, Cao, Alessandro, Bonifazi, Alexandra, Gadiano, Rana, Rais, Barbara, Slusher, Amy Hauck, Newman, and Zheng-Xiong, Xi
Subjects: Male, Nociception, Indoles, Reinforcement Schedule, Behavior, Animal, Dopaminergic Neurons, Ventral Tegmental Area, Receptors, Dopamine D3, Self Administration, Piperazines, Article, Rats, Analgesics, Opioid, Optogenetics, Self Stimulation, Reward, Animals, Dopamine Antagonists, Rats, Long-Evans, Oxycodone
Abstract: Prescription opioid abuse is a global crisis. New treatment strategies for pain and opioid use disorders are urgently required. We evaluated the effects of R-VK4-40, a highly selective dopamine (DA) D(3) receptor (D(3)R) antagonist, on the rewarding and analgesic effects of oxycodone, the most commonly abused prescription opioid, in rats and mice. Systemic administration of R-VK4-40 dose-dependently inhibited oxycodone self-administration and shifted oxycodone dose-response curves downward in rats. Pretreatment with R-VK4-40 also dose-dependently lowered break-points for oxycodone under a progressive-ratio schedule. To determine whether a DA-dependent mechanism underlies the impact of D(3) antagonism in reducing opioid reward, we used optogenetic approaches to examine intracranial self-stimulation (ICSS) maintained by optical activation of ventral tegmental area (VTA) DA neurons in DAT-Cre mice. Photoactivation of VTA DA in non-drug treated mice produced robust ICSS behavior. Lower doses of oxycodone enhanced, while higher doses inhibited, optical ICSS. Pretreatment with R-VK4-40 blocked oxycodone-enhanced brain-stimulation reward. By itself, R-VK4-40 produced a modest dose-dependent reduction in optical ICSS. Pretreatment with R-VK4-40 did not compromise the antinociceptive effects of oxycodone in rats, and R-VK4-40 alone produced mild antinociceptive effects without altering open-field locomotion or rotarod locomotor performance. Together, these findings suggest R-VK4-40 may permit a lower dose of prescription opioids for pain management, potentially mitigating tolerance and dependence, while diminishing reward potency. Hence, development of R-VK4-40 as a therapy for the treatment of opioid use disorders and/or pain is currently underway.
Published: 2018

23. Dopamine D

Author: Zhi-Bing, You, Guo-Hua, Bi, Ewa, Galaj, Vivek, Kumar, Jianjing, Cao, Alexandra, Gadiano, Rana, Rais, Barbara S, Slusher, Eliot L, Gardner, Zheng-Xiong, Xi, and Amy Hauck, Newman
Subjects: Male, Analgesics, Sucrose, Indoles, Reinforcement Schedule, Dose-Response Relationship, Drug, Self Administration, Piperazines, Article, Extinction, Psychological, Rats, Conditioning, Psychological, Animals, Dopamine Antagonists, Drug Interactions, Oxycodone, Pain Measurement
Abstract: Prescription opioids such as oxycodone are highly effective analgesics for clinical pain management, but their misuse and abuse have led to the current opioid epidemic in the United States. In order to ameliorate this public health crisis, the development of effective pharmacotherapies for the prevention and treatment of opioid abuse and addiction is essential and urgently required. In this study, we evaluated—in laboratory rats—the potential utility of VK4-116, a novel and highly selective dopamine D3 receptor (D3R) antagonist, for the prevention and treatment of prescription opioid use disorders. Pretreatment with VK4-116 (5–25 mg/kg, i.p.) dose-dependently inhibited the acquisition and maintenance of oxycodone self-administration. VK4-116 also lowered the break-point (BP) for oxycodone self-administration under a progressive-ratio schedule of reinforcement, shifted the oxycodone dose–response curve downward, and inhibited oxycodone extinction responding and reinstatement of oxycodone-seeking behavior. In addition, VK4-116 pretreatment dose-dependently enhanced the antinociceptive effects of oxycodone and reduced naloxone-precipitated conditioned place aversion in rats chronically treated with oxycodone. In contrast, VK4-116 had little effect on oral sucrose self-administration. Taken together, these findings indicate a central role for D3Rs in opioid reward and support further development of VK4-116 as an effective agent for mitigating the development of opioid addiction, reducing the severity of withdrawal and preventing relapse.
Published: 2018

