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1. Effect of the P-Selectin Inhibitor Crizanlizumab on Survival Free of Organ Support in Patients Hospitalized for COVID-19: A Randomized Controlled Trial.

Author

Solomon, Scott, Lowenstein, Charles, Bhatt, Ankeet, Peikert, Alexander, Vardeny, Orly, Kosiborod, Mikhail, Berger, Jeffrey, Reynolds, Harmony, Mavromichalis, Stephanie, Barytol, Anya, Althouse, Andrew, Luther, James, Leifer, Eric, Kindzelski, Andrei, Cushman, Mary, Gong, Michelle, Khatri, Pooja, Kim, Keri, Baumann Kreuziger, Lisa, Wahid, Lana, Kirwan, Bridget-Anne, Geraci, Mark, Neal, Matthew, Hochman, Judith, and Kornblith, Lucy

Subjects
COVID-19, P-selectin, crizanlizumab, Humans, COVID-19, SARS-CoV-2, P-Selectin, Endothelial Cells, Treatment Outcome
Abstract

BACKGROUND: COVID-19 has been associated with endothelial injury, resultant microvascular inflammation and thrombosis. Activated endothelial cells release and express P-selectin and von Willebrand factor, both of which are elevated in severe COVID-19 and may be implicated in the disease pathophysiology. We hypothesized that crizanlizumab, a humanized monoclonal antibody to P-selectin, would reduce morbidity and death in patients hospitalized for COVID-19. METHODS: An international, adaptive, randomized controlled platform trial, funded by the National Heart, Lung, and Blood Institute, randomly assigned 422 patients hospitalized with COVID-19 with moderate or severe illness to receive either a single infusion of the P-selectin inhibitor crizanlizumab (at a dose of 5 mg/kg) plus standard of care or standard of care alone in an open-label 1:1 ratio. The primary outcome was organ support-free days, evaluated on an ordinal scale consisting of the number of days alive free of organ support through the first 21 days after trial entry. RESULTS: The study was stopped for futility by the data safety monitoring committee. Among 421 randomized patients with known 21-day outcomes, 163 patients (77%) randomized to the crizanlizumab plus standard-of-care arm did not require any respiratory or cardiovascular organ support compared with 169 (80%) in the standard-of-care-alone arm. The adjusted odds ratio for the effect of crizanlizumab on organ support-free days was 0.70 (95% CI, 0.43-1.16), where an odds ratio >1 indicates treatment benefit, yielding a posterior probability of futility (odds ratio 1] = 0.879). CONCLUSIONS: Crizanlizumab, a P-selectin inhibitor, did not result in improvement in organ support-free days in patients hospitalized with COVID-19. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04505774.

Published
2023

2. A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels

Author

Abe, Namiko, Abecasis, Gonçalo, Aguet, Francois, Albert, Christine, Almasy, Laura, Alonso, Alvaro, Ament, Seth, Anderson, Peter, Anugu, Pramod, Applebaum-Bowden, Deborah, Ardlie, Kristin, Arking, Dan, Arnett, Donna K, Ashley-Koch, Allison, Aslibekyan, Stella, Assimes, Tim, Auer, Paul, Avramopoulos, Dimitrios, Ayas, Najib, Balasubramanian, Adithya, Barnard, John, Barnes, Kathleen, Barr, R. Graham, Barron-Casella, Emily, Barwick, Lucas, Beaty, Terri, Beck, Gerald, Becker, Diane, Becker, Lewis, Beer, Rebecca, Beitelshees, Amber, Benjamin, Emelia, Benos, Takis, Bezerra, Marcos, Bielak, Larry, Bis, Joshua, Blackwell, Thomas, Blangero, John, Blue, Nathan, Boerwinkle, Eric, Bowden, Donald W., Bowler, Russell, Brody, Jennifer, Broeckel, Ulrich, Broome, Jai, Brown, Deborah, Bunting, Karen, Burchard, Esteban, Bustamante, Carlos, Buth, Erin, Cade, Brian, Cardwell, Jonathan, Carey, Vincent, Carrier, Julie, Carson, April P., Carty, Cara, Casaburi, Richard, Casas Romero, Juan P, Casella, James, Castaldi, Peter, Chaffin, Mark, Chang, Christy, Chang, Yi-Cheng, Chasman, Daniel, Chavan, Sameer, Chen, Bo-Juen, Chen, Wei-Min, Ida Chen, Yii-Der, Cho, Michael, Choi, Seung Hoan, Chuang, Lee-Ming, Chung, Mina, Chung, Ren-Hua, Clish, Clary, Comhair, Suzy, Conomos, Matthew, Cornell, Elaine, Correa, Adolfo, Crandall, Carolyn, Crapo, James, Cupples, L. Adrienne, Curran, Joanne, Curtis, Jeffrey, Custer, Brian, Damcott, Coleen, Darbar, Dawood, David, Sean, Davis, Colleen, Daya, Michelle, de Andrade, Mariza, de las Fuentes, Lisa, de Vries, Paul, DeBaun, Michael, Deka, Ranjan, DeMeo, Dawn, Devine, Scott, Dinh, Huyen, Doddapaneni, Harsha, Duan, Qing, Dugan-Perez, Shannon, Duggirala, Ravi, Durda, Jon Peter, Dutcher, Susan K., Eaton, Charles, Ekunwe, Lynette, El Boueiz, Adel, Ellinor, Patrick, Emery, Leslie, Erzurum, Serpil, Farber, Charles, Farek, Jesse, Fingerlin, Tasha, Flickinger, Matthew, Fornage, Myriam, Franceschini, Nora, Frazar, Chris, Fu, Mao, Fullerton, Stephanie M., Fulton, Lucinda, Gabriel, Stacey, Gan, Weiniu, Gao, Shanshan, Gao, Yan, Gass, Margery, Geiger, Heather, Gelb, Bruce, Geraci, Mark, Germer, Soren, Gerszten, Robert, Ghosh, Auyon, Gibbs, Richard, Gignoux, Chris, Gladwin, Mark, Glahn, David, Gogarten, Stephanie, Gong, Da-Wei, Goring, Harald, Graw, Sharon, Gray, Kathryn J., Grine, Daniel, Gross, Colin, Gu, C. Charles, Guan, Yue, Guo, Xiuqing, Gupta, Namrata, Haessler, Jeff, Hall, Michael, Han, Yi, Hanly, Patrick, Harris, Daniel, Hawley, Nicola L., He, Jiang, Heavner, Ben, Heckbert, Susan, Hernandez, Ryan, Herrington, David, Hersh, Craig, Hidalgo, Bertha, Hixson, James, Hobbs, Brian, Hokanson, John, Hong, Elliott, Hoth, Karin, Hsiung, Chao (Agnes), Hu, Jianhong, Hung, Yi-Jen, Huston, Haley, Hwu, Chii Min, Irvin, Marguerite Ryan, Jackson, Rebecca, Jain, Deepti, Jaquish, Cashell, Johnsen, Jill, Johnson, Andrew, Johnson, Craig, Johnston, Rich, Jones, Kimberly, Kang, Hyun