67 results on '"Peddi S"'
Search Results
2. B355 Comparing postoperative analgesic effectiveness ofultrasound guided ilioinguinal-iliohypogastric transversusplaneblock and transmuscular quadratuslumborum plane block in caesarian section
- Author
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Peddi, S, primary, Aarumulla, SP, additional, and Kandukuru, K, additional
- Published
- 2022
- Full Text
- View/download PDF
3. B267 Old wine in a new bottle- us guided continuous caudal anesthesia for cesarean section in a parturient with thoracic gibbus & difficult airway: a case report
- Author
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Arumulla, SP, primary, Peddi, S, additional, and Chaithanya, K, additional
- Published
- 2022
- Full Text
- View/download PDF
4. LB19 Old wine in a new bottle- US guided continuous caudal anesthesia for cesarean section in a parturient with thoracic gibbus & difficult airway: a case report
- Author
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Arumulla, SP, primary, Peddi, S, additional, and Chaithanya, K, additional
- Published
- 2022
- Full Text
- View/download PDF
5. LB15 Comparing postoperative analgesic effectiveness ofultrasound guided ilioinguinal-iliohypogastric transversusplaneblock and transmuscular quadratuslumborum plane block in caesarian section
- Author
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Peddi, S, primary, Aarumulla, SP, additional, and Kandukuru, K, additional
- Published
- 2022
- Full Text
- View/download PDF
6. LB6 Caudal anaesthesia can be a good alternative in adult patients with severe vertebral column anomalies
- Author
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Peddi, S, primary and Aarumulla, SP, additional
- Published
- 2022
- Full Text
- View/download PDF
7. Assessing the cardiology community position on transradial intervention and the use of bivalirudin in patients with acute coronary syndrome undergoing invasive management: results of an EAPCI survey
- Author
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Adamo, Marianna, Byrne, Robert A., Baumbach, Andreas, Haude, Michael, Windecker, Stephan, Valgimigli, Marco, Aaroe, J., Abdeltawab, A. A., Accardi, R., Addad, F., Agostoni, P., Alajab, A., Alcázar, E., Alhabil, B., Altug Cakmak, H., Amico, F., Amoroso, G., Anderson, R., Andò, G., Andreou, A. Y., Antoniadis, D., Aquilina, M., Aramberry, L., Auer, J., Auffret, V., Ausiello, A., Austin, D., Avram, A., Ayman, E., Babunashvili, V., Bagur, R., Bakotic, Z., Balducelli, M., Ballesteros, S. M., Baptista, S., Baranauskas, A., Barbeau, G., Bax, M., Benchimol, C., Berroth, R., Biasco, L., Bilal, A., Binias, K., Blanco Mata, R., Boccuzzi, G., Bolognese, L., Boskovic, S., Bourboulis, N., Briguori, C., Bunc, M., Buysschaert, I., Calabro’, P., Campo, G., Candiello, A., Caprotta, U. F., Cardenas, M., Carrilho-Ferreira, P., Carrizo, S., Caruso, M., Cassar, A., Cernigliaro, C., Chacko, G., Chamie, D., Clapp, B., Coceani, M., Colangelo, S., Colombo, A., Comeglio, M., Connaughton, M., Conway, D., Cortese, B., Cosgrave, J., Costa, F., Couvoussis, E., Crimi, G., Crook, R., Cruz-Alvarado, J. E., Curello, S., D’Ascenzo, F., D’Urbano, M., Dana, A., De Backer, O., De Carlo, M., De Cesare, N., De Iaco, G., De La Torre, H. J. M., De Oliveira Netoj, B., Devlin, G. P., Di Lorenzo, E., Díaz, A., Dina, C., Dorsel, T. H., Eberli, F. R., Echeverría, R., Eftychiou, C., Elguindy, A., Ercilla, J., Ernst, A., Esposito, G., Ettori, F., Eufracino, Null, Ezquerra Aguilera, W., Falcone, C., Falu, R. M., Feres, F., Ferlini, M., Fernández, G., Fernández-Rodríguez, D., Fileti, L., Fischetti, D., Florescu, N., Formigli, D., Fouladvand, F., Franco, N., Fresco, C., Frigoli, E., Furmaniuk, J., Gabaldo, K., Galli, M., Galli, S., Garbo, R., Garducci, S., Garg, S., Gavrielatos, G., Gensch, J., Giacchi, G., Giunio, L., Giustino, G., Goldberg, L., Goldsmit, R., Gommeaux, A., González Godínez, H., Gosselin, G., Govorov, A., Grimfjard, P., Gross, E., Grosz, C., Guagliumi, G., Hadad, W., Hadadi, L., Hansen, P. R., Harb, S., Hatrick, R., Hayrapetyan, H. G., Hernández-Enríquez, M., Ho Heo, J., Horvath, I. G., Huan Loh, P., Ibrahim, A. M., Ierna, S., Ilic, I., Imperadore, F., Ionescu-Silva, E., Jacksch, R., James, S., Janiak, B., Jensen, S. E., Jeroen, S., Jugessur, R. K., Kala, P., Kambis, M., Kanakakis, J., Karamasis, G., Karchevsky, D., Karpovskiy, A., Kayaert, P., Kedev, S., Kemala, E., Ketteler, T., Khan, S. Q., Kharlamov, A., Kiernan, T., Kiviniem, T., Koltowski, L., Koskinas, K. C., Kouloumpinis, A., Kraaijeveld, A. O., Krizanic, F., Krötz, B., Kuczmik, W., Kukreja, N., Kuksa, D., Yav, K., Kyriakos, D., Labrunie, A., Laine, M., Lapin, O., Larosa, C., Latib, A., Lattuca, B., Lauer, B., Lefèvre, T., Legrand, V., Lehto, P., Leiva-Pons, J. L., Leone, A. M., Lev, G., Lim, R., Limbruno, U., Linares Vicente, J. A., Lindsay, S., Linnartz, C., Liso, A., Lluberas, R., Locuratolo, N., Lokshyn, S., Lunde, K., Lupi, A., Magnavacchi, P., Maia, F., Mainar, V., Mancone, M., Manolios, M. G., Mansour, S., Mariano, E., Marques, K., Martins, H., Mckenzie, D., Meco, S., Meemook, K., Mehmed, K., Melikyan, A., Mellwig, K. P., Mendiz, O. A., Merkulov, E., Mesquita, H. G., Mezzapelle, G., Miloradovic, V., Mohamed, S., Mohammed, B., Mohammed, F., Mohammed, K., Mohanad, A., Morawiec, B., More, R., Moreno-Martínez, F. L., Mrevlje, B., Muhammad, F., Näveri, H., Nazzaro, M. S., Neary, P., Negus, B. H., Nelson Durval, F. G., Nick, H., Nilva, E., Oldroyd, K. G., Olivares Asencio, C., Omerovic, E., Ortiz, M. A., Ota, H., Otasevic, P., Otieno, H. A., Paizis, I., Papp, E., Pasquetto, G., Patsourakos, N. G., Peels, J., Pelliccia, F., Pennacchi, M., Penzo, C., Perez, P., Perkan, A., Petrou, E., Phipathananunth, W., Pierri, A., Pinheiro, L. F., Pipa, J. L., Piva, T., Polad, J., Porto, I., Poveda, J., Predescu, L., Prog, R., Puri, R., Raco, D. L., Ramazan, O., Ramazzotti, V., Rao, S. V., Raungaard, B., Reczuch, K., Rekik, S., Rhouati, A., Rigattieri, S., Rodríguez-Olivares, R., Roik, M., Romagnoli, E., Román, A. J., Routledge, H., Rubartelli, P., Rubboli, A., Ruiz-García, J., Russo, F., Ruzsa, Z., Ryding, A., Saad, Aly, Sabate, M., Sabouret, P., Sadowski, M., Saia, F., Sanchez Perez, I., Santoro, G. M., Sarenac, D., Saririan, M., Sarma, J., Schuetz, T., Sciahbasi, A., Sebastian, M., Sebik, R., Sesana, M., Hur, Seung-Ho, Sganzerla, P., Shalva, R., Sharma, S., Sheiban, I., Shein, K. K., Shiekh, I. A., Sinha, M., Slhessarenko, J., Smith, D., Smyth, D. W., Sönmez, K., Sood, N., Sourgounis, A., Srdanovic, I., Stables, R. H., Stefanini, G. G., Stewart, J., Stoyanov, N., Suliman, A. A., Suryadevara, R., Suwannasom, P., Tange Veien, K., Tauchert, S., Tebet, M., Testa, L., Thury, A., Tilsted, H. H., Tiroch, K., Torres, A., Tosi, P., Traboulsi, M., Trani, C., Tresoldi, S., Tsigkas, G., Tueller, D., Turri, M., Udovichenko, A. E., Uretsky, B., Van Der Harst, P., Van Houwelingen, K. G., Vandoni, P., Vandormael, M., Varbella, F., Venkitachalam, C. G., Vercellino, M., Vidal-Perez, R., Vigna, C., Vignali, L., Vogt, F., Voudris, V., Vranckx, P., Vrolix, M., Vydt, T., Webster, M., Wijns, W., Woody, W., Wykrzykowska, J., Yazdani, S., Yildiz, A., Yurlevich, D., Zauith, R., Zekanovic, D., Zhao, M., Zimarino, M., Zingarelli, A., Abdelsamad, A. Y., Abo Shaera, E. S., Afshar, M. S., Agatiello, C., Aguiar, P., Ahmad, A. M., Akin, I., Alameda, M., Alegría-Barrero, E., Alejos, R., Alkhashab, K., Alkutshan, R. S. A., Almorraweh, A., Altnji, I., Alvarez Iorio, C., Anchidin, O., Angel, J., Antonopoulos, A., Apshilava, G., Arana, C., Ashikaga, T., Assomull, R., Atef, S. Z., Azmus, A. D., Azzalini, L., Azzouz, A., Baglioni, P., Bampas, G., Basil, M. P., Baumbach, A., Besh, D., Bhushan Sharm, A., Bien Hsien, H., Bihui, L., Bing-Chen, L., Biryukov, S., Blatt, A., Bocchi, E., Boghdady, A., Bonarjee, V. V. S., Bosnjak, I., Bravo Baptista, S., Brinckman, S. L., Buchter, B., Burzotta, F., Cacucci, M., Cagliyan, C. E., Calabrò, P., Cernetti, C., Chávez Mizraym, R., Choo, W. S., Choudhury, R., Cicco, N., Cisneros Clavijo, P., Çitaku, H., Collet, J. P., Consuegra-Sánchez, L., Conte, M., Corral, J. M., Damonte, A., Dangoisse, V., Dastani, M., Della Rosa, F., Deora, S., Devadathan, S., Dharma, S., Di Giorgio, A., Diez, J. L., Dinesha, B., Duplančić, D., El Behwashi, M. F., Elghawaby, H., Elshahawy, O., Eskola, M. J., Etman, A., Eun Gyu, L., Fabiano, L., Facta, A., Fan, Y., Fang-Yang, H., Farag, E., Fathi, Y., Fazeli, N., Federico, P., Fereidoun, M. Z., Fernandez-Nofrerias, E., Flensted Lassen, J., Flessas, D., Fouad, H., Franco-Pelaez, J. A., Fu, Q., Furtado, R., Gadepalli, R., Gallino, R., Gasparetto, V., Gentiletti, A., Gholoobi, A., Ghosh, A. K., Gkizas, S., Golchha, S. K., Goncharov, A., Gössl, M., Götberg, M., Greco, F., Grundeken, M. J., Gupta, D., Gupta, S., Guray, U., Hahalis, G., Hakim Vista, J., Hamid, M. A., Hammoudeh, A., Hasan, A. R. I., Hatsumura, F. E., Heintzen, M. P., Helal, T., Hetherington, S., Hewarathna, U. I., Hioki, H., Hissein, F., Ho-Ping, Y., Homs, S., Huber, K., Ibarra, F. M., Ielasi, A., Ipek, E., Jambunathan, R., Jamshidi, P., Jarrad, I., Javier, W., Jensen, J., Jimenez-Quevedo, P., Kalpak, O., Kan, J., Kanaan, T., Kao, D. H. M., Karamfiloff, K., Karegren, A., Karjalainen, P. P., Kasabov, R., Katsimagklis, G. D., Kaul, U., Khan, A., Kiemeneij, E., Kiviniemi, T., Kleiban, A., Komiyama, N., Konteva, M., Koshy, G., Krepsky, A. M., Kuljit, S., Kulkarni, P., Kumar, V., Kuznetsov, I., Lai, G., Lateef, M. A., Lawand, S., Le Hong, T., Lettieri, C., Levy, G., Lindvall, P., Maitra, A., Makowski, M., Mamas, M. A., Mandal, S. C., Mangalanandan, P., Marin, R., Mashhadi, M., Matsukage, T., Meier, B., Milosavljevic, B., Miro, S. S., Mitov, A., Moeriel, M., Moguel, R., Mohanty, A., Montalescot, G., Mörsdorf, W., Moscato, F., Muniz, A., Muraglia, S., Myć, J., Nada, A., Nair, P., Namazi, M. H., Naraghipour, F., Nguyen, Q. N., Nicosia, A., Nikas, D., Ober, M., Ocaranza-Sánchez, R., Olivecrona, G., Pahlajani, D., Pandey, B. P., Parma, A., Parma, R., Patsilinakos, S. P., Pattam, J., Peddi, S., Perez, P. R., Peruga, J. Z., Pescoller, F., Petrov, I., Piatti, L., Pico-Aracil, F., Pina, J., Piroth, Z., Popa, V., Pourbehi, M. R., Pradhan, A. K., Prida, X. E., Purohit, B. V., Pyun, W. B., Quang Hung, D., Rada, I., Rafizadeh, O., Rahman, M. A., Rai, L., Ramsewak, A., Ravindran, R., Rodriguez De Leiras, O. S., Rodríguez Esteban, M., Roque Figueira, H., Saket, A., Sakhov, O., Saktheeswaran, M. K., Salachas, A., Sallam, A., Sampaolesi, A., Samy, A., Sanchis, J., Santaera, O., Santarelli, A., Santharaj, W. S., Sarango, B., Satheesh, S., Schmitz, T., Schühlen, H., Seewoosagur, R., Segev, A., Seisembekov, V., Semitko, S., Sengottuvelu, G., Sepulveda