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9. Towards bend-contour-free dislocation imaging via diffraction contrast STEM

Author

Zhu, Yuanyuan, Ophus, Colin, Toloczko, Mychailo B, and Edwards, Danny J

Subjects
Chemical Sciences, Physical Chemistry, STEM, Dislocation image, Diffraction contrast, Reciprocity, Bend contour, Atomic, Molecular, Nuclear, Particle and Plasma Physics, Optical Physics, Other Physical Sciences, Microscopy, Biochemistry and cell biology, Physical chemistry, Condensed matter physics
Abstract

Dislocation imaging using transmission electron microscopy (TEM) has been an invaluable tool for characterizing crystallographic defects in metals. Compared to conventional TEM imaging, diffraction contrast imaging scanning transmission electron microscopy (DCI STEM) with appropriate setting can provide better defect contrast with almost negligible bend contour artifacts, enabling more effective analysis of dislocation structures. Here, we investigated why STEM can suppresses bend contour, and how dislocation contrast behaves along with different STEM imaging parameters. Using a body-centered cubic HT-9 ferritic/martensitic alloy as an example, a simple procedure and operational theory are described at the beginning to help set up DCI STEM experiments. Comparing with conventional TEM and the STEM strictly complying with the principle of reciprocity, we found that a pair of STEM convergence and collection semi-angles, αS and βS, a few milliradians in size is essential for bend-contour-free defect imaging. It works in concert such that the convergence STEM probe opens up the reciprocal space, and then a comparable collection region evens out the rocking-curve oscillation and alleviates bend contours from the reciprocal space. This fundamental advantage is unique in DCI STEM. Practical guidelines regarding STEM parameters and specimen orientation and thickness are then provided for DCI STEM dislocation imaging. Lastly, we show that coupling DCI STEM with spectrum images of electron energy loss spectroscopy and of energy-dispersive X-ray Spectroscopy offers a comprehensive characterization of crystallographic defects and chemical information of complex microstructures.

Published
2018

11. Deubiquitination and control of the Hippo pathway

Author

Toloczko, Aleksandra, Tournier, Cathy, and Dunne, Mark

Subjects
571.8, TEAD, TAZ, YAP, Lats kinase, USP9X, Hippo pathway
Abstract

The Hippo signalling pathway is an evolutionarily conserved kinase cascade responsible for the cell proliferation, tissue growth and apoptosis during development and its dysregulation contributes to tumourigenesis. This signalling pathway was initially discovered in Drosophila and soon after that, it was shown to be highly conserved in mammals. The core Lats kinases of this tumour suppressive pathway phosphorylate and inhibit the downstream transcriptional co-activators YAP and TAZ, which are implicated in various cancers. Latest reports revealed various E3 ubiquitin ligases to negatively regulate the Hippo pathway through ubiquitination, yet few deubiquitinating enzymes have been described. In the present study, we report USP9X deubiquitinating enzyme as an essential regulator of the central components of this pathway. USP9X interacted strongly with Lats2 kinase and to a lesser extent with WW45, Kibra and Angiomotin family proteins. The knockdown of USP9X resulted in notable downregulation and destabilisation of Lats kinase and to lesser extents WW45, Kibra and Amot. This resulted in enhanced nuclear localisation of YAP and TAZ accompanied with activation of their target genes, CTGF and CYR61. USP9X was shown to stabilise Hippo components through its deubiquitinating activity. USP9X enzyme defective mutant lost the activity to stabilise Lats2, WW45, Kibra and Angiomotins through deubiquitination, leading to their ubiquitination. In the absence of USP9X, cells exhibited epithelial to mesenchymal transition phenotype and additionally gained anchorage-independent growth in soft agar. Moreover, USP9X knockdown disrupted acinar organisation of breast cells in three-dimensional acini cultures. In addition, YAP/TAZ target gene activation in USP9X knockdown cells could be rescued by knockdown of YAP, TAZ and TEAD2. Lastly, USP9X protein expression showed a positive correlation with Lats kinases, but negative correlation with YAP/TAZ in pancreatic cancer tissues as well as pancreatic and breast cancer cell lines. The results strongly indicate that USP9X cooperates with Lats2 and other important Hippo components to suppress tumour growth.

