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1. A qubit, a coin, and an advice string walk into a relational problem

Author

Aaronson, S. (Scott), Buhrman, H.M. (Harry), Kretschmer, W. (William), Aaronson, S. (Scott), Buhrman, H.M. (Harry), and Kretschmer, W. (William)

Abstract

Relational problems (those with many possible valid outputs) are different from decision problems, but it is easy to forget just how different. This paper initiates the study of FBQP/qpoly, the class of relational problems solvable in quantum polynomial-Time with the help of polynomial-sized quantum advice, along with its analogues for deterministic and randomized computation (FP, FBPP) and advice (/poly, /rpoly). Our first result is that FBQP/qpoly/= FBQP/poly, unconditionally, with no oracle - a striking contrast with what we know about the analogous decision classes. The proof repurposes the separation between quantum and classical one-way communication complexities due to Bar-Yossef, Jayram, and Kerenidis. We discuss how this separation raises the prospect of near-Term experiments to demonstrate "quantum information supremacy," a form of quantum supremacy that would not depend on unproved complexity assumptions. Our second result is that FBPP/ FP/poly - that is, Adleman s Theorem fails for relational problems - unless PSPACE NP/poly. Our proof uses IP = PSPACE and time-bounded Kolmogorov complexity. On the other hand, we show that proving FBPP/FP/poly will be hard, as it implies a superpolynomial circuit lower bound for PromiseBPEXP. We prove the following further results: Unconditionally, FP/= FBPP and FP/poly/= FBPP/poly (even when these classes are carefully defined). FBPP/poly = FBPP/rpoly (and likewise for FBQP). For sampling problems, by contrast, SampBPP/poly/= SampBPP/rpoly (and likewise for SampBQP).

Published
2024
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25. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.

Author

Goodwin, G. M., Aaronson, S. T., Alvarez, O., Arden, P. C., Baker, A., Bennett, J. C., Bird, C., Blom, R. E., Brennan, C., Brusch, D., Burke, L., Campbell-Coker, K., Carhart-Harris, R., Cattell, J., Daniel, A., DeBattista, C., Dunlop, B. W., Eisen, K., Feifel, D., and Forbes, M. K.

Abstract

Background: Psilocybin is being studied for use in treatment-resistant depression. Methods: In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits). Results: A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups. Conclusions: In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. [ABSTRACT FROM AUTHOR]

Published
2022
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27. Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders

Author

Poulikakos, P., primary, Wu, X., additional, Yang, X., additional, Xiong, Y., additional, Ito, T., additional, Ahmed, T., additional, Karoulia, Z., additional, Adamopoulos, C., additional, Li, R., additional, Wang, H., additional, Wang, L., additional, Xie, L., additional, Liu, J., additional, Ueberheide, B., additional, Aaronson, S., additional, Chen, X., additional, Buchanan, S., additional, Sellers, W., additional, and Jin, J., additional

Published
2020
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28. Long-term safety and frequency of repeat zuranolone treatment in patients with major depressive disorder rolling over from the randomised CORAL Study into the open-label SHORELINE Study.

Author

Mattingly, G. W., Mathew, S. J., Parikh, S. V., Aaronson, S. T., Baune, B. T., Czysz, A., Nandy, I., Ona, V., Brown, C., Kyaga, S., Forrestal, F., Levin, S., Doherty, J., and Mattingly, G.

Subjects
HAMILTON Depression Inventory, GABA receptors, POSTPARTUM depression, MENTAL depression, SUICIDAL ideation
Abstract