Varela, P., Sethi, A., Sharma, A., Sharma, R. K., Shi, Hy., Şimşek, M. A., Siqueira, B., Skalidis, E., Slawin, J., Sorokhtey, L., Spaulding, C., Srinivas, B., Srinivasan, M., Stakos, D., Stefanini, G., Stojkovic, S., Tacoy, G., Tawade, M., Tiecco, F., Tondi, S., Torresani, E. M., Tousek, P., Tran, T., Trantalis, G., Triantafyllou, K., Trivedi, R., Trivisonno, A., Tsui, K. L., Türkoğlu, C., Tzung-Dau, W., Ueno, H., Urban, U., Uretsky, B. F., Uscumlic, A., Venugopal, V., Verney, R., Vilar, J. V., Villacorta, V. G., Vishwanath, R., Vlachojannis, G. J., Vlachojannis, M., Vlad, V., Von Birgelen, C., Vukcevic, V., Wahab, A., Waksman, R., Wei-Wen, L., Weisz, G., Whittaker, A., Yadav, A., Yokoi, Y., Zacharoulis, A., Zahran, M., Zamani, J., Ziakas, A., Zimmermann, J. P., Adamo, M., Byrne, R. A., Baumbach, A., Haude, M., Windecker, S., Valgimigli, M., Aaroe, J., Abdeltawab, A. A., Accardi, R., Addad, F., Agostoni, P., Alajab, A., Alcazar, E., Alhabil, B., Altug Cakmak, H., Amico, F., Amoroso, G., Anderson, R., Ando, G., Andreou, A. Y., Antoniadis, D., Aquilina, M., Aramberry, L., Auer, J., Auffret, V., Ausiello, A., Austin, D., Avram, A., Ayman, E., Babunashvili, V., Bagur, R., Bakotic, Z., Balducelli, M., Ballesteros, S. M., Baptista, S., Baranauskas, A., Barbeau, G., Bax, M., Benchimol, C., Berroth, R., Biasco, L., Bilal, A., Binias, K., Blanco Mata, R., Boccuzzi, G., Bolognese, L., Boskovic, S., Bourboulis, N., Briguori, C., Bunc, M., Buysschaert, I., Calabro', P., Campo, G., Candiello, A., Caprotta, U. F., Cardenas, M., Carrilho-Ferreira, P., Carrizo, S., Caruso, M., Cassar, A., Cernigliaro, C., Chacko, G., Chamie, D., Clapp, B., Coceani, M., Colangelo, S., Colombo, A., Comeglio, M., Connaughton, M., Conway, D., Cortese, B., Cosgrave, J., Costa, F., Couvoussis, E., Crimi, G., Crook, R., Cruz-Alvarado, J. E., Curello, S., D'Ascenzo, F., D'Urbano, M., Dana, A., De Backer, O., De Carlo, M., De Cesare, N., De Iaco, G., De La Torre, H. J. M., De Oliveira Netoj, B., Devlin, G. P., Di Lorenzo, E., Diaz, A., Dina, C., Dorsel, T. H., Eberli, F. R., Echeverria, R., Eftychiou, C., Elguindy, A., Ercilla, J., Ernst, A., Esposito, G., Ettori, F., Eufracino, Ezquerra Aguilera, W., Falcone, C., Falu, R. M., Feres, F., Ferlini, M., Fernandez, G., Fernandez-Rodriguez, D., Fileti, L., Fischetti, D., Florescu, N., Formigli, D., Fouladvand, F., Franco, N., Fresco, C., Frigoli, E., Furmaniuk, J., Gabaldo, K., Galli, M., Galli, S., Garbo, R., Garducci, S., Garg, S., Gavrielatos, G., Gensch, J., Giacchi, G., Giunio, L., Giustino, G., Goldberg, L., Goldsmit, R., Gommeaux, A., Gosselin, G., Govorov, A., Gonzalez Godinez, H., Gross, E., Grosz, C., Guagliumi, G., Hadad, W., Hadadi, L., Hansen, P. R., Harb, S., Hatrick, R., Hayrapetyan, H. G., Hernandez-Enriquez, M., Ho Heo, J., Horvath, I. G., Huan Loh, P., Ibrahim, A. M., Ierna, S., Ilic, I., Imperadore, F., Ionescu-Silva, E., Jacksch, R., James, S., Janiak, B., Jensen, S. E., Jeroen, S., Jugessur, R. K., Kala, P., Kambis, M., Kanakakis, J., Karamasis, G., Karchevsky, D., Karpovskiy, A., Kayaert, P., Kedev, S., Kemala, E., Ketteler, T., Khan, S. Q., Kharlamov, A., Kiernan, T., Kiviniem, T., Koltowski, L., Koskinas, K. C., Kouloumpinis, A., Kraaijeveld, A. O., Krizanic, F., Krotz, B., Kuczmik, W., Kukreja, N., Kuksa, D., Yav, K., Kyriakos, D., Labrunie, A., Laine, M., Lapin, O., Larosa, C., Latib, A., Lattuca, B., Lauer, B., Lefevre, T., Legrand, V., Lehto, P., Leiva-Pons, J. L., Leone, A. M., Lev, G., Lim, R., Limbruno, U., Linares Vicente, J. A., Lindsay, S., Linnartz, C., Liso, A., Lluberas, R., Locuratolo, N., Lokshyn, S., Lunde, K., Lupi, A., Magnavacchi, P., Maia, F., Mainar, V., Mancone, M., Manolios, M. G., Mansour, S., Mariano, E., Marques, K., Martins, H., Mckenzie, D., Meco, S., Meemook, K., Mehmed, K., Melikyan, A., Mellwig, K. P., Mendiz, O. A., Merkulov, E., Mesquita, H. G., Mezzapelle, G., Miloradovic, V., Mohamed, S., Mohammed, B., Mohammed, F., Mohammed, K., Mohanad, A., Morawiec, B., More, R., Moreno-Martinez, F. L., Mrevlje, B., Muhammad, F., Naveri, H., Nazzaro, M. S., Neary, P., Negus, B. H., Nelson Durval, F. G., Nick, H., Nilva, E., Oldroyd, K. G., Olivares Asencio, C., Omerovic, E., Ortiz, M. A., Ota, H., Otasevic, P., Otieno, H. A., Paizis, I., Papp, E., Pasquetto, G., Patsourakos, N. G., Peels, J., Pelliccia, F., Pennacchi, M., Penzo, C., Perez, P., Perkan, A., Petrou, E., Phipathananunth, W., Pierri, A., Pinheiro, L. F., Pipa, J. L., Piva, T., Polad, J., Porto, I., Poveda, J., Predescu, L., Prog, R., Puri, R., Raco, D. L., Ramazan, O., Ramazzotti, V., Rao, S. V., Raungaard, B., Reczuch, K., Rekik, S., Rhouati, A., Rigattieri, S., Rodriguez-Olivares, R., Roik, M., Romagnoli, E., Roman, A. J., Routledge, H., Rubartelli, P., Rubboli, A., Ruiz-Garcia, J., Russo, F., Ruzsa, Z., Ryding, A., Saad, A., Sabate, M., Sabouret, P., Sadowski, M., Saia, F., Sanchez Perez, I., Santoro, G. M., Sarenac, D., Saririan, M., Sarma, J., Schuetz, T., Sciahbasi, A., Sebastian, M., Sebik, R., Sesana, M., Hur, S. -H., Sganzerla, P., Shalva, R., Sharma, S., Sheiban, I., Shein, K. K., Shiekh, I. A., Sinha, M., Slhessarenko, J., Smith, D., Smyth, D. W., Sonmez, K., Sood, N., Sourgounis, A., Srdanovic, I., Stables, R. H., Stefanini, G. G., Stewart, J., Stoyanov, N., Suliman, A. A., Suryadevara, R., Suwannasom, P., Tange Veien, K., Tauchert, S., Tebet, M., Testa, L., Thury, A., Tilsted, H. H., Tiroch, K., Torres, A., Tosi, P., Traboulsi, M., Trani, C., Tresoldi, S., Tsigkas, G., Tueller, D., Turri, M., Udovichenko, A. E., Uretsky, B., Van Der Harst, P., Van Houwelingen, K. G., Vandoni, P., Vandormael, M., Varbella, F., Venkitachalam, C. G., Vercellino, M., Vidal-Perez, R., Vigna, C., Vignali, L., Vogt, F., Voudris, V., Vranckx, P., Vrolix, M., Vydt, T., Webster, M., Wijns, W., Woody, W., Wykrzykowska, J., Yazdani, S., Yildiz, A., Yurlevich, D., Zauith, R., Zekanovic, D., Zhao, M., Zimarino, M., Zingarelli, A., Abdelsamad, A. Y., Abo Shaera, E. S., Afshar, M. S., Agatiello, C., Aguiar, P., Ahmad, A. M., Akin, I., Alameda, M., Alegria-Barrero, E., Alejos, R., Alkhashab, K., Alkutshan, R. S. A., Almorraweh, A., Altnji, I., Alvarez Iorio, C., Anchidin, O., Angel, J., Antonopoulos, A., Apshilava, G., Arana, C., Ashikaga, T., Assomull, R., Atef, S. Z., Azmus, A. D., Azzalini, L., Azzouz, A., Baglioni, P., Bampas, G., Basil, M. P., Besh, D., Bhushan Sharm, A., Bien Hsien, H., Bihui, L., Bing-Chen, L., Biryukov, S., Blatt, A., Bocchi, E., Boghdady, A., Bonarjee, V. V. S., Bosnjak, I., Bravo Baptista, S., Brinckman, S. L., Buchter, B., Burzotta, F., Cacucci, M., Cagliyan, C. E., Cernetti, C., Chavez Mizraym, R., Choo, W. S., Choudhury, R., Cicco, N., Cisneros Clavijo, P., Citaku, H., Collet, J. P., Consuegra-Sanchez, L., Conte, M., Corral, J. M., Damonte, A., Dangoisse, V., Dastani, M., Della Rosa, F., Deora, S., Devadathan, S., Dharma, S., Di Giorgio, A., Diez, J. L., Dinesha, B., Duplancic, D., El Behwashi, M. F., Elghawaby, H., Elshahawy, O., Eskola, M. J., Etman, A., Eun Gyu, L., Fabiano, L., Facta, A., Fan, Y., Fang-Yang, H., Farag, E., Fathi, Y., Fazeli, N., Federico, P., Fereidoun, M. Z., Fernandez-Nofrerias, E., Flensted Lassen, J., Flessas, D., Fouad, H., Franco-Pelaez, J. A., Fu, Q., Furtado, R., Gadepalli, R., Gallino, R., Gasparetto, V., Gentiletti, A., Gholoobi, A., Ghosh, A. K., Gkizas, S., Golchha, S. K., Goncharov, A., Gossl, M., Gotberg, M., Greco, F., Grundeken, M. J., Gupta, D., Gupta, S., Guray, U., Hahalis, G., Hakim Vista, J., Hamid, M. A., Hammoudeh, A., Hasan, A. R. I., Hatsumura, F. E., Heintzen, M. P., Helal, T., Hetherington, S., Hewarathna, U. I., Hioki, H., Hissein, F., Ho-Ping, Y., Homs, S., Huber, K., Ibarra, F. M., Ielasi, A., Ipek, E., Jambunathan, R., Jamshidi, P., Jarrad, I., Javier, W., Jensen, J., Jimenez-Quevedo, P., Kalpak, O., Kan, J., Kanaan, T., Kao, D. H. M., Karamfiloff, K., Karegren, A., Karjalainen, P. P., Kasabov, R., Katsimagklis, G. D., Kaul, U., Khan, A., Kiemeneij, E., Kiviniemi, T., Kleiban, A., Komiyama, N., Konteva, M., Koshy, G., Krepsky, A. M., Kuljit, S., Kulkarni, P., Kumar, V., Kuznetsov, I., Lai, G., Lateef, M. A., Lawand, S., Le Hong, T., Lettieri, C., Levy, G., Lindvall, P., Maitra, A., Makowski, M., Mamas, M. A., Mandal, S. C., Mangalanandan, P., Marin, R., Mashhadi, M., Matsukage, T., Meier, B., Milosavljevic, B., Miro, S. S., Mitov, A., Moeriel, M., Moguel, R., Mohanty, A., Montalescot, G., Morsdorf, W., Moscato, F., Muniz, A., Muraglia, S., Myc, J., Nada, A., Nair, P., Namazi, M. H., Naraghipour, F., Nguyen, Q. N., Nicosia, A., Nikas, D., Ober, M., Ocaranza-Sanchez, R., Olivecrona, G., Pahlajani, D., Pandey, B. P., Parma, A., Parma, R., Patsilinakos, S. P., Pattam, J., Peddi, S., Perez, P. R., Peruga, J. Z., Pescoller, F., Petrov, I., Piatti, L., Pico-Aracil, F., Pina, J., Piroth, Z., Popa, V., Pourbehi, M. R., Pradhan, A. K., Prida, X. E., Purohit, B. V., Pyun, W. B., Quang Hung, D., Rada, I., Rafizadeh, O., Rahman, M. A., Rai, L., Ramsewak, A., Ravindran, R., Rodriguez De Leiras, O. S., Rodriguez Esteban, M., Roque Figueira, H., Saket, A., Sakhov, O., Saktheeswaran, M. K., Salachas, A., Sallam, A., Sampaolesi, A., Samy, A., Sanchis, J., Santaera, O., Santarelli, A., Santharaj, W. S., Sarango, B., Satheesh, S., Schmitz, T., Schuhlen, H., Seewoosagur, R., Segev, A., Seisembekov, V., Semitko, S., Sengottuvelu, G., Sepulveda Varela, P., Sethi, A., Sharma, A., Sharma, R. K., Shi, Hy., Simsek, M. A., Siqueira, B., Skalidis, E., Slawin, J., Sorokhtey, L., Spaulding, C., Srinivas, B., Srinivasan, M., Stakos, D., Stojkovic, S., Tacoy, G., Tawade, M., Tiecco, F., Tondi, S., Torresani, E. M., Tousek, P., Tran, T., Trantalis, G., Triantafyllou, K., Trivedi, R., Trivisonno, A., Tsui, K. L., Turkoglu, C., Tzung-Dau, W., Ueno, H., Urban, U., Uretsky, B. F., Uscumlic, A., Venugopal, V., Verney, R., Vilar, J. V., Villacorta, V. G., Vishwanath, R., Vlachojannis, G. J., Vlachojannis, M., Vlad, V., Von Birgelen, C., Vukcevic, V., Wahab, A., Waksman, R., Wei-Wen, L., Weisz, G., Whittaker, A., Yadav, A., Yokoi, Y., Zacharoulis, A., Zahran, M., Zamani, J., Ziakas, A., Zimmermann, J. P., and Cardiology
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Hirudin ,Percutaneous ,Antithrombin ,medicine.medical_treatment ,Psychological intervention ,030204 cardiovascular system & hematology ,medical ,0302 clinical medicine ,Peptide Fragment ,Surveys and Questionnaires ,Surveys and Questionnaire ,Medicine ,Bivalirudin ,030212 general & internal medicine ,Societies, Medical ,Transradial ,Anticoagulant ,Hirudins ,Middle Aged ,Recombinant Protein ,Recombinant Proteins ,Femoral Artery ,Radial Artery ,Cardiology ,acute coronary syndrome ,bivalirudin ,transradial ,adult ,antithrombins ,cardiology ,femoral artery ,hirudins ,humans ,middle aged ,peptide fragments ,percutaneous coronary intervention ,recombinant proteins ,societies, medical ,surveys and questionnaires ,attitude of health personnel ,radial artery ,Acute coronary syndrome ,Cardiology and Cardiovascular Medicine ,Human ,medicine.drug ,Adult ,medicine.medical_specialty ,Attitude of Health Personnel ,medicine.drug_class ,MEDLINE ,Antithrombins ,03 medical and health sciences ,societies ,Percutaneous Coronary Intervention ,Internal medicine ,Humans ,Acute Coronary Syndrome ,Peptide Fragments ,Management of acute coronary syndrome ,business.industry ,Percutaneous coronary intervention ,medicine.disease ,business - Abstract
