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Wei Yang, Phu Tran, Ziad Khan, Sherif Rezk, Susan O'Brien
No abstract text is available yet for this article.
October 24, 2016: Leukemia & Lymphoma
Daniel Gehlbach, Prasad Koduru, George John, Franklin Fuda, Arthur E Frankel, Weina Chen
No abstract text is available yet for this article.
October 24, 2016: British Journal of Haematology
Maulik Vyas, Ann-Charlott Schneider, Olga Shatnyeva, Katrin S Reiners, Samir Tawadros, Stephan Kloess, Ulrike Köhl, Michael Hallek, Hinrich P Hansen, Elke Pogge von Strandmann
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia that affects B lymphocytes in adults. Natural killer (NK) cells in CLL patients are intrinsically potent but display poor in situ effector functions. NKG2D is an activating receptor found on NK and CD8(+) T cells and plays a role in immunosurveillance of CLL. In this study, we developed mono- and dual-targeting triplebodies utilizing a natural ligand for human NKG2D receptor (ULBP2) to retarget NK cells against tumor cells. Triplebodies in both formats showed better ability to induce NK-cell-dependent killing of target cells compared to bispecific counterparts...
2016: Oncoimmunology
Hubo Li, Brenton G Mar, Huadi Zhang, Rishi V Puram, Francisca Vazquez, Barbara A Weir, William C Hahn, Benjamin Ebert, David Pellman
Acute myeloid leukemia (AML) is a heterogeneous disease with complex molecular pathophysiology. To systematically characterize AML's genetic dependencies, we conducted genome-scale shRNA screens in 17 AML cell lines and analyzed dependencies relative to parallel screens in 199 cell lines of other cancer types. We identified 353 genes specifically required for AML cell proliferation. To validate the in vivo relevance of genetic dependencies observed in human cell lines, we performed a secondary screen in a syngeneic murine AML model driven by the MLL-AF9 oncogenic fusion protein...
October 18, 2016: Blood
Fei Lu, Xiaojun Wu, Feng Yin, Christina Chia-Fang Lee, Min Yu, Ivailo S Mihaylov, Jiekai Yu, Hong Sun, Hui Zhang
DNA replication licensing occurs on chromatin, but how the chromatin template is regulated for replication remains mostly unclear. Here, we have analyzed the requirement of histone methyltransferases for a specific type of replication: the DNA re-replication induced by the downregulation of either Geminin, an inhibitor of replication licensing protein CDT1, or the CRL4CDT2 ubiquitin E3 ligase. We found that siRNA-mediated reduction of essential components of the MLL-WDR5-RBBP5 methyltransferase complexes including WDR5 or RBBP5, which transfer methyl groups to histone H3 at K4 (H3K4), suppressed DNA re-replication and chromosomal polyploidy...
October 15, 2016: Biology Open
E Dietzel, J Floehr, E Van de Leur, R Weiskirchen, W Jahnen-Dechent
STUDY QUESTION: Does fetuin-B inhibit premature zona pellucida (ZP) hardening in mouse oocytes in vitro and thus increase IVF rate? SUMMARY ANSWER: Supplementation of oocyte in vitro maturation (IVM) media with recombinant mouse fetuin-B (rmFetuB) increased fertilization rate without affecting mouse embryo development into blastocysts. WHAT IS KNOWN ALREADY: Mice deficient in fetuin-B are infertile owing to premature ZP hardening. Premature ZP hardening also occurs during oocyte IVM leading to decreased fertilization rate...
October 12, 2016: Molecular Human Reproduction
Rima Koka, Candace B Mainor, Arnob Banerjee, Maria R Baer, Ying S Zou
No abstract text is available yet for this article.
October 12, 2016: Leukemia & Lymphoma
Min Huang, Jacqueline S Garcia, Daniel Thomas, Li Zhu, Le Xuan Truong Nguyen, Steven M Chan, Ravindra Majeti, Bruno C Medeiros, Beverly S Mitchell
The mechanisms underlying activation of the BET pathway in AML cells remain poorly understood. We have discovered that autophagy is activated in acute leukemia cells expressing mutant nucleophosmin 1 (NPMc+) or MLL-fusion proteins. Autophagy activation results in the degradation of NPM1 and HEXIM1, two negative regulators of BET pathway activation. Inhibition of autophagy with pharmacologic inhibitors or through knocking down autophagy-related gene 5 (Atg5) expression increases the expression of both NPM1 and HEXIM1...
October 6, 2016: Oncotarget
Dong-Dong Li, Zhi-Hui Wang, Wei-Lin Chen, Yi-Yue Xie, Qi-Dong You, Xiao-Ke Guo
WDR5 is an essential protein for enzymatic activity of MLL1. Targeting the protein-protein interaction (PPI) between MLL1 and WDR5 represents a new potential therapeutic strategy for MLL leukemia. Based on the structure of reported inhibitor WDR5-0103, a class of ester compounds were designed and synthetized to disturb MLL1-WDR5 PPI. These inhibitors efficiently inhibited the histone methyltransferase activity in vitro. Especially, WL-15 was one of the most potent inhibitors, blocking the interaction of MLL1-WDR5 with IC50 value of 26...
