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1. Development and validation of an oxygen dissociation assay, a screening platform for discovering, and characterizing hemoglobin–oxygen affinity modifiers

Author

Patel MP, Siu V, Silva-Garcia A, Xu Q, Li Z, and Oksenberg D

Subjects
hemoglobin modifiers, in vitro assays, small molecule screening, oxygen affinity, Therapeutics. Pharmacology, RM1-950
Abstract

Mira P Patel,1 Vincent Siu,1 Abel Silva-Garcia,1 Qing Xu,2 Zhe Li,2 Donna Oksenberg1 1Biology Department, Global Blood Therapeutics Inc., South San Francisco, CA, USA; 2Chemistry Department, Global Blood Therapeutics Inc., South San Francisco, CA, USA Introduction: Hemoglobin (Hb) is a critical molecule necessary for all vertebrates to maintain aerobic metabolism. Hb–oxygen (O2) affinity modifiers have been studied to address various diseases including sickle cell disease, hypoxemia, tumor hypoxia, and wound healing. However, drug development of exogenous Hb modifiers has been hindered by the lack of a technique to rapidly screen compounds for their ability to alter Hb–O2 affinity. We have developed a novel screening assay based upon the spectral changes observed during Hb deoxygenation and termed it the oxygen dissociation assay (ODA). Methodology: ODA allows for the quantitation of oxygenated Hb at given time points during Hb deoxygenation on a 96-well plate. This assay was validated by comparing the ability of 500 Hb modifiers to alter the Hb–O2 affinity in the ODA vs the oxygen equilibrium curves obtained using the industry standard Hemox Analyzer instrument. Results: A correlation (R2) of 0.7 indicated that the ODA has the potential to screen and identify potent exogenous Hb modifiers. In addition, it allows for concurrent comparison of compounds, concentrations, buffers, or pHs on the level of Hb oxygenation. Conclusion: With a cost-effective, simple, rapid, and highly adaptable assay, the ODA will allow researchers to rapidly characterize Hb–O2 affinity modifiers. Keywords: hemox analyzer, in vitro assays, small-molecule screening, voxelotor

Published
2018

2. Biochemical and Hematologic Manifestations of Gastric Intrinsic Factor (GIF) Deficiency: A Treatable Cause of B12 Deficiency in the Old Order Mennonite Population of Southwestern Ontario

Author

Ferrand, A., Siu, V. M., Rupar, C. A., Napier, M. P., Al-Dirbashi, O. Y., Chakraborty, P., Prasad, C., Zschocke, Johannes, Editor-in-chief, Baumgartner, Matthias, Series editor, Gibson, K Michael, Editor-in-chief, Patterson, Marc, Series editor, Rahman, Shamima, Series editor, Morava, Eva, editor, and Peters, Verena, editor

Published
2015
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3. Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders.

Author

Levy, MA, McConkey, H, Kerkhof, J, Barat-Houari, M, Bargiacchi, S, Biamino, E, Bralo, MP, Cappuccio, G, Ciolfi, A, Clarke, A, DuPont, BR, Elting, MW, Faivre, L, Fee, T, Fletcher, RS, Cherik, F, Foroutan, A, Friez, MJ, Gervasini, C, Haghshenas, S, Hilton, BA, Jenkins, Z, Kaur, S, Lewis, S, Louie, RJ, Maitz, S, Milani, D, Morgan, AT, Oegema, R, Østergaard, E, Pallares, NR, Piccione, M, Pizzi, S, Plomp, AS, Poulton, C, Reilly, J, Relator, R, Rius, R, Robertson, S, Rooney, K, Rousseau, J, Santen, GWE, Santos-Simarro, F, Schijns, J, Squeo, GM, St John, M, Thauvin-Robinet, C, Traficante, G, van der Sluijs, PJ, Vergano, SA, Vos, N, Walden, KK, Azmanov, D, Balci, T, Banka, S, Gecz, J, Henneman, P, Lee, JA, Mannens, MMAM, Roscioli, T, Siu, V, Amor, DJ, Baynam, G, Bend, EG, Boycott, K, Brunetti-Pierri, N, Campeau, PM, Christodoulou, J, Dyment, D, Esber, N, Fahrner, JA, Fleming, MD, Genevieve, D, Kerrnohan, KD, McNeill, A, Menke, LA, Merla, G, Prontera, P, Rockman-Greenberg, C, Schwartz, C, Skinner, SA, Stevenson, RE, Vitobello, A, Tartaglia, M, Alders, M, Tedder, ML, Sadikovic, B, Levy, MA, McConkey, H, Kerkhof, J, Barat-Houari, M, Bargiacchi, S, Biamino, E, Bralo, MP, Cappuccio, G, Ciolfi, A, Clarke, A, DuPont, BR, Elting, MW, Faivre, L, Fee, T, Fletcher, RS, Cherik, F, Foroutan, A, Friez, MJ, Gervasini, C, Haghshenas, S, Hilton, BA, Jenkins, Z, Kaur, S, Lewis, S, Louie, RJ, Maitz, S, Milani, D, Morgan, AT, Oegema, R, Østergaard, E, Pallares, NR, Piccione, M, Pizzi, S, Plomp, AS, Poulton, C, Reilly, J, Relator, R, Rius, R, Robertson, S, Rooney, K, Rousseau, J, Santen, GWE, Santos-Simarro, F, Schijns, J, Squeo, GM, St John, M, Thauvin-Robinet, C, Traficante, G, van der Sluijs, PJ, Vergano, SA, Vos, N, Walden, KK, Azmanov, D, Balci, T, Banka, S, Gecz, J, Henneman, P, Lee, JA, Mannens, MMAM, Roscioli, T, Siu, V, Amor, DJ, Baynam, G, Bend, EG, Boycott, K, Brunetti-Pierri, N, Campeau, PM, Christodoulou, J, Dyment, D, Esber, N, Fahrner, JA, Fleming, MD, Genevieve, D, Kerrnohan, KD, McNeill, A, Menke, LA, Merla, G, Prontera, P, Rockman-Greenberg, C, Schwartz, C, Skinner, SA, Stevenson, RE, Vitobello, A, Tartaglia, M, Alders, M, Tedder, ML, and Sadikovic, B

Abstract

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

Published
2022

4. Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care

Author

Sawyer, S. L., Hartley, T., Dyment, D. A., Beaulieu, C. L., Schwartzentruber, J., Smith, A., Bedford, H. M., Bernard, G., Bernier, F. P., Brais, B., Bulman, D. E., Chardon, Warman J., Chitayat, D., Deladoëy, J., Fernandez, B. A., Frosk, P., Geraghty, M. T., Gerull, B., Gibson, W., Gow, R. M., Graham, G. E., Green, J. S., Heon, E., Horvath, G., Innes, A. M., Jabado, N., Kim, R. H., Koenekoop, R. K., Khan, A., Lehmann, O. J., Mendoza-Londono, R., Michaud, J. L., Nikkel, S. M., Penney, L. S., Polychronakos, C., Richer, J., Rouleau, G. A., Samuels, M. E., Siu, V. M., Suchowersky, O., Tarnopolsky, M. A., Yoon, G., Zahir, F. R., Majewski, J., and Boycott, K. M.

Published
2016
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12. Cornelia de Lange syndrome in diverse populations.

Author

Dowsett, L, Porras, AR, Kruszka, P, Davis, B, Hu, T, Honey, E, Badoe, E, Thong, M-K, Leon, E, Girisha, KM, Shukla, A, Nayak, SS, Shotelersuk, V, Megarbane, A, Phadke, S, Sirisena, ND, Dissanayake, VHW, Ferreira, CR, Kisling, MS, Tanpaiboon, P, Uwineza, A, Mutesa, L, Tekendo-Ngongang, C, Wonkam, A, Fieggen, K, Batista, LC, Moretti-Ferreira, D, Stevenson, RE, Prijoles, EJ, Everman, D, Clarkson, K, Worthington, J, Kimonis, V, Hisama, F, Crowe, C, Wong, P, Johnson, K, Clark, RD, Bird, L, Masser-Frye, D, McDonald, M, Willems, P, Roeder, E, Saitta, S, Anyane-Yeoba, K, Demmer, L, Hamajima, N, Stark, Z, Gillies, G, Hudgins, L, Dave, U, Shalev, S, Siu, V, Ades, A, Dubbs, H, Raible, S, Kaur, M, Salzano, E, Jackson, L, Deardorff, M, Kline, A, Summar, M, Muenke, M, Linguraru, MG, Krantz, ID, Dowsett, L, Porras, AR, Kruszka, P, Davis, B, Hu, T, Honey, E, Badoe, E, Thong, M-K, Leon, E, Girisha, KM, Shukla, A, Nayak, SS, Shotelersuk, V, Megarbane, A, Phadke, S, Sirisena, ND, Dissanayake, VHW, Ferreira, CR, Kisling, MS, Tanpaiboon, P, Uwineza, A, Mutesa, L, Tekendo-Ngongang, C, Wonkam, A, Fieggen, K, Batista, LC, Moretti-Ferreira, D, Stevenson, RE, Prijoles, EJ, Everman, D, Clarkson, K, Worthington, J, Kimonis, V, Hisama, F, Crowe, C, Wong, P, Johnson, K, Clark, RD, Bird, L, Masser-Frye, D, McDonald, M, Willems, P, Roeder, E, Saitta, S, Anyane-Yeoba, K, Demmer, L, Hamajima, N, Stark, Z, Gillies, G, Hudgins, L, Dave, U, Shalev, S, Siu, V, Ades, A, Dubbs, H, Raible, S, Kaur, M, Salzano, E, Jackson, L, Deardorff, M, Kline, A, Summar, M, Muenke, M, Linguraru, MG, and Krantz, ID

Abstract

Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.