Min, Kaplan, Robert, Kardia, Sharon, Kelly, Shannon, Kenny, Eimear, Kessler, Michael, Khan, Alyna, Khan, Ziad, Kim, Wonji, Kimoff, John, Kinney, Greg, Konkle, Barbara, Kooperberg, Charles, Kramer, Holly, Lange, Christoph, Lange, Ethan, Lange, Leslie, Laurie, Cathy, Laurie, Cecelia, LeBoff, Meryl, Lee, Jiwon, Lee, Sandra, Lee, Wen-Jane, LeFaive, Jonathon, Levine, David, Levy, Dan, Lewis, Joshua, Li, Xiaohui, Li, Yun, Lin, Henry, Lin, Honghuang, Lin, Xihong, Liu, Simin, Liu, Yongmei, Liu, Yu, Loos, Ruth J. F., Lubitz, Steven, Lunetta, Kathryn, Luo, James, Magalang, Ulysses, Mahaney, Michael, Make, Barry, Manichaikul, Ani, Manning, Alisa, Manson, JoAnn, Martin, Lisa, Marton, Melissa, Mathai, Susan, Mathias, Rasika, May, Susanne, McArdle, Patrick, McDonald, Merry-Lynn, McFarland, Sean, McGarvey, Stephen, McGoldrick, Daniel, McHugh, Caitlin, McNeil, Becky, Mei, Hao, Meigs, James, Menon, Vipin, Mestroni, Luisa, Metcalf, Ginger, Meyers, Deborah A, Mignot, Emmanuel, Mikulla, Julie, Min, Nancy, Minear, Mollie, Minster, Ryan L, Mitchell, Braxton D., Moll, Matt, Momin, Zeineen, Montasser, May E., Montgomery, Courtney, Muzny, Donna, Mychaleckyj, Josyf C, Nadkarni, Girish, Naik, Rakhi, Naseri, Take, Natarajan, Pradeep, Nekhai, Sergei, Nelson, Sarah C., Neltner, Bonnie, Nessner, Caitlin, Nickerson, Deborah, Nkechinyere, Osuji, North, Kari, O'Connell, Jeff, O'Connor, Tim, Ochs-Balcom, Heather, Okwuonu, Geoffrey, Pack, Allan, Paik, David T., Palmer, Nicholette, Pankow, James, Papanicolaou, George, Parker, Cora, Peloso, Gina, Peralta, Juan Manuel, Perez, Marco, Perry, James, Peters, Ulrike, Peyser, Patricia, Phillips, Lawrence S, Pleiness, Jacob, Pollin, Toni, Post, Wendy, Becker, Julia Powers, Boorgula, Meher Preethi, Preuss, Michael, Psaty, Bruce, Qasba, Pankaj, Qiao, Dandi, Qin, Zhaohui, Rafaels, Nicholas, Raffield, Laura, Rajendran, Mahitha, Ramachandran, Vasan S., Rao, D. C., Rasmussen-Torvik, Laura, Ratan, Aakrosh, Redline, Susan, Reed, Robert, Reeves, Catherine, Regan, Elizabeth, Reiner, Alex, Reupena, Muagututi‘a Sefuiva, Rice, Ken, Rich, Stephen, Robillard, Rebecca, Robine, Nicolas, Roden, Dan, Roselli, Carolina, Rotter, Jerome, Ruczinski, Ingo, Runnels, Alexi, Russell, Pamela, Ruuska, Sarah, Ryan, Kathleen, Sabino, Ester Cerdeira, Saleheen, Danish, Salimi, Shabnam, Salvi, Sejal, Salzberg, Steven, Sandow, Kevin, Sankaran, Vijay G., Santibanez, Jireh, Schwander, Karen, Schwartz, David, Sciurba, Frank, Seidman, Christine, Seidman, Jonathan, Sériès, Frédéric, Sheehan, Vivien, Sherman, Stephanie L., Shetty, Amol, Shetty, Aniket, Hui-Heng Sheu, Wayne, Shoemaker, M. Benjamin, Silver, Brian, Silverman, Edwin, Skomro, Robert, Smith, Albert Vernon, Smith, Jennifer, Smith, Josh, Smith, Nicholas, Smith, Tanja, Smoller, Sylvia, Snively, Beverly, Snyder, Michael, Sofer, Tamar, Sotoodehnia, Nona, Stilp, Adrienne M., Storm, Garrett, Streeten, Elizabeth, Su, Jessica Lasky, Sung, Yun Ju, Sylvia, Jody, Szpiro, Adam, Taliun, Daniel, Tang, Hua, Taub, Margaret, Taylor, Kent D., Taylor, Matthew, Taylor, Simeon, Telen, Marilyn, Thornton, Timothy A., Threlkeld, Machiko, Tinker, Lesley, Tirschwell, David, Tishkoff, Sarah, Tiwari, Hemant, Tong, Catherine, Tracy, Russell, Tsai, Michael, Vaidya, Dhananjay, Van Den Berg, David, VandeHaar, Peter, Vrieze, Scott, Walker, Tarik, Wallace, Robert, Walts, Avram, Wang, Fei Fei, Wang, Heming, Wang, Jiongming, Watson, Karol, Watt, Jennifer, Weeks, Daniel E., Weinstock, Joshua, Weir, Bruce, Weiss, Scott T, Weng, Lu-Chen, Wessel, Jennifer, Willer, Cristen, Williams, Kayleen, Williams, L. Keoki, Wilson, Carla, Wilson, James, Winterkorn, Lara, Wong, Quenna, Wu, Joseph, Xu, Huichun, Yanek, Lisa, Yang, Ivana, Yu, Ketian, Zekavat, Seyedeh Maryam, Zhang, Yingze, Zhao, Snow Xueyan, Zhao, Wei, Zhu, Xiaofeng, Ziv, Elad, Zody, Michael, Zoellner, Sebastian, Lindstrom, Sara, Wang, Lu, Smith, Erin N., Gordon, William, van Hylckama Vlieg, Astrid, Brody, Jennifer A., Pattee, Jack W., Haessler, Jeffrey, Brumpton, Ben M., Chasman, Daniel I., Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L., MacDonald, James, Braekkan, Sigrid K., Armasu, Sebastian M., Pankratz, Nathan, Jackson, Rabecca D., Nielsen, Jonas B., Giulianini, Franco, Puurunen, Marja K., Ibrahim, Manal, Heckbert, Susan R., Bammler, Theo K., Frazer, Kelly A., McCauley, Bryan M., Taylor, Kent, Pankow, James S., Reiner, Alexander P., Gabrielsen, Maiken E., Deleuze, Jean-François, O'Donnell, Chris J., Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R., Heit, John A., Psaty, Bruce M., Tang, Weihong, Hveem, Kristian, Ridker, Paul M., Morange, Pierre-Emmanuel, Johnson, Andrew D., Kabrhel, Christopher, AlexandreTrégouët, David, Smith, Nicholas L., de Vries, Paul S., Reventun, Paula, Brown, Michael R., Heath, Adam S., Huffman, Jennifer E., Le, Ngoc-Quynh, Bebo, Allison, Temprano-Sagrera, Gerard, Raffield, Laura M., Ozel, Ayse Bilge, Thibord, Florian, Lewis, Joshua P., Rodriguez, Benjamin A. T., Polasek, Ozren, Yanek, Lisa R., Carrasquilla, German D., Marioni, Riccardo E., Kleber, Marcus E., Trégouët, David-Alexandre, Yao, Jie, Li-Gao, Ruifang, Joshi, Peter K., Trompet, Stella, Martinez-Perez, Angel, Ghanbari, Mohsen, Howard, Tom E., Reiner, Alex P., Arvanitis, Marios, Ryan, Kathleen A., Bartz, Traci M., Rudan, Igor, Faraday, Nauder, Linneberg, Allan, Davies, Gail, Delgado, Graciela E., Klaric, Lucija, Noordam, Raymond, van Rooij, Frank, Curran, Joanne E., Wheeler, Marsha M., Osburn, William O., O'Connell, Jeffrey R., Beswick, Andrew, Kolcic, Ivana, Souto, Juan Carlos, Becker, Lewis C., Hansen, Torben, Doyle, Margaret F., Harris, Sarah E., Moissl, Angela P., Rich, Stephen S., Campbell, Harry, Stott, David J., Soria, Jose Manuel, de Maat, Moniek P. M., Brody, Lawrence C., Auer, Paul L., Ben-Shlomo, Yoav, Hayward, Caroline, Mathias, Rasika A., Kilpeläinen, Tuomas O., Lange, Leslie A., Cox, Simon R., März, Winfried, Rotter, Jerome I., Mook-Kanamori, Dennis O., Wilson, James F., van der Harst, Pim, Jukema, J. Wouter, Ikram, M. Arfan, Desch, Karl C., Sabater-Lleal, Maria, Lowenstein, Charles J., and Morrison, Alanna C.

