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1,828 results on '"Rippe A"'

4. Performance of a Molecular Test for Group A Streptococcus Pharyngitis

Author

Robert R, Tanz, Lauren E, Heaberlin, Erin, Harvey, Yiannis L, Katsogridakis, Rebecca Ruhana, Burns, Jason, Rippe, and Stanford T, Shulman

Subjects
Infectious Diseases, Pediatrics, Perinatology and Child Health, General Medicine
Abstract

We performed a prospective study to determine if the pretest probability of a positive loop-mediated isothermal amplification test is greater when there are more signs and symptoms of GAS pharyngitis. Patients were enrolled if a clinician obtained a GAS RADT. The McIsaac score was calculated. The prevalence of positive LAMP and RADT results increased as the McIsaac score increased. The calculated sensitivity of LAMP was superior to RADT.

Published
2022
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6. The added value of advance demand information for the planning of a repair kit

Author

Christoph Rippe and Gudrun Kiesmüller

Subjects
Management Science and Operations Research
Abstract

In this paper the repair kit problem is studied, where technicians have to visit several customers to repair broken appliances (such as copiers or heating systems) and they can only take a limited set of parts with them (called the repair kit). In this problem, it has to be decided which spare parts to include in the repair kit. We consider a version of this problem in which partial advance demand information is available. That means we divide the set of parts into two subsets, where the condition of parts in one subset is monitored by sensors. In case an appliance fails and a repair job is requested by a customer the service provider is able to access this sensor data before a technician visits the customer. For this setting, we derive an expression for the job fill rate, which is used as a constraint in the optimization model, where holding and replenishment costs are minimized. We use a greedy heuristic to determine near-optimal repair kits. In a numerical study, we find that integrating advance demand information yields substantial cost savings. In order to find out for which parts having advance demand information is most valuable, we examine the effect of parts’ demand probabilities and their prices. We find that monitoring parts that are expensive and likely to fail leads to the largest cost savings. In particular, the price of the monitored parts and the achievable cost savings are strongly correlated.

Published
2022
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7. Cement Choice and the Fatigue Performance of Monolithic Zirconia Restorations

Author

L F, Guilardi, Gkr, Pereira, J C, Giordani, C J, Kleverlaan, L F, Valandro, and M P, Rippe

Subjects
Dental Stress Analysis, Ceramics, Dental Materials, Glass Ionomer Cements, Surface Properties, Materials Testing, Dental Bonding, Dental Cements, Zirconium, General Dentistry, Resin Cements
Abstract

SUMMARY This study investigated the fatigue failure load of simplified monolithic yttria partially stabilized zirconia polycrystal restorations cemented to a dentin-like substrate using different luting systems. Disc-shaped ceramic (Zenostar T, 10 mm Ø × 0.7 mm thick) and dentin-like substrate (10 mm Ø × 2.8 mm thick) were produced and randomly allocated into eight groups, without or with thermocycling (TC=5–55°C/12,000×): “cement” (RelyX Luting 2 – glass ionomer cement [Ion], [Ion/TC]; RelyX U200 – self-adhesive resin cement [Self], [Self/TC]; Single Bond Universal+RelyX Ultimate – MDP-containing adhesive + resin cement [MDPAD + RC], [MDP-AD + RC/TC]; ED Primer II+Panavia F 2.0 – Primer + MDP-containing resin cement [PR + MDP-RC], [PR + MDP-RC/TC])). Each luting system was used as recommended by the manufacturer. Staircase methodology (20 Hz; 250,000 cycles) was applied for obtaining the fatigue failure loads. Fractographic characteristics were also assessed. At baseline, the Ion group presented the lowest fatigue load, although it was statistically similar to the Self group. The resin-based cement systems presented the highest fatigue performance, with the Ion group being only statistically equal to the Self group. Thermocycling influenced the groups differently. After aging, the MDP-AD + RC presented the highest mean, followed by the PR + MDP-RC and Self groups, while the Ion group had the lowest mean. Fractographic analysis depicted all failures as radial cracks starting at the zirconia intaglio surface. The luting system with MDP-containing adhesive applied prior to the resin cement presented the highest fatigue failure load after aging, presenting the best predictability of stable performance. Despite this, monolithic zirconia presents high load-bearing capability regardless of the luting agent.

Published
2022
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10. Adhesion to a Zirconia-reinforced Lithium Silicate Ceramic: Effects of Ceramic Surface Treatments and Resin Cements

Author

F, Dalla-Nora, L F, Guilardi, C P, Zucuni, L F, Valandro, and M P, Rippe

Subjects
Ceramics, Surface Properties, Silicates, Materials Testing, Dental Bonding, Starch, Zirconium, Lithium, Dental Porcelain, General Dentistry, Resin Cements
Abstract

SUMMARY Objective This study had the objective to test the effect of ceramic surface treatments on the microshear bond strength (μSBS) of different resin cements to a zirconia-reinforced lithium silicate (ZLS). Methods and Materials ZLS blocks were sectioned, embedded in acrylic resin, and then allocated into nine groups considering two study factors: “ceramic surface treatment” (HF - hydrofluoric acid; EP - self-etching primer; TBS - tribochemical silica coating) and “resin cements” (nMDP - without MDP monomer; MDP - with MDP monomer; SA - self-adhesive). Starch tubes (n=36) were placed on the treated ceramic surface and the cement was applied. Starch tubes were removed after 24 hours of storage, and the specimens were thermocycled (5,000×; 5°C–55°C). Next, the μSBS test was performed using the wire-loop technique, and topographic and failure analyses were performed. Results The factors “ceramic surface treatment” and “resin cement” statistically influenced the μSBS results. Considering the surface treatment factor, the TBS produced statistically lower values when the MDP resin cement was applied, being only similar to the MDP plus EP group. For the resin cement factor, no difference was found for nMDP and SA groups, apart from the surface treatments. Failure analysis showed that the groups treated with EP had a greater number of pre-test failures. The surface treatments induced noteworthy topographic alterations when compared to control (no treatment). Conclusion The ZLS ceramic surface treatment with tribochemical silica coating associated with the MDP-containing resin cement resulted in lower bond strength values.

Published
2022
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11. Subliminal attentional bias modification training for itch

Author

Becker, Jennifer M., Van Ryckeghem, Dimitri M. L., Van Damme, Stefaan, Crombez, Geert, Schoot, Yalou, Wiers, Reinout W. H. J., Rippe, Ralph C. A., and van Laarhoven, Antoinette I. M.

Subjects
General Medicine
Abstract

IntroductionItch is unpleasant and induces the urge to scratch. This is adaptive to remove the itch-inducing stimulus from the skin. Accordingly, itch draws attention to protect our bodily integrity. Recent studies investigated whether attention is preferentially drawn towards its location, i.e., attentional bias (AB), and also whether this bias could be changed in healthy individuals. So far, results are mixed concerning the existance of an attentional bias towards itch stimuli in healthy individuals as well as the impact of modifications. However, available studies have typically focused on conscious processing and might miss preconscious aspects of attention and potential biases at these stages.MethodsThis study included 117 healthy individuals who underwent a subliminal Attentional Bias Modification (ABM)- training for itch based on a dot-probe paradigm with itch- related pictures. Participants were randomly assigned to a training towards itch group, a training away from itch group and a control group. This was done by manipulating the itch-target congruency of the dot-probe task during a training block. Pre- and post-training assessments were regular dot-probe tasks. Exploratorily, also attentional inhibition, cognitive flexibility and itch-related cognitions were assessed. Lastly, participants received an itchy stimulus on the inner forearm before and after the ABM-training to assess potential effects on itch sensitivity.ResultsResults showed no AB towards itch across groups at baseline, i.e., pre-training, but an AB away from itch, hence, avoidance of itch, post-training. Further analyses showed that this effect was driven by an attentional bias away from itch in the control group, while there were no significant effects in the experimental groups. There was no effect on itch sensitivity.ConclusionThese findings are in line with recent studies on conscious ABM-training for itch and pain that also did not find significant training effects. Therefore, it is suggested that the field of AB might need to reconsider the current assessment of AB. Moreover, AB is probably a dynamic process that is highly dependent on current itch-related goals and relevance of itch in a specific situation. This suggests that processes probably differ in patients with chronic itch and that also ABM-training might work differently in these populations.Clinical trial registrationhttps://trialsearch.who.int/Trial2.aspx?TrialID=NTR7561, identifier NTR7561.

Published
2023
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12. Dimensions of Religion Associated with Suicide Attempt and Ideation:A 15-Month Prospective Study in a Dutch Psychiatric Population

Author

Bart van den Brink, Matthias Jongkind, Ralph C. A. Rippe, Nathan van der Velde, Arjan W. Braam, Hanneke Schaap-Jonker, Beliefs and Practices, and CLUE+

Subjects
suicidal ideation, moral objections to suicide, religious service attendance, religion, depression, Religious studies, God representation, prayer
Abstract

Dimensions of religion contribute in different ways to the in general protective effect of religiosity and spirituality (R/S) against suicidality. Few studies have included a substantial number of dimensions, and even fewer a follow-up, to clarify the stability and contribution of R/S over the course of psychopathology. In this follow-up study among 155 religiously affiliated in- and outpatients with major depression, religious service attendance, frequency of prayer, type of God representation, moral objections to suicide, and social support were re-assessed in 59 subjects. Diverse statistical analyses show a partial change in R/S parameters. Supportive R/S is persistently associated with lower suicidality. R/S at T0 or change in R/S is not associated with additional changes in suicidality over time. The results suggest that the most important change in suicidality can be understood as an effect of a decline in depressive symptomatology, not of changes in R/S. Despite the limited follow-up and sample size, these results emphasize the importance of longitudinal and dynamic evaluation of especially affective and supportive aspects of R/S in suicidal persons.

Published
2023
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14. Data from KMT9 Controls Stemness and Growth of Colorectal Cancer

Author

Roland Schüle, Eric Metzger, Rebecca Kesselring, Stefan Fichtner-Feigl, Florian R. Greten, Valentina Petrocelli, Mark Schmitt, Karsten Rippe, Lisa Marx, Stephan M. Tirier, Sylvia Urban, Dominica Willmann, Félicie Cottard, and Christopher Berlin

Abstract

Colorectal cancer is among the leading causes of cancer-associated deaths worldwide. Treatment failure and tumor recurrence due to survival of therapy-resistant cancer stem/initiating cells represent major clinical issues to overcome. In this study, we identified lysine methyltransferase 9 (KMT9), an obligate heterodimer composed of KMT9α and KMT9β that monomethylates histone H4 at lysine 12 (H4K12me1), as an important regulator in colorectal tumorigenesis. KMT9α and KMT9β were overexpressed in colorectal cancer and colocalized with H4K12me1 at promoters of target genes involved in the regulation of proliferation. Ablation of KMT9α drastically reduced colorectal tumorigenesis in mice and prevented the growth of murine as well as human patient-derived tumor organoids. Moreover, loss of KMT9α impaired the maintenance and function of colorectal cancer stem/initiating cells and induced apoptosis specifically in this cellular compartment. Together, these data suggest that KMT9 is an important regulator of colorectal carcinogenesis, identifying KMT9 as a promising therapeutic target for the treatment of colorectal cancer.Significance:The H4K12 methyltransferase KMT9 regulates tumor cell proliferation and stemness in colorectal cancer, indicating that targeting KMT9 could be a useful approach for preventing and treating this disease.

Published
2023
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16. My future-self has (not) quit smoking: An experimental study into the effect of a future-self intervention on smoking-related self-identity constructs

Author

Kristell M. Penfornis, Winifred A. Gebhardt, Ralph C.A. Rippe, Colette Van Laar, Bas van den Putte, and Eline Meijer

Subjects
Health (social science), History and Philosophy of Science, Smoking Self-identity Future-self intervention Psychosocial factors Longitudinal design Multilevel analyses
Abstract

Envisioning one's (non)smoking future may make (un)desired future identities more accessible, salient, and personally relevant and facilitate smoking cessation. The current study assessed whether a future-self intervention can weaken smoker self-identity and expected identity loss when quitting smoking, and strengthen quitter- and nonsmoker self-identity, while accounting for personal factors—socioeconomic position, nicotine dependence, consideration of future consequences, and clarity of the envisioned future-self. Additionally, it examined the association between smoking-related identity and quitting intention and behavior. ispartof: Social Science & Medicine vol:320 status: Published online

Published
2023

18. Bone Marrow Immune Signatures in Multiple Myeloma Are Linked to Tumor Heterogeneity and Treatment Outcome

Author

Simon Steiger, Raphael Lutz, Nina Prokoph, Subarna Palit, Stephan M Tirier, Philipp Reichert, Anja Baumann, Nadine Hefner, Sabrina Schumacher, Dominik Vonficht, Florian Grünschläger, Alexandra M Poos, Lukas John, Laleh Haghverdi, Jan-Philipp Mallm, Elias K Mai, Mirco Friedrich, Katharina Kriegsmann, Mohamed H.S. Awwad, Anna Jauch, Uta Bertsch, Diana Tichy, Carsten Müller-Tidow, Roland Schroers, Hans Salwender, Britta Besemer, Roland Fenk, Katja Weisel, Hartmut Goldschmidt, Stefanie Huhn, Michael Hundemer, Karsten Rippe, Simon Haas, Niels Weinhold, and Marc S Raab

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022
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19. Functional organization of RNA polymerase II in nuclear subcompartments

Author

Karsten Rippe and Argyris Papantonis

Subjects
Cell Nucleus, Transcription, Genetic, RNA, RNA Polymerase II, Cell Biology, Chromatin
Abstract

Distinct clusters of RNA polymerase II are responsible for gene transcription inside eukaryotic cell nuclei. Despite the functional implications of such subnuclear organization, the attributes of these clusters and the mechanisms underlying their formation remain only partially understood. Recently, the concept of proteins and RNA phase-separating into liquid-like droplets was proposed to drive the formation of transcriptionally-active subcompartments. Here, we attempt to reconcile previous with more recent findings, and discuss how the different ways of assembling the active RNA polymerase II transcriptional machinery relate to nuclear compartmentalization.