Introduction: Zuranolone (ZRN) is a positive allosteric modulator of both synaptic and extrasynaptic gamma-aminobutyric acid type A receptors and a neuroactive steroid approved as an oral, once-daily, 14-day treatment course for adults with postpartum depression in the US and under investigation for adults with major depressive disorder (MDD). The randomised, double-blind, placebo-controlled, Phase 3 CORAL Study assessed the efficacy and safety of ZRN 50 mg vs placebo, each co-initiated with an open-label standard-of-care antidepressant (ADT). Patients who completed CORAL could roll over into open-label SHORELINE, which assessed the safety and tolerability of ZRN 50 mg and need for repeat treatment courses in adults with MDD. Objectives: To assess the safety and tolerability (primary endpoint) and need for repeat ZRN 50 mg treatment courses (secondary endpoint) in adults with MDD who previously enrolled in CORAL. Methods: CORAL enrolled adults (18–64 years) with MDD and 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥24. After completing the 6-week CORAL Study, patients who enrolled in SHORELINE could enter a 46-week observation period to assess the safety and need for 14-day repeat ZRN treatment course(s), with a total of ≤4 repeat treatment courses permitted. Patients were screened every 2 weeks with the 9-item Patient Health Questionnaire, and scores ≥10 prompted a HAMD-17 assessment within 1 week. Patients with HAMD-17 total score ≥20 were eligible for repeat ZRN course(s) ≥8 weeks after completing the prior ZRN treatment course. Results: Among the 190 patients from CORAL who rolled over into SHORELINE and received ≥1 ZRN treatment course in either study, 133 (70.0%) had received ZRN+ADT and 57 (30.0%) received placebo+ADT in CORAL. Overall, 118 rollover patients received ≥1 open-label ZRN treatment course in SHORELINE. For patients who received ≥1 ZRN treatment course in either study, 76.8% received 1 (54.2%; 103/190) or 2 (22.6%; 43/190) total ZRN treatment courses across both studies in up to 1 year in study. The most common (>5%) treatment-emergent adverse events (TEAEs) during treatment and 14 days following the last ZRN dose were somnolence (16.1% of patients), dizziness (8.5%), headache (8.5%), fatigue (7.6%), sedation (5.9%), and nausea (5.1%); study-period TEAEs (73.7%; 87/118) for the majority of patients were mild/moderate (69.5%; 82/118) in severity and occurred primarily during the treatment period (58.5%; 69/118). No signals for increased suicidal ideation/behaviour were observed. Conclusions: Safety and tolerability among rollover patients were consistent with previous studies; most of the TEAEs reported by adults with MDD who received ZRN were mild/moderate in severity. Most patients who rolled over from CORAL to SHORELINE received ≤2 total treatment courses in up to 1 year in study. Disclosure of Interest: G. Mattingly Grant / Research support from: Akili, Alkermes, Allergan (now AbbVie), Axsome, Boehringer, Janssen, Lundbeck, Medgenics, NLS-1 Pharma AG, Otsuka, Reckitt Benckiser, Roche, Sage, Sunovion, Supernus, Takeda, and Teva, Consultant of: Akili, Alkermes, Allergan (now AbbVie), Axsome, Ironshore, Intra-Cellular Therapies, Janssen, Lundbeck, Neos Therapeutics, Otsuka, Purdue, Rhodes, Sage, Sunovion, Takeda, and Teva, Speakers bureau of: Alkermes, Allergan (now AbbVie), Ironshore, Janssen, Lundbeck, Otsuka, Sunovion, and Takeda, S. Mathew Grant / Research support from: Biohaven Pharmaceuticals, Boehringer-Ingelheim, Janssen, Merck, Sage Therapeutics, Inc., and VistaGen Therapeutics, Consultant of: Allergan (now AbbVie), Alkermes, Almatica Pharma, Axsome Therapeutics, BioXcel Therapeutics, Boehringer-Ingelheim, Clexio Biosciences, COMPASS Pathways, Eleusis, EMA Wellness, Engrail Therapeutics, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Levo Therapeutics, Perception Neurosciences, Praxis Precision Medicines, Neumora, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Inc., Seelos Therapeutics, Signant Health, and Sunovion, S. Parikh Grant / Research support from: Aifred, Assurex, Janssen, Mensante, Sage Therapeutics, Inc., and Takeda, S. Aaronson Grant / Research support from: COMPASS Pathways and Neuronetics; has served as a consultant to Genomind, Inc., Janssen, LivaNova PLC, Neuronetics; and Sage Therapeutics, Inc., Speakers bureau of: Janssen and Sunovion Pharmaceuticals, Inc., B. Baune Speakers bureau of: Angelini, AstraZeneca, Biogen, Bristol Myers Squibb, Janssen, LivaNova, Lundbeck, Novartis, Otsuka, Pfizer, Servier, Sumitomo Pharma, Wyeth, and Boehringer-Ingelheim, A. Czysz Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., I. Nandy Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., V. Ona Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., C. Brown Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., S. Kyaga Employee of: Biogen Inc., F. Forrestal Employee of: Biogen Inc., S. Levin Employee of: Biogen Inc., J. Doherty Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., G. Mattingly: None Declared [ABSTRACT FROM AUTHOR]

