keyword
https://read.qxmd.com/read/33852859/functional-analyses-of-human-luc7-like-proteins-involved-in-splicing-regulation-and-myeloid-neoplasms
#21
JOURNAL ARTICLE
Noah J Daniels, Courtney E Hershberger, Xiaorong Gu, Caroline Schueger, William M DiPasquale, Jonathan Brick, Yogen Saunthararajah, Jaroslaw P Maciejewski, Richard A Padgett
Vertebrates have evolved three paralogs, termed LUC7L, LUC7L2, and LUC7L3, of the essential yeast U1 small nuclear RNA (snRNA)-associated splicing factor Luc7p. We investigated the mechanistic and regulatory functions of these putative splicing factors, of which one (LUC7L2) is mutated or deleted in myeloid neoplasms. Protein interaction data show that all three proteins bind similar core but distinct regulatory splicing factors, probably mediated through their divergent arginine-serine-rich domains, which are not present in Luc7p...
April 13, 2021: Cell Reports
https://read.qxmd.com/read/33764430/%C3%AE-hemoglobinopathies-lead-the-way
#22
COMMENT
Yogen Saunthararajah
No abstract text is available yet for this article.
March 25, 2021: Blood
https://read.qxmd.com/read/33603144/clonal-trajectories-and-cellular-dynamics-of-myeloid-neoplasms-with-sf3b1-mutations
#23
JOURNAL ARTICLE
Hassan Awada, Cassandra M Kerr, Arda Durmaz, Vera Adema, Carmelo Gurnari, Simona Pagliuca, Misam Zawit, Sunisa Kongkiatkamon, Heesun J Rogers, Yogen Saunthararajah, Mikkael A Sekeres, Hetty Carraway, Jaroslaw P Maciejewski, Valeria Visconte
No abstract text is available yet for this article.
November 2021: Leukemia
https://read.qxmd.com/read/33509443/dna-methylation-inhibition-in-myeloma-experience-from-a-phase-1b-study-of-low-dose-continuous-azacitidine-in-combination-with-lenalidomide-and-low-dose-dexamethasone-in-relapsed-or-refractory-multiple-myeloma
#24
JOURNAL ARTICLE
Jack Khouri, Beth M Faiman, Dale Grabowski, Reda Z Mahfouz, Shahper N Khan, Wei Wei, Jason Valent, Robert Dean, Christy Samaras, Babal K Jha, Hillard Lazarus, Erica L Campagnaro, Ehsan Malek, Janice Reed, Mary Ann Karam, Kimberly Hamilton, Sherry Fada, Matt Kalaycio, Hien Liu, Ronald Sobecks, Yogen Saunthararajah, Yap Chew, Mohammed Orloff, Frederic J Reu
The DNA methyltransferase inhibitor azacytidine (aza) may reactivate pathways associated with plasma cell differentiation, cell cycle control, apoptosis, and immune recognition and thereby restore sensitivity to lenalidomide (len) and dexamethasone (dex) in relapsed and/or refractory multiple myeloma (RRMM). We aimed to develop an aza regimen that reaches epigenetically active levels 8 times in 28 days with less bone marrow toxicity than the myeloid malignancy standard of 7 consecutive doses to enable safe combination with len...
January 2021: Seminars in Hematology
https://read.qxmd.com/read/33509441/a-pilot-clinical-trial-of-oral-tetrahydrouridine-decitabine-for-noncytotoxic-epigenetic-therapy-of-chemoresistant-lymphoid-malignancies
#25
JOURNAL ARTICLE
Brian Hill, Deepa Jagadeesh, Brad Pohlman, Robert Dean, Neetha Parameswaran, Joel Chen, Tomas Radivoyevitch, Ashley Morrison, Sherry Fada, Meredith Dever, Shelley Robinson, Daniel Lindner, Mitchell Smith, Yogen Saunthararajah
One mechanism by which lymphoid malignancies resist standard apoptosis-intending (cytotoxic) treatments is genetic attenuation of the p53/p16-CDKN2A apoptosis axis. Depletion of the epigenetic protein DNA methyltransferase 1 (DNMT1) using the deoxycytidine analog decitabine is a validated approach to cytoreduce malignancy independent of p53/p16. In vivo decitabine activity, however, is restricted by rapid catabolism by cytidine deaminase (CDA). We, therefore, combined decitabine with the CDA-inhibitor tetrahydrouridine and conducted a pilot clinical trial in patients with relapsed lymphoid malignancies: the doses of tetrahydrouridine/decitabine used (∼10/0...