Published
2022
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20. Vaccines

Author

Andrew P. Chastain, Matéa M. Rippe, Tia M. Solh, and Jennifer Simms Zorn

Subjects
General Medicine
Published
2022
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21. Decreased mismatch negativity and elevated frontal-lateral connectivity in first-episode psychosis

Author

Dost Öngür, Gregor Leicht, Jaelin Rippe, Mahmut Yüksel, and Michael Murphy

Subjects
medicine.medical_specialty, Psychosis, medicine.medical_treatment, Population, Mismatch negativity, Audiology, Electroencephalography, behavioral disciplines and activities, Article, First episode psychosis, medicine, Humans, education, Antipsychotic, Biological Psychiatry, education.field_of_study, medicine.diagnostic_test, business.industry, Brain, medicine.disease, Psychiatry and Mental health, medicine.anatomical_structure, Acoustic Stimulation, Psychotic Disorders, Occipital scalp, Scalp, Evoked Potentials, Auditory, business, Biomarkers, Antipsychotic Agents
Abstract

Decreased mismatch negativity (MMN) is a proposed biomarker for psychotic disorders. However, the magnitude of the effect appears to be attenuated in first-episode populations. Furthermore, how mismatch negativity amplitudes are related to brain connectivity in this population is unclear. In this study, we used high-density EEG to record duration-deviant MMN from 22 patients with first-episode psychosis (FEP) and 23 age-matched controls (HC). Consistent with past work, we found decreased MMN amplitude in FEP over a large area of the frontal scalp. We also found decreased latency over the occipital scalp. MMN amplitude was negatively correlated with antipsychotic dose. We used Granger causality to investigate directional connectivity between frontal, midline, left, and right scalp during MMN and found reduced connectivity in FEP compared to HC and following deviant stimuli compared to standard stimuli. FEP participants with smaller decreases in connectivity from standard to deviant stimuli had worse disorganization symptoms. On the other hand, connectivity from the front of the scalp following deviant stimuli was relatively preserved in FEP compared to controls. Our results suggest that a relative imbalance of bottom-up and top-down perceptual processing is present in the early stages of psychotic disorders.

Published
2021
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24. A deep learning system accurately classifies primary and metastatic cancers using passenger mutation patterns

