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2. Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

Author

Dareng, Eileen, Coetzee, Simon, Tyrer, Jonathan, Peng, Pei-Chen, Rosenow, Will, Chen, Stephanie, Davis, Brian, Dezem, Felipe, Seo, Ji-Heui, Nameki, Robbin, Reyes, Alberto, Aben, Katja, Anton-Culver, Hoda, Antonenkova, Natalia, Aravantinos, Gerasimos, Bandera, Elisa, Beane Freeman, Laura, Beckmann, Matthias, Beeghly-Fadiel, Alicia, Benitez, Javier, Bernardini, Marcus, Bjorge, Line, Black, Amanda, Bogdanova, Natalia, Bolton, Kelly, Brenton, James, Budzilowska, Agnieszka, Butzow, Ralf, Cai, Hui, Campbell, Ian, Cannioto, Rikki, Chang-Claude, Jenny, Chanock, Stephen, Chen, Kexin, Chenevix-Trench, Georgia, Chiew, Yoke-Eng, Cook, Linda, DeFazio, Anna, Dennis, Joe, Doherty, Jennifer, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana, Ene, Gabrielle, Fasching, Peter, Flanagan, James, Fortner, Renée, Fostira, Florentia, Gentry-Maharaj, Aleksandra, Giles, Graham, Goodman, Marc, Gronwald, Jacek, Haiman, Christopher, Håkansson, Niclas, Heitz, Florian, Hildebrandt, Michelle, Høgdall, Estrid, Høgdall, Claus, Huang, Ruea-Yea, Jensen, Allan, Jones, Michael, Kang, Daehee, Karlan, Beth, Karnezis, Anthony, Kelemen, Linda, Kennedy, Catherine, Khusnutdinova, Elza, Kiemeney, Lambertus, Kjaer, Susanne, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Larson, Melissa, Le, Nhu, Lester, Jenny, Li, Lian, Lubiński, Jan, Lush, Michael, Marks, Jeffrey, Matsuo, Keitaro, May, Taymaa, McLaughlin, John, McNeish, Iain, Menon, Usha, Missmer, Stacey, Modugno, Francesmary, Moffitt, Melissa, Monteiro, Alvaro, Moysich, Kirsten, Narod, Steven, Nguyen-Dumont, Tu, Odunsi, Kunle, Olsson, Håkan, Onland-Moret, N, Park, Sue, Pejovic, Tanja, Permuth, Jennifer, Piskorz, Anna, and Prokofyeva, Darya

Subjects
GWAS, epithelial ovarian cancer risk, fine mapping, functional mechanisms, Humans, Female, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Ovarian Neoplasms, Genetic Predisposition to Disease, Carcinoma, Ovarian Epithelial, Transcriptome, Risk Factors, Genomics, Case-Control Studies, Multiomics
Abstract

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value

Published
2024

3. Expression, purification, and characterization of anuran saxiphilins using thermofluor, fluorescence polarization, and isothermal titration calorimetry

Author

Chen, Zhou, Zakrzewska, Sandra, Hajare, Holly S, Du Bois, J, and Minor, Daniel L

Subjects
Biochemistry and Cell Biology, Biological Sciences, Infectious Diseases, Life on Land, Good Health and Well Being, Saxitoxin, Neurotoxins, Calorimetry, Fluorescence Polarization, Protein Biochemistry, Protein expression and purification, Structural Biology
Abstract

Anuran saxiphilins (Sxphs) are "toxin sponge" proteins thought to prevent the lethal effects of small-molecule neurotoxins through sequestration. Here, we present a protocol for the expression, purification, and characterization of Sxphs. We describe steps for using thermofluor, fluorescence polarization, and isothermal titration calorimetry assays that probe Sxph:saxitoxin interactions using a range of sample quantities. These assays are generalizable and can be used for other paralytic shellfish poisoning toxin-binding proteins. For complete details on the use and execution of this protocol, please refer to Chen et al. (2022).1.