24. N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs

Author: Andrej Jančařík, Rana Rais, Lenka Monincová, Ranjeet Prasad Dash, Sarah C. Zimmermann, Barbara S. Slusher, Gregory J. Riggins, Jan Vávra, Pavel Majer, Alexandra J. Gadiano, Ying Wu, Lukáš Tenora, C. Ethan Slusher, Tomáš Tichý, and Eva Prchalova
Subjects: 0301 basic medicine, Male, Nitrogen, Mebendazole, Administration, Oral, Biological Availability, 03 medical and health sciences, Mice, Structure-Activity Relationship, 0302 clinical medicine, Dogs, Drug Stability, Drug Discovery, Aqueous solubility, medicine, Structure–activity relationship, Animals, Prodrugs, Tissue Distribution, Anthelmintic, Solubility, Anthelmintics, Chemistry, Water, Prodrug, Bioavailability, 030104 developmental biology, 030220 oncology & carcinogenesis, Molecular Medicine, medicine.drug, Nuclear chemistry, Biological availability
Abstract: Mebendazole (MBZ) was developed as a broad-spectrum anthelmintic but has recently shown efficacy as an anticancer agent. The use of MBZ for cancer, however, is challenging due to its poor solubility leading to poor bioavailability. Herein, we developed a prodrug approach with various N-linked promoieties including acyloxymethyl, aminoacyloxymethyl, and substituted phosphonooxymethyl in attempt to improve these characteristics. Compound 12, containing an (((((isopropoxycarbonyl)oxy)methoxy)phosphoryl)oxy)methyl promoiety, showed a >10 000-fold improvement in aqueous solubility. When evaluated in mice, 12 displayed a 2.2-fold higher plasma AUC0–t and a 1.7-fold improvement in brain AUC0–t with a calculated oral bioavailability of 52%, as compared to 24% for MBZ-polymorph C (MBZ-C), the most bioavailable polymorph. In dogs, 12 showed a 3.8-fold higher plasma AUC0–t with oral bioavailability of 41% compared to 11% for MBZ-C. In summary, we have identified a prodrug of MBZ with better physicochemical propertie...
Published: 2018

25. The highly selective dopamine D R antagonist, R-VK4-40 attenuates oxycodone reward and augments analgesia in rodents

Author: Jordan, Chloe J., primary, Humburg, Bree, additional, Rice, Myra, additional, Bi, Guo-Hua, additional, You, Zhi-Bing, additional, Shaik, Anver Basha, additional, Cao, Jianjing, additional, Bonifazi, Alessandro, additional, Gadiano, Alexandra, additional, Rais, Rana, additional, Slusher, Barbara, additional, Newman, Amy Hauck, additional, and Xi, Zheng-Xiong, additional
Published: 2019
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26. Structure–Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter: Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability

Author: Slack, Rachel D., primary, Ku, Therese C., additional, Cao, Jianjing, additional, Giancola, JoLynn B., additional, Bonifazi, Alessandro, additional, Loland, Claus J., additional, Gadiano, Alexandra, additional, Lam, Jenny, additional, Rais, Rana, additional, Slusher, Barbara S., additional, Coggiano, Mark, additional, Tanda, Gianluigi, additional, and Newman, Amy Hauck, additional
Published: 2019
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27. Investigation of Novel Primary and Secondary Pharmacophores and 3-Substitution in the Linking Chain of a Series of Highly Selective and Bitopic Dopamine D3 Receptor Antagonists and Partial Agonists

Author: Shaik, Anver Basha, primary, Kumar, Vivek, additional, Bonifazi, Alessandro, additional, Guerrero, Adrian M., additional, Cemaj, Sophie L., additional, Gadiano, Alexandra, additional, Lam, Jenny, additional, Xi, Zheng-Xiong, additional, Rais, Rana, additional, Slusher, Barbara S., additional, and Newman, Amy Hauck, additional
Published: 2019
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28. Abstract 3602: JHU395, a nervous tissue penetrant glutamine antagonist, restricts growth of malignant peripheral nerve sheath tumor with inhibition of nucleotide synthesis

Author: Lemberg, Kathryn M., primary, Zhao, Liang, additional, Wu, Ying, additional, Alt, Jesse, additional, Aguilar, Joanna Marie H., additional, Lam, Jenny, additional, Gadiano, Alexandra J., additional, Rais, Rana, additional, Majer, Pavel, additional, Blakeley, Jaishri, additional, and Slusher, Barbara S., additional
Published: 2019
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29. Tumor-Targeted Delivery of 6-Diazo-5-oxo-l-norleucine (DON) Using Substituted Acetylated Lysine Prodrugs

Author: Tenora, Lukáš, primary, Alt, Jesse, additional, Dash, Ranjeet P., additional, Gadiano, Alexandra J., additional, Novotná, Kateřina, additional, Veeravalli, Vijayabhaskar, additional, Lam, Jenny, additional, Kirkpatrick, Quinn R., additional, Lemberg, Kathryn M., additional, Majer, Pavel, additional, Rais, Rana, additional, and Slusher, Barbara S., additional
Published: 2019
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30. DPTIP, a newly identified potent brain penetrant neutral sphingomyelinase 2 inhibitor, regulates astrocyte-peripheral immune communication following brain inflammation

