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1. Erratum to: Methods for evaluating medical tests and biomarkers

Author

Gowri Gopalakrishna, Miranda Langendam, Rob Scholten, Patrick Bossuyt, Mariska Leeflang, Anna Noel-Storr, James Thomas, Iain Marshall, Byron Wallace, Penny Whiting, Clare Davenport, Gowri GopalaKrishna, Isabel de Salis, Sue Mallett, Robert Wolff, Richard Riley, Marie Westwood, Jos Kleinen, Gary Collins, Hans Reitsma, Karel Moons, Antonia Zapf, Annika Hoyer, Katharina Kramer, Oliver Kuss, J. Ensor, J. J. Deeks, E. C. Martin, R. D. Riley, Gerta Rücker, Susanne Steinhauser, Martin Schumacher, Joie Ensor, Kym Snell, Brian Willis, Thomas Debray, Jon Deeks, Lavinia Ferrante di Ruffano, Sian Taylor-Phillips, Chris Hyde, Stuart A. Taylor, Gauraang Batnagar, STREAMLINE COLON Investigators, STREAMLINE LUNG Investigators, METRIC Investigators, Lavinia Ferrante Di Ruffano, Farah Seedat, Aileen Clarke, Sarah Byron, Frances Nixon, Rebecca Albrow, Thomas Walker, Carla Deakin, Zhivko Zhelev, Harriet Hunt, Yaling Yang, Lucy Abel, James Buchanan, Thomas Fanshawe, Bethany Shinkins, Laure Wynants, Jan Verbakel, Sabine Van Huffel, Dirk Timmerman, Ben Van Calster, Aeliko Zwinderman, Jason Oke, Jack O’Sullivan, Rafael Perera, Brian Nicholson, Hannah L. Bromley, Tracy E. Roberts, Adele Francis, Denniis Petrie, G. Bruce Mann, Kinga Malottki, Holly Smith, Lucinda Billingham, Alice Sitch, Oke Gerke, Mie Holm-Vilstrup, Eivind Antonsen Segtnan, Ulrich Halekoh, Poul Flemming Høilund-Carlsen, Bernard G. Francq, Jac Dinnes, Julie Parkes, Walter Gregory, Jenny Hewison, Doug Altman, William Rosenberg, Peter Selby, Julien Asselineau, Paul Perez, Aïssatou Paye, Emilie Bessede, Cécile Proust-Lima, Christiana Naaktgeboren, Joris de Groot, Anne Rutjes, Johannes Reitsma, Emmanuel Ogundimu, Jonathan Cook, Yannick Le Manach, Yvonne Vergouwe, Romin Pajouheshnia, Rolf Groenwold, Karen Moons, Linda Peelen, Daan Nieboer, Bavo De Cock, Micael J. Pencina, Ewout W. Steyerberg, Jennifer Cooper, Nick Parsons, Chris Stinton, Steve Smith, Andy Dickens, Rachel Jordan, Alexandra Enocson, David Fitzmaurice, Peymane Adab, Charles Boachie, Gaj Vidmar, Karoline Freeman, Martin Connock, Rachel Court, Carl Moons, Jessica Harris, Andrew Mumford, Zoe Plummer, Kurtis Lee, Barnaby Reeves, Chris Rogers, Veerle Verheyden, Gianni D. Angelini, Gavin J. Murphy, Jeremy Huddy, Melody Ni, Katherine Good, Graham Cooke, George Hanna, Jie Ma, K. G. M. (Carl) Moons, Joris A. H. de Groot, Doug G. Altman, Johannes B. Reitsma, Gary S. Collins, Karel G. M. Moons, Douglas G. Altman, Adina Najwa Kamarudin, Ruwanthi Kolamunnage-Dona, Trevor Cox, Simone Borsci, Teresa Pérez, M.Carmen Pardo, Angel Candela-Toha, Alfonso Muriel, Javier Zamora, Sabina Sanghera, Syed Mohiuddin, Richard Martin, Jenny Donovan, Joanna Coast, Mikyung Kelly Seo, John Cairns, Elizabeth Mitchell, Alison Smith, Judy