Published
2024

4. Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago

Author

Perrone, Gennaro, Giuffrida, Mario, Abu-Zidan, Fikri, Kruger, Vitor F., Livrini, Marco, Petracca, Gabriele Luciano, Rossi, Giorgio, Tarasconi, Antonio, Tian, Brian W. C. A., Bonati, Elena, Mentz, Ricardo, Mazzini, Federico N., Campana, Juan P., Gasser, Elisabeth, Kafka-Ritsch, Reinhold, Felsenreich, Daniel M., Dawoud, Christopher, Riss, Stefan, Gomes, Carlos Augusto, Gomes, Felipe Couto, Gonzaga, Ricardo Alessandro Teixeira, Canton, Cassio Alfred Brattig, Pereira, Bruno Monteiro, Fraga, Gustavo P., Zem, Leticia Gonçalves, Cordeiro-Fonseca, Vinicius, de Mesquita Tauil, Renato, Atanasov, Boyko, Belev, Nikolay, Kovachev, Nikola, Meléndez, L. Juan José, Dimova, Ana, Dimov, Stefan, Zelić, Zdravko, Augustin, Goran, Bogdanić, Branko, Morić, Trpimir, Chouillard, Elie, Bajul, Melinda, De Simone, Belinda, Panis, Yves, Esposito, Francesco, Notarnicola, Margherita, Lauka, Lelde, Fabbri, Anna, Hentati, Hassen, Fnaiech, Iskander, Aurélien, Venara, Bougard, Marie, Roulet, Maxime, Demetrashvili, Zaza, Pipia, Irakli, Merabishvili, Giorgi, Bouliaris, Konstantinos, Koukoulis, Georgios, Doudakmanis, Christos, Xenaki, Sofia, Chrysos, Emmanuel, Kokkinakis, Stamatios, Vassiliu, Panteleimon, Michalopoulos, Nikolaos, Margaris, Ioannis, Kechagias, Aristotelis, Avgerinos, Konstantinos, Katunin, Jevgeni, Lostoridis, Eftychios, Nagorni, Eleni-Aikaterini, Pujante, Antonio, Mulita, Francesk, Maroulis, Ioannis, Vailas, Michail, Marinis, Athanasios, Siannis, Ioannis, Bourbouteli, Eirini, Manatakis, Dimitrios K., Tasis, Nikolaos, Acheimastos, Vasileios, Maria, Sotiropoulou, Stylianos, Kapiris, Kuzeridis, Harilaos, Korkolis, Dimitrios, Fradelos, Evangelos, Kavalieratos, George, Petropoulou, Thalia, Polydorou, Andreas, Papacostantinou, Ioannis, Triantafyllou, Tania, Kimpizi, Despina, Theodorou, Dimitrios, Toutouzas, Konstantinos, Chamzin, Alexandros, Frountzas, Maximos, Schizas, Dimitrios, Karavokyros, Ioannis, Syllaios, Athanasios, Charalabopoulos, Alexandros, Boura, Maria, Baili, Efstratia, Ioannidis, Orestis, Loutzidou, Lydia, Anestiadou, Elissavet, Tsouknidas, Ioannis, Petrakis, Georgios, Polenta, Eleni, Bains, Lovenish, Gupta, Rahul, Singh, Sudhir K., Khanduri, Archana, Bala, Miklosh, Kedar, Asaf, Pisano, Marcello, Podda, Mauro, Pisanu, Adolfo, Martines, Gennaro, Trigiante, Giuseppe, Lantone, Giuliano, Agrusa, Antonino, Di Buono, Giuseppe, Buscemi, Salvatore, Veroux, Massimiliano, Gioco, Rossella, Veroux, Gastone, Oragano, Luigi, Zonta, Sandro, Lovisetto, Federico, Feo, Carlo V., Pesce, Antonio, Fabbri, Nicolò, Lantone, Giulio, Marino, Fabio, Perrone, Fabrizio, Vincenti, Leonardo, Papagni, Vincenzo, Picciariello, Arcangelo, Rossi, Stefano, Picardi, Biagio, Del Monte, Simone Rossi, Visconti, Diego, Osella, Giulia, Petruzzelli, Luca, Pignata, Giusto, Andreuccetti, Jacopo, D’Alessio, Rossella, Buonfantino, Massimo, Guaitoli, Eleonora, Spinelli, Stefano, Sampietro, Gianluca Matteo, Corbellini, Carlo, Lorusso, Leonardo, Frontali, Alice, Pezzoli, Isabella, Bonomi, Alessandro, Chierici, Andrea, Cotsoglou, Christian, Manca, Giuseppe, Delvecchio, Antonella, Musa, Nicola, Casati, Massimiliano, Letizia, Laface, Abate, Emmanuele, Ercolani, Giorgio, D’Acapito, Fabrizio, Solaini, Leonardo, Guercioni, Gianluca, Cicconi, Simone, Sasia, Diego, Borghi, Felice, Giraudo, Giorgio, Sena, Giuseppe, Castaldo, Pasquale, Cardamone, Eugenia, Portale, Giuseppe, Zuin, Matteo, Spolverato, Ylenia, Esposito, Marialusia, Isernia, Roberta Maria, Di Salvo, Maria, Manunza, Romina, Esposito, Giuseppe, Agus, Marcello, Asti, Emanuele Luigi Giuseppe, Bernardi, Daniele Tiziano, Tonucci, Tommaso Panici, Luppi, Davide, Casadei, Massimiliano, Bonilauri, Stefano, Pezzolla, Angela, Panebianco, Annunziata, Laforgia, Rita, De Luca, Maurizio, Zese, Monica, Parini, Dario, Jovine, Elio, De Sario, Giuseppina, Lombardi, Raffaele, Aprea, Giovanni, Palomba, Giuseppe, Capuano, Marianna, Argenio, Giulio, Orio, Gianluca, Armellino, Mariano Fortunato, Troian, Marina, Guerra, Martina, Nagliati, Carlo, Biloslavo, Alan, Germani, Paola, Aizza, Giada, Monsellato, Igor, Chahrour, Ali Chaouki, Anania, Gabriele, Bombardini, Cristina, Bagolini, Francesco, Sganga, Gabriele, Fransvea, Pietro, Bianchi, Valentina, Boati, Paolo, Ferrara, Francesco, Palmieri, Francesco, Cianci, Pasquale, Gattulli, Domenico, Restini, Enrico, Cillara, Nicola, Cannavera, Alessandro, Nita, Gabriela Elisa, Sarnari, Jlenia, Roscio, Francesco, Clerici, Federico, Scandroglio, Ildo, Berti, Stefano, Cadeo, Alessandro, Filippelli, Alice, Conti, Luigi, Grassi, Carmine, Cattaneo, Gaetano Maria, Pighin, Marina, Papis, Davide, Gambino, Giovanni, Bertino, Vanessa, Schifano, Domenico, Prando, Daniela, Fogato, Luisella, Cavallo, Fabio, Ansaloni, Luca, Picheo, Roberto, Pontarolo, Nicholas, Depalma, Norma, Spampinato, Marcello, D’Ugo, Stefano, Lepre, Luca, Capponi, Michela Giulii, Campa, Rossella Domenica, Sarro, Giuliano, Dinuzzi, Vincenza Paola, Olmi, Stefano, Uccelli, Matteo, Ferrari, Davide, Inama, Marco, Moretto, Gianluigi, Fontana, Michele, Favi, Francesco, Picariello, Erika, Rampini, Alessia, Barberis, Andrea, Azzinnaro, Antonio, Oliva, Alba, Totaro, Luigi, Benzoni, Ilaria, Ranieri, Valerio, Capolupo, Gabriella Teresa, Carannante, Filippo, Caricato, Marco, Ronconi, Maurizio, Casiraghi, Silvia, Casole, Giovanni, Pantalone, Desire, Alemanno, Giovanni, Scheiterle, Maximilian, Ceresoli, Marco, Cereda, Marco, Fumagalli, Chiara, Zanzi, Federico, Bolzon, Stefano, Guerra, Enrico, Lecchi, Francesca, Cellerino, Paola, Ardito, Antonella, Scaramuzzo, Rosa, Balla, Andrea, Lepiane, Pasquale, Tartaglia, Nicola, Ambrosi, Antonio, Pavone, Giovanna, Palini, Gian