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1. Modification of the third phase in the framework for vertebrate species persistence in urban mosaic environments

Author

Downs, Colleen T., Alexander, Jarryd, Brown, Mark, Chibesa, Moses, Ehlers Smith, Yvette C., Gumede, S. Thobeka, Hart, Lorinda, Josiah, Kyrone K., Kalle, Riddhika, Maphalala, Machawe, Maseko, Mfundo, McPherson, Shane, Ngcobo, Samukelisiwe P., Patterson, Lindsay, Pillay, Kerushka, Price, Cormac, Raji, Islamiat Abidemi, Ramesh, Tharmalingam, Schmidt, Warren, Senoge, Ntaki D., Shivambu, Tinyiko C., Shivambu, Ndivhuwo, Singh, Nikisha, Singh, Preshnee, Streicher, Jarryd, Thabethe, Vuyisile, Thatcher, Harriet, Widdows, Craig, Wilson, Amy-Leigh, Zungu, Manqoba M., and Ehlers Smith, David A.

Published
2021
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2. Correction to: Modification of the third phase in the framework for vertebrate species persistence in urban mosaic environments

Author

Downs, Colleen T., Alexander, Jarryd, Brown, Mark, Chibesa, Moses, Ehlers Smith, Yvette C., Gumede, S. Thobeka, Hart, Lorinda, Josiah, Kyrone K., Kalle, Riddhika, Maphalala, Machawe, Maseko, Mfundo, McPherson, Shane, Ngcobo, Samukelisiwe P., Patterson, Lindsay, Pillay, Kerushka, Price, Cormac, Raji, Islamiat Abidemi, Ramesh, Tharmalingam, Schmidt, Warren, Senoge, Ntaki D., Shivambu, Tinyiko C., Shivambu, Ndivhuwo, Singh, Nikisha, Singh, Preshnee, Streicher, Jarryd, Thabethe, Vuyisile, Thatcher, Harriet, Widdows, Craig, Wilson, Amy-Leigh, Zungu, Manqoba M., and Ehlers Smith, David A.

Published
2021
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3. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials

Author

Gadano, Adrian, Martins, Marcelo, Angus, Peter, Bate, John, Danta, Mark, George, Jacob, Hodge, Alexander, Kontorinis, Nickolas, Roberts, Stuart, Sanagapalli, Santosh, Skoien, Richard, Thompson, Alexander, Zekry, Amany, Stauber, Rudolf, Trauner, Michael, Moreno, Christophe, Reynaert, Hendrik, Verbeke, Len, Silva, Mario Reis Alvares da, Parise, Edison, Oliveira, Claudia Pinto Marques Souza de, Araujo, Roberta Chaves, Martinelli, Ana de Lourdes Candolo, Borman, Meredith, Chandok, Natasha, Elkhashab, Magdy, Fraser, Hughie, Kaita, Kelly, Ma, Mang, Marotta, Paul, Ramji, Alnoor, Tam, Edward, Yoshida, Eric, Swain, Mark, Sebastiani, Giada, Petrunia, Denis, Abergel, Armando, Anty, Rodolphe, Bourlière, Marc, Boursier, Jérôme, Bureau, Christophe, Castera, Laurent, Habersetzer, François, Hézode, Christophe, Ledinghen, Victor De, Leroy, Vincent, Loustaud-Ratti, Véronique, Mathurin, Philippe, Pol, Stanislas, Zoulim, Fabien, Hinrichsen, Holger, Ingiliz, Patrick, Lammert, Frank, Manns, Michael, Schattenberg, Jörn, Schiefke, Ingolf, Trautwein, Christian, Zeuzem, Stefan, Hui, Aric, Li, King-Kong, Wong, Vincent, Acharya, Subrat, Chowdhury, Abhijit, Duseja, Ajay, Kapoor, Dharmesh, Mukewar, Shrikant, Sarin, Shiv, Shah, Samir, Shalimar, Sood, Ajit, Tantry, BV, Ben-Ari, Ziv, Katchman, Helena, Safadi, Rifaat, Veitsman, Ella, Zuckerman, Eli, Brunetto, Maurizia, Lampertico, Pietro, Mangia, Alessandra, Akahane, Takemi, Akuta, Norio, Eguchi, Yuichiro, Fujiyama, Shigetoshi, Genda, Takuya, Hiasa, Yoichi, Ido, Akio, Ikeda, Fusao, Ikegami, Tadashi, Imajo, Kento, Itoh, Yoshito, Iwasa, Motoh, Karino, Yoshiyasu, Kato, Naoya, Kawaguchi, Takumi, Kawanaka, Miwa, Kido, Masahiro, Kobayashi, Tomoo, Kurosaki, Masayuki, Matsuzaki, Yasushi, Mita, Eiji, Mizukoshi, Eishiro, Nakahara, Takashi, Nomura, Hideyuki, Notsumata, Kazuo, Okanoue, Takeshi, Saito, Satoshi, Sakugawa, Hiroshi, Suzuki, Yoshiyuki, Takaguchi, Koichi, Takaki, Akinobu, Takashima, Tomoyuki, Tanaka, Saiyu, Tsuji, Keiji, Ueno, Yoshiyuki, Umemura, Takeji, Uto, Hirofumi, Yamashita, Nobuyuki, Yanase, Mikio, Yatsuhashi, Hiroshi, Yoneda, Masashi, Chan, Wah Kheong, Tan, Soek Siam, Garza, Laura Cisneros, Ladron De Guevara Cetina, Alma, Angeles, Rocio Guadalupe Vargas, Silva, Francisca Martinez, Van Erpecum, Karel, Orr, David, Jabłkowski, Maciej, Jaroszewicz, Jerzy, Ramos, Jose, Ahmed, Taufique, Ang, Tiing, Dan, Yock young, Goh, Boon Bee, Kaliyaperumal, Kalaiyarasi, Yip, Cherng Hann, Baik, Soon Koo, Jang, Byoung Kuk, Jun, Dae Won, Kim, Won, Kim, Hyung Joon, Kim, Ji Hoon, Lee, Kwan Sik, Lee, Chun Kyon, Lim, Young-Suk, Park, Jun Yong, Tak, Won Young, Augustin, Salvador, Perez, Salvador Benlloch, Caballeria, Juan, Luis, Jose, Panero, Calleja, Rodríguez, Jose Carrión, Garcia, Javier Crespo, Samaniego, Javier Garcia, Gibert, Pere Ginès, Prieto, Martin, Gomez, Manuel Romero, Turnes, Juan, Dufour, Jean-Francois, Moriggia, Alberto, Sheen, I-Shyan, Kao, Jia-Horng, Cheng, Pin-Nan, Huang, Jee-Fu, Yang, Sheng-Shun, Su, Wei-Wen, Chen, Chi-Yi, Chien, Rong-Nan, Lo, Gin-Ho, Chu, Chi-Jen, Wang, Horng-Yuan, Hu, Jui-Ting, Huang, Yi Wen, Agarwal, Kosh, Allison, Michael, Anstee, Quentin, Austin, Andrew, Fowell, Andrew, Ch'ng, Chin Lye, Manousou, Pinelopi, Newsome, Philip, Ryder, Stephen, Shankar, Arun, Abdelmalek, Manal, Abrams, Gary, Aguilar, Humberto, Alam, Imtiaz, Alba, Laura, Alkhouri, Naim, Allen, Alina, Aqel, Bashar, Balart, Luis, Barritt, A. Sidney, IV, Behari, Jaideep, Bennett, Michael, Bernstein, David, Bhandari, Bal