Author: Rojas, Camilo, primary, Barnaeva, Elena, additional, Thomas, Ajit G., additional, Hu, Xin, additional, Southall, Noel, additional, Marugan, Juan, additional, Chaudhuri, Amrita Datta, additional, Yoo, Seung-Wan, additional, Hin, Niyada, additional, Stepanek, Ondrej, additional, Wu, Ying, additional, Zimmermann, Sarah C., additional, Gadiano, Alexandra G., additional, Tsukamoto, Takashi, additional, Rais, Rana, additional, Haughey, Norman, additional, Ferrer, Marc, additional, and Slusher, Barbara S., additional
Published: 2018
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31. Ghrelin agonist HM01 attenuates chemotherapy-induced neurotoxicity in rodent models

Author: Chiorazzi, Alessia, primary, Wozniak, Krystyna M., additional, Rais, Rana, additional, Wu, Ying, additional, Gadiano, Alexandra J., additional, Farah, Mohamed H., additional, Liu, Ying, additional, Canta, Annalisa, additional, Alberti, Paola, additional, Rodriguez-Menendez, Virginia, additional, Meregalli, Cristina, additional, Fumagalli, Giulia, additional, Monza, Laura, additional, Pozzi, Eleonora, additional, Vornov, James J., additional, Polydefkis, Michael, additional, Pietra, Claudio, additional, Slusher, Barbara S., additional, and Cavaletti, Guido, additional
Published: 2018
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32. Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain

Author: Pavel Majer, Jan Vávra, Lenka Monincová, Jesse Alt, Rana Rais, Alexandra J. Gadiano, Ying Wu, Sarah C. Zimmermann, Takashi Tsukamoto, Krystyna M. Wozniak, C. Ethan Slusher, Tomáš Tichý, Barbara S. Slusher, Cyril Bařinka, Ranjeet Prasad Dash, and Lukáš Tenora
Subjects: Glutamate Carboxypeptidase II, Male, Stereochemistry, Metabolite, Administration, Oral, Hydroxamic Acids, 01 natural sciences, Article, Rats, Sprague-Dawley, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Pharmacokinetics, Oral administration, Drug Discovery, Glutamate carboxypeptidase II, Animals, Humans, Prodrugs, Carboxylate, Enzyme Inhibitors, Benzoic acid, Analgesics, Esterification, 010405 organic chemistry, Chemistry, Prodrug, In vitro, 0104 chemical sciences, Rats, Molecular Medicine, Neuralgia, 030217 neurology & neurosurgery
Abstract: 4-Carboxy-α-[3-(hydroxyamino)-3-oxopropyl]-benzenepropanoic acid 1 is a potent hydroxamate-based inhibitor of glutamate carboxypeptidase II. In an attempt to improve its poor oral pharmacokinetics, we synthesized a series of prodrugs by masking its hydrophilic hydroxamate group. Prodrugs were evaluated for oral availability in mice and showed varying degree of plasma exposure to 1. Of these, para-acetoxybenzyl-based, 4-(5-(((4-acetoxybenzyl)oxy)amino)-2-carboxy-5-oxopentyl)benzoic acid, 12, provided 5-fold higher plasma levels of 1 compared to oral administration of 1 itself. Subsequently, para-acetoxybenzyl-based prodrugs with additional ester promoiety(ies) on carboxylate(s) were examined for their ability to deliver 1 to plasma. Isopropyloxycarbonyloxymethyl (POC) ester 30 was the only prodrug that achieved substantial plasma levels of 1. In vitro metabolite identification studies confirmed stability of the ethyl ester of benzoate while the POC group was rapidly hydrolyzed. At oral daily dose-equivalent of 3 mg/kg, 12 exhibited analgesic efficacy comparable to dose of 10 mg/kg of 1 in the rat chronic constrictive injury model of neuropathic pain.
Published: 2017

33. N-(Pivaloyloxy)alkoxy-carbonyl Prodrugs of the Glutamine Antagonist 6-Diazo-5-oxo-L-norleucine (DON) as a Potential Treatment for HIV Associated Neurocognitive Disorders

