Science.gov

Sample records for patienten mit aml

  1. [COPD und Klangtherapie: Pilotstudie zur Wirksamkeit einer Behandlung mit Körpertambura bei COPD-Patienten].

    PubMed

    Hartwig, Bernhard; Schmidt, Stefan; Hartwig, Isabella

    2016-01-01

    Hintergrund: Erkrankungen der Atemorgane treten mit steigendem Alter öfter auf, nehmen weltweit zu und sind häufige Ursachen für Morbidität und Mortalität. In dieser Pilotstudie wurde der Frage nachgegangen, ob eine einmalige 10-minütige Behandlung mit einer Körpertambura eine signifikante und effektive Verbesserung der Lungenfunktion von Patienten mit chronisch-obstruktiver Lungenerkrankung (COPD; GOLD-Stadium A oder B) erbringen kann. Patienten und Methoden: 54 Probanden konnten je zur Hälfte in eine Behandlungsgruppe (Körpertambura) und eine aktive Kontrollgruppe (Atemtherapie) randomisiert werden. Eine Bestimmung der Lungenfunktionsmessparameter «Einsekundenkapazität» (FEV1) und «inspiratorische Vitalkapazität» (IVC) zu den Zeitpunkten T1 (Baseline), T2 (direkt nach Behandlung) und als Follow-up etwa 3 Wochen nach T1 (T3). Ergebnisse: Die Behandlungsgruppe zeigte sich der Kontrollgruppe in beiden Werten signifikant überlegen. Die Zeit-×-Gruppe-Interaktion (Varianzanalyse) ergab p = 0,001 (FEV1) bzw. p = 0,04 (IVC). Die Behandlungsgruppe zeigte bei beiden Werten eine Verbesserung von klinischer Relevanz. Schlussfolgerung: Diese Ergebnisse zeigen, dass die Klangbehandlung mittels einer Körpertambura - neben den schulmedizinischen, leitliniengerechten Therapien - eine zusätzliche, nebenwirkungsarme, aber durchaus klinisch wirksame Option für die Behandlung von COPD-Patienten darstellen kann, um deren Lebensqualität zu stabilisieren und zu verbessern. PMID:27606616

  2. Acute myelogenous leukemia (AML) - children

    MedlinePlus

    Acute myelogenous leukemia - children; AML; Acute myeloid leukemia - children; Acute granulocytic leukemia - children; Acute myeloblastic leukemia - children; Acute non-lymphocytic leukemia (ANLL) - children

  3. Diagnose und Therapie einer Depression im höheren Lebensalter – Einflüsse von Patienten- und Arztmerkmalen

    PubMed Central

    von dem Knesebeck, Olaf; Bönte, Markus; Siegrist, Johannes; Marceau, Lisa; Link, Carol; McKinlay, John

    2013-01-01

    Zusammenfassung Studienergebnissee aus dem englischsprachigen Raum zeigen, dass diagnostische und therapeutische Entscheidungen von Hausärzten bei der Versorgung von depressiven Patienten systematischen Einflüssen unterliegen, und dass sowohl Merkmale des Arztes als auch des Patienten unabhängig vom Krankheitsbild Einfluss auf diese Entscheidungen haben. In der vorliegenden Arbeit werden Ergebnisse einer deutschen Studie präsentiert, in der die Einflüsse von Patienten- und Arztmerkmalen auf diagnostische und therapeutische ärztliche Entscheidungen bei einer Depression untersucht wurden. Unter Anwendung eines faktoriellen Experimentaldesigns spielten professionelle Schauspieler in Videofilmen die Rolle von Patienten, die Symptome für eine depressive Erkrankung äußern. In den Videofilmen, die alle auf einem identischen Skript basieren, wurden systematisch die Patientenmerkmale Alter (55 vs. 75 Jahre), Geschlecht und sozialer Status (Hausmeister vs. Lehrer) variiert. Die randomisierte Ärztestichprobe wurde nach dem Arztgeschlecht und professioneller Erfahrung (< 5 vs. > 15 Jahre) geschichtet. Der Videofilm wurde insgesamt 128 niedergelassenen Ärzten für Allgemeinmedizin und hausärztlich tätigen Internisten in ihrer Praxis vorgespielt. Danach wurden die Ärzte zu unterschiedlichen Aspekten von Diagnose und Therapie befragt. Es wurde erhoben, ob der Arzt dem Patienten über das gezeigte Gespräch hinausgehende Fragen stellen würde, welche Diagnosen er für wahrscheinlich hält, wie sicher er sich mit seiner Diagnose ist, welche diagnostischen Tests er anordnen würde, ob er den Patienten überweisen würde oder ob er Medikamente verordnen oder ihm Empfehlungen zur Änderung seines Lebensstils geben würde. Die Ergebnisse weisen darauf hin, dass sowohl die Diagnose als auch die Therapie einer Depression durch niedergelassene Hausärzte in Deutschland nur geringfügig durch die untersuchten Merkmale der Patienten und der behandelnden Ärzte beeinflusst wird

  4. AML Guide: Information for Patients and Caregivers

    MedlinePlus

    ... Planning About AML Treatments Relapsed or Refractory AML Stem Cell Transplantation Acute Promyelocytic Leukemia (APL) Treatment Acute Monocytic ... are made in the marrow. They begin as stem cells. Stem cells become red cells, white cells and ...

  5. AML Guide: Information for Patients and Caregivers

    MedlinePlus

    ... an example. The AML Guide I page 27 Late effects are medical problems that do not show up until years after treatment ends. Heart disease is ... AML need to see the doctor for follow-up care. Children who are treated for AML may ... should talk with their doctors about any long-term or late effects that may be related to their treatment. ...

  6. AML1/ETO oncoprotein is directed to AML1 binding regions and co-localizes with AML1 and HEB on its targets.

    PubMed

    Gardini, Alessandro; Cesaroni, Matteo; Luzi, Lucilla; Okumura, Akiko J; Biggs, Joseph R; Minardi, Simone P; Venturini, Elisa; Zhang, Dong-Er; Pelicci, Pier Giuseppe; Alcalay, Myriam

    2008-11-01

    A reciprocal translocation involving chromosomes 8 and 21 generates the AML1/ETO oncogenic transcription factor that initiates acute myeloid leukemia by recruiting co-repressor complexes to DNA. AML1/ETO interferes with the function of its wild-type counterpart, AML1, by directly targeting AML1 binding sites. However, transcriptional regulation determined by AML1/ETO probably relies on a more complex network, since the fusion protein has been shown to interact with a number of other transcription factors, in particular E-proteins, and may therefore target other sites on DNA. Genome-wide chromatin immunoprecipitation and expression profiling were exploited to identify AML1/ETO-dependent transcriptional regulation. AML1/ETO was found to co-localize with AML1, demonstrating that the fusion protein follows the binding pattern of the wild-type protein but does not function primarily by displacing it. The DNA binding profile of the E-protein HEB was grossly rearranged upon expression of AML1/ETO, and the fusion protein was found to co-localize with both AML1 and HEB on many of its regulated targets. Furthermore, the level of HEB protein was increased in both primary cells and cell lines expressing AML1/ETO. Our results suggest a major role for the functional interaction of AML1/ETO with AML1 and HEB in transcriptional regulation determined by the fusion protein. PMID:19043539

  7. Rational Combinations of Targeted Agents in AML

    PubMed Central

    Bose, Prithviraj; Grant, Steven

    2015-01-01

    Despite modest improvements in survival over the last several decades, the treatment of AML continues to present a formidable challenge. Most patients are elderly, and these individuals, as well as those with secondary, therapy-related, or relapsed/refractory AML, are particularly difficult to treat, owing to both aggressive disease biology and the high toxicity of current chemotherapeutic regimens. It has become increasingly apparent in recent years that coordinated interruption of cooperative survival signaling pathways in malignant cells is necessary for optimal therapeutic results. The modest efficacy of monotherapy with both cytotoxic and targeted agents in AML testifies to this. As the complex biology of AML continues to be elucidated, many “synthetic lethal” strategies involving rational combinations of targeted agents have been developed. Unfortunately, relatively few of these have been tested clinically, although there is growing interest in this area. In this article, the preclinical and, where available, clinical data on some of the most promising rational combinations of targeted agents in AML are summarized. While new molecules should continue to be combined with conventional genotoxic drugs of proven efficacy, there is perhaps a need to rethink traditional philosophies of clinical trial development and regulatory approval with a focus on mechanism-based, synergistic strategies. PMID:26113989

  8. The applicability of the WHO classification in paediatric AML. A NOPHO-AML study.

    PubMed

    Sandahl, Julie D; Kjeldsen, Eigil; Abrahamsson, Jonas; Ha, Shau-Yin; Heldrup, Jesper; Jahnukainen, Kirsi; Jónsson, Ólafur G; Lausen, Birgitte; Palle, Josefine; Zeller, Bernward; Forestier, Erik; Hasle, Henrik

    2015-06-01

    The World Health Organization (WHO) classification of myeloid leukaemia was revised in 2008. It incorporates newly recognized entities and emphasizes the pivotal role of cytogenetic abnormalities. The aim of this study was to evaluate the usability of the WHO classification when applied to a large population-based paediatric acute myeloid leukaemia (AML) cohort. We included children diagnosed with de novo AML, 0-18 years of age from the Nordic countries and Hong Kong from 1993 to 2012. Data were retrieved from the Nordic Society for Paediatric Haematology and Oncology AML database and patients classified according to the WHO 2008 classification. A successful karyotype was available in 97% of the cases. AML with recurrent genetic abnormalities were present in 262 (41%) and 94 (15%) were classified as AML with myelodysplasia-related changes (AML-MDS). WHO classifies patients with monosomy 7 and del(7q) into one group. We found that -7 (n = 14) had significantly poorer outcome than del(7q) (n = 11); 5-year event-free survival 26% vs. 67%, (P = 0·02), and 5-year overall survival 51% vs. 90%, (P = 0·04). The largest group was the highly heterogeneous AML not otherwise specified (NOS) (n = 280) (44%). In conclusion, the WHO classification allocated 15% to AML-MDS, 44% to NOS and grouped together entities with clearly different outcome, therefore limiting the applicability of the current WHO classification in children with AML. PMID:25819835

  9. Prognostic Factors in Childhood Leukemia (ALL or AML)

    MedlinePlus

    ... for childhood leukemias Prognostic factors in childhood leukemia (ALL or AML) Certain factors that can affect a ... myelogenous leukemia (AML). Prognostic factors for children with ALL Children with ALL are often divided into risk ...

  10. The chimeric genes AML1/DS1 and AML1/EAP inhibit AML1B activation at the CSF1R promoter, but only AML1/MDS1 has tumor-promoter properties

    SciTech Connect

    Zent, C.S.; Matheiu, C.; Rowley, J.D.

    1996-02-06

    The (3;21)(q26;q22) translocation associated with treatment-related myelodysplastic syndrome, treatment-related acute myeloid leukemia, and blast crisis of chronic myeloid leukemia results in the expression of the chimeric genes AML1/EAP, AML1MDS1, and AML1/EVI1. AML1 (CBFA2), which codes for the {alpha} subunit of the heterodimeric transcription factor CBF, is also involved in the t(8;21), and the gene coding for the {beta} subunit (CBFB) is involved in the inv(16). These are two of the most common recurring chromosomal rearrangements in acute myeloid leukemia. CBF corresponds to the murine Pebp2 factor, and CBF binding sites are found in a number of eukaryotic and viral enhancers and promoters. We studied the effects of AML1/EAP and AML1/MDS1 at the AML1 binding site of the CSF1R (macrophage-colony-stimulating factor receptor gene) promoter by using reporter gene assays, and we analyzed the consequences of the expression of both chimeric proteins in an embryonic rat fibroblast cell line (Rat1A) in culture and after injection into athymic nude mice. Unlike AML1, which is an activator of the CSF1R promoter, the chimeric proteins did not transactivate the CSF1R promoter site but acted as inhibitors of AMLI (CBFA2). AML1/EAP and AML1/MDS1 expressed in adherent Rat1A cells decreased contact inhibition of growth, and expression of AML1/MDS1 was associated with acquisition of the ability to grow in suspension culture. Expression of AML1/MDS1 increased the tumorigenicity of Rat1A cells injected into athymic nude mice, whereas AML1/EAP expression provented tumor growth. These results suggest that expression of AML1/MDS1 can interfere with normal AML1 function, and that AML1/MDS1 has tumor-promoting properties in an embryonic rat fibroblast cell line. 26 refs., 5 figs.

  11. AML engraftment in the NOD/SCID assay reflects the outcome of AML: implications for our understanding of the heterogeneity of AML

    PubMed Central

    Pearce, Daniel J.; Taussig, David; Zibara, Kazem; Smith, Lan-Lan; Ridler, Christopher M.; Preudhomme, Claude; Young, Bryan D.; Rohatiner, Ama Z.; Lister, T. Andrew; Bonnet, Dominique

    2006-01-01

    The nonobese diabetic/severe combined immunodeficient (NOD/SCID) assay is the current model for assessment of human normal and leukemic stem cells. We explored why 51% of 59 acute myeloid leukemia (AML) patients were unable to initiate leukemia in NOD/SCID mice. Increasing the cell dose, using more permissive recipients, and alternative tissue sources did not cause AML engraftment in most previously nonengrafting AML samples. Homing of AML cells to the marrow was the same between engrafters and nonengrafters. FLT3 internal tandem duplication (ITD) and nucleophosmin mutations occurred at a similar frequency in engrafters and nonengrafters. The only variable that was related to engraftment ability was the karyotypically defined risk stratification of individual AML cases. Of interest, follow-up of younger patients with intermediate-risk AML revealed a significant difference in overall survival between NOD/SCID engrafting and nonengrafting AMLs. Hence, the ability of AML to engraft in the NOD/SCID assay seems to be an inherent property of AML cells, independent of homing, conditioning, or cell frequency/source, which is directly related to prognosis. Our results suggest an important difference between leukemic initiating cells between engrafting and nonengrafting AML cases that correlates with treatment response. PMID:16234360

  12. MIT: Shaping the Future.

    ERIC Educational Resources Information Center

    Manning, Kenneth R., Ed.

    This book provides 16 essays by faculty and staff of the Massachusetts Institute of Technology (MIT) concerning what MIT is like today and offering a guide to its possible future. Emphasis is placed on local, national, and global issues, providing a current sampling of the state of concerns and opinions around MIT. Topics include the question of…

  13. Update on rational targeted therapy in AML.

    PubMed

    Shafer, Danielle; Grant, Steven

    2016-07-01

    Acute myeloid leukemia (AML) remains a challenge to both patients and clinicians. Despite improvements in our understanding of the disease, treatment has changed minimally and outcomes remain poor for the majority of patients. Within the last decade, there have been an increasing number of potential targets and pathways identified for development in AML. The classes of agents described in this review include but are not limited to epigenetic modifiers such as IDH inhibitors, BET inhibitors, and HDAC inhibitors as well as cell cycle and signaling inhibitors such as Aurora kinase inhibitors and CDK inhibitors. While the developments are encouraging, it is unlikely that targeting a single pathway will result in long-term disease control. Accordingly, we will also highlight potential rational partners for the novel agents described herein. PMID:26972558

  14. Update on rational targeted therapy in AML

    PubMed Central

    Shafer, Danielle; Grant, Steven

    2016-01-01

    Acute myeloid leukemia (AML) remains a challenge to both patients and clinicians. Despite improvements in our understanding of the disease, treatment has changed minimally and outcomes remain poor for the majority of patients. Within the last decade, there have been an increasing number of potential targets and pathways identified for development in AML. The classes of agents described in this review include but are not limited to epigenetic modifiers such as IDH inhibitors, BET inhibitors, and HDAC inhibitors as well as cell cycle and signaling inhibitors such as Aurora kinase inhibitors and CDK inhibitors. While the developments are encouraging, it is unlikely that targeting a single pathway will result in long-term disease control. Accordingly, we will also highlight potential rational partners for the novel agents described herein. PMID:26972558

  15. [Radiation-induced and therapy-related AML/MDS].

    PubMed

    Inaba, Toshiya

    2009-10-01

    Radiation induced acute myeloid leukemia (AML) was recognized a century ago, soon after mankind found radiation. Atomic bomb survivors developed de novo AML with relatively short latency with very high frequency. By contrast, excess occurrence of myelodysplastic syndrome (MDS) as well as solid tumors was found decades late. This difference may be due to etiology that many de novo AML patients harbor chimeric leukemogenic genes caused by chromosomal translocations, while MDS patients rarely carry chimeras. In addition, epigenetic change would play important roles. Therapy related leukemia is mainly caused by topoisomerase II inhibitors that cause de novo AML with an 11q23 translocation or by alkyrating agents that induce MDS/AML with an AML1 point mutation and monosomy 7. PMID:19860183

  16. New study reveals relatively few mutations in AML genomes - TCGA

    Cancer.gov

    Investigators for The Cancer Genome Atlas (TCGA) Research Network have detailed and broadly classified the genomic alterations that frequently underlie the development of acute myeloid leukemia (AML).

  17. Aberrant splicing and drug resistance in AML.

    PubMed

    de Necochea-Campion, Rosalia; Shouse, Geoffrey P; Zhou, Qi; Mirshahidi, Saied; Chen, Chien-Shing

    2016-01-01

    The advent of next-generation sequencing technologies has unveiled a new window into the heterogeneity of acute myeloid leukemia (AML). In particular, recurrent mutations in spliceosome machinery and genome-wide aberrant splicing events have been recognized as a prominent component of this disease. This review will focus on how these factors influence drug resistance through altered splicing of tumor suppressor and oncogenes and dysregulation of the apoptotic signaling network. A better understanding of these factors in disease progression is necessary to design appropriate therapeutic strategies recognizing specific alternatively spliced or mutated oncogenic targets. PMID:27613060

  18. Advanced Manned Launch System (AMLS) study

    NASA Technical Reports Server (NTRS)

    Ehrlich, Carl F., Jr.; Potts, Jack; Brown, Jerry; Schell, Ken; Manley, Mary; Chen, Irving; Earhart, Richard; Urrutia, Chuck; Randolph, Ray; Morris, Jim

    1992-01-01

    To assure national leadership in space operations and exploration in the future, NASA must be able to provide cost effective and operationally efficient space transportation. Several NASA studies and the joint NASA/DoD Space Transportation Architecture Studies (STAS) have shown the need for a multi-vehicle space transportation system with designs driven by enhanced operations and low costs. NASA is currently studying an advanced manned launch system (AMLS) approach to transport crew and cargo to the Space Station Freedom. Several single and multiple stage systems from air-breathing to all-rocket concepts are being examined in a series of studies potential replacements for the Space Shuttle launch system in the 2000-2010 time frame. Rockwell International Corporation, under contract to the NASA Langley Research Center, has analyzed a two-stage all-rocket concept to determine whether this class of vehicles is appropriate for the AMLS function. The results of the pre-phase A study are discussed.

  19. Nassi-Schneiderman Diagram in HTML Based on AML

    ERIC Educational Resources Information Center

    Menyhárt, László

    2013-01-01

    In an earlier work I defined an extension of XML called Algorithm Markup Language (AML) for easy and understandable coding in an IDE which supports XML editing (e.g. NetBeans). The AML extension contains annotations and native language (English or Hungarian) tag names used when coding our algorithm. This paper presents a drawing tool with which…

  20. CNS Involvement in AML Patient Treated with 5-Azacytidine

    PubMed Central

    Vasilatou, Diamantina; Papageorgiou, Sotirios; Bazani, Efthymia; Prasouli, Athina; Economopoulou, Christina; Roumpakis, Christoforos; Karakitsos, Petros; Dimitriadis, George; Pappa, Vasiliki

    2014-01-01

    Central nervous system (CNS) involvement in acute myeloid leukemia (AML) is a rare complication of the disease and is associated with poor prognosis. Sometimes the clinical presentation can be unspecific and the diagnosis can be very challenging. Here we report a case of CNS infiltration in a patient suffering from AML who presented with normal complete blood count and altered mental status. PMID:25197583

  1. CNS Involvement in AML Patient Treated with 5-Azacytidine.

    PubMed

    Vasilatou, Diamantina; Papageorgiou, Sotirios; Bazani, Efthymia; Prasouli, Athina; Economopoulou, Christina; Roumpakis, Christoforos; Karakitsos, Petros; Dimitriadis, George; Pappa, Vasiliki

    2014-01-01

    Central nervous system (CNS) involvement in acute myeloid leukemia (AML) is a rare complication of the disease and is associated with poor prognosis. Sometimes the clinical presentation can be unspecific and the diagnosis can be very challenging. Here we report a case of CNS infiltration in a patient suffering from AML who presented with normal complete blood count and altered mental status. PMID:25197583

  2. Are immunoconjugates approaching "standard of care" in AML?

    PubMed

    Estey, Elihu

    2013-09-01

    It seems clear that immunoconjugates, the combinations of antibodies with toxins, will play a role in therapy of acute myeloid leukemia (AML). It is also clear that sole emphasis on an average trial result is misplaced in AML, as the example of gentuzumab ozogamicin illustrates. Gemtuzumab added to chemotherapy can improve survival in many patients with newly diagnosed disease. The future of immunoconjugates, however, may rest on further defining the relation between CD33 and the AML stem cell and its importance in therapy. Three immunoconjugates with the cell surface antigens CD33, CD45, and CD30 will be reviewed here. PMID:24309528

  3. Proteomic and Genetic Approaches Identify Syk as an AML Target

    PubMed Central

    Hahn, Cynthia K.; Berchuck, Jacob E.; Ross, Kenneth N.; Kakoza, Rose M.; Clauser, Karl; Schinzel, Anna C.; Ross, Linda; Galinsky, Ilene; Davis, Tina N.; Silver, Serena J.; Root, David E.; Stone, Richard M.; DeAngelo, Daniel J.; Carroll, Martin; Hahn, William C.; Carr, Steven A.; Golub, Todd R.; Kung, Andrew L.; Stegmaier, Kimberly

    2009-01-01

    SUMMARY Cell-based screening can facilitate rapid identification of compounds inducing complex cellular phenotypes. Advancing a compound toward the clinic, however, generally requires identification of precise mechanisms of action. We previously found that epidermal growth factor receptor (EGFR) inhibitors induce acute myeloid leukemia (AML) differentiation via a non-EGFR mechanism. In this report, we integrated proteomic and RNAi-based strategies to identify their off-target anti-AML mechanism. These orthogonal approaches identified Syk as a target in AML. Genetic and pharmacological inactivation of Syk with a drug in clinical trial for other indications promoted differentiation of AML cells and attenuated leukemia growth in vivo. These results demonstrate the power of integrating diverse chemical, proteomic, and genomic screening approaches to identify therapeutic strategies for cancer. PMID:19800574

  4. Acute Myeloid Leukemia (AML) Treatment in Adults (Beyond the Basics)

    MedlinePlus

    ... and returned by IV infusion. Because the transplanted stem cells do not come from another person, there is no "graft versus ... leukemia (AML) (The Basics) Patient information: Leukemia in adults (The ... (bone marrow transplantation) (Beyond the Basics) Professional ...

  5. MPD work at MIT

    NASA Technical Reports Server (NTRS)

    Martinez-Sanchez, Manuel

    1991-01-01

    MPD work at MIT is presented in the form of the view-graphs. The following subject areas are covered: the MIT program, its goals, achievements, and roadblocks; quasi one-dimensional modeling; two-dimensional modeling - transport effects and Hall effect; microscopic instabilities in MPD flows and modified two stream instability; electrothermal stability theory; separation of onset and anode depletion; exit plane spectroscopic measurements; phenomena of onset as performance limiter; explanations of onset; geometry effects on onset; onset at full ionization and its consequences; relationship to anode depletion; summary on self-field MPD; applied field MPD - the logical growth path; the case for AF; the challenges of AF MPD; and recommendations.

  6. Genomic, immunophenotypic, and NPM1/FLT3 mutational studies on 17 patients with normal karyotype acute myeloid leukemia (AML) followed by aberrant karyotype AML at relapse.

    PubMed

    Wang, Eunice S; Sait, Sheila N J; Gold, David; Mashtare, Terry; Starostik, Petr; Ford, Laurie Ann; Wetzler, Meir; Nowak, Norma J; Deeb, George

    2010-10-15

    Normal karyotype (NK) is the most common cytogenetic group in acute myeloid leukemia (AML) diagnosis; however, up to 50% of these patients at relapse will have aberrant karyotype (AK) AML. To determine the etiology of relapsed AK AML cells, we evaluated cytogenetic, immunophenotypic, and molecular results of 17 patients with diagnostic NK AML and relapsed AK AML at our institute. AK AML karyotype was diverse, involving no favorable and largely (8 of 17) complex cytogenetics. Despite clear cytogenetic differences, immunophenotype and NPM1/FLT3 gene mutation status did not change between presentation and relapse in 83% (10 of 12) and 94% (15 of 16) cases, respectively. High-resolution array-based comparative genomic hybridization (aCGH) performed via paired aCGH on NK AML and AK AML samples from the same patient confirmed cytogenetic aberrations only in the relapse sample. Analysis of 16 additional diagnostic NK AML samples revealed no evidence of submicroscopic aberrations undetected by conventional cytogenetics in any case. These results favor evolution of NK AML leukemia cells with acquisition of novel genetic changes as the most common etiology of AK AML relapse as opposed to secondary leukemogenesis. Additional studies are needed to confirm whether AK AML cells represent selection of rare preexisting clones below aCGH detection and to further characterize the molecular lesions found at time of AK AML relapse. PMID:20875872

  7. Sequencing the AML Genome, Transcriptome, and Epigenome

    PubMed Central

    Mardis, Elaine R.

    2014-01-01

    Leukemia is a disease that develops as a result of changes in the genomes of hematopoietic cells, a fact first appreciated by microscopic examination of the bone marrow cell chromosomes of affected patients. These studies revealed that specific subtypes of leukemia diagnosis correlated with specific chromosomal abnormalities, such as the t(15;17) of acute promyelocytic leukemia1 and the t(9;22) of chronic myeloid leukemia2. Over time, our genomic characterization of hematologic malignancies has moved beyond the resolution of the microscope to that of individual nucleotides in the analysis of whole genome sequencing data using state-of-the-art massively parallel sequencing (MPS) instruments and algorithmic analyses of the resulting data. In addition to studying the genomic sequence alterations that occur in patient’s genomes, these same instruments can decode the methylation landscape of the leukemia genome and the resulting RNA expression landscape of the leukemia transcriptome. Broad correlative analyses can then integrate these three data types to better inform researchers and clinicians about the biology of individual acute myeloid leukemia (AML) cases, facilitating improvements in care and prognosis. PMID:25311738

  8. Standard anatomical medullary locking (AML) versus tricalcium phosphate-coated AML femoral prostheses

    PubMed Central

    Johnston, D.W.C. (Bill); Davies, Donna M.; Beaupré, Lauren A.; Lavoie, Guy

    2001-01-01

    Objectives To compare the preliminary rate and amount of bony ingrowth and calcar resorption between patients receiving either a standard anatomical medullary locking (AML) or a tricalcium phosphate (TCP)-coated AML femoral prosthesis and to compare preliminary clinical results. Design A prospective, randomized, double-blind clinical trial. Setting An acute care tertiary institution. Patients Between January 1993 and March 1995, 92 patients underwent primary total hip arthroplasty (THA). They were randomized to 2 groups of 46 — a control group or a treatment group. Of the 46 subjects enrolled in each group, no significant differences were seen preoperatively with respect to age, sex, diagnosis, clinical and radiographic assessment. Seventy-one patients were followed up for 24 months. Interventions Insertion of either a standard AML femoral implant (control group) or a TCP-coated AML femoral implant (treatment group). Outcome measures The degree of hypertrophy, calcar atrophy and the number of spot welds on standard postoperative radiographs at 6, 12 and 24 months. Clinically, assessment according to the Société internationale de chirurgie orthopédique et de traumatologie (SICOT) scale and a 100-point visual analogue scale (VAS) for pain. Results There were no prosthetic stem revisions in either group at the 24-month follow-up. Radiographically, bony ingrowth was not significantly different in the TCP-coated stem, by χ2 analysis of the degree of hypertrophy and number of spot welds present. Also by χ2 analysis, the degree of calcar atrophy was not significantly different between groups. The mean VAS score for pain at 24 months was 12.5 for the control and 12.1 for the treatment group. No significant differences were seen in any of the clinical categories of the SICOT Scale over the 24-month interval. Conclusion The objective of TCP-coating — to increase the rate and amount of bony ingrowth while reducing the rate of calcar resorption in non-cemented THA

  9. Mouse models of human AML accurately predict chemotherapy response

    PubMed Central

    Zuber, Johannes; Radtke, Ina; Pardee, Timothy S.; Zhao, Zhen; Rappaport, Amy R.; Luo, Weijun; McCurrach, Mila E.; Yang, Miao-Miao; Dolan, M. Eileen; Kogan, Scott C.; Downing, James R.; Lowe, Scott W.

    2009-01-01

    The genetic heterogeneity of cancer influences the trajectory of tumor progression and may underlie clinical variation in therapy response. To model such heterogeneity, we produced genetically and pathologically accurate mouse models of common forms of human acute myeloid leukemia (AML) and developed methods to mimic standard induction chemotherapy and efficiently monitor therapy response. We see that murine AMLs harboring two common human AML genotypes show remarkably diverse responses to conventional therapy that mirror clinical experience. Specifically, murine leukemias expressing the AML1/ETO fusion oncoprotein, associated with a favorable prognosis in patients, show a dramatic response to induction chemotherapy owing to robust activation of the p53 tumor suppressor network. Conversely, murine leukemias expressing MLL fusion proteins, associated with a dismal prognosis in patients, are drug-resistant due to an attenuated p53 response. Our studies highlight the importance of genetic information in guiding the treatment of human AML, functionally establish the p53 network as a central determinant of chemotherapy response in AML, and demonstrate that genetically engineered mouse models of human cancer can accurately predict therapy response in patients. PMID:19339691

  10. Mouse models of human AML accurately predict chemotherapy response.

    PubMed

    Zuber, Johannes; Radtke, Ina; Pardee, Timothy S; Zhao, Zhen; Rappaport, Amy R; Luo, Weijun; McCurrach, Mila E; Yang, Miao-Miao; Dolan, M Eileen; Kogan, Scott C; Downing, James R; Lowe, Scott W

    2009-04-01

    The genetic heterogeneity of cancer influences the trajectory of tumor progression and may underlie clinical variation in therapy response. To model such heterogeneity, we produced genetically and pathologically accurate mouse models of common forms of human acute myeloid leukemia (AML) and developed methods to mimic standard induction chemotherapy and efficiently monitor therapy response. We see that murine AMLs harboring two common human AML genotypes show remarkably diverse responses to conventional therapy that mirror clinical experience. Specifically, murine leukemias expressing the AML1/ETO fusion oncoprotein, associated with a favorable prognosis in patients, show a dramatic response to induction chemotherapy owing to robust activation of the p53 tumor suppressor network. Conversely, murine leukemias expressing MLL fusion proteins, associated with a dismal prognosis in patients, are drug-resistant due to an attenuated p53 response. Our studies highlight the importance of genetic information in guiding the treatment of human AML, functionally establish the p53 network as a central determinant of chemotherapy response in AML, and demonstrate that genetically engineered mouse models of human cancer can accurately predict therapy response in patients. PMID:19339691

  11. Abdichtungen mit Bitumenbahnen

    NASA Astrophysics Data System (ADS)

    Rahn, Axel C.; Unger, Wolfram

    Das Werk Bauwerksabdichtung von Karl Lufsky, im allgemeinen Sprachgebrauch auch Der Lufsky genannt, war immer das Standardwerk für Flächenabdichtungen mit Bitumenwerkstoffen. Karl Lufsky war erst Mitarbeiter des Geschäftsführers Otto Latendorf der 1924 in Berlin gegründeten Firma ARIDO Abdichtungs-GmbH und später ihr Geschäftsführer [8.1]. Eine Baustelle war seit 1950 der Keller der neuen Sowjetischen Botschaft Unter den Linden. Eines Tages sprach dort einer der russischen Ingenieur-Offiziere Otto Latendorf an und fragte ihn, ob er wohl eine schriftliche Zusammenfassung aller technischen Probleme der bituminösen Bauwerksabdichtung für ihn verfassen könnte. Mit dieser Schrift würde er sich dann zu seinem Abschlussexamen in Moskau melden. Vergüten wollte er den Arbeitsaufwand mit Lebensmittellieferungen. Otto Latendorf willigte ein und machte sich gemeinsam mit Karl Lufsky an die Arbeit. Dies war offensichtlich der Impuls für Karl Lufsky, einige Zeit später im Leipziger Teubner Verlag die erste Auflage des Buchs "Bauwerksabdichtungen“ herauszugeben, womit der Grundstein gelegt wurde, aus einer "Moskauer Examensarbeit“ in den letzten 50 Jahren ein bedeutendes Fachbuch zu machen.

  12. PU.1 downregulation in murine radiation-induced acute myeloid leukaemia (AML): from molecular mechanism to human AML

    PubMed Central

    Verbiest, Tom; Bouffler, Simon; Nutt, Stephen L.; Badie, Christophe

    2015-01-01

    The transcription factor PU.1, encoded by the murine Sfpi1 gene (SPI1 in humans), is a member of the Ets transcription factor family and plays a vital role in commitment and maturation of the myeloid and lymphoid lineages. Murine studies directly link primary acute myeloid leukaemia (AML) and decreased PU.1 expression in specifically modified strains. Similarly, a radiation-induced chromosome 2 deletion and subsequent Sfpi1 point mutation in the remaining allele lead to murine radiation-induced AML. Consistent with murine data, heterozygous deletion of the SPI1 locus and mutation of the −14kb SPI1 upstream regulatory element were described previously in human primary AML, although they are rare events. Other mechanisms linked to PU.1 downregulation in human AML include TP53 deletion, FLT3-ITD mutation and the recurrent AML1-ETO [t(8;21)] and PML-RARA [t(15;17)] translocations. This review provides an up-to-date overview on our current understanding of the involvement of PU.1 in the initiation and development of radiation-induced AML, together with recommendations for future murine and human studies. PMID:25750172

  13. Multiple Functional Domains of AML1: PU.1 and C/EBPα Synergize with Different Regions of AML1

    PubMed Central

    Petrovick, Martha S.; Hiebert, Scott W.; Friedman, Alan D.; Hetherington, Christopher J.; Tenen, Daniel G.; Zhang, Dong-Er

    1998-01-01

    Control elements of many genes are regulated by multiple activators working in concert to confer the maximal level of expression, but the mechanism of such synergy is not completely understood. The promoter of the human macrophage colony-stimulating factor (M-CSF) receptor presents an excellent model with which we can study synergistic, tissue-specific activation for two reasons. First, myeloid-specific expression of the M-CSF receptor is regulated transcriptionally by three factors which are crucial for normal hematopoiesis: PU.1, AML1, and C/EBPα. Second, these proteins interact in such a way as to demonstrate at least two examples of synergistic activation. We have shown that AML1 and C/EBPα activate the M-CSF receptor promoter in a synergistic manner. As we report here, AML1 also synergizes, and interacts physically, with PU.1. Detailed analysis of the physical and functional interaction of AML1 with PU.1 and C/EBPα has revealed that the proteins contact one another through their DNA-binding domains and that AML1 exhibits cooperative DNA binding with C/EBPα but not with PU.1. This difference in DNA-binding abilities may explain, in part, the differences observed in synergistic activation. Furthermore, the activation domains of all three factors are required for synergistic activation, and the region of AML1 required for synergy with PU.1 is distinct from that required for synergy with C/EBPα. These observations present the possibility that synergistic activation is mediated by secondary proteins contacted through the activation domains of AML1, C/EBPα, and PU.1. PMID:9632776

  14. Significance of oncogenes and tumor suppressor genes in AML prognosis.

    PubMed

    Kavianpour, Maria; Ahmadzadeh, Ahmad; Shahrabi, Saeid; Saki, Najmaldin

    2016-08-01

    Acute myeloid leukemia (AML) is a heterogeneous disorder among hematologic malignancies. Several genetic alterations occur in this disease, which cause proliferative progression, reducing differentiation and apoptosis in leukemic cells as well as increasing their survival. In the genetic study of AML, genetic translocations, gene overexpression, and mutations effective upon biology and pathogenesis of this disease have been recognized. Proto-oncogenes and tumor suppressor genes, which are important in normal development of myeloid cells, are involved in the regulation of cell cycle and apoptosis, undergo mutation in this type of leukemia, and are effective in prognosis of AML subtypes. This review deals with these genes, the assessment of which can be important in the diagnosis and prognosis of patients as well as therapeutic outcome. PMID:27179964

  15. MicroRNAs Distinguish Cytogenetic Subgroups in Pediatric AML and Contribute to Complex Regulatory Networks in AML-Relevant Pathways

    PubMed Central

    Daschkey, Svenja; Röttgers, Silja; Giri, Anamika; Bradtke, Jutta; Teigler-Schlegel, Andrea; Meister, Gunter; Borkhardt, Arndt; Landgraf, Pablo

    2013-01-01

    Background The role of microRNAs (miRNAs), important post-transcriptional regulators, in the pathogenesis of acute myeloid leukemia (AML) is just emerging and has been mainly studied in adults. First studies in children investigate single selected miRNAs, however, a comprehensive overview of miRNA expression and function in children and young adults is missing so far. Methodology/Principal Findings We here globally identified differentially expressed miRNAs between AML subtypes in a survey of 102 children and adolescent. Pediatric samples with core-binding factor AML and promyelocytic leukemia could be distinguished from each other and from MLL-rearranged AML subtypes by differentially expressed miRNAs including miR-126, -146a, -181a/b, -100, and miR-125b. Subsequently, we established a newly devised immunoprecipitation assay followed by rapid microarray detection for the isolation of Argonaute proteins, the hallmark of miRNA targeting complexes, from cell line models resembling core-binding factor and promyelocytic leukemia. Applying this method, we were able to identify Ago-associated miRNAs and their targeted mRNAs. Conclusions/Significance miRNAs as well as their mRNA-targets showed binding preferences for the different Argonaute proteins in a cell context-dependent manner. Bioinformatically-derived pathway analysis suggested a concerted action of all four Argonaute complexes in the regulation of AML-relevant pathways. For the first time, to our knowledge, a complete AML data set resulting from carefully devised biochemical isolation experiments and analysis of Ago-associated miRNAs and their target-mRNAs is now available. PMID:23418555

  16. Preclinical efficacy of MEK inhibition in Nras-mutant AML

    PubMed Central

    Burgess, Michael R.; Hwang, Eugene; Firestone, Ari J.; Huang, Tannie; Xu, Jin; Zuber, Johannes; Bohin, Natacha; Wen, Tiffany; Kogan, Scott C.; Haigis, Kevin M.; Sampath, Deepak; Lowe, Scott; Shannon, Kevin

    2014-01-01

    Oncogenic NRAS mutations are highly prevalent in acute myeloid leukemia (AML). Genetic analysis supports the hypothesis that NRAS mutations cooperate with antecedent molecular lesions in leukemogenesis, but have limited independent prognostic significance. Using short hairpin RNA–mediated knockdown in human cell lines and primary mouse leukemias, we show that AML cells with NRAS/Nras mutations are dependent on continued oncogene expression in vitro and in vivo. Using the Mx1-Cre transgene to inactivate a conditional mutant Nras allele, we analyzed hematopoiesis and hematopoietic stem and progenitor cells (HSPCs) under normal and stressed conditions and found that HSPCs lacking Nras expression are functionally equivalent to normal HSPCs in the adult mouse. Treating recipient mice transplanted with primary NrasG12D AMLs with 2 potent allosteric mitogen-activated protein kinase kinase (MEK) inhibitors (PD0325901 or trametinib/GlaxoSmithKline 1120212) significantly prolonged survival and reduced proliferation but did not induce apoptosis, promote differentiation, or drive clonal evolution. The phosphatidylinositol 3-kinase inhibitor GDC-0941 was ineffective as a single agent and did not augment the activity of PD0325901. All mice ultimately succumbed to progressive leukemia. Together, these data validate oncogenic N-Ras signaling as a therapeutic target in AML and support testing combination regimens that include MEK inhibitors. PMID:25361812

  17. Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy.

    PubMed

    Bruedigam, Claudia; Bagger, Frederik O; Heidel, Florian H; Paine Kuhn, Catherine; Guignes, Solene; Song, Axia; Austin, Rebecca; Vu, Therese; Lee, Erwin; Riyat, Sarbjit; Moore, Andrew S; Lock, Richard B; Bullinger, Lars; Hill, Geoffrey R; Armstrong, Scott A; Williams, David A; Lane, Steven W

    2014-12-01

    Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer maintained by rare populations of leukemia stem cells (LSCs). Selective targeting of LSCs is a promising approach for treating AML and preventing relapse following chemotherapy, and developing such therapeutic modalities is a key priority. Here, we show that targeting telomerase activity eradicates AML LSCs. Genetic deletion of the telomerase subunit Terc in a retroviral mouse AML model induces cell-cycle arrest and apoptosis of LSCs, and depletion of telomerase-deficient LSCs is partially rescued by p53 knockdown. Murine Terc(-/-) LSCs express a specific gene expression signature that can be identified in human AML patient cohorts and is positively correlated with patient survival following chemotherapy. In xenografts of primary human AML, genetic or pharmacological inhibition of telomerase targets LSCs, impairs leukemia progression, and delays relapse following chemotherapy. Altogether, these results establish telomerase inhibition as an effective strategy for eliminating AML LSCs. PMID:25479751

  18. Telomerase Inhibition Effectively Targets Mouse and Human AML Stem Cells and Delays Relapse Following Chemotherapy

    PubMed Central

    Bruedigam, Claudia; Bagger, Frederik O.; Heidel, Florian H.; Kuhn, Catherine Paine; Guignes, Solene; Song, Axia; Austin, Rebecca; Vu, Therese; Lee, Erwin; Riyat, Sarbjit; Moore, Andrew S.; Lock, Richard B.; Bullinger, Lars; Hill, Geoffrey R.; Armstrong, Scott A.; Williams, David A.; Lane, Steven W.

    2014-01-01

    SUMMARY Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer maintained by rare populations of leukemia stem cells (LSCs). Selective targeting of LSCs is a promising approach for treating AML and preventing relapse following chemotherapy, and developing such therapeutic modalities is a key priority. Here, we show that targeting telomerase activity eradicates AML LSCs. Genetic deletion of the telomerase subunit Terc in a retroviral mouse AML model induces cell cycle arrest and apoptosis of LSCs, and depletion of telomerase-deficient LSCs is partially rescued by p53 knockdown. Murine Terc−/− LSCs express a specific gene expression signature that can be identified in human AML patient cohorts and is positively correlated with patient survival following chemotherapy. In xenografts of primary human AML, genetic or pharmacological inhibition of telomerase targets LSCs, impairs leukemia progression, and delays relapse following chemotherapy. Together, these results establish telomerase inhibition as an effective strategy for eliminating AML LSCs. PMID:25479751

  19. How I treat MDS and AML in Fanconi anemia.

    PubMed

    Peffault de Latour, Régis; Soulier, Jean

    2016-06-16

    Fanconi anemia (FA) is the most frequent inherited cause of bone marrow failure (BMF). Most FA patients experience hematopoietic stem cell attrition and cytopenia during childhood, which along with intrinsic chromosomal instability, favor clonal evolution and the frequent emergence in their teens or young adulthood of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). To early identify and further predict bone marrow (BM) clonal progression and enable timely treatment, the follow-up of FA patients includes regular BM morphological and cytogenetic examinations. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment of FA patients with MDS or AML. Although questions remain concerning HSCT itself (including the need for pretransplant chemotherapy, the best conditioning regimen, and the optimal long-term follow-up of such patients especially regarding secondary malignancies), clonal evolution in the absence of significant BM dysplasia and blast cells can be difficult to address in FA patients, for whom the concept of preemptive HSCT is discussed. Illustrated by 3 representative clinical vignettes showing specific features of MDS and AML in FA patients, this paper summarizes our practical approach from diagnosis through treatment in this particular situation. PMID:27020090

  20. Reduced-intensity conditioned allogeneic SCT in adults with AML.

    PubMed

    Reshef, R; Porter, D L

    2015-06-01

    AML is currently the most common indication for reduced-intensity conditioned (RIC) allo-SCT. Reduced-intensity regimens allow a potent GVL response to occur with minimized treatment-related toxicity in patients of older age or with comorbidities that preclude the use of myeloablative conditioning. Whether RIC SCT is appropriate for younger and more standard risk patients is not well defined and the field is changing rapidly; a prospective randomized trial of myeloablative vs RIC (BMT-CTN 0901) was recently closed when early results indicated better outcomes for myeloablative regimens. However, detailed results are not available, and all patients in that study were eligible for myeloablative conditioning. RIC transplants will likely remain the standard of care as many patients with AML are not eligible for myeloablative conditioning. Recent publication of mature results from retrospective and prospective cohorts provide contemporary efficacy and toxicity data for these attenuated regimens. In addition, recent studies explore the use of alternative donors, introduce regimens that attempt to reduce toxicity without reducing intensity, and identify predictive factors that pave the way to personalized approaches. These studies paint a picture of the future of RIC transplants. Here we review the current status of RIC allogeneic SCT in AML. PMID:25730186

  1. MIT-CSR XIS Project

    NASA Technical Reports Server (NTRS)

    1998-01-01

    This report outlines the proposers' progress toward MIT's contribution to the X-Ray Imaging Spectrometer (XIS) experiment on the Japanese ASTRO-E mission. The report discusses electrical system design, mechanical system design, and ground support equipment.

  2. MIT research in telerobotics

    NASA Technical Reports Server (NTRS)

    Sheridan, T. B.

    1987-01-01

    Ongoing MIT research in telerobotics (vehicles capable of some autonomous sensing and manipulating, having some remote supervisory control by people) and teleoperation (vehicles for sensing and manipulating which are fully controlled remotely by people) is discussed. The current efforts mix human and artificial intelligence/control. The idea of adjustable impedance at either end of pure master-slave teleoperation, and simultaneous coordinated control of teleoperator/telerobotic systems which have more than six degrees of freedom (e.g., a combined vehicle and arm, each with five or six DOF) are discussed. A new cable-controlled parallel link arm which offers many advantages over conventional arms for space is briefly described. Predictor displays to compensate for time delay in teleoperator loops, the use of state estimation to help human control decisions in space, and ongoing research in supervisory command language are covered. Finally, efforts to build a human flyable real-time dynamic computer-graphic telerobot simulator are described. These projects represent most, but not all, of the telerobotics research in our laboratory, supported by JPL, NASA Ames and NOAA.

  3. Transcriptome Profiling of Pediatric Core Binding Factor AML

    PubMed Central

    Hsu, Chih-Hao; Nguyen, Cu; Yan, Chunhua; Ries, Rhonda E.; Chen, Qing-Rong; Hu, Ying; Ostronoff, Fabiana; Stirewalt, Derek L.; Komatsoulis, George; Levy, Shawn

    2015-01-01

    The t(8;21) and Inv(16) translocations disrupt the normal function of core binding factors alpha (CBFA) and beta (CBFB), respectively. These translocations represent two of the most common genomic abnormalities in acute myeloid leukemia (AML) patients, occurring in approximately 25% pediatric and 15% of adult with this malignancy. Both translocations are associated with favorable clinical outcomes after intensive chemotherapy, and given the perceived mechanistic similarities, patients with these translocations are frequently referred to as having CBF-AML. It remains uncertain as to whether, collectively, these translocations are mechanistically the same or impact different pathways in subtle ways that have both biological and clinical significance. Therefore, we used transcriptome sequencing (RNA-seq) to investigate the similarities and differences in genes and pathways between these subtypes of pediatric AMLs. Diagnostic RNA from patients with t(8;21) (N = 17), Inv(16) (N = 14), and normal karyotype (NK, N = 33) were subjected to RNA-seq. Analyses compared the transcriptomes across these three cytogenetic subtypes, using the NK cohort as the control. A total of 1291 genes in t(8;21) and 474 genes in Inv(16) were differentially expressed relative to the NK controls, with 198 genes differentially expressed in both subtypes. The majority of these genes (175/198; binomial test p-value < 10−30) are consistent in expression changes among the two subtypes suggesting the expression profiles are more similar between the CBF cohorts than in the NK cohort. Our analysis also revealed alternative splicing events (ASEs) differentially expressed across subtypes, with 337 t(8;21)-specific and 407 Inv(16)-specific ASEs detected, the majority of which were acetylated proteins (p = 1.5x10-51 and p = 1.8x10-54 for the two subsets). In addition to known fusions, we identified and verified 16 de novo fusions in 43 patients, including three fusions involving NUP98 in six patients

  4. Valproic acid triggers differentiation and apoptosis in AML1/ETO-positive leukemic cells specifically.

    PubMed

    Zapotocky, Michal; Mejstrikova, Ester; Smetana, Karel; Stary, Jan; Trka, Jan; Starkova, Julia

    2012-06-28

    Valproic acid (VPA) has extensive effects on leukemic blasts through its inhibition of histone deacetylases. The main goal of this study was to identify the subgroup of patients who may benefit most from VPA treatment. We examined the significance of t(8;21) chromosomal aberration for VPA treatment response among acute myeloid leukemia (AML) patients by direct comparison of AML1/ETO-negative vs. positive leukemic cell-lines as well as bone marrow blasts from AML patients. In t(8;21) AML, leukemogenesis is supposed to be induced via aberrant recruitment of histone deacetylases. AML cell lines of different genotypes (Kasumi-1, Kasumi-6, MV4;11, K562) and diagnostic bone marrow samples from patients were treated with VPA. VPA induced apoptosis in AML1/ETO-positive and MLL-AF4-positive cells in a dose-dependent manner. Differentiation, as indicated by changes in immunophenotype, was observed only in AML1/ETO-positive cells. VPA increased the expression of AML1 target genes - PU.1, C/EBPa, BPI and IGFBP7 only in AML1/ETO-positive cells. This AML1/ETO-specific effect was confirmed also using patient blasts isolated at the time of diagnosis. AML1/ETO-positive leukemia shows specific mechanism of VPA residing from differentiation followed by apoptosis that is accompanied by an increase in the expression of repressed AML1 target genes. Our data suggest that AML1/ETO-positive patients might derive the greatest benefit from VPA treatment. PMID:22261333

  5. Age-dependent frequencies of NPM1 mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML).

    PubMed

    Schneider, Friederike; Hoster, Eva; Schneider, Stephanie; Dufour, Annika; Benthaus, Tobias; Kakadia, Purvi M; Bohlander, Stefan K; Braess, Jan; Heinecke, Achim; Sauerland, Maria C; Berdel, Wolfgang E; Buechner, Thomas; Woermann, Bernhard J; Feuring-Buske, Michaela; Buske, Christian; Creutzig, Ursula; Thiede, Christian; Zwaan, Michel C; van den Heuvel-Eibrink, Marry M; Reinhardt, Dirk; Hiddemann, Wolfgang; Spiekermann, Karsten

    2012-01-01

    Prognosis of AML in elderly patients is poor due to adverse patient characteristics and comorbidities. In addition, disease-associated parameters reveal differences between older and younger patients with AML. Survival in normal karyotype AML (NK-AML) is influenced by different clinical and molecular markers. The aim of this work was to investigate the frequencies of molecular markers in patients with NK-AML with a focus on NPM1 mutations and FLT3-ITD in different age groups. In the present study, we analyzed the frequencies of mutations of NPM1 and FLT3-ITD in a cohort of 1,321 adult patients and 148 children with AML treated within the AMLCG99, the AML98, and AML04 trials and their distribution in different age groups. Additionally, the frequencies of mutations in CEBPA genes, FLT3-TKD, and MLL-PTD were analyzed in the cohort with NK-AML (n = 729). Our data show that the presence of mutations of NPM1 (from 60% to 40%) and FLT3-ITD (from 50% to 20%) significantly decreased with age in adult AML. Consequently, the proportion of NPM1-/FLT3-ITD- patients increased with age. The decreasing frequency of NPM1 mutations in elderly patients was paralleled by a reduced complete remission (CR) rate in the elderly of 55% compared to 80% in the younger patients. By contrast, the frequencies of other gene mutations, like FLT3-TKD and MLL-PTD, and mutations in CEBPA were not age-dependent. The decreasing frequency of the favorable NPM1 mutations with increasing age may partially explain the worse outcome in the elderly patients. Furthermore, the increasing amount of elderly patients without NPM1 mutations or FLT3-ITD suggests that other molecular and clinical risk factors may influence prognosis in this age group. PMID:21744003

  6. MIT's interferometer CST testbed

    NASA Technical Reports Server (NTRS)

    Hyde, Tupper; Kim, ED; Anderson, Eric; Blackwood, Gary; Lublin, Leonard

    1990-01-01

    The MIT Space Engineering Research Center (SERC) has developed a controlled structures technology (CST) testbed based on one design for a space-based optical interferometer. The role of the testbed is to provide a versatile platform for experimental investigation and discovery of CST approaches. In particular, it will serve as the focus for experimental verification of CSI methodologies and control strategies at SERC. The testbed program has an emphasis on experimental CST--incorporating a broad suite of actuators and sensors, active struts, system identification, passive damping, active mirror mounts, and precision component characterization. The SERC testbed represents a one-tenth scaled version of an optical interferometer concept based on an inherently rigid tetrahedral configuration with collecting apertures on one face. The testbed consists of six 3.5 meter long truss legs joined at four vertices and is suspended with attachment points at three vertices. Each aluminum leg has a 0.2 m by 0.2 m by 0.25 m triangular cross-section. The structure has a first flexible mode at 31 Hz and has over 50 global modes below 200 Hz. The stiff tetrahedral design differs from similar testbeds (such as the JPL Phase B) in that the structural topology is closed. The tetrahedral design minimizes structural deflections at the vertices (site of optical components for maximum baseline) resulting in reduced stroke requirements for isolation and pointing of optics. Typical total light path length stability goals are on the order of lambda/20, with a wavelength of light, lambda, of roughly 500 nanometers. It is expected that active structural control will be necessary to achieve this goal in the presence of disturbances.

