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https://www.readbyqxmd.com/read/28525840/indole-carboxylic-acid-esters-of-melampomagnolide-b-are-potent-anticancer-agents-against-both-hematological-and-solid-tumor-cells
#1
Shobanbabu Bommagani, Jessica Ponder, Narsimha R Penthala, Venumadhav Janganati, Craig T Jordan, Michael J Borrelli, Peter A Crooks
A series of novel, heteroaryl carboxylic acid conjugates of the sesquiterpene melampomagnolide-B (MMB, 3) has been evaluated as antitumor agents against an NCI panel of 64 human hematopoetic and solid tumor cell lines. The indole-3-acrylic acid conjugate 7j and the indole-3-carboxylic acid conjugate 7k were found to be the most potent analogs in the series. Compounds 7j and 7k exhibited remarkable growth inhibition, with GI50 values in the range 0.03-0.30 μM and 0.04-0.28 μM, respectively, against the cell lines in the leukemia sub-panel, and GI50 values of 0...
May 11, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28518151/disulfiram-copper-selectively-eradicates-aml-leukemia-stem-cells-in-vitro-and-in-vivo-by-simultaneous-induction-of-ros-jnk-and-inhibition-of-nf-%C3%AE%C2%BAb-and-nrf2
#2
Bing Xu, Shiyun Wang, Rongwei Li, Kai Chen, Lingli He, Manman Deng, Vinodh Kannappan, Jie Zha, Huijuan Dong, Weiguang Wang
Acute myeloid leukemia (AML) is a heterogeneous malignancy. Despite the advances in past decades, the clinical outcomes of AML patients remain poor. Leukemia stem cells (LSCs) is the major cause of the recurrence of AML even after aggressive treatment making, promoting development of LSC-targeted agents is an urgent clinical need. Although the antitumor activity of disulfiram (DS), an approved anti-alcoholism drug, has been demonstrated in multiple types of tumors including hematological malignancies such as AML, it remains unknown whether this agent would also be able to target cancer stem cells like LSCs...
May 18, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28518092/isolation-of-the-side-population-in-myc-induced-t-cell-acute-lymphoblastic-leukemia-in-zebrafish
#3
Margaret M Pruitt, Wilfredo Marin, Michael R Waarts, Jill L O de Jong
Heterogeneous cell populations, from either healthy or malignant tissues, may contain a population of cells characterized by a differential ability to efflux the DNA-binding dye Hoechst 33342. This "side population" of cells can be identified using flow cytometric methods after the Hoechst 33342 dye is excited by an ultraviolet (UV) laser. The side population of many cell types contains stem- or progenitor-like cells. However, not all cell types have an identifiable side population. Danio rerio, zebrafish, have a robust in vivo model of T-cell acute lymphoblastic leukemia (T-ALL), but whether these zebrafish T-ALLs have a side population is unknown...
May 4, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28507111/real-life-assessment-of-the-safety-and-effectiveness-of-the-new-tablet-and-intravenous-formulations-of-posaconazole-in-the-prophylaxis-of-invasive-fungal-infections-analysis-of-343-courses
#4
Frank P Tverdek, Sang Taek Heo, Samuel L Aitken, Bruno Granwehr, Dimitrios P Kontoyiannis
BACKGROUND: Posaconazole is the preferred mold-active azole for prophylaxis against invasive fungal infection (IFI) in patients with hematologic malignancy (HM). Delayed release tablet and intravenous formulations of posaconazole have recently become available, but clinical data are limited. We sought to examine the real-world pharmacokinetics and prophylactic effectiveness of the new formulations of posaconazole given as prophylaxis in patients with HM. METHODS: A retrospective cohort of all consecutive adult inpatients with HM who received ≥3 days of posaconazole as tablet or intravenous from 12/1/2013-12/31/2015 for primary IFI prophylaxis at MD Anderson Cancer center...