October 1, 2016: Bioorganic & Medicinal Chemistry
Rajasree Pia Chowdry, Elisa Ledet, Lahiru Ranasinghe, Alton Oliver Sartor
The mixed-lineage leukemia (MLL) protein acts as a histone methyltransferase regulating multiple genetic elements. Rearrangements of the MLL gene result in expression of MLL-fusion proteins that occur in some acute leukemias and are associated with poor prognosis. The MLL protein complex has been shown to interact with the androgen receptor via the MLL-menin subunit, thus promoting gene activation. The presence of MLL translocation has not been previously reported in patients with castrate resistant prostate cancer (CRPC)...
October 2016: Canadian Journal of Urology
Luca Trentin, Silvia Bresolin, Emanuela Giarin, Michela Bardini, Valentina Serafin, Benedetta Accordi, Franco Fais, Claudya Tenca, Paola De Lorenzo, Maria Grazia Valsecchi, Giovanni Cazzaniga, Geertruy Te Kronnie, Giuseppe Basso
To induce and sustain the leukaemogenic process, MLL-AF4+ leukaemia seems to require very few genetic alterations in addition to the fusion gene itself. Studies of infant and paediatric patients with MLL-AF4+ B cell precursor acute lymphoblastic leukaemia (BCP-ALL) have reported mutations in KRAS and NRAS with incidences ranging from 25 to 50%. Whereas previous studies employed Sanger sequencing, here we used next generation amplicon deep sequencing for in depth evaluation of RAS mutations in 36 paediatric patients at diagnosis of MLL-AF4+ leukaemia...
October 4, 2016: Scientific Reports
Meng-Ju Li, Hsi-Che Liu, Hsiu-Ju Yen, Tang-Her Jaing, Dong-Tsamn Lin, Chao-Ping Yang, Kai-Hsin Lin, Iou-Jih Hung, Shiann-Tarng Jou, Meng-Yao Lu, Chih-Cheng Hsiao, Ching-Tien Peng, Tai-Tsung Chang, Shih-Chung Wang, Ming-Tsan Lin, Jiann-Shiuh Chen, Te-Kau Chang, Giun-Yi Hung, Kang-Hsi Wu, Yung-Li Yang, Hsiu-Hao Chang, Shih-Hsiang Chen, Ting-Chi Yeh, Chao-Neng Cheng, Pei-Chin Lin, Shyh-Shin Chiou, Jiunn-Ming Sheen, Shin-Nan Cheng, Shu-Huey Chen, Yu-Hsiang Chang, Wan-Ling Ho, Yu-Hua Chao, Rong-Long Chen, Bow-Wen Chen, Jinn-Li Wang, Yuh-Lin Hsieh, Yu-Mei Liao, Shang-Hsien Yang, Wan-Hui Chang, Yu-Mei Y Chao, Der-Cherng Liang
BACKGROUND: Reinduction therapy has improved the outcomes in children with acute lymphoblastic leukemia (ALL). We sought to determine the optimal course(s) of reinduction therapy for standard-risk (SR, or "low-risk" in other groups) patients. Also, we evaluated outcomes using triple intrathecal therapy without cranial radiation (CrRT) for central nervous system (CNS) preventive therapy. PROCEDURE: From 2002 to 2012, all newly diagnosed children with ALL in Taiwan were enrolled in Taiwan Pediatric Oncology Group ALL-2002 protocol...
October 3, 2016: Pediatric Blood & Cancer
Ghayas C Issa, Hagop M Kantarjian, C Cameron Yin, Wei Qiao, Farhad Ravandi, Deborah Thomas, Nicholas J Short, Koji Sasaki, Guillermo Garcia-Manero, Tapan M Kadia, Jorge E Cortes, Naval Daver, Gautam Borthakur, Nitin Jain, Marina Konopleva, Issa Khouri, Partow Kebriaei, Richard E Champlin, Sherry Pierce, Susan M O'Brien, Elias Jabbour
BACKGROUND: The introduction of novel prognostic factors such as minimal residual disease (MRD) and genomic profiling has led to the reevaluation of the role of cytogenetics and other conventional factors in risk stratification for acute lymphoblastic leukemia (ALL). METHODS: This study assessed the impact of baseline cytogenetics on the outcomes of 428 adult patients with Philadelphia chromosome-negative ALL who were receiving frontline chemotherapy. Three hundred thirty patients (77%) were treated with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone-based regimens, and 98 (23%) were treated with the augmented Berlin-Frankfurt-Munster regimen...
October 3, 2016: Cancer
Alvaro Muñoz-López, Damià Romero-Moya, Cristina Prieto, Verónica Ramos-Mejía, Antonio Agraz-Doblas, Ignacio Varela, Marcus Buschbeck, Anna Palau, Xonia Carvajal-Vergara, Alessandra Giorgetti, Anthony Ford, Majlinda Lako, Isabel Granada, Neus Ruiz-Xivillé, Sandra Rodríguez-Perales, Raul Torres-Ruíz, Ronald W Stam, Jose Luis Fuster, Mario F Fraga, Mahito Nakanishi, Gianni Cazzaniga, Michela Bardini, Isabel Cobo, Gustavo F Bayon, Agustin F Fernandez, Clara Bueno, Pablo Menendez
Induced pluripotent stem cells (iPSCs) are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL) has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes...