Raj, Bonacini, Maurizio, Borg, Brian, Brown, Kimberly, Bzowej, Natalie, Caldwell, Stephen, Chami, Tawfik, Coates, Allan, Cueli, Adolfo, Davis, Mitchell, deLemos, Andrew, Desai, Archita, Dunn, Winston, Ferreira, Nelson, Fine, Michael, Firpi-Morell, Roberto, Freedland, Curtis, Freilich, Bradley, Fuchs, Michael, Galambos, Michael, Gallegos-Orozco, Juan, Galler, Greg, Ghali, Maged, Ghalib, Reem, Gill, Satinder, Gillis, Marcum, Gilroy, Richard, Gordon, Stuart, Gunn, Nadege, Halegoua-DeMarzio, Dina, Hassan, Mohamed, Hassanein, Tarek, Herring, Robert, Jr., Hong, John, Huang, Jonathan, Kabler, Heidi, Kayali, Zeid, Knapple, Whitfield, Kolli, Geetha, Kowdley, Kris, Krause, Richard, Lawitz, Eric, Lidofsky, Steven, Lim, Joseph, Lipkis, Donald, Loomba, Rohit, Mahgoub, Amar, Malespin, Miguel, Manch, Richard, Mannis, Steven, Manos, Paul, McDonald, Thomas, McKenzie, Mark, Mena, Edward, Merriman, Raphael, Moehlen, Martin William, Montgomery, Richard, Murphy, Robert, Natarajan, Yamini, Neff, Guy, Noureddin, Mazen, Ortiz-Lasanta, Grisell, Pagadala, Mangesh, Patel, Keyur, Patton, Heather, Peyton, Adam, Pimstone, Neville, Poulos, John, Pound, David, Pyrsopoulos, Nikolaos, Rafiq, Nila, Ravendhran, Natarajan, Ravinuthala, Ravi, Reddy, K. Rajendar, Reindollar, Robert, Reynolds, Justin, Rinella, Mary, Rizvi, Syed, Rockey, Don, Rodriguez-Perez, Federico, Ruane, Peter, Rubin, Raymond, Ryan, Michael, Saeian, Kia, Sanyal, Arun, Sarkar, Souvik, Scanga, Andrew, Schiff, Eugene, Schmidt, Warren, Schneider, Jeffrey, Sepe, Thomas, Shah, Dhiren, Shaikh, Obaid, Shankar, Uday, Sheikh, Aasim, Sheikh, Muhammad, Sherman, Kenneth, Shiffman, Mitchell, Siddique, Asma, Smith, Matthew, Suarez, Rosa, Talal, Andrew, Te, Helen, Tekola, Bezawit, Tetri, Brent, Thuluvath, Paul, Toro, Doris, Torres, Dawn, Trinh, Huy, Trotter, James, Vento, Angel, Vierling, John, Vuppalanchi, Raj, Waters, Michael, Weisberg, Ilan, Wieland, Amanda, Williams, Alonzo, Younes, Ziad, Adams, Leon, Harding, Damian, Hodge, Alex, Kontorinis, Nick, Strasser, Simone, Thompson, Alex, Horsmans, Yves, Steenkiste, Christophe Van, Bailey, Robert, Giard, Jeanne-Marie, Montano-Loza, Aldo, Puglia, Marco, Tsoi, Keith, Larrey, Dominique, Nguyen-Khac, Eric, Ratziu, Vlad, Spengler, Ulrich, Wiegand, Johannes, Hui, Aric Josun, Acharya, Subrat Kumar, Sarin, Shiv Kumar, Tantry, Vishwanath, Braun, Marius, Hazzan, Rawi, Lurie, Yoav, Colombo, Massimo, Fujii, Hideki, Hashimoto, Etsuko, Kato, Masaki, Ogawa, Koji, Takehara, Tetsuo, Tokushige, Katsutoshi, Garza, Laura Esthela Cisneros, Ladrón De Guevara, Alma Laura, Schultz, Michael, Janczewska, Ewa, Toro, Doris H., Jeong, Sook-Hyang, Kim, Yoon Jun, Lee, Jin-Woo, Ang, Tiing Leong, Bee, George Goh Boon, Benlloch, Salvador, Caballería, Juan, Calleja, José Luis, Rodríguez, Jose A. Carrión, Crespo, Javier, Diago, Moises, Fernandez-Rodriguez, Conrado, García-Samaniego, Javier, Ginès, Pere, Romero, Manuel, Dufour, Jean-François, Alazawi, William, Ch'ng, Chin-Lye, Forton, Daniel, Priest, Matthew, Sheridan, David, Ankoma-Sey, Victor, Balakrishnan, Maya, Bambha, Kiran, Barritt, A. Sidney, Bhandari, Bal, Brandman, Danielle, Chang, Charissa, Corey, Kathleen, Feldman, Michael, Gholam, Pierre, Goff, John, Marzio, Dina Halegoua-De, Harrison, Stephen, Hellstern, Paul, Jr., Herring, Robert, Iyer, Rajalakshmi, Jakiche, Antoine, Kohli, Anita, Krok, Karen, Kugelmas, Marcelo, Kumar, Sonal, Lai, Michelle, Mahmoud, Mitchell, Mantry, Parvez, Marsano, Luis, Nguyen, Tuan, Park, James, Patton, Heather M., Pockros, Paul, Reddy, Rajender, Rodriguez, Miguel, Sarles, Harry, Satapathy, Sanjaya, Sedghi, Shahriar, Shah, Nikunj, Sheikh, Muhammad Yasin, Sigal, Samuel, Stanca, Carmen, Steinbook, Michael, Szabo, Gyongyi, Terrault, Norah, Tong, Myron, Victor, David, Zervos, Xaralambos, Harrison, Stephen A., Wong, Vincent Wai-Sun, Caldwell, Stephen H., Shiffman, Mitchell L., Camargo, Marianne, Li, Georgia, Kersey, Kathryn, Jia, Catherine, Zhu, Yanni, Djedjos, C. Stephen, Subramanian, G. Mani, Myers, Robert P., Anstee, Quentin M., Romero-Gomez, Manuel, Goodman, Zachary, Lawitz, Eric J., and Younossi, Zobair

