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Verdiperstat in Amyotrophic Lateral Sclerosis
Hayden, Douglas * deceased, Lai, Po-Ying, Donahue, Rachel, Chen, Hao-Wun, Nm, Mathai, Lopes, Gabriela, McCaffrey, Alexandra, Scalia, Jennifer , Luppino, Sarah , Lagier‐Tourenne, Clotilde , Sadri‐Vakili, Ghazaleh , Heintzman, Sarah, Sufit, Robert , Szymanski, April, Jenkins, Liberty, Martín, Alan, Greene, Ericka , Liao, Bing , Whitaker, Charles H. , Clawson, Lora , Uchil, Alpa, Riley, Kristen M., Arneklev, JinAe, Grogan, James , Su, Xiaowei , Mamarabadi, Mansoureh , Malcolm, Amber, Bazan, Tracy, Rad, Nassim, Wang, Leo H. , Piccione, Ezequiel, Thaisetthawatkul, Pariwat , Farmakidis, Constantine , Jabari, Duaa, Pasnoor, Mamatha , Brown, Robert H. , Houmani, Hajar, Douthwright, Catherine, Daniello, Kate, Suresh, Niraja, Farias, Jerrica, Chen, I-Hweii A. , Steijlen, Kara , Bhavaraju‐Sanka, Ratna, Jacobsen, Bill , Milliard, Jourdan, Bowser, Robert , Deboo, Anahita, Cartwright, Michael S. , Nance, Christopher , Yasek, Julia , Harms, Matthew B. , Burford, Matthew, Shrilla, David, Jones, Sarah , Solórzano, Guillermo, Li, Xiaoyan , Mahuwala, Zabeen , Kumaraswamy, Vishakhadatta Mathur, Baer, Michael , Bhuvaneswaran, Karthikeyan, Kaur, Jasdeep , Walk, David , Maiser, Sam , Mundwiler, Andrew, Meyer, Jenny A. , Soliven, Betty , Roos, Raymond, Mozaffar, Tahseen , Korb, Manisha Kak , Mullen, Jeffrey, Stommel, Elijah W. , Carberry, Nathan , Govindarajan, Raghav , Fournier, C. , Darki, Leila, Rodriguez, Rodrigo , McNeely, Whitney, Diaz‐Abad, Montserrat , Jin, Peter H., Chauhan, Chandana, Bobenhouse, James, Hayat, Ghazala , Bailey, Abbey, Bailey, Jesse, Barlow, Victoria , Bulat, Allison, Changkuon, Genevive, Cirino, Melissa, Deignan, Cristina, Deirmendjian, Emma, Mattos, Annette De, DiStefano, Sofia, Drake, Kristin, Estes, Michaela, Faulconer, Kenneth, Figueroa-Szostek, Precious, Garozzo, Tessa, Hasenoehrl, Meredith Gibbons, Henrique, Jennifer, Henrique, Natalie, Hurwitz, Samuel , Igne, Courtney, Irwin, Liam, Jentoft, Katie, Jordan, Boglarka, Katsovskiy, Igor, Kharakozova, Olga, Kolvek, Taylor, Korin, Alexander, La, Thuong, Li, Haining , Nguyen, Joey, Novak, Ilya, Ortiz, Ricardo, Ostrow, Joe, Pagliaro, Jaclyn , Palillo, Jack, Patterson, J.C., Phan, Minh , Popel, Najla , Proueng, Serena, Rosenthal, Jesse, Small, Catherine B. , Tarasenko, Natalia, Thomas, M., Vigneswaran, Prasha, Wahab, Yusra, Whitworth, Isaac, Wright, Spencer, Santiago, Diana De, Félix, Adrián, Garrett, Karly, Hamilton, Jenny, Khan, Kamran, Lovett, Marlee, Nelson, Linda S., Pabon, Marissa, Rede, Diana, Bolger, Patrick, Fetouh, Ahmed , Woodcook, Joan, Kamp, Cornelia , Kennedy, Julie, McGarry, Andrew , Torti, Margherita , Andrews, Jinsy , Quintana, Melanie , Saville, Benjamin R. , Detry, Michelle A. , Vestrucci, Matteo, Marion, Joseph , Young, Eufrosina , Chase, Marianne, Pothier, Lindsay , Harkey, Brittney, Yu, Hong , Sherman, Alex, Hall, Meghan, Kittle, Gale, Connolly, Mariah, D’Agostino, Derek, Tustison, Eric, Scirocco, Erica, Alameda, Gustavo, Locatelli, Eduardo, Ho, Doreen , Quick, Adam , Heitzman, Daragh, Ajroud‐Driss, Senda , Appel, Stanley H. , Shroff, Sheetal , Katz, Jonathan, Felice, Kevin J. , Maragakis, Nicholas J., Simmons, Zachary , Olney, Nicholas , Miller, Timothy M. , Fernandes, Joseph Americo, Ilieva, Hristelina , Jawdat, Omar, Weiss, Michael D. , Foster, Laura A. , Owegi, Margaret, Newman, Daniel S. , Arcila-Londono, Ximena , Jackson, Carlayne E. , Heiman‐Patterson, Terry , Fee, Dominic , Lewis, Richard A. , Rosenfeld, Jeffrey , Johnson, Kristin, Elliott, Matthew, Kasarskis, Edward J. , Rutkove, Seward B. , McIlduff, Courtney, Bedlack, Richard , Elman, Lauren , Goyal, Namita , Rezania, Kourosh , Twydell, Paul, Benatar, Michael , Glass, Jonathan D. , Jones, Vovanti , Zilliox, Lindsay , Wymer, James , Beydoun, Said R., Shah, Jaimin , Pattee, Gary L. , Martinez‐Thompson, Jennifer M. , Nayar, Shakti, Donohue, Mary V., Grossman, Katheryn, Campbell, Daniel , Qureshi, Irfan , Babu, Suma , Group, HEALEY ALS Platform Trial Study, Maragakis, Nicholas J. , Scirocco, Erica , Martinez-Thompson, Jennifer, Scirocco, Erica , Simmons, Zachary , Maragakis, Nicholas , Bedlack, Richard S , Walk, David , Hayden, Douglas, Wang, Jianing , Mathai, N. M., Kolb, Stephen J. , Szymanski, April L., Liao, Bing, Arneklev, JinAe, Malcolm, Amber, Feldman, Eva L. , Statland, Jeffrey , Dimachkie, Mazen M. , Ghasemi, Mehdi , Houmani, Hajar, Pasinelli, Piera , Milliard, Jourdan, Gutmann, Ludwig , Diaz, Frank , Shrilla, David, Rakočević, Goran , Quinn, Colin , Borg, David, Bhuvaneswaran, Karthikeyan, Robbins, Nathaniel M. , Oskarsson, Björn , Chuquilin, Miguel , McNeely, Whitney, Bobenhouse, James, Staff, Nathan P. , Arroyave, Luisa, Bulat, Allison , Changkuon, Genevive, Cirino, Melissa, Deignan, Cristina, Deirmendjian, Emma, Estes, Michaela, Figueroa-Szostek, Precious, Garozzo, Tessa, Henrique, Jennifer, Henrique, Natalie, Hurwitz, Samuel, Irwin, Liam, Jordan, Boglarka, Kolvek, Taylor, Korin, Alexander, Nguyen, Joey, Novak, Ilya, Ostrow, Joe, Palillo, Jack, Patel, Payal, Patterson, Janae, Phan, Minh, Proueng, Serena, Rosenthal, Jesse, Small, Catherine, Thomas, Mirna, Felix, Adrian, Khan, Kamran, Lovett, Marlee, Nelson, Linda, Rede, Diana, Bolger, Patrick, Fetouh, Ahmed, Woodcook, Joan, Kennedy, Julie, Paganoni, Sabrina , Macklin, Eric A. , Chibnik, Lori Beth , McGlothlin, Anna , Shefner, Jeremy M. , Berry, James D. , Giacomelli, Elisa , Goutman, Stephen A. , Fernandes, J. Americo, Vu, Tuan , Ladha, Shafeeq , Newman, Daniel S., Swenson, Andrea , Caress, James B. , Peltier, Amanda , Johnson, Kristin, Cohen, Jeffrey Allen , Granit, Volkan , Donohue, Mary, Cudkowicz, Merit , Group, HEALEY ALS Platform Trial Study

