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Milan Škorvaga, Matúš Durdík, Pavol Košík, Eva Marková, Marek Holop, Miroslav Kubeš, Judita Puškáčová, Alexandra Kolenová, Igor Belyaev
The first event in origination of many childhood leukemias is a specific preleukemic fusion gene (PFG) that arises, often in utero, in hematopoietic stem/progenitor cells (HSPC) from misrepaired DNA double strand break (DSB). An immanently elevated level of DSB and impaired apoptosis may contribute to origination and persistence of PFG and donor cell-derived leukemia in recipients of allogeneic transplantation of umbilical cord blood (UCB). We investigated DSB, apoptosis and PFG in the backtracked UCB cells of leukemic patients...
April 10, 2018: Oncotarget
Edward Allan R Sison, Daniel Magoon, Li Li, Colleen E Annesley, Barbara Romagnoli, Garry J Douglas, Gerald Tuffin, Johann Zimmermann, Patrick Brown
The importance of the cell surface receptor CXCR4 and the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) is well-established in normal and malignant hematopoiesis. The Protein Epitope Mimetic POL5551 is a novel and potent antagonist of CXCR4. POL5551 efficiently mobilizes hematopoietic stem and progenitor cells, but its effects in acute lymphoblastic leukemia (ALL) have not been reported. Here, we demonstrate that POL5551 is a potent antagonist of CXCR4 in pre-B and T cell ALL cell lines and pediatric ALL primary samples...
October 13, 2015: Oncotarget
Yang Shen, Ya-Kai Fu, Yong-Mei Zhu, Yin-Jun Lou, Zhao-Hui Gu, Jing-Yi Shi, Bing Chen, Chao Chen, Hong-Hu Zhu, Jiong Hu, Wei-Li Zhao, Jian-Qing Mi, Li Chen, Hong-Ming Zhu, Zhi-Xiang Shen, Jie Jin, Zhen-Yi Wang, Jun-Min Li, Zhu Chen, Sai-Juan Chen
BACKGROUND: Acute promyelocytic leukemia (APL) is a model for synergistic target cancer therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which yields a very high 5-year overall survival (OS) rate of 85 to 90%. Nevertheless, about 15% of APL patients still get early death or relapse. We performed this study to address the possible impact of additional gene mutations on the outcome of APL. METHODS: We included a consecutive series of 266 cases as training group, and then validated the results in a testing group of 269 patients to investigate the potential prognostic gene mutations, including FLT3-ITD or -TKD, N-RAS, C-KIT, NPM1, CEPBA, WT1, ASXL1, DNMT3A, MLL (fusions and PTD), IDH1, IDH2 and TET2...
June 2015: EBioMedicine
Zafar Iqbal, Tanveer Akhtar, Tashfin Awan, Aamer Aleem, Noreen Sabir, Mahmood Rasool, Muhammad Absar, Afia M Akram, Masood A Shammas, Ijaz H Shah, Muhammad Khalid, Abid S Taj, Abid Jameel, Abdullah Alanazi, Ammara T Gill, Jamil Amjad Hashmi, Akhtar Hussain, Muhammad Farooq Sabar, Ahmad M Khalid, Mehmood Hussain Qazi, Sajjad Karim, Muhammad Hassan Siddiqi, Aamir Mahmood, Mudassar Iqbal, Anjum Saeed, Muhammad Imran Irfan
BACKGROUND: Fusion oncogenes (FOs) resulting from chromosomal abnormalities have an important role in leukemogenesis in pediatric B cell acute lymphoblastic leukemia (ALL). The most common FOs are BCR-ABL, MLL-AF4, ETV6-RUNX1, and TCF3-PBX1, all of which have important prognostic and drug selection implications. Moreover, frequencies of FOs have ethnic variations. We studied Pakistani frequencies of FOs, clinical pattern, and outcome in pediatric B-ALL. METHODS: FOs were studied in 188 patients at diagnosis using reverse transcriptase-polymerase chain reaction (RT-PCR) and interphase fluorescent in situ hybridization (FISH)...