Published
2020
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4. Improved Survival Among all Interferon-α-Treated Patients in HCV-002, a Veterans Affairs Hepatitis C Cohort of 2211 Patients, Despite Increased Cirrhosis Among Nonresponders

Author

Cozen, Myrna L, Ryan, James C, Shen, Hui, Cheung, Ramsey, Kaplan, David E, Pocha, Christine, Brau, Norbert, Aytaman, Ayse, Schmidt, Warren N, Pedrosa, Marcos, Anand, Bhupinderjit S, Chang, Kyong-Mi, Morgan, Timothy, and Monto, Alexander

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Hepatitis, Emerging Infectious Diseases, Chronic Liver Disease and Cirrhosis, Digestive Diseases, Infectious Diseases, Rare Diseases, Substance Misuse, Clinical Research, Liver Disease, Hepatitis - C, Clinical Trials and Supportive Activities, Cancer, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Infection, Good Health and Well Being, Adult, Cohort Studies, Female, Hepatitis C, Humans, Interferon-alpha, Liver Cirrhosis, Male, Middle Aged, Proportional Hazards Models, Ribavirin, United States, United States Department of Veterans Affairs, Hepatitis C therapy, Cirrhosis, Hepatocellular carcinoma, Survival, Gastroenterology & Hepatology, Clinical sciences
Abstract

BackgroundAs the era of interferon-alpha (IFN)-based therapy for hepatitis C ends, long-term treatment outcomes are now being evaluated.AimTo more fully understand the natural history of hepatitis C infection by following a multisite cohort of patients.MethodsPatients with chronic HCV were prospectively enrolled in 1999-2000 from 11 VA medical centers and followed through retrospective medical record review.ResultsA total of 2211 patients were followed for an average of 8.5 years after enrollment. Thirty-one percent of patients received HCV antiviral therapy, 15 % with standard IFN/ribavirin only, 16 % with pegylated IFN/ribavirin, and 26.7 % of treated patients achieved sustained virologic response (SVR). Cirrhosis developed in 25.8 % of patients. Treatment nonresponders had a greater than twofold increase in the hazard of cirrhosis and hepatocellular carcinoma, compared to untreated patients, whereas SVR patients were only marginally protected from cirrhosis. Nearly 6 % developed hepatocellular carcinoma, and 27.1 % died during the follow-up period. Treated patients, regardless of response, had a significant survival benefit compared to untreated patients (HR 0.58, CI 0.46-0.72). Improved survival was also associated with college education, younger age, lower levels of alcohol consumption, and longer duration of medical service follow-up-factors typically associated with treatment eligibility.ConclusionsAs more hepatitis C patients are now being assessed for all-oral combination therapy, these results highlight that patient compliance and limiting harmful behaviors contribute a significant proportion of the survival benefit in treated patients and that the long-term clinical benefits of SVR may be less profound than previously reported.

