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https://www.readbyqxmd.com/read/28331319/humanized-cd7-nanobody-based-immunotoxins-exhibit-promising-anti-t-cell-acute-lymphoblastic-leukemia-potential
#1
Yuan Yu, Jialu Li, Xuejun Zhu, Xiaowen Tang, Yangyi Bao, Xiang Sun, Yuhui Huang, Fang Tian, Xiaomei Liu, Lin Yang
BACKGROUND: Nanobodies, named as VHHs (variable domain of heavy chain of HCAb [heavy-chain antibodies]), are derived from heavy-chain-only antibodies that circulate in sera of camelids. Their exceptional physicochemical properties, possibility of humanization, and unique antigen recognition properties make them excellent candidates for targeted delivery of biologically active components, including immunotoxins. In our previous efforts, we have successfully generated the monovalent and bivalent CD7 nanobody-based immunotoxins, which can effectively trigger the apoptosis of CD7-positive malignant cells...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28321121/dnmt3a-regulates-t-cell-development-and-suppresses-t-all-transformation
#2
A C Kramer, A Kothari, W C Wilson, H Celik, J Nikitas, C Mallaney, E L Ostrander, E Eultgen, A Martens, M C Valentine, A L Young, T E Druley, M E Figueroa, B Zhang, G A Challen
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors, and comprises approximately 15 and 25% of pediatric and adult ALL cases respectively. It is well-established that activating NOTCH1 mutations are the major genetic lesions driving T-ALL in most patients, but efforts to develop targeted therapies against this pathway have produced limited success in decreasing leukemic burden and come with significant clinical side effects...
March 21, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28318489/deletion-of-the-mad2l1-spindle-assembly-checkpoint-gene-is-tolerated-in-mouse-models-of-acute-t-cell-lymphoma-and-hepatocellular-carcinoma
#3
Floris Foijer, Lee A Albacker, Bjorn Bakker, Diana C Spierings, Ying Yue, Stephanie Z Xie, Stephanie H Davis, Annegret Lutum-Jehle, Darin Takemoto, Brian Hare, Brinley Furey, Roderick T Bronson, Peter M Lansdorp, Allan Bradley, Peter K Sorger
Chromosome instability (CIN) is deleterious to normal cells because of the burden of aneuploidy. However, most human solid tumors have an abnormal karyotype implying that gain and loss of chromosomes by cancer cells confers a selective advantage. CIN can be induced in the mouse by inactivating the spindle assembly checkpoint. This is lethal in the germline but we show here that adult T cells and hepatocytes can survive conditional inactivation of the Mad2l1 SAC gene and resulting CIN. This causes rapid onset of acute lymphoblastic leukemia (T-ALL) and progressive development of hepatocellular carcinoma (HCC), both lethal diseases...
March 20, 2017: ELife
https://www.readbyqxmd.com/read/28296250/different-genetic-alteration-of-a20-in-a-s%C3%A3-zary-syndrome-case-with-v%C3%AE-2-j%C3%AE-22-t-cell-clone
#4
Lingling Zhou, Haitao Zheng, Xin Huang, Lihua Zhu, Suijing Wu, Chengwu Zeng, Lijian Yang, Shaohua Chen, Gengxin Luo, Xin Du, Yangqiu Li
BACKGROUND: The comprehensive genetic alterations underlying the pathogenesis of Sézary syndrome (SS) remains largely unknown. Previous studies showed that alterations of tumor necrosis factor-α-induced protein 3 gene (TNFAIP3; A20) are frequent in SS. In this study, we characterized the mutation and polymorphisms of A20 in a case with SS and compared with the genetic feature of A20 in T-cell acute lymphoblastic leukemia (T-ALL). METHODS: Using a novel approach based on the combination of fine-tiling array comparative genomic hybridization ( and ligation-mediated polymerase chain reaction (LM-PCR) to identify SS clone, the polymorphisms in the A20 gene (promoter, exons 2-9 [coding region] and 3'UTR) were detected by PCR and sequencing...