October 2015: Molecular Diagnosis & Therapy
Anita Chopra, Sushant Soni, Deepak Verma, Dev Kumar, Rahul Dwivedi, Anjali Vishwanathan, Garima Vishwakama, Sameer Bakhshi, Rachna Seth, Ajay Gogia, Lalit Kumar, Rajive Kumar
AIM: Information about fusion transcripts in acute lymphoblastic leukemia (ALL) is used to risk-stratify patients, decide on the treatment and to detect minimal residual disease. This study was conducted to determine the frequency of common fusion transcripts BCR-ABL, TEL-AML1, MLL-AF4 and E2A-PBX1 for B-ALL and SIL-TAL1 for T-ALL as seen at a tertiary care center in India. METHODS: Up to 304 new cases of ALL (271 B-ALL and 33 T-ALL) diagnosed on morphology, cytochemistry and immunophenotyping were studied...
December 2015: Asia-Pacific Journal of Clinical Oncology
Hiroto Inaba, Yinmei Zhou, Oussama Abla, Souichi Adachi, Anne Auvrignon, H Berna Beverloo, Eveline de Bont, Tai-Tsung Chang, Ursula Creutzig, Michael Dworzak, Sarah Elitzur, Alcira Fynn, Erik Forestier, Henrik Hasle, Der-Cherng Liang, Vincent Lee, Franco Locatelli, Riccardo Masetti, Barbara De Moerloose, Dirk Reinhardt, Laura Rodriguez, Nadine Van Roy, Shuhong Shen, Takashi Taga, Daisuke Tomizawa, Allen E J Yeoh, Martin Zimmermann, Susana C Raimondi
Comprehensive clinical studies of patients with acute megakaryoblastic leukemia (AMKL) are lacking. We performed an international retrospective study on 490 patients (age ≤18 years) with non-Down syndrome de novo AMKL diagnosed from 1989 to 2009. Patients with AMKL (median age 1.53 years) comprised 7.8% of pediatric AML. Five-year event-free (EFS) and overall survival (OS) were 43.7% ± 2.7% and 49.0% ± 2.7%, respectively. Patients diagnosed in 2000 to 2009 were treated with higher cytarabine doses and had better EFS (P = ...
September 24, 2015: Blood
S Angelova, B Spassov, V Nikolova, I Christov, N Tzvetkov, M Simeonova
The aim of our study was 1) to define if the amplification of c-MYC, MLL and RUNX1 genes is related to the progressive changes of the karyotype in patients with AML and MDS with trisomy 8, 11 and 21 (+8, +11 and +21) in bone marrow and 2) can that amplification be accepted as part of the clonal evolution (CE). Karyotype analysis was performed in 179 patients with AML or MDS with the different chromosomal aberrations (CA) aged 16-81. The findings were distributed as follow: initiating balanced CA (n = 60), aneuploidia (n = 55), unbalanced CA (n = 64)...
May 2015: T︠S︡itologii︠a︡ i Genetika
G A Tsaur, T O Riger, A M Popov, T V Nasedkina, A M Kustanovich, A G Solodovnikov, O V Streneva, E V Shorikov, S V Tsvirenko, L I Saveliev, L G Fechina
The occurrence of minimal residual disease is an important prognostic factor under acute lymphoblastic leucosis in children and adults. In overwhelming majority of research studies bone marrow is used to detect minimal residual disease. The comparative characteristic of detection of minimal residual disease in peripheral blood and bone marrow was carried out. The prognostic role of occurrence of minimal residual disease in peripheral blood and bone marrow under therapy according protocol MLL-Baby was evaluated...
April 2015: Klinicheskaia Laboratornaia Diagnostika
Md Jobayer Hossain, Li Xie, Emi H Caywood
Growing insight into prognosis of pediatric acute myeloid leukemia (AML) survival has led to improved outcome over time and could be further enhanced through investigation using a large number of patients. To characterize the extent of the association of pediatric AML survival with its identified prognostic factors, we analyzed the United States population-based Surveillance Epidemiology and End Results (SEER) large dataset of 3442 pediatric AML patients diagnosed and followed between 1973 and 2011 using a Cox proportional hazards model stratified by year of diagnosis...
October 2015: Cancer Epidemiology
Etienne Danis, Taylor Yamauchi, Kristen Echanique, Jessica Haladyna, Roshni Kalkur, Simone Riedel, Nan Zhu, Huafeng Xie, Kathrin M Bernt, Stuart H Orkin, Scott A Armstrong, Tobias Neff
Polycomb repressive complex 2 (PRC2) is a chromatin regulator with central roles in development and cancer. The canonical function of PRC2 is the trimethylation of histone 3 on lysine residue 27. This epigenetic modification is associated with gene silencing. Both tumor suppressor and oncogenic functions have been reported for PRC2, depending on cellular context. In leukemia mediated by the leukemogenic fusion MLL-AF9, complete ablation of canonical PRC2 function by genetic inactivation of the core component embryonic ectoderm development (Eed) or by combined pharmacologic inhibition of the PRC2 methyltransferases EZH2 and EZH1 has a strong anti-leukemic effect, and this effect has been linked to de-repression of the PRC2 target locus Cdkn2a...