Marco, Veneroni, Simone, Garulli, Gianluca, Ricci, Claudio, Torre, Beatrice, Russo, Iris Shari, Rottoli, Matteo, Tanzanu, Marta, Belvedere, Angela, Milone, Marco, Manigrasso, Michele, De Palma, Giovanni Domenico, Piccoli, Micaela, Pattacini, Gianmaria Casoni, Magnone, Stefano, Bertoli, Paolo, Pisano, Michele, Massucco, Paolo, Palisi, Marco, Luzzi, Andrea-Pierre, Fleres, Francesco, Clarizia, Guglielmo, Spolini, Alessandro, Kobe, Yoshiro, Toma, Takayuki, Shimamura, Fumihiko, Parker, Robert, Ranketi, Sinkeet, Mitei, Mercy, Svagzdys, Saulius, Pauzas, Henrikas, Zilinskas, Justas, Poskus, Tomas, Kryzauskas, Marius, Jakubauskas, Matas, Zakaria, Andee Dzulkarnaen, Zakaria, Zaidi, Wong, Michael Pak-Kai, Jusoh, Asri Che, Zakaria, Muhammad Nazreen, Cruz, Daniel Rios, Elizalde, Aurea Barbara Rodriguez, Reynaud, Alejandro Bañon, Hernandez, Edgard Efren Lozada, Monroy, Jose maria Victor Palomo, Hinojosa-Ugarte, Diego, Quiodettis, Martha, Du Bois, María Esther, Latorraca, José, Major, Piotr, Pędziwiatr, Michał, Pisarska-Adamczyk, Magdalena, Walędziak, Maciej, Kwiatkowski, Andrzej, Czyżykowski, Łukasz, da Costa, Silvia Dantas, Pereira, Bela, Ferreira, Ana Rita Oliveira, Almeida, Filipe, Rocha, Ricardo, Carneiro, Carla, Perez, Diego Pita, Carvas, João, Rocha, Catarina, Ferreira, Cátia, Marques, Rita, Fernandes, Urânia, Leao, Pedro, Goulart, André, Pereira, Rita Gonçalves, Patrocínio, Sara Daniela Direito, de Mendonça, Nuno Gonçalo Gonçalves, Manso, Maria Isabel Cerqueira, Morais, Henrique Manuel Cardoso, Cardoso, Paulo Sebastião, Calu, Valentin, Miron, Adrian, Toma, Elena Adelina, Gachabayov, Mahir, Abdullaev, Abakar, Litvin, Andrey, Nechay, Taras, Tyagunov, Alexander, Yuldashev, Anvar, Bradley, Alison, Wilson, Michael, Panyko, Arpád, Látečková, Zuzana, Lacko, Vladimír, Lesko, Dusan, Soltes, Marek, Radonak, Jozef, Turrado-Rodriguez, Victor, Termes-Serra, Roser, Morales-Sevillano, Xavier, Lapolla, Pierfrancesco, Mingoli, Andrea, Brachini, Gioia, Degiuli, Maurizio, Sofia, Silvia, Reddavid, Rossella, de Manzoni Garberini, Andrea, Buffone, Angelica, del Pozo, Eduardo Perea, Aparicio-Sánchez, Daniel, Dos Barbeito, Sandra, Estaire-Gómez, Mercedes, Vitón-Herrero, Rebeca, de los Ángeles Gil Olarte-Marquez, Mª, Gil-Martínez, José, Alconchel, Felipe, Nicolás-López, Tatiana, Rahy-Martin, Aida Cristina, Pelloni, María, Bañolas-Suarez, Raquel, Mendoza-Moreno, Fernando, Nisa, Francisca García-Moreno, Díez-Alonso, Manuel, Rodas, María Elisa Valle, Agundez, María Carmona, Andrés, María Inmaculada Pérez, Moreira, Claudia Cristina Lopes, Perez, Aintzane Lizarazu, Ponce, Iñigo Augusto, González-Castillo, Ana María, Membrilla-Fernández, Estela, Salvans, Silvia, Serradilla-Martín, Mario, Pardo, Pablo Sancho, Rivera-Alonso, Daniel, Dziakova, Jana, Huguet, Jose Mugüerza, Valle, Naila Pagès, Ruiz, Enrique Colás, Valcárcel, Cristina Rey, Moreno, Cristina Ruiz, Salazar, Yeniffer Tatiana Moreno, García, Juan Jesús Rubio, Micó, Silvia Sevila, López, Joaquín Ruiz, Farré, Silvia Pérez, Gomez, Maite Santamaria, Petit, Nuria Mestres, Titos-García, Alberto, Aranda-Narváez, Jose Manuel, Romacho-López, Laura, Sánchez-Guillén, Luis, Aranaz-Ostariz, Veronica, Bosch-Ramírez, Marina, Martínez-Pérez, Aleix, Martínez-López, Elías, Sebastián-Tomás, Juan Carlos, Jimenez-Riera, Granada, Jimenez-Vega, Javier, Cuellar, Jose Aurelio Navas, Campos-Serra, Andrea, Muñoz-Campaña, Anna, Gràcia-Roman, Raquel, Alegre, Javier Martínez, Pinto, Francisca Lima, O’Sullivan, Sara Nuñez, Antona, Francisco Blanco, Jiménez, Beatriz Muñoz, López-Sánchez, Jaime, Carmona, Zahira Gómez, Fernández, Rocio Torres, Sierra, Isabel Blesa, de León, Laura Román García, Moreno, Verónica Polaino, Iglesias, Eva, Cumplido, Paola Lora, Bravo, Altea Arango, Simó, Ignacio Rey, Domínguez, Carlota López, Caamaño, Aloia Guerreiro, Lozano, Rafael Calleja, Martínez, Manuel Durán, Torres, Álvaro Naranjo, de Quiros, Javier Tomas Morales Bernaldo, Pellino, Gianluca, Cloquell, Miriam Moratal, Moller, Elsa García, Jalal-Eldin, Sami, Abdoun, Ahmed K., Hamid, Hytham K. S., Lohsiriwat, Varut, Mongkhonsupphawan, Aitsariya, Baraket, Oussama, Ayed, Karim, Abbassi, Imed, Ali, Ali Ben, Ammar, Houssem, Kchaou, Ali, Tlili, Ahmed, Zribi, Imen, Colak, Elif, Polat, Suleyman, Koylu, Zehra Alan, Guner, Ali, Usta, Mehmet Arif, Reis, Murat Emre, Mantoglu, Baris, Gonullu, Emre, Akin, Emrah, Altintoprak, Fatih, Bayhan, Zulfu, Firat, Necattin, Isik, Arda, Memis, Ufuk, Bayrak, Mehmet, Altıntaş, Yasemin, Kara, Yasin, Bozkurt, Mehmet Abdussamet, Kocataş, Ali, Das, Koray, Seker, Ahmet, Ozer, Nazmi, Atici, Semra Demirli, Tuncer, Korhan, Kaya, Tayfun, Ozkan, Zeynep, Ilhan, Onur, Agackiran, Ibrahim, Uzunoglu, Mustafa Yener, Demirbas, Eren, Altinel, Yuksel, Meric, Serhat, Hacım, Nadir Adnan, Uymaz, Derya Salim, Omarov, Nail, Balık, Emre, Tebala, Giovanni D., Khalil, Hany, Rana, Mridul, Khan, Mansoor, Florence, Charlotte, Swaminathan, Christie, Leo, Cosimo Alex, Liasis, Lampros, Watfah, Josef, Trostchansky, Ivan, Delgado, Edward, Pontillo, Marcelo, Latifi, Rifat, Coimbra, Raul, Edwards, Sara, Lopez, Ana, Velmahos, George, Dorken, Ander, Gebran, Anthony, Palmer, Amanda, Oury, Jeffrey, Bardes, James M., Seng, Sirivan Suon, Coffua, Lauren S., Ratnasekera, Asanthi, Egodage, Tanya, Echeverria-Rosario, Karla, Armento, Isabella, Napolitano, Lena M., Sangji, Naveen F., Hemmila, Mark, Quick, Jacob A., Austin, Tyler R., Hyman, Theodore S., Curtiss, William, McClure, Amanda, Cairl, Nicholas, Biffl, Walter L., Truong, Hung P., Schaffer, Kathryn, Reames, Summer, Banchini, Filippo, Capelli, Patrizio, Coccolini, Federico, Sartelli, Massimo, Bravi, Francesca, Vallicelli, Carlo, Agnoletti, Vanni, Baiocchi, Gian Luca, and Catena, Fausto