Author

Jiao, Wei, Atwal, Gurnit, Polak, Paz, Karlic, Rosa, Cuppen, Edwin, Al-Shahrour, Fatima, Bailey, Peter J, Biankin, Andrew V, Boutros, Paul C, Campbell, Peter J, Chang, David K, Cooke, Susanna L, Deshpande, Vikram, Faltas, Bishoy M, Faquin, William C, Garraway, Levi, Getz, Gad, Grimmond, Sean M, Haider, Syed, Hoadley, Katherine A, Kaiser, Vera B, Kato, Mamoru, Kübler, Kirsten, Lazar, Alexander J, Li, Constance H, Louis, David N, Margolin, Adam, Martin, Sancha, Nahal-Bose, Hardeep K, Nielsen, G Petur, Nik-Zainal, Serena, Omberg, Larsson, P’ng, Christine, Perry, Marc D, Rheinbay, Esther, Rubin, Mark A, Semple, Colin A, Sgroi, Dennis C, Shibata, Tatsuhiro, Siebert, Reiner, Smith, Jaclyn, Stein, Lincoln D, Stobbe, Miranda D, Sun, Ren X, Thai, Kevin, Wright, Derek W, Wu, Chin-Lee, Yuan, Ke, Zhang, Junjun, Danyi, Alexandra, de Ridder, Jeroen, van Herpen, Carla, Lolkema, Martijn P, Steeghs, Neeltje, Morris, Quaid D, Aaltonen, Lauri A, Abascal, Federico, Abeshouse, Adam, Aburatani, Hiroyuki, Adams, David J, Agrawal, Nishant, Ahn, Keun Soo, Ahn, Sung-Min, Aikata, Hiroshi, Akbani, Rehan, Akdemir, Kadir C, Al-Ahmadie, Hikmat, Al-Sedairy, Sultan T, Alawi, Malik, Albert, Monique, Aldape, Kenneth, Alexandrov, Ludmil B, Ally, Adrian, Alsop, Kathryn, Alvarez, Eva G, Amary, Fernanda, Amin, Samirkumar B, Aminou, Brice, Ammerpohl, Ole, Anderson, Matthew J, Ang, Yeng, Antonello, Davide, Anur, Pavana, Aparicio, Samuel, Appelbaum, Elizabeth L, Arai, Yasuhito, Aretz, Axel, Arihiro, Koji, Ariizumi, Shun-ichi, Armenia, Joshua, Arnould, Laurent, Asa, Sylvia, Assenov, Yassen, Aukema, Sietse, Auman, J Todd, Aure, Miriam RR, Awadalla, Philip, Aymerich, Marta, Bader, Gary D, Baez-Ortega, Adrian, Bailey, Matthew H, Balasundaram, Miruna, Balu, Saianand, Bandopadhayay, Pratiti, Banks, Rosamonde E, Barbi, Stefano, Barbour, Andrew P, Barenboim, Jonathan, Barnholtz-Sloan, Jill, Barr, Hugh, Barrera, Elisabet, Bartlett, John, Bartolome, Javier, Bassi, Claudio, Bathe, Oliver F, Baumhoer, Daniel, Bavi, Prashant, Baylin, Stephen B, Bazant, Wojciech, Beardsmore, Duncan, Beck, Timothy A, Behjati, Sam, Behren, Andreas, Niu, Beifang, Bell, Cindy, Beltran, Sergi, Benz, Christopher, Berchuck, Andrew, Bergmann, Anke K, Bergstrom, Erik N, Berman, Benjamin P, Berney, Daniel M, Bernhart, Stephan H, Beroukhim, Rameen, Berrios, Mario, Bersani, Samantha, Bertl, Johanna, Betancourt, Miguel, Bhandari, Vinayak, Bhosle, Shriram G, Bieg, Matthias, Bigner, Darell, Binder, Hans, Birney, Ewan, Birrer, Michael, Biswas, Nidhan K, Bjerkehagen, Bodil, Bodenheimer, Tom, Boice, Lori, Bonizzato, Giada, De Bono, Johann S, Boot, Arnoud, Bootwalla, Moiz S, Borg, Ake, Borkhardt, Arndt, Boroevich, Keith A, Borozan, Ivan, Borst, Christoph, Bosenberg, Marcus, Bosio, Mattia, Boultwood, Jacqueline, Bourque, Guillaume, Bova, G Steven, Bowen, David T, Bowlby, Reanne, Bowtell, David DL, Boyault, Sandrine, Boyce, Rich, Boyd, Jeffrey, Brazma, Alvis, Brennan, Paul, Brewer, Daniel S, Brinkman, Arie B, Bristow, Robert G, Broaddus, Russell R, Brock, Jane E, Brock, Malcolm, Broeks, Annegien, Brooks, Angela N, Brooks, Denise, Brors, Benedikt, Brunak, Søren, Bruxner, Timothy JC, Bruzos, Alicia L, Buchanan, Alex, Buchhalter, Ivo, Buchholz, Christiane, Bullman, Susan, Burke, Hazel, Burkhardt, Birgit, Burns, Kathleen H, Busanovich, John, Bustamante, Carlos D, Butler, Adam P, Butte, Atul J, Byrne, Niall J, Børresen-Dale, Anne-Lise, Caesar-Johnson, Samantha J, Cafferkey, Andy, Cahill, Declan, Calabrese, Claudia, Caldas, Carlos, Calvo, Fabien, Camacho, Niedzica, Campo, Elias, Cantù, Cinzia, Cao, Shaolong, Carey, Thomas E, Carlevaro-Fita, Joana, Carlsen, Rebecca, Cataldo, Ivana, Cazzola, Mario, Cebon, Jonathan, Cerfolio, Robert, Chadwick, Dianne E, Chakravarty, Dimple, Chalmers, Don, Chan, Calvin Wing Yiu, Chan, Kin, Chan-Seng-Yue, Michelle, Chandan, Vishal S, Chanock, Stephen J, Chantrill, Lorraine A, Chateigner, Aurélien, Chatterjee, Nilanjan, Chayama, Kazuaki, Chen, Hsiao-Wei, Chen, Jieming, Chen, Ken, Chen, Yiwen, Chen, Zhaohong, Cherniack, Andrew D, Chien, Jeremy, Chiew, Yoke-Eng, Chin, Suet-Feung, Cho, Juok, Cho, Sunghoon, Choi, Jung Kyoon, Choi, Wan, Chomienne, Christine, Chong, Zechen, Choo, Su Pin, Chou, Angela, Christ, Angelika N, Christie, Elizabeth L, Chuah, Eric, Cibulskis, Carrie, Cibulskis, Kristian, Cingarlini, Sara, Clapham, Peter, Claviez, Alexander, Cleary, Sean, Cloonan, Nicole, Cmero, Marek, Collins, Colin C, Connor, Ashton A, Cooper, Colin S, Cope, Leslie, Corbo, Vincenzo, Cordes, Matthew G, Cordner, Stephen M, Cortés-Ciriano, Isidro, Covington, Kyle, Cowin, Prue A, Craft, Brian, Craft, David, Creighton, Chad J, Cun, Yupeng, Curley, Erin, Cutcutache, Ioana, Czajka, Karolina, Czerniak, Bogdan, Dagg, Rebecca A, Danilova, Ludmila, Davi, Maria Vittoria, Davidson, Natalie R, Davies, Helen, Davis, Ian J, Davis-Dusenbery, Brandi N, Dawson, Kevin J, De La Vega, Francisco M, De Paoli-Iseppi, Ricardo, Defreitas, Timothy, Dei Tos, Angelo P, Delaneau, Olivier, Demchok, John A, Demeulemeester, Jonas, Demidov, German M, Demircioğlu, Deniz, Dennis, Nening M, Denroche, Robert E, Dentro, Stefan C, Desai, Nikita, Deshwar, Amit G, Desmedt, Christine, Deu-Pons, Jordi, Dhalla, Noreen, Dhani, Neesha C, Dhingra, Priyanka, Dhir, Rajiv, DiBiase, Anthony, Diamanti, Klev, Ding, Li, Ding, Shuai, Dinh, Huy Q, Dirix, Luc, Doddapaneni, HarshaVardhan, Donmez, Nilgun, Dow, Michelle T, Drapkin, Ronny, Drechsel, Oliver, Drews, Ruben M, Serge, Serge, Dudderidge, Tim, Dueso-Barroso, Ana, Dunford, Andrew J, Dunn, Michael, Dursi, Lewis Jonathan, Duthie, Fraser R, Dutton-Regester, Ken, Eagles, Jenna, Easton, Douglas F, Edmonds, Stuart, Edwards, Paul A, Edwards, Sandra E, Eeles, Rosalind A, Ehinger, Anna, Eils, Juergen, Eils, Roland, El-Naggar, Adel, Eldridge, Matthew, Ellrott, Kyle, Erkek, Serap, Escaramis, Georgia, Espiritu, Shadrielle MG, Estivill, Xavier, Etemadmoghadam, Dariush, Eyfjord, Jorunn E, Fan, Daiming, Fan, Yu, Farcas, Claudiu, Fassan, Matteo, Fatima, Aquila, Favero, Francesco, Fayzullaev, Nodirjon, Felau, Ina, Fereday, Sian, Ferguson, Martin L, Ferretti, Vincent, Feuerbach, Lars, Field, Matthew A, Fink, J Lynn, Finocchiaro, Gaetano, Fisher, Cyril, Fittall, Matthew W, Fitzgerald, Anna, Fitzgerald, Rebecca C, Flanagan, Adrienne M, Fleshner, Neil E, Flicek, Paul, Foekens, John A, Fong, Kwun M, Fonseca, Nuno A, Foster, Christopher S, Fox, Natalie S, Fraser, Michael, Frazer, Scott, Frenkel-Morgenstern, Milana, Friedman, William, Frigola, Joan, Fronick, Catrina C, Fujimoto, Akihiro, Fujita, Masashi, Fukayama, Masashi, Fulton, Lucinda A, Fulton, Robert S, Furuta, Mayuko, Futreal, P Andrew, Füllgrabe, Anja, Gabriel, Stacey B, Gallinger, Steven, Gambacorti-Passerini, Carlo, Gao, Jianjiong, Gao, Shengjie, Garred, Øystein, Garrison, Erik, Garsed, Dale W, Gehlenborg, Nils, Gelpi, Josep LL, George, Joshy, Gerhard, Daniela S, Gerhauser, Clarissa, Gershenwald, Jeffrey E, Gerstein, Mark, Gerstung, Moritz, Ghori, Mohammed, Ghossein, Ronald, Giama, Nasra H, Gibbs, Richard A, Gibson, Bob, Gill, Anthony J, Gill, Pelvender, Giri, Dilip D, Glodzik, Dominik, Gnanapragasam, Vincent J, Goebler, Maria Elisabeth, Goldman, Mary J, Gomez, Carmen, Gonzalez, Santiago, Gonzalez-Perez, Abel, Gordenin, Dmitry A, Gossage, James, Gotoh, Kunihito, Govindan, Ramaswamy, Grabau, Dorthe, Graham, Janet S, Grant, Robert C, Green, Anthony R, Green, Eric, Greger, Liliana, Grehan, Nicola, Grimaldi, Sonia, Grossman, Robert L, Grundhoff, Adam, Gundem, Gunes, Guo, Qianyun, Gupta, Manaswi, Gupta, Shailja, Gut, Ivo G, Gut, Marta, Göke, Jonathan, Ha, Gavin, Haake, Andrea, Haan, David, Haas, Siegfried, Haase, Kerstin, Haber, James E, Habermann, Nina, Hach, Faraz, Hama, Natsuko, Hamdy, Freddie C, Hamilton, Anne, Hamilton, Mark P, Han, Leng, Hanna, George B, Hansmann, Martin, Haradhvala, Nicholas J, Harismendy, Olivier, Harliwong, Ivon, Harmanci, Arif O, Harrington, Eoghan, Hasegawa, Takanori, Haussler, David, Hawkins, Steve, Hayami, Shinya, Hayashi, Shuto, Hayes, D Neil, Hayes, Stephen J, Hayward, Nicholas K, Hazell, Steven, He, Yao, Heath, Allison P, Heath, Simon C, Hedley, David, Hegde, Apurva M, Heiman, David I, Heinold, Michael C, Heins, Zachary, Heisler, Lawrence E, Hellstrom-Lindberg, Eva, Helmy, Mohamed, Heo, Seong Gu, Hepperla, Austin J, Heredia-Genestar, José María, Herrmann, Carl, Hersey, Peter, Hess, Julian M, Hilmarsdottir, Holmfridur, Hinton, Jonathan, Hirano, Satoshi, Hiraoka, Nobuyoshi, Hobolth, Asger, Hodzic, Ermin, Hoell, Jessica I, Hoffmann, Steve, Hofmann, Oliver, Holbrook, Andrea, Holik, Aliaksei Z, Hollingsworth, Michael A, Holmes, Oliver, Holt, Robert A, Hong, Chen, Hong, Eun Pyo, Hong, Jongwhi H, Hooijer, Gerrit K, Hornshøj, Henrik, Hosoda, Fumie, Hou, Yong, Hovestadt, Volker, Howat, William, Hoyle, Alan P, Hruban, Ralph H, Hu, Jianhong, Hu, Taobo, Hua, Xing, Huang, Kuan-lin, Huang, Mei, Huang, Mi Ni, Huang, Vincent, Huang, Yi, Huber, Wolfgang, Hudson, Thomas J, Hummel, Michael, Hung, Jillian A, Huntsman, David, Hupp, Ted R, Huse, Jason, Huska, Matthew R, Hutter, Barbara, Hutter, Carolyn M, Hübschmann, Daniel, Iacobuzio-Donahue, Christine A, Imbusch, Charles David, Imielinski, Marcin, Imoto, Seiya, Isaacs, William B, Isaev, Keren, Ishikawa, Shumpei, Iskar, Murat, Islam, SM Ashiqul, Ittmann, Michael, Ivkovic, Sinisa, Izarzugaza, Jose MG, Jacquemier, Jocelyne, Jakrot, Valerie, Jamieson, Nigel B, Jang, Gun Ho, Jang, Se Jin, Jayaseelan, Joy C, Jayasinghe, Reyka, Jefferys, Stuart R, Jegalian, Karine, Jennings, Jennifer L, Jeon, Seung-Hyup, Jerman, Lara, Ji, Yuan, Johansson, Peter A, Johns, Amber L, Johns, Jeremy, Johnson, Rory, Johnson, Todd A, Jolly, Clemency, Joly, Yann, Jonasson, Jon G, Jones, Corbin D, Jones, David R, Jones, David TW, Jones, Nic, Jones, Steven JM, Jonkers, Jos, Ju, Young Seok, Juhl, Hartmut, Jung, Jongsun, Juul, Malene, Juul, Randi Istrup, Juul, Sissel, Jäger, Natalie, Kabbe, Rolf, Kahles, Andre, Kahraman, Abdullah, Kakavand, Hojabr, Kalimuthu, Sangeetha, von Kalle, Christof, Kang, Koo Jeong, 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Kiran, Kumar, Pardeep, Kumar, Sushant, Kumar, Yogesh, Kundra, Ritika, Küppers, Ralf, Lagergren, Jesper, Lai, Phillip H, Laird, Peter W, Lakhani, Sunil R, Lalansingh, Christopher M, Lalonde, Emilie, Lamaze, Fabien C, Lambert, Adam, Lander, Eric, Landgraf, Pablo, Landoni, Luca, Langerød, Anita, Lanzós, Andrés, Larsimont, Denis, Larsson, Erik, Lathrop, Mark, Lau, Loretta MS, Lawerenz, Chris, Lawlor, Rita T, Lawrence, Michael S, Lazic, Ana Mijalkovic, Le, Xuan, Lee, Darlene, Lee, Donghoon, Lee, Eunjung Alice, Lee, Hee Jin, Lee, Jake June-Koo, Lee, Jeong-Yeon, Lee, Juhee, Lee, Ming Ta Michael, Lee-Six, Henry, Lehmann, Kjong-Van, Lehrach, Hans, Lenze, Dido, Leonard, Conrad R, Leongamornlert, Daniel A, Leshchiner, Ignaty, Letourneau, Louis, Letunic, Ivica, Levine, Douglas A, Lewis, Lora, Ley, Tim, Li, Chang, Li, Haiyan Irene, Li, Jun, Li, Lin, Li, Shantao, Li, Siliang, Li, Xiaobo, Li, Xiaotong, Li, Xinyue, Li, Yilong, Liang, Han, Liang, Sheng-Ben, Lichter, Peter, Lin, Pei, Lin, Ziao, Linehan, WM, Lingjærde, Ole Christian, Liu, Dongbing, Liu, Eric Minwei, Liu, Fei-Fei Fei, Liu, Fenglin, Liu, Jia, Liu, Xingmin, Livingstone, Julie, Livitz, Dimitri, Livni, Naomi, Lochovsky, Lucas, Loeffler, Markus, Long, Georgina V, Lopez-Guillermo, Armando, Lou, Shaoke, Lovat, Laurence B, Lu, Yiling, Lu, Yong-Jie, Lu, Youyong, Luchini, Claudio, Lungu, Ilinca, Luo, Xuemei, Luxton, Hayley J, Lynch, Andy G, Lype, Lisa, López, Cristina, López-Otín, Carlos, Z, Eric, Ma, Yussanne, MacGrogan, Gaetan, MacRae, Shona, Macintyre, Geoff, Madsen, Tobias, Maejima, Kazuhiro, Mafficini, Andrea, Maglinte, Dennis T, Maitra, Arindam, Majumder, Partha P, Malcovati, Luca, Malikic, Salem, Malleo, Giuseppe, Mann, Graham J, Mantovani-Löffler, Luisa, Marchal, Kathleen, Marchegiani, Giovanni, Mardis, Elaine R, Margolin, Adam A, Marin, Maximillian G, Markowetz, Florian, Markowski, Julia, Marks, Jeffrey, Marques-Bonet, Tomas, Marra, Marco A, Marsden, Luke, Martens, John WM, Martin-Subero, Jose I, Martincorena, Iñigo, Martinez-Fundichely, Alexander, Maruvka, Yosef E, Mashl, R Jay, Massie, Charlie E, Matthew, Thomas J, Matthews, Lucy, Mayer, Erik, Mayes, Simon, Mayo, Michael, Mbabaali, Faridah, McCune, Karen, McDermott, Ultan, McGillivray, Patrick D, McLellan, Michael D, McPherson, John D, McPherson, John R, McPherson, Treasa A, Meier, Samuel R, Meng, Alice, Meng, Shaowu, Menzies, Andrew, Merrett, Neil D, Merson, Sue, Meyerson, Matthew, Meyerson, William, Mieczkowski, Piotr A, Mihaiescu, George L, Mijalkovic, Sanja, Mikkelsen, Tom, Milella, Michele, Mileshkin, Linda, Miller, Christopher A, Miller, David K, Miller, Jessica K, Mills, Gordon B, Milovanovic, Ana, Minner, Sarah, Miotto, Marco, Arnau, Gisela Mir, Mirabello, Lisa, Mitchell, Chris, Mitchell, Thomas J, Miyano, Satoru, Miyoshi, Naoki, Mizuno, Shinichi, Molnár-Gábor, Fruzsina, Moore, Malcolm J, Moore, Richard A, Morganella, Sandro, Morrison, Carl, Mose, Lisle E, Moser, Catherine D, Muiños, Ferran, Mularoni, Loris, Mungall, Andrew J, Mungall, Karen, Musgrove, Elizabeth A, Mustonen, Ville, Mutch, David, Muyas, Francesc, Muzny, Donna M, Muñoz, Alfonso, Myers, Jerome, Myklebost, Ola, Möller, Peter, Nagae, Genta, Nagrial, Adnan M, Nakagama, Hitoshi, Nakagawa, Hidewaki, Nakamura, Hiromi, Nakamura, Toru, Nakano, Kaoru, Nandi, Tannistha, Nangalia, Jyoti, Nastic, Mia, Navarro, Arcadi, Navarro, Fabio CP, Neal, David E, Nettekoven, Gerd, Newell, Felicity, Newhouse, Steven J, Newton, Yulia, Ng, Alvin Wei Tian, Ng, Anthony, Nicholson, Jonathan, Nicol, David, Nie, Yongzhan, Nielsen, Morten Muhlig, Noble, Michael S, Nones, Katia, Northcott, Paul A, Notta, Faiyaz, O’Connor, Brian D, O’Donnell, Peter, O’Donovan, Maria, O’Meara, Sarah, O’Neill, Brian Patrick, O’Neill, J Robert, Ocana, David, Ochoa, Angelica, Oesper, Layla, Ogden, Christopher, Ohdan, Hideki, Ohi, Kazuhiro, Ohno-Machado, Lucila, Oien, Karin A, Ojesina, Akinyemi I, Ojima, Hidenori, Okusaka, Takuji, Ong, Choon Kiat, Ossowski, Stephan, Ott, German, Ouellette, BF Francis, Paczkowska, Marta, Paiella, Salvatore, Pairojkul, Chawalit, Pajic, Marina, Pan-Hammarström, Qiang, Papaemmanuil, Elli, Papatheodorou, Irene, Paramasivam, Nagarajan, Park, Ji Wan, Park, Joong-Won, Park, Keunchil, Park, Kiejung, Park, Peter J, Parker, Joel S, Parsons, Simon L, Pass, Harvey, Pasternack, Danielle, Pastore, Alessandro, Patch, Ann-Marie, Pauporté, Iris, Pea, Antonio, Pearson, John V, Pedamallu, Chandra Sekhar, Pedersen, Jakob Skou, Pederzoli, Paolo, Peifer, Martin, Pennell, Nathan A, Perou, Charles M, Petersen, Gloria M, Peto, Myron, Petrelli, Nicholas, Petryszak, Robert, Pfister, Stefan M, Phillips, Mark, Pich, Oriol, Pickett, Hilda A, Pihl, Todd D, Pillay, Nischalan, Pinder, Sarah, Pinese, Mark, Pinho, Andreia V, Pitkänen, Esa, Pivot, Xavier, Piñeiro-Yáñez, Elena, Planko, Laura, Plass, Christoph, Pons, Tirso, Popescu, Irinel, Potapova, Olga, Prasad, Aparna, Preston, Shaun R, Prinz, Manuel, Pritchard, Antonia L, Prokopec, Stephenie D, Provenzano, Elena, Puente, Xose S, Puig, Sonia, Puiggròs, Montserrat, Pulido-Tamayo, Sergio, Pupo, Gulietta M, Purdie, Colin A, Quinn, Michael C, Rabionet, Raquel, Rader, Janet S, Radlwimmer, Bernhard, Radovic, Petar, Raeder, Benjamin, Raine, Keiran M, Ramakrishna, Manasa, Ramakrishnan, Kamna, Ramalingam, Suresh, Raphael, Benjamin J, Rathmell, W Kimryn, Rausch, Tobias, Reifenberger, Guido, Reimand, Jüri, Reis-Filho, Jorge, Reuter, Victor, Reyes-Salazar, Iker, Reyna, Matthew A, Reynolds, Sheila M, Riazalhosseini, Yasser, Richardson, Andrea L, Richter, Julia, Ringel, Matthew, Ringnér, Markus, Rino, Yasushi, Rippe, Karsten, Roach, Jeffrey, Roberts, Lewis R, Roberts, Nicola D, Roberts, Steven A, Robertson, A Gordon, Robertson, Alan J, Rodriguez, Javier Bartolomé, Rodriguez-Martin, Bernardo, Rodríguez-González, F Germán, Roehrl, Michael HA, Rohde, Marius, Rokutan, Hirofumi, Romieu, Gilles, Rooman, Ilse, Roques, Tom, Rosebrock, Daniel, Rosenberg, Mara, Rosenstiel, Philip C, Rosenwald, Andreas, Rowe, Edward W, Royo, Romina, 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Johan, Stadler, Peter F, Staib, Peter, Stark, Stefan G, Stebbings, Lucy, Stefánsson, Ólafur Andri, Stegle, Oliver, Stenhouse, Alasdair, Stewart, Chip, Stilgenbauer, Stephan, Stratton, Michael R, Stretch, Jonathan R, Struck, Adam J, Stuart, Joshua M, Stunnenberg, Henk G, Su, Hong, Su, Xiaoping, Sungalee, Stephanie, Susak, Hana, Suzuki, Akihiro, Sweep, Fred, Szczepanowski, Monika, Sültmann, Holger, Yugawa, Takashi, Tam, Angela, Tamborero, David, Tan, Benita Kiat Tee, Tan, Donghui, Tan, Patrick, Tanaka, Hiroko, Taniguchi, Hirokazu, Tanskanen, Tomas J, Tarabichi, Maxime, Tarnuzzer, Roy, Tarpey, Patrick, Taschuk, Morgan L, Tatsuno, Kenji, Tavaré, Simon, Taylor, Darrin F, Taylor-Weiner, Amaro, Teague, Jon W, Teh, Bin Tean, Tembe, Varsha, Temes, Javier, Thayer, Sarah P, Thiessen, Nina, Thomas, Gilles, Thomas, Sarah, Thompson, Alan, Thompson, Alastair M, Thompson, John FF, Thompson, R Houston, Thorne, Heather, Thorne, Leigh B, Thorogood, Adrian, Tiao, Grace, Tijanic, Nebojsa, Timms, Lee E, Tirabosco, Roberto, Tojo, Marta, Tommasi, Stefania, Toon, Christopher W, Toprak, Umut H, Torrents, David, Tortora, Giampaolo, Tost, Jörg, Totoki, Yasushi, Townend, David, Traficante, Nadia, Treilleux, Isabelle, Trotta, Jean-Rémi, Trümper, Lorenz HP, Tsao, Ming, Tsunoda, Tatsuhiko, MC Tubio, Jose, Tucker, Olga, Turkington, Richard, Turner, Daniel J, Tutt, Andrew, Ueno, Masaki, Ueno, Naoto T, Umbricht, Christopher, Umer, Husen M, Underwood, Timothy J, Urban, Lara, Urushidate, Tomoko, Ushiku, Tetsuo, Uusküla-Reimand, Liis, Valencia, Alfonso, Van Den Berg, David J, Van Laere, Steven, Van Loo, Peter, Van Meir, Erwin G, Van den Eynden, Gert G, Van der Kwast, Theodorus, Vasudev, Naveen, Vazquez, Miguel, Vedururu, Ravikiran, Veluvolu, Umadevi, Vembu, Shankar, Verbeke, Lieven PC, Vermeulen, Peter, Verrill, Clare, Viari, Alain, Vicente, David, Vicentini, Caterina, VijayRaghavan, K, Viksna, Juris, Vilain, Ricardo E, Villasante, Izar, Vincent-Salomon, Anne, Visakorpi, Tapio, Voet, Douglas, Vyas, Paresh, Vázquez-García, Ignacio, Waddell, Nick M, Waddell, Nicola, Wadelius, Claes, Wadi, Lina, Wagener, Rabea, Wala, Jeremiah A, Wang, Jian, Wang, Jiayin, Wang, Linghua, Wang, Qi, Wang, Wenyi, Wang, Yumeng, Wang, Zhining, Waring, Paul M, Warnatz, Hans-Jörg, Warrell, Jonathan, Warren, Anne Y, Waszak, Sebastian M, Wedge, David C, Weichenhan, Dieter, Weinberger, Paul, Weinstein, John N, Weischenfeldt, Joachim, Weisenberger, Daniel J, Welch, Ian, Wendl, Michael C, Werner, Johannes, Whalley, Justin P, Wheeler, David A, Whitaker, Hayley C, Wigle, Dennis, Wilkerson, Matthew D, Williams, Ashley, Wilmott, James S, Wilson, Gavin W, Wilson, Julie M, Wilson, Richard K, Winterhoff, Boris, Wintersinger, Jeffrey A, Wiznerowicz, Maciej, Wolf, Stephan, Wong, Bernice H, Wong, Tina, Wong, Winghing, Woo, Youngchoon, Wood, Scott, Wouters, Bradly G, Wright, Adam J, Wright, Mark H, Wu, Dai-Ying, Wu, Guanming, Wu, Jianmin, Wu, Kui, Wu, Yang, Wu, Zhenggang, Xi, Liu, Xia, Tian, Xiang, Qian, Xiao, Xiao, Xing, Rui, Xiong, Heng, Xu, Qinying, Xu, Yanxun, Xue, Hong, Yachida, Shinichi, Yakneen, Sergei, Yamaguchi, Rui, Yamaguchi, Takafumi N, Yamamoto, Masakazu, Yamamoto, Shogo, Yamaue, Hiroki, Yang, Fan, Yang, Huanming, Yang, Jean Y, Yang, Liming, Yang, Lixing, Yang, Shanlin, Yang, Tsun-Po, Yang, Yang, Yao, Xiaotong, Yaspo, Marie-Laure, Yates, Lucy, Yau, Christina, Ye, Chen, Ye, Kai, Yellapantula, Venkata D, Yoon, Christopher J, Yoon, Sung-Soo, Yousif, Fouad, Yu, Jun, Yu, Kaixian, Yu, Willie, Yu, Yingyan, Yuan, Yuan, Yuen, Denis, Yung, Christina K, Zaikova, Olga, Zamora, Jorge, Zapatka, Marc, Zenklusen, Jean C, Zenz, Thorsten, Zeps, Nikolajs, Zhang, Cheng-Zhong, Zhang, Fan, Zhang, Hailei, Zhang, Hongwei, Zhang, Hongxin, Zhang, Jiashan, Zhang, Jing, Zhang, Xiuqing, Zhang, Xuanping, Zhang, Yan, Zhang, Zemin, Zhao, Zhongming, Zheng, Liangtao, Zheng, Xiuqing, Zhou, Wanding, Zhou, Yong, Zhu, Bin, Zhu, Hongtu, Zhu, Jingchun, Zhu, Shida, Zou, Lihua, Zou, Xueqing, deFazio, Anna, van As, Nicholas, van Deurzen, Carolien HM, van de Vijver, Marc J, Veer, L van’t, and von Mering, Christian

