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https://www.readbyqxmd.com/read/29690576/nuc041-a-prodrug-of-the-dna-methytransferase-inhibitor-5-aza-2-2-difluorodeoxycytidine-nuc013-leads-to-tumor-regression-in-a-model-of-non-small-cell-lung-cancer
#1
Richard Daifuku, Sheila Grimes, Murray Stackhouse
5-aza-2′,2′-difluorodeoxycytidine (NUC013) has been shown to be significantly safer and more effective than decitabine in xenograft models of human leukemia and colon cancer. However, it suffers from a similar short half-life as other DNA methyltransferase inhibitors with a 5-azacytosine base, which is problematic for nucleosides that primarily target tumor cells in S phase. Because of the relative instability of 5-azanucleosides, a prodrug approach was developed to improve the pharmacology of NUC013...
April 23, 2018: Pharmaceuticals
https://www.readbyqxmd.com/read/29685952/hypomethylating-agents-in-relapsed-and-refractory-aml-outcomes-and-their-predictors-in-a-large-international-patient-cohort
#2
Maximilian Stahl, Michelle DeVeaux, Pau Montesinos, Raphael Itzykson, Ellen K Ritchie, Mikkael A Sekeres, John D Barnard, Nikolai A Podoltsev, Andrew M Brunner, Rami S Komrokji, Vijaya R Bhatt, Aref Al-Kali, Thomas Cluzeau, Valeria Santini, Amir T Fathi, Gail J Roboz, Pierre Fenaux, Mark R Litzow, Sarah Perreault, Tae Kon Kim, Thomas Prebet, Norbert Vey, Vivek Verma, Ulrich Germing, Juan Miguel Bergua, Josefina Serrano, Steven D Gore, Amer M Zeidan
Although hypomethylating agents (HMAs) are frequently used in the frontline treatment of older acute myeloid leukemia (AML) patients, little is known about their effectiveness in relapsed or primary treatment-refractory (RR)-AML. Using an international multicenter retrospective database, we studied the effectiveness of HMAs in RR-AML and evaluated for predictors of response and overall survival (OS). A total of 655 patients from 12 centers received azacitidine (57%) or decitabine (43%), including 290 refractory (44%) and 365 relapsed (56%) patients...
April 24, 2018: Blood Advances
https://www.readbyqxmd.com/read/29674693/methylation-associated-silencing-of-basp1-contributes-to-leukemogenesis-in-t-8-21-acute-myeloid-leukemia
#3
Lei Zhou, Lin Fu, Na Lv, Jing Liu, Yan Li, Xiaosu Chen, Qingyu Xu, Guofeng Chen, Baoxu Pang, Lili Wang, Yonghui Li, Xiaodong Zhang, Li Yu
The AML1-ETO fusion protein (A/E), which results from the t(8;21) translocation, is considered to be a leukemia-initiating event. Identifying the mechanisms underlying the oncogenic activity of A/E remains a major challenge. In this study, we identified a specific down-regulation of brain acid-soluble protein 1 (BASP1) in t(8;21) acute myeloid leukemia (AML). A/E recognized AML1-binding sites and recruited DNA methyltransferase 3a (DNMT3a) to the BASP1 promoter sequence, which triggered DNA methylation-mediated silencing of BASP1...
April 20, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29668607/successful-treatment-of-high-risk-myelodysplastic-syndrome-with-decitabine-based-chemotherapy-followed-by-haploidentical-lymphocyte-infusion-a-case-report-and-literature-review
#4
Yuanyuan Ma, Jianliang Shen, Li-Xin Wang
RATIONALE: The current therapy for elderly patients with high-risk myelodysplastic syndromes (MDSs) remains unsatisfactory. Decitabine, which has been approved to treat MDS, cannot eliminate malignant clones of MDS. PATIENT CONCERNS: A 68-year-old woman presented with multiple divergent bleeding points in the subcutaneous tissue of the limb. Two years earlier, she had been diagnosed with invasive ductal carcinoma of the left breast and had undergone left modified radical mastectomy and local radiation therapy...