Published
2024
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31. International randomized-controlled trial of transcranial Direct Current Stimulation in depression

Author

Loo, CK, Husain, MM, McDonald, WM, Aaronson, S, O'Reardon, JP, Alonzo, A ; https://orcid.org/0000-0003-3304-4387, Weickert, CS ; https://orcid.org/0000-0002-4560-0259, Martin, DM ; https://orcid.org/0000-0002-8452-0390, McClintock, SM, Mohan, A ; https://orcid.org/0000-0001-9613-6073, Lisanby, SH, Krystal, AD, Peterchev, AV, Davis, W, Sklar, J, Colagiuri, B, Galvez, V, Loo, Colleen ; https://orcid.org/0000-0003-3267-0554, Loo, CK, Husain, MM, McDonald, WM, Aaronson, S, O'Reardon, JP, Alonzo, A ; https://orcid.org/0000-0003-3304-4387, Weickert, CS ; https://orcid.org/0000-0002-4560-0259, Martin, DM ; https://orcid.org/0000-0002-8452-0390, McClintock, SM, Mohan, A ; https://orcid.org/0000-0001-9613-6073, Lisanby, SH, Krystal, AD, Peterchev, AV, Davis, W, Sklar, J, Colagiuri, B, Galvez, V, and Loo, Colleen ; https://orcid.org/0000-0003-3267-0554

Abstract

Background Evidence suggests that transcranial Direct Current Stimulation (tDCS) has antidepressant effects in unipolar depression, but there is limited information for patients with bipolar depression. Additionally, prior research suggests that brain derived neurotrophic factor (BDNF) Val66Met genotype may moderate response to tDCS. Objective To examine tDCS efficacy in unipolar and bipolar depression and assess if BDNF genotype is associated with antidepressant response to tDCS. Methods 130 participants diagnosed with a major depressive episode were randomized to receive active (2.5 milliamps (mA), 30 min) or sham (0.034 mA and two 60-second current ramps up to 1 and 0.5 mA) tDCS to the left prefrontal cortex, administered in 20 sessions over 4 weeks, in a double-blinded, international multisite study. Mixed effects repeated measures analyses assessed change in mood and neuropsychological scores in participants with at least one post-baseline rating in the unipolar (N = 84) and bipolar (N = 36) samples. Results Mood improved significantly over the 4-week treatment period in both unipolar (p = 0.001) and bipolar groups (p < 0.001). Among participants with unipolar depression, there were more remitters in the sham treatment group (p = 0.03). There was no difference between active and sham stimulation in the bipolar sample. BDNF genotype was unrelated to antidepressant outcome. Conclusions Overall, this study found no antidepressant difference between active and sham stimulation for unipolar or bipolar depression. However, the possibility that the low current delivered in the sham tDCS condition was biologically active cannot be discounted. Moreover, BDNF genotype did not moderate antidepressant outcome. Clinical Trials Registration www.clinicaltrials.gov, NCT01562184.