May 15, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28504724/single-cell-transcriptomics-uncovers-distinct-molecular-signatures-of-stem-cells-in-chronic-myeloid-leukemia
#5
Alice Giustacchini, Supat Thongjuea, Nikolaos Barkas, Petter S Woll, Benjamin J Povinelli, Christopher A G Booth, Paul Sopp, Ruggiero Norfo, Alba Rodriguez-Meira, Neil Ashley, Lauren Jamieson, Paresh Vyas, Kristina Anderson, Åsa Segerstolpe, Hong Qian, Ulla Olsson-Strömberg, Satu Mustjoki, Rickard Sandberg, Sten Eirik W Jacobsen, Adam J Mead
Recent advances in single-cell transcriptomics are ideally placed to unravel intratumoral heterogeneity and selective resistance of cancer stem cell (SC) subpopulations to molecularly targeted cancer therapies. However, current single-cell RNA-sequencing approaches lack the sensitivity required to reliably detect somatic mutations. We developed a method that combines high-sensitivity mutation detection with whole-transcriptome analysis of the same single cell. We applied this technique to analyze more than 2,000 SCs from patients with chronic myeloid leukemia (CML) throughout the disease course, revealing heterogeneity of CML-SCs, including the identification of a subgroup of CML-SCs with a distinct molecular signature that selectively persisted during prolonged therapy...
May 15, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28503404/wnt-signaling-in-normal-and-malignant-stem-cells
#6
Dheeraj Bhavanasi, Peter S Klein
Wnt signaling plays important roles in stem cell self-renewal and differentiation in adults as well as in embryonic development. Mutations that activate canonical Wnt/β-catenin signaling also initiate and maintain several cancer states, including colorectal cancer and leukemia, and hence Wnt inhibitors are currently being explored as therapeutic options. In this review, we summarize previous studies and update recent findings on canonical Wnt signaling and its components, as well as their roles in somatic stem cell homeostasis and maintenance of cancer initiating cells...
December 2016: Current Stem Cell Reports
https://www.readbyqxmd.com/read/28502334/ap-1-expression-and-its-clinical-relevance-in-immune-disorders-and-cancer
#7
REVIEW
Shivtia Trop-Steinberg, Yehudit Azar
The inflammatory response is known to have a significant role in certain autoimmune diseases and malignancies. We review current knowledge regarding the functions of activator protein 1 (AP-1) as an important modulator in several immune disorders and carcinomas. AP-1 is overexpressed in rheumatoid arthritis and in long-term allogeneic hematopoietic stem cell transplantation survivors; however, decreased expression of AP-1 has been observed in psoriasis, systematic lupus erythematosus and in patients who do not survive after hematopoietic stem cell transplantation...
May 2017: American Journal of the Medical Sciences
https://www.readbyqxmd.com/read/28499784/gsk-3-as-a-novel-prognostic-indicator-in-leukemia
#8
REVIEW
Peter P Ruvolo
While leukemias represent a diverse set of diseases with malignant cells derived from myeloid or lymphoid origin, a common feature is the dysregulation of signal transduction pathways that influence leukemogeneisis, promote drug resistance, and favor leukemia stem cells. Mutations in PI3K, PTEN, RAS, or other upstream regulators can activate the AKT kinase which has central roles in supporting cell proliferation and survival. A major target of AKT is Glycogen Synthase Kinase 3 (GSK3). GSK3 has two isoforms (alpha and beta) that were studied as regulators of metabolism but emerged as central players in cancer in the early 1990s...