April 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29668549/epigenetic-therapy-in-a-patient-with-down-syndrome-and-refractory-acute-myeloid-leukemia
#5
Kerri Becktell, Kerri Houser, Michael J Burke
Acute myeloid leukemia (AML) associated with Down syndrome (DS-AML) is a unique entity of AML with superior treatment response and overall survival compared with children with non-DS-AML. Despite good outcomes in DS-AML, those who relapse or have refractory disease have poor survival. Successful treatment of these patients is challenged by increased incidence of treatment-related toxicities often encountered with high-dose chemotherapy. Here we report the experience of epigenetic modifying agents (decitabine and vorinostat) followed by fludarabine, cytarabine, and granulocyte colony stimulating growth factor for a child with refractory DS-AML...
April 17, 2018: Journal of Pediatric Hematology/oncology
https://www.readbyqxmd.com/read/29665900/-investigation-of-pram1-expression-features-and-their-clinical-significance-in-aml-via-gene-expression-microarray-database
#6
Na Lv, Kun Qian, Jing Liu, Li-Li Wang, Yong-Hui Li, Li Yu
OBJECTIVE: To study the clinical phenotype and its prognostic value of PRAM1 in patients with acute myeloid leukemia(AML). METHODS: Based on the gene expression microarray platform of 486 AML cases, the PRAM1 expression phenotypes were summarized in all of AML subtypes. The PRAM1 expression features were explored in every differentiation stage of hematocytes through normal human stem cell chips and bone marrow gene expression microarray. The clinical drugs which could up-regulate PRAM1 expression in AML cell lines should be found out...
April 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/29663379/phase-ib-ii-study-of-safety-and-efficacy-of-low-dose-decitabine-primed-chemo-immunotherapy-in-patients-with-drug-resistant-relapsed-refractory-alimentary-tract-cancer
#7
Meixia Chen, Jing Nie, Yang Liu, Xiang Li, Yan Zhang, Malcolm V Brock, Kaichao Feng, Zhiqiang Wu, Xiaolei Li, Lu Shi, Suxia Li, Mingzhou Guo, Qian Mei, Weidong Han
The pressing need for improved therapeutic outcomes provides a good rationale for identifying effective strategies for alimentary tract (AT) cancer treatment. The potential re-sensitivity property to chemo- and immunotherapy of low-dose decitabine has been evident both preclinically and in previous phase I trials. We conducted a phase Ib/II trial evaluating low-dose decitabine primed chemo-immunotherapy in patients with drug-resistant relapsed/refractory esophageal, gastric or colorectal cancers. Forty-five patients received either the 5-day decitabine treatment with subsequent re-administration of the previously resistant chemotherapy (decitabine primed chemotherapy, D-C cohort) or the aforementioned regimen followed by cytokine-induced killer cells therapy (decitabine primed chemotherapy and CIK treatment, D-C+CIK cohort) based on their treatment history...
April 16, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29622799/low-dose-decitabine-enhances-the-effect-of-pd-1-blockade-in-colorectal-cancer-with-microsatellite-stability-by-re-modulating-the-tumor-microenvironment
#8
Ganjun Yu, Yanfeng Wu, Wenying Wang, Jia Xu, Xiaoping Lv, Xuetao Cao, Tao Wan
PD-1 blockade has demonstrated impressive clinical outcomes in colorectal cancers that have high microsatellite instability. However, the therapeutic efficacy for patients with tumors with low microsatellite instability or stable microsatellites needs further improvement. Here, we have demonstrated that low-dose decitabine could increase the expression of immune-related genes such as major histocompatibility complex genes and cytokine-related genes as well as the number of lymphocytes at the tumor site in CT26 colorectal cancer-bearing mice...