AIMS Our aim was to report on a survey initiated by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) collecting the opinion of the cardiology community on the invasive management of acute coronary syndrome (ACS), before and after the MATRIX trial presentation at the American College of Cardiology (ACC) 2015 Scientific Sessions. METHODS AND RESULTS A web-based survey was distributed to all individuals registered on the EuroIntervention mailing list (n=15,200). A total of 572 and 763 physicians responded to the pre- and post-ACC survey, respectively. The radial approach emerged as the preferable access site for ACS patients undergoing invasive management with roughly every other responder interpreting the evidence for mortality benefit as definitive and calling for a guidelines upgrade to class I. The most frequently preferred anticoagulant in ACS patients remains unfractionated heparin (UFH), due to higher costs and greater perceived thrombotic risks associated with bivalirudin. However, more than a quarter of participants declared the use of bivalirudin would increase after MATRIX. CONCLUSIONS The MATRIX trial reinforced the evidence for a causal association between bleeding and mortality and triggered consensus on the superiority of the radial versus femoral approach. The belief that bivalirudin mitigates bleeding risk is common, but UFH still remains the preferred anticoagulant based on lower costs and thrombotic risks.
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- 2016
8. Design Synthesis and Biological Evaluation of Dithiocarbamate Substituted 2-Aminobenzothiazole Derivatives as Proviral Integration Site of Moloney Murine Leukaemia Virus 1 Kinase Inhibitors
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HARSHITA, P. SAI, primary, SUPRIYA, CH., additional, SRAVANTHI, SELINA, additional, JYOTHI, V., additional, PEDDI, S. R., additional, MANGA, VIJJULATHA, additional, SADDANAPU, V., additional, and JYOSTNA, T. SARITHA, additional
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- 2020
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9. Validating Cortical Surface Analysis of Medial Prefrontal Cortex
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Ratnanather, J.T., Botteron, K.N., Nishino, T., Massie, A.B., Lal, R.M., Patel, S.G., Peddi, S., Todd, R.D., and Miller, M.I.
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- 2001
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10. Geometry−Affinity Relationships of the Selective Serotonin Receptor Ligand 9-(Aminomethyl)-9,10-dihydroanthracene
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Runyon, S. P., Peddi, S., Savage, J. E., Roth, B. L., Glennon, R. A., and Westkaemper, R. B.
- Abstract
With the exception of its two aromatic rings and basic nitrogen atom, 9-(aminomethyl)-9,10-dihydroanthracene (AMDA;
1 ) is remarkably devoid of the pharmacophore features usually associated with high-affinity receptor ligands such as the heteroatom hydrogen bonding features of the endogenous ligand serotonin. AMDA does contain a phenylethylamine skeleton within a tricyclic ring system, and the presence of the second aromatic group is necessary for optimal receptor affinity. The structural requirements for the binding of AMDA at 5-HT2A receptors were investigated with respect to the geometric relationship between the two aromatic rings. It appears that the geometry of the AMDA parent is in the optimal range for fold angle between aromatic moieties. Evaluation of conformationally constrained derivatives of AMDA suggests that a chain extended trans, gauche form is most likely responsible for high affinity.- Published
- 2002
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11. Induction of genetic variability in okra [Abelmoschus esculentus (L.) Moench] by gamma and ems.
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Peddi Sudharshan Reddy, L. K. Dhaduk
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Okra ,Variability ,Induced Mutations ,Gamma rays ,Plant culture ,SB1-1110 - Abstract
An investigation was carried out to study the extent of genetic variability induced through physical and chemical mutagens in okra. Seeds of two popular okra varieties viz. GO-2 and GJO-3 were treated with 20 kR, 30 kR and 40 kR of gamma rays and 0.15% and 0.25% EMS to raise M1 generation in summer 2011 and the seed obtained from all of the M1 competitive plants were used to raise M2 in progeny rows of each of the treatments including control (the untreated one) in kharif 2011.In M2 generation, increase in GCV, heritability and genetic advance was considerable under different mutagenic treatments for most of the traits studied in both varieties. In GO-2, high heritability and genetic advance was observed for some important yield contributing characters like fruit length at 40 kR and 0.25% EMS; fruit weight at 20 kR and 40 kR; and fruit yield per plant at 20, 30, 40 kR and 0.15% EMS.Similarly in GJO-3, high heritability coupled with high genetic advance was observed for fruit length at 30 kR and fruit yield per plant at 20 kR. YVMV percentage exhibited high PCV and GCV with high heritability and genetic advance in 0.25% EMS treatment in GO-2 and 40kR treatment in GJO-3. Thus selection for these characters at specific mutagenic treatments will be effective for improvement in okra.
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- 2014
12. Characterization of APOBEC3G binding to 7SL RNA
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Lakkaraju Asvin, Mangeat Bastien, Peddi Shyam, Bach Daniel, Strub Katharina, and Trono Didier
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Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Human APOBEC3 proteins are editing enzymes that can interfere with the replication of exogenous retroviruses such as human immunodeficiency virus (HIV), hepadnaviruses such as hepatitis B virus (HBV), and with the retrotransposition of endogenous retroelements such as long-interspersed nuclear elements (LINE) and Alu. Here, we show that APOBEC3G, but not other APOBEC3 family members, binds 7SL RNA, the common ancestor of Alu RNAs that is specifically recruited into HIV virions. Our data further indicate that APOBEC3G recognizes 7SL RNA and Alu RNA by its common structure, the Alu domain, suggesting a mechanism for APOBEC3G- mediated inhibition of Alu retrotransposition. However, we also demonstrate that APOBEC3F and APOBEC3G are normally recruited into and inhibit the infectivity of ΔVif HIV1 virions when 7SLRNA is prevented from accessing particles by RNA interference against SRP14 or by over expression of SRP19, both components of the signal recognition particle. We thus conclude that 7SL RNA is not an essential mediator of the virion packaging of these antiviral cytidine deaminases.
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- 2008
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13. Surgical Resection of a Giant Hepatic Hemangioma in a Hepatitis B-positive Patient: A Case Report.
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Thatipalli N, Gattani RG, Peddi S, Sagar S, and Sapkale B
- Abstract
This case report describes the successful surgical removal of a giant hemangioma in a 41-year-old female with hepatitis B. The patient came with stomach distension, right upper quadrant, and right lumbar region pain. Imaging studies showed a mass measuring 12x7.6x11 cm emerging from the left lobe of the liver, causing compression of surrounding structures. The patient has undergone a laparotomy with successful anatomical resection of the hemangioma. Postoperative recovery was uneventful, and the patient was discharged on the fifth postoperative day. This case highlights the significance of considering surgery for symptomatic giant hemangiomas and normal follow-up to screen for recurrence and aims to present the successful surgical management of a giant hemangioma., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Thatipalli et al.)
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- 2024
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14. Decoding Autism: Uncovering patterns in brain connectivity through sparsity analysis with rs-fMRI data.
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Bandyopadhyay S, Peddi S, Sarma M, and Samanta D
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- Humans, Magnetic Resonance Imaging methods, Brain Mapping methods, Brain diagnostic imaging, Biomarkers, Autistic Disorder diagnostic imaging, Autism Spectrum Disorder diagnostic imaging
- Abstract
Background: In the realm of neuro-disorders, precise diagnosis and treatment rely heavily on objective imaging-based biomarker identification. This study employs a sparsity approach on resting-state fMRI to discern relevant brain region connectivity for predicting Autism., New Method: The proposed methodology involves four key steps: (1) Utilizing three probabilistic brain atlases to extract functionally homogeneous brain regions from fMRI data. (2) Employing a hybrid approach of Graphical Lasso and Akaike Information Criteria to optimize sparse inverse covariance matrices for representing the brain functional connectivity. (3) Employing statistical techniques to scrutinize functional brain structures in Autism and Control subjects. (4) Implementing both autoencoder-based feature extraction and entire feature-based approach coupled with AI-based learning classifiers to predict Autism., Results: The ensemble classifier with the extracted feature set achieves a classification accuracy of 84.7% ± 0.3% using the MSDL atlas. Meanwhile, the 1D-CNN model, employing all features, exhibits superior classification accuracy of 88.6% ± 1.7% with the Smith 2009 (rsn70) atlas., Comparison With Existing Method (s): The proposed methodology outperforms the conventional correlation-based functional connectivity approach with a notably high prediction accuracy of more than 88%, whereas considering all direct and noisy indirect region-based functional connectivity, the traditional methods bound the prediction accuracy within 70% to 79%., Conclusions: This study underscores the potential of sparsity-based FC analysis using rs-fMRI data as a prognostic biomarker for detecting Autism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
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- 2024
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15. Endobronchial Primary Pulmonary Meningioma: A Rare Cause of Right Main Bronchus Obstruction.