Wright, Peter Hall, Michael Messenger, Nicola Calder, Nyantara Wickramasekera, Karen Vinall-Collier, Andrew Lewington, Johanna Damen, David Cairns, Michelle Hutchinson, Cathie Sturgeon, Liz Mitchel, Rebecca Kift, Sofia Christakoudi, Manohursingh Rungall, Paula Mobillo, Rosa Montero, Tjir-Li Tsui, Sui Phin Kon, Beatriz Tucker, Steven Sacks, Chris Farmer, Terry Strom, Paramit Chowdhury, Irene Rebollo-Mesa, Maria Hernandez-Fuentes, Johanna A. A. G. Damen, Thomas P. A. Debray, Pauline Heus, Lotty Hooft, Rob J. P. M. Scholten, Ewoud Schuit, Ioanna Tzoulaki, Camille M. Lassale, George C. M. Siontis, Virginia Chiocchia, Corran Roberts, Michael Maia Schlüssel, Stephen Gerry, James A. Black, Yvonne T. van der Schouw, Linda M. Peelen, Graeme Spence, David McCartney, Ann van den Bruel, Daniel Lasserson, Gail Hayward, Werner Vach, Antoinette de Jong, Coreline Burggraaff, Otto Hoekstra, Josée Zijlstra, Henrica de Vet, Sara Graziadio, Joy Allen, Louise Johnston, Rachel O’Leary, Michael Power, Louise Johnson, Ray Waters, John Simpson, Thomas R. Fanshawe, Peter Phillips, Andrew Plumb, Emma Helbren, Steve Halligan, Alastair Gale, Peggy Sekula, Willi Sauerbrei, Julia R. Forman, Susan J. Dutton, Yemisi Takwoingi, Elizabeth M. Hensor, Thomas E. Nichols, Emmanuelle Kempf, Raphael Porcher, Jennifer de Beyer, Douglas Altman, Sally Hopewell, John Dennis, Beverley Shields, Angus Jones, William Henley, Ewan Pearson, Andrew Hattersley, on behalf of the MASTERMIND consortium, Fueloep Scheibler, Anne Rummer, Sibylle Sturtz, Robert Großelfinger, Katie Banister, Craig Ramsay, Augusto Azuara-Blanco, Jennifer Burr, Manjula Kumarasamy, Rupert Bourne, Ijeoma Uchegbu, Jennifer Murphy, Alex Carter, Jen Murphy, Joachim Marti, Julie Eatock, Julie Robotham, Maria Dudareva, Mark Gilchrist, Alison Holmes, Phillip Monaghan, Sarah Lord, Andrew StJohn, Sverre Sandberg, Christa Cobbaert, Lieselotte Lennartz, Wilma Verhagen-Kamerbeek, Christoph Ebert, Andrea Horvath, for the Test Evaluation Working Group of the European Federation of Clinical Chemistry and Laboratory Medicine, Kevin Jenniskens, Jaime Peters, Bogdan Grigore, Obi Ukoumunne, Brooke Levis, Andrea Benedetti, Alexander W. Levis, John P. A. Ioannidis, Ian Shrier, Pim Cuijpers, Simon Gilbody, Lorie A. Kloda, Dean McMillan, Scott B Patten, Russell J. Steele, Roy C Ziegelstein, Charles H. Bombardier, Flavia de Lima Osório, Jesse R. Fann, Dwenda Gjerdingen, Femke Lamers, Manote Lotrakul, Sonia R Loureiro, Bernd Löwe, Juwita Shaaban, Lesley Stafford, Henk C. P. M. van Weert, Mary A. Whooley, Linda S. Williams, Karin A. Wittkampf, Albert S. Yeung, Brett D. Thombs, Chris Cooper, Tom Nieto, Claire Smith, Olga Tucker, Janine Dretzke, Andrew Beggs, Nirmala Rai, Sue Bayliss, Simon Stevens, Sue Mallet, Sudha Sundar, Emma Hall, Nuria Porta, David Lorente Estelles, Johann de Bono, and on behalf of the CTC-STOP protocol development group