Published
2018

32. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Author

Galluzzi, Lorenzo, Vitale, Ilio, Aaronson, S. A., Abrams, J. M., Adam, Dieter, Agostinis, Patrizia, Alnemri, E. S., Altucci, Lucia, Amelio, Ivano, Andrews, D. W., Annicchiarico-Petruzzelli, Margherita, Antonov, A. V., Arama, Eli, Baehrecke, E. H., Barlev, N. A., Bazan, N. G., Bernassola, Francesca, Bertrand, M. J. M., Bianchi, Katiuscia, Blagosklonny, M. V., Blomgren, Kla, Borner, Christoph, Boya, Patricia, Brenner, Catherine, Campanella, Michelangelo, Candi, Eleonora, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, F. K. -M., Chandel, N. S., Cheng, E. H., Chipuk, J. E., Cidlowski, J. A., Ciechanover, Aaron, Cohen, G. M., Conrad, Marcu, Cubillos-Ruiz, J. R., Czabotar, P. E., D’Angiolella, Vincenzo, Dawson, T. M., Dawson, V. L., de Laurenzi, Vincenzo, De Maria Marchiano, Ruggero, Debatin, Klaus-Michael, Deberardinis, R. J., Deshmukh, Mohanish, Di Daniele, Nicola, Di Virgilio, Francesco, Dixit, V. M., Dixon, S. J., Duckett, C. S., Dynlacht, B. D., El-Deiry, W. S., Elrod, J. W., Fimia, Gian Maria, Fulda, Simone, García-Sáez, A. J., Garg, A. D., Garrido, Carmen, Gavathiotis, Evripidi, Golstein, Pierre, Gottlieb, Eyal, Green, D. R., Greene, L. A., Gronemeyer, Hinrich, Gross, Atan, Hajnoczky, Gyorgy, Hardwick, J. M., Harris, I. S., Hengartner, M. O., Hetz, Claudio, Ichijo, Hidenori, Jäättelä, Marja, Joseph, Bertrand, Jost, P. J., Juin, P. P., Kaiser, W. J., Karin, Michael, Kaufmann, Thoma, Kepp, Oliver, Kimchi, Adi, Kitsis, R. N., Klionsky, D. J., Knight, R. A., Kumar, Sharad, Lee, S. W., Lemasters, J. J., Levine, Beth, Linkermann, Andrea, Lipton, S. A., Lockshin, R. A., López-Otín, Carlo, Lowe, S. W., Luedde, Tom, Lugli, Enrico, Macfarlane, Marion, Madeo, Frank, Malewicz, Michal, Malorni, Walter, Manic, Gwenola, Marine, Jean-Christophe, Martin, S. J., Martinou, Jean-Claude, Medema, Jan Paul, Mehlen, Patrick, Meier, Pascal, Melino, Sonia, Miao, E. A., Molkentin, J. D., Moll, U. M., Muñoz-Pinedo, Cristina, Nagata, Shigekazu, Nuñez, Gabriel, Oberst, Andrew, Oren, Moshe, Overholtzer, Michael, Pagano, Michele, Panaretakis, Theochari, Pasparakis, Manoli, Penninger, J. M., Pereira, D. M., Pervaiz, Shazib, Peter, M. E., Piacentini, Mauro, Pinton, Paolo, Prehn, J. H. M., Puthalakath, Hamsa, Rabinovich, G. A., Rehm, Marku, Rizzuto, Rosario, Rodrigues, C. M. P., Rubinsztein, D. C., Rudel, Thoma, Ryan, K. M., Sayan, Emre, Scorrano, Luca, Shao, Feng, Shi, Yufang, Silke, John, Simon, Hans-Uwe, Sistigu, Antonella, Stockwell, B. R., Strasser, Andrea, Szabadkai, Gyorgy, Tait, S. W. G., Tang, Daolin, Tavernarakis, Nektario, Thorburn, Andrew, Tsujimoto, Yoshihide, Turk, Bori, Vanden Berghe, Tom, Vandenabeele, Peter, Vander Heiden, M. G., Villunger, Andrea, Virgin, H. W., Vousden, K. H., Vucic, Domagoj, Wagner, E. F., Walczak, Henning, Wallach, David, Wang, Ying, Wells, J. A., Wood, Will, Yuan, Junying, Zakeri, Zahra, Zhivotovsky, Bori, Zitvogel, Laurence, Melino, Gerry, Kroemer, Guido, De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Sistigu, Antonella (ORCID:0000-0002-2528-1238), Galluzzi, Lorenzo, Vitale, Ilio, Aaronson, S. A., Abrams, J. M., Adam, Dieter, Agostinis, Patrizia, Alnemri, E. S., Altucci, Lucia, Amelio, Ivano, Andrews, D. W., Annicchiarico-Petruzzelli, Margherita, Antonov, A. V., Arama, Eli, Baehrecke, E. H., Barlev, N. A., Bazan, N. G., Bernassola, Francesca, Bertrand, M. J. M., Bianchi, Katiuscia, Blagosklonny, M. V., Blomgren, Kla, Borner, Christoph, Boya, Patricia, Brenner, Catherine, Campanella, Michelangelo, Candi, Eleonora, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, F. K. -M., Chandel, N. S., Cheng, E. H., Chipuk, J. E., Cidlowski, J. A., Ciechanover, Aaron, Cohen, G. M., Conrad, Marcu, Cubillos-Ruiz, J. R., Czabotar, P. E., D’Angiolella, Vincenzo, Dawson, T. M., Dawson, V. L., de Laurenzi, Vincenzo, De Maria Marchiano, Ruggero, Debatin, Klaus-Michael, Deberardinis, R. J., Deshmukh, Mohanish, Di Daniele, Nicola, Di Virgilio, Francesco, Dixit, V. M., Dixon, S. J., Duckett, C. S., Dynlacht, B. D., El-Deiry, W. S., Elrod, J. W., Fimia, Gian Maria, Fulda, Simone, García-Sáez, A. J., Garg, A. D., Garrido, Carmen, Gavathiotis, Evripidi, Golstein, Pierre, Gottlieb, Eyal, Green, D. R., Greene, L. A., Gronemeyer, Hinrich, Gross, Atan, Hajnoczky, Gyorgy, Hardwick, J. M., Harris, I. S., Hengartner, M. O., Hetz, Claudio, Ichijo, Hidenori, Jäättelä, Marja, Joseph, Bertrand, Jost, P. J., Juin, P. P., Kaiser, W. J., Karin, Michael, Kaufmann, Thoma, Kepp, Oliver, Kimchi, Adi, Kitsis, R. N., Klionsky, D. J., Knight, R. A., Kumar, Sharad, Lee, S. W., Lemasters, J. J., Levine, Beth, Linkermann, Andrea, Lipton, S. A., Lockshin, R. A., López-Otín, Carlo, Lowe, S. W., Luedde, Tom, Lugli, Enrico, Macfarlane, Marion, Madeo, Frank, Malewicz, Michal, Malorni, Walter, Manic, Gwenola, Marine, Jean-Christophe, Martin, S. J., Martinou, Jean-Claude, Medema, Jan Paul, Mehlen, Patrick, Meier, Pascal, Melino, Sonia, Miao, E. A., Molkentin, J. D., Moll, U. M., Muñoz-Pinedo, Cristina, Nagata, Shigekazu, Nuñez, Gabriel, Oberst, Andrew, Oren, Moshe, Overholtzer, Michael, Pagano, Michele, Panaretakis, Theochari, Pasparakis, Manoli, Penninger, J. M., Pereira, D. M., Pervaiz, Shazib, Peter, M. E., Piacentini, Mauro, Pinton, Paolo, Prehn, J. H. M., Puthalakath, Hamsa, Rabinovich, G. A., Rehm, Marku, Rizzuto, Rosario, Rodrigues, C. M. P., Rubinsztein, D. C., Rudel, Thoma, Ryan, K. M., Sayan, Emre, Scorrano, Luca, Shao, Feng, Shi, Yufang, Silke, John, Simon, Hans-Uwe, Sistigu, Antonella, Stockwell, B. R., Strasser, Andrea, Szabadkai, Gyorgy, Tait, S. W. G., Tang, Daolin, Tavernarakis, Nektario, Thorburn, Andrew, Tsujimoto, Yoshihide, Turk, Bori, Vanden Berghe, Tom, Vandenabeele, Peter, Vander Heiden, M. G., Villunger, Andrea, Virgin, H. W., Vousden, K. H., Vucic, Domagoj, Wagner, E. F., Walczak, Henning, Wallach, David, Wang, Ying, Wells, J. A., Wood, Will, Yuan, Junying, Zakeri, Zahra, Zhivotovsky, Bori, Zitvogel, Laurence, Melino, Gerry, Kroemer, Guido, De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), and Sistigu, Antonella (ORCID:0000-0002-2528-1238)