November 2015: Experimental Hematology
Yuan-Yuan Ren, Yao Zou, Li-Xian Chang, Wen-Bin An, Yang Wan, Jing-Liao Zhang, Tian-Feng Liu, Xiao-Fan Zhu
OBJECTIVE: To ovaluate the prognostic value of prednisone response in treatment regimes of children with acute lymphoblastic leukemia. METHODS: A total of 598 newly diagnosed ALL patients were enrolled and received prednisone pre-treatment. Based on the peripheral lymphoblast count on day 8, these patients were divided into 2 groups: prednisone good response (PGR) and prednisone poor response (PPR). PPR patients were classified into high risk group immediately and then received intensed chemotherapy...
June 2015: Zhongguo Shi Yan Xue Ye Xue za Zhi
Ting-Fu Su, Herng-Sheng Lee, Hong-Wei Gao, Shin Nieh, Chih-Kung Lin
Massive localized lymphedema (MLL) is an uncommon benign skin lesion typically presenting with prominent edema and vascular proliferation in the adipose tissue of lower limbs. When rarely occurring in scrotum, it instead is characterized by a striking proliferation of dermal smooth muscle bundles mimicking acquired smooth muscle hamartoma of dartos. The authors report a rare case of scrotal MLL. A 57-year-old obese man with a history of previous surgery for rectal adenocarcinoma, 20 years earlier, presented with progressive nodular enlargement of the scrotum for 2 years, causing discomfort, difficulty in ambulation, and cosmetic problems...
July 2015: American Journal of Dermatopathology
A Pigneux, M Labopin, J Maertens, C Cordonnier, L Volin, G Socié, D Blaise, C Craddock, N Milpied, U Bacher, F Malard, J Esteve, A Nagler, M Mohty
Acute myeloid leukemia (AML) with 11q23/MLL rearrangement (MLL-r AML) is allocated to the intermediate- or high-risk cytogenetic prognostic category depending on the MLL fusion partner. A more favorable outcome has been reported in patients receiving an allogeneic hematopoietic stem-cell transplantation (alloHSCT), but this has not been confirmed in large series. We analyzed the outcome of alloHSCT among adult patients reported to the Acute Leukemia Working Party between 2000 and 2010. We identified 159 patients with 11q23/MLL rearranged AML allografted in first complete remission (CR1, n=138) or CR2, mostly corresponding to t(9;11), t(11;19), t(6;11) and t(10;11) translocations...
December 2015: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Joseph J Ferry, Robert F Smith, Natalie Denney, Colin P Walsh, Lauren McCauley, Jie Qian, Haiching Ma, Kurumi Y Horiuchi, Konrad T Howitz
Methylation of histone H3 lysine-4 (H3K4) is an important, regulatory, epigenetic post-translational modification associated with actively transcribed genes. In humans, the principal mediators of this modification are part of the MLL/SET1 family of methyltransferases, which comprises six members, MLLs1-4 and SET1A/SET1B. Aberrations in the structure, expression, and regulation of these enzymes are implicated in various disease states, making them important potential targets for drug discovery, particularly for oncology indications...
May 2015: Assay and Drug Development Technologies
Luyun Peng, Xin Yang, Yingchi Zhang, Tianyuan Hu, Weili Wang, Xiaomin Wang, Jing Xu, Tao Cheng, Weiping Yuan, Yingdai Gao
OBJECTIVE: To establish the ADAR1 (adenosine deaminase that act on RNA 1) knockout MLL-AF9 acute myeloid leukemia (AML) mouse model, and to preliminarily investigate the effects of ADAR1 deletion on the development of AML. METHODS: The lineage⁻ (Lin⁻) cells of ER-CreADAR1(lox/lox) mice and their ADAR1(lox/lox) counterparts were enriched by magnetic activated cell sorting (MACS) and then transduced with retrovirus carrying MSCV- MLL/AF9-IRES-GFP fusion gene. The efficiency of transduction was detected by flow cytometry, and equal number of GFP⁺ cells were transplanted into lethally irradiated recipient mice...