October 11, 2016: Stem Cell Reports
James R P Worth, Shota Sakaguchi, Karl D Rann, Clarence J W Bowman, Motomi Ito, Gregory J Jordan, David M J S Bowman
Global increases in fire frequency driven by anthropogenic greenhouse emissions and land use change could threaten unique and ancient species by creeping into long-term fire refugia. The perhumid and mountainous western half of Tasmania is a globally important refugium for palaeo-endemic, fire intolerant lineages, especially conifers. Reproductive strategy will be crucial to the resilience of these organisms under warmer, dryer and more fire prone climates. This study analysed clonal versus sexual reproduction in old growth plots dominated by the palaeo-endemic conifer Athrotaxis cupressoides (Cupressaceae), a species that lacks any traits to tolerate frequent landscape fire...
September 26, 2016: Scientific Reports
Alexandre Rouette, Assya Trofimov, David Haberl, Geneviève Boucher, Vincent-Philippe Lavallée, Giovanni D'Angelo, Josée Hébert, Guy Sauvageau, Sébastien Lemieux, Claude Perreault
Based on transcriptomic analyses of thousands of samples from The Cancer Genome Atlas, we report that expression of constitutive proteasome (CP) genes (PSMB5, PSMB6, PSMB7) and immunoproteasome (IP) genes (PSMB8, PSMB9, PSMB10) is increased in most cancer types. In breast cancer, expression of IP genes was determined by the abundance of tumor infiltrating lymphocytes and high expression of IP genes was associated with longer survival. In contrast, IP upregulation in acute myeloid leukemia (AML) was a cell-intrinsic feature that was not associated with longer survival...
2016: Scientific Reports
Zhenhua Yang, Kushani Shah, Alireza Khodadadi-Jamayran, Hao Jiang
As the major histone H3K4 methyltransferases in mammals, the Set1/Mll complexes play important roles in animal development and are associated with many diseases, including hematological malignancies. However, the role of the H3K4 methylation activity of these complexes in fate determination of hematopoietic stem and progenitor cells (HSCs and HPCs) remains elusive. Here, we address this question by generating a conditional knockout mouse for Dpy30, which is a common core subunit of all Set1/Mll complexes and facilitates genome-wide H3K4 methylation in cells...
September 19, 2016: Journal of Experimental Medicine
Ariz Akhter, Muhammad Kashif Mughal, Ghaleb Elyamany, Gary Sinclair, Raja Zahratul Azma, Noraidah Masir, Salwati Shuib, Fariborz Rashid-Kolvear, Meer-Taher Shabani-Rad, Douglas Allan Stewart, Adnan Mansoor
BACKGROUND: The World Health Organization (WHO) classification system defines recurrent chromosomal translocations as the sole diagnostic and prognostic criteria for acute leukemia (AL). These fusion transcripts are pivotal in the pathogenesis of AL. Clinical laboratories universally employ conventional karyotype/FISH to detect these chromosomal translocations, which is complex, labour intensive and lacks multiplexing capacity. Hence, it is imperative to explore and evaluate some newer automated, cost-efficient multiplexed technologies to accommodate the expanding genetic landscape in AL...
2016: Diagnostic Pathology
Isabel Morgado-Palacin, Amanda Day, Matilde Murga, Vanesa Lafarga, Marta Elena Anton, Anthony Tubbs, Hua-Tang Chen, Aysegul Ergan, Rhonda Anderson, Avinash Bhandoola, Kurt G Pike, Bernard Barlaam, Elaine Cadogan, Xi Wang, Andrew J Pierce, Chad Hubbard, Scott A Armstrong, André Nussenzweig, Oscar Fernandez-Capetillo
Among the various subtypes of acute myeloid leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies because of an attenuated response by p53, a protein that induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AML(MLL) cells (with an MLL-ENL fusion and a constitutively active N-RAS independently of p53...
September 13, 2016: Science Signaling
Edith Schneider, Anna Staffas, Linda Röhner, Kathrin Krowiorz, Michael Heuser, Konstanze Döhner, Lars Bullinger, Hartmut Döhner, Linda Fogelstrand, Arefeh Rouhi, Florian Kuchenbauer, Lars Palmqvist
MicroRNA-155 (miR-155) is an oncogenic miRNA upregulated in various tumor types and leukemias and has been suggested as a potential drug target. Based on our previous work detecting high miR-155 levels in response to Meis1 overexpression in a murine Hox leukemia model, we show here the relationship among HOXA9, MEIS1, and miR-155 levels in MLL-translocated acute myeloid leukemia (AML) patients. Using mouse bone marrow cells transformed by MLL-fusion genes expressing graduated levels of Meis1, we show a positive correlation between miR-155 and Meis1...
September 13, 2016: Experimental Hematology
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