Published
2016

10. Metalloprotoporphyrin Inhibition of HCV NS3-4A Protease: Structure–Activity Relationships

Author

Hu, Katherine, Zhu, Zhaowen, Mathahs, Meleah M, Tran, Huy, Bommer, Jerry, Testa, Charles A, and Schmidt, Warren N

Subjects
hepatitis C virus, Dose-Response Relationship, Drug, Molecular Structure, Hepacivirus, Microbial Sensitivity Tests, Viral Nonstructural Proteins, porphyrins, Virus Replication, Antiviral Agents, Structure-Activity Relationship, Humans, Protease Inhibitors, Serine Proteases, hepatitis C genotype, Cells, Cultured, Original Research
Abstract

Background Antiviral actions of tetrapyrroles have been described in a number of systems. Our goal was to evaluate antagonism of the HCV NS3-4A protease by a variety of common porphyrins and characterize structure–activity relationships that may be useful for future drug design of HCV and related Flaviviruses. Methods Using fluorometric assays, common metalloprotoporphyrins (MPP) all inhibited NS3-4A protease with IC50 values in low micromolar ranges [CoPP (1.4 µM) < ZnPP = MnPP = SnPP < CuPP < FePP (6.5 µM) = protoporphyrin]. Results Lineweaver–Burk plots confirmed that MPP: NS3 inhibition was basically competitive. All tested MPPs inhibited HCV genotype 1A, 1B, 2A and 3A recombinant proteases with the same fidelity suggesting wide antagonistic capabilities. However, when the MPPs were tested in cellular incubations with HCV replicons only Zn, Fe and free-base protoporphyrin showed comparable EC50 and IC50 values suggesting that there may be critical differences in MPP uptake and intracellular availability. Meso, deutero, and isohematoporphyrin derivatives, with or without metal substitution, all showed less anti-protease and antiviral activities as compared to protoporphyrins, suggesting that the planar, vinyl side chains are important for protease active site binding. MPPs were also active against three common protease mutants (T54A, A156T, and V36M) with equivalent or better IC50 values as compared to wild type enzyme. Conclusion These findings document the versatility of MPPs as antiviral agents with an expanded sensitivity for HCV genotypes and resistance to some common viral mutations. The results also suggest that further study of MPP structure and function will be useful for the development of new antiviral agents.