Subjects
Human Biology & Physiology, Ecology,Evolution & Ethology, Tumour Biology, Genetics & Genomics, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

In cancer, the primary tumour’s organ of origin and histopathology are the strongest determinants of its clinical behaviour, but in 3% of cases a patient presents with a metastatic tumour and no obvious primary. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we train a deep learning classifier to predict cancer type based on patterns of somatic passenger mutations detected in whole genome sequencing (WGS) of 2606 tumours representing 24 common cancer types produced by the PCAWG Consortium. Our classifier achieves an accuracy of 91% on held-out tumor samples and 88% and 83% respectively on independent primary and metastatic samples, roughly double the accuracy of trained pathologists when presented with a metastatic tumour without knowledge of the primary. Surprisingly, adding information on driver mutations reduced accuracy. Our results have clinical applicability, underscore how patterns of somatic passenger mutations encode the state of the cell of origin, and can inform future strategies to detect the source of circulating tumour DNA.

Published
2023
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25. Optical coherence properties of Kramers' rare-earth ions at the nanoscale for quantum applications

Author

Alqedra, Mohammed K., Deshmukh, Chetan, Liu, Shuping, Serrano, Diana, Horvath, Sebastian P., Rafie-Zinedine, Safi, Abdelatief, Abdullah, Rippe, Lars, Kröll, Stefan, Casabone, Bernardo, Ferrier, Alban, Tallaire, Alexandre, Goldner, Philippe, de Riedmatten, Hugues, and Walther, Andreas

Subjects
Quantum Physics, FOS: Physical sciences, Quantum Physics (quant-ph)
Abstract

Rare-earth (RE) ion doped nano-materials are promising candidates for a range of quantum technology applications. Among RE ions, the so-called Kramers' ions possess spin transitions in the GHz range at low magnetic fields, which allows for high-bandwidth multimode quantum storage, fast qubit operations as well as interfacing with superconducting circuits. They also present relevant optical transitions in the infrared. In particular, Er$^{3+}$ has an optical transition in the telecom band, while Nd$^{3+}$ presents a high-emission-rate transition close to 890 nm. In this paper, we measure spectroscopic properties that are of relevance to using these materials in quantum technology applications. We find the inhomogeneous linewidth to be 10.7 GHz for Er$^{3+}$ and 8.2 GHz for Nd$^{3+}$, and the excited state lifetime T$_1$ to be 13.68 ms for Er$^{3+}$ and 540 $\mu$s for Nd$^{3+}$. We study the dependence of homogeneous linewidth on temperature for both samples, with the narrowest linewidth being 379 kHz (T$_2$ = 839 ns) for Er$^{3+}$ measured at 3 K, and 62 kHz (T$_2$ = 5.14 $\mu$s) for Nd$^{3+}$ measured at 1.6 K. Further, we investigate time-dependent homogeneous linewidth broadening due to spectral diffusion and the dependence of homogeneous linewidth on magnetic field, in order to get additional clarity of mechanisms that can influence the coherence time. In light of our results, we discuss two applications: single qubit-state readout and a Fourier-limited single photon source., Comment: 9 pages, 5 figures

Published
2023
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26. Combined burden and functional impact tests for cancer driver discovery using DriverPower

Author

Shuai, Shimin, Abascal, Federico, Amin, Samirkumar B, Bader, Gary D, Bandopadhayay, Pratiti, Barenboim, Jonathan, Beroukhim, Rameen, Bertl, Johanna, Boroevich, Keith A, Brunak, Søren, Campbell, Peter J, Carlevaro-Fita, Joana, Chakravarty, Dimple, Chan, Calvin Wing Yiu, Chen, Ken, Choi, Jung Kyoon, Deu-Pons, Jordi, Dhingra, Priyanka, Diamanti, Klev, Feuerbach, Lars, Fink, J Lynn, Fonseca, Nuno A, Frigola, Joan, Gambacorti-Passerini, Carlo, Garsed, Dale W, Gerstein, Mark, Getz, Gad, Guo, Qianyun, Gut, Ivo G, Haan, David, Hamilton, Mark P, Haradhvala, Nicholas J, Harmanci, Arif O, Helmy, Mohamed, Herrmann, Carl, Hess, Julian M, Hobolth, Asger, Hodzic, Ermin, Hong, Chen, Hornshøj, Henrik, Isaev, Keren, Izarzugaza, Jose MG, Johnson, Rory, Johnson, Todd A, Juul, Malene, Juul, Randi Istrup, Kahles, Andre, Kahraman, Abdullah, Kellis, Manolis, Khurana, Ekta, Kim, Jaegil, Kim, Jong K, Kim, Youngwook, Komorowski, Jan, Korbel, Jan O, Kumar, Sushant, Lanzós, Andrés, Larsson, Erik, Lawrence, Michael S, Lee, Donghoon, Lehmann, Kjong-Van, Li, Shantao, Li, Xiaotong, Lin, Ziao, Liu, Eric Minwei, Lochovsky, Lucas, Lou, Shaoke, Madsen, Tobias, Marchal, Kathleen, Martincorena, Iñigo, Martinez-Fundichely, Alexander, Maruvka, Yosef E, McGillivray, Patrick D, Meyerson, William, Muiños, Ferran, Mularoni, Loris, Nakagawa, Hidewaki, Nielsen, Morten Muhlig, Paczkowska, Marta, Park, Keunchil, Park, Kiejung, Pedersen, Jakob Skou, Pons, Tirso, Pulido-Tamayo, Sergio, Raphael, Benjamin J, Reimand, Jüri, Reyes-Salazar, Iker, Reyna, Matthew A, Rheinbay, Esther, Rubin, Mark A, Rubio-Perez, Carlota, Sahinalp, S Cenk, Saksena, Gordon, Salichos, Leonidas, Sander, Chris, Schumacher, Steven E, Shackleton, Mark, Shapira, Ofer, Shen, Ciyue, Shrestha, Raunak, Sidiropoulos, Nikos, Sieverling, Lina, Sinnott-Armstrong, Nasa, Stein, Lincoln D, Stuart, Joshua M, Tamborero, David, Tiao, Grace, Tsunoda, Tatsuhiko, Umer, Husen M, Uusküla-Reimand, Liis, Valencia, Alfonso, Vazquez, Miguel, Verbeke, Lieven PC, Wadelius, Claes, Wadi, Lina, Wang, Jiayin, Warrell, Jonathan, Waszak, Sebastian M, Weischenfeldt, Joachim, Wheeler, David A, Wu, Guanming, Yu, Jun, Zhang, Jing, Zhang, Xuanping, Zhang, Yan, Zhao, Zhongming, Zou, Lihua, von Mering, Christian, Gallinger, Steven, Aaltonen, Lauri A, Abeshouse, Adam, Aburatani, Hiroyuki, Adams, David J, Agrawal, Nishant, Ahn, Keun Soo, Ahn, Sung-Min, Aikata, Hiroshi, Akbani, Rehan, Akdemir, Kadir C, Al-Ahmadie, Hikmat, Al-Sedairy, Sultan T, Al-Shahrour, Fatima, Alawi, Malik, Albert, Monique, Aldape, Kenneth, Alexandrov, Ludmil B, Ally, Adrian, Alsop, Kathryn, Alvarez, Eva G, Amary, Fernanda, Aminou, Brice, Ammerpohl, Ole, Anderson, Matthew J, Ang, Yeng, Antonello, Davide, Anur, Pavana, Aparicio, Samuel, Appelbaum, Elizabeth L, Arai, Yasuhito, Aretz, Axel, Arihiro, Koji, Ariizumi, Shun-ichi, Armenia, Joshua, Arnould, Laurent, Asa, Sylvia, Assenov, Yassen, Atwal, Gurnit, Aukema, Sietse, Auman, J Todd, Aure, Miriam RR, Awadalla, Philip, Aymerich, Marta, Baez-Ortega, Adrian, Bailey, Matthew H, Bailey, Peter J, Balasundaram, Miruna, Balu, Saianand, Banks, Rosamonde E, Barbi, Stefano, Barbour, Andrew P, Barnholtz-Sloan, Jill, Barr, Hugh, Barrera, Elisabet, Bartlett, John, Bartolome, Javier, Bassi, Claudio, Bathe, Oliver F, Baumhoer, Daniel, Bavi, Prashant, Baylin, Stephen B, Bazant, Wojciech, Beardsmore, Duncan, Beck, Timothy A, Behjati, Sam, Behren, Andreas, Niu, Beifang, Bell, Cindy, Beltran, Sergi, Benz, Christopher, Berchuck, Andrew, Bergmann, Anke K, Bergstrom, Erik N, Berman, Benjamin P, Berney, Daniel M, Bernhart, Stephan H, Berrios, Mario, Bersani, Samantha, Betancourt, Miguel, Bhandari, Vinayak, Bhosle, Shriram G, Biankin, Andrew V, Bieg, Matthias, Bigner, Darell, Binder, Hans, Birney, Ewan, Birrer, Michael, Biswas, Nidhan K, Bjerkehagen, Bodil, Bodenheimer, Tom, Boice, Lori, Bonizzato, Giada, De Bono, Johann S, Boot, Arnoud, Bootwalla, Moiz S, Borg, Ake, Borkhardt, Arndt, Borozan, Ivan, Borst, Christoph, Bosenberg, Marcus, Bosio, Mattia, 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Subjects
Human Biology & Physiology, Ecology,Evolution & Ethology, Tumour Biology, Genetics & Genomics, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