Abstract

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

Published
2018

35. Mammalian Cell Transformation by a Recombinant Murine Retrovirus Containing the Avian Erythroblastosis Virus erbB Gene

Author

Pierce, J. H., Gazit, A., Di Fiore, P. P., Kraus, M., Pennington, C. Y., Holmes, K. L., Davidson, W. F., Morse, H. C., III, Aaronson, S. A., Clarke, A., editor, Compans, R. W., editor, Cooper, M., editor, Eisen, H., editor, Goebel, W., editor, Koprowski, H., editor, Melchers, F., editor, Oldstone, M., editor, Vogt, P. K., editor, Wagner, H., editor, Wilson, I., editor, Melchers, Fritz, editor, and Potter, Michael, editor

Published
1986
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42. Study design and methodology for a multicentre, randomised controlled trial of transcranial direct current stimulation as a treatment for unipolar and bipolar depression

Author

Alonzo, A ; https://orcid.org/0000-0003-3304-4387, Aaronson, S, Bikson, M, Husain, M, Lisanby, S, Martin, D ; https://orcid.org/0000-0002-8452-0390, McClintock, SM, McDonald, WM, O'Reardon, J, Esmailpoor, Z, Loo, C ; https://orcid.org/0000-0003-3267-0554, Alonzo, A ; https://orcid.org/0000-0003-3304-4387, Aaronson, S, Bikson, M, Husain, M, Lisanby, S, Martin, D ; https://orcid.org/0000-0002-8452-0390, McClintock, SM, McDonald, WM, O'Reardon, J, Esmailpoor, Z, and Loo, C ; https://orcid.org/0000-0003-3267-0554

Abstract

Transcranial Direct Current Stimulation (tDCS) is a new, non-invasive neuromodulation approach for treating depression that has shown promising efficacy. The aim of this trial was to conduct the first international, multicentre randomised controlled trial of tDCS as a treatment for unipolar and bipolar depression. The study recruited 120 participants across 6 sites in the USA and Australia. Participants received active or sham tDCS (2.5 mA, 20 sessions of 30 min duration over 4 weeks), followed by a 4-week open label active treatment phase and a 4-week taper phase. Mood and neuropsychological outcomes were assessed with the primary antidepressant outcome measure being the Montgomery-Asberg Depression Rating Scale (MADRS). A neuropsychological battery was administered to assess safety and examine cognitive effects. The study also investigated the possible influence of genetic polymorphisms on outcomes. The trial was triple-blinded. Participants, tDCS treaters and study raters were blinded to each participant's tDCS group allocation in the sham-controlled phase. Specific aspects of tDCS administration, device operation and group allocation were designed to optimise the integrity of blinding. Outcome measures will be tested using a mixed effects repeated measures analysis with the primary factors being Time as a repeated measure, tDCS condition (sham or active) and Diagnosis (unipolar or bipolar). A restricted number of random and fixed factors will be included as required to account for extraneous differences. As a promising treatment, tDCS has excellent potential for translation into widespread clinical use, being cost effective, portable, easy to operate and well tolerated.

Published
2016

48. Expression cDNA Cloning of a Transforming Gene Encoding the Wild-Type Gα12 Gene Product

Author

Chan, A M, Fleming, T P, McGovern, E S, Chedid, M, Miki, T, and Aaronson, S A

Subjects
Sequence Homology, Amino Acid, Molecular Sequence Data, 3T3 Cells, DNA, Oncogenes, Suramin, Cell Biology, Blotting, Northern, Mice, Cell Transformation, Neoplastic, GTP-Binding Proteins, Tumor Cells, Cultured, Animals, Humans, Electrophoresis, Polyacrylamide Gel, Amino Acid Sequence, Cloning, Molecular, Molecular Biology, Research Article, Gene Library
Abstract

Using an expression cDNA cloning approach, we examined human tumor cell lines for novel oncogenes that might evade detection by conventional techniques. We isolated a transforming sequence that was highly efficient in transforming NIH 3T3 mouse fibroblasts. DNA sequence analysis identified the gene as the human homolog of a recently cloned alpha subunit of mouse GTP-binding protein G alpha 12. NIH 3T3 cells transfected with G alpha 12 cDNA grew in soft agar and were tumorigenic in nude mice. There were no apparent mutations in the cloned cDNA in comparison with a G alpha 12 cDNA clone isolated from a normal human epithelial cell library, implying that overexpression alone was sufficient to cause NIH 3T3 cell transformation. The observed altered growth properties mediated by G alpha 12 showed a certain degree of dependency on serum factors, and its mitogenic potential was also potently inhibited by suramin treatment.