Published
2024
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4. Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma

Author

Abe, Namiko, Abecasis, Gonçalo, Aguet, Francois, Albert, Christine, Almasy, Laura, Alonso, Alvaro, Ament, Seth, Anderson, Peter, Anugu, Pramod, Applebaum-Bowden, Deborah, Ardlie, Kristin, Arking, Dan, Arnett, Donna K., Ashley-Koch, Allison, Aslibekyan, Stella, Assimes, Tim, Auer, Paul, Avramopoulos, Dimitrios, Ayas, Najib, Balasubramanian, Adithya, Barnard, John, Barnes, Kathleen, Barr, R. Graham, Barron-Casella, Emily, Barwick, Lucas, Beaty, Terri, Beck, Gerald, Becker, Diane, Becker, Lewis, Beer, Rebecca, Beitelshees, Amber, Benjamin, Emelia, Benos, Takis, Bezerra, Marcos, Bielak, Larry, Bis, Joshua, Blackwell, Thomas, Blangero, John, Blue, Nathan, Boerwinkle, Eric, Bowden, Donald W., Bowler, Russell, Brody, Jennifer, Broeckel, Ulrich, Broome, Jai, Brown, Deborah, Bunting, Karen, Burchard, Esteban, Bustamante, Carlos, Buth, Erin, Cade, Brian, Cardwell, Jonathan, Carey, Vincent, Carrier, Julie, Carson, April P., Carty, Cara, Casaburi, Richard, Casas Romero, Juan P., Casella, James, Castaldi, Peter, Chaffin, Mark, Chang, Christy, Chang, Yi-Cheng, Chasman, Daniel, Chavan, Sameer, Chen, Bo-Juen, Chen, Wei-Min, Ida Chen, Yii-Der, Cho, Michael, Choi, Seung Hoan, Chuang, Lee-Ming, Chung, Mina, Chung, Ren-Hua, Clish, Clary, Comhair, Suzy, Conomos, Matthew, Cornell, Elaine, Correa, Adolfo, Crandall, Carolyn, Crapo, James, Cupples, L. Adrienne, Curran, Joanne, Curtis, Jeffrey, Custer, Brian, Damcott, Coleen, Darbar, Dawood, David, Sean, Davis, Colleen, Daya, Michelle, de Andrade, Mariza, de las Fuentes, Lisa, de Vries, Paul, DeBaun, Michael, Deka, Ranjan, DeMeo, Dawn, Devine, Scott, Dinh, Huyen, Doddapaneni, Harsha, Duan, Qing, Dugan-Perez, Shannon, Duggirala, Ravi, Durda, Jon Peter, Dutcher, Susan K., Eaton, Charles, Ekunwe, Lynette, El Boueiz, Adel, Ellinor, Patrick, Emery, Leslie, Erzurum, Serpil, Farber, Charles, Farek, Jesse, Fingerlin, Tasha, Flickinger, Matthew, Fornage, Myriam, Franceschini, Nora, Frazar, Chris, Fu, Mao, Fullerton, Stephanie M., Fulton, Lucinda, Gabriel, Stacey, Gan, Weiniu, Gao, Shanshan, Gao, Yan, Gass, Margery, Geiger, Heather, Gelb, Bruce, Geraci, Mark, Germer, Soren, Gerszten, Robert, Ghosh, Auyon, Gibbs, Richard, Gignoux, Chris, Gladwin, Mark, Glahn, David, Gogarten, Stephanie, Gong, Da-Wei, Goring, Harald, Graw, Sharon, Gray, Kathryn J., Grine, Daniel, Gross, Colin, Gu, C. Charles, Guan, Yue, Guo, Xiuqing, Gupta, Namrata, Haessler, Jeff, Hall, Michael, Han, Yi, Hanly, Patrick, Harris, Daniel, Hawley, Nicola L., He, Jiang, Heavner, Ben, Heckbert, Susan, Hernandez, Ryan, Herrington, David, Hersh, Craig, Hidalgo, Bertha, Hixson, James, Hobbs, Brian, Hokanson, John, Hong, Elliott, Hoth, Karin, Hsiung, Chao (Agnes), Hu, Jianhong, Hung, Yi-Jen, Huston, Haley, Hwu, Chii Min, Irvin, Marguerite Ryan, Jackson, Rebecca, Jain, Deepti, Jaquish, Cashell, Johnsen, Jill, Johnson, Andrew, Johnson, Craig, Johnston, Rich, Jones, Kimberly, Kang, Hyun Min, Kaplan, Robert, Kardia, Sharon, Kelly, Shannon, Kenny, Eimear, Kessler, Michael, Khan, Alyna, Khan, Ziad, Kim, Wonji, Kimoff, John, Kinney, Greg, Konkle, Barbara, Kooperberg, Charles, Kramer, Holly, Lange, Christoph, Lange, Ethan, Lange, Leslie, Laurie, Cathy, Laurie, Cecelia, LeBoff, Meryl, Lee, Jiwon, Lee, Sandra, Lee, Wen-Jane, LeFaive, Jonathon, Levine, David, Levy, Daniel, Lewis, Joshua, Li, Xiaohui, Li, Yun, Lin, Henry, Lin, Honghuang, Lin, Xihong, Liu, Simin, Liu, Yongmei, Liu, Yu, Loos, Ruth J.F., Lubitz, Steven, Lunetta, Kathryn, Luo, James, Magalang, Ulysses, Mahaney, Michael, Make, Barry, Manichaikul, Ani, Manning, Alisa, Manson, JoAnn, Martin, Lisa, Marton, Melissa, Mathai, Susan, Mathias, Rasika, May, Susanne, McArdle, Patrick, McDonald, Merry-Lynn, McFarland, Sean, McGarvey, Stephen, McGoldrick, Daniel, McHugh, Caitlin, McNeil, Becky, Mei, Hao, Meigs, James, Menon, Vipin, Mestroni, Luisa, Metcalf, Ginger, Meyers, Deborah A., Mignot, Emmanuel, Mikulla, Julie, Min, Nancy, Minear, Mollie, Minster, Ryan L., Mitchell, Braxton D., Moll, Matt, Momin, Zeineen, Montasser, May E., Montgomery, Courtney, Muzny, Donna, Mychaleckyj, Josyf C., Nadkarni, Girish, Naik, Rakhi, Naseri, Take, Natarajan, Pradeep, Nekhai, Sergei, Nelson, Sarah C., Neltner, Bonnie, Nessner, Caitlin, Nickerson, Deborah, Nkechinyere, Osuji, North, Kari, O'Connell, Jeff, O'Connor, Tim, Ochs-Balcom, Heather, Okwuonu, Geoffrey, Pack, Allan, Paik, David T., Palmer, Nicholette, Pankow, James, Papanicolaou, George, Parker, Cora, Peloso, Gina, Peralta, Juan Manuel, Perez, Marco, Perry, James, Peters, Ulrike, Peyser, Patricia, Phillips, Lawrence S., Pleiness, Jacob, Pollin, Toni, Post, Wendy, Powers Becker, Julia, Preethi Boorgula, Meher, Preuss, Michael, Psaty, Bruce, Qasba, Pankaj, Qiao, Dandi, Qin, Zhaohui, Rafaels, Nicholas, Raffield, Laura, Rajendran, Mahitha, Ramachandran, Vasan S., Rao, D.C., Rasmussen-Torvik, Laura, Ratan, Aakrosh, Redline, Susan, Reed, Robert, Reeves, Catherine, Regan, Elizabeth, Reiner, Alex, Reupena, Muagututi‘a Sefuiva, Rice, Ken, Rich, Stephen, Robillard, Rebecca, Robine, Nicolas, Roden, Dan, Roselli, Carolina, Rotter, Jerome, Ruczinski, Ingo, Runnels, Alexi, Russell, Pamela, Ruuska, Sarah, Ryan, Kathleen, Sabino, Ester Cerdeira, Saleheen, Danish, Salimi, Shabnam, Salvi, Sejal, Salzberg, Steven, Sandow, Kevin, Sankaran, Vijay G., Santibanez, Jireh, Schwander, Karen, Schwartz, David, Sciurba, Frank, Seidman, Christine, Seidman, Jonathan, Sériès, Frédéric, Sheehan, Vivien, Sherman, Stephanie L., Shetty, Amol, Shetty, Aniket, Sheu, Wayne Hui-Heng, Shoemaker, M. Benjamin, Silver, Brian, Silverman, Edwin, Skomro, Robert, Smith, Albert Vernon, Smith, Jennifer, Smith, Josh, Smith, Nicholas, Smith, Tanja, Smoller, Sylvia, Snively, Beverly, Snyder, Michael, Sofer, Tamar, Sotoodehnia, Nona, Stilp, Adrienne M., Storm, Garrett, Streeten, Elizabeth, Su, Jessica Lasky, Sung, Yun Ju, Sylvia, Jody, Szpiro, Adam, Taliun, Daniel, Tang, Hua, Taub, Margaret, Taylor, Kent, Taylor, Matthew, Taylor, Simeon, Telen, Marilyn, Thornton, Timothy A., Threlkeld, Machiko, Tinker, Lesley, Tirschwell, David, Tishkoff, Sarah, Tiwari, Hemant, Tong, Catherine, Tracy, Russell, Tsai, Michael, Vaidya, Dhananjay, Van Den Berg, David, VandeHaar, Peter, Vrieze, Scott, Walker, Tarik, Wallace, Robert, Walts, Avram, Wang, Fei Fei, Wang, Heming, Wang, Jiongming, Watson, Karol, Watt, Jennifer, Weeks, Daniel E., Weinstock, Joshua, Weir, Bruce, Weiss, Scott T., Weng, Lu-Chen, Wessel, Jennifer, Willer, Cristen, Williams, Kayleen, Williams, L. Keoki, Williams, Scott, Wilson, Carla, Wilson, James, Winterkorn, Lara, Wong, Quenna, Wu, Baojun, Wu, Joseph, Xu, Huichun, Yanek, Lisa, Yang, Ivana, Yu, Ketian, Zekavat, Seyedeh Maryam, Zhang, Yingze, Zhao, Snow Xueyan, Zhao, Wei, Zhu, Xiaofeng, Ziv, Elad, Zody, Michael, Zoellner, Sebastian, Recto, Kathryn, Kachroo, Priyadarshini, Huan, Tianxiao, Lee, Gha Young, Bui, Helena, Lee, Dong Heon, Gereige, Jessica, Yao, Chen, Hwang, Shih-Jen, Joehanes, Roby, O’Connor, George T., and DeMeo, Dawn L.

Published
2023
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5. Transcriptomic profiles in pulmonary arterial hypertension associate with disease severity and identify novel candidate genes.

Author

Romanoski, Casey E, Qi, Xinshuai, Sangam, Shreya, Vanderpool, Rebecca R, Stearman, Robert S, Conklin, Austin, Gonzalez-Garay, Manuel, Rischard, Franz, Ayon, Ramon J, Wang, Jian, Simonson, Tatum, Babicheva, Aleksandra, Shi, Yinan, Tang, Haiyang, Makino, Ayako, Kanthi, Yogendra, Geraci, Mark W, Garcia, Joe GN, Yuan, Jason X-J, and Desai, Ankit A

Subjects
PBMC, RNAseq, pulmonary arterial hypertension, transcriptome profiling, Cardiorespiratory Medicine and Haematology
Abstract

Using RNAseq, we identified a 61 gene-based circulating transcriptomic profile most correlated with four indices of pulmonary arterial hypertension severity. In an independent dataset, 13/61 (21%) genes were differentially expressed in lung tissues of pulmonary arterial hypertension cases versus controls, highlighting potentially novel candidate genes involved in pulmonary arterial hypertension development.

Published
2020

6. Use of targeted therapies for advanced renal cell carcinoma in the Veterans Health Administration

Author

Aspinall, Sherrie L, Zhao, Xinhua, Geraci, Mark C, Good, Chester B, Cunningham, Francesca E, Heron, Bernadette B, Becker, Daniel, Lee, Steve, Prasad, Vinay, Passero, Vida, Shields, Jenna, Stone, Roslyn A, Carico, Ron, Szymanski, John, Taqi, Alyssa, Blauvelt, Amy, Sanderson, Jennifer, Gass, Michael, Minor, Chelsea, LaPlant, Kourtney, Suliman, Iman, Twedt, Elaine, Nelson, Megan, Paul, Betsy, Dowd, Robert, Keefe, Sean, Wenzell, Candice, Horn, Greg, Carroll, Brett, Wenzell, Rob, Panning, David, Kaster, Lindsay, Hunt, Lindsey, Butler, Katerina, Carr, Robert, Kampschmidt, Camille, Nawarskas, Ann, Tonnu‐Mihara, Ivy, Wu, Ni‐Chi, Tseng, Eugene, Banaszynski, Megan, Crawford, Russell, Do, Brian, Crandall, Bailey, Serbas, Lianna, Hammond, Julia, Chillari, Kelly, Tague, Marshall, Stauder, Alison, Crawford, Brooke, Bullington, Susan, Mutziger, Jill, Meier, Joy, Sawyer, Tatiana, Taylor, Janice, and Bena, Jason

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Orphan Drug, Cancer, Clinical Research, Rare Diseases, Kidney Disease, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Aged, Antineoplastic Agents, Carcinoma, Renal Cell, Female, Humans, Indazoles, Kidney Neoplasms, Male, Middle Aged, Molecular Targeted Therapy, Pyrimidines, Retrospective Studies, Sirolimus, Sulfonamides, Sunitinib, Survival Analysis, Treatment Outcome, United States, United States Department of Veterans Affairs, renal cell carcinoma, treatment, Veterans, Targeted Therapies in Veterans with RCC Study Group, Biochemistry and Cell Biology, Oncology and carcinogenesis
Abstract

BackgroundThe objective of this study is to describe the use of targeted therapies for the treatment of advanced renal cell carcinoma (RCC) and overall survival (OS) among patients in clinical practice in the Veterans Health Administration (VHA).MethodsA retrospective cohort of 286 patients from 24 VHA Medical Centers diagnosed with advanced clear cell RCC between Fiscal Year (FY) 2010 and FY2014 was followed through September 30, 2016. Among patients who received targeted therapy, we described the medications taken, duration of therapy, and overall survival. We also assessed the effect of the first therapy received on overall survival using Cox Proportional Hazards models.ResultsThere were 66 patients who did not receive therapy for their advanced RCC. Of the 220 treated patients, the mean (sd) number of medications received was 1.9 (1.1). The medications most commonly used first were sunitinib (61.8%), pazopanib (17.3%), and temsirolimus (10.9%). The median duration of first-line therapy was 86 days (interquartile range [IQR] 42, 210). Median total duration of therapy was 159 days (IQR 58, 397). 62.3% of patients had ≥ 1 dose of therapy held or reduced, mainly due to an adverse drug event (ADE). Median survival from the start of treatment to death was 1.08 years (IQR 0.80, 1.31). Finally, receipt of temsirolimus vs sunitinib (HR 1.95 [95%CI 1.09,3.47]) as the first targeted therapy was independently associated with an increased hazard of death.ConclusionOur analysis of targeted therapies for advanced RCC in VHA suggests duration of treatment is shorter in a real-world setting than in clinical trials, and dose reductions and ADEs are more common.

