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Yogen Saunthararajah

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https://www.readbyqxmd.com/read/28726739/5-aza-2-2-difluroro-deoxycytidine-nuc013-a-novel-nucleoside-dna-methyl-transferase-inhibitor-and-ribonucleotide-reductase-inhibitor-for-the-treatment-of-cancer
#1
Richard Daifuku, Zhenbo Hu, Yogen Saunthararajah
Tumor suppressor genes can be silenced genetically as well as epigenetically. One approach to reversing epigenetic suppression of tumor suppressor genes is to inhibit DNA methyl transferase. 5-aza-2',2'-diflurorodeoxycytidine (NUC013) is a novel DNA methyl transferase and ribonucleotide reductase inhibitor that is a more potent inhibitor of growth than decitabine in the NCI 60 cancer cell line panel. NUC013 is more active than decitabine against p53-null/mutant cancer cell lines (p = 0.027) but is even more so against p53 wild-type (WT) cell lines (p = 0...
July 20, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28561650/higher-level-pathway-objectives-of-epigenetic-therapy-a-solution-to-the-p53-problem-in-cancer
#2
Vamsidhar Velcheti, Tomas Radivoyevitch, Yogen Saunthararajah
Searches for effective yet nontoxic oncotherapies are searches for exploitable differences between cancer and normal cells. In its core of cell division, cancer resembles normal life, coordinated by the master transcription factor MYC. Outside of this core, apoptosis and differentiation programs, which dominantly antagonize MYC to terminate cell division, necessarily differ between cancer and normal cells, as apoptosis is suppressed by biallelic inactivation of the master regulator of apoptosis, p53, or its cofactor p16/CDKN2A in approximately 80% of cancers...
2017: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/28031539/recurrent-genetic-defects-on-chromosome-5q-in-myeloid-neoplasms
#3
Naoko Hosono, Hideki Makishima, Reda Mahfouz, Bartlomiej Przychodzen, Kenichi Yoshida, Andres Jerez, Thomas LaFramboise, Chantana Polprasert, Michael J Clemente, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Masashi Sanada, Edward Cui, Amit K Verma, Michael A McDevitt, Alan F List, Yogen Saunthararajah, Mikkael A Sekeres, Jacqueline Boultwood, Seishi Ogawa, Jaroslaw P Maciejewski
BACKGROUND: Deletion of chromosome 5q (del(5q)) is the most common karyotypic abnormality in myeloid neoplasms. MATERIALS AND METHODS: To define the pathogenic molecular features associated with del(5q), next-generation sequencing was applied to 133 patients with myeloid neoplasms (MDS; N = 69, MDS/MPN; N = 5, sAML; N = 29, pAML; N = 30) with del(5q) as a sole abnormally or a part of complex karyotype and results were compared to molecular features of patients diploid for chr5...
January 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/27992414/dynamics-of-clonal-evolution-in-myelodysplastic-syndromes
#4
Hideki Makishima, Tetsuichi Yoshizato, Kenichi Yoshida, Mikkael A Sekeres, Tomas Radivoyevitch, Hiromichi Suzuki, Bartlomiej Przychodzen, Yasunobu Nagata, Manja Meggendorfer, Masashi Sanada, Yusuke Okuno, Cassandra Hirsch, Teodora Kuzmanovic, Yusuke Sato, Aiko Sato-Otsubo, Thomas LaFramboise, Naoko Hosono, Yuichi Shiraishi, Kenichi Chiba, Claudia Haferlach, Wolfgang Kern, Hiroko Tanaka, Yusuke Shiozawa, Inés Gómez-Seguí, Holleh D Husseinzadeh, Swapna Thota, Kathryn M Guinta, Brittney Dienes, Tsuyoshi Nakamaki, Shuichi Miyawaki, Yogen Saunthararajah, Shigeru Chiba, Satoru Miyano, Lee-Yung Shih, Torsten Haferlach, Seishi Ogawa, Jaroslaw P Maciejewski
To elucidate differential roles of mutations in myelodysplastic syndromes (MDS), we investigated clonal dynamics using whole-exome and/or targeted sequencing of 699 patients, of whom 122 were analyzed longitudinally. Including the results from previous reports, we assessed a total of 2,250 patients for mutational enrichment patterns. During progression, the number of mutations, their diversity and clone sizes increased, with alterations frequently present in dominant clones with or without their sweeping previous clones...