Published
1993
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49. Essential versus accessory aspects of cell death: Recommendations of the NCCD 2015

Author

Galluzzi, L., Bravo-San Pedro, J. M., Vitale, Ilio, Aaronson, S. A., Abrams, J. M., Adam, D., Alnemri, E. S., Altucci, L., Andrews, D., Annicchiarico-Petruzzelli, M., Baehrecke, E. H., Bazan, N. G., Bertrand, M. J., Bianchi, K., Blagosklonny, M. V., Blomgren, K., Borner, C., Bredesen, D. E., Brenner, C., Campanella, M., Candi, E., Cecconi, F., Chan, F. K., Chandel, N. S., Cheng, E. H., Chipuk, J. E., Cidlowski, J. A., Ciechanover, A., Dawson, T. M., Dawson, V. L., De Laurenzi, V., De Maria Marchiano, Ruggero, Debatin, K. -M., Di Daniele, N., Dixit, V. M., Dynlacht, B. D., El-Deiry, W. S., Fimia, G. M., Flavell, R. A., Fulda, S., Garrido, C., Gougeon, M. -L., Green, D. R., Gronemeyer, H., Hajnoczky, G., Hardwick, J. M., Hengartner, M. O., Ichijo, H., Joseph, B., Jost, P. J., Kaufmann, T., Kepp, O., Klionsky, D. J., Knight, R. A., Kumar, S., Lemasters, J. J., Levine, B., Linkermann, A., Lipton, S. A., Lockshin, R. A., López-Otín, C., Lugli, E., Madeo, F., Malorni, W., Marine, J. -C., Martin, S. J., Martinou, J. -C., Medema, Jan Paul, Meier, P., Melino, S., Mizushima, N., Moll, U., Muñoz-Pinedo, C., Nuñez, G., Oberst, A., Panaretakis, T., Penninger, J. M., Peter, M. E., Piacentini, M., Calzavara Pinton, Piergiacomo, Prehn, J. H., Puthalakath, H., Rabinovich, G. A., Ravichandran, K. S., Rizzuto, R., Rodrigues, C. M., Rubinsztein, D. C., Rudel, T., Shi, Y., Simon, H. -U., Stockwell, B. R., Szabadkai, G., Tait, S. W., Tang, H. L., Tavernarakis, N., Tsujimoto, Y., Vanden Berghe, T., Vandenabeele, P., Villunger, A., Wagner, E. F., Walczak, H., White, E., Wood, W. G., Yuan, J., Zakeri, Z., Zhivotovsky, B., Melino, G., Kroemer, G., Vitale, I., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Medema, J. P., Calzavara Pinton, P., Galluzzi, L., Bravo-San Pedro, J. M., Vitale, Ilio, Aaronson, S. A., Abrams, J. M., Adam, D., Alnemri, E. S., Altucci, L., Andrews, D., Annicchiarico-Petruzzelli, M., Baehrecke, E. H., Bazan, N. G., Bertrand, M. J., Bianchi, K., Blagosklonny, M. V., Blomgren, K., Borner, C., Bredesen, D. E., Brenner, C., Campanella, M., Candi, E., Cecconi, F., Chan, F. K., Chandel, N. S., Cheng, E. H., Chipuk, J. E., Cidlowski, J. A., Ciechanover, A., Dawson, T. M., Dawson, V. L., De Laurenzi, V., De Maria Marchiano, Ruggero, Debatin, K. -M., Di Daniele, N., Dixit, V. M., Dynlacht, B. D., El-Deiry, W. S., Fimia, G. M., Flavell, R. A., Fulda, S., Garrido, C., Gougeon, M. -L., Green, D. R., Gronemeyer, H., Hajnoczky, G., Hardwick, J. M., Hengartner, M. O., Ichijo, H., Joseph, B., Jost, P. J., Kaufmann, T., Kepp, O., Klionsky, D. J., Knight, R. A., Kumar, S., Lemasters, J. J., Levine, B., Linkermann, A., Lipton, S. A., Lockshin, R. A., López-Otín, C., Lugli, E., Madeo, F., Malorni, W., Marine, J. -C., Martin, S. J., Martinou, J. -C., Medema, Jan Paul, Meier, P., Melino, S., Mizushima, N., Moll, U., Muñoz-Pinedo, C., Nuñez, G., Oberst, A., Panaretakis, T., Penninger, J. M., Peter, M. E., Piacentini, M., Calzavara Pinton, Piergiacomo, Prehn, J. H., Puthalakath, H., Rabinovich, G. A., Ravichandran, K. S., Rizzuto, R., Rodrigues, C. M., Rubinsztein, D. C., Rudel, T., Shi, Y., Simon, H. -U., Stockwell, B. R., Szabadkai, G., Tait, S. W., Tang, H. L., Tavernarakis, N., Tsujimoto, Y., Vanden Berghe, T., Vandenabeele, P., Villunger, A., Wagner, E. F., Walczak, H., White, E., Wood, W. G., Yuan, J., Zakeri, Z., Zhivotovsky, B., Melino, G., Kroemer, G., Vitale, I., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Medema, J. P., and Calzavara Pinton, P.