Published
2024
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6. Time Tetris: a longitudinal study on compressed schedules and workplace well-being at IKEA

Author

Kristen du Bois, Stijn Baert, Louis Lippens, and Eva Derous

Subjects
Compressed schedule, Psychological detachment, Exhaustion, Burnout, Well-being, Public aspects of medicine, RA1-1270
Abstract

Abstract Background Compressed schedules, where workers perform longer daily hours to enjoy additional days off, are increasingly promoted as a workplace well-being intervention. Nevertheless, their implications for work-related well-being outcomes, such as recovery from work and burnout risk, are understudied. This gap leaves employers with little evidence on whether and how the arrangement contributes to workplace well-being. Methods IKEA Belgium offered its employees the option to enter compressed schedules in the aftermath of a national labour reform aimed at improving well-being and reducing burnout. We collected data on psychological detachment from work, work-related exhaustion, and burnout risk in four waves before and after implementation. We used mixed-effects growth models to estimate the within-subjects changes in these three domains, and two-way fixed effects models to compare changes with those from a non-treated comparison group. Results Workers experienced increased psychological detachment from work in compressed schedules, yet we saw no decrease in work-related exhaustion or burnout risk. While between-subjects analyses confirm that the increase in psychological detachment is related to treatment, they also hint that this association may fade out during summer when all workers take more extended breaks from work. Conclusions While workers in compressed schedules may mentally switch off from work more effectively, this does not translate into decreased burnout risk scores. Consistent with theoretical expectations, policymakers and employers should be cautious in assuming that the arrangements significantly reduce burnout.

Published
2025
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7. Visual Angles and Emotional Valence Affect Temporal Dynamics of Neural Representations of Facial Expression: An MEG Study

Author

Sanjeev Nara, Dheeraj Rathee, Nicola Molinaro, Naomi Du Bois, Braj Bhushan, and Girijesh Prasad

Subjects
Magnetoencephalography (MEG), temporal dynamics, emotion processing, multivariate pattern analysis (MVPA), Medical technology, R855-855.5, Therapeutics. Pharmacology, RM1-950
Abstract

Emotion processing has been a focus of research in Cognitive Neuroscience for decades. While the evoked neural markers as brain activations in response to different emotions have been reported, the temporal dynamics of emotion processing have received little attention. Furthermore, behavioral studies have found that the right side of the human face expresses emotions more accurately than the left side. Therefore, accounting for both the content of the emotion and the visual angle of the presentation from the viewer’s perspective, we have investigated temporal dynamics and variability in the processing of happy and sad emotions using magnetoencephalography (MEG), when the visual angle of presentation was either Positive (right side of the face) or Negative (left side of the face). Our results showed that decodable processing of happy emotions emerged earlier than that for sad emotions, irrespective of visual angle. However, the amplitude of the evoked response to sad emotions was higher than that to happy emotions, when faces were presented at Positive visual angles only. Source reconstructed Event Related Fields (ERFs) showed localized activities in ventral and dorsal streams including fusiform gyrus, lingual gyrus, putamen and pre and post central gyrus. Multivariate pattern analysis also demonstrated successful decoding of happy and sad emotions only when the facial expression was viewed from a positive visual angle.