February 2017: Nature Genetics
https://www.readbyqxmd.com/read/27453764/association-of-tumor-and-plasma-microrna-expression-with-tumor-monosomy-3-in-patients-with-uveal-melanoma
#5
Pierre L Triozzi, Susan Achberger, Wayne Aldrich, John W Crabb, Yogen Saunthararajah, Arun D Singh
BACKGROUND: Epigenetic events mediated by methylation and histone modifications have been associated with the development of metastasis in patients with uveal melanoma. The role of epigenetic events mediated by microRNA (miR) is less clear. Tumor and plasma miR expression was examined in patients with primary uveal melanoma with tumor monosomy-3, a predictor of metastasis. RESULTS: miR profiling of tumors by microarray found six miRs over-expressed and 19 under-expressed in 33 tumors with monosomy-3 compared to 22 without...
2016: Clinical Epigenetics
https://www.readbyqxmd.com/read/26964622/gsk-3-inhibition-sensitizes-acute-myeloid-leukemia-cells-to-1-25d-mediated-differentiation
#6
Kalpana Gupta, Tammy Stefan, James Ignatz-Hoover, Stephen Moreton, Gary Parizher, Yogen Saunthararajah, David N Wald
1,25-dihydroxyvitamin D3 (1,25D), the biologically active form of vitamin D, is widely considered a promising therapy for acute myeloid leukemia (AML) based on its ability to drive differentiation of leukemic cells. However, clinical trials have been disappointing in part to dose-limiting hypercalcemia. Here we show how inhibiting glycogen synthase kinase 3 (GSK3) can improve the differentiation response of AML cells to 1,25D-mediated differentiation. GSK3 inhibition in AML cells enhanced the differentiating effects of low concentrations of 1,25D...
May 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/26883273/identification-of-a-small-molecule-that-overcomes-hdmx-mediated-suppression-of-p53
#7
Goutam Karan, Huaiyu Wang, Amit Chakrabarti, Sukanya Karan, Zhigang Liu, Zhiqiang Xia, Mahesh Gundluru, Stephen Moreton, Yogen Saunthararajah, Mark W Jackson, Mukesh K Agarwal, David N Wald
Inactivation of the p53 tumor suppressor by mutation or overexpression of negative regulators occurs frequently in cancer. As p53 plays a key role in regulating proliferation or apoptosis in response to DNA-damaging chemotherapies, strategies aimed at reactivating p53 are increasingly being sought. Strategies to reactivate wild-type p53 include the use of small molecules capable of releasing wild-type p53 from key, cellular negative regulators, such as Hdm2 and HdmX. Derivatives of the Hdm2 antagonist Nutlin-3 are in clinical trials...
April 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/26858356/the-lsd1-inhibitor-rn-1-recapitulates-the-fetal-pattern-of-hemoglobin-synthesis-in-baboons-p-anubis
#8
Angela Rivers, Kestis Vaitkus, Vinzon Ibanez, Maria Armila Ruiz, Ramasamy Jagadeeswaran, Yogen Saunthararajah, Shuaiying Cui, James D Engel, Joseph DeSimone, Donald Lavelle
Increased fetal hemoglobin levels lessen the severity of symptoms and increase the lifespan of patients with sickle cell disease. Hydroxyurea, the only drug currently approved for the treatment of sickle cell disease, is not effective in a large proportion of patients and therefore new pharmacological agents that increase fetal hemoglobin levels have long been sought. Recent studies identifying LSD-1 as a repressor of γ-globin expression led to experiments demonstrating that the LSD-1 inhibitor RN-1 increased γ-globin expression in the sickle cell mouse model...