JAMA Neurology | February 17, 2025 | Volume: 82 | Issue: 4 | Pages: 333

10.1001/jamaneurol.2024.5249 | PMID 40067754 Get It

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510
Pridopidine in Amyotrophic Lateral Sclerosis
Hayden, Douglas, Lai, Po-Ying, Donahue, Rachel, Chen, H.Y., Mathai, Nithya, Lopes, Gabriela, McCaffrey, Alexandra, Scalia, Jennifer , Luppino, Sarah , Lagier‐Tourenne, Clotilde , Sadri‐Vakili, Ghazaleh , Heintzman, Sarah, Sufit, Robert , Szymanski, April, Jenkins, Liberty, Martin, A. D. , Greene, Ericka , Thonhoff, Jason R., Liao, Bing , Whitaker, Charles H. , Clawson, Lora , Uchil, Alpa, Riley, Kristen M., Arneklev, JinAe, Grogan, James , Su, Xiaowei , Mamarabadi, Mansoureh , Malcolm, Amber, Bazan, Tracy, Rad, Nassim, Wang, Leo H. , Piccione, Ezequiel, Thaisetthawatkul, Pariwat , Farmakidis, Constantine , Jabari, Duaa, Pasnoor, Mamatha , Brown, Robert H. , Ghasemi, Mehdi, Houmani, Hajar, Douthwright, Catherine, Daniello, Kate, Suresh, Niraja, Farias, Jerrica, Chen, I-Hweii A. , Steijlen, Kara , Bhavaraju‐Sanka, Ratna, Jacobsen, Bill , Milliard, Jourdan, Bowser, Robert , Deboo, Anahita, Cartwright, Michael S. , Nance, Christopher , Yasek, Julia , Harms, Matthew , Burford, Matthew, Shrilla, David, Jones, Sarah , Solórzano, Guillermo, Li, Xiaoyan , Mahuwala, Zabeen , Kumaraswamy, Vishakhadatta Mathur, Baer, Michael , Bhuvaneswaran, Karthikeyan, Maiser, Sam , Mundwiler, Andrew, Meyer, Jenny, Soliven, Betty , Roos, Raymond P. , Habib, Ali A. , Mozaffar, Tahseen , Korb, Manisha Kak , Mullen, Jeffrey, Stommel, Elijah W. , Carberry, Nathan , Govindarajan, Raghav , Glass, Jonathan D. , Fournier, Christina , Darki, Leila, Rodriguez, Rodrigo , McNeely, Whitney, Diaz‐Abad, Montserrat , Jin, Peter H., Chauhan, Chandana, Bobenhouse, James, Hayat, Ghazala , Bailey, Abbey, Bailey, Jesse, Barlow, Victoria , Bulat, Allison, Changkuon, Genevive, Cirino, Melissa, Deignan, Cristina, Deirmendjian, Emma, Mattos, Annette De, DiStefano, Sofia, Drake, Kristin, Estes, Michaela, Faulconer, Kenneth, Figueroa-Szostek, Precious, Garozzo, Tessa, Hasenoehrl, Meredith Gibbons, Henrique, Jennifer, Henrique, Natalie, Hurwitz, Samuel , Igne, Courtney, Irwin, L. R., Jentoft, Katie, Jordan, Boglarka, Katsovskiy, Igor, Kharakozova, Olga, Kolvek, Taylor, Korin, Alexander, La, Thuong, Li, Haining , Nguyen, Joey, Novak, Ilya, Ortiz, Ricardo, Ostrow, Joe, Pagliaro, Jaclyn , Palillo, Jack, Patel, Payal , Patterson, Janae, Phan, Minh , Popel, Najla , Proueng, Serena, Rosenthal, Jesse, Small, Catherine B. , Tarasenko, Natalia, Thomas, Mirna, Vigneswaran, Prasha, Wahab, Yusra, Whitworth, Isaac, Wright, Spencer, Connolly, Mariah, Santiago, Diana De, Felix, A. John William , Garrett, Karly, Hamilton, Jenny, Khan, Kamran , Lovett, Marlee, Nelson, Linda S., Pabon, Marissa, Rede, Diana, Bolger, Patrick, Fetouh, Ahmed , Woodcook, Joan, Kamp, Cornelia , Kennedy, Julie, McGarry, Andrew , Torti, Margherita , Quintana, Melanie , Saville, Benjamin R. , Detry, Michelle A. , Vestrucci, Matteo, Marion, Joe , Heiman‐Patterson, Terry , Chase, Marianne, Pothier, Lindsay , Harkey, Brittney, Yu, Hong , Sherman, Alexander , Hall, Meghan, Kittle, Gale, Andrews, Jinsy , D’Agostino, Derek, Tustison, Eric, Scirocco, Erica , Alameda, Gustavo, Locatelli, Eduardo, Ho, Doreen , Quick, Adam , Ajroud‐Driss, Senda , Katz, Jonathan, Heitzman, Daragh, Appel, Stanley H. , Shroff, Sheetal , Felice, Kevin J. , Maragakis, Nicholas J., Simmons, Zachary , Olney, Nicholas , Weiss, Michael D. , Fernandes, Joseph Americo, Jawdat, Omar, Owegi, Margaret, Foster, Laura A. , Ilieva, Hristelina , Newman, Daniel S. , Arcila-Londono, Ximena , Jackson, Carlayne E. , Lewis, Richard A. , Fee, Dominic , Elliott, Matthew, Bedlack, Richard , Kasarskis, Edward J. , Elman, Lauren , Rosenfeld, Jeffrey , Walk, David , McIlduff, Courtney, Twydell, Paul, Young, Eufrosina , Johnson, Kristin, Rezania, Kourosh , Goyal, Namita , Benatar, Michael , Jones, Vovanti , Shah, Jaimin , Beydoun, Said R., Wymer, James , Zilliox, Lindsay , Nayar, Shakti, Pattee, Gary L. , Martinez‐Thompson, Jennifer M. , Leitner, Melanie , Chen, Kelly , Goldberg, Y. Paul, Cohen, Yaël C. , Geva, Michal , Hayden, Michael R. , Group, HEALEY ALS Platform Trial Study, Scirocco, Erica , Martinez-Thompson, Jennifer, Simmons, Zachary , Bedlack, Richard S , Walk, David , Wang, Jianing , Mathai, N. M., Kolb, Stephen J. , Szymanski, April L., Martin, Alan, Liao, Bing, Arneklev, JinAe, Malcolm, Amber, Feldman, Eva L. , Statland, Jeffrey , Dimachkie, Mazen M. , Ghasemi, Mehdi , Houmani, Hajar, Pasinelli, Piera , Milliard, Jourdan, Gutmann, Ludwig , Harms, Matthew B. , Diaz, Frank , Shrilla, David, Rakočević, Goran , Quinn, Colin , Borg, David, Bhuvaneswaran, Karthikeyan, Kaur, Jasdeep, Rutkove, Seward B. , Rao, Pooja, Robbins, Nathaniel M. , Granit, Volkan , Chuquilin, Miguel , McNeely, Whitney, Bobenhouse, James, Staff, Nathan P. , Arroyave, Luisa, Bulat, Allison , Changkuon, Genevive, Cirino, Melissa, Deignan, Cristina, Deirmendjian, Emma, Figueroa-Szostek, Precious, Garozzo, Tessa, Henrique, Jennifer, Henrique, Natalie, Hurwitz, Samuel, Irwin, Liam, Kolvek, Taylor, Korin, Alexander, Ostrow, Joe, Palillo, Jack, Phan, Minh, Proueng, Serena, Rosenthal, Jesse, Small, Catherine, Thomas, Mirna, Garrett, Karly, Nelson, Linda, Rede, Diana, Bolger, Patrick, Fetouh, Ahmed, Woodcook, Joan, Kennedy, Julie, Shefner, Jeremy M. , Oskarsson, Björn , Macklin, Eric A. , Chibnik, Lori Beth , McGlothlin, Anna , Berry, James D. , Babu, Suma , Giacomelli, Elisa , Maragakis, Nicholas J. , Mill, Jonathan , Goutman, Stephen A. , Fernandes, J. Americo, Vu, Tuan , Newman, Daniel S., Ladha, Shafeeq , Caress, James B. , Swenson, Andrea , Peltier, Amanda , Johnson, Kristin, Cohen, Jeffrey Allen , Goldberg, Y. Paul, Paganoni, Sabrina , Cudkowicz, Merit

JAMA | February 17, 2025 | Volume: 333 | Issue: 13 | Pages: 1128

10.1001/jama.2024.26429 | PMID 40067755 Get It

ImportanceAmyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.ObjectiveTo determine the effects of pridopidine, a σ1-receptor agonist, in ALS.Design, Settings, and ParticipantsPridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.InterventionsEligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.ResultsAmong 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR <1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).Conclusions and RelevanceIn this 24-week study, pridopidine did not impact the progression of ALS.Trial RegistrationClinicalTrials.gov Identifiers: NCT04297683, NCT04615923
Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis
Fournier, Christina , Quintana, Melanie , Saville, Benjamin R. , Detry, Michelle A. , Vestrucci, Matteo, Marion, Joe , Ajroud‐Driss, Senda , Chase, Marianne, Pothier, Lindsay , Harkey, Brittney, Yu, Hong , Sherman, Alexander , Hall, Meghan, Kittle, Gale, Babu, Suma , Andrews, Jinsy , D’Agostino, Derek, Tustison, Eric, Scirocco, Erica , Alameda, Gustavo, Locatelli, Eduardo, Ho, Doreen , Quick, Adam , Katz, Jonathan, Heitzman, Daragh, Appel, Stanley H., Shroff, Sheetal , Felice, Kevin J. , Maragakis, Nicholas J., Simmons, Zachary , Miller, Timothy M. , Olney, Nicholas , Weiss, Michael D. , Fernandes, Joseph Americo, Jawdat, Omar, Owegi, Margaret, Foster, Laura A. , Ilieva, Hristelina , Newman, Daniel S. , Arcila-Londono, Ximena , Jackson, Carlayne E. , Heiman‐Patterson, Terry , Lewis, Richard A. , Fee, Dominic , Elliott, Matthew, Bedlack, Richard , Kasarskis, Edward J. , Elman, Lauren , Rosenfeld, Jeffrey , Walk, David , McIlduff, Courtney, Twydell, Paul, Young, Eufrosina , Johnson, Kristin, Rezania, Kourosh , Goyal, Namita , Benatar, Michael, Jones, Vovanti , Glass, Jonathan D. , Shah, Jaimin , Beydoun, Said R., Wymer, James , Zilliox, Lindsay , Nayar, Shakti, Pattee, Gary L. , Martinez‐Thompson, Jennifer M. , Patel, Shital , Mahoney, Paul, Duda, Petra W., Group, HEALEY ALS Platform Trial Study, Hayden, Douglas * deceased, Lai, Po-Ying, Donahue, Rachel A., Chen, Hao-Wun, Mathai, Nithya, Lopes, Gabriela, McCaffrey, Alexandra, Scalia, Jennifer , Luppino, Sarah , Lagier‐Tourenne, Clotilde , Sadri‐Vakili, Ghazaleh , Heintzman, Sarah, Sufit, Robert , Szymanski, April, Jenkins, Liberty, Martin, A. D. , Greene, Ericka , Thonhoff, Jason R., Liao, Bing , Whitaker, Charles H. , Clawson, Lora , Uchil, Alpa, Riley, Kristen M., Arneklev, JinAe, Grogan, James , Su, Xiaowei , Mamarabadi, Mansoureh , Malcolm, Amber, Bazan, Tracy, Rad, Nassim, Wang, Leo H. , Piccione, Ezequiel, Thaisetthawatkul, Pariwat , Farmakidis, Constantine , Jabari, Duaa, Pasnoor, Mamatha , Dimachkie, Mazen M. , Brown, Robert H. , Ghasemi, Mehdi, Houmani, Hajar, Douthwright, Catherine, Daniello, Kate, Suresh, Niraja, Farias, Jerrica, Chen, I-Hweii A. , Steijlen, Kara , Bhavaraju‐Sanka, Ratna, Jacobsen, Bill , Milliard, Jourdan, Bowser, Robert , Deboo, Anahita, Cartwright, Michael S. , Nance, Christopher , Yasek, Julia , Harms, Matthew , Burford, Matthew, Shrilla, David, Jones, Sarah , Solórzano, Guillermo, Li, Xiaoyan , Mahuwala, Zabeen , Kumaraswamy, Vishakhadatta Mathur, Baer, Michael , Bhuvaneswaran, Karthikeyan, Maiser, Sam , Rutkove, Seward B. , Mundwiler, Andrew, Meyer, Jenny, Soliven, Betty , Roos, Raymond P. , Habib, Ali A. , Mozaffar, Tahseen , Korb, Manisha Kak , Mullen, Jeffrey, Stommel, Elijah W. , Carberry, Nathan , Govindarajan, Raghav , Darki, Leila, Rodriguez, Rodrigo , McNeely, Whitney, Diaz‐Abad, Montserrat , Jin, Peter H., Chauhan, Chandana, Bobenhouse, James, Staff, Nathan P. , Hayat, Ghazala , Bailey, Abbey, Bailey, Jesse, Barlow, Victoria , Bulat, Allison, Changkuon, Genevive, Cirino, Melissa, Deignan, Cristina, Deirmendjian, Emma, Mattos, Annette De, DiStefano, Sofia, Drake, Kristin, Estes, Michaela, Faulconer, Kenneth, Figueroa-Szostek, Precious, Garozzo, Tessa, Hasenoehrl, Meredith Gibbons, Henrique, Jennifer, Henrique, Natalie, Hurwitz, Samuel , Igne, Courtney, Irwin, L. R., Jentoft, Katie, Jordan, Boglarka, Katsovskiy, Igor, Kharakozova, Olga, Kolvek, Taylor, Korin, Alexander, La, Thuong, Li, Haining , Nguyen, Joey, Novak, Ilya, Ortiz, Ricardo, Ostrow, Joe, Pagliaro, Jaclyn , Palillo, Jack, Patel, Payal , Patterson, Janae, Phan, Minh , Popel, Najla , Proueng, Serena, Rosenthal, Jesse, Small, Catherine B. , Tarasenko, Natalia, Thomas, Mirna, Vigneswaran, Prasha, Wahab, Yusra, Whitworth, Isaac, Wright, Spencer, Connolly, Mariah, Santiago, Diana De, Felix, A. John William , Garrett, Karly, Hamilton, Jenny, Khan, Kamran , Lovett, Marlee, Nelson, Linda S., Pabon, Marissa, Rede, Diana, Bolger, Patrick, Fetouh, Ahmed , Woodcook, Joan, Kamp, Cornelia , Kennedy, Julie, McGarry, Andrew , Torti, Margherita , Maragakis, Nicholas J. , Martinez-Thompson, Jennifer, Scirocco, Erica , Simmons, Zachary , Staff, Nathan P , Maragakis, Nicholas , Bedlack, Richard S , Dimachkie, Mazen M , Walk, David , Paganoni, Sabrina , Macklin, Eric A. , Chibnik, Lori Beth , McGlothlin, Anna , Shefner, Jeremy M. , Berry, James D. , Giacomelli, Elisa , Appel, Stanley H. , Goutman, Stephen A. , Fernandes, J. Americo, Vu, Tuan , Newman, Daniel S., Ladha, Shafeeq , Caress, James B. , Swenson, Andrea , Peltier, Amanda , Johnson, Kristin, Cohen, Jeffrey Allen , Harvey, Brittany, Mahoney, Paul, Cudkowicz, Merit , Group, HEALEY ALS Platform Trial Study, Hayden, Douglas * deceased, Donahue, Rachel A., Chen, Hao-Wun, Wang, Jianing, Mathai, N. M., Kolb, Stephen J. , Szymanski, April, Martin, Alan, Liao, Bing, Riley, Kristen M., Malcolm, Amber, Feldman, Eva L. , Statland, Jeffrey , Ghasemi, Mehdi , Pasinelli, Piera , Gutmann, Ludwig , Harms, Matthew B. , Diaz, Frank , Rakočević, Goran , Quinn, Colin , Borg, David, Kaur, Jasdeep, Rao, Pooja, Robbins, Nathaniel M. , Granit, Volkan , Oskarsson, Björn , Chuquilin, Miguel , Arroyave, Luisa, Bailey, Abbey, Bulat, Allison , Hurwitz, Samuel, Irwin, Liam, Jordan, Boglarka, Korin, Alexander, Novak, Ilya, Patterson, Janae, Phan, Minh, Rosenthal, Jesse, Small, Catherine, Thomas, Mirna, Wahab, Yusra, Wright, Spencer, Garrett, Karly, Lovett, Marlee, Nelson, Linda, Pabon, Marissa, Bolger, Patrick, Fetouh, Ahmed, Kennedy, Julie

