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6. Ethics in pre-ART genetics:a missed X-linked Menkes disease case

Author

Gerdes, A. M.A., Møller, L. Birk, Horn, N., Gerdes, A. M.A., Møller, L. Birk, and Horn, N.

Abstract

Assisted reproductive technology (ART) has experienced dramatic progress over the last 30 years, and gamete donation is routine in fertility clinics. Major advances in genetic diagnostics are part of this development due to the ability to analyze multiple genes or whole genomes fast and to an affordable prize. This requires knowledge and capability to evaluate genetic variants correctly in a clinical setting. Here we report a Menkes disease case, born after ART, where genetic screening and variant scoring failed to identify an egg donor as carrier of this fatal X-linked disorder. The gene variant is a deletion of a single base pair leading to a frameshift and premature termination of the protein, predicted to result in no or severely diminished function. The variant would be classified as likely pathogenic (class 4) and should be readily detectable by molecular genetic screening techniques. We wish to highlight this case to prevent future similar cases. IVI Igenomix has developed and embarked on an ambitious screening program to detect and prevent a large number of inherited severe childhood disorders in ART pregnancies. The company has recently achieved ISO 15189 certification with competence to evaluate and deliver timely, accurate, and reliable results. Failure to identify a pathogenic variant in the ATP7A gene leading to birth of two boys with Menkes disease invokes the required procedures to screen and detect disease-causing gene variants. This calls for ethical and legal considerations in ART diagnostics to prevent fatal errors like the present., Assisted reproductive technology (ART) has experienced dramatic progress over the last 30 years, and gamete donation is routine in fertility clinics. Major advances in genetic diagnostics are part of this development due to the ability to analyze multiple genes or whole genomes fast and to an affordable prize. This requires knowledge and capability to evaluate genetic variants correctly in a clinical setting. Here we report a Menkes disease case, born after ART, where genetic screening and variant scoring failed to identify an egg donor as carrier of this fatal X-linked disorder. The gene variant is a deletion of a single base pair leading to a frameshift and premature termination of the protein, predicted to result in no or severely diminished function. The variant would be classified as likely pathogenic (class 4) and should be readily detectable by molecular genetic screening techniques. We wish to highlight this case to prevent future similar cases. IVI Igenomix has developed and embarked on an ambitious screening program to detect and prevent a large number of inherited severe childhood disorders in ART pregnancies. The company has recently achieved ISO 15189 certification with competence to evaluate and deliver timely, accurate, and reliable results. Failure to identify a pathogenic variant in the ATP7A gene leading to birth of two boys with Menkes disease invokes the required procedures to screen and detect disease-causing gene variants. This calls for ethical and legal considerations in ART diagnostics to prevent fatal errors like the present.

Published
2023

8. Pre-surgery Optimization of Patients’ Expectations to Improve Outcome in Heart Surgery: Study Protocol of the Randomized Controlled Multicenter PSY-HEART-II Trial

Author

Salzmann, S., additional, Laferton, J., additional, Shedden-Mora, M., additional, Horn, N., additional, Gärtner, L., additional, Schröder, L., additional, Rau, J., additional, Schade-Brittinger, C., additional, Murmann, K., additional, Rastan, A., additional, Andrási, T., additional, Böning, A., additional, Salzmann-Djufri, M., additional, Löwe, B., additional, Brickwedel, J., additional, Albus, C., additional, Wahlers, T., additional, Hamm, A., additional, Hilker, L., additional, Albert, W., additional, Zimmermann, T., additional, Ismail, I., additional, Strauß, B., additional, Doenst, T., additional, Schedlowski, M., additional, Moosdorf, R., additional, and Rief, W., additional

Published
2023
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14. Thrombectomy in Extensive Stroke May Not Be Beneficial and Is Associated with Increased Risk for Hemorrhage

Author

Meyer, L. Bechstein, M. Bester, M. Hanning, U. Brekenfeld, C. Flottmann, F. Kniep, H. Van Horn, N. Deb-Chatterji, M. Thomalla, G. Sporns, P. Yeo, L.L.-L. Tan, B.Y.-Q. Gopinathan, A. Kastrup, A. Politi, M. Papanagiotou, P. Kemmling, A. Fiehler, J. Broocks, G.