June 2016: Haematologica
https://www.readbyqxmd.com/read/26751067/correction-methylation-profiles-reveal-distinct-subgroup-of-hepatocellular-carcinoma-patients-with-poor-prognosis
#9
Way-Champ Mah, Thomas Thurnherr, Pierce K H Chow, Alexander Y F Chung, London L P J Ooi, Han Chong Toh, Bin Tean Teh, Yogen Saunthararajah, Caroline G L Lee
No abstract text is available yet for this article.
2016: PloS One
https://www.readbyqxmd.com/read/26553780/prospective-clinical-study-of-precision-oncology-in-solid-tumors
#10
Davendra P S Sohal, Brian I Rini, Alok A Khorana, Robert Dreicer, Jame Abraham, Gary W Procop, Yogen Saunthararajah, Nathan A Pennell, James P Stevenson, Robert Pelley, Bassam Estfan, Dale Shepard, Pauline Funchain, Paul Elson, David J Adelstein, Brian J Bolwell
Systematic studies evaluating clinical benefit of tumor genomic profiling are lacking. We conducted a prospective study in 250 patients with select solid tumors at the Cleveland Clinic. Eligibility required histopathologic diagnosis, age of 18 years or older, Eastern Cooperative Oncology Group performance status 0-2, and written informed consent. Tumors were sequenced using FoundationOne (Cambridge, MA). Results were reviewed at the Cleveland Clinic Genomics Tumor Board. Outcomes included feasibility and clinical impact...
March 2016: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/26375552/cx25-contributes-to-leukemia-cell-communication-and-chemosensitivity
#11
Maksim Sinyuk, Alvaro G Alvarado, Pavel Nesmiyanov, Jeremy Shaw, Erin E Mulkearns-Hubert, Jennifer T Eurich, James S Hale, Anna Bogdanova, Masahiro Hitomi, Jaroslaw Maciejewski, Alex Y Huang, Yogen Saunthararajah, Justin D Lathia
Leukemia encompasses several hematological malignancies with shared phenotypes that include rapid proliferation, abnormal leukocyte self-renewal, and subsequent disruption of normal hematopoiesis. While communication between leukemia cells and the surrounding stroma supports tumor survival and expansion, the mechanisms underlying direct leukemia cell-cell communication and its contribution to tumor growth are undefined. Gap junctions are specialized intercellular connections composed of connexin proteins that allow free diffusion of small molecules and ions directly between the cytoplasm of adjacent cells...
October 13, 2015: Oncotarget
https://www.readbyqxmd.com/read/26305875/itraq-quantitative-proteomic-comparison-of-metastatic-and-non-metastatic-uveal-melanoma-tumors
#12
COMPARATIVE STUDY
John W Crabb, Bo Hu, John S Crabb, Pierre Triozzi, Yogen Saunthararajah, Raymond Tubbs, Arun D Singh
BACKGROUND: Uveal melanoma is the most common malignancy of the adult eye. The overall mortality rate is high because this aggressive cancer often metastasizes before ophthalmic diagnosis. Quantitative proteomic analysis of primary metastasizing and non-metastasizing tumors was pursued for insights into mechanisms and biomarkers of uveal melanoma metastasis. METHODS: Eight metastatic and 7 non-metastatic human primary uveal melanoma tumors were analyzed by LC MS/MS iTRAQ technology with Bruch's membrane/choroid complex from normal postmortem eyes as control tissue...