Published
2019

7. Systems Analysis of the Human Pulmonary Arterial Hypertension Lung Transcriptome

Author

Stearman, Robert S, Bui, Quan M, Speyer, Gil, Handen, Adam, Cornelius, Amber R, Graham, Brian B, Kim, Seungchan, Mickler, Elizabeth A, Tuder, Rubin M, Chan, Stephen Y, and Geraci, Mark W

Subjects
Lung, Rare Diseases, Biotechnology, Cardiovascular, Heart Disease, Genetics, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Adult, Aged, Child, Child, Preschool, Female, Gene Expression Regulation, Gene Ontology, Humans, Infant, Male, Middle Aged, Pulmonary Arterial Hypertension, Sex Characteristics, Signal Transduction, Systems Analysis, Transcriptome, Young Adult, pulmonary arterial hypertension, lung transcriptomics, bioinformatics, Cardiorespiratory Medicine and Haematology, Respiratory System
Abstract

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary artery pressure and vascular resistance, typically leading to right heart failure and death. Current therapies improve quality of life of the patients but have a modest effect on long-term survival. A detailed transcriptomics and systems biology view of the PAH lung is expected to provide new testable hypotheses for exploring novel treatments. We completed transcriptomics analysis of PAH and control lung tissue to develop disease-specific and clinical data/tissue pathology gene expression classifiers from expression datasets. Gene expression data were integrated into pathway analyses. Gene expression microarray data were collected from 58 PAH and 25 control lung tissues. The strength of the dataset and its derived disease classifier was validated using multiple approaches. Pathways and upstream regulators analyses was completed with standard and novel graphical approaches. The PAH lung dataset identified expression patterns specific to PAH subtypes, clinical parameters, and lung pathology variables. Pathway analyses indicate the important global role of TNF and transforming growth factor signaling pathways. In addition, novel upstream regulators and insight into the cellular and innate immune responses driving PAH were identified. Finally, WNT-signaling pathways may be a major determinant underlying the observed sex differences in PAH. This study provides a transcriptional framework for the PAH-diseased lung, supported by previously reported findings, and will be a valuable resource to the PAH research community. Our investigation revealed novel potential targets and pathways amenable to further study in a variety of experimental systems.

Published
2019

8. Training the physician-scientist: views from program directors and aspiring young investigators.

Author

Williams, Christopher, Iness, Audra, Baron, Rebecca, Ajijola, Olujimi, Hu, Patrick, Vyas, Jatin, Baiocchi, Robert, Adami, Alexander, Lever, Jeremie, Klein, Peter, Demer, Linda, Madaio, Michael, Geraci, Mark, Brass, Lawrence, Blanchard, Melvin, Salata, Robert, and Zaidi, Mone

Subjects
Awards and Prizes, Biomedical Research, Career Choice, Charities, Education, Education, Medical, Education, Medical, Graduate, Foundations, Humans, National Institutes of Health (U.S.), Physicians, Research Personnel, Societies, Medical, Students, Medical, Surveys and Questionnaires, Training Support, United States, Workforce
Abstract

There is growing concern that the physician-scientist is endangered due to a leaky training pipeline and prolonged time to scientific independence (1). The NIH Physician-Scientist Workforce Working Group has concluded that as many as 1,000 individuals will need to enter the pipeline each year to sustain the workforce (2). Moreover, surveys of postgraduate training programs document considerable variability in disposition and infrastructure (3). Programs can be broadly grouped into two classes: physician-scientist training programs (PSTPs) that span residency and fellowship training, and research-in-residency programs (RiRs), which are limited to residency but trainees are able to match into PSTPs upon transitioning to fellowship (Figure 1). Funding sources for RiRs and PSTPs are varied and include NIH KL2 and T32 awards, charitable foundations, philanthropy, and institutional support. Furthermore, standards for research training and tools for evaluating programmatic success are lacking. Here, we share consensus generated from iterative workshops hosted by the Alliance of Academic Internal Medicine (AAIM) and the student-led American Physician Scientists Association (APSA).

Published
2018

9. Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease

Author

Hemnes, Anna R., Leopold, Jane A., Radeva, Milena K., Beck, Gerald J., Abidov, Aiden, Aldred, Micheala A., Barnard, John, Rosenzweig, Erika B., Borlaug, Barry A., Chung, Wendy K., Comhair, Suzy A.A., Desai, Ankit A., Dubrock, Hilary M., Erzurum, Serpil C., Finet, J. Emanuel, Frantz, Robert P., Garcia, Joe G.N., Geraci, Mark W., Gray, Michael P., Grunig, Gabriele, Hassoun, Paul M., Highland, Kristin B., Hill, Nicholas S., Hu, Bo, Kwon, Deborah H., Jacob, Miriam S., Jellis, Christine L., Larive, A. Brett, Lempel, Jason K., Maron, Bradley A., Mathai, Stephen C., McCarthy, Kevin, Mehra, Reena, Nawabit, Rawan, Newman, John H., Olman, Mitchell A., Park, Margaret M., Ramos, Jose A., Renapurkar, Rahul D., Rischard, Franz P., Sherer, Susan G., Tang, W.H. Wilson, Thomas, James D., Vanderpool, Rebecca R., Waxman, Aaron B., Wilcox, Jennifer D., Yuan, Jason X.-J., and Horn, Evelyn M.

Published
2022
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12. NHLBI-CMREF Workshop Report on Pulmonary Vascular Disease Classification: JACC State-of-the-Art Review

Author

Oldham, William M., Hemnes, Anna R., Aldred, Micheala A., Barnard, John, Brittain, Evan L., Chan, Stephen Y., Cheng, Feixiong, Cho, Michael H., Desai, Ankit A., Garcia, Joe G.N., Geraci, Mark W., Ghiassian, Susan D., Hall, Kathryn T., Horn, Evelyn M., Jain, Mohit, Kelly, Rachel S., Leopold, Jane A., Lindstrom, Sara, Modena, Brian D., Nichols, William C., Rhodes, Christopher J., Sun, Wei, Sweatt, Andrew J., Vanderpool, Rebecca R., Wilkins, Martin R., Wilmot, Beth, Zamanian, Roham T., Fessel, Joshua P., Aggarwal, Neil R., Loscalzo, Joseph, and Xiao, Lei

Published
2021
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13. Business of Medicine: Developing Leaders in Academic Medicine and Learning Health Systems.

Author

Sotto-Santiago, Sylk, Neal, Chemen, Caudill, Darren, Gist, Amanda, Eastwick, Susannah, Palmer, Megan M, Geraci, Mark W, and Aronoff, David M

Subjects
ACADEMIC medical centers, LEADERSHIP, UNIVERSITIES & colleges, DESCRIPTIVE statistics, BUSINESS, PROFESSIONAL employee training, RESEARCH methodology, ABILITY, FINANCIAL management, NEEDS assessment, CASE studies, COMMITMENT (Psychology), PHYSICIANS, PROFESSIONAL competence, TRAINING, CRITICAL thinking
Abstract

Purpose: To develop healthcare professionals as clinical leaders in academic medicine and learning health system; and uncover organizational barriers, as well as pathways and practices to facilitate career growth and professional fulfillment. Methods: The Department of Medicine strategic plan efforts prompted the development of a business of medicine program informed by a needs assessment and realignment between academic departments and the healthcare system. The business of medicine leadership program launched in 2017. This descriptive case study presents its 5th year evaluation. Competencies were included from the Physician MBA program and from specific departmental needs and goals. Results: The program hosted a total of 102 clinical faculty. We had a 37% response rate of those retained at Indiana University School of Medicine. Overall, responses conveyed a positive experience in the course. Over 80% of participants felt that they gained skills in professional reflection, professional socialization, goal orientation, critical thinking, and commitment to profession. Financial literacy was overwhelmingly the skill that was reported to be the most valuable. Finance and accounting were mentioned as the most difficult concepts to understand. Familiar concepts included communication, LEAN, and wellness related topics. One hundred percent of participants said they are utilizing the skills gained in this program in their current role and that they would recommend the course to others. Conclusion: Business of medicine courses are more common now with programs describing elements informed by health system operations. However, few programs incorporate aspects of wellness, equity, diversity, inclusion, and health equity. Our program makes the case for multiple ways to develop inclusive leaders through a focused five-month program. It also recognizes that to really impact the learning health system, health professionals need leadership development and leaders suited to work alongside career administrators, all aiming towards a common goal of equitable patient-centered care. [ABSTRACT FROM AUTHOR]