Abstract

Background and Purpose: This study evaluates the benefit of endovascular treatment (EVT) for patients with extensive baseline stroke compared with best medical treatment. Methods: This retrospective, multicenter study compares EVT and best medical treatment for computed tomography (CT)-based selection of patients with extensive baseline infarcts (Alberta Stroke Program Early CT Score ≤5) attributed to anterior circulation stroke. Patients were selected from the German Stroke Registry and 3 tertiary stroke centers. Primary functional end points were rates of good (modified Rankin Scale score of ≤3) and very poor outcome (modified Rankin Scale score of ≥5) at 90 days. Secondary safety end point was the occurrence of symptomatic intracerebral hemorrhage. Angiographic outcome was evaluated with the modified Thrombolysis in Cerebral Infarction Scale. Results: After 1:1 pair matching, a total of 248 patients were compared by treatment arm. Good functional outcome was observed in 27.4% in the EVT group, and in 25% in the best medical treatment group (P=0.665). Advanced age (adjusted odds ratio, 1.08 [95% CI, 1.05-1.10], P

Published
2021

15. Global impact of COVID-19 on stroke care

Author

Nogueira, R.G. Abdalkader, M. Qureshi, M.M. Frankel, M.R. Mansour, O.Y. Yamagami, H. Qiu, Z. Farhoudi, M. Siegler, J.E. Yaghi, S. Raz, E. Sakai, N. Ohara, N. Piotin, M. Mechtouff, L. Eker, O. Chalumeau, V. Kleinig, T.J. Pop, R. Liu, J. Winters, H.S. Shang, X. Vasquez, A.R. Blasco, J. Arenillas, J.F. Martinez-Galdamez, M. Brehm, A. Psychogios, M.-N. Lylyk, P. Haussen, D.C. Al-Bayati, A.R. Mohammaden, M.H. Fonseca, L. Luís Silva, M. Montalverne, F. Renieri, L. Mangiafico, S. Fischer, U. Gralla, J. Frei, D. Chugh, C. Mehta, B.P. Nagel, S. Mohlenbruch, M. Ortega-Gutierrez, S. Farooqui, M. Hassan, A.E. Taylor, A. Lapergue, B. Consoli, A. Campbell, B.C.V. Sharma, M. Walker, M. Van Horn, N. Fiehler, J. Nguyen, H.T. Nguyen, Q.T. Watanabe, D. Zhang, H. Le, H.V. Nguyen, V.Q. Shah, R. Devlin, T. Khandelwal, P. Linfante, I. Izzath, W. Lavados, P.M. Olavarría, V.V. Sampaio Silva, G. de Carvalho Sousa, A.V. Kirmani, J. Bendszus, M. Amano, T. Yamamoto, R. Doijiri, R. Tokuda, N. Yamada, T. Terasaki, T. Yazawa, Y. Morris, J.G. Griffin, E. Thornton, J. Lavoie, P. Matouk, C. Hill, M.D. Demchuk, A.M. Killer-Oberpfalzer, M. Nahab, F. Altschul, D. Ramos-Pachón, A. Pérez de la Ossa, N. Kikano, R. Boisseau, W. Walker, G. Cordina, S.M. Puri, A. Luisa Kuhn, A. Gandhi, D. Ramakrishnan, P. Novakovic-White, R. Chebl, A. Kargiotis, O. Czap, A. Zha, A. Masoud, H.E. Lopez, C. Ozretic, D. Al-Mufti, F. Zie, W. Duan, Z. Yuan, Z. Huang, W. Hao, Y. Luo, J. Kalousek, V. Bourcier, R. Guile, R. Hetts, S. Al-Jehani, H.M. AlHazzani, A. Sadeghi-Hokmabadi, E. Teleb, M. Payne, J. Lee, J.S. Hong, J.M. Sohn, S.-I. Hwang, Y.-H. Shin, D.H. Roh, H.G. Edgell, R. Khatri, R. Smith, A. Malik, A. Liebeskind, D. Herial, N. Jabbour, P. Magalhaes, P. Ozdemir, A.O. Aykac, O. Uwatoko, T. Dembo, T. Shimizu, H. Sugiura, Y. Miyashita, F. Fukuda, H. Miyake, K. Shimbo, J. Sugimura, Y. Beer-Furlan, A. Joshi, K. Catanese, L. Abud, D.G. Neto, O.G. Mehrpour, M. Al Hashmi, A. Saqqur, M. Mostafa, A. Fifi, J.T. Hussain, S. John, S. Gupta, R. Sivan-Hoffmann, R. Reznik, A. Sani, A.F. Geyik, S. Akıl, E. Churojana, A. Ghoreishi, A. Saadatnia, M. Sharifipour, E. Ma, A. Faulder, K. Wu, T. Leung, L. Malek, A. Voetsch, B. Wakhloo, A. Rivera, R. Barrientos Iman, D.M. Pikula, A. Lioutas, V.-A. Thomalla, G. Birnbaum, L. Machi, P. Bernava, G. McDermott, M. Kleindorfer, D. Wong, K. Patterson, M.S. Fiorot, J.A., Jr. Huded, V. Mack, W. Tenser, M. Eskey, C. Multani, S. Kelly, M. Janardhan, V. Cornett, O. Singh, V. Murayama, Y. Mokin, M. Yang, P. Zhang, X. Yin, C. Han, H. Peng, Y. Chen, W. Crosa, R. Frudit, M.E. Pandian, J.D. Kulkarni, A. Yagita, Y. Takenobu, Y. Matsumaru, Y. Yamada, S. Kono, R. Kanamaru, T. Yamazaki, H. Sakaguchi, M. Todo, K. Yamamoto, N. Sonoda, K. Yoshida, T. Hashimoto, H. Nakahara, I. Cora, E. Volders, D. Ducroux, C. Shoamanesh, A. Ospel, J. Kaliaev, A. Ahmed, S. Rashid, U. Rebello, L.C. Pereira, V.M. Fahed, R. Chen, M. Sheth, S.A. Palaiodimou, L. Tsivgoulis, G. Chandra, R. Koyfman, F. Leung, T. Khosravani, H. Dharmadhikari, S. Frisullo, G. Calabresi, P. Tsiskaridze, A. Lobjanidze, N. Grigoryan, M. Czlonkowska, A. de Sousa, D.A. Demeestere, J. Liang, C. Sangha, N. Lutsep, H.L. Ayo-Martín, Ó. Cruz-Culebras, A. Tran, A.D. Young, C.Y. Cordonnier, C. Caparros, F. De Lecinana, M.A. Fuentes, B. Yavagal, D. Jovin, T. Spelle, L. Moret, J. Khatri, P. Zaidat, O. Raymond, J. Martins, S. Nguyen, T.