January 2021: Seminars in Hematology
https://read.qxmd.com/read/33509437/epigenetic-modifier-directed-therapeutics-to-unleash-healthy-genes-in-unhealthy-cells
#26
EDITORIAL
Babal K Jha, Yogen Saunthararajah
A common thread through malignant and nonmalignant diseases alerts us to a therapeutic opportunity to seize: disease may originate from genetic mutations, but resulting maladaptive/unhealthy cell fates and functions are mediated by epigenetic enzymes, that are druggable. Epigenetic enzymes modify DNA, and/or the histones around which DNA is organized, to regulate access to genes by the basal transcription factor machinery that transcribes genes. Epigenetic enzymes can be divided usefully into those that facilitate gene transcription ("on" enzymes or coactivators) and those that favor gene repression ("off" enzymes or corepressors)...
January 2021: Seminars in Hematology
https://read.qxmd.com/read/33224617/liver-background-uptake-of-18-f-flt-in-pet-imaging
#27
JOURNAL ARTICLE
Olga Sergeeva, Yifan Zhang, Jonathan Kenyon, Galen Miller-Atkins, Maxim Sergeev, Emily Verbus, Renuka Iyer, Sandra Sexton, Vladimir Kepe, Norbert Avril, Yogen Saunthararajah, Ernst Ricky Chan, Zhenghong Lee
High liver uptake presents a problem for 3'-deoxy-3'-[18 F]fluorothymidine ([18 F]FLT) as a radiotracer for imaging cellular proliferation in the liver with positron emission tomography (PET). This investigation re-visited some issues related to the high liver background uptake of [18 F]FLT with an animal model of woodchucks. Several enzymes involved in the hepatic catabolism of FLT, thymidine phosphorylase (TP, TYMP), uridine 5'-diphospho-glucuronosyl-transferases (UDP-GTs, short for UGTs), and β-glucuronidase (GUSB), their homology as well as hepatic expression between the human and the woodchuck was examined...
2020: American Journal of Nuclear Medicine and Molecular Imaging
https://read.qxmd.com/read/33054042/mysteries-of-partial-dihydroorotate-dehydrogenase-inhibition-and-leukemia-terminal-differentiation
#28
EDITORIAL
Yogen Saunthararajah
No abstract text is available yet for this article.
September 1, 2020: Haematologica
https://read.qxmd.com/read/32895473/context-dependent-effects-of-ascorbic-acid-treatment-in-tet2-mutant-myeloid-neoplasia
#29
JOURNAL ARTICLE
Yihong Guan, Edward F Greenberg, Metis Hasipek, Shi Chen, Xiaochen Liu, Cassandra M Kerr, Daniel Gackowski, Ewelina Zarakowska, Tomas Radivoyevitch, Xiaorong Gu, Belinda Willard, Valeria Visconte, Hideki Makishima, Aziz Nazha, Mridul Mukherji, Mikkael A Sekeres, Yogen Saunthararajah, Ryszard Oliński, Mingjiang Xu, Jaroslaw P Maciejewski, Babal K Jha
Loss-of-function TET2 mutations (TET2MT ) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2MT thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of TET2MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2MT myeloid neoplasia (MN), clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of TET2MT ...
September 7, 2020: Communications Biology
https://read.qxmd.com/read/32770088/decitabine-and-5-azacytidine-resistance-emerges-from-adaptive-responses-of-the-pyrimidine-metabolism-network
#30
JOURNAL ARTICLE
Xiaorong Gu, Rita Tohme, Benjamin Tomlinson, Nneha Sakre, Metis Hasipek, Lisa Durkin, Caroline Schuerger, Dale Grabowski, Asmaa M Zidan, Tomas Radivoyevitch, Changjin Hong, Hetty Carraway, Betty Hamilton, Ronald Sobecks, Bhumika Patel, Babal K Jha, Eric D Hsi, Jaroslaw Maciejewski, Yogen Saunthararajah
Mechanisms-of-resistance to decitabine and 5-azacytidine, mainstay treatments for myeloid malignancies, require investigation and countermeasures. Both are nucleoside analog pro-drugs processed by pyrimidine metabolism into a deoxynucleotide analog that depletes the key epigenetic regulator DNA methyltranseferase 1 (DNMT1). Here, upon serial analyses of DNMT1 levels in patients' bone marrows on-therapy, we found DNMT1 was not depleted at relapse. Showing why, bone marrows at relapse exhibited shifts in expression of key pyrimidine metabolism enzymes in directions adverse to pro-drug activation...
