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timothy ley

Maria C Trissal, Terrence N Wong, Juo-Chin Yao, Rahul Ramaswamy, Iris Kuo, Jack D Baty, Yaping Sun, Gloria Jih, Nishi Parikh, Melissa M Berrien-Elliott, Todd A Fehniger, Timothy J Ley, Ivan Maillard, Pavan Reddy, Daniel C Link
Point mutations in the seed sequence of miR-142-3p are present in a subset of AML and in several subtypes of B cell lymphoma. Here we show that mutations associated with AML result both in loss of miR-142-3p function and in decreased miR-142-5p expression. Mir142 loss altered the hematopoietic differentiation of multipotent hematopoietic progenitors, enhancing their myeloid potential while suppressing their lymphoid potential. During hematopoietic maturation, loss of Mir142 increased Ash1l protein expression and consequently resulted in the aberrant maintenance of Hoxa gene expression in myeloid-committed hematopoietic progenitors...
May 3, 2018: Cancer Research
Timothy J Zerk, Peter W Moore, Joshua S Harbort, Sharon Chow, Lindsay Byrne, George A Koutsantonis, Jeffrey R Harmer, Manuel Martínez, Craig M Williams, Paul V Bernhardt
The Ley-Griffith reaction is utilized extensively in the selective oxidation of alcohols to aldehydes or ketones. The central catalyst is commercially available tetra- n -propylammonium perruthenate (TPAP, n -Pr4 N[RuO4 ]) which is used in combination with the co-oxidant N -methylmorpholine N -oxide (NMO). Although this reaction has been employed for more than 30 years, the mechanism remains unknown. Herein we report a comprehensive study of the oxidation of diphenylmethanol using the Ley-Griffith reagents to show that the rate determining step involves a single alcohol molecule, which is oxidised by a single perruthenate anion; NMO does not appear in rate law...
December 1, 2017: Chemical Science
Meagan A Jacoby, Eric J Duncavage, Gue Su Chang, Christopher A Miller, Jin Shao, Kevin Elliott, Joshua Robinson, Robert S Fulton, Catrina C Fronick, Michelle O'Laughlin, Sharon E Heath, Iskra Pusic, John S Welch, Daniel C Link, John F DiPersio, Peter Westervelt, Timothy J Ley, Timothy A Graubert, Matthew J Walter
Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment for myelodysplastic syndromes (MDS), but patients who relapse after transplant have poor outcomes. In order to understand the contribution of tumor clonal evolution to disease progression,we applied exome and error-corrected targeted sequencing coupled with copy number analysis to comprehensively define changes in the clonal architecture of MDS in response to therapy using 51 serially acquired tumor samples from 9 patients who progressed after an alloHCT...
March 8, 2018: JCI Insight
Terrence N Wong, Christopher A Miller, Matthew R M Jotte, Nusayba Bagegni, Jack D Baty, Amy P Schmidt, Amanda F Cashen, Eric J Duncavage, Nichole M Helton, Mark Fiala, Robert S Fulton, Sharon E Heath, Megan Janke, Kierstin Luber, Peter Westervelt, Ravi Vij, John F DiPersio, John S Welch, Timothy A Graubert, Matthew J Walter, Timothy J Ley, Daniel C Link
Hematopoietic clones harboring specific mutations may expand over time. However, it remains unclear how different cellular stressors influence this expansion. Here we characterize clonal hematopoiesis after two different cellular stressors: cytotoxic therapy and hematopoietic transplantation. Cytotoxic therapy results in the expansion of clones carrying mutations in DNA damage response genes, including TP53 and PPM1D. Analyses of sorted populations show that these clones are typically multilineage and myeloid-biased...
January 31, 2018: Nature Communications
Wayne A Warner, David H Spencer, Maria Trissal, Brian S White, Nichole Helton, Timothy J Ley, Daniel C Link
Small nucleolar RNAs (snoRNAs) are noncoding RNAs that contribute to ribosome biogenesis and RNA splicing by modifying ribosomal RNA and spliceosome RNAs, respectively. We optimized a next-generation sequencing approach and a custom analysis pipeline to identify and quantify expression of snoRNAs in acute myeloid leukemia (AML) and normal hematopoietic cell populations. We show that snoRNAs are expressed in a lineage- and development-specific fashion during hematopoiesis. The most striking examples involve snoRNAs located in 2 imprinted loci, which are highly expressed in hematopoietic progenitors and downregulated during myeloid differentiation...