Published
2017

12. A Cognitive Model of Language Teacher Fossilization.

Author

Toloczko, Ewa

Subjects
CAREER development, HUMAN information processing, LANGUAGE teachers, FOREIGN language education, FOSSILIZATION
Abstract

Expertise in foreign language teaching has been widely discussed in the literature as inherently related to accumulated classroom experience and, hence, extensive practical knowledge. Even though current conceptualizations are increasingly focusing on teachers’ ability to reflect on their performance and continuously develop a repertoire of didactic resources regardless of their career stage, effective human information processing in the profession remains under-researched. This paper sees the concept of expertise from the perspective of cognitive processes, and specifically operations involved in problem-solving. The author presents a theoretical model of teacher fossilization, discussing attention, knowledge, reasoning, and judgment as potential inhibitors of intellectual vitality and growth in individuals. When neglected, these factors might lead experienced teachers to make just as incompetent decisions as novice educators. The model highlights the external and internal forces that cause practitioners to minimize, rather than maximize, their learning opportunities in a workplace. The new concept has implications for teachers’ day-to-day practice as well as for in-service professional development initiatives. It serves as a guiding principle for the successful utilization of one’s cognitive capital and outlines both the purpose and direction of one’s mental effort. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Prognostic gene expression signature for high-grade serous ovarian cancer

Author

Bowtell, D., Chenevix-Trench, G., Green, A., Webb, P., DeFazio, A., Gertig, D., Traficante, N., Fereday, S., Moore, S., Hung, J., Harrap, K., Sadkowsky, T., Pandeya, N., Malt, M., Mellon, A., Robertson, R., Vanden Bergh, T., Jones, M., Mackenzie, P., Maidens, J., Nattress, K., Chiew, Y.E., Stenlake, A., Sullivan, H., Alexander, B., Ashover, P., Brown, S., Corrish, T., Green, L., Jackman, L., Ferguson, K., Martin, K., Martyn, A., Ranieri, B., White, J., Jayde, V., Mamers, P., Bowes, L., Galletta, L., Giles, D., Hendley, J., Alsop, K., Schmidt, T., Shirley, H., Ball, C., Young, C., Viduka, S., Tran, Hoa, Bilic, Sanela, Glavinas, Lydia, Brooks, Julia, Stuart-Harris, R., Kirsten, F., Rutovitz, J., Clingan, P., Glasgow, A., Proietto, A., Braye, S., Otton, G., Shannon, J., Bonaventura, T., Stewart, J., Begbie, S., Friedlander, M., Bell, D., Baron-Hay, S., Ferrier,a, A., Gard, G., Nevell, D., Pavlakis, N., Valmadre, S., Young, B., Camaris, C., Crouch, R., Edwards, L., Hacker, N., Marsden, D., Robertson, G., Beale, P., Beith, J., Carter, J., Dalrymple, C., Houghton, R., Russell, P., Links, M., Grygiel, J., Hill, J., Brand, A., Byth, K., Jaworski, R., Harnett, P., Sharma, R., Wain, G., Ward, B., Papadimos, D., Crandon, A., Cummings, M., Horwood, K., Obermair, A., Perrin, L., Wyld, D., Nicklin, J., Davy, M., Oehler, M.K., Hall, C., Dodd, T., Healy, T., Pittman, K., Henderson, D., Miller, J., Pierdes, J., Blomfield, P., Challis, D., McIntosh, R., Parker, A., Brown, B., Rome, R., Allen, D., Grant, P., Hyde, S., Laurie, R., Robbie, M., Healy, D., Jobling, T., Manolitsas, T., McNealage, J., Rogers, P., Susil, B., Sumithran, E., Simpson, I., Phillips, K., Rischin, D., Fox, S., Johnson, D., Lade, S., Loughrey, M., O’Callaghan, N., Murray, W., Waring, P., Billson, V., Pyman, J., Neesham, D., Quinn, M., Underhill, C., Bell, R., Ng, L.F., Blum, R., Ganju, V., Hammond, I., Leung, Y., McCartney, A., Buck, M., Haviv, I., Purdie, D., Whiteman, D., Zeps, N., Millstein, J., Budden, T., Goode, E.L., Anglesio, M.S., Talhouk, A., Intermaggio, M.P., Leong, H.S., Chen, S., Elatre, W., Gilks, B., Nazeran, T., Volchek, M., Bentley, R.C., Wang, C., Chiu, D.S., Kommoss, S., Leung, S.C.Y., Senz, J., Lum, A., Chow, V., Sudderuddin, H., Mackenzie, R., George, J., Steed, H., Koziak, J.M., Köbel, M., McNeish, I.A., Goranova, T., Ennis, D., Macintyre, G., Silva De Silva, D., Ramón y Cajal, T., García-Donas, J., Hernando Polo, S., Rodriguez, G.C., Cushing-Haugen, K.L., Harris, H.R., Greene, C.S., Zelaya, R.A., Behrens, S., Fortner, R.T., Sinn, P., Herpel, E., Lester, J., Lubiński, J., Oszurek, O., Tołoczko, A., Cybulski, C., Menkiszak, J., Pearce, C.L., Pike, M.C., Tseng, C., Alsop, J., Rhenius, V., Song, H., Jimenez-Linan, M., Piskorz, A.M., Gentry-Maharaj, A., Karpinskyj, C., Widschwendter, M., Singh, N., Kennedy, C.J., Harnett, P.R., Gao, B., Johnatty, S.E., Sayer, R., Boros, J., Winham, S.J., Keeney, G.L., Kaufmann, S.H., Larson, M.C., Luk, H., Hernandez, B.Y., Thompson, P.J., Wilkens, L.R., Carney, M.E., Trabert, B., Lissowska, J., Brinton, L., Sherman, M.E., Bodelon, C., Hinsley, S., Lewsley, L.A., Glasspool, R., Banerjee, S.N., Stronach, E.A., Haluska, P., Ray-Coquard, I., Mahner, S., Winterhoff, B., Slamon, D., Levine, D.A., Kelemen, L.E., Benitez, J., Chang-Claude, J., Gronwald, J., Wu, A.H., Menon, U., Goodman, M.T., Schildkraut, J.M., Wentzensen, N., Brown, R., Berchuck, A., deFazio, A., Gayther, S.A., García, M.J., Henderson, M.J., Rossing, M.A., Beeghly-Fadiel, A., Fasching, P.A., Orsulic, S., Karlan, B.Y., Konecny, G.E., Huntsman, D.G., Bowtell, D.D., Brenton, J.D., Doherty, J.A., Pharoah, P.D.P., and Ramus, S.J.