Abstract

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.

Published
2015

50. Olanzapine versus divalproex versus placebo in the treatment of mild to moderate mania: a randomized, 12-week, double-blind study

Author

Tohen, M., Eduard Vieta, Goodwin, G. M., Sun, B., Amsterdam, J. D., Banov, M., Shekhar, A., Aaronson, S. T., Bardenstein, L., Grecu-Gaboş, I., Tochilov, V., Prelipceanu, D., Oliff, H. S., Kryzhanovskaya, L., and Bowden, C.

Abstract

OBJECTIVE: To evaluate the efficacy and safety of olanzapine, divalproex, and placebo in a randomized, double-blind trial in mild to moderate mania (DSM-IV-TR criteria). METHOD: The study was conducted from October 2004 to December 2006. A total of 521 patients from private practices, hospitals, and university clinics were randomly assigned to olanzapine (5-20 mg/day), divalproex (500-2500 mg/day), or placebo for 3 weeks; those completing continued with a 9-week double-blind extension. Efficacy (mean change in Young Mania Rating Scale [YMRS] total score was the primary outcome) and safety were assessed. RESULTS: After 3 weeks of treatment, olanzapine-treated (N = 215) and placebo-treated (N = 105) patients significantly differed in YMRS baseline-to-endpoint total score change (p = .034; least squares [LS] mean: -9.4 and -7.4, respectively). Such changes were not significantly different between olanzapine vs. divalproex (N = 201) or divalproex vs. placebo. After 12 weeks of treatment, olanzapine- and divalproex-treated patients significantly differed in YMRS baseline-to-endpoint changes (p = .004; LS mean: -13.3 and -10.7, respectively). Of observed cases, 35.4% (35/99; 3 weeks) to 57.1% (28/49; 12 weeks) had valproate plasma concentrations lower than the recommended valproate therapeutic range, but these patients' YMRS scores were lower than those of patients with valproate concentrations above/within range. Compared with divalproex, after 12 weeks, olanzapine-treated patients had significant increases in weight (p < .001) and in glucose (p < .001), triglyceride (p = .003), cholesterol (p = .024), uric acid (p = .027), and prolactin (p < .001) levels. Divalproex-treated patients had significant decreases in leukocytes (p = .044) and platelets (p < .001) compared with olanzapine after 12 weeks of treatment. The incidence of potentially clinically significant weight gain (>/= 7% from baseline) was higher with olanzapine than with divalproex (3-week: p = .064, 6.4% vs. 2.7%; 12-week: p = .002, 18.8% vs. 8.5%; respectively). CONCLUSION: Olanzapine was significantly more efficacious than placebo but not divalproex at 3 weeks and significantly more efficacious than divalproex at 12 weeks. Olanzapine-treated patients had significantly greater increases in weight and in glucose, cholesterol, triglyceride, uric acid, and prolactin levels than divalproex-treated patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00094549.

Published
2008

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