Published
2020

12. Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis

Author

Frenette, Catherine, primary, Kayali, Zeid, additional, Mena, Edward, additional, Mantry, Parvez S., additional, Lucas, Kathryn J., additional, Neff, Guy, additional, Rodriguez, Miguel, additional, Thuluvath, Paul J., additional, Weinberg, Ethan, additional, Bhandari, Bal R., additional, Robinson, James, additional, Wedick, Nicole, additional, Chan, Jean L., additional, Hagerty, David T., additional, Kowdley, Kris V., additional, Corey, Kathleen, additional, Bernstein, David, additional, Noureddin, Mazen, additional, Kemmer, Nyingi, additional, DeLemos, Andrew, additional, Pyrsopoulos, Nikolaos, additional, Lee, William, additional, Ghabril, Marwan, additional, Scanga, Andrew, additional, McKenzie, Mark, additional, Lawitz, Eric, additional, Figueroa-Diaz, Viviana, additional, Simonetto, Douglas, additional, Frederick, Richard, additional, Brown, Kimberly, additional, Therapondos, George, additional, Sheikh, Aasim, additional, Brandman, Danielle, additional, Stein, Lance, additional, Ankoma-Sey, Victor, additional, Bhamidimarri, Kalyan, additional, Landis, Charles, additional, Fortune, Brett, additional, Vargas, Hugo, additional, Abdelmalek, Manal, additional, Freilich, Bradley, additional, Rockey, Don, additional, Vierling, John, additional, Tatum, Harvey, additional, Curry, Michael, additional, Shiffman, Mitchell, additional, Bambha, Kiran, additional, Ghalib, Reem, additional, Stratton, Amy, additional, Anwar, Nadeem, additional, Caldwell, Stephen, additional, Koteish, Ayman, additional, Siddiqui, Mohammad, additional, Saab, Sammy, additional, Shah, Nikunj, additional, Kohli, Anita, additional, Rinella, Mary, additional, Sarkar, Souvik, additional, Torres, Dawn, additional, Verna, Elizabeth, additional, Ravendhran, Ravi, additional, Reynolds, Justin, additional, Thomason, Ray, additional, Kim, Ray, additional, Membreno, Fernando, additional, Jakab, Sofia, additional, Gonzalez, Stevan, additional, Keaveny, Andrew, additional, Pan, Jen-Jung, additional, Gill, Satinder, additional, Huang, Jonathan, additional, Strobel, James, additional, Wieland, Amanda, additional, Morelli, Giuseppe, additional, Amankonah, Thomas, additional, Roytman, Marina, additional, Schmidt, Warren, additional, Abrams, Gary, additional, and Patel, Bhaktasharan, additional

Published
2021
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13. Metalloprotoporphyrin Inhibition of HCV NS3-4A Protease: Structure–Activity Relationships

Author

Hu,Katherine, Zhu,Zhaowen, Mathahs,Meleah M, Tran,Huy, Bommer,Jerry, Testa,Charles A, Schmidt,Warren N, Hu,Katherine, Zhu,Zhaowen, Mathahs,Meleah M, Tran,Huy, Bommer,Jerry, Testa,Charles A, and Schmidt,Warren N

Abstract

Katherine Hu, 1, 2 Zhaowen Zhu, 1, 2 Meleah M Mathahs, 1, 2 Huy Tran, 1, 2 Jerry Bommer, 3, 4 Charles A Testa, 5 Warren N Schmidt 1, 2 1Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA 52246, USA; 2Department of Internal Medicine of the Roy G. And Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; 3Frontier Scientific, Logan, UT 84321, USA; 4Echelon Biosciences Inc, Salt Lake City, UT 84108, USA; 5Curza, Provo, UT and Cambridge, MA, USACorrespondence: Warren N SchmidtDepartment of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 4553 JCP, Iowa City, IA 52242, USATel +1 319 353-7048Fax +1 319 356-7918Email warren-schmidt@uiowa.eduBackground: Antiviral actions of tetrapyrroles have been described in a number of systems. Our goal was to evaluate antagonism of the HCV NS3-4A protease by a variety of common porphyrins and characterize structure–activity relationships that may be useful for future drug design of HCV and related Flaviviruses.Methods: Using fluorometric assays, common metalloprotoporphyrins (MPP) all inhibited NS3-4A protease with IC 50 values in low micromolar ranges [CoPP (1.4 μM) < ZnPP = MnPP = SnPP < CuPP < FePP (6.5 μM) = protoporphyrin].Results: Lineweaver–Burk plots confirmed that MPP: NS3 inhibition was basically competitive. All tested MPPs inhibited HCV genotype 1A, 1B, 2A and 3A recombinant proteases with the same fidelity suggesting wide antagonistic capabilities. However, when the MPPs were tested in cellular incubations with HCV replicons only Zn, Fe and free-base protoporphyrin showed comparable EC 50 and IC 50 values suggesting that there may be critical differences in MPP uptake and intracellular availability. Meso, deutero, and isohematoporphyrin derivatives, with or without metal substitution, all showed less anti-protease and antiviral activities as compared to protop