Published
2020
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14. Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women.

Author

Rebbeck, Timothy R, Friebel, Tara M, Mitra, Nandita, Wan, Fei, Chen, Stephanie, Andrulis, Irene L, Apostolou, Paraskevi, Arnold, Norbert, Arun, Banu K, Barrowdale, Daniel, Benitez, Javier, Berger, Raanan, Berthet, Pascaline, Borg, Ake, Buys, Saundra S, Caldes, Trinidad, Carter, Jonathan, Chiquette, Jocelyne, Claes, Kathleen BM, Couch, Fergus J, Cybulski, Cezary, Daly, Mary B, de la Hoya, Miguel, Diez, Orland, Domchek, Susan M, Nathanson, Katherine L, Durda, Katarzyna, Ellis, Steve, EMBRACE, Evans, D Gareth, Foretova, Lenka, Friedman, Eitan, Frost, Debra, Ganz, Patricia A, Garber, Judy, Glendon, Gord, Godwin, Andrew K, Greene, Mark H, Gronwald, Jacek, Hahnen, Eric, Hallberg, Emily, Hamann, Ute, Hansen, Thomas VO, HEBON, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, Janavicius, Ramunas, Jaworska-Bieniek, Katarzyna, John, Esther M, Karlan, Beth Y, Kaufman, Bella, Investigators, KConFab, Kwong, Ava, Laitman, Yael, Lasset, Christine, Lazaro, Conxi, Lester, Jenny, Loman, Niklas, Lubinski, Jan, Manoukian, Siranoush, Mitchell, Gillian, Montagna, Marco, Neuhausen, Susan L, Nevanlinna, Heli, Niederacher, Dieter, Nussbaum, Robert L, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Park, Sue Kyung, Piedmonte, Marion, Radice, Paolo, Rappaport-Fuerhauser, Christine, Rookus, Matti A, Seynaeve, Caroline, Simard, Jacques, Singer, Christian F, Soucy, Penny, Southey, Melissa, Stoppa-Lyonnet, Dominique, Sukiennicki, Grzegorz, Szabo, Csilla I, Tancredi, Mariella, Teixeira, Manuel R, Teo, Soo-Hwang, Terry, Mary Beth, Thomassen, Mads, Tihomirova, Laima, Tischkowitz, Marc, Toland, Amanda Ewart, Toloczko-Grabarek, Aleksandra, Tung, Nadine, van Rensburg, Elizabeth J, Villano, Danylo, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weitzel, Jeffrey N, Zidan, Jamal, and Zorn, Kristin K

Subjects
EMBRACE, HEBON, Humans, Breast Neoplasms, Population Surveillance, Heterozygote, Phenotype, Loss of Heterozygosity, Germ-Line Mutation, Alleles, Genes, BRCA1, Genes, BRCA2, Exons, Female, Promoter Regions, Genetic, BRCA1, BRCA2, Hereditary breast and ovarian cancer, Transheterozygosity, Genes, Promoter Regions, Genetic, Clinical Research, Breast Cancer, Cancer, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract

BackgroundMost BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood.MethodsFrom 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.ResultsThe majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p