April 2021: Leukemia
https://read.qxmd.com/read/31736067/extended-experience-with-a-non-cytotoxic-dnmt1-targeting-regimen-of-decitabine-to-treat-myeloid-malignancies
#31
JOURNAL ARTICLE
Hassan Awada, Reda Z Mahfouz, Ashwin Kishtagari, Teodora Kuzmanovic, Jibran Durrani, Cassandra M Kerr, Bhumika J Patel, Valeria Visconte, Tomas Radivoyevitch, Alan Lichtin, Hetty E Carraway, Jaroslaw P Maciejewski, Yogen Saunthararajah
The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular-targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non-cytotoxic DNMT1-depletion can cytoreduce even p53-null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1-0·2 mg/kg) that deplete DNMT1 without off-target anti-metabolite effects/cytotoxicity, and then administered these well-tolerated doses frequently 1-2X/week to increase S-phase dependent DNMT1-depletion, and used a Myeloid Malignancy Registry to evaluate long-term outcomes in 69 patients treated this way...
November 17, 2019: British Journal of Haematology
https://read.qxmd.com/read/31703407/-18-f-clofarabine-for-pet-imaging-of-hepatocellular-carcinoma
#32
JOURNAL ARTICLE
Olga Sergeeva, Vladimir Kepe, Yifan Zhang, Galen A Miller-Atkins, Jonathan D Keynon, Renuka Iyer, Sandra Sexton, Amad Awadallah, Wei Xin, Yogen Saunthararajah, E Ricky Chan, Zhenghong Lee
Clinical diagnosis of hepatocellular carcinoma (HCC) relies heavily on radiological imaging. However, information pertaining to liver cancer treatment such as the proliferation status is lacking. Imaging tumor proliferation can be valuable in patient management. This study investigated 18 F-labeled clofarabine ([18 F]CFA) targeting deoxycytidine kinase (dCK) for PET imaging of dCK-dependent proliferation in HCC. Since clinical PET scans showed a high liver background uptake of [18 F]CFA, the aim of this study was to reduce this liver background uptake...
November 7, 2019: Cancers
https://read.qxmd.com/read/31646061/molecular-profiling-of-primary-uveal-melanomas-with-tumor-infiltrating-lymphocytes
#33
JOURNAL ARTICLE
Pierre L Triozzi, Lynn Schoenfield, Thomas Plesec, Yogen Saunthararajah, Raymond R Tubbs, Arun D Singh
In contrast to other cancers, the presence of tumor-infiltrating lymphocytes (TILs) in uveal melanoma is associated with a poor prognosis. However, how TILs may promote disease progression and what regulates their infiltration has not yet been established. To address these clinically relevant outstanding questions, T cell, immune regulatory, and chemokine gene expression profiles of 57 enucleated uveal melanoma tumors were compared, encompassing 27 with TILs and 30 without,. Tumors with infiltrating lymphocytes expressed more CD8A mRNA, as well as IFNG , TGFB1 , and FOXP3 transcripts...
2019: Oncoimmunology
https://read.qxmd.com/read/31399526/targeting-sickle-cell-disease-root-cause-pathophysiology-with-small-molecules
#34
REVIEW
Yogen Saunthararajah
The complex, frequently devastating, multi-organ pathophysiology of sickle cell disease has a single root cause: polymerization of deoxygenated sickle hemoglobin. A logical approach to disease modification is, therefore, to interdict this root cause. Ideally, such interdiction would utilize small molecules that are practical and accessible for worldwide application. Two types of such small molecule strategies are actively being evaluated in the clinic. The first strategy intends to shift red blood cell precursor hemoglobin manufacturing away from sickle hemoglobin and towards fetal hemoglobin, which inhibits sickle hemoglobin polymerization by a number of mechanisms...
September 2019: Haematologica
https://read.qxmd.com/read/31101629/cytokine-regulated-phosphorylation-and-activation-of-tet2-by-jak2-in-hematopoiesis
#35
JOURNAL ARTICLE
Jong Jin Jeong, Xiaorong Gu, Ji Nie, Sriram Sundaravel, Hui Liu, Wen-Liang Kuo, Tushar D Bhagat, Kith Pradhan, John Cao, Sangeeta Nischal, Kathy L McGraw, Sanchari Bhattacharyya, Michael R Bishop, Andrew Artz, Michael J Thirman, Alison Moliterno, Peng Ji, Ross L Levine, Lucy A Godley, Ulrich Steidl, James J Bieker, Alan F List, Yogen Saunthararajah, Chuan He, Amit Verma, Amittha Wickrema
Even though the Ten-eleven translocation (TET) enzymes catalyze the generation of 5-hydroxymethylcytosines required for lineage commitment and subsequent differentiation of stem cells into erythroid cells, the mechanisms that link extracellular signals to TET activation and DNA hydroxymethylation are unknown. We demonstrate that hematopoietic cytokines phosphorylate TET2, leading to its activation in erythroid progenitors. Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964...