Abstract

Background: The COVID-19 pandemic led to profound changes in the organization of health care systems worldwide. Aims: We sought to measure the global impact of the COVID-19 pandemic on the volumes for mechanical thrombectomy, stroke, and intracranial hemorrhage hospitalizations over a three-month period at the height of the pandemic (1 March–31 May 2020) compared with two control three-month periods (immediately preceding and one year prior). Methods: Retrospective, observational, international study, across 6 continents, 40 countries, and 187 comprehensive stroke centers. The diagnoses were identified by their ICD-10 codes and/or classifications in stroke databases at participating centers. Results: The hospitalization volumes for any stroke, intracranial hemorrhage, and mechanical thrombectomy were 26,699, 4002, and 5191 in the three months immediately before versus 21,576, 3540, and 4533 during the first three pandemic months, representing declines of 19.2% (95%CI, −19.7 to −18.7), 11.5% (95%CI, −12.6 to −10.6), and 12.7% (95%CI, −13.6 to −11.8), respectively. The decreases were noted across centers with high, mid, and low COVID-19 hospitalization burden, and also across high, mid, and low volume stroke/mechanical thrombectomy centers. High-volume COVID-19 centers (−20.5%) had greater declines in mechanical thrombectomy volumes than mid- (−10.1%) and low-volume (−8.7%) centers (p < 0.0001). There was a 1.5% stroke rate across 54,366 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.9% (784/20,250) of all stroke admissions. Conclusion: The COVID-19 pandemic was associated with a global decline in the volume of overall stroke hospitalizations, mechanical thrombectomy procedures, and intracranial hemorrhage admission volumes. Despite geographic variations, these volume reductions were observed regardless of COVID-19 hospitalization burden and pre-pandemic stroke/mechanical thrombectomy volumes. © 2021 World Stroke Organization.