March 14, 2017: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28295194/anti-leukaemic-activity-of-the-tyk2-selective-inhibitor-ndi-031301-in-t-cell-acute-lymphoblastic-leukaemia
#5
Koshi Akahane, Zhaodong Li, Julia Etchin, Alla Berezovskaya, Evisa Gjini, Craig E Masse, Wenyan Miao, Jennifer Rocnik, Rosana Kapeller, Jeremy R Greenwood, Hong Tiv, Takaomi Sanda, David M Weinstock, A Thomas Look
Activation of tyrosine kinase 2 (TYK2) contributes to the aberrant survival of T-cell acute lymphoblastic leukaemia (T-ALL) cells. Here we demonstrate the anti-leukaemic activity of a novel TYK2 inhibitor, NDI-031301. NDI-031301 is a potent and selective inhibitor of TYK2 that induced robust growth inhibition of human T-ALL cell lines. NDI-031301 treatment of human T-ALL cell lines resulted in induction of apoptosis that was not observed with the JAK inhibitors tofacitinib and baricitinib. Further investigation revealed that NDI-031301 treatment uniquely leads to activation of three mitogen-activated protein kinases (MAPKs), resulting in phosphorylation of ERK, SAPK/JNK and p38 MAPK coincident with PARP cleavage...
March 14, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28280276/regulation-of-pi3k-signaling-in-t-cell-acute-lymphoblastic-leukemia-a-novel-pten-ikaros-mir-26b-mechanism-reveals-a-critical-targetable-role-for-pik3cd
#6
T Yuan, Y Yang, J Chen, W Li, W Li, Q Zhang, Y Mi, R S Goswami, J Q You, D Lin, M D Qian, S Calin, Y Liang, R N Miranda, G A Calin, X Zhou, L Ma, P A Zweidler-Mc, B Liu, A P Weng, L J Medeiros, Y Zhang, M J You
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, and T-ALL patients are prone to early disease relapse and suffer from poor outcomes. The PTEN, PI3K/AKT, and Notch pathways are frequently altered in T-ALL. PTEN is a tumor suppressor that inactivates the PI3K pathway. We profiled miRNAs in Pten-deficient mouse T-ALL and identified miR-26b as a potentially dysregulated gene. We validated decreased expression levels of miR-26b in mouse and human T-ALL cells. In addition, expression of exogenous miR-26b reduced proliferation and promoted apoptosis of T-ALL cells in vitro, and hindered progression of T-ALL in vivo...
March 10, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28275904/on-progress-in-epidemiologic-academia
#7
Olli S Miettinen
Professor Hofman, in his capacity as the Editor-in-Chief of this journal of "epidemiology," invited me to write an essay for it, given that I've been immersed in epidemiologic academia for a good half-century already. He thought that I likely would have something noteworthy to say, based on my personal experience, about the evolution of "epidemiology" in those decades past, and perhaps also in decades yet to come. In this response to Hofman's invitation I naturally focus on my experience with the research-and-teaching (R & T) that are the core business of epidemiologic academia...
March 8, 2017: European Journal of Epidemiology
https://www.readbyqxmd.com/read/28270453/activation-of-the-lmo2-oncogene-through-a-somatically-acquired-neomorphic-promoter-in-t-cell-acute-lymphoblastic-leukemia
#8
Sunniyat Rahman, Michael Magnussen, Theresa E León, Nadine Farah, Zhaodong Li, Brian J Abraham, Krisztina Z Alapi, Rachel J Mitchell, Tom Naughton, Adele K Fielding, Arnold Pizzey, Sophia Bustraan, Christopher Allen, Teodora Popa, Karin Pike-Overzet, Laura Garcia-Perez, Rosemary E Gale, David C Linch, Frank J T Staal, Richard A Young, A Thomas Look, Marc R Mansour
Somatic mutations within non-coding genomic regions that aberrantly activate oncogenes have remained poorly characterized. Here we describe recurrent activating intronic mutations of LMO2, a prominent oncogene in T-cell acute lymphoblastic leukemia (T-ALL). Heterozygous mutations were identified in PF-382 and DU.528 T-ALL cell lines, in addition to 3.7% (6/160) of pediatric and 5.5% (9/163) of adult T-ALL patient samples. The majority of indels harbour putative de novo MYB, ETS1 or RUNX1 consensus binding sites...
March 7, 2017: Blood
https://www.readbyqxmd.com/read/28270163/t-all-and-thymocytes-a-message-of-noncoding-rnas
#9
REVIEW
Annelynn Wallaert, Kaat Durinck, Tom Taghon, Pieter Van Vlierberghe, Frank Speleman
In the last decade, the role for noncoding RNAs in disease was clearly established, starting with microRNAs and later expanded towards long noncoding RNAs. This was also the case for T cell acute lymphoblastic leukemia, which is a malignant blood disorder arising from oncogenic events during normal T cell development in the thymus. By studying the transcriptomic profile of protein-coding genes, several oncogenic events leading to T cell acute lymphoblastic leukemia (T-ALL) could be identified. In recent years, it became apparent that several of these oncogenes function via microRNAs and long noncoding RNAs...