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Prasad VP, Mohammed Abdul N, Peddi S, Vaddepally CR, Reddy DR, and Maturu VN
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- Humans, Bronchi diagnostic imaging, Bronchoscopy, Trachea, Meningioma complications, Meningioma diagnostic imaging, Meningioma surgery, Meningeal Neoplasms
- Abstract
Competing Interests: Disclosure: There is no conflict of interest or other disclosures.
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- 2023
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16. Engineering Chiral Induction in Centrally Functionalized o -Phenylenes.
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Peddi S, Livieri JM, Vemuri GN, and Hartley CS
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Work on foldamers, nonbiological oligomers that mimic the hierarchical structure of biomacromolecules, continues to yield new architectures of ever increasing complexity. o -Phenylenes, a class of helical aromatic foldamers, are well-suited to this area because of their structural simplicity and the straightforward characterization of their folding in solution. However, control of structure requires, by definition, control over folding handedness. Control over o -phenylene twist sense is currently lacking. While chiral induction from groups at o -phenylene termini has been demonstrated, it would be useful to instead direct twisting from internal positions to leave the ends free. Here, we explore chiral induction in a series of o -phenylenes with chiral imides at their centers. Conformational behavior has been studied by nuclear magnetic resonance and circular dichroism spectroscopies and density functional theory calculations. Chiral induction in otherwise unfunctionalized o -phenylenes is generally poor. However, strategic functionalization of the helix surface with trifluoromethyl or methyl groups allows it to better interact with the imide groups, greatly increasing diastereomeric excesses. The sense of chiral induction is consistent with computational models that suggest that it primarily arises from a steric effect.
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- 2023
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17. Preprocedural ultrasonography as an adjunct to landmark technique for identification of epidural space in parturients for labor analgesia.
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Jayanth MN, Arumulla SP, Kesana P, Kandukuru KC, Basireddy HR, and Peddi S
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Background: Pregnancy-induced softening of tissues and ligaments may increase the false-positive rates when identifying the epidural space in parturients by the landmark technique. To mitigate these problems, Ultrasonography (USG), which has now become the eye of anesthesiologists, can be used as a reliable tool to facilitate more accurate epidural needle placement in parturients. This study was conducted to know the efficacy of USG when compared to the traditional landmark method., Methods: After the approval from the institutional ethics committee and CTRI registration, 62 parturients of ASA-2 requesting labor analgesia were randomized into 2 groups of 31 each: Group-L (conventional landmark technique) and Group-U (preprocedural USG done before epidural). In group-U, Tuohy's needle was introduced through the USG predetermined insertion point and epidural space was located using the LOR technique., Results: USG increased the success rate of epidural at first attempt from 51.6% in group "L" to 87% in group "U." Fewer needle attempts ( P -value - 0.001) were required in group "U" as compared to group "L." No accidental dural puncture in group-U, compared to 2 in group-L. Mean Depth of epidural space (cm) ultrasound depth (UD) = 3.89 ± 0.45 cm and needle depth (ND) = 4.05 ± 0.37 cm. Side effects profile in the ultrasound group was better., Conclusion: Preprocedural ultrasonography is a simple safe, accurate tool with less number of attempts to determine the needle insertion site, decrease the incidence of accidental dural punctures, and assess epidural space depth in parturients., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Saudi Journal of Anesthesia.)
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- 2023
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18. Hydra-Elastin-like Polypeptides Increase Rapamycin Potency When Targeting Cell Surface GRP78.
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Avila H, Yu J, Boddu G, Phan A, Truong A, Peddi S, Guo H, Lee SJ, Alba M, Canfield E, Yamamoto V, Paton JC, Paton AW, Lee AS, and MacKay JA
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- Animals, Drug Carriers chemistry, Elastin chemistry, Endoplasmic Reticulum Chaperone BiP, Female, Humans, Peptides chemistry, Sirolimus chemistry, Sirolimus pharmacology, TOR Serine-Threonine Kinases therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Hydra metabolism
- Abstract
Rapalogues are powerful therapeutic modalities for breast cancer; however, they suffer from low solubility and dose-limiting side effects. To overcome these challenges, we developed a long-circulating multiheaded drug carrier called 5FA, which contains rapamycin-binding domains linked with elastin-like polypeptides (ELPs). To target these "Hydra-ELPs" toward breast cancer, we here linked 5FA with four distinct peptides which are reported to engage the cell surface form of the 78 kDa glucose-regulated protein (csGRP78). To determine if these peptides affected the carrier solubility, this library was characterized by light scattering and mass spectrometry. To guide in vitro selection of the most potent functional carrier for rapamycin, its uptake and inhibition of mTORC1 were monitored in a ductal breast cancer model (BT474). Using flow cytometry to track cellular association, it was found that only the targeted carriers enhanced cellular uptake and were susceptible to proteolysis by SubA, which specifically targets csGRP78. The functional inhibition of mTOR was monitored by Western blot for pS6K, whereby the best carrier L-5FA reduced mTOR activity by 3-fold compared to 5FA or free rapamycin. L-5FA was further visualized using super-resolution confocal laser scanning microscopy, which revealed that targeting increased exposure to the carrier by ∼8-fold. This study demonstrates how peptide ligands for GRP78, such as the L peptide (RLLDTNRPLLPY), may be incorporated into protein-based drug carriers to enhance targeting.
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- 2022
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19. Mobile Nanobots for Prevention of Root Canal Treatment Failure.
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Dasgupta D, Peddi S, Saini DK, and Ghosh A
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- Anti-Bacterial Agents pharmacology, Dental Pulp Cavity, Dentin, Humans, Treatment Failure, Enterococcus faecalis, Root Canal Irrigants
- Abstract
Millions of root canal treatments fail worldwide due to remnant bacteria deep in the dentinal tubules located within the dentine tissue of human teeth. The complex and narrow geometry of the tubules renders current techniques relying on passive diffusion of antibacterial agents ineffective. Here, the potential of actively maneuvered nanobots is investigated to disinfect dentinal tubules, which can be incorporated during a standard root canal procedure. It is demonstrated that magnetically driven nanobots can reach the depths of the tubules not possible with current clinical practices. Subtle alterations of the magnetic drive allow both deep implantations of the nanobots isotopically distributed throughout the dentine and spatially controlled recovery from selected regions, further supported by numerical simulations. Finally, the integration of bactericidal therapeutic modality with the nanobots is demonstrated, thereby validating the tremendous potential of nanobots in dentistry and nanomedicine in general., (© 2022 Wiley-VCH GmbH.)
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- 2022
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20. Guest-Driven Control of Folding in a Crown-Ether-Functionalized ortho -Phenylene.
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Peddi S, Bookout MC, Vemuri GN, and Hartley CS
- Subjects
- Ether, Magnetic Resonance Spectroscopy, Crown Ethers chemistry
- Abstract
A crown-ether-functionalized o -phenylene tetramer has been synthesized and coassembled with monotopic and ditopic, achiral and chiral secondary ammonium ion guests. NMR spectroscopy shows that the o -phenylene forms both 1:1 and 1:2 complexes with monotopic guests while remaining well-folded. Binding of an elongated ditopic guest, however, forces the o -phenylene to misfold by pulling the terminal rings apart. A chiral ditopic guest biases the o -phenylene twist sense.
- Published
- 2022
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21. Evaluation of Gingival Crevicular Fluid and Serum Tartrate-resistant Acid Phosphatase Levels in Subjects with Clinically Healthy Periodontium and Chronic Periodontitis - A Clinico-biochemical Study.
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Baddam H, Vivekanandan G, Kondreddy K, Peddi S, Chitnis PP, Singh YP, and Tiwar RVC
- Abstract
Background: Periodontitis is a chronic inflammatory disease with conglomerate etiology making it difficult to diagnose at the early stages. Potential biomarkers in gingival crevicular fluid (GCF) would determine the presence of the current disease activity, predict sites vulnerable for future breakdown, and assess the response to periodontal interventions. Merely elevated levels of inflammatory soft-tissue markers do not indicate bone destruction. Since there is no single ideal biomarker established, bone-related biomarkers such as telopeptide of type I collagen, osteocalcin, calprotectin, osteopontin, and tartrate-resistant acid phosphatase (TRAP) seem to hold great promise as predictive markers to determine bone destruction and active phases in the disease progression. The present study is intended to explore the biologic plausibility of the levels of TRAP in health and chronic periodontitis., Materials and Methods: The present cross-sectional clinico-biochemical study comprised 30 systemically healthy subjects with 15 periodontally healthy and 15 chronic periodontitis subjects who were age and gender matched. GCF and blood samples were collected from all the patients. TRAP estimation was done in both the samples using an enzyme-linked immunosorbent assay kit. The data were analyzed using independent t -test and Pearson correlation test., Results: Serum and GCF TRAP levels in chronic periodontitis subjects were significantly higher when compared to the periodontally healthy group. There were no significant correlations found among serum and GCF TRAP levels with increasing age and gender in both the groups. An increase in disease severity, i.e., increase in probing pocket depth and clinical attachment level, did not show correlation with the GCF and serum TRAP levels in the chronic periodontitis group., Conclusion: Based on the findings of the present study, increased GCF TRAP levels in chronic periodontitis seem to be a potential marker for identifying ongoing periodontal destruction., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Pharmacy and Bioallied Sciences.)
- Published
- 2021
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22. Intralacrimal Sustained Delivery of Rapamycin Shows Therapeutic Effects without Systemic Toxicity in a Mouse Model of Autoimmune Dacryoadenitis Characteristic of Sjögren's Syndrome.
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Ju Y, Edman MC, Guo H, Janga SR, Peddi S, Louie SG, Junge JA, MacKay JA, and Hamm-Alvarez SF
- Subjects
- Animals, Disease Models, Animal, Male, Mice, Mice, Inbred NOD, Sirolimus, Tears, Dacryocystitis, Lacrimal Apparatus, Sjogren's Syndrome
- Abstract
Sjögren's syndrome (SS) is an autoimmune disease associated with severe exocrinopathy, which is characterized by profound lymphocytic infiltration (dacryoadenitis) and loss of function of the tear-producing lacrimal glands (LGs). Systemic administration of Rapamycin (Rapa) significantly reduces LG inflammation in the male Nonobese Diabetic (NOD) model of SS-associated autoimmune dacryoadenitis. However, the systemic toxicity of this potent immunosuppressant limits its application. As an alternative, this paper reports an intra-LG delivery method using a depot formulation comprised of a thermoresponsive elastin-like polypeptide (ELP) and FKBP, the cognate receptor for Rapa (5FV). Depot formation was confirmed in excised whole LG using cleared tissue and observation by both laser-scanning confocal and lightsheet microscopy. The LG depot was evaluated for safety, efficacy, and intra-LG pharmacokinetics in the NOD mouse disease model. Intra-LG injection with the depot formulation (5FV) retained Rapa in the LG for a mean residence time (MRT) of 75.6 h compared to Rapa delivery complexed with a soluble carrier control (5FA), which had a MRT of 11.7 h in the LG. Compared to systemic delivery of Rapa every other day for 2 weeks (seven doses), a single intra-LG depot of Rapa representing 16-fold less total drug was sufficient to inhibit LG inflammation and improve tear production. This treatment modality further reduced markers of hyperglycemia and hyperlipidemia while showing no evidence of necrosis or fibrosis in the LG. This approach represents a potential new therapy for SS-related autoimmune dacryoadenitis, which may be adapted for local delivery at other sites of inflammation; furthermore, these findings reveal the utility of optical imaging for monitoring the disposition of locally administered therapeutics.
- Published
- 2021
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23. Adaptable antibody Nanoworms designed for non-Hodgkin lymphoma.