Published
2021

16. Global impact of COVID-19 on stroke care

Author

Nogueira, RG, Abdalkader, M, Qureshi, MM, Frankel, MR, Mansour, OY, Yamagami, H, Qiu, Z, Farhoudi, M, Siegler, JE, Yaghi, S, Raz, E, Sakai, N, Ohara, N, Piotin, M, Mechtouff, L, Eker, O, Chalumeau, V, Kleinig, TJ, Pop, R, Liu, J, Winters, HS, Shang, X, Rodriguez Vasquez, A, Blasco, J, Arenillas, JF, Martinez-Galdamez, M, Brehm, A, Psychogios, M-N, Lylyk, P, Haussen, DC, Al-Bayati, AR, Mohammaden, MH, Fonseca, L, Luis Silva, M, Montalverne, F, Renieri, L, Mangiafico, S, Fischer, U, Gralla, J, Frei, D, Chugh, C, Mehta, BP, Nagel, S, Mohlenbruch, M, Ortega-Gutierrez, S, Farooqui, M, Hassan, AE, Taylor, A, Lapergue, B, Consoli, A, Campbell, BCV, Sharma, M, Walker, M, Van Horn, N, Fiehler, J, Huy, TN, Nguyen, QT, Watanabe, D, Zhang, H, Le, HV, Nguyen, VQ, Shah, R, Devlin, T, Khandelwal, P, Linfante, I, Izzath, W, Lavados, PM, Olavarria, VV, Silva, GS, de Carvalho Sousa, AV, Kirmani, J, Bendszus, M, Amano, T, Yamamoto, R, Doijiri, R, Tokuda, N, Yamada, T, Terasaki, T, Yazawa, Y, Morris, JG, Griffin, E, Thornton, J, Lavoie, P, Matouk, C, Hill, MD, Demchuk, AM, Killer-Oberpfalzer, M, Nahab, F, Altschul, D, Ramos-Pachon, A, Perez de la Ossa, N, Kikano, R, Boisseau, W, Walker, G, Cordina, SM, Puri, A, Kuhn, AL, Gandhi, D, Ramakrishnan, P, Novakovic-White, R, Chebl, A, Kargiotis, O, Czap, A, Zha, A, Masoud, HE, Lopez, C, Ozretic, D, Al-Mufti, F, Zie, W, Duan, Z, Yuan, Z, Huang, W, Hao, Y, Luo, J, Kalousek, V, Bourcier, R, Guile, R, Hetts, S, Al-Jehani, HM, AlHazzani, A, Sadeghi-Hokmabadi, E, Teleb, M, Payne, J, Lee, JS, Hong, JM, Sohn, S-I, Hwang, Y-H, Shin, DH, Roh, HG, Edgell, R, Khatri, R, Smith, A, Malik, A, Liebeskind, D, Herial, N, Jabbour, P, Magalhaes, P, Ozdemir, AO, Aykac, O, Uwatoko, T, Dembo, T, Shimizu, H, Sugiura, Y, Miyashita, F, Fukuda, H, Miyake, K, Shimbo, J, Sugimura, Y, Beer-Furlan, A, Joshi, K, Catanese, L, Abud, DG, Pontes Neto, O, Mehrpour, M, Al Hashmi, A, Saqqur, M, Mostafa, A, Fifi, JT, Hussain, S, John, S, Gupta, R, Sivan-Hoffmann, R, Reznik, A, Sani, AF, Geyik, S, Akil, ECR, Churojana, A, Ghoreishi, A, Saadatnia, M, Sharifipour, E, Ma, A, Faulder, K, Wu, T, Leung, L, Malek, A, Voetsch, B, Wakhloo, A, Rivera, R, Barrientos Iman, DM, Pikula, A, Lioutas, V-A, Thomalla, G, Birnbaum, L, Machi, P, Bernava, G, McDermott, M, Kleindorfer, D, Wong, K, Patterson, MS, Fiorot, JA, Huded, V, Mack, W, Tenser, M, Eskey, C, Multani, S, Kelly, M, Janardhan, V, Cornett, O, Singh, V, Murayama, Y, Mokin, M, Yang, P, Zhang, X, Yin, C, Han, H, Peng, Y, Chen, W, Crosa, R, Frudit, ME, Pandian, JD, Kulkarni, A, Yagita, Y, Takenobu, Y, Matsumaru, Y, Yamada, S, Kono, R, Kanamaru, T, Yamazaki, H, Sakaguchi, M, Todo, K, Yamamoto, N, Sonoda, K, Yoshida, T, Hashimoto, H, Nakahara, I, Cora, E, Volders, D, Ducroux, C, Shoamanesh, A, Ospel, J, Kaliaev, A, Ahmed, S, Rashid, U, Rebello, LC, Pereira, VM, Fahed, R, Chen, M, Sheth, SA, Palaiodimou, L, Tsivgoulis, G, Chandra, R, Koyfman, F, Leung, T, Khosravani, H, Dharmadhikari, S, Frisullo, G, Calabresi, P, Tsiskaridze, A, Lobjanidze, N, Grigoryan, M, Czlonkowska, A, de Sousa, DA, Demeestere, J, Liang, C, Sangha, N, Lutsep, HL, Ayo-Martin, O, Cruz-Culebras, A, Tran, AD, Young, CY, Cordonnier, C, Caparros, F, Alonso De