April 5, 2018: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/29616840/decitabine-in-combination-with-g-csf-low-dose-cytarabine-and-aclarubicin-is-as-effective-as-standard-dose-chemotherapy-in-the-induction-treatment-for-patients-aged-from-55-to-69-years-old-with-newly-diagnosed-acute-myeloid-leukemia
#9
Jiayu Huang, Ming Hong, Yu Zhu, Huihui Zhao, Xiaoyan Zhang, Yujie Wu, Yun Lian, Xiaoli Zhao, Jianyong Li, Sixuan Qian
We retrospectively studied 87 patients aged from 55 to 69 years old with acute myeloid leukemia (AML) who received decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin (DCAG) or standard dose chemotherapy as induction therapy. Patients receiving DCAG had a similar overall response rate (ORR) (p = .6105) and complete remission (CR) rate (p = .3615) compared to those undergoing standard induction. The median overall survival (OS) and relapse-free survival (RFS) was also similar between the two groups although more 'older' (aged from 60 to 69 years old) and 'unfit' patients underwent DCAG regimen...
April 4, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29581862/doxorubicin-induced-loss-of-dna-topoisomerase-ii-and-dnmt1-dependent-suppression-of-mir-125b-induces-chemoresistance-in-alk-positive-cells
#10
Annabelle Congras, Nina Caillet, Nouritza Torossian, Cathy Quelen, Camille Daugrois, Pierre Brousset, Laurence Lamant, Fabienne Meggetto, Coralie Hoareau-Aveilla
Systemic anaplastic large-cell lymphoma (ALCL) is a childhood T cell neoplasm defined by the presence or absence of translocations that lead to the ectopic expression of anaplastic lymphoma kinase (ALK), with nucleophosmin-ALK (NPM-ALK) fusions being the most common. Polychemotherapy involving doxorubicin is the standard first-line treatment but for the 25 to 35% of patients who relapse and develop resistance the prognosis remains poor. We studied the potential role of the microRNA miR-125b in the development of resistance to doxorubicin in NPM-ALK(+) ALCL...
March 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29567781/a-novel-regimen-for-relapsed-refractory-adult-acute-myeloid-leukemia-using-a-kmt2a-partial-tandem-duplication-targeted-therapy-results-of-phase-1-study-nci-8485
#11
Alice S Mims, Anjali Mishra, Shelley Orwick, James Blachly, Rebecca B Klisovic, Ramiro Garzon, Alison R Walker, Steven M Devine, Katherine J Walsh, Sumithira Vasu, Susan Whitman, Guido Marcucci, Daniel Jones, Nyla A Heerema, Gerard Lozanski, Michael A Caligiuri, Clara D Bloomfield, John C Byrd, Richard Piekarz, Michael R Grever, William Blum
KMT2A partial tandem duplication occurs in approximately 5-10% of patients with acute myeloid leukemia and is associated with adverse prognosis. KMT2A wild type is epigenetically silenced in KMT2A partial tandem duplication; re-expression can be induced with DNA methyltransferase and/or histone deacetylase inhibitors in vitro, sensitizing myeloid blasts to chemotherapy. We hypothesized that epigenetic silencing of KMT2A wildtype contributes to KMT2A partial tandem duplication-associated leukemogenesis and pharmacologic re-expression activates apoptotic mechanisms important for chemo-response...
March 22, 2018: Haematologica
https://www.readbyqxmd.com/read/29566279/recurrent-transcriptional-loss-of-the-pcdh17-tumor-suppressor-in-laryngeal-squamous-cell-carcinoma-is-partially-mediated-by-aberrant-promoter-dna-methylation
#12
Ewa Byzia, Natalia Soloch, Magdalena Bodnar, Marcin Szaumkessel, Katarzyna Kiwerska, Magdalena Kostrzewska-Poczekaj, Malgorzata Jarmuz-Szymczak, Lukasz Szylberg, Malgorzata Wierzbicka, Anna Bartochowska, Ewelina Kalinowicz, Reidar Grenman, Krzysztof Szyfter, Andrzej Marszalek, Maciej Giefing
Protocadherins are cell-cell adhesion molecules encoded by a large family of genes. Recent reports demonstrate recurrent silencing of protocadherin genes in tumors and provide strong arguments for their tumor supresor functionality. Loss of protocadherins may contribute to cancer development not only by altering cell-cell adhesion, that is a hallmark of cancer, but also by enhancing proliferation and epithelial mesenchymal transition of cells via deregulation of the WNT signaling pathway. In this study we have further corroborated our previous findings on the involvement of PCDH17 in laryngeal squamous cell carcinoma (LSCC)...