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Lee C, Peddi S, Anderson C, Su H, Cui H, Epstein AL, and MacKay JA
- Subjects
- Antigens, CD20, B-Lymphocytes, Humans, Lymphoma, B-Cell drug therapy, Lymphoma, Non-Hodgkin drug therapy, Single-Chain Antibodies
- Abstract
Despite advancements in antibody-based therapies for non-Hodgkin lymphoma (NHL), at least two major therapeutic needs remain unmet: i) heterogenous activation of host immunity towards B cell NHL; and ii) lack of antibody-based therapeutics for T cell NHL. This study explores the molecular characteristics of an adaptable modality called antibody Nanoworms and demonstrates their receptor clustering activity as a means to overcome and address abovementioned needs. To test this, four selected therapeutic receptors of B cell (CD19, CD20, HLA-DR10) and T cell (CD3) NHL were targeted by Nanoworms. Regardless of the target or the cell type, Nanoworms inherently clustered bound receptors on the cell-surface through their multivalency and activated intracellular signaling without any secondary crosslinker. As a sole agent, Nanoworms induced apoptosis by clustering CD20 or HLA-DR10, and arrested the cell cycle upon CD19 clustering. Interestingly, CD3 clustering was particularly advantageous in inducing activation-induced cell death (AICD) in an aggressive form of T cell NHL named Sézary syndrome that is fatal, limited in antibody-based therapeutics, and has poor outcomes to traditional chemotherapy. As Nanoworms can be easily designed to target any receptor for which a scFv is available, they may provide solutions and add therapeutic novelty to underserved diseases., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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24. Berunda Polypeptides Carrying Rapalogues Inhibit Tumor mTORC1 Better than Oral Everolimus.
- Author
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Peddi S and MacKay JA
- Subjects
- Animals, Female, Humans, Mechanistic Target of Rapamycin Complex 1, Mice, Peptides, Sirolimus pharmacology, Breast Neoplasms drug therapy, Everolimus
- Abstract
Rapalogues are a unique class of drugs with both cytostatic and immunosuppressive properties. Two founding members, rapamycin (Rapa) and its chemical derivative everolimus (Eve), are extremely potent, but their clinical use presents multiple challenges. Being water-insoluble, administration is restricted to the oral route, which results in a low bioavailability of <10%. Human studies of rapalogues are reported to yield a high blood to plasma ratio and poor correlation between blood concentration and dose. Moreover, treatment results in dose-limiting toxicities such as stomatitis and pneumonitis, which often leads to discontinuation of therapy. We previously reported an elastin-like polypeptide decorated with two-headed FKBP rapalogue-binding domains. Called "FAF", this biomacromolecular drug-carrier solubilizes, retargets, and releases rapalogues within disease sites. FAF-rapalogue formulations are free of cosolvents or surfactants, which promotes their parenteral administration. In this study, subcutaneously given FAF-Rapa significantly suppressed tumor growth in a mouse model of hormone receptor positive (HR+) breast cancer, compared to an oral formulation of Eve (Affinitor). Additionally, mTOR, the pharmacological target of rapalogues, was inhibited to a greater extent in tumors of FAF-Rapa and FAF-Eve groups compared to mice that received oral Eve. No signaling suppression was detected in the liver and spleen, which were evaluated to represent off-target organs exposed to the circulating formulation.
- Published
- 2020
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25. Nanotoxicology of an Elastin-like Polypeptide Rapamycin Formulation for Breast Cancer.
- Author
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Peddi S, Roberts SK, and MacKay JA
- Subjects
- Animals, Drug Carriers therapeutic use, Female, Humans, Mice, Peptides therapeutic use, Sirolimus pharmacology, Breast Neoplasms drug therapy, Elastin therapeutic use
- Abstract
The clinical utility of rapamycin (Rapa) is limited by solubility, bioavailability, and side effects. To overcome this, our team recently reported an elastin-like polypeptide (ELP) nanoparticle with high affinity, noncovalent drug binding, and integrin-mediated cellular uptake. Given the scarcity of pharmacology/toxicology studies of ELP-based drug carriers, this article explores safety and efficacy of ELP-Rapa. ELP-Rapa nanoparticles tested negative for hemolysis, did not interfere in plasma coagulation nor in platelet function, and did not activate the complement. Upon incubation with HepG2 cells, ELP-Rapa revealed significant cellular uptake and trafficking to acidic organelles, consistent with lysosomes. Internalized ELP-Rapa nanoparticles increased oxidative stress 4-fold compared to free drug or free ELP controls. However, mice bearing orthotopic hormone receptor positive BT-474 breast tumors, given a high dose (∼10-fold above therapeutic dose) of 1 month administration of ELP-Rapa, did not induce hepatotoxicity. On the other hand, tumor growth and mTOR signaling were suppressed without affecting body weight. Nanoparticles assembled using ELP technology appear to be a safe and efficient strategy for delivering Rapa.
- Published
- 2020
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26. The humanin peptide mediates ELP nanoassembly and protects human retinal pigment epithelial cells from oxidative stress.
- Author
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Li Z, Sreekumar PG, Peddi S, Hinton DR, Kannan R, and MacKay JA
- Subjects
- Apoptosis drug effects, Cells, Cultured, Epithelial Cells pathology, Humans, Macular Degeneration metabolism, Macular Degeneration pathology, Retinal Pigment Epithelium pathology, Elastin chemistry, Elastin pharmacology, Epithelial Cells metabolism, Intracellular Signaling Peptides and Proteins chemistry, Intracellular Signaling Peptides and Proteins pharmacology, Nanoparticles chemistry, Oxidative Stress drug effects, Peptides chemistry, Peptides pharmacology, Retinal Pigment Epithelium metabolism
- Abstract
Humanin (HN) is a hydrophobic 24-amino acid peptide derived from mitochondrial DNA that modulates cellular responses to oxidative stress and protects human retinal pigment epithelium (RPE) cells from apoptosis. To solubilize HN, this report describes two genetically-encoded fusions between HN and elastin-like polypeptides (ELP). ELPs provide steric stabilization and/or thermo-responsive phase separation. Fusions were designed to either remain soluble or phase separate at the physiological temperature of the retina. Interestingly, the soluble fusion assembles stable colloids with a hydrodynamic radius of 39.1 nm at 37°C. As intended, the thermo-responsive fusion forms large coacervates (>1,000 nm) at 37°C. Both fusions bind human RPE cells and protect against oxidative stress-induction of apoptosis (TUNEL, caspase-3 activation). Their activity is mediated through STAT3; furthermore, STAT3 inhibition eliminates their protection. These findings suggest that HN polypeptides may facilitate cellular delivery of biodegradable nanoparticles with potential protection against age-related diseases, including macular degeneration., (Copyright © 2019. Published by Elsevier Inc.)
- Published
- 2020
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27. Molecular Targeting of Immunosuppressants Using a Bifunctional Elastin-Like Polypeptide.
- Author
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Ju Y, Guo H, Yarber F, Edman MC, Peddi S, Janga SR, MacKay JA, and Hamm-Alvarez SF
- Subjects
- Amino Acid Sequence, Animals, Immunosuppressive Agents metabolism, Immunosuppressive Agents pharmacokinetics, Intercellular Adhesion Molecule-1 metabolism, Male, Mice, Peptides metabolism, Peptides pharmacokinetics, Protein Transport, Sirolimus chemistry, Tissue Distribution, Tumor Necrosis Factor-alpha pharmacology, Elastin chemistry, Immunosuppressive Agents chemistry, Immunosuppressive Agents pharmacology, Molecular Targeted Therapy, Peptides chemistry, Peptides pharmacology
- Abstract
Elastin-Like Polypeptides (ELP) are environmentally responsive protein polymers which are easy to engineer and biocompatible, making them ideal candidates as drug carriers. Our team has recently utilized ELPs fused to FKBP12 to carry Rapamycin (Rapa), a potent immunosuppressant. Through high affinity binding to Rapa, FKBP carriers can yield beneficial therapeutic effects and reduce the off-site toxicity of Rapa. Since ICAM-1 is significantly elevated at sites of inflammation in diverse diseases, we hypothesized that a molecularly targeted ELP carrier capable of binding ICAM-1 might have advantageous properties. Here we report on the design, characterization, pharmacokinetics, and biodistribution of a new ICAM-1-targeted ELP Rapa carrier (IBPAF) and its preliminary characterization in a murine model exhibiting elevated ICAM-1. Lacrimal glands (LG) of male NOD mice, a disease model recapitulating the autoimmune dacryoadenitis seen in Sjögren's Syndrome patients, were analyzed to confirm that ICAM-1 was significantly elevated in the LG relative to control male BALB/c mice (3.5-fold, p < 0.05, n = 6). In vitro studies showed that IBPAF had significantly higher binding to TNF-α-stimulated bEnd.3 cells which overexpress surface ICAM-1, relative to nontargeted control ELP (AF)(4.0-fold, p < 0.05). A pharmacokinetics study in male NOD mice showed no significant differences between AF and IBPAF for plasma half-life, clearance, and volume of distribution. However, both constructs maintained a higher level of Rapa in systemic circulation compared to free Rapa. Interestingly, in the male NOD mouse, the accumulation of IBPAF was significantly higher in homogenized LG extracts compared to AF at 2 h (8.6 ± 6.6% versus 1.3 ± 1.3%, respectively, n = 5, p < 0.05). This accumulation was transient with no differences detected at 8 or 24 h. This study describes the first ICAM-1 targeted protein-polymer carrier for Rapa that specifically binds to ICAM-1 in vitro and accumulates in ICAM-1 overexpressing tissue in vivo, which may be useful for molecular targeting in diverse inflammatory diseases where ICAM-1 is elevated.
- Published
- 2019
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28. Berunda Polypeptides: Biheaded Rapamycin Carriers for Subcutaneous Treatment of Autoimmune Dry Eye Disease.
- Author
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Lee C, Guo H, Klinngam W, Janga SR, Yarber F, Peddi S, Edman MC, Tiwari N, Liu S, Louie SG, Hamm-Alvarez SF, and MacKay JA
- Subjects
- Animals, Cathepsins analysis, Disease Models, Animal, Drug Carriers pharmacokinetics, Drug Liberation, Drug Stability, Elastin chemistry, Immunosuppressive Agents blood, Immunosuppressive Agents chemistry, Injections, Subcutaneous, Male, Mice, Mice, Inbred NOD, Sirolimus blood, Sirolimus chemistry, Sjogren's Syndrome blood, Tacrolimus Binding Protein 1A chemistry, Drug Carriers chemistry, Drug Compounding methods, Immunosuppressive Agents administration & dosage, Immunosuppressive Agents therapeutic use, Peptides chemistry, Sirolimus administration & dosage, Sirolimus therapeutic use, Sjogren's Syndrome drug therapy
- Abstract
The USFDA-approved immunosuppressive drug rapamycin (Rapa), despite its potency, is limited by poor bioavailability and a narrow therapeutic index. In this study, we sought to improve bioavailability of Rapa with subcutaneous (SC) administration and to test its therapeutic feasibility and practicality in a murine model of Sjögren's syndrome (SS), a systemic autoimmune disease with no approved therapies. To improve its therapeutic index, we formulated Rapa with a carrier termed FAF, a fusion of the human cytosolic FK506-binding protein 12 (FKBP12) and an elastin-like polypeptide (ELP). The resulting 97 kDa FAF (i) has minimal burst release, (ii) is "humanized", (iii) is biodegradable, (iv) solubilizes two Rapa per FAF, and (v) avoids organic solvents or amphiphilic carriers. Demonstrating high stability, FAF remained soluble and monodisperse with a hydrodynamic radius of 8 nm at physiological temperature. A complete pharmacokinetic (PK) analysis of FAF revealed that the bioavailability of SC FAF was 60%, with significantly higher blood concentration during the elimination phase compared to IV FAF. The plasma concentration of Rapa delivered by FAF was 8-fold higher with a significantly increased plasma-to-whole blood ratio relative to free Rapa, 24 h after injection. To evaluate therapeutic effects, FAF-Rapa was administered SC every other day for 2 weeks to male non-obese diabetic (NOD) mice, which develop an SS-like autoimmune-mediated lacrimal gland (LG) inflammation and other characteristic features of SS. Both FAF-Rapa and free Rapa exhibited immunomodulatory effects by significantly suppressing lymphocytic infiltration, gene expression of IFN-γ, MHC II, type I collagen and IL-12a, and cathepsin S (CTSS) activity in LG compared to controls. Serum chemistry and histopathological analyses in major organs revealed no apparent toxicity of FAF-Rapa. Given its improved PK and equipotent therapeutic efficacy compared to free Rapa, FAF-Rapa is of further interest for systemic treatments for autoimmune diseases like SS.
- Published
- 2019
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29. Comparison of Marginal and Internal Defects of Indirect Inlay Patterns Fabricated Using Additive Manufacturing and Traditional Methods - An Ex Vivo Study.