May 8, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/28484153/single-institutional-retrospective-analysis-of-japanese-patients-with-chronic-lymphocytic-leukemia
#9
Risa Hashida, Sumiko Kohashi, Jun Kato, Taku Kikuchi, Masatoshi Sakurai, Takaaki Toyama, Yuya Koda, Yusuke Yamane, Ryohei Abe, Takayuki Shimizu, Rie Yamazaki, Takayuki Mitsuhashi, Mitsuru Murata, Shinichiro Okamoto, Takehiko Mori
Unlike in Western countries, chronic lymphocytic leukemia (CLL) is a rare lymphoid malignancy in Japan, and its clinical features remain to be elucidated in the Japanese population. Therefore, we retrospectively analyzed 29 Japanese CLL patients newly diagnosed at our institute. Seventeen (59%) were male, and their median age was 62 years. With a median follow-up period from diagnosis of 69 months (range, 3-170 months), 9 patients received some form of treatment for CLL. Three patients died of disease progression with or without infection (n=2) or skin cancer (n=1)...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28481221/gene-expression-and-mutation-guided-synthetic-lethality-eradicates-proliferating-and-quiescent-leukemia-cells
#10
Margaret Nieborowska-Skorska, Katherine Sullivan, Yashodhara Dasgupta, Paulina Podszywalow-Bartnicka, Grazyna Hoser, Silvia Maifrede, Esteban Martinez, Daniela Di Marcantonio, Elisabeth Bolton-Gillespie, Kimberly Cramer-Morales, Jaewong Lee, Min Li, Artur Slupianek, Daniel Gritsyuk, Sabine Cerny-Reiterer, Ilona Seferynska, Tomasz Stoklosa, Lars Bullinger, Huaqing Zhao, Vera Gorbunova, Katarzyna Piwocka, Peter Valent, Curt I Civin, Markus Muschen, John E Dick, Jean C Y Wang, Smita Bhatia, Ravi Bhatia, Kolia Eppert, Mark D Minden, Stephen M Sykes, Tomasz Skorski
Quiescent and proliferating leukemia cells accumulate highly lethal DNA double-strand breaks that are repaired by 2 major mechanisms: BRCA-dependent homologous recombination and DNA-dependent protein kinase-mediated (DNA-PK-mediated) nonhomologous end-joining, whereas DNA repair pathways mediated by poly(ADP)ribose polymerase 1 (PARP1) serve as backups. Here we have designed a personalized medicine approach called gene expression and mutation analysis (GEMA) to identify BRCA- and DNA-PK-deficient leukemias either directly, using reverse transcription-quantitative PCR, microarrays, and flow cytometry, or indirectly, by the presence of oncogenes such as BCR-ABL1...
May 8, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28479592/a-novel-agent-sl-401-induces-anti-myeloma-activity-by-targeting-plasmacytoid-dendritic-cells-osteoclastogenesis-and-cancer-stem-like-cells
#11
A Ray, D S Das, Y Song, V Macri, P Richardson, C L Brooks, D Chauhan, K C Anderson
Novel therapies for multiple myeloma (MM) can target mechanism(s) in the host-MM bone marrow (BM) microenvironment mediating MM progression and chemoresistance. Our studies showed increased numbers of tumor-promoting, immunosuppressive, and drug-resistant plasmacytoid dendritic cells (pDCs) in the MM BM microenvironment. pDC-MM cell interactions upregulate interleukin-3 (IL-3), which stimulates both pDC survival and MM cell growth. Since IL-3R is highly expressed on pDCs in the MM BM milieu, we here targeted pDCs using a novel IL-3R-targeted therapeutic SL-401...
May 8, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28479420/cbp-catenin-antagonists-targeting-lsc-s-achilles-heel
#12
REVIEW
Yong-Mi Kim, EunJi Gang, Michael Kahn
Cancer Stem Cells (CSCs) including Leukemia Stem Cells (LSCs) exhibit self-renewal capacity and differentiation potential, and have the capacity to maintain or renew and propagate a tumor/leukemia. The initial isolation of CSCs/LSCs was in adult myelogenous leukemia, although more recently, the existence of CSCs in a wide variety of other cancers has been demonstrated. CSCs in general, and LSCs specifically in regards to this review, are responsible for initiation of disease, therapeutic resistance and ultimately disease relapse...