  7. The molecular signature of AML mesenchymal stromal cells reveals candidate genes related to the leukemogenic process.

    PubMed

    Binato, Renata; de Almeida Oliveira, Nathalia Correa; Du Rocher, Barbara; Abdelhay, Eliana

    2015-12-01

    Acute myeloid leukemia (AML) is a heterogeneous disease characterized by myeloid precursor proliferation in the bone marrow, apoptosis reduction and differentiation arrest. Although there are several studies in this field, events related to disease initiation and progression remain unknown. The malignant transformation of hematopoietic stem cells (HSC) is thought to generate leukemic stem cells, and this transformation could be related to changes in mesenchymal stromal cell (hMSC) signaling. Thus, the aim of this work was to analyze the gene expression profile of hMSC from AML patients (hMSC-AML) compared to healthy donors hMSCs (hMSC-HD). The results showed a common molecular signature for all hMSC-AML. Other assays were performed with a large number of patients and the results confirmed a molecular signature that is capable of distinguishing hMSC-AML from hMSC-HD. Moreover, CCL2 and BMP4 genes encode secreted proteins that could affect HSCs. To verify whether these proteins are differentially expressed in AML patients, ELISA was performed with plasma samples. CCL2 and BMP4 proteins are differentially expressed in AML patients, indicating changes in hMSC-AML signaling. Altogether, hMSCs-AML signaling alterations could be an important factor in the leukemic transformation process. PMID:26279521

  8. MIT Space Engineering Research Center

    NASA Technical Reports Server (NTRS)

    Crawley, Edward F.; Miller, David W.

    1990-01-01

    The Space Engineering Research Center (SERC) at MIT, started in Jul. 1988, has completed two years of research. The Center is approaching the operational phase of its first testbed, is midway through the construction of a second testbed, and is in the design phase of a third. We presently have seven participating faculty, four participating staff members, ten graduate students, and numerous undergraduates. This report reviews the testbed programs, individual graduate research, other SERC activities not funded by the Center, interaction with non-MIT organizations, and SERC milestones. Published papers made possible by SERC funding are included at the end of the report.

  9. MIT January Operational Internship Experience

    NASA Technical Reports Server (NTRS)

    Bosanac, Natasha; DeVivero, Charlie; James, Jillian; Perez-Martinez, Carla; Pino, Wendy; Wang, Andrew; Willett, Ezekiel; Williams, Kwami

    2010-01-01

    This viewgraph presentation describes the MIT January Operational Internship Experience (JOIE) program. The topics include: 1) Landing and Recovery; 2) Transportation; 3) Shuttle Processing; 4) Constellation Processing; 5) External Tank; 6) Launch Pad; 7) Ground Operations; 8) Hypergolic Propellants; 9) Environmental; 10) Logistics; 11) Six Sigma; 12) Systems Engineering; and 13) Human Factors.

  10. GFI1 as a novel prognostic and therapeutic factor for AML/MDS.

    PubMed

    Hönes, J M; Botezatu, L; Helness, A; Vadnais, C; Vassen, L; Robert, F; Hergenhan, S M; Thivakaran, A; Schütte, J; Al-Matary, Y S; Lams, R F; Fraszscak, J; Makishima, H; Radivoyevitch, T; Przychodzen, B; da Conceição Castro, S V; Görgens, A; Giebel, B; Klein-Hitpass, L; Lennartz, K; Heuser, M; Thiede, C; Ehninger, G; Dührsen, U; Maciejewski, J P; Möröy, T; Khandanpour, C

    2016-06-01

    Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor, exerts its function by recruiting histone deacetylases to target genes. We present data that low expression of GFI1 is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1 expression (GFI1-KD). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1 expression. Leukemic cells from animals that express low levels of GFI1 show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1 expression, resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KD mice and from AML patients with low GFI1 levels were more sensitive to treatment with histone acetyltransferase inhibitors than cells with normal GFI1 expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 levels are involved in epigenetic regulation, which could open new therapeutic approaches for AML patients. PMID:26847026

  11. Spontaneous remission in three cases of AML M5 with NPM1 mutation

    PubMed Central

    Camus, Vincent; Etancelin, Pascaline; Jardin, Fabrice; Lenain, Pascal; Contentin, Nathalie; Daliphard, Sylvie; Buchonnet, Gérard; Lemasle, Emilie; Lanic, Hélène; Leprêtre, Stéphane; Penther, Dominique; Dubois, Sydney; Tilly, Hervé; Bastard, Christian; Stamatoullas, Aspasia

    2015-01-01

    Key Clinical Message Patients with NPM1-mutated AML M5 who develop spontaneous remission (SR) after antibiotic therapy at diagnosis seem to form a favorable prognosis and chemo sensitive subtype. We report three cases of AML M5 patients with the same genotype that experienced transient SR and are now leukemia free after standard treatment. PMID:26576281

  12. Epigenetic therapy as a novel approach for GFI136N-associated murine/human AML.

    PubMed

    Botezatu, Lacramioara; Michel, Lars C; Helness, Anne; Vadnais, Charles; Makishima, Hideki; Hönes, Judith M; Robert, François; Vassen, Lothar; Thivakaran, Aniththa; Al-Matary, Yahya; Lams, Robert F; Schütte, Judith; Giebel, Bernd; Görgens, André; Heuser, Michael; Medyouf, Hind; Maciejewski, Jaroslaw; Dührsen, Ulrich; Möröy, Tarik; Khandanpour, Cyrus

    2016-08-01

    Epigenetic changes can contribute to development of acute myeloid leukemia (AML), a malignant disease of the bone marrow. A single-nucleotide polymorphism of transcription factor growth factor independence 1 (GFI1) generates a protein with an asparagine at position 36 (GFI1(36N)) instead of a serine at position 36 (GFI1(36S)), which is associated with de novo AML in humans. However, how GFI1(36N) predisposes to AML is poorly understood. To explore the mechanism, we used knock-in mouse strains expressing GFI1(36N) or GFI1(36S). Presence of GFI1(36N) shortened the latency and increased the incidence of AML in different murine models of myelodysplastic syndrome/AML. On a molecular level, GFI1(36N) induced genomewide epigenetic changes, leading to expression of AML-associated genes. On a therapeutic level, use of histone acetyltransferase inhibitors specifically impeded growth of GFI1(36N)-expressing human and murine AML cells in vitro and in vivo. These results establish, as a proof of principle, how epigenetic changes in GFI1(36N)-induced AML can be targeted. PMID:27216773

  13. Structure of the AML1-ETO eTAFH domain-HEB peptide complex and its contribution to AML1-ETO activity.

    PubMed

    Park, Sangho; Chen, Wei; Cierpicki, Tomasz; Tonelli, Marco; Cai, Xiongwei; Speck, Nancy A; Bushweller, John H

    2009-04-01

    AML1-ETO is the chimeric protein product of the t(8;21) in acute myeloid leukemia. The ETO portion of the fusion protein includes the eTAFH domain, which is homologous to several TATA binding protein-associated factors (TAFs) and interacts with E proteins (E2A and HEB). It has been proposed that AML1-ETO-mediated silencing of E protein function might be important for t(8;21) leukemogenesis. Here, we determined the solution structure of a complex between the AML1-ETO eTAFH domain and an interacting peptide from HEB. On the basis of the structure, key residues in AML1-ETO for HEB association were mutated. These mutations do not impair the ability of AML1-ETO to enhance the clonogenic capacity of primary mouse bone marrow cells and do not eliminate its ability to repress proliferation or granulocyte differentiation. Therefore, the eTAFH-E protein interaction appears to contribute relatively little to the activity of AML1-ETO. PMID:19204326

  14. Educational Outreach at MIT PSFC

    NASA Astrophysics Data System (ADS)

    Rivenberg, P.; Thomas, P.; Censabella, V.

    2001-10-01

    At the MIT PSFC student and staff volunteers work together to increase the public's knowledge of fusion and plasma-related experiments. Seeking to generate excitement about science and engineering, the PSFC hosts a number of outreach activities throughout the year, including Middle and High School Outreach Days. Key to the success of these tours is the interactive ``C-Mod, Jr.," which helps students understand magnetic confinement in MIT's Alcator C-Mod tokamak. The PSFC also has an in-school science demonstration program on the theme of magnetism. As ``Mr. Magnet" Technical Supervisor Paul Thomas brings a truck-load of hands-on demonstrations to K-12 schools, challenging students to help him with experiments. While teaching fundamentals of magnetism and electricity he shows that science is fun for all, and that any student can have a career in science. This year he reached 77 schools -- 30,000 teachers and students. We have also collaborated with the MIT Museum to create an interactive plasma demonstration device which students and the general public can use to create plasmas from different gasses. Pinch and deflection magnets are moveable along the axis of the display, allowing investigation of the magnetic behavior of plasmas.

  15. Repression of GSK3 restores NK cell cytotoxicity in AML patients

    PubMed Central

    Parameswaran, Reshmi; Ramakrishnan, Parameswaran; Moreton, Stephen A.; Xia, Zhiqiang; Hou, Yongchun; Lee, Dean A.; Gupta, Kalpana; deLima, Marcos; Beck, Rose C.; Wald, David N.

    2016-01-01

    Natural killer cells from acute myeloid leukaemia patients (AML-NK) show a dramatic impairment in cytotoxic activity. The exact reasons for this dysfunction are not fully understood. Here we show that the glycogen synthase kinase beta (GSK3β) expression is elevated in AML-NK cells. Interestingly, GSK3 overexpression in normal NK cells impairs their ability to kill AML cells, while genetic or pharmacological GSK3 inactivation enhances their cytotoxic activity. Mechanistic studies reveal that the increased cytotoxic activity correlates with an increase in AML-NK cell conjugates. GSK3 inhibition promotes the conjugate formation by upregulating LFA expression on NK cells and by inducing ICAM-1 expression on AML cells. The latter is mediated by increased NF-κB activation in response to TNF-α production by NK cells. Finally, GSK3-inhibited NK cells show significant efficacy in human AML mouse models. Overall, our work provides mechanistic insights into the AML-NK dysfunction and a potential NK cell therapy strategy. PMID:27040177

  16. MYST2 acetyltransferase expression and Histone H4 Lysine acetylation are suppressed in AML.

    PubMed

    Sauer, Tim; Arteaga, Maria Francisca; Isken, Fabienne; Rohde, Christian; Hebestreit, Katja; Mikesch, Jan-Henrik; Stelljes, Matthias; Cui, Chunhong; Zhou, Fengbiao; Göllner, Stefanie; Bäumer, Nicole; Köhler, Gabriele; Krug, Utz; Thiede, Christian; Ehninger, Gerhard; Edemir, Bayram; Schlenke, Peter; Berdel, Wolfgang E; Dugas, Martin; Müller-Tidow, Carsten

    2015-09-01

    Chromatin-modifying enzymes are frequently altered in acute myeloid leukemia (AML). In the current study, we identified MYST2, a core histone acetyltransferase, to be suppressed in blast cells from AML patients compared with nonmalignant hematopoietic progenitor cells. Functionally, loss of MYST2 accelerated leukemic growth and colony formation, while forced expression of MYST2 induced H4K5 acetylation (H4K5Ac) and suppressed hematopoietic progenitor cell growth. Consistently, global H4K5Ac levels were frequently decreased in AML blasts. Low levels of H4K5Ac were most prominent in patients with complex karyotype AML and were associated with inferior overall survival in univariate but not multivariate analysis. ChIP-seq experiments in primary AML patients' blasts revealed widespread H4K5Ac deregulation, most prominent at gene promoters. Taken together, MYST2 is a repressed growth suppressor in AML mediating reduced acetylation of histone 4 at residue 5 and is associated with inferior AML patient survival. PMID:26072331

  17. Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML.

    PubMed

    Wong, Terrence N; Miller, Christopher A; Klco, Jeffery M; Petti, Allegra; Demeter, Ryan; Helton, Nichole M; Li, Tiandao; Fulton, Robert S; Heath, Sharon E; Mardis, Elaine R; Westervelt, Peter; DiPersio, John F; Walter, Matthew J; Welch, John S; Graubert, Timothy A; Wilson, Richard K; Ley, Timothy J; Link, Daniel C

    2016-02-18

    There is interest in using leukemia-gene panels and next-generation sequencing to assess acute myelogenous leukemia (AML) response to induction chemotherapy. Studies have shown that patients with AML in morphologic remission may continue to have clonal hematopoiesis with populations closely related to the founding AML clone and that this confers an increased risk of relapse. However, it remains unknown how induction chemotherapy influences the clonal evolution of a patient's nonleukemic hematopoietic population. Here, we report that 5 of 15 patients with genetic clearance of their founding AML clone after induction chemotherapy had a concomitant expansion of a hematopoietic population unrelated to the initial AML. These populations frequently harbored somatic mutations in genes recurrently mutated in AML or myelodysplastic syndromes and were detectable at very low frequencies at the time of AML diagnosis. These results suggest that nonleukemic hematopoietic stem and progenitor cells, harboring specific aging-acquired mutations, may have a competitive fitness advantage after induction chemotherapy, expand, and persist long after the completion of chemotherapy. Although the clinical importance of these "rising" clones remains to be determined, it will be important to distinguish them from leukemia-related populations when assessing for molecular responses to induction chemotherapy. PMID:26631115

  18. [Molecular target drugs for AML--current state and prospects for the future].

    PubMed

    Kohgo, Yutaka; Inamura, Junki; Shindo, Motohiro

    2014-06-01

    Acute myeloblastic leukemia (AML) is a disease which may be completely cured by intensive chemotherapy or stem cell transplantation. However, the prognoses are poor in elderly, refractory or recurrence cases. Molecular targeted drugs have been expected to improve the prognoses of patients with various cancers, but there are few kinds of molecular target drugs for AML. On the other hand, excellent drug exists such as tretinoin for acute promyelocytic leukemia. Molecular mechanisms have been elucidated in AML cells, and the molecules which can be the good target of the treatment have been identified. Novel molecular target drugs are also expected. PMID:25016805

  19. The leukemogenic t(8;21) fusion protein AML1-ETO controls ribosomal RNA genes and associates with nucleolar organizing regions at mitotic chromosomes

    PubMed Central

    Bakshi, Rachit; Zaidi, Sayyed K.; Pande, Sandhya; Hassan, Mohammad Q.; Young, Daniel W.; Lian, Jane B.; van Wijnen, Andre J.; Stein, Janet L.; Stein, Gary S.

    2010-01-01

    SUMMARY RUNX1/AML1 is required for definitive hematopoiesis and is frequently targeted by chromosomal translocation in acute myeloid leukemias (AML). The t(8;21) related AML1-ETO fusion protein blocks differentiation of myeloid progenitors. Here, we show by immunofluorescence microscopy that during interphase, endogenous AML1-ETO localizes to nuclear microenvironments distinct from those containing native RUNX1/AML1 protein. At mitosis, we clearly detect binding of AML1-ETO to nucleolar organizing regions (NORs) in AML derived Kasumi-1 cells and binding of RUNX1/AML1 to NORs in Jurkat cells. Both RUNX1/AML1 and AML1-ETO occupy ribosomal DNA repeats during interphase, as well as interact with the endogenous RNA Pol I transcription factor UBF-1. Promoter cytosine methylation analysis indicates that RUNX1/AML1 binds to rDNA repeats that are more highly CpG methylated than those bound by AML1-ETO. Down-regulation by RNA interference reveals that RUNX1/AML1 negatively regulates rDNA transcription, while AML1-ETO is a positive regulator in Kasumi-1 cells. Taken together, our findings identify a novel role for the leukemia-related AML1-ETO protein in epigenetic control of cell growth through upregulation of RNA Pol I-mediated ribosomal gene transcription, consistent with the hyper-proliferative phenotype of myeloid cells in AML patients. PMID:19001502

  20. MicroRNA–mRNA Pairs Associated with Outcome in AML: From In Vitro Cell-Based Studies to AML Patients

    PubMed Central

    Bhise, Neha S.; Chauhan, Lata; Shin, Miyoung; Cao, Xueyuan; Pounds, Stanley; Lamba, Vishal; Lamba, Jatinder K.

    2016-01-01

    Cytarabine is the primary chemotherapeutic agent used for treatment of acute myeloid leukemia (AML). Disease relapse after initial remission remains one of the most pressing therapeutic challenges in the treatment of AML. Relapsed disease is often resistant to cytarabine and subsequent salvage therapy is ineffective. Recent studies have shown that some microRNAs (miRNAs) are associated with prognosis, but have not yet explored the role of miRNAs in cellular response to cytarabine. We identified 20 miRNAs that associate with the in vitro cytarabine chemo-sensitivity or apoptotic response of eight AML cell lines. Out of the 20 miRNAs, data on 18 miRNAs was available in AML patients from The Cancer Genome Atlas database. Our stepwise-integrated analyses (step 1 – miRNA–target mRNA that were significantly correlated in AML patients; step 2 – mRNAs from step 1 with significant association with overall survival (OS)) identified 23 unique miRNA–mRNA pairs predictive of OS in AML patients. As expected HOX genes (HOXA9, HOXB7, and HOXA10) were identified to be regulated by miRs as well as predictive of worse OS. Additionally, miR107-Myb, miR-378-granzyme B involved in granzyme signaling and miR10a-MAP4K4 were identified to be predictive of outcome through integrated analysis. Although additional functional validations to establish clinical/pharmacologic importance of miRNA–mRNA pairs are needed, our results from RNA electrophoretic mobility shift assay confirmed binding of miR-10a, miR-378, and miR-107 with their target genes GALNT1, GZMB, and MYB, respectively. Integration of pathogenic and pharmacologically significant miRNAs and miRNA–mRNA relationships identified in our study opens up opportunities for development of targeted/miRNA-directed therapies. PMID:26858643

  1. Timothy Ley, M.D., Advocates for Personalized Medicine in AML - TCGA

    Cancer.gov

    Oncologist Dr. Timothy Ley talks about how repurposing of existing drugs based on better understanding of the genetic basis of acute myeloid leukemia (AML) can help patients receive personalized care.

  2. What If the Leukemia Doesn't Respond or Comes Back After Treatment? (AML)

    MedlinePlus

    ... about acute myeloid leukemia? What if acute myeloid leukemia doesn’t respond or comes back after treatment? For most types of acute myeloid leukemia If acute myeloid leukemia (AML) doesn’t go ...

  3. Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials.

    PubMed

    Gibson, B E S; Wheatley, K; Hann, I M; Stevens, R F; Webb, D; Hills, R K; De Graaf, S S N; Harrison, C J

    2005-12-01

    Between 1988 and 2002, 758 children with acute myeloid leukaemia (AML) were treated on Medical Research Council (MRC) AML 10 and AML 12. MRC AML 10 tested the role of bone marrow transplantation following four blocks of intensive chemotherapy and found that while both allogeneic bone marrow transplant (allo-BMT) and autologous bone marrow transplant (A-BMT) significantly reduced the relapse risk (RR), this did not translate into a significant improvement in overall survival (OS). A risk group stratification based on cytogenetics and response to the first course of chemotherapy derived from MRC AML 10 was used to deliver risk-directed therapy in MRC AML 12. Allo-BMT was limited to standard and poor risk patients and A-BMT was not employed. Instead, the benefit of an additional block of treatment was tested by randomising children to receive either four or five blocks of treatment in total. While the results of MRC AML 12 remain immature, there appears to be no survival advantage for a fifth course of treatment. The 5 year OS, disease-free survival (DFS), event-free survival (EFS) and RR in MRC AML 12 are 66, 61, 56 and 35%, respectively; at present superior to MRC AML 10, which had a 5-year OS, DFS, EFS and RR of 58, 53, 49 and 42%, respectively. MRC AML trials employ a short course of triple intrathecal chemotherapy alone for CNS-directed treatment and CNS relapse is uncommon. Improvements in supportive care have contributed to improved outcomes and the number of deaths in remission fell between trials. Anthracycline-related cardiotoxicity remains a concern and the current MRC AML 15 trial tests the feasibility of reducing anthracycline dosage without compromising outcome by comparing standard MRC anthracycline-based consolidation with high-dose ara-C. MRC studies suggest that the role of allo-BMT is limited in 1st CR and that there may be a ceiling of benefit from current or conventional chemotherapy. PMID:16304572

  4. miR-9 is a tumor suppressor in pediatric AML with t(8;21).

    PubMed

    Emmrich, S; Katsman-Kuipers, J E; Henke, K; Khatib, M E; Jammal, R; Engeland, F; Dasci, F; Zwaan, C M; den Boer, M L; Verboon, L; Stary, J; Baruchel, A; de Haas, V; Danen-van Oorschot, A A; Fornerod, M; Pieters, R; Reinhardt, D; Klusmann, J H; van den Heuvel-Eibrink, M M

    2014-05-01

    MicroRNAs (miRNAs) play a pivotal role in the regulation of hematopoiesis and development of leukemia. Great interest emerged in modulating miRNA expression for therapeutic purposes. In order to identify miRNAs, which specifically suppress leukemic growth of acute myeloid leukemia (AML) with t(8;21), inv(16) or mixed lineage leukemia (MLL) rearrangement by inducing differentiation, we conducted a miRNA expression profiling in a cohort of 90 cytogenetically characterized, de novo pediatric AML cases. Four miRNAs, specifically downregulated in MLL-rearranged, t(8;21) or inv(16) AMLs, were characterized by their tumor-suppressive properties in cell lines representing those respective cytogenetic groups. Among those, forced expression of miR-9 reduced leukemic growth and induced monocytic differentiation of t(8;21) AML cell lines in vitro and in vivo. The tumor-suppressive functions of miR-9 were specifically restricted to AML cell lines and primary leukemic blasts with t(8;21). On the other hand, these functions were not evident in AML blasts from patients with MLL rearrangements. We showed that miR-9 exerts its effects through the cooperation with let-7 to repress the oncogenic LIN28B/HMGA2 axis. Thus, miR-9 is a tumor suppressor-miR which acts in a stringent cell context-dependent manner. PMID:24270738

  5. Sex disparity in childhood and young adult acute myeloid leukemia (AML) survival: Evidence from US population data.

    PubMed

    Hossain, Md Jobayer; Xie, Li

    2015-12-01

    Sex variation has been persistently investigated in studies concerning acute myeloid leukemia (AML) survival outcomes but has not been fully explored among pediatric and young adult AML patients. We detected sex difference in the survival of AML patients diagnosed at ages 0-24 years and explored distinct effects of sex across subgroups of age at diagnosis, race-ethnicity and AML subtypes utilizing the United States Surveillance Epidemiology and End Results (SEER) population based dataset of 4865 patients diagnosed with AML between 1973 and 2012. Kaplan-Meier survival function, propensity scores and stratified Cox proportional hazards regression were used for data analyses. After controlling for other prognostic factors, females showed a significant survival advantage over their male counterparts, adjusted hazard ratio (aHR, 95% confidence interval (CI): 1.09, 1.00-1.18). Compared to females, male patients had substantially increased risk of mortality in the following subgroups of: ages 20-24 years at diagnosis (aHR1.30), Caucasian (1.14), acute promyelocytic leukemia (APL) (1.35), acute erythroid leukemia (AEL) (1.39), AML with inv(16)(p13.1q22) (2.57), AML with minimum differentiation (1.47); and had substantially decreased aHR in AML t(9;11)(p22;q23) (0.57) and AML with maturation (0.82). Overall, females demonstrated increased survival over males and this disparity was considerably large in patients ages 20-24 years at diagnosis, Caucasians, and in AML subtypes of AML inv(16), APL and AEL. In contrast, males with AML t(9;11)(p22;q23), AML with maturation and age at diagnosis of 10-14 years showed survival benefit. Further investigations are needed to detect the biological processes influencing the mechanisms of these interactions. PMID:26520618

  6. Trisomy 8 in pediatric acute myeloid leukemia: A NOPHO-AML study.

    PubMed

    Laursen, Anne Cathrine Lund; Sandahl, Julie Damgaard; Kjeldsen, Eigil; Abrahamsson, Jonas; Asdahl, Peter; Ha, Shau-Yin; Heldrup, Jesper; Jahnukainen, Kirsi; Jónsson, Ólafur G; Lausen, Birgitte; Palle, Josefine; Zeller, Bernward; Forestier, Erik; Hasle, Henrik

    2016-09-01

    Trisomy 8 (+8) is a common cytogenetic aberration in acute myeloid leukemia (AML); however, the impact of +8 in pediatric AML is largely unknown. We retrospectively investigated 609 patients from the NOPHO-AML database to determine the clinical and cytogenetic characteristics of +8 in pediatric AML and to investigate its prognostic impact. Complete cytogenetic data were available in 596 patients (98%) aged 0-18 years, diagnosed from 1993 to 2012, and treated according to the NOPHO-AML 1993 and 2004 protocols in the Nordic countries and Hong Kong. We identified 86 patients (14%) with +8. Trisomy 8 was combined with other cytogenetic aberrations in 68 patients (11%) (+8 other) and in 18 patients (3%), it was the sole abnormality (+8 alone). Trisomy 8 was associated with FAB M5 (36%) but otherwise clinically comparable with non-trisomy 8 patients. Trisomy 8 was favorable in patients of young age and with t(9;11). Trisomy 8 alone was associated with older age (median age 10.1 years), FAB M2 (33%), and FLT3-ITD mutations (58%). The 5-year event-free survival for patients with +8 alone was 50% and 5-year overall survival was 75%. In conclusion, +8 is one of the most common cytogenetic aberrations in pediatric AML. Trisomy 8 positive AML is a heterogeneous group and the majority of cases have additional cytogenetic aberrations. Patients with +8 alone differed from patients with +8 other and were associated with older age, FAB M2, and FLT3-ITD aberrations. There were no differences in survival despite the more frequent occurrence of FLT3-ITD in +8 alone. © 2016 Wiley Periodicals, Inc. PMID:27153159

  7. A stable transcription factor complex nucleated by oligomeric AML1–ETO controls leukaemogenesis

    SciTech Connect

    Sun, Xiao-Jian; Wang, Zhanxin; Wang, Lan; Jiang, Yanwen; Kost, Nils; Soong, T. David; Chen, Wei-Yi; Tang, Zhanyun; Nakadai, Tomoyoshi; Elemento, Olivier; Fischle, Wolfgang; Melnick, Ari; Patel, Dinshaw J.; Nimer, Stephen D.; Roeder, Robert G.

    2013-06-30

    Transcription factors are frequently altered in leukaemia through chromosomal translocation, mutation or aberrant expression. AML1–ETO, a fusion protein generated by the t(8;21) translocation in acute myeloid leukaemia, is a transcription factor implicated in both gene repression and activation. AML1–ETO oligomerization, mediated by the NHR2 domain, is critical for leukaemogenesis, making it important to identify co-regulatory factors that ‘read’ the NHR2 oligomerization and contribute to leukaemogenesis. Here we show that, in human leukaemic cells, AML1–ETO resides in and functions through a stable AML1–ETO-containing transcription factor complex (AETFC) that contains several haematopoietic transcription (co)factors. These AETFC components stabilize the complex through multivalent interactions, provide multiple DNA-binding domains for diverse target genes, co-localize genome wide, cooperatively regulate gene expression, and contribute to leukaemogenesis. Within the AETFC complex, AML1–ETO oligomerization is required for a specific interaction between the oligomerized NHR2 domain and a novel NHR2-binding (N2B) motif in E proteins. Crystallographic analysis of the NHR2–N2B complex reveals a unique interaction pattern in which an N2B peptide makes direct contact with side chains of two NHR2 domains as a dimer, providing a novel model of how dimeric/oligomeric transcription factors create a new protein-binding interface through dimerization/oligomerization. Intriguingly, disruption of this interaction by point mutations abrogates AML1–ETO-induced haematopoietic stem/progenitor cell self-renewal and leukaemogenesis. These results reveal new mechanisms of action of AML1–ETO, and provide a potential therapeutic target in t(8;21)-positive acute myeloid leukaemia.

  8. Identification of Transcription Factor AML-1 Binding Site Upstream of Human Cytomegalovirus UL111A Gene

    PubMed Central

    Zheng, Xiaoqun; Gao, Yan; Zhang, Qi; Liu, Yanqing; Peng, Ying; Fu, Miao; Ji, Yanhong

    2015-01-01

    Human cytomegalovirus (HCMV) interleukin-10 (hcmvIL-10), encoded by HCMV UL111A gene, is a homolog of human IL-10. It exerts immunomodulatory effects that allow HCMV to evade host defense mechanisms. However, the exact mechanism underlying the regulation of hcmvIL-10 expression is not well understood. The transcription factor acute myeloid leukemia 1 (AML-1) plays an important role in the regulation of various genes involved in the differentiation of hematopoietic lineages. A putative AML-1 binding site is present within the upstream regulatory region (URR) of UL111A gene. To provide evidence that AML-1 is involved in regulating UL111A gene expression, we examined the interaction of AML-1 with the URR of UL111A in HCMV-infected human monocytic THP-1 cells using a chromatin immunoprecipitation assay. HcmvIL-10 transcription was detected in differentiated THP-1 cells, but not in undifferentiated ones. Furthermore, the URR of UL111A showed a higher intensity of AML-1 binding, a higher level of histone H3 acetyl-K9, but a lower level of histone H3 dimethyl-K9 in differentiated THP-1 cells than undifferentiated cells. Down-regulation of AML1 by RNA interference decreased the expression of the UL111A gene. Our results suggest that AML-1 may contribute to the epigenetic regulation of UL111A gene via histone modification in HCMV-infected differentiated THP-1 cells. This finding could be useful for the development of new anti-viral therapies. PMID:25658598

  9. Positive Werkzeuge mit hohem IQ

    NASA Astrophysics Data System (ADS)

    Luik, Matthias

    Fräsen ist ein Verfahren, auf welches im modernen Produktionsprozess nicht verzichtet werden kann. Dabei stellt die zunehmende Komplexität der zu fertigenden Bauteile ganz neue Herausforderungen an ein Werkzeug. Konnten früher Bauteile nur mit hohem Aufwand durch Erodieren oder Außenräumen hergestellt werden, müssen heute bereits Fräswerkzeuge für solche Bearbeitungsaufgaben aus Zeitund Kostengründen eingesetzt werden. Dies führt dazu, dass viele Bauteile heute in einer Aufspannung bearbeitbar sind, welche früher nur durch mehrmaliges Umspannen erzeugt werden konnten. Um Bearbeitungszeiten und -kosten dabei gering zu halten, müssen aber dennoch universelle Werkzeuge eingesetzt werden, welche für verschiedenste Bearbeitungsaufgaben ausgelegt sind.

  10. UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO

    PubMed Central

    Goyama, Susumu; Schibler, Janet; Gasilina, Anjelika; Shrestha, Mahesh; Lin, Shan; Link, Kevin A.; Chen, Jianjun; Whitman, Susan P.; Bloomfield, Clara D.; Nicolet, Deedra; Assi, Salam; Ptasinska, Anetta; Heidenreich, Olaf; Bonifer, Constanze; Kitamura, Toshio; Nassar, Nicolas N.; Mulloy, James C.

    2015-01-01

    The t(8;21) rearrangement, which creates the AML1-ETO fusion protein, represents the most common chromosomal translocation in acute myeloid leukemia (AML). Clinical data suggest that CBL mutations are a frequent event in t(8;21) AML, but the role of CBL in AML1-ETO-induced leukemia has not been investigated. In this study, we demonstrate that CBL mutations collaborate with AML1-ETO to expand human CD34+ cells both in vitro and in a xenograft model. CBL depletion by shRNA also promotes the growth of AML1-ETO cells, demonstrating the inhibitory function of endogenous CBL in t(8;21) AML. Mechanistically, loss of CBL function confers hyper-responsiveness to thrombopoietin and enhances STAT5/AKT/ERK/Src signaling in AML1-ETO cells. Interestingly, we found the protein tyrosine phosphatase UBASH3B/Sts-1, which is known to inhibit CBL function, is upregulated by AML1-ETO through transcriptional and miR-9-mediated regulation. UBASH3B/Sts-1 depletion induces an aberrant pattern of CBL phosphorylation and impairs proliferation in AML1-ETO cells. The growth-inhibition caused by UBASH3B/Sts-1 depletion can be rescued by ectopic expression of CBL mutants, suggesting that UBASH3B/Sts-1 supports the growth of AML1-ETO cells partly through modulation of CBL function. Our study reveals a role of CBL in restricting myeloid proliferation of human AML1-ETO-induced leukemia, and identifies UBASH3B/Sts-1 as a potential target for pharmaceutical intervention. PMID:26449661

  11. Initiation of MLL-rearranged AML is dependent on C/EBPα

    PubMed Central

    Ohlsson, Ewa; Hasemann, Marie Sigurd; Willer, Anton; Lauridsen, Felicia Kathrine Bratt; Rapin, Nicolas; Jendholm, Johan

    2014-01-01

    MLL-fusion proteins are potent inducers of oncogenic transformation, and their expression is considered to be the main oncogenic driving force in ∼10% of human acute myeloid leukemia (AML) patients. These oncogenic fusion proteins are responsible for the initiation of a downstream transcriptional program leading to the expression of factors such as MEIS1 and HOXA9, which in turn can replace MLL-fusion proteins in overexpression experiments. To what extent MLL fusion proteins act on their own during tumor initiation, or if they collaborate with other transcriptional regulators, is unclear. Here, we have compared gene expression profiles from human MLL-rearranged AML to normal progenitors and identified the myeloid tumor suppressor C/EBPα as a putative collaborator in MLL-rearranged AML. Interestingly, we find that deletion of Cebpa rendered murine hematopoietic progenitors completely resistant to MLL-ENL–induced leukemic transformation, whereas C/EBPα was dispensable in already established AMLs. Furthermore, we show that Cebpa-deficient granulocytic-monocytic progenitors were equally resistant to transformation and that C/EBPα collaborates with MLL-ENL in the induction of a transcriptional program, which is also apparent in human AML. Thus, our studies demonstrate a key role of C/EBPα in MLL fusion–driven transformation and find that it sharply demarcates tumor initiation and maintenance. PMID:24367003

  12. Coordinate regulation of residual bone marrow function by paracrine trafficking of AML exosomes.

    PubMed

    Huan, J; Hornick, N I; Goloviznina, N A; Kamimae-Lanning, A N; David, L L; Wilmarth, P A; Mori, T; Chevillet, J R; Narla, A; Roberts, C T; Loriaux, M M; Chang, B H; Kurre, P

    2015-12-01

    We recently demonstrated that acute myeloid leukemia (AML) cell lines and patient-derived blasts release exosomes that carry RNA and protein; following an in vitro transfer, AML exosomes produce proangiogenic changes in bystander cells. We reasoned that paracrine exosome trafficking may have a broader role in shaping the leukemic niche. In a series of in vitro studies and murine xenografts, we demonstrate that AML exosomes downregulate critical retention factors (Scf, Cxcl12) in stromal cells, leading to hematopoietic stem and progenitor cell (HSPC) mobilization from the bone marrow. Exosome trafficking also regulates HSPC directly, and we demonstrate declining clonogenicity, loss of CXCR4 and c-Kit expression, and the consistent repression of several hematopoietic transcription factors, including c-Myb, Cebp-β and Hoxa-9. Additional experiments using a model of extramedullary AML or direct intrafemoral injection of purified exosomes reveal that the erosion of HSPC function can occur independent of direct cell-cell contact with leukemia cells. Finally, using a novel multiplex proteomics technique, we identified candidate pathways involved in the direct exosome-mediated modulation of HSPC function. In aggregate, this work suggests that AML exosomes participate in the suppression of residual hematopoietic function that precedes widespread leukemic invasion of the bone marrow directly and indirectly via stromal components. PMID:26108689

  13. Oncogene- and drug resistance-associated alternative exon usage in acute myeloid leukemia (AML).

    PubMed

    Mohamed, Aminetou Mint; Balsat, Marie; Thenoz, Morgan; Koering, Catherine; Payen-Gay, Lea; Cheok, Meyling; Mortada, Hussein; Auboeuf, Didier; Pinatel, Christiane; El-Hamri, Mohamed; Dumontet, Charles; Cros, Emeline; Flandrin-Gresta, Pascale; Nibourel, Olivier; Preudhomme, Claude; Michallet, Mauricette; Thomas, Xavier; Nicolini, Franck; Solly, Françoise; Guyotat, Denis; Campos, Lydia; Wattel, Eric; Mortreux, Franck

    2016-01-19

    In addition to spliceosome gene mutations, oncogene expression and drug resistance in AML might influence exon expression. We performed exon-array analysis and exon-specific PCR (ESPCR) to identify specific landscapes of exon expression that are associated with DEK and WT1 oncogene expression and the resistance of AML cells to AraC, doxorubicin or azacitidine. Data were obtained for these five conditions through exon-array analysis of 17 cell lines and 24 patient samples and were extended through qESPCR of samples from 152 additional AML cases. More than 70% of AEUs identified by exon-array were technically validated through ESPCR. In vitro, 1,130 to 5,868 exon events distinguished the 5 conditions from their respective controls while in vivo 6,560 and 9,378 events distinguished chemosensitive and chemoresistant AML, respectively, from normal bone marrow. Whatever the cause of this effect, 30 to 80% of mis-spliced mRNAs involved genes unmodified at the whole transcriptional level. These AEUs unmasked new functional pathways that are distinct from those generated by transcriptional deregulation. These results also identified new putative pathways that could help increase the understanding of the effects mediated by DEK or WT1, which may allow the targeting of these pathways to prevent resistance of AML cells to chemotherapeutic agents. PMID:26284582

  14. E protein silencing by the leukemogenic AML1-ETO fusion protein.

    PubMed

    Zhang, Jinsong; Kalkum, Markus; Yamamura, Soichiro; Chait, Brian T; Roeder, Robert G

    2004-08-27

    The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 15% of acute myeloid leukemia (AML) cases. This study shows that AML1-ETO, as well as ETO, inhibits transcriptional activation by E proteins through stable interactions that preclude recruitment of p300/CREB-binding protein (CBP) coactivators. These interactions are mediated by a conserved ETO TAF4 homology domain and a 17-amino acid p300/CBP and ETO target motif within AD1 activation domains of E proteins. In t(8;21) leukemic cells, very stable interactions between AML1-ETO and E proteins underlie a t(8;21) translocation-specific silencing of E protein function through an aberrant cofactor exchange mechanism. These studies identify E proteins as AML1-ETO targets whose dysregulation may be important for t(8;21) leukemogenesis, as well as an E protein silencing mechanism that is distinct from that associated with differentiation-inhibitory proteins. PMID:15333839

  15. CHK1 as a therapeutic target to bypass chemoresistance in AML.

    PubMed

    David, Laure; Fernandez-Vidal, Anne; Bertoli, Sarah; Grgurevic, Srdana; Lepage, Benoît; Deshaies, Dominique; Prade, Naïs; Cartel, Maëlle; Larrue, Clément; Sarry, Jean-Emmanuel; Delabesse, Eric; Cazaux, Christophe; Didier, Christine; Récher, Christian; Manenti, Stéphane; Hoffmann, Jean-Sébastien

    2016-01-01

    The nucleoside analog cytarabine, an inhibitor of DNA replication fork progression that results in DNA damage, is currently used in the treatment of acute myeloid leukemia (AML). We explored the prognostic value of the expression of 72 genes involved in various aspects of DNA replication in a set of 198 AML patients treated by cytarabine-based chemotherapy. We unveiled that high expression of the DNA replication checkpoint gene CHEK1 is a prognostic marker associated with shorter overall, event-free, and relapse-free survivals and determined that the expression of CHEK1 can predict more frequent and earlier postremission relapse. CHEK1 encodes checkpoint kinase 1 (CHK1), which is activated by the kinase ATR when DNA replication is impaired by DNA damage. High abundance of CHK1 in AML patient cells correlated with higher clonogenic ability and more efficient DNA replication fork progression upon cytarabine treatment. Exposing the patient cells with the high abundance of CHK1 to SCH900776, an inhibitor of the kinase activity of CHK1, reduced clonogenic ability and progression of DNA replication in the presence of cytarabine. These results indicated that some AML cells rely on an efficient CHK1-mediated replication stress response for viability and that therapeutic strategies that inhibit CHK1 could extend current cytarabine-based treatments and overcome drug resistance. Furthermore, monitoring CHEK1 expression could be used both as a predictor of outcome and as a marker to select AML patients for CHK1 inhibitor treatments. PMID:27625304

  16. Allogeneic hematopoietic cell transplant for AML: no impact of pre-transplant extramedullary disease on outcome.

    PubMed

    Goyal, S D; Zhang, M-J; Wang, H-L; Akpek, G; Copelan, E A; Freytes, C; Gale, R P; Hamadani, M; Inamoto, Y; Kamble, R T; Lazarus, H M; Marks, D I; Nishihori, T; Olsson, R F; Reshef, R; Ritchie, D S; Saber, W; Savani, B N; Seber, A; Shea, T C; Tallman, M S; Wirk, B; Bunjes, D W; Devine, S M; de Lima, M; Weisdorf, D J; Uy, G L

    2015-08-01

    The impact of extramedullary disease (EMD) in AML on the outcomes of allogeneic hematopoietic cell transplantation (alloHCT) is unknown. Using data from the Center for International Blood and Marrow Transplant Research, we compared the outcomes of patients who had EMD of AML at any time before transplant, with a cohort of AML patients without EMD. We reviewed data from 9797 AML patients including 814 with EMD from 310 reporting centers and 44 different countries, who underwent alloHCT between and 1995 and 2010. The primary outcome was overall survival (OS) after alloHCT. Secondary outcomes included leukemia-free survival (LFS), relapse rate and treatment-related mortality (TRM). In a multivariate analysis, the presence of EMD did not affect either OS (hazard ratio 1.00, 95% confidence interval (CI) 0.91-1.09), LFS (0.98, 0.89-1.09), TRM (relative risk 0.92, 95% CI 0.80-1.16, P=0.23) or relapse (relative risk=1.03, 95% CI, 0.92-1.16; P=0.62). Furthermore, the outcome of patients with EMD was not influenced by the location, timing of EMD, or intensity of conditioning regimen. The presence of EMD in AML does not affect transplant outcomes and should not be viewed as an independent adverse prognostic feature. PMID:25915806

  17. The relapse risk of AML patients undergoing autologous transplantation correlates with the stem cell mobilizing potential.

    PubMed

    von Grünigen, Isabelle; Raschle, Joëlle; Rüsges-Wolter, Ilka; Taleghani, Behrouz Mansouri; Mueller, Beatrice U; Pabst, Thomas

    2012-11-01

    Autologous stem cell transplantation (ASCT) is widely used to consolidate first remission in AML. We determined the significance of circulating CD34+ cells at the day of blood stem cell collection in 78 AML patients. Patients mobilizing more than 60,000 CD34+ cells/ml had shorter overall survival (OS; P=0.0274), shorter time to progression (TTP; P=0.0014), and a higher relapse rate (P=0.0177). High levels of CD34+ cells were an independent marker for shorter OS and TTP in a multivariate analysis. These data suggest that ASCT is associated with unfavorable outcome in AML patients with high levels of mobilized peripheral CD34+ cells. PMID:22727508

  18. Prognostic factors of childhood and adolescent acute myeloid leukemia (AML) survival: evidence from four decades of US population data.

    PubMed

    Hossain, Md Jobayer; Xie, Li; Caywood, Emi H

    2015-10-01

    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. Patients diagnosed between 10 and 19 years of age were at a higher risk of death compared to those diagnosed before age 10 (adjusted hazard ratio (aHR): 1.30, 95% confidence interval (CI): 1.17-1.44). African Americans (1.27, 1.09-1.48) and Hispanics (1.15, 1.00-1.32) had an elevated risk of mortality than Caucasians. Compared to the subtype acute promyelocytic leukemia, AML with minimal differentiation (2.44, 1.78-3.35); acute erythroid leukemia (2.34, 1.60-3.40); AML without maturation (1.87, 1.35-2.59); and most other AML subtypes had a higher risk of mortality, whereas AML with inv(16) had a substantially lower risk. Age at diagnosis, race-ethnicity, AML subtype, county level poverty and geographic region appeared as significant prognostic factors of pediatric AML survival in the US. Contrary to previous findings, the subtypes of AML with t(9;11)(p22;q23)MLLT3-MLL, AML without maturation and acute myelomonocytic leukemia emerged to be indicative of poor outcome. PMID:26159683

  19. AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB.

    PubMed

    Hornick, Noah I; Doron, Ben; Abdelhamed, Sherif; Huan, Jianya; Harrington, Christina A; Shen, Rongkun; Cambronne, Xiaolu A; Chakkaramakkil Verghese, Santhosh; Kurre, Peter

    2016-01-01

    Exosomes are paracrine regulators of the tumor microenvironment and contain complex cargo. We previously reported that exosomes released from acute myeloid leukemia (AML) cells can suppress residual hematopoietic stem and progenitor cell (HSPC) function indirectly through stromal reprogramming of niche retention factors. We found that the systemic loss of hematopoietic function is also in part a consequence of AML exosome-directed microRNA (miRNA) trafficking to HSPCs. Exosomes isolated from cultured AML or the plasma from mice bearing AML xenografts exhibited enrichment of miR-150 and miR-155. HSPCs cocultured with either of these exosomes exhibited impaired clonogenicity, through the miR-150- and miR-155-mediated suppression of the translation of transcripts encoding c-MYB, a transcription factor involved in HSPC differentiation and proliferation. To discover additional miRNA targets, we captured miR-155 and its target transcripts by coimmunoprecipitation with an attenuated RNA-induced silencing complex (RISC)-trap, followed by high-throughput sequencing. This approach identified known and previously unknown miR-155 target transcripts. Integration of the miR-155 targets with information from the protein interaction database STRING revealed proteins indirectly affected by AML exosome-derived miRNA. Our findings indicate a direct effect of AML exosomes on HSPCs that, through a stroma-independent mechanism, compromises hematopoiesis. Furthermore, combining miRNA target data with protein-protein interaction data may be a broadly applicable strategy to define the effects of exosome-mediated trafficking of regulatory molecules within the tumor microenvironment. PMID:27601730

  20. Unfälle mit Pkw

    NASA Astrophysics Data System (ADS)

    Burg, Heinz

    Der Verkehrsunfall ereignete sich innerorts auf einer Kreuzung mit rechts vor links Regelung. Es galt dort die allgemeine Geschwindigkeitsbegrenzung auf 50 km/h. Zur Unfallzeit war es hell und trocken. Die Fahrbahn hatte eine Schwarzdecke.

  1. Workstation-assisted education at MIT

    NASA Astrophysics Data System (ADS)

    Champine, George A.

    1992-06-01

    MIT launched a major new initiative called Project Athena in 1983 to improve the quality of education through the introduction of a high-quality computing infrastructure throughout the campus. Implementation of the Project Athena computing environment required eight years, cost about 100 million, and was sponsored by Digital Equipment and IBM in addition to MIT. The Athena computing environment is based almost entirely on workstations from these two vendors using the Unix operating system. Project Athena is now complete. The resulting computer system has been turned over to the campus computing organization for ongoing operation and maintenance. The computing environment available at MIT for education has been significantly improved. Students are graduating today that have never known life at MIT without the ubiquitous availability of high-quality computing. This article provides an overview of the initial objectives and strategies of Project Athena at MIT relative to its educational use. The specific strategies that MIT employed in the use of work-stations in educational are then described. These strategies are contrasted with other available strategies. Specific examples of the use of workstations are presented. An important element in current and future education delivery is multimedia. Athena in conjunction with the MIT Media Lab has one of the largest efforts in multimedia development of any of the universities, and MIT is using multimedia in education on a daily basis. A new laboratory, the Center for Educational Computing Initiatives, has been established with a major focus on multimedia. Finally the lessons learned from Athena relative to its primary objective — that of improving education — are reviewed.

  2. Photovoltaik Hybrid-Solarzellen mit Nanopartikeln

    NASA Astrophysics Data System (ADS)

    Leute, Angelika

    2004-09-01

    Die organische Photovoltaik auf der Basis halbleitender Polymere bietet eine kostengünstige Alternative zu Solarzellen aus Silizium. Allerdings weisen die organischen Materialien relativ schlechte Ladungstransporteigenschaften auf. Hybrid-Solarzellen, in denen Polymere mit geeigneten anorganischen Halbleitern kombiniert sind, besitzen einerseits die praktischen Vorteile der Organik und andererseits die hohe Elektronenbeweglichkeit der anorganischen Materialien. Wissenschaftler der Technischen Universität Eindhoven haben kürzlich Hybrid-Solarzellen vorgestellt, die aus einem halbleitenden Polymer mit Zinkoxid-Nanopartikeln bestehen.

  3. An Implementation and Evaluation of the AMLS Method for SparseEigenvalue Problems

    SciTech Connect

    Gao, Weiguo; Li, Xiaoye S.; Yang, Chao; Bai, Zhaojun

    2006-02-14

    We describe an efficient implementation and present aperformance study of an algebraic multilevel sub-structuring (AMLS)method for sparse eigenvalue problems. We assess the time and memoryrequirements associated with the key steps of the algorithm, and compareitwith the shift-and-invert Lanczos algorithm in computational cost. Oureigenvalue problems come from two very different application areas: theaccelerator cavity design and the normal mode vibrational analysis of thepolyethylene particles. We show that the AMLS method, when implementedcarefully, is very competitive with the traditional method in broadapplication areas, especially when large numbers of eigenvalues aresought.

  4. Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial.

    PubMed

    Schweitzer, Jana; Zimmermann, Martin; Rasche, Mareike; von Neuhoff, Christine; Creutzig, Ursula; Dworzak, Michael; Reinhardt, Dirk; Klusmann, Jan-Henning

    2015-08-01

    Despite recent advances in the treatment of children with acute megakaryoblastic leukemia (AMKL) using intensified treatment protocols, clear prognostic indicators, and treatment recommendations for this acute myeloid leukemia (AML) subgroup are yet to be defined. Here, we report the outcome of 97 pediatric patients with de novo AMKL (excluding Down syndrome [DS]) enrolled in the prospective multicenter studies AML-BFM 98 and AML-BFM 04 (1998-2014). AMKL occurred in 7.4 % of pediatric AML cases, at younger age (median 1.44 years) and with lower white blood cell count (mean 16.5 × 10(9)/L) as compared to other AML subgroups. With 60 ± 5 %, children with AMKL had a lower 5-year overall survival (5-year OS; vs. 68 ± 1 %, P log rank = 0.038). Yet, we achieved an improved 5-year OS in AML-BFM 04 compared to AML-BFM 98 (70 ± 6 % vs. 45 ± 8 %, P log rank = 0.041). Allogeneic hematopoietic stem cell transplantation in first remission did not provide a significant survival benefit (5-year OS 70 ± 11 % vs. 63 ± 6 %; P Mantel-Byar = 0.85). Cytogenetic data were available for n = 78 patients. AMKL patients with gain of chromosome 21 had a superior 5-year OS (80 ± 9 %, P log rank = 0.034), whereas translocation t(1;22)(p13;q13) was associated with an inferior 5-year event-free survival (38 ± 17 %, P log rank = 0.04). However, multivariate analysis showed that treatment response (bone marrow morphology on day 15 and 28) was the only independent prognostic marker (RR = 4.39; 95 % CI, 1.97-9.78). Interestingly, GATA1-mutations were detected in six patients (11 %) without previously known trisomy 21. Thus, AMKL (excluding DS) remains an AML subgroup with inferior outcome. Nevertheless, with intensive therapy regimens, a steep increase in the survival rates was achieved. PMID:25913479

  5. ELMO1 is upregulated in AML CD34+ stem/progenitor cells, mediates chemotaxis and predicts poor prognosis in normal karyotype AML.

    PubMed

    Capala, Marta E; Vellenga, Edo; Schuringa, Jan Jacob

    2014-01-01

    Both normal as well leukemic hematopoietic stem cells critically depend on their microenvironment in the bone marrow for processes such as self-renewal, survival and differentiation, although the exact pathways that are involved remain poorly understood. We performed transcriptome analysis on primitive CD34+ acute myeloid leukemia (AML) cells (n = 46), their more differentiated CD34- leukemic progeny, and normal CD34+ bone marrow cells (n = 31) and focused on differentially expressed genes involved in adhesion and migration. Thus, Engulfment and Motility protein 1 (ELMO1) was identified amongst the top 50 most differentially expressed genes. ELMO1 is a crucial link in the signaling cascade that leads to activation of RAC GTPases and cytoskeleton rearrangements. We confirmed increased ELMO1 expression at the mRNA and protein level in a panel of AML samples and showed that high ELMO1 expression is an independent negative prognostic factor in normal karyotype (NK) AML in three large independent patient cohorts. Downmodulation of ELMO1 in human CB CD34+ cells did not significantly alter expansion, progenitor frequency or differentiation in stromal co-cultures, but did result in a decreased frequency of stem cells in LTC-IC assays. In BCR-ABL-transduced human CB CD34+ cells depletion of ELMO1 resulted in a mild decrease in proliferation, but replating capacity of progenitors was severely impaired. Downregulation of ELMO1 in a panel of primary CD34+ AML cells also resulted in reduced long-term growth in stromal co-cultures in two out of three cases. Pharmacological inhibition of the ELMO1 downstream target RAC resulted in a severely impaired proliferation and survival of leukemic cells. Finally, ELMO1 depletion caused a marked decrease in SDF1-induced chemotaxis of leukemic cells. Taken together, these data show that inhibiting the ELMO1-RAC axis might be an alternative way to target leukemic cells. PMID:25360637

  6. Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML.