Author: Andrej Jančařík, Rana Rais, Caroline Garrett, Michael T. Nedelcovych, Ranjeet Prasad Dash, Alexandra J. Gadiano, Gerald Brandacher, Boe-Hyun Kim, Jennifer Kelschenbach, Georg J. Furtmüller, Eran Hadas, Eva Prchalova, Lukáš Tenora, Pavel Majer, Byoung Chol Oh, David J. Volsky, Wei Chao, Barbara S. Slusher, Jesse Alt, and Sarah C. Zimmermann
Subjects: 0301 basic medicine, Male, Swine, Diazooxonorleucine, Neurocognitive Disorders, Glutamic Acid, HIV Infections, Pharmacology, Neurotransmission, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Drug Stability, Glutaminase, Drug Discovery, medicine, Animals, Humans, Prodrugs, Nootropic Agents, Aminocaproates, Microglia, Glutamate receptor, Antagonist, Brain, Prodrug, Viral Load, 6-Diazo-5-oxo-L-norleucine, Glutamine, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Blood, chemistry, Molecular Medicine, Female, Azo Compounds, 030217 neurology & neurosurgery, Isopropyl
Abstract: Aberrant excitatory neurotransmission associated with overproduction of glutamate has been implicated in the development of HIV-associated neurocognitive disorders (HAND). The glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON, 14) attenuates glutamate synthesis in HIV-infected microglia/macrophages, offering therapeutic potential for HAND. We show that 14 prevents manifestation of spatial memory deficits in chimeric EcoHIV-infected mice, a model of HAND. 14 is not clinically available, however, because its development was hampered by peripheral toxicities. We describe the synthesis of several substituted N-(pivaloyloxy)alkoxy-carbonyl prodrugs of 14 designed to circulate inert in plasma and be taken up and biotransformed to 14 in the brain. The lead prodrug, isopropyl 6-diazo-5-oxo-2-(((phenyl(pivaloyloxy)methoxy)-carbonyl)amino)hexanoate (13d), was stable in swine and human plasma but liberated 14 in swine brain homogenate. When dosed systemically in swine, 13d provided a 15-fold enhanced CSF-to-plasma ratio and a 9-fold enhanced brain-to-plasma ratio relative to 14, opening a possible clinical path for the treatment of HAND.
Published: 2017

34. Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its γ-Substituted Ester Prodrugs

Author: Andrej Jančařík, Elie Pommier, Sarah C. Zimmermann, Barbara S. Slusher, Michael T. Nedelcovych, Alexandra J. Gadiano, Ajit G. Thomas, Ying Wu, Ranjeet Prasad Dash, Krystyna M. Wozniak, Rana Rais, Lukáš Tenora, Camilo Rojas, Pavel Majer, Caroline Garrett, Kristen R. Hollinger, and Jesse Alt
Subjects: 0301 basic medicine, Glutamate Carboxypeptidase II, Male, Pharmaceutical Science, Pharmacology, Blood–brain barrier, Article, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Organophosphorus Compounds, Pharmacokinetics, Drug Discovery, Glutamate carboxypeptidase II, medicine, Animals, Prodrugs, Tissue Distribution, Rats, Wistar, Administration, Intranasal, Cerebrospinal Fluid, Chemistry, Glutamate receptor, Brain, Esters, Prodrug, Macaca mulatta, Olfactory bulb, Rats, 030104 developmental biology, medicine.anatomical_structure, Neuroprotective Agents, Blood-Brain Barrier, Molecular Medicine, Nasal administration, Administration, Intravenous, 030217 neurology & neurosurgery
Abstract: 2-(Phosphonomethyl)pentanedioic acid (2-PMPA) is a potent and selective inhibitor of glutamate carboxypeptidase-II (GCPII) with efficacy in multiple neurological and psychiatric disease models, but its clinical utility is hampered by low brain penetration due to the inclusion of multiple acidic functionalities. We recently reported an improvement in the brain-to-plasma ratio of 2-PMPA after intranasal (IN) dosing in both rodents and primates. Herein, we describe the synthesis of several 2-PMPA prodrugs with further improved brain delivery of 2-PMPA after IN administration by masking of the γ-carboxylate. When compared to IN 2-PMPA in rats at 1 h post dose, γ-(4-acetoxybenzyl)-2-PMPA (compound 1) resulted in significantly higher 2-PMPA delivery to both plasma (4.1-fold) and brain (11-fold). Subsequent time-dependent evaluation of 1 also showed high brain as well as plasma 2-PMPA exposures with brain-to-plasma ratios of 2.2, 0.48, and 0.26 for olfactory bulb, cortex, and cerebellum, respectively, as well as an improved sciatic nerve to plasma ratio of 0.84. In contrast, IV administration of compound 1 resulted in similar plasma exposure of 2-PMPA versus the IN route (AUCIV: 76 ± 9 h·nmol/mL versus AUCIN: 99 ± 24 h·nmol/mL); but significantly lower nerve and brain tissue exposures with tissue-to-plasma ratios of 0.21, 0.03, 0.04, and 0.04 in nerve, olfactory bulb, cortex, and cerebellum, respectively. In primates, IN administration of 1 more than doubled 2-PMPA concentrations in the cerebrospinal fluid relative to previously reported levels following IN 2-PMPA. The results of these experiments provide a promising strategy for testing GCPII inhibition in neurological and psychiatric disorders.
Published: 2017