Published
2016

19. A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases

Author

Meagher, Nicola S., Wang, Linyuan, Rambau, Peter F., Intermaggio, Maria P., Huntsman, David G., Wilkens, Lynne R., El-Bahrawy, Mona A., Ness, Roberta B., Odunsi, Kunle, Steed, Helen, Herpel, Esther, Anglesio, Michael S., Zhang, Bonnie, Lambie, Neil, Swerdlow, Anthony J., Lubiński, Jan, Vierkant, Robert A., Goode, Ellen L., Menon, Usha, Toloczko-Grabarek, Aleksandra, Oszurek, Oleg, Bilic, Sanela, Talhouk, Aline, García-Closas, Montserrat, Wang, Qin, Tan, Adeline, Farrell, Rhonda, Kennedy, Catherine J., Jimenez-Linan, Mercedes, Sundfeldt, Karin, Etter, John L., Menkiszak, Janusz, Goodman, Marc T., Klonowski, Paul, Leung, Yee, Winham, Stacey J., Moysich, Kirsten B., Behrens, Sabine, Kluz, Tomasz, Edwards, Robert P., Gronwald, Jacek, Modugno, Francesmary, Hernandez, Brenda Y, Chow, Christine, Kelemen, Linda E., Keeney, Gary L., Carney, Michael E., Natanzon, Yanina, Robertson, Gregory, Sharma, Raghwa, Gayther, Simon A., Alsop, Jennifer, Luk, Hugh, Karpinskyj, Chloe, Campbell, Ian, Sinn, Peter, Gentry-Maharaj, Aleksandra, Coulson, Penny, Chang-Claude, Jenny, Shah, Mitul, Widschwendter, Martin, Tang, Katrina, Schoemaker, Minouk J., Koziak, Jennifer M., Cook, Linda S., Brenton, James D., Daley, Frances, Kristjansdottir, Björg, Mateoiu, Constantina, Larson, Melissa C., Harnett, Paul R., Jung, Audrey, deFazio, Anna, Gorringe, Kylie L., Pharoah, Paul D.P., Minoo, Parham, Stewart, Colin, Bathe, Oliver F., Gui, Xianyong, Cohen, Paul, Ramus, Susan J., and Köbel, Martin

Published
2019
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24. MyD88 and TLR4 Expression in Epithelial Ovarian Cancer

Author

Bowtell, D., Chenevix-Trench, G., Green, A., Webb, P., DeFazio, A., Gertig, D., Traficante, N., Fereday, S., Moore, S., Hung, J., Harrap, K., Sadkowsky, T., Pandeya, N., Malt, M., Mellon, A., Robertson, R., Vanden Bergh, T., Jones, M., Mackenzie, P., Maidens, J., Nattress, K., Chiew, Y.E., Stenlake, A., Sullivan, H., Alexander, B., Ashover, P., Brown, S., Corrish, T., Green, L., Jackman, L., Ferguson, K., Martin, K., Martyn, A., Ranieri, B., White, J., Jayde, V., Mamers, P., Bowes, L., Galletta, L., Giles, D., Hendley, J., Alsop, K., Schmidt, T., Shirley, H., Ball, C., Young, C., Viduka, S., Tran, Hoa, Bilic, Sanela, Glavinas, Lydia, Brooks, Julia, Stuart-Harris, R., Kirsten, F., Rutovitz, J., Clingan, P., Glasgow, A., Proietto, A., Braye, S., Otton, G., Shannon, J., Bonaventura, T., Stewart, J., Begbie, S., Friedlander, M., Bell, D., Baron-Hay, S., Ferrier, A., Gard, G., Nevell, D., Pavlakis, N., Valmadre, S., Young, B., Camaris, C., Crouch, R., Edwards, L., Hacker, N., Marsden, D., Robertson, G., Beale, P., Beith, J., Carter, J., Dalrymple, C., Houghton, R., Russell, P., Links, M., Grygiel, J., Hill, J., Brand, A., Byth, K., Jaworski, R., Harnett, P., Sharma, R., Wain, G., Ward, B., Papadimos, D., Crandon, A., Cummings, M., Horwood, K., Obermair, A., Perrin, L., Wyld, D., Nicklin, J., Davy, M., Oehler, M.K., Hall, C., Dodd, T., Healy, T., Pittman, K., Henderson, D., Miller, J., Pierdes, J., Blomfield, P., Challis, D., McIntosh, R., Parker, A., Brown, B., Rome, R., Allen, D., Grant, P., Hyde, S., Laurie, R., Robbie, M., Healy, D., Jobling, T., Manolitsas, T., McNealage, J., Rogers, P., Susil, B., Sumithran, E., Simpson, I., Phillips, K., Rischin, D., Fox, S., Johnson, D., Lade, S., Loughrey, M., O'Callaghan, N., Murray, W., Waring, P., Billson, V., Pyman, J., Neesham, D., Quinn, M., Underhill, C., Bell, R., Ng, L.F., Blum, R., Ganju, V., Hammond, I., Leung, Y., McCartney, A., Buck, M., Haviv, I., Purdie, D., Whiteman, D., Zeps, N., Block, Matthew S., Vierkant, Robert A., Rambau, Peter F., Winham, Stacey J., Wagner, Philipp, Traficante, Nadia, Tołoczko, Aleksandra, Tiezzi, Daniel G., Taran, Florin Andrei, Sinn, Peter, Sieh, Weiva, Sharma, Raghwa, Rothstein, Joseph H., Ramón y Cajal, Teresa, Paz-Ares, Luis, Oszurek, Oleg, Orsulic, Sandra, Ness, Roberta B., Nelson, Gregg, Modugno, Francesmary, Menkiszak, Janusz, McGuire, Valerie, McCauley, Bryan M., Mack, Marie, Lubiński, Jan, Longacre, Teri A., Li, Zheng, Lester, Jenny, Kennedy, Catherine J., Kalli, Kimberly R., Jung, Audrey Y., Johnatty, Sharon E., Jimenez-Linan, Mercedes, Jensen, Allan, Intermaggio, Maria P., Hung, Jillian, Herpel, Esther, Hernandez, Brenda Y., Hartkopf, Andreas D., Harnett, Paul R., Ghatage, Prafull, García-Bueno, José M., Gao, Bo, Fereday, Sian, Eilber, Ursula, Edwards, Robert P., de Sousa, Christiani B., de Andrade, Jurandyr M., Chudecka-Głaz, Anita, Chenevix-Trench, Georgia, Cazorla, Alicia, Brucker, Sara Y., Alsop, Jennifer, Whittemore, Alice S., Steed, Helen, Staebler, Annette, Moysich, Kirsten B., Menon, Usha, Koziak, Jennifer M., Kommoss, Stefan, Kjaer, Susanne K., Kelemen, Linda E., Karlan, Beth Y., Huntsman, David G., Høgdall, Estrid, Gronwald, Jacek, Goodman, Marc T., Gilks, Blake, García, María José, Fasching, Peter A., de Fazio, Anna, Deen, Suha, Chang-Claude, Jenny, Candido dos Reis, Francisco J., Campbell, Ian G., Brenton, James D., Bowtell, David D., Benítez, Javier, Pharoah, Paul D.P., Köbel, Martin, Ramus, Susan J., and Goode, Ellen L.