The discovery of driver mutations is one of the key motivations for cancer genome sequencing. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we describe DriverPower, a software package that uses mutational burden and functional impact evidence to identify driver mutations in coding and non-coding sites within cancer whole genomes. Using a total of 1373 genomic features derived from public sources, DriverPower’s background mutation model explains up to 93% of the regional variance in the mutation rate across multiple tumour types. By incorporating functional impact scores, we are able to further increase the accuracy of driver discovery. Testing across a collection of 2583 cancer genomes from the PCAWG project, DriverPower identifies 217 coding and 95 non-coding driver candidates. Comparing to six published methods used by the PCAWG Drivers and Functional Interpretation Working Group, DriverPower has the highest F1 score for both coding and non-coding driver discovery. This demonstrates that DriverPower is an effective framework for computational driver discovery.

Published
2023
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27. Integrative pathway enrichment analysis of multivariate omics data

Author

Paczkowska, Marta, Barenboim, Jonathan, Sintupisut, Nardnisa, Fox, Natalie S, Zhu, Helen, Abd-Rabbo, Diala, Mee, Miles W, Boutros, Paul C, Abascal, Federico, Amin, Samirkumar B, Bader, Gary D, Beroukhim, Rameen, Bertl, Johanna, Boroevich, Keith A, Brunak, Søren, Campbell, Peter J, Carlevaro-Fita, Joana, Chakravarty, Dimple, Chan, Calvin Wing Yiu, Chen, Ken, Choi, Jung Kyoon, Deu-Pons, Jordi, Dhingra, Priyanka, Diamanti, Klev, Feuerbach, Lars, Fink, J Lynn, Fonseca, Nuno A, Frigola, Joan, Gambacorti-Passerini, Carlo, Garsed, Dale W, Gerstein, Mark, Getz, Gad, Gonzalez-Perez, Abel, Guo, Qianyun, Gut, Ivo G, Haan, David, Hamilton, Mark P, Haradhvala, Nicholas J, Harmanci, Arif O, Helmy, Mohamed, Herrmann, Carl, Hess, Julian M, Hobolth, Asger, Hodzic, Ermin, Hong, Chen, Hornshøj, Henrik, Isaev, Keren, Izarzugaza, Jose MG, Johnson, Rory, Johnson, Todd A, Juul, Malene, Juul, Randi Istrup, Kahles, Andre, Kahraman, Abdullah, Kellis, Manolis, Khurana, Ekta, Kim, Jaegil, Kim, Jong K, Kim, Youngwook, Komorowski, Jan, Korbel, Jan O, Kumar, Sushant, Lanzós, Andrés, Lawrence, Michael S, Lee, Donghoon, Lehmann, Kjong-Van, Li, Shantao, Li, Xiaotong, Lin, Ziao, Liu, Eric Minwei, Lochovsky, Lucas, Lou, Shaoke, Madsen, Tobias, Marchal, Kathleen, Martincorena, Iñigo, Martinez-Fundichely, Alexander, Maruvka, Yosef E, McGillivray, Patrick D, Meyerson, William, Muiños, Ferran, Mularoni, Loris, Nakagawa, Hidewaki, Nielsen, Morten Muhlig, Park, Keunchil, Park, Kiejung, Pedersen, Jakob Skou, Pich, Oriol, Pons, Tirso, Pulido-Tamayo, Sergio, Raphael, Benjamin J, Reyes-Salazar, Iker, Reyna, Matthew A, Rheinbay, Esther, Rubin, Mark A, Rubio-Perez, Carlota, Sabarinathan, Radhakrishnan, Sahinalp, S Cenk, Saksena, Gordon, Salichos, Leonidas, Sander, Chris, Schumacher, Steven E, Shackleton, Mark, Shapira, Ofer, Shen, Ciyue, Shrestha, Raunak, Shuai, Shimin, Sidiropoulos, Nikos, Sieverling, Lina, Sinnott-Armstrong, Nasa, Stein, Lincoln D, Stuart, Joshua M, Tamborero, David, Tiao, Grace, Tsunoda, 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Vijver, Marc J, and Veer, L van’t

Subjects
Human Biology & Physiology, Ecology,Evolution & Ethology, Tumour Biology, Genetics & Genomics, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

Multi-omics datasets represent distinct aspects of the central dogma of molecular biology. Such high-dimensional molecular profiles pose challenges to data interpretation and hypothesis generation. ActivePathways is an integrative method that discovers significantly enriched pathways across multiple datasets using statistical data fusion, rationalizes contributing evidence and highlights associated genes. As part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumor types, we integrated genes with coding and non-coding mutations and revealed frequently mutated pathways and additional cancer genes with infrequent mutations. We also analyzed prognostic molecular pathways by integrating genomic and transcriptomic features of 1780 breast cancers and highlighted associations with immune response and anti-apoptotic signaling. Integration of ChIP-seq and RNA-seq data for master regulators of the Hippo pathway across normal human tissues identified processes of tissue regeneration and stem cell regulation. ActivePathways is a versatile method that improves systems-level understanding of cellular organization in health and disease through integration of multiple molecular datasets and pathway annotations.

Published
2023
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28. Pathway and network analysis of more than 2500 whole cancer genomes

Author

Reyna, Matthew A, Haan, David, Paczkowska, Marta, Verbeke, Lieven PC, Vazquez, Miguel, Kahraman, Abdullah, Pulido-Tamayo, Sergio, Barenboim, Jonathan, Wadi, Lina, Dhingra, Priyanka, Shrestha, Raunak, Getz, Gad, Lawrence, Michael S, Pedersen, Jakob Skou, Rubin, Mark A, Wheeler, David A, Brunak, Søren, Izarzugaza, Jose MG, Khurana, Ekta, Marchal, Kathleen, von Mering, Christian, Sahinalp, S Cenk, Valencia, Alfonso, Abascal, Federico, Amin, Samirkumar B, Bader, Gary D, Bandopadhayay, Pratiti, Beroukhim, Rameen, Bertl, Johanna, Boroevich, Keith A, Busanovich, John, Campbell, Peter J, Carlevaro-Fita, Joana, Chakravarty, Dimple, Chan, Calvin Wing Yiu, Chen, Ken, Choi, Jung Kyoon, Deu-Pons, Jordi, Diamanti, Klev, Feuerbach, Lars, Fink, J Lynn, Fonseca, Nuno A, Frigola, Joan, Gambacorti-Passerini, Carlo, Garsed, Dale W, Gerstein, Mark, Guo, Qianyun, Gut, Ivo G, Hamilton, Mark P, Haradhvala, Nicholas J, Harmanci, Arif O, Helmy, Mohamed, Herrmann, Carl, Hess, Julian M, Hobolth, Asger, Hodzic, 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Subjects
Human Biology & Physiology, Ecology,Evolution & Ethology, Tumour Biology, Genetics & Genomics, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

The catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notably TERT promoter mutations, have been reported. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancer across 38 tumor types, we perform multi-faceted pathway and network analyses of non-coding mutations across 2583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project that was motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes. While few non-coding genomic elements are recurrently mutated in this cohort, we identify 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression in TP53, TLE4, and TCF4. We find that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing is primarily altered by non-coding mutations in this cohort, and samples containing non-coding mutations in well-known RNA splicing factors exhibit similar gene expression signatures as samples with coding mutations in these genes. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments.

Published
2023
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29. Divergent mutational processes distinguish hypoxic and normoxic tumours