May 4, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28458519/detection-approaches-for-multidrug-resistance-genes-of-leukemia
#13
REVIEW
Ying Du, Baoan Chen
Leukemia is a clonal malignant hematopoietic stem cell disease. It is the sixth most lethal cancer and accounts for 4% of all cancers. The main form of treatment for leukemia is chemotherapy. While some cancer types with a higher incidence than leukemia, such as lung and gastric cancer, have shown a sharp decline in mortality rates in recent years, leukemia has not followed this trend. Drug resistance is often regarded as the main clinical obstacle to effective chemotherapy in patients diagnosed with leukemia...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28455005/outcomes-of-allogeneic-hematopoietic-cell-transplantation-in-acute-myeloid-leukemia-patients-with-abnormalities-of-the-short-arm-of-chromosome-17
#14
Jinichi Mori, Masamitsu Yanada, Naoyuki Uchida, Takahiro Fukuda, Toru Sakura, Michihiro Hidaka, Kyoko Watakabe-Inamoto, Heiwa Kanamori, Hiroyasu Ogawa, Tatsuo Ichinohe, Junji Tanaka, Yoshiko Atsuta, Shingo Yano
We retrospectively analyzed a Japanese nationwide database to elucidate the impact of abnormalities in the short arm of chromosome 17 (abnl[17p]) on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia. Of 10923 patients, 262 (2.4%) had abnl(17p), 235 of whom were classified into the poor cytogenetic risk group according to the National Comprehensive Cancer Network criteria. The median follow-up period was 1425 days. In abnl(17p) vs. non-abnl(17p) patients of poor cytogenetic risk group, overall survival (OS), disease-free survival, cumulative incidence of disease relapse, and non-relapse mortality rates at 5 years post-allo-HSCT were 9...
April 25, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28454291/thioridazine-has-potent-antitumor-effects-on-lung-cancer-stem-like-cells
#15
Jiani Shen, Buyun Ma, Xinmin Zhang, Xiaozhu Sun, Jiancui Han, Yigang Wang, Liang Chu, Haineng Xu, Yu Yang
Thioridazine (TDZ), originally an anti-psychotic drug, suppresses several types of cancer and has specificity for leukemia stem cells. The present study was performed to assess its effect on lung cancer stem-like cells, as its effect remains unknown. TDZ was utilized to treat lung cancer stem-like cells (A549 sphere cells) and its cytotoxic effect and mechanism were evaluated in vitro and in vivo. TDZ elicited cytotoxicity in A549 sphere cells and inhibited their proliferation in a dose-dependent pattern. A549 sphere cells treated with TDZ showed nuclear fragmentation, increased G0/G1 phase distribution, positive Annexin V staining, and a change in the expression of caspase family and cell cycle-associated proteins...
March 2017: Oncology Letters
https://www.readbyqxmd.com/read/28453744/significance-of-low-mtorc1-activity-in-defining-the-characteristics-of-brain-tumor-stem-cells
#16
Yi-Peng Han, Atsushi Enomoto, Yukihiro Shiraki, Shen-Qi Wang, Xiaoze Wang, Shinya Toyokuni, Naoya Asai, Kaori Ushida, Hosne Ara, Fumiharu Ohka, Toshihiko Wakabayashi, Jie Ma, Atsushi Natsume, Masahide Takahashi
Background.: The significance of mammalian target of rapamycin complex 1 (mTORC1) activity in the maintenance of cancer stem cells (CSCs) remains controversial. Previous findings showed that mTORC1 activation depleted the population of leukemia stem cells in leukemia, while maintaining the stemness in pancreatic CSCs. The purpose of this study was to examine the currently unknown role and significance of mTORC1 activity in brain tumor stem cells (BTSCs). Methods.: Basal mTORC1 activity and its kinetics were investigated in BTSC clones isolated from patients with glioblastoma and their differentiated progenies (DIFFs)...
May 1, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28450183/hematopoietic-stem-cell-transplant-activity-in-pediatric-cancer-between-2008-and-2014-in-the-united-states-a-cibmtr-report
#17
Pooja Khandelwal, Heather R Millard, Elizabeth Thiel, Hisham Abdel-Azim, Allistair A Abraham, Jeffery J Auletta, Farid Boulad, Valerie I Brown, Bruce M Camitta, Ka Wah Chan, Sonali Chaudhury, Morton J Cowan, Miguel Angel-Diaz, Shahinaz M Gadalla, Robert Peter Gale, Gregory Hale, Kimberly A Kasow, Amy K Keating, Carrie L Kitko, Margaret L MacMillan, Richard F Olsson, Kristin M Page, Adriana Seber, Angela R Smith, Anne B Warwick, Baldeep Wirk, Parinda A Mehta
This CIBMTR report describes the use of hematopoietic stem cell transplantation (HSCT) in 4408 pediatric patients with cancer undergoing allogeneic (allo) and 3076 undergoing autologous (auto) HSCT in the United States between 2008 and 2014. In both settings, there was a greater proportion of males (n=4327; 57%), children<10 years of age (n=4412; 59%), Caucasians (n=5787; 77%) and children with a performance score ≥ 90% at HSCT (n=6187; 83%). Leukemia was the most common indication for an allo-transplant (n=4170; 94%), and among these, acute lymphoblastic leukemia (ALL) in second complete remission (n=829; 20%) and acute myeloid leukemia in first complete remission (n=800; 19%) were the most common...