Lecinana, M, Fuentes, B, Yavagal, D, Jovin, T, Spelle, L, Moret, J, Khatri, P, Zaidat, O, Raymond, J, Martins, S, Thanh, N, Nogueira, RG, Abdalkader, M, Qureshi, MM, Frankel, MR, Mansour, OY, Yamagami, H, Qiu, Z, Farhoudi, M, Siegler, JE, Yaghi, S, Raz, E, Sakai, N, Ohara, N, Piotin, M, Mechtouff, L, Eker, O, Chalumeau, V, Kleinig, TJ, Pop, R, Liu, J, Winters, HS, Shang, X, Rodriguez Vasquez, A, Blasco, J, Arenillas, JF, Martinez-Galdamez, M, Brehm, A, Psychogios, M-N, Lylyk, P, Haussen, DC, Al-Bayati, AR, Mohammaden, MH, Fonseca, L, Luis Silva, M, Montalverne, F, Renieri, L, Mangiafico, S, Fischer, U, Gralla, J, Frei, D, Chugh, C, Mehta, BP, Nagel, S, Mohlenbruch, M, Ortega-Gutierrez, S, Farooqui, M, Hassan, AE, Taylor, A, Lapergue, B, Consoli, A, Campbell, BCV, Sharma, M, Walker, M, Van Horn, N, Fiehler, J, Huy, TN, Nguyen, QT, Watanabe, D, Zhang, H, Le, HV, Nguyen, VQ, Shah, R, Devlin, T, Khandelwal, P, Linfante, I, Izzath, W, Lavados, PM, Olavarria, VV, Silva, GS, de Carvalho Sousa, AV, Kirmani, J, Bendszus, M, Amano, T, Yamamoto, R, Doijiri, R, Tokuda, N, Yamada, T, Terasaki, T, Yazawa, Y, Morris, JG, Griffin, E, Thornton, J, Lavoie, P, Matouk, C, Hill, MD, Demchuk, AM, Killer-Oberpfalzer, M, Nahab, F, Altschul, D, Ramos-Pachon, A, Perez de la Ossa, N, Kikano, R, Boisseau, W, Walker, G, Cordina, SM, Puri, A, Kuhn, AL, Gandhi, D, Ramakrishnan, P, Novakovic-White, R, Chebl, A, Kargiotis, O, Czap, A, Zha, A, Masoud, HE, Lopez, C, Ozretic, D, Al-Mufti, F, Zie, W, Duan, Z, Yuan, Z, Huang, W, Hao, Y, Luo, J, Kalousek, V, Bourcier, R, Guile, R, Hetts, S, Al-Jehani, HM, AlHazzani, A, Sadeghi-Hokmabadi, E, Teleb, M, Payne, J, Lee, JS, Hong, JM, Sohn, S-I, Hwang, Y-H, Shin, DH, Roh, HG, Edgell, R, Khatri, R, Smith, A, Malik, A, Liebeskind, D, Herial, N, Jabbour, P, Magalhaes, P, Ozdemir, AO, Aykac, O, Uwatoko, T, Dembo, T, Shimizu, H, Sugiura, Y, Miyashita, F, Fukuda, H, Miyake, K, Shimbo, J, Sugimura, Y, Beer-Furlan, A, Joshi, K, Catanese, L, Abud, DG, Pontes Neto, O, Mehrpour, M, Al Hashmi, A, Saqqur, M, Mostafa, A, Fifi, JT, Hussain, S, John, S, Gupta, R, Sivan-Hoffmann, R, Reznik, A, Sani, AF, Geyik, S, Akil, ECR, Churojana, A, Ghoreishi, A, Saadatnia, M, Sharifipour, E, Ma, A, Faulder, K, Wu, T, Leung, L, Malek, A, Voetsch, B, Wakhloo, A, Rivera, R, Barrientos Iman, DM, Pikula, A, Lioutas, V-A, Thomalla, G, Birnbaum, L, Machi, P, Bernava, G, McDermott, M, Kleindorfer, D, Wong, K, Patterson, MS, Fiorot, JA, Huded, V, Mack, W, Tenser, M, Eskey, C, Multani, S, Kelly, M, Janardhan, V, Cornett, O, Singh, V, Murayama, Y, Mokin, M, Yang, P, Zhang, X, Yin, C, Han, H, Peng, Y, Chen, W, Crosa, R, Frudit, ME, Pandian, JD, Kulkarni, A, Yagita, Y, Takenobu, Y, Matsumaru, Y, Yamada, S, Kono, R, Kanamaru, T, Yamazaki, H, Sakaguchi, M, Todo, K, Yamamoto, N, Sonoda, K, Yoshida, T, Hashimoto, H, Nakahara, I, Cora, E, Volders, D, Ducroux, C, Shoamanesh, A, Ospel, J, Kaliaev, A, Ahmed, S, Rashid, U, Rebello, LC, Pereira, VM, Fahed, R, Chen, M, Sheth, SA, Palaiodimou, L, Tsivgoulis, G, Chandra, R, Koyfman, F, Leung, T, Khosravani, H, Dharmadhikari, S, Frisullo, G, Calabresi, P, Tsiskaridze, A, Lobjanidze, N, Grigoryan, M, Czlonkowska, A, de Sousa, DA, Demeestere, J, Liang, C, Sangha, N, Lutsep, HL, Ayo-Martin, O, Cruz-Culebras, A, Tran, AD, Young, CY, Cordonnier, C, Caparros, F, Alonso De Lecinana, M, Fuentes, B, Yavagal, D, Jovin, T, Spelle, L, Moret, J, Khatri, P, Zaidat, O, Raymond, J, Martins, S, and Thanh, N