JAMA Network Open | February 17, 2025 | Volume: 8 | Issue: 2 | Pages: e2459058

10.1001/jamanetworkopen.2024.59058 | PMID 39960672 Get It

Importance The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; <1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration ClinicalTrials.gov Identifier: NCT04297683
CNM-Au8 in Amyotrophic Lateral Sclerosis
Hayden, Douglas, Lai, Po-Ying, Donahue, Rachel, Chen, H., Mathai, N. M., Lopes, Gabriela, McCaffrey, Alexandra, Scalia, Jennifer , Luppino, Sarah , Lagier‐Tourenne, Clotilde , Sadri‐Vakili, Ghazaleh , Heintzman, Sarah, Sufit, Robert , Szymanski, April, Jenkins, Liberty, Martin, A. D. , Greene, Ericka , Thonhoff, Jason R., Liao, Bing , Whitaker, Charles H. , Clawson, Lora , Uchil, Alpa, Riley, Kristen M., Arneklev, JinAe, Grogan, James , Su, Xiaowei , Mamarabadi, Mansoureh , Malcolm, Amber, Bazan, Tracy, Rad, Nassim, Wang, Leo H. , Piccione, Ezequiel, Thaisetthawatkul, Pariwat , Farmakidis, Constantine , Jabari, Duaa, Pasnoor, Mamatha , Brown, Robert H. , Houmani, Hajar, Douthwright, Catherine, Daniello, Kate, Suresh, Niraja, Farias, Jerrica, Chen, I-Hweii A. , Steijlen, Kara , Bhavaraju‐Sanka, Ratna, Jacobsen, Bill , Milliard, Jourdan, Bowser, Robert , Deboo, Anahita, Cartwright, Michael S. , Nance, Christopher , Yasek, Julia , Harms, Matthew, Burford, Matthew, Shrilla, David, Jones, Sarah, Solórzano, Guillermo, Mahuwala, Zabeen , Kumaraswamy, Vishakhadatta Mathur, Baer, Michael , Bhuvaneswaran, Karthikeyan, Maiser, Sam , Mundwiler, Andrew, Meyer, Jenny, Roos, Raymond P. , Habib, Ali A. , Mozaffar, Tahseen , Korb, Manisha Kak , Carberry, Nathan , Govindarajan, Raghav , Fournier, Christina , Darki, Leila, Rodriguez, Rodrigo , Chuguilin, Miguel, McNeely, Whitney, Diaz‐Abad, Montserrat , Jin, Peter H., Chauhan, Chandana, Bobenhouse, James, Staff, N., Hayat, Ghazala , Bailey, Abbey, Bailey, Jesse, Barlow, Victoria , Bulat, Allison , Changkuon, Genevive, Cirino, Melissa, Deignan, Cristina, Deirmendjian, Emma, Mattos, Annette De, DiStefano, Sofia, Drake, Kristin, Estes, M L, Faulconer, Kenneth, Figueroa-Szostek, Precious, Garozzo, Tessa, Hasenoehrl, Meredith Gibbons, Henrique, Jennifer, Henrique, Natalie, Hurwitz, Samuel , Igne, Courtney, Irwin, L. R., Jentoft, Katie, Jordan, Boglarka, Katsovskiy, Igor, Kharakozova, Olga, Kolvek, Taylor, Korin, Alexander, La, Thuong, Nguyen, Joey, Novak, Ilya, Ortiz, Ricardo, Ostrow, Joe, Pagliaro, Jaclyn , Palillo, Jack, Patterson, Janae, Phan, Minh, Popel, Najla , Proueng, Serena, Rosenthal, Jesse, Small, Catherine B. , Tarasenko, Natalia, Thomas, Mirna, Vigneswaran, Prasha, Wahab, Yusra, Whitworth, Isaac, Wright, Spencer, Connolly, Mariah, Santiago, Diana De, Félix, Adrián, Garrett, Karly, Hamilton, Jenny, Lovett, Marlee, Nelson, Linda S., Pabón, M. Vargas, Rede, Diana, Bolger, Patrick, Fetouh, Ahmed , Woodcook, Joan, Kamp, Cornelia , Kennedy, Julie, McGarry, Andrew , Torti, Margherita , Maragakis, Nicholas J. , Quintana, Melanie , Saville, Benjamin R. , Detry, Michelle A. , Vestrucci, Matteo, Marion, Joseph , Stommel, Elijah W. , Chase, Marianne, Pothier, Lindsay , Harkey, Brittney, Yu, Hong , Sherman, Alex, Hall, Meghan, Kittle, Gale, Babu, Suma , Andrews, Jinsy , D’Agostino, Derek, Tustison, Eric, Scirocco, Erica, Alameda, Gustavo, Locatelli, Eduardo, Ho, Doreen , Quick, Adam , Ajroud‐Driss, Senda , Katz, Jonathan, Heitzman, Daragh, Appel, Stanley H. , Shroff, Sheetal , Felice, Kevin J. , Simmons, Zachary, Miller, Timothy M. , Olney, Nicholas , Weiss, Michael D. , Fernandes, Joseph Americo, Jawdat, Omar, Owegi, Margaret, Foster, Laura A. , Ilieva, Hristelina , Newman, Daniel S. , Arcila-Londono, Ximena , Jackson, Carlayne E. , Heiman‐Patterson, Terry , Lewis, Richard A. , Fee, Dominic , Elliott, Matthew , Bedlack, Richard , Kasarskis, Edward J. , Elman, Lauren , Rosenfeld, Jeffrey V. , Walk, David , McIlduff, Courtney, Twydell, Paul, Young, Eufrosina , Johnson, Kristin, Rezania, Kourosh , Goyal, Namita , Benatar, Michael, Jones, Vovanti , Glass, Jonathan D. , Shah, Jaimin , Beydoun, Said R., Wymer, James , Zilliox, Lindsay , Nayar, Shakti, Pattee, Gary L. , Martinez‐Thompson, Jennifer M. , Rynders, Austin, Evan, Jacob, Evan, Jeremy, Hartford, Alan , Sepassi, Marjan , Ho, Karen S. , Glanzman, Robert , Hotchkin, Michael T. , Group, HEALEY ALS Platform Trial Study, Simmons, Zachary , Scirocco, Erica , Martinez-Thompson, Jennifer, Scirocco, Erica , Simmons, Zachary , Maragakis, Nicholas , Bedlack, Richard S , Walk, David , Wang, Jianing , Kolb, Stephen J. , Szymanski, April L., Martin, Alan, Liao, Bing, Arneklev, JinAe, Malcolm, Amber, Feldman, Eva L. , Statland, Jeffrey , Dimachkie, Mazen M. , Ghasemi, Mehdi , Houmani, Hajar, Pasinelli, Piera , Milliard, Jourdan, Gutmann, Ludwig , Harms, Matthew, Diaz, Frank , Shrilla, David, Rakočević, Goran , Li, Xiaoyan , Quinn, Colin , Borg, David, Bhuvaneswaran, Karthikeyan, Kaur, Jasdeep, Rutkove, Seward B. , Rao, Pooja, Mullen, Jeffrey, Robbins, Nathaniel M. , Granit, Volkan , Oskarsson, Björn , McNeely, Whitney, Bobenhouse, James, Arroyave, Luisa, Changkuon, Genevive, Cirino, Melissa, Deignan, Cristina, Deirmendjian, Emma, Estes, Michaela, Figueroa-Szostek, Precious, Garozzo, Tessa, Henrique, Jennifer, Henrique, Natalie, Hurwitz, Samuel, Irwin, Liam, Kolvek, Taylor, Korin, Alexander, Li, Haining, Nguyen, Joey, Ostrow, Joe, Palillo, Jack, Patel, Payal , Proueng, Serena, Rosenthal, Jesse, Small, Catherine, Thomas, Mirna, Santiago, Diana De, Felix, Adrian, Garrett, Karly, Khan, Kamran, Nelson, Linda, Rede, Diana, Bolger, Patrick, Fetouh, Ahmed, Woodcook, Joan, Kennedy, Julie, Berry, James D. , Macklin, Eric A. , Chibnik, Lori Beth , McGlothlin, Anna , Shefner, Jeremy M. , Giacomelli, Elisa , Goutman, Stephen A. , Fernandes, J. Americo, Vu, Tuan , Newman, Daniel S., Ladha, Shafeeq , Caress, James B. , Swenson, Andrea , Peltier, Amanda , Elliott, Matthew, Johnson, Kristin, Cohen, Jeffrey Allen , Greenberg, Benjamin , Paganoni, Sabrina , Cudkowicz, Merit

JAMA | February 17, 2025 | Volume: 333 | Issue: 13 | Pages: 1138

10.1001/jama.2024.27643 | PMID 40067821 Get It

Importance Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD + , resulting in an increase of cellular adenosine triphosphate production. Objective To determine the effects of CNM-Au8 on ALS disease progression. Design, Setting, and Participants CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses. Interventions Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks. Main Outcomes and Measures The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation. Results Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]). Conclusions and Relevance No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks. Trial Registration ClinicalTrials.gov Identifiers: NCT04297683 , NCT04414345
Polygenic risk score calibration and association with breast cancer in diverse ancestries.
Kucera, Matthew, Hughes, Elisha , Mabey, Brent, Hullinger, Brooke, Gordon, Ora, Klemp, Jennifer R. , Pruthi, Sandhya , Whitworth, Pat W. , Slavin, Thomas P., Gutin, Alexander , Pederson, Holly J. , Pal, Tuya , Domchek, Susan M. , Eng, Charis , Garber, Judy E. , Mukherjee, Semanti , Vijai, Joseph , Kurian, Allison W. , Lanchbury, Jerry S. , Olopade, Olufunmilayo I.

Journal of Clinical Oncology | June 4, 2023 | Volume: 41 | Issue: 16_suppl | Pages: 10505-10505

10.1200/jco.2023.41.16_suppl.10505 Get It

10505 Background: Polygenic risk scores (PRS) have been shown to substantially improve breast cancer (BC) risk prediction when incorporated into traditional risk assessment models. However, PRS developed primarily in women of European ancestry have shown poor performance when applied to non-European populations. We previously described development and validation of a multiple-ancestry PRS (MA-PRS) that is based on individual ancestral genetic composition. MA-PRS has been incorporated into the Tyrer-Cuzick model for use in clinical practice and has been shown to provide independent value to the model. Here, we describe performance of the MA-PRS in a large cohort of women from diverse ancestral backgrounds. Methods: The study cohort included 203,586 patients who were referred for hereditary cancer testing and negative for pathogenic variants in genes associated with BC. MA-PRS was calculated as previously described based on 149 SNPs (93 BC and 56 ancestry-informative). Association of MA-PRS with invasive BC status (affected vs unaffected) was analyzed using logistic regression adjusted for personal and family cancer history, age, and ancestry. Calibration was assessed by examining the MA-PRS distribution within unaffected patients, and through goodness-of-fit tests. All analyses were conducted within the full cohort and within ancestral subpopulations. Odds ratios (ORs) are reported per standard deviation. Results: One-fifth (43,782/203,586, 21.5%) of patients were diagnosed with invasive BC, and 60,657 (29.8%) of patients reported BC in a first degree relative. The MA-PRS distribution was centered around zero among unaffected patients overall and within each subpopulation. MA-PRS significantly improved BC risk prediction over clinical factors in the full cohort (OR = 1.43, 95% CI:1.41-1.44) and within each ancestral subpopulation (Table). The strongest associations were observed in Ashkenazi Jewish (OR = 1.56, 95% CI:1.39-1.76) and South Asian (OR = 1.49,95% CI: 1.23-1.81) populations. The top decile of the MA-PRS consistently identified patients with two-fold increased risk of developing BC. Goodness-of-fit tests showed that the MA-PRS was well calibrated and predicted BC risk accurately in the tails of the distribution for both European and non-European women. Conclusions: The breast cancer MA-PRS based on genetic ancestral composition is well-calibrated and strongly associated with BC in all tested ancestral populations. Incorporation of PRS adds independent information to risk models and supports equitable access to personalized BC risk management. [Table: see text]
Abstract PD14-05: PD14-05 Prospective longitudinal validation of a breast cancer risk prediction model in a cohort of 130,058 women
Mabey, Brent, Hughes, Elisha , Probst, Braden , Simmons, Timothy , Hullinger, Brooke, Gary, Monique, Klemp, Jennifer R. , Offit, Kenneth , Pruthi, Sandhya , Whitworth, Pat, Wagner, Susanne , Slavin, Thomas P. , Gutin, Alexander , Pederson, Holly J. , Morris, Brian, Domchek, Susan M. , Eng, Charis , Mukherjee, Semanti , Vijai, Joseph , Olopade, Olufunmilayo I. , Kurian, Allison W. , Robson, Mark E. , Lanchbury, Jerry S.