Published
2024
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14. Blood Transcriptional Biomarkers for Active Tuberculosis among Patients in the United States: a Case-Control Study with Systematic Cross-Classifier Evaluation

Author

Walter, Nicholas D, Miller, Mikaela A, Vasquez, Joshua, Weiner, Marc, Chapman, Adam, Engle, Melissa, Higgins, Michael, Quinones, Amy M, Rosselli, Vanessa, Canono, Elizabeth, Yoon, Christina, Cattamanchi, Adithya, Davis, J Lucian, Phang, Tzu, Stearman, Robert S, Datta, Gargi, Garcia, Benjamin J, Daley, Charles L, Strong, Michael, Kechris, Katerina, Fingerlin, Tasha E, Reves, Randall, and Geraci, Mark W

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Emerging Infectious Diseases, Clinical Research, Lung, Rare Diseases, Genetics, Tuberculosis, Sexually Transmitted Infections, HIV/AIDS, Infectious Diseases, 4.1 Discovery and preclinical testing of markers and technologies, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Infection, Good Health and Well Being, Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers, Case-Control Studies, Female, Gene Expression Profiling, Humans, Latent Tuberculosis, Male, Middle Aged, Mycobacterium tuberculosis, Pneumonia, ROC Curve, Transcriptome, United States, Young Adult, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Microbiology, Clinical sciences, Medical microbiology
Abstract

UnlabelledBlood transcriptional signatures are promising for tuberculosis (TB) diagnosis but have not been evaluated among U.S.PatientsTo be used clinically, transcriptional classifiers need reproducible accuracy in diverse populations that vary in genetic composition, disease spectrum and severity, and comorbidities. In a prospective case-control study, we identified novel transcriptional classifiers for active TB among U.S. patients and systematically compared their accuracy to classifiers from published studies. Blood samples from HIV-uninfected U.S. adults with active TB, pneumonia, or latent TB infection underwent whole-transcriptome microarray. We used support vector machines to classify disease state based on transcriptional patterns. We externally validated our classifiers using data from sub-Saharan African cohorts and evaluated previously published transcriptional classifiers in our population. Our classifier distinguishing active TB from pneumonia had an area under the concentration-time curve (AUC) of 96.5% (95.4% to 97.6%) among U.S. patients, but the AUC was lower (90.6% [89.6% to 91.7%]) in HIV-uninfected Sub-Saharan Africans. Previously published comparable classifiers had AUC values of 90.0% (87.7% to 92.3%) and 82.9% (80.8% to 85.1%) when tested in U.S.PatientsOur classifier distinguishing active TB from latent TB had AUC values of 95.9% (95.2% to 96.6%) among U.S. patients and 95.3% (94.7% to 96.0%) among Sub-Saharan Africans. Previously published comparable classifiers had AUC values of 98.0% (97.4% to 98.7%) and 94.8% (92.9% to 96.8%) when tested in U.S.PatientsBlood transcriptional classifiers accurately detected active TB among U.S. adults. The accuracy of classifiers for active TB versus that of other diseases decreased when tested in new populations with different disease controls, suggesting additional studies are required to enhance generalizability. Classifiers that distinguish active TB from latent TB are accurate and generalizable across populations and can be explored as screening assays.

Published
2016

16. Transcriptional Adaptation of Drug-tolerant Mycobacterium tuberculosis During Treatment of Human Tuberculosis

Author

Walter, Nicholas D, Dolganov, Gregory M, Garcia, Benjamin J, Worodria, William, Andama, Alfred, Musisi, Emmanuel, Ayakaka, Irene, Van, Tran T, Voskuil, Martin I, de Jong, Bouke C, Davidson, Rebecca M, Fingerlin, Tasha E, Kechris, Katerina, Palmer, Claire, Nahid, Payam, Daley, Charles L, Geraci, Mark, Huang, Laurence, Cattamanchi, Adithya, Strong, Michael, Schoolnik, Gary K, and Davis, John Lucian

Subjects
Genetics, Human Genome, Orphan Drug, Emerging Infectious Diseases, Tuberculosis, Infectious Diseases, Biotechnology, Rare Diseases, 2.2 Factors relating to the physical environment, Aetiology, Infection, Good Health and Well Being, Adaptation, Physiological, Antitubercular Agents, Drug Resistance, Bacterial, Gene Expression Regulation, Bacterial, Humans, Mycobacterium tuberculosis, RNA, Messenger, Sputum, Transcription, Genetic, Transcriptome, Tuberculosis, Pulmonary, Uganda, gene expression profiling, genetics, physiology, pulmonary, epidemiology, sputum, microbiology, tuberculosis, Mycobacterium tuberculosis/genetics, Mycobacterium tuberculosis/physiology, pulmonary/epidemiology, sputum/microbiology, Biological Sciences, Medical and Health Sciences, Microbiology
Abstract

BackgroundTreatment initiation rapidly kills most drug-susceptible Mycobacterium tuberculosis, but a bacterial subpopulation tolerates prolonged drug exposure. We evaluated drug-tolerant bacilli in human sputum by comparing messenger RNA (mRNA) expression of drug-tolerant bacilli that survive the early bactericidal phase with treatment-naive bacilli.MethodsM. tuberculosis gene expression was quantified via reverse-transcription polymerase chain reaction in serial sputa from 17 Ugandans treated for drug-susceptible pulmonary tuberculosis.ResultsWithin 4 days, bacterial mRNA abundance declined >98%, indicating rapid killing. Thereafter, the rate of decline slowed >94%, indicating drug tolerance. After 14 days, 16S ribosomal RNA transcripts/genome declined 96%, indicating slow growth. Drug-tolerant bacilli displayed marked downregulation of genes associated with growth, metabolism, and lipid synthesis and upregulation in stress responses and key regulatory categories-including stress-associated sigma factors, transcription factors, and toxin-antitoxin genes. Drug efflux pumps were upregulated. The isoniazid stress signature was induced by initial drug exposure, then disappeared after 4 days.ConclusionsTranscriptional patterns suggest that drug-tolerant bacilli in sputum are in a slow-growing, metabolically and synthetically downregulated state. Absence of the isoniazid stress signature in drug-tolerant bacilli indicates that physiological state influences drug responsiveness in vivo. These results identify novel drug targets that should aid in development of novel shorter tuberculosis treatment regimens.

Published
2015

17. Functional Prostacyclin Synthase Promoter Polymorphisms. Impact in Pulmonary Arterial Hypertension

Author

Stearman, Robert S, Cornelius, Amber R, Lu, Xiao, Conklin, David S, Del Rosario, Mark J, Lowe, Anita M, Elos, Mihret T, Fettig, Lynsey M, Wong, Randall E, Hara, Naoko, Cogan, Joy D, Phillips, John A, Taylor, Matthew R, Graham, Brian B, Tuder, Rubin M, Loyd, James E, and Geraci, Mark W

Subjects
Rare Diseases, Human Genome, Genetics, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Bone Morphogenetic Protein Receptors, Type II, Case-Control Studies, Cytochrome P-450 Enzyme System, Disease Progression, Familial Primary Pulmonary Hypertension, Female, Haplotypes, Heterozygote, Humans, Hypertension, Pulmonary, Intramolecular Oxidoreductases, Male, Mutation, Polymerase Chain Reaction, Polymorphism, Genetic, lung diseases, pulmonary hypertension, genetic polymorphism, genetic predisposition to disease, Medical and Health Sciences, Respiratory System
Abstract

RationalePulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary artery pressure, vascular remodeling, and ultimately right ventricular heart failure. PAH can have a genetic component (heritable PAH), most often through mutations of bone morphogenetic protein receptor 2, and idiopathic and associated forms. Heritable PAH is not completely penetrant within families, with approximately 20% concurrence of inactivating bone morphogenetic protein receptor 2 mutations and delayed onset of PAH disease. Because one of the treatment options is using prostacyclin analogs, we hypothesized that prostacyclin synthase promoter sequence variants associated with increased mRNA expression may play a protective role in the bone morphogenetic protein receptor 2 unaffected carriers.ObjectivesTo characterize the range of prostacyclin synthase promoter variants and assess their transcriptional activities in PAH-relevant cell types. To determine the distribution of prostacyclin synthase promoter variants in PAH, unaffected carriers in heritable PAH families, and control populations.MethodsPolymerase chain reaction approaches were used to genotype prostacyclin synthase promoter variants in more than 300 individuals. Prostacyclin synthase promoter haplotypes' transcriptional activities were determined with luciferase reporter assays.Measurements and main resultsWe identified a comprehensive set of prostacyclin synthase promoter variants and tested their transcriptional activities in PAH-relevant cell types. We demonstrated differences of prostacyclin synthase promoter activities dependent on their haplotype.ConclusionsProstacyclin synthase promoter sequence variants exhibit a range of transcriptional activities. We discovered a significant bias for more active prostacyclin synthase promoter variants in unaffected carriers as compared with affected patients with PAH.