Abstract

BACKGROUND: The COVID-19 pandemic led to profound changes in the organization of health care systems worldwide. AIMS: We sought to measure the global impact of the COVID-19 pandemic on the volumes for mechanical thrombectomy, stroke, and intracranial hemorrhage hospitalizations over a three-month period at the height of the pandemic (1 March-31 May 2020) compared with two control three-month periods (immediately preceding and one year prior). METHODS: Retrospective, observational, international study, across 6 continents, 40 countries, and 187 comprehensive stroke centers. The diagnoses were identified by their ICD-10 codes and/or classifications in stroke databases at participating centers. RESULTS: The hospitalization volumes for any stroke, intracranial hemorrhage, and mechanical thrombectomy were 26,699, 4002, and 5191 in the three months immediately before versus 21,576, 3540, and 4533 during the first three pandemic months, representing declines of 19.2% (95%CI, -19.7 to -18.7), 11.5% (95%CI, -12.6 to -10.6), and 12.7% (95%CI, -13.6 to -11.8), respectively. The decreases were noted across centers with high, mid, and low COVID-19 hospitalization burden, and also across high, mid, and low volume stroke/mechanical thrombectomy centers. High-volume COVID-19 centers (-20.5%) had greater declines in mechanical thrombectomy volumes than mid- (-10.1%) and low-volume (-8.7%) centers (p < 0.0001). There was a 1.5% stroke rate across 54,366 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.9% (784/20,250) of all stroke admissions. CONCLUSION: The COVID-19 pandemic was associated with a global decline in the volume of overall stroke hospitalizations, mechanical thrombectomy procedures, and intracranial hemorrhage admission volumes. Despite geographic variations, these volume reductions were observed regardless of COVID-19 hospitalization burden and pre-pandemic stroke/mechanical thrombectomy volumes.

Published
2021

18. Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D

Author

Kennedy, S. A., Jarboui, M. -A, Srihari, S., Raso, C., Bryan, K., Dernayka, L., Charitou, T., Bernal-Llinares, M., Herrera-Montavez, C., Krstic, A., Matallanas, D., Kotlyar, M., Jurisica, I., Curak, J., Wong, V., Stagljar, I., LeBihan, T., Imrie, L., Pillai, P., Lynn, M. A., Fasterius, Erik, Al-Khalili Szigyarto, Cristina, Breen, J., Kiel, C., Serrano, L., Rauch, N., Rukhlenko, O., Kholodenko, B. N., Iglesias-Martinez, L. F., Ryan, C. J., Pilkington, R., Cammareri, P., Sansom, O., Shave, S., Auer, M., Horn, N., Klose, F., Ueffing, M., Boldt, K., Lynn, D. J., Kolch, W., Kennedy, S. A., Jarboui, M. -A, Srihari, S., Raso, C., Bryan, K., Dernayka, L., Charitou, T., Bernal-Llinares, M., Herrera-Montavez, C., Krstic, A., Matallanas, D., Kotlyar, M., Jurisica, I., Curak, J., Wong, V., Stagljar, I., LeBihan, T., Imrie, L., Pillai, P., Lynn, M. A., Fasterius, Erik, Al-Khalili Szigyarto, Cristina, Breen, J., Kiel, C., Serrano, L., Rauch, N., Rukhlenko, O., Kholodenko, B. N., Iglesias-Martinez, L. F., Ryan, C. J., Pilkington, R., Cammareri, P., Sansom, O., Shave, S., Auer, M., Horn, N., Klose, F., Ueffing, M., Boldt, K., Lynn, D. J., and Kolch, W.

Abstract

Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes., QC 20200304

Published
2020
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19. CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module