January 23, 2018: Blood Advances
Christopher B Cole, David A Russler-Germain, Shamika Ketkar, Angela M Verdoni, Amanda M Smith, Celia V Bangert, Nichole M Helton, Mindy Guo, Jeffery M Klco, Shelly O'Laughlin, Catrina Fronick, Robert Fulton, Gue Su Chang, Allegra A Petti, Christopher A Miller, Timothy J Ley
The gene that encodes de novo DNA methyltransferase 3A (DNMT3A) is frequently mutated in acute myeloid leukemia genomes. Point mutations at position R882 have been shown to cause a dominant negative loss of DNMT3A methylation activity, but 15% of DNMT3A mutations are predicted to produce truncated proteins that could either have dominant negative activities or cause loss of function and haploinsufficiency. Here, we demonstrate that 3 of these mutants produce truncated, inactive proteins that do not dimerize with WT DNMT3A, strongly supporting the haploinsufficiency hypothesis...
October 2, 2017: Journal of Clinical Investigation
Jin Zhang, Malachi Griffith, Christopher A Miller, Obi L Griffith, David H Spencer, Jason R Walker, Vincent Magrini, Sean D McGrath, Amy Ly, Nichole M Helton, Maria Trissal, Daniel C Link, Ha X Dang, David E Larson, Shashikant Kulkarni, Matthew G Cordes, Catrina C Fronick, Robert S Fulton, Jeffery M Klco, Elaine R Mardis, Timothy J Ley, Richard K Wilson, Christopher A Maher
To detect diverse and novel RNA species comprehensively, we compared deep small RNA and RNA sequencing (RNA-seq) methods applied to a primary acute myeloid leukemia (AML) sample. We were able to discover previously unannotated small RNAs using deep sequencing of a library method using broader insert size selection. We analyzed the long noncoding RNA (lncRNA) landscape in AML by comparing deep sequencing from multiple RNA-seq library construction methods for the sample that we studied and then integrating RNA-seq data from 179 AML cases...
November 2017: Experimental Hematology
Geary W Olsen, David C Mair, Cleston C Lange, Laura M Harrington, Timothy R Church, Corinne L Goldberg, Ross M Herron, Hank Hanna, John B Nobiletti, Jorge A Rios, William K Reagen, Carol A Ley
In 2015, thirteen per- and polyfluoroalkyl substances (PFAS), including perfluorohexanesulfonate (PFHxS), perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), and perfluorodecanoate (PFDA) were analyzed in human plasma that were collected from a total of 616 American Red Cross male and female blood donors (ages 20-69) at 6 regional blood collection centers. Plasma samples were analyzed using a validated solvent precipitation-isotope dilution direction-liquid chromatography tandem mass spectrometry method...
August 2017: Environmental Research
Sara C Fallon, Jacob C Langer, Shawn D St Peter, KuoJen Tsao, Caroline M Kellagher, Dave R Lal, Jill S Whitehouse, Diana L Diesen, Michael D Rollins, Elizabeth Pontarelli, Marcus M Malek, Corey W Iqbal, Jeffrey S Upperman, Charles M Leys, Mark L Wulkan, Sarah J Hill, Martin L Blakely, Timothy D Kane, David E Wesson
OBJECTIVE: To perform a multicenter review of outcomes in patients with H-type tracheoesophageal fistula (TEF) in order to better understand the incidence and causes of post-operative complications. BACKGROUND: H-type TEF without esophageal atresia (EA) is a rare anomaly with a fundamentally different management algorithm than the more common types of EA/TEF. Outcomes after surgical treatment of H-type TEF are largely unknown, but many authoritative textbooks describe a high incidence of respiratory complications...
November 2017: Journal of Pediatric Surgery
David H Spencer, David A Russler-Germain, Shamika Ketkar, Nichole M Helton, Tamara L Lamprecht, Robert S Fulton, Catrina C Fronick, Michelle O'Laughlin, Sharon E Heath, Marwan Shinawi, Peter Westervelt, Jacqueline E Payton, Lukas D Wartman, John S Welch, Richard K Wilson, Matthew J Walter, Daniel C Link, John F DiPersio, Timothy J Ley
DNMT3A mutations occur in ∼25% of acute myeloid leukemia (AML) patients. The most common mutation, DNMT3AR882H , has dominant negative activity that reduces DNA methylation activity by ∼80% in vitro. To understand the contribution of DNMT3A-dependent methylation to leukemogenesis, we performed whole-genome bisulfite sequencing of primary leukemic and non-leukemic cells in patients with or without DNMT3AR882 mutations. Non-leukemic hematopoietic cells with DNMT3AR882H displayed focal methylation loss, suggesting that hypomethylation antedates AML...