Published
2014

18. Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma

Author

Recto, Kathryn, primary, Kachroo, Priyadarshini, additional, Huan, Tianxiao, additional, Van Den Berg, David, additional, Lee, Gha Young, additional, Bui, Helena, additional, Lee, Dong Heon, additional, Gereige, Jessica, additional, Yao, Chen, additional, Hwang, Shih-Jen, additional, Joehanes, Roby, additional, Weiss, Scott T., additional, O’Connor, George T., additional, Levy, Daniel, additional, DeMeo, Dawn L., additional, Abe, Namiko, additional, Abecasis, Gonçalo, additional, Aguet, Francois, additional, Albert, Christine, additional, Almasy, Laura, additional, Alonso, Alvaro, additional, Ament, Seth, additional, Anderson, Peter, additional, Anugu, Pramod, additional, Applebaum-Bowden, Deborah, additional, Ardlie, Kristin, additional, Arking, Dan, additional, Arnett, Donna K., additional, Ashley-Koch, Allison, additional, Aslibekyan, Stella, additional, Assimes, Tim, additional, Auer, Paul, additional, Avramopoulos, Dimitrios, additional, Ayas, Najib, additional, Balasubramanian, Adithya, additional, Barnard, John, additional, Barnes, Kathleen, additional, Barr, R. Graham, additional, Barron-Casella, Emily, additional, Barwick, Lucas, additional, Beaty, Terri, additional, Beck, Gerald, additional, Becker, Diane, additional, Becker, Lewis, additional, Beer, Rebecca, additional, Beitelshees, Amber, additional, Benjamin, Emelia, additional, Benos, Takis, additional, Bezerra, Marcos, additional, Bielak, Larry, additional, Bis, Joshua, additional, Blackwell, Thomas, additional, Blangero, John, additional, Blue, Nathan, additional, Boerwinkle, Eric, additional, Bowden, Donald W., additional, Bowler, Russell, additional, Brody, Jennifer, additional, Broeckel, Ulrich, additional, Broome, Jai, additional, Brown, Deborah, additional, Bunting, Karen, additional, Burchard, Esteban, additional, Bustamante, Carlos, additional, Buth, Erin, additional, Cade, Brian, additional, Cardwell, Jonathan, additional, Carey, Vincent, additional, Carrier, Julie, additional, Carson, April P., additional, Carty, Cara, additional, Casaburi, Richard, additional, Casas Romero, Juan P., additional, Casella, James, additional, Castaldi, Peter, additional, Chaffin, Mark, additional, Chang, Christy, additional, Chang, Yi-Cheng, additional, Chasman, Daniel, additional, Chavan, Sameer, additional, Chen, Bo-Juen, additional, Chen, Wei-Min, additional, Ida Chen, Yii-Der, additional, Cho, Michael, additional, Choi, Seung Hoan, additional, Chuang, Lee-Ming, additional, Chung, Mina, additional, Chung, Ren-Hua, additional, Clish, Clary, additional, Comhair, Suzy, additional, Conomos, Matthew, additional, Cornell, Elaine, additional, Correa, Adolfo, additional, Crandall, Carolyn, additional, Crapo, James, additional, Cupples, L. Adrienne, additional, Curran, Joanne, additional, Curtis, Jeffrey, additional, Custer, Brian, additional, Damcott, Coleen, additional, Darbar, Dawood, additional, David, Sean, additional, Davis, Colleen, additional, Daya, Michelle, additional, de Andrade, Mariza, additional, de las Fuentes, Lisa, additional, de Vries, Paul, additional, DeBaun, Michael, additional, Deka, Ranjan, additional, DeMeo, Dawn, additional, Devine, Scott, additional, Dinh, Huyen, additional, Doddapaneni, Harsha, additional, Duan, Qing, additional, Dugan-Perez, Shannon, additional, Duggirala, Ravi, additional, Durda, Jon Peter, additional, Dutcher, Susan K., additional, Eaton, Charles, additional, Ekunwe, Lynette, additional, El Boueiz, Adel, additional, Ellinor, Patrick, additional, Emery, Leslie, additional, Erzurum, Serpil, additional, Farber, Charles, additional, Farek, Jesse, additional, Fingerlin, Tasha, additional, Flickinger, Matthew, additional, Fornage, Myriam, additional, Franceschini, Nora, additional, Frazar, Chris, additional, Fu, Mao, additional, Fullerton, Stephanie M., additional, Fulton, Lucinda, additional, Gabriel, Stacey, additional, Gan, Weiniu, additional, Gao, Shanshan, additional, Gao, Yan, additional, Gass, Margery, additional, Geiger, Heather, additional, Gelb, Bruce, additional, Geraci, Mark, additional, Germer, Soren, additional, Gerszten, Robert, additional, Ghosh, Auyon, additional, Gibbs, Richard, additional, Gignoux, Chris, additional, Gladwin, Mark, additional, Glahn, David, additional, Gogarten, Stephanie, additional, Gong, Da-Wei, additional, Goring, Harald, additional, Graw, Sharon, additional, Gray, Kathryn J., additional, Grine, Daniel, additional, Gross, Colin, additional, Gu, C. Charles, additional, Guan, Yue, additional, Guo, Xiuqing, additional, Gupta, Namrata, additional, Haessler, Jeff, additional, Hall, Michael, additional, Han, Yi, additional, Hanly, Patrick, additional, Harris, Daniel, additional, Hawley, Nicola L., additional, He, Jiang, additional, Heavner, Ben, additional, Heckbert, Susan, additional, Hernandez, Ryan, additional, Herrington, David, additional, Hersh, Craig, additional, Hidalgo, Bertha, additional, Hixson, James, additional, Hobbs, Brian, additional, Hokanson, John, additional, Hong, Elliott, additional, Hoth, Karin, additional, Hsiung, Chao (Agnes), additional, Hu, Jianhong, additional, Hung, Yi-Jen, additional, Huston, Haley, additional, Hwu, Chii Min, additional, Irvin, Marguerite Ryan, additional, Jackson, Rebecca, additional, Jain, Deepti, additional, Jaquish, Cashell, additional, Johnsen, Jill, additional, Johnson, Andrew, additional, Johnson, Craig, additional, Johnston, Rich, additional, Jones, Kimberly, additional, Kang, Hyun Min, additional, Kaplan, Robert, additional, Kardia, Sharon, additional, Kelly, Shannon, additional, Kenny, Eimear, additional, Kessler, Michael, additional, Khan, Alyna, additional, Khan, Ziad, additional, Kim, Wonji, additional, Kimoff, John, additional, Kinney, Greg, additional, Konkle, Barbara, additional, Kooperberg, Charles, additional, Kramer, Holly, additional, Lange, Christoph, additional, Lange, Ethan, additional, Lange, Leslie, additional, Laurie, Cathy, additional, Laurie, Cecelia, additional, LeBoff, Meryl, additional, Lee, Jiwon, additional, Lee, Sandra, additional, Lee, Wen-Jane, additional, LeFaive, Jonathon, additional, Levine, David, additional, Lewis, Joshua, additional, Li, Xiaohui, additional, Li, Yun, additional, Lin, Henry, additional, Lin, Honghuang, additional, Lin, Xihong, additional, Liu, Simin, additional, Liu, Yongmei, additional, Liu, Yu, additional, Loos, Ruth J.F., additional, Lubitz, Steven, additional, Lunetta, Kathryn, additional, Luo, James, additional, Magalang, Ulysses, additional, Mahaney, Michael, additional, Make, Barry, additional, Manichaikul, Ani, additional, Manning, Alisa, additional, Manson, JoAnn, additional, Martin, Lisa, additional, Marton, Melissa, additional, Mathai, Susan, additional, Mathias, Rasika, additional, May, Susanne, additional, McArdle, Patrick, additional, McDonald, Merry-Lynn, additional, McFarland, Sean, additional, McGarvey, Stephen, additional, McGoldrick, Daniel, additional, McHugh, Caitlin, additional, McNeil, Becky, additional, Mei, Hao, additional, Meigs, James, additional, Menon, Vipin, additional, Mestroni, Luisa, additional, Metcalf, Ginger, additional, Meyers, Deborah A., additional, Mignot, Emmanuel, additional, Mikulla, Julie, additional, Min, Nancy, additional, Minear, Mollie, additional, Minster, Ryan L., additional, Mitchell, Braxton D., additional, Moll, Matt, additional, Momin, Zeineen, additional, Montasser, May E., additional, Montgomery, Courtney, additional, Muzny, Donna, additional, Mychaleckyj, Josyf C., additional, Nadkarni, Girish, additional, Naik, Rakhi, additional, Naseri, Take, additional, Natarajan, Pradeep, additional, Nekhai, Sergei, additional, Nelson, Sarah C., additional, Neltner, Bonnie, additional, Nessner, Caitlin, additional, Nickerson, Deborah, additional, Nkechinyere, Osuji, additional, North, Kari, additional, O'Connell, Jeff, additional, O'Connor, Tim, additional, Ochs-Balcom, Heather, additional, Okwuonu, Geoffrey, additional, Pack, Allan, additional, Paik, David T., additional, Palmer, Nicholette, additional, Pankow, James, additional, Papanicolaou, George, additional, Parker, Cora, additional, Peloso, Gina, additional, Peralta, Juan Manuel, additional, Perez, Marco, additional, Perry, James, additional, Peters, Ulrike, additional, Peyser, Patricia, additional, Phillips, Lawrence S., additional, Pleiness, Jacob, additional, Pollin, Toni, additional, Post, Wendy, additional, Powers Becker, Julia, additional, Preethi Boorgula, Meher, additional, Preuss, Michael, additional, Psaty, Bruce, additional, Qasba, Pankaj, additional, Qiao, Dandi, additional, Qin, Zhaohui, additional, Rafaels, Nicholas, additional, Raffield, Laura, additional, Rajendran, Mahitha, additional, Ramachandran, Vasan S., additional, Rao, D.C., additional, Rasmussen-Torvik, Laura, additional, Ratan, Aakrosh, additional, Redline, Susan, additional, Reed, Robert, additional, Reeves, Catherine, additional, Regan, Elizabeth, additional, Reiner, Alex, additional, Reupena, Muagututi‘a Sefuiva, additional, Rice, Ken, additional, Rich, Stephen, additional, Robillard, Rebecca, additional, Robine, Nicolas, additional, Roden, Dan, additional, Roselli, Carolina, additional, Rotter, Jerome, additional, Ruczinski, Ingo, additional, Runnels, Alexi, additional, Russell, Pamela, additional, Ruuska, Sarah, additional, Ryan, Kathleen, additional, Sabino, Ester Cerdeira, additional, Saleheen, Danish, additional, Salimi, Shabnam, additional, Salvi, Sejal, additional, Salzberg, Steven, additional, Sandow, Kevin, additional, Sankaran, Vijay G., additional, Santibanez, Jireh, additional, Schwander, Karen, additional, Schwartz, David, additional, Sciurba, Frank, additional, Seidman, Christine, additional, Seidman, Jonathan, additional, Sériès, Frédéric, additional, Sheehan, Vivien, additional, Sherman, Stephanie L., additional, Shetty, Amol, additional, Shetty, Aniket, additional, Sheu, Wayne Hui-Heng, additional, Shoemaker, M. Benjamin, additional, Silver, Brian, additional, Silverman, Edwin, additional, Skomro, Robert, additional, Smith, Albert Vernon, additional, Smith, Jennifer, additional, Smith, Josh, additional, Smith, Nicholas, additional, Smith, Tanja, additional, Smoller, Sylvia, additional, Snively, Beverly, additional, Snyder, Michael, additional, Sofer, Tamar, additional, Sotoodehnia, Nona, additional, Stilp, Adrienne M., additional, Storm, Garrett, additional, Streeten, Elizabeth, additional, Su, Jessica Lasky, additional, Sung, Yun Ju, additional, Sylvia, Jody, additional, Szpiro, Adam, additional, Taliun, Daniel, additional, Tang, Hua, additional, Taub, Margaret, additional, Taylor, Kent, additional, Taylor, Matthew, additional, Taylor, Simeon, additional, Telen, Marilyn, additional, Thornton, Timothy A., additional, Threlkeld, Machiko, additional, Tinker, Lesley, additional, Tirschwell, David, additional, Tishkoff, Sarah, additional, Tiwari, Hemant, additional, Tong, Catherine, additional, Tracy, Russell, additional, Tsai, Michael, additional, Vaidya, Dhananjay, additional, VandeHaar, Peter, additional, Vrieze, Scott, additional, Walker, Tarik, additional, Wallace, Robert, additional, Walts, Avram, additional, Wang, Fei Fei, additional, Wang, Heming, additional, Wang, Jiongming, additional, Watson, Karol, additional, Watt, Jennifer, additional, Weeks, Daniel E., additional, Weinstock, Joshua, additional, Weir, Bruce, additional, Weng, Lu-Chen, additional, Wessel, Jennifer, additional, Willer, Cristen, additional, Williams, Kayleen, additional, Williams, L. Keoki, additional, Williams, Scott, additional, Wilson, Carla, additional, Wilson, James, additional, Winterkorn, Lara, additional, Wong, Quenna, additional, Wu, Baojun, additional, Wu, Joseph, additional, Xu, Huichun, additional, Yanek, Lisa, additional, Yang, Ivana, additional, Yu, Ketian, additional, Zekavat, Seyedeh Maryam, additional, Zhang, Yingze, additional, Zhao, Snow Xueyan, additional, Zhao, Wei, additional, Zhu, Xiaofeng, additional, Ziv, Elad, additional, Zody, Michael, additional, and Zoellner, Sebastian, additional