Author

Dougherty, G.W., Mizuno, K., Nöthe-Menchen, T., Ikawa, Y., Boldt, K., Ta-Shma, A., Aprea, I., Minegishi, K., Pang, Y.P., Pennekamp, P., Loges, N.T., Raidt, J., Hjeij, R., Wallmeier, J., Mussaffi, H., Perles, Z., Elpeleg, O., Rabert, F., Shiratori, H., Letteboer, S.J.F., Horn, N., Young, S., Strünker, T., Stumme, F., Werner, C., Olbrich, H., Takaoka, K., Ide, T., Twan, W.K., Biebach, L., Große-Onnebrink, J., Klinkenbusch, J.A., Praveen, K., Bracht, D.C., Höben, I.M., Junger, K., Gützlaff, J., Cindrić, S., Aviram, M., Kaiser, T., Memari, Y., Dzeja, P.P., Dworniczak, B., Ueffing, M., Roepman, R., Bartscherer, K., Katsanis, N., Davis, E.E., Amirav, I., Hamada, H., Omran, H., Dougherty, G.W., Mizuno, K., Nöthe-Menchen, T., Ikawa, Y., Boldt, K., Ta-Shma, A., Aprea, I., Minegishi, K., Pang, Y.P., Pennekamp, P., Loges, N.T., Raidt, J., Hjeij, R., Wallmeier, J., Mussaffi, H., Perles, Z., Elpeleg, O., Rabert, F., Shiratori, H., Letteboer, S.J.F., Horn, N., Young, S., Strünker, T., Stumme, F., Werner, C., Olbrich, H., Takaoka, K., Ide, T., Twan, W.K., Biebach, L., Große-Onnebrink, J., Klinkenbusch, J.A., Praveen, K., Bracht, D.C., Höben, I.M., Junger, K., Gützlaff, J., Cindrić, S., Aviram, M., Kaiser, T., Memari, Y., Dzeja, P.P., Dworniczak, B., Ueffing, M., Roepman, R., Bartscherer, K., Katsanis, N., Davis, E.E., Amirav, I., Hamada, H., and Omran, H.

Abstract

Contains fulltext : 229376.pdf (publisher's version ) (Open Access), Axonemal dynein ATPases direct ciliary and flagellar beating via adenosine triphosphate (ATP) hydrolysis. The modulatory effect of adenosine monophosphate (AMP) and adenosine diphosphate (ADP) on flagellar beating is not fully understood. Here, we describe a deficiency of cilia and flagella associated protein 45 (CFAP45) in humans and mice that presents a motile ciliopathy featuring situs inversus totalis and asthenospermia. CFAP45-deficient cilia and flagella show normal morphology and axonemal ultrastructure. Proteomic profiling links CFAP45 to an axonemal module including dynein ATPases and adenylate kinase as well as CFAP52, whose mutations cause a similar ciliopathy. CFAP45 binds AMP in vitro, consistent with structural modelling that identifies an AMP-binding interface between CFAP45 and AK8. Microtubule sliding of dyskinetic sperm from Cfap45(-/-) mice is rescued with the addition of either AMP or ADP with ATP, compared to ATP alone. We propose that CFAP45 supports mammalian ciliary and flagellar beating via an adenine nucleotide homeostasis module.

Published
2020

20. Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D.

Author

Kennedy, SA, Jarboui, M-A, Srihari, S, Raso, C, Bryan, K, Dernayka, L, Charitou, T, Bernal-Llinares, M, Herrera-Montavez, C, Krstic, A, Matallanas, D, Kotlyar, M, Jurisica, I, Curak, J, Wong, V, Stagljar, I, LeBihan, T, Imrie, L, Pillai, P, Lynn, MA, Fasterius, E, Al-Khalili Szigyarto, C, Breen, J, Kiel, C, Serrano, L, Rauch, N, Rukhlenko, O, Kholodenko, BN, Iglesias-Martinez, LF, Ryan, CJ, Pilkington, R, Cammareri, P, Sansom, O, Shave, S, Auer, M, Horn, N, Klose, F, Ueffing, M, Boldt, K, Lynn, DJ, Kolch, W, Kennedy, SA, Jarboui, M-A, Srihari, S, Raso, C, Bryan, K, Dernayka, L, Charitou, T, Bernal-Llinares, M, Herrera-Montavez, C, Krstic, A, Matallanas, D, Kotlyar, M, Jurisica, I, Curak, J, Wong, V, Stagljar, I, LeBihan, T, Imrie, L, Pillai, P, Lynn, MA, Fasterius, E, Al-Khalili Szigyarto, C, Breen, J, Kiel, C, Serrano, L, Rauch, N, Rukhlenko, O, Kholodenko, BN, Iglesias-Martinez, LF, Ryan, CJ, Pilkington, R, Cammareri, P, Sansom, O, Shave, S, Auer, M, Horn, N, Klose, F, Ueffing, M, Boldt, K, Lynn, DJ, and Kolch, W

Abstract

Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.

Published
2020

35. Molecular analysis of the regulation of nisin immunity

Author

Dodd, H.M., Horn, N., Chan, W.C., Giffard, C.J., Bycroft, B.W., Roberts, G.C.K., and Gasson, M.J.