Published
2019

17. Mutations in cohesion complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominat mental retardation

Author

Deardoff MA, Kaur M, Yaeger D, Rampuria A, Korolev S, Pie J, Gil-Rodriguez C, Arnedo M, Loeys B, Kloine AD, Wilson M, Lillquist K, Siu V, Ramos FJ, Musio A, Jackson LS, Dorsett D, and Krantz ID

Subjects
biological phenomena, cell phenomena, and immunity
Abstract

Mutations in the cohesin regulators NIPBL and ESCO2 are causative of the Cornelia de Lange syndrome (CdLS) and Roberts or SC phocomelia syndrome, respectively. Recently, mutations in the cohesin complex structural component SMC1A have been identified in two probands with features of CdLS. Here, we report the identification of a mutation in the gene encoding the complementary subunit of the cohesin heterodimer, SMC3, and 14 additional SMC1A mutations. All mutations are predicted to retain an open reading frame, and no truncating mutations were identified. Structural analysis of the mutant SMC3 and SMC1A proteins indicate that all are likely to produce functional cohesin complexes, but we posit that they may alter their chromosome binding dynamics. Our data indicate that SMC3 and SMC1A mutations (1) contribute to approximately 5% of cases of CdLS, (2) result in a consistently mild phenotype with absence of major structural anomalies typically associated with CdLS, and (3) in some instances, result in a phenotype that approaches that of apparently nonsyndromic mental retardation.

Published
2007

18. Genetic characterization of two autosomal recessive disorders, Majewski-like and cerebral atrophy syndromes

Author

Lahiry, P, Robinson, J F, Siu, V, Puffenberger, E G, Strauss, K A, Hegele, R A, Rupar, C A, Lahiry, P, Robinson, J F, Siu, V, Puffenberger, E G, Strauss, K A, Hegele, R A, and Rupar, C A

Abstract

Introduction: We recently identified two lethal recessive disorders segregating within the same Old Order Amish pedigree. The first disorder, Majewski-like syndrome (MLS), has features that overlap with both Majewski short rib-polydactyly syndrome and hydrolethalus syndrome. MLS is a lethal multi-system disorder that affects the development of the brain, adrenal glands, pituitary gland and bone. The second disorder, cerebral atrophy syndrome (CAS), is characterized by progressive and global loss of brain tissue. Affected children present early in life with microcephaly, seizures, and psychomotor retardation, and possess distinctive MRI findings. The objective of this study was to identify the genetic bases of these disorders to provide prompt and reliable diagnosis for families. Methods: Assuming recessive inheritance and mutation homogeneity (autozygosity), we used Affymetrix 10,000-single nucleotide polymorphism (10K-SNP) to genotype all affected individuals and identify candidate regions. SNP data were analyzed using Agilent GT autozygosity mapping software. LOD scores were used to identify candidate regions, and genes within these regions were prioritized for sequencing. Results and Conclusion: Because the Ontario Anabaptist population is relatively small, genetically isolated, and historically young, we were able to robustly map candidate regions using relatively low marker density and only a few affected individuals. Our preliminary data is consistent with the clinical observation that MLS and CAS segregate independently, as recessive conditions, within the pedigree. Thus far, we have sequenced 12 genes within the MLS locus, all of which were normal. For CAS, autozygosity mapping yielded two loci with comparable linkage scores, one of which contained no observable mutations. Once the causative mutations have been identified for MLS and CAS, we intend to study their population frequencies and also to pursue in vitro studies of gene and protein functions.

Published
2007

19. ANGIOGENESIS AND INVASION

Author

Hu, Y.-L., primary, De Lay, M., additional, Rose, S. D., additional, Carbonell, W. S., additional, Aghi, M. K., additional, Hu, Y.-L., additional, Paquette, J., additional, Tokuyasu, T., additional, Tsao, S., additional, Chaumeil, M., additional, Ronen, S., additional, Matlaf, L. A., additional, Soroceanu, L., additional, Cobbs, C., additional, Matlaf, L., additional, Harkins, L., additional, Garzon-Muvdi, T., additional, Rhys, C. a., additional, Smith, C., additional, Kim, D.-H., additional, Kone, L., additional, Farber, H., additional, An, S., additional, Levchenko, A., additional, Quinones-Hinojosa, A., additional, Lemke, D., additional, Pfenning, P.-N., additional, Sahm, F., additional, Klein, A.-C., additional, Kempf, T., additional, Schnolzer, M., additional, Platten, M., additional, Wick, W., additional, Smith, S. J., additional, Rahman, R., additional, Rahman, C., additional, Barrow, J., additional, Macarthur, D., additional, Rose, F., additional, Grundy, R. G., additional, Kaley, T. J., additional, Huse, J., additional, Karimi, S., additional, Rosenblum, M., additional, Omuro, A., additional, DeAngelis, L. M., additional, de Groot, J. F., additional, Kong, L.-Y., additional, Wei, J., additional, Wang, T., additional, Piao, Y., additional, Liang, J., additional, Fuller, G. N., additional, Qiao, W., additional, Heimberger, A. B., additional, Jhaveri, N., additional, Cho, H., additional, Torres, S., additional, Wang, W., additional, Schonthal, A., additional, Petasis, N., additional, Louie, S. G., additional, Hofman, F., additional, Chen, T. C., additional, Yamada, R., additional, Sumual, S., additional, Buljan, V., additional, Bennett, M. R., additional, McDonald, K. L., additional, Weiler, M., additional, Thiepold, A.-L., additional, Jestaedt, L., additional, Gronych, J., additional, Dittmann, L. M., additional, Jugold, M., additional, Kosch, M., additional, Combs, S. E., additional, von Deimling, A., additional, Weller, M., additional, Bendszus, M., additional, Kwiatkowska, A., additional, Paulino, V., additional, Tran, N. L., additional, Symons, M., additional, Stockham, A. L., additional, Borden, E., additional, Peereboom, D., additional, Hu, Y., additional, Chaturbedi, A., additional, Hamamura, M., additional, Mark, E., additional, Zhou, Y.-H., additional, Abbadi, S., additional, Guerrero-Cazares, H., additional, Pistollato, F., additional, Smith, C. L., additional, Ruff, W., additional, Puppa, A. D., additional, Basso, G., additional, Monje, M., additional, Freret, M. E., additional, Masek, M., additional, Fisher, P. G., additional, Haddix, T., additional, Vogel, H., additional, Kijima, N., additional, Hosen, N., additional, Kagawa, N., additional, Hashimoto, N., additional, Fujimoto, Y., additional, Kinoshita, M., additional, Sugiyama, H., additional, Yoshimine, T., additional, Anneke, N., additional, Bob, H., additional, Pieter, W., additional, Arend, H., additional, William, L., additional, Eoli, M., additional, Calleri, A., additional, Cuppini, L., additional, Anghileri, E., additional, Pellegatta, S., additional, Prodi, E., additional, Bruzzone, M. G., additional, Bertolini, F., additional, Finocchiaro, G., additional, Zhu, D., additional, Hunter, S. B., additional, Vertino, P. M., additional, Van Meir, E. G., additional, Cork, S. M., additional, Kaur, B., additional, Cooper, L., additional, Saltz, J. H., additional, Sandberg, E. M., additional, Burrell, K., additional, Hill, R., additional, Zadeh, G., additional, Parker, J. J., additional, Dionne, K., additional, Massarwa, R., additional, Klaassen, M., additional, Niswander, L., additional, Kleinschmidt-DeMasters, B. K., additional, Waziri, A., additional, Jalali, S., additional, Wataya, T., additional, Salehi, F., additional, Croul, S., additional, Gentili, F., additional, Foltz, W., additional, Lee, J.-I., additional, Agnihorti, S., additional, Menard, C., additional, Chung, C., additional, Schonthal, A. H., additional, Hofman, F. M., additional, Elena, P., additional, Faivre, G., additional, Demopoulos, A., additional, Taillibert, S., additional, Kirsch, M., additional, Martin, K. D., additional, Bertram, A., additional, uckermann, O., additional, Leipnitz, E., additional, Weigel, P., additional, Temme, A., additional, Schackert, G., additional, Geiger, K., additional, Gerstner, E., additional, Jennings, D., additional, Chi, A. S., additional, Plotkin, S., additional, Kwon, S. J., additional, Pinho, M., additional, Polaskova, P., additional, Batchelor, T. T., additional, Sorensen, A. G., additional, Hossain, M. B., additional, Gururaj, A. E., additional, Cortes-Santiago, N., additional, Gabrusiewicz, K., additional, Yung, W. K. A., additional, Fueyo, J., additional, Gomez-Manzano, C., additional, Gil, O. D., additional, Noticewala, S., additional, Ivkovic, S., additional, Esencay, M., additional, Zagzagg, D., additional, Rosenfeld, S., additional, Bruce, J. N., additional, Canoll, P., additional, Chang, J. H., additional, Seol, H. J., additional, Weeks, A., additional, Smith, C. A., additional, Rutka, J. T., additional, Georges, J., additional, Samuelson, G., additional, Misra, A., additional, Joy, A., additional, Huang, Y., additional, McQuilkin, M., additional, Yoshihiro, A., additional, Carpenter, D., additional, Butler, L., additional, Feuerstein, B., additional, Murphy, S. F., additional, Vaghaiwalla, T., additional, Wotoczek-Obadia, M., additional, Albright, R., additional, Mack, D., additional, Lawn, S., additional, Henderson, F., additional, Jung, M., additional, Dakshanamurthy, S., additional, Brown, M., additional, Forsyth, P., additional, Brem, S., additional, Sadr, M. S., additional, Maret, D., additional, Sadr, E. S., additional, Siu, V., additional, Alshami, J., additional, Trinh, G., additional, Denault, J.-S., additional, Faury, D., additional, Jabado, N., additional, Nantel, A., additional, and Del Maestro, R., additional