Published
2023
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19. Protective Role of IL-6 in Vascular Remodeling in Schistosoma Pulmonary Hypertension

Author

Graham, Brian B, Chabon, Jacob, Kumar, Rahul, Kolosionek, Ewa, Gebreab, Liya, Debella, Elias, Edwards, Michael, Diener, Katrina, Shade, Ted, Bifeng, Gao, Bandeira, Angela, Butrous, Ghazwan, Jones, Kenneth, Geraci, Mark, and Tuder, Rubin M

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Clinical Sciences, Lung, Vector-Borne Diseases, Genetics, Rare Diseases, Biotechnology, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Cardiovascular, Good Health and Well Being, Animals, Disease Models, Animal, Familial Primary Pulmonary Hypertension, Gene Expression Profiling, Humans, Hypertension, Pulmonary, Interleukin-6, Mice, Mice, Inbred C57BL, Mice, Knockout, NFATC Transcription Factors, Pulmonary Artery, RNA, Messenger, STAT3 Transcription Factor, Schistosoma mansoni, Schistosomiasis mansoni, Signal Transduction, pulmonary hypertension, schistosomiasis, gene expression profiling, IL-6, Cardiorespiratory Medicine and Haematology, Respiratory System, Biochemistry and cell biology, Cardiovascular medicine and haematology
Abstract

Schistosomiasis is one of the most common causes of pulmonary arterial hypertension worldwide, but the pathogenic mechanism by which the host inflammatory response contributes to vascular remodeling is unknown. We sought to identify signaling pathways that play protective or pathogenic roles in experimental Schistosoma-induced pulmonary vascular disease via whole-lung transcriptome analysis. Wild-type mice were experimentally exposed to Schistosoma mansoni ova by intraperitoneal sensitization followed by tail-vein augmentation, and the phenotype was assessed by right ventricular catheterization and tissue histology, as well as RNA and protein analysis. Whole-lung transcriptome analysis by microarray and RNA sequencing was performed, and RNA sequencing was analyzed according to two bioinformatics methods. Functional testing of the candidate IL-6 pathway was determined using IL-6 knockout mice and the signal transducers and activators of transcription protein-3 (STAT3) inhibitor S3I-201. Wild-type mice exposed to S. mansoni demonstrated increased right ventricular systolic pressure and thickness of the pulmonary vascular media. Whole-lung transcriptome analysis determined that the IL-6-STAT3-nuclear factor of activated T cells c2(NFATc2) pathway was up-regulated, as confirmed by PCR and the immunostaining of lung tissue from S. mansoni-exposed mice and patients who died of the disease. Mice lacking IL-6 or treated with S3I-201 developed pulmonary hypertension, associated with significant intima remodeling after exposure to S. mansoni. Whole-lung transcriptome analysis identified the up-regulation of the IL-6-STAT3-NFATc2 pathway, and IL-6 signaling was found to be protective against Schistosoma-induced intimal remodeling.

Published
2013

20. Supplementary Figure Legend from Application of SNP Microarrays to the Genome-Wide Analysis of Chromosomal Instability in Premalignant Airway Lesions

Author

Nakachi, Ichiro, primary, Rice, Jessica L., primary, Coldren, Christopher D., primary, Edwards, Michael G., primary, Stearman, Robert S., primary, Glidewell, Steven C., primary, Varella-Garcia, Marileila, primary, Franklin, Wilbur A., primary, Keith, Robert L., primary, Lewis, Marina T., primary, Gao, Bifeng, primary, Merrick, Daniel T., primary, Miller, York E., primary, and Geraci, Mark W., primary

Published
2023
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23. Supplementary Figure 3 from Application of SNP Microarrays to the Genome-Wide Analysis of Chromosomal Instability in Premalignant Airway Lesions

Author

Nakachi, Ichiro, primary, Rice, Jessica L., primary, Coldren, Christopher D., primary, Edwards, Michael G., primary, Stearman, Robert S., primary, Glidewell, Steven C., primary, Varella-Garcia, Marileila, primary, Franklin, Wilbur A., primary, Keith, Robert L., primary, Lewis, Marina T., primary, Gao, Bifeng, primary, Merrick, Daniel T., primary, Miller, York E., primary, and Geraci, Mark W., primary

Published
2023
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24. Data from Oral Iloprost Improves Endobronchial Dysplasia in Former Smokers

Author

Keith, Robert L., primary, Blatchford, Patrick J., primary, Kittelson, John, primary, Minna, John D., primary, Kelly, Karen, primary, Massion, Pierre P., primary, Franklin, Wilbur A., primary, Mao, Jenny, primary, Wilson, David O., primary, Merrick, Daniel T., primary, Hirsch, Fred R., primary, Kennedy, Timothy C., primary, Bunn, Paul A., primary, Geraci, Mark W., primary, and Miller, York E., primary

Published
2023
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25. Supplementary Figure S1 from Oral Iloprost Improves Endobronchial Dysplasia in Former Smokers

Author

Keith, Robert L., primary, Blatchford, Patrick J., primary, Kittelson, John, primary, Minna, John D., primary, Kelly, Karen, primary, Massion, Pierre P., primary, Franklin, Wilbur A., primary, Mao, Jenny, primary, Wilson, David O., primary, Merrick, Daniel T., primary, Hirsch, Fred R., primary, Kennedy, Timothy C., primary, Bunn, Paul A., primary, Geraci, Mark W., primary, and Miller, York E., primary

Published
2023
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26. Supplementary Figure 4 from Application of SNP Microarrays to the Genome-Wide Analysis of Chromosomal Instability in Premalignant Airway Lesions

Author

Nakachi, Ichiro, primary, Rice, Jessica L., primary, Coldren, Christopher D., primary, Edwards, Michael G., primary, Stearman, Robert S., primary, Glidewell, Steven C., primary, Varella-Garcia, Marileila, primary, Franklin, Wilbur A., primary, Keith, Robert L., primary, Lewis, Marina T., primary, Gao, Bifeng, primary, Merrick, Daniel T., primary, Miller, York E., primary, and Geraci, Mark W., primary

Published
2023
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27. Data from Application of SNP Microarrays to the Genome-Wide Analysis of Chromosomal Instability in Premalignant Airway Lesions

Author

Nakachi, Ichiro, primary, Rice, Jessica L., primary, Coldren, Christopher D., primary, Edwards, Michael G., primary, Stearman, Robert S., primary, Glidewell, Steven C., primary, Varella-Garcia, Marileila, primary, Franklin, Wilbur A., primary, Keith, Robert L., primary, Lewis, Marina T., primary, Gao, Bifeng, primary, Merrick, Daniel T., primary, Miller, York E., primary, and Geraci, Mark W., primary

Published
2023
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30. Supplementary Figure 2 from Application of SNP Microarrays to the Genome-Wide Analysis of Chromosomal Instability in Premalignant Airway Lesions

Author

Nakachi, Ichiro, primary, Rice, Jessica L., primary, Coldren, Christopher D., primary, Edwards, Michael G., primary, Stearman, Robert S., primary, Glidewell, Steven C., primary, Varella-Garcia, Marileila, primary, Franklin, Wilbur A., primary, Keith, Robert L., primary, Lewis, Marina T., primary, Gao, Bifeng, primary, Merrick, Daniel T., primary, Miller, York E., primary, and Geraci, Mark W., primary