Published
2025
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8. A Neighborhood-level analysis of mental health distress and income inequality as quasi-longitudinal risk of reported COVID-19 infection and mortality outcomes in Chicago

Author

Ramos, Stephen D, Kannout, Lynn, Khan, Humza, Klasko-Foster, Lynne, Chronister, Briana NC, and Du Bois, Steff

Subjects
Human Geography, Public Health, Health Sciences, Human Society, Clinical Research, Mental Health, Infectious Diseases, Behavioral and Social Science, Coronaviruses Disparities and At-Risk Populations, Basic Behavioral and Social Science, Emerging Infectious Diseases, Women's Health, Coronaviruses, Brain Disorders, Mental health, Good Health and Well Being, Reduced Inequalities, COVID-19 infection, COVID-19 mortality, Income inequality, Mental health distress, Neighborhood-level analysis
Abstract

Extant literature investigates the impact of COVID-19 on mental health outcomes, however there is a paucity of work examining mental health distress as a risk factor for COVID-19 outcomes. While systemic variables like income inequality relate to both mental health and COVID-19, more work is needed to test theoretically informed models including such variables. Using a social-ecological framework, we aimed to address these gaps in the literature by conducting a neighborhood-level analysis of potential mental health distress and systemic- (income inequality) level predictors of reported COVID-19 infection and mortality over time in Chicago. Neighborhood-level comparisons revealed differences in mental health distress, income inequality, and reported COVID-19 mortality, but not reported COVID-19 infection. Specifically, Westside and Southside neighborhoods generally reported higher levels of mental health distress and greater concentration of poverty. The Central neighborhood showed a decline in reported mortality rates over time. Multi-level negative binomial models established that Zip-codes with greater mental health distress were at increased reported COVID-19 infection risk, yet lower mortality risk; Zip-codes with more poverty were at increased reported COVID-19 infection risk, yet lower mortality risk; and Zip-codes with the highest percentage of People of Color were at decreased risk of reported COVID-19 mortality. Taken together, these findings substantiate Chicago neighborhood-level disparities in mental health distress, income inequality, and reported COVID-19 mortality; identify unique differential associations of mental health distress and income inequality to reported COVID-19 infection and reported mortality risk; and, offer an alternative lens towards understanding COVID-19 outcomes in terms of race/ethnicity.

Published
2023

10. The Crisis: A Record of the Darker Races, Vol. I, No. 4

Author

Du Bois, W.E.B.

Subjects
The Crisis: A Record of the Darker Races, vol. 1, no. 4 (Periodical), Literature/writing
Abstract

LibriVox recording of The Crisis: A Record of the Darker Races, Vol. I, No. 4 by W. E. B. Du Bois. Read in English by LibriVox Volunteers. The Crisis is [...]

Published
2024

13. Impact of metformin, statins, and beta blockers on survival in patients with primary ovarian cancer: combined analysis of four prospective trials of AGO-OVAR and ENGOT/GCIG collaborators

Author

Denschlag, Dominik, Heitz, Florian, Pfisterer, Jacobus, Tutschkow, Darja, Reuss, Alexander, Meier, Werner, Harter, Philipp, Wimberger, Pauline, Mirza, Mansoor Raza, Ray-Coquard, Isabelle, Scambia, Giovanni, Kim, Jae-Weon, Colombo, Nicoletta, Oaknin, Ana, Sehouli, Jalid, Lindemann, Kristina, Lebreton, Coriolan, Eichbaum, Michael, Spiegelberg, Stefan, Woopen, Hannah, and du Bois, Andreas

Published
2024
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14. The Crisis: A Record of the Darker Races, Vol. I, No. 3

Author

Du Bois, W.E.B.

Subjects
The Crisis: A Record of the Darker Races, vol. 1, no. 3 (Periodical), Literature/writing
Abstract

LibriVox recording of The Crisis: A Record of the Darker Races, Vol. I, No. 3 by W. E. B. Du Bois. Read in English by LibriVox Volunteers The Crisis is [...]

Published
2024

15. Dark Princess

Author

Du Bois, W.E.B.

Subjects
Dark Princess (Novel), Literature/writing
Abstract

LibriVox recording of Dark Princess by W. E. B. Du Bois. Read in English by Verla Viera This story begins as Matthew Towns, a brilliant young Black medical student, is [...]

Published
2024

16. Definition of a saxitoxin (STX) binding code enables discovery and characterization of the anuran saxiphilin family

Author

Chen, Zhou, Zakrzewska, Sandra, Hajare, Holly S, Alvarez-Buylla, Aurora, Abderemane-Ali, Fayal, Bogan, Maximiliana, Ramirez, Dave, O’Connell, Lauren A, Du Bois, J, and Minor, Daniel L

Subjects
Biochemistry and Cell Biology, Biological Sciences, Foodborne Illness, Animals, Saxitoxin, Ligands, Neurotoxins, Guanidine, Carrier Proteins, Rana catesbeiana, saxitoxin, saxiphilin, toxin resistance, anuran
Abstract

American bullfrog (Rana castesbeiana) saxiphilin (RcSxph) is a high-affinity "toxin sponge" protein thought to prevent intoxication by saxitoxin (STX), a lethal bis-guanidinium neurotoxin that causes paralytic shellfish poisoning (PSP) by blocking voltage-gated sodium channels (NaVs). How specific RcSxph interactions contribute to STX binding has not been defined and whether other organisms have similar proteins is unclear. Here, we use mutagenesis, ligand binding, and structural studies to define the energetic basis of Sxph:STX recognition. The resultant STX "recognition code" enabled engineering of RcSxph to improve its ability to rescue NaVs from STX and facilitated discovery of 10 new frog and toad Sxphs. Definition of the STX binding code and Sxph family expansion among diverse anurans separated by ∼140 My of evolution provides a molecular basis for understanding the roles of toxin sponge proteins in toxin resistance and for developing novel proteins to sense or neutralize STX and related PSP toxins.

Published
2022

18. Lubiprostone is non-selective activator of cAMP-gated ion channels and Clc-2 has a minor role in its prosecretory effect in intestinal epithelial cells.