    PubMed

    Morgado-Palacin, Isabel; Day, Amanda; Murga, Matilde; Lafarga, Vanesa; Anton, Marta Elena; Tubbs, Anthony; Chen, Hua-Tang; Ergan, Aysegul; Anderson, Rhonda; Bhandoola, Avinash; Pike, Kurt G; Barlaam, Bernard; Cadogan, Elaine; Wang, Xi; Pierce, Andrew J; Hubbard, Chad; Armstrong, Scott A; Nussenzweig, André; Fernandez-Capetillo, Oscar

    2016-01-01

    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. Moreover, ATR inhibition as a single agent exhibited antitumoral activity, both reducing tumor burden after establishment and preventing tumors from growing, in an immunocompetent allograft mouse model of AML(MLL) and in xenografts of a human AML-MLL cell line. We also found that inhibition of ATM, a kinase that senses DNA double-strand breaks, also promoted the survival of the AML(MLL) mice. Collectively, these data indicated that ATR or ATM inhibition represent potential therapeutic strategies for the treatment of AML, especially MLL-driven leukemias. PMID:27625305

  7. The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice

    PubMed Central

    Schessl, Christina; Rawat, Vijay P.S.; Cusan, Monica; Deshpande, Aniruddha; Kohl, Tobias M.; Rosten, Patricia M.; Spiekermann, Karsten; Humphries, R. Keith; Schnittger, Susanne; Kern, Wolfgang; Hiddemann, Wolfgang; Quintanilla-Martinez, Leticia; Bohlander, Stefan K.; Feuring-Buske, Michaela; Buske, Christian

    2005-01-01

    The molecular characterization of leukemia has demonstrated that genetic alterations in the leukemic clone frequently fall into 2 classes, those affecting transcription factors (e.g., AML1-ETO) and mutations affecting genes involved in signal transduction (e.g., activating mutations of FLT3 and KIT). This finding has favored a model of leukemogenesis in which the collaboration of these 2 classes of genetic alterations is necessary for the malignant transformation of hematopoietic progenitor cells. The model is supported by experimental data indicating that AML1-ETO and FLT3 length mutation (FLT3-LM), 2 of the most frequent genetic alterations in AML, are both insufficient on their own to cause leukemia in animal models. Here we report that AML1-ETO collaborates with FLT3-LM in inducing acute leukemia in a murine BM transplantation model. Moreover, in a series of 135 patients with AML1-ETO–positive AML, the most frequently identified class of additional mutations affected genes involved in signal transduction pathways including FLT3-LM or mutations of KIT and NRAS. These data support the concept of oncogenic cooperation between AML1-ETO and a class of activating mutations, recurrently found in patients with t(8;21), and provide a rationale for therapies targeting signal transduction pathways in AML1-ETO–positive leukemias. PMID:16025155

  8. Phase I Trial of the Selective Inhibitor of Nuclear Export, KPT-330, in Relapsed Childhood ALL and AML

    ClinicalTrials.gov

    2016-08-03

    Relapsed Acute Lymphoblastic Leukemia (ALL); Refractory Acute Lymphoblastic Leukemia (ALL); Relapsed Acute Myelogenous Leukemia (AML); Refractory Acute Myelogenous Leukemia (AML); Relapsed Mixed Lineage Leukemia; Refractory Mixed Lineage Leukemia; Relapsed Biphenotypic Leukemia; Refractory Biphenotypic Leukemia; Chronic Myelogenous Leukemia (CML) in Blast Crisis

  9. Deletion of CBFB in a patient with acute myelomonocytic leukemia (AML M4Eo) and inversion 16.

    PubMed

    Egan, Nicole; O'Reilly, John; Chipper, Lucia; Higgins, Melinda; Herrmann, Richard; Cannell, Paul

    2004-10-01

    Acute myelomonocytic leukemia with bone marrow eosinophilia (AML M4Eo) is a subtype of AML with distinct morphological features. Inversion (16)(p13.1q22), t(16;16)(p13.1;q22), and del(16)(q22) are nonrandom abnormalities associated with AML M4Eo and a favorable prognosis, compared with the standard risk group for AML. Deletions of the proximal region of the MYH11 gene located at 16p13.1 have been detected in about 20% of patients with inv(16), with an undetermined effect on patient survival. We present the case of a patient with AML M4Eo and inversion 16 with a distal deletion of the CBFB gene at 16q22 detected with fluorescence in situ hybridization. To our knowledge, only one previous report of a similar deletion has appeared in the literature. PMID:15381374

  10. Decitabine enhances anti-CD33 monoclonal antibody BI 836858-mediated natural killer ADCC against AML blasts.

    PubMed

    Vasu, Sumithira; He, Shun; Cheney, Carolyn; Gopalakrishnan, Bhavani; Mani, Rajeswaran; Lozanski, Gerard; Mo, Xiaokui; Groh, Veronica; Whitman, Susan P; Konopitzky, Renate; Kössl, Christian; Bucci, Donna; Lucas, David M; Yu, Jianhua; Caligiuri, Michael A; Blum, William; Adam, Paul J; Borges, Eric; Rueter, Bjoern; Heider, Karl-Heinz; Marcucci, Guido; Muthusamy, Natarajan

    2016-06-01

    Acute myeloid leukemia (AML) is the most common type of acute leukemia, affecting older individuals at a median age of 67 years. Resistance to intensive induction chemotherapy is the major cause of death in elderly AML; hence, novel treatment strategies are warranted. CD33-directed antibody-drug conjugates (gemtuzumab ozogamicin) have been shown to improve overall survival, validating CD33 as a target for antibody-based therapy of AML. Here, we report the in vitro efficacy of BI 836858, a fully human, Fc-engineered, anti-CD33 antibody using AML cell lines and primary AML blasts as targets. BI 836858-opsonized AML cells significantly induced both autologous and allogeneic natural killer (NK)-cell degranulation and NK-cell-mediated antibody-dependent cellular cytotoxicity (ADCC). In vitro treatment of AML blasts with decitabine (DAC) or 5-azacytidine, 2 hypomethylating agents that show efficacy in older patients, did not compromise BI 836858-induced NK-cell-mediated ADCC. Evaluation of BI 836858-mediated ADCC in serial marrow AML aspirates in patients who received a 10-day course of DAC (pre-DAC, days 4, 11, and 28 post-DAC) revealed significantly higher ADCC in samples at day 28 post-DAC when compared with pre-DAC treatment. Analysis of ligands to activating receptors (NKG2D) showed significantly increased NKG2D ligand [NKG2DL] expression in day 28 post-DAC samples compared with pre-DAC samples; when NKG2DL receptor was blocked using antibodies, BI 836858-mediated ADCC was significantly decreased, suggesting that DAC enhances AML blast susceptibility to BI 836858 by upregulating NKG2DL. These data provide a rationale for combination therapy of Fc-engineered antibodies such as BI 836858 with azanucleosides in elderly patients with AML. PMID:27013443

  11. A Crowdsourcing Approach to Developing and Assessing Prediction Algorithms for AML Prognosis.

    PubMed

    Noren, David P; Long, Byron L; Norel, Raquel; Rrhissorrakrai, Kahn; Hess, Kenneth; Hu, Chenyue Wendy; Bisberg, Alex J; Schultz, Andre; Engquist, Erik; Liu, Li; Lin, Xihui; Chen, Gregory M; Xie, Honglei; Hunter, Geoffrey A M; Boutros, Paul C; Stepanov, Oleg; Norman, Thea; Friend, Stephen H; Stolovitzky, Gustavo; Kornblau, Steven; Qutub, Amina A

    2016-06-01

    Acute Myeloid Leukemia (AML) is a fatal hematological cancer. The genetic abnormalities underlying AML are extremely heterogeneous among patients, making prognosis and treatment selection very difficult. While clinical proteomics data has the potential to improve prognosis accuracy, thus far, the quantitative means to do so have yet to be developed. Here we report the results and insights gained from the DREAM 9 Acute Myeloid Prediction Outcome Prediction Challenge (AML-OPC), a crowdsourcing effort designed to promote the development of quantitative methods for AML prognosis prediction. We identify the most accurate and robust models in predicting patient response to therapy, remission duration, and overall survival. We further investigate patient response to therapy, a clinically actionable prediction, and find that patients that are classified as resistant to therapy are harder to predict than responsive patients across the 31 models submitted to the challenge. The top two performing models, which held a high sensitivity to these patients, substantially utilized the proteomics data to make predictions. Using these models, we also identify which signaling proteins were useful in predicting patient therapeutic response. PMID:27351836

  12. A Crowdsourcing Approach to Developing and Assessing Prediction Algorithms for AML Prognosis

    PubMed Central

    Noren, David P.; Long, Byron L.; Norel, Raquel; Rrhissorrakrai, Kahn; Hess, Kenneth; Hu, Chenyue Wendy; Bisberg, Alex J.; Schultz, Andre; Engquist, Erik; Liu, Li; Lin, Xihui; Chen, Gregory M.; Xie, Honglei; Hunter, Geoffrey A. M.; Norman, Thea; Friend, Stephen H.; Stolovitzky, Gustavo; Kornblau, Steven; Qutub, Amina A.

    2016-01-01

    Acute Myeloid Leukemia (AML) is a fatal hematological cancer. The genetic abnormalities underlying AML are extremely heterogeneous among patients, making prognosis and treatment selection very difficult. While clinical proteomics data has the potential to improve prognosis accuracy, thus far, the quantitative means to do so have yet to be developed. Here we report the results and insights gained from the DREAM 9 Acute Myeloid Prediction Outcome Prediction Challenge (AML-OPC), a crowdsourcing effort designed to promote the development of quantitative methods for AML prognosis prediction. We identify the most accurate and robust models in predicting patient response to therapy, remission duration, and overall survival. We further investigate patient response to therapy, a clinically actionable prediction, and find that patients that are classified as resistant to therapy are harder to predict than responsive patients across the 31 models submitted to the challenge. The top two performing models, which held a high sensitivity to these patients, substantially utilized the proteomics data to make predictions. Using these models, we also identify which signaling proteins were useful in predicting patient therapeutic response. PMID:27351836

  13. Activity of 8F4, a T-cell receptor-like anti-PR1/HLA-A2 antibody, against primary human AML in vivo.

    PubMed

    Sergeeva, A; He, H; Ruisaard, K; St John, L; Alatrash, G; Clise-Dwyer, K; Li, D; Patenia, R; Hong, R; Sukhumalchandra, P; You, M J; Gagea, M; Ma, Q; Molldrem, J J

    2016-07-01

    The PR1 peptide, derived from the leukemia-associated antigens proteinase 3 and neutrophil elastase, is overexpressed on HLA-A2 in acute myeloid leukemia (AML). We developed a high-affinity T-cell receptor-like murine monoclonal antibody, 8F4, that binds to the PR1/HLA-A2 complex, mediates lysis of AML and inhibits leukemia colony formation. Here, we explored whether 8F4 was active in vivo against chemotherapy-resistant AML, including secondary AML. In a screening model, coincubation of AML with 8F4 ex vivo prevented engraftment of all tested AML subtypes in immunodeficient NSG (NOD scid IL-2 receptor γ-chain knockout) mice. In a treatment model of established human AML, administration of 8F4 significantly reduced or eliminated AML xenografts and extended survival compared with isotype antibody-treated mice. Moreover, in secondary transfer experiments, mice inoculated with bone marrow from 8F4-treated mice showed no evidence of AML engraftment, supporting the possible activity of 8F4 against the subset of AML with self-renewing potential. Our data provide evidence that 8F4 antibody is highly active in AML, including chemotherapy-resistant disease, supporting its potential use as a therapeutic agent in patients with AML. PMID:27055866

  14. Impact of obesity in favorable-risk AML patients receiving intensive chemotherapy.

    PubMed

    Tavitian, Suzanne; Denis, Amélia; Vergez, François; Berard, Emilie; Sarry, Audrey; Huynh, Anne; Delabesse, Eric; Luquet, Isabelle; Huguet, Françoise; Récher, Christian; Bertoli, Sarah

    2016-02-01

    We assessed the influence of obesity on the characteristics and prognosis of acute myeloid leukemia (AML). Indeed, safety of intensive chemotherapy and outcome of obese AML patients in a real-life setting are poorly described, and chemotherapy dosing remains challenging. We included 619 consecutive genetically-defined cases of AML treated with intensive chemotherapy between 2004 and 2012. In this cohort, 93 patients (15%) were classified in the obese category according to WHO classification; 59% of them received capped doses of chemotherapy because of a body surface area above 2 m(2) . Obese patients were older and presented more often with cardiovascular comorbidities. Although obese patients had more frequently de novo AML, main characteristics of AML including white blood cell count, karyotype and mutations were well-balanced between obese and non-obese patients. After induction chemotherapy, early death and complete remission rates were similar. Overall (OS), event-free (EFS) and disease-free (DFS) survival were not significantly different compared to non-obese patients. However, in the European LeukemiaNet (ELN) favorable subgroup, obese patients had lower median OS, EFS and DFS than non-obese patients (18.4, 16.8 and 17.2 vs. 43.6, 31.8 and 29.7 months, respectively) and obesity showed a significant impact on OS (OR 2.54; P = 0.02) in multivariate models. Although we did not find any significant impact of obesity on outcome in the whole series, this study suggests that special efforts for chemotherapy dose optimization are needed in the ELN favorable subgroup since dose capping may be deleterious. PMID:26509505

  15. Development of ZMYM2-FGFR1 driven AML in human CD34+ cells in immunocompromised mice.

    PubMed

    Ren, Mingqiang; Qin, Haiyan; Wu, Qing; Savage, Natasha M; George, Tracy I; Cowell, John K

    2016-08-15

    Acute myelogenous leukemia (AML) has an overall poor survival rate and shows considerable molecular heterogeneity in its etiology. In the WHO classification there are >50 cytogenetic subgroups of AML, many showing highly specific chromosome translocations that lead to constitutive activation of individual kinases. In a rare stem cell leukemia/lymphoma syndrome, translocations involving 8p11 lead to constitutive activation of the fibroblast growth factor receptor 1 (FGFR1) kinase. This disorder shows myeloproliferative disease with almost invariable progresses to AML and conventional therapeutic strategies are largely unsuccessful. Because of the rare nature of this syndrome, models that faithfully recapitulate the human disease are needed to evaluate therapeutic strategies. The t(8;13)(p11;q12) chromosome translocation is most common rearrangement seen in this syndrome and creates a ZMYM2-FGFR1 chimeric kinase. To understand more about the molecular etiology of AML induced by this particular rearrangement, we have created a model human CD34+ cells transplanted into immunocompromized mice which develop myeloproliferative disease that progresses to AML with a long (>12 months) latency period. As in humans, these mice show hepatospenomegaly, hypercellular bone marrow and a CD45 + CD34 + CD13+ immunophenotype. Molecular studies demonstrate upregulation of genes such as KLF4 and FLT3 that promote stemness, and overexpression of MYC, which is associated with suppression of myeloid cell differentiation. This murine model, therefore, provides an opportunity to develop therapeutic strategies against the most common subtype within these FGFR1 driven neoplasms and study the molecular etiology in more depth. PMID:27005999

  16. Mediator Kinase Inhibition Further Activates Super-Enhancer Associated Genes in AML

    PubMed Central

    Nitulescu, Ioana I.; Tangpeerachaikul, Anupong; Poss, Zachary C.; Da Silva, Diogo H.; Caruso, Brittany T.; Arefolov, Alexander; Fadeyi, Olugbeminiyi; Christie, Amanda L.; Du, Karrie; Banka, Deepti; Schneider, Elisabeth V.; Jestel, Anja; Zou, Ge; Si, Chong; Ebmeier, Christopher C.; Bronson, Roderick T.; Krivtsov, Andrei V.; Myers, Andrew G.; Kohl, Nancy E.; Kung, Andrew L.; Armstrong, Scott A.; Lemieux, Madeleine E.; Taatjes, Dylan J.; Shair, Matthew D.

    2015-01-01

    Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors (TFs), and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling TFs and oncogenes 1, 2. BRD4 and CDK7 are positive regulators of SE-mediated transcription3,4,5. In contrast, negative regulators of SE-associated genes have not been well described. Here we report that Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We determined that the natural product cortistatin A (CA) selectively inhibited Mediator kinases, had antileukaemic activity in vitro and in vivo, and disproportionately induced upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the TFs CEBPA, IRF8, IRF1 and ETV6 6, 7, 8. The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has antileukaemic activity. Individually increasing or decreasing expression of these TFs suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types and can be pharmacologically targeted as a therapeutic approach to AML. PMID:26416749

  17. Mediator kinase inhibition further activates super-enhancer-associated genes in AML.

    PubMed

    Pelish, Henry E; Liau, Brian B; Nitulescu, Ioana I; Tangpeerachaikul, Anupong; Poss, Zachary C; Da Silva, Diogo H; Caruso, Brittany T; Arefolov, Alexander; Fadeyi, Olugbeminiyi; Christie, Amanda L; Du, Karrie; Banka, Deepti; Schneider, Elisabeth V; Jestel, Anja; Zou, Ge; Si, Chong; Ebmeier, Christopher C; Bronson, Roderick T; Krivtsov, Andrei V; Myers, Andrew G; Kohl, Nancy E; Kung, Andrew L; Armstrong, Scott A; Lemieux, Madeleine E; Taatjes, Dylan J; Shair, Matthew D

    2015-10-01

    Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes. BRD4 and CDK7 are positive regulators of SE-mediated transcription. By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo, and disproportionately induces upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the transcription factors CEBPA, IRF8, IRF1 and ETV6 (refs 6-8). The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types, and can be pharmacologically targeted as a therapeutic approach to AML. PMID:26416749

  18. Defining AML and MDS second cancer risk dynamics after diagnoses of first cancers treated or not with radiation.

    PubMed

    Radivoyevitch, T; Sachs, R K; Gale, R P; Molenaar, R J; Brenner, D J; Hill, B T; Kalaycio, M E; Carraway, H E; Mukherjee, S; Sekeres, M A; Maciejewski, J P

    2016-02-01

    Risks of acute myeloid leukemia (AML) and/or myelodysplastic syndromes (MDS) are known to increase after cancer treatments. Their rise-and-fall dynamics and their associations with radiation have, however, not been fully characterized. To improve risk definition we developed SEERaBomb R software for Surveillance, Epidemiology and End Results second cancer analyses. Resulting high-resolution relative risk (RR) time courses were compared, where possible, to results of A-bomb survivor analyses. We found: (1) persons with prostate cancer receiving radiation therapy have increased RR of AML and MDS that peak in 1.5-2.5 years; (2) persons with non-Hodgkin lymphoma (NHL), lung and breast first cancers have the highest RR for AML and MDS over the next 1-12 years. These increased RR are radiation specific for lung and breast cancer but not for NHL; (3) AML latencies were brief compared to those of A-bomb survivors; and (4) there was a marked excess risk of acute promyelocytic leukemia in persons receiving radiation therapy. Knowing the type of first cancer, if it was treated with radiation, the interval from first cancer diagnosis to developing AML or MDS, and the type of AML, can improve estimates of whether AML or MDS cases developing in this setting are due to background versus other processes. PMID:26460209

  19. Mutant WT1 is associated with DNA hypermethylation of PRC2 targets in AML and responds to EZH2 inhibition.

    PubMed

    Sinha, Subarna; Thomas, Daniel; Yu, Linda; Gentles, Andrew J; Jung, Namyoung; Corces-Zimmerman, M Ryan; Chan, Steven M; Reinisch, Andreas; Feinberg, Andrew P; Dill, David L; Majeti, Ravindra

    2015-01-01

    Acute myeloid leukemia (AML) is associated with deregulation of DNA methylation; however, many cases do not bear mutations in known regulators of cytosine guanine dinucleotide (CpG) methylation. We found that mutations in WT1, IDH2, and CEBPA were strongly linked to DNA hypermethylation in AML using a novel integrative analysis of The Cancer Genome Atlas data based on Boolean implications, if-then rules that identify all individual CpG sites that are hypermethylated in the presence of a mutation. Introduction of mutant WT1 (WT1mut) into wild-type AML cells induced DNA hypermethylation, confirming mutant WT1 to be causally associated with DNA hypermethylation. Methylated genes in WT1mut primary patient samples were highly enriched for polycomb repressor complex 2 (PRC2) targets, implicating PRC2 dysregulation in WT1mut leukemogenesis. We found that PRC2 target genes were aberrantly repressed in WT1mut AML, and that expression of mutant WT1 in CD34(+) cord blood cells induced myeloid differentiation block. Treatment of WT1mut AML cells with short hairpin RNA or pharmacologic PRC2/enhancer of zeste homolog 2 (EZH2) inhibitors promoted myeloid differentiation, suggesting EZH2 inhibitors may be active in this AML subtype. Our results highlight a strong association between mutant WT1 and DNA hypermethylation in AML and demonstrate that Boolean implications can be used to decipher mutation-specific methylation patterns that may lead to therapeutic insights. PMID:25398938

  20. MIT 12 Tesla Coil test results

    NASA Astrophysics Data System (ADS)

    Steeves, M. M.; Hoenig, M. O.

    1985-07-01

    Test results from the MIT 12 Tesla Coil experiment are presented. The coil was tested in the High Field Test Facility (HFTF) of the Lawrence Livermore National Laboratory in October 1984 and January 1985. The experiment measured the performance of an Internally Cooled, Cabled Superconductor (ICCS) of practical size, intended for use in magnetic fusion experiments. The MIT coil carried 15 kA at 11 T for 5 min with no sign of instability. A half turn length in a 10 T field was able to absorb a heat load in 4 msec of more than 200 mJ sub cm of cable volume while carrying a current of 12 kA. The MIT coil successfully met the performance requirements of the Department of Energy's 12 Tesla Coil Program.

  1. DNMT3A R882 Mutations Predict a Poor Prognosis in AML

    PubMed Central

    Yuan, Xiao-Qing; Peng, Li; Zeng, Wen-Jing; Jiang, Bin-Yuan; Li, Guan-Cheng; Chen, Xiao-Ping

    2016-01-01

    Abstract DNA (cytosine-5)-methyltransferase 3 alpha (DNMT3A) mutations were widely believed to be independently associated with inferior prognosis in acute myeloid leukemia (AML) patients. As dominant missense alterations in DNMT3A mutations, R882 mutations cause the focal hypomethylation phenotype. However, there remains debate on the influence of R882 mutations on AML prognosis. Thus, this meta-analysis aimed at further illustrating the prognostic power of DNMT3A R882 mutations in AML patients. Eligible studies were identified from 5 databases containing PubMed, Embase, Web of Science, Clinical Trials, and the Cochrane Library (up to October 25, 2015). Effects (hazard ratios [HRs] with 95% confidence interval [CI]) of relapse-free survival (RFS) and overall survival (OS) were pooled to estimate the prognostic power of mutant DNMT3A R882 in overall patients and subgroups of AML patients. Eight competent studies with 4474 AML patients including 694 with DNMT3A R882 mutations were included. AML patients with DNMT3A R882 mutations showed significant shorter RFS (HR = 1.40, 95% CI = 1.24–1.59, P < 0.001) and OS (HR = 1.47, 95% CI = 1.17–1.86, P = 0.001) in the overall population. DNMT3A R882 mutations predicted worse RFS and OS among the subgroups of patients under age 60 (RFS: HR = 1.44, 95% CI = 1.25–1.66, P < 0.001; OS: HR = 1.48, 95% CI = 1.15–1.90, P = 0.002), over age 60 (RFS: HR = 2.03, 95% CI = 1.40–2.93, P < 0.001; OS: HR = 1.85, 95% CI = 1.36–2.53, P < 0.001), cytogenetically normal (CN)-AML (RFS: HR = 1.52, 95% CI = 1.26–1.83, P < 0.001; OS: HR = 1.67, 95% CI = 1.16–2.41, P = 0.006), and non-CN-AML (RFS: HR = 1.96, 95% CI = 1.20–3.21, P = 0.006; OS: HR = 2.51, 95% CI = 1.52–4.15, P = 0.0038). DNMT3A R882 mutations possessed significant unfavorable prognostic influence on RFS and OS in AML patients. PMID:27149454

  2. Hyperferritinemia at diagnosis predicts relapse and overall survival in younger AML patients with intermediate-risk cytogenetics.

    PubMed

    Lebon, Delphine; Vergez, François; Bertoli, Sarah; Harrivel, Véronique; De Botton, Stéphane; Micol, Jean-Baptiste; Marolleau, Jean-Pierre; Récher, Christian

    2015-08-01

    The prognostic value of ferritin level at diagnosis in AML patients is unknown. We studied 162 younger AML patients with intermediate-risk cytogenetics who received intensive chemotherapy. The median ferritin level at diagnosis was 633 μg/L and 128 (79%) patients had a ferritin level above the upper normal limit. Hyperferritinemia was significantly associated with a higher cumulative incidence of relapse as well as poorer disease-free and overall survival. In multivariate analysis, hyperferritinemia remained an independent poor prognosis factor. The level of ferritin at diagnosis has a major impact on relapse suggesting a link between inflammation, oxidative stress and chemoresistance in AML. PMID:26002512

  3. Incentives in IT Yield Success at MIT.

    ERIC Educational Resources Information Center

    Hanson, Mary

    2001-01-01

    Describes the role of information technology (IT) at the Massachusetts Institute of Technology, explaining that attention to the unique characteristics of an MIT education and incentives for sustainable change are central to its IT efforts. Discusses various IT initiatives, such as Project Athena, provision on campus, international efforts, and…

  4. Erfahrungen mit den Pentax SDHF-Refraktoren.

    NASA Astrophysics Data System (ADS)

    de Lignie, J.

    1996-10-01

    Behandelt werden: die SDHF-Refraktoren, mechanische Eigenschaften und Verarbeitung, die Montierung MS-3n, Beobachtungen mit der SDHF-Optik und optische Qualität, der 75 SDHF, der 105 SDHF. Fotografischer Teil: die Pentax 645 als Astrokamera, fotografische Abbildung der Objektive zur Pentax 645 und der SDHF-Optik, Zubehör.

  5. Wrestling with Pedagogical Change: The TEAL Initiative at MIT

    ERIC Educational Resources Information Center

    Breslow, Lori

    2010-01-01

    In the late 1990s, the physics department at the Massachusetts Institute of Technology (MIT) had a problem. The department was responsible for teaching the two required physics courses that are part of the General Institute Requirements (GIRs), MIT's core curriculum--Physics I (mechanics, or in MIT parlance, 8.01) and Physics II (electricity and…

  6. Two methods for the quantitative analysis of surface antigen expression in acute myeloid leukemia (AML).

    PubMed

    Woźniak, Jolanta

    2004-01-01

    The expression of lineage molecules (CD13 and CD33), c-Kit receptor (CD117), CD34, HLA-DR and adhesion molecule CD49d was assessed in acute myeloid leukemia (AML) blast cells from 32 cases, using direct and indirect quantitative cytometric analysis. High correlation (r=0.8) was found between antigen expression intensity values calculated by direct analysis method (ABC) and by indirect analysis method (RFI). Moreover, the differences in expression intensity of CD13, CD117 and CD34 antigens were found between leukemic and normal myeloblasts. This may be helpful in identification of leukemic cells in the diagnostics of minimal residual disease after treatment in AML patients. PMID:15493582

  7. Molecular cytogenetic findings in a three-way novel variant of t(1;8;21)(p35;q22;q22): a unique relocation of the AML1/ETO fusion gene 1p35 in AML-M2.

    PubMed

    Ahmad, Firoz; Kokate, Prajakta; Chheda, Pratiksha; Dalvi, Rupa; Das, Bibhu Ranjan; Mandava, Swarna

    2008-01-15

    Acute myeloid leukemia (AML) is a malignant neoplasm of hematopoietic stem cells characterized by an abnormal proliferation of myeloid precursors, a reduced rate of apoptosis, and an arrest in cellular differentiation. The present report deals with the results of hematologic, immunophenotypic, cytogenetic, fluorescence in situ hybridization (FISH), and molecular analyses of a 53-year-old female patient diagnosed with AML-M2. Cytogenetic and FISH analysis revealed a complex translocation involving three chromosomes showing t(1;8;21)(p35;q22;q22). The observation of breakpoints at 8q22 and 21q22 suggests a rearrangement of the ETO and AML1 genes, respectively. Using a dual-color FISH test with ETO and AML1 probes, an AML1/ETO fusion signal on the derivative 1p35 instead of der(8) was demonstrated. To the best of our knowledge, this is the first report about the relocation of the AML1/ETO fusion gene to the 1p35 rather than der(8), suggesting the presence of a novel variant of t(8;21)(q22;q22) in the observed patient. PMID:18206543

  8. The NAE inhibitor pevonedistat interacts with the HDAC inhibitor belinostat to target AML cells by disrupting the DDR.

    PubMed

    Zhou, Liang; Chen, Shuang; Zhang, Yu; Kmieciak, Maciej; Leng, Yun; Li, Lihong; Lin, Hui; Rizzo, Kathryn A; Dumur, Catherine I; Ferreira-Gonzalez, Andrea; Rahmani, Mohamed; Povirk, Lawrence; Chalasani, Sri; Berger, Allison J; Dai, Yun; Grant, Steven

    2016-05-01

    Two classes of novel agents, NEDD8-activating enzyme (NAE) and histone deacetylase (HDAC) inhibitors, have shown single-agent activity in acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS). Here we examined mechanisms underlying interactions between the NAE inhibitor pevonedistat (MLN4924) and the approved HDAC inhibitor belinostat in AML/MDS cells. MLN4924/belinostat coadministration synergistically induced AML cell apoptosis with or without p53 deficiency or FLT3-internal tandem duplication (ITD), whereas p53 short hairpin RNA (shRNA) knockdown or enforced FLT3-ITD expression significantly sensitized cells to the regimen. MLN4924 blocked belinostat-induced antiapoptotic gene expression through nuclear factor-κB inactivation. Each agent upregulated Bim, and Bim knockdown significantly attenuated apoptosis. Microarrays revealed distinct DNA damage response (DDR) genetic profiles between individual vs combined MLN4924/belinostat exposure. Whereas belinostat abrogated the MLN4924-activated intra-S checkpoint through Chk1 and Wee1 inhibition/downregulation, cotreatment downregulated multiple homologous recombination and nonhomologous end-joining repair proteins, triggering robust double-stranded breaks, chromatin pulverization, and apoptosis. Consistently, Chk1 or Wee1 shRNA knockdown significantly sensitized AML cells to MLN4924. MLN4924/belinostat displayed activity against primary AML or MDS cells, including those carrying next-generation sequencing-defined poor-prognostic cancer hotspot mutations, and CD34(+)/CD38(-)/CD123(+) populations, but not normal CD34(+) progenitors. Finally, combined treatment markedly reduced tumor burden and significantly prolonged animal survival (P < .0001) in AML xenograft models with negligible toxicity, accompanied by pharmacodynamic effects observed in vitro. Collectively, these findings argue that MLN4924 and belinostat interact synergistically by reciprocally disabling the DDR in AML/MDS cells. This strategy

  9. Is it important to decipher the heterogeneity of "normal karyotype AML"?

    PubMed

    Nimer, Stephen D

    2008-03-01

    Almost half of adult acute myelogenous leukemia (AML) is normal cytogenetically, and this subgroup shows a remarkable heterogeneity of genetic mutations at the molecular level and an intermediate response to therapy. The finding of recurrent cytogenetic abnormalities has influenced, in a primary way, the understanding and treatment of leukemias. Yet "normal karyotype AML" lacks such obvious abnormalities, but has a variety of prognostically important genetic abnormalities. Thus, the presence of a FLT3-ITD (internal tandem duplication), MLL-PTD (partial tandem duplication), or the increased expression of ERG or EVI1 mRNAs confer a poor prognosis, and an increased risk of relapse. In contrast, the presence of cytoplasmic nucleophosmin or C/EBPA mutations is associated with lower relapse rates and improved survival. Although resistance to treatment is associated with specific mutations, the degree to which the leukemia resembles a stem cell in its functional properties may provide greater protection from the effects of treatment. Although usually all of the circulating leukemia cells are cleared following treatment, a small residual population of leukemic cells in the bone marrow persists, making this disease hard to eradicate. Increased understanding of the biological consequences of at least some of these mutations in "normal karyotype AML" is leading to more targeted approaches to develop more effective treatments for this disease. PMID:18342811

  10. Involvement of Aerospatiale Matra Lanceurs (AML) in the Exploration of Mars

    NASA Astrophysics Data System (ADS)

    Berthe, Ph.; Bonnefond, Francine

    2000-07-01

    The goal of this paper is to present to the workshop participants the Aerospatiale Matra Lanceurs company and its activities in the field of Mars exploration. Aerospatiale Matra Lanceurs (AML) is a subsidiary of the EADS ("EADS in formation") group. This company has all the expertise required to develop strategic missiles, space launchers, orbital transfer vehicles, re-entry vehicles and equipment for space research and interplanetary exploration. Therefore, it can provide useful information and answers to the "how" and "when" questions in this workshop: AML is the Industrial Architect for Ariane 4 and for all the different, present and future versions of Ariane 5. It has built the thermal protection system of the Huygens Titan Probe which is carried by Cassini. In addition to the thermal protection production, Aerospatiale Matra Lanceurs has also performed all the studies linked to the entry and descent system, including the aerodynamic studies, trajectories, heat and radiation flux in an atmosphere, the one of Titan, different from ours. AML has also been the prime contractor of the Atmospheric Reentry Demonstrator (ARD), launched by Ariane 5, which flew flawlessly in October 1998. Due to its prominent role in Europe, Aerospatiale Matra Lanceurs is now playing an important part in the present and future French and European endeavors regarding the exploration of Mars. For some elements, such as Beagle-2, the involvement of Aerospatiale Matra Lanceurs has already been decided, for some others, this is still a competitive process.

  11. AML cells are differentially sensitive to chemotherapy treatment in a human xenograft model.

    PubMed

    Wunderlich, Mark; Mizukawa, Benjamin; Chou, Fu-Sheng; Sexton, Christina; Shrestha, Mahesh; Saunthararajah, Yogen; Mulloy, James C

    2013-03-21

    As acute myeloid leukemia (AML) xenograft models improve, the potential for using them to evaluate novel therapeutic strategies becomes more appealing. Currently, there is little information on using standard chemotherapy regimens in AML xenografts. Here we have characterized the immunodeficient mouse response to combined Ara-C (cytarabine) and doxorubicin treatment. We observed significant toxicity associated with doxorubicin that required optimization of the route of injection as well as the maximum-tolerated dose for immunodeficient strains. Mice treated with an optimized 5-day induction protocol showed transient weight loss, short-term reduction of peripheral blood cell and platelet counts, and slight anemia. Considerable cytotoxicity was observed in the bone marrow (BM), with primitive LSK cells having a significant survival advantage relative to more mature cells, consistent with the idea of chemotherapy targeting actively growing cells. Treated leukemic mice demonstrated reduced disease burden and increased survival, demonstrating efficacy. AML cells showed significantly increased sensitivity to doxorubicin-containing therapy compared with murine BM cells. Although early treatment could result in some cures, mice with significant leukemia grafts were not cured by using induction therapy alone. Overall, the data show that this model system is useful for the evaluation of novel chemotherapies in combination with standard induction therapy. PMID:23349390

  12. Problems getting from the laboratory to the field: Reclamation of an AML site

    SciTech Connect

    Dick, W.A.; Stehouwer, R.C.; Bigham, J.M.; Beeghly, J.H.

    1994-12-31

    Acid and toxic abandoned mineland sites provide an opportunity whereby flue gas desulfurization (FGD) by-product can be beneficially used as a reclamation amendment material. Studies are needed to compare the effectiveness of FGD by-product, as compared with resoil, for reclamation purposes. Initial studies provided information about the chemical and physical properties of the FGD by-product and how to transport and blend the FGD by-product with yard waste compost. Greenhouse studies indicated that rates of 125 dry tons/acre of FGD and 50 dry tons/acre of yard waste compost would provide optimum results for reclamation of acid and toxic spoil contained at the Fleming abandoned mineland (AML) site. Their results showed that heavy metal loading rates were much lower using the FGD/compost mixture than using resoil material. Dioxin in the mixture was also less than the 5 ppt level considered as normal background. The technical problems of using FGD by-product for reclamation of an AML site were solved. However, considerable efforts to educate the public about the merits of reclaiming the Fleming AML site using this FGD/compost mixture were required before initiating field reclamation activities. Education efforts must continue if FGD by-products are to achieve general acceptance as a reclamation alternative to resoil in cases where resoil is of scarce supply.

  13. The blind men and the AML elephant: can we feel the progress?

    PubMed Central

    Tauro, S

    2016-01-01

    The pharmacological therapy of non-promyelocytic acute myeloid leukemia (AML) has remained unchanged for over 40 years with an anthracycline–cytarabine combination forming the backbone of induction treatments. Nevertheless, the survival of younger patients has increased due to improved management of the toxicity of therapies including stem cell transplantation. Older patients and those with infirmity that precludes treatment-intensification have, however, not benefited from improvements in supportive care and continue to experience poor outcomes. An increased understanding of the genomic heterogeneity of AML raises the possibility of treatment-stratification to improve prognosis. Thus, efforts to identify agents with non-conventional anti-leukemic effects have paralleled those aiming to optimize leukemia cell-kill with conventional chemotherapy, resulting in a number of randomized controlled trials (RCT). In the last 18 months, RCTs investigating the effects of vosaroxin, azacitidine and gemtuzumab ozogamycin and daunorubicin dose have been reported with some studies indicating a statistically significant survival benefit with the investigational agent compared with standard therapy and potentially, a new era in AML therapeutics. Given the increasing costs of cancer care, a review of these studies, with particular attention to the magnitude of clinical benefit with the newer agents would be useful, especially for physicians treating patients in single-payer health systems. PMID:27176800

  14. Drug resistance: Still a daunting challenge to the successful treatment of AML

    PubMed Central

    Shaffer, Brian C.; Gillet, Jean-Pierre; Patel, Chirayu; Baer, Maria R.; Bates, Susan E.; Gottesman, Michael M.

    2012-01-01

    Resistance to chemotherapy remains a challenging issue for patients and their physicians. P-glycoprotein (Pgp, MDR1, ABCB1), as well as a family of structurally and functionally related proteins, are plasma membrane transporters able to efflux a variety of substrates from the cell cytoplasm, including chemotherapeutic agents. The discovery of ABCB1 made available a potential target for pharmacologic down-regulation of efflux-mediated chemotherapy resistance. In patients with acute myeloid leukemia (AML), a neoplasm characterized by proliferation of poorly differentiated myeloid progenitor cells, leukemic cells often express ABCB1 at high levels, which may lead to the development of resistance to chemotherapy. Thus, AML seemed to be a likely cancer for which the addition of drug efflux inhibitors to the chemotherapeutic regimen would improve outcomes in patients. Despite this rational hypothesis, the majority of clinical trials evaluating this strategy have failed to reach a positive endpoint, most recently the Eastern Cooperative Oncology Group E3999 trial. Here we review data suggesting the importance of ABCB1 in AML, address the failure of clinical trials to support a therapeutic strategy aimed at modulating ABCB1-mediated resistance, and consider the type of research that should be conducted in this field going forward. PMID:22409994

  15. Supraphysiologic levels of the AML1-ETO isoform AE9a are essential for transformation.

    PubMed

    Link, Kevin A; Lin, Shan; Shrestha, Mahesh; Bowman, Melissa; Wunderlich, Mark; Bloomfield, Clara D; Huang, Gang; Mulloy, James C

    2016-08-01

    Chromosomal translocation 8;21 is found in 40% of the FAB M2 subtype of acute myeloid leukemia (AML). The resultant in-frame fusion protein AML1-ETO (AE) acts as an initiating oncogene for leukemia development. AE immortalizes human CD34(+) cord blood cells in long-term culture. We assessed the transforming properties of the alternatively spliced AE isoform AE9a (or alternative splicing at exon 9), which is fully transforming in a murine retroviral model, in human cord blood cells. Full activity was realized only upon increased fusion protein expression. This effect was recapitulated in the AE9a murine AML model. Cotransduction of AE and AE9a resulted in a strong selective pressure for AE-expressing cells. In the context of AE, AE9a did not show selection for increased expression, affirming observations of human t(8;21) patient samples where full-length AE is the dominant protein detected. Mechanistically, AE9a showed defective transcriptional regulation of AE target genes that was partially corrected at high expression. Together, these results bring an additional perspective to our understanding of AE function and highlight the contribution of oncogene expression level in t(8;21) experimental models. PMID:27457952

  16. The blind men and the AML elephant: can we feel the progress?

    PubMed

    Tauro, S

    2016-01-01

    The pharmacological therapy of non-promyelocytic acute myeloid leukemia (AML) has remained unchanged for over 40 years with an anthracycline-cytarabine combination forming the backbone of induction treatments. Nevertheless, the survival of younger patients has increased due to improved management of the toxicity of therapies including stem cell transplantation. Older patients and those with infirmity that precludes treatment-intensification have, however, not benefited from improvements in supportive care and continue to experience poor outcomes. An increased understanding of the genomic heterogeneity of AML raises the possibility of treatment-stratification to improve prognosis. Thus, efforts to identify agents with non-conventional anti-leukemic effects have paralleled those aiming to optimize leukemia cell-kill with conventional chemotherapy, resulting in a number of randomized controlled trials (RCT). In the last 18 months, RCTs investigating the effects of vosaroxin, azacitidine and gemtuzumab ozogamycin and daunorubicin dose have been reported with some studies indicating a statistically significant survival benefit with the investigational agent compared with standard therapy and potentially, a new era in AML therapeutics. Given the increasing costs of cancer care, a review of these studies, with particular attention to the magnitude of clinical benefit with the newer agents would be useful, especially for physicians treating patients in single-payer health systems. PMID:27176800

  17. NKG2D Signaling Leads to NK Cell Mediated Lysis of Childhood AML

    PubMed Central

    Schlegel, Patrick; Ditthard, Kerstin; Lang, Peter; Mezger, Markus; Michaelis, Sebastian; Handgretinger, Rupert; Pfeiffer, Matthias

    2015-01-01

    Natural killer cells have been shown to be relevant in the recognition and lysis of acute myeloid leukemia. In childhood acute lymphoblastic leukemia, it was shown that HLA I expression and KIR receptor-ligand mismatch significantly impact ALL cytolysis. We characterized 14 different primary childhood AML blasts by flow cytometry including NKG2D ligands. Further HLA I typing of blasts was performed and HLA I on the AML blasts was quantified. In two healthy volunteer NK cell donors HLA I typing and KIR genotyping were done. Blasts with high NKG2D ligand expression had significantly higher lysis by isolated NK cells. Grouping the blasts by NKG2D ligand expression led to a significant inverse correlation of HLA I expression and cytolysis in NKG2D low blasts. Furthermore, a significant positive correlation of NKG2D ligand expression and blast cytolysis was shown. No impact of KIR ligand-ligand mismatch was found but a significantly increased lysis of homozygous C2 blasts by KIR2DL1 negative NK cells (donor B) was revealed. In conclusion, NKG2D signaling leads to NK cell mediated lysis of childhood AML despite high HLA I expression. PMID:26236752

  18. Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance.

    PubMed

    Vukovic, Milica; Guitart, Amelie V; Sepulveda, Catarina; Villacreces, Arnaud; O'Duibhir, Eoghan; Panagopoulou, Theano I; Ivens, Alasdair; Menendez-Gonzalez, Juan; Iglesias, Juan Manuel; Allen, Lewis; Glykofrydis, Fokion; Subramani, Chithra; Armesilla-Diaz, Alejandro; Post, Annemarie E M; Schaak, Katrin; Gezer, Deniz; So, Chi Wai Eric; Holyoake, Tessa L; Wood, Andrew; O'Carroll, Dónal; Ratcliffe, Peter J; Kranc, Kamil R

    2015-12-14

    Leukemogenesis occurs under hypoxic conditions within the bone marrow (BM). Knockdown of key mediators of cellular responses to hypoxia with shRNA, namely hypoxia-inducible factor-1α (HIF-1α) or HIF-2α, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1α or HIF-2α as therapeutic targets. However, genetic deletion of Hif-1α has no effect on mouse AML maintenance and may accelerate disease development. Here, we report the impact of conditional genetic deletion of Hif-2α or both Hif-1α and Hif-2α at different stages of leukemogenesis in mice. Deletion of Hif-2α accelerates development of leukemic stem cells (LSCs) and shortens AML latency initiated by Mll-AF9 and its downstream effectors Meis1 and Hoxa9. Notably, the accelerated initiation of AML caused by Hif-2α deletion is further potentiated by Hif-1α codeletion. However, established LSCs lacking Hif-2α or both Hif-1α and Hif-2α propagate AML with the same latency as wild-type LSCs. Furthermore, pharmacological inhibition of the HIF pathway or HIF-2α knockout using the lentiviral CRISPR-Cas9 system in human established leukemic cells with MLL-AF9 translocation have no impact on their functions. We therefore conclude that although Hif-1α and Hif-2α synergize to suppress the development of AML, they are not required for LSC maintenance. PMID:26642852

  19. Roles of HIPK1 and HIPK2 in AML1- and p300-dependent transcription, hematopoiesis and blood vessel formation.

    PubMed

    Aikawa, Yukiko; Nguyen, Lan Anh; Isono, Kyoichi; Takakura, Nobuyuki; Tagata, Yusuke; Schmitz, M Lienhard; Koseki, Haruhiko; Kitabayashi, Issay

    2006-09-01

    Histone acetyltransferases (HATs) p300 and CREB-binding protein (CBP) function as co-activators for a variety of sequence-specific transcription factors, including AML1. Here, we report that homeodomain-interacting protein kinase-2 (HIPK2) forms a complex with AML1 and p300, and phosphorylates both AML1 and p300 to stimulate transcription activation as well as HAT activities. Phosphorylation of p300 is triggered by phosphorylated AML1 as well as by PU.1, c-MYB, c-JUN and c-FOS, and is inhibited by dominant-negative HIPK2. Phosphorylation of p300 and AML1 is impaired in Hipk1/2 double-deficient mouse embryos. Double-deficient mice exhibit defects in primitive/definitive hematopoiesis, vasculogenesis, angiogenesis and neural tube closure. These phenotypes are in part similar to those observed in p300- and CBP-deficient mice. HIPK2 also phosphorylates another co-activator, MOZ, in an AML1-dependent manner. We discuss a possible mechanism by which transcription factors could regulate local histone acetylation and transcription of their target genes. PMID:16917507

  20. Lower frequency of NPM1 and FLT3-ITD mutations in a South African adult de novo AML cohort

    PubMed Central

    Marshall, R. C.; Tlagadi, A.; Bronze, M.; Kana, V.; Naidoo, S.; Wiggill, T. M.; Carmona, S. C.

    2014-01-01

    Introduction Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of haemopoietic progenitor cells diagnosed in individuals of any age, but with a median age of 67 years at presentation in adults. Assessment of the mutation status of Nucleophosmin protein-1 (NPM1) and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) are essential for the diagnosis, prognosis and treatment of AML. Methods A total of 160 de novo AML cases, both cytogenetically normal and abnormal, were analyzed for the presence of NPM1 and FLT3-ITD mutations and the results assessed in conjunction with epidemiological, clinical and laboratory findings. Results NPM1 mutations were found in 7.5%, while FLT3-ITD was present in 12% of these cases. Both of these were lower than expected. The median age at diagnosis of AML was 41 years and for the FLT3-ITD only cases, median age was 33 years; these ages were younger than expected. Conclusion The lower reported frequencies and younger median age at diagnosis of AML and these specific mutations may be contributed to by a number of factors including; effects of race on age of presentation, inclusion of patients diagnosed with de novo AML only and a generally younger median age of the South African population. PMID:24666762

  1. Telomerase reverse transcriptase (TERT) A1062T mutation as a prognostic factor in Egyptian patients with acute myeloid leukemia (AML).

    PubMed

    Aref, Salah; El-Ghonemy, Mohamed Sabry; Abouzeid, Tarek Elsayed; El-Sabbagh, Amr Mohamed; El-Baiomy, Mohamed Ali

    2014-09-01

    This study aimed to evaluate the incidence and clinical and prognostic impact of TERT A1062T mutation in AML patients treated at Mansoura Oncology Center. Screening for TERT A1062T mutation in exon 15 of the TERT gene was performed on diagnostic DNA samples from 153 AML patients and 197 healthy subjects as a control group by using sequence-specific primers. TERT A1062T mutation was detected in 18 cases out of 153 patients (11.8 %) and in one out of 197 control group subjects (0.51 %). The achievement of complete remission was significantly higher in AML group with wild type as compared to that in the mutant one (53.3 vs 16.7 %, respectively). In addition, the relapse rate was significantly higher in the mutant patients as compared to those with wild type (62.5 vs 28.2 %, respectively). The AML patients with TERT (A1062T) mutation had shorter overall survival than patients with wild type (P = 0.001). In a multivariable analysis, TERT (A1062T) mutational status is independently worse predictor factor (P = 0.007) when controlling for cytogenetic status (P = <0.001), performance status (P = <0.001) and bone marrow blast cells (P = 0.001). In conclusion, TERT A1062T mutation is an independent negative prognostic factor in AML patients. Therefore, molecular testing for TERT A1062T mutation in patients with AML is recommended in order to delineate their prognostic status. PMID:25108601

  2. Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance

    PubMed Central

    Vukovic, Milica; Guitart, Amelie V.; Sepulveda, Catarina; Villacreces, Arnaud; O'Duibhir, Eoghan; Panagopoulou, Theano I.; Ivens, Alasdair; Menendez-Gonzalez, Juan; Iglesias, Juan Manuel; Allen, Lewis; Glykofrydis, Fokion; Subramani, Chithra; Armesilla-Diaz, Alejandro; Post, Annemarie E.M.; Schaak, Katrin; Gezer, Deniz; So, Chi Wai Eric; Holyoake, Tessa L.; Wood, Andrew; O'Carroll, Dónal; Ratcliffe, Peter J.

    2015-01-01

    Leukemogenesis occurs under hypoxic conditions within the bone marrow (BM). Knockdown of key mediators of cellular responses to hypoxia with shRNA, namely hypoxia-inducible factor-1α (HIF-1α) or HIF-2α, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1α or HIF-2α as therapeutic targets. However, genetic deletion of Hif-1α has no effect on mouse AML maintenance and may accelerate disease development. Here, we report the impact of conditional genetic deletion of Hif-2α or both Hif-1α and Hif-2α at different stages of leukemogenesis in mice. Deletion of Hif-2α accelerates development of leukemic stem cells (LSCs) and shortens AML latency initiated by Mll-AF9 and its downstream effectors Meis1 and Hoxa9. Notably, the accelerated initiation of AML caused by Hif-2α deletion is further potentiated by Hif-1α codeletion. However, established LSCs lacking Hif-2α or both Hif-1α and Hif-2α propagate AML with the same latency as wild-type LSCs. Furthermore, pharmacological inhibition of the HIF pathway or HIF-2α knockout using the lentiviral CRISPR-Cas9 system in human established leukemic cells with MLL-AF9 translocation have no impact on their functions. We therefore conclude that although Hif-1α and Hif-2α synergize to suppress the development of AML, they are not required for LSC maintenance. PMID:26642852

  3. Flight research with the MIT Daedalus prototype

    NASA Technical Reports Server (NTRS)

    Bussolari, Steven R.; Youngren, Harold H.; Langford, John S.

    1987-01-01

    The MIT Light Eagle human-powered aircraft underwent long-duration testing over Rogers Dry Lake in California during January, 1987. Designed as a prototype for the MIT Daedalus Project, the Light Eagle's forty-eight flights provided pilot training, established new distance records for human-powered flight, and provided quantitative data through a series of instrumented flight experiments. The experiments focused on: (1) evaluating physiological loads on the pilot, (2) determining airframe power requirements, and (3) developing an electronic flight control system. This paper discusses the flight test program, its results and their implications for the follow-on Daedalus aircraft, and the potential uses of the Light Eagle as a low Reynolds number testbed.

  4. Grundlegende Steuerungsverfahren im heterogenen Logistiknetz mit Kanban

    NASA Astrophysics Data System (ADS)

    Dickmann, Eva; Dickmann, Philipp; Lödding, Hermann; Möller, Niklas; Rücker, Thomas; Schneider, Herfried M.; Zäh, Michael F.

    In vielen Unternehmen werden heterogene (verschiedene) Steuerungen in einem abgestimmten Konzept kombiniert. Je nach Anwendungsfall und Rahmenbedingungen werden Kombinationen allgemein bekannter Steuerungen oder Steuerungsvarianten gemischt eingesetzt, um eine optimale Steuerung für unterschiedliche Fälle zu erreichen. Hierbei stehen neben den bekannten und weit verbreiteten Methoden, wie Material Requirements Planning (MRP) oder Kanban, auch weniger bekannte oder neue Methoden zur Auswahl, wie die Produktionssteuerung mit dezentraler, bestandsorientierter Fertigungsregelung (DBF). Kanban ist ein simples und effizientes Steuerungskonzept, das in der klassischen Form für spezifische einfache Anwendungsfälle umsetzbar ist. Hochentwickelte Steuerungsalgorithmen können helfen, komplexe Abläufe optimal abzubilden. Mit einer grundlegenden Vereinfachung der Abläufe kann allerdings in vielen Fällen ein wesentlich stärkerer und umfassender Verbesserungseffekt erzielt werden. Die wesentliche Fragestellung sollte folglich lauten: Warum ist der Ablauf nicht mit einer einfachen Steuerung wie Kanban abzubilden? Um die Vorteile des Konzepts auch in untypischen Bereichen anwenden zu können, sind jedoch verschiedene Varianten oder Kanban-ähnliche Steuerungsmethoden entstanden. Darüber hinaus sind in der Praxis hybride Steuerungen im Einsatz, welche so kombiniert werden, dass die Zusammensetzung anspruchsvolle Eigenschaftsbilder noch exakt abbildet. In der Praxis basieren die Steuerungsentscheidungen nur zu einem kleinen Teil auf den eigentlichen Steuerungsalgorithmen, wie sie uns das MRP-System zur Verfügung stellt. Moderne Steuerungswelten" schließen alle relevanten Informationsquellen in eine heterogene Entscheidungsmatrix mit ein. Letztlich zählt nicht, ob die Entscheidung auf den Informationen aus dem MRP-System oder auf Softfacts basierend getroffen wurde, sondern nur, ob die Entscheidung erfolgreich war.

  5. Mishap Investigation Team (MIT) - Barksdale AFB, Louisiana

    NASA Technical Reports Server (NTRS)

    Stepaniak, Philip

    2005-01-01

    The Shuttle Program is organized to support a Shuttle mishap using the resources of the MIT. The afternoon of Feb. 1, 2003, the MIT deployed to Barksdale AFB. This location became the investigative center and interim storage location for crewmembers received from the Lufkin Disaster Field Office (DFO). Working under the leadership of the MIT Lead, the medical team executed a short-term plan that included search, recovery, and identification including coordination with the Armed Forces Institute of Pathology Temporary operations was set up at Barksdale Air Force Base for two weeks. During this time, coordination with the DFO field recovery teams, AFIP personnel, and the crew surgeons was on going. In addition, the crewmember families and NASA management were updated daily. The medical team also dealt with public reports and questions concerning biological and chemical hazards, which were coordinated with SPACEHAB, Inc., Kennedy Space Center (KSC) Medical Operations and the Johnson Space Center (JSC) Space Medicine office. After operations at Barksdale were concluded the medical team transitioned back to Houston and a long-term search, recovery and identification plan was developed.

  6. Design of the randomized, Phase III, QUAZAR AML Maintenance trial of CC-486 (oral azacitidine) maintenance therapy in acute myeloid leukemia.