March 7, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28260788/apobec-signature-mutation-generates-an-oncogenic-enhancer-that-drives-lmo1-expression-in-t-all
#10
Z Li, B J Abraham, A Berezovskaya, N Farah, Y Liu, T Leon, A Fielding, S H Tan, T Sanda, A S Weintraub, B Li, S Shen, J Zhang, M R Mansour, R A Young, A T Look
Oncogenic driver mutations are those that provide a proliferative or survival advantage to neoplastic cells resulting in clonal selection. Although most cancer causing mutations have been detected in the protein-coding regions of the cancer genome, driver mutations have recently also been discovered within noncoding genomic sequences. Thus, a current challenge is to gain precise understanding of how these unique genomic elements function in cancer pathogenesis, while clarifying mechanisms of gene regulation and identifying new targets for therapeutic intervention...
March 6, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28244454/applicability-of-a-single-5-color-cytoplasmic-markers-tube-as-primary-panel-for-immunophenotyping-of-acute-leukemia-a-gujarat-cancer-and-research-institute-experience
#11
B P Parikh, S P Patel, B N Raiya, H H Vora, D H Jetly
INTRODUCTION: Flow cytometry is highly sensitive for detection and quantitative analysis of surface and intracellular antigens in malignant hemopoietic cells. Immunophenotyping is a routine practice for classification and lineage assignment of acute leukemia. In the present study, our aim is to identify the role of a single 5 color, CD45, myeloperoxidase (MPO), cCD79a, cCD3, and Tdt, cytoplasmic markers combination as a primary tube. We compared with final diagnosis on the basis of morphology, cytochemistry, and primary and secondary panels of immunophenotyping and also with other study...
July 2016: Indian Journal of Cancer
https://www.readbyqxmd.com/read/28240214/genomic-alterations-of-non-coding-regions-underlie-human-cancer-lessons-from-t-all
#12
REVIEW
Adrian Rivera-Reyes, Katharina E Hayer, Craig H Bassing
It has been appreciated for decades that somatic genomic alterations that change coding sequences of proto-oncogenes, translocate enhancers/promoters near proto-oncogenes, or create fusion oncogenes can drive cancer by inducing oncogenic activities. An explosion of genome-wide technologies over the past decade has fueled discoveries of the roles of three-dimensional chromosome structure and powerful cis-acting elements (super-enhancers) in regulating gene transcription. In recent years, studies of human T cell acute lymphoblastic leukemia (T-ALL) using genome-wide technologies have provided paradigms for how non-coding genomic region alterations can disrupt 3D chromosome architecture or establish super-enhancers to activate oncogenic transcription of proto-oncogenes...
December 2016: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28229259/acidicapsa-ferrireducens-sp-nov-acidicapsa-acidiphila-sp-nov-and-granulicella-acidiphila-sp-nov-novel-acidobacteria-isolated-from-metal-rich-acidic-waters
#13
Carmen Falagán, Bärbel Foesel, Barrie Johnson
Four novel strains of Acidobacteria were isolated from water samples taken from pit lakes at two abandoned metal mines in the Iberian Pyrite Belt mining district, south-west Spain. Three of the isolates belong to the genus Acidicapsa (MCF9(T), MCF10(T), and MCF14) and one of them to the genus Granulicella (MCF40(T)). All isolates are moderately acidophilic (pH growth optimum 3.8-4.1) and mesophilic (temperature growth optima 30-32 °C). Isolates MCF10(T) and MCF40(T) grew at pH lower (<3.0) than previously reported for all other acidobacteria...
February 22, 2017: Extremophiles: Life Under Extreme Conditions
https://www.readbyqxmd.com/read/28225168/correlations-between-epstein-barr-virus-and-acute-leukemia
#14
Hongzai Guan, Hongxia Miao, Na Ma, Wei Lu, Bing Luo
Infection with Epstein-Barr virus (EBV) may be correlated to the onset of acute leukemia (AL). Studies were performed to investigate the relationship between EBV infection and immunophenotyping of acute lymphoblastic leukemia (ALL) and chromosome aberrations. Additionally, the effects of EBV on clinical prognosis were described. Fluorescence quantitative polymerase chain reaction (FQ-PCR) was used to detect EBV-DNA copy numbers from bone marrow in 110 cases of patients with ALL, 75 cases of patients with acute myeloid leukemia (AML), and 37 cases of hematologically healthy control subjects...
February 22, 2017: Journal of Medical Virology
https://www.readbyqxmd.com/read/28211568/targeted-therapies-for-t-cell-acute-lymphoblastic-leukaemia-t-all-what-makes-t-all-tyk
#15
EDITORIAL
David J Curtis
No abstract text is available yet for this article.