Subjects
Immunogenetics -- Research, Biosynthesis -- Genetic aspects, Biological sciences
Abstract

The putative response regulator of nisin biosynthesis, the nisR gene product, was discovered to be an essential part of the induction mechanism of the control of nisin immunity. This protein is a component of a two-part regulatory system which controls the expression of genes needed in nisin immunity and biosynthesis. Findings revealed that the 12 amino-terminal residues of the molecule are a minimum requirement for induction, with an intact ring A being a vital part.

Published
1996

36. Structure-activity relationships in the peptide antibiotic nisin: role of dehydroalanine 5

Author

Chan, W.C., Dodd, H.M., Horn, N., Maclean, K., Lian, L.-Y., Bycroft, B.W., Gasson, M.J., and Roberts, G.C.K.

Subjects
Antibiotics -- Research, Bacteria -- Growth, Alanine -- Research, Growth factors -- Physiological aspects, Biological sciences
Abstract

Substitution of dehydroalanine residue at position 5 in nisin by alanine leaves nisin's bacterial growth inhibiting activity unaffected. However, it reduces its activity as an inhibitor of the outgrowth of spores. The bacterial growth and spore outgrowth inhibitive activities of both nisin and subtilin are based on different structure-activity relationships and therefore the two activities arise from different molecular mechanisms. The presence of dehydroalanine residue at position 5 is unnecessary for inhibiting Lactococcus lactis and Micrococcus luteus growth.

Published
1996

37. CiliaCarta: An integrated and validated compendium of ciliary genes

Author

Dam, T.J.P. van, Kennedy, J., Lee, R. van der, Vrieze, E. de, Wunderlich, K.A., Rix, S., Dougherty, G.W., Lambacher, N.J., Li, C., Jensen, V.L., Leroux, M.R., Hjeij, R., Horn, N., Texier, Y., Wissinger, Y., Reeuwijk, J. van, Wheway, G., Knapp, B., Scheel, J.F., Franco, B., Mans, D.A., WIjk, E. van, Kepes, F., Slaats, G.G., Toedt, G., Kremer, H., Omran, H., Szymanska, K., Koutroumpas, K., Ueffing, M., Nguyen, T.T.M., Letteboer, S.J.F., Oud, M.M., Beersum, S.E.C. van, Schmidts, M., Beales, P.L., Lu, Q., Giles, R.H., Szklarczyk, R., Russell, R.B., Gibson, T.J., Johnson, C.A., Blacque, O.E., Wolfrum, U., Boldt, K., Roepman, R., Hernandez-Hernandez, V., Huynen, M.A., Dam, T.J.P. van, Kennedy, J., Lee, R. van der, Vrieze, E. de, Wunderlich, K.A., Rix, S., Dougherty, G.W., Lambacher, N.J., Li, C., Jensen, V.L., Leroux, M.R., Hjeij, R., Horn, N., Texier, Y., Wissinger, Y., Reeuwijk, J. van, Wheway, G., Knapp, B., Scheel, J.F., Franco, B., Mans, D.A., WIjk, E. van, Kepes, F., Slaats, G.G., Toedt, G., Kremer, H., Omran, H., Szymanska, K., Koutroumpas, K., Ueffing, M., Nguyen, T.T.M., Letteboer, S.J.F., Oud, M.M., Beersum, S.E.C. van, Schmidts, M., Beales, P.L., Lu, Q., Giles, R.H., Szklarczyk, R., Russell, R.B., Gibson, T.J., Johnson, C.A., Blacque, O.E., Wolfrum, U., Boldt, K., Roepman, R., Hernandez-Hernandez, V., and Huynen, M.A.

Abstract

Contains fulltext : 204265.pdf (publisher's version ) (Open Access), The cilium is an essential organelle at the surface of mammalian cells whose dysfunction causes a wide range of genetic diseases collectively called ciliopathies. The current rate at which new ciliopathy genes are identified suggests that many ciliary components remain undiscovered. We generated and rigorously analyzed genomic, proteomic, transcriptomic and evolutionary data and systematically integrated these using Bayesian statistics into a predictive score for ciliary function. This resulted in 285 candidate ciliary genes. We generated independent experimental evidence of ciliary associations for 24 out of 36 analyzed candidate proteins using multiple cell and animal model systems (mouse, zebrafish and nematode) and techniques. For example, we show that OSCP1, which has previously been implicated in two distinct non-ciliary processes, causes ciliogenic and ciliopathy-associated tissue phenotypes when depleted in zebrafish. The candidate list forms the basis of CiliaCarta, a comprehensive ciliary compendium covering 956 genes. The resource can be used to objectively prioritize candidate genes in whole exome or genome sequencing of ciliopathy patients and can be accessed at http://bioinformatics.bio.uu.nl/john/syscilia/ciliacarta/.

Published
2019

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