April 24, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28436985/functional-screen-of-msi2-interactors-identifies-an-essential-role-for-syncrip-in-myeloid-leukemia-stem-cells
#18
Ly P Vu, Camila Prieto, Elianna M Amin, Sagar Chhangawala, Andrei Krivtsov, M Nieves Calvo-Vidal, Timothy Chou, Arthur Chow, Gerard Minuesa, Sun Mi Park, Trevor S Barlowe, James Taggart, Patrick Tivnan, Raquel P Deering, Lisa P Chu, Jeong-Ah Kwon, Cem Meydan, Javier Perales-Paton, Arora Arshi, Mithat Gönen, Christopher Famulare, Minal Patel, Elisabeth Paietta, Martin S Tallman, Yuheng Lu, Jacob Glass, Francine E Garret-Bakelman, Ari Melnick, Ross Levine, Fatima Al-Shahrour, Marcus Järås, Nir Hacohen, Alexia Hwang, Ralph Garippa, Christopher J Lengner, Scott A Armstrong, Leandro Cerchietti, Glenn S Cowley, David Root, John Doench, Christina Leslie, Benjamin L Ebert, Michael G Kharas
The identity of the RNA-binding proteins (RBPs) that govern cancer stem cells remains poorly characterized. The MSI2 RBP is a central regulator of translation of cancer stem cell programs. Through proteomic analysis of the MSI2-interacting RBP network and functional shRNA screening, we identified 24 genes required for in vivo leukemia. Syncrip was the most differentially required gene between normal and myeloid leukemia cells. SYNCRIP depletion increased apoptosis and differentiation while delaying leukemogenesis...
April 24, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28416638/eya2-a-target-activated-by-plzf-is-critical-for-plzf-rara-induced-leukemogenesis
#19
Ryoichi Ono, Masahiro Masuya, Satomi Ishii, Naoyuki Katayama, Tetsuya Nosaka
PLZF is a transcription factor that confers aberrant self-renewal in leukemogenesis, and the PLZF-RARA fusion gene causes acute promyelocytic leukemia (APL) through differentiation block. However, the molecular mechanisms of aberrant self-renewal underlying PLZF-mediated leukemogenesis are poorly understood. To investigate these mechanisms, comprehensive expression profiling of mouse hematopoietic stem/progenitor cells transduced with Plzf was performed, which revealed the involvement of a key transcriptional coactivator, Eya2, a target molecule shared by Plzf and PLZF-RARA, in the aberrant self-renewal...
April 17, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28404896/retargeting-of-t-lymphocytes-to-psca-or-psma-positive-prostate-cancer-cells-using-the-novel-modular-chimeric-antigen-receptor-platform-technology-unicar
#20
Anja Feldmann, Claudia Arndt, Ralf Bergmann, Simon Loff, Marc Cartellieri, Dominik Bachmann, Roberta Aliperta, Mirjam Hetzenecker, Florian Ludwig, Susann Albert, Pauline Ziller-Walter, Alexandra Kegler, Stefanie Koristka, Sebastian Gärtner, Marc Schmitz, Armin Ehninger, Gerhard Ehninger, Jens Pietzsch, Jörg Steinbach, Michael Bachmann
New treatment options especially of solid tumors including for metastasized prostate cancer (PCa) are urgently needed. Recent treatments of leukemias with chimeric antigen receptors (CARs) underline their impressive therapeutic potential. However CARs currently applied in the clinics cannot be repeatedly turned on and off potentially leading to severe life threatening side effects. To overcome these problems, we recently described a modular CAR technology termed UniCAR: UniCAR T cells are inert but can be turned on by application of one or multiple target modules (TMs)...
May 9, 2017: Oncotarget
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