- Author
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Peddi SS, Taduri V, and Shivakumar A
- Subjects
- Dental Materials, Humans, Computer-Aided Design, Dental Marginal Adaptation, Dental Prosthesis Design, Inlays
- Abstract
Introduction: This study aimed at exploring clinical translation of additive manufacturing methods for fabrication of inlay restorations., Materials and Methods: On a selected human premolar tooth sample an inlay cavity was prepared. A silicon impression of the tooth was recorded and ten die-casts were poured. Ten inlay wax patterns were fabricated using traditional method. An optical impression of the tooth model was obtained and 20 computeraided inlay designs were fabricated and optimised for additive manufacturing. Ten models were fabricated by micro-stereolithography and the other ten were fabricated using selective laser sintering. 30 inlay patterns were cast into cobalt chromium metal inlays. For 30 metal inlays, marginal and internal gaps were measured using a silicone-replica-technique, observed under a scanning electron microscope., Results: The measured internal gaps were: Internal-gaps in Conventional lost wax technique (138 ± 8.7), micro-stereolithography (200 ± 7.4) and selective laser sintering (203 ± 11.8). The marginal gaps were: Conventional lost wax technique (162.12 ± 6.8), micro-stereolithography (198 ± 10.3) and scanning laser sintering (203 ± 6.6) Conclusions: The marginal gap and internal gap of a conventional lost wax technique were significantly improved compared with microstereolithography and selective laser sintering (P⟨0.05). However, according to previous criteria for maximum allowable discrepancy (100 - 200 μm) microstereolithography may represent a potential future alternative for indirect inlay fabrication., (Copyright© 2019 Dennis Barber Ltd.)
- Published
- 2019
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30. Computational studies on N-phenyl pyrrole derivatives as MmpL3 inhibitors in Mycobacterium tuberculosis.
- Author
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Munnaluri R, Reddy Peddi S, Kanth Sivan S, and Manga V
- Subjects
- Bacterial Proteins metabolism, Membrane Transport Proteins metabolism, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Pyrroles chemistry, Bacterial Proteins antagonists & inhibitors, Computer-Aided Design, Mycobacterium tuberculosis drug effects, Pyrroles pharmacology
- Abstract
The fight against tuberculosis (TB) is a time immemorial one and the emergence of new drug resistant strains of Mycobacterium tuberculosis keeps throwing new challenges to the scientific community immersed in finding mechanisms to control this dreaded disease. Computer aided drug designing (CADD) is one of the several approaches that can assist in identifying the potent actives against Mycobacterium. In this work, a series of 109 known Mycobacterial membrane proteins large 3 (MmpL3) inhibitors were pooled and atom based 3D QSAR analysis was performed to understand the structural features essential for inhibitory activity against the MmpL3, known to be a key player in transporting substances critical for cell wall integrity of Mycobacterium. The data set employed was randomly split into training set and test set molecules. The training set of 74 molecules was used to derive CoMFA and CoMSIA models that were statistically reliable (CoMFA: q
2 loo = 0.53; r2 ncv = 0.93 and CoMSIA: q2 loo = 0.60; r2 ncv = 0.93). The derived models also exhibited good external predictive ability (CoMFA: r2 pred = 0.78 and CoMSIA: r2 pred = 0.79). The results are quite encouraging and information derived from these analyses was applied to design new molecules. The designed molecule showed appreciable predicted activity values and reasonably good ADMET profile. The strategy used in designing new molecules can be pursued in the hunt for new chemical entities targeting MmpL3, expanding the existing arsenal against TB., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2019
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31. Correction to Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-Negative Bacteria.
- Author
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Gerasyuto AI, Arnold MA, Wang J, Chen G, Zhang X, Smith S, Woll MG, Baird J, Zhang N, Almstead NG, Narasimhan J, Peddi S, Dumble M, Sheedy J, Weetall M, Branstrom AA, Prasad JVN, and Karp GM
- Published
- 2018
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32. Intracellular Delivery of Rapamycin From FKBP Elastin-Like Polypeptides Is Consistent With Macropinocytosis.
- Author
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Peddi S, Pan X, and MacKay JA
- Abstract
Rapamycin (Rapa) is a highly potent drug; however, its clinical potential is limited by poor solubility, bioavailability, and cytotoxicity. To improve Rapa delivery, our team has fused the cognate protein receptor for Rapa, FKBP12, to high molecular weight elastin-like polypeptides (ELPs). One construct, FAF, includes an FKBP domain at each termini of an ELP. In a recent report, FAF/Rapa outperformed a family of related carriers with higher tumor accumulation and efficacy. Despite apparent efficacy, an explanation for how FAF carries Rapa into cells has not been elucidated. This manuscript explores the intracellular fate of FAF in MDA-MB-468, a triple negative (ER-/PR-/HER2-) breast cancer line. Based on a lack of displacement by excess unlabeled FAF, no evidence was found for the involvement of a receptor in cell-surface binding. Cellular association showed no dose-dependent saturation at concentrations up to 100 μM, which is consistent with uptake through fluid phase endocytosis. FAF does colocalize with dextran, a marker of fluid phase endocytosis. Upon internalization, both FAF and dextran target low pH intracellular compartments similarly. Despite likely exposure to lysosomal pH and proteolytic activity, intracellular FAF is eliminated from cells with a relatively long half-life of 17.7 and 19.0 h by confocal microscopy and SDS-PAGE respectively. A split luciferase reporter assay demonstrated that FAF delays the cytosolic access of Rapa in comparison to free drug by 30 min. A specific macropinocytosis inhibitor, amiloride, completely inhibits the cytosolic delivery of Rapa from FAF. Each of these results are consistent with macropinocytosis as the mechanism of cellular uptake necessary for the hand-off of Rapa from FKBP-based drug carriers like FAF to endogenous FKBP12 in the cytosol.
- Published
- 2018
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33. Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria.
- Author
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Gerasyuto AI, Arnold MA, Wang J, Chen G, Zhang X, Smith S, Woll MG, Baird J, Zhang N, Almstead NG, Narasimhan J, Peddi S, Dumble M, Sheedy J, Weetall M, Branstrom AA, Prasad JVN, and Karp GM
- Subjects
- Animals, Anti-Bacterial Agents chemistry, Female, Mice, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Protein Conformation, Pyridines chemistry, Sepsis microbiology, Structure-Activity Relationship, Topoisomerase II Inhibitors chemistry, Anti-Bacterial Agents pharmacology, DNA Topoisomerases, Type II chemistry, Drug Discovery, Drug Resistance, Multiple, Bacterial drug effects, Gram-Negative Bacteria drug effects, Sepsis drug therapy, Topoisomerase II Inhibitors pharmacology
- Abstract
There exists an urgent medical need to identify new chemical entities (NCEs) targeting multidrug resistant (MDR) bacterial infections, particularly those caused by Gram-negative pathogens. 4-Hydroxy-2-pyridones represent a novel class of nonfluoroquinolone inhibitors of bacterial type II topoisomerases active against MDR Gram-negative bacteria. Herein, we report on the discovery and structure-activity relationships of a series of fused indolyl-containing 4-hydroxy-2-pyridones with improved in vitro antibacterial activity against fluoroquinolone resistant strains. Compounds 6o and 6v are representative of this class, targeting both bacterial DNA gyrase and topoisomerase IV (Topo IV). In an abbreviated susceptibility screen, compounds 6o and 6v showed improved MIC
90 values against Escherichia coli (0.5-1 μg/mL) and Acinetobacter baumannii (8-16 μg/mL) compared to the precursor compounds. In a murine septicemia model, both compounds showed complete protection in mice infected with a lethal dose of E. coli.- Published
- 2018
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34. 4-Hydroxy-2-pyridones: Discovery and evaluation of a novel class of antibacterial agents targeting DNA synthesis.
- Author
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Arnold MA, Gerasyuto AI, Wang J, Du W, Gorske YJK, Arasu T, Baird J, Almstead NG, Narasimhan J, Peddi S, Ginzburg O, Lue SW, Hedrick J, Sheedy J, Lagaud G, Branstrom AA, Weetall M, Prasad JVNV, and Karp GM
- Subjects
- Animals, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Azabicyclo Compounds metabolism, Azabicyclo Compounds pharmacology, Azabicyclo Compounds therapeutic use, DNA chemistry, Drug Evaluation, Preclinical, Escherichia coli drug effects, Escherichia coli pathogenicity, Gram-Negative Bacteria drug effects, Gram-Negative Bacterial Infections drug therapy, Gram-Negative Bacterial Infections microbiology, Gram-Negative Bacterial Infections veterinary, Half-Life, Mice, Microbial Sensitivity Tests, Niacin metabolism, Niacin pharmacology, Niacin therapeutic use, Pyridines metabolism, Pyridines pharmacology, Pyridines therapeutic use, Structure-Activity Relationship, Anti-Bacterial Agents metabolism, Azabicyclo Compounds chemistry, DNA metabolism, Niacin analogs & derivatives, Pyridines chemistry
- Abstract
The continued emergence of bacteria resistant to current standard of care antibiotics presents a rapidly growing threat to public health. New chemical entities (NCEs) to treat these serious infections are desperately needed. Herein we report the discovery, synthesis, SAR and in vivo efficacy of a novel series of 4-hydroxy-2-pyridones exhibiting activity against Gram-negative pathogens. Compound 1c, derived from the N-debenzylation of 1b, preferentially inhibits bacterial DNA synthesis as determined by standard macromolecular synthesis assays. The structural features of the 4-hydroxy-2-pyridone scaffold required for antibacterial activity were explored and compound 6q, identified through further optimization of the series, had an MIC
90 value of 8 μg/mL against a panel of highly resistant strains of E. coli. In a murine septicemia model, compound 6q exhibited a PD50 of 8 mg/kg in mice infected with a lethal dose of E. coli. This novel series of 4-hydroxy-2-pyridones serves as an excellent starting point for the identification of NCEs treating Gram-negative infections., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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35. Bifunctional Elastin-like Polypeptide Nanoparticles Bind Rapamycin and Integrins and Suppress Tumor Growth in Vivo.
- Author
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Dhandhukia JP, Shi P, Peddi S, Li Z, Aluri S, Ju Y, Brill D, Wang W, Janib SM, Lin YA, Liu S, Cui H, and MacKay JA
- Subjects
- Animals, Antibiotics, Antineoplastic pharmacokinetics, Antibiotics, Antineoplastic pharmacology, Antibiotics, Antineoplastic therapeutic use, Breast drug effects, Breast metabolism, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Line, Tumor, Drug Delivery Systems, Female, Humans, Mice, Mice, Nude, Nanoparticles chemistry, Peptides chemistry, Sirolimus pharmacokinetics, Sirolimus pharmacology, Sirolimus therapeutic use, Antibiotics, Antineoplastic administration & dosage, Breast Neoplasms drug therapy, Drug Carriers chemistry, Elastin chemistry, Integrins metabolism, Sirolimus administration & dosage
- Abstract
Recombinant protein-polymer scaffolds such as elastin-like polypeptides (ELPs) offer drug-delivery opportunities including biocompatibility, monodispersity, and multifunctionality. We recently reported that the fusion of FK-506 binding protein 12 (FKBP) to an ELP nanoparticle (FSI) increases rapamycin (Rapa) solubility, suppresses tumor growth in breast cancer xenografts, and reduces side effects observed with free-drug controls. This new report significantly advances this carrier strategy by demonstrating the coassembly of two different ELP diblock copolymers containing drug-loading and tumor-targeting domains. A new ELP nanoparticle (ISR) was synthesized that includes the canonical integrin-targeting ligand (Arg-Gly-Asp, RGD). FSI and ISR mixed in a 1:1 molar ratio coassemble into bifunctional nanoparticles containing both the FKBP domain for Rapa loading and the RGD ligand for integrin binding. Coassembled nanoparticles were evaluated for bifunctionality by performing in vitro cell-binding and drug-retention assays and in vivo MDA-MB-468 breast tumor regression and tumor-accumulation studies. The bifunctional nanoparticle demonstrated superior cell target binding and similar drug retention to FSI; however, it enhanced the formulation potency, such that tumor growth was suppressed at a 3-fold lower dose compared to an untargeted FSI-Rapa control. This data suggests that ELP-mediated scaffolds are useful tools for generating multifunctional nanomedicines with potential activity in cancer.
- Published
- 2017
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36. Berunda Polypeptides: Multi-Headed Fusion Proteins Promote Subcutaneous Administration of Rapamycin to Breast Cancer In Vivo .