February 17, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28195849/detection-and-alterations-of-acetylcarnitine-in-human-skeletal-muscles-by-1h-mrs-at-7-t
#16
Radka Klepochová, Ladislav Valkovič, Martin Gajdošík, Thomas Hochwartner, Harald Tschan, Michael Krebs, Siegfried Trattnig, Martin Krššák
OBJECTIVES: The aims of this study were to detect the acetylcarnitine resonance line at 2.13 ppm in the human vastus lateralis and soleus muscles, assess T1 and T2 relaxation times, and investigate the diurnal and exercise-related changes in absolute concentration noninvasively, using proton magnetic resonance spectroscopy at 7 T. MATERIALS AND METHODS: All measurements were performed on a 7 T whole-body Magnetom MR system with a 28-channel knee coil. Five healthy, moderately trained volunteers participated in the assessment of the detectability, repeatability, and relaxation times of acetylcarnitine...
February 10, 2017: Investigative Radiology
https://www.readbyqxmd.com/read/28179281/scl-tal1-a-multi-faceted-regulator-from-blood-development-to-disease
#17
Catherine Porcher, Hedia Chagraoui, Maiken S Kristiansen
SCL/TAL1 is an essential transcription factor in normal and malignant hematopoiesis. It is required for specification of the blood program during development, adult hematopoietic stem cell (HSC) survival and quiescence, and terminal maturation of select blood lineages. Following ectopic expression, SCL contributes to oncogenesis in T-cell acute lymphoblastic leukemia (T-ALL). Remarkably, SCL's activities are all mediated through nucleation of a core quaternary protein complex (SCL:E-protein:LMO2:LDB1) and dynamic recruitment of conserved combinatorial associations of additional regulators in a lineage- and stage-specific context...
February 8, 2017: Blood
https://www.readbyqxmd.com/read/28174276/synergistic-antileukemic-therapies-in-notch1-induced-t-all
#18
Marta Sanchez-Martin, Alberto Ambesi-Impiombato, Yue Qin, Daniel Herranz, Mukesh Bansal, Tiziana Girardi, Elisabeth Paietta, Martin S Tallman, Jacob M Rowe, Kim De Keersmaecker, Andrea Califano, Adolfo A Ferrando
The Notch1 gene is a major oncogenic driver and therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL). However, inhibition of NOTCH signaling with γ-secretase inhibitors (GSIs) has shown limited antileukemic activity in clinical trials. Here we performed an expression-based virtual screening to identify highly active antileukemic drugs that synergize with NOTCH1 inhibition in T-ALL. Among these, withaferin A demonstrated the strongest cytotoxic and GSI-synergistic antileukemic effects in vitro and in vivo...
February 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28171800/epigenetic-drug-combination-overcomes-osteoblast-induced-chemoprotection-in-pediatric-acute-lymphoid-leukemia
#19
Anthony Quagliano, Anilkumar Gopalakrishnapillai, Sonali P Barwe
Although there has been much progress in the treatment of acute lymphoblastic leukemia (ALL), decreased sensitivity to chemotherapy remains a significant issue. Recent studies have shown how interactions with the bone marrow microenvironment can protect ALL cells from chemotherapy and allow for the persistence of the disease. Epigenetic drugs have been used for the treatment of ALL, but there are no reports on whether these drugs can overcome bone marrow-induced chemoprotection. Our study investigates the ability of the DNA methyltransferase inhibitor azacitidine and the histone deacetylase inhibitor panobinostat to overcome chemoprotective effects mediated by osteoblasts...
January 27, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28159681/the-dual-specificity-pi3k-mtor-inhibitor-pki-587-displays-efficacy-against-t-cell-acute-lymphoblastic-leukemia-t-all
#20
Mohiuddin Gazi, Sausan A Moharram, Alissa Marhäll, Julhash U Kazi
Although significant improvements have been made in the treatment of acute lymphoblastic leukemia (ALL), there is a substantial subset of high-risk T-cell ALL (T-ALL) patients with relatively poor prognosis. Like in other leukemia types, alterations of the PI3K/mTOR pathway are predominant in ALL which is also responsible for treatment failure and relapse. In this study, we show that relapsed T-ALL patients display an enrichment of the PI3K/mTOR pathway. Using a panel of inhibitors targeting multiple components of the PI3K/mTOR pathway, we observed that the dual-specific PI3K/mTOR inhibitor PKI-587 was the most selective inhibitor for T-ALL cells dependent on the PI3K/mTOR pathway...
February 1, 2017: Cancer Letters
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