    PubMed

    Roboz, Gail J; Montesinos, Pau; Selleslag, Dominik; Wei, Andrew; Jang, Jun-Ho; Falantes, Jose; Voso, Maria T; Sayar, Hamid; Porkka, Kimmo; Marlton, Paula; Almeida, Antonio; Mohan, Sanjay; Ravandi, Farhad; Garcia-Manero, Guillermo; Skikne, Barry; Kantarjian, Hagop

    2016-02-01

    Older patients with acute myeloid leukemia (AML) have worse rates of complete remission and shorter overall survival than younger patients. The epigenetic modifier CC-486 is an oral formulation of azacitidine with promising clinical activity in patients with AML in Phase I studies. The Phase III, randomized, double-blind, placebo-controlled QUAZAR AML Maintenance trial (CC-486-AML-001) examines CC-486 maintenance therapy (300 mg/day for 14 days of 28-day treatment cycles) for patients aged ≥55 years with AML in first complete remission. The primary end point is overall survival. Secondary end points include relapse-free survival, safety, health-related quality of life and healthcare resource utilization. This trial will investigate whether CC-486 maintenance can prolong remission and improve survival for older patients with AML. PMID:26785287

  7. Esculetin Downregulates the Expression of AML1-ETO and C-Kit in Kasumi-1 Cell Line by Decreasing Half-Life of mRNA

    PubMed Central

    Sawney, Sharad; Arora, Rashi; Aggarwal, Kamal K.; Saluja, Daman

    2015-01-01

    One of the most frequent genetic aberrations in acute myeloid leukemia (AML) is chromosomal translocation between AML1/RUNX1 on chromosome 21 and ETO gene on chromosome 8 resulting in the expression of chimeric oncogene AML1-ETO. Although patients with t(8;21) translocation have good prognosis, 5-year survival is observed only in 50% of the cases. AML1-ETO translocation is usually accompanied by overexpression of mutant C-Kit, a tyrosine kinase, which contributes to uncontrolled proliferation of premature blood cells leading to relapse and poor prognosis. We illustrate the potential use of esculetin on leukemic cell line, Kasumi-1, bearing t(8;21) translocation and mutated C-Kit gene. Esculetin decreases the expression of AML1-ETO at both protein and transcript level within 24 hours of treatment. Half-life of AML1-ETO mRNA was reduced from 7 hours to 1.5 hours. Similarly half-life of C-Kit mRNA was reduced to 2 hours from 5 hours in esculetin treated cells. Esculetin also perturbed the expression of ectopically expressed AML1-ETO in U937 cells. The decreased expression of AML1-ETO chimeric gene was associated with increased expression of LAT1 and RUNX3 genes, targets of AML1. We envisage that discovery of a drug candidate which could target both these mutated genes would be a considerable breakthrough for future application. PMID:25861270

  8. [15-year results following implantation of a stem type AML hip prosthesis].

    PubMed

    Schwerter, K; Meyenberg, A; Sander, K; Layher, F; Roth, A

    2013-06-01

    The trend in arthroplasty of the hip joint to implement new models is partly based on theoretical considerations. In order to verify to which extent the philosophy of individual models is ultimately successful, the presentation of long-term results is required. In the years 1991 and 1992, 433 patients with primary implantation of an uncemented total hip replacement in primary coxarthrosis with a stem type AML (anatomic medullary locking) were treated surgically. 283 of them got a cementless cup type Duraloc. In 311 (71.8 %) patients the mean survival rate of the prosthesis could be determined at a mean follow-up of 15.5 years. 145 (33.5 %) patients were followed up completely both clinically and radiologically. Radiographically, the stem position, changes of the periprosthetic bone of the stem and the cup, as well as the wear of the cups were examined. The cumulative survival rate of the AML stem after 15.5 years was 97.5 %, of the Duraloc cup 88.2 %. The clinical results of the hip scores according to Harris and Merle d'Aubigné were good and excellent and patient satisfaction was very high. There was no relationship between stem position, stress shielding and surrounding lyses at the femur and the acetabulum and survival of stem or cup. There was no correlation between inlay wear and survival of the Duraloc cup. A subsiding of the stem in 2 cases had no effect on the clinical symptoms and quality of life. The press-fit implanted AML stem and the Duraloc cup revealed very good results during the investigation period. Like other implants, the survival rate is limited at the presented implant mainly by the cup. PMID:23696163

  9. DNMT3A R882 Mutations Predict a Poor Prognosis in AML: A Meta-Analysis From 4474 Patients.

    PubMed

    Yuan, Xiao-Qing; Peng, Li; Zeng, Wen-Jing; Jiang, Bin-Yuan; Li, Guan-Cheng; Chen, Xiao-Ping

    2016-05-01

    DNA (cytosine-5)-methyltransferase 3 alpha (DNMT3A) mutations were widely believed to be independently associated with inferior prognosis in acute myeloid leukemia (AML) patients. As dominant missense alterations in DNMT3A mutations, R882 mutations cause the focal hypomethylation phenotype. However, there remains debate on the influence of R882 mutations on AML prognosis. Thus, this meta-analysis aimed at further illustrating the prognostic power of DNMT3A R882 mutations in AML patients.Eligible studies were identified from 5 databases containing PubMed, Embase, Web of Science, Clinical Trials, and the Cochrane Library (up to October 25, 2015). Effects (hazard ratios [HRs] with 95% confidence interval [CI]) of relapse-free survival (RFS) and overall survival (OS) were pooled to estimate the prognostic power of mutant DNMT3A R882 in overall patients and subgroups of AML patients.Eight competent studies with 4474 AML patients including 694 with DNMT3A R882 mutations were included. AML patients with DNMT3A R882 mutations showed significant shorter RFS (HR = 1.40, 95% CI = 1.24-1.59, P < 0.001) and OS (HR = 1.47, 95% CI = 1.17-1.86, P = 0.001) in the overall population. DNMT3A R882 mutations predicted worse RFS and OS among the subgroups of patients under age 60 (RFS: HR = 1.44, 95% CI = 1.25-1.66, P < 0.001; OS: HR = 1.48, 95% CI = 1.15-1.90, P = 0.002), over age 60 (RFS: HR = 2.03, 95% CI = 1.40-2.93, P < 0.001; OS: HR = 1.85, 95% CI = 1.36-2.53, P < 0.001), cytogenetically normal (CN)-AML (RFS: HR = 1.52, 95% CI = 1.26-1.83, P < 0.001; OS: HR = 1.67, 95% CI = 1.16-2.41, P = 0.006), and non-CN-AML (RFS: HR = 1.96, 95% CI = 1.20-3.21, P = 0.006; OS: HR = 2.51, 95% CI = 1.52-4.15, P = 0.0038).DNMT3A R882 mutations possessed significant unfavorable prognostic influence on RFS and OS in AML patients. PMID:27149454

  10. Pressurized grout remote backfilling at AML sites near Beulah and Zap, North Dakota

    SciTech Connect

    Weiner, E.J.; Dodd, W.E.

    1999-07-01

    The Abandoned Mine Lands (AML) Division of the North Dakota Public Service Commission (PSC) is charged with the reclamation of hazardous abandoned mine sites in North Dakota. Several underground lignite coalmines were operated near the cities of Beulah and Zap, North Dakota, from the early 1900's until about 1955. Coal seams in this area were relatively thick and the overburden generally shallow. As these mines have deteriorated with time, deep collapse features, or sinkholes, have surfaced in many areas. These features are very dangerous, especially when they occur at or near residential and commercial areas and public roads. In the past five years, sinkholes have surfaced beneath a commercial building (boat dealership, lounge, and gas station) and beneath a nearby occupied mobile home north of Beulah. sinkholes have also surfaced near KHOL Radio Station in Beulah and in the right of way of a public road south of Zap. The AML Division has conducted several emergency sinkhole-filling projects in these areas. In 1995--97, the AML Division conducted exploratory drilling which confirmed the presence of collapsing underground mines at these sites. The remediation of these sites around Beulah/Zap will take place over several years and involve three or more separate contracts due to budget considerations. In 1997, the AML Division began reclamation at these sties utilizing pressurized grout remote backfilling. In this technique, a cementitious grout is pumped through cased drill holes directly into the mine cavities to fill them and thereby stabilize the surface from collapse. The successful contractor for Phase One of the project was The Concrete Doctor, Inc. (TCDI). This paper will concentrate on Phase One of this work performed from June through September 1997. This project is especially interesting because grout was pumped through holes drilled inside the occupied commercial building. Grout was also pumped through angled holes that intercepted mined workings directly

  11. Design and kinetic analysis of hammerhead ribozyme and DNAzyme that specifically cleave TEL-AML1 chimeric mRNA

    SciTech Connect

    Choi, Woo-Hyung; Choi, Bo-Ra; Kim, Jae Hyun; Yeo, Woon-Seok; Oh, Sangtaek; Kim, Dong-Eun

    2008-09-12

    In order to develop the oligonucleotides to abolish an expression of TEL-AML1 chimeric RNA, which is a genetic aberration that causes the acute lymphoblastic leukemia (ALL), hammerhead ribozymes and deoxyoligoribozymes that can specifically cleave TEL-AML1 fusion RNA were designed. Constructs of the deoxyribozyme with an asymmetric substrate binding arm (Dz26) and the hammerhead ribozyme with a 4 nt-bulged substrate binding arm in the stem III (buRz28) were able to cleave TEL-AML1 chimeric RNA specifically at sites close to the junction in vitro, without cleaving the normal TEL and AML1 RNA. Single-turnover kinetic analysis under enzyme-excess condition revealed that the buRz28 is superior to the Dz26 in terms of substrate binding and RNA-cleavage. In conjunction with current progress in a gene-delivery technology, the designed oligonucleotides that specifically cleave the TEL-AML1 chimeric mRNA are hoped to be applicable for the treatment of ALL in vivo.

  12. Pre-transplant MRD predicts outcome following reduced-intensity and myeloablative allogeneic hemopoietic SCT in AML.

    PubMed

    Anthias, C; Dignan, F L; Morilla, R; Morilla, A; Ethell, M E; Potter, M N; Shaw, B E

    2014-05-01

    The presence of minimal residual disease (MRD) by multiparametric flow cytometry (MFC) has been associated with adverse outcomes in AML patients treated with chemotherapy alone, but its impact in the setting of allogeneic hematopoietic SCT (HSCT) is less clear. We studied 88 patients who underwent myeloablative (MA) or reduced-intensity conditioned allogeneic HSCT for AML in first or subsequent remission at our center. MRD status was determined using three-color MFC on pre-HSCT BM aspirates, and patients were stratified by MRD status into MRD-negative, low-level MRD-positive (<1%) or high-level MRD-positive groups (1-4.9%). Two-year survival estimates in these groups were 66.8%, 51% and 30%, respectively (P=0.012), and 2-year estimates of relapse were 7.6, 37 and 70% (P<0.001). Pre-HSCT MRD was related to disease characteristics including secondary AML (P=0.002) and primary induction failure (P=0.005), but, despite these strong correlations, MRD remained independently associated with poorer survival in multivariate analysis (hazard ratio, 1.92; P=0.014). Pre-HSCT MRD is associated with adverse clinical outcomes in AML patients undergoing reduced-intensity or MA HSCT in first or subsequent remission and should be integrated into transplant strategies for patients with AML. PMID:24510069

  13. Infectious complications in children with acute myeloid leukemia: decreased mortality in multicenter trial AML-BFM 2004

    PubMed Central

    Bochennek, K; Hassler, A; Perner, C; Gilfert, J; Schöning, S; Klingebiel, T; Reinhardt, D; Creutzig, U; Lehrnbecher, T

    2016-01-01

    Infections are an important cause for morbidity and mortality in pediatric acute myeloid leukemia (AML). We therefore characterized infectious complications in children treated according to the trial AML-BFM 2004. Patients with Down syndrome were excluded from the analysis. Data were gathered from the medical records in the hospital where the patients were treated. A total of 405 patients (203 girls; median age 8.4 years) experienced 1326 infections. Fever without identifiable source occurred in 56.1% of the patients and clinically and microbiologically documented infections in 17.5% and 32.4% of the patients, respectively. In all, 240 Gram-positive (112 viridans group streptococci) and 90 Gram-negative isolates were recovered from the bloodstream. Invasive fungal infection was diagnosed in 3% of the patients. Three children each died of Gram-negative bacteremia and invasive aspergillosis, respectively. As compared with the results of AML-BFM 93 with lower dose intensity, infection-related morbidity was slightly higher in AML-BFM 2004 (3.3. versus 2.8 infections per patient), whereas infection-related mortality significantly decreased (1.5% versus 5.4% P=0.003). Specific anti-infective recommendations included in the treatment protocol, regular training courses for pediatric hematologists and increasing experience may be the reason for reduced infection-related mortality in children with AML. Further studies are needed to decrease infection-related morbidity. PMID:26771808

  14. PRMT1 interacts with AML1-ETO to promote its transcriptional activation and progenitor cell proliferative potential

    PubMed Central

    Shia, Wei-Jong; Okumura, Akiko J.; Yan, Ming; Sarkeshik, Ali; Lo, Miao-Chia; Matsuura, Shinobu; Komeno, Yukiko; Zhao, Xinyang; Nimer, Stephen D.; Yates, John R.

    2012-01-01

    Fusion protein AML1-ETO, resulting from t(8;21) translocation, is highly related to leukemia development. It has been reported that full-length AML1-ETO blocks AML1 function and requires additional mutagenic events to promote leukemia. We have previously shown that the expression of AE9a, a splice isoform of AML1-ETO, can rapidly cause leukemia in mice. To understand how AML1-ETO is involved in leukemia development, we took advantage of our AE9a leukemia model and sought to identify its interacting proteins from primary leukemic cells. Here, we report the discovery of a novel AE9a binding partner PRMT1 (protein arginine methyltransferase 1). PRMT1 not only interacts with but also weakly methylates arginine 142 of AE9a. Knockdown of PRMT1 affects expression of a specific group of AE9a-activated genes. We also show that AE9a recruits PRMT1 to promoters of AE9a-activated genes, resulting in enrichment of H4 arginine 3 methylation, H3 Lys9/14 acetylation, and transcription activation. More importantly, knockdown of PRMT1 suppresses the self-renewal capability of AE9a, suggesting a potential role of PRMT1 in regulating leukemia development. PMID:22498736

  15. AML Subtypes

    MedlinePlus

    ... M6 Acute erythroid leukemia M7 Acute megakaryoblastic leukemia World Health Organization (WHO) Classification System In 1999, the World Health Organization (WHO) developed a new classification system, ...

  16. NPM1 but not FLT3-ITD mutations predict early blast cell clearance and CR rate in patients with normal karyotype AML (NK-AML) or high-risk myelodysplastic syndrome (MDS).

    PubMed

    Schneider, Friederike; Hoster, Eva; Unterhalt, Michael; Schneider, Stephanie; Dufour, Annika; Benthaus, Tobias; Mellert, Gudrun; Zellmeier, Evelin; Bohlander, Stefan K; Feuring-Buske, Michaela; Buske, Christian; Braess, Jan; Fritsch, Susanne; Heinecke, Achim; Sauerland, Maria C; Berdel, Wolfgang E; Buechner, Thomas; Woermann, Bernhard J; Hiddemann, Wolfgang; Spiekermann, Karsten

    2009-05-21

    Mutations in the NPM1 gene represent the most frequent genetic alterations in patients with acute myeloid leukemia (AML) and are associated with a favorable outcome. In 690 normal karyotype (NK) AML patients the complete remission rates (CRs) and the percentage of patients with adequate in vivo blast cell reduction 1 week after the end of the first induction cycle were significantly higher in NPM1(+) (75% and 80%, respectively) than in NPM1(-) (57% and 57%, respectively) patients, but were unaffected by the FLT3-ITD status. Multivariate analyses revealed the presence of a NPM1 mutation as an independent positive prognostic factor for the achievement of an adequate day-16 blast clearance and a CR. In conclusion, NPM1(+) blast cells show a high in vivo sensitivity toward induction chemotherapy irrespective of the FLT3-ITD mutation status. These findings provide insight into the pathophysiology and help to understand the favorable clinical outcome of patients with NPM1(+) AML. PMID:19279329

  17. The MIT Program, Competition, and Ethics

    NASA Astrophysics Data System (ADS)

    Bradt, Hale V.

    2013-01-01

    The MIT program in x-ray astronomy was, and still is, diverse and productive. Bruno Rossi and later George Clark, as the nominal leaders of the “x-ray astronomy group” created a “hands-off” culture wherein individual researchers could develop their own independent programs. Walter Lewin, Claude Canizares, and I as well as those in the next academic generations, e.g., Saul Rappaport and George Ricker, were able to thrive in this environment. MIT researchers were principal investigators or providers of x-ray instruments on sounding rockets and balloons in the 1960s and then in later years on nine satellite missions, OSO-7, SAS-3, HEAO-1, Einstein, ASCA, RXTE, Chandra, HETE-2, and Suzaku. Such a diverse program involved collaborations with other institutions and of course striving for primacy in discovery and competition for NASA resources. Looking back, I see a high degree of ethical behavior among the observational x-ray community during those years. In competition, we remembered that we might well be collaborating the following year and behaved accordingly. Many of us in the x-ray community had been friends since graduate school days and did not want to lose those relationships. Am I viewing the past through rose colored glasses? I think not. A vignette on this topic: In 1967, I was debating vigorously with Herb Gursky of AS&E about which institution, MIT or AS&E, should be the lead on the fourth paper (Oda et al. 1967, ApJ 148, L5) based on data from the 1966 AS&E rocket flight which had led to Allan Sandage’s (and Japanese) identification of Sco X-1 (Sandage, et al. 1966, ApJ. 146, 316). I and my Italian colleague, Gianfranco Spada, and our Japanese colleague, Minoru Oda, both then visiting MIT, had actively supported that flight. After one rather heated discussion with Herb about this, - I was the heated one; he always remained calm - he left my office saying: “Hale, however this comes out, let’s remain friends.” I treasured that comment and

  18. MIT Space Engineering Research Center testbed programs

    NASA Technical Reports Server (NTRS)

    Crawley, Edward F.; Miller, David W.

    1991-01-01

    The Space Engineering Research Center (SERC) at M.I.T., started in July 1988, has completed two and one-half years of research. This Semi-Annual Report presents annotated viewgraph material presented at the January 1991 Steering Committee and Technical Representative Review. The objective of the Space Engineering Research Center is to develop and disseminate a unified technology of controlled structures. There has been continued evolution of the concept of intelligent structures (including in this past year the first successful embedding of a microelectronic component into a structural element).

  19. Sorafenib plus all-trans retinoic acid for AML patients with FLT3-ITD and NPM1 mutations.

    PubMed

    Guenounou, Sarah; Delabesse, Eric; Récher, Christian

    2014-12-01

    Knowledge of the molecular basis of acute myeloid leukaemia has increased considerably in the past few years, and therapies targeting specific molecular defects of this disease are intensively investigated. Patients with both NPM1 and FLT3-ITD mutations encompass 20% of cytogenetically normal AML. The multikinase and FLT3 inhibitor, sorafenib, has shown some efficacy in patients with relapsed FLT3-ITD(+) AML. In addition, it is suggested that all-trans retinoic acid (ATRA) used in combination with chemotherapy has shown to improve outcome of patients harbouring NPM1 mutations. We report here the clinical course of three patients with refractory or relapsed FLT3-ITD(+) /NPM1(+) AML who achieved significant response upon sorafenib and ATRA combination. PMID:24689895

  20. Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia (AML)

    PubMed Central

    Herrmann, Harald; Blatt, Katharina; Shi, Junwei; Gleixner, Karoline V.; Cerny-Reiterer, Sabine; Müllauer, Leonhard; Vakoc, Christopher R.; Sperr, Wolfgang R.; Horny, Hans-Peter; Bradner, James E.; Zuber, Johannes; Valent, Peter

    2012-01-01

    Acute myeloid leukemia (AML) is a life-threatening stem cell disease characterized by uncontrolled proliferation and accumulation of myeloblasts. Using an advanced RNAi screen-approach in an AML mouse model we have recently identified the epigenetic ‘reader’ BRD4 as a promising target in AML. In the current study, we asked whether inhibition of BRD4 by a small-molecule inhibitor, JQ1, leads to growth-inhibition and apoptosis in primary human AML stem- and progenitor cells. Primary cell samples were obtained from 37 patients with freshly diagnosed AML (n=23) or refractory AML (n=14). BRD4 was found to be expressed at the mRNA and protein level in unfractionated AML cells as well as in highly enriched CD34+/CD38− and CD34+/CD38+ stem- and progenitor cells in all patients examined. In unfractionated leukemic cells, submicromolar concentrations of JQ1 induced major growth-inhibitory effects (IC50 0.05-0.5 μM) in most samples, including cells derived from relapsed or refractory patients. In addition, JQ1 was found to induce apoptosis in CD34+/CD38− and CD34+/CD38+ stem- and progenitor cells in all donors examined as evidenced by combined surface/Annexin-V staining. Moreover, we were able to show that JQ1 synergizes with ARA-C in inducing growth inhibition in AML cells. Together, the BRD4-targeting drug JQ1 exerts major anti-leukemic effects in a broad range of human AML subtypes, including relapsed and refractory patients and all relevant stem- and progenitor cell compartments, including CD34+/CD38− and CD34+/CD38+ AML cells. These results characterize BRD4-inhibition as a promising new therapeutic approach in AML which should be further investigated in clinical trials. PMID:23249862

  1. AML sensitivity to YM155 is modulated through AKT and Mcl-1.

    PubMed

    de Necochea-Campion, Rosalia; Diaz Osterman, Carlos J; Hsu, Heng-Wei; Fan, Junjie; Mirshahidi, Saied; Wall, Nathan R; Chen, Chien-Shing

    2015-09-28

    HL60 and U937 (acute myeloid leukemia (AML) cell lines) were assessed for sensitivity to YM155, and found to have distinct sensitive and resistant phenotypes, respectively. In HL60 cells, YM155 inhibition of growth proliferation was due to apoptosis which was measured by annexin V/PI staining. YM155 induced apoptosis through activation of intrinsic and extrinsic pathways that also culminated in caspase-3 activity and PARP cleavage. YM155 sensitivity was partially associated with this compound's ability to down-regulate survivin transcription since this was more pronounced in the HL60 cell line. However, marked differences were also observed in XIAP, Bcl-2, and Mcl-1L, and Mcl-1s. Furthermore, YM155 treatment completely inhibited production of total Akt protein in HL60, but not U937 cells. Importantly, Akt activity (pAkt-Ser473) levels were maintained in YM155 treated U937 cells which may help stabilize other anti-apoptotic proteins. Combination treatments with an Akt inhibitor, MK-2206, reduced levels of pAkt-Ser473 in U937 cells and synergistically sensitized them to YM155 cytotoxicity. Collectively our results indicate that Akt signaling may be an important factor mediating YM155 response in AML, and combinatorial therapies with Akt inhibitors could improve treatment efficacy in YM155-resistant cells. PMID:26118775

  2. Peripheral Blood WT1 Expression Predicts Relapse in AML Patients Undergoing Allogeneic Stem Cell Transplantation

    PubMed Central

    Malagola, Michele; Skert, Cristina; Ruggeri, Giuseppina; Ribolla, Rossella; Bernardi, Simona; Borlenghi, Erika; Pagani, Chiara; Rossi, Giuseppe; Caimi, Luigi; Russo, Domenico

    2014-01-01

    To evaluate if WT1 expression may predict relapse after allo-SCT, we analyzed WT1 levels on peripheral blood (PB) and bone marrow (BM) before and after allo-SCT in 24 AML patients with WT1 overexpression at diagnosis. Five copies of WT1/ABL × 104 from PB were identified as the threshold value that correlated with relapse after allo-SCT. The same correlation was not identified when WT1 expression was assessed from bone marrow (BM). Eight out of 11 (73%) patients with a pre-allo-SCT PB-WT1 ≥ 5 and 4/13 (31%) patients with a pre-allo-SCT PB-WT1 < 5 relapsed, respectively (P = 0.04). The incidence of relapse was higher in patients with PB-WT1 ≥ 5 measured after allo-SCT, at the 3rd (56% versus 38%; P = 0.43) and at the 6th month (71% versus 20%; P = 0.03). Patients with pretransplant PB-WT1 < 5 had significantly better 2-year OS and LFS than patients with a PB-WT1 ≥ 5 (81% versus 0% and 63% versus 20%) (P = 0.02). Our data suggest the usefulness of WT1 monitoring from PB to predict the relapse in allotransplanted AML patients and to modulate the intensity of conditioning and/or the posttransplant immunosuppression in an attempt to reduce the posttransplant relapse risk. PMID:25202702

  3. Data-driven phenotypic dissection of AML reveals progenitor-like cells that correlate with prognosis

    PubMed Central

    Levine, Jacob H.; Simonds, Erin F.; Bendall, Sean C.; Davis, Kara L.; Amir, El-ad D.; Tadmor, Michelle; Litvin, Oren; Fienberg, Harris; Jager, Astraea; Zunder, Eli; Finck, Rachel; Gedman, Amanda L.; Radtke, Ina; Downing, James R.; Pe’er, Dana; Nolan, Garry P.

    2015-01-01

    SUMMARY Acute myeloid leukemia (AML) manifests as phenotypically and functionally diverse cells, often within the same patient. Intratumor phenotypic and functional heterogeneity have been linked primarily by physical sorting experiments, which assume that functionally distinct subpopulations can be prospectively isolated by surface phenotypes. This assumption has proven problematic and we therefore developed a data-driven approach. Using mass cytometry, we profiled surface and intracellular signaling proteins simultaneously in millions of healthy and leukemic cells. We developed PhenoGraph, which algorithmically defines phenotypes in high-dimensional single-cell data. PhenoGraph revealed that the surface phenotypes of leukemic blasts do not necessarily reflect their intracellular state. Using hematopoietic progenitors, we defined a signaling-based measure of cellular phenotype, which led to isolation of a gene expression signature that was predictive of survival in independent cohorts. This study presents new methods for large-scale analysis of single-cell heterogeneity and demonstrates their utility, yielding insights into AML pathophysiology. PMID:26095251

  4. SIMILAR OUTCOMES USING MYELOABLATIVE VERSUS REDUCED INTENSITY ALLOGENEIC TRANSPLANT PREPARATIVE REGIMENS FOR AML OR MDS

    PubMed Central

    Luger, Selina M.; Ringdén, Olle; Zhang, Mei-Jie; Pérez, Waleska S.; Bishop, Michael R.; Bornhauser, Martin; Bredeson, Christopher N.; Cairo, Mitchell S.; Copelan, Edward A.; Gale, Robert Peter; Giralt, Sergio A.; Gulbas, Zafer; Gupta, Vikas; Hale, Gregory A.; Lazarus, Hillard M.; Lewis, Victor Anthony; Lill, Michael C.; McCarthy, Philip L.; Weisdorf, Daniel J.; Pulsipher, Michael A.

    2011-01-01

    Although reduced intensity (RIC) and nonmyeloablative (NMA) conditioning regimens have been used for over a decade, their relative efficacy versus myeloablative (MA) approaches to allogeneic hematopoietic cell transplantation (HCT) in patients with acute myelogenous leukemia (AML) and myelodysplasia (MDS) is unknown. We compared disease status, donor, graft and recipient characteristics with outcomes of 3731 MA with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004. Five year univariate probabilities and multivariate relative risk (RR) outcomes of relapse, transplant related mortality (TRM), disease free survival (DFS) and overall survival (OS) are reported. Adjusted OS at 5 years was 34%, 33%, and 26% for MA, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior DFS and OS but there was no difference in DFS and OS between RIC and MA regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. Our data suggest higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs. leukemia in these diseases. Prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MA or RIC/NMA conditioning. PMID:21441963

  5. miR-133 regulates Evi1 expression in AML cells as a potential therapeutic target

    PubMed Central

    Yamamoto, Haruna; Lu, Jun; Oba, Shigeyoshi; Kawamata, Toyotaka; Yoshimi, Akihide; Kurosaki, Natsumi; Yokoyama, Kazuaki; Matsushita, Hiromichi; Kurokawa, Mineo; Tojo, Arinobu; Ando, Kiyoshi; Morishita, Kazuhiro; Katagiri, Koko; Kotani, Ai

    2016-01-01

    The Ecotropic viral integration site 1 (Evi1) is a zinc finger transcription factor, which is located on chromosome 3q26, over-expression in some acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Elevated Evi1 expression in AML is associated with unfavorable prognosis. Therefore, Evi1 is one of the strong candidate in molecular target therapy for the leukemia. MicroRNAs (miRNAs) are small non-coding RNAs, vital to many cell functions that negatively regulate gene expression by translation or inducing sequence-specific degradation of target mRNAs. As a novel biologics, miRNAs is a promising therapeutic target due to its low toxicity and low cost. We screened miRNAs which down-regulate Evi1. miR-133 was identified to directly bind to Evi1 to regulate it. miR-133 increases drug sensitivity specifically in Evi1 expressing leukemic cells, but not in Evi1-non-expressing cells The results suggest that miR-133 can be promising therapeutic target for the Evi1 dysregulated poor prognostic leukemia. PMID:26754824

  6. Pediatric donor cell leukemia after allogeneic hematopoietic stem cell transplantation in AML patient from related donor.

    PubMed

    Bobadilla-Morales, Lucina; Pimentel-Gutiérrez, Helia J; Gallegos-Castorena, Sergio; Paniagua-Padilla, Jenny A; Ortega-de-la-Torre, Citlalli; Sánchez-Zubieta, Fernando; Silva-Cruz, Rocio; Corona-Rivera, Jorge R; Zepeda-Moreno, Abraham; González-Ramella, Oscar; Corona-Rivera, Alfredo

    2015-01-01

    Here we present a male patient with acute myeloid leukemia (AML) initially diagnosed as M5 and with karyotype 46,XY. After induction therapy, he underwent a HLA-matched allogeneic hematopoietic stem cell transplantation, and six years later he relapsed as AML M1 with an abnormal karyotype //47,XX,+10[2]/47,XX,+11[3]/48,XX,+10,+11[2]/46,XX[13]. Based on this, we tested the possibility of donor cell origin by FISH and molecular STR analysis. We found no evidence of Y chromosome presence by FISH and STR analysis consistent with the success of the allogeneic hematopoietic stem cell transplantation from the female donor. FISH studies confirmed trisomies and no evidence of MLL translocation either p53 or ATM deletion. Additionally 28 fusion common leukemia transcripts were evaluated by multiplex reverse transcriptase-polymerase chain reaction assay and were not rearranged. STR analysis showed a complete donor chimerism. Thus, donor cell leukemia (DCL) was concluded, being essential the use of cytological and molecular approaches. Pediatric DCL is uncommon, our patient seems to be the sixth case and additionally it presented a late donor cell leukemia appearance. Different extrinsic and intrinsic mechanisms have been considered to explain this uncommon finding as well as the implications to the patient. PMID:25674158

  7. Paclitaxel Induced MDS and AML: A Case Report and Literature Review

    PubMed Central

    Bhatnagar, Udit Bhaskar; Singh, Daulath; Glazyrin, Alexy; Moormeier, Jill

    2016-01-01

    Therapy related acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) have been classically linked to alkylating agents and topoisomerase inhibitors. They constitute about 1% of all AMLs. There is less evidence on association of taxanes (paclitaxel and docetaxel) with these myeloid neoplasms. We present a case of paclitaxel therapy related acute myelogenous leukemia after treatment of endometrial cancer with a regimen containing paclitaxel and carboplatin. A 63-year-old female underwent surgery followed by a total of 6 cycles of chemotherapy with carboplatin and paclitaxel. Six months after last cycle of chemotherapy, she was diagnosed with myelodysplastic syndrome with refractory anemia and excess blasts. Six weeks later, she had worsening anemia and thrombocytopenia which prompted a bone marrow biopsy which revealed acute myelomonocytic leukemia. A thorough literature review revealed 12 other case reports where taxanes have been implicated in the development of therapy related myeloid neoplasm. Based on the timeline of events in our patient, paclitaxel is the likely culprit in the pathogenesis of this myeloid neoplasm. This rare but significantly grave adverse effect should be kept in consideration when deciding on treatment options for gynecological malignancies. PMID:27057370

  8. Mutated Nucleophosmin-1 (NPM1) in patients with Acute Myeloid Leukemia (AML) in remission and relapse

    PubMed Central

    Jain, Preetesh; Kantarjian, Hagop; Patel, Keyur; Faderl, Stefan; Garcia-Manero, Guillermo; Benjamini, Ohad; Borthakur, Gautam; Pemmaraju, Naveen; Kadia, Tapan; Daver, Naval; Nazha, Aziz; Luthra, Raja; Pierce, Sherry; Cortes, Jorge; Ravandi, Farhad

    2014-01-01

    Patients with newly diagnosed AML (n=360) including 137 (38%) with normal karyotype (NK) were evaluated. Overall, 60 (16.6%) patients including 46 of the 137 (33.5%) NK patients had NPM1 mutation at baseline. Thirty nine patients (30 NK) had available NPM1 status at the time of CR and all (100%) were negative for mutated NPM1. Among the patients with mutated NPM1 at baseline, 10/39 overall (25%) and 7/30 NK (23%) patients relapsed. NPM1 status was available for 8 patients (6 with NK) at the time of relapse. Among them, 7/8 overall (87%) and 5/6 NK (83%) patients had mutated NPM1, while 1/8 overall (12%) and 1/6 NK (16%) patients remained NPM1 wild type. Among the 300 patients (including 91 with NK) with wild type NPM1 at diagnosis, none acquired a mutated NPM1 clone, either at CR or at relapse. We conclude that mutated NPM1 is a stable and reliable prognostic marker in AML and can be used to assess MRD. PMID:24004182

  9. Chronic GVHD induced GVL effect after unmanipulated haploidentical hematopoietic SCT for AML and myelodysplastic syndrome.

    PubMed

    Mo, X-D; Xu, L-P; Zhang, X-H; Liu, D-H; Wang, Y; Chen, H; Yan, C-H; Chen, Y-H; Han, W; Wang, F-R; Wang, J-Z; Liu, K-Y; Huang, X-J

    2015-01-01

    The aim of this study was to investigate the impact of occurrence of chronic GVHD (cGVHD) and its severity on transplantation outcomes in a consecutive cohort of AML and myelodysplastic syndrome (MDS) patients who received unmanipulated haploidentical hematopoietic SCT (haplo-HSCT; n=324). The cumulative incidence of relapse was significantly decreased in patients with cGVHD compared with the non-cGVHD group (1 year: 3.2% vs 11.9%, P=0.002; 3 years: 6.0% vs 16.3%, P=0.002), particularly in those with mild cGVHD. The cumulative incidence of non-relapse mortality was comparable between patients with and without cGVHD. The probabilities of disease-free survival (DFS) were significantly better in patients with cGVHD than in those in the non-cGVHD group (1 year: 90.5% vs 78.5%, P=0.002; 3 years: 86.5% vs 71.5%, P<0.001), particularly in those with mild or moderate cGVHD; however, no significant impact of severe cGVHD on DFS was seen. Our findings highlight the close relationship between cGVHD and the immune-mediated GVL effect in patients with AML and MDS receiving unmanipulated haplo-HSCT; however, only mild or moderate cGVHD was associated with a lower risk of relapse translating into improved DFS. PMID:25387095

  10. Achieving stringent CR is essential before reduced-intensity conditioning allogeneic hematopoietic cell transplantation in AML.

    PubMed

    Ustun, C; Wiseman, A C; Defor, T E; Yohe, S; Linden, M A; Oran, B; Burke, M; Warlick, E; Miller, J S; Weisdorf, D

    2013-11-01

    Reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT) can cure patients with AML in CR. However, relapse after RIC allo-HCT may indicate heterogeneity in the stringency of CR. Strict definition of CR requires no evidence of leukemia by both morphologic and flow cytometric criteria. We re-evaluated 85 AML patients receiving RIC allo-HCT in CR to test if a strict definition of CR had direct implications for the outcome. These patients had leukemia immunophenotype documented at diagnosis and analyzed at allo-HCT. Eight (9.4%) had persistent leukemia by flow cytometric criteria at allo-HCT. The patients with immunophenotypic persistent leukemia had a significantly increased relapse (hazard ratio (HR): 3.7; 95% confidence interval (CI): 1.3-10.3, P=0.01) and decreased survival (HR: 2.9; 95% CI: 1.3-6.4, P<0.01) versus 77 patients in CR by both morphology and flow cytometry. However, the pre-allo-HCT bone marrow (BM) blast count (that is, 0-4%) was not significantly associated with risks of relapse or survival. These data indicate the presence of leukemic cells, but not the BM blast count affects survival. A strict morphologic and clinical lab flow cytometric definition of CR predicts outcomes after RIC allo-HCT, and therefore is critical to achieve at transplantation. PMID:23933764

  11. Cellular Intrinsic Mechanism Affecting the Outcome of AML Treated with Ara-C in a Syngeneic Mouse Model

    PubMed Central

    Tan, Dongming; Su, Guangsong; Zheng, Yanwen; He, Chao; Mao, Zhengwei J.; Singleton, Timothy P.; Yin, Bin

    2014-01-01

    The mechanisms underlying acute myeloid leukemia (AML) treatment failure are not clear. Here, we established a mouse model of AML by syngeneic transplantation of BXH-2 derived myeloid leukemic cells and developed an efficacious Ara-C-based regimen for treatment of these mice. We proved that leukemic cell load was correlated with survival. We also demonstrated that the susceptibility of leukemia cells to Ara-C could significantly affect the survival. To examine the molecular alterations in cells with different sensitivity, genome-wide expression of the leukemic cells was profiled, revealing that overall 366 and 212 genes became upregulated or downregulated, respectively, in the resistant cells. Many of these genes are involved in the regulation of cell cycle, cellular proliferation, and apoptosis. Some of them were further validated by quantitative PCR. Interestingly, the Ara-C resistant cells retained the sensitivity to ABT-737, an inhibitor of anti-apoptosis proteins, and treatment with ABT-737 prolonged the life span of mice engrafted with resistant cells. These results suggest that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C. Incorporation of apoptosis inhibitors, such as ABT-737, into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C. This work provided direct in vivo evidence that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C, suggesting that incorporation of apoptosis inhibitors into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C. PMID:25314317

  12. Successful management of pulmonary hemorrhage and aspergillosis in a patient with acute myeloid leukemia (AML-M3).

    PubMed

    Gunbatar, Hulya; Demir, Cengiz; Kara, Erdal; Esen, Ramazan; Sertogullarindan, Bunyamin; Asker, Selvi

    2015-01-01

    A 35-year-old man presented with a one month history of gingival bleeding. He was diagnosed with Acute Myeloid Leukemia (AML-M3). During treatment he developed alveolar hemorrhage for which he was treated with a steroid. After the steroid treatment he developed a nodule, a cavitary lesion and atelectasia in the left lung. He was treated with voriconazole. After therapy with voriconazole his lesion significantly decreased. This case illustrates the efficacy and safety of antifungal therapy with voriconazole for aspergillosis complicated by AML. PMID:26744658

  13. Successful management of pulmonary hemorrhage and aspergillosis in a patient with acute myeloid leukemia (AML-M3)

    PubMed Central

    Gunbatar, Hulya; Demir, Cengiz; Kara, Erdal; Esen, Ramazan; Sertogullarindan, Bunyamin; Asker, Selvi

    2015-01-01

    A 35-year-old man presented with a one month history of gingival bleeding. He was diagnosed with Acute Myeloid Leukemia (AML-M3). During treatment he developed alveolar hemorrhage for which he was treated with a steroid. After the steroid treatment he developed a nodule, a cavitary lesion and atelectasia in the left lung. He was treated with voriconazole. After therapy with voriconazole his lesion significantly decreased. This case illustrates the efficacy and safety of antifungal therapy with voriconazole for aspergillosis complicated by AML. PMID:26744658

  14. Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells

    PubMed Central

    Fiskus, Warren; Sharma, Sunil; Saha, Saikat; Shah, Bhavin; Devaraj, Santhana G. T.; Sun, Baohua; Horrigan, Stephen; Leveque, Christopher; Zu, Youli; Iyer, Swaminathan; Bhalla, Kapil N.

    2014-01-01

    The canonical WNT-β-catenin pathway is essential for self-renewal, growth and survival of AML stem/blast progenitor cells (BPCs). Deregulated WNT signaling inhibits degradation of β-catenin, causing increased nuclear translocation and co-factor activity of β-catenin with the transcriptional regulator TCF4/LEF1 in AML BPCs. Here, we determined the pre-clinical anti-AML activity of the anthraquinone oxime-analog BC2059 (BC), known to attenuate β-catenin levels. BC treatment disrupted the binding of β-catenin with the scaffold protein TBL1 (transducin β-like 1) and proteasomal degradation and decline in the nuclear levels of β-catenin. This was associated with reduced transcriptional activity of TCF4 and expression of its target genes, cyclin D1, c-MYC and survivin. BC treatment dose-dependently induced apoptosis of cultured and primary AML BPCs. Treatment with BC also significantly improved the median survival of immune-depleted mice engrafted with either cultured or primary AML BPCs exhibiting nuclear expression of β-catenin. Co-treatment with the pan-histone deacetylase inhibitor panobinostat and BC synergistically induced apoptosis of cultured and primary AML BPCs, including those expressing FLT3-ITD, as well as further significantly improved the survival of immune-depleted mice engrafted with primary AML BPCs. These findings underscore the promising pre-clinical activity and warrant further testing of BC against human AML, especially those expressing FLT3-ITD. PMID:25482131

  15. Increased expression of amyloid precursor protein promotes proliferation and migration of AML1/ETO-positive leukemia cells and be inhibited by panobinostat.

    PubMed

    Wang, C L; Ding, B J; Jiang, L; Yin, C X; Zhong, Q X; Yu, G P; Li, X D; Meng, F Y

    2015-01-01

    Amyloid precursor protein (APP) is a highly conserved integral membrane protein extensively expressed in various types of cells. Previously we found that overexpression of APP in patients with AML1/ETO-positive acute myeloid leukemia (AML) associated with a higher incidence of extramedullary infiltrationin and indicate a poor prognosis. In this study, we attempted to define the roles of APP in AML1/ETO-positive leukemia cells. Western blotting and qRT-PCR analysis showed that protein levels of APP are significantly higher in Kasumi-1, a t(8;21)/ AML1/ETO-positive M2-type AML cell line. Stable knockdown of APP by lentivirus-based RNA interference (RNAi) dramatically impaired colony-formation and migration ability of Kasumi-1 cells, whereas APP knockdown had very little effect on cell viability, apoptosis, cell cycle and differentiation. We further explored whether the pan-histone deacetylase inhibitor panobinostat could deplete the protein levels of APP in Kasumi-1 cells. Treatment with panobinostat caused depletion of APP in Kasumi-1 cells. These findings indicate that overexpression of APP is involved in promoting proliferation and migration of AML1/ETO-positive leukemia cells and can be inhibited by panobinostat, which provide an attractive prospect for treatment of AML1/ETO-positive AML. PMID:26458322

  16. Epigenomic analysis of the HOX gene loci reveals mechanisms that may control canonical expression patterns in AML and normal hematopoietic cells

    PubMed Central

    Spencer, David H.; Young, Margaret A.; Lamprecht, Tamara L.; Helton, Nichole M.; Fulton, Robert; O’Laughlin, Michelle; Fronick, Catrina; Magrini, Vincent; Demeter, Ryan T.; Miller, Christopher A.; Klco, Jeffery M.; Wilson, Richard K.; Ley, Timothy J.

    2015-01-01

    HOX genes are highly expressed in many acute myeloid leukemia (AML) samples, but the patterns of expression and associated regulatory mechanisms are not clearly understood. We analyzed RNA sequencing data from 179 primary AML samples and normal hematopoietic cells to understand the range of expression patterns in normal versus leukemic cells. HOX expression in AML was restricted to specific genes in the HOXA or HOXB loci, and was highly correlated with recurrent cytogenetic abnormalities. However, the majority of samples expressed a canonical set of HOXA and HOXB genes that was nearly identical to the expression signature of normal hematopoietic stem/progenitor cells (HSPCs). Transcriptional profiles at the HOX loci were similar between normal cells and AML samples, and involved bidirectional transcription at the center of each gene cluster. Epigenetic analysis of a subset of AML samples also identified common regions of chromatin accessibility in AML samples and normal CD34+ cells that displayed differences in methylation depending on HOX expression patterns. These data provide an integrated epigenetic view of the HOX gene loci in primary AML samples, and suggest that HOX expression in most AML samples represents a normal stem cell program that is controlled by epigenetic mechanisms at specific regulatory elements. PMID:25600023

  17. Epigenomic analysis of the HOX gene loci reveals mechanisms that may control canonical expression patterns in AML and normal hematopoietic cells.

    PubMed

    Spencer, D H; Young, M A; Lamprecht, T L; Helton, N M; Fulton, R; O'Laughlin, M; Fronick, C; Magrini, V; Demeter, R T; Miller, C A; Klco, J M; Wilson, R K; Ley, T J

    2015-06-01

    HOX genes are highly expressed in many acute myeloid leukemia (AML) samples, but the patterns of expression and associated regulatory mechanisms are not clearly understood. We analyzed RNA sequencing data from 179 primary AML samples and normal hematopoietic cells to understand the range of expression patterns in normal versus leukemic cells. HOX expression in AML was restricted to specific genes in the HOXA or HOXB loci, and was highly correlated with recurrent cytogenetic abnormalities. However, the majority of samples expressed a canonical set of HOXA and HOXB genes that was nearly identical to the expression signature of normal hematopoietic stem/progenitor cells. Transcriptional profiles at the HOX loci were similar between normal cells and AML samples, and involved bidirectional transcription at the center of each gene cluster. Epigenetic analysis of a subset of AML samples also identified common regions of chromatin accessibility in AML samples and normal CD34(+) cells that displayed differences in methylation depending on HOX expression patterns. These data provide an integrated epigenetic view of the HOX gene loci in primary AML samples, and suggest that HOX expression in most AML samples represents a normal stem cell program that is controlled by epigenetic mechanisms at specific regulatory elements. PMID:25600023

  18. Historisches Rätsel Physik mit Gewehr und Eiern

    NASA Astrophysics Data System (ADS)

    Loos, Andreas

    2003-11-01

    Es fing schon gut an: Mit zehn Jahren saß der begabte Junge bereits in der Universität, wo ihn kein Geringerer als sein Vater persönlich unterrichtete. Damit schlug dieser zwei Fliegen mit einer Klappe: Sein Sohn lernte etwas Gescheites, und er war zugleich in sicherer Obhut.

  19. MMPI and MIT Discriminators of Biogenic and Psychogenic Impotence

    ERIC Educational Resources Information Center

    Beutler, Larry E.; And Others

    1975-01-01

    Male patients complaining of impotence (N=32) were administered the Male Impotence Test (MIT) and the Minnesota Multiphasic Personality Inventory (MMPI). The results suggested that the MIT is without value for differentiating between psychogenic and biogenic impotence, whereas two rules from the MMPI appropriately classified 90 percent of the…

  20. Physik gestern und heute: Visualisierung mit der Schlierenmethode

    NASA Astrophysics Data System (ADS)

    Heering, Peter

    2006-07-01

    Der Name des österreichischen Forschers Ernst Mach ist heute noch mit der Schallgeschwindigkeit verbunden. Diese Auszeichnung resultiert aus Machs Untersuchungen, wie sich Projektile mit Überschallgeschwindigkeit durch die Luft bewegen. Gerade in jüngster Zeit hat die Anwendung derartiger Methoden durch technische Modifikationen wieder einen Aufschwung erfahren.

  1. The M.I.T. INSITE Space System.

    ERIC Educational Resources Information Center

    Cyros, Kreon L.

    1989-01-01

    The M.I.T. INSITE (INstitutional Space Inventory TEchniques) system, a management information system developed specifically to provide facilities management information for decision making in the planning stages, is described. Since 1973, M.I.T. has shared the INSITE technology with a consortium of users from academic, health care, corporate and…

  2. Survival of AML patients relapsing after allogeneic hematopoietic cell transplantation: a CIBMTR study

    PubMed Central

    Bejanyan, Nelli; Weisdorf, Daniel J.; Logan, Brent R.; Wang, Hai-Lin; Devine, Steven M.; de Lima, Marcos; Bunjes, Donald W.; Zhang, Mei-Jie

    2015-01-01

    Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (alloHCT) remains a major therapeutic challenge. We studied outcomes of 1788 AML patients relapsing after alloHCT (1990–2010) during first or second complete remission (CR) to identify factors associated with longer post-relapse survival. Median time of post HCT relapse was 7 months (mo; range, 1–177). At relapse, 1231 patients (69%) received intensive therapy, including chemotherapy (CT) alone (n=660), donor lymphocyte infusion (DLI)±CT (n=202; %), or 2nd alloHCT±CT ±DLI (n=369), with subsequent CR rates of 29%. Median follow-up after relapse was 39 mo (range, <1–193). Survival for all patients was 23% at 1 year post-relapse; however, 3-yr overall survival correlated with time from HCT to relapse (4% for relapse during 1–6 mo period, 12% during 6 mo-2 yr, 26% during 2–3 yr, and 38% for ≥3 yr). In multivariable analysis, lower mortality was significantly associated with longer time from alloHCT to relapse (RR 0.55 for 6 mo-2 yr, RR 0.39 for 2–3 yr, and RR 0.28 for ≥3 yr; p<0.0001) and a 1st HCT using reduced-intensity conditioning (RR=0.77; 95% CI 0.66–0.88, p=0.0002). In contrast, inferior survival was associated with age >40 yr (RR=1.42, 95% CI 1.24–1.64; p<0.0001), active GVHD at relapse (RR=1.25, 95% CI 1.13–1.39; p<0.0001), adverse cytogenetics (RR=1.37, 95% CI 1.09–1.71; p=0.0062), mismatched URD (RR=1.61, 95% CI 1.22–2.13; p=0.0008), and use of cord blood for 1st HCT (RR=1.23, 95% CI 1.06–1.42; p=0.0078). AML relapse after alloHCT predicted poor survival; however, patients who relapsed ≥6 mo after their initial alloHCT had better survival and may benefit from intensive therapy such as 2nd alloHCT±DLI. PMID:25460355

  3. Combination of galectin inhibitor GCS-100 and BH3 mimetics eliminates both p53 wild type and p53 null AML cells.

    PubMed

    Ruvolo, Peter P; Ruvolo, Vivian R; Benton, Christopher B; AlRawi, Ahmed; Burks, Jared K; Schober, Wendy; Rolke, James; Tidmarsh, George; Hail, Numsen; Davis, R Eric; Andreeff, Michael

    2016-04-01

    Galectin 3 (LGALS3) expression is prognostic for poor survival in acute myeloid leukemia (AML) patients. GCS-100 is a novel galectin inhibitor that may prove useful for AML therapy. In this study, we found that GCS-100 induced apoptosis in AML cells. The agent reduced MCL-1 expression suggesting that GCS-100 could be more effective when combined with a BH3 mimetic. Indeed, potent synergistic cytotoxicity was achieved when GCS-100 was combined with ABT-737 or ABT-199. Furthermore, the GCS-100/ABT-199 combination was effective against primary AML blast cells from patients with FLT3 ITD mutations, which is another prognostic factor for poor outcome in AML. This activity may involve wild-type p53 as shRNA knockdown of LGALS3 or galectin 1 (LGALS1) sensitized wild-type p53 OCI-AML3 cells to GCS-100/ABT-737-induced apoptosis to a much greater extent than p53 null THP-1 cells. Suppression of LGALS3 by shRNA inhibited MCL-1 expression in OCI-AML3 cells, but not THP-1 cells, suggesting the induced sensitivity to ABT-737 may involve a MCL-1 mediated mechanism. OCI-AML3 cells with LGALS1 shRNA were also sensitized to ABT-737. However, these cells exhibited increased MCL-1 expression, so MCL-1 reduction is apparently not required in this process. A role for p53 appears important as GCS-100 induces p53 expression and shRNA knockdown of p53 protected OCI-AML3 cells from the cytotoxic effects of the GCS-100/ABT-737 treatment combination. Our results suggest that galectins regulate a survival axis in AML cells, which may be targeted via combined inhibition with drugs such as GCS-100 and ABT-199. PMID:26704388

  4. AGS67E, an Anti-CD37 Monomethyl Auristatin E Antibody–Drug Conjugate as a Potential Therapeutic for B/T-Cell Malignancies and AML: A New Role for CD37 in AML

    PubMed Central

    Pereira, Daniel S.; Guevara, Claudia I.; Jin, Liqing; Mbong, Nathan; Verlinsky, Alla; Hsu, Ssucheng J.; Aviña, Hector; Karki, Sher; Abad, Joseph D.; Yang, Peng; Moon, Sung-Ju; Malik, Faisal; Choi, Michael Y.; An, Zili; Morrison, Kendall; Challita-Eid, Pia M.; Doñate, Fernando; Joseph, Ingrid B.J.; Kipps, Thomas J.; Dick, John E.; Stover, David R.

    2015-01-01

    CD37 is a tetraspanin expressed on malignant B cells. Recently, CD37 has gained interest as a therapeutic target. We developed AGS67E, an antibody–drug conjugate that targets CD37 for the potential treatment of B/T-cell malignancies. It is a fully human monoclonal IgG2 antibody (AGS67C) conjugated, via a protease-cleavable linker, to the microtubule-disrupting agent mono-methyl auristatin E (MMAE). AGS67E induces potent cytotoxicity, apoptosis, and cell-cycle alterations in many non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) cell lines and patient-derived samples in vitro. It also shows potent antitumor activity in NHL and CLL xenografts, including Rituxan-refractory models. During profiling studies to confirm the reported expression of CD37 in normal tissues and B-cell malignancies, we made the novel discovery that the CD37 protein was expressed in T-cell lymphomas and in AML. AGS67E bound to >80% of NHL and T-cell lymphomas, 100% of CLL and 100% of AML patient-derived samples, including CD34+CD38− leukemic stem cells. It also induced cytotoxicity, apoptosis, and cell-cycle alterations in AML cell lines and antitumor efficacy in orthotopic AML xenografts. Taken together, this study shows not only that AGS67E may serve as a potential therapeutic for B/T-cell malignancies, but it also demonstrates, for the first time, that CD37 is well expressed and a potential drug target in AML. PMID:25934707

  5. High Bad and Bax mRNA expression correlate with negative outcome in acute myeloid leukemia (AML).

    PubMed

    Köhler, T; Schill, C; Deininger, M W; Krahl, R; Borchert, S; Hasenclever, D; Leiblein, S; Wagner, O; Niederwieser, D

    2002-01-01

    The search for molecular markers in AML that allow prediction of outcome has recently focused on genes involved in the regulation of programmed cell death (PCD). The aim of our study was to determine whether mRNA levels of Mdm-2, Bcl-2, Bcl-x(L), Bad, and Bax are independent prognostic parameters for outcome. Transcript levels were analyzed by real-time quantitative RT-PCR in 232 samples collected either at diagnosis or following induction chemotherapy (ICT). Multivariate COX regression analysis adjusted for chemotherapy protocol, de novo vs secondary AML, and de novo vs relapsed AML indicated: (1) At diagnosis, high expression of Bad (P = 0.015) and even more so high Bax and Bad levels (P = 0.018) predicted adverse outcome, regardless of the response to ICT. In patients who subsequently failed to enter complete remission (CR), high levels of Bad, Bax and Bax high/Bad high were associated with an increased relative risk (RR) to die from tumor (RR = 5.0 for Bad, 3.4 for Bax and 6.14 for Bax high/Bad high). (2) Following ICT, high expression of Bax (P= 0.005) and high Bcl-2/Bax ratios (P = 0.004) were independent predictors of unfavorable outcome, regardless of response to ICT. We conclude that high levels of Bax and Bad correlate with poor outcome, particularly in patients who do not enter CR and may serve as prognostic markers in AML. PMID:11840259

  6. 30 CFR 872.20 - What will OSM do with unappropriated AML funds currently allocated to the Rural Abandoned Mine...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 3 2010-07-01 2010-07-01 false What will OSM do with unappropriated AML funds currently allocated to the Rural Abandoned Mine Program ? 872.20 Section 872.20 Mineral Resources OFFICE OF... MONEYS AVAILABLE TO ELIGIBLE STATES AND INDIAN TRIBES § 872.20 What will OSM do with unappropriated...