Author

Bhandari, Vinayak, Li, Constance H, Bristow, Robert G, Boutros, Paul C, Aaltonen, Lauri A, Abascal, Federico, Abeshouse, Adam, Aburatani, Hiroyuki, Adams, David J, Agrawal, Nishant, Ahn, Keun Soo, Ahn, Sung-Min, Aikata, Hiroshi, Akbani, Rehan, Akdemir, Kadir C, Al-Ahmadie, Hikmat, Al-Sedairy, Sultan T, Al-Shahrour, Fatima, Alawi, Malik, Albert, Monique, Aldape, Kenneth, Alexandrov, Ludmil B, Ally, Adrian, Alsop, Kathryn, Alvarez, Eva G, Amary, Fernanda, Amin, Samirkumar B, Aminou, Brice, Ammerpohl, Ole, Anderson, Matthew J, Ang, Yeng, Antonello, Davide, Anur, Pavana, Aparicio, Samuel, Appelbaum, Elizabeth L, Arai, Yasuhito, Aretz, Axel, Arihiro, Koji, Ariizumi, Shun-ichi, Armenia, Joshua, Arnould, Laurent, Asa, Sylvia, Assenov, Yassen, Atwal, Gurnit, Aukema, Sietse, Auman, J Todd, Aure, Miriam RR, Awadalla, Philip, Aymerich, Marta, Bader, Gary D, Baez-Ortega, Adrian, Bailey, Matthew H, Bailey, Peter J, Balasundaram, Miruna, Balu, Saianand, Bandopadhayay, Pratiti, Banks, Rosamonde E, 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Richard, Saller, Charles, Salvia, Roberto, Sam, Michelle, Samra, Jaswinder S, Sanchez-Vega, Francisco, Sander, Chris, Sanders, Grant, Sarin, Rajiv, Sarrafi, Iman, Sasaki-Oku, Aya, Sauer, Torill, Sauter, Guido, Saw, Robyn PM, Scardoni, Maria, Scarlett, Christopher J, Scarpa, Aldo, Scelo, Ghislaine, Schadendorf, Dirk, Schein, Jacqueline E, Schilhabel, Markus B, Schlesner, Matthias, Schlomm, Thorsten, Schmidt, Heather K, Schramm, Sarah-Jane, Schreiber, Stefan, Schultz, Nikolaus, Schumacher, Steven E, Schwarz, Roland F, Scolyer, Richard A, Scott, David, Scully, Ralph, Seethala, Raja, Segre, Ayellet V, Selander, Iris, Semple, Colin A, Senbabaoglu, Yasin, Sengupta, Subhajit, Sereni, Elisabetta, Serra, Stefano, Sgroi, Dennis C, Shackleton, Mark, Shah, Nimish C, Shahabi, Sagedeh, Shang, Catherine A, Shang, Ping, Shapira, Ofer, Shelton, Troy, Shen, Ciyue, Shen, Hui, Shepherd, Rebecca, Shi, Ruian, Shi, Yan, Shiah, Yu-Jia, Shibata, Tatsuhiro, Shih, Juliann, Shimizu, Eigo, Shimizu, Kiyo, Shin, Seung Jun, Shiraishi, Yuichi, Shmaya, Tal, Shmulevich, Ilya, Shorser, Solomon I, Short, Charles, Shrestha, Raunak, Shringarpure, Suyash S, Shriver, Craig, Shuai, Shimin, Sidiropoulos, Nikos, Siebert, Reiner, Sieuwerts, Anieta M, Sieverling, Lina, Signoretti, Sabina, Sikora, Katarzyna O, Simbolo, Michele, Simon, Ronald, Simons, Janae V, Simpson, Jared T, Simpson, Peter T, Singer, Samuel, Sinnott-Armstrong, Nasa, Sipahimalani, Payal, Skelly, Tara J, Smid, Marcel, Smith, Jaclyn, Smith-McCune, Karen, Socci, Nicholas D, Sofia, Heidi J, Soloway, Matthew G, Song, Lei, Sood, Anil K, Sothi, Sharmila, Sotiriou, Christos, Soulette, Cameron M, Span, Paul N, Spellman, Paul T, Sperandio, Nicola, Spillane, Andrew J, Spiro, Oliver, Spring, Jonathan, Staaf, Johan, Stadler, Peter F, Staib, Peter, Stark, Stefan G, Stebbings, Lucy, Stefánsson, Ólafur Andri, Stegle, Oliver, Stein, Lincoln D, Stenhouse, Alasdair, Stewart, Chip, Stilgenbauer, Stephan, Stobbe, Miranda D, Stratton, Michael R, Stretch, Jonathan R, Struck, Adam J, Stuart, Joshua M, Stunnenberg, Henk G, Su, Hong, Su, Xiaoping, Sun, Ren X, Sungalee, Stephanie, Susak, Hana, Suzuki, Akihiro, Sweep, Fred, Szczepanowski, Monika, Sültmann, Holger, Yugawa, Takashi, Tam, Angela, Tamborero, David, Tan, Benita Kiat Tee, Tan, Donghui, Tan, Patrick, Tanaka, Hiroko, Taniguchi, Hirokazu, Tanskanen, Tomas J, Tarabichi, Maxime, Tarnuzzer, Roy, Tarpey, Patrick, Taschuk, Morgan L, Tatsuno, Kenji, Tavaré, Simon, Taylor, Darrin F, Taylor-Weiner, Amaro, Teague, Jon W, Teh, Bin Tean, Tembe, Varsha, Temes, Javier, Thai, Kevin, Thayer, Sarah P, Thiessen, Nina, Thomas, Gilles, Thomas, Sarah, Thompson, Alan, Thompson, Alastair M, Thompson, John FF, Thompson, R Houston, Thorne, Heather, Thorne, Leigh B, Thorogood, Adrian, Tiao, Grace, Tijanic, Nebojsa, Timms, Lee E, Tirabosco, Roberto, Tojo, Marta, Tommasi, Stefania, Toon, Christopher W, Toprak, Umut H, Torrents, David, Tortora, Giampaolo, Tost, Jörg, Totoki, Yasushi, Townend, David, Traficante, Nadia, 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Wenyi, Wang, Yumeng, Wang, Zhining, Waring, Paul M, Warnatz, Hans-Jörg, Warrell, Jonathan, Warren, Anne Y, Waszak, Sebastian M, Wedge, David C, Weichenhan, Dieter, Weinberger, Paul, Weinstein, John N, Weischenfeldt, Joachim, Weisenberger, Daniel J, Welch, Ian, Wendl, Michael C, Werner, Johannes, Whalley, Justin P, Wheeler, David A, Whitaker, Hayley C, Wigle, Dennis, Wilkerson, Matthew D, Williams, Ashley, Wilmott, James S, Wilson, Gavin W, Wilson, Julie M, Wilson, Richard K, Winterhoff, Boris, Wintersinger, Jeffrey A, Wiznerowicz, Maciej, Wolf, Stephan, Wong, Bernice H, Wong, Tina, Wong, Winghing, Woo, Youngchoon, Wood, Scott, Wouters, Bradly G, Wright, Adam J, Wright, Derek W, Wright, Mark H, Wu, Chin-Lee, Wu, Dai-Ying, Wu, Guanming, Wu, Jianmin, Wu, Kui, Wu, Yang, Wu, Zhenggang, Xi, Liu, Xia, Tian, Xiang, Qian, Xiao, Xiao, Xing, Rui, Xiong, Heng, Xu, Qinying, Xu, Yanxun, Xue, Hong, Yachida, Shinichi, Yakneen, Sergei, Yamaguchi, Rui, Yamaguchi, Takafumi N, Yamamoto, Masakazu, Yamamoto, Shogo, Yamaue, Hiroki, Yang, Fan, Yang, Huanming, Yang, Jean Y, Yang, Liming, Yang, Lixing, Yang, Shanlin, Yang, Tsun-Po, Yang, Yang, Yao, Xiaotong, Yaspo, Marie-Laure, Yates, Lucy, Yau, Christina, Ye, Chen, Ye, Kai, Yellapantula, Venkata D, Yoon, Christopher J, Yoon, Sung-Soo, Yousif, Fouad, Yu, Jun, Yu, Kaixian, Yu, Willie, Yu, Yingyan, Yuan, Ke, Yuan, Yuan, Yuen, Denis, Yung, Christina K, Zaikova, Olga, Zamora, Jorge, Zapatka, Marc, Zenklusen, Jean C, Zenz, Thorsten, Zeps, Nikolajs, Zhang, Cheng-Zhong, Zhang, Fan, Zhang, Hailei, Zhang, Hongwei, Zhang, Hongxin, Zhang, Jiashan, Zhang, Jing, Zhang, Junjun, Zhang, Xiuqing, Zhang, Xuanping, Zhang, Yan, Zhang, Zemin, Zhao, Zhongming, Zheng, Liangtao, Zheng, Xiuqing, Zhou, Wanding, Zhou, Yong, Zhu, Bin, Zhu, Hongtu, Zhu, Jingchun, Zhu, Shida, Zou, Lihua, Zou, Xueqing, deFazio, Anna, van As, Nicholas, van Deurzen, Carolien HM, van de Vijver, Marc J, Veer, L van’t, and von Mering, Christian

Subjects
Human Biology & Physiology, Ecology,Evolution & Ethology, Tumour Biology, Genetics & Genomics, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited comprehension of its associations with specific mutational processes, non-coding driver genes and evolutionary features. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we quantify hypoxia in 1188 tumours spanning 27 cancer types. Elevated hypoxia associates with increased mutational load across cancer types, irrespective of underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology directly associates with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in hypoxic tumours, and mutations in PTEN interact with hypoxia to direct tumour evolutionary trajectories. Overall, hypoxia plays a critical role in shaping the genomic and evolutionary landscapes of cancer.

Published
2023
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32. Intestinal B-cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling

Author

Elena Kotsiliti, Valentina Leone, Svenja Schuehle, Olivier Govaere, Hai Li, Monika J. Wolf, Helena Horvatic, Sandra Bierwirth, Jana Hundertmark, Donato Inverso, Laimdota Zizmare, Avital Sarusi-Portuguez, Revant Gupta, Tracy O’Connor, Anastasios D. Giannou, Ahmad Mustafa Shiri, Yehuda Schlesinger, Maria Garcia Beccaria, Charlotte Rennert, Dominik Pfister, Rupert Öllinger, Iana Gadjalova, Pierluigi Ramadori, Mohammad Rahbari, Nuh Rahbari, Marc Healy, Mirian Fernández-Vaquero, Neda Yahoo, Jakob Janzen, Indrabahadur Singh, Chaofan Fan, Xinyuan Liu, Monika Rau, Martin Feuchtenberger, Eva Schwaneck, Sebastian J. Wallace, Simon Cockell, John Wilson-Kanamori, Prakash Ramachandran, Celia Kho, Timothy J. Kendall, Anne-Laure Leblond, Selina J. Keppler, Piotr Bielecki, Katja Steiger, Maike Hofmann, Karsten Rippe, Horst Zitzlesberger, Achim Weber, Nisar Malek, Tom Lüdde, Mihael Vucur, Hellmut G. Augustin, Richard Flavell, Oren Parnas, Roland Rad, Olivier Pabst, Neil C. Henderson, Samuel Huber, Andrew Macpherson, Percy Knolle, Manfred Claasen, Andreas Geier, Christoph Trautwein, Kristian Unger, Eran Elinav, Ari Waisman, Zeinab Abdullah, Dirk Haller, Frank Tacke, Quentin M. Anstee, and Mathias Heikenwalder

Subjects
Hepatology, 610 Medicine & health
Abstract

BACKGROUND & AIMS: The progression of nonalcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC.METHODS: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH diets (for example, choline-deficient high-fat diet, CD-HFD) or chow diet for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a CD-HFD, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with NAFL, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and scRNA-Seq analysis were performed in liver and gastrointestinal tissue for immune cells in mice and humans.RESULTS: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen-specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B-cells and showed a positive correlation between IgA levels and activated FcRγ+ hepatic myeloid cells as well extent of liver fibrosis.CONCLUSIONS: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for treating NASH.IMPACT AND IMPLICATIONS: Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory condition on the rise and can lead to hepatocellular carcinoma (HCC), the 3rd most common cause of cancer-related death worldwide. Currently, there is no effective treatment for this progressive disease that correlates with a marked risk of HCC mortality and carries a substantial healthcare burden. To date, among all the solid tumours, especially in HCC, the incidence and mortality rates are almost the same, making it crucial to find curative treatments for chronic diseases, such as NASH, which highly predispose to tumorigenesis. We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we could show that the absence of B cells prevented HCC development. B-cell intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets in combinatorial NASH therapies against inflammation and fibrosis.

Published
2023
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33. Genomic footprints of activated telomere maintenance mechanisms in cancer