Published
2011
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20. Angiogenesis and Invasion

Author

Fishman, R. A., primary, Happ, E., additional, Stevens, T., additional, Kunschner, L., additional, Jaworski, D. M., additional, Stradecki, H. M., additional, Penar, P. L., additional, Pendlebury, W. W., additional, Pennington, C. J., additional, Edwards, D. R., additional, Broaddus, W. C., additional, Fillmore, H. L., additional, Mukherjee, J., additional, Hawkins, C., additional, Guha, A., additional, Pioli, P. D., additional, Milani, S., additional, Linskey, M. E., additional, Zhou, Y.-H., additional, Marchetti, V., additional, Barnett, F., additional, Wang, M., additional, Scheppke, L., additional, Sanchez-Cespedes, J., additional, De Rossi, C., additional, Nemerow, G., additional, Torbett, B., additional, Friedlander, M., additional, Goldlust, S. A., additional, Singer, S., additional, DeAngelis, L. M., additional, Lassman, A. B., additional, Nolan, C. P., additional, Yang, S.-H., additional, Lee, S. W., additional, Chen, Z.-p., additional, Liu, X.-m., additional, Wojton, J. A., additional, Chu, Z., additional, Qi, X., additional, Kaur, B., additional, Hu, Y., additional, Siegel, E., additional, Ro, D. I., additional, Marlon, S., additional, Hsu, N., additional, Milani, S. N., additional, Mohan, S., additional, Yu, L., additional, Hess, K. R., additional, Liu, Y., additional, Carson-Walter, E., additional, Walter, K., additional, Raghu, H., additional, Gondi, C. S., additional, Gujrati, M., additional, Dinh, D. H., additional, Rao, J. S., additional, Narayana, A., additional, Kunnakkat, S. D., additional, Medabalmi, P., additional, Golfinos, J., additional, Parker, E., additional, Knopp, E., additional, Zagzag, D., additional, Gruber, D., additional, Gruber, M. L., additional, Burrell, K., additional, Jelveh, S., additional, Lindsey, P., additional, Hill, R., additional, Zadeh, G., additional, Ivkovic, S., additional, Beadle, C., additional, Massey, S. C., additional, Swanson, K. R., additional, Canoll, P., additional, Rosenfeld, S. S., additional, McAllister, S., additional, Soroceanu, L., additional, Pakdel, A., additional, Limbad, C., additional, Adrados, I., additional, Desprez, P.-Y., additional, Nakada, M., additional, Nambu, E., additional, Furuyama, N., additional, Yoshida, Y., additional, Kita, D., additional, Hayashi, Y., additional, Hamada, J.-i., additional, Seyed Sadr, M., additional, Maret, D., additional, Seyed Sadr, E., additional, Siu, V., additional, Alshami, J., additional, Denault, J.-S., additional, Faury, D., additional, Jabado, N., additional, Nantel, A., additional, Del Maestro, R., additional, Perretta, D., additional, Nagaiah, G., additional, Almubarak, M., additional, Torres-Trejo, A., additional, Newton,, M., additional, Willey, P., additional, Altaha, R., additional, Murphy, S. F., additional, Banasiak, M., additional, Yee, G.-T., additional, Wotoczek-Obadia, M., additional, Tran, Y., additional, Prak, A., additional, Albright, R., additional, Mullan, M., additional, Paris, D., additional, Brem, S., additional, Yang, Y.-P., additional, Ennis, M., additional, Tran, N., additional, Symons, M., additional, Najbauer, J., additional, Huszthy, P. C., additional, Garcia, E., additional, Metz, M. Z., additional, Gutova, M., additional, Frank, R. T., additional, Miletic, H., additional, Glackin, C. A., additional, Barish, M. E., additional, Bjerkvig, R., additional, Aboody, K. S., additional, Clump, D. A., additional, Engh, J. A., additional, Mintz, A. H., additional, Cunnick, J., additional, Flynn, D. C., additional, Clark, A. J., additional, Butowski, N. A., additional, Chang, S. M., additional, Prados, M. D., additional, Clarke, J., additional, Polley, M.-Y. C., additional, Sughrue, M. E., additional, McDermott, M. W., additional, Parsa, A. T., additional, Berger, M. S., additional, Aghi, M. K., additional, Megyesi, J. F., additional, Costello, P., additional, Macdonald, W., additional, Dyer, E., additional, Macdonald, D., additional, Hammond, R., additional, Kalache, Y., additional, Easaw, J., additional, McIntyre, J., additional, Williams, S. C., additional, Karajannis, M. A., additional, Chiriboga, L., additional, von Deimling, A., additional, Ajlan, A., additional, Husaine, S., additional, Petrecca, K., additional, Magnus, N., additional, Garnier, D., additional, Meehan, B., additional, and Rak, J., additional

Published
2010
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21. Cell Biology and Signaling