  7. Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML.

    PubMed

    Volk, Andrew; Li, Jing; Xin, Junping; You, Dewen; Zhang, Jun; Liu, Xinli; Xiao, Yechen; Breslin, Peter; Li, Zejuan; Wei, Wei; Schmidt, Rachel; Li, Xingyu; Zhang, Zhou; Kuo, Paul C; Nand, Sucha; Zhang, Jianke; Chen, Jianjun; Zhang, Jiwang

    2014-06-01

    Leukemic stem cells (LSCs) isolated from acute myeloid leukemia (AML) patients are more sensitive to nuclear factor κB (NF-κB) inhibition-induced cell death when compared with hematopoietic stem and progenitor cells (HSPCs) in in vitro culture. However, inadequate anti-leukemic activity of NF-κB inhibition in vivo suggests the presence of additional survival/proliferative signals that can compensate for NF-κB inhibition. AML subtypes M3, M4, and M5 cells produce endogenous tumor necrosis factor α (TNF). Although stimulating HSPC with TNF promotes necroptosis and apoptosis, similar treatment with AML cells (leukemic cells, LCs) results in an increase in survival and proliferation. We determined that TNF stimulation drives the JNK-AP1 pathway in a manner parallel to NF-κB, leading to the up-regulation of anti-apoptotic genes in LC. We found that we can significantly sensitize LC to NF-κB inhibitor treatment by blocking the TNF-JNK-AP1 signaling pathway. Our data suggest that co-inhibition of both TNF-JNK-AP1 and NF-κB signals may provide a more comprehensive treatment paradigm for AML patients with TNF-expressing LC. PMID:24842373

  8. Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML

    PubMed Central

    Volk, Andrew; Li, Jing; Xin, Junping; You, Dewen; Zhang, Jun; Liu, Xinli; Xiao, Yechen; Breslin, Peter; Li, Zejuan; Wei, Wei; Schmidt, Rachel; Li, Xingyu; Zhang, Zhou; Kuo, Paul C.; Nand, Sucha; Zhang, Jianke; Chen, Jianjun

    2014-01-01

    Leukemic stem cells (LSCs) isolated from acute myeloid leukemia (AML) patients are more sensitive to nuclear factor κB (NF-κB) inhibition-induced cell death when compared with hematopoietic stem and progenitor cells (HSPCs) in in vitro culture. However, inadequate anti-leukemic activity of NF-κB inhibition in vivo suggests the presence of additional survival/proliferative signals that can compensate for NF-κB inhibition. AML subtypes M3, M4, and M5 cells produce endogenous tumor necrosis factor α (TNF). Although stimulating HSPC with TNF promotes necroptosis and apoptosis, similar treatment with AML cells (leukemic cells, LCs) results in an increase in survival and proliferation. We determined that TNF stimulation drives the JNK–AP1 pathway in a manner parallel to NF-κB, leading to the up-regulation of anti-apoptotic genes in LC. We found that we can significantly sensitize LC to NF-κB inhibitor treatment by blocking the TNF–JNK–AP1 signaling pathway. Our data suggest that co-inhibition of both TNF–JNK–AP1 and NF-κB signals may provide a more comprehensive treatment paradigm for AML patients with TNF-expressing LC. PMID:24842373

  9. High-affinity FRβ-specific CAR T cells eradicate AML and normal myeloid lineage without HSC toxicity.

    PubMed

    Lynn, R C; Feng, Y; Schutsky, K; Poussin, M; Kalota, A; Dimitrov, D S; Powell, D J

    2016-06-01

    Acute myeloid leukemia (AML) is an aggressive malignancy, and development of new treatments to prolong remissions is warranted. Chimeric antigen receptor (CAR) T-cell therapies appear promising but on-target, off-tumor recognition of antigen in healthy tissues remains a concern. Here we isolated a high-affinity (HA) folate receptor beta (FRβ)-specific single-chain variable fragment (2.48 nm KD) for optimization of FRβ-redirected CAR T-cell therapy for AML. T cells stably expressing the HA-FRβ CAR exhibited greatly enhanced antitumor activity against FRβ(+) AML in vitro and in vivo compared with a low-affinity FRβ CAR (54.3 nm KD). Using the HA-FRβ immunoglobulin G, FRβ expression was detectable in myeloid-lineage hematopoietic cells; however, expression in CD34(+) hematopoietic stem cells (HSCs) was nearly undetectable. Accordingly, HA-FRβ CAR T cells lysed mature CD14(+) monocytes, while HSC colony formation was unaffected. Because of the potential for elimination of mature myeloid lineage, mRNA CAR electroporation for transient CAR expression was evaluated. mRNA-electroporated HA-FRβ CAR T cells retained effective antitumor activity in vitro and in vivo. Together, our results highlight the importance of antibody affinity in target protein detection and CAR development and suggest that transient delivery of potent HA-FRβ CAR T cells is highly effective against AML and reduces the risk for long-term myeloid toxicity. PMID:26898190

  10. Teaching ``The Physics of Energy'' at MIT

    NASA Astrophysics Data System (ADS)

    Jaffe, Robert

    2009-05-01

    New physics courses on energy are popping up at colleges and universities across the country. Many require little or no previous physics background, aiming to introduce a broad audience to this complex and critical problem, often augmenting the scientific message with economic and policy discussions. Others are advanced courses, focussing on highly specialized subjects like solar voltaics, nuclear physics, or thermal fluids, for example. About two years ago Washington Taylor and I undertook to develop a course on the ``Physics of Energy'' open to all MIT students who had taken MIT's common core of university level calculus, physics, and chemistry. By avoiding higher level prerequisites, we aimed to attract and make the subject relevant to students in the life sciences, economics, etc. --- as well as physical scientists and engineers --- who want to approach energy issues in a sophisticated and analytical fashion, exploiting their background in calculus, mechanics, and E & M, but without having to take advanced courses in thermodynamics, quantum mechanics, or nuclear physics beforehand. Our object was to interweave teaching the fundamental physics principles at the foundations of energy science with the applications of those principles to energy systems. We envisioned a course that would present the basics of statistical, quantum, and fluid mechanics at a fairly sophisticated level and apply those concepts to the study of energy sources, conversion, transport, losses, storage, conservation, and end use. In the end we developed almost all of the material for the course from scratch. The course debuted this past fall. I will describe what we learned and what general lessons our experience might have for others who contemplate teaching energy physics broadly to a technically sophisticated audience.

  11. Treosulfan, Fludarabine and 2 Gy Total Body Irradiation Followed by Allogeneic Hematopoietic Cell Transplantation in Patients with MDS and AML

    PubMed Central

    Gyurkocza, Boglarka; Gutman, Jonathan; Nemecek, Eneida R.; Bar, Merav; Milano, Filippo; Ramakrishnan, Aravind; Scott, Bart; Fang, Min; Wood, Brent; Pagel, John M.; Baumgart, Joachim; Delaney, Colleen; Maziarz, Richard T.; Sandmaier, Brenda M.; Estey, Elihu H.; Appelbaum, Frederick R.; Storer, Barry E.; Deeg, H. Joachim

    2014-01-01

    Allogeneic hematopoietic cell transplantation (HCT) offers curative therapy for many patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics. In this prospective phase II trial we assessed the efficacy and toxicity of treosulfan, fludarabine and 2 Gy total body irradiation (TBI) as conditioning for allogeneic HCT in patients with MDS or AML. Ninety-six patients with MDS (n=36; 15 RMCD; 10 RAEB-1; 10 RAEB-2; 1 CMML-1) or AML (n=60; 35 CR1; 18 CR2; 3 advanced CR; 4 refractory relapse) were enrolled; median age was 51 (range: 1–60) years. Twelve patients had undergone a prior HCT with high intensity conditioning. Patients received intravenous (IV) treosulfan, 14 g/m2/day on days −6 to −4, IV fludarabine, 30 mg/m2/day on days −6 to −2, and 2 Gy TBI on day 0, followed by infusion of hematopoietic cells from related (n=27) or unrelated (n=69) donors. Graft-vs.-host disease prophylaxis consisted of tacrolimus and methotrexate. With a median follow-up of 30 months, the 2-year overall survival (OS), relapse incidence and non-relapse mortality were 73%, 27% and 8%, respectively. The incidences of grades II–IV (III–IV) acute and chronic graft-versus-host disease were 59% (10%) and 47%, respectively. Two-year OS was not significantly different between MDS patients with poor risk and good/intermediate risk cytogenetics (69% and 85%, respectively), or between AML patients with unfavorable and favorable/intermediate risk cytogenetics (64% and 76%, respectively). In AML patients, minimal residual disease (MRD; n=10) at the time of HCT predicted higher relapse incidence (70% vs. 18%) and lower OS (41% vs. 79%) at 2 years, when compared to patients without MRD. In conclusion, treosulfan, fludarabine and low-dose TBI provided effective conditioning for allogeneic HCT in patients with MDS or AML, and resulted in low relapse incidence, regardless

  12. Mixed lineage leukaemia histone methylases 1 collaborate with ERα to regulate HOXA10 expression in AML

    PubMed Central

    Yao, Jie; Fang, Li-Chao; Yang, Zai-Lin; Huang, Hui; Li, Yan; Deng, Jun; Zheng, Junsong

    2014-01-01

    HOXA10, a homeobox-containing gene involved in definitive haematopoiesis, which implicated in the pathogenesis of AML (acute myeloid leukaemia), has been studied extensively. But the regulatory mechanism that drives HOXA10 expression is still unclear. In the present paper, HOXA10 regulated by MLL1 (mixed lineage leukaemia histone methylase 1) with an epigenetic way has been demonstrated. The HOXA10 promoter contains several EREs (oestrogen response elements), including ERE1 and ERE2, which are close to the transcription start site, and are associated with E2-mediated activation of HOXA10. It has been shown that knockdown of the ERα (oestrogen receptor α) suppresses E2-mediated activation of HOXA10. Similarly, knockdown of MLL1 suppresses activation of HOXA10 and is bound to the ERE of HOXA10 promoter in an E2-dependent manner by forming complex with ERα. Knockdown of ERα affects the E2-dependent binding of MLL1 into HOXA10 EREs, suggesting critical roles of ERα in recruiting MLL on the HOXA10 promoter. More interestingly, the methylation status of histone protein H3K4 (H3 at lysine 4) with E2 is much higher than without E2 treatment in leukaemia cell. On the contrary, the methylation status of HOXA10 promoter with E2 treatment is much lower, which elevate the HOXA10 expression. Moreover, with ERα knockdown, the H3K4 methylation level is also decrease in myeloid cell. Overall, it has been clearly demonstrated that HOXA10 is transcriptionally regulated by MLL1, which, in coordination with ERα, plays a critical role in this process with epigenetic way and suggests a potential anti-E2 treatment of AML. PMID:25307539

  13. Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups.

    PubMed

    Luskin, Marlise R; Lee, Ju-Whei; Fernandez, Hugo F; Abdel-Wahab, Omar; Bennett, John M; Ketterling, Rhett P; Lazarus, Hillard M; Levine, Ross L; Litzow, Mark R; Paietta, Elisabeth M; Patel, Jay P; Racevskis, Janis; Rowe, Jacob M; Tallman, Martin S; Sun, Zhuoxin; Luger, Selina M

    2016-03-24

    The initial report of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group trial E1900 (#NCT00049517) showed that induction therapy with high-dose (HD) daunorubicin (90 mg/m(2)) improved overall survival in adults <60 years old with acute myeloid leukemia (AML); however, at initial analysis, the benefit was restricted to younger patients (<50 years) and patients without unfavorable cytogenetics or aFLT3-ITD mutation. Here, we update the results of E1900 after longer follow-up (median, 80.1 months among survivors), focusing on the benefit of HD daunorubicin on common genetic subgroups. Compared with standard-dose daunorubicin (45 mg/m(2)), HD daunorubicin is associated with a hazard ratio (HR) for death of 0.74 (P= .001). Younger patients (<50 years) benefited from HD daunorubicin (HR, 0.66;P= .002), as did patients with favorable and intermediate cytogenetics (HR, 0.51;P= .03 and HR, 0.68;P= .01, respectively). Patients with unfavorable cytogenetics were shown to benefit from HD daunorubicin on multivariable analysis (adjusted HR, 0.66;P= .04). Patients withFLT3-ITD (24%),DNMT3A(24%), andNPM1(26%) mutant AML all benefited from HD daunorubicin (HR, 0.61,P= .009; HR, 0.62,P= .02; and HR, 0.50,P= .002; respectively). HD benefit was seen in the subgroup of older patients (50-60 years) with theFLT3-ITD orNPM1mutation. Additionally, the presence of anNPM1mutation confers a favorable prognosis only for patients receiving anthracycline dose intensification during induction. PMID:26755712

  14. [Correlation of adult AML Npm1 mutations with prognosis and its relationship with gene mutation of FLT3 and CEBPA].

    PubMed

    Bao, Li-Yan; Wang, Ji-Shi

    2010-02-01

    This study was aimed to investigate the correlation of 12th exon mutations in the npm1 gene with prognosis of adult AML patients and to explore the relationship of 12th exon mutation with other gene mutations. The specimen of bone marrow and peripheral blood from AML patients, the informations of medical history, symptoms, related image examinations, blood routine examination, NAP, oxygen saturation level in artery blood and EPO level in serum were collected; the bcr/abl fusion gene was detected by routine examination of bone marrow + biopsy + chromosome mapping + FISH. The patients were typed according to WHO classification. The DNA in cells was extracted, the npm1 gene mutation was detected by allele specific PCR combined were the sequencing. The results indicated that the npm1 heterozygote gene mutation was found in 72 out of 150 AML patients with normal cytogenetics (48%, 72/150). 48% patients showed a frameshift mutation in the C-terminal region of the NPM1 protein. The AML patients with npm1 gene mutation had specific clinical, phenotypic and genetic characteristics. The statistical analysis demonstrated the relationship between npm1 and flt3 ITDs. The patients with npm1 mutation showed a better response to induction therapy, furthermore, the overall survival (OS) rate of patients without flt3 ITD mutation was enhanced. The multivariate analysis demonstrated that the npm1 gene mutation and cebpa mutation positively correlated to the OS rate, and the correlation of flt3 mutation to OS rate showed negative. It is concluded that npm1 mutation is a favorable independent prognostic factor for adult AML patients with normal cytogenetics under conditions without FIT3 gene mutation. PMID:20137111

  15. A new model to predict remission status in AML patients based on day 14 bone marrow biopsy.

    PubMed

    Norkin, Maxim; Chang, Myron; An, Qi; Leather, Helen; Katragadda, Lakshmikanth; Li, Ying; Moreb, Jan S; May, W Stratford; Brown, Randy A; Hsu, Jack W; Hiemenz, John W; Wingard, John R; Cogle, Christopher R

    2016-07-01

    Although bone marrow evaluation on day 14 after initiation of induction chemotherapy (D14 BM) is a widely accepted practice in patients with acute myeloid leukemia (AML), it has suboptimal predictive value for predicting complete remission. We retrospectively analyzed pretreatment characteristics and post-induction response in a cohort of AML patients to determine if adding clinical and laboratory characteristics can improve the predictive value of the D14 BM evaluation. Among 297 patients treated for AML at the single institution 183 patients (61%) had leukemia-positive D14 BM. Of those, 94 were given reinduction chemotherapy and 89 were not. Of the 89 patients who did not receive reinduction, 32 (36%) subsequently achieved complete remission (CR) or complete remission with incomplete count recovery (CRi), and 57 (64%) had persistent disease. Persistent disease after positive D14 BM was more likely associated with higher percentage of D14 myeloblasts, a history of relapsed disease before induction, and higher risk disease compared to patients who subsequently achieved CR. Age, diagnostic white blood cell count, and the D14 BM cellularity did not influence the subsequent likelihood of achieving remission in patients with a positive D14 BM. A new mathematical equation was created and resulted in a positive predictive value of 83%, negative predictive value 90% and accuracy 88% for correctly identifying remission status after positive D14 BM in AML. The accuracy of predicting response using these additional parameters was significantly higher than without (0.88 vs. 0.80, P=0.002). Our new model provides better accuracy for predicting the likelihood of achieving remission and if validated in future studies may be useful for managing AML patients. PMID:27132034

  16. Ibrutinib synergizes with poly(ADP-ribose) glycohydrolase inhibitors to induce cell death in AML cells via a BTK-independent mechanism

    PubMed Central

    Rotin, Lianne E.; Gronda, Marcela; MacLean, Neil; Hurren, Rose; Wang, XiaoMing; Lin, Feng-Hsu; Wrana, Jeff; Datti, Alessandro; Barber, Dwayne L.; Minden, Mark D.; Slassi, Malik; Schimmer, Aaron D.

    2016-01-01

    Targeting Bruton's tyrosine kinase (BTK) with the small molecule BTK inhibitor ibrutinib has significantly improved patient outcomes in several B-cell malignancies, with minimal toxicity. Given the reported expression and constitutive activation of BTK in acute myeloid leukemia (AML) cells, there has been recent interest in investigating the anti-AML activity of ibrutinib. We noted that ibrutinib had limited single-agent toxicity in a panel of AML cell lines and primary AML samples, and therefore sought to identify ibrutinib-sensitizing drugs. Using a high-throughput combination chemical screen, we identified that the poly(ADP-ribose) glycohydrolase (PARG) inhibitor ethacridine lactate synergized with ibrutinib in TEX and OCI-AML2 leukemia cell lines. The combination of ibrutinib and ethacridine induced a synergistic increase in reactive oxygen species that was functionally important to explain the observed cell death. Interestingly, synergistic cytotoxicity of ibrutinib and ethacridine was independent of the inhibitory effect of ibrutinib against BTK, as knockdown of BTK did not sensitize TEX and OCI-AML2 cells to ethacridine treatment. Thus, our findings indicate that ibrutinib may have a BTK-independent role in AML and that PARG inhibitors may have utility as part of a combination therapy for this disease. PMID:26624983

  17. Ibrutinib synergizes with poly(ADP-ribose) glycohydrolase inhibitors to induce cell death in AML cells via a BTK-independent mechanism.

    PubMed

    Rotin, Lianne E; Gronda, Marcela; MacLean, Neil; Hurren, Rose; Wang, XiaoMing; Lin, Feng-Hsu; Wrana, Jeff; Datti, Alessandro; Barber, Dwayne L; Minden, Mark D; Slassi, Malik; Schimmer, Aaron D

    2016-01-19

    Targeting Bruton's tyrosine kinase (BTK) with the small molecule BTK inhibitor ibrutinib has significantly improved patient outcomes in several B-cell malignancies, with minimal toxicity. Given the reported expression and constitutive activation of BTK in acute myeloid leukemia (AML) cells, there has been recent interest in investigating the anti-AML activity of ibrutinib. We noted that ibrutinib had limited single-agent toxicity in a panel of AML cell lines and primary AML samples, and therefore sought to identify ibrutinib-sensitizing drugs. Using a high-throughput combination chemical screen, we identified that the poly(ADP-ribose) glycohydrolase (PARG) inhibitor ethacridine lactate synergized with ibrutinib in TEX and OCI-AML2 leukemia cell lines. The combination of ibrutinib and ethacridine induced a synergistic increase in reactive oxygen species that was functionally important to explain the observed cell death. Interestingly, synergistic cytotoxicity of ibrutinib and ethacridine was independent of the inhibitory effect of ibrutinib against BTK, as knockdown of BTK did not sensitize TEX and OCI-AML2 cells to ethacridine treatment. Thus, our findings indicate that ibrutinib may have a BTK-independent role in AML and that PARG inhibitors may have utility as part of a combination therapy for this disease. PMID:26624983

  18. Survivin is highly expressed in CD34+38− leukemic stem/progenitor cells and predicts poor clinical outcomes in AML

    PubMed Central

    Qiu, Yihua; Huang, Xuelin; Diao, Lixia; Zhang, Nianxiang; Coombes, Kevin R.; Mak, Duncan H.; Konopleva, Marina; Cortes, Jorge; Kantarjian, Hagop M.; Mills, Gordon B.; Andreeff, Michael

    2012-01-01

    Survivin, a member of the inhibitors of apoptosis protein family, plays important roles in cell proliferation and survival and is highly expressed in various malignancies, including leukemias. To better understand its role in acute myeloid leukemia (AML), we profiled survivin expression in samples obtained from 511 newly diagnosed AML patients and in CD34+38− AML stem/progenitor cells using a validated reverse-phase protein array; we correlated its levels with clinical outcomes and with levels of other proteins in the same sample set. We found that survivin levels were higher in bone marrow than in paired peripheral blood leukemic cells (n = 140, P = .0001) and that higher survivin levels significantly predicted shorter overall (P = .016) and event-free (P = .023) survival in multivariate Cox model analysis. Importantly, survivin levels were significantly higher in CD34+38− AML stem/progenitor cells than in bulk blasts and total CD34+ AML cells (P < .05). Survivin expression correlated with the expressions of multiple proteins involved with cell proliferation and survival. Particularly, its expression strongly correlated with HIF1α in the stem/progenitor cell compartment. These results suggest that survivin is a prognostic biomarker in AML and that survivin, which is overexpressed in AML stem/progenitor cells, remains a potentially important target for leukemia therapy. PMID:22645176

  19. Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells.

    PubMed

    Martelli, Maria Paola; Gionfriddo, Ilaria; Mezzasoma, Federica; Milano, Francesca; Pierangeli, Sara; Mulas, Floriana; Pacini, Roberta; Tabarrini, Alessia; Pettirossi, Valentina; Rossi, Roberta; Vetro, Calogero; Brunetti, Lorenzo; Sportoletti, Paolo; Tiacci, Enrico; Di Raimondo, Francesco; Falini, Brunangelo

    2015-05-28

    Nucleophosmin (NPM1) mutations represent an attractive therapeutic target in acute myeloid leukemia (AML) because they are common (∼30% AML), stable, and behave as a founder genetic lesion. Oncoprotein targeting can be a successful strategy to treat AML, as proved in acute promyelocytic leukemia by treatment with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO), which degrade the promyelocytic leukemia (PML)-retinoic acid receptor fusion protein. Adjunct of ATRA to chemotherapy was reported to be beneficial for NPM1-mutated AML patients. Leukemic cells with NPM1 mutation also showed sensibility to ATO in vitro. Here, we explore the mechanisms underlying these observations and show that ATO/ATRA induce proteasome-dependent degradation of NPM1 leukemic protein and apoptosis in NPM1-mutated AML cell lines and primary patients' cells. We also show that PML intracellular distribution is altered in NPM1-mutated AML cells and reverted by arsenic through oxidative stress induction. Interestingly, similarly to what was described for PML, oxidative stress also mediates ATO-induced degradation of the NPM1 mutant oncoprotein. Strikingly, NPM1 mutant downregulation by ATO/ATRA was shown to potentiate response to the anthracyclin daunorubicin. These findings provide experimental evidence for further exploring ATO/ATRA in preclinical NPM1-mutated AML in vivo models and a rationale for exploiting these compounds in chemotherapeutic regimens in clinics. PMID:25795919

  20. Stochastic noise characteristics in matrix inversion tomosynthesis (MITS).

    PubMed

    Godfrey, Devon J; McAdams, H P; Dobbins, James T Third

    2009-05-01

    Matrix inversion tomosynthesis (MITS) uses known imaging geometry and linear systems theory to deterministically separate in-plane detail from residual tomographic blur in a set of conventional tomosynthesis ("shift-and-add") planes. A previous investigation explored the effect of scan angle (ANG), number of projections (N), and number of reconstructed planes (NP) on the MITS impulse response and modulation transfer function characteristics, and concluded that ANG = 20 degrees, N = 71, and NP = 69 is the optimal MITS imaging technique for chest imaging on our prototype tomosynthesis system. This article examines the effect of ANG, N, and NP on the MITS exposure-normalized noise power spectra (ENNPS) and seeks to confirm that the imaging parameters selected previously by an analysis of the MITS impulse response also yield reasonable stochastic properties in MITS reconstructed planes. ENNPS curves were generated for experimentally acquired mean-subtracted projection images, conventional tomosynthesis planes, and MITS planes with varying combinations of the parameters ANG, N, and NP. Image data were collected using a prototype tomosynthesis system, with 11.4 cm acrylic placed near the image receptor to produce lung-equivalent beam hardening and scattered radiation. Ten identically acquired tomosynthesis data sets (realizations) were collected for each selected technique and used to generate ensemble mean images that were subtracted from individual image realizations prior to noise power spectra (NPS) estimation. NPS curves were normalized to account for differences in entrance exposure (as measured with an ion chamber), yielding estimates of the ENNPS for each technique. Results suggest that mid- and high-frequency noise in MITS planes is fairly equivalent in magnitude to noise in conventional tomosynthesis planes, but low-frequency noise is amplified in the most anterior and posterior reconstruction planes. Selecting the largest available number of projections (N

  1. Final Technical Report for the MIT Annular Fuel Research Project

    SciTech Connect

    Mujid S. Kazimi; Pavel Hejzlar

    2008-01-31

    MIT-NFC-PR-082 (January 2006) Abstract This summary provides an overview of the results of the U.S. DOE funded NERI (Nuclear Research ENergy Initiative) program on development of the internally and externally cooled annular fuel for high power density PWRs. This new fuel was proposed by MIT to allow a substantial increase in poer density (on the order of 30% or higher) while maintaining or improving safety margins. A comprehensive study was performed by a team consisting of MIT (lead organization), Westinghuse Electric Corporation, Gamma Engineering Corporation, Framatome ANP(formerly Duke Engineering) and Atomic Energy of Canada Limited.

  2. Unfälle mit motorisierten Zweirädern

    NASA Astrophysics Data System (ADS)

    Tschirschwitz, Christian

    Der Fahrer eines Pkw Opel Astra überquerte mit seinem Pkw von einer untergeordneten Einmündung kommend eine außerörtliche Bundesstraße in gerade Richtung. Dabei kam es zur Kollision mit einem sich von rechts vorfahrtsberechtigt annähernden Krad Suzuki RGV250. Der Anprall des Krades erfolgte mit dem Heck an die rechte Pkw-Flanke zwischen vorderem Radausschnitt und Fahrzeugecke. Der Krad-Fahrer, welcher sofort tot war und das Zweirad verklemmten sich am Pkw und verblieben relativ zu selbigem annähernd in Kollisionsstellung.

  3. Stochastic noise characteristics in matrix inversion tomosynthesis (MITS)

    SciTech Connect

    Godfrey, Devon J.; McAdams, H. P.; Dobbins, James T. III

    2009-05-15

    Matrix inversion tomosynthesis (MITS) uses known imaging geometry and linear systems theory to deterministically separate in-plane detail from residual tomographic blur in a set of conventional tomosynthesis (''shift-and-add'') planes. A previous investigation explored the effect of scan angle (ANG), number of projections (N), and number of reconstructed planes (NP) on the MITS impulse response and modulation transfer function characteristics, and concluded that ANG=20 deg., N=71, and NP=69 is the optimal MITS imaging technique for chest imaging on our prototype tomosynthesis system. This article examines the effect of ANG, N, and NP on the MITS exposure-normalized noise power spectra (ENNPS) and seeks to confirm that the imaging parameters selected previously by an analysis of the MITS impulse response also yield reasonable stochastic properties in MITS reconstructed planes. ENNPS curves were generated for experimentally acquired mean-subtracted projection images, conventional tomosynthesis planes, and MITS planes with varying combinations of the parameters ANG, N, and NP. Image data were collected using a prototype tomosynthesis system, with 11.4 cm acrylic placed near the image receptor to produce lung-equivalent beam hardening and scattered radiation. Ten identically acquired tomosynthesis data sets (realizations) were collected for each selected technique and used to generate ensemble mean images that were subtracted from individual image realizations prior to noise power spectra (NPS) estimation. NPS curves were normalized to account for differences in entrance exposure (as measured with an ion chamber), yielding estimates of the ENNPS for each technique. Results suggest that mid- and high-frequency noise in MITS planes is fairly equivalent in magnitude to noise in conventional tomosynthesis planes, but low-frequency noise is amplified in the most anterior and posterior reconstruction planes. Selecting the largest available number of projections (N=71) does

  4. Genomic DNA breakpoints in AML1/RUNX1 and ETO cluster with topoisomerase II DNA cleavage and DNase I hypersensitive sites in t(8;21) leukemia

    PubMed Central

    Zhang, Yanming; Strissel, Pamela; Strick, Reiner; Chen, Jianjun; Nucifora, Giuseppina; Le Beau, Michelle M.; Larson, Richard A.; Rowley, Janet D.

    2002-01-01

    The translocation t(8;21)(q22;q22) is one of the most frequent chromosome translocations in acute myeloid leukemia (AML). AML1/RUNX1 at 21q22 is involved in t(8;21), t(3;21), and t(16;21) in de novo and therapy-related AML and myelodysplastic syndrome as well as in t(12;21) in childhood B cell acute lymphoblastic leukemia. Although DNA breakpoints in AML1 and ETO (at 8q22) cluster in a few introns, the mechanisms of DNA recombination resulting in t(8;21) are unknown. The correlation of specific chromatin structural elements, i.e., topoisomerase II (topo II) DNA cleavage sites, DNase I hypersensitive sites, and scaffold-associated regions, which have been implicated in chromosome recombination with genomic DNA breakpoints in AML1 and ETO in t(8;21) is unknown. The breakpoints in AML1 and ETO were clustered in the Kasumi 1 cell line and in 31 leukemia patients with t(8;21); all except one had de novo AML. Sequencing of the breakpoint junctions revealed no common DNA motif; however, deletions, duplications, microhomologies, and nontemplate DNA were found. Ten in vivo topo II DNA cleavage sites were mapped in AML1, including three in intron 5 and seven in intron 7a, and two were in intron 1b of ETO. All strong topo II sites colocalized with DNase I hypersensitive sites and thus represent open chromatin regions. These sites correlated with genomic DNA breakpoints in both AML1 and ETO, thus implicating them in the de novo 8;21 translocation. PMID:11867721

  5. Review of recent work on MPD thrusters at MIT

    NASA Technical Reports Server (NTRS)

    Hastings, Daniel

    1992-01-01

    The topics are presented in viewgraph form and include the following: basic philosophy of MIT SSPL work; 2-D numerical magnetoplasmadynamic (MPD) simulations; analysis of MPD boundary layers; and ignition of MPD thrusters.

  6. MIT gets good marks for fighting gender discrimination

    NASA Astrophysics Data System (ADS)

    Gwynne, Peter

    2011-05-01

    The Massachusetts Institute of Technology (MIT) has made "significant progress" in increasing the number of female faculty members, with their numbers in science and engineering almost doubling over the last decade.

  7. MIT ASTROMAG 1.7 meter disk magnet design report

    NASA Technical Reports Server (NTRS)

    Marston, P. G.; Hale, J. R.; Vieira, R.; Zhukovsky, A.; Titus, P. H.; Sullivan, J. D.; Dawson, A. M.

    1990-01-01

    MIT has proposed a magnet design for ASTROMAG, which has demonstrated substantial improvement in performance as compared with the present HEAO baseline design. Several advantages of the MIT disk design are listed along with design characteristics. Details of field contours and active field regions are shown along with comparisons with other designs. Three alternative design configurations for the ASTROMAG disk coils are summarized. The parameters of the conductors are listed and basic parameters for each of the complete systems are shown.

  8. Bisphosphonates and statins inhibit expression and secretion of MIP-1α via suppression of Ras/MEK/ERK/AML-1A and Ras/PI3K/Akt/AML-1A pathways.

    PubMed

    Tsubaki, Masanobu; Takeda, Tomoya; Sakamoto, Kotaro; Shimaoka, Hirotaka; Fujita, Arisa; Itoh, Tatsuki; Imano, Motohiro; Mashimo, Kenji; Fujiwara, Daiichiro; Sakaguchi, Katsuhiko; Satou, Takao; Nishida, Shozo

    2015-01-01

    Osteolytic bone disease in multiple myeloma (MM) is associated with upregulated osteoclast activity. Macrophage inflammatory protein-1α (MIP-1α) is crucially involved in the development of osteolytic bone lesions in MM. We previously reported that minodronate inhibited lipopolysaccharide-induced MIP-1α secretion in mouse myeloma cells. However, it remains unknown whether bisphosphonates and statins inhibit MIP-1α secretion by human MM cells. In present study, we investigated whether bisphosphonates and statins had any inhibitory effect on MIP-1α secretion by human myeloma cells and the mechanism underlying this effect. In this study, we found that bisphosphonates and statins inhibited MIP-1α mRNA and MIP-1α secretion and suppressed extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation by inhibiting Ras prenylation. Moreover, bisphosphonates and statins suppressed the expression of acute myeloid leukemia-1A (AML-1A) mRNA, a MIP-1α transcription factor. These results indicate that bisphosphonates and statins suppress the Ras/mitogen-activated protein kinase kinase/ERK/AML-1A and Ras/phosphatidylinositol-3 kinase/Akt/AML-1A pathways, thereby inhibiting MIP-1α secretion by MM cells. Therefore, use of MIP-1α expression inhibitors such as bisphosphonates and statins may provide a new therapeutic approach to inhibiting tumour progression and bone destruction in MM patients. PMID:25628928

  9. Saponin-Based Nanoemulsification Improves the Antioxidant Properties of Vitamin A and E in AML-12 Cells.

    PubMed

    Choudhry, Qaisra Naheed; Kim, Mi Jeong; Kim, Tae Gyun; Pan, Jeong Hoon; Kim, Jun Ho; Park, Sung Jin; Lee, Jin Hyup; Kim, Young Jun

    2016-01-01

    Our work aimed to investigate the protective effects of saponin-based nanoemulsions of vitamin A and E against oxidative stress-induced cellular damage in AML-12 cells. Saponin nanoemulsions of vitamin A (SAN) and vitamin E (SEN) were prepared by high-pressure homogenization and characterized in terms of size, zeta potential, and polydispersity index. SEN and SAN protect AML-12 cells against oxidative stress-induced cellular damage more efficiently via scavenging reactive oxygen species (ROS), and reducing DNA damage, protein carbonylation, and lipid peroxidation. These results provide valuable information for the development of nanoemulsion-based delivery systems that would improve the antioxidant properties of vitamin A and E. PMID:27571071

  10. Chemo-genomic interrogation of CEBPA mutated AML reveals recurrent CSF3R mutations and subgroup sensitivity to JAK inhibitors.

    PubMed

    Lavallée, Vincent-Philippe; Krosl, Jana; Lemieux, Sébastien; Boucher, Geneviève; Gendron, Patrick; Pabst, Caroline; Boivin, Isabel; Marinier, Anne; Guidos, Cynthia J; Meloche, Sylvain; Hébert, Josée; Sauvageau, Guy

    2016-06-16

    In this study, we analyzed RNA-sequencing data of 14 samples characterized by biallelic CEBPA (CEBPA(bi)) mutations included in the Leucegene collection of 415 primary acute myeloid leukemia (AML) specimens, and describe for the first time high frequency recurrent mutations in the granulocyte colony-stimulating factor receptor gene CSF3R, which signals through JAK-STAT proteins. Chemical interrogation of these primary human specimens revealed a uniform and specific sensitivity to all JAK inhibitors tested irrespective of their CSF3R mutation status, indicating a general sensitization of JAK-STAT signaling in this leukemia subset. Altogether, these results identified the co-occurrence of mutations in CSF3R and CEBPA in a well-defined AML subset, which uniformly responds to JAK inhibitors and paves the way to personalized clinical trials for this disease. PMID:27034432

  11. Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG mice.

    PubMed

    Etchin, J; Montero, J; Berezovskaya, A; Le, B T; Kentsis, A; Christie, A L; Conway, A S; Chen, W C; Reed, C; Mansour, M R; Ng, C E L; Adamia, S; Rodig, S J; Galinsky, I A; Stone, R M; Klebanov, B; Landesman, Y; Kauffman, M; Shacham, S; Kung, A L; Wang, J C Y; Letai, A; Look, A T

    2016-01-01

    Currently available combination chemotherapy for acute myeloid leukemia (AML) often fails to result in long-term remissions, emphasizing the need for novel therapeutic strategies. We reasoned that targeted inhibition of a prominent nuclear exporter, XPO1/CRM1, could eradicate self-renewing leukemia-initiating cells (LICs) whose survival depends on timely XPO1-mediated transport of specific protein and RNA cargoes. Using an immunosuppressed mouse model bearing primary patient-derived AML cells, we demonstrate that selinexor (KPT-330), an oral antagonist of XPO1 that is currently in clinical trials, has strong activity against primary AML cells while sparing normal stem and progenitor cells. Importantly, limiting dilution transplantation assays showed that this cytotoxic activity is not limited to the rapidly proliferating bulk population of leukemic cells but extends to the LICs, whose inherent drug resistance and unrestricted self-renewal capacity has been implicated in the difficulty of curing AML patients with conventional chemotherapy alone. PMID:26202935

  12. Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG mice

    PubMed Central

    Etchin, J; Montero, J; Berezovskaya, A; Le, BT; Kentsis, A; Christie, AL; Conway, AS; Chen, WC; Reed, C; Mansour, MR; Ng, CEL; Adamia, S; Rodig, SJ; Galinsky, IA; Stone, RM; Klebanov, B; Landesman, Y; Kauffman, M; Shacham, S; Kung, AL; Wang, JCY; Letai, A; Look, AT

    2016-01-01

    Currently available combination chemotherapy for acute myeloid leukemia (AML) often fails to result in long-term remissions, emphasizing the need for novel therapeutic strategies. We reasoned that targeted inhibition of a prominent nuclear exporter, XPO1/CRM1, could eradicate self-renewing leukemia-initiating cells (LICs) whose survival depends on timely XPO1-mediated transport of specific protein and RNA cargoes. Using an immunosuppressed mouse model bearing primary patient-derived AML cells, we demonstrate that selinexor (KPT-330), an oral antagonist of XPO1 that is currently in clinical trials, has strong activity against primary AML cells while sparing normal stem and progenitor cells. Importantly, limiting dilution transplantation assays showed that this cytotoxic activity is not limited to the rapidly proliferating bulk population of leukemic cells but extends to the LICs, whose inherent drug resistance and unrestricted self-renewal capacity has been implicated in the difficulty of curing AML patients with conventional chemotherapy alone. PMID:26202935

  13. Celastrol Induces Cell Apoptosis and Inhibits the Expression of the AML1-ETO/C-KIT Oncoprotein in t(8;21) Leukemia.

    PubMed

    Yu, Xianjun; Ruan, Xuzhi; Zhang, Jingxuan; Zhao, Qun

    2016-01-01

    Resistance to chemotherapy is a major challenge to improving overall survival in Acute Myeloid Leukemia (AML). Therefore, the development of innovative therapies and the identification of more novel agents for AML are urgently needed. Celastrol, a compound extracted from the Chinese herb Tripterygium wilfordii Hook, exerts anticancer activity. We investigated the effect of celastrol in the t(8;21) AML cell lines Kasumi-1 and SKNO-1. We demonstrated that inhibition of cell proliferation activated caspases and disrupted mitochondrial function. In addition, we found that celastrol downregulated the AML1-ETO fusion protein, therefore downregulating C-KIT kinases and inhibiting AKT, STAT3 and Erk1/2. These findings provide clear evidence that celastrol might provide clinical benefits to patients with t(8;21) leukemia. PMID:27144550

  14. PEBP2 alpha B/mouse AML1 consists of multiple isoforms that possess differential transactivation potentials.

    PubMed

    Bae, S C; Ogawa, E; Maruyama, M; Oka, H; Satake, M; Shigesada, K; Jenkins, N A; Gilbert, D J; Copeland, N G; Ito, Y

    1994-05-01

    A murine transcription factor, PEBP2, is composed of two subunits, alpha and beta. There are two genes in the mouse genome, PEBP2 alpha A and PEBP2 alpha B, which encode the alpha subunit. Two types of the alpha B cDNA clones, alpha B1 and alpha B2, were isolated from mouse fibroblasts and characterized. They were found to represent 3.8- and 7.9-kb transcripts, respectively. The 3.8-kb RNA encodes the previously described alpha B protein referred to as alpha B1, while the 7.9-kb RNA encodes a 387-amino-acid protein, termed alpha B2, which is identical to alpha B1 except that it has an internal deletion of 64 amino acid residues. Both alpha B1 and alpha B2 associate with PEBP2 beta and form a heterodimer. The alpha B2/beta complex binds to the PEBP2 binding site two- to threefold more strongly than the alpha B1/beta complex does. alpha B1 stimulates transcription through the PEBP2 site about 40-fold, while alpha B2 is only about 25 to 45% as active as alpha B1. Transactivation domain is located downstream of the 128-amino-acid runt homology region, referred to as the Runt domain. Mouse chromosome mapping studies revealed that alpha A, alpha B, and beta genes are mapped to chromosomes 17, 16, and 8, respectively. The last two genes are syntenic with the human AML1 on chromosome 21q22 and PEBP2 beta/CBF beta on 16q22 detected at the breakpoints of characteristic chromosome translocations of the two different subtypes of acute myeloid leukemia. These results suggest that previously described chimeric gene products, AML1/MTG8(ETO) and AML1-EAP generated by t(8;21) and t(3;21), respectively, lack the transactivation domain of AML1. PMID:8164679

  15. Phase I Trial of Maintenance Sorafenib after Allogeneic Hematopoietic Stem Cell Transplantation for FLT3-ITD AML

    PubMed Central

    Chen, Yi-Bin; Li, Shuli; Lane, Andrew A.; Connolly, Christine; Del Rio, Candice; Valles, Betsy; Curtis, Morgan; Ballen, Karen; Cutler, Corey; Dey, Bimalangshu R.; El-Jawahri, Areej; Fathi, Amir T.; Ho, Vincent T.; Joyce, Amy; McAfee, Steven; Rudek, Michelle; Rajkhowa, Trivikram; Verselis, Sigitas; Antin, Joseph H.; Spitzer, Thomas R.; Levis, Mark; Soiffer, Robert

    2014-01-01

    The FLT3-ITD mutation is associated with a high relapse rate for patients with AML even after allogeneic hematopoietic stem cell transplantation (HSCT). Sorafenib is a tyrosine kinase inhibitor which inhibits the FLT3 tyrosine kinase and has shown encouraging activity in FLT3-ITD AML. We conducted a phase I trial of maintenance sorafenib after HSCT in patients with FLT3-ITD AML (ClinicalTrials.gov NCT01398501). Patients received a variety of conditioning regimens and graft sources. A dose escalation 3+3 cohort design was used to define the maximum tolerated dose (MTD) with an additional 10 patients treated at the MTD. Sorafenib was initiated between days 45 and 120 after HSCT continued for twelve 28-day cycles. Twenty-two patients were enrolled (status at HSCT: CR1=16, CR2=3, refractory=3). The MTD was established at 400 mg BID with one DLT observed (pericardial effusion). Two patients died of transplant-related causes, both unrelated to sorafenib. Two patients stopped sorafenib after relapse and 5 stopped due to attributable toxicities after the DLT period. Median follow-up for surviving patients is 16.7 months after HSCT (range, 8.1–35.0). There was one case of grade II acute GVHD after starting sorafenib and the 12-month cumulative incidence of chronic GVHD was 38% (90% CI, 21%–56%). For all patients, one-year progression-free survival (PFS) is 85% (90% CI, 66%–94%) and one-year overall survival (OS) is 95% (90% CI, 79%–99%) after HSCT. For patients in CR1 / CR2 prior to HSCT (n=19), one-year PFS is 95% (90% CI, 76%–99%) and one-year OS is 100% with only one patient who has relapsed. Sorafenib is safe after HSCT for FLT3-ITD AML and merits further investigation for the prevention of relapse. PMID:25239228

  16. High affinity FRβ-specific CAR T cells eradicate AML and normal yeloid lineage without HSC toxicity

    PubMed Central

    Lynn, Rachel C; Feng, Yang; Schutsky, Keith; Poussin, Mathilde; Kalota, Anna; Dimitrov, Dimiter S; Powell, Daniel J

    2016-01-01

    Acute myeloid leukemia (AML) is an aggressive malignancy, and development of new treatments to prolong remissions is warranted. Chimeric antigen receptor (CAR) T-cell therapies appear promising but on-target, off-tumor recognition of antigen in healthy tissues remains a concern. Here, we isolated a high affinity (HA) folate receptor beta (FRβ)-specific scFv (2.48nM KD) for optimization of FRβ-redirected CAR T-cell therapy for AML. T-cells stably expressing the HA-FRβ CAR exhibited greatly enhanced antitumor activity against FRβ+ AML in vitro and in vivo compared to a low affinity (LA) FRβ CAR (54.3nM KD). Using the HA-FRβ IgG, FRβ expression was detectable in myeloid-lineage hematopoietic cells; however, expression in CD34+ hematopoietic stem cells (HSCs) was nearly undetectable. Accordingly, HA-FRβ CAR T-cells lysed mature CD14+ monocytes, while HSC colony formation was unaffected. Because of the potential for elimination of mature myeloid lineage, mRNA CAR electroporation for transient CAR expression was evaluated. mRNA-electroporated HA-FRβ CAR T-cells retained effective anti-tumor activity in vitro and in vivo. Together, our results highlight the importance of antibody affinity in target protein detection and CAR development and suggest that transient delivery of potent HA-FRβ CAR T-cells is highly effective against AML and reduces the risk for long-term myeloid toxicity. PMID:26898190

  17. Case report of FLT3-ITD-positive AML patient 11 years after living donor liver transplantation.

    PubMed

    Taniai, N; Yoshida, H; Kawano, Y; Uchida, E

    2014-04-01

    With the increasing number of long-term survivors of living donor liver transplantation, the occurrence of secondary cancer is sometimes reported. Solid tumors such as lymphomas are mainly observed. However, only 8 cases of leukemia have been reported so far. For patients younger than 15 years old, leukemia developed in 4 within 3 years after the liver transplantation, whereas acute lymphoblastic leukemia developed in only 1 patient. This is the first case report of a patient in whom FLT3-ITD-positive acute myeloid leukemia (AML) developed more than 10 years after living donor liver transplantation for congenital biliary atresia. AML developed in a 14-year-old boy 11 years after living donor liver transplantation from his father. The patient received the transplant at the age of 3 years and was treated with tacrolimus and methylprednisolone for transplant rejection. Eleven years posttransplantation, he visited the hospital with general malaise and anemia. Blood tests revealed an elevated white blood cell count of 60,100/μL, and the patient was diagnosed with AML. Chromosome analysis revealed a t(6; 9) (p23 q34) translocation; moreover, genetic testing revealed a FLT3-ITD-positive mutation. We started treatment in accordance with the Tokyo Children's Cancer Study Group AML99 protocol. With chemotherapy treatment, the patient achieved complete remission. After chemotherapy, we performed stem cell transplantation from his father. Other patients were reported in relatively early stages after liver transplantation, but our case was more than 10 years posttransplantation. The association with the onset of congenital bile duct atresia and leukemia is still not clear, but we consider the possibility that long-term immunosuppressive drugs contribute to developing leukemia. PMID:24767404

  18. Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5.

    PubMed

    Carter, Bing Z; Mak, Duncan H; Schober, Wendy D; Dietrich, Martin F; Pinilla, Clemencia; Vassilev, Lyubomir T; Reed, John C; Andreeff, Michael

    2008-04-01

    Acute myeloid leukemia (AML) cells are relatively resistant to tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL). We previously reported that triptolide, a potent anticancer agent from a Chinese herb, decreases XIAP in leukemic cells. We evaluated the combination of triptolide and TRAIL and found synergistic promotion of apoptosis in AML cells. XIAP-overexpressing U937 cells (U937XIAP) were more resistant to TRAIL than U937neo cells, and inhibition of XIAP with the small-molecule inhibitor 1396-11 enhanced TRAIL-induced apoptosis, implying XIAP as a resistance factor in AML. Furthermore, triptolide increased DR5 levels in OCI-AML3, while the DR5 increase was blunted in p53-knockdown OCI-AML3 and p53-mutated U937 cells, confirming a role for p53 in the regulation of DR5. In support of this finding, disruption of MDM2-p53 binding with subsequent increase in p53 levels by nutlin3a increased DR5 levels and sensitized OCI-AML3 cells to TRAIL. The combination of 1396-11 plus nutlin3a plus TRAIL was more effective than either the 1396-11 and TRAIL or nutlin3a and TRAIL combinations in OCI-AML3 cells, further supporting the role of triptolide as a sensitizer to TRAIL-induced apoptosis in part by independent modulation of XIAP expression and p53 signaling. Thus, the combination of triptolide and TRAIL may provide a novel strategy for treating AML by overcoming critical mechanisms of apoptosis resistance. PMID:18187663

  19. Establishment of xenotransplantation model of human CN-AML with FLT3-ITD (mut) /NPM1 (-) in NOD/SCID mice.

    PubMed

    Shang, Zhen; Wang, Jue; Wang, Di; Xiao, Min; Li, Tong-juan; Wang, Na; Huang, Liang; Zhou, Jian-feng

    2013-06-01

    Patients with FLT3-ITD (mut) /NPM1 (-) cytogenetically normal acute myeloid leukemia (CN-AML), as high-risk molecular group in CN-AML, are associated with a worse prognosis than other CN-AML patients. It is beneficial to generate xenotransplantation model of FLT3-ITD (mut) /NPM1 (-) CN-AML to better understand the pathogenesis and therapeutic strategies of such AML subtype. The purpose of present study was to establish the xenotransplantation model in NOD/SCID mice with FLT3-ITD (mut) /NPM1 (-) CN-AML primary cells. The FLT3-ITD (mut) /NPM1 (-) CN-AML primary cells from 3 of 7 cases were successfully transplanted into NOD/SCID mice, and human CD45 positive cells were detected in the peripheral blood, spleen and bone marrow of mice by using flow cytometry. Infiltration of human leukemia cells in various organs of mice was observed by using immunohistochemistry. Gene analysis confirmed sustained FLT3/ITD mutation without NPM1 mutation in mice. By performing serial transplantation, it was found that characteristics of the leukemia cells in secondary and tertiary generation models remained unchanged. Moreover, in vivo cytarabine administration could extend survival of NOD/SCID mice, which was consistent with clinical observation. In conclusion, we successfully established xenotransplantation model of human FLT3-ITD (mut) /NPM1 (-) CN-AML in NOD/SCID mice. The model was able to present primary disease and suitable to evaluate the curative effects of new drugs or therapy strategies. PMID:23771655

  20. Theoretical and experimental study of DOA estimation using AML algorithm for an isotropic and non-isotropic 3D array

    NASA Astrophysics Data System (ADS)

    Asgari, Shadnaz; Ali, Andreas M.; Collier, Travis C.; Yao, Yuan; Hudson, Ralph E.; Yao, Kung; Taylor, Charles E.

    2007-09-01

    The focus of most direction-of-arrival (DOA) estimation problems has been based mainly on a two-dimensional (2D) scenario where we only need to estimate the azimuth angle. But in various practical situations we have to deal with a three-dimensional scenario. The importance of being able to estimate both azimuth and elevation angles with high accuracy and low complexity is of interest. We present the theoretical and the practical issues of DOA estimation using the Approximate-Maximum-Likelihood (AML) algorithm in a 3D scenario. We show that the performance of the proposed 3D AML algorithm converges to the Cramer-Rao Bound. We use the concept of an isotropic array to reduce the complexity of the proposed algorithm by advocating a decoupled 3D version. We also explore a modified version of the decoupled 3D AML algorithm which can be used for DOA estimation with non-isotropic arrays. Various numerical results are presented. We use two acoustic arrays each consisting of 8 microphones to do some field measurements. The processing of the measured data from the acoustic arrays for different azimuth and elevation angles confirms the effectiveness of the proposed methods.

  1. Induced Mitogenic Activity in AML-12 Mouse Hepatocytes Exposed to Low-dose Ultra-Wideband Electromagnetic Radiation

    PubMed Central

    Dorsey, W. C.; Ford, B. D.; Roane, L.; Haynie, D. T.; Tchounwou, P. B.

    2005-01-01

    Ultra–wideband (UWB) technology has increased with the use of various civilian and military applications. In the present study, we hypothesized that low-dose UWB electromagnetic radiation (UWBR) could elicit a mitogenic effect in AML-12 mouse hepatocytes, in vitro. To test this hypothesis, we exposed AML-12 mouse hepatocytes, to UWBR in a specially constructed gigahertz transverse electromagnetic mode (GTEM) cell. Cells were exposed to UWBR for 2 h at a temperature of 23°C, a pulse width of 10 ns, a repetition rate of 1 kHz, and field strength of 5–20 kV/m. UWB pulses were triggered by an external pulse generator for UWBR exposure but were not triggered for the sham exposure. We performed an MTT Assay to assess cell viability for UWBR-treated and sham-exposed hepatocytes. Data from viability studies indicated a time-related increase in hepatocytes at time intervals from 8–24 h post exposure. UWBR exerted a statistically significant (p < 0.05) dose-dependent response in cell viability in both serum-treated and serum free medium (SFM) -treated hepatocytes. Western blot analysis of hepatocyte lysates demonstrated that cyclin A protein was induced in hepatocytes, suggesting that increased MTT activity after UWBR exposure was due to cell proliferation. This study indicates that UWBR has a mitogenic effect on AML-12 mouse hepatocytes and implicates a possible role for UWBR in hepatocarcinoma. PMID:16705798

  2. Invasive fungal infections in AML/MDS patients treated with azacitidine: a risk worth considering antifungal prophylaxis?

    PubMed

    Pomares, Helena; Arnan, Montserrat; Sánchez-Ortega, Isabel; Sureda, Anna; Duarte, Rafael F

    2016-08-01

    The aim of this study is to analyse the risk of invasive fungal infection (IFI) and the need for antifungal prophylaxis in patients with acute myeloid leukaemia and myelodysplastic syndromes (AML/MDS) treated with azacitidine. We retrospectively analysed the incidence of IFI according to EORTC-MSG criteria in 121 consecutive AML/MDS patients receiving 948 azacitidine courses (median 5, range 1-43) between June 2007 and June 2015. Four cases of IFI (two possible, one probable aspergillosis and one proven candidemia) occurred in this series. The incidence rate of proven/probable IFI was 0.21% per treatment cycle and 1.6% per patient treated for the whole series, and 0.73% per treatment cycle and 4.1% per patient treated in those with severe neutropenia. Two patients died from IFI, leading to an IFI-attributable mortality rate of 1.65% per patient and 0.21% per treatment cycle. The numbers needed to treat with prophylaxis to prevent one case of IFI are 238 azacitidine cycles or 30 patients throughout their whole treatment course, and 137 azacitidine cycles or 24 patients among those with severe neutropenia. AML/MDS patients treated with azacitidine, including those with severe prolonged neutropenia, have a very low risk of IFI which does not justify the use of antifungal prophylaxis. PMID:27027972

  3. Association between prolonged neutropenia and reduced relapse risk in pediatric AML: A report from the children's oncology group.