Published
2018
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25. Quantitative assessment of retinal thickness and vessel density using optical coherence tomography angiography in patients with Alzheimer's disease and glaucoma.

Author

Przemyslaw Zabel, Jakub J Kaluzny, Katarzyna Zabel, Martyna Kaluzna, Aleksander Lamkowski, Damian Jaworski, Jaroslaw Makowski, Martyna Gebska-Toloczko, and Robert Kucharski

Subjects
Medicine, Science
Abstract

PurposeAssessment and a direct comparison of retinal vessel density with the thickness of inner retinal layer (IRL) and outer retinal layer (ORL) in the same regions of the macula in subjects with Alzheimer's disease (AD) and primary open-angle glaucoma (POAG).MethodsWe analyzed data from 48 eyes of healthy control (HC) participants, 71 eyes with POAG, and 49 eyes of AD patients. Ophthalmic examination included optical coherence tomography (OCT) imaging to measure IRL and ORL thickness and OCT angiography (OCTA) in the same region for the imaging of vessel density in the superficial vascular plexus (SVP) and deep vascular plexus (DVP) of the retina. A direct comparison of vessel density and retinal layers thickness, which different dynamic ranges, was obtained by normalizing values as percentage losses.ResultsPatients with AD presented significantly greater losses of vascular density in the DVP and ORL thickness compared to POAG (p ConclusionsAnalysis of ORL thickness and vessel density in DVP could potentially improve diagnostic capabilities and may provide a valuable approach for predicting of AD.

Published
2021
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27. Cell entry of a host-targeting protein of oomycetes requires gp96

Author

Franziska Trusch, Lars Loebach, Stephan Wawra, Elaine Durward, Andreas Wuensch, Nurul Aqilah Iberahim, Irene de Bruijn, Kevin MacKenzie, Ariane Willems, Aleksandra Toloczko, Javier Diéguez-Uribeondo, Tim Rasmussen, Thomas Schrader, Peter Bayer, Chris J. Secombes, and Pieter van West

Subjects
Science
Abstract

The pathogenic oomycete Saprolegnia parasitica secretes effector proteins that translocate into host cells through unclear mechanisms. Here, Trusch et al. show that the uptake of effector protein SpHtp3, resulting in RNA degradation, depends on a gp96-like host receptor and a second effector protein.

Published
2018
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39. CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