Published
2020

14. Ombitasvir/paritaprevir/ritonavir and dasabuvir±ribavirin for chronic HCV infection in US veterans with psychiatric disorders

Author

Fuchs, Michael, primary, Monto, Alexander, additional, Bräu, Norbert, additional, Charafeddine, Mariem, additional, Schmidt, Warren, additional, Kozal, Michael, additional, Naggie, Susanna, additional, Cheung, Ramsey, additional, Schnell, Gretja, additional, Yu, Yao, additional, Richards, Kristine, additional, Mullally, Victoria, additional, Cohen, Daniel E., additional, and Toro, Doris, additional

Published
2020
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15. Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity.

Author

Zhaowen Zhu, Huy Tran, Huy, Mathahs, Meleah M., Fink, Brian D., Albert, John A., Moninger, Thomas O., Meier, Jeffery L., Ming Li, and Schmidt, Warren N.

Subjects
TELOMERASE, TELOMERASE reverse transcriptase, BIOFLUORESCENCE, ZINC-finger proteins, CONFOCAL fluorescence microscopy, DNA synthesis, CELL imaging
Abstract

Zinc protoporphyrin (ZnPP), a naturally occurring metalloprotoporphyrin (MPP), is currently under development as a chemotherapeutic agent although its mechanism is unclear. When tested against other MPPs, ZnPP was the most effective DNA synthesis and cellular proliferation inhibitor while promoting apoptosis in telomerase positive but not telomerase negative cells. Concurrently, ZnPP down-regulated telomerase expression and was the best overall inhibitor of telomerase activity in intact cells and cellular extracts with IC50 and EC50 values of ca 2.5 and 6 µM, respectively. The natural fluorescence properties of ZnPP enabled direct imaging in cellular fractions using non-denaturing agarose gel electrophoresis, western blots, and confocal fluorescence microscopy. ZnPP localized to large cellular complexes (>600 kD) that contained telomerase and dysskerin as confirmed with immunocomplex mobility shift, immunoprecipitation, and immunoblot analyses. Confocal fluorescence studies showed that ZnPP co-localized with telomerase reverse transcriptase (TERT) and telomeres in the nucleus of synchronized S-phase cells. Zn PP also co-localized with TERT in the perinuclear regions of log phase cells but did not co-localize with telomeres on the ends of metaphase chromosomes, a site known to be devoid of telomerase complexes. Overall, these results suggest that ZnPP does not bind to telomeric sequences per se, but alternatively, interacts with other structural components of the telomerase complex to inhibit telomerase activity. In conclusion, ZnPP actively interferes with telomerase activity in neoplastic cells, thus promoting pro-apoptotic and anti-proliferative properties. These data support further development of natural or synthetic protoporphyrins for use as chemotherapeutic agents to augment current treatment protocols for neoplastic disease. [ABSTRACT FROM AUTHOR]

Published
2021
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19. Finally sofosbuvir: an oral anti-HCV drug with wide performance capability

Author

Schmidt, Warren and Kayali,Zeid

Subjects
Pharmacogenomics and Personalized Medicine
Abstract

Zeid Kayali,1 Warren N Schmidt2,3 1Division of Gastroenterology and Hepatology, University of Southern California, Los Angeles, CA, USA; 2Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA, USA; 3Roy G and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, USA Abstract: Chronic Hepatitis C virus (HCV) infection is the leading cause of advanced liver disease worldwide. The virus successfully evades host immune detection and for many years has hampered efforts to find a safe, uncomplicated, and reliable oral antiviral therapy. Initially, interferon and ribavirin therapy was the treatment standard of care, but it offered limited performance across the wide spectrum of HCV disease and was fraught with excessive and often limiting side effects. Sofosbuvir (SOF) is a potent first-in-class nucleoside inhibitor that has recently been approved for treatment of HCV. The drug has low toxicity, a high resistance barrier, and minimal drug interactions with other HCV direct-acting antiviral agents such as protease inhibitors or anti-NS5A agents. SOF is safe and can be used across different viral genotypes, disease stages, and special patient groups, such as those coinfected with human immunodeficiency virus. When used in combination with ribavirin or another direct-acting antiviral agent, SOF has revolutionized the HCV treatment spectrum and set the stage for nearly universal HCV antiviral therapy. More so than any other anti-HCV drug developed to date, SOF offers the widest applicability for all infected patients, and new regimens will be tailored to maximize performance. Keywords: Hepatitis C virus, sofosbuvir, polymerase inhibitors, interferon-free treatment