Published
2023
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31. Supplementary Figure 1 from Application of SNP Microarrays to the Genome-Wide Analysis of Chromosomal Instability in Premalignant Airway Lesions

Author

Nakachi, Ichiro, primary, Rice, Jessica L., primary, Coldren, Christopher D., primary, Edwards, Michael G., primary, Stearman, Robert S., primary, Glidewell, Steven C., primary, Varella-Garcia, Marileila, primary, Franklin, Wilbur A., primary, Keith, Robert L., primary, Lewis, Marina T., primary, Gao, Bifeng, primary, Merrick, Daniel T., primary, Miller, York E., primary, and Geraci, Mark W., primary

Published
2023
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33. Supplementary Table S1 from Oral Iloprost Improves Endobronchial Dysplasia in Former Smokers

Author

Keith, Robert L., primary, Blatchford, Patrick J., primary, Kittelson, John, primary, Minna, John D., primary, Kelly, Karen, primary, Massion, Pierre P., primary, Franklin, Wilbur A., primary, Mao, Jenny, primary, Wilson, David O., primary, Merrick, Daniel T., primary, Hirsch, Fred R., primary, Kennedy, Timothy C., primary, Bunn, Paul A., primary, Geraci, Mark W., primary, and Miller, York E., primary

Published
2023
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34. Supplementary Table 1 from Application of SNP Microarrays to the Genome-Wide Analysis of Chromosomal Instability in Premalignant Airway Lesions

Author

Nakachi, Ichiro, primary, Rice, Jessica L., primary, Coldren, Christopher D., primary, Edwards, Michael G., primary, Stearman, Robert S., primary, Glidewell, Steven C., primary, Varella-Garcia, Marileila, primary, Franklin, Wilbur A., primary, Keith, Robert L., primary, Lewis, Marina T., primary, Gao, Bifeng, primary, Merrick, Daniel T., primary, Miller, York E., primary, and Geraci, Mark W., primary

Published
2023
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35. Perspective on This Article from Oral Iloprost Improves Endobronchial Dysplasia in Former Smokers

Author

Keith, Robert L., primary, Blatchford, Patrick J., primary, Kittelson, John, primary, Minna, John D., primary, Kelly, Karen, primary, Massion, Pierre P., primary, Franklin, Wilbur A., primary, Mao, Jenny, primary, Wilson, David O., primary, Merrick, Daniel T., primary, Hirsch, Fred R., primary, Kennedy, Timothy C., primary, Bunn, Paul A., primary, Geraci, Mark W., primary, and Miller, York E., primary

Published
2023
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36. Supplementary Figure 5 from Application of SNP Microarrays to the Genome-Wide Analysis of Chromosomal Instability in Premalignant Airway Lesions

Author

Nakachi, Ichiro, primary, Rice, Jessica L., primary, Coldren, Christopher D., primary, Edwards, Michael G., primary, Stearman, Robert S., primary, Glidewell, Steven C., primary, Varella-Garcia, Marileila, primary, Franklin, Wilbur A., primary, Keith, Robert L., primary, Lewis, Marina T., primary, Gao, Bifeng, primary, Merrick, Daniel T., primary, Miller, York E., primary, and Geraci, Mark W., primary

Published
2023
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38. Data from Altered Cell-Cycle Control, Inflammation, and Adhesion in High-Risk Persistent Bronchial Dysplasia

Author

Merrick, Daniel T., primary, Edwards, Michael G., primary, Franklin, Wilbur A., primary, Sugita, Michio, primary, Keith, Robert L., primary, Miller, York E., primary, Friedman, Micah B., primary, Dwyer-Nield, Lori D., primary, Tennis, Meredith A., primary, O'Keefe, Mary C., primary, Donald, Elizabeth J., primary, Malloy, Jessica M., primary, van Bokhoven, Adrie, primary, Wilson, Storey, primary, Koch, Peter J., primary, O'Shea, Charlene, primary, Coldren, Christopher, primary, Orlicky, David J., primary, Lu, Xian, primary, Baron, Anna E., primary, Hickey, Greg, primary, Kennedy, Timothy C., primary, Powell, Roger, primary, Heasley, Lynn, primary, Bunn, Paul A., primary, Geraci, Mark, primary, and Nemenoff, Raphael A., primary

Published
2023
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39. Supplementary data, tables and figures from Altered Cell-Cycle Control, Inflammation, and Adhesion in High-Risk Persistent Bronchial Dysplasia

Author

Merrick, Daniel T., primary, Edwards, Michael G., primary, Franklin, Wilbur A., primary, Sugita, Michio, primary, Keith, Robert L., primary, Miller, York E., primary, Friedman, Micah B., primary, Dwyer-Nield, Lori D., primary, Tennis, Meredith A., primary, O'Keefe, Mary C., primary, Donald, Elizabeth J., primary, Malloy, Jessica M., primary, van Bokhoven, Adrie, primary, Wilson, Storey, primary, Koch, Peter J., primary, O'Shea, Charlene, primary, Coldren, Christopher, primary, Orlicky, David J., primary, Lu, Xian, primary, Baron, Anna E., primary, Hickey, Greg, primary, Kennedy, Timothy C., primary, Powell, Roger, primary, Heasley, Lynn, primary, Bunn, Paul A., primary, Geraci, Mark, primary, and Nemenoff, Raphael A., primary

Published
2023
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43. Integrative Multiomics to Dissect the Lung Transcriptional Landscape of Pulmonary Arterial Hypertension

Author

Hong, Jason, primary, Wong, Brenda, additional, Rhodes, Christopher J., additional, Kurt, Zeyneb, additional, Schwantes-An, Tae-Hwi, additional, Mickler, Elizabeth A., additional, Gräf, Stefan, additional, Eyries, Mélanie, additional, Lutz, Katie A., additional, Pauciulo, Michael W., additional, Trembath, Richard C., additional, Montani, David, additional, Morrell, Nicholas W., additional, Wilkins, Martin R., additional, Nichols, William C., additional, Trégouët, David-Alexandre, additional, Aldred, Micheala A., additional, Desai, Ankit A., additional, Tuder, Rubin M., additional, Geraci, Mark W., additional, Eghbali, Mansoureh, additional, Stearman, Robert S., additional, and Yang, Xia, additional

Published
2023
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44. Integrative Multiomics to Dissect the Lung Transcriptional Landscape of Pulmonary Arterial Hypertension

Author

Hong, Jason, Wong, Brenda, Rhodes, Christopher J., Kurt, Zeyneb, Schwantes-An, Tae-Hwi, Mickler, Elizabeth A., Gräf, Stefan, Eyries, Mélanie, Lutz, Katie A., Pauciulo, Michael W., Trembath, Richard C., Montani, David, Morrell, Nicholas W., Wilkins, Martin R., Nichols, William C., Trégouët, David-Alexandre, Aldred, Micheala A., Desai, Ankit A., Tuder, Rubin M., Geraci, Mark W., Eghbali, Mansoureh, Stearman, Robert S., and Yang, Xia

Subjects
Article
Abstract

Pulmonary arterial hypertension (PAH) remains an incurable and often fatal disease despite currently available therapies. Multiomics systems biology analysis can shed new light on PAH pathobiology and inform translational research efforts. Using RNA sequencing on the largest PAH lung biobank to date (96 disease and 52 control), we aim to identify gene co-expression network modules associated with PAH and potential therapeutic targets. Co-expression network analysis was performed to identify modules of co-expressed genes which were then assessed for and prioritized by importance in PAH, regulatory role, and therapeutic potential via integration with clinicopathologic data, human genome-wide association studies (GWAS) of PAH, lung Bayesian regulatory networks, single-cell RNA-sequencing data, and pharmacotranscriptomic profiles. We identified a co-expression module of 266 genes, called the pink module, which may be a response to the underlying disease process to counteract disease progression in PAH. This module was associated not only with PAH severity such as increased PVR and intimal thickness, but also with compensated PAH such as lower number of hospitalizations, WHO functional class and NT-proBNP. GWAS integration demonstrated the pink module is enriched for PAH-associated genetic variation in multiple cohorts. Regulatory network analysis revealed that BMPR2 regulates the main target of FDA-approved riociguat, GUCY1A2, in the pink module. Analysis of pathway enrichment and pink hub genes (i.e. ANTXR1 and SFRP4) suggests the pink module inhibits Wnt signaling and epithelial-mesenchymal transition. Cell type deconvolution showed the pink module correlates with higher vascular cell fractions (i.e. myofibroblasts). A pharmacotranscriptomic screen discovered ubiquitin-specific peptidases (USPs) as potential therapeutic targets to mimic the pink module signature. Our multiomics integrative study uncovered a novel gene subnetwork associated with clinicopathologic severity, genetic risk, specific vascular cell types, and new therapeutic targets in PAH. Future studies are warranted to investigate the role and therapeutic potential of the pink module and targeting USPs in PAH.

Published
2023

46. Integrative genetic and genomic networks identify microRNA associated with COPD and ILD

Author

Pavel, Ana B., primary, Garrison, Carly, additional, Luo, Lingqi, additional, Liu, Gang, additional, Taub, Daniel, additional, Xiao, Ji, additional, Juan-Guardela, Brenda, additional, Tedrow, John, additional, Alekseyev, Yuriy O., additional, Yang, Ivana V., additional, Geraci, Mark W., additional, Sciurba, Frank, additional, Schwartz, David A., additional, Kaminski, Naftali, additional, Beane, Jennifer, additional, Spira, Avrum, additional, Lenburg, Marc E., additional, and Campbell, Joshua D., additional

Published
2022
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50. Prostacyclin and Lung Cancer Chemoprevention

Author

Keith, Robert L., Miller, York E., Bunn, Paul A., Jr., Nana-Sinkam, Patrick, Nemenoff, Raphael A., Geraci, Mark W., Teicher, Beverly A., editor, Kelloff, Gary J., editor, Hawk, Ernest T., editor, and Sigman, Caroline C., editor

Published
2004
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