- Author
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Dhandhukia JP, Li Z, Peddi S, Kakan S, Mehta A, Tyrpak D, Despanie J, and MacKay JA
- Subjects
- Animals, Female, Mice, Nanoparticles chemistry, Tacrolimus Binding Proteins metabolism, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms metabolism, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Optical Imaging methods, Peptides chemistry, Sirolimus chemistry, Sirolimus therapeutic use
- Abstract
Recombinant Elastin-Like Polypeptides (ELPs) serve as attractive scaffolds for nanoformulations because they can be charge-neutral, water soluble, high molecular weight, monodisperse, biodegradable, and decorated with functional proteins. We recently reported that fusion of the FK-506 binding protein 12 (FKBP) to an ELP nanoparticle (FSI) reduces rapamycin (Rapa) toxicity and enables intravenous (IV) therapy in both a xenograft breast cancer model and a murine autoimmune disease model. Rapa has poor solubility, which leads to variable oral bioavailability or drug precipitation following parenteral administration. While IV administration is routine during chemotherapy, cytostatic molecules like Rapa would require repeat administrations in clinical settings. To optimize FKBP/Rapa for subcutaneous (SC) administration, this manuscript expands upon first-generation FSI nanoparticles ( R
h ~ 25 nm) and compares them with two second-generation carriers (FA and FAF) that: i) do not self-assemble; ii) retain a hydrodynamic radius ( Rh ~ 7 nm) above the renal filtration cutoff; iii) increase tumor accumulation; and iv) have either one (FA) or two (FAF) drug-binding FKBP domains per ELP protein. Methods: The carriers were compared and evaluated for temperature-concentration phase behavior by UV-Vis spectrophotometry; equilibrium binding and thermodynamics by Isothermal Titration Calorimetry; drug retention and formulation stability by Dialysis and Dynamic Light Scattering; in vitro efficacy using a cell proliferation assay; in vivo efficacy in human MDA-MB-468 orthotopic breast cancer xenografts; downstream target inhibition using western blot; tissue histopathology; and bio-distribution via optical imaging in the orthotopic xenograft mouse model. Results: Named after the two-headed bird in Hindu mythology, the 'Berunda polypeptide' FAF with molecular weight of 97 kDa and particle size, Rh ~ 7 nm demonstrated polypeptide conformation of a soluble hydrated coiled polymer, retained formulation stability for one month post Rapa loading, eliminated toxicity observed with free Rapa after SC administration, suppressed tumor growth, decreased phosphorylation of a downstream target, and increased tumor accumulation in orthotopic breast tumor xenografts. Conclusion: This comprehensive manuscript demonstrates the versatility of recombinant protein-polymers to investigate drug carrier architectures. Furthermore, their facilitation of SC administration of poorly soluble drugs, like Rapa, may enable chronic self-administration in patients., Competing Interests: Competing Interests: J.P.D., S.P., and J.A.M are inventors on a patent describing subcutaneous delivery of small molecules using protein polymer fusions related to this work. All other authors declare no competing financial interests.- Published
- 2017
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37. Acute renal failure in a patient with mantle cell lymphoma.
- Author
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Peddi S, Ram R, Kataru SR, Chennu KK, Nandyala R, Kottu R, and Kumar VS
- Subjects
- Humans, Lymphoma, Mantle-Cell pathology, Male, Middle Aged, Acute Kidney Injury etiology, Lymphoma, Mantle-Cell etiology, Renal Dialysis methods
- Abstract
Mantle cell lymphoma is a rare form of B-cell lymphoma. We present a 54-year-old gentleman with mantle cell lymphoma. It was diagnosed based on the demonstration of B-cell antigens CD20 and CD5. It was further confirmed by demonstration of overexpression of cyclin D1 on these atypical lymphocytes in the immunohistochemical staining. He also had acute renal failure and proteinuria. Renal biopsy revealed crescents and lymphomatous infiltration of tubulointerstitium. The presence of infiltrating cells with similar markers in both the lymph node and the kidney confirmed the infiltration of kidney with lymphomatous cells. Our present patient, after a thorough literature search, is found to be the second one with a glomerular lesion and tubulointerstitial infiltration by malignant lymphoma cells., (© 2014 International Society for Hemodialysis.)
- Published
- 2015
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38. Ligand-Controlled Regioselective Copper-Catalyzed Trifluoromethylation To Generate (Trifluoromethyl)allenes.
- Author
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Ambler BR, Peddi S, and Altman RA
- Subjects
- Alkadienes chemistry, Catalysis, Hydrocarbons, Fluorinated chemistry, Ligands, Molecular Structure, Stereoisomerism, Alkadienes chemical synthesis, Copper chemistry, Hydrocarbons, Fluorinated chemical synthesis
- Abstract
"Cu-CF3" species have been used historically for a broad spectrum of nucleophilic trifluoromethylation reactions. Although recent advancements have employed ligands to stabilize and harness the reactivity of this key organometallic intermediate, the ability of a ligand to differentiate a regiochemical outcome of a Cu-CF3-mediated or -catalyzed reaction has not been previously reported. Herein, we report the first example of a Cu-catalyzed trifluoromethylation reaction in which a ligand controls the regiochemical outcome. More specifically, we demonstrate the ability of bipyridyl-derived ligands to control the regioselectivity of the Cu-catalyzed nucleophilic trifluoromethylation reactions of propargyl electrophiles to generate (trifluoromethyl)allenes. This method provides a variety of di-, tri-, and tetrasubstituted (trifluoromethyl)allenes, which can be further modified to generate complex fluorinated substructures.
- Published
- 2015
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39. Identification and structure-activity relationship study of carvacrol derivatives as Mycobacterium tuberculosis chorismate mutase inhibitors.
- Author
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Alokam R, Jeankumar VU, Sridevi JP, Matikonda SS, Peddi S, Alvala M, Yogeeswari P, and Sriram D
- Subjects
- Anti-Bacterial Agents chemical synthesis, Chorismate Mutase metabolism, Cymenes, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Monoterpenes chemical synthesis, Monoterpenes chemistry, Mycobacterium tuberculosis cytology, Mycobacterium tuberculosis drug effects, Structure-Activity Relationship, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Chorismate Mutase antagonists & inhibitors, Enzyme Inhibitors pharmacology, Monoterpenes pharmacology, Mycobacterium tuberculosis enzymology
- Abstract
In the present study, we identified carvacrol, a major phenolic component of oregano oil as a novel small molecule inhibitor of Mycobacterium tuberculosis (MTB) chorismate mutase (CM) enzyme with IC50 of 1.06 ± 0.4 µM. Virtual screening of the BITS-Pilani in-house database using the crystal structure of the MTB CM bound transition state intermediate (PDB: 2FP2) as framework identified carvacrol as a potential lead. Further various carvacrol derivatives were evaluated in vitro for their ability to inhibit MTB CM enzyme, whole cell MTB and cytotoxicity as steps toward the derivation of structure-activity relationships (SAR) and lead optimization.
- Published
- 2014
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40. Copper-Catalyzed Decarboxylative Trifluoromethylation of Propargyl Bromodifluoroacetates.
- Author
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Ambler BR, Peddi S, and Altman RA
- Abstract
The development of efficient methods for accessing fluorinated functional groups is desirable. Herein, we report a two-step method that utilizes catalytic Cu for the decarboxylative trifluoromethylation of propargyl bromodifluoroacetates. This protocol affords a mixture of propargyl trifluoromethanes and trifluoromethyl allenes.
- Published
- 2014
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41. Central nervous system toxicities of chemotherapeutic agents.
- Author
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Peddi PF, Peddi S, Santos ES, and Morgensztern D
- Subjects
- Antineoplastic Agents therapeutic use, Cisplatin adverse effects, Cytarabine adverse effects, Fluorouracil adverse effects, Humans, Ifosfamide adverse effects, Methotrexate adverse effects, Methotrexate therapeutic use, Vidarabine adverse effects, Vidarabine analogs & derivatives, Vincristine adverse effects, Antineoplastic Agents adverse effects, Central Nervous System Diseases chemically induced, Neurotoxicity Syndromes etiology, Posterior Leukoencephalopathy Syndrome chemically induced
- Abstract
Although there has been a significant progress in the recognition and management of the most common chemotherapy side effects, there is limited data on CNS toxicities. Since CNS toxicities can cause significant morbidity and delay or interruption of potentially effective therapies, there is a need for better understanding, early detection, prompt discontinuation of the offending drug, and use of antidotes when available. This review describes neurological toxicities from some of the commonly used chemotherapy agents.
- Published
- 2014
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42. Saccharopolyspora indica sp. nov., an actinomycete isolated from the rhizosphere of Callistemon citrinus (Curtis).
- Author
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Vaddavalli R, Peddi S, Kothagauni SY, Begum Z, Gaddam B, Periketi M, and Linga VR
- Subjects
- Bacterial Typing Techniques, Base Composition, DNA, Bacterial genetics, Diaminopimelic Acid chemistry, Fatty Acids chemistry, India, Molecular Sequence Data, Nucleic Acid Hybridization, Peptidoglycan chemistry, RNA, Ribosomal, 16S genetics, Saccharopolyspora genetics, Saccharopolyspora isolation & purification, Sequence Analysis, DNA, Vitamin K 2 analogs & derivatives, Vitamin K 2 chemistry, Myrtaceae microbiology, Phylogeny, Rhizosphere, Saccharopolyspora chemistry, Soil Microbiology
- Abstract
A novel actinomycete strain, designated VRC122T, was isolated from a Callistemon citrinus rhizosphere sample collected from New Delhi, India, and its taxonomic status was determined by using a polyphasic approach. Strain VRC122T was a Gram-stain-positive, aerobic, non-motile, non-acid-alcohol-fast strain. Phylogenetic analysis based on 16S rRNA gene sequences showed the strain was placed in a well-separated sub-branch within the genus Saccharopolyspora. The highest levels of 16S rRNA gene sequence similarity were found with Saccharopolyspora hirsuta subsp. kobensis JCM 9109T (98.71%), Saccharopolyspora antimicrobica I05-00074T (98.69%) and Saccharopolyspora jiangxiensis W12T (98.66%); 16S rRNA gene sequence similarities with type strains of all other species of the genus Saccharopolyspora were below 98%. Chemosystematic studies revealed that it contained meso-diaminopimelic acid. Arabinose and galactose were the predominant whole-cell sugars. Diagnostic polar lipids were diphosphatidylglycerol, phosphatidylinositol and phosphatidylcholine. MK-9(H6) was the predominant menaquinone. C14:0, C16:0, iso-C15:0, iso-C16:0, iso-C17:0, anteiso-C15:0, anteiso-C17:0, C17:0 cyclo and summed feature 3 (C16:1ω7c and/or C16:1ω6c) were the major cellular fatty acids. The G+C content of the genomic DNA was 69.5 mol%. The results of DNA-DNA hybridization (30%, 22% and 25%, respectively) with type strains of the above-mentioned species, in combination with differences in physiological and biochemical data supported that strain VRC122T represents a novel species of the genus Saccharopolyspora, for which the name Saccharopolyspora indica sp. nov., is proposed. The type strain is VRC122T (=KCTC 29208T=MTCC 11564T=MCC 2206T=ATCC BAA-2551T).
- Published
- 2014
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43. Discovery and structure optimization of a series of isatin derivatives as Mycobacterium tuberculosis chorismate mutase inhibitors.
- Author
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Jeankumar VU, Alokam R, Sridevi JP, Suryadevara P, Matikonda SS, Peddi S, Sahithi S, Alvala M, Yogeeswari P, and Sriram D
- Subjects
- Crystallography, X-Ray, Enzyme Activation drug effects, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Molecular Structure, Structure-Activity Relationship, Chorismate Mutase antagonists & inhibitors, Drug Discovery, Isatin chemistry, Isatin pharmacology, Mycobacterium tuberculosis enzymology
- Abstract
In this study, the crystal structure of the Mycobacterium tuberculosis (MTB) enzyme chorismate mutase (CM) bound to transition state analogue (PDB: 2FP2) was used as a framework for virtual screening of the BITS-Pilani in-house database (2500 compounds) to identify new scaffold. We identified isatin as novel small molecule MTB CM inhibitors; further twenty-four isatin derivatives were synthesized and evaluated in vitro for their ability to inhibit MTB CM, and activity against M. tuberculosis as steps towards the derivation of structure-activity relationships (SAR) and lead optimization. Compound 3-(4-nitrobenzylidene)indolin-2-one, 24 emerged as the most promising lead with an IC50 of 1.01 ± 0.22 μm for purified CM and MIC of 23.5 μm for M. tuberculosis, with little or no cytotoxicity., (© 2014 John Wiley & Sons A/S.)
- Published
- 2014
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44. Nocardia bhagyanesis sp. nov., a novel actinomycete isolated from the rhizosphere of Callistemon citrinus (Curtis), India.