Author

Kang, E-Y, Weir, A, Meagher, NS, Farrington, K, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Bolithon, A, Popovic, G, Leung, B, Tang, K, Lambie, N, Millstein, J, Alsop, J, Anglesio, MS, Ataseven, B, Barlow, E, Beckmann, MW, Berger, J, Bisinotto, C, Boesmueller, H, Boros, J, Brand, AH, Brooks-Wilson, A, Brucker, SY, Carney, ME, Casablanca, Y, Cazorla-Jimenez, A, Cohen, PA, Conrads, TP, Cook, LS, Coulson, P, Courtney-Brooks, M, Cramer, DW, Crowe, P, Cunningham, JM, Cybulski, C, Darcy, KM, El-Bahrawy, MA, Elishaev, E, Erber, R, Farrell, R, Fereday, S, Fischer, A, Garcia, MJ, Gayther, SA, Gentry-Maharaj, A, Gilks, CB, Grube, M, Harnett, PR, Harrington, SP, Harter, P, Hartmann, A, Hecht, JL, Heikaus, S, Hein, A, Heitz, F, Hendley, J, Hernandez, BY, Hernando Polo, S, Heublein, S, Hirasawa, A, Hogdall, E, Hogdall, CK, Horlings, HM, Huntsman, DG, Huzarski, T, Jewell, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Khabele, D, Kommoss, FKF, Kruitwagen, RFPM, Lambrechts, D, Le, ND, Lener, M, Lester, J, Leung, Y, Linder, A, Loverix, L, Lubinski, J, Madan, R, Maxwell, GL, Modugno, F, Neuhausen, SL, Olawaiye, A, Olbrecht, S, Orsulic, S, Palacios, J, Pearce, CL, Pike, MC, Quinn, CM, Mohan, GR, Rodriguez-Antona, C, Ruebner, M, Ryan, A, Salfinger, SG, Sasamoto, N, Schildkraut, JM, Schoemaker, MJ, Shah, M, Sharma, R, Shvetsov, YB, Singh, N, Sonke, GS, Steele, L, Stewart, CJR, Sundfeldt, K, Swerdlow, AJ, Talhouk, A, Tan, A, Taylor, SE, Terry, KL, Toloczko, A, Traficante, N, Van de Vijver, KK, van der Aa, MA, Van Gorp, T, Van Nieuwenhuysen, E, Van-Wagensveld, L, Vergote, I, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Wu, AH, Benitez, J, Berchuck, A, Candido Dos Reis, FJ, DeFazio, A, Fasching, PA, Goode, EL, Goodman, MT, Gronwald, J, Karlan, BY, Kommoss, S, Menon, U, Sinn, H-P, Staebler, A, Brenton, JD, Bowtell, DD, Pharoah, PDP, Ramus, SJ, Kobel, M, Kang, E-Y, Weir, A, Meagher, NS, Farrington, K, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Bolithon, A, Popovic, G, Leung, B, Tang, K, Lambie, N, Millstein, J, Alsop, J, Anglesio, MS, Ataseven, B, Barlow, E, Beckmann, MW, Berger, J, Bisinotto, C, Boesmueller, H, Boros, J, Brand, AH, Brooks-Wilson, A, Brucker, SY, Carney, ME, Casablanca, Y, Cazorla-Jimenez, A, Cohen, PA, Conrads, TP, Cook, LS, Coulson, P, Courtney-Brooks, M, Cramer, DW, Crowe, P, Cunningham, JM, Cybulski, C, Darcy, KM, El-Bahrawy, MA, Elishaev, E, Erber, R, Farrell, R, Fereday, S, Fischer, A, Garcia, MJ, Gayther, SA, Gentry-Maharaj, A, Gilks, CB, Grube, M, Harnett, PR, Harrington, SP, Harter, P, Hartmann, A, Hecht, JL, Heikaus, S, Hein, A, Heitz, F, Hendley, J, Hernandez, BY, Hernando Polo, S, Heublein, S, Hirasawa, A, Hogdall, E, Hogdall, CK, Horlings, HM, Huntsman, DG, Huzarski, T, Jewell, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Khabele, D, Kommoss, FKF, Kruitwagen, RFPM, Lambrechts, D, Le, ND, Lener, M, Lester, J, Leung, Y, Linder, A, Loverix, L, Lubinski, J, Madan, R, Maxwell, GL, Modugno, F, Neuhausen, SL, Olawaiye, A, Olbrecht, S, Orsulic, S, Palacios, J, Pearce, CL, Pike, MC, Quinn, CM, Mohan, GR, Rodriguez-Antona, C, Ruebner, M, Ryan, A, Salfinger, SG, Sasamoto, N, Schildkraut, JM, Schoemaker, MJ, Shah, M, Sharma, R, Shvetsov, YB, Singh, N, Sonke, GS, Steele, L, Stewart, CJR, Sundfeldt, K, Swerdlow, AJ, Talhouk, A, Tan, A, Taylor, SE, Terry, KL, Toloczko, A, Traficante, N, Van de Vijver, KK, van der Aa, MA, Van Gorp, T, Van Nieuwenhuysen, E, Van-Wagensveld, L, Vergote, I, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Wu, AH, Benitez, J, Berchuck, A, Candido Dos Reis, FJ, DeFazio, A, Fasching, PA, Goode, EL, Goodman, MT, Gronwald, J, Karlan, BY, Kommoss, S, Menon, U, Sinn, H-P, Staebler, A, Brenton, JD, Bowtell, DD, Pharoah, PDP, Ramus, SJ, and Kobel, M