    PubMed

    Sung, Lillian; Aplenc, Richard; Alonzo, Todd A; Gerbing, Robert B; Wang, Yi-Cheng; Meshinchi, Soheil; Gamis, Alan S

    2016-11-01

    Objective was to describe the relationship between the number of sterile site infections and duration of neutropenia during the first four cycles of chemotherapy and the risk of recurrence and overall survival in children with newly diagnosed acute myeloid leukemia (AML). AAML0531 was a Children's Oncology Group randomized phase 3 clinical trial that included 1022 children with de novo AML. For this analysis, we focused on non-Down syndrome favorable and standard risk patients who completed at least 4 cycles of chemotherapy without recurrence or withdrawal during protocol therapy. Those receiving hematopoietic stem cell transplantation in first remission were excluded. Five hundred and sixty-nine patients were included; 274 (48.2%) were favorable risk. The median cumulative time with neutropenia between Induction II to completion of Intensification II was 96 (range 54-204) days. Number of sterile site infections did not influence the risk of relapse or overall survival. However, longer duration of neutropenia was associated with a lower risk of relapse (hazard ratio 0.81 per 20 days neutropenia, p = 0.007). Longer duration of neutropenia was associated with a reduced risk of relapse for children with favorable and standard risk AML. Toxicity may be influenced by pharmacogenomics suggesting that individualized chemotherapy dosing may be an effective strategy. PMID:27312107

  4. A Polyethylenimine-Containing and Transferrin-Conjugated Lipid Nanoparticle System for Antisense Oligonucleotide Delivery to AML

    PubMed Central

    Yuan, Yiming; Zhang, Lijing; Cao, Hua; Yang, Yi; Zheng, Yu; Yang, Xiao-juan

    2016-01-01

    Limited success of antisense oligonucleotides (ASO) in clinical anticancer therapy calls for more effective delivery carriers. The goal of this study was to develop a nanoparticle system for delivery of ASO G3139, which targets mRNA of antiapoptotic protein Bcl-2, to acute myeloid leukemia (AML) cells. The synthesized nanoparticle Tf-LPN-G3139 contained a small molecular weight polyethylenimine and two cationic lipids as condensing agents, with transferrin on its surface for selective binding and enhanced cellular uptake. The optimized nitrogen to phosphate (N/P) ratio was 4 to achieve small particle size and high G3139 entrapment efficiency. The Tf-LPN-G3139 exhibited excellent colloidal stability during storage for at least 12 weeks and remained intact for 4 hours in nuclease-containing serum. The cellular uptake results showed extensive internalization of fluorescence-labelled G3139 in MV4-11 cells through Tf-LPN. Following transfection, Tf-LPN-G3139 at 1 µM ASO level induced 54% Bcl-2 downregulation and >20-fold apoptosis compared to no treatment. When evaluated in mice bearing human xenograft AML tumors, Tf-LPN-G3139 suppressed tumor growth by ~60% at the end of treatment period, accompanied by remarkable pharmacological effect of Bcl-2 inhibition in tumor. In conclusion, Tf-LPN-G3139 is a promising nanoparticle system for ASO G3139 delivery to AML and warrants further investigations. PMID:27034925

  5. The t(8;21) Fusion Product, AML-1–ETO, Associates with C/EBP-α, Inhibits C/EBP-α-Dependent Transcription, and Blocks Granulocytic Differentiation

    PubMed Central

    Westendorf, Jennifer J.; Yamamoto, Cindy M.; Lenny, Noel; Downing, James R.; Selsted, Michael E.; Hiebert, Scott W.

    1998-01-01

    AML-1B is a hematopoietic transcription factor that is functionally inactivated by multiple chromosomal translocations in human acute myeloblastic and B-cell lymphocytic leukemias. The t(8;21)(q22;q22) translocation replaces the C terminus, including the transactivation domain of AML-1B, with ETO, a nuclear protein of unknown function. We previously showed that AML-1–ETO is a dominant inhibitor of AML-1B-dependent transcriptional activation. Here we demonstrate that AML-1–ETO also inhibits C/EBP-α-dependent activation of the myeloid cell-specific, rat defensin NP-3 promoter. AML-1B bound the core enhancer motifs present in the NP-3 promoter and activated transcription approximately sixfold. Similarly, C/EBP-α bound NP-3 promoter sequences and activated transcription approximately sixfold. Coexpression of C/EBP-α with AML-1B or its family members, AML-2 and murine AML-3, synergistically activated the NP-3 promoter up to 60-fold. The t(8;21) product, AML-1–ETO, repressed AML-1B-dependent activation of NP-3 and completely inhibited C/EBP-α-dependent activity as well as the synergistic activation. In contrast, the inv(16) product, which indirectly targets AML family members by fusing their heterodimeric DNA binding partner, CBF-β, to the myosin heavy chain, inhibited AML-1B but not C/EBP-α activation or the synergistic activation. AML-1–ETO and C/EBP-α were coimmunoprecipitated and thus physically interact in vivo. Deletion mutants demonstrated that the C terminus of ETO was required for AML-1–ETO-mediated repression of the synergistic activation but not for association with C/EBP-α. Finally, overexpression of AML-1–ETO in myeloid progenitor cells prevented granulocyte colony-stimulating factor-induced differentiation. Thus, AML-1–ETO may contribute to leukemogenesis by specifically inhibiting C/EBP-α- and AML-1B-dependent activation of myeloid promoters and blocking differentiation. PMID:9418879

  6. 5-azacytidine enhances efficacy of multiple chemotherapy drugs in AML and lung cancer with modulation of CpG methylation.

    PubMed

    Füller, Mathias; Klein, Miriam; Schmidt, Eva; Rohde, Christian; Göllner, Stefanie; Schulze, Isabell; Qianli, Jiang; Berdel, Wolfgang E; Edemir, Bayram; Müller-Tidow, Carsten; Tschanter, Petra

    2015-03-01

    The DNA methyltransferase (DNMT) inhibitory drugs such as 5-azacytidine induce DNA hypomethylation by inhibiting DNA methyltransferases. While clinically effective, DNMT inhibitors are not curative. A combination with cytotoxic drugs might be beneficial, but this is largely unexplored. In the present study, we analyzed potential synergisms between cytotoxic drugs and 5-azacytidine in acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC) cells. Lung cancer and leukemia cell lines were exposed to low doses of 5-azacytidine with varying doses of cytarabine or etoposide for AML cells (U937 and HL60) as well as cisplatin or gemcitabine for NSCLC cells (A549 and HTB56) for 48 h. Drug interaction and potential synergism was analyzed according to the Chou-Talalay algorithm. Further analyses were based on soft agar colony formation assays, active caspase-3 staining and BrdU incorporation flow cytometry. To identify effects on DNA methylation patterns, we performed genome wide DNA methylation analysis using 450K bead arrays. Azacytidine at low doses was synergistic with cytotoxic drugs in NSCLC and in AML cell lines. Simultaneous exposure to 5-azacytidine with cytotoxic drugs showed strong synergistic activity. In colony formation assays these synergisms were repeatedly verified for 5-azacytidine (25 nM) with low doses of anticancer agents. 5-azacytidine neither affected the cell cycle nor increased apoptosis. 450K methylation bead arrays revealed 1,046 CpG sites in AML and 1,778 CpG sites in NSCLC cells with significant DNA hypomethylation (24-h exposure) to 5-azacytidine combined with the cytotoxic drugs. These CpG-sites were observed in the candidate tumor-suppressor genes MGMT and THRB. Additional incubation time after 24-h treatment led to a 4.1-fold increase of significant hypomethylated CpG-sites in NSCLC cells. These results suggest that the addition of DNA demethylating agents to cytotoxic anticancer drugs exhibits synergistic activity in AML and NSCLC

  7. Single-cell mass cytometry reveals intracellular survival/proliferative signaling in FLT3-ITD-mutated AML stem/progenitor cells.

    PubMed

    Han, Lina; Qiu, Peng; Zeng, Zhihong; Jorgensen, Jeffrey L; Mak, Duncan H; Burks, Jared K; Schober, Wendy; McQueen, Teresa J; Cortes, Jorge; Tanner, Scott D; Roboz, Gail J; Kantarjian, Hagop M; Kornblau, Steven M; Guzman, Monica L; Andreeff, Michael; Konopleva, Marina

    2015-04-01

    Understanding the unique phenotypes and complex signaling pathways of leukemia stem cells (LSCs) will provide insights and druggable targets that can be used to eradicate acute myeloid leukemia (AML). Current work on AML LSCs is limited by the number of parameters that conventional flow cytometry (FCM) can analyze because of cell autofluorescence and fluorescent dye spectral overlap. Single-cell mass cytometry (CyTOF) substitutes rare earth elements for fluorophores to label antibodies, which allows measurements of up to 120 parameters in single cells without correction for spectral overlap. The aim of this study was the evaluation of intracellular signaling in antigen-defined stem/progenitor cell subsets in primary AML. CyTOF and conventional FCM yielded comparable results on LSC phenotypes defined by CD45, CD34, CD38, CD123, and CD99. Intracellular phosphoprotein responses to ex vivo cell signaling inhibitors and cytokine stimulation were assessed in myeloid leukemia cell lines and one primary AML sample. CyTOF and conventional FCM results were confirmed by western blotting. In the primary AML sample, we investigated the cell responses to ex vivo stimulation with stem cell factor and BEZ235-induced inhibition of PI3K and identified activation patterns in multiple PI3K downstream signaling pathways including p-4EBP1, p-AKT, and p-S6, particularly in CD34(+) subsets. We evaluated multiple signaling pathways in antigen-defined subpopulations in primary AML cells with FLT3-ITD mutations. The data demonstrated the heterogeneity of cell phenotype distribution and distinct patterns of signaling activation across AML samples and between AML and normal samples. The mTOR targets p-4EBP1 and p-S6 were exclusively found in FLT3-ITD stem/progenitor cells, but not in their normal counterparts, suggesting both as novel targets in FLT3 mutated AML. Our data suggest that CyTOF can identify functional signaling pathways in antigen-defined subpopulations in primary AML, which may

  8. Single-cell mass cytometry reveals intracellular survival/proliferative signaling in FLT3-ITD-mutated AML stem/progenitor cells

    PubMed Central

    Han, Lina; Qiu, Peng; Zeng, Zhihong; Jorgensen, Jeffrey L; Mak, Duncan H; Burks, Jared K; Schober, Wendy; McQueen, Teresa J; Cortes, Jorge; Tanner, Scott D; Roboz, Gail J; Kantarjian, Hagop M; Kantarjian, Hagop M; Kornblau, Steven M; Guzman, Monica L; Andreeff, Michael; Konopleva, Marina

    2015-01-01

    Understanding the unique phenotypes and complex signaling pathways of leukemia stem cells (LSCs) will provide insights and druggable targets that can be used to eradicate acute myeloid leukemia (AML). Current work on AML LSCs is limited by the number of parameters that conventional flow cytometry (FCM) can analyze because of cell autofluorescence and fluorescent dye spectral overlap. Single-cell mass cytometry (CyTOF) substitutes rare earth elements for fluorophores to label antibodies, which allows measurements of up to 120 parameters in single cells without correction for spectral overlap. The aim of this study was the evaluation of intracellular signaling in antigen-defined stem/progenitor cell subsets in primary AML. CyTOF and conventional FCM yielded comparable results on LSC phenotypes defined by CD45, CD34, CD38, CD123, and CD99. Intracellular phosphoprotein responses to ex vivo cell signaling inhibitors and cytokine stimulation were assessed in myeloid leukemia cell lines and one primary AML sample. CyTOF and conventional FCM results were confirmed by western blotting. In the primary AML sample, we investigated the cell responses to ex vivo stimulation with stem cell factor (SCF) and BEZ235-induced inhibition of PI3K and identified activation patterns in multiple PI3K downstream signaling pathways including p-4EBP1, p-AKT, and p-S6, particularly in CD34+ subsets. We evaluated multiple signaling pathways in antigen-defined subpopulations in primary AML cells with FLT3-ITD mutations. The data demontrated the heterogeneity of cell phenotype distribution and distinct patterns of signaling activation across AML samples and between AML and normal samples. The mTOR targets p-4EBP1 and p-S6 were exclusively found in FLT3-ITD stem/progenitor cells, but not in their normal counterparts, suggesting both as novel targets in FLT3 mutated AML. Our data suggest that CyTOF can identify functional signaling pathways in antigen-defined subpopulations in primary AML, which

  9. Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation.

    PubMed

    Schmid, Christoph; Labopin, Myriam; Socié, Gerard; Daguindau, Etienne; Volin, Liisa; Huynh, Anne; Bourhis, Jean Henri; Milpied, Noel; Cornelissen, Jan; Chevallier, Patrice; Maertens, Johan; Jindra, Pavel; Blaise, Didier; Lenhoff, Stig; Ifrah, Norbert; Baron, Frédéric; Ciceri, Fabio; Gorin, Claude; Savani, Bipin; Giebel, Sebastian; Polge, Emmanuelle; Esteve, Jordi; Nagler, Arnon; Mohty, Mohamad

    2015-10-22

    To analyze the influence of distinct combinations of molecular aberrations on outcome after allogeneic hematopoietic stem cell transplantation (HSCT) for cytogenetically normal acute myeloid leukemia (CN-AML), a retrospective registry analysis was performed on 702 adults undergoing HSCT in first complete remission (CR). Patients were grouped according to presence or absence of NPM1 mutations (NPM1(mut)) and FLT3 internal tandem duplications (FLT3-ITD). Double-negative patients were evaluated for mutations of the CCAAT/enhancer binding protein α gene (CEBPα). The influence of genotypes on relapse, non-relapse mortality, leukemia-free survival (LFS) and overall survival (OS), and a prognostic classification combining NPM1/FLT3-ITD profile and classical risk factors were calculated. Two-year OS from HSCT was 81 ± 5% in NPM1(mut)/FLT3(wt), 75 ± 3% in NPM1(wt)/FLT3(wt), 66 ± 3% in NPM1(mut)/FLT3-ITD, and 54 ± 7% in NPM1(wt)/FLT3-ITD (P = .003). Analysis of CEBPα among patients with NPM1(wt)/FLT3(wt) revealed excellent results both in patients with CEBPα(mut) and with a triple negative genotype (2-year OS: 100%/77 ± 3%). In a Cox-model of predefined variables, age, FLT3-ITD and >1 course of chemotherapy to reach CR were risk factors associated with inferior outcome, regardless of NPM1 mutational status, variations of transplant protocols, or development of graft-versus-host disease. In a prognostic risk classification, 2-year OS/LFS rates were 88 ± 3%/79 ± 4% without any, 77 ± 2%/73 ± 3% with one, and 53 ± 4%/50 ± 4 with ≥2 risk factors (P = .003/.002). PMID:26351297

  10. Parthenolide Induces Apoptosis in Committed Progenitor AML Cell line U937 via Reduction in Osteopontin

    PubMed Central

    Zahedpanah, Mahdi; Shaiegan, Mojgan; Ghaffari, Seyed Hamidollah; Nikbakht, Mohsen; Nikugoftar, Mahin; Mohammadi, Saeed

    2016-01-01

    Background: Interfering with cell proliferation and survival is a critical role for antineoplastic drugs leading to cell death through induction of apoptosis. Alternative treatments with herbal extracts offer insights into acute myeloid leukemia (AML) therapy. Parthenolide (PTL), an extract from feverfew, induces apoptosis in primary human leukemia stem cells (LSCs) and bulk leukemic cell populations. Osteopontin (OPN) preserves cell viability in response to anticancer agents and its receptors could be utilized for therapeutic targeting of cancer cells. Methods: U937 cells were cultured in RPMI 1640 with concentrations of 2, 4, 6, 8, and 10 µM PTL for 20-24 hours for MTT assays. Apoptosis assays were performed with Annexin V-Alexa Fluor-488/PI as Annexin V+/PI- and Annexin V+/PI+ to measure early and late apoptosis, respectively. Quantitative real-time PCR was used to measure OPN gene expression using the 2-ΔΔCt method. The PTL–treated cells were stained with FITC-CD38 antibody for flow cytometry analyses. Data were compared using one-way analysis of variance (ANOVA) by SPSS 19. Results: Parthenolide inhibited growth of U937 cells with IC25 and IC50 values of 4 and 5.8 µM, respectively. Death induction with PTL was apoptotic. Flow cytometry showed a significant decrease in the percentage of CD38+ U937 cells in response to PTL. Osteopontin gene expression decreased in response to PTL. Conclusion: PTL induced apoptosis and reduced OPN gene expression in U937 cells.

  11. Loss of RUNX1/AML1 arginine-methylation impairs peripheral T cell homeostasis.

    PubMed

    Mizutani, Shinsuke; Yoshida, Tatsushi; Zhao, Xinyang; Nimer, Stephen D; Taniwaki, Masafumi; Okuda, Tsukasa

    2015-09-01

    RUNX1 (previously termed AML1) is a frequent target of human leukaemia-associated gene aberrations, and it encodes the DNA-binding subunit of the Core-Binding Factor transcription factor complex. RUNX1 expression is essential for the initiation of definitive haematopoiesis, for steady-state thrombopoiesis, and for normal lymphocytes development. Recent studies revealed that protein arginine methyltransferase 1 (PRMT1), which accounts for the majority of the type I PRMT activity in cells, methylates two arginine residues in RUNX1 (R206 and R210), and these modifications inhibit corepressor-binding to RUNX1 thereby enhancing its transcriptional activity. In order to elucidate the biological significance of these methylations, we established novel knock-in mouse lines with non-methylable, double arginine-to-lysine (RTAMR-to-KTAMK) mutations in RUNX1. Homozygous Runx1(KTAMK) (/) (KTAMK) mice are born alive and appear normal during adulthood. However, Runx1(KTAMK) (/) (KTAMK) mice showed a reduction in CD3(+) T lymphoid cells and a decrease in CD4(+) T cells in peripheral lymphoid organs, in comparison to their wild-type littermates, leading to a reduction in the CD4(+) to CD8(+) T-cell ratio. These findings suggest that arginine-methylation of RUNX1 in the RTAMR-motif is dispensable for the development of definitive haematopoiesis and for steady-state platelet production, however this modification affects the role of RUNX1 in the maintenance of the peripheral CD4(+) T-cell population. PMID:26010396

  12. Loss of RUNX1/AML1 arginine-methylation impairs in peripheral T cell homeostasis

    PubMed Central

    Mizutani, Shinsuke; Yoshida, Tatsushi; Zhao, Xinyang; Nimer, Stephen D.; Taniwaki, Masafumi; Okuda, Tsukasa

    2016-01-01

    Summary RUNX1 (previously termed AML1) is a frequent target of human leukaemia-associated gene aberrations, and it encodes the DNA-binding subunit of the Core-Binding Factor transcription factor complex. RUNX1 expression is essential for the initiation of definitive haematopoiesis, for steady-state thrombopoiesis, and for normal lymphocytes development. Recent studies revealed that protein arginine methyltransferase 1 (PRMT1), which accounts for the majority of the type I PRMT activity in cells, methylates two arginine residues in RUNX1 (R206 and R210), and these modifications inhibit corepressor-binding to RUNX1 thereby enhancing its transcriptional activity. In order to elucidate the biological significance of these methylations, we established novel knock-in mouse lines with non-methylable, double arginine-to-lysine (RTAMR-to-KTAMK) mutations in RUNX1. Homozygous Runx1KTAMK/KTAMK mice are born alive and appear normal during adulthood. However, Runx1KTAMK/KTAMK mice showed a reduction in CD3+ T lymphoid cells and a decrease in CD4+ T cells in peripheral lymphoid organs, in comparison to their wild-type littermates, leading to a reduction in the CD4+ to CD8+ T-cell ratio. These findings suggest that arginine-methylation of RUNX1 in the RTAMR-motif is dispensable for the development of definitive haematopoiesis and for steady-state platelet production, however this modification affects the role of RUNX1 in the maintenance of the peripheral CD4+ T-cell population. PMID:26010396

  13. Impact of loss of BH3-only proteins on the development and treatment of MLL-fusion gene-driven AML in mice.

    PubMed

    Bilardi, Rebecca A; Anstee, Natasha S; Glaser, Stefan P; Robati, Mikara; Vandenberg, Cassandra J; Cory, Suzanne

    2016-01-01

    Inhibition of the apoptosis pathway controlled by opposing members of the Bcl-2 protein family plays a central role in cancer development and resistance to therapy. To investigate how pro-apoptotic Bcl-2 homology domain 3 (BH3)-only proteins impact on acute myeloid leukemia (AML), we generated mixed lineage leukemia (MLL)-AF9 and MLL-ENL AMLs from BH3-only gene knockout mice. Disease development was not accelerated by loss of Bim, Puma, Noxa, Bmf, or combinations thereof; hence these BH3-only proteins are apparently ineffectual as tumor suppressors in this model. We tested the sensitivity of MLL-AF9 AMLs of each genotype in vitro to standard chemotherapeutic drugs and to the proteasome inhibitor bortezomib, with or without the BH3 mimetic ABT-737. Loss of Puma and/or Noxa increased resistance to cytarabine, daunorubicin and etoposide, while loss of Bim protected against cytarabine and loss of Bmf had no impact. ABT-737 increased sensitivity to the genotoxic drugs but was not dependent on any BH3-only protein tested. The AML lines were very sensitive to bortezomib and loss of Noxa conveyed significant resistance. In vivo, several MLL-AF9 AMLs responded well to daunorubicin and this response was highly dependent on Puma and Noxa but not Bim. Combination therapy with ABT-737 provided little added benefit at the daunorubicin dose trialed. Bortezomib also extended survival of AML-bearing mice, albeit less than daunorubicin. In summary, our genetic studies reveal the importance of Puma and Noxa for the action of genotoxics currently used to treat MLL-driven AML and suggest that, while addition of ABT-737-like BH3 mimetics might enhance their efficacy, new Noxa-like BH3 mimetics targeting Mcl-1 might have greater potential. PMID:27584789

  14. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients

    PubMed Central

    Russell, Nigel H.; Hills, Robert K.; Kell, Jonathan; Cavenagh, Jamie; Kjeldsen, Lars; McMullin, Mary-Frances; Cahalin, Paul; Dennis, Mike; Friis, Lone; Thomas, Ian F.; Milligan, Don; Clark, Richard E.

    2015-01-01

    Modifying induction therapy in acute myeloid leukemia (AML) may improve the remission rate and reduce the risk of relapse, thereby improving survival. Escalation of the daunorubicin dose to 90 mg/m2 has shown benefit for some patient subgroups when compared with a dose of 45 mg/m2, and has been recommended as a standard of care. However, 60 mg/m2 is widely used and has never been directly compared with 90 mg/m2. As part of the UK National Cancer Research Institute (NCRI) AML17 trial, 1206 adults with untreated AML or high-risk myelodysplastic syndrome, mostly younger than 60 years of age, were randomized to a first-induction course of chemotherapy, which delivered either 90 mg/m2 or 60 mg/m2 on days 1, 3, and 5 combined with cytosine arabinoside. All patients then received a second course that included daunorubicin 50 mg/m2 on days 1, 3, and 5. There was no overall difference in complete remission rate (73% vs 75%; odds ratio, 1.07 [0.83-1.39]; P = .6) or in any recognized subgroup. The 60-day mortality was increased in the 90 mg/m2 arm (10% vs 5% (hazard ratio [HR] 1.98 [1.30-3.02]; P = .001), which resulted in no difference in overall 2-year survival (59% vs 60%; HR, 1.16 [0.95-1.43]; P = .15). In an exploratory subgroup analysis, there was no subgroup that showed significant benefit, although there was a significant interaction by FLT3 ITD mutation. This trial is registered at http://www.isrctn.com as #ISRCTN55675535. PMID:25833957

  15. Education Outreach at MIT Plasma Science and Fusion Center

    NASA Astrophysics Data System (ADS)

    Censabella, V.; Rivenberg, P.

    1999-11-01

    Outreach at the MIT PSFC consists of volunteers working together to increase the public's knowledge of fusion and plasma-related experiments. Seeking to generate excitement about science, engineering and mathematics, the PSFC holds a number of outreach activities throughout the year, such as Middle and High School Outreach Days. Outreach also includes the Mr. Magnet Program, which uses an interactive strategy to engage elementary school children. The PSFC maintains a Home Page on the World Widee Web, which can be reached at http://psfc.mit.edu.

  16. The US DOE/MIT Innovation Acceleration Competition

    SciTech Connect

    None, None

    2009-06-30

    The Competition asked student teams from several US Universities to propose business models, technological systems, and policy framework to accelerate the penetration of new vehicle and fuel technologies into the markets. In May 2009 the final selection of teams was announced and four of five finalist teams flew to Washington DC to present to the US Department of Energy. The five finalist teams were 1. Filter Sensing Technologies (FST) (MIT), 2. Flex Cathode Technology for Electric Vehicle Batteries, 3. Green Guidance (RPI), 4. Levant Power (MIT), and 5. Wind-Driven Paddlewheel Cylinder for Energy Storage in Freighter Trucks (Villanova). The five finalists entries are described.

  17. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts.

    PubMed

    Dombret, Hervé; Seymour, John F; Butrym, Aleksandra; Wierzbowska, Agnieszka; Selleslag, Dominik; Jang, Jun Ho; Kumar, Rajat; Cavenagh, James; Schuh, Andre C; Candoni, Anna; Récher, Christian; Sandhu, Irwindeep; Bernal del Castillo, Teresa; Al-Ali, Haifa Kathrin; Martinelli, Giovanni; Falantes, Jose; Noppeney, Richard; Stone, Richard M; Minden, Mark D; McIntyre, Heidi; Songer, Steve; Lucy, Lela M; Beach, C L; Döhner, Hartmut

    2015-07-16

    This multicenter, randomized, open-label, phase 3 trial evaluated azacitidine efficacy and safety vs conventional care regimens (CCRs) in 488 patients age ≥65 years with newly diagnosed acute myeloid leukemia (AML) with >30% bone marrow blasts. Before randomization, a CCR (standard induction chemotherapy, low-dose ara-c, or supportive care only) was preselected for each patient. Patients then were assigned 1:1 to azacitidine (n = 241) or CCR (n = 247). Patients assigned to CCR received their preselected treatment. Median overall survival (OS) was increased with azacitidine vs CCR: 10.4 months (95% confidence interval [CI], 8.0-12.7 months) vs 6.5 months (95% CI, 5.0-8.6 months), respectively (hazard ratio [HR] was 0.85; 95% CI, 0.69-1.03; stratified log-rank P = .1009). One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively (difference, 12.3%; 95% CI, 3.5%-21.0%). A prespecified analysis censoring patients who received AML treatment after discontinuing study drug showed median OS with azacitidine vs CCR was 12.1 months (95% CI, 9.2-14.2 months) vs 6.9 months (95% CI, 5.1-9.6 months; HR, 0.76; 95% CI, 0.60-0.96; stratified log-rank P = .0190). Univariate analysis showed favorable trends for azacitidine compared with CCR across all subgroups defined by baseline demographic and disease features. Adverse events were consistent with the well-established safety profile of azacitidine. Azacitidine may be an important treatment option for this difficult-to-treat AML population. This trial was registered at www.clinicaltrials.gov as #NCT01074047. PMID:25987659

  18. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts

    PubMed Central

    Seymour, John F.; Butrym, Aleksandra; Wierzbowska, Agnieszka; Selleslag, Dominik; Jang, Jun Ho; Kumar, Rajat; Cavenagh, James; Schuh, Andre C.; Candoni, Anna; Récher, Christian; Sandhu, Irwindeep; Bernal del Castillo, Teresa; Al-Ali, Haifa Kathrin; Martinelli, Giovanni; Falantes, Jose; Noppeney, Richard; Stone, Richard M.; Minden, Mark D.; McIntyre, Heidi; Songer, Steve; Lucy, Lela M.; Beach, C. L.; Döhner, Hartmut

    2015-01-01

    This multicenter, randomized, open-label, phase 3 trial evaluated azacitidine efficacy and safety vs conventional care regimens (CCRs) in 488 patients age ≥65 years with newly diagnosed acute myeloid leukemia (AML) with >30% bone marrow blasts. Before randomization, a CCR (standard induction chemotherapy, low-dose ara-c, or supportive care only) was preselected for each patient. Patients then were assigned 1:1 to azacitidine (n = 241) or CCR (n = 247). Patients assigned to CCR received their preselected treatment. Median overall survival (OS) was increased with azacitidine vs CCR: 10.4 months (95% confidence interval [CI], 8.0-12.7 months) vs 6.5 months (95% CI, 5.0-8.6 months), respectively (hazard ratio [HR] was 0.85; 95% CI, 0.69-1.03; stratified log-rank P = .1009). One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively (difference, 12.3%; 95% CI, 3.5%-21.0%). A prespecified analysis censoring patients who received AML treatment after discontinuing study drug showed median OS with azacitidine vs CCR was 12.1 months (95% CI, 9.2-14.2 months) vs 6.9 months (95% CI, 5.1-9.6 months; HR, 0.76; 95% CI, 0.60-0.96; stratified log-rank P = .0190). Univariate analysis showed favorable trends for azacitidine compared with CCR across all subgroups defined by baseline demographic and disease features. Adverse events were consistent with the well-established safety profile of azacitidine. Azacitidine may be an important treatment option for this difficult-to-treat AML population. This trial was registered at www.clinicaltrials.gov as #NCT01074047. PMID:25987659

  19. Exosomes Secreted by Apoptosis-Resistant Acute Myeloid Leukemia (AML) Blasts Harbor Regulatory Network Proteins Potentially Involved in Antagonism of Apoptosis.

    PubMed

    Wojtuszkiewicz, Anna; Schuurhuis, Gerrit J; Kessler, Floortje L; Piersma, Sander R; Knol, Jaco C; Pham, Thang V; Jansen, Gerrit; Musters, René J P; van Meerloo, Johan; Assaraf, Yehuda G; Kaspers, Gertjan J L; Zweegman, Sonja; Cloos, Jacqueline; Jimenez, Connie R

    2016-04-01

    Expression of apoptosis-regulating proteins (B-cell CLL/lymphoma 2 - BCL-2, Myeloid Cell Leukemia 1 - MCL-1, BCL-2 like 1 - BCL-X and BCL-2-associated X protein - BAX) in acute myeloid leukemia (AML) blasts at diagnosis is associated with disease-free survival. We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. Herein, we further explored this aspect of dynamic apoptosis regulation in AML. First, we showed that the intraindividualex vivoapoptosis-related profiles of normal lymphocytes and AML blasts within the bone marrow of AML patients were highly correlated. The expression values of apoptosis-regulating proteins were far beyond healthy control lymphocytes, which implicates the influence of microenvironmental factors. Second, we demonstrated that apoptosis-resistant primary AML blasts, as opposed to apoptosis-sensitive cells, were able to up-regulate BCL-2 expression in sensitive AML blasts in contact cultures (p= 0.0067 andp= 1.0, respectively). Using secretome proteomics, we identified novel proteins possibly engaged in apoptosis regulation. Intriguingly, this analysis revealed that major functional protein clusters engaged in global gene regulation, including mRNA splicing, protein translation, and chromatin remodeling, were more abundant (p= 4.01E-06) in secretomes of apoptosis-resistant AML. These findings were confirmed by subsequent extracellular vesicle proteomics. Finally, confocal-microscopy-based colocalization studies show that splicing factors-containing vesicles secreted by high AAI cells are taken up by low AAI cells. The current results constitute the first comprehensive analysis of proteins released by apoptosis-resistant and sensitive primary AML cells. Together, the data point to vesicle-mediated release of global gene regulatory protein clusters as a plausible novel mechanism of induction of apoptosis resistance. Deciphering the modes of communication

  20. Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the Study Alliance Leukemia.

    PubMed

    Müller-Tidow, C; Tschanter, P; Röllig, C; Thiede, C; Koschmieder, A; Stelljes, M; Koschmieder, S; Dugas, M; Gerss, J; Butterfaß-Bahloul, T; Wagner, R; Eveslage, M; Thiem, U; Krause, S W; Kaiser, U; Kunzmann, V; Steffen, B; Noppeney, R; Herr, W; Baldus, C D; Schmitz, N; Götze, K; Reichle, A; Kaufmann, M; Neubauer, A; Schäfer-Eckart, K; Hänel, M; Peceny, R; Frickhofen, N; Kiehl, M; Giagounidis, A; Görner, M; Repp, R; Link, H; Kiani, A; Naumann, R; Brümmendorf, T H; Serve, H; Ehninger, G; Berdel, W E; Krug, U

    2016-03-01

    DNA methylation changes are a constant feature of acute myeloid leukemia. Hypomethylating drugs such as azacitidine are active in acute myeloid leukemia (AML) as monotherapy. Azacitidine monotherapy is not curative. The AML-AZA trial tested the hypothesis that DNA methyltransferase inhibitors such as azacitidine can improve chemotherapy outcome in AML. This randomized, controlled trial compared the efficacy of azacitidine applied before each cycle of intensive chemotherapy with chemotherapy alone in older patients with untreated AML. Event-free survival (EFS) was the primary end point. In total, 214 patients with a median age of 70 years were randomized to azacitidine/chemotherapy (arm-A) or chemotherapy (arm-B). More arm-A patients (39/105; 37%) than arm-B (25/109; 23%) showed adverse cytogenetics (P=0.057). Adverse events were more frequent in arm-A (15.44) versus 13.52 in arm-B, (P=0.26), but early death rates did not differ significantly (30-day mortality: 6% versus 5%, P=0.76). Median EFS was 6 months in both arms (P=0.96). Median overall survival was 15 months for patients in arm-A compared with 21 months in arm-B (P=0.35). Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients. PMID:26522083

  1. MIT Research Program on Communications Policy; First Annual Report.

    ERIC Educational Resources Information Center

    Massachusetts Inst. of Tech., Cambridge. Research Program on Communications Policy.

    The first year's activities of the Massachusetts Institute of Technology (MIT) Research Program on Communication Policy are described. Among the projects undertaken were studies of: (1) land mobile radio systems, (2) direct satellite broadcasting in foreign countries, (3) communications regulation policy, (4) international data communication, and…

  2. MIT Orients Course Materials Online to K-12

    ERIC Educational Resources Information Center

    Cavanagh, Sean

    2008-01-01

    Many science and mathematics educators across the country are taking advantage of a Web site created by the Massachusetts Institute of Technology (MIT), the famed research university located in Cambridge, Massachusetts, which offers free video, audio, and print lectures and course material taken straight from the school's classes. Those resources…

  3. MIT Mints a Valuable New Form of Academic Currency

    ERIC Educational Resources Information Center

    Carey, Kevin

    2012-01-01

    The Massachusetts Institute of Technology (MIT) has invented or improved many world-changing things--radar, information theory, and synthetic self-replicating molecules, to name a few. Last month the university announced, to mild fanfare, an invention that could be similarly transformative, this time for higher education itself. It is called MITx.…

  4. The Creation of OpenCourseWare at MIT

    ERIC Educational Resources Information Center

    Abelson, Hal

    2008-01-01

    This paper traces the genesis of the MIT OpenCourseWare project from its initial strategic precursors in 1999 and 2000, through its launch in 2001 and its subsequent evolution. The story told here illuminates the interplay among institutional leadership, and strategic planning, and with university culture in launching major educational technology…

  5. Increased C-kit intensity is a poor prognostic factor for progression-free and overall survival in patients with newly diagnosed AML.

    PubMed

    Advani, Anjali S; Rodriguez, Cristina; Jin, Tao; Jawde, Rony Abou; Saber, Wael; Baz, Rachid; Kalaycio, Matt; Sobecks, Ronald; Sekeres, Mikkael; Tripp, Barbara; Hsi, Eric

    2008-06-01

    C-kit, a tyrosine kinase receptor, is expressed on most myeloid blasts and is thought to be important in the pathogenesis of AML. Activation of the c-kit receptor leads to phosphorylation and activation of downstream signaling proteins, which are important for cell survival and proliferation. Here, we discuss the prognostic impact of c-kit intensity, measured using the mean fluorescent index (MFI) in patients with newly diagnosed AML. On multivariate analysis, c-kit MFI>20.3 correlated with a decreased progression-free survival and overall survival, independent of known prognostic factors (age, white blood count at diagnosis and cytogenetics). Whether inhibiting c-kit in patients with AML will alter prognosis is the basis of ongoing clinical trials. PMID:17928050

  6. MLL-AF9 Expression in Hematopoietic Stem Cells Drives a Highly Invasive AML Expressing EMT-Related Genes Linked to Poor Outcome.

    PubMed

    Stavropoulou, Vaia; Kaspar, Susanne; Brault, Laurent; Sanders, Mathijs A; Juge, Sabine; Morettini, Stefano; Tzankov, Alexandar; Iacovino, Michelina; Lau, I-Jun; Milne, Thomas A; Royo, Hélène; Kyba, Michael; Valk, Peter J M; Peters, Antoine H F M; Schwaller, Juerg

    2016-07-11

    To address the impact of cellular origin on acute myeloid leukemia (AML), we generated an inducible transgenic mouse model for MLL-AF9-driven leukemia. MLL-AF9 expression in long-term hematopoietic stem cells (LT-HSC) in vitro resulted in dispersed clonogenic growth and expression of genes involved in migration and invasion. In vivo, 20% LT-HSC-derived AML were particularly aggressive with extensive tissue infiltration, chemoresistance, and expressed genes related to epithelial-mesenchymal transition (EMT) in solid cancers. Knockdown of the EMT regulator ZEB1 significantly reduced leukemic blast invasion. By classifying mouse and human leukemias according to Evi1/EVI1 and Erg/ERG expression, reflecting aggressiveness and cell of origin, and performing comparative transcriptomics, we identified several EMT-related genes that were significantly associated with poor overall survival of AML patients. PMID:27344946

  7. Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies.

    PubMed

    Lewinsohn, Maya; Brown, Anna L; Weinel, Luke M; Phung, Connie; Rafidi, George; Lee, Ming K; Schreiber, Andreas W; Feng, Jinghua; Babic, Milena; Chong, Chan-Eng; Lee, Young; Yong, Agnes; Suthers, Graeme K; Poplawski, Nicola; Altree, Meryl; Phillips, Kerry; Jaensch, Louise; Fine, Miriam; D'Andrea, Richard J; Lewis, Ian D; Medeiros, Bruno C; Pollyea, Daniel A; King, Mary-Claire; Walsh, Tom; Keel, Siobán; Shimamura, Akiko; Godley, Lucy A; Hahn, Christopher N; Churpek, Jane E; Scott, Hamish S

    2016-02-25

    Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3%) with DDX41 mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novel mutations were identified, including missense mutations within important functional domains and start-loss and splicing mutations predicted to result in truncated proteins. We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41 mutations. With an increasing number of both inherited and acquired mutations in this gene being identified, further study of how DDX41 disruption leads to hematologic malignancies is critical. PMID:26712909

  8. Single-agent GVHD prophylaxis with posttransplantation cyclophosphamide after myeloablative, HLA-matched BMT for AML, ALL, and MDS

    PubMed Central

    Kanakry, Christopher G.; Tsai, Hua-Ling; Bolaños-Meade, Javier; Smith, B. Douglas; Gojo, Ivana; Kanakry, Jennifer A.; Kasamon, Yvette L.; Gladstone, Douglas E.; Matsui, William; Borrello, Ivan; Huff, Carol Ann; Swinnen, Lode J.; Powell, Jonathan D.; Pratz, Keith W.; DeZern, Amy E.; Showel, Margaret M.; McDevitt, Michael A.; Brodsky, Robert A.; Levis, Mark J.; Ambinder, Richard F.; Fuchs, Ephraim J.; Rosner, Gary L.; Jones, Richard J.

    2014-01-01

    High-dose, posttransplantation cyclophosphamide (PTCy) reduces severe graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT), but the impact of PTCy on long-term, disease-specific outcomes is unclear. We conducted a retrospective study of 209 consecutive adult patients transplanted for acute myeloid leukemia (AML, n = 138), myelodysplastic syndrome (n = 28), or acute lymphoblastic leukemia (ALL, n = 43) using PTCy as sole GVHD prophylaxis after myeloablative conditioning and HLA-matched–related or –unrelated T-cell–replete allografting. At alloBMT, 30% of patients were not in morphologic complete remission. The cumulative incidences of grades II to IV and III to IV acute GVHD at 100 days and chronic GVHD at 2 years were 45%, 11%, and 13%, respectively. Forty-three percent of patients did not require immunosuppression for any reason beyond PTCy. At 3 years, relapse cumulative incidence was 36%, disease-free survival was 46%, survival free of disease and chronic GVHD was 39%, and overall survival was 58%. Lack of remission at alloBMT, adverse cytogenetics, and low allograft nucleated cell dose were associated with inferior survival for AML patients. Minimal residual disease but not t(9;22) was associated with inferior outcomes for ALL patients. The ability to limit posttransplantation immunosuppression makes PTCy a promising transplantation platform for the integration of postgrafting strategies to prevent relapse. PMID:25316679

  9. Exposure to armament wastes and leukemia: a case-control study within a cluster of AML and CML in Germany.

    PubMed

    Kilian, P H; Skrzypek, S; Becker, N; Havemann, K

    2001-10-01

    An unusually high incidence of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) concentrated in a specific locality of a region in Germany motivated a descriptive incidence study in that region which showed a near 10-fold increased risk of CML among males but not among females (Kolb G, Becker N, Scheller S, Zugmaier G, Pralle H, Wahrendorf J, Havemann K. Increased risk of acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) in a County of Hesse, Germany, Soc Prev Med 1993;38:190-195). Since a serious environmental contamination of areas in this locality with armament wastes containing toluene-derivatives has been known for a long time, the hypothesis arose that TNT production and the related severe contamination of soil and water might be responsible for the observed higher risk. We carried out a case-control study within the cluster to test this hypothesis. Overall, the results do not confirm the hypothesis. There is an indication of a relationship of an increased odds ratio with the exposure for a small group of persons who lived at a particular site in one of the two communities involved during the peak phase of TNT production during the 1940s. However, this finding is spurious and cannot explain the large majority of cases which occurred in that area in the 1980s. At the moment, no other explanation can be given for the increased risk of leukemias in that area. PMID:11532515

  10. Immune responses to WT1 in patients with AML or MDS after chemotherapy and allogeneic stem cell transplantation.

    PubMed

    Casalegno-Garduño, Rosaely; Schmitt, Anita; Spitschak, Alf; Greiner, Jochen; Wang, Lei; Hilgendorf, Inken; Hirt, Carsten; Ho, Anthony D; Freund, Mathias; Schmitt, Michael

    2016-04-01

    Wilms' tumor gene 1 (WT1) is overexpressed in leukemia and WT1-derived CD8(+) T-cell epitopes for immunotherapies targeting WT1 have been defined. Here, we analyzed expression of WT1 in 226 peripheral blood and bone marrow samples from patients with acute myeloid leukemia or myelodysplastic syndrome (AML/MDS) before and after allogeneic stem cell transplantation (SCT). Transcripts were assessed by quantitative polymerase chain reaction, and WT1-specific CD8+ cytotoxic T cells (CTL) were monitored by tetramer staining and enzyme-linked immunospot (ELISPOT) assays. Reduction of WT1 levels correlated with a longer survival (p < 0.01). Increment of WT1 transcripts eventually resulted in relapse and subsequent death of the patients. In patients with longer survival and continuous complete remission (cCR) after SCT, higher and enduring frequencies of WT1-specific CTL than in patients developing a relapse were detected. These cells were effector T cells secreting interferon gamma and granzyme B. In summary, WT1 is a suitable marker for the detection of minimal residual disease after SCT or chemotherapy. A rising WT1 signal correlated with a dismal prognosis of the patients. WT1-specific CD8(+) T cells might contribute to the maintenance of a cCR. Targeting WT-1 by peptide/protein vaccination as well as adoptive transfer of genetically modified T cells are future options in the individualized therapy for AML/MDS patients. PMID:26519872

  11. Recovery of ovarian function and pregnancy in a patient with AML after myeloablative busulphan-based conditioning regimen.

    PubMed

    Balashov, Dmitry N; Papusha, Ludmila I; Nazarenko, Tatiana A; Trakhtman, Pavel E; Revishvili, Nino A; Maschan, Alexei A; Persiantseva, Marina I; Andriutsa, Anna V; Skorobogatova, Elena V; Skvortsova, Yulia V; Rumiantsev, Alexander G

    2011-05-01

    We report a rare case of ovarian function recovery and pregnancy after hormone-replacement therapy (HRT) in the acute myeloblastic leukemia (AML) patient in third complete remission received hematopoietic stem cell transplantation (HSCT) with busulphan-based conditioning regimen. Successful engraftment of the donor cells and full donor's chimerism was achieved without the signs of leukemia. One year after HSCT the patient received a course of HRT as a treatment of hypergonadotropic hypogonadism. After 12 months of HRT the recovery of ovarian function was confirmed. Eight years after the HSCT spontaneous pregnancy occurred; heartbeat of the fetus was registered on week 7. Three weeks later a nonsevere vaginal bleeding occurred and the ultrasound examination showed a nondeveloping pregnancy. Genetic examination of the abortion material showed a full triploid genotype (69 XXX). To our knowledge this is a first case of ovarian function restoration and spontaneous pregnancy in a AML patient after multiple courses of high-dose chemotherapy and busulphan-based myeloablative conditioning for HSCT. PMID:21423042

  12. Transcription-Coupled Translation Control of AML1/RUNX1 Is Mediated by Cap- and Internal Ribosome Entry Site-Dependent Mechanisms

    PubMed Central

    Pozner, Amir; Goldenberg, Dalia; Negreanu, Varda; Le, Shu-Yun; Elroy-Stein, Orna; Levanon, Ditsa; Groner, Yoram

    2000-01-01

    AML1/RUNX1 belongs to the runt domain transcription factors that are important regulators of hematopoiesis and osteogenesis. Expression of AML1 is regulated at the level of transcription by two promoters, distal (D) and proximal (P), that give rise to mRNAs bearing two distinct 5′ untranslated regions (5′UTRs) (D-UTR and P-UTR). Here we show that these 5′UTRs act as translation regulators in vivo. AML1 mRNAs bearing the uncommonly long (1,631-bp) P-UTR are poorly translated, whereas those with the shorter (452-bp) D-UTR are readily translated. The low translational efficiency of the P-UTR is attributed to its length and the cis-acting elements along it. Transfections and in vitro assays with bicistronic constructs demonstrate that the D-UTR mediates cap-dependent translation whereas the P-UTR mediates cap-independent translation and contains a functional internal ribosome entry site (IRES). The IRES-containing bicistronic constructs are more active in hematopoietic cell lines that normally express the P-UTR-containing mRNAs. Furthermore, we show that the IRES-dependent translation increases during megakaryocytic differentiation but not during erythroid differentiation, of K562 cells. These results strongly suggest that the function of the P-UTR IRES-dependent translation in vivo is to tightly regulate the translation of AML1 mRNAs. The data show that AML1 expression is regulated through usage of alternative promoters coupled with IRES-mediated translation control. This IRES-mediated translation regulation adds an important new dimension to the fine-tuned control of AML1 expression. PMID:10713153

  13. [Clinical efficacy of decitabine combined with modified CAG regimen for relapsed-refractory acute myeloid leukemia with AML1-ETO⁺].

    PubMed

    Jing, Yu; Zhu, Cheng-Ying; Zhang, Qi; Niu, Jian-Hua; Yang, Hua; Liu, Shi-Yan; Zhu, Hai-Yan; Yu, Li

    2014-10-01

    This study was aimed to investigate the clinical characteristics of relapsed-refractory acute myeloid leukemia (AML) with AML1-ETO⁺, and its therapeutic efficacy and side effects when decitabine combined with modified CAG regimen was used. Clinical data of 5 cases of AML with AML1-ETO⁺ from January 2013 to Agust 2013 were analyzed retrospectively. The analyzed data included age, sex, initial symptoms, peripheral blood and bone marrow characteristics. Meanwhile, the therapeutic effecacy and side effects of decitabine combined with modified CAG regimen were evaluated. The 5 patients were with median age of 35 (17-43) years. Among these 5 patients, 2 patients were relapsed and other 3 patients were relapsed-refractory patients, their median white blood cell count was 12.55 (7.8-66.55) × 10⁹/L, median platelets count was 44 (20-72) × 10⁹/L, median hemoglobin level was 110 (77-128) g/L, median lactate dehydrogenase level was 312.9 U/L (123.6-877.8) at the initial diagnosis. The results showed that after decitabine combined with modified CAG regimen was administered, 4 patients achieved complete remission, 1 patient did not achieve remission, the overall remission rate was 80% (4/5). The main side effects of this regimen was myelosuppression, these were no new lung infection and other serious complications, one case without complete remission treated with FLAG once again died of heart failure when being mobilized for transplantation. It is concluded that according to preliminary results of decitabine combined with modified CAG regimen for relapsed and refractory AML patients with AML1-ETO⁺ displays higher remission rate and lower side effects, which worthy to further explore for clinal application. PMID:25338566

  14. Isolation and characterization of My23, a myeloid cell-derived antigen reactive with the monoclonal antibody AML-2-23.

    PubMed

    Maliszewski, C R; Ball, E D; Graziano, R F; Fanger, M W

    1985-09-01

    In this study, we describe the isolation and characterization of My23, a human myeloid antigen defined by the monoclonal antibody (MoAb) AML-2-23. Cells of the HL-60 human promyelocytic cell line, when cultured in the presence of 1,25-dihydroxyvitamin D3 (calcitriol), express a surface protein of approximately 50 to 55 kilodaltons (Kd) which was immunoprecipitated with the AML-2-23 MoAb. Furthermore, after 2 days of exposure to calcitriol, HL-60 cells began to release My23 into culture medium, as determined by the ability of culture supernatant from these cells to block the binding of AML-2-23 to myeloid cells. My23 release was almost totally inhibited by incubation of cells at 4 degrees C, and was partially blocked by treatment of cells with cycloheximide or tunicamycin. The culture supernatant blocking factor, soluble My23, was identified as a 45 to 50 Kd protein by Western blot/immune overlay, using AML-2-23 and an 125I-labeled second antibody. My23, which was affinity-purified from culture supernatant, retained the ability to block AML-2-23 binding to myeloid cells. The affinity-purified antigen migrated on SDS-PAGE as a diffuse band in the m.w. range of 44 to 52 Kd. On treatment with endoglycosidase, the apparent m.w. of My23 decreased to approximately 40,000, indicating the presence of carbohydrate residues on My23. Serum from mice immunized with the purified antigen reacted with the same spectrum of myeloid cells as AML-2-23 MoAb, reacted with the My23 soluble protein in immunoblots, and competed with AML-2-23 for binding to myeloid cells. Binding of this antiserum to myeloid cells was blocked by cell supernatant from both monocytes and calcitriol-treated HL-60 cells, suggesting, along with results from m.w. determinations of the two preparations, that the soluble and cell surface forms of My23 are similar. Moreover, based on our finding that human plasma specifically inhibits the binding of AML-2-23 to myeloid cells, My23 may also be released in vivo. The

  15. Funktionelle Elektrostimulation Paraplegischer Patienten

    PubMed Central

    2014-01-01

    Functional Electrical Stimulation on Paraplegic Patients. We report on clinical and physiological effects of 8 months Functional Electrical Stimulation (FES) of quadriceps femoris muscle on 16 paraplegic patients. Each patient had muscle biopsies, CT-muscle diameter measurements, knee extension strength testing carried out before and after 8 months FES training. Skin perfusion was documented through infrared telethermography and xenon clearance, muscle perfusion was recorded through thallium scintigraphy. After 8 months FES training baseline skin perfusion showed 86 % increase, muscle perfusion was augmented by 87 %. Muscle fiber diameters showed an average increase of 59 % after 8 months FES training. Muscles in patients with spastic paresis as well as in patients with denervation showed an increase in aerob and anaerob muscle enzymes up to the normal range. Even without axonal neurotropic substances FES was able to demonstrate fiberhypertrophy, enzyme adaptation and intracellular structural benefits in denervated muscles. The increment in muscle area as visible on CT-scans of quadriceps femoris was 30 % in spastic paraplegia and 10 % in denervated patients respectively. FES induced changes were less in areas not directly underneath the surface electrodes. We strongly recommend the use of Kern’s current for FES in denervated muscles to induce tetanic muscle contractions as we formed a very critical opinion of conventional exponential current. In patients with conus-cauda-lesions FES must be integrated into modern rehabilitation to prevent extreme muscle degeneration and decubital ulcers. Using FES we are able to improve metabolism and induce positive trophic changes in our patients lower extremities. In spastic paraplegics the functions „rising and walking“ achieved through FES are much better training than FES ergometers. Larger muscle masses are activated and an increased heart rate is measured, therefore the impact on cardiovascular fitness and metabolism is much greater. This effectively addresses and prevents all problems which result from inactivity in paraplegic patients. PMID:26913132

  16. Chromatin organization as a possible factor in the control of susceptibility to radiation-induced AML in mice

    NASA Astrophysics Data System (ADS)

    Maranon, David G.

    The studies described in this dissertation involve the use and comparison of two mouse strains: one sensitive (CBA/CaJ) and another resistant (C57BL/6J) to radiation-induced acute myeloid leukemia (AML). The purpose of these studies was to identify factors that may account for the large difference in the susceptibility of these strains to radiation-induced AML. The present study was initiated to determine whether the distances between breakpoint clusters on chromosome 2 are in closer proximity in the bone marrow cells of the CBA/CaJ mouse strain than in the C57BL/6J strain. Bacterial artificial chromosomes (BACs) were selected as markers of the central portion of the proximal and distal deletion breakpoint clusters as well as mdr on chromosome 2, where the preponderance of breaks occurs. Distance measurements were made by three dimensional fluorescent in situ hybridization (3DFISH) image analysis of hundreds of cells using Metamorph and ImageJ for data collection and Autoquant software for deconvolution and reconstruction of the three dimensional cell nuclei. Comparing bone marrow cells of CBA/CaJ and C57BL/6J mice, no differences were found between the proximity of the two regions represented for the selected markers compared in both murine strains. For the markers chosen the distribution of the distances showed similarities between the same cell types from both mouse strains; namely, fibroblasts, whole bone marrow (WBM), and hematopoietic stem cells (HSC). However, there was not found a change in the distance distributions toward the closer distances expected between the clusters in HSC and WBM compared with fibroblasts in both mouse strains. There was; however, a tissue-dependent distance distribution between the markers Specifically, the average distances of the clusters in fibroblasts (2.55 um for CBA/CaJ and 3.09 um for C57BL/6) were larger than the distance in blood cells (1.74 um in BM and 1.53 um in HSC for CBA/CaJ; and 1.79 um in BM and 1.77 um in HSC for

  17. Chromatin organization as a possible factor in the control of susceptibility to radiation-induced AML in mice

    NASA Astrophysics Data System (ADS)

    Maranon, David G.