2015: PloS One
https://www.readbyqxmd.com/read/26031919/the-lsd1-inhibitor-rn-1-induces-fetal-hemoglobin-synthesis-and-reduces-disease-pathology-in-sickle-cell-mice
#13
Shuaiying Cui, Kim-Chew Lim, Lihong Shi, Mary Lee, Natee Jearawiriyapaisarn, Greggory Myers, Andrew Campbell, David Harro, Shigeki Iwase, Raymond C Trievel, Angela Rivers, Joseph DeSimone, Donald Lavelle, Yogen Saunthararajah, James Douglas Engel
Inhibition of lysine-specific demethylase 1 (LSD1) has been shown to induce fetal hemoglobin (HbF) levels in cultured human erythroid cells in vitro. Here we report the in vivo effects of LSD1 inactivation by a selective and more potent inhibitor, RN-1, in a sickle cell disease (SCD) mouse model. Compared with untreated animals, RN-1 administration leads to induced HbF synthesis and to increased frequencies of HbF-positive cells and mature erythrocytes, as well as fewer reticulocytes and sickle cells, in the peripheral blood of treated SCD mice...
July 16, 2015: Blood
https://www.readbyqxmd.com/read/25977578/targets-of-opportunity-for-precision-medicine
#14
COMMENT
Yogen Saunthararajah
No abstract text is available yet for this article.
May 14, 2015: Blood
https://www.readbyqxmd.com/read/25920683/inherited-and-somatic-defects-in-ddx41-in-myeloid-neoplasms
#15
Chantana Polprasert, Isabell Schulze, Mikkael A Sekeres, Hideki Makishima, Bartlomiej Przychodzen, Naoko Hosono, Jarnail Singh, Richard A Padgett, Xiaorong Gu, James G Phillips, Michael Clemente, Yvonne Parker, Daniel Lindner, Brittney Dienes, Eckhard Jankowsky, Yogen Saunthararajah, Yang Du, Kevin Oakley, Nhu Nguyen, Sudipto Mukherjee, Caroline Pabst, Lucy A Godley, Jane E Churpek, Daniel A Pollyea, Utz Krug, Wolfgang E Berdel, Hans-Ulrich Klein, Martin Dugas, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Kenichi Yoshida, Seishi Ogawa, Carsten Müller-Tidow, Jaroslaw P Maciejewski
Most cases of adult myeloid neoplasms are routinely assumed to be sporadic. Here, we describe an adult familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DEAD/H-box helicase gene DDX41. DDX41 was also found to be affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. Moreover, corresponding deletions on 5q35.3 present in 6% of cases led to haploinsufficient DDX41 expression. DDX41 lesions caused altered pre-mRNA splicing and RNA processing...
May 11, 2015: Cancer Cell
https://www.readbyqxmd.com/read/25621498/evaluation-of-noncytotoxic-dnmt1-depleting-therapy-in-patients-with-myelodysplastic-syndromes
#16
Yogen Saunthararajah, Mikkael Sekeres, Anjali Advani, Reda Mahfouz, Lisa Durkin, Tomas Radivoyevitch, Ricki Englehaupt, Joy Juersivich, Kathleen Cooper, Holleh Husseinzadeh, Bartlomiej Przychodzen, Matthew Rump, Sean Hobson, Marc Earl, Ronald Sobecks, Robert Dean, Frederic Reu, Ramon Tiu, Betty Hamilton, Edward Copelan, Alan Lichtin, Eric Hsi, Matt Kalaycio, Jaroslaw Maciejewski
BACKGROUND: Mutational inactivation in cancer of key apoptotic pathway components, such as TP53/p53, undermines cytotoxic therapies that aim to increase apoptosis. Accordingly, TP53 mutations are reproducibly associated with poor treatment outcomes. Moreover, cytotoxic treatments destroy normal stem cells with intact p53 systems, a problem especially for myeloid neoplasms, as these cells reverse the low blood counts that cause morbidity and death. Preclinical studies suggest that noncytotoxic concentrations of the DNA methyltransferase 1 (DNMT1) inhibitor decitabine produce p53-independent cell-cycle exits by reversing aberrant epigenetic repression of proliferation-terminating (MYC-antagonizing) differentiation genes in cancer cells...