Published
2014

20. Resolve disputes with 5 questions

Author

Schmidt, Warren H. and Hateley, BJ Gallagher

Subjects
Business, general
Abstract

You can't break through a negotiating stalemate or a dispute by yourself. You need your opponent to be equally involved. Here are five questions that can help you create a [...]

Published
2021

22. A Peacock in the Land of Penguins : A Fable about Creativity and Courage Ed. 4

Author

Gallagher, Bj, Schmidt, Warren, Gallagher, Bj, Gallagher, Bj, Schmidt, Warren, and Gallagher, Bj

Abstract

?This is a book for everyone who wishes to contribute their unique gifts to the world.? ?Archbishop Desmond Tutu, Nobel Peace Laureate This brand new edition of a classic, international bestseller continues to bring keen insight to an important topic?workforce diversity. Written in a charming, engaging style, it is a contemporary corporate fable?a tale for our times. This special 20th anniversary edition includes many new tips, tools, and strategies for peacocks and penguins alike?as well as an entirely new bonus parable. Through the story of Perry the Peacock and his fine feathered friends, authors Gallagher and Schmidt bring to life the challenges of birds of different feathers who struggle to be successful in the conformity-minded Land of Penguins. Their travails illuminate the challenges of creating a pluralistic corporate culture in which the talent, energy, and commitment of all employees are fully engaged. People who have new ideas that differ from business as usual are often ignored or criticized for the very thing that makes them valuable: their originality and creativity. This unique book helps organizations break out of "penguin thinking? in order to tap into and leverage the creativity of diversity. Learn how to cultivate an organizational culture in which new ideas can flourish and innovation can take flight.

Published
2015

23. ODER AUTORITÄR?

Author

TANNENBAUM, ROBERT and SCHMIDT, WARREN H.

Published
2019

24. THE LONG REACH OF THE LOG CABIN COLLEGE.

Author

Schmidt, Warren R.

Abstract

The article discusses the lives of the 11 students who were in the first class of the Log Cabin College, the first college for Lutheran Church–Missouri Synod including Lydia Buenger, Christoph Loeber and Theodor Schubert.

Published
2015

25. Finally sofosbuvir: an oral anti-HCV drug with wide performance capability.

Author

Kayali, Zeid and Schmidt, Warren N.

Subjects
PERFORMANCE, DRUGS, DISEASES, PATIENTS, RIBAVIRIN
Abstract

Chronic Hepatitis C virus (HCV) infection is the leading cause of advanced liver disease worldwide. The virus successfully evades host immune detection and for many years has hampered efforts to find a safe, uncomplicated, and reliable oral antiviral therapy. Initially, interferon and ribavirin therapy was the treatment standard of care, but it offered limited performance across the wide spectrum of HCV disease and was fraught with excessive and often limiting side effects. Sofosbuvir (SOF) is a potent first-in-class nucleoside inhibitor that has recently been approved for treatment of HCV. The drug has low toxicity, a high resistance barrier, and minimal drug interactions with other HCV direct-acting antiviral agents such as protease inhibitors or anti-NS5A agents. SOF is safe and can be used across different viral genotypes, disease stages, and special patient groups, such as those coinfected with human immunodeficiency virus. When used in combination with ribavirin or another direct-acting antiviral agent, SOF has revolutionized the HCV treatment spectrum and set the stage for nearly universal HCV antiviral therapy. More so than any other anti-HCV drug developed to date, SOF offers the widest applicability for all infected patients, and new regimens will be tailored to maximize performance. [ABSTRACT FROM AUTHOR]

Published
2014
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