    The studies described in this dissertation involve the use and comparison of two mouse strains: one sensitive (CBA/CaJ) and another resistant (C57BL/6J) to radiation-induced acute myeloid leukemia (AML). The purpose of these studies was to identify factors that may account for the large difference in the susceptibility of these strains to radiation-induced AML. The present study was initiated to determine whether the distances between breakpoint clusters on chromosome 2 are in closer proximity in the bone marrow cells of the CBA/CaJ mouse strain than in the C57BL/6J strain. Bacterial artificial chromosomes (BACs) were selected as markers of the central portion of the proximal and distal deletion breakpoint clusters as well as mdr on chromosome 2, where the preponderance of breaks occurs. Distance measurements were made by three dimensional fluorescent in situ hybridization (3DFISH) image analysis of hundreds of cells using Metamorph and ImageJ for data collection and Autoquant software for deconvolution and reconstruction of the three dimensional cell nuclei. Comparing bone marrow cells of CBA/CaJ and C57BL/6J mice, no differences were found between the proximity of the two regions represented for the selected markers compared in both murine strains. For the markers chosen the distribution of the distances showed similarities between the same cell types from both mouse strains; namely, fibroblasts, whole bone marrow (WBM), and hematopoietic stem cells (HSC). However, there was not found a change in the distance distributions toward the closer distances expected between the clusters in HSC and WBM compared with fibroblasts in both mouse strains. There was; however, a tissue-dependent distance distribution between the markers Specifically, the average distances of the clusters in fibroblasts (2.55 um for CBA/CaJ and 3.09 um for C57BL/6) were larger than the distance in blood cells (1.74 um in BM and 1.53 um in HSC for CBA/CaJ; and 1.79 um in BM and 1.77 um in HSC for

  18. The MIT / NASA Langley Magnetic Suspension/Balance System

    NASA Technical Reports Server (NTRS)

    1991-01-01

    A shuttle model is magnetically suspended in the transparent octagonal test section of the MIT / NASA Langley 6 Inch MSBS. Massive power supplies are required to drive electromagnets for model position control. A unique electromagnetic position sensor, similar to a linear variable differential transformer, provides five degrees of freedom for the test model. The low speed (Mach 0.5) wind tunnel was hand crafted from mahogany. Aerodynamic forces on the test model are measured by the proportional electrical current used to hold the model in place. The system was built by MIT in the late sixties and was relocated to Langley in the mid eighties. In a joint effort with Old Dominion University in 1992 the MSBS was used to test the aerodynamics of store separation, simulating a bomb released from an aircraft. The system has been donated to Old Dominion University.

  19. MIT LMFBR blanket research project. Final summary report

    SciTech Connect

    Driscoll, M.J.

    1983-08-01

    This is a final summary report on an experimental and analytical program for the investigation of LMFBR blanket characteristics carried out at MIT in the period 1969 to 1983. During this span of time, work was carried out on a wide range of subtasks, ranging from neutronic and photonic measurements in mockups of blankets using the Blanket Test Facility at the MIT Research Reactor, to analytic/numerical investigations of blanket design and economics. The main function of this report is to serve as a resource document which will permit ready reference to the more detailed topical reports and theses issued over the years on the various aspects of project activities. In addition, one aspect of work completed during the final year of the project, on doubly-heterogeneous blanket configurations, is documented for the record.

  20. The Harvard-MIT PHD Program in Bioastronautics

    NASA Astrophysics Data System (ADS)

    Young, Laurence R.; Natapoff, Alan

    2008-06-01

    The National Space Biomedical Research Institute (NSBRI)1 supports a PhD program in Space Life Sciences with a specialty in Bioastronautics at MIT. (A sibling program operates at TAMU.) It gives broad training in life sciences, emphasizes hands-on field experience, provides access to laboratories in the Harvard-MIT community for thesis research, and prepares students for many options in space biomedicine. The Program trains prospective leaders in the field able to manage the challenges of design for the life-hostile space environment. Beyond subject and thesis work, students participate in a summer internship and a clinical preceptorship at a NASA center--and an introduction to clinical medicine and medical engineering.

  1. Stationäre Motorvermessung mit verschiedenen Methoden und Modellen

    NASA Astrophysics Data System (ADS)

    Kötter, Hinrich; Sequenz, Heiko

    Die kontinuierliche Verschärfung der gesetzlichen Vorgaben bezüglich Emissionen stellt die Motorenentwickler vor neue Herausforderungen (Bild 6-1, [1, 2]). Gleichzeitig ist zu erwarten, dass sich der langfristige Trend der letzten Jahren bei den Kraftstoffpreisen [3] trotz kurzzeitiger Schwankungen fortsetzen wird (Bild 6-1 rechts, Jahresmittelwerte). Auf die steigenden Kraftstoffpreise sowie die Verpflichtungen bezüglich der CO2- Emissionswerte kann dauerhaft nur mit Kraftstoff sparenden Motoren reagiert werden.

  2. A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS.

    PubMed

    Keilholz, Ulrich; Letsch, Anne; Busse, Antonia; Asemissen, Anne Marie; Bauer, Sandra; Blau, Igor Wolfgang; Hofmann, Wolf-Karsten; Uharek, Lutz; Thiel, Eckhard; Scheibenbogen, Carmen

    2009-06-25

    This study investigated the immunogenicity of Wilms tumor gene product 1 (WT1)-peptide vaccination in WT1-expressing acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients without curative treatment option. Vaccination consisted of granulocyte-macrophage colony-stimulating factor subcutaneously days 1 to 4, and WT1.126-134 peptide and 1 mg keyhole limpet hemocyanin on day 3. The initial 9 patients received 4 vaccinations biweekly, then monthly, and the subsequent 10 patients received continual biweekly vaccination. Seventeen AML patients and 2 refractory anemia with excess blasts patients received a median of 11 vaccinations. Treatment was well tolerated. Objective responses in AML patients were 10 stable diseases (SDs) including 4 SDs with more than 50% blast reduction and 2 with hematologic improvement. An additional 4 patients had clinical benefit after initial progression, including 1 complete remission and 3 SDs. WT1 mRNA levels decreased at least 3-fold from baseline in 35% of patients. In 8 of 18 patients, WT1-tetramer(+) T cells increased in blood and in 8 of 17 patients in bone marrow, with a median frequency in bone marrow of 0.18% at baseline and 0.41% in week 18. This WT1 vaccination study provides immunologic, molecular, and preliminary evidence of potential clinical efficacy in AML patients, warranting further investigations. PMID:19389880

  3. Single cell genotyping of exome sequencing-identified mutations to characterize the clonal composition and evolution of inv(16) AML in a CBL mutated clonal hematopoiesis.

    PubMed

    Niemöller, Christoph; Renz, Nathalie; Bleul, Sabine; Blagitko-Dorfs, Nadja; Greil, Christine; Yoshida, Kenichi; Pfeifer, Dietmar; Follo, Marie; Duyster, Justus; Claus, Rainer; Ogawa, Seishi; Lübbert, Michael; Becker, Heiko

    2016-08-01

    We recently described the development of an inv(16) acute myeloid leukemia (AML) in a CBL mutated clonal hematopoiesis. Here, we further characterized the clonal composition and evolution of the AML based on the genetic information from the bulk specimen and analyses of individual bone marrow cells for mutations in CAND1, PTPRT, and DOCK6. To control for allele dropout, heterozygous polymorphisms located close to the respective mutation loci were assessed in parallel. The clonal composition concluded from exome sequencing suggested a proliferation advantage associated with the acquisition of mutations in CAND1, PTPRT, and DOCK6. Out of 102 single cell sequencing reactions on these mutations and the respective polymorphisms, analyses yielded conclusive results for at least 2 mutation sites in 12 cells. The single cell genotyping not only confirmed the co-occurrence of the PTPRT, CAND1 and DOCK6 mutations in the same AML clone but also revealed a clonal hierarchy, as the PTPRT mutation was likely acquired after the CAND1 and DOCK6 mutations. This insight had not been possible based solely on the exome sequencing data and suggests that the mutation in PTPRT, which encodes a STAT3-inhibiting protein tyrosine phosphatase, contributed to the AML development at a later stage by enhancing proliferation. PMID:27244256

  4. Generation of a cord blood-derived Wilms Tumor 1 dendritic cell vaccine for AML patients treated with allogeneic cord blood transplantation

    PubMed Central

    de Haar, Colin; Plantinga, Maud; Blokland, Nina JG; van Til, Niek P; Flinsenberg, Thijs WH; Van Tendeloo, Viggo F; Smits, Evelien L; Boon, Louis; Spel, Lotte; Boes, Marianne; Boelens, Jaap Jan; Nierkens, Stefan

    2015-01-01

    The poor survival rates of refractory/relapsed acute myeloid leukemia (AML) patients after haematopoietic cell transplantation (HCT) requires the development of additional immune therapeutic strategies. As the elicitation of tumor-antigen specific cytotoxic T lymphocytes (CTLs) is associated with reduced relapses and enhanced survival, enhanced priming of these CTLs using an anti-AML vaccine may result in long-term immunity against AML. Cord blood (CB), as allogeneic HCT source, may provide a unique setting for such post-HCT vaccination, considering its enhanced graft-versus-leukemia (GvL) effects and population of highly responsive naïve T cells. It is our goal to develop a powerful and safe immune therapeutic strategy composed of CB-HCT followed by vaccination with CB CD34+-derived dendritic cells (DCs) presenting the oncoprotein Wilms Tumor-1 (WT1), which is expressed in AML-blasts in the majority of patients. Here, we describe the optimization of a clinically applicable DC culture protocol. This two-step protocol consisting of an expansion phase followed by the differentiation toward DCs, enables us to generate sufficient cord blood-derived DCs (CBDCs) in the clinical setting. At the end of the culture, the CBDCs exhibit a mature surface phenotype, are able to migrate, express tumor antigen (WT1) after electroporation with mRNA encoding the full-length WT1 protein, and stimulate WT1-specific T cells. PMID:26451309

  5. Chidamide, a novel histone deacetylase inhibitor, inhibits the viability of MDS and AML cells by suppressing JAK2/STAT3 signaling

    PubMed Central

    Zhao, Sida; Guo, Juan; Zhao, Youshan; Fei, Chengming; Zheng, Qingqing; Li, Xiao; Chang, Chunkang

    2016-01-01

    Many studies have indicated that histone deacetylase (HDAC) activity is always increased in a lot of human tumors, and inhibition of HDAC activity is a promising new strategy in the treatment of cancers. Chidamide, a novel HDAC inhibitor of the benzamide class, is currently under clinical trials. In this study, we aimed to investigate the antitumor activity of Chidamide on myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) cell lines and explore the possible mechanism. Chidamide exhibited efficient anti-proliferative activity on MDS and AML cells in a time- and dose-dependent manner, accompanied by cell cycle arrest at G0/G1 phase and cell apoptosis. Importantly, Chidamide possessed potent HDAC inhibition property, as evaluated by HDAC activity analysis and acetylation of histone H3 and H4. Moreover, Chidamide significantly increased the expression of Suppressors of cytokine signaling 3 (SOCS3), reduced the expression of Janus activated kinases 2 (JAK2) and Signal transducer and activator of transcription 3 (STAT3), and inhibited STAT3 downstream genes, including c-Myc, Bcl-xL, and Mcl-1, which are involved in cell cycle progression and anti-apoptosis. Therefore, we demonstrate that Chidamide exhibits potent inhibitory effect on cell viability of MDS and AML cells, and the possible mechanism may lie in the downregulation of JAK2/STAT3 signaling through SOCS3 upregulation. Our data provide rationale for clinical investigations of Chidamide in MDS and AML. PMID:27508038

  6. Sorafenib in combination with low-dose-homoharringtonine as a salvage therapy in primary refractory FLT3-ITD-positive AML: a case report and review of literature

    PubMed Central

    Xu, Gaixiang; Mao, Liping; Liu, Hui; Yang, Min; Jin, Jie; Qian, Wenbin

    2015-01-01

    The presence of internal tandem duplications (ITD) in the Fms-related tyrosine kinase 3 receptor (FLT3) has been associated with a poor prognosis in acute myeloid leukemia (AML). Over the past decade, FLT3 is a promising target in FLT3-ITD-positive AML. Sorafenib which is one of the commonly focused FLT3 inhibitors may improve outcome, but only few patients display long-term responses in previously reported cases, prompting the search for underlying resistance mechanisms and therapeutic strategies to overcome them. To the best of our knowledge, this is the first case report about sorafenib in combination with low-dose-homoharringtonine as a salvage therapy successfully administrated and got complete remission (CR) in primary refractory FLT3-ITD-positive AML. Our result demonstrates the combination of this two drugs may be a good choice for the primary refractory FLT3-ITD-positive AML patient, although cooperative studies of large numbers of these patients are needed to evaluate and optimize this combination. PMID:26884901

  7. Selective AKR1C3 Inhibitors Potentiate Chemotherapeutic Activity in Multiple Acute Myeloid Leukemia (AML) Cell Lines.

    PubMed

    Verma, Kshitij; Zang, Tianzhu; Gupta, Nehal; Penning, Trevor M; Trippier, Paul C

    2016-08-11

    We report the design, synthesis, and evaluation of potent and selective inhibitors of aldo-keto reductase 1C3 (AKR1C3), an important enzyme in the regulatory pathway controlling proliferation, differentiation, and apoptosis in myeloid cells. Combination treatment with the nontoxic AKR1C3 inhibitors and etoposide or daunorubicin in acute myeloid leukemia cell lines, elicits a potent adjuvant effect, potentiating the cytotoxicity of etoposide by up to 6.25-fold and the cytotoxicity of daunorubicin by >10-fold. The results validate AKR1C3 inhibition as a common adjuvant target across multiple AML subtypes. These compounds in coadministration with chemotherapeutics in clinical use enhance therapeutic index and may avail chemotherapy as a treatment option to the pediatric and geriatric population currently unable to tolerate the side effects of cancer drug regimens. PMID:27563402

  8. Role of autologous hematopoietic stem cell transplantation according to the NPM1/FLT3-ITD molecular status for cytogenetically normal AML patients: a GOELAMS study.

    PubMed

    Guièze, Romain; Cornillet-Lefebvre, Pascale; Lioure, Bruno; Blanchet, Odile; Pigneux, Arnaud; Recher, Christian; Bonmati, Caroline; Fegueux, Nathalie; Bulabois, Claude-Eric; Bouscary, Didier; Vey, Norbert; Delain, Martine; Turlure, Pascal; Himberlin, Chantal; Harousseau, Jean-Luc; Dreyfus, Francois; Béné, Marie C; Ifrah, Norbert; Chevallier, Patrice

    2012-12-01

    The choice of postremission therapy for acute myeloid leukemia (AML) patients is now based on the blasts' cytogenetic and molecular profile. However, the potential benefit of autologous hematopoietic stem cell transplantation (auto-HSCT) according to the NPM1/FLT3-ITD status has been poorly studied in AML patients with a normal karyotype (NK). Therefore, we evaluated the NPM1/FLT3-ITD molecular status in 135 NK-AML patients treated by allogeneic HSCT (allo-HSCT), auto-HSCT, or chemotherapy as consolidation therapy within the GOELAMS LAM-2001 trial. In univariate analyzes, 4-year leukemia-free survival (LFS) and overall survival (OS) were significantly higher for NPM1+/FLT3-ITD- patients compared with patients presenting another molecular profile (61 vs. 43% and 72 vs. 48%, P = 0.02 and P = 0.01, respectively). In the NPM1+/FLT3-ITD- subgroup, there was no benefit for allo-HSCT or auto-HSCT vs. chemotherapy (4-year LFS: 71, 56, and 60%; 4-year OS: 73, 71, and 60%, respectively; P = NS). For patients with other NPM1/FLT3-ITD molecular profiles, allo-HSCT was found to be the best consolidation therapy, whereas auto-HSCT was associated with a better outcome when compared with chemotherapy (allo-HSCT-, auto-HSCT-, and chemotherapy-related 4-year LFS: 68, 44, and 36%, P = 0.004; 4-year OS: 68, 52, and 29%, respectively, P = 0.02). Our study indicates that allo-HSCT and auto-HSCT provide similar outcomes compared with chemotherapy as consolidation for NPM1+/FLT3-ITD- NK-AML patients. For NK-AML patients with an adverse molecular profile, auto-HSCT could represent an alternative therapeutic approach when no human leukocyte antigen-matched allogeneic donor is available. PMID:22911473

  9. Transient potential receptor melastatin-2 (Trpm2) does not influence murine MLL-AF9-driven AML leukemogenesis or in vitro response to chemotherapy.

    PubMed

    Haladyna, Jessica N; Pastuer, Taylor; Riedel, Simone S; Perraud, Anne-Laure; Bernt, Kathrin M

    2016-07-01

    Transient potential receptor melastatin-2 (TRPM2) is a nonselective cationic, Ca(2+)-permeable transmembrane pore that is preferentially expressed in cells of the myeloid lineage and modulates signaling pathways converging into NF-kB. This is of potential interest for acute myeloid leukemia (AML) therapy, as NF-κB signaling is emerging as a key pathway, mediating drug resistance and leukemia-initiating cell survival in AML. Inhibition of NF-κB signaling has been found to be synergistic with chemotherapy. TRPM2 is overexpressed in AML compared with normal bone marrow, with the highest levels in the FAB M3-6 subtypes. To determine the effect of TRPM2 depletions in a defined genetic model, we established MLL-AF9-driven AML on a Trpm2(-/-) genetic background. Trpm2(-/-) MLL-AF9 leukemias displayed reduced NF-κB phosphorylation as well as nuclear translocation. In vivo, primary and secondary recipients of Trpm2(-/-) MLL-AF9 leukemias exhibit increased latency compared with recipients of wild-type leukemia cells. However, the difference in latency was small and was lost in tertiary transplants. The effect of loss of Trpm2 in a BCR-ABL/NUP98-HOXA9 fusion model was even smaller. Given reports that loss or inhibition of TRPM2 enhanced killing by DNA-damaging agents in neuroblastoma, breast cancer, and prostate cancer cell lines, we exposed Trpm2(-/-) and Trpm2(wt) primary MLL-AF9 leukemias to doxorubicin, cytarabine, and etoposide, but found no difference in IC50 values. The in vitro response to decitabine was also unaffected. In summary, Trpm2 does not seem to play a major role in myeloid leukemogenesis. Additionally, loss of Trpm2 does not augment the cytotoxicity of standard AML chemotherapeutic agents. PMID:27033163

  10. HDAC inhibition by SNDX-275 (Entinostat) restores expression of silenced leukemia-associated transcription factors Nur77 and Nor1 and of key pro-apoptotic proteins in AML.

    PubMed

    Zhou, L; Ruvolo, V R; McQueen, T; Chen, W; Samudio, I J; Conneely, O; Konopleva, M; Andreeff, M

    2013-06-01

    Nur77 and Nor1 are highly conserved orphan nuclear receptors. We have recently reported that nur77(-/-)nor1(-/-) mice rapidly develop acute myeloid leukemia (AML) and that Nur77 and Nor1 transcripts were universally downregulated in human AML blasts. These findings indicate that Nur77 and Nor1 function as leukemia suppressors. We further demonstrated silencing of Nur77 and Nor1 in leukemia stem cells (LSCs). We here report that inhibition of histone deacetylase (HDAC) using the specific class I HDAC inhibitor SNDX-275 restored the expression of Nur77/Nor1 and induced expression of activator protein 1 transcription factors c-Jun and JunB, and of death receptor TRAIL, in AML cells and in CD34(+)/38(-) AML LSCs. Importantly, SNDX-275 induced extensive apoptosis in AML cells, which could be suppressed by silencing nur77 and nor1. In addition, pro-apoptotic proteins Bim and Noxa were transcriptionally upregulated by SNDX-275 in AML cells and in LSCs. Our present work is the first report of a novel mechanism of HDAC inhibitor-induced apoptosis in AML that involves restoration of the silenced nuclear receptors Nur77 and Nor1, activation of activator protein 1 transcription factors, a death receptor and pro-apoptotic proteins. PMID:23247046

  11. NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

    PubMed Central

    Shah, N M; Zaitseva, L; Bowles, K M; MacEwan, D J; Rushworth, S A

    2015-01-01

    Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5′ untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics. PMID:25323587

  12. Comments on the MIT Assessment of the Mars One Plan

    NASA Technical Reports Server (NTRS)

    Jones, Harry W.

    2015-01-01

    The MIT assessment of the Mars One mission plan reveals design assumptions that would cause significant difficulties. Growing crops in the crew chamber produces excessive oxygen levels. The assumed in-situ resource utilization (ISRU) equipment has too low a Technology Readiness Level (TRL). The required spare parts cause a large and increasing launch mass logistics burden. The assumed International Space Station (ISS) Environmental Control and Life Support (ECLS) technologies were developed for microgravity and therefore are not suitable for Mars gravity. Growing food requires more mass than sending food from Earth. The large number of spares is due to the relatively low reliability of ECLS and the low TRL of ISRU. The Mars One habitat design is similar to past concepts but does not incorporate current knowledge. The MIT architecture analysis tool for long-term settlements on the Martian surface includes an ECLS system simulation, an ISRU sizing model, and an analysis of required spares. The MIT tool showed the need for separate crop and crew chambers, the large spare parts logistics, that crops require more mass than Earth food, and that more spares are needed if reliability is lower. That ISRU has low TRL and ISS ECLS was designed for microgravity are well known. Interestingly, the results produced by the architecture analysis tool - separate crop chamber, large spares mass, large crop chamber mass, and low reliability requiring more spares - were also well known. A common approach to ECLS architecture analysis is to build a complex model that is intended to be all-inclusive and is hoped will help solve all design problems. Such models can struggle to replicate obvious and well-known results and are often unable to answer unanticipated new questions. A better approach would be to survey the literature for background knowledge and then directly analyze the important problems.

  13. The MIT TEAL Simulations and Visualizations in Electromagnetism

    NASA Astrophysics Data System (ADS)

    Belcher, John

    2007-03-01

    The Technology Enabled Active Learning (TEAL) Project at MIT has developed a broad range of 3D visualizations and simulations to foster student intuition about electromagnetic fields and phenomena (see http://web.mit.edu/8.02t/www/802TEAL3D/). In this talk we discuss the software approaches we use to create these simulations, including Macromedia Shockwave and Java 3D applets for interactive visualization, passive animations created with 3ds max, and the Dynamic Line Integral Convolution (DLIC) method for constructing time dependent representations of the electromagnetic field at close to the resolution of the computer display (Sundquist, 2003). The DLIC method, in particular, is far superior in delineating the spatial and temporal structure of fields as compared to e.g. field line displays or vector field grids. We also report on the use of these visualizations in instruction at the freshmen level. Our strong opinion is that for effective student learning, such visualizations must be embedded in a software framework for their interactive delivery. This ``guided inquiry'' framework is essential to influence and optimize what students take away from the visualizations. In our current research, we are delivering our visualizations using a commercial package, Addison Wesley's MasteringPhysics (MP), although any guided inquiry delivery system such as MP will be able to interact with our simulation software. We have released our Java 3D simulation software as open source with a liberal open source license (see http://jlearn.mit.edu/tealsim/ ), with support from the Davis Educational Foundation.

  14. Research in Boron Neutron Capture Therapy at MIT LABA

    SciTech Connect

    Yanch, J.C.; Shefer, R.E.; Klinkowstein, R.E.; Howard, W.B.; Song, H.; Blackburn, B.; Binello, E.

    1997-02-01

    A 4.1 MeV tandem electrostatic accelerator designed for research into Boron Neutron Capture Therapy (BNCT) has recently been installed in the MIT Laboratory for Accelerator Beam Applications (LABA). This accelerator uses a very high current switch mode high voltage power supply in conjunction with a multi-cusp negative ion source to supply the multimilliampere current required for clinical BNCT applications. A number of individual research projects aimed at evaluating the potential of this accelerator design as a hospital-based neutron source for radiation therapy of both tumors and rheumatoid arthritis are described here. {copyright} {ital 1997 American Institute of Physics.}

  15. Characteristics of the MIT microwiggler for free electron laser applications

    SciTech Connect

    Catravas, P.; Stoner, R.; Bekefi, G.

    1995-12-31

    We report work on the development of microwiggler technology for free electron laser research. The MIT microwiggler is a pulsed electromagnet with 70 periods of 8.8 mm each which generates a peak on-axis field of 4.2 kG. The wiggler is characterized by extensive tunability. We developed a novel tuning regimen to control 140 degrees of freedom afforded by the individually tunable half periods and achieved an rms spread in the peak amplitudes of 0.08%. This is the lowest attained to date in any sub-cm period wiggler. The microwiggler design and comprehensive measurements of its characteristics will be described.

  16. Sicheres Navigieren in dynamischen Umgebungen mit 3D-Kollisionsvermeidung

    NASA Astrophysics Data System (ADS)

    Stiene, Stefan; Hertzberg, Joachim

    Diese Papier stellt eine neuartige Methode vor, die 3D-Hindernisvermeidung ermöglicht. Die Sensorkonfiguration beruht auf sechs Laserscannern, die die gesamte Roboteroberfläche abdecken. Die Daten der sechs Laserscanner werden zu einem virtuellen, zweidimensionalen, horizontal ausgerichteten 360°-Laserscanner kombiniert. Da der virtuelle Laserscanner die 3D-Umgebung in einem zweidimensionalen Datensatz repräsentiert, ermöglicht er in Kombination mit klassischen Hindernisvermeidungsalgorithmen wie der Vector Field Histogram Methode eine 3D-Hindernisvermeidung.

  17. Mit Mathematik zu Mehr Intelligenz in der Logistik

    NASA Astrophysics Data System (ADS)

    Möhring, Rolf H.; Schenk, Michael

    Die Lösung logistischer Probleme ist ein wichtiger Aspekt menschlichen Handelns seit Menschen gemeinsam zielgerichtet tätig wurden. Die Grundlagen dessen, was wir heute Logistik nennen, entstammen dem militärischen Bereich. So basierte z. B. das römische Imperium in starkem Maße auf militärisch-logistischen Glanzleistungen. Ob damals bereits mathematische Überlegungen eine Rolle spielten, wissen wir heute nicht. Jedoch versuchte z. B. Napoleon, der mit den bedeutendsten Mathematikern seiner Zeit befreundet war, den Transport seiner Truppen und die Verbreitung von Informationen zu optimieren und strategisch einzusetzen.1,2

  18. Was hat das Universum mit uns zu tun?

    NASA Astrophysics Data System (ADS)

    Lesch, Harald

    Was hat das Universum mit uns zu tun? Da der Mensch ein Teil des Universums ist, muss er etwas mit dem Universum zu tun haben. Das Universum stellt ja ganz allgemein den größten Ursache-Wirkung-Zusammenhang dar, über den hinaus zwar noch gedacht und gerechnet, aber nichts mehr beobachtet oder gemessen werden kann. Es definiert also nicht nur die Möglichkeiten materiell-energetischer Seinsformen sondern auch deren Grenzen. Leben, bzw. menschliches Leben stellt im Universum dann zwar eine spezielle Form, aber eben nur eine Form materieller Daseinsstruktur dar. Neben Galaxien, Gas, Sternen, Planeten, Asteroiden und anderen Formen unbelebter Materie gibt es eben auch noch Lebewesen. Das klingt nach Inventur, nach Aufzählung ohne Unterschied. Diese einfache erste Betrachtung liefert vielleicht die ein oder andere Anregung für ein weiteres Suchen nach Substanzen, aber ein wesentliches Moment geht hier verloren. Ich meine die empirische, sehr gut abgesicherte Tatsache, dass das Universum, wie alles was es enthält, eine Entwicklung durchlaufen hat und auch weiterhin durchläuft - nennen wir diese Entwicklung die kosmische Evolution.

  19. MIT image reconstruction based on edge-preserving regularization.

    PubMed

    Casanova, R; Silva, A; Borges, A R

    2004-02-01

    Tikhonov regularization has been widely used in electrical tomography to deal with the ill-posedness of the inverse problem. However, due to the fact that discontinuities are strongly penalized, this approach tends to produce blurred images. Recently, a lot of interest has been devoted to methods with edge-preserving properties, such as those related to total variation, wavelets and half-quadratic regularization. In the present work, the performance of an edge-preserving regularization method, called ARTUR, is evaluated in the context of magnetic induction tomography (MIT). ARTUR is a deterministic method based on half-quadratic regularization, where complementary a priori information may be introduced in the reconstruction algorithm by the use of a nonnegativity constraint. The method is first tested using an MIT analytical model that generates projection data given the position, the radius and the magnetic permeability of a single nonconductive cylindrical object. It is shown that even in the presence of strong Gaussian additive noise, it is still able to recover the main features of the object. Secondly, reconstructions based on real data for different configurations of conductive nonmagnetic cylindrical objects are presented and some of their parameters estimated. PMID:15005316

  20. DynaMIT: the dynamic motif integration toolkit

    PubMed Central

    Dassi, Erik; Quattrone, Alessandro

    2016-01-01

    De-novo motif search is a frequently applied bioinformatics procedure to identify and prioritize recurrent elements in sequences sets for biological investigation, such as the ones derived from high-throughput differential expression experiments. Several algorithms have been developed to perform motif search, employing widely different approaches and often giving divergent results. In order to maximize the power of these investigations and ultimately be able to draft solid biological hypotheses, there is the need for applying multiple tools on the same sequences and merge the obtained results. However, motif reporting formats and statistical evaluation methods currently make such an integration task difficult to perform and mostly restricted to specific scenarios. We thus introduce here the Dynamic Motif Integration Toolkit (DynaMIT), an extremely flexible platform allowing to identify motifs employing multiple algorithms, integrate them by means of a user-selected strategy and visualize results in several ways; furthermore, the platform is user-extendible in all its aspects. DynaMIT is freely available at http://cibioltg.bitbucket.org. PMID:26253738

  1. Education Outreach at MIT Plasma Science Fusion Center

    NASA Astrophysics Data System (ADS)

    Censabella, V.; Nachtrieb, R.; Rivenberg, P.

    1998-11-01

    Outreach at the MIT PSFC consists of volunteers working together to increase the public's knowledge of fusion and plasma-related experiments. Seeking to generate excitement about science, engineering and mathematics, the PSFC holds a number of outreach activities throughout the year, such as Middle and High School Outreach Days. Outreach also includes the Mr. Magnet Program, which uses an interactive strategy to engage elementary school children. Included in this year's presentation will be a live demo of a compressed-air bottle rocket (really a one-liter plastic soda bottle) for use in high school science classrooms that researchers at the Cambridge Physics Outlet (a PSFC spin-off company) have developed. To prepare the rocket for launch, the bottle is filled with compressed air at pressures up to 80 psi and the end is plugged. The rocket is released when the plug is pulled. The gas escapes at supersonic velocities and accelerates the bottle at over 1000 m/s^2. The velocity of the bottle is measured at many locations along its ``trajectory". A simple thermodynamic model predicts performance in excellent agreement with observation. The PSFC maintains a Home Page on the World Wide Web, which can be reached at http://pfc.mit.edu.

  2. PROPOSAL FOR A CAVITY POLARIMETER AT MIT-BATES.

    SciTech Connect

    CAMERON,P.; BARRY,W.; CONTE,M.; GOLDBERG,D.A.; JACOBS,K.; LUCCIO,A.; PALAZZI,M.; PUSTERLA,M.; MACKAY,W.

    2001-06-18

    The possibility of successfully implementing a cavity polarimeter[1] has been greatly improved by the discovery[2] of a cavity mode for which the magnitude of the Stern-Gerlach force experienced by a magnetic moment traversing the cavity varies as the square of the relativistic factor gamma, so that the signal power varies as the fourth power of gamma. In addition, the interaction of this cavity mode with the beam charge varies as the inverse of the interaction with the magnetic moment, so that the background due to the beam charge varies as the inverse fourth power of gamma, If these gamma dependencies of moment and charge interaction with the pickup cavity do in fact exists the possibility is opened for very fast, accurate, and inexpensive polarimetry at accelerators like MIT-Bates and RHIC. In addition, it might become possible to seriously consider Stern-Gerlach polarization of beams at LHC. We present details of a quick polarimeter test at the electron storage ring at MIT-Bates, and of an extension of this test to a working polarimeter in the RHIC rings.

  3. Material Identification Technology (MIT) concept technical feasibility study

    SciTech Connect

    Jones, J.L.; Harker, Y.D.; Yoon, W.Y.; Johnson, L.O.

    1993-09-01

    The Idaho National Engineering Laboratory (INEL) has initiated the design and development of a novel pulsed accelerator-based, active interrogation concept. The proposed concept, referred to as the Material Identification Technology (MIT), enables rapid (between accelerator pulses), non-destructive, elemental composition analysis of both nuclear and non-nuclear materials. Applications of this technique include material monitoring in support of counter-proliferation activities, such as export controls (at domestic and international inspection locations), SNM controls, nuclear weapon dismantlement, and chemical weapon verification. Material Identification Technology combines a pulsed, X-ray source (an electron accelerator) and a gamma detection system. The accelerator must maximize neutron production (pulse width, beam current, beam energy, and repetition rate) and minimize photon dose to the object. Current available accelerator technology can meet these requirements. The detection system must include detectors which provide adequate gamma energy resolution capability, rapid recovery after the initial X-ray interrogation pulse, and multiple single gamma event detection between accelerator pulses. Further research is required to develop the detection system. This report provides the initial feasibility assessment of the MIT concept.

  4. A novel variant three-way translocation of inversion 16 in a case of AML-M4eo following low dose methotrexate therapy.

    PubMed

    Li, S; Couzi, R J; Thomas, G H; Friedman, A D; Borowitz, M J

    2001-02-01

    We report a case of acute myelomonocytic leukemia with eosinophilia (AML-M4eo) in a 65-year-old man following low dose methotrexate treatment for pemphigus vulgaris. Cytogenetic studies at diagnosis revealed a complex karyotype including a reciprocal translocation between 11q14.2 and 16q22, an inversion of chromosome 16(p13.1q22), and an apparently terminal deletion of 7q31. The presence of inv(16) was confirmed by reverse transcription-polymerase chain reaction which demonstrated a Type A fusion transcript derived from the core binding factor (CBF) beta and the smooth muscle myosin heavy chain (MYH11) genes. The patient was in complete hematologic and cytogenetic remission 6 months following intensive chemotherapy. Because AML-M4eo with inv(16) has a favorable prognosis, molecular studies should be performed in case the identification of inv(16) by conventional cytogenetics is difficult due to a complex karyotype. PMID:11297772

  5. HLA-E upregulation on IFN-gamma-activated AML blasts impairs CD94/NKG2A-dependent NK cytolysis after haplo-mismatched hematopoietic SCT.

    PubMed

    Nguyen, S; Beziat, V; Dhedin, N; Kuentz, M; Vernant, J P; Debre, P; Vieillard, V

    2009-05-01

    Natural killer (NK) cells generated after haploidentical hematopoietic SCT in patients with AML are characterized by specific phenotypic features and impaired functioning that may affect transplantation outcome. We show that IFN-gamma produced by immature CD56(bright) NK cells upregulates cell surface expression of HLA-E on AML blasts and that this upregulation protects leukemic cells from NK-mediated cell lysis through the mediation of CD94/NKG2A, an inhibitory receptor overexpressed on NK cells after haploidentical SCT. Two years after transplantation, however, maturing NK cells were functionally active, as evidenced by high cytotoxicity and poor IFN-gamma production. This implies that maturation of NK cells is the key to improved immune responses and transplantation outcome. PMID:19011664

  6. Identification of TEL-AML1 (ETV6-RUNX1) associated DNA and its impact on mRNA and protein output using ChIP, mRNA expression arrays and SILAC

    PubMed Central

    Linka, Yvonne; Ginzel, Sebastian; Borkhardt, Arndt; Landgraf, Pablo

    2014-01-01

    The contribution of the most common reciprocal translocation in childhood B-cell precursor leukemia t(12;21)(p13;q22) to leukemia development is still under debate. Direct as well as secondary indirect effects of the TEL-AML1 fusion protein are commonly recorded by using cell lines and patient samples, often bearing the TEL-AML1 fusion protein for decades. To identify direct targets of the fusion protein a short-term induction of TEL-AML1 is needed. We here describe in detail the experimental procedure, quality controls and contents of the ChIP, mRNA expression and SILAC datasets associated with the study published by Linka and colleagues in the Blood Cancer Journal [1] utilizing a short term induction of TEL-AML1 in an inducible precursor B-cell line model. PMID:26484077

  7. M.I.T. and the Federal Government. An Examination of the Effects of Government Regulation and Research Support on Selected Parts of M.I.T.

    ERIC Educational Resources Information Center

    Garvin, David

    A self-study was undertaken at the Massachusetts Institute of Technology (M.I.T.) to examine the impact of the federal government on it. M.I.T. is a large institution with an enrollment of 8,000, a faculty of 950, and a total teaching staff of 1,700. Of its operating expenses by far the largest source of funds in recent years has been sponsored…

  8. Multifunction Instrument Tree (MIT) Neutron and Gamma Probe Acceptance for Beneficial Use (ABU)

    SciTech Connect

    CANNON, N.S.

    1999-08-08

    The multifunction instrument tree (MIT) probe program has been developed to modify existing Liquid Observation Well (LOW) neutron and gamma probes for use in the validation shafts of the two MITs installed in Tank 241-SY-101. One of the program objectives is that the modified MIT probes be completely compatible with the existing LOW van instrumentation and procedures. The major program objective is to produce neutron and gamma scans from Tank 241-SY-101 that would assist in evaluating waste feature structure and elevation. The MIT probe program is described in greater detail in the engineering task plan (HNF-3322). In accordance with the engineering task plan, a test plan (HNF-3595) was written, reduced diameter (allowing insertion into the MIT validation tube) neutron and gamma probes were acquired, an acceptance and operational test procedure (HNF-3838) was written, acceptance and operational testing of the MIT probes was performed, and a report of these test results (HNF-4369) has been issued. A number of neutron and gamma probe scans have been obtained from the Tank 241-SY-101 MITs, starting on February 8, 1999, in cooperation with Operations. Now that the MIT probes are fully demonstrated, this document transfers ownership of these probes to Operations, utilizing the final acceptance for beneficial use (ABU) form that follows in Section 3.0.

  9. Announcing the Availability of the MIT SMASS and SMASSIR Data Sets

    NASA Technical Reports Server (NTRS)

    Binzel, R. P.; Bus, S. J.; Burbine, T. H.; Rivkin, A. S.

    2001-01-01

    We announce the release of visible and near-infrared reflectance spectroscopy measurements for nearly 2000 asteroids obtained by the MIT Small Main-Belt Asteroid Spectroscopic Survey (SMASS) program. Data are being released via http://smass.mit.edu. Additional information is contained in the original extended abstract.

  10. MIT(1), a black mamba toxin with a new and highly potent activity on intestinal contraction.

    PubMed

    Schweitz, H; Pacaud, P; Diochot, S; Moinier, D; Lazdunski, M

    1999-11-19

    Mamba intestinal toxin (MIT(1)) isolated from Dendroaspis polylepis venom is a 81 amino acid polypeptide cross-linked by five disulphide bridges. MIT(1) has a very potent action on guinea-pig intestinal contractility. MIT(1) (1 nM) potently contracts longitudinal ileal muscle and distal colon, and this contraction is equivalent to that of 40 mM K(+). Conversely MIT(1) relaxes proximal colon again as potently as 40 mM K(+). The MIT(1)-induced effects are antagonised by tetrodotoxin (1 microM) in proximal and distal colon but not in longitudinal ileum. The MIT(1)-induced relaxation of the proximal colon is reversibly inhibited by the NO synthase inhibitor L-NAME (200 microM). (125)I-labelled MIT(1) binds with a very high affinity to both ileum and brain membranes (K(d)=1.3 pM and 0.9 pM, and B(max)=30 fmol/mg and 26 fmol/mg, respectively). MIT(1) is a very highly selective toxin for a receptor present both in the CNS and in the smooth muscle and which might be an as yet unidentified K(+) channel. PMID:10567694

  11. Scratch that: MIT's Mitchel Resnick Says Kids Should Do It for Themselves

    ERIC Educational Resources Information Center

    Traylor, Scott

    2008-01-01

    Mitchel Resnick is a researcher, inventor, and professor at MIT's Media Laboratory in Cambridge, MA, and the founder of the Lifelong Kindergarten Group at MIT. He is the lead innovator behind many cutting-edge learning technologies and projects for children, including the Computer Clubhouse, PicoCrickets, and the wildly successful consumer…

  12. Assessing International Product Design and Development Graduate Courses: The MIT-Portugal Program

    ERIC Educational Resources Information Center

    Dori, Yehudit Judy; Silva, Arlindo

    2010-01-01

    The Product Design and Development (PDD) course is part of the graduate curriculum in the Engineering Design and Advanced Manufacturing (EDAM) study in the MIT-Portugal Program. The research participants included about 110 students from MIT, EDAM, and two universities in Portugal, Instituto Superior Técnico-Universidade Técnica de Lisboa (IST) and…

  13. Mobile-IT Education (MIT.EDU): M-Learning Applications for Classroom Settings

    ERIC Educational Resources Information Center

    Sung, M.; Gips, J.; Eagle, N.; Madan, A.; Caneel, R.; DeVaul, R.; Bonsen, J.; Pentland, A.

    2005-01-01

    In this paper, we describe the Mobile-IT Education (MIT.EDU) system, which demonstrates the potential of using a distributed mobile device architecture for rapid prototyping of wireless mobile multi-user applications for use in classroom settings. MIT.EDU is a stable, accessible system that combines inexpensive, commodity hardware, a flexible…

  14. Pleiotropic effects of spongean alkaloids on mechanisms of cell death, cell cycle progression and DNA damage response (DDR) of acute myeloid leukemia (AML) cells.

    PubMed

    Stuhldreier, Fabian; Kassel, Stefanie; Schumacher, Lena; Wesselborg, Sebastian; Proksch, Peter; Fritz, Gerhard

    2015-05-28

    We investigated cytotoxic mechanisms evoked by the spongean alkaloids aaptamine (Aa) and aeroplysinin-1 (Ap), applied alone and in combination with daunorubicin, employing acute myeloid leukemia (AML) cells. Aa and Ap reduced the viability of AML cells in a dose dependent manner with IC50 of 10-20 µM. Ap triggered apoptotic cell death more efficiently than Aa. Both alkaloids increased the protein level of S139-phosphorylated H2AX (γH2AX), which however was independent of the induction of DNA damage. Expression of the senescence markers p21 and p16 was increased, while the phosphorylation level of p-Chk-2 was reduced following Aa treatment. As a function of dose, Aa and Ap protected or sensitized AML cells against daunorubicin. Protection by Aa was paralleled by reduced formation of ROS and lower level of DNA damage. Both Aa and Ap attenuated daunorubicin-stimulated activation of the DNA damage response (DDR) as reflected on the levels of γH2AX, p-Kap-1 and p-Chk-1. Specifically Ap restored the decrease in S10 phosphorylation of histone H3 resulting from daunorubicin treatment. The cytoprotective effects of Aa and Ap were independent of daunorubicin import/export. Both Aa and Ap abrogated daunorubicin-induced accumulation of cells in S-phase. Inhibition of DNA synthesis was specific for Ap. The data show that Aa and Ap have both congruent and agent-specific pleiotropic effects that are preferential for anticancer drugs. Since Ap showed a broader spectrum of anticancer activities, this compound is suggested as novel lead compound for forthcoming in vivo studies elucidating the usefulness of spongean alkaloids in AML therapy. PMID:25697484

  15. Azacitidine might be beneficial in a subgroup of older AML patients compared to intensive chemotherapy: a single centre retrospective study of 227 consecutive patients

    PubMed Central

    2013-01-01

    Background Treatment options in older acute myeloid leukaemia (AML) patients include intensive chemotherapy, best supportive care (BSC), and hypomethylating agents. Currently, limited data is available on hypomethylating agents in older AML patients in unselected patient populations. Methods To compare the effectiveness of azacitidine with conventional therapy, we collected data of 227 consecutive AML patients (≥60 years) who were treated with azacitidine (N = 26), intensive chemotherapy (N = 90), or BSC (N = 97). Results Azacitidine-treated patients were older and had more comorbidities, but lower white blood cell- and bone marrow blast counts compared with intensive chemotherapy patients. Complete or partial response was achieved in 42% of azacitidine-treated patients and in 73% of intensive chemotherapy patients (P = 0.005). However, the overall survival (OS) was similar (1-year-OS 57% versus 56%, P = 0.93; 2-year-OS 35% versus 35%, P = 0.92), and remained similar after correction for risk factors in a multivariate analysis. Patients treated with BSC had an inferior OS (1-year- and 2-year-OS 16% and 2%, P < 0.001). Compared to intensive chemotherapy, azacitidine-treated patients spent less days in the hospital (median in first three months 0.5 versus 56, P < 0.001), and needed less red blood cell and platelet transfusions (median per month 2.7 versus 7, P < 0.001 and 0.3 versus 5, P < 0.001) in the first three months. Conclusions Azacitidine treatment is associated with a comparable OS but higher tolerability in a subgroup of older AML patients compared with intensive chemotherapy. Patients receiving BSC had a poor prognosis. PMID:23587459

  16. The Broad Anti-AML Activity of the CD33/CD3 BiTE Antibody Construct, AMG 330, Is Impacted by Disease Stage and Risk

    PubMed Central

    Laszlo, George S.; Newhall, Kathryn J.; Sinclair, Angus M.; Frankel, Stanley R.; Kischel, Roman; Chen, Guang; Walter, Roland B.

    2015-01-01

    The CD33/CD3-bispecific T-cell engaging (BiTE) antibody construct, AMG 330, potently lyses CD33+ leukemic cells in vitro. Using specimens from 41 patients with acute myeloid leukemia (AML), we studied the factors that might contribute to clinical response or resistance. For this purpose, thawed aliquots of primary AML samples were immunophenotypically characterized and subjected to various doses of AMG 330 in the presence or absence of healthy donor T-cells. After 48 hours, drug-specific cytotoxicity was quantified and correlated with CD33 expression levels, amounts of T-cells present, and other disease characteristics. AMG 330 caused modest cytotoxicity that was correlated with the amount of autologous T-cells (P = 0.0001) but not CD33 expression, as AMG 330 exerted marked cytotoxic effects in several specimens with minimal CD33 expression. With healthy donor T-cells added, AMG 330 cytotoxicity depended on the drug dose and effector:target (E:T) cell ratio. High cytotoxic activity was observed even with minimal CD33 expression, and AMG 330 cytotoxicity and CD33 expression correlated only at high E:T cell ratio and high AMG 330 doses (P<0.003). AMG 330 resulted in significantly higher cytotoxicity in specimens from patients with newly diagnosed AML than those with relapsed/refractory disease despite similar levels of CD33 on myeloblasts. AMG 330 cytotoxicity also appeared greater in specimens from patients with favorable-risk disease as compared to other specimens. Together, our data demonstrate that AMG 330 is highly active in primary AML specimens across the entire disease spectrum, while suggesting the presence of yet undefined, CD33-independent, relative resistance mechanisms in specific patient subsets. PMID:26305211

  17. Donor Haplotype B of NK KIR Receptor Reduces the Relapse Risk in HLA-Identical Sibling Hematopoietic Stem Cell Transplantation of AML Patients.

    PubMed

    Impola, Ulla; Turpeinen, Hannu; Alakulppi, Noora; Linjama, Tiina; Volin, Liisa; Niittyvuopio, Riitta; Partanen, Jukka; Koskela, Satu

    2014-01-01

    Successful allogeneic hematopoietic stem cell transplantation (HSCT) depends not only on good HLA match but also on T-cell mediated graft-versus-leukemia (GvL) effect. Natural killer (NK) cells are able to kill malignant cells by receiving activation signal from the killer-cell immunoglobulin-like receptors (KIR) recognizing HLA molecules on a cancer cell. It has been recently reported that the risk of relapse in allogeneic hematopoietic stem cell transplantation (HSCT) is reduced in acute myeloid leukemia (AML) patients whose donors have several activating KIR genes or KIR B-motifs in unrelated donor setting, obviously due to enhanced GvL effect by NK cells. We studied the effect on relapse rate of donor KIR haplotypes in the HLA-identical adult sibling HSCT, done in a single center, in Helsinki University Central Hospital, Helsinki, Finland. Altogether, 134 patients with 6 different diagnoses were identified. Their donors were KIR genotyped using the Luminex and the SSP techniques. The clinical endpoint, that is, occurrence of relapse, was compared with the presence or absence of single KIR genes. Also, time from transplantation to relapse was analyzed. The patients with AML whose donors have KIR2DL2 or KIR2DS2 had statistically significantly longer relapse-free survival (P = 0.015). Our data support previous reports that donors with KIR B-haplotype defining genes have a lower occurrence of relapse in HSCT of AML patients. Determination of donor KIR haplotypes could be a useful addition for a risk assessment of HSCT especially in AML patients. PMID:25202311

  18. Donor Haplotype B of NK KIR Receptor Reduces the Relapse Risk in HLA-Identical Sibling Hematopoietic Stem Cell Transplantation of AML Patients

    PubMed Central

    Impola, Ulla; Turpeinen, Hannu; Alakulppi, Noora; Linjama, Tiina; Volin, Liisa; Niittyvuopio, Riitta; Partanen, Jukka; Koskela, Satu

    2014-01-01

    Successful allogeneic hematopoietic stem cell transplantation (HSCT) depends not only on good HLA match but also on T-cell mediated graft-versus-leukemia (GvL) effect. Natural killer (NK) cells are able to kill malignant cells by receiving activation signal from the killer-cell immunoglobulin-like receptors (KIR) recognizing HLA molecules on a cancer cell. It has been recently reported that the risk of relapse in allogeneic hematopoietic stem cell transplantation (HSCT) is reduced in acute myeloid leukemia (AML) patients whose donors have several activating KIR genes or KIR B-motifs in unrelated donor setting, obviously due to enhanced GvL effect by NK cells. We studied the effect on relapse rate of donor KIR haplotypes in the HLA-identical adult sibling HSCT, done in a single center, in Helsinki University Central Hospital, Helsinki, Finland. Altogether, 134 patients with 6 different diagnoses were identified. Their donors were KIR genotyped using the Luminex and the SSP techniques. The clinical endpoint, that is, occurrence of relapse, was compared with the presence or absence of single KIR genes. Also, time from transplantation to relapse was analyzed. The patients with AML whose donors have KIR2DL2 or KIR2DS2 had statistically significantly longer relapse-free survival (P = 0.015). Our data support previous reports that donors with KIR B-haplotype defining genes have a lower occurrence of relapse in HSCT of AML patients. Determination of donor KIR haplotypes could be a useful addition for a risk assessment of HSCT especially in AML patients. PMID:25202311

  19. Spontaneous Dissociation of Anatomic Medullary Locking A Plus (AML A Plus) Femoral Component at the Head-Neck Interface

    PubMed Central

    Pande, Ketan; Leong, Juzaily Fekry; Lo, Ngai Nung

    2015-01-01

    Introduction: Innovations in the design of total hip arthroplasty components have been developed to address certain limitations with the use of standard monoblock prosthesis. With increasing use and long-term follow up, certain complications particularly related to fretting, corrosion and fatigue have been recognized. Case Report: A 31 year old active male patient presented with spontaneous dissociation of the Anatomic Medullary Locking A Plus (AML A Plus) Femoral Component at head and neck interface 10 years after surgery. At revision surgery, wear of the acetabular liner and head and neck taper was noted. Definitive treatment required complete revision of the femoral component and change of acetabular liner. Conclusion: While modularity allows change of worn out components, this case highlights the importance of various factors in avoiding this complication and the need for surgeon to be prepared to use ‘taper sleeves’ or revise the components if taper exchange fails particularly in cases with dissociation of head-neck interface which is usually associated with taper damage. PMID:27299068

  20. OBESITY DOES NOT PRECLUDE SAFE AND EFFECTIVE MYELOABLATIVE HEMATOPOIETIC CELL TRANSPLANTATION (HCT) FOR ACUTE MYELOID LEUKEMIA (AML) IN ADULTS

    PubMed Central

    Navarro, Willis H.; Agovi, Manza-A.; Logan, Brent R.; Ballen, Karen; Bolwell, Brian J.; Frangoul, Haydar; Gupta, Vikas; Hahn, Theresa; Ho, Vincent T.; Juckett, Mark; Lazarus, Hillard M.; Litzow, Mark R.; Liesveld, Jane L.; Moreb, Jan S.; Marks, David I.; McCarthy, Philip L.; Pasquini, Marcelo C.; Rizzo, J. Douglas

    2010-01-01

    The incidence of excessive adiposity is increasing worldwide and is associated with numerous adverse health outcomes. We compared outcomes by body mass index (BMI) for adult patients with acute myeloid leukemia (AML) who underwent autologous (auto, n=373), related donor (RD, n=2041), or unrelated donor (URD, n=1801) allogeneic myeloablative hematopoietic cell transplantation (HCT) using marrow or peripheral blood stem cells reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1995-2004. Four weight groups by BMI (kg/m2) were defined: underweight < 18; normal 18 – 25; overweight >25 – 30; and obese > 30. Multivariable analysis referenced to the normal weight group showed an increased risk of death for underweight patients in the RD group (RR, 1.92; 95% CI, 1.28-2.89; P = 0.002) but not in the URD group. There were no other differences in outcomes among the other weight groups within the other HCT groups. Overweight and obese patients enjoyed a modest decrease in relapse incidence, though this did not translate into a survival benefit. Small numbers of patients limit the ability to better characterize the adverse outcomes seen in the underweight RD but not the underweight URD allogeneic HCT patients. Obesity alone should not be considered a barrier to HCT. PMID:20412867

  1. Outpatient supportive therapy after induction to remission therapy in adult acute myelogenous leukaemia (AML) is feasible: a multicentre study.