35. The highly selective dopamine D R antagonist, R-VK4-40 attenuates oxycodone reward and augments analgesia in rodents

Author: Guo Hua Bi, Chloe J. Jordan, Zheng-Xiong Xi, Anver Basha Shaik, Jianjing Cao, Myra Rice, Barbara S. Slusher, Rana Rais, Alessandro Bonifazi, Zhi Bing You, Alexandra J. Gadiano, Amy Hauck Newman, and Bree A. Humburg
Subjects: 0301 basic medicine, Pharmacology, business.industry, Analgesic, Ventral tegmental area, 03 medical and health sciences, Cellular and Molecular Neuroscience, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Opioid, Dopamine receptor D3, Dopamine, medicine, Brain stimulation reward, business, Self-administration, Oxycodone, 030217 neurology & neurosurgery, medicine.drug
Abstract: Prescription opioid abuse is a global crisis. New treatment strategies for pain and opioid use disorders are urgently required. We evaluated the effects of R-VK4-40, a highly selective dopamine (DA) D3 receptor (D3R) antagonist, on the rewarding and analgesic effects of oxycodone, the most commonly abused prescription opioid, in rats and mice. Systemic administration of R-VK4-40 dose-dependently inhibited oxycodone self-administration and shifted oxycodone dose-response curves downward in rats. Pretreatment with R-VK4-40 also dose-dependently lowered break-points for oxycodone under a progressive-ratio schedule. To determine whether a DA-dependent mechanism underlies the impact of D3 antagonism in reducing opioid reward, we used optogenetic approaches to examine intracranial self-stimulation (ICSS) maintained by optical activation of ventral tegmental area (VTA) DA neurons in DAT-Cre mice. Photoactivation of VTA DA in non-drug treated mice produced robust ICSS behavior. Lower doses of oxycodone enhanced, while higher doses inhibited, optical ICSS. Pretreatment with R-VK4-40 blocked oxycodone-enhanced brain-stimulation reward. By itself, R-VK4-40 produced a modest dose-dependent reduction in optical ICSS. Pretreatment with R-VK4-40 did not compromise the antinociceptive effects of oxycodone in rats, and R-VK4-40 alone produced mild antinociceptive effects without altering open-field locomotion or rotarod locomotor performance. Together, these findings suggest R-VK4-40 may permit a lower dose of prescription opioids for pain management, potentially mitigating tolerance and dependence, while diminishing reward potency. Hence, development of R-VK4-40 as a therapy for the treatment of opioid use disorders and/or pain is currently underway. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'.
Published: 2019

36. Abstract 3602: JHU395, a nervous tissue penetrant glutamine antagonist, restricts growth of malignant peripheral nerve sheath tumor with inhibition of nucleotide synthesis

Author: Kathryn M. Lemberg, Liang Zhao, Ying Wu, Jesse Alt, Joanna Marie H. Aguilar, Jenny Lam, Alexandra J. Gadiano, Rana Rais, Pavel Majer, Jaishri Blakeley, and Barbara S. Slusher
Subjects: Cancer Research, Oncology
Abstract: Malignant peripheral nerve sheath tumor (MPNST) is a sarcoma that occurs in ~10% of patients with neurofibromatosis type I (NF1). Incomplete surgical resection at diagnosis leads to a 4-year event-free survival rate of 30 micromolar). JHU395 delivered GA to MPNST cells with >4-fold higher cell-to-plasma ratio compared to native GA and maintained ~2.5-fold higher tumor-to-plasma GA levels in vivo. Mice treated with JHU395 had >40% smaller mean tumor volume compared to controls with no overt toxicity. Quantitiative bioanalysis revealed that JHU395 treated tumors had >60% higher glutamine levels compared to controls 30 minutes after oral dosing. In vivo flux analysis demonstrated that JHU395 preferentially affects tumor glutamine utilization for nucleotide synthesis, while glutamine-derived substrates for the citric acid cycle appear unaffected. In summary, JHU395 inhibits growth of MPNST with inhibition of glutamine utilization in nucleotide synthesis and is well-tolerated. Nervous tissue penetrant glutamine antagonism is a feasible and effective therapeutic approach in preclinical models of MPNST. Future studies will investigate JHU395 in combination with nucleotide synthesis inhibitors in MPNST and investigate JHU395 efficacy in additional sarcoma models including patient-derived samples. Citation Format: Kathryn M. Lemberg, Liang Zhao, Ying Wu, Jesse Alt, Joanna Marie H. Aguilar, Jenny Lam, Alexandra J. Gadiano, Rana Rais, Pavel Majer, Jaishri Blakeley, Barbara S. Slusher. JHU395, a nervous tissue penetrant glutamine antagonist, restricts growth of malignant peripheral nerve sheath tumor with inhibition of nucleotide synthesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3602.
Published: 2019

37. Dopamine D3R antagonist VK4-116 attenuates oxycodone self-administration and reinstatement without compromising its antinociceptive effects

Author: You, Zhi-Bing, primary, Bi, Guo-Hua, additional, Galaj, Ewa, additional, Kumar, Vivek, additional, Cao, Jianjing, additional, Gadiano, Alexandra, additional, Rais, Rana, additional, Slusher, Barbara S., additional, Gardner, Eliot L., additional, Xi, Zheng-Xiong, additional, and Newman, Amy Hauck, additional
Published: 2018
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38. Abstract 3524: Novel prodrugs of the glutamine antagonist 6-diazo-5-oxo-norleucine (DON) as treatment for malignant peripheral nerve sheath tumor