Author

Long, P. M., primary, Wesley, U. V., additional, Jaworski, D. M., additional, Rana, M., additional, Kiehl, T.-R., additional, So, K., additional, Gould, P., additional, Ajewung, N., additional, Kamnasaran, D., additional, Emmett, M. R., additional, Wang, X., additional, Marshall, A. G., additional, Ji, Y., additional, Fokt, I., additional, Skora, S., additional, Conrad, C. A., additional, Priebe, W., additional, Zhu, H., additional, Cao, X., additional, Keir, S., additional, Ali-Osman, F., additional, Lo, H.-W., additional, Da Fonseca, C. O., additional, Arun, V., additional, Wiley, J. C., additional, Kaur, H., additional, Guha, A., additional, Fenton, K., additional, Abdelwahab, M. G., additional, Stafford, P., additional, Rho, J. M., additional, Preul, M. C., additional, Scheck, A. C., additional, Brossier, N. M., additional, Carroll, S. L., additional, Gajadhar, A., additional, Mukherjee, J., additional, Wolf, A., additional, Hawkins, C., additional, Costa, P., additional, Cardoso, A. L. C., additional, de Almeida, L. P., additional, de Lima, M. C. P., additional, Canoll, P., additional, Bruce, J., additional, Lavon, I., additional, Granit, A., additional, Einstein, O., additional, Ben-Hur, T., additional, Siegal, T., additional, Pang, J. C., additional, Poon, W. S., additional, Zhou, L., additional, Ng, H.-K., additional, Rovin, R. A., additional, Lawrence, J. E., additional, Segula, J. J., additional, Winn, R. J., additional, Patil, S., additional, Burzynski, S. R., additional, Mrowczynski, E., additional, Grela, K., additional, Cheng, S., additional, Liu, K., additional, Feng, H., additional, Bacho, R., additional, Kazlauskas, A., additional, Smith, E. M., additional, Symes, K., additional, Hu, B., additional, Lee, C. Y., additional, Fotovati, A., additional, Dunn, S. E., additional, Proescholdt, M. A., additional, Storr, E.-M., additional, Lohmeier, A., additional, Brawanski, A., additional, Jarzynka, M. J., additional, Ravichandran, K. S., additional, Vuori, K., additional, Tang, C., additional, Nshikawa, R., additional, Johns, T. G., additional, Furnari, F. B., additional, Cavenee, W. K., additional, Zhong, J., additional, O'Neill, G. M., additional, Deleyrolle, L. P., additional, Rahman, M., additional, Dunbar, E. M., additional, Caldeira, M. A., additional, Reynolds, B. A., additional, Liu, X., additional, Yacyshyn, S., additional, Dasgupta, B., additional, Han, X., additional, Yang, X., additional, Wheeler, C. G., additional, Filippova, N., additional, Langford, C. P., additional, Ding, Q., additional, Fathallah, H. M., additional, Gillespie, G. Y., additional, Nabors, L. B., additional, Davidson, T. B., additional, Gortalum, F., additional, Ji, L., additional, Engell, K., additional, Sposto, R., additional, Asgharzadeh, S., additional, Erdreich-Epstein, A., additional, Lawn, S. O., additional, Weiss, S., additional, Senger, D., additional, Forsyth, P., additional, Latha, K., additional, Chumbalkar, V., additional, Li, M., additional, Gururaj, A., additional, Hwang, Y., additional, Maywald, R., additional, Dakeng, S., additional, Dao, L., additional, Baggerly, K., additional, Sawaya, R., additional, Aldape, K., additional, Cavenee, W., additional, Furnari, F., additional, Bogler, O., additional, Arumugam, J., additional, Sim, H., additional, Pineda, C. A., additional, Pan, Y., additional, Viapiano, M. S., additional, Van Schaick, J. A., additional, Akagi, K., additional, Burkett, S., additional, DiFabio, C., additional, Tuskan, R., additional, Walrath, J., additional, Reilly, K., additional, Dai, B., additional, Jing, Z., additional, Kang, S.-H., additional, Li, D., additional, Xie, K., additional, Huang, S., additional, Gong, X., additional, Vuong, Y., additional, Bota, D. A., additional, Stegh, A. H., additional, Inda, M.-d.-M., additional, Bonavia, R., additional, Mukasa, A., additional, Narita, Y., additional, Sah, D., additional, Vandenberg, S., additional, Brennan, C., additional, Johns, T., additional, Bachoo, R., additional, Hadwiger, P., additional, Tan, P., additional, DePinho, R., additional, Kusne, Y., additional, Meerson, A., additional, Rushing, E. J., additional, Yang, W., additional, McDonough, W., additional, Kislin, K., additional, Loftus, J. C., additional, Berens, M., additional, Lu, Z., additional, Ghosh, S., additional, Verma, A., additional, Zhou, H., additional, Chin, S., additional, Bruggers, C., additional, Kestle, J., additional, Khatua, S., additional, Broekman, M. L., additional, Maas, N. S., additional, Skog, J., additional, Breakefield, X. O., additional, Sena-Esteves, M., additional, de Vrij, J., additional, Lamfers, M., additional, Maas, N., additional, Dirven, C., additional, Esteves, M., additional, Broekman, M., additional, Chidambaram, A., additional, Dumur, C. I., additional, Graf, M., additional, Vanmeter, T. E., additional, Fillmore, H. L., additional, Broaddus, W. C., additional, Silber, J., additional, Ozawa, T., additional, Kastenhuber, E., additional, Djaballah, H., additional, Holland, E. C., additional, Huse, J. T., additional, Agnihotri, S., additional, Munoz, D., additional, Han, J. E., additional, Albesiano, E., additional, Pradilla, G., additional, Lim, M., additional, Alshami, J., additional, Sabau, C., additional, Seyed Sadr, M., additional, Anan, M., additional, Seyed Sadr, E., additional, Siu, V., additional, Del Maestro, R., additional, Trinh, G., additional, Le, P., additional, Petrecca, K., additional, Sonabend, A. M., additional, Soderquist, C., additional, Lei, L., additional, Guarnieri, P., additional, Leung, R., additional, Yun, J., additional, Sisti, J., additional, Castelli, M., additional, Bruce, S., additional, Bruce, R., additional, Ludwig, T., additional, Rosenfeld, S., additional, Bruce, J. N., additional, Phillips, J. J., additional, Huillard, E., additional, Polley, M.-Y., additional, Rosen, S. D., additional, Rowitch, D. H., additional, Werb, Z., additional, Sarkar, C., additional, Jha, P., additional, Pathak, P., additional, Suri, V., additional, Sharma, M. C., additional, Chattopadhyay, P., additional, Chosdol, K., additional, Suri, A., additional, Gupta, D., additional, Mahapatra, A. K., additional, Kapoor, G. S., additional, Zhan, Y., additional, Boockvar, J. A., additional, O'Rourke, D. M., additional, Kwatra, M. M., additional, Kim, J. W., additional, Park, C.-K., additional, Han, J. H., additional, Park, S. H., additional, Kim, S.-K., additional, Jung, H.-W., additional, Narayanan, R., additional, Levin, B. S., additional, Maeder, M. L., additional, Joung, J. K., additional, Nutt, C. L., additional, Louis, D. N., additional, Dudley, A., additional, Jayaram, P., additional, Pei, Z., additional, Shi, X., additional, Laterra, J., additional, Watkins, P. A., additional, Mawrin, C., additional, Rempel, S. A., additional, McClung, H. M., additional, McFarland, B. C., additional, Nozell, S. E., additional, Huszar, D., additional, Benveniste, E. N., additional, Burton, T., additional, Eisenstat, D. D., additional, Gibson, S. B., additional, Lukiw, W. J., additional, Cui, J. G., additional, Li, Y. Y., additional, Zhao, Y., additional, Culicchia, F., additional, See, W., additional, Pieper, R., additional, Luchman, A., additional, Stechishin, O., additional, Nguyen, S., additional, Kelly, J., additional, Blough, M., additional, Cairncross, G., additional, Shah, S. R., additional, Mohyeldin, A., additional, Adams, H., additional, Garzon-Muvdi, T., additional, Aprhys, C., additional, Quinones-Hinojosa, A., additional, Weeks, A. C., additional, Restrepo, A., additional, Ivanchuk, S., additional, Smith, C., additional, Rutka, J. T., additional, Sengupta, R., additional, Yang, L., additional, Burbassi, S., additional, Zhang, B., additional, Markant, S. L., additional, Yang, Z.-j., additional, Meucci, O., additional, Wechsler-Reya, R. J., additional, Rubin, J. B., additional, Wykosky, J., additional, Chin, L., additional, Auvergne, R. M., additional, Sim, F. J., additional, Wang, S., additional, Chandler-Militello, D., additional, Burch, J., additional, Li, X., additional, Bennet, A., additional, Mohile, N., additional, Pilcher, W., additional, Walter, K., additional, Johnson, M., additional, Achanta, P., additional, Natesan, S., additional, Goldman, S. A., additional, Beauchamp, A. S., additional, Gibo, D. M., additional, Debinski, W., additional, Jiang, H., additional, Martin, V., additional, Gomez-Manzano, C., additional, Johnson, D. G., additional, Alonso, M., additional, White, E. J., additional, Xu, J., additional, McDonnell, T., additional, Shinojima, N., additional, Fueyo, J., additional, Sandhya Rani, M. R., additional, Huang, P., additional, Prayson, R., additional, Hedayat, H., additional, Sloan, A. E., additional, Novacki, A., additional, Ahluwalia, M. S., additional, Tipps, R., additional, Gladson, C. L., additional, Liu, J.-L., additional, Mao, Z., additional, Yung, W. K. A., additional, Bhat, K., additional, Salazar, K., additional, Balasubramaniyan, V., additional, Vaillant, B., additional, Hollingsworth, F., additional, Gumin, J., additional, Diefes, K., additional, Patel, D., additional, Lang, F., additional, Colman, H., additional, Parsyan, A., additional, Shahbazian, D., additional, Alain, T., additional, Martineau, Y., additional, Petroulakis, E., additional, Larsson, O., additional, Gkogkas, C., additional, Topisirovic, I., additional, Mathonnet, G., additional, Tettweiler, G., additional, Hellen, C., additional, Pestova, T., additional, Svitkin, Y., additional, Sonenberg, N., additional, Zerrouqi, A., additional, Pyrzynska, B., additional, Van Meir, E., additional, Twitty, G. B., additional, Hong, S. W., additional, Lee, H. K., additional, Finniss, S., additional, Xiang, C., additional, Cazacu, S., additional, Brodie, C., additional, Ginn, K. F., additional, Wise, A., additional, Farassati, F., additional, Brown, C., additional, Barish, M., additional, deCarvalho, A. C., additional, Hasselbach, L., additional, Nelson, K., additional, Lemke, N., additional, Schultz, L., additional, Mikkelsen, T., additional, Onvani, S., additional, Kongkham, P., additional, Smith, C. A., additional, Bier, A., additional, Hershkovitz, H., additional, Kahana, S., additional, Decarvalho, A., additional, Massey, S. C., additional, and Swanson, K. R., additional

Published
2010
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22. Surgical Therapies

Author

Kim, C.-Y., primary, Tate, M., additional, Chang, E., additional, Polley, M.-Y., additional, Berger, M., additional, Mercier, L., additional, Del Maestro, R. F., additional, Petrecca, K., additional, Collins, D. L., additional, Doglietto, F., additional, Salehi, F., additional, Ridout, R., additional, Gentili, F., additional, Zadeh, G., additional, Shrivastava, R. K., additional, Ghesani, M., additional, Sen, C., additional, Tabaee, A., additional, Lee, K. D., additional, DePowell, J. J., additional, Air, E., additional, Dwivedi, A. K., additional, McPherson, C. M., additional, Mishra, M. V., additional, Andrews, D., additional, Evans, J., additional, Glass, J., additional, Dicker, A. P., additional, Lawrence, Y. R., additional, Kirsch, M., additional, Juratli, T., additional, Meyer, K., additional, Schackert, G., additional, Cho, J. M., additional, Kim, E. H., additional, Oh, M. C., additional, Chang, J. H., additional, Kim, S. H., additional, Lee, K. S., additional, Adams, H., additional, Avendano, J., additional, Raza, S. M., additional, Olivi, A., additional, Quinones-Hinojosa, A., additional, Siu, V., additional, Seyed sadr, M., additional, Alshami, J., additional, Sabau, C., additional, Seyed sadr, E., additional, Anan, M., additional, Guiot, M.-C., additional, Samani, A., additional, Del Maestro, P., additional, Galameau, A., additional, Greaves, K., additional, Pouliot, J.-F., additional, Mangano, F., additional, Pruitt, D., additional, and Hummel, T., additional