Author

Oak, Apurva, Chu, Tifany, Yottasan, Pattareeya, Chhetri, Parth, Zhu, Jie, Du Bois, Justin, and Cil, Onur

Subjects
CFTR ion transporters, chloride channels
Abstract

Loss of prosecretory Cl- channel CFTR activity is considered as the key cause of gastrointestinal disorders in cystic fibrosis including constipation and meconium ileus. Clc-2 is proposed as an alternative Cl- channel in intestinal epithelia that can compensate for CFTR loss-of-function. Lubiprostone is an FDA-approved drug with Clc-2 activation as its presumed mechanism of action. However, relative contribution of Clc-2 in intestinal Cl- secretion and the mechanism of action of lubiprostone remain controversial due to lack of selective Clc-2 inhibitors. Using recently identified selective Clc-2 inhibitor AK-42, we characterized the roles of Clc-2 in Cl- secretion in human intestinal epithelial T84 cells. Clc-2 inhibitor AK-42 had minimal (15%) inhibitory effect on secretory short-circuit current (Isc) induced by cAMP agonists, where subsequently applied CFTR inhibitor (CFTRinh-172) caused 2-3 fold greater inhibition. Similarly, AK-42 inhibited lubiprostone-induced secretory Isc by 20%, whereas CFTRinh-172 caused 2-3 fold greater inhibition. In addition to increasing CFTR and Clc-2-mediated apical Cl- conductance, lubiprostone increased basolateral membrane K+ conductance, which was completely reversed by cAMP-activated K+ channel inhibitor BaCl2 All components of lubiprostone-induced secretion (Clc-2, CFTR and K+ channels) were inhibited by ~65% with the extracellular Ca2+-sensing receptor (CaSR) activator cinacalcet that stimulates cAMP hydrolysis. Lastly, EP4 prostaglandin receptor inhibitor GW627368 pretreatment inhibited lubiprostone-induced secretion by 40% without any effect on forskolin response. Our findings suggest that Clc-2 has minor role in cAMP-induced intestinal Cl- secretion; and lubiprostone is not a selective Clc-2 activator, but general activator of cAMP-gated ion channels in human intestinal epithelial cells. Significance Statement Cl- channel Clc-2 activation is the proposed mechanism of action of the FDA-approved constipation drug lubiprostone. Using first-in-class selective Clc-2 inhibitor AK-42, we showed that Clc-2 has minor contribution in intestinal Cl- secretion induced by lubiprostone and cAMP agonists. We also found that lubiprostone is a general activator of cAMP-gated ion channels in human intestinal epithelial cells (via EP4 receptors). Our findings clarify the roles of Clc-2 in intestinal Cl- secretion and elucidate the mechanism of action of approved-drug lubiprostone.

Published
2022

19. Schwann cell-secreted PGE2 promotes sensory neuron excitability during development

Author

Kantarci, Husniye, Elvira, Pablo D., Thottumkara, Arun P., O’Connell, Emma M., Iyer, Manasi, Donovan, Lauren J., Dugan, Micaela Quinn, Ambiel, Nicholas, Granados, Alejandro, Zeng, Hong, Saw, Nay L., Brosius Lutz, Amanda, Sloan, Steven A., Gray, Erin E., Tran, Khanh V., Vichare, Aditi, Yeh, Ashley K., Münch, Alexandra E., Huber, Max, Agrawal, Aditi, Morri, Maurizio, Zhong, Haining, Shamloo, Mehrdad, Anderson, Thomas Anthony, Tawfik, Vivianne L., Du Bois, J., and Zuchero, J. Bradley

Published
2024
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23. Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author

Dareng, Eileen O, Tyrer, Jonathan P, Barnes, Daniel R, Jones, Michelle R, Yang, Xin, Aben, Katja KH, Adank, Muriel A, Agata, Simona, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Aravantinos, Gerasimos, Arun, Banu K, Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V, Barkardottir, Rosa B, Barrowdale, Daniel, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q, Bjorge, Line, Black, Amanda, Bogdanova, Natalia V, Bonanni, Bernardo, Borg, Ake, Brenton, James D, Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S, Cai, Hui, Caligo, Maria A, Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K, Claes, Kathleen BM, Colonna, Sarah, Cook, Linda S, Couch, Fergus J, Daly, Mary B, Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A, Domchek, Susan M, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M, Eliassen, Heather A, Engel, Christoph, Evans, Gareth D, Fasching, Peter A, Flanagan, James M, Fortner, Renée T, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A, Garber, Judy, Gensini, Francesca, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goodman, Marc T, Greene, Mark H, Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Estrid, Høgdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, Huntsman, David G, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, James, Paul A, and Janavicius, Ramunas

Subjects
GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, OPAL Study Group, AOCS Group, KConFab Investigators, HEBON Investigators, OCAC Consortium, CIMBA Consortium, Genetics, Clinical Sciences, Genetics & Heredity
Published
2022

24. MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma

Author

Kang, Eun Young, Millstein, Joshua, Popovic, Gordana, Meagher, Nicola S, Bolithon, Adelyn, Talhouk, Aline, Chiu, Derek S, Anglesio, Michael S, Leung, Betty, Tang, Katrina, Lambie, Neil, Pavanello, Marina, Da-anoy, Annalyn, Lambrechts, Diether, Loverix, Liselore, Olbrecht, Siel, Bisinotto, Christiani, Garcia-Donas, Jesus, Ruiz-Llorente, Sergio, Yagüe-Fernandez, Monica, Edwards, Robert P, Elishaev, Esther, Olawaiye, Alexander, Taylor, Sarah, Ataseven, Beyhan, du Bois, Andreas, Harter, Philipp, Lester, Jenny, Høgdall, Claus K, Armasu, Sebastian M, Huang, Yajue, Vierkant, Robert A, Wang, Chen, Winham, Stacey J, Heublein, Sabine, Kommoss, Felix KF, Cramer, Daniel W, Sasamoto, Naoko, van-Wagensveld, Lilian, Lycke, Maria, Mateoiu, Constantina, Joseph, Janine, Pike, Malcolm C, Odunsi, Kunle, Tseng, Chiu-Chen, Pearce, Celeste L, Bilic, Sanela, Conrads, Thomas P, Hartmann, Arndt, Hein, Alexander, Jones, Michael E, Leung, Yee, Beckmann, Matthias W, Ruebner, Matthias, Schoemaker, Minouk J, Terry, Kathryn L, El-Bahrawy, Mona A, Coulson, Penny, Etter, John L, LaVigne-Mager, Katherine, Andress, Juergen, Grube, Marcel, Fischer, Anna, Neudeck, Nina, Robertson, Greg, Farrell, Rhonda, Barlow, Ellen, Quinn, Carmel, Hettiaratchi, Anusha, Casablanca, Yovanni, Erber, Ramona, Stewart, Colin JR, Tan, Adeline, Yu, Yu, Boros, Jessica, Brand, Alison H, Harnett, Paul R, Kennedy, Catherine J, Nevins, Nikilyn, Morgan, Terry, Fasching, Peter A, Vergote, Ignace, Swerdlow, Anthony J, Candido dos Reis, Francisco J, Maxwell, G Larry, Neuhausen, Susan L, Barquin-Garcia, Arantzazu, Modugno, Francesmary, Moysich, Kirsten B, Crowe, Philip J, Hirasawa, Akira, Heitz, Florian, Karlan, Beth Y, Goode, Ellen L, Sinn, Peter, Horlings, Hugo M, Høgdall, Estrid, Sundfeldt, Karin, Kommoss, Stefan, and Staebler, Annette