March 22, 2018: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/29560286/-pan3-psma2-fusion-resulting-from-a-novel-t-7-13-p14-q12-chromosome-translocation-in-a-myelodysplastic-syndrome-that-evolved-into-acute-myeloid-leukemia
#13
Ioannis Panagopoulos, Ludmila Gorunova, Hege Kilen Andersen, Astrid Bergrem, Anders Dahm, Kristin Andersen, Francesca Micci, Sverre Heim
Background: Acquired primary chromosomal changes in cancer are sometimes found as sole karyotypic abnormalities. They are specifically associated with particular types of neoplasia, essential in establishing the neoplasm, and they often lead to the generation of chimeric genes of pathogenetic, diagnostic, and prognostic importance. Thus, the report of new primary cancer-specific chromosomal aberrations is not only of scientific but also potentially of clinical interest, as is the detection of their gene-level consequences...
2018: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/29555582/suberanilohydroxamic-acid-prevents-tgf-%C3%AE-1-induced-cox-2-repression-in-human-lung-fibroblasts-post-transcriptionally-by-tia-1-downregulation
#14
Alice Pasini, Oliver J Brand, Gisli Jenkins, Alan J Knox, Linhua Pang
Cyclooxygenase-2 (COX-2), with its main antifibrotic metabolite PGE2 , is regarded as an antifibrotic gene. Repressed COX-2 expression and deficient PGE2 have been shown to contribute to the activation of lung fibroblasts and excessive deposition of collagen in pulmonary fibrosis. We have previously demonstrated that COX-2 expression in lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) is epigenetically silenced and can be restored by epigenetic inhibitors. This study aimed to investigate whether COX-2 downregulation induced by the profibrotic cytokine transforming growth factor-β1 (TGF-β1) in normal lung fibroblasts could be prevented by epigenetic inhibitors...
May 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29543073/epigenetic-therapy-azacytidine-and-decitabine-in-acute-myeloid-leukemia
#15
Stephan R Bohl, Lars Bullinger, Frank G Rücker
The majority of patients with acute myeloid leukemia (AML) are older and exhibit a poor prognosis even after intensive therapy. Inducing differentiation and apoptosis of leukemic blasts by DNA-hypomethylating agents, like e.g. azacytidine (AZA) and decitabine (DAC), represent well-tolerated alternative treatment approaches. Both agents show convincing response as single agents in AML. However, there is a lack of knowledge regarding molecular mechanisms and predictive biomarkers for these agents. Areas covered: This review will (i) provide an overview of the current knowledge of molecular mechanisms underlying the action of these drugs, (ii) report promising predictive biomarkers, (iii) elude on new combined treatment options, and (iv) discuss novel approaches to improve outcomes...
March 27, 2018: Expert Review of Hematology
https://www.readbyqxmd.com/read/29541236/differential-sensitization-of-two-human-colon-cancer-cell-lines-to-the-antitumor-effects-of-irinotecan-combined-with-5-aza-2-deoxycytidine
#16
Shuko Hakata, Jun Terashima, Yu Shimoyama, Kouji Okada, Shiho Fujioka, Erika Ito, Wataru Habano, Shogo Ozawa
Irinotecan (CPT-11) is a key therapeutic drug used in the treatment of colorectal cancer, although acquired or constitutive resistance to CPT-11 (and its activated metabolite SN-38) can lead to tumor progression. Since the acquisition of drug resistance can result from DNA hypermethylation, the antitumor activity of CPT-11 and SN-38 was assessed in combination with a known DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, also known as decitabine (DAC). DAC potentiated the antitumor activity of CPT-11 additively, and that of SN-38 synergistically, as measured by colony formation in the human colorectal cancer HCT116 cell line...