Published
2010
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23. Ongoing Clinical Trials

Author

Clarke, J. L., primary, Ennis, M. M., additional, Lamborn, K. R., additional, Prados, M. D., additional, Puduvalli, V. K., additional, Penas-Prado, M., additional, Gilbert, M. R., additional, Groves, M. D., additional, Hess, K. R., additional, Levin, V. A., additional, de Groot, J., additional, Colman, H., additional, Conrad, C. A., additional, Loghin, M. E., additional, Hunter, K., additional, Yung, W. K., additional, Chen, C., additional, Damek, D., additional, Liu, A., additional, Gaspar, L. E., additional, Waziri, A., additional, Lillehei, K., additional, Kavanagh, B., additional, Finlay, J. L., additional, Haley, K., additional, Dhall, G., additional, Gardner, S., additional, Allen, J., additional, Cornelius, A., additional, Olshefski, R., additional, Garvin, J., additional, Pradhan, K., additional, Etzl, M., additional, Goldman, S., additional, Atlas, M., additional, Thompson, S., additional, Hirt, A., additional, Hukin, J., additional, Comito, M., additional, Bertolone, S., additional, Torkildson, J., additional, Joyce, M., additional, Moertel, C., additional, Letterio, J., additional, Kennedy, G., additional, Walter, A., additional, Ji, L., additional, Sposto, R., additional, Dorris, K., additional, Wagner, L., additional, Hummel, T., additional, Drissi, R., additional, Miles, L., additional, Leach, J., additional, Chow, L., additional, Turner, R., additional, Gragert, M. N., additional, Pruitt, D., additional, Sutton, M., additional, Breneman, J., additional, Crone, K., additional, Fouladi, M., additional, Friday, B. B., additional, Buckner, J., additional, Anderson, S. K., additional, Giannini, C., additional, Kugler, J., additional, Mazurczac, M., additional, Flynn, P., additional, Gross, H., additional, Pajon, E., additional, Jaeckle, K., additional, Galanis, E., additional, Badruddoja, M. A., additional, Pazzi, M. A., additional, Stea, B., additional, Lefferts, P., additional, Contreras, N., additional, Bishop, M., additional, Seeger, J., additional, Carmody, R., additional, Rance, N., additional, Marsella, M., additional, Schroeder, K., additional, Sanan, A., additional, Swinnen, L. J., additional, Rankin, C., additional, Rushing, E. J., additional, Hutchins, L. F., additional, Damek, D. M., additional, Barger, G. R., additional, Norden, A. D., additional, Lesser, G., additional, Hammond, S. N., additional, Drappatz, J., additional, Fadul, C. E., additional, Batchelor, T. T., additional, Quant, E. C., additional, Beroukhim, R., additional, Ciampa, A., additional, Doherty, L., additional, LaFrankie, D., additional, Ruland, S., additional, Bochacki, C., additional, Phan, P., additional, Faroh, E., additional, McNamara, B., additional, David, K., additional, Rosenfeld, M. R., additional, Wen, P. Y., additional, Phuphanich, S., additional, Reardon, D., additional, Wong, E. T., additional, Plotkin, S. R., additional, Mintz, A., additional, Raizer, J. J., additional, Kaley, T. J., additional, Smith, K. H., additional, Chamberlain, M. C., additional, Graham, C., additional, Mrugala, M., additional, Johnston, S., additional, Kreisl, T. N., additional, Smith, P., additional, Iwamoto, F., additional, Sul, J., additional, Butman, J. A., additional, Fine, H. A., additional, Westphal, M., additional, Heese, O., additional, Warmuth-Metz, M., additional, Pietsch, T., additional, Schlegel, U., additional, Tonn, J.-C., additional, Schramm, J., additional, Schackert, G., additional, Melms, A., additional, Mehdorn, H. M., additional, Seifert, V., additional, Geletneky, K., additional, Reuter, D., additional, Bach, F., additional, Khasraw, M., additional, Abrey, L. E., additional, Lassman, A. B., additional, Hormigo, A., additional, Nolan, C., additional, Gavrilovic, I. T., additional, Mellinghoff, I. K., additional, Reiner, A. S., additional, DeAngelis, L., additional, Omuro, A. M., additional, Burzynski, S. R., additional, Weaver, R. A., additional, Janicki, T. J., additional, Burzynski, G. S., additional, Szymkowski, B., additional, Acelar, S. S., additional, Mechtler, L. L., additional, O'Connor, P. C., additional, Kroon, H.-A., additional, Vora, T., additional, Kurkure, P., additional, Arora, B., additional, Gupta, T., additional, Dhamankar, V., additional, Banavali, S., additional, Moiyadi, A., additional, Epari, S., additional, Merchant, N., additional, Jalali, R., additional, Moller, S., additional, Grunnet, K., additional, Hansen, S., additional, Schultz, H., additional, Holmberg, M., additional, Sorensen, M. M., additional, Poulsen, H. S., additional, Lassen, U., additional, Reardon, D. A., additional, Vredenburgh, J. J., additional, Desjardins, A., additional, Janney, D. E., additional, Peters, K., additional, Sampson, J., additional, Gururangan, S., additional, Friedman, H. S., additional, Jeyapalan, S., additional, Constantinou, M., additional, Evans, D., additional, Elinzano, H., additional, O'Connor, B., additional, Puthawala, M. Y., additional, Goldman, M., additional, Oyelese, A., additional, Cielo, D., additional, Dipetrillo, T., additional, Safran, H., additional, Anan, M., additional, Seyed Sadr, M., additional, Alshami, J., additional, Sabau, C., additional, Seyed Sadr, E., additional, Siu, V., additional, Guiot, M.-C., additional, Samani, A., additional, Del Maestro, R., additional, Bogdahn, U., additional, Stockhammer, G., additional, Mahapatra, A. K., additional, Venkataramana, N. K., additional, Oliushine, V. E., additional, Parfenov, V. E., additional, Poverennova, I. E., additional, Hau, P., additional, Jachimczak, P., additional, Heinrichs, H., additional, Schlingensiepen, K.-H., additional, Shibui, S., additional, Kayama, T., additional, Wakabayashi, T., additional, Nishikawa, R., additional, de Groot, M., additional, Aronica, E., additional, Vecht, C. J., additional, Toering, S. T., additional, Heimans, J. J., additional, Reijneveld, J. C., additional, Batchelor, T., additional, Mulholland, P., additional, Neyns, B., additional, Nabors, L. B., additional, Campone, M., additional, Wick, A., additional, Mason, W., additional, Mikkelsen, T., additional, Ashby, L. S., additional, DeGroot, J. F., additional, Gattamaneni, H. R., additional, Cher, L. M., additional, Rosenthal, M. A., additional, Payer, F., additional, Xu, J., additional, Liu, Q., additional, van den Bent, M., additional, Nabors, B., additional, Fink, K., additional, Chan, M., additional, Trusheim, J., additional, Raval, S., additional, Hicking, C., additional, Henslee-Downey, J., additional, Picard, M., additional, Schiff, D., additional, Karimi, S., additional, DeAngelis, L. M., additional, Nolan, C. P., additional, Omuro, A., additional, Gavrilovic, I., additional, Norden, A., additional, Purow, B. W., additional, Lieberman, F. S., additional, Hariharan, S., additional, Perez-Larraya, J. G., additional, Honnorat, J., additional, Chinot, O., additional, Catry-Thomas, I., additional, Taillandier, L., additional, Guillamo, J. S., additional, Campello, C., additional, Monjour, A., additional, Tanguy, M. L., additional, Delattre, J. Y., additional, Franz, D. N., additional, Krueger, D. A., additional, Care, M. M., additional, Holland-Bouley, K., additional, Agricola, K., additional, Tudor, C., additional, Mangeshkar, P., additional, Byars, A. W., additional, Sahmoud, T., additional, Alonso-Basanta, M., additional, Lustig, R. A., additional, Dorsey, J. F., additional, Lai, R. K., additional, Recht, L. D., additional, Paleologos, N., additional, Groves, M., additional, Meech, S., additional, Davis, T., additional, Pavlov, D., additional, Marshall, M. A., additional, Slot, M., additional, Peerdeman, S. M., additional, Beauchesne, P. D., additional, Faure, G., additional, Noel, G., additional, Schmitt, T., additional, Kerr, C., additional, Jadaud, E., additional, Martin, L., additional, Carnin, C., additional, Peters, K. B., additional, Herndon, J. E., additional, Kirkpatrick, J. P., additional, Nayak, L., additional, Panageas, K. S., additional, and Deangelis, L. M., additional

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2010
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25. Evaluation of the Electromagnetic Hazard of intense THz pulses on neural cells

Author

Peccianti, M., primary, Sadr, M. Seyed, additional, Sabau, C., additional, Sharma, G., additional, Blanchard, F., additional, Razzari, L., additional, Maret, D., additional, Sadr, E. Seyed, additional, Alshami, J., additional, Siu, V., additional, Gobbi, G., additional, Ozaki, T., additional, Maestro, R. Del, additional, and Morandotti, R., additional