- Author
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Vaddavalli R, Peddi S, Kothagauni SY, and Linga VR
- Subjects
- Actinomycetales chemistry, Actinomycetales genetics, Actinomycetales isolation & purification, Molecular Sequence Data, Phenotype, Phylogeny, RNA, Ribosomal, 16S genetics, Actinomycetales classification, Rhizosphere, Tracheophyta microbiology
- Abstract
A novel actinomycete strain, designated VRC07(T), was isolated from a Callistemon citrinus rhizosphere sample collected from Hyderabad, India. Its taxonomic status was determined by using polyphasic approach. It is a Gram-positive, aerobic, non-motile, weakly acid-fast strain. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain VRC07(T) is a member of the genus Nocardia. The highest levels of 16S rRNA gene sequence similarity was found between the strains Nocardia niwae W9241(T) (99.6 %), Nocardia amikacinitolerans W9988(T) (99.3 %) and Nocardia arthritidis IFM 10035(T) (98.9 %); similarity to other type strains of the genus Nocardia was below 98.7 %. The organism had chemical and morphological features consistent with its classification in the genus Nocardia such as meso-diaminopimelic acid as the diagnostic diamino acid in the cell wall peptidoglycan. Arabinose and galactose as the diagnostic sugars. Diagnostic polar lipids were phosphatidylinositol, diphosphatidylglycerol, and phosphatidylglycerol. The predominant menaquinone was MK-8(H4, ω-cycl). The major fatty acids were C16:0, C18:0, C18:1 w9c, C18:0 10-methyl TBSA and sum in feature 3 (16:1 w7c/16:1 w6c). The G+C content of the genomic DNA was 68.5 mol%. The DNA-DNA relatedness data, together with phenotypic differences clearly distinguished the isolate from its closest relatives. On the basis of these phenotypic and genotypic data, the isolate represents a novel species, for which the name Nocardia bhagyanesis sp. nov., is proposed. The type strain is VRC07(T) (=KCTC 29209(T) = MTCC 11725(T) = ATCC BAA-2548).
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- 2014
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45. Multiple metastatic infections in a hemodialysis patient with untunneled internal jugular catheter.
- Author
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Peddi S, Ram R, Boreddy VD, Avssn S, Chennu KK, and Vishnubotla SK
- Subjects
- Humans, Male, Radiography, Abscess diagnostic imaging, Abscess etiology, Central Venous Catheters adverse effects, Jugular Veins, Kidney Failure, Chronic therapy, Pneumonia, Bacterial diagnostic imaging, Pneumonia, Bacterial etiology, Positron-Emission Tomography
- Abstract
We present an end-stage renal disease patient on dialysis with fever. The primary source was right internal jugular vein catheter which had metastatic infections in the body probably via an arteriovenous communication in a cavity in left lung. Patient had right psoas muscle abscess and a left kidney abscess. An (18) F-fluorodeoxyglucose-positron emission spectroscopy scan was done to find out left kidney abscess. A search of literature did not reveal many patients of psoas abscess secondary to infection of hemodialysis access., (© 2013 International Society for Hemodialysis.)
- Published
- 2014
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46. KCNQ2/3 openers show differential selectivity and site of action across multiple KCNQ channels.
- Author
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Zhang D, Thimmapaya R, Zhang XF, Anderson DJ, Baranowski JL, Scanio M, Perez-Medrano A, Peddi S, Wang Z, Patel JR, DeGoey DA, Gopalakrishnan M, Honore P, Yao BB, and Surowy CS
- Subjects
- Carbamates pharmacology, HEK293 Cells, Humans, Ion Channel Gating genetics, KCNQ Potassium Channels genetics, KCNQ Potassium Channels metabolism, KCNQ Potassium Channels physiology, KCNQ2 Potassium Channel genetics, KCNQ2 Potassium Channel physiology, KCNQ3 Potassium Channel genetics, KCNQ3 Potassium Channel physiology, Mutation, Phenylenediamines pharmacology, Ion Channel Gating drug effects, KCNQ2 Potassium Channel metabolism, KCNQ3 Potassium Channel metabolism, Thallium pharmacokinetics
- Abstract
KCNQ2/3 voltage-gated potassium channels conduct low-threshold, slowly activating and non-inactivating currents to repolarize the neuronal resting membrane potential. The channels negatively regulate neuronal excitability and KCNQ2/3 openers are efficacious in hyperexcited states such as epilepsy and pain. We developed and utilized thallium influx assays to profile novel KCNQ2/3 channel openers with respect to selectivity across KCNQ subtypes and on requirement for tryptophan 236 of KCNQ2, a critical residue for activity of the KCNQ opener retigabine. Using distinct chemical series of openers, a quinazolinone series showed relatively poor selectivity across multiple KCNQ channels and lacked activity at the KCNQ2(W236L) mutant channel. In contrast, several novel benzimidazole openers showed selectivity for KCNQ2/3 and KCNQ2 and retain activity at KCNQ2(W236L). Profiling of several hundred KCNQ2/3 openers across multiple diverse chemical series revealed that openers show differential degrees of selectivity across subtypes, with selectivity most difficult to achieve against KCNQ2. In addition, we report the significant finding that KCNQ openers can pharmacologically differentiate between homomeric and heteromeric channels containing subtypes in common. Moreover, most openers assayed were dependent on the W236 for activity, whereas only a small number appear to use a distinct mechanism. Collectively, we provide novel insights into the molecular pharmacology of KCNQ channels by demonstrating differential selectivity and site of action for KCNQ2/3 openers. The high-throughput thallium influx assays should prove useful for rapid characterization of KCNQ openers and in guiding efforts to identify selective compounds for advancement towards the clinic., (Copyright © 2011 Elsevier B.V. All rights reserved.)
- Published
- 2011
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47. Synthesis and in vitro activity of N-benzyl-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine P2X(7) antagonists.
- Author
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Perez-Medrano A, Donnelly-Roberts DL, Florjancic AS, Nelson DW, Li T, Namovic MT, Peddi S, Faltynek CR, Jarvis MF, and Carroll WA
- Subjects
- Amines chemistry, Amines pharmacology, Animals, Humans, Inhibitory Concentration 50, Molecular Structure, Protein Binding drug effects, Purinergic P2X Receptor Antagonists chemistry, Rats, Structure-Activity Relationship, Tetrazoles chemistry, Tetrazoles pharmacology, Amines chemical synthesis, Purinergic P2X Receptor Antagonists chemical synthesis, Purinergic P2X Receptor Antagonists pharmacology, Tetrazoles chemical synthesis
- Abstract
Synthesis and biological evaluation of a novel class of substituted N-benzyl-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine derivatives resulted in the identification of potent P2X(7) antagonists. These compounds were assayed for activity at both the human and rat P2X(7) receptors. On the benzyl moiety, a variety of functional groups were tolerated, including both electron-withdrawing and electron-donating substituents. Ortho-substitution on the benzyl group provided the greatest potency. The ortho-substituted analogs showed approximately 2.5-fold greater potency at human compared to rat P2X(7) receptors. Compounds 12 and 38 displayed hP2X(7)pIC(50)s>7.8 with less than 2-fold difference in potency at the rP2X(7)., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
48. Structure-function analyses point to a polynucleotide-accommodating groove essential for APOBEC3A restriction activities.
- Author
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Bulliard Y, Narvaiza I, Bertero A, Peddi S, Röhrig UF, Ortiz M, Zoete V, Castro-Díaz N, Turelli P, Telenti A, Michielin O, Weitzman MD, and Trono D
- Subjects
- APOBEC-3G Deaminase, Animals, Base Sequence, Cytidine Deaminase genetics, DNA, Single-Stranded genetics, DNA, Single-Stranded metabolism, Dependovirus genetics, Dependovirus metabolism, HEK293 Cells, Haplorhini, HeLa Cells, Humans, Long Interspersed Nucleotide Elements genetics, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Plasmids, Polynucleotides chemistry, Proteins genetics, Retroelements genetics, Sequence Alignment, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Structure-Activity Relationship, Substrate Specificity, Cytidine Deaminase chemistry, Cytidine Deaminase metabolism, DNA, Single-Stranded physiology, Dependovirus physiology, Long Interspersed Nucleotide Elements physiology, Polynucleotides metabolism, Proteins chemistry, Proteins metabolism
- Abstract
Members of the human APOBEC3 family of editing enzymes can inhibit various mobile genetic elements. APOBEC3A (A3A) can block the retrotransposon LINE-1 and the parvovirus adeno-associated virus type 2 (AAV-2) but does not inhibit retroviruses. In contrast, APOBEC3G (A3G) can block retroviruses but has only limited effects on AAV-2 or LINE-1. What dictates this differential target specificity remains largely undefined. Here, we modeled the structure of A3A based on its homology with the C-terminal domain of A3G and further compared the sequence of human A3A to those of 11 nonhuman primate orthologues. We then used these data to perform a mutational analysis of A3A, examining its ability to restrict LINE-1, AAV-2, and foreign plasmid DNA and to edit a single-stranded DNA substrate. The results revealed an essential functional role for the predicted single-stranded DNA-docking groove located around the A3A catalytic site. Within this region, amino acid differences between A3A and A3G are predicted to affect the shape of the polynucleotide-binding groove. Correspondingly, transferring some of these A3A residues to A3G endows the latter protein with the ability to block LINE-1 and AAV-2. These results suggest that the target specificity of APOBEC3 family members is partly defined by structural features influencing their interaction with polynucleotide substrates.
- Published
- 2011
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49. 9-Aminomethyl-9,10-dihydroanthracene (AMDA) analogs as structural probes for steric tolerance in 5-HT2A and H1 receptor binding sites.
- Author
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Shah JR, Mosier PD, Peddi S, Roth BL, and Westkaemper RB
- Subjects
- Binding Sites physiology, Humans, Stereoisomerism, Structure-Activity Relationship, Anthracenes chemistry, Anthracenes metabolism, Receptor, Serotonin, 5-HT2A metabolism, Receptors, Serotonin, 5-HT1 metabolism
- Abstract
Synthesis, radioligand binding and molecular modeling studies of several 9-aminomethyl-9,10-dihydroanthracene (AMDA) analogs were carried out to determine the extent of the steric tolerance associated with expansion of the tricyclic ring system and amine substitution at 5-HT(2A) and H(1) receptors. A mixture of (7,12-dihydrotetraphene-12-yl)methanamine and (6,11-dihydrotetracene-11-yl)methanamine in a 75-25% ratio was found to have an apparent K(i) of 10nM at the 5-HT(2A) receptor. A substantial binding affinity for (7,12-dihydrotetraphene-3-methoxy-12-yl)methanamine at the 5-HT(2A) receptor (K(i)=21 nM) was also observed. Interestingly, this compound was found to have 100-fold selectivity for 5-HT(2A) over the H(1) receptor (K(i)=2500 nM). N-Phenylalkyl-AMDA derivatives, in which the length of the alkyl chain varied from methylene to n-butylene, were found to have only weak affinity for both 5-HT(2A) and H(1) receptors (K(i)=223 to 964 nM). Our results show that large rigid annulated AMDA analogs can be sterically accommodated within the proposed 5-HT(2A) binding site., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
50. Neisseria gonorrhoeae penicillin-binding protein 3 demonstrates a pronounced preference for N(epsilon)-acylated substrates.
- Author
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Peddi S, Nicholas RA, and Gutheil WG
- Subjects
- Acylation, Bacterial Proteins metabolism, Binding Sites, Catalysis, Cell Wall metabolism, Kinetics, Models, Molecular, Neisseria gonorrhoeae metabolism, Penicillin-Binding Proteins metabolism, Peptides metabolism, Substrate Specificity, Bacterial Proteins chemistry, Neisseria gonorrhoeae enzymology, Penicillin-Binding Proteins chemistry
- Abstract
Penicillin-binding proteins (PBPs) are bacterial enzymes involved in the final stages of cell wall biosynthesis and are the lethal targets of beta-lactam antibiotics. Despite their importance, their roles in cell wall biosynthesis remain enigmatic. A series of eight substrates, based on variation of the pentapeptide Boc-l-Ala-gamma-d-Glu-l-Lys-d-Ala-d-Ala, were synthesized to test specificity for three features of PBP substrates: (1) the presence or absence of an N(epsilon)-acyl group, (2) the presence of d-IsoGln in place of gamma-d-Glu, and (3) the presence or absence of the N-terminal l-Ala residue. The capacity of these peptides to serve as substrates for Neisseria gonorrhoeae (NG) PBP3 was assessed. NG PBP3 demonstrated good catalytic efficiency (2.5 x 10(5) M(-1) s(-1)) with the best of these substrates, with a pronounced preference (50-fold) for N(epsilon)-acylated substrates over N(epsilon)-nonacylated substrates. This observation suggests that NG PBP3 is specific for the approximately d-Ala-d-Ala moiety of pentapeptides engaged in cross-links in the bacterial cell wall, such that NG PBP3 would act after transpeptidase-catalyzed reactions generate the acylated amino group required for its specificity. NG PBP3 demonstrated low selectivity for gamma-d-Glu vs d-IsoGln and for the presence or absence of the terminal l-Ala residue. The implications of this substrate specificity of NG PBP3 with respect to its possible role in cell wall biosynthesis, and for understanding the substrate specificity of the LMM PBPs in general, are discussed.
- Published
- 2009
- Full Text
- View/download PDF
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