May 2015: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Anna Wojtuszkiewicz, Godefridus J Peters, Nicole L van Woerden, Boas Dubbelman, Gabriele Escherich, Kjeld Schmiegelow, Edwin Sonneveld, Rob Pieters, Peter M van de Ven, Gerrit Jansen, Yehuda G Assaraf, Gertjan J L Kaspers, Jacqueline Cloos
BACKGROUND: Methotrexate (MTX) eradicates leukemic cells by disrupting de novo nucleotide biosynthesis and DNA replication, resulting in cell death. Since its introduction in 1947, MTX-containing chemotherapeutic regimens have proven instrumental in achieving curative effects in acute lymphoblastic leukemia (ALL). However, drug resistance phenomena pose major obstacles to efficacious ALL chemotherapy. Moreover, clinically relevant molecular mechanisms underlying chemoresistance remain largely obscure...
2015: Journal of Hematology & Oncology
Rajesh C Rao, Yali Dou
Histone-lysine N-methyltransferase 2 (KMT2) family proteins methylate lysine 4 on the histone H3 tail at important regulatory regions in the genome and thereby impart crucial functions through modulating chromatin structures and DNA accessibility. Although the human KMT2 family was initially named the mixed-lineage leukaemia (MLL) family, owing to the role of the first-found member KMT2A in this disease, recent exome-sequencing studies revealed KMT2 genes to be among the most frequently mutated genes in many types of human cancers...
June 2015: Nature Reviews. Cancer
Kateřina Zdráhalová, Jaroslav Štěrba, Jiří Domanský, Bohumír Blažek, Hana Ptoszková, Vladimír Mihál, Zbyněk Novák, Jiří Hak, Daniela Procházková, Zdena Černá, Pavel Timr, Yahia Jabali, Petr Sedláček, Petr Smíšek, Zuzana Zemanová, Marie Jarošová, Alena Houdková, Ester Mejstříková, Ondřej Hrušák, Jan Zuna, Iveta Janotová, Jan Trka, Jan Starý
BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most frequent childhood malignancy. Treatment has been unified in the middle of 1980 in the Czech Republic. In 2002-2007 children and adolescents with acute lymphoblastic leukemia were treated in an international randomized trial ALL-IC BFM 2002 in the Czech Republic. 291 patients aged 1-18 years were enrolled; infants below 1 year entered a separate trial. METHODS AND RESULTS: Patients were stratified into three risk groups according to their age, initial leukocyte count, prednisone response, presence of fusion genes BCR/ABL or MLL/AF4, bone marrow D+15 and remission status D+33...
2015: Casopís Lékar̆ů C̆eských
U Creutzig, M Dworzak, M Zimmermann, J-P Bourquin, B Gruhn, G Fleischhack, N Graf, T Klingebiel, B Kremens, T Lehrnbecher, C von Neuhoff, A von Stackelberg, J Stray, D Reinhardt
BACKGROUND: The outcome in children and adolescents with high-risk (HR) acute myeloid leukemia (AML) is still unsatisfactory. Therefore, in study AML-BFM 2004 we aimed to improve outcome of HR-patients by adding moderately dosed 2-Chloro-2-Deoxyadenosine (2-CDA) to the respective consolidation treatment backbone without increasing toxicity. The aim was to improve prognosis especially in FAB M4/M5/MLL patients, who represent the largest subgroup of HR patients. PATIENTS AND METHODS: In total, 343 children and adolescents with HR-AML were randomized to receive or not 2-CDA (6 mg/m²/d, days 1, 3) in combination with cytarabine/idarubicine (AI=500 mg/m² cytarabine 5 days continuous infusion plus 7 mg/m²/d idarubicin, days 3 and 5)...
May 2015: Klinische Pädiatrie
Leonardo K Teixeira, Xianlong Wang, Yongjiang Li, Susanna Ekholm-Reed, Xiaohua Wu, Pei Wang, Steven I Reed
Cell-cycle progression is regulated by the cyclin-dependent kinase (Cdk) family of protein kinases, so named because their activation depends on association with regulatory subunits known as cyclins. Cyclin E normally accumulates at the G1/S boundary, where it promotes S phase entry and progression by activating Cdk2. In normal cells, cyclin E/Cdk2 activity is associated with DNA replication-related functions. However, deregulation of cyclin E leads to inefficient assembly of pre-replication complexes, replication stress, and chromosome instability...
May 18, 2015: Current Biology: CB
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