Published
2010
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26. The temozolomide O6-methylguanine-DNA methyltransferase (MGMT) study: A phase II trial to evaluate the effect of low-dose preoperative neoadjuvant temozolomide on brain tumour MGMT activity in glioma patients

Author

Del Maestro, R. F., primary, Siu, V., additional, Seyed Sadr, M., additional, Alshami, J., additional, Sabau, C., additional, Seyed Sadr, E., additional, Samani, A., additional, Assadian, S., additional, Greaves, K., additional, and Pouliot, J., additional

Published
2009
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28. Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5

Author

Puffenberger, E. G., primary, Strauss, K. A., additional, Ramsey, K. E., additional, Craig, D. W., additional, Stephan, D. A., additional, Robinson, D. L., additional, Hendrickson, C. L., additional, Gottlieb, S., additional, Ramsay, D. A., additional, Siu, V. M., additional, Heuer, G. G., additional, Crino, P. B., additional, and Morton, D. H., additional

Published
2007
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32. A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10

Author

Lyonnet, S., primary, Bolino, A., additional, Pelet, A., additional, Abel, L., additional, Nihoul-Fékété, C., additional, Briard, M. L., additional, Mok-Siu, V., additional, Kaariainen, H., additional, Martucciello, G., additional, Lerone, M., additional, Puliti, A., additional, Luo, Yin, additional, Weissenbach, J., additional, Devoto, M., additional, Munnich, A., additional, and Romeo, G., additional

Published
1993
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35. Chromosomal jumping from the DXS165 locus allows molecular characterization of four microdeletions and a de novo chromosome X/13 translocation associated with choroideremia.

Author

Cremers, F P, van de Pol, D J, Wieringa, B, Collins, F S, Sankila, E M, Siu, V M, Flintoff, W F, Brunsmann, F, Blonden, L A, and Ropers, H H

Abstract

Choroideremia (tapeto-choroidal dystrophy, TCD), an X chromosome-linked disorder of retina and choroid, causes progressive nightblindness and central blindness in affected males by the third to fourth decade of life. Recently, we have been able to map the TCD gene to a small region of overlap between five different, male-viable Xq21 deletions that were found in patients with TCD and other clinical features. Two families were identified in which classical, nonsyndromic TCD is associated with small interstitial deletions that are only detectable with probe p1bD5 (DXS165). To characterize these and two other deletions that were identified more recently, we have used the chromosome walking and jumping techniques to generate a set of five chromosomal-jumping clones flanking the DXS165 locus at various distances. With these clones, we could localize four of the eight deletion endpoints and the breakpoint on the X chromosome of a female with a de novo X/13 translocation and choroideremia. These studies assign the TCD gene, or part of it, to a DNA segment of only 15-20 kilobases.

Published
1989
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38. Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders

Author

Michael A. Levy, Raissa Relator, Haley McConkey, Erinija Pranckeviciene, Jennifer Kerkhof, Mouna Barat‐Houari, Sara Bargiacchi, Elisa Biamino, María Palomares Bralo, Gerarda Cappuccio, Andrea Ciolfi, Angus Clarke, Barbara R. DuPont, Mariet W. Elting, Laurence Faivre, Timothy Fee, Marco Ferilli, Robin S. Fletcher, Florian Cherick, Aidin Foroutan, Michael J. Friez, Cristina Gervasini, Sadegheh Haghshenas, Benjamin A. Hilton, Zandra Jenkins, Simranpreet Kaur, Suzanne Lewis, Raymond J. Louie, Silvia Maitz, Donatella Milani, Angela T. Morgan, Renske Oegema, Elsebet Østergaard, Nathalie R. Pallares, Maria Piccione, Astrid S. Plomp, Cathryn Poulton, Jack Reilly, Rocio Rius, Stephen Robertson, Kathleen Rooney, Justine Rousseau, Gijs W. E. Santen, Fernando Santos‐Simarro, Josephine Schijns, Gabriella M. Squeo, Miya St John, Christel Thauvin‐Robinet, Giovanna Traficante, Pleuntje J. van der Sluijs, Samantha A. Vergano, Niels Vos, Kellie K. Walden, Dimitar Azmanov, Tugce B. Balci, Siddharth Banka, Jozef Gecz, Peter Henneman, Jennifer A. Lee, Marcel M. A. M. Mannens, Tony Roscioli, Victoria Siu, David J. Amor, Gareth Baynam, Eric G. Bend, Kym Boycott, Nicola Brunetti‐Pierri, Philippe M. Campeau, Dominique Campion, John Christodoulou, David Dyment, Natacha Esber, Jill A. Fahrner, Mark D. Fleming, David Genevieve, Delphine Heron, Thomas Husson, Kristin D. Kernohan, Alisdair McNeill, Leonie A. Menke, Giuseppe Merla, Paolo Prontera, Cheryl Rockman‐Greenberg, Charles Schwartz, Steven A. Skinner, Roger E. Stevenson, Marie Vincent, Antonio Vitobello, Marco Tartaglia, Marielle Alders, Matthew L. Tedder, Bekim Sadikovic, Human genetics, Amsterdam Reproduction & Development (AR&D), Pediatrics, Levy M.A., Relator R., McConkey H., Pranckeviciene E., Kerkhof J., Barat-Houari M., Bargiacchi S., Biamino E., Palomares Bralo M., Cappuccio G., Ciolfi A., Clarke A., DuPont B.R., Elting M.W., Faivre L., Fee T., Ferilli M., Fletcher R.S., Cherick F., Foroutan A., Friez M.J., Gervasini C., Haghshenas S., Hilton B.A., Jenkins Z., Kaur S., Lewis S., Louie R.J., Maitz S., Milani D., Morgan A.T., Oegema R., Ostergaard E., Pallares N.R., Piccione M., Plomp A.S., Poulton C., Reilly J., Rius R., Robertson S., Rooney K., Rousseau J., Santen G.W.E., Santos-Simarro F., Schijns J., Squeo G.M., John M.S., Thauvin-Robinet C., Traficante G., van der Sluijs P.J., Vergano S.A., Vos N., Walden K.K., Azmanov D., Balci T.B., Banka S., Gecz J., Henneman P., Lee J.A., Mannens M.M.A.M., Roscioli T., Siu V., Amor D.J., Baynam G., Bend E.G., Boycott K., Brunetti-Pierri N., Campeau P.M., Campion D., Christodoulou J., Dyment D., Esber N., Fahrner J.A., Fleming M.D., Genevieve D., Heron D., Husson T., Kernohan K.D., McNeill A., Menke L.A., Merla G., Prontera P., Rockman-Greenberg C., Schwartz C., Skinner S.A., Stevenson R.E., Vincent M., Vitobello A., Tartaglia M., Alders M., Tedder M.L., Sadikovic B., Levy, Michael A, Relator, Raissa, Mcconkey, Haley, Pranckeviciene, Erinija, Kerkhof, Jennifer, Barat-Houari, Mouna, Bargiacchi, Sara, Biamino, Elisa, Bralo, María Palomare, Cappuccio, Gerarda, Ciolfi, Andrea, Clarke, Angu, Dupont, Barbara R, Elting, Mariet W, Faivre, Laurence, Fee, Timothy, Ferilli, Marco, Fletcher, Robin S, Cherick, Florian, Foroutan, Aidin, Friez, Michael J, Gervasini, Cristina, Haghshenas, Sadegheh, Hilton, Benjamin A, Jenkins, Zandra, Kaur, Simranpreet, Lewis, Suzanne, Louie, Raymond J, Maitz, Silvia, Milani, Donatella, Morgan, Angela T, Oegema, Renske, Østergaard, Elsebet, Pallares, Nathalie Ruiz, Piccione, Maria, Plomp, Astrid S, Poulton, Cathryn, Reilly, Jack, Rius, Rocio, Robertson, Stephen, Rooney, Kathleen, Rousseau, Justine, Santen, Gijs W E, Santos-Simarro, Fernando, Schijns, Josephine, Squeo, Gabriella Maria, John, Miya St, Thauvin-Robinet, Christel, Traficante, Giovanna, van der Sluijs, Pleuntje J, Vergano, Samantha A, Vos, Niel, Walden, Kellie K, Azmanov, Dimitar, Balci, Tugce B, Banka, Siddharth, Gecz, Jozef, Henneman, Peter, Lee, Jennifer A, Mannens, Marcel M A M, Roscioli, Tony, Siu, Victoria, Amor, David J, Baynam, Gareth, Bend, Eric G, Boycott, Kym, Brunetti-Pierri, Nicola, Campeau, Philippe M, Campion, Dominique, Christodoulou, John, Dyment, David, Esber, Natacha, Fahrner, Jill A, Fleming, Mark D, Genevieve, David, Heron, Delphine, Husson, Thoma, Kernohan, Kristin D, Mcneill, Alisdair, Menke, Leonie A, Merla, Giuseppe, Prontera, Paolo, Rockman-Greenberg, Cheryl, Schwartz, Charle, Skinner, Steven A, Stevenson, Roger E, Vincent, Marie, Vitobello, Antonio, Tartaglia, Marco, Alders, Marielle, Tedder, Matthew L, Sadikovic, Bekim, Human Genetics, General Paediatrics, Graduate School, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ARD - Amsterdam Reproduction and Development, ANS - Cellular & Molecular Mechanisms, ANS - Complex Trait Genetics, and ACS - Pulmonary hypertension & thrombosis

Subjects
DNA methylation, clinical diagnostics, Syndrome, DNA methylation, clinical diagnostics, episignatures, neurodevelopmental syndromes, neurodevelopmental syndromes, Epigenesis, Genetic, Neurodevelopmental Disorders, Genetics, Humans, CpG Islands, DNA, Intergenic, episignatures, Episignature, Genetics (clinical)
Abstract

An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes which can share significant overlap amongst different conditions. In this study we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders. This article is protected by copyright. All rights reserved.