April 2018: Oncology Letters
https://www.readbyqxmd.com/read/29534238/targeting-epigenetic-dna-and-histone-modifications-to-treat-kidney-disease
#17
Miguel Fontecha-Barriuso, Diego Martin-Sanchez, Olga Ruiz-Andres, Jonay Poveda, Maria Dolores Sanchez-Niño, Lara Valiño-Rivas, Marta Ruiz-Ortega, Alberto Ortiz, Ana Belén Sanz
Epigenetics refers to heritable changes in gene expression patterns not caused by an altered nucleotide sequence, and includes non-coding RNAs and covalent modifications of DNA and histones. This review focuses on functional evidence for the involvement of DNA and histone epigenetic modifications in the pathogenesis of kidney disease and the potential therapeutic implications. There is evidence of activation of epigenetic regulatory mechanisms in acute kidney injury (AKI), chronic kidney disease (CKD) and the AKI-to-CKD transition of diverse aetiologies, including ischaemia-reperfusion injury, nephrotoxicity, ureteral obstruction, diabetes, glomerulonephritis and polycystic kidney disease...
March 9, 2018: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/29524566/high-level-embryonic-globin-production-with-efficient-erythroid-differentiation-from-a-k562-erythroleukemia-cell-line
#18
Naoya Uchida, Juan J Haro-Mora, Selami Demirci, Atsushi Fujita, Lydia Raines, Matthew M Hsieh, John F Tisdale
A reliable cell line capable of robust in vitro erythroid differentiation would be useful to investigate red blood cell (RBC) biology and genetic strategies for RBC diseases. K562 cells are widely utilized for erythroid differentiation; however, current differentiation methods are insufficient to analyze globin proteins. In this study, we sought to improve erythroid differentiation from K562 cells to enable protein-level globin analysis. K562 cells were exposed to a variety of reagents including hemin, rapamycin, imatinib, and/or decitabine (known erythroid inducers), and cultured in basic culture media or erythropoietin-based differentiation media...
March 7, 2018: Experimental Hematology
https://www.readbyqxmd.com/read/29519804/two-novel-epigenetic-pathways-regulate-nfe2-overexpression-in-myeloproliferative-neoplasms
#19
Jan C Peeken, Jonas S Jutzi, Julius Wehrle, Christoph Koellerer, Felix Staehle, Heiko Becker, Elias Schoenwandt, Thalia S Seeger, Daniel H Schanne, Monika Gothwal, Christopher J Ott, Albert Gründer, Heike L Pahl
The transcription factor "Nuclear Factor Erythroid 2" (NFE2) is overexpressed in the majority of patients with Myeloproliferative Neoplasms (MPN). In murine models, elevated NFE2 levels cause an MPN phenotype with spontaneous leukemic transformation. However, both the molecular mechanisms leading to NFE2 overexpression and its downstream targets remain incompletely understood. Here we show that the histone demethylase JMJD1C constitutes a novel NFE2 target gene. JMJD1C levels are significantly elevated in PV and PMF patients; concomitantly, global H3K9me1 and H3K9me2 levels are significantly decreased...
March 8, 2018: Blood
https://www.readbyqxmd.com/read/29478947/azacitidine-use-for-myeloid-neoplasms
#20
REVIEW
Riad El Fakih, Rami Komrokji, Marwan Shaheen, Fahad Almohareb, Walid Rasheed, Mona Hassanein
Azacitidine and decitabine are hypomethylating agents frequently used interchangeably to treat myeloid neoplasms in different settings. Azacitidine is metabolized intracellularly into decitabine. Hypomethylating agents work by inhibiting DNA methyltransferases, causing demethylation of aberrantly methylated promoter regions of genes involved in the pathogenesis of myeloid neoplasms. Azacitidine was the first agent approved by the US Food and Drug Administration for treatment of myelodysplastic syndrome in 2004, after which, the use of azacitidine in other myeloid neoplasms increased significantly...
February 8, 2018: Clinical Lymphoma, Myeloma & Leukemia
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