Cancer Research | March 2, 2023 | Volume: 83 | Issue: 5_Supplement | Pages: PD14-05-PD14-05

10.1158/1538-7445.sabcs22-pd14-05 Get It

Abstract Background: Personalized breast cancer (BC) risk assessment depends on known traditional risk factors, specific germline mutations, and genome-wide polygenic risk scores (PRS). PRS explains a substantial proportion of genetic BC susceptibility. Accuracy of BC risk prediction may be improved by combining a PRS with traditional risk factors. We recently developed and validated a 149-SNP PRS for women of diverse ancestries using ancestry-informative genetic markers and combined this with version 7 of the Tyrer-Cuzick (TC) model to generate a Combined Risk Score (CRS). Here, we describe a pre-specified prospective longitudinal clinical validation of CRS as a predictor of BC risk. Methods: Women in the U.S. who were referred for clinical genetic testing between January 2017 and February 2019 were matched to medical and hospital claims in an anonymized dataset. Women with a pathogenic mutation in a BC-related gene were excluded from analysis. Follow-up began 4 months after testing and extended to the earliest date of BC diagnosis, censoring at the time of BC preventive treatment, or November 1, 2019. Incident BC events were determined by an ICD10 code of C50.* and confirmed by relevant treatment codes. CRS calibration was evaluated by the ratio of observed (O) to expected (E) incident BCs for the full cohort, and for women split into event-based 5-year CRS risk deciles. Cox proportional hazards models were used to evaluate discriminatory accuracy in terms of hazard ratios (HR) with 95% confidence intervals (CI) and p-values from likelihood ratio chi-squared statistics. Kaplan-Meier analysis was used to examine risk for women split into high- or low-risk groups according to a 3% 5-year CRS risk threshold. Results: 130,058 women with 148,349 total patient years met study eligibility criteria and were matched to claims data. Over a median (range) follow-up of 12.1 (4.0-29.5) months, 340 incident BC events were observed. The CRS was well calibrated in the overall cohort with an O/E ratio of 1.11 (95% CI=0.99-1.23) and within deciles of predicted risk (Table). Importantly, in the highest risk decile, the O/E was 0.91 (95% CI=0.63-1.27) with CRS, but 0.67 (95% CI=0.46-0.94) with TC alone, illustrating the superior calibration of CRS. In a Cox model adjusted for age at testing, PRS had an HR per standard deviation (SD) of 1.48 (95% CI=1.33-1.64, p=2.55×10-13); the HR/SD was 1.43 (95% CI=1.29-1.59, p=1.61×10-11) after adjusting for family history. In a bivariate analysis using both CRS and TC to predict time to BC, CRS added significantly to the model after accounting for TC (HR/SD=2.89, 95% CI=2.12-3.94, p=1.20×10-11), whereas TC did not add significant information after accounting for CRS. 15,986 (12.3%) women were above the CRS high-risk threshold, including 123 with events. A total of 10,248 (7.9%) women were reclassified by the CRS model compared to the TC model. Among women who were classified as high-risk by TC, 32.6% were reclassified as low-risk by CRS; among those classified as low-risk by TC, 4.3% were reclassified as high-risk by CRS. The CRS high-risk group experienced events at over three times the rate of the low-risk group (HR=3.75, 95% CI=3.00-4.68, p=6.39×10-27). Conclusion: The CRS was well-calibrated in predicting BC and significantly improved upon a traditional risk factor model. Clinical use of the CRS may lead to improved BC prevention and screening strategies. Table: Absolute risk calibration by 5-year risk decile Incidence is reported per 1,000 women-years. 34 breast cancers were observed per decile. Citation Format: Brent Mabey, Elisha Hughes, Braden Probst, Holly J. Pederson, Timothy Simmons, Brian Morris, Brooke Hullinger, Susan Domchek, Charis Eng, Monique Gary, Jennifer Klemp, Semanti Mukherjee, Vijai Joseph, Kenneth Offit, Olufunmilayo I. Olopade, Sandhya Pruthi, Allison W. Kurian, Mark E. Robson, Pat Whitworth, Susanne Wagner, Jerry Lanchbury, Thomas Slavin, Alexander Gutin. PD14-05 Prospective longitudinal validation of a breast cancer risk prediction model in a cohort of 130,058 women [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD14-05.
Limited Expansion of Human Hepatocytes in FAH/ RAG2 -Deficient Swine
Nelson, Erek , Larson, Ellen L. , Glorioso, Jaime , Rmilah, Anan Abu , Zhou, Wei , Mounajjed, Taofic, Bois, Melanie C. , Wood, Adam J. , Whitworth, Kristin M. , Wells, Kevin D. , Spate, A. M., Samuel, Melissa , Minshew, Anna, Rinaldo, Piero, Lillegard, Joseph B. , Johnson, Aaron J. , Amiot, Bruce , Platt, Jeffrey L. , Nyberg, Scott L. , Nelson, Erek David , Larson, Ellen, Joo, Dong Jin , Mao, Shennen, Abu Rmilah, Anan, Jia, Yao, Bois, Melanie, Wood, Adam, Johnson, Aaron , Hickey, Raymond , Nyberg, Scott L , Larson, Ellen L , Mao, Shennen A. , Yao, Jia , Shi, Min , Jin, Fang , Walters, Eric M. , Johnson, Aaron J. , Prather, Randall S.

Tissue Engineering Part A | July 26, 2021 | Volume: 28 | Issue: 3-4 | Pages: 150-160