Author

Sieverling, Lina, Hong, Chen, Koser, Sandra D, Ginsbach, Philip, Kleinheinz, Kortine, Hutter, Barbara, Braun, Delia M, Cortés-Ciriano, Isidro, Xi, Ruibin, Kabbe, Rolf, Park, Peter J, Eils, Roland, Schlesner, Matthias, Akdemir, Kadir C, Alvarez, Eva G, Baez-Ortega, Adrian, Beroukhim, Rameen, Boutros, Paul C, Bowtell, David DL, Brors, Benedikt, Burns, Kathleen H, Campbell, Peter J, Chan, Kin, Chen, Ken, Dueso-Barroso, Ana, Dunford, Andrew J, Edwards, Paul A, Estivill, Xavier, Etemadmoghadam, Dariush, Feuerbach, Lars, Fink, J Lynn, Frenkel-Morgenstern, Milana, Garsed, Dale W, Gerstein, Mark, Gordenin, Dmitry A, Haan, David, Haber, James E, Hess, Julian M, Imielinski, Marcin, Jones, David TW, Ju, Young Seok, Kazanov, Marat D, Klimczak, Leszek J, Koh, Youngil, Korbel, Jan O, Kumar, Kiran, Lee, Eunjung Alice, Lee, Jake June-Koo, Li, Yilong, Lynch, Andy G, Macintyre, Geoff, Markowetz, Florian, Martincorena, Iñigo, Martinez-Fundichely, Alexander, Meyerson, Matthew, Miyano, Satoru, Nakagawa, Hidewaki, Navarro, Fabio CP, Ossowski, Stephan, Pearson, John V, Puiggròs, Montserrat, Rippe, Karsten, Roberts, Nicola D, Roberts, Steven A, Rodriguez-Martin, Bernardo, Schumacher, Steven E, Scully, Ralph, Shackleton, Mark, Sidiropoulos, Nikos, Stewart, Chip, Torrents, David, MC Tubio, Jose, Villasante, Izar, Waddell, Nicola, Wala, Jeremiah A, Weischenfeldt, Joachim, Yang, Lixing, Yao, Xiaotong, Yoon, Sung-Soo, Zamora, Jorge, Zhang, Cheng-Zhong, Aaltonen, Lauri A, Abascal, Federico, Abeshouse, Adam, Aburatani, Hiroyuki, Adams, David J, Agrawal, Nishant, Ahn, Keun Soo, Ahn, Sung-Min, Aikata, Hiroshi, Akbani, Rehan, Al-Ahmadie, Hikmat, Al-Sedairy, Sultan T, Al-Shahrour, Fatima, Alawi, Malik, Albert, Monique, Aldape, Kenneth, Alexandrov, Ludmil B, Ally, Adrian, Alsop, Kathryn, Amary, Fernanda, Amin, Samirkumar B, Aminou, Brice, Ammerpohl, Ole, Anderson, Matthew J, Ang, Yeng, Antonello, Davide, Anur, Pavana, Aparicio, Samuel, Appelbaum, Elizabeth L, Arai, Yasuhito, Aretz, Axel, Arihiro, 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Staaf, Johan, Stadler, Peter F, Staib, Peter, Stark, Stefan G, Stebbings, Lucy, Stefánsson, Ólafur Andri, Stegle, Oliver, Stein, Lincoln D, Stenhouse, Alasdair, Stilgenbauer, Stephan, Stobbe, Miranda D, Stratton, Michael R, Stretch, Jonathan R, Struck, Adam J, Stuart, Joshua M, Stunnenberg, Henk G, Su, Hong, Su, Xiaoping, Sun, Ren X, Sungalee, Stephanie, Susak, Hana, Suzuki, Akihiro, Sweep, Fred, Szczepanowski, Monika, Sültmann, Holger, Yugawa, Takashi, Tam, Angela, Tamborero, David, Tan, Benita Kiat Tee, Tan, Donghui, Tan, Patrick, Tanaka, Hiroko, Taniguchi, Hirokazu, Tanskanen, Tomas J, Tarabichi, Maxime, Tarnuzzer, Roy, Tarpey, Patrick, Taschuk, Morgan L, Tatsuno, Kenji, Tavaré, Simon, Taylor, Darrin F, Taylor-Weiner, Amaro, Teague, Jon W, Teh, Bin Tean, Tembe, Varsha, Temes, Javier, Thai, Kevin, Thayer, Sarah P, Thiessen, Nina, Thomas, Gilles, Thomas, Sarah, Thompson, Alan, Thompson, Alastair M, Thompson, John FF, Thompson, R Houston, Thorne, Heather, Thorne, Leigh B, Thorogood, Adrian, Tiao, Grace, Tijanic, Nebojsa, Timms, Lee E, Tirabosco, Roberto, Tojo, Marta, Tommasi, Stefania, Toon, Christopher W, Toprak, Umut H, Tortora, Giampaolo, Tost, Jörg, Totoki, Yasushi, Townend, David, Traficante, Nadia, Treilleux, Isabelle, Trotta, Jean-Rémi, Trümper, Lorenz HP, Tsao, Ming, Tsunoda, Tatsuhiko, Tucker, Olga, Turkington, Richard, Turner, Daniel J, Tutt, Andrew, Ueno, Masaki, Ueno, Naoto T, Umbricht, Christopher, Umer, Husen M, Underwood, Timothy J, Urban, Lara, Urushidate, Tomoko, Ushiku, Tetsuo, Uusküla-Reimand, Liis, Valencia, Alfonso, Van Den Berg, David J, Van Laere, Steven, Van Loo, Peter, Van Meir, Erwin G, Van den Eynden, Gert G, Van der Kwast, Theodorus, Vasudev, Naveen, Vazquez, Miguel, Vedururu, Ravikiran, Veluvolu, Umadevi, Vembu, Shankar, Verbeke, Lieven PC, Vermeulen, Peter, Verrill, Clare, Viari, Alain, Vicente, David, Vicentini, Caterina, VijayRaghavan, K, Viksna, Juris, Vilain, Ricardo E, Vincent-Salomon, Anne, Visakorpi, Tapio, Voet, Douglas, Vyas, Paresh, Vázquez-García, Ignacio, Waddell, Nick M, Wadelius, Claes, Wadi, Lina, Wagener, Rabea, Wang, Jian, Wang, Jiayin, Wang, Linghua, Wang, Qi, Wang, Wenyi, Wang, Yumeng, Wang, Zhining, Waring, Paul M, Warnatz, Hans-Jörg, Warrell, Jonathan, Warren, Anne Y, Waszak, Sebastian M, Wedge, David C, Weichenhan, Dieter, Weinberger, Paul, Weinstein, John N, Weisenberger, Daniel J, Welch, Ian, Wendl, Michael C, Werner, Johannes, Whalley, Justin P, Wheeler, David A, Whitaker, Hayley C, Wigle, Dennis, Wilkerson, Matthew D, Williams, Ashley, Wilmott, James S, Wilson, Gavin W, Wilson, Julie M, Wilson, Richard K, Winterhoff, Boris, Wintersinger, Jeffrey A, Wiznerowicz, Maciej, Wolf, Stephan, Wong, Bernice H, Wong, Tina, Wong, Winghing, Woo, Youngchoon, Wood, Scott, Wouters, Bradly G, Wright, Adam J, Wright, Derek W, Wright, Mark H, Wu, Chin-Lee, Wu, Dai-Ying, Wu, Guanming, Wu, Jianmin, Wu, Kui, Wu, Yang, Wu, Zhenggang, Xi, Liu, Xia, Tian, Xiang, Qian, Xiao, Xiao, Xing, Rui, Xiong, Heng, Xu, Qinying, Xu, Yanxun, Xue, Hong, Yachida, Shinichi, Yakneen, Sergei, Yamaguchi, Rui, Yamaguchi, Takafumi N, Yamamoto, Masakazu, Yamamoto, Shogo, Yamaue, Hiroki, Yang, Fan, Yang, Huanming, Yang, Jean Y, Yang, Liming, Yang, Shanlin, Yang, Tsun-Po, Yang, Yang, Yaspo, Marie-Laure, Yates, Lucy, Yau, Christina, Ye, Chen, Ye, Kai, Yellapantula, Venkata D, Yoon, Christopher J, Yousif, Fouad, Yu, Jun, Yu, Kaixian, Yu, Willie, Yu, Yingyan, Yuan, Ke, Yuan, Yuan, Yuen, Denis, Yung, Christina K, Zaikova, Olga, Zapatka, Marc, Zenklusen, Jean C, Zenz, Thorsten, Zeps, Nikolajs, Zhang, Fan, Zhang, Hailei, Zhang, Hongwei, Zhang, Hongxin, Zhang, Jiashan, Zhang, Jing, Zhang, Junjun, Zhang, Xiuqing, Zhang, Xuanping, Zhang, Yan, Zhang, Zemin, Zhao, Zhongming, Zheng, Liangtao, Zheng, Xiuqing, Zhou, Wanding, Zhou, Yong, Zhu, Bin, Zhu, Hongtu, Zhu, Jingchun, Zhu, Shida, Zou, Lihua, Zou, Xueqing, deFazio, Anna, van As, Nicholas, van Deurzen, Carolien HM, van de Vijver, Marc J, Veer, L van’t, and von Mering, Christian

Subjects
Human Biology & Physiology, Ecology,Evolution & Ethology, Tumour Biology, Genetics & Genomics, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXXtrunc) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXXtrunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.

Published
2023
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34. O papel dos 'Food Hubs' na construção de relacionamentos entre produtores de alimentos orgânicos e consumidores sob a ótica das cadeias curtas em Porto Alegre (RS)

Author

Adriano Diego Klein, Caroline Rippe de Mello Klein, and Glauco Schultz

Subjects
Comercialização, Orgânicos, General Engineering, Cadeias curtas, Food Hubs
Abstract

Este artigo visa analisar o papel de food hubs, cujo conceito pode ser entendido como o de multiplataformas que comercializam produtos orgânicos frescos, que geram relacionamentos interativos entre produtores e consumidores. Partindo dessa premissa, para que possamos compreender essa transcendência conceitual, foram escolhidos 3 food hubs na região metropolitana de Porto Alegre como estudo para verificar e perceber como ocorrem essas relações. Através da pesquisa, numa primeira análise, foi possível observar as várias iniciativas que geram fidelização, engajamento, empatia entre as partes e, sobretudo, o incentivo que leva à interação e conhecimento mútuo. Dessa forma, esses food hubs se mostraram como promotores da relação produtor-consumidor, muito além da mera comunicação de informações, que acabam por incentivar as interações a longo prazo e a empatia entre os interessados envolvidos em todo o processo.

Published
2022

35. Nucleosome repositioning in chronic lymphocytic leukaemia

Author

Kristan V. Piroeva, Charlotte McDonald, Charalampos Xanthopoulos, Chelsea Fox, Christopher T. Clarkson, Jan-Philipp Mallm, Yevhen Vainshtein, Luminita Ruje, Lara C. Klett, Stephan Stilgenbauer, Daniel Mertens, Efterpi Kostareli, Karsten Rippe, and Vladimir B. Teif

Abstract

The location of nucleosomes in the human genome determines the primary chromatin structure and regulates access to regulatory regions. However, genome-wide information on deregulated nucleosome occupancy and its implications in primary cancer cells is scarce. Here, we performed a systematic comparison of high-resolution nucleosome maps in peripheral-blood B-cells from patients with chronic lymphocytic leukaemia (CLL) and healthy individuals at single base pair resolution. Our investigation uncovered significant changes of both nucleosome positioning and packing in CLL. Globally, the spacing between nucleosomes (the nucleosome repeat length, NRL) was shortened in CLL. This effect was stronger in the more aggressive IGHV-unmutated than IGHV-mutated CLL subtype. Changes in nucleosome occupancy at specific sites were linked to active chromatin remodelling and reduced DNA methylation. Nucleosomes lost or gained in CLL in comparison with non-malignant B-cells marked differential binding of 3D chromatin organisers such as CTCF as well as immune response-related transcription factors, allowing delineating epigenetic mechanisms affected in CLL. Furthermore, patients could be better assigned to CLL subtypes according to nucleosome occupancy at cancer-specific sites than based on DNA methylation or gene expression. Thus, nucleosome positioning constitutes a novel readout to dissect molecular mechanisms of disease progression and to stratify patients. Furthermore, we anticipate that the global nucleosome positioning changes detected in our study, like the reduced NRL, can be exploited for liquid biopsy applications based on cell-free DNA to monitor disease progression.

Published
2022
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36. Mass-balance threshold matching of geoelectric and seismic data: a case study from Ketzin

Author

Wolfgang Weinzierl, Merlin Ganzer, Dennis Rippe, Stefan Lüth, and Cornelia Schmidt-Hattenberger

Subjects
Geology, Ocean Engineering, Water Science and Technology
Abstract

Seismic and geoelectric methods are used as complementary tools for the identification of fluid/gas effects in underground storage and production scenarios. Both methods present a different resolution. Seismic data tend to be acquired by much more dense geometrical layouts, and geoelectric acquisition as a potential field method shows information integrated over spatial distances. We present results matching seismic and electrical resistivity tomography (ERT) results from two repeat surveys performed during CO 2 storage operations at the Ketzin pilot site in Germany. The approach is based on data acquired in 2009 and 2012 at different stages of total injected CO 2 volume. Masses are obtained from the averaged change in acoustic impedance and are compared to masses inferred from inverted electrical resistivities. Archie's equation is used to obtain saturations from the ERT models. The sensitivity of the background resistivity, R 0 , as a relevant parameter in determining the mass of injected CO 2 is analysed. A specific threshold analysis based on seismic thickness by bin has been applied to investigate the matching of seismically and ERT obtained masses. Both mass estimates match comparatively well, but show inherent sensitive parameters and their corresponding impact as temporal and spatial uncertainties that may cause mass differences for the areas of investigation.

Published
2022
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37. Testing an attachment- and trauma-informed intervention approach for parents and young children after interparental violence: protocol for a randomized controlled trial

Author

Sabine van der Asdonk, Ashwina R. Kesarlal, Carlo Schuengel, Nina Draaisma, Carlijn de Roos, Karine Zuidgeest, Ralph C. A. Rippe, Lenneke R. A. Alink, Clinical Child and Family Studies, LEARN! - Child rearing, APH - Aging & Later Life, and APH - Mental Health

Subjects
Parents, Domestic Violence, SDG 16 - Peace, Eye Movement Desensitization Reprocessing, Parenting, SDG 16 - Peace, Justice and Strong Institutions, Infant, Medicine (miscellaneous), Justice and Strong Institutions, Stress Disorders, Post-Traumatic, Treatment Outcome, Child, Preschool, Humans, Multicenter Studies as Topic, Pharmacology (medical), Child, Randomized Controlled Trials as Topic
Abstract

Background Interparental violence has persistent adverse effects on victimized parents and children. Young children, including infants and toddlers, are at particular risk to develop long-lasting negative outcomes, and yet specific evidence on effective intervention approaches for this vulnerable group is still lacking. This study will test the effectiveness of an attachment- and trauma-informed intervention approach in a sample of parent-child dyads who have experienced severe interparental violence. We test the individual and combined effects of two interventions: (1) “Nederlandse Interventie Kortdurend op Atypisch oudergedrag” (NIKA; Dutch, short-term intervention focused on atypical parenting behavior) aimed at improving the attachment relationship and (2) eye movement desensitization and reprocessing (EMDR) therapy aimed at reducing parental post-traumatic stress disorder (PTSD) symptoms. Methods This study uses a multicenter randomized controlled design across multiple domestic violence shelters in the Netherlands. We aim to recruit 150 parent-child dyads with children aged between 0.5 and 6 years old. The study design consists of two phases. During the first phase for testing the effect of NIKA only, eligible dyads are randomly allocated to either NIKA or a waitlist usual care group. A pre-test is conducted prior to the treatment period and a post-test takes place directly afterwards (6 weeks after the pre-test). Phase 2 follows directly for testing the effects of EMDR and the combination of NIKA and EMDR. Parents who report clinical PTSD symptoms are randomly allocated to either EMDR therapy or a waitlist usual care group. Parents who do not report clinical PTSD symptoms only receive care as usual. Six weeks later, a post-test of phase 2 is conducted for all participating dyads. Primary study outcomes are disrupted parenting behavior, sensitive parenting behavior, and parental PTSD symptoms. Secondary study outcomes include PTSD symptoms and behavioral and emotional problems of the child. Discussion This study will inform and enhance the clinical field by providing new insights regarding effective treatment combinations for traumatized parents and their young children after interparental violence. Trial registration Netherlands Trial Register (NTR) NL9179. Registered 7 January 2021

Published
2022
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38. Environmental drivers of genetic adaptation in Florida corals

Author

Kristina Black, John Rippe, and Mikhail Matz

Abstract

Thermally induced coral bleaching is a major cause of reef decline, though it could be offset by coral adaptation. Here we used three complementary approaches to identify which environmental gradients drive local adaptation in two common Florida corals, Porites astreoides and Agaricia agaricites. Depth is the most important factor for both species: each contains three genetically distinct lineages segregated by depth. Additionally, each lineage harbors genetic variation aligning with other environmental gradients, though elevated temperature is typically not one of them. In A. agaricites, nitrogen variation predicts genetic divergence in the deep and mid-depth lineages, while cold temperature is the most important driver within the shallow lineage. Nitrogen and cold are also associated with genetic variation in P. astreoides, and high temperature was highlighted only once in the deep lineage of P. astreoides. In both species, lineages don’t share environment-associated groups of SNPs, indicating that lineages adapt independently. Overall, the locally available genetic variation in our two corals species seems unlikely to provide thermally adaptive genetic variants for future warming. Our results map the environmental gradients that create the strongest genetic barriers for corals, which could serve as a guide for reef restoration.