Abstract

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Published
2023

40. MEDI5752FINALSupplementaryMaterial.docx from Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells

Author

Dovedi, Simon J., primary, Elder, Matthew J., primary, Yang, Chunning, primary, Sitnikova, Suzanne I., primary, Irving, Lorraine, primary, Hansen, Anna, primary, Hair, James, primary, Jones, Des C., primary, Hasani, Sumati, primary, Wang, Bo, primary, Im, Seock-Ah, primary, Tran, Ben, primary, Subramaniam, Deepa S., primary, Gainer, Shelby D., primary, Vashisht, Kapil, primary, Lewis, Arthur, primary, Jin, Xiaofang, primary, Kentner, Stacy, primary, Mulgrew, Kathy, primary, Wang, Yaya, primary, Overstreet, Michael G., primary, Dodgson, James, primary, Wu, Yanli, primary, Palazon, Asis, primary, Morrow, Michelle, primary, Rainey, Godfrey J., primary, Browne, Gareth J., primary, Neal, Frances, primary, Murray, Thomas V., primary, Toloczko, Aleksandra D., primary, Dall'Acqua, William, primary, Achour, Ikbel, primary, Freeman, Daniel J., primary, Wilkinson, Robert W., primary, and Mazor, Yariv, primary

Published
2023
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41. Data from Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells

Author

Dovedi, Simon J., primary, Elder, Matthew J., primary, Yang, Chunning, primary, Sitnikova, Suzanne I., primary, Irving, Lorraine, primary, Hansen, Anna, primary, Hair, James, primary, Jones, Des C., primary, Hasani, Sumati, primary, Wang, Bo, primary, Im, Seock-Ah, primary, Tran, Ben, primary, Subramaniam, Deepa S., primary, Gainer, Shelby D., primary, Vashisht, Kapil, primary, Lewis, Arthur, primary, Jin, Xiaofang, primary, Kentner, Stacy, primary, Mulgrew, Kathy, primary, Wang, Yaya, primary, Overstreet, Michael G., primary, Dodgson, James, primary, Wu, Yanli, primary, Palazon, Asis, primary, Morrow, Michelle, primary, Rainey, Godfrey J., primary, Browne, Gareth J., primary, Neal, Frances, primary, Murray, Thomas V., primary, Toloczko, Aleksandra D., primary, Dall'Acqua, William, primary, Achour, Ikbel, primary, Freeman, Daniel J., primary, Wilkinson, Robert W., primary, and Mazor, Yariv, primary

Published
2023
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44. Insurance lesions: Does a second lesion make a difference?

Author

Alexandra Toloczko, Skylar Buchan, Mathews John, Allison Post, and Mehdi Razavi

Subjects
Insurance, Radiofrequency Ablation, Heart Ventricles, Physiology (medical), Catheter Ablation, Humans, Heart Atria, Cardiology and Cardiovascular Medicine
Abstract

In radiofrequency ablation procedures for cardiac arrhythmia, the efficacy of creating repeated lesions at the same location ("insurance lesions") remains poorly studied. We assessed the effect of type of tissue, power, and time on the resulting lesion geometry during such multiple ablation procedures.A custom ex vivo ablation model was used to assess lesion formation. An ablation catheter was oriented perpendicular to the tissue and used to create lesions that varied by type of tissue (atrial or ventricular free wall), power (30 or 50 W), and time (30, 40, or 50 s for standard ablations and 5, 10, or 15 s for high-power, short-duration [HPSD] ablations). Lesion dimensions were recorded and then analyzed. Radiofrequency ablations were performed on 57 atrial tissue samples (28 HPSD, 29 standard) and 28 ventricular tissue samples (all standard).With ablation parameters held constant, performing multiple ablations significantly increased lesion depth in ventricular tissue when ablations were performed at 30 W for 50 s. No other set of ablation parameters was shown to affect the width or depth of the resulting lesions in either tissue type.Multiple ablations created with the same power and time, delivered within 30 s of each other at the same exact location, offer no meaningful benefit in lesion depth or width over single ablations, with the exception of ventricular ablation at 30 W for 50 s. Given the risks associated with excessive ablation, our results suggest that this practice should be re-evaluated by clinical electrophysiologists.