10.1089/ten.tea.2021.0057 | PMID 34309416 Get It

The mammalian liver's regenerative ability has led researchers to engineer animals as incubators for expansion of human hepatocytes. The expansion properties of human hepatocytes in immunodeficient mice are well known. However, little has been reported about larger animals that are more scalable and practical for clinical purposes. Therefore, we engineered immunodeficient swine to support expansion of human hepatocytes and identify barriers to their clinical application. Immunodeficient swine were engineered by knockout of the recombinase-activating gene 2 ( RAG2 ) and fumarylacetoacetate hydrolase (FAH). Immature human hepatocytes (ihHCs) were injected into fetal swine by intrauterine cell transplantation (IUCT) at day 40 of gestation. Human albumin was measured as a marker of engraftment. Cytotoxicity against ihHCs was measured in transplanted piglets and control swine. We initially detected higher levels of human albumin in cord blood of newborn FAH/ RAG2 -deficient (FR) pigs compared with immunocompetent controls (196.26 ng/dL vs. 39.29 ng/dL, p = 0.008), indicating successful engraftment of ihHCs after IUCT and adaptive immunity in the fetus. Although rare hepatocytes staining positive for human albumin were observed, levels of human albumin did not rise after birth, but declined, suggesting rejection of xenografted ihHCs. Cytotoxicity against ihHCs increased after birth by 3.8% (95% CI: [2.1%–5.4%], p < 0.001) and inversely correlated with declining levels of human albumin ( p = 2.1 × 10 −5 , R 2 = 0.17). Circulating numbers of T cells and B cells were negligible in FR pigs. However, circulating natural killer (NK) cells exerted cytotoxicity against ihHCs. NK cell activity was lower in immunodeficient piglets after IUCT than in naive controls (30.4% vs. 40.1%, p = 0.011, 95% CI for difference [2.7%–16.7%]). In conclusion, ihHCs were successfully engrafted in FR swine after IUCT. NK cells were a significant barrier to expansion of hepatocytes. New approaches are needed to overcome this hurdle and allow large-scale expansion of human hepatocytes in immunodeficient swine. Impact statement There is currently a need for robust expansion of human hepatocytes. We describe an immunodeficient swine model into which we engrafted immature human hepatocytes (ihHCs). We identified the mechanism of the eventual graft rejection by the intact NK cell population, which has not been previously shown to have a significant role in xenograft rejection. By both improving engraftment and reducing NK cell-mediated cytotoxicity toward the graft through intrauterine cell transfer, we confirmed the presence of residual adaptive immunity in this model of immunodeficiency and the ability to induce hyposensitization in the NK cell population by taking advantage of the fetal microenvironment.
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1
Klionsky, Daniel J., Abdel‐Aziz, Amal Kamal , Abdellatif, Mahmoud , Abdoli, Asghar , Abel, Steffen , Abeliovich, Hagai , Abildgaard, Marie H. , Abudu, Yakubu Princely , Acevedo‐Arozena, Abraham , Adamopoulos, Iannis E. , Adeli, Khosrow , Adolph, Timon E. , Adornetto, Annagrazia , Aflaki, Elma, Agam, Galila , Aggarwal, Bharat B. , Agnello, Maria, Agostinis, Patrizia , Agrewala, Javed N. , Agrotis, Alexander , Aguilar, Patricia V., Ahmad, S. Tariq, Ahumada-Castro, Ulises , Aits, Sonja , Aizawa, Shu, Akkoç, Yunus , Akoumianaki, Tonia, Akpinar, Hafize Aysin , Al‐Abd, Ahmed M. , Al-Akra, Lina, Gharaibeh, Abeer , Alaoui‐Jamali, Moulay A. , Alberti, Simon , Alessandri, Cristiano , Alonso, Alicia , Altan‐Bonnet, Nihal , Álvarez, Élida, Alves, Sara , Costa, Cristine Alvès da , Alzaharna, Mazen M. , Amadio, Marialaura , Amantini, Consuelo , Amaral, Cristina , Ambrosio, Susanna , Amer, Amal O. , Ammanathan, Veena , An, Zhenyi, Andrabi, Shaida A. , Andres, Allen M. , Ann, David K. , Anozie, Uche C. , Ansari, Mohammad Y. , Antas, Pedro , Antebi, Adam , Antón, Zuriñe , Anwar, Tahira , Apétoh, Lionel , Araki, Toshiyuki , Araki, Yasuhiro , Araya, Jun , Arévalo, María‐Ángeles , Argüelles, Sandro , Arias, Esperanza , Arikkath, Jyothi , Ariosa, Aileen, Aroca, Ángeles , Arroyo, Daniela S., Arsov, Ivica, Artero, Rubén , Asaro, Dalia Maria Lucia, Ashur‐Fabian, Osnat , Atanasov, Atanas G. , Au, Alicia K. , Auberger, Patrick , Auner, Holger W. , Aurelian, Laure , Avagliano, Laura , Ávalos, Yenniffer , Aveleira, Célia A. , Aydın, Yücel , Ayyadevara, Srinivas , Azzopardi, Maria , Baba, Misuzu, Backer, Jonathan , Bae, Soo Han , Baehrecke, Eric H. , Bagetta, Giacinto , Bagniewska‐Zadworna, Agnieszka , Bai, Hua , Bai, Xiyuan , Bairagi, Nandadulal , Baksi, Shounak , Balbi, Teresa , Ballester, María , Balazadeh, Salma , Balzan, Rena , Bandopadhyay, Rina , Banerjee, Sulagna , Bánréti, Ágnes , Baracca, Alessandra , Barbati, Cristiana , Bargiela, Ariadna , Barilà, Daniela , Barlow, Peter G. , Barmada, Sami J. , Barreiro, Esther , Bártek, Jiří , Bartel, Bonnie , Bartolomé, Alberto , Barve, Gaurav , Bassham, Diane C. , Baulieu, E.E. , Baumgarner, Bradley L. , Bayry, Jagadeesh , Beale, Rupert , Beau, Isabelle , Beaumatin, Florian , Bechara, Luiz Roberto Grassmann , Beck, George R. , Beers, Michael F. , Begun, Jakob , Behrends, Christian , Bejarano, Eloy , Bel, Shai , Belaïd, Amine , Belgareh‐Touzé, Naïma, Bellarosa, Cristina , Belleudi, Francesca , Belló-Pérez, Melissa , Beltran, Jackeline Soares de Oliveira , Beltran, Sebastián, Benbrook, Doris M. , Bendorius, Mykolas , Benítez, Bruno A. , Benito‐Cuesta, Irene , Bensalem, Julien , Berchtold, Martin W. , Berezowska, Sabina , Bergamaschi, Daniele , Berliocchi, Laura , Berlioz‐Torrent, Clarisse , Bernard, Amélie , Besirli, Cagri G. , Besteiro, Sébastien , Betin, Virginie M.S., Beyaert, Rudi , Bezbradica, Jelena S. , Bhaskar, Kiran , Bhatia‐Kiššová, Ingrid, Bhattacharya, Sujoy , Bhuiyan, Md. Shenuarin , Bi, Xiaolin , Biden, Trevor J. , Bijian, Krikor , Billes, Viktor , Binart, Nadine , Bincoletto, Cláudia , Blanco, Gonzalo , Blas‐García, Ana , Błasiak, Janusz , Blomgran, Robert , Blum, Janice S. , Boada-Romero, Emilio, Boban, Mirta , Boeuf, Philippe , Boland, Barry , Bomont, Pascale , Bonaldo, Paolo , Bonam, Srinivasa Reddy , Bonfili, Laura , Bootman, Martin D. , Bordi, Matteo , Borner, Christoph , Bornhäuser, Beat , Bose, Santanu , Botas, Juan , Boulanger, Chantal M. , Bourgeois, Benjamin , Bourke, Nollaig M. , Bousquet, Guilhem , Boya, Patricia , Bozhkov, Peter V. , Bozi, Luiz H. M. , Bozkurt, Tolga O. , Pedro, José Manuel Bravo‐San , Brest, Patrick , Bringer, Marie-Agnès , Briones‐Herrera, Alfredo , Broaddus, V. Courtney, Brodersen, Peter , Brodsky, Jeffrey L. , Bronson, Paola G. , Bronstein, Jeff M. , Brown, Rhoderick E. , Brum, Patrı́cia C. , Bruno, Daniele , Bryson‐Richardson, Robert J. , Bucci, Cecilia , Buchrieser, Carmen , Bueno, Marta , Buchan, J. Ross , Buckingham, Erin M., Budak, Hikmet , Budini, Mauricio , Bultynck, Geert , Burada, Florin , Burgoyne, Joseph R. , Burón, María I. , Bustos, Victor , Büttner, Sabrina , Byrd, Aaron , Cabas, Isabel , Cabrera, Sandra , Cadwell, Ken , Cai, Jingjing , Cai, Lu , Cai, Qian , Calbet, José A. L. , Caldwell, Guy A. , Call, Jarrod A. , Calvani, Riccardo , Calvo, Ana Cristina , Calvo‐Rubio, Miguel , Câmara, Niels Olsen Saraiva , Camonis, Jacques , Camougrand, Nadine , Campanella, Michelangelo , Campbell, Edward M. , Campos, Juliane C. , Camuzard, Olivier , Cancino, Jorge , Caniggia, Isabella , Canonico, Barbara , Cantı́, Carles , Cao, Bin , Caramés, B. , Cardenal‐Muñoz, Elena , Cárdenas, César , Cárdenas, Luis , Cardoso, Sandra M. , Carew, Jennifer S. , Carle, Georges F. , Carleton, Gillian , Carloni, Silvia , Carneiro, Letícia A. M. , Carosi, Julian M. , Carra, Serena , Carrier, Alice , Carter, A. Brent, Carvalho, Andreia Neves , Casanova, Magali , Casas, Josefina , Cassioli, Chiara , Castillo, Karen , Castillo‐Lluva, Sonia , Castoldi, Francesca , Castori, Marco , Castro, Ariel F. , Castro‐Hernández, Javier , Cavadas, Cláudia , Cavaliere, Federica, Cavallini, Gabriella , Cavinato, Maria , Rica, Paula Cebollada , Cechowska‐Pasko, Marzanna , Cerqueira, João , Cerutti, Janete M. , Çetintaş, Vildan Bozok , Cetrullo, Silvia , Chagin, Andrei S. , Chai, Chee‐Yin , Chakrabarti, Gopal , Chakraborty, Tapas , Chakraborty, Trinad , Chami, Mounia , Chamilos, Georgios , Chan, David W. , Chan, Edmond Y. W., Chan, Ho Yin Edwin , Chan, Helen H., Chan, Hung , Chan, Matthew T.V. , Chan, Yau Sang , Chang, Hao‐Chun , Chang, Kai , Chao, Jie , Charlet‐Berguerand, Nicolas , Chatterjee, Samrat , Chaube, Shail K. , Chaudhary, Anu , Chauhan, Santosh , Chaum, Edward , Checler, Frédéric , Cheetham, Michael E. , Chen, Chang‐Shi , Chen, Jian‐Fu , Chen, Liam L., Chen, Mingliang , Chen, Mu‐Kuan , Chen, Ning , Chen, Wei , Chen, Xinming , Chen, Xiongwen , Chen, Yan , Chen, Ye‐Guang , Chen, Yingyu , Chen, Yongqiang , Chen, Zhefan Stephen , Chen, Zhihua , Cheng, Xiu‐Tang , Cheng, Yiyun , Cheng, Zhiyong , Cheong, Jit Kong , Cherry, Sara , Cheung, Chi F., Cheung, Chun Hei Antonio , Cheung, King‐Ho , Chevet, Éric , Chi, Richard J., Chiaradonna, Ferdinando , Chiariello, M , Chica, Nathalia , Chiocca, Susanna , Chiong, Mario , Chiou, Shih‐Hwa , Chiramel, Abhilash I., Chiurchiù, Valerio , Cho, Dong-Hyung, Choe, Seong‐Kyu , Choi, Augustine M.K. , Choi, Mary E. , Choudhury, Kamalika Roy , Chow, Norman , Chua, Jason P. , Chua, John Jia En , Chung, Hyewon , Chung, Kin Pan , Chung, So‐Hyang , Chung, Yuen-Li, Ciechomska, Iwona A. , Cinque, Laura , Çırak, Sebahattin , Clarke, Robert , Clementi, Emilio , Coccia, Eliana M. , Codogno, Patrice , Colasanti, Tania , Colasuonno, Fiorella , Colbert, Robert A. , Colell, Anna , Coll, Núria S. , Collins, Mark O. , Colombo, Marı́a I. , Colón‐Ramos, Daniel A. , Cominetti, Márcia R. , Consiglio, Antonella , Conte, A. , Contu, Viorica Raluca , Cookson, Mark , Coombs, Kevin M. , Costa, Maria do Carmo , Costantino, Sarah , Costelli, Paola , Criollo, Alfredo , Crippa, V. , Cristofani, Riccardo , Csizmadia, Tamás , Cui, Bing , Cui, Yixian , Culetto, Emmanuel , Cumino, Andrea C. , Cybulsky, Andrey V. , Czaja, Mark J. , Czuczwar, Stanisław J. , D’Adamo, Stefania , D’Amelio, Marcello , D’Orazi, Gabriella , Silva, James Almada da , Dafsari, Hormos Salimi , Daglia, Maria , Dai, Xiaoxia , Dai, Yun , Dai, Yuyuan , Col, Jessica Dal , Dalhaimer, Paul , Valle, Luisa Dalla , Dallenga, Tobias , Dalmasso, Guillaume , Dando, Ilaria , Das, Hiranmoy , Dasari, Santosh K. , Dash, Srikanta, Dauphinee, Adrian N. , Davies, Jeffrey S. , Dávila, Valeria A. , Davis, Roger J. , Naidu, Sharadha Dayalan , Bosscher, Karolien De , Leonibus, Chiara De , Barbosa, Mayara Garcia de Mattos , Meyer, Guido R.Y. De , Palma, Clara De , Virgilio, Claudio De , Zio, Daniela De , Decuypere, Jean-Paul , Deehan, Mark , Deflorian, Gianluca , Dehay, Benjamin , Delaney, Joe R. , Delorme‐Axford, Elizabeth , Demers, Nicholas D. , Deng, Hongbin , Dengjel, Jörn , Dent, Paul, DePamphilis, Melvin L., Descoteaux, Albert , Devis, Laura , Devkota, Sushil , Devuyst, Olivier , Dewson, Grant , Dharmasivam, Mahendiran , Domenico, Fabio Di , Fazio, Pietro Di , Fonzo, Alessio Di , Guardo, Giovanni Di , Guglielmo, Gianni M. Di , Leo, Luca Di , Malta, Chiara Di , Nardo, Alessia Di, Rienzo, Martina Di , Diao, Jiajie , Diaz-Araya, Guillermo, Díaz‐Laviada, Inés , Dickinson, Jared M. , Diederich, Marc , Dieudé, Mélanie , Ding, Shiping , Ding, Wen-Xing, Dinić, Jelena , Dinić, Miroslav , Dinkova‐Kostova, Albena T. , Distler, Jörg H. W. , Đokić, Jelena , Emre, Serap , Dong, Xiaonan , Dong, Zhiwu , Dorn, Gerald W. , Dou, Juan, Dowaidar, Moataz , Drucker, Liat , Du, Ailian , Du, Guangwei , Du, Hai‐Ning , Toit, André du , Duan, Shao-Bin , Duan, Xiaoqiong , Duarte, Sónia , Dupont, Nicolas , Durán, Raúl V. , Dyshlovoy, Sergey A. , Ebrahimi‐Fakhari, Darius , Eckhart, Leopold , Edelstein, Charles L. , Efferth, Thomas , Eid, Nabil , Eisenberg, Tobias , Eissa, N. Tony, Ejarque, Miriam , Andaloussi, Abdeljabar El, El‐Hage, Nazira , Eleuteri, Anna Maria , El‐Shafey, Eman S. , Elgendy, Mohamed , Elizalde, María Mercedes , Elsässer, Hans‐Peter , Elsherbiny, Eslam S. , Emre, N. C. Tolga , Eng, Christina H. , Engedal, Nikolai , Engelsen, Agnete S. T. , Enserink, Jorrit M. , Escalante, Ricardo , Esclatine, Audrey , Eskelinen, Eeva‐Liisa , Espert, Lucile , Eusebio, Makandjou-Ola , Facchiano, Antonio , Facchiano, Francesco , Fadeel, Bengt , Fader, Claudio M., Faesen, Alex C. , Fairlie, W. 