Published
2022
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39. 1332. Population structure and genomic analysis of pediatric Streptococcus pyogenes clinical isolates in the United States, 2020 – 2022

Author

Egon A Ozer, Samuel W Gatesy, Ami B Patel, Judith A Guzman-Cottrill, Katherine E Fleming-Dutra, Sopio Chochua, Bernard Beall, Preeti Jaggi, Christine L Inguglia, Yiannis L Katsogridakis, Stanford Shulman, Robert R Tanz, and Jason Rippe

Subjects
Infectious Diseases, Oncology
Abstract

Background Streptococcus pyogenes (GAS) is the major cause of bacterial pharyngitis in children. GAS can cause conditions ranging from asymptomatic pharyngeal carriage to invasive infection. We compared the genomic characteristics of GAS pharyngeal and invasive isolates from U.S. children. Methods We cultured GAS from throat swabs collected from children aged 3–18 years with acute GAS pharyngitis, diagnosed by rapid antigen or molecular test, and from a convenience sample of asymptomatic children during 1/2020 to 3/2022 in Chicago, IL; Atlanta, GA; Portland, OR; Phoenix, AZ. We collected invasive isolates in Chicago. Whole-genome sequencing (WGS) was performed on the Illumina MiSeq for species confirmation, isolate typing, and virulence and antimicrobial gene identification. Reference-based read alignment was used for whole genome phylogenetic analysis. Results Of 1144 collected throat swabs, 684 were from children with pharyngitis and 460 from asymptomatic children. 13 invasive GAS isolates were collected. GAS were cultured from 359 pharyngitis and 20 asymptomatic swabs. Of these, 371 GAS isolates could be recovered and underwent WGS. Thirty isolates (8%) were either low-quality sequences and/or identified as species other than S. pyogenes and were excluded. Whole-genome phylogenetic analysis of 341 GAS (215 pharyngitis, 13 asymptomatic, 13 invasive) identified 25 related clusters and 8 singletons (Figure 1). Virulence gene complements within given emm types were generally concordant with recently published CDC strain data. The most frequently identified resistance genes were tetM and ermB. 281 isolates (82%) carried no antibiotic resistance genes. Some clusters were significantly more represented at certain sites within apparent geographically defined clusters of nearly indistinguishable isolates (Figure 1): cluster 1 in Chicago, emm type 3; cluster 14 in Phoenix and Portland, emm 28, 12; and cluster 15 in Atlanta, emm 89. No major genomic factors were significantly associated with asymptomatic vs pharyngitis vs invasive presentation. Figure 1:Whole genome phylogenetic tree of pediatric GAS isolates Maximum likelihood phylogenetic analysis based on whole-genome alignment of 371 Group A Streptococcus isolates. Tip colors represent cluster assignments based on genetic similarity. Inner ring represents geographic location of GAS isolation. Outer ring represents patient presentation: asymptomatic colonization, symptomatic pharyngitis, or invasive infection. Conclusion Pharyngeal and invasive GAS in children within individual clonal complexes are co-included in closely related clusters, with evidence of close transmission within individual sites Disclosures All Authors: No reported disclosures.

Published
2022
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40. 1321. Increased Prevalence of Group A Streptococcus (GAS) High Level Macrolide Resistance During the COVID-19 Pandemic

Author

Ami B Patel, Judith A Guzman-Cottrill, Katherine E Fleming-Dutra, Sopio Chochua, Bernard Beall, Preeti Jaggi, Jason Rippe, Christine L Inguglia, Yiannis L Katsogridakis, Egon A Ozer, Stanford Shulman, and Robert R Tanz

Subjects
Infectious Diseases, Oncology
Abstract

Background COVID-19 affected the epidemiology of many respiratory pathogens including GAS. Assessing genetic heterogeneity (emm type, antimicrobial resistance, virulence factors) can inform treatment recommendations and targets for potential GAS vaccines. We assessed GAS clinical antibiotic susceptibility and performed whole genome sequencing (WGS) among pediatric pharyngeal isolates from 2020–2022. Methods From 1/2020–3/2022 we collected throat swabs in pediatric clinics and EDs from children aged 3-18 years in Chicago, IL; Atlanta, GA; Portland, OR; and Phoenix, AZ: 1) with acute GAS pharyngitis and 2) among a convenience sample of asymptomatic children to assess for GAS colonization. Swabs were plated on blood agar. E-tests were used to assess clinical susceptibility to erythromycin (ERY) and ciprofloxacin (CIP). emm type and antimicrobial resistance genes (ERY, Clindamycin (CLI), and fluoroquinolones) were assessed by WGS. Results 1144 pharyngeal swabs were collected: 359/684 (52%) from children with GAS pharyngitis by rapid test and 20/460 (4.3%) from asymptomatic children yielded GAS on culture. Phenotypic resistance: 55/364 (15%) tested isolates were ERY resistant and 5/364 (1.4%) CIP resistant. The proportion of isolates with ERY resistance increased significantly from 2020 (6%) to 2021–2022 (25%) (χ2 = 23.70, p< .00001) (Figure 1). MICs were high among ERY resistant GAS (Table 1). Genotypic resistance: Of 304 sequenced GAS isolates 40/304 (13%) were ERY resistant, 35/304 (11.5%) were both ERY resistant and CLI (inducible or constitutive) resistant, and 4/304 (1.3%) fluoroquinolone resistant. ermB (62%) was the most common gene for ERY resistance and constitutive CLI resistance, followed by ermTR (23%) and ermT (11%) both conferring inducible CLI resistance. Among the 20 isolates from asymptomatic children no ERY, CLI, or CIP resistance occurred, and no resistance genes were identified. emm types 11, 9, 77, 58 and 94 were associated with ERY and CLI resistance. Conclusion ERY resistance increased from 2020–2022. The high rate of CLI resistance among ERY resistant GAS was associated with erm genes. These results are important to inform treatment recommendations for GAS pharyngitis and targets for vaccine development that can reduce antimicrobial-resistant GAS disease. Disclosures All Authors: No reported disclosures.

Published
2022
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43. The influence of roughness on the resistance to impact of different CAD/CAM dental ceramics

Author

Luis Felipe Guilardi, Arie Werner, Niek de Jager, Gabriel Kalil Rocha Pereira, Cornelis Johannes Kleverlaan, Marilia Pivetta Rippe, Luiz Felipe Valandro, Dental Material Sciences, and Oral Regenerative Medicine (ORM)

Subjects
Ceramics, resistance to impact, Surface Properties, Silicates, Dental Porcelain, computer-aided design/computer-aided manufacturing, Materials Testing, and Infrastructure, Computer-Aided Design, surface properties, Zirconium, SDG 9 - Industry, Innovation, and Infrastructure, Innovation, General Dentistry, SDG 9 - Industry
Abstract

This study aimed to investigate the effect of surface roughness (polished vs. CAD/CAM milling simulation) on impact strength of five dental ceramics for manufacturing CAD/CAM monolithic restorations. Specimens of five ceramics (FC- feldspathic glass-ceramic; PICN- polymer-infiltrated ceramic-network; ZLS- zirconia-reinforced lithium silicate glass-ceramic; LD- lithium disilicate glass-ceramic; YZ- yttria-stabilized tetragonal zirconia polycrystal ceramic) to be tested under impact (15×10×2mm3; n= 15) were divided into two groups, according to surface treatment: polishing (pol) and grinding (gri) as CAD/CAM milling simulation. Impact strength was tested using the Dynstat method. Roughness, topographic, fractographic and finite element analyses were performed. The impact strength data were analyzed by Weibull, and Pearson correlation was used to correlate roughness and impact strength data. The CAD/CAM milling simulation led to significantly (p

Published
2021
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44. Nicola Vicentino - sein Tonsystem und seine Instrumente

Author

Volker Rippe

Subjects
Music
Abstract

1 N. Vicentino, L'antica musica ridotta alla moderna pratuca (1555), Faks.-Neudruck hrsg. von E. E. Lowinsky, Kassel u.a. 1959. Die Sekundarliteratur erwahnt Vicentino und seine Arbeiten oft nur en passant oder beschrankt sich auf Teilaspekte: H.Riemann (Geschichte der Musiktheorie im IX.-XIX. Jahrhundert, Berlin 1918, S. 367 ff.) last Vicentinos Tonsystem und seine Instrumente vollig auser acht und ist vielmehr an den Ausfuhrungen Vicentinos uber Konsonanzund Dissonanzbehandlung, kontrapunktische Schreibweisen und Mensurierung von Tondauern interessiert. L. Kallenbach-Greller (Die historischen Grundlagen der Vierteltone, in: AfMw VIII, 1926, S. 473-485) nennt Vicentino als einen der Wegbereiter fur Mikrotonsysteme; sie erwahnt die von ihm verwendeten Tongeschlechter und Instrumente und schreibt irrtumlicherweise, das er den Ganzton mit Hilfe von grosen und kleinen Diesen vierfach unterteilt, macht dazu aber keine genauen Angaben. H.Zenck (Nicola Vicentinos „L'antica musica" (1555), in: Festschrift Theodor Kroyer, Regensburg 1933, S. 86-101) liefert im wesentlichen eine kommentierte Inhaltsangabe der „L'antica musica", ohne naher auf theoretische Einzelheiten einzugehen. J. M. Barbour ( Tuning and Temperament. A Historical Survey, East Lansing 1953, S. 117 f.) gibt eine knappe Beschreibung des Archicembalos und geht kurz auf dessen Stimmung mit 31 Tonen ein, die er anscheinend als gleichmasig temperiert ansieht. W. Durr (Rezension von Vicentinos „L'antica musica" (Faksimile), in: Mf XIV, 1961, S. 446-448) beschrankt sich verstandlicherweise auf eine allgemeine Inhaltsangabe. F. Blume (Artikel Renaissance, in: MGG XI, 1963, Sp.224ff.) zieht nur Vicentinos Ausfuhrungen uber antike und herrschende Musikstile heran. C.V.Palisca (Artikel Vicentino, in: MGG XIII, 1966, Sp. 1582 ff.) geht in kurzester Form auf Vicentinos Gedankengut ein und erwahnt seine Instrumente und eine seiner Stimmungen, ohne jedoch damit verknupfte Probleme zu behandeln. S.Schneider (Mikrotone in der Musik des 20. Jahrhunderts. Untersuchungen zu Theorie und Gestaltungsprinzipien moderner Kompositionen mit Mikrofonen, Bonn-Bad Godesberg 1975, S.20f.) fuhrt Vicentinos theoretische Schriften an, seine Unterteilung des Ganztons in funf Diesen und die damit verbundene Darstellungsmoglichkeit der antiken griechischen Genera auf den von ihm entwickelten Instrumenten, ebenfalls ohne ins Detail zu gehen. M. Vogel (Die Lehre von den Tonbeziehungen. Mit einem Tafelanhang von M. Kahler, Bonn-Bad Godesberg 1975, S. 303 ff.) erwahnt kurz Vicentinos Instrumente und gibt eine allgemeine Berechnung des gleichmasig temperierten 31stufigen Tonsystems an, halt Vicentinos System aber nicht fur absolut gleichmasig temperiert. W. Dupont (Geschichte der musikalischen Temperatur, Kassel 1935, S.51ff.) weist auf Vicentinos Instrumente zur Darstellung von Mikrotonen hin, ohne auf technische Einzelheiten einzugehen, erklart aber in Kurzform die von Vicentino verwendete Notationsweise (wobei er sich auf den zweiten Band von Johannes Wolfs Handbuch der Notationskunde stutzt) und bringt eine mit Centangaben versehene Aufstellung der 31 Tone des Vicentinoschen Systems, das er fur gleichmasig temperiert halt. D.Harran (Vicentino and his Rules of Text Underlay, in: MQ LIX, 1973, S. 620-632) analysiert die Beziehungen von Musik und Text in den Werken Vicentinos und beschaftigt sich aufgrund dieser

Published
2021
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