February 23, 2017: Cell
Cara Lunn Shirai, Brian S White, Manorama Tripathi, Roberto Tapia, James N Ley, Matthew Ndonwi, Sanghyun Kim, Jin Shao, Alexa Carver, Borja Saez, Robert S Fulton, Catrina Fronick, Michelle O'Laughlin, Chandraiah Lagisetti, Thomas R Webb, Timothy A Graubert, Matthew J Walter
Somatic mutations in spliceosome genes are detectable in ∼50% of patients with myelodysplastic syndromes (MDS). We hypothesize that cells harbouring spliceosome gene mutations have increased sensitivity to pharmacological perturbation of the spliceosome. We focus on mutant U2AF1 and utilize sudemycin compounds that modulate pre-mRNA splicing. We find that haematopoietic cells expressing mutant U2AF1(S34F), including primary patient cells, have an increased sensitivity to in vitro sudemycin treatment relative to controls...
January 9, 2017: Nature Communications
John S Welch, Allegra A Petti, Christopher A Miller, Catrina C Fronick, Michelle O'Laughlin, Robert S Fulton, Richard K Wilson, Jack D Baty, Eric J Duncavage, Bevan Tandon, Yi-Shan Lee, Lukas D Wartman, Geoffrey L Uy, Armin Ghobadi, Michael H Tomasson, Iskra Pusic, Rizwan Romee, Todd A Fehniger, Keith E Stockerl-Goldstein, Ravi Vij, Stephen T Oh, Camille N Abboud, Amanda F Cashen, Mark A Schroeder, Meagan A Jacoby, Sharon E Heath, Kierstin Luber, Megan R Janke, Andrew Hantel, Niloufer Khan, Madina J Sukhanova, Randall W Knoebel, Wendy Stock, Timothy A Graubert, Matthew J Walter, Peter Westervelt, Daniel C Link, John F DiPersio, Timothy J Ley
BACKGROUND: The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. METHODS: We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles...
November 24, 2016: New England Journal of Medicine
Christopher A Miller, Joshua McMichael, Ha X Dang, Christopher A Maher, Li Ding, Timothy J Ley, Elaine R Mardis, Richard K Wilson
BACKGROUND: Massively-parallel sequencing at depth is now enabling tumor heterogeneity and evolution to be characterized in unprecedented detail. Tracking these changes in clonal architecture often provides insight into therapeutic response and resistance. In complex cases involving multiple timepoints, standard visualizations, such as scatterplots, can be difficult to interpret. Current data visualization methods are also typically manual and laborious, and often only approximate subclonal fractions...
November 7, 2016: BMC Genomics
Oleksandr Holovachov, Sven Boström, Irma Tandingan De Ley, Rory J Mc Donnell, Salomon Alvarado, Timothy D Paine, Paul De Ley
A new species of Alloionema Schneider, 1859, A. similis n. sp., and the known species A. appendiculatum Schneider, 1859 were isolated from cadavers of invasive slugs in California. Both species are described based on morphology, morphometrics and molecular data. Alloionema similis n. sp. is morphologically very similar to A. appendiculatum but can be distinguished by a more posterior position of the excretory pore in the Kleinform females and longer tail in the Kleinform males. Substantial differences between the two species are, however, found in both 18S and 28S rDNA sequences...
November 2016: Systematic Parasitology
Zhi Su, Deborah Widomski, Ji Ma, Marian Namovic, Arthur Nikkel, Laura Leys, Lauren Olson, Katherine Salte, Diana Donnelly-Roberts, Timothy Esbenshade, Steve McGaraughty
BACKGROUND: Obese ZSF-1 rats display many features of human type II diabetes including nephropathy (DN). The study aimed to further understand the relevance of this model to DN, for which glomerular filtration rate (GFR), renal fibrosis and several urinary/tissue biomarkers was followed over 24 weeks in ZSF-1 rats. METHODS: Intact/sham or uninephrectomized male and female ZSF-1 rats were studied. GFR was measured by transdermal clearance of fluorescein isothiocyanate-sinistrin...
2016: American Journal of Nephrology
Timothy J Zerk, Peter W Moore, Craig M Williams, Paul V Bernhardt
The redox and ligand exchange reactions of oxido-ruthenium complexes are central to the function of the Sharpless and Griffith-Ley one-step alcohol oxidation protocols. However, their mechanisms have not been elucidated. Cyclic voltammetry and UV-vis spectroelectrochemical analysis of [RuO4](-) has provided new insight into the key ruthenium oxidation states involved in catalysis. Furthermore, the oxidation states sensitive to the presence of the N-oxide co-oxidant N-methylmorpholine N-oxide (NMO), and its role in catalysis, have been determined...