Published
2022

39. The search for pyruvate kinase-R activators; from a HTS screening hit via an impurity to the discovery of a lead series.

Author

Yu C, Setti LQ, Nilar S, Li Z, Yu M, Partridge J, Choy R, Siu V, Strutt S, Zang R, Rademacher P, Bahmanjah S, Myslovaty Y, and Zancanella M

Subjects
Humans, Drug Discovery, Structure-Activity Relationship, Urea chemistry, Urea pharmacology, Enzyme Activators pharmacology, Enzyme Activators chemistry, Enzyme Activators chemical synthesis, Molecular Structure, Animals, Pyruvate Kinase metabolism, Pyruvate Kinase antagonists & inhibitors, High-Throughput Screening Assays
Abstract

Pyruvate kinase (PK) is an essential component of cellular metabolism, converting ADP and phosphoenolpyruvate (PEP) to pyruvate in the final step of glycolysis. Of the four unique isoforms of pyruvate kinase, R (PKR) is expressed exclusively in red blood cells and is a tetrameric enzyme that depends on fructose-1,6-bisphosphate (FBP) for activation. PKR deficiency leads to hemolysis of red blood cells resulting in anemia. Activation of PKR in both sickle cell disease and beta-thalassemia patients could lead to improved red blood cell fitness and survival. The discovery of a novel series of substituted urea PKR activators, via the serendipitous identification and diligent characterization of a minor impurity in an High Throughput Screening (HTS) hit will be discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Published
2024
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40. First In-Human Use of a Novel Perfusion Balloon Catheter in the Management of Coronary Perforation.

Author

Siu V, Parfrey S, Li C, Graham JJ, Wijeysundera HC, Bagai A, Pang J, Kalra S, Džavík V, Bhindi R, Overgaard CB, and Vijayaraghavan R

Subjects
Humans, Male, Angioplasty, Balloon, Coronary methods, Angioplasty, Balloon, Coronary instrumentation, Heart Injuries etiology, Heart Injuries diagnosis, Heart Injuries therapy, Equipment Design, Cardiac Catheters, Middle Aged, Coronary Vessels diagnostic imaging, Coronary Vessels injuries, Coronary Angiography methods
Published
2024
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41. Vitamin D, Folate, Vitamin B 12 , and Iron Status in Pregnant/Postpartum Old Order Anabaptist Women in Southwestern Ontario.

Author

Randall Simpson J.A. RD, PhD, Miller N. RD, MScFN, Hartwig T. RD, BASc, Leach J. RN, BSN, Purdy M. RN, MN, NP-PHC, Roth E. RMW, BHSc, Mok Siu V. MD, Soulliere C. RMW, MHSc, Tam J. RN, BScN, and Watt A. RD, MSc

Abstract

Purpose: To assess vitamin D, folate, vitamin B 12 , and iron status in Old Order Anabaptist (OOA) pregnant/postpartum women. Methods: Blood was analyzed for plasma 25 hydroxy vitamin D (25(OH)D), red blood cell (RBC) folate, serum vitamin B 12 , and iron status indicators. Dietary intakes (food and supplements) from 3-day estimated records were compared to Dietary Reference Intakes and Canada's Food Guide (2007). Results: Fifty women participated in this descriptive cross-sectional study. Concentrations of 25(OH)D were low (<50 nmol/L for 20% and < 75 nmol/L for 63%); 42% had total vitamin D intakes < estimated average requirement (EAR). All women had RBC folate above the 1360 mmol/L cut-off. Nineteen percent had folate intakes upper limit. One woman had low serum vitamin B 12 (<148 pmol/L); serum vitamin B 12 was high (>652 pmol/L) for 24%. None had vitamin B 12 intakes 12 . These findings provide guidance to ensure appropriate dietary and supplement intakes in this potentially vulnerable and rarely studied population.

Published
2024
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42. Spontaneous celiac artery aneurysms in 13-year-old and 10-year-old brothers with PLOD1 -related kyphoscoliotic Ehlers-Danlos syndrome.

Author

Bhandari A, Siu V, and Duncan AA

Abstract

PLOD1 -related kyphoscoliotic Ehlers-Danlos syndrome is a rare, autosomal recessive connective tissue disorder characterized by congenital hypotonia, early-onset, progressive kyphoscoliosis, and generalized joint hypermobility. PLOD1 -kyphoscoliotic Ehlers-Danlos syndrome is also associated with heightened vascular fragility, resulting in an elevated susceptibility to recurrent vascular complications such as arterial aneurysms, dissection, and spontaneous arterial rupture. We report the cases of two affected brothers: a 13-year-old boy presenting with spontaneous rupture of a celiac artery aneurysm and a 10-year-old boy presenting with a rapidly enlarging celiac artery aneurysm requiring urgent repair., Competing Interests: None., (© 2024 The Authors.)

Published
2024
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43. Evaluation of guideline implementation for dispensing driving-impairing medicines by National Pharmacy Organizations.

Author

de Gier H, Bogaard L, Siu VF, Todorov B, Pinto GS, Viegas R, Aldarij N, van Dijk L, and Borgsteede SD

Abstract

Background: In 2004, the International Pharmaceutical Federation (FIP) adopted a Statement of Professional Standard on the supply of medicines affecting driving performance, transformed to FIP guidelines in 2014. In 2011, the final report from the European initiative on Driving Under the Influence of Drugs, Alcohol and Medicines (DRUID) was published. Both documents provided recommendations for improving dispensing guidelines for driving-impairing medicines for patients who use psychoactive medicines., Objective: This study investigated the extent that European professional organizations of pharmacists (POPs) implemented existing guidelines and DRUID results., Methods: An online questionnaire survey was conducted in April-May 2022. Questionnaires were sent by e-mail to POPs in 46 European countries. The questionnaire addressed the following topics: awareness of FIP guidelines and DRUID outcomes (a), development of dispensing guidelines (b), target groups for information materials (c), evaluations of dispensing practices (d), examples of projects on medicines affecting driving fitness (e), development of ICT (Information and Communication Technology) -support (f), collaboration with organizations of physicians (g), and patients (h). The data were analyzed by indicating implementation initiatives in different countries. Open-ended questions were assessed qualitatively., Results: POPs in 23 European countries responded to the invitation (response rate: 50%). Guidelines for improving dispensing practices were available in 5 countries targeted at professionals, patients, and the general population. Patient and physician organizations were involved in 4 and 3 countries, respectively. Implementation was supported by computerized dispensing systems (5 countries) and public campaigns (5 countries)., Conclusions: Twenty years after the introduction of FIP guidelines and ten years after the DRUID outcomes, only 5 European POPs have implemented this knowledge. Different activities were performed to support implementation, resulting in examples of successful use of recommendations for driving-impairing medicines in pharmacy practice. Implementation needs further attention. The successful practices that have been developed are an example for dissemination to other countries., Competing Interests: None., (© 2024 The Authors.)

Published
2024
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44. Evaluation and management of drug-eluting stent in-stent restenosis.

Author

Parfrey S, Siu V, Graham JJ, Vijayaraghavan R, Li C, Pang J, Kalra S, Džavík V, Wijeysundera HC, and Bagai A

Subjects
Humans, Treatment Outcome, Coronary Angiography, Prosthesis Design, Drug-Eluting Stents adverse effects, Coronary Restenosis etiology, Coronary Restenosis therapy, Angioplasty, Balloon, Coronary adverse effects, Percutaneous Coronary Intervention adverse effects
Abstract

Purpose of Review: In-stent restenosis (ISR) is the most common cause of stent failure. Although the rate of ISR is significantly lower with contemporary drug-eluting stents (DES), it remains a challenging clinical entity to treat., Recent Findings: In this review, we focus on a practical approach to management of DES ISR with intravascular imaging at its core, as supported by several recently published articles. This facilitates assessment of the underlying mechanism(s) essential to the successful treatment of ISR allowing for a tailored selection of treatment modalities., Summary: The successful treatment of DES ISR requires identification of the causative mechanism(s). Individualized treatment may include high-pressure balloon angioplasty alone, cutting or scoring balloons, intravascular lithotripsy, atheroablative therapies and a selection of either repeat DES implantation or drug-coated balloon treatment., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Published
2023
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45. Focused Jurisdictional Scan of Glomerulonephritis Medication Access in Canada: A Program Report.