Author: Lemberg, Kathryn, primary, Wu, Ying, additional, Alt, Jesse, additional, Zhao, Liang, additional, Gadiano, Alexandra J., additional, Rodriguez, Chabely, additional, Rais, Rana, additional, Majer, Pavel, additional, Blakeley, Jaishri, additional, and Slusher, Barbara, additional
Published: 2018
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39. N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs

Author: Zimmermann, Sarah C., primary, Tichý, Tomáš, additional, Vávra, Jan, additional, Dash, Ranjeet P., additional, Slusher, C. Ethan, additional, Gadiano, Alexandra J., additional, Wu, Ying, additional, Jančařík, Andrej, additional, Tenora, Lukáš, additional, Monincová, Lenka, additional, Prchalová, Eva, additional, Riggins, Gregory J., additional, Majer, Pavel, additional, Slusher, Barbara S., additional, and Rais, Rana, additional
Published: 2018
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40. Pharmacokinetics of Intranasal versus Subcutaneous Insulin in the Mouse

Author: Nedelcovych, Michael T., primary, Gadiano, Alexandra J., additional, Wu, Ying, additional, Manning, Arena A., additional, Thomas, Ajit G., additional, Khuder, Saja S., additional, Yoo, Seung-Wan, additional, Xu, Jiadi, additional, McArthur, Justin C., additional, Haughey, Norman J., additional, Volsky, David J., additional, Rais, Rana, additional, and Slusher, Barbara S., additional
Published: 2017
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41. Abstract 3524: Novel prodrugs of the glutamine antagonist 6-diazo-5-oxo-norleucine (DON) as treatment for malignant peripheral nerve sheath tumor

Author: Liang Zhao, Rana Rais, Jaishri O. Blakeley, Barbara S. Slusher, Alexandra J. Gadiano, Kathryn M. Lemberg, Pavel Majer, Ying Wu, Jesse Alt, and Chabely Rodriguez
Subjects: 0301 basic medicine, Cancer Research, business.industry, Cell growth, Cancer, Malignant peripheral nerve sheath tumor, Prodrug, medicine.disease, Glutamine, 03 medical and health sciences, 030104 developmental biology, Oncology, Cell culture, medicine, Cancer research, Cytotoxic T cell, Sarcoma, business
Abstract: Neurofibromatosis Type I (NF1) is a heritable tumor predisposition syndrome in which up to 10% of patients develop malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma. For MPNST that is incompletely resected at diagnosis, traditional cytotoxic chemotherapeutic strategies offer a 5 year event-free survival of less than 40%; thus new therapeutic strategies are desperately needed. Reprogramming of energy metabolism, whereby tumor cells take up more glutamine than healthy cells and direct this substrate to replenish metabolites for proliferation, is a hallmark of several cancers that has not been effectively leveraged for treatment of MPNST. Our group has recently described JHU 395, a nervous system targeted prodrug of the glutamine antagonist 6-diazo-5-oxo-norleucine (DON) which delivers DON preferentially to the brain resulting in less gastrointestinal toxicity, which was the main toxicity of DON in past clinical trials. The primary goals of this study were to evaluate glutamine antagonism and JHU 395 activity in MPNST. Using multiple Schwann and MPNST cell lines we investigated cell proliferation in culture under glutamine deprivation and antagonism. Mass spectrometry (MS)-based metabolomic profiling was used to characterize differences between MPNST cells treated with vehicle versus DON. MS-based bioanalytical methods were also used to investigate DON delivery to tumor cells by JHU 395. We found that growth of MPNST cells in culture is preferentially inhibited by glutamine deprivation and DON treatment when compared to immortalized Schwann cells derived from non-tumored nerve (IC50 of 8-9 micromolar versus >30 micromolar). Targeted metabolomics analyses of DON treated human MPNST cells demonstrated multiple differences in downstream glutamine-dependent metabolites including intermediates in purine synthesis and amino acid synthesis, suggesting that DON acts broadly within the tumor cell to inhibit growth. While DON showed limited partitioning into MPNST cells versus plasma, JHU 395 preferentially delivered DON into MPNST with over 5-fold higher cell-to-plasma ratio. Prodrug pharmacokinetic studies in mouse demonstrated that oral administration of the prodrug safely delivered DON at micromolar concentrations to peripheral nerve. In conclusion, compared to healthy Schwann cells, MPNST cells have unique vulnerability to antagonizing glutamine utilization. The nervous system directed prodrug JHU 395 enhances DON delivery to MPNST and represents a novel potential therapeutic approach for these aggressive tumors. Based on these results we have initiated efficacy studies of JHU 395 in the murine NPcis (NF1+/-;p53+/-) model of MPNST. Citation Format: Kathryn Lemberg, Ying Wu, Jesse Alt, Liang Zhao, Alexandra J. Gadiano, Chabely Rodriguez, Rana Rais, Pavel Majer, Jaishri Blakeley, Barbara Slusher. Novel prodrugs of the glutamine antagonist 6-diazo-5-oxo-norleucine (DON) as treatment for malignant peripheral nerve sheath tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3524.
Published: 2018

42. <italic>N</italic>-(Pivaloyloxy)alkoxy-carbonyl Prodrugs of the Glutamine Antagonist 6-Diazo-5-oxo-l-norleucine (DON) as a Potential Treatment for HIV Associated Neurocognitive Disorders.