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Fielding , Henkel, Vanessa, Herb, Marc , Herman-Antosiewicz, Anna , Hernández, Agustín , Hernández, Carlos , Hernández-Díaz, Sergio , Hernández–Gea, Virginia , Herpin, Amaury , Herreros, Judit , Hervás, Javier H. , Hesselson, Daniel , Hetz, Claudio , Higuchi, Yujiro , Hilfiker, Sabine , Hill, Joseph A., Ho, Emmanuel A. , Ho, Idy H. T. , Ho, Philip Wing‐Lok , Ho, Shu‐Leong , Ho, Wan Yun, Hoet, Peter , Hofius, Daniel , Höhn, Annika , Hong, Yi-Ren Hong Chang-Won, Hooper, Lora V. , Hsin, I‐Lun , Hu, Bing , Hu, Dong , Hu, Wei , Hu, Zhuowei , Hua, Jinlian, Huan, Chongmin , Huang, Chuanshu , Huang, Chunling , Huang, Haishan , Huang, Michael , Huang, Shan , Huang, Tianzhi , Huang, Xing , Huang, Yuxiang , Hubert, Virginie , Hübner, Christian A. , Hughes, Stephanie M. , Hughes, William E. , Hummer, Gerhard , Hurley, James H. , Hussain, Sabah N. 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Razaul , Kato, Masaru , Kauppinen, Anu , Kaushal, Gur P. , Kawasaki, Kiyoshi, Kazan, Kemal , Keber, Ursula , Keller, Kate E. , Kenific, Candia M. , Kepp, Oliver , Kern, Andreas , Keulers, Tom G. , Khalfin, Boris , Khalil, Hany , Khan, Shahid Y. , Khandelwal, Vinoth Kumar Megraj, Khandia, Rekha , Kho, Widuri , Khobrekar, Noopur V. , Khuansuwan, Sataree , Khundadze, Mukhran , Killackey, Samuel A. , Kim, Dasol , Kim, Deok Ryong, Kim, Do‐Hyung , Kim, Dong‐Eun , Kim, Eun‐Kyoung , Kim, Hak-Rim, Kim, Hee-Sik , Kim, Hyung-Ryong, Kim, Jeong Hun , Kim, Joungmok , Kim, Seong‐Jun , Kimball, Scot R., Kimchi, Adi , Kimmelman, Alec , Kimura, Tomonori , King, Matthew, Kinsey, Conan G. , Kirshenbaum, Lorrie A. , Kishi, Shuji , Kitamoto, Katsuhiko , Kitaoka, Yasushi , Kitazato, Kaio, Kitsis, Richard N. , Kjærulff, Ole , Klein, Peter S. , Klopstock, Thomas , Klucken, Jochen , Knævelsrud, Helene , Ko, Fred , Kobayashi, Satoru, Koch, Ina , Koch, Jan Christoph , Kögel, Donat , Koh, Young Ho , Kocatürk, Nur Mehpare , Komatsu, Masaaki, König, Jeannette , Kono, Toru, Korkmaz, Gözde , Korsnes, Mónica Suárez , Koskela, Ali , Kota, Janaiah , Kotake, Yaichiro , Kotler, Monica L., Kou, Yanjun , Koukourakis, Michael I., Koustas, Evangelos , Kovács, Tibor , Kovács, Tibor, Kraft, Claudine , Krainc, Dimitri, Krämer, Helmut, Krasnodembskaya, Anna , Kretz‐Remy, Carole , Kroemer, Guido, Kuenen, Sabine , Kuerschner, Lars , Kukar, Thomas , Kumar, Ajay , Kumar, Deepak, Kumar, Dhiraj, Kumar, Sharad , Kume, Shinji , Kumsta, Caroline , Kundu, Chanakya Nath , Kundu, Mondira, Kunnumakkara, Ajaikumar B. , Kutlu, Özlem , Kwak, SeongAe , Kwon, Yong Tae , Spada, Albert La, Labonté, Patrick , Ladoire, Sylvain , Laface, Ilaria, Lafont, Frank , Lagace, Diane C. , Lahiri, Vikramjit , Lai, Zhibing, Laird, Angela S. , Lakkaraju, Aparna , Lan, Sheng‐Hui , Landajuela, Ane , Lane, Darius J.R. , Lange, Carsten , Langer, Rupert , Lapaquette, Pierre, Laporte, Jocelyn , Lastres-Becker, Isabel, Lau, Wilson Chun Yu , Laurie, Gordon W. , Le, Weidong, Stunff, Hervé Le , Leary, Alexandre Y , Lebrun, Jean-Jacques, Leck, Lionel , Lee, Changwook , Lee, Chung‐Pei , Lee, Da-Hye , Lee, Edward B., Lee, Erinna F. , Lee, Gyun Min, Lee, He-Jin, Lee, Heung Kyu , Lee, Jason S. , Lee, Jin-A, Lee, Joo‐Yong , Lee, Michael , Lee, Min Goo , Lee, Min Jae, Lee, Myung‐Shik , Lee, Sangyoon , Lee, Stella Y. , Lee, Sung, Lee, Won Hee , Lee, Yong‐ho , Lee, Youngil , Lei, Yu L., Lei, Yuchen , Leikin, Sergey , Lemus, Leticia , Leng, Shuilong, Lenoir, Olivia , Lenz, Guido , Lenz, Heinz Josef, Lenzi, Paola, León, Yolanda , Leschczyk, Christoph, Leskelä, Stina, Letellier, Elisabeth , Leung, Chi-Ting, Leung, Po Sing , Leventhal, Jeremy S. , Levine, Beth, Lewis, Patrick A. , Ley, Klaus , Li, Bin , Li, Da‐Qiang , Li, Jian‐Ming , Li, Jiong , Li, Liwu , Li, Mei , Li, Ming , Li, Mingchuan , Li, Pin‐Lan, Li, Ming‐Qing , Li, Qing , Li, Sheng , Li, Wei , Li, Wenming , Li, Xue , Li, Yi-Ping, Li, Yuan , Li, Zhiqiang, Li, Zhiyong , Li, Zhiyuan , Lian, Jiqin, Liang, Chengyu, Liang, Qiangrong, Liang, Weicheng , Liang, Yongheng, Liang, YongTian , Liao, Guanghong , Liao, Lujian , Liao, Yung-Feng, Librizzi, Mariangela, Lie, Pearl P.Y. , Lim, Hyunjung J., Lima, Thania Rios Rossi , Limana, Federica , Lin, Chao , Lin, Chih-Wen, Lin, Dar‐Shong , Lin, Fu‐Cheng , Lin, Jiandie D. , Lin, Kurt M., Lin, Kwang‐Huei , Lin, Qiong, Lin, Shaofeng , Lin, Su-Ju, Lin, Wenyu , Lin, Yao‐Xin , Lin, Yee‐Shin, Linden, Rafael, Lindner, Paula , Lipinski, Marta M. , Lipovšek, Saška, Lisiak, Natalia , Liton, Paloma B. , Liu, Chao , Liu, Ching‐Hsuan , Liu, Fang , Liu, Hua-feng , Liu, Huifang , Liu, Jia , Liu, Jing , Liu, Leyuan, Liu, Wei , Liu, Wende , Liu, Xiao-Hong, Liu, Xu , Liu, Yanfen , Liu, Yang, Liu, Yang, Liu, Yueyang , Liu, Yule , Livingston, J. 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H. , Ma, Ning-Fang, Ma, Quanhong , Ma, Xinliang , Ma, Yueyun , Ma, Zhenyi , MacDougald, Ormond A. , MacIntosh, Gustavo C. , Macleod, Kay F. , Maday, Sandra , Madeo, Frank , Madesh, Muniswamy , Madl, Tobias , Madrigal‐Matute, Julio , Maeda, Akiko, Maejima, Yasuhiro , Magariños, Marta , Mahavadi, Poornima , Maiani, Emiliano , Maiese, Kenneth , Maiti, Panchanan , Maiuri, Maria Chiara , Major, Michael Ben, Makareeva, Elena , Malik, Fayaz , Mallilankaraman, Karthik , Maloyan, Alina , Mammadova, Najiba, Man, Gene Chi Wai , Manai, Federico , Mancias, Joseph D. , Mandelkow, Eva‐Maria , Manfredi, Angelo A. , Manshian, Bella B. , Manzano, Raquel , Marchese, Chiara , Marchetti, Sandrine , Marcucci, F, Mardente, Stefania , Mareninova, Olga A. , Mari, Muriel , Marinelli, Sara , Mariño, Guillermo , Mariotto, Sofia , Martin, Alexandre , Martin, Katie R. , Martin, Sara L. , Martín‐Segura, Adrián , Martin-Burriel, Inmaculada, Martín-Rincón, Marcos , Martín‐Sanz, Paloma , Martinez, Aitor , Martı́nez, Ana , Martinez-Lopez, Nuria, Martínez‐Vicente, Marta , Martins, Daniel Oliveira , Martins, Joilson O. , Martins, Waleska K. , Martins-Marques, Tania, Marzetti, Emanuele , Masaldan, Shashank , Masclaux-Daubresse, Celine, Mashek, Douglas G. , Massa, Valentina , Massieu, Lourdes , Masyuk, Anatoliy I. , Masyuk, Tetyana V., Matheu, Ander , Matoba, Satoaki , Matsuzaki, Sachiko , Mattar, Pamela , Mattè, Alessandro , Mauriz, José L., Mauthe, Mario , Maycotte, Paola , Mayer, Johanna , Mazzoni, Cristina , Mazzulli, Joseph R. , McCarty, Nami , McGill, Mitchell R. , McKenna, Sharon L. , McLoughlin, Fionn , McNiven, Mark A., McWilliams, Thomas G. , Medeiros, Tania , Medina, Diego L., Megeney, Lynn A. , Megyeri, Klára , Mehrpour, Maryam , Mehta, Jawahar L. , Meijer, Alfred J., Mejlvang, Jakob , Meléndez, Alicia , Melk, Annette, Memişoğlu, Gönen , Mendes, A.F. , Meng, Delong , Meng, Fei, Mercier, A., Mergny, Jean‐Louis , Merkley, Seth D. , Meske, Volker, Mestre, Ana Cecilia, Metur, Shree Padma, Meyer, C., Meyer, Hemmo , Mi, Wenyi , Mialet‐Perez, Jeanne , Miao, Jun‐Ying, Micale, Lucia , Miki, Yasuo, Milan, Enrico , Milczarek, Małgorzata , Miller, Samuel I. , Millward, Steven W. , Mirzaei, Hamed, Mirzaei, Hamid Reza , Mirzaei, Mehdi , Mishra, Amit , Mishra, Nandita , Mishra, Paras Kumar, Misirkić, Maja , Misasi, Roberta, Misra, Amit , Misso, Gabriella , Mitchell, Claire H. , Mitou, Géraldine, Miura, Tetsuji , Miyazaki, Makoto, Miyazaki, Mitsunori , Miyazaki, Taiga , Miyazawa, Keisuke, Mizushima, Noboru , Mogensen, Trine H. , Mohammadinejad, Reza , Mohamud, Yasir , Mohanty, Abhishek , Möhlmann, Torsten , Moley, Kelle H. , Möller, Andreas, Mollereau, Bertrand , Mollinedo, Faustino, Montagna, Costanza , Monteiro, Mervyn J. , Montella, Andrea , Montes, L. Ruth , Montico, Barbara , Mony, Vinod K., Compagnoni, Giacomo Monzio , Moore, Michael N. , Moosavi, Mohammad Amin , Morales‐Álamo, David , Moratalla, Rosario , Moreira, Paula I. , Morelli, Elena , Moreno-Blas, Daniel , Morgan, Alwena H. , Morin, Fabrice , Morishita, Hideaki , Moriyama, Mariko , Moriyasu, Yuji, Morleo, Manuela , Morselli, Eugenia , Moruno-Manchon, Jose F. , Moscat, Jorge , Motori, Elisa , Moura, Andréa Felinto , Mrakovcic, Maria, Muciño-Hernández, Gabriel, Mukherjee, Anupam , Mukhopadhyay, Subhadip , Levy, Jean M. Mulcahy , Mulero, Victoriano, Muller, Sylviane, Münch, Christian , Muñoz-Cánoves, Pura, Muñoz‐Galdeano, Teresa , Murakawa, Tomokazu , Murphy, Brona M. , Murthy, Aditya, Myöhänen, Timo T. , Mysorekar, Indira U. , Mytych, Jennifer , Nabavi, Seyed Mohammad , Nagy, Péter , Nahimana, Aimable , Nakagawa, Ichiro, Nakamura, Ken , Nandi, Shyam Sundar , Nanjundan, Meera, Nanni, Monica , Napolitano, Gennaro , Narita, Masashi, Nassif, Melissa , Nathan, Ilana , Natsumeda, Manabu , Naudé, Ryno J., Naumann, Christin , Naveiras, Olaia , Navid, Fatemeh , Nawrocki, Steffan T., Nazarko, Taras Y. , Nazio, Francesca , Negoita, Florentina , Neill, Thomas , Neisch, Amanda L. , Netea, Mihai G. , Neubert, Patrick , Neumann, Dietbert , Neutzner, Albert , Newton, Phillip T. , Ney, Paul A., Ng, Charlene Cheuk Wing, Ng, T.B., Nguyen, Hang Thi Thu , Nguyen, Long T. , Ni, Hong-Min, Cheallaigh, Clíona Ní , Ni, Zhenhong , Nicolao, M. Celeste, Nicoli, Francesco , Nieto‐Díaz, Manuel , Niranjan, Rituraj , Nishimune, Hiroshi , Niso-Santano, Mireia, Nixon, Ralph A. , Nobili, Annalisa , Noda, Takeshi , Nogueira-Recalde, Uxía , Nombela, Iván , Novak, Ivana, Novoa, Beatriz , Nukina, Nobuyuki , Nussbaum-Krammer, Carmen, Nylandsted, Jesper , O’Donovan, Tracey R. , O’Leary, Seónadh M. , O’Rourke, Eyleen J. , O’Sullivan, Mary P. , O’Sullivan, Timothy E., Oddo, Salvatore , Oehme, Ina, Ogawa, Michinaga , Ogier‐Denis, Éric , Ögmundsdóttir, Margrét H. , Öğretmen, Besim , Oh, Goo Taeg , Oh, Seon‐Hee , Oh, Young J. , Ohama, Takashi, Ohashi, Yohei , Ohmuraya, Masaki, Oikonomou, Vasileios , Ojha, Rani , Okazawa, Hitoshi , Oku, M., Oliván, Sara , Oliveira, Jorge M.A. , Ollmann, Michael, Olzmann, James A. , Omari, Shakib , Önal, Gizem, Ondrej, Martin , Ong, Sang‐Bing , Onnis, Anna , Orellana, Juan , Orellana‐Muñoz, Sara , Ortega-Villaizán, María del Mar , Ortiz‐González, Xilma R. , Osiewacz, Heinz D. , Osman, Abdel‐Hamid K. , Otsu, Kinya, Ott, Christiane , Ou, Jing-hsiung James, Outeiro, Tiago F., Öztürk, Melek , Pagès, Gilles, Pahari, Susanta , Pajares, Marta, Pal, Rituraj, Paladino, Simona , Palmieri, Michela , Palmisano, Giuseppe , Pan, Qingjun , Pan, Xin , Panasyuk, Ganna , Pandey, Rahul , Pandey, Udai B., Pandya, Vrajesh , Paneni, Francesco , Pang, Shirley Yin-Yu, Papademetrio, Daniela L. , Papinski, Daniel, Papp, Diana , Park, Hwan Tae , Park, Ji-Man, Park, Jong‐In , Park, Junsoo, Park, Sang-Youel, Pasquier, Adrien , Pasquier, Benoit , Passos, João F. , Pastore, Nunzia , Patschan, Daniel , Pattingre, Sophie , Pedraza‐Alva, Gustavo , Pedraza-Chaverri, Jose, Pedrozo, Zully , Pei, Gang , Pei, Jianming , Peled-Zehavi, Hadas, Pellegrini, Joaquín Miguel , Pelletier, Joffrey , Peñalva, Miguel A., Peng, Di , Peng, Ying , Pennuto, Maria , Pentimalli, Francesca , Pereira, Cláudia MF, Pereira, Gustavo J.S. , Pereira, Lílian Cristina , Almeida, Luís Pereira de , Perera, Nirma D. , Pérez-Lara, Ángel, Pérez‐Oliva, Ana B. , Perl, András , Pestell, Richard G. , Petrache, I., Petrovski, Goran , Pfirrmann, Thorsten , Pfister, Astrid S., Pi, Huifeng , Pickrell, Alicia M. , Picot, Sandy, Pierantoni, Giovanna Maria , Pierre, Philippe , Pierrefite‐Carle, Valérie , Pierzynowska, Karolina , Pietruczuk, Mirosława , Pimentel-Muiños, Felipe X., Pinar, Mario , Pinheiro, Roberta Olmo , Pinkas‐Kramarski, Ronit , Pircs, Karolina , Piya, Sujan , Pizzo, Paola , Platta, Harald W. , Plomann, Markus , Pocock, Roger , Pöggeler, Stefanie , Pohl, Christian, Poirot, Marc , Poletti, Angelo , Ponpuak, Marisa , Popelka, Hana , Popova, Bilyana , Porta, Helena, Alcón, Soledad Porte , Portilla-Fernández, Eliana , Potts, Malia B. , Powers, Ted, Prahlad, Veena , Prajsnar, Tomasz K. , Praticò, Domenico , Prencipe, Rosaria, Priault, Muriel , Proikas‐Cezanne, Tassula , Puertollano, Rosa , Puglielli, Luigi, Pulinilkunnil, Thomas , Puri, Deepika , Puri, Rajat, Puyal, Julien , Qi, Yongmei , Quadrilatero, Joe , Quarleri, Jorge, Raben, Nina, Rabinowich, Hannah, Ragona, Debora, Rahmati, Marveh , Raia, Valeria, Raimundo, Nuno , Rajasekaran, Namakkal-Soorappan, Rao, Sriganesh Ramachandra , Rami, Abdelhaq, Ramírez‐Pardo, Ignacio , Ramsden, D. , Randow, Felix , Ranieri, Danilo , Rao, Hai , Rao, Rekha , Rathore, Sumit , Ratnayaka, J. Arjuna , Ratovitski, Edward A., Ravanan, Palaniyandi, Ravegnini, Gloria , Ray, Swapan K. , Rebecca, Vito, Reggiori, Fulvio , Reigada, David , Reiling, Jan H., Rein, Theo , Reipert, Siegfried , Rekha, Rokeya Sultana , Ren, Hongmei, Ren, Jun , Ren, Weichao , Renault, Tristan, Renga, Giorgia , Reue, Karen, Rewitz, Kim , Ramos, Bruna Ribeiro de Andrade , Riazuddin, S. Amer, Ribeiro‐Rodrigues, Teresa , Riccio, Victoria , Richardson, Des R. , Risbud, Makarand V. , Risueño, Ruth M. , Ritis, Konstantinos, Rizza, Salvatore , Rizzuto, Rosario , Roberts, Scott J. , Roberts, Luke D., Robinson, Katherine J. , Rocchi, Stéphane , Rodrigues, Tiago , Silva, Vagner Ramon Rodrigues , Rodriguez-Barrueco, Ruth, Rodríguez‐Henche, Nieves , Rogers, Robert S. , Rogov, Vladimir V., Rojo, Ana I. , Romanello, Vanina, Romani, Luigina , Romano, Alessandra , Romano, Patricia Silvia , Romeo-Guitart, David, Romero, Luís C. , Romero, Montserrat , Roney, Joseph C. , Rongo, Christopher , Rosenfeldt, Mathias T. , Rosenstiel, Philip , Rosenwald, Anne , Roth, Steven, Rouschop, Kasper M.A. , Roussel, Benoit D. , Roux, Sophie , Rovere–Querini, Patrizia, Roy, Ajit , Rozières, Aurore , Ruano, Diego , Rubtsova, Maria P. , Ruckdeschel, Klaus, Ruckenstuhl, Christoph , Rudolf, Emil, Rudolf, Rüdiger, Ruggieri, Alessandra , Ruparelia, Avnika A. , Rusmini, P. , Russell, Ryan R., Russo, Gian Luigi , Russo, Maria , Russo, Rossella , Ryabaya, O. O. , Sabater-Arcis, María , Sacher, M, Sachse, Carsten , Sadhu, Abhishek , Säftig, Paul , Sahebkar, Amirhossein, Şahin, Mustafa , Şahin, Özgür , Saito, Nayuta , Saito, Tsunenori , Sakai, Yasuyoshi , Sakamaki, Jun-Ichi , Saksela, Kalle , Salazar, Gloria , Salazar-Degracia, Anna, Salekdeh, Ghasem Hosseini , Saluja, Ashok K. , Sampaio‐Marques, Belém , Sánchez, Marı́a C. , Sánchez-Alcázar, José A., Sanchez‐Vera, Victoria , Sancho‐Shimizu, Vanessa , Santambrogio, Laura , Santana, Magda M., Santoni, G, Sanz, Alberto , Saran, Shweta , Sardiello, Marco, Sargeant, Timothy J. , Sarin, Apurva , Sarkar, Chinmoy, Sarkar, Sovan , Sarrias, Maria-Rosa, Sarkar, Surajit , Sarmah, Dipanka Tanu, Sarparanta, J. , Sathyanarayan, Aishwarya , Ranganayaki, S. , Scaglione, K. Matthew , Scatozza, Francesca , Schafer, Zachary T. , Schaible, Ulrich E., Schapira, Anthony H.V. , Scharl, Michael , Schein, Catherine H. , Schiaffino, Maria Vittoria , Schiappacassi, Mónica , Schindl, Rainer , Schlattner, Uwe , Schmidt, Oliver, Schmitt, Roland , Schmidt, Stephen D., Schmitz, Ingo , Schmukler, Eran, Schneider, Anja , Schneider, Bianca E. , Schober, Romana , Schoijet, Alejandra C. , Schramm, M., Schröder, Bernd , Schuh, Kai , Schüller, Christoph , Schulze, Ryan J. , Schürmanns, Lea , Schwamborn, Jens C. , Schwarten, Melanie , Scott, Melanie J. , Scotto, Kathleen W., Scrima, Andrea , Scrivo, Aurora , Sebastián, David , Sebti, Salwa , Sedej, Simon , Segev, Nava , Seglen, Per O., Selleck, Scott B. , Selsby, Joshua, Sendtner, Michael , Şentürk, Şerif , Seranova, Elena, Sergi, Consolato M., Serra-Moreno, Ruth , Sesaki, Hiromi , Settembre, Carmine, Setty, Subba Rao Gangi , Sgarbi, Gianluca , Sha, Ou , Shacka, John J., Shah, Javeed A. , Shang, Dantong, Shao, Feng, Sharbati, Soroush , Sharkey, Lisa M. , Sharma, Dipali , Sharma, Gaurav, Sharma, Kulbhushan , Sharma, Pawan , Sharma, Surendra, Shen, Han‐Ming , Shen, Hongtao , Shen, Jiangang , Shen, Ming , Shen, Weili , Shen, Zheni, Sheng, Rui , Sheng, Zu-Hang, Shi, Jianjian , Shi, Ying–Hong , Shiba‐Fukushima, Kahori, Shieh, Jeng‐Jer , Shimada, Yohta , Shimizu, Shigeomi, Shimozawa, Makoto , Shintani, Takahiro , Shoemaker, Christopher J. , Shojaei, Shahla, Shoji, Ikuo , Shravage, Bhupendra V. , Shridhar, Viji, Shu, Chih‐Wen , Shu, Hong-Bing, Shui, Ke, Shukla, Arvind Kumar , Shutt, Timothy E. , Sica, Valentina , Siddiqui, Aleem , Sierra-Torre, Virginia, Signorelli, Santiago , Silva, Bruno Jorge de Andrade , Silva, Johnatas D. , Silva-Pavez, Eduardo , Silvente‐Poirot, Sandrine , Simmonds, Rachel E. , Singh, Anurag K. , Singh, Rajat Kumar , Singh, Shivendra V. , Singh, Shrawan Kumar , Singh, Sudha , Singh, Sunaina , Singh, Surinder Pal , Sinha, Debasish, Sinha, Rohit A. , Sinha, Sangita, Sirko, Agnieszka , Sivridis, Efthimios L., Skendros, Panagiotis , Sohn, Eun Jung , Sok, Sophia P. 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David , Sze, Stephen Cho Wing , Szewczyk, Nathaniel J. , Tabęcka-Łonczynska, Anna, Tabolacci, Claudio , Taegtmeyer, Heinrich, Tagaya, Mitsuo , Tai, Haoran , Tait, Stephen W. G., Takahashi, Yoshinori , Tam, Chit , Tam, Shing Yau , Tampellini, Davide , Tamura, Atsushi , Tan, Eng-King, Tan, Ya‐Qin , Tanaka, Masaki , Tang, Daolin , Tang, Jingfeng , Tang, Tie-Shan , Tao, Zhipeng , Taouis, Mohammed , Tavernarakis, Nektarios, Taylor, Allen, Teixeira, Natércia , Tekirdağ, Kumsal Ayşe, Tencomnao, Tewin , Tenreiro, Sandra , Tharaux, Pierre‐Louis , Thedieck, Kathrin , Thekkinghat, Arvind A. , Thinwa, Josephine , Thirumalaikumar, Venkatesh P. , Thomes, Paul G. , Thorburn, Andrew , Thum, Thomas, Thumm, Michael , Tian, Ling, Tichý, Aleš , Timmerman, Vincent , Titorenko, Vladimir I. , Toivonen, Janne M. , Tomaipitinca, Luana , Tomar, Dhanendra , Tomás‐Zapico, Cristina , Tomić, Sergej , Tong, Chao, Tong, Xin , Torgersen, Maria L., Torii, Satoru , Torres-López, Liliana , Torriglia, Alicia , Towers, Christina G. , Towns, Roberto, Tran, Quynh‐Giao , Travassos, Leonardo H. , Tremel, Shirley , Trougakos, Ioannis P., Tsao, Betty P. , Tse, Tak Fu, Tsvetkov, Andrey S. , Tumbarello, David A. , Tyler, Jessica K., Tyutereva, Elena V. , Uchiyama, Yasuo , Ugun‐Klusek, Aslihan , Uhlig, Holm H. , Ułamek-Kozioł, Marzena, Ulasov, Ilya V. , Umekawa, Midori, Ungermann, Christian , Urbe, Sylvie, Uribe-Carretero, Elisabet , Uversky, Vladimir N. , Vaccaro, María I. , Vahsen, Björn F. , Vakifahmetoglu-Norberg, Helin, Valdor, Rut , Valente, Maria João , Valko, Ayelén , Vallée, Richard, Valverde, Ángela M. , Berghe, Greet Van den, Veen, Stijn van der , Kaer, Luc Van , Loosdregt, Jorg van , Wijk, Sjoerd J. L. van , Vandenberghe, Wim , Vanhorebeek, Ilse , Vannier-Santos, Marcos A., Vannini, Nicola , Vanrell, M. Cristina, Vantaggiato, Chiara , Varela‐Nieto, Isabel , Varga, Máté , Vasconcelos, M. Helena , Vats, Somya , Vega-Rubín-de-Celis, Silvia , Velasco, Guillermo , Velázquez, Ariadna P., Vellai, Tibor , Vellenga, Edo , Verdier, Mireille , Verginis, Panayotis , Vergne, Isabelle , Verkade, Paul , Verma, Manish , Verstreken, Patrik , Vervliet, Tim , Vervoorts, Jörg , Víctor, Víctor M., Vidoni, Chiara , Vieira, Otília V. , Vierstra, Richard D., Viganò, Sonia , Vihinen, Helena , Vijayan, Vinoy, Vila, Miquel , Villalba, José M., Villalobo, Antonio , Villarejo‐Zori, Beatriz , Vincent, Olivier , Vindis, Cécile , Viret, Christophe , Vocadlo, David J. , Voitsekhovskaja, Olga V. , Volonté, Cinzia , Volta, Mattia , Vomero, Marta , Haefen, Clarissa von, Vooijs, Marc , Voos, Wolfgang , Vučićević, Ljubica , Waguri, Satoshi , Waite, Kenrick A., Wakatsuki, Shuji , Walker, David W., Walker, Mark J. , Walter, Jochen, Wandosell, Francisco , Wang, Bo , Wang, Chao-Yung, Wang, Chen , Wang, Chenran, Wang, Chenwei , Wang, Cun-Yu, Wang, Fengming, Wang, Han, Wang, Hexiang , Wang, Hong‐Gang , Wang, Jianrong, Wang, Jigang , Wang, Jun-Dong , Wang, Kui , Wang, Lianrong, Wang, Liming , Wang, Maggie Haitian, Wang, Meiqing , Wang, Nanbu , Wang, Pengwei , Wang, Ping , Wang, Ping, Wang, Q., Wang, Qiong , Wang, Wentao , Wang, Xinnan, Wang, Xuejun , Wang, Yan, Wang, Yanchang , Wang, Yanzhuang , Wang, Yihua , Wang, Yu , Wang, Yuqi , Wang, Zhe, Wang, Zhenyu , Wang, Zhouguang , Watanabe, Eizo, Watchon, Maxinne , Wawrzyńska, Anna , Weaver, Timothy E., Węgrzyn, Grzegorz, Wehman, Ann M. , Wei, Huafeng , Wei, Taotao , Wei, Yongjie, Weiergräber, Oliver H. , Weihl, Conrad C., Weindl, Günther , Weiskirchen, Ralf , Wen, Runxia H. , Werner, Antonia, Weykopf, Beatrice , Whitton, J. 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N. , Bei, Roberto , Behl, Christian , Bello‐Morales, Raquel , Beltrán, Sebastián , Bergami, Matteo , Bergmann, Andreas , Berthoux, Lionel , Bhattacharya, Resham , Bhattacharyya, Shalmoli , Bhutia, Sujit Kumar , Bi, Lanrong , Birgisdottir, Åsa Birna , Bjørkøy, Geir , Blomgren, Klas , Boada-Romero, Emilio , Boesze‐Battaglia, Kathleen , Bonifacino, Juan S. , Boone, Brian A. , Borthakur, Gautam , Bosch, Jürgen , Bose, Santanu , Botana, Luis Miguel , Boulton, Michael E. , Bourdenx, Mathieu , Brackney, Doug E. , Brandts, Christian , Braun, Ralf J. , Braus, Gerhard H. , Bravo, Roberto , Brody, Steven L. , Brown, Carolyn Nicole , Brumell, John Hunter , Brunetti‐Pierri, Nicola , Buitrago‐Molina, Laura Elisa , Buraschi, Simone , Buch, Shilpa J. , Butturini, Elena , Cairó, Montserrat , Caldwell, Kim A. , Campbell‐Valois, François‐Xavier , Campello, Silvia , Campesi, Ilaria , Almeida, Danilo Cândido de , Canesi, Laura , Caraglia, Michele , Carchman, Evie H. , Carmona‐Gutiérrez, Didac , Carnevali, Oliana , Carrier, Lucie , Carroll, Bernadette , Carter, A. Brent , Casas, Caty , Castillo, Eliseo F. , Castro‐Caldas, Margarida , Castro‐Obregón, Susana , Catz, Sergio , Cayuela, María Luisa , Cecarini, Valentina , Cecconi, Francesco , Cenci, Simone , Ceperuelo‐Mallafré, Victòria , Cervia, Davide , Chae, Han–Jung , Chakrabarti, Oishee , Chan, Edmond Y. 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Autophagy | March 24, 2021 | Volume: 17 | Issue: 1 | Pages: 1-382