August 11, 2016: Chemical Communications: Chem Comm
Malachi Griffith, Obi L Griffith, Kilannin Krysiak, Zachary L Skidmore, Matthew J Christopher, Jeffery M Klco, Avinash Ramu, Tamara L Lamprecht, Alex H Wagner, Katie M Campbell, Robert Lesurf, Jasreet Hundal, Jin Zhang, Nicholas C Spies, Benjamin J Ainscough, David E Larson, Sharon E Heath, Catrina Fronick, Shelly O'Laughlin, Robert S Fulton, Vincent Magrini, Sean McGrath, Scott M Smith, Christopher A Miller, Christopher A Maher, Jacqueline E Payton, Jason R Walker, James M Eldred, Matthew J Walter, Daniel C Link, Timothy A Graubert, Peter Westervelt, Shashikant Kulkarni, John F DiPersio, Elaine R Mardis, Richard K Wilson, Timothy J Ley
The genomic events responsible for the pathogenesis of relapsed adult B-lymphoblastic leukemia (B-ALL) are not yet clear. We performed integrative analysis of whole-genome, whole-exome, custom capture, whole-transcriptome (RNA-seq), and locus-specific genomic assays across nine time points from a patient with primary de novo B-ALL. Comprehensive genome and transcriptome characterization revealed a dramatic tumor evolution during progression, yielding a tumor with complex clonal architecture at second relapse...
July 2016: Experimental Hematology
Charles Lu, Mingchao Xie, Michael C Wendl, Jiayin Wang, Michael D McLellan, Mark D M Leiserson, Kuan-Lin Huang, Matthew A Wyczalkowski, Reyka Jayasinghe, Tapahsama Banerjee, Jie Ning, Piyush Tripathi, Qunyuan Zhang, Beifang Niu, Kai Ye, Heather K Schmidt, Robert S Fulton, Joshua F McMichael, Prag Batra, Cyriac Kandoth, Maheetha Bharadwaj, Daniel C Koboldt, Christopher A Miller, Krishna L Kanchi, James M Eldred, David E Larson, John S Welch, Ming You, Bradley A Ozenberger, Ramaswamy Govindan, Matthew J Walter, Matthew J Ellis, Elaine R Mardis, Timothy A Graubert, John F Dipersio, Timothy J Ley, Richard K Wilson, Paul J Goodfellow, Benjamin J Raphael, Feng Chen, Kimberly J Johnson, Jeffrey D Parvin, Li Ding
Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C, PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively)...
December 22, 2015: Nature Communications
Malachi Griffith, Christopher A Miller, Obi L Griffith, Kilannin Krysiak, Zachary L Skidmore, Avinash Ramu, Jason R Walker, Ha X Dang, Lee Trani, David E Larson, Ryan T Demeter, Michael C Wendl, Joshua F McMichael, Rachel E Austin, Vincent Magrini, Sean D McGrath, Amy Ly, Shashikant Kulkarni, Matthew G Cordes, Catrina C Fronick, Robert S Fulton, Christopher A Maher, Li Ding, Jeffery M Klco, Elaine R Mardis, Timothy J Ley, Richard K Wilson
Tumors are typically sequenced to depths of 75-100× (exome) or 30-50× (whole genome). We demonstrate that current sequencing paradigms are inadequate for tumors that are impure, aneuploid or clonally heterogeneous. To reassess optimal sequencing strategies, we performed ultra-deep (up to ~312×) whole genome sequencing (WGS) and exome capture (up to ~433×) of a primary acute myeloid leukemia, its subsequent relapse, and a matched normal skin sample. We tested multiple alignment and variant calling algorithms and validated ~200,000 putative SNVs by sequencing them to depths of ~1,000×...
September 23, 2015: Cell Systems
Terrence N Wong, Christopher A Miller, Jeffery M Klco, Allegra Petti, Ryan Demeter, Nichole M Helton, Tiandao Li, Robert S Fulton, Sharon E Heath, Elaine R Mardis, Peter Westervelt, John F DiPersio, Matthew J Walter, John S Welch, Timothy A Graubert, Richard K Wilson, Timothy J Ley, Daniel C Link
There is interest in using leukemia-gene panels and next-generation sequencing to assess acute myelogenous leukemia (AML) response to induction chemotherapy. Studies have shown that patients with AML in morphologic remission may continue to have clonal hematopoiesis with populations closely related to the founding AML clone and that this confers an increased risk of relapse. However, it remains unknown how induction chemotherapy influences the clonal evolution of a patient's nonleukemic hematopoietic population...
February 18, 2016: Blood
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