Author: Nedelcovych, Michael T., Tenora, Lukás, Boe-Hyun Kim, Kelschenbach, Jennifer, Wei Chao, Hadas, Eran, Jancarík, Andrej, Prchalova, Eva, Zimmermann, Sarah C., Dash, Ranjeet P., Gadiano, Alexandra J., Garrett, Gadiano, Furtmuller, Georg, Oh, Byoungchol, Brandacher, Gerald, Alt, Jesse, Majer, Pavel, Volsky, David J., Rais, Rana, and Slusher, Barbara S.
Published: 2017
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43. Local enema treatment to inhibit FOLH1 /GCPII as a novel therapy for inflammatory bowel disease

Author: Date, Abhijit A., primary, Rais, Rana, additional, Babu, Taarika, additional, Ortiz, Jairo, additional, Kanvinde, Pranjali, additional, Thomas, Ajit G., additional, Zimmermann, Sarah C., additional, Gadiano, Alexandra J., additional, Halpert, Gilad, additional, Slusher, Barbara S., additional, and Ensign, Laura M., additional
Published: 2017
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44. Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain

Author: Rais, Rana, primary, Vávra, Jan, additional, Tichý, Tomáš, additional, Dash, Ranjeet P., additional, Gadiano, Alexandra J., additional, Tenora, Lukáš, additional, Monincová, Lenka, additional, Bařinka, Cyril, additional, Alt, Jesse, additional, Zimmermann, Sarah C., additional, Slusher, C. Ethan, additional, Wu, Ying, additional, Wozniak, Krystyna, additional, Majer, Pavel, additional, Tsukamoto, Takashi, additional, and Slusher, Barbara S., additional
Published: 2017
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45. Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its γ-Substituted Ester Prodrugs

Author: Nedelcovych, Michael, primary, Dash, Ranjeet P., additional, Tenora, Lukáš, additional, Zimmermann, Sarah C., additional, Gadiano, Alexandra J., additional, Garrett, Caroline, additional, Alt, Jesse, additional, Hollinger, Kristen R., additional, Pommier, Elie, additional, Jančařík, Andrej, additional, Rojas, Camilo, additional, Thomas, Ajit G., additional, Wu, Ying, additional, Wozniak, Krystyna, additional, Majer, Pavel, additional, Slusher, Barbara S., additional, and Rais, Rana, additional
Published: 2017
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46. N-(Pivaloyloxy)alkoxy-carbonyl Prodrugs of the Glutamine Antagonist 6-Diazo-5-oxo-l-norleucine (DON) as a Potential Treatment for HIV Associated Neurocognitive Disorders

Author: Nedelcovych, Michael T., primary, Tenora, Lukáš, additional, Kim, Boe-Hyun, additional, Kelschenbach, Jennifer, additional, Chao, Wei, additional, Hadas, Eran, additional, Jančařík, Andrej, additional, Prchalová, Eva, additional, Zimmermann, Sarah C., additional, Dash, Ranjeet P., additional, Gadiano, Alexandra J., additional, Garrett, Caroline, additional, Furtmüller, Georg, additional, Oh, Byoungchol, additional, Brandacher, Gerald, additional, Alt, Jesse, additional, Majer, Pavel, additional, Volsky, David J., additional, Rais, Rana, additional, and Slusher, Barbara S., additional
Published: 2017
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47. Structure–Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter: Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability

Author: Slack, Rachel D., Ku, Therese C., Cao, Jianjing, Giancola, JoLynn B., Bonifazi, Alessandro, Loland, Claus J., Gadiano, Alexandra, Lam, Jenny, Rais, Rana, Slusher, Barbara S., Coggiano, Mark, Tanda, Gianluigi, and Newman, Amy Hauck
Abstract: Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in preclinical models of psychostimulant abuse. In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. While further development of 3bis ongoing, diastereomeric separation, as well as improvements in potency and pharmacokinetics were desirable for discovering pipeline drug candidates. Thus, a series of bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines, where the piperazine-2-propanol scaffold was modified, were designed, synthesized, and evaluated for binding affinities at DAT, as well as the serotonin transporter and σ1receptors. Within the series, 14ashowed improved DAT affinity (Ki= 23 nM) over 3b(Ki= 230 nM), moderate metabolic stability in human liver microsomes, and a hERG/DAT affinity ratio = 28. While 14aincreased locomotor activity relative to vehicle, it was significantly lower than activity produced by cocaine. These results support further investigation of 14aas a potential treatment for psychostimulant use disorders.
Published: 2020
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48. Investigation of Novel Primary and Secondary Pharmacophores and 3‑Substitution in the Linking Chain of a Series of Highly Selective and Bitopic Dopamine D3 Receptor Antagonists and Partial Agonists.