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Women's Health, Infectious Diseases, Rare Diseases, HIV/AIDS, Genetics, Sexually Transmitted Infections, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Biomarkers, Tumor, Cell Proliferation, Cystadenocarcinoma, Serous, Female, Humans, Ki-67 Antigen, Minichromosome Maintenance Complex Component 3, Ovarian Neoplasms, RNA, Messenger, Survival Rate, High-grade serous carcinoma, Proliferation, MCM3, Clinical Sciences, Pathology, Clinical sciences
Abstract

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p

Published
2022

25. Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author

Dareng, Eileen O, Tyrer, Jonathan P, Barnes, Daniel R, Jones, Michelle R, Yang, Xin, Aben, Katja KH, Adank, Muriel A, Agata, Simona, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Aravantinos, Gerasimos, Arun, Banu K, Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V, Barkardottir, Rosa B, Barrowdale, Daniel, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q, Bjorge, Line, Black, Amanda, Bogdanova, Natalia V, Bonanni, Bernardo, Borg, Ake, Brenton, James D, Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S, Cai, Hui, Caligo, Maria A, Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K, Claes, Kathleen BM, Colonna, Sarah, Cook, Linda S, Couch, Fergus J, Daly, Mary B, Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A, Domchek, Susan M, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M, Eliassen, Heather A, Engel, Christoph, Evans, Gareth D, Fasching, Peter A, Flanagan, James M, Fortner, Renée T, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A, Garber, Judy, Gensini, Francesca, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goodman, Marc T, Greene, Mark H, Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Estrid, Høgdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, Huntsman, David G, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, James, Paul A, and Janavicius, Ramunas

Subjects
Prevention, Cancer, Ovarian Cancer, Rare Diseases, Good Health and Well Being, Bayes Theorem, Breast Neoplasms, Carcinoma, Ovarian Epithelial, Female, Genetic Predisposition to Disease, Humans, Male, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, OPAL Study Group, AOCS Group, KConFab Investigators, HEBON Investigators, OCAC Consortium, CIMBA Consortium, Genetics, Clinical Sciences, Genetics & Heredity
Abstract

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

Published
2022

27. Fibroblast Growth Factor Receptors and Ligands in Context of Bevacizumab Response in Ovarian Carcinoma: An Exploratory Analysis of AGO-OVAR11/ICON-7

Author

Heublein, Sabine, Pfisterer, Jacobus, du Bois, Andreas, Anglesio, Michael, Aminossadati, Behnaz, Bhatti, Irfan, Sehouli, Jalid, Wimberger, Pauline, Schochter, Fabienne, Hilpert, Felix, Hillemanns, Peter, Kalder, Matthias, Schroeder, Willibald, Mahner, Sven, Burges, Alexander, Canzler, Ulrich, Gropp-Meier, Martina, Jackisch, Christian, Harter, Philipp, Kommoss, Stefan, and Marmé, Frederik

Published
2024
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30. Kwaheri

Author

Cleynhens, Greta Du Bois

Subjects
Arts, visual and performing, Literature/writing
Abstract

ON a sunny afternoon in early July 1962, I was standing in the corridor of the train that would take me away from Africa. Leaning on the wooden ledge of [...]

Published
2023

32. Expression, purification, and characterization of anuran saxiphilins using thermofluor, fluorescence polarization, and isothermal titration calorimetry

Author

Zhou Chen, Sandra Zakrzewska, Holly S. Hajare, J. Du Bois, and Daniel L. Minor, Jr.

Subjects
Protein Biochemistry, Protein expression and purification, Structural Biology, Science (General), Q1-390
Abstract

Summary: Anuran saxiphilins (Sxphs) are “toxin sponge” proteins thought to prevent the lethal effects of small-molecule neurotoxins through sequestration. Here, we present a protocol for the expression, purification, and characterization of Sxphs. We describe steps for using thermofluor, fluorescence polarization, and isothermal titration calorimetry assays that probe Sxph:saxitoxin interactions using a range of sample quantities. These assays are generalizable and can be used for other paralytic shellfish poisoning toxin-binding proteins.For complete details on the use and execution of this protocol, please refer to Chen et al. (2022).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Published
2024
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35. Evidence that toxin resistance in poison birds and frogs is not rooted in sodium channel mutations and may rely on “toxin sponge” proteins

Author

Abderemane-Ali, Fayal, Rossen, Nathan D, Kobiela, Megan E, Craig, Robert A, Garrison, Catherine E, Chen, Zhou, Colleran, Claire M, O’Connell, Lauren A, Du Bois, J, Dumbacher, John P, and Minor, Daniel L

Subjects
Zoology, Biological Sciences, Life on Land, Animals, Batrachotoxins, Birds, Mutation, Poisons, Sodium Channels, Physiology, Medical Physiology, Biochemistry and cell biology, Medical physiology
Abstract

Many poisonous organisms carry small-molecule toxins that alter voltage-gated sodium channel (NaV) function. Among these, batrachotoxin (BTX) from Pitohui poison birds and Phyllobates poison frogs stands out because of its lethality and unusual effects on NaV function. How these toxin-bearing organisms avoid autointoxication remains poorly understood. In poison frogs, a NaV DIVS6 pore-forming helix N-to-T mutation has been proposed as the BTX resistance mechanism. Here, we show that this variant is absent from Pitohui and poison frog NaVs, incurs a strong cost compromising channel function, and fails to produce BTX-resistant channels in poison frog NaVs. We also show that captivity-raised poison frogs are resistant to two NaV-directed toxins, BTX and saxitoxin (STX), even though they bear NaVs sensitive to both. Moreover, we demonstrate that the amphibian STX "toxin sponge" protein saxiphilin is able to protect and rescue NaVs from block by STX. Taken together, our data contradict the hypothesis that BTX autoresistance is rooted in the DIVS6 N→T mutation, challenge the idea that ion channel mutations are a primary driver of toxin resistance, and suggest the possibility that toxin sequestration mechanisms may be key for protecting poisonous species from the action of small-molecule toxins.