Published
2022
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45. MEDI5752FINALSupplementaryMaterial.docx from Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells

Author

Yariv Mazor, Robert W. Wilkinson, Daniel J. Freeman, Ikbel Achour, William Dall'Acqua, Aleksandra D. Toloczko, Thomas V. Murray, Frances Neal, Gareth J. Browne, Godfrey J. Rainey, Michelle Morrow, Asis Palazon, Yanli Wu, James Dodgson, Michael G. Overstreet, Yaya Wang, Kathy Mulgrew, Stacy Kentner, Xiaofang Jin, Arthur Lewis, Kapil Vashisht, Shelby D. Gainer, Deepa S. Subramaniam, Ben Tran, Seock-Ah Im, Bo Wang, Sumati Hasani, Des C. Jones, James Hair, Anna Hansen, Lorraine Irving, Suzanne I. Sitnikova, Chunning Yang, Matthew J. Elder, and Simon J. Dovedi

Abstract

Supplementary Materials and Methods, and Supplementary Figures

Published
2023
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46. Data from Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells

Author

Yariv Mazor, Robert W. Wilkinson, Daniel J. Freeman, Ikbel Achour, William Dall'Acqua, Aleksandra D. Toloczko, Thomas V. Murray, Frances Neal, Gareth J. Browne, Godfrey J. Rainey, Michelle Morrow, Asis Palazon, Yanli Wu, James Dodgson, Michael G. Overstreet, Yaya Wang, Kathy Mulgrew, Stacy Kentner, Xiaofang Jin, Arthur Lewis, Kapil Vashisht, Shelby D. Gainer, Deepa S. Subramaniam, Ben Tran, Seock-Ah Im, Bo Wang, Sumati Hasani, Des C. Jones, James Hair, Anna Hansen, Lorraine Irving, Suzanne I. Sitnikova, Chunning Yang, Matthew J. Elder, and Simon J. Dovedi

Abstract

The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate with significant immune-related adverse events suboptimally limiting the doses of anti-CTLA4 mAb that can be used. MEDI5752 is a monovalent bispecific antibody designed to suppress the PD-1 pathway and provide modulated CTLA4 inhibition favoring enhanced blockade on PD-1+ activated T cells. We show that MEDI5752 preferentially saturates CTLA4 on PD-1+ T cells versus PD-1− T cells, reducing the dose required to elicit IL2 secretion. Unlike conventional PD-1/CTLA4 mAbs, MEDI5752 leads to the rapid internalization and degradation of PD-1. Moreover, we show that MEDI5752 preferentially localizes and accumulates in tumors providing enhanced activity when compared with a combination of mAbs targeting PD-1 and CTLA4 in vivo. Following treatment with MEDI5752, robust partial responses were observed in two patients with advanced solid tumors. MEDI5752 represents a novel immunotherapy engineered to preferentially inhibit CTLA4 on PD-1+ T cells.Significance:The unique characteristics of MEDI5752 represent a novel immunotherapy engineered to direct CTLA4 inhibition to PD-1+ T cells with the potential for differentiated activity when compared with current conventional mAb combination strategies targeting PD-1 and CTLA4. This molecule therefore represents a step forward in the rational design of cancer immunotherapy.See related commentary by Burton and Tawbi, p. 1008.This article is highlighted in the In This Issue feature, p. 995

Published
2023
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47. Data from Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Mediated Proliferation of Tumor Cells with Receptor-Proximal Apoptosis Defects

Author

Irmela Jeremias, Klaus-Michael Debatin, Harald Ehrhardt, Christian Beltinger, Irene Schmid, Uta Fuchs, Agnieszka Toloczko, and Eva Baader

Abstract

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) might represent a future cytotoxic drug to treat cancer as it induces apoptosis in tumor cells without toxicity in animal trials. We recently described that in contrast to apoptosis, TRAIL mediates tumor cell survival and proliferation in certain tumor cells. Here we studied the effect of TRAIL on 18 cell lines and 53 primary leukemia cells and classified these tumor cells into four groups: TRAIL, anti-DR4 or anti-DR5 induced apoptosis in group A cells, whereas they had no effect on group 0 cells and mediated proliferation in group P cells. To our surprise, TRAIL induced simultaneous apoptosis and proliferation in group AP cells. More than 20% of all cells tested belonged to group P and showed TRAIL-mediated proliferation even in the presence of certain cytotoxic drugs but not inhibitors of nuclear factor-κB. Transfection with B-cell leukemia/lymphoma protein 2 transformed group A cells into group 0 cells, whereas transfection with Fas-associated polypeptide with death domain (FADD)–like interleukin-1-converting enzyme–inhibitory protein (FLIP) transformed them into group AP cells. Loss of caspase-8 or transfection of dominant-negative FADD transformed group A cells into group P cells. Taken together, our data suggest that proliferation is a frequent effect of TRAIL on tumor cells, which is related to receptor-proximal apoptosis defects at the level of the death-inducing signaling complex and should be prevented during antitumor therapy with TRAIL.

Published
2023
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48. Supplementary Figures 1-3 from Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Mediated Proliferation of Tumor Cells with Receptor-Proximal Apoptosis Defects

Author

Irmela Jeremias, Klaus-Michael Debatin, Harald Ehrhardt, Christian Beltinger, Irene Schmid, Uta Fuchs, Agnieszka Toloczko, and Eva Baader

Abstract

Supplementary Figures 1-3 from Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Mediated Proliferation of Tumor Cells with Receptor-Proximal Apoptosis Defects

Published
2023
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