Author: Shaik, Anver Basha, Kumar, Vivek, Bonifazi, Alessandro, Guerrero, Adrian M., Cemaj, Sophie L., Gadiano, Alexandra, Lam, Jenny, Xi, Zheng-Xiong, Rais, Rana, Slusher, Barbara S., and Newman, Amy Hauck
Published: 2019
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49. Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its γ-Substituted Ester Prodrugs

Author: Nedelcovych, Michael, Dash, Ranjeet P., Tenora, Lukáš, Zimmermann, Sarah C., Gadiano, Alexandra J., Garrett, Caroline, Alt, Jesse, Hollinger, Kristen R., Pommier, Elie, Jančařík, Andrej, Rojas, Camilo, Thomas, Ajit G., Wu, Ying, Wozniak, Krystyna, Majer, Pavel, Slusher, Barbara S., and Rais, Rana
Abstract: 2-(Phosphonomethyl)pentanedioic acid (2-PMPA) is a potent and selective inhibitor of glutamate carboxypeptidase-II (GCPII) with efficacy in multiple neurological and psychiatric disease models, but its clinical utility is hampered by low brain penetration due to the inclusion of multiple acidic functionalities. We recently reported an improvement in the brain-to-plasma ratio of 2-PMPA after intranasal (IN) dosing in both rodents and primates. Herein, we describe the synthesis of several 2-PMPA prodrugs with further improved brain delivery of 2-PMPA after IN administration by masking of the γ-carboxylate. When compared to IN 2-PMPA in rats at 1 h post dose, γ-(4-acetoxybenzyl)-2-PMPA (compound 1) resulted in significantly higher 2-PMPA delivery to both plasma (4.1-fold) and brain (11-fold). Subsequent time-dependent evaluation of 1also showed high brain as well as plasma 2-PMPA exposures with brain-to-plasma ratios of 2.2, 0.48, and 0.26 for olfactory bulb, cortex, and cerebellum, respectively, as well as an improved sciatic nerve to plasma ratio of 0.84. In contrast, IV administration of compound 1resulted in similar plasma exposure of 2-PMPA versus the IN route (AUCIV: 76 ± 9 h·nmol/mL versus AUCIN: 99 ± 24 h·nmol/mL); but significantly lower nerve and brain tissue exposures with tissue-to-plasma ratios of 0.21, 0.03, 0.04, and 0.04 in nerve, olfactory bulb, cortex, and cerebellum, respectively. In primates, IN administration of 1more than doubled 2-PMPA concentrations in the cerebrospinal fluid relative to previously reported levels following IN 2-PMPA. The results of these experiments provide a promising strategy for testing GCPII inhibition in neurological and psychiatric disorders.
Published: 2024
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50. Investigation of Novel Primary and Secondary Pharmacophores and 3-Substitution in the Linking Chain of a Series of Highly Selective and Bitopic Dopamine D3Receptor Antagonists and Partial Agonists

Author: Shaik, Anver Basha, Kumar, Vivek, Bonifazi, Alessandro, Guerrero, Adrian M., Cemaj, Sophie L., Gadiano, Alexandra, Lam, Jenny, Xi, Zheng-Xiong, Rais, Rana, Slusher, Barbara S., and Newman, Amy Hauck
Abstract: Dopamine D3receptors (D3R) play a critical role in neuropsychiatric conditions including substance use disorders (SUD). Recently, we reported a series of N-(3-hydroxy-4-(4-phenylpiperazin-1-yl)butyl)-1H-indole-2-carboxamide analogues as high affinity and selective D3R lead molecules for the treatment of opioid use disorders (OUD). Further optimization led to a series of analogues that replaced the 3-OH with a 3-F in the linker between the primary pharmacophore (PP) and secondary pharmacophore (SP). Among the 3-F-compounds, 9bdemonstrated the highest D3R binding affinity (Ki= 0.756 nM) and was 327-fold selective for D3R over D2R. In addition, modification of the PP or SP with a 3,4-(methylenedioxy)phenyl group was also examined. Further, an enantioselective synthesis as well as chiral HPLC methods were developed to give enantiopure R- and S-enantiomers of the four lead compounds. Off-target binding affinities, functional efficacies, and metabolic profiles revealed critical structural components for D3R selectivity as well as drug-like features required for development as pharmacotherapeutics.
Published: 2019
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