Subjects
Medicine (General), R5-920
Published
2017
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2. De novo design of tunable, pH-driven conformational changes

Author

Vicki H. Wysocki, Aniruddha Sahasrabuddhe, David Baker, Kelly K. Lee, Banumathi Sankaran, Zibo Chen, Kathy Y. Wei, Mengxuan Jia, Scott E. Boyken, Alexander Mileant, Carl Walkey, Florian Busch, Edgar A. Hodge, Neil P. King, Alfredo Quijano-Rubio, Mark A. Benhaim, Heejun Choi, Sarah Byron, Jason C. Klima, Jennifer Lippincott-Schwartz, and Matthew J. Bick

Subjects
Multidisciplinary, General Science & Technology, Chemistry, Protein Conformation, Protein Stability, Protein design, Protonation, Cooperativity, Hydrogen-Ion Concentration, Protein Engineering, Article, Steric repulsion, Hydrophobic effect, Membrane, Protein structure, Biophysics, Generic health relevance, sense organs, Protein Multimerization, Histidine
Abstract

The ability of naturally occurring proteins to change conformation in response to environmental changes is critical to biological function. Although there have been advances in the de novo design of stable proteins with a single, deep free-energy minimum, the design of conformational switches remains challenging. We present a general strategy to design pH-responsive protein conformational changes by precisely preorganizing histidine residues in buried hydrogen-bond networks. We design homotrimers and heterodimers that are stable above pH 6.5 but undergo cooperative, large-scale conformational changes when the pH is lowered and electrostatic and steric repulsion builds up as the network histidine residues become protonated. The transition pH and cooperativity can be controlled through the number of histidine-containing networks and the strength of the surrounding hydrophobic interactions. Upon disassembly, the designed proteins disrupt lipid membranes both in vitro and after being endocytosed in mammalian cells. Our results demonstrate that environmentally triggered conformational changes can now be programmed by de novo protein design.

Published
2018

3. Abstract CT073: Peds-plan, pediatric precision laboratory advanced neuroblastoma therapy: Molecular guided therapy for high risk neuroblastoma at diagnosis

Author

Sarah Byron, Valerie I. Brown, Kathleen A. Neville, Genevieve Bergendahl, William S. Ferguson, Deanna Mitchell, Gina Hanna, Abhinav Nagulapally, Jeffrey M. Trent, Randal K. Wada, William P.D. Hendricks, Javier Oesterheld, Jessica Foley, Jeffrey P. Bond, Giselle Saulnier Sholler, William Roberts, Michael S. Isakoff, Jawhar Rawwas, and Jacqeline Kraveka

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Chemotherapy, business.industry, medicine.medical_treatment, Dinutuximab, Induction chemotherapy, Immunotherapy, medicine.disease, Targeted therapy, Clinical trial, Maintenance therapy, Neuroblastoma, Internal medicine, medicine, business
Abstract

BACKGROUND: While the poor prognosis for high risk neuroblastoma (HRNB) underscores the need for new treatment strategies, the elucidation of specific biologic subsets of neuroblastoma suggests a way to improve disease management. The identification of agents that target specific molecular pathways associated with the development or progression of diseases holds promise. The hypotheses for this study were that: 1) the incorporation of a targeted therapy, selected based upon upfront genomic interrogation of the tumor, into standardized induction chemotherapy for HRNB is feasible and may increase the PR/CR/VGPR response rate at the end of Induction therapy; and 2) that the addition of DFMO as maintenance therapy during and for 2 years after the completion of immunotherapy is safe and may decrease the relapse rate. METHODS: A prospective, multicenter feasibility pilot clinical trial in subjects with newly diagnosed HRNB within the Beat Childhood Cancer Consortium. At diagnosis, patients' tumors underwent DNA exome and RNA sequencing which were analyzed within a molecular tumor board to identify the single best drug out of 6 targeted agents to be added to cycles 3-6 of induction chemotherapy. After consolidation with ASCT and radiation, the patients received DFMO along with standard dinutuximab and retinoic acid and DFMO for 2 years after immunotherapy. Patients were evaluated for additional toxicities with the addition of targeted agents and DFMO in addition to induction response. RESULTS: The pilot study of 20 eligible patients has shown this process to be feasible. To date, 20 patients have completed induction through immunotherapy portions of the study. The combination of targeted agent with chemotherapy was shown to be safe without any unexpected toxicities. Delays experienced between induction cycles were less than 2 weeks and related to surgery, infection, or thrombocytopenia. The induction response demonstrated an 88% CR/VGPR/PR rate, which suggests improvement over historical 80%. In addition, the combination of DFMO with dinutuximab and retinoic acid was well tolerated and safe without additional toxicities. CONCLUSION: The pilot study of 20 patients has shown the process of sequencing and the addition of a targeted agent to upfront chemotherapy is feasible and safe without any unexpected toxicities. Citation Format: Jacqeline Kraveka, Valerie Brown, William Ferguson, Genevieve Bergendahl, William Roberts, Jessica Foley, Deanna Mitchell, Javier Oesterheld, Michael Isakoff, Kathleen Neville, Randal Wada, Jawhar Rawwas, Gina Hanna, Abhinav Beeravally Nagulapally, Jeffrey Bond, Jeffrey Trent, William Hendricks, Sarah Byron, Giselle L. Saulnier Sholler. Peds-plan, pediatric precision laboratory advanced neuroblastoma therapy: Molecular guided therapy for high risk neuroblastoma at diagnosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT073.

Published
2018
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