March 2, 2015: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/25481243/splicing-factor-3b-subunit-1-sf3b1-haploinsufficient-mice-display-features-of-low-risk-myelodysplastic-syndromes-with-ring-sideroblasts
#17
Valeria Visconte, Ali Tabarroki, Li Zhang, Yvonne Parker, Edy Hasrouni, Reda Mahfouz, Kyoichi Isono, Haruhiko Koseki, Mikkael A Sekeres, Yogen Saunthararajah, John Barnard, Daniel Lindner, Heesun J Rogers, Ramon V Tiu
BACKGROUND: The presence of somatic mutations in splicing factor 3b subunit 1 (SF3B1) in patients with Myelodysplastic syndromes with ring sideroblasts (MDS-RS) highlights the importance of the RNA-splicing machinery in MDS. We previously reported the presence of bone marrow (BM) RS in Sf3b1 heterozygous (Sf3b1 (+/-)) mice which are rarely found in mouse models of MDS. Sf3b1 (+/-) mice were originally engineered to study the interaction between polycomb genes and other proteins. METHODS: We used routine blood tests and histopathologic analysis of BM, spleen, and liver to evaluate the hematologic and morphologic characteristics of Sf3b1 (+/-) mice in the context of MDS by comparing the long term follow-up (15 months) of Sf3b1 (+/-) and Sf3b1 (+/+) mice...
December 7, 2014: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/25442074/genomic-microarray-analysis-on-formalin-fixed-paraffin-embedded-material-for-uveal-melanoma-prognostication
#18
Eugen C Minca, Raymond R Tubbs, Bryce P Portier, Zhen Wang, Christopher Lanigan, Mary E Aronow, Pierre L Triozzi, Arun Singh, James R Cook, Yogen Saunthararajah, Thomas P Plesec, Lynn Schoenfield, Victoria Cawich, Scott Sulpizio, Roger A Schultz
Cytogenetic alterations are strong outcome prognosticators in uveal melanoma (UVM). Monosomy 3 (-3) and MYC amplification at 8q24 are commonly tested by fluorescence in situ hybridization (FISH). Alternatively, microarray analysis provides whole genome data, detecting partial chromosome loss, loss of heterozygosity (LOH), or abnormalities unrepresented by FISH probes. Nonfixed frozen tissue is conventionally used for microarray analysis but may not always be available. We assessed the feasibility of genomic microarray analysis for high resolution interrogation of UVM using formalin-fixed paraffin-embedded tissue (FFPET) as an alternative to frozen tissue (FZT)...
July 2014: Cancer Genetics
https://www.readbyqxmd.com/read/25093504/methylation-profiles-reveal-distinct-subgroup-of-hepatocellular-carcinoma-patients-with-poor-prognosis
#19
Way-Champ Mah, Thomas Thurnherr, Pierce K H Chow, Alexander Y F Chung, London L P J Ooi, Han Chong Toh, Bin Tean Teh, Yogen Saunthararajah, Caroline G L Lee
Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-associated mortality worldwide. However, the role of epigenetic changes such as aberrant DNA methylation in hepatocarcinogenesis remains largely unclear. In this study, we examined the methylation profiles of 59 HCC patients. Using consensus hierarchical clustering with feature selection, we identified three tumor subgroups based on their methylation profiles and correlated these subgroups with clinicopathological parameters. Interestingly, one tumor subgroup is different from the other 2 subgroups and the methylation profile of this subgroup is the most distinctly different from the non-tumorous liver tissues...
2014: PloS One
https://www.readbyqxmd.com/read/25089909/decitabine-suspends-human-cd34-cell-differentiation-and-proliferation-during-lentiviral-transduction
#20
Naoya Uchida, Matthew M Hsieh, Charlotte Platner, Yogen Saunthararajah, John F Tisdale
Efficient ex vivo transduction of hematopoietic stem cells (HSCs) is encumbered by differentiation which reduces engraftment. We hypothesized that inhibiting DNA methyltransferase with decitabine would block differentiation of transduced CD34+ cells under cytokine stimulation and thus improve transduction efficiency for engrafting HSCs. Human CD34+ cells in cytokine-containing media were treated with or without decitabine for 24 or 48 hours, and then these cells were transduced with a GFP-expressing lentiviral vector...
2014: PloS One
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