Published
2021

36. Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer

Author

Quinn, Michael CJ, McCue, Karen, Shi, Wei, Johnatty, Sharon E, Beesley, Jonathan, Civitarese, Andrew, O'Mara, Tracy A, Glubb, Dylan M, Tyrer, Jonathan P, Armasu, Sebastian M, Ong, Jue-Sheng, Gharahkhani, Puya, Lu, Yi, Gao, Bo, Patch, Ann-Marie, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Edwards, Digna R Velez, Beeghly-Fadiel, Alicia, Benitez, Javier, Garcia, Maria J, Goodman, Marc T, Dörk, Thilo, Dürst, Matthias, Modugno, Francesmary, Moysich, Kirsten, du Bois, Andreas, Pfisterer, Jacobus, Bauman, Klaus, Group, for the AGO Study, Karlan, Beth Y, Lester, Jenny, Cunningham, Julie M, Larson, Melissa C, McCauley, Bryan M, Kjaer, Susanne K, Jensen, Allan, Hogdall, Claus K, Hogdall, Estrid, Schildkraut, Joellen M, Riggan, Marjorie J, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bjorge, Line, Webb, Penelope M, Group, for the OPAL Study, Friedlander, Michael, Pejovic, Tanja, Moffitt, Melissa, Glasspool, Rosalind, May, Taymaa, Ene, Gabrielle EV, Huntsman, David G, Woo, Michelle, Carney, Michael E, Hinsley, Samantha, Heitz, Florian, Fereday, Sian, Kennedy, Catherine J, Edwards, Stacey L, Winham, Stacey J, deFazio, Anna, Group, for Australian Ovarian Cancer Study, Pharoah, Paul DP, Goode, Ellen L, MacGregor, Stuart, and Chenevix-Trench, Georgia

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Ovarian Cancer, Rare Diseases, Cancer, Women's Health, Human Genome, 2.1 Biological and endogenous factors, Autophagy-Related Protein-1 Homolog, Biomarkers, Tumor, Carcinoma, Ovarian Epithelial, Female, Gene Knockout Techniques, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Progression-Free Survival, AGO Study Group, OPAL Study Group, for Australian Ovarian Cancer Study Group, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundMany loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance.MethodsWe carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy.ResultsWe found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro.ConclusionsThe locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association.ImpactThis finding provides insight into genetic markers associated with EOC outcome and potential treatment options.See related commentary by Peres and Monteiro, p. 1604.

Published
2021

45. Lymph node staging in grade 1–2 endometrioid ovarian carcinoma apparently confined to the ovary: Is it worth?

Author

Bizzarri, Nicolò, Imterat, Majdi, Fruscio, Robert, Giannarelli, Diana, Perrone, Anna Myriam, Mancari, Rosanna, Traut, Alexander, Rosati, Andrea, du Bois, Andreas, Ferrari, Debora, De Iaco, Pierandrea, Ergasti, Raffaella, Ataseven, Beyhan, Bianchi, Tommaso, Di Stanislao, Marco, Perri, Maria Teresa, Heitz, Florian, Concin, Nicole, Fanfani, Francesco, Vizza, Enrico, Scambia, Giovanni, Harter, Philipp, and Fagotti, Anna

Published
2023
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50. CryoEM structures of the human CLC-2 voltage-gated chloride channel reveal a ball-and-chain gating mechanism

Author

Mengyuan Xu, Torben Neelands, Alexander S Powers, Yan Liu, Steven D Miller, Grigore D Pintilie, J Du Bois, Ron O Dror, Wah Chiu, and Merritt Maduke

Subjects
ion channel mechanisms, voltage-dependent gating, ion channel pharmacology, cryo-electron microscopy, electrophysiology, molecular dynamics simulations, Medicine, Science, Biology (General), QH301-705.5
Abstract

CLC-2 is a voltage-gated chloride channel that contributes to electrical excitability and ion homeostasis in many different tissues. Among the nine mammalian CLC homologs, CLC-2 is uniquely activated by hyperpolarization, rather than depolarization, of the plasma membrane. The molecular basis for the divergence in polarity of voltage gating among closely related homologs has been a long-standing mystery, in part because few CLC channel structures are available. Here, we report cryoEM structures of human CLC-2 at 2.46 – 2.76 Å, in the presence and absence of the selective inhibitor AK-42. AK-42 binds within the extracellular entryway of the Cl–-permeation pathway, occupying a pocket previously proposed through computational docking studies. In the apo structure, we observed two distinct conformations involving rotation of one of the cytoplasmic C-terminal domains (CTDs). In the absence of CTD rotation, an intracellular N-terminal 15-residue hairpin peptide nestles against the TM domain to physically occlude the Cl–-permeation pathway. This peptide is highly conserved among species variants of CLC-2 but is not present in other CLC homologs. Previous studies suggested that the N-terminal domain of CLC-2 influences channel properties via a “ball-and-chain” gating mechanism, but conflicting data cast doubt on such a mechanism, and thus the structure of the N-terminal domain and its interaction with the channel has been uncertain. Through electrophysiological studies of an N-terminal deletion mutant lacking the 15-residue hairpin peptide, we support a model in which the N-terminal hairpin of CLC-2 stabilizes a closed state of the channel by blocking the cytoplasmic Cl–-permeation pathway.

Published
2024
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