May 17, 2019: Cancer Discovery
https://read.qxmd.com/read/30936220/ezh2-inhibitors-take-it-ezy-it-is-all-about-context
#36
COMMENT
Vamsidhar Velcheti, Kwok-Kin Wong, Yogen Saunthararajah
Even in diffuse large B-cell lymphoma (DLBCL), a cancer of professional antigen-presenting cells, response rates to immune checkpoint blockade therapy have been limited. One reason for DLBCL immune evasion is epigenetic repression instead of activation of the antigen-presenting MHC-a dissection of mechanisms underlying this repression suggests an opening for restoring B-cell maturation and, along the way, MHC expression as a novel modality of cytoreducing DLBCL and simultaneously augmenting possibilities for immunotherapy...
April 2019: Cancer Discovery
https://read.qxmd.com/read/30872721/tracking-decitabine-incorporation-into-malignant-myeloid-cell-dna-in-vitro-and-in-vivo-by-lc-ms-ms-with-enzymatic-digestion
#37
JOURNAL ARTICLE
Sujatha Chilakala, Ye Feng, Lan Li, Reda Mahfouz, Ebrahem Quteba, Yogen Saunthararajah, Yan Xu
The DNA hypomethylating agents decitabine and 5-azacytidine are the only two drugs approved for treatment of all subtypes of the myeloid malignancy myelodysplastic syndromes (MDS). The key to drug activity is incorporation into target cell DNA, however, a practical method to measure this incorporation is un-available. Here, we report a sensitive and specific LC-MS/MS method to simultaneously measure decitabine incorporation and DNA hypomethylation. A stable heavy isotope of 2'-deoxycytidine was used as an internal standard and one-step multi-enzyme digestion was used to release the DNA bound drug...
March 14, 2019: Scientific Reports
https://read.qxmd.com/read/30814222/oas-rnase-l-innate-immune-pathway-mediates-the-cytotoxicity-of-a-dna-demethylating-drug
#38
JOURNAL ARTICLE
Shuvojit Banerjee, Elona Gusho, Christina Gaughan, Beihua Dong, Xiaorong Gu, Elise Holvey-Bates, Manisha Talukdar, Yize Li, Susan R Weiss, Frank Sicheri, Yogen Saunthararajah, George R Stark, Robert H Silverman
Drugs that reverse epigenetic silencing, such as the DNA methyltransferase inhibitor (DNMTi) 5-azacytidine (AZA), have profound effects on transcription and tumor cell survival. AZA is an approved drug for myelodysplastic syndromes and acute myeloid leukemia, and is under investigation for different solid malignant tumors. AZA treatment generates self, double-stranded RNA (dsRNA), transcribed from hypomethylated repetitive elements. Self dsRNA accumulation in DNMTi-treated cells leads to type I IFN production and IFN-stimulated gene expression...
March 12, 2019: Proceedings of the National Academy of Sciences of the United States of America
https://read.qxmd.com/read/30599207/low-dose-azacitidine-with-dnmt1-level-monitoring-to-treat-post-transplantation-acute-myelogenous-leukemia-or-myelodysplastic-syndrome-relapse
#39
JOURNAL ARTICLE
Masumi Ueda, Najla El-Jurdi, Brenda Cooper, Paolo Caimi, Linda Baer, Merle Kolk, Lauren Brister, David N Wald, Folashade Otegbeye, Hillard M Lazarus, Brenda M Sandmaier, Basem William, Yogen Saunthararajah, Philip Woost, James W Jacobberger, Marcos de Lima
Patients with early relapse of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after hematopoietic cell transplantation (HCT) have a poor prognosis, and no standard treatment. Twenty-nine patients with early disease recurrence post-transplantation were treated with azacitidine (AZA; median dose, 40 mg/m2 /day for 5 to 7 days). At a median follow-up of 6.3 months (range, 1.3 to 41.1 months), 7 patients (27%) had a response to AZA, defined as complete remission, hematologic improvement, or improved donor chimerism...
December 30, 2018: Biology of Blood and Marrow Transplantation
https://read.qxmd.com/read/30231326/ultimate-precision-targeting-cancer-but-not-normal-self-replication
#40
REVIEW
Vamsidhar Velcheti, David Schrump, Yogen Saunthararajah
Self-replication is the engine that drives all biologic evolution, including neoplastic evolution. A key oncotherapy challenge is to target this, the heart of malignancy, while sparing the normal self-replication mandatory for health and life. Self-replication can be demystified: it is activation of replication, the most ancient of cell programs, uncoupled from activation of lineage-differentiation, metazoan programs more recent in origin. The uncoupling can be physiologic, as in normal tissue stem cells, or pathologic, as in cancer...
May 23, 2018: American Society of Clinical Oncology Educational Book
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