10.1080/15548627.2020.1797280 | PMID 33634751 Get It

Cancer Risks Associated With GermlinePALB2Pathogenic Variants: An International Study of 524 Families
Yang, Xin , Doroszuk, Alicja, Schneider, Sandra , Allen, Jamie , Decker, Brennan , Redman, James , Scarth, James A. , Plaskocinska, Inga, Luccarini, Craig , Shah, Mitul , Pooley, Karen A. , Dorling, Leila , Lee, Andrew , Adank, Muriel A. , Aittomäki, Kristiina, Andrulis, Irene L. , Ang, Peter , Bernstein, Jonine L. , Bobolis, Kristie, Borg, Åke , Blomqvist, Carl , Claes, Kathleen , Cuggia, Adeline , Culver, Julie O. , Damiola, Francesca , Pauw, Antoine De , Dolinsky, Jill S. , Engel, Christoph , Evans, D. Gareth , Goode, Ellen L. , Gruber, Stephen B., Hahnen, Eric , Hake, Christopher R., Heikkinen, Tuomas , Hurley, Judith , Janavičius, Ramūnas , Kleibl, Zdeněk , Kleiblová, Petra , Konstantopoulou, Irene , Kvist, Anders , LaDuca, Holly , Lee, Ann S. G. , Lesueur, Fabienne , Mannermaa, Arto, Manoukian, Siranoush , McFarland, Rachel, McKinnon, Wendy, Meindl, Alfons , Metcalfe, Kelly , Taib, Nur Aishah Mohd , Moilanen, Jukka S. , Nathanson, Katherine L. , Ng, Pei Sze , Nguyen‐Dumont, Tú , Nielsen, Sarah M. , Obermair, Florian , Offit, Kenneth, Olopade, Olufunmilayo I. , Ottini, Laura , Penkert, Judith , Pylkäs, Katri , Ramus, Susan J. , Rudaitis, Vilius , Side, Lucy, Silva‐Smith, Rachel , Silvestri, Valentina , Skytte, Anne‐Bine , Slavin, Thomas, Soukupová, Jana , Trainer, Alison H., Unzeitig, Gary, Usha, Lydia , Hansen, Thomas van Overeem , Whitworth, James , Wood, Marie , Yip, Cheng Har , Yoon, Sook‐Yee , Yussuf, Amal , Zogopoulos, George , Goldgar, David E. , Chenevix‐Trench, Georgia , George, Sophia , Houdayer, Claude , James, Paul A. , El-Haffaf, Zaki, Ehrencrona, Hans , Janatová, Markéta , Peterlongo, Paolo , Nevanlinna, Heli, Schmutzler, Rita K., Teo, Soo‐Hwang , Weitzel, Jeffrey N. , Elliott, Aaron , Winqvist, Robert , Easton, Douglas F. , Antoniou, Antonis C. , Houdayer, Claude , James, Paul , Lesueur, Fabienne , Peterlongo, Paolo , Ramus, Susan J , Teo, Soo H , Weitzel, Jeffrey N , Claes, Kathleen B M , Ehrencrona, Hans , Evans, D Gareth , Konstantopoulou, Irene , Olopade, Olufunmilayo I , Silvestri, Valentina , Nathanson, Katherine L , Engel, Christoph , Nguyen-Dumont, Tu , Chenevix-Trench, Georgia , Ottini, Laura , Metcalfe, Kelly A , Pylkäs, Katri , Janatova, Marketa , Soukupova, Jana , Hansen, Thomas van Overeem , Kleibl, Zdenek , Manoukian, Siranoush , Mohd Taib, Nur Aishah , Decker, Brennan , Leslie, Goska , Dunning, Alison M. , Adlard, Julian , Barwell, Julian , CONCANNON, PATRICK J. , Dı́ez, Orland , Domchek, Susan M. , Fostira, Florentia , Garber, Judy E. , Golmard, Lisa , Maher, Eamonn R. , Mannermaa, Arto, Meindl, Alfons , Neuhausen, Susan L. , Radice, Paolo , Slavin, Thomas P. , Tondini, Carlo Alberto , Hopper, John L. , Pharoah, Paul D.P. , Balmañà, Judith , El-Haffaf, Zaki, Nevanlinna, Heli , Robson, Mark E. , Pal, Tuya , Couch, Fergus J. , Southey, Melissa C. , Foulkes, William D. , Tischkowitz, Marc D.

Journal of Clinical Oncology | December 16, 2019 | Volume: 38 | Issue: 7 | Pages: 674-685

10.1200/jco.19.01907 | PMID 31841383 Get It

PURPOSETo estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized.METHODSWe analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes.RESULTSWe found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10−76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10−3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10−3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10−2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( P for trend = 2.0 × 10−3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer.CONCLUSIONThese results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.
Clinical Trial in Progress: The FLEX Big Data Platform explores new gene expression profiles and investigator-initiated protocols in early-stage breast cancer.
Untch, Sarah, Srkalović, Gordan , Brufsky, Adam , Crozier, Jennifer A. , Habibi, Mehran , Whitworth, Pat W. , Cox, Charles E., D’Abreo, Nina , Audeh, William , Yoder, Erin , Grady, Ian , Brufsky, Adam M

Journal of Clinical Oncology | May 27, 2019 | Volume: 37 | Issue: 15_suppl | Pages: TPS3155-TPS3155

10.1200/jco.2019.37.15_suppl.tps3155 Get It

TPS3155 Background: Genomic signatures are revolutionizing the definition, identification, and treatment of breast cancer. To precisely stratify breast cancers into actionable subgroups, full genome expression data and matching clinical data must be aggregated into a large data set. Such a data set will accelerate research and discovery, especially for smaller patient subsets who are not as widely represented within the current body of literature. Methods: FLEX is a multicenter, prospective, population-based, observational trial for patients with Stage I, II, and III breast cancer. All patients with stage I to III breast cancer who receive MammaPrint, with or without BluePrint on a primary breast tumor are eligible for enrollment. The study’s primary aim is to create a large scale, population-based registry of full genome expression data matched with clinical data to investigate new gene associations with prognostic and/or predictive value. Secondary objectives include utilizing the shared study infrastructure to examine and generate hypotheses for targeted subset analyses and/or trials based on full genome expression data. The design of FLEX allows targeted sub-studies and sub-analyses to be added as appendices after the initial baseline study is opened. Patients enrolled in the initial study are also eligible for inclusion in sub-studies where they meet all criteria and additional consent is not required. Additional clinical data will be collected as specified in the appendix protocols. The FLEX collaborative platform allows participating investigators the opportunity to author their own sub-study protocols, as approved by the FLEX Steering Committee of their peers. 13 sub-studies have already been identified and are under development. Eligibility: The study will enroll a minimum of 10000 patients aged ≥18 years with histologically proven invasive stage I-III breast cancer who signed informed consent. Enrollment began April 2017 and 1506 patients have been enrolled. Clinical trial information: NCT03053193.