Author

Naipaul R, Marques C, Ng J, Barbour S, Lo C, Hildebrand AM, Siu V, Prasad B, Laurin LP, Wazny LD, Armstrong S, Tran J, Sheffield M, Jauhal A, and Hladunewich MA

Abstract

Purpose of Program: Glomerulonephritis (GN) is a group of rare kidney diseases that is increasingly being managed with higher cost immunosuppressive (IS) agents in Canada. Ontario Health's Ontario Renal Network (ORN) oversees the management and delivery of GN services in the province. Stakeholder surveys previously conducted by ORN identified that both clinicians and patients do not perceive access to GN medications as comprehensive or timely. The program conducted a focused jurisdictional scan among 7 provinces to inform ORN initiatives to improve access to GN medications. Specifically, the program examined clinician experience with GN access, public drug coverage criteria, and timelines for public coverage for select IS agents (ie, tacrolimus, cyclosporine, mycophenolate mofetil [MMF], mycophenolate sodium, rituximab, and eculizumab) used to manage GN in adults who live in Canada., Methods: For the selected IS agents, a focused jurisdictional scan on medication access was conducted by ORN in 2018 and updated in July 2022. Information was obtained by searching the gray literature and/or credible online sources for public funding policies and eligibility criteria. Findings were supplemented by personal communications with provincial drug programs and consulting GN clinical experts from 7 provinces (ie, Alberta, British Columbia, Saskatchewan, Manitoba, Ontario, Nova Scotia, and Quebec)., Key Findings: Clinicians from different provinces prescribe IS agents similarly for GN indications, despite distinctions in public drug funding policies. While patients can obtain public funding for many IS agents, for GN, most provinces rely on case-by-case review processes. In addition, provinces can vary in their funding criteria and which IS agents are listed on the public formulary. For IS agents that require prior authorization or case-by-case review, timelines vary by province with decisions taking a few days to weeks. British Columbia, with a GN-specific drug formulary, had the most integrated and efficient system for patients and prescribers., Limitations: This scan primarily relied on publicly available information for drug coverage criteria and clinician experience with access in their province. Since this scan was conducted, public drug coverage criteria and/or application processes may have changed., Implications: While patients in most provinces have similar needs and nephrologists similar prescribing patterns, gaps still exist for publicly funded GN medications. Interprovincial differences in the drugs funded, funding criteria, and application process may affect timely and equitable access to GN medications across Canada. Given the rarity of GN, a pan-Canadian funding approach may be warranted to improve the current state., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Published
2023
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46. Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.

Author

Kaur M, Blair J, Devkota B, Fortunato S, Clark D, Lawrence A, Kim J, Do W, Semeo B, Katz O, Mehta D, Yamamoto N, Schindler E, Al Rawi Z, Wallace N, Wilde JJ, McCallum J, Liu J, Xu D, Jackson M, Rentas S, Tayoun AA, Zhe Z, Abdul-Rahman O, Allen B, Angula MA, Anyane-Yeboa K, Argente J, Arn PH, Armstrong L, Basel-Salmon L, Baynam G, Bird LM, Bruegger D, Ch'ng GS, Chitayat D, Clark R, Cox GF, Dave U, DeBaere E, Field M, Graham JM Jr, Gripp KW, Greenstein R, Gupta N, Heidenreich R, Hoffman J, Hopkin RJ, Jones KL, Jones MC, Kariminejad A, Kogan J, Lace B, Leroy J, Lynch SA, McDonald M, Meagher K, Mendelsohn N, Micule I, Moeschler J, Nampoothiri S, Ohashi K, Powell CM, Ramanathan S, Raskin S, Roeder E, Rio M, Rope AF, Sangha K, Scheuerle AE, Schneider A, Shalev S, Siu V, Smith R, Stevens C, Tkemaladze T, Toimie J, Toriello H, Turner A, Wheeler PG, White SM, Young T, Loomes KM, Pipan M, Harrington AT, Zackai E, Rajagopalan R, Conlin L, Deardorff MA, McEldrew D, Pie J, Ramos F, Musio A, Kline AD, Izumi K, Raible SE, and Krantz ID

Subjects
Humans, Transcription Factors genetics, Cell Cycle Proteins genetics, Phenotype, Mutation, Genomics, Genetic Association Studies, Transcriptional Elongation Factors genetics, Histone Deacetylases genetics, Repressor Proteins genetics, Nuclear Proteins genetics, De Lange Syndrome diagnosis, De Lange Syndrome genetics, De Lange Syndrome pathology
Abstract

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population., (© 2023 Wiley Periodicals LLC.)

Published
2023
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47. GBT021601 improves red blood cell health and the pathophysiology of sickle cell disease in a murine model.

Author

Dufu K, Alt C, Strutt S, Partridge J, Tang T, Siu V, Liao-Zou H, Rademacher P, Williams AT, Muller CR, Geng X, Pochron MP, Dang AN, Cabrales P, Li Z, Oksenberg D, and Cathers BE

Subjects
Humans, Animals, Mice, Disease Models, Animal, Oxygen, Erythrocytes, Hemoglobins, Hemoglobin, Sickle, Hemolysis, Anemia, Sickle Cell drug therapy
Abstract

The pathophysiologic mechanism of sickle cell disease (SCD) involves polymerization of deoxygenated haemoglobin S (HbS), leading to red blood cell (RBC) sickling, decreased RBC deformability, microvascular obstruction, haemolysis, anaemia and downstream clinical complications. Pharmacological increase in the concentration of oxygenated HbS in RBCs has been shown to be a novel approach to inhibit HbS polymerization and reduce RBC sickling and haemolysis. We report that GBT021601, a small molecule that increases HbS-oxygen affinity, inhibits HbS polymerization and prevents RBC sickling in blood from patients with SCD. Moreover, in a murine model of SCD (SS mice), GBT021601 reduces RBC sickling, improves RBC deformability, prolongs RBC half-life and restores haemoglobin levels to the normal range, while improving oxygen delivery and increasing tolerance to severe hypoxia. Notably, oral dosing of GBT021601 in animals results in higher levels of Hb occupancy than voxelotor and suggests the feasibility of once-daily dosing in humans. In summary, GBT021601 improves RBC health and normalizes haemoglobin in SS mice, suggesting that it may be useful for the treatment of SCD. These data are being used as a foundation for clinical research and development of GBT021601., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Published
2023
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49. Recent Advances in Clinical Applications of Imaging in Retinal Diseases.

Author

Szeto SK, Hui VWK, Siu V, Mohamed S, Chan CKM, Cheung CYL, Hsieh YT, Tan CS, Chhablani J, Lai TYY, and Ng DS

Subjects
Humans, Fluorescein Angiography methods, Retina, Tomography, Optical Coherence methods, Diabetic Retinopathy, Macular Edema diagnostic imaging, Retinal Diseases diagnosis, Central Serous Chorioretinopathy diagnosis
Abstract

Many diseases that cause visual impairment, as well as systemic conditions, manifest in the posterior segment of the eye. With the advent of high-speed, high-resolution, reliable, and noninvasive imaging techniques, ophthalmologists are becoming more dependent on ocular imaging for disease diagnosis, classification, and management in clinical practice. There are rapid advances on the indications of multimodal retinal imaging techniques, including the application of ultra-widefield fundus angiography, fundus autofluorescence, optical coherence tomography, as well as optical coherence tomography angiography. This review summarizes and highlights the clinical applications, latest indications, and interpretations of multimodal imaging in age-related macular degeneration, polypoidal choroidal vasculopathy, diabetic macular edema, central serous chorioretinopathy, diabetic retinopathy, retinal vein occlusion, and uveitis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.)

Published
2023
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50. Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders.

Author

Levy MA, Relator R, McConkey H, Pranckeviciene E, Kerkhof J, Barat-Houari M, Bargiacchi S, Biamino E, Palomares Bralo M, Cappuccio G, Ciolfi A, Clarke A, DuPont BR, Elting MW, Faivre L, Fee T, Ferilli M, Fletcher RS, Cherick F, Foroutan A, Friez MJ, Gervasini C, Haghshenas S, Hilton BA, Jenkins Z, Kaur S, Lewis S, Louie RJ, Maitz S, Milani D, Morgan AT, Oegema R, Østergaard E, Pallares NR, Piccione M, Plomp AS, Poulton C, Reilly J, Rius R, Robertson S, Rooney K, Rousseau J, Santen GWE, Santos-Simarro F, Schijns J, Squeo GM, John MS, Thauvin-Robinet C, Traficante G, van der Sluijs PJ, Vergano SA, Vos N, Walden KK, Azmanov D, Balci TB, Banka S, Gecz J, Henneman P, Lee JA, Mannens MMAM, Roscioli T, Siu V, Amor DJ, Baynam G, Bend EG, Boycott K, Brunetti-Pierri N, Campeau PM, Campion D, Christodoulou J, Dyment D, Esber N, Fahrner JA, Fleming MD, Genevieve D, Heron D, Husson T, Kernohan KD, McNeill A, Menke LA, Merla G, Prontera P, Rockman-Greenberg C, Schwartz C, Skinner SA, Stevenson RE, Vincent M, Vitobello A, Tartaglia M, Alders M, Tedder ML, and Sadikovic B

Subjects
CpG Islands genetics, DNA, Intergenic, Epigenesis, Genetic, Humans, Syndrome, DNA Methylation genetics, Neurodevelopmental Disorders diagnosis, Neurodevelopmental Disorders genetics
Abstract

An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive, and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes, which can share significant overlap among different conditions. In this study, we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders., (© 2022 Wiley Periodicals LLC.)

Published
2022
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