    PubMed

    Ruiz-Argüelles, G J; Apreza-Molina, M G; Alemán-Hoey, D D; Gómez-Almaguer, D; Marín-López, A; Mercado-Díaz, L

    1995-01-01

    Twenty-four adult patients with AML were treated with standard "7 + 3" chemotherapy. After administering the myeloablative drugs in the hospital, patients were instructed to continue their supportive treatment on an outpatient basis; they received ciprofloxacin, cotrimoxasole and itraconazole vo until the absolute granulocyte count rose above 1 x 10(9)/l. Platelet concentrates were given every other day until the platelet count rose above 20 x 10(9)/l. Complete remission (CR) was obtained in 87%. Fever developed in 29% and 2 cases were complicated by indwelling-catheter-related Pseudomona aeruginosa septicaemia, 1 Entamoeba hystolytica enteritis and 1 Pneumocystis carinii pneumonia; these patients were hospitalized to treat these infections specifically. In no case was the infection fatal. The median disease free-survival (DFS) was 17 months, 12-month DFS was 66%, and 30-month DFS was 17%. Our calculations have shown that 1700 USD/patient were saved by avoiding prolonged hospitalization; this may provide not only economical, but also psychological advantages to patients. PMID:7859871

  2. Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and biological entity: a collaborative study by the International-Berlin-Frankfurt-Münster AML-study group

    PubMed Central

    Coenen, Eva A.; Zwaan, C. Michel; Reinhardt, Dirk; Harrison, Christine J.; Haas, Oskar A.; de Haas, Valerie; Mihál, Vladimir; De Moerloose, Barbara; Jeison, Marta; Rubnitz, Jeffrey E.; Tomizawa, Daisuke; Johnston, Donna; Alonzo, Todd A.; Hasle, Henrik; Auvrignon, Anne; Dworzak, Michael; Pession, Andrea; van der Velden, Vincent H. J.; Swansbury, John; Wong, Kit-fai; Terui, Kiminori; Savasan, Sureyya; Winstanley, Mark; Vaitkeviciene, Goda; Zimmermann, Martin; Pieters, Rob; van den Heuvel-Eibrink, Marry M.

    2013-01-01

    In pediatric acute myeloid leukemia (AML), cytogenetic abnormalities are strong indicators of prognosis. Some recurrent cytogenetic abnormalities, such as t(8;16)(p11;p13), are so rare that collaborative studies are required to define their prognostic impact. We collected the clinical characteristics, morphology, and immunophenotypes of 62 pediatric AML patients with t(8;16)(p11;p13) from 18 countries participating in the International Berlin-Frankfurt-Münster (I-BFM) AML study group. We used the AML-BFM cohort diagnosed from 1995-2005 (n = 543) as a reference cohort. Median age of the pediatric t(8;16)(p11;p13) AML patients was significantly lower (1.2 years). The majority (97%) had M4-M5 French-American-British type, significantly different from the reference cohort. Erythrophagocytosis (70%), leukemia cutis (58%), and disseminated intravascular coagulation (39%) occurred frequently. Strikingly, spontaneous remissions occurred in 7 neonates with t(8;16)(p11;p13), of whom 3 remain in continuous remission. The 5-year overall survival of patients diagnosed after 1993 was 59%, similar to the reference cohort (P = .14). Gene expression profiles of t(8;16)(p11;p13) pediatric AML cases clustered close to, but distinct from, MLL-rearranged AML. Highly expressed genes included HOXA11, HOXA10, RET, PERP, and GGA2. In conclusion, pediatric t(8;16)(p11;p13) AML is a rare entity defined by a unique gene expression signature and distinct clinical features in whom spontaneous remissions occur in a subset of neonatal cases. PMID:23974201

  3. Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17-92 cluster in differentiating AML cells.

    PubMed

    Yan, Y; Hanse, E A; Stedman, K; Benson, J M; Lowman, X H; Subramanian, S; Kelekar, A

    2016-07-01

    PHLPP2, a member of the PH-domain leucine-rich repeat protein phosphatase (PHLPP) family, which targets oncogenic kinases, has been actively investigated as a tumor suppressor in solid tumors. Little is known, however, regarding its regulation in hematological malignancies. We observed that PHLPP2 protein expression, but not its mRNA, was suppressed in late differentiation stage acute myeloid leukemia (AML) subtypes. MicroRNAs (miR or miRNAs) from the miR-17-92 cluster, oncomir-1, were shown to inhibit PHLPP2 expression and these miRNAs were highly expressed in AML cells that lacked PHLPP2 protein. Studies showed that miR-17-92 cluster regulation was, surprisingly, independent of transcription factors c-MYC and E2F in these cells; instead all-trans-retinoic acid (ATRA), a drug used for terminally differentiating AML subtypes, markedly suppressed miR-17-92 expression and increased PHLPP2 protein levels and phosphatase activity. Finally, we demonstrate that the effect of ATRA on miR-17-92 expression is mediated through its target, transcription factor C/EBPβ, which interacts with the intronic promoter of the miR-17-92 gene to inhibit transactivation of the cluster. These studies reveal a novel mechanism for upregulation of the phosphatase activity of PHLPP2 through C/EBPβ-mediated repression of the miR-17-92 cluster in terminally differentiating myeloid cells. PMID:26868909

  4. Revealing very small FLT3 ITD mutated clones by ultra-deep sequencing analysis has important clinical implications in AML patients

    PubMed Central

    Zuffa, Elisa; Franchini, Eugenia; Papayannidis, Cristina; Baldazzi, Carmen; Simonetti, Giorgia; Testoni, Nicoletta; Abbenante, Maria Chiara; Paolini, Stefania; Sartor, Chiara; Parisi, Sarah; Marconi, Giovanni; Cattina, Federica; Bochicchio, Maria Teresa; Venturi, Claudia; Ottaviani, Emanuela; Cavo, Michele; Martinelli, Giovanni

    2015-01-01

    FLT3 internal tandem duplication (ITD), one of the most frequent mutations in Acute Myeloid Leukemia (AML), is reported to be an unstable marker, as it can evolve from FLT3 ITD- to ITD+ during the disease course. A single-gene sensitive mutational screening approach may be helpful for better clarifying the exact timing of mutation occurrence, especially when FLT3 ITD appears to occur late, at disease progression. We developed an amplicon-based ultra-deep-sequencing (UDS) approach for FLT3 mutational screening. We exploited this highly sensitive technology for the retrospective screening of diagnosis, relapse and follow-up samples of 5 out of 256 cytogenetically normal (CN-) AML who were FLT3 wild-type at presentation, but tested ITD+ at relapse or disease progression. Our study revealed that all patients carried a small ITD+ clone at diagnosis, which was undetectable by routine analysis (0,2–2% abundance). The dynamics of ITD+ clones from diagnosis to disease progression, assessed by UDS, reflected clonal evolution under treatment pressure. UDS appears as a valuable tool for FLT3 mutational screening and for the assessment of minimal residual disease (MRD) during follow-up, by detecting small ITD+ clones that may survive chemotherapy, evolve over time and definitely worsen the prognosis of CN-AML patients. PMID:26384303

  5. Fms like tyrosine kinase (FLT3) and nucleophosmin 1 (NPM1) mutations in de novo normal karyotype acute myeloid leukemia (AML).

    PubMed

    Dunna, Nageswara Rao; Rajappa, Senthil; Digumarti, Raghunadharao; Vure, Sugunakar; Kagita, Sailaja; Damineni, Surekha; Rao, V R; Yadav, Satish Kumar; Ravuri, Rajasekhara Reddy; Satti, Vishnupriya

    2010-01-01

    Mutations in FLT3 and NPM1 are important prognostic factors in AML, influencing outcome in normal karyotype cases. We here analysed incidences of FLT3/ITD, D 835 and NPM1 mutations in patients with de novo normal karyotype AML using PCR and gene sequencing, along with laboratory parameters and treatment outcomes. There were 128 patients with a median age of 45 years (range, 19-65). FLT3/ITD mutations were detected in 26 (20.3%), FLT3/D835 in 8 (6.2%) and NPM1 in 22 (17.1%). The incidence of FLT3/ITD was higher in those with elevated lactate dehydrogenase (LDH) and peripheral blasts (p=< 0.002, < 0.001) while NPM1 mutations or both NPM1 and FLT3/ITD was more common in elevated total leukocyte counts (TLC), LDH and peripheral blasts (p=<0.0001). Complete response and disease free survival were lower in those with FLT3/ITD mutations (p=0.04, 0.03). The incidence of FLT3 and NPM1 mutations was found to be low in Indian patients with normal karyotype AML. PMID:21338238

  6. The FLT3ITD mRNA level has a high prognostic impact in NPM1 mutated, but not in NPM1 unmutated, AML with a normal karyotype.

    PubMed

    Schneider, Friederike; Hoster, Eva; Unterhalt, Michael; Schneider, Stephanie; Dufour, Annika; Benthaus, Tobias; Mellert, Gudrun; Zellmeier, Evelyn; Kakadia, Purvi M; Bohlander, Stefan K; Feuring-Buske, Michaela; Buske, Christian; Braess, Jan; Heinecke, Achim; Sauerland, Maria C; Berdel, Wolfgang E; Büchner, Thomas; Wörmann, Bernhard J; Hiddemann, Wolfgang; Spiekermann, Karsten

    2012-05-10

    The impact of a FLT3-internal tandem duplication (FLT3ITD) on prognosis of patients with acute myeloid leukemia (AML) is dependent on the ratio of mutated to wild-type allele. In 648 normal karyotype (NK) AML patients, we found a significant independent effect of the quantitative FLT3ITD mRNA level--measured as (FLT3ITD/wtFLT3)/(FLT3ITD/wtFLT3+1)--on outcome. Moreover, this effect was clearly seen in 329 patients with a mutated NPM1 gene (NPM1+), but not in 319 patients without a NPM1 mutation (wtNPM1). In a multivariate Cox regression model, the quantitative FLT3ITD mRNA level showed an independent prognostic impact on overall survival (OS) and relapse-free survival (RFS) only in the NPM1+ subgroup (OS: hazard ratio, 5.9; [95% confidence interval [CI]: 3.1-11.2]; RFS: hazard ratio, 7.5 [95% CI: 3.4-16.5]). The FLT3ITD mRNA level contributes to relapse risk stratification and might help to guide postremission therapy in NPM1-mutated AML. PMID:22374696

  7. Protective effect of CMV reactivation on relapse after allogeneic hematopoietic cell transplantation in AML patients is influenced by their conditioning regimen

    PubMed Central

    Manjappa, Shivaprasad; Bhamidipati, Pavan Kumar; Stokerl-Goldstein, Keith E.; DiPersio, John F.; Uy, Geoffrey L.; Westervelt, Peter; Liu, Jingxia; Schroeder, Mark A.; Vij, Ravi; Abboud, Camille N.; Fehniger, Todd A; Cashen, Amanda F.; Pusic, Iskra; Jacoby, Meagan; Meera, Srinidhi J.; Romee, Rizwan

    2014-01-01

    Cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplant (allo-HCT) has been associated with reduced risk of relapse in patients with acute myeloid leukemia (AML). However the influence of the conditioning regimen on this protective effect of CMV reactivation after allo-HCT is relatively unexplored. To address this, we evaluated the risk of relapse in 264 AML patients who received T cell replete, 6/6 HLA matched sibling or 10/10 HLA matched unrelated donor transplantation at a single institution between 2006 and 2011. Out of these 264 patients, 206 received myeloablative (MA) and 58 received reduced intensity conditioning (RIC) regimens. CMV reactivation was observed in 88 patients with MA conditioning and 37 patients with RIC. At a median follow up of 299 days, CMV reactivation was associated with significantly lower risk of relapse in patients who received MA conditioning both in univariate (P= .01) and multivariate analyses (hazard ratio of 0.5246, P= .006), however CMV reactivation did not significantly affect the risk of relapse in our RIC cohort. These results confirm the protective effect of CMV reactivation on relapse in AML patients after allo-HCT reported by previous studies, however they suggest that this protective effect of CMV reactivation on relapse is influenced by the conditioning regimen used with the transplant. PMID:24120526

  8. Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS

    PubMed Central

    List, A F; Bennett, J M; Sekeres, M A; Skikne, B; Fu, T; Shammo, J M; Nimer, S D; Knight, R D; Giagounidis, A

    2014-01-01

    Lenalidomide is the approved treatment for patients with red blood cell (RBC) transfusion-dependent lower-risk myelodysplastic syndromes (MDS) and chromosome 5q deletion (del(5q)). We report the long-term outcomes (median follow-up 3.2 years) in patients treated with lenalidomide in the MDS-003 trial. RBC transfusion independence (TI) ⩾8 weeks was achieved in 97 of 148 treated patients (65.5%), with a median response duration of 2.2 years. Partial or complete cytogenetic response was achieved by 63 of 88 evaluable patients (71.6%). Median overall survival (OS) was longer in patients achieving RBC-TI ⩾8 weeks (4.3 vs 2.0 years in non-responders; P<0.0001) or cytogenetic response (4.9 vs 3.1 years in non-responders; P=0.010). Time to acute myeloid leukemia (AML) progression was longer in patients achieving RBC-TI ⩾8 weeks or any cytogenetic response versus non-responders (P=0.001 and P=0.0002, respectively). In a landmark multivariate analysis, RBC-TI ⩾8 weeks was associated with prolonged OS (P<0.001) and a trend toward reduced relative risk of AML progression (P=0.080). Among these lower-risk MDS patients with del(5q), lenalidomide was associated with prolonged RBC-TI and cytogenetic responses, which were linked to improved OS and reduced risk of AML progression. PMID:24150217

  9. Role for c-jun N-terminal kinase in treatment-refractory acute myeloid leukemia (AML): signaling to multidrug-efflux and hyperproliferation.

    PubMed

    Cripe, L D; Gelfanov, V M; Smith, E A; Spigel, D R; Phillips, C A; Gabig, T G; Jung, S-H; Fyffe, J; Hartman, A D; Kneebone, P; Mercola, D; Burgess, G S; Boswell, H S

    2002-05-01

    A relationship was proved between constitutive activity of leukemic cell c-jun-N-terminal kinase (JNK) and treatment failure in AML. Specifically, early treatment failure was predicted by the presence of constitutive JNK activity. The mechanistic origins of this association was sought. A multidrug resistant leukemic cell line, HL-60/ADR, characterized by hyperexpression of c-jun and JNK activity, was transfected with a mutant c-jun vector, whose substrate N-terminal c-jun serines were mutated. Down-regulated expression occurred of c-jun/AP-1-dependent genes, catalase and glutathione-S-transferase (GST) pi, which participate in cellular homeostasis to oxidative stress and xenobiotic exposure. MRP-efflux was abrogated in HL-60/ADR cells with dominant-negative c-jun, perhaps because MRP1 protein expression was also lost. Heightened sensitivity to daunorubicin resulted in cells subjected to this change. Biochemical analysis in 67 primary adult AML samples established a statistical correlation between cellular expression of c-jun and JNK activity, JNK activity with hyperleukocytosis at presentation of disease, and with exuberant MRP efflux. These findings reflect the survival role for c-jun/AP-1 and its regulatory kinase previously demonstrated for yeast in homeostatic response to oxidative stress and in operation of ATP-binding cassette efflux pumps, and may support evolutionary conservation of such function. Thus, JNK and c-jun may be salient drug targets in multidrug resistant AML. PMID:11986940

  10. Temperature-driven and photo-induced MIT behaviors of VO2 nanowires

    NASA Astrophysics Data System (ADS)

    Sohn, Ahrum; Kim, Dong-Wook; Byun, Ji-Won; Baik, Jeong Min

    2014-03-01

    VO2 shows a metal-insulator transition (MIT) and structural phase transition (SPT) at critical temperature (Tc) of 343K. It has been known that the MIT and SPT behaviors of VO2 can be tuned by external stimuli such as light, electric-field, and strain. We carried out comparative studies of MIT behaviors of VO2 nanowires during heating-cooling cycles with and without illumination using several light sources (red, blue, and UV). Light can induce change in Tc and hysteresis width of the resistance change. We have investigated influences of light on SPT during MIT. In this presentation, we will discuss possible physical origins for the photo-induced effects on the MIT behaviors of the VO2 nanowires.

  11. Child Care is Everybody's Baby: A Comprehensive Report of Child Care Services, Past, Present, and Future at M.I.T. Final Child Care Proposals as Accepted by M.I.T.

    ERIC Educational Resources Information Center

    Swartz, Marilyn S.

    The report on child care services at M.I.T. explores the following areas: (1) Planning Issues: Why Should M.I.T. Be Involved in Child Care?--educational concerns, services, benefits and costs, priorities, resource allocation; (2) Background for Planning; Current Institute Child Care Programs--a concise history, M.I.T. summer day camp, the…

  12. MIT-KSC space life sciences telescience testbed

    NASA Technical Reports Server (NTRS)

    1989-01-01

    A Telescience Life Sciences Testbed is being developed. The first phase of this effort consisted of defining the experiments to be performed, investigating the various possible means of communication between KSC and MIT, and developing software and hardware support. The experiments chosen were two vestibular sled experiments: a study of ocular torsion produced by Y axis linear acceleration, based on the Spacelab D-1 072 Vestibular Experiment performed pre- and post-flight at KSC; and an optokinetic nystagmus (OKN)/linear acceleration interaction experiment. These two experiments were meant to simulate actual experiments that might be performed on the Space Station and to be representative of space life sciences experiments in general in their use of crew time and communications resources.

  13. Microfiche Image Transmission System (MITS) demonstration field evaluation of microfacsimile

    NASA Astrophysics Data System (ADS)

    Endicott, D. L., Jr.

    1983-05-01

    The MITS Demonstration was conducted for a 6-month period between 14 December 1981 and 11 June 1982. During that period, more than 1000 microfiche containing about 22,000 personnel document images were electronically transmitted between NMPC and the Personnel Support Detachment, Anacostia. These fiche represented nearly 300 active Navy personnel records. The average turnaround time was 46 minutes between making a request and receiving a facsimile record. This time included retrieval of the master microfiche, duplication, scanning, data transmission, and facsimile recording. The average scanning/transmission time was 15 minutes per record slightly less than 8 seconds per document image. The facsimile documents were found to be useful to the recipients, but improvements in both the output quality and the system itself are necessary to ensure effective implementation of an operational configuration.

  14. [R]MIT Research Centre at Delft University of Technology: A Bridge between Research, Education, Society and Profession

    ERIC Educational Resources Information Center

    Zijlstra, Hielkje

    2009-01-01

    In 2006, we launched the [R]MIT Research Centre (Modification, Intervention Transformation) at the Faculty of Architecture at Delft University of Technology. [R]MIT was founded to respond to the need for an integrated, multi-disciplinary approach to the transformation of the built environment. [R]MIT aims to bring momentum to the renewal of…

  15. CD4(+)and CD8(+)T-cell reactions against leukemia-associated- or minor-histocompatibility-antigens in AML-patients after allogeneic SCT.

    PubMed

    Steger, Brigitte; Milosevic, Slavoljub; Doessinger, Georg; Reuther, Susanne; Liepert, Anja; Braeu, Marion; Schick, Julia; Vogt, Valentin; Schuster, Friedhelm; Kroell, Tanja; Busch, Dirk H; Borkhardt, Arndt; Kolb, Hans-Jochem; Tischer, Johanna; Buhmann, Raymund; Schmetzer, Helga

    2014-04-01

    T-cells play an important role in the remission-maintenance in AML-patients (pts) after SCT, however the role of LAA- (WT1, PR1, PRAME) or minor-histocompatibility (mHag, HA1) antigen-specific CD4(+) and CD8(+)T-cells is not defined. A LAA/HA1-peptide/protein stimulation, cloning and monitoring strategy for specific CD8(+)/CD4(+)T-cells in AML-pts after SCT is given. Our results show that (1) LAA-peptide-specific CD8+T-cells are detectable in every AML-pt after SCT. CD8(+)T-cells, recognizing two different antigens detectable in 5 of 7 cases correlate with long-lasting remissions. Clonal TCR-Vβ-restriction exemplarily proven by spectratyping in PRAME-specific CD8(+)T-cells; high PRAME-peptide-reactivity was CD4(+)-associated, as shown by IFN-γ-release. (2) Two types of antigen-presenting cells (APCs) were tested for presentation of LAA/HA1-proteins to CD4(+)T-cells: miniEBV-transduced lymphoblastoid cells (B-cell-source) and CD4-depleted MNC (source for B-cell/monocyte/DC). We provide a refined cloning-system for proliferating, CD40L(+)CD4(+)T-cells after LAA/HA1-stimulation. CD4(+)T-cells produced cytokines (GM-CSF, IFN-γ) upon exposure to LAA/HA1-stimulation until after at least 7 restimulations and demonstrated cytotoxic activity against naive blasts, but not fibroblasts. Antileukemic activity of unstimulated, stimulated or cloned CD4(+)T-cells correlated with defined T-cell-subtypes and the clinical course of the disease. In conclusion we provide immunological tools to enrich and monitor LAA/HA1-CD4(+)- and CD8(+)T-cells in AML-pts after SCT and generate data with relevant prognostic value. We were able to demonstrate the presence of LAA-peptide-specific CD8(+)T-cell clones in AML-pts after SCT. In addition, we were also able to enrich specific antileukemic reactive CD4(+)T-cells without GvH-reactivity upon repeated LAA/HA1-protein stimulation and limiting dilution cloning. PMID:24315637

  16. 2mit, an Intronic Gene of Drosophila melanogaster timeless2, Is Involved in Behavioral Plasticity

    PubMed Central

    Benna, Clara; Leonardi, Emanuela; Romoli, Ottavia; Cognolato, Moira; Tosatto, Silvio C. E.; Costa, Rodolfo; Sandrelli, Federica

    2013-01-01

    Background Intronic genes represent ~6% of the total gene complement in Drosophila melanogaster and ~85% of them encode for proteins. We recently characterized the D. melanogaster timeless2 (tim2) gene, showing its active involvement in chromosomal stability and light synchronization of the adult circadian clock. The protein coding gene named 2mit maps on the 11th tim2 intron in the opposite transcriptional orientation. Methodology/Principal Findings Here we report the molecular and functional characterization of 2mit. The 2mit gene is expressed throughout Drosophila development, localizing mainly in the nervous system during embryogenesis and mostly in the mushroom bodies and ellipsoid body of the central complex in the adult brain. In silico analyses revealed that 2mit encodes a putative leucine-Rich Repeat transmembrane receptor with intrinsically disordered regions, harboring several fully conserved functional interaction motifs in the cytosolic side. Using insertional mutations, tissue-specific over-expression, and down-regulation approaches, it was found that 2mit is implicated in adult short-term memory, assessed by a courtship conditioning assay. In D. melanogaster, tim2 and 2mit do not seem to be functionally related. Bioinformatic analyses identified 2MIT orthologs in 21 Drosophilidae, 4 Lepidoptera and in Apis mellifera. In addition, the tim2-2mit host-nested gene organization was shown to be present in A. mellifera and maintained among Drosophila species. Within the Drosophilidae 2mit-hosting tim2 intron, in silico approaches detected a neuronal specific transcriptional binding site which might have contributed to preserve the specific host-nested gene association across Drosophila species. Conclusions/Significance Taken together, these results indicate that 2mit, a gene mainly expressed in the nervous system, has a role in the behavioral plasticity of the adult Drosophila. The presence of a putative 2mit regulatory enhancer within the 2mit-hosting tim2

  17. Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML.

    PubMed

    Stirewalt, D L; Pogosova-Agadjanyan, E L; Tsuchiya, K; Joaquin, J; Meshinchi, S

    2014-01-01

    Patients with high FLT3 internal tandem duplication allelic ratios (FLT3/ITD-ARs) have a poor prognosis. Single-nucleotide polymorphism/comparative genomic hybridization, single-cell PCR and colony-forming assays were used to evaluate genotypic evolution of high FLT3/ITD-ARs in 85 acute myeloid leukemia (AML) patients. Microarrays were used to examine molecular pathways disrupted in leukemic blasts with high FLT3/ITD-ARs. Copy-neutral loss of heterozygosity (CN-LOH) was identified at the FLT3 locus in diagnostic samples with high FLT3/ITD-ARs (N=11), but not in samples with low FLT3/ITD-ARs (N=24), FLT3-activating loop mutations (N=11) or wild-type FLT3 (N=39). Single-cell assays showed that homozygous FLT3/ITD genotype was present in subsets of leukemic blasts at diagnosis but became the dominant clone at relapse. Less differentiated CD34(+)/CD33(-) progenitor colonies were heterozygous for FLT3/ITD, whereas more differentiated CD34(+)/CD33(+) progenitor colonies were homozygous for FLT3/ITD. Expression profiling revealed that samples harboring high FLT3/ITD-ARs aberrantly expressed genes within the recombination/DNA repair pathway. Thus, the development of CN-LOH at the FLT3 locus, which results in high FLT3/ITD-ARs, likely represents a late genomic event that occurs after the acquisition of the FLT3/ITD. Although the etiology underlying the development of CN-LOH remains to be clarified, the disruption in recombination/DNA repair pathway, which is present before the development of LOH, may have a role. PMID:24786392

  18. Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML

    PubMed Central

    Stirewalt, D L; Pogosova-Agadjanyan, E L; Tsuchiya, K; Joaquin, J; Meshinchi, S

    2014-01-01

    Patients with high FLT3 internal tandem duplication allelic ratios (FLT3/ITD-ARs) have a poor prognosis. Single-nucleotide polymorphism/comparative genomic hybridization, single-cell PCR and colony-forming assays were used to evaluate genotypic evolution of high FLT3/ITD-ARs in 85 acute myeloid leukemia (AML) patients. Microarrays were used to examine molecular pathways disrupted in leukemic blasts with high FLT3/ITD-ARs. Copy-neutral loss of heterozygosity (CN-LOH) was identified at the FLT3 locus in diagnostic samples with high FLT3/ITD-ARs (N=11), but not in samples with low FLT3/ITD-ARs (N=24), FLT3-activating loop mutations (N=11) or wild-type FLT3 (N=39). Single-cell assays showed that homozygous FLT3/ITD genotype was present in subsets of leukemic blasts at diagnosis but became the dominant clone at relapse. Less differentiated CD34+/CD33− progenitor colonies were heterozygous for FLT3/ITD, whereas more differentiated CD34+/CD33+ progenitor colonies were homozygous for FLT3/ITD. Expression profiling revealed that samples harboring high FLT3/ITD-ARs aberrantly expressed genes within the recombination/DNA repair pathway. Thus, the development of CN-LOH at the FLT3 locus, which results in high FLT3/ITD-ARs, likely represents a late genomic event that occurs after the acquisition of the FLT3/ITD. Although the etiology underlying the development of CN-LOH remains to be clarified, the disruption in recombination/DNA repair pathway, which is present before the development of LOH, may have a role. PMID:24786392

  19. Numerical impairment of nestin(+) bone marrow niches in acute GvHD after allogeneic hematopoietic stem cell transplantation for AML.

    PubMed

    Medinger, M; Krenger, W; Jakab, A; Halter, J; Buser, A; Bucher, C; Passweg, J; Tzankov, A

    2015-11-01

    The nestin(+) perivascular bone marrow (BM) stem cell niche (N(+)SCN) may be involved in GvHD. To investigate whether acute GvHD (aGvHD) reduces the number of N(+)SCN, we examined patients with AML who had undergone allogeneic hematopoietic stem cell transplantation. In the test cohort (n=8), the number of N(+)SCN per mm(2) in BM biopsies was significantly reduced in aGvHD patients at the time of aGvHD compared with patients who did not have aGvHD (1.2±0.78 versus 2.6±0.93, P=0.04). In the validation cohort (n=40), the number of N(+)SCN was reduced (1.9±0.99 versus 2.6±0.90 N(+)SCN/mm(2), P=0.05) in aGvHD patients. Receiver operating curves suggested that the cutoff score that best discriminated between patients with and without aGvHD was 2.29 N(+)SCN/mm(2). Applying this cutoff score, 9/11 patients with clinically relevant aGvHD (⩾grade 2) and 13/20 with any type of GvHD had decreased N(+)SCN numbers compared with only 10/29 patients without clinically relevant aGvHD (P=0.007) and 6/20 patients without any type of GvHD (P=0.028). In patients tracked over time, N(+)SCN density returned to normal after aGvHD resolved or remained stable in patients who did not have aGvHD. Our results show a decrease in the number of N(+)SCN in aGvHD. PMID:26301968

  20. Star in Deep Freeze Chills Theory, MIT Researchers Report

    NASA Astrophysics Data System (ADS)

    2001-09-01

    CAMBRIDGE, Mass. -- Like a frozen turkey that just won't thaw, a strange star near the center of the Milky Way is surprising MIT experts and colleagues with its remarkably low temperature. The odd behavior is chilling current theories of stellar physics. A famously battered neutron star named KS 1731-260 appears no hotter than some of its tranquil brethren, despite enduring the heat of constant thermonuclear explosions with the force of billions of hydrogen bombs every second across a region only a few miles wide for the past 12 years. Dr. Rudi Wijnands, an astrophysicist at MIT's Center for Space Research, used the Chandra X-ray Observatory to measure the temperature of the neutron star at a very opportune moment, only months after the nuclear war apparently ended and the smoke cleared. He presented his team's findings September 5 in Washington, D.C. at a scientific conference entitled "Two Years of Science with Chandra." "Twelve years of constant thermonuclear explosions: One would think that would heat things up," said Wijnands. "This leaves us wondering whether some neutron stars are in the freezer for a much longer time than previously thought and consequently take a long time to heat up, or whether they cool down incredibly fast. Either explanation has profound implications for our field." Neutron stars are the dense, core remains of stars once many times more massive than our Sun. They are created in dazzling supernovas, in which the outer shell of the star explodes into space, and the core, containing about as much mass as the Sun, implodes and collapses into a sphere no wider than Cambridge, Massachusetts. Despite their tiny size, neutron stars are visible in several ways. One is through accretion. Neutron stars are a strong source of gravity. When they exist in binary star systems, such as KS 1731-260, they can attract the gas from what is often a "healthy" hydrogen-burning companion star (although the nature of KS 1731-260's companion is not clear.) Gas

  1. Having Fun with Physics at the MIT Plasma Science and Fusion Center

    NASA Astrophysics Data System (ADS)

    Rivenberg, P.; Thomas, P.; Censabella, V.; Granville, J.; Nachtrieb, R.; Gangadhara, S.

    1997-11-01

    MIT Plasma Science and Fusion Center staff and students are convinced that students learn best not by studying but by doing. This was the impetus behind a group of MIT graduate students who created Cambridge Physics Outlet, a PSFC spin-off company dedicated to creating hands-on experiments. The same impulse fostered the award-winning Mr. Magnet Program, a traveling presentation which uses a hands-on strategy to engage elementary school children. A number of ingenious experiments will be demonstrated. The PSFC maintains a Home Page on the World Wide Web, which can be reached at HTTP://PFC.MIT.EDU.

  2. BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3-TKI in AML cells expressing FLT-ITD.

    PubMed

    Fiskus, Warren; Sharma, Sunil; Qi, Jun; Shah, Bhavin; Devaraj, Santhana G T; Leveque, Christopher; Portier, Bryce P; Iyer, Swaminathan; Bradner, James E; Bhalla, Kapil N

    2014-10-01

    Recently, treatment with bromodomain and extraterminal protein antagonist (BA) such as JQ1 has been shown to inhibit growth and induce apoptosis of human acute myelogenous leukemia (AML) cells, including those expressing FLT3-ITD. Here, we demonstrate that cotreatment with JQ1 and the FLT3 tyrosine kinase inhibitor (TKI) ponatinib or AC220 synergistically induce apoptosis of cultured and primary CD34(+) human AML blast progenitor cells (BPC) expressing FLT3-ITD. Concomitantly, as compared with each agent alone, cotreatment with JQ1 and the FLT3-TKI caused greater attenuation of c-MYC, BCL2, and CDK4/6. Simultaneously, cotreatment with JQ1 and the FLT3-TKI increased the levels of p21, BIM, and cleaved PARP, as well as mediated marked attenuation of p-STAT5, p-AKT, and p-ERK1/2 levels in AML BPCs. Conversely, cotreatment with JQ1 and FLT3-TKI was significantly less active against CD34(+) normal bone marrow progenitor cells. Knockdown of BRD4 by short hairpin RNA also sensitized AML cells to FLT3-TKI. JQ1 treatment induced apoptosis of mouse Ba/F3 cells ectopically expressing FLT3-ITD with or without FLT3-TKI-resistant mutations F691L and D835V. Compared with the parental human AML FLT3-ITD-expressing MOLM13, MOLM13-TKIR cells resistant to AC220 were markedly more sensitive to JQ1-induced apoptosis. Furthermore, cotreatment with JQ1 and the pan-histone deacetylase inhibitor (HDI) panobinostat synergistically induced apoptosis of FLT3-TKI-resistant MOLM13-TKIR and MV4-11-TKIR cells. Collectively, these findings support the rationale for determining the in vivo activity of combined therapy with BA and FLT3-TKI against human AML cells expressing FLT3-ITD or with BA and HDI against AML cells resistant to FLT3-TKI. PMID:25053825

  3. Solution of the inverse problem of magnetic induction tomography (MIT).

    PubMed

    Merwa, Robert; Hollaus, Karl; Brunner, Patricia; Scharfetter, Hermann

    2005-04-01

    Magnetic induction tomography (MIT) of biological tissue is used to reconstruct the changes in the complex conductivity distribution inside an object under investigation. The measurement principle is based on determining the perturbation DeltaB of a primary alternating magnetic field B0, which is coupled from an array of excitation coils to the object under investigation. The corresponding voltages DeltaV and V0 induced in a receiver coil carry the information about the passive electrical properties (i.e. conductivity, permittivity and permeability). The reconstruction of the conductivity distribution requires the solution of a 3D inverse eddy current problem. As in EIT the inverse problem is ill-posed and on this account some regularization scheme has to be applied. We developed an inverse solver based on the Gauss-Newton-one-step method for differential imaging, and we implemented and tested four different regularization schemes: the first and second approaches employ a classical smoothness criterion using the unit matrix and a differential matrix of first order as the regularization matrix. The third method is based on variance uniformization, and the fourth method is based on the truncated singular value decomposition. Reconstructions were carried out with synthetic measurement data generated with a spherical perturbation at different locations within a conducting cylinder. Data were generated on a different mesh and 1% random noise was added. The model contained 16 excitation coils and 32 receiver coils which could be combined pairwise to give 16 planar gradiometers. With 32 receiver coils all regularization methods yield fairly good 3D-images of the modelled changes of the conductivity distribution, and prove the feasibility of difference imaging with MIT. The reconstructed perturbations appear at the right location, and their size is in the expected range. With 16 planar gradiometers an additional spurious feature appears mirrored with respect to the median

  4. Internationalizing Practical ChE Education: The M.I.T. Practice School in Japan.

    ERIC Educational Resources Information Center

    O'Connor, Andrea J.; Kandas, Angelo W.; Natori, Yukikazu; Hatton, T. Alan

    1999-01-01

    Describes the establishment, benefits, and difficulties of an overseas branch of the Massachusetts Institute of Technology's (MIT) chemical engineering Practice School for student internship study at the Mitsubishi Chemical Corporation's Mizushima Plant in Kurashiki, Japan. (WRM)

  5. Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial.

    PubMed

    Middeke, J M; Herbst, R; Parmentier, S; Bug, G; Hänel, M; Stuhler, G; Schäfer-Eckart, K; Rösler, W; Klein, S; Bethge, W; Bitz, U; Büttner, B; Knoth, H; Alakel, N; Schaich, M; Morgner, A; Kramer, M; Sockel, K; von Bonin, M; Stölzel, F; Platzbecker, U; Röllig, C; Thiede, C; Ehninger, G; Bornhäuser, M; Schetelig, J

    2016-02-01

    In patients with relapsed or refractory (r/r) acute myeloid leukemia (AML), long-term disease control can only be achieved by allogeneic hematopoietic stem cell transplantation (HSCT). We studied the safety and efficacy of clofarabine-based salvage therapy. The study was designed as phase II, multicenter, intent-to-transplant (ITT) study. A total of 84 patients with r/r AML were enrolled. All patients received at least one cycle of CLARA (clofarabine 30 mg/m(2) and cytarabine 1 g/m(2), days 1-5). Chemo-responsive patients with a donor received HSCT in aplasia after first CLARA. Generally, HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine (4 × 30 mg/m(2)) and melphalan (140 mg/m(2)). The median patient age was 61 years (range 40-75). On day 15 after start of CLARA, 26% of patients were in a morphologically leukemia-free state and 79% exposed a reduction in bone marrow blasts. Overall, 67% of the patients received HSCT within the trial. The primary end point, defined as complete remission after HSCT, was achieved by 60% of the patients. According to the ITT, overall survival at 2 years was 43% (95% confidence interval (CI), 32-54%). The 2-year disease-free survival for transplanted patients was 52% (95% CI, 40-69%). Clofarabine-based salvage therapy combined with allogeneic HSCT in aplasia shows promising results in patients with r/r AML. PMID:26283567

  6. Research Experiences for Undergraduates at MIT Haystack Observatory

    NASA Astrophysics Data System (ADS)

    Salah, J. E.; Erickson, P. J.; Pratap, P.

    2005-12-01

    Initiated in 1987, the NSF-supported Research Experiences for Undergraduates (REU) program at MIT Haystack Observatory has provided internships in upper atmospheric physics and radio astronomy to over 150 science and engineering students recruited nationally. Post-REU surveys by Haystack indicate that the majority of the students elected to pursue graduate education and careers in science and engineering, with many of them citing the REU program as an important influence in their decision process. During their internships at Haystack, the students have utilized the Observatory's radar and radio telescope facilities and analyzed the resulting measurements, they developed instrumentation or software that were implemented as part of our projects, and they participated in professional conferences where they presented their project results. Mentored by a Haystack researcher, each undergraduate student selected a research project that was part of the Observatory's overall program and became engaged in a full research experience from inception to publication. The students also interacted with local area pre-college teachers and students who were actively pursuing educational outreach programs at Haystack that were synergistic with the REU efforts.

  7. Lessons learned from the MIT Tara control and data system

    SciTech Connect

    Gaudreau, M.P.J.; Sullivan, J.D.; Fredian, T.W.; Irby, J.H.; Karcher, C.A.; Rameriz, R.A.; Sevillano, E.; Stillerman, J.A.; Thomas, P.

    1987-10-01

    The control and data system of the MIT Tara Tandem Mirror has worked successfully throughout the lifetime of the experiment (1983 through 1987). As the Tara project winds down, it is appropriate to summarize the lessons learned from the implementation and operation of the control and data system over the years and in its final form. The control system handled approx.2400 I/0 points in real time throughout the 5 to 10 minute shot cycle while the data system, in near real time, handled approx.1000 signals with a total of 5 to 7 Mbytes of data each shot. The implementation depended upon a consistent approach based on separating physics and engineering functions and on detailed functional diagrams with narrowly defined cross communication. This paper is a comprehensive treatment of the principal successes, residual problems, and dilemmas that arose from the beginning until the final hardware and software implementation. Suggestions for future systems of either similar size or of larger scale such as CIT are made in the conclusion. 11 refs., 1 fig.

  8. Educational Outreach at the MIT Plasma Science and Fusion Center

    NASA Astrophysics Data System (ADS)

    Rivenberg, Paul; Thomas, Paul

    2006-10-01

    At the MIT PSFC, student and staff volunteers work together to increase the public's knowledge of fusion science and plasma technology. Seeking to generate excitement in young people about science and engineering, the PSFC hosts a number of educational outreach activities throughout the year, including Middle and High School Outreach Days. The PSFC also has an in-school science demonstration program on the theme of magnetism. The Mr. Magnet Program, headed by Mr. Paul Thomas, has been bringing lively demonstrations on magnetism into local elementary and middle schools for 15 years. This year Mr. Magnet presented the program to nearly 30,000 students at over 67 schools and other events, reaching kindergartners through college freshmen. In addition to his program on magnetism, he is offering an interactive lecture about plasma to high schools. The "Traveling Plasma Lab" encourages students to learn more about plasma science while having fun investigating plasma properties using actual laboratory techniques and equipment. Beyond the classroom, Paul Thomas has provided technical training for Boston Museum of Science staff in preparation for the opening of a Star Wars exhibit. His hands-on demos have also been filmed by the History Channel for a one-hour program about Magnetism, which aired in June 2006.

  9. Echtzeit-Ultraschallsimulation auf Grafik-Prozessoren mit CUDA

    NASA Astrophysics Data System (ADS)

    Reichl, Tobias; Passenger, Josh; Acosta, Oscar; Salvado, Olivier

    Trotz der zunehmenden Verbreitung jüngerer bildgebender Verfahren bleibt medizinischer Ultraschall (US) weiterhin ein wichtiges Hilfsmittel bei chirurgischen Eingriffen und der klinischen Diagnose. Viele US-gestützte medizinische Prozeduren erfordern allerdings ausgiebiges Training, so dass es wünschenswert ist, eine realistische Simulation von US-Bildern zur Verfügung zu stellen. Im Gegensatz zu früheren Ansätzen simulieren wir solche Bilder auf der "Graphics Processing Unit“. Wir erweitern hierzu eine Methode, die von Wein et al. für die Abschätzung von US-Reflexionen aus Daten der Computertomographie (CT) vorgeschlagen wurde, zu einer leichter zu berechnenden Form. Zusätzlich schätzen wir die US-Absorption aus den CT-Daten ab. Mit Hilfe von NVIDIAs "Compute Unified Device Architecture“ (CUDA) simulieren wir Reflexion, Verschattung, Rauschen und radiale Unschärfe, ausgehend von unbearbeiteten CT-Daten in Echtzeit und ohne Vorausberechnung.

  10. Interactions and relevance of blast percentage and treatment strategy among younger and older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

    PubMed

    DiNardo, Courtney D; Garcia-Manero, Guillermo; Pierce, Sherry; Nazha, Aziz; Bueso-Ramos, Carlos; Jabbour, Elias; Ravandi, Farhad; Cortes, Jorge; Kantarjian, Hagop

    2016-02-01

    Acute myeloid leukemia (AML) is defined as ≥20% myeloblasts, representing a change from original guidelines where ≤30% blasts were considered as myelodysplastic syndromes (MDS), and 20-29% blasts classified as refractory anemia with excess blasts in transformation (RAEB-T). Whether the diagnostic bone marrow blast percentage has current value with regards to patient prognostication or identification of optimal treatment strategies is unclear. We retrospectively studied 1652 treatment-naïve adults with MDS or AML and ≥10% blasts from January 2000 to April 2014. Patients with 20-29% blasts were more similar to MDS patients in terms of advanced age, increased frequency of poor-risk cytogenetics, lower WBC count, and less frequent NPM1 and FLT3-ITD mutations. Median overall survival of MDS and RAEB-T were similar, 16.0 and 16.0 months, compared to 13.5 months for AML with ≥30% blasts (P = 0.045). Multivariate analysis showed inferior survival with increased age (HR 1.81 age 60-69, HR 2.68 age ≥70, P < 0.0005); poor-risk cytogenetics (HR 2.25, P < 0.0005); therapy-related disease (HR 1.44, P < 0.0005); and markers of proliferative disease including WBC ≥25 × 10(9) /L (HR 1.35, P = 0.0003), elevated LDH count (HR 1.24, P = 0.0015), and peripheral blasts (HR 1.25, P = 0.004). Among younger patients (≤60 years), intensive AML-type therapy resulted in similar outcomes regardless of blast percentage, suggesting this to be optimal therapy in this context. Among older patients (≥70 years), patients with 20-29% blasts had similar outcomes to patients with <20% blasts, and better than those with ≥30% blasts. In addition, among older patients, epigenetic therapy provided at least equivalent outcome to intensive chemotherapy. PMID:26799610

  11. [Correlation of NPM1, FLT3-ITD mutations with leukocyte count and myeloblasts percentage in AML patients with normal karyotype].

    PubMed

    Su, Long; Li, Wei; Cui, Jiu-Wei; Tan, Ye-Hui; Yang, Yan; Liu, Xiao-Liang; Yu, Ping; Hu, Rui-Ping; Wang, Li-Li; Gao, Su-Jun

    2013-06-01

    This study was aimed to investigate the correlation of NPM1 and FLT3-ITD mutations with leukocyte count in peripheral blood and bone marrow blasts in patients with acute myeloid leukemia (AML). Fifty-one acute myeloid leukemia patients with normal karyotype from January 2009 to December 2011 were enrolled in this study. The clinical data of 51 cases were analyzed retrospectively. Out of 52 cases 22 were male, and 29 were female. The median age was 47 years old (ranged from 14 to 83 years old). The de novo patients were examined by bone marrow cytomorphology and blood routine analysis. Polymerase chain reaction was used to analyze the NPM1 and FLT3-ITD mutations. The results showed that the patients with NPM1 mutations had higher leukocyte count compared with those without mutations (30.7×10(9)/L vs 8.6×10(9)/L, P = 0.002). FLT3-ITD mutation was related to higher leukocyte count (42.38×10(9)/L vs 11.45×10(9)/L without mutation, P = 0.033) and blasts (74.0% vs 60.25% without mutation, P = 0.036). The leukocyte count and percentage of bone marrow blasts were lowest in the patients with neither mutations, and gradually increasing in the NPM1(-) mutation, FLT3-ITD(-) mutation, and NPM1(+) mutation, FLT3-ITDI(+) mutation, and NPM1(+)/FLT3-ITD(+) mutation groups (P < 0.05). The patients tended to have NPM1 (P = 0.002) and FLT3-ITD (P = 0.033) mutations when their leukocyte counts were more than 12.55×10(9)/L and 37.85×10(9)/L, respectively. Those with bone marrow blast more than 72.25% showed higher rate of FLT3-ITD mutation (P = 0.008). Patients with NPM1 mutations had higher complete remission rate than those without NPM1 mutation (78.13% vs 40.0%, χ(2) = 4.651, P = 0.031) after remission induction therapy. It is concluded that both NPM1 and FLT3-ITD mutations are linked to higher leukocyte count and blast percentage, suggesting that both mutations may be associated with increased proliferation of leukemia cells, and may have a synergistic function in stimulating

  12. High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML.

    PubMed

    Zhao, Yue; Liu, Qi; Acharya, Pankaj; Stengel, Kristy R; Sheng, Quanhu; Zhou, Xiaofan; Kwak, Hojoong; Fischer, Melissa A; Bradner, James E; Strickland, Stephen A; Mohan, Sanjay R; Savona, Michael R; Venters, Bryan J; Zhou, Ming-Ming; Lis, John T; Hiebert, Scott W

    2016-08-16

    Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML. PRO-seq also identified an enhancer 3' to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRNAs, including MIR29C and MIR29B2, that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was upregulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET-inhibitor-induced cell death. PMID:27498870

  13. Identification of an inversion 16 coexisting with an isochromosome 22q by in situ hybridization in a case of childhood AML M4e.

    PubMed

    Gad, S G; Callen, D F; Kuss, B; Downing, J R; Behm, F; Head, D; Ribeiro, R C; Raimondi, S C

    1993-10-01

    Rearrangements involving chromosome 16, including inv(16) (p13q22), del(16)(q22), and t(16;16)(p13;q22), are frequent findings in acute myeloblastic leukemia (AML). Each of these rearrangements can occur as the sole karyotypic change or in association with additional chromosomal abnormalities, including in decreasing order of frequency: trisomy 22, trisomy 8, and deletion of the long arm of chromosome 7. We report a pediatric case of de novo AML, M4e subtype, with a unique combination of inv(16) (p13q22) and i(22q) occurring within the same leukemic clone. The inv(16) was detected by fluorescence in situ hybridization (FISH) analysis with two cosmid probes specific for sequences flanking the inv(16) breakpoint on the long arm of chromosome 16. Use of a chromosome-22-specific painting probe unequivocally identified a small metacentric chromosome as an i(22q). This case illustrates a variation in the association of trisomy 22 with inv(16) and suggests that duplication of the long arm of chromosome 22 may contain critical gene(s) involved in the multistep process of evolution of leukemia with 16q22 abnormalities. PMID:8412329

  14. The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial.

    PubMed

    Burnett, Alan K; Milligan, Donald; Goldstone, Anthony; Prentice, Archibald; McMullin, Mary-Frances; Dennis, Michael; Sellwood, Elizabeth; Pallis, Monica; Russell, Nigel; Hills, Robert K; Wheatley, Keith

    2009-05-01

    The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m(2) vs. 35 mg/m(2); (ii) Cytarabine 200 mg/m(2) vs. 400 mg/m(2) in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m(2) were also randomized to receive, or not, the multidrug resistance modulator PSC-833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5-year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC-833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC-833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress. PMID:19291085

  15. Daunorubicin Versus Mitoxantrone Versus Idarubicin As Induction and Consolidation Chemotherapy for Adults With Acute Myeloid Leukemia: The EORTC and GIMEMA Groups Study AML-10

    PubMed Central

    Mandelli, Franco; Vignetti, Marco; Suciu, Stefan; Stasi, Roberto; Petti, Maria-Concetta; Meloni, Giovanna; Muus, Petra; Marmont, Filippo; Marie, Jean-Pierre; Labar, Boris; Thomas, Xavier; Di Raimondo, Francesco; Willemze, Roel; Liso, Vincenzo; Ferrara, Felicetto; Baila, Liliana; Fazi, Paola; Zittoun, Robert; Amadori, Sergio; de Witte, Theo

    2009-01-01

    Purpose To compare the antitumor efficacy of three different anthracyclines in combination with cytarabine and etoposide in adult patients with newly diagnosed acute myeloid leukemia (AML). Patients and Methods We randomly assigned 2,157 patients (age range, 15 to 60 years) to receive intensive induction-consolidation chemotherapy containing either daunorubicin, idarubicin, or mitoxantrone. After achieving complete remission (CR), patients were assigned to undergo either allogeneic or autologous stem-cell transplantation (SCT), depending on the availability of a sibling donor. Results The overall CR rate (69%) was similar in the three groups. Autologous SCT was performed in 37% of cases in the daunorubicin arm versus only 29% and 31% in mitoxantrone and idarubicin, respectively (P < .001). However, the disease-free survival (DFS) and survival from CR were significantly shorter in the daunorubicin arm: the 5-year DFS was 29% versus 37% and 37% in mitoxantrone and idarubicin, respectively. The proportion of patients who underwent allogeneic SCT (22%) was equivalent in the three treatment groups, and the outcome was similar as well: the 5-year overall survival rates were 34%, 34%, and 31%, respectively. Conclusion In adult patients with AML who do not receive an allogeneic SCT, the use of mitoxantrone or idarubicin instead of daunorubicin enhances the long-term efficacy of chemotherapy. PMID:19826132

  16. Toxicity and efficacy of busulfan and fludarabine myeloablative conditioning for HLA-identical sibling allogeneic hematopoietic cell transplantation in AML and MDS.

    PubMed

    De La Serna, J; Sanz, J; Bermúdez, A; Cabrero, M; Serrano, D; Vallejo, C; Gómez, V; Moraleda, J M; Perez, S G; Caballero, M D; Conde, E; Lahuerta, J J; Sanz, G

    2016-07-01

    The safety and efficacy of a 4-day myeloablative conditioning (MAC) regimen consisting of Bu 3.2 mg/kg and fludarabine 40 mg/m(2)/day for HLA-identical sibling allogeneic hematopoietic cell transplantation (HCT) in myeloid malignancies was investigated in 133 patients (median age, 47 years; range 19-74 years) with de novo AML (60%), secondary AML (20%) or myelodysplastic syndrome (20%). All patients engrafted. Hepatic veno-occlusive disease occurred in five patients (4%), and severe toxicities, mostly mucositis, occurred in twenty-three (17%) patients. The non-relapse mortality (NRM) at 100 days was 1.5%. The incidences of acute GVHD grade 2-4 and grade 3-4 were 32 and 13%, respectively. At a median follow-up of 38 months, the cumulative incidence of chronic GVHD was 67%. The relapse incidence was 30% (27 and 31%, respectively, in patients with early- and late-stage disease), and the overall NRM was 15%. The actuarial 4-year disease-free survival (DFS) and overall survival (OS) were 54 and 62%, respectively. Patients aged <50 years had better outcomes compared with older patients (DFS 64 vs 42%, P=0.006; OS 73 vs 47%, P<0.001, respectively). PMID:26950372

  17. Nucleosome Presence at AML-1 Binding Sites Inversely Correlates with Ly49 Expression: Revelations from an Informatics Analysis of Nucleosomes and Immune Cell Transcription Factors

    PubMed Central

    Ioshikhes, Ilya; Makrigiannis, Andrew P.

    2016-01-01

    Beyond its role in genomic organization and compaction, the nucleosome is believed to participate in the regulation of gene transcription. Here, we report a computational method to evaluate the nucleosome sensitivity for a transcription factor over a given stretch of the genome. Sensitive factors are predicted to be those with binding sites preferentially contained within nucleosome boundaries and lacking 10 bp periodicity. Based on these criteria, the Acute Myeloid Leukemia-1a (AML-1a) transcription factor, a regulator of immune gene expression, was identified as potentially sensitive to nucleosomal regulation within the mouse Ly49 gene family. This result was confirmed in RMA, a cell line with natural expression of Ly49, using MNase-Seq to generate a nucleosome map of chromosome 6, where the Ly49 gene family is located. Analysis of this map revealed a specific depletion of nucleosomes at AML-1a binding sites in the expressed Ly49A when compared to the other, silent Ly49 genes. Our data suggest that nucleosome-based regulation contributes to the expression of Ly49 genes, and we propose that this method of predicting nucleosome sensitivity could aid in dissecting the regulatory role of nucleosomes in general. PMID:27124577

  18. Do AML patients with DNMT3A exon 23 mutations benefit from idarubicin as compared to daunorubicin? A single center experience

    PubMed Central

    Sarry, Jean-Emmanuel; Mansat-De Mas, Véronique; Dobbelstein, Sophie; Dastugue, Nicole; Strzelecki, Anne-Claire; Cavelier, Cindy; Creancier, Laurent; Pillon, Arnaud; Kruczynski, Anna; Demur, Cécile; Sarry, Audrey; Huguet, Françoise; Huynh, Anne

    2011-01-01

    Mutations in DNMT3A encoding DNA methyltransferase 3A were recently described in patients with acute myeloid leukemia. To assess their prognostic significance, we determined the mutational status of DNMT3A exon 23 in 288 patients with AML excluding acute promyelocytic leukemia, aged from 18 to 65 years and treated in Toulouse University Hospital. A mutation was detected in 39 patients (13.5%). All DNMT3A exon 23+ patients had intermediate-risk cytogenetics. Mutations significantly correlated with a higher WBC count (p<0.001), NPM1 (p<0.001) and FLT3-ITD mutations (p=0.027). DNMT3A mutations were conserved through xenotransplantation in immunodeficient mice. No difference in outcome between DNMT3A exon 23+ and DNMT3A exon 23- patients was found even if the results were stratified by NPM1 or FLT3-ITD status. However, DNMT3A exon 23+ patients had better median DFS (not reached vs 11.6 months, p=0.009) and OS (not reached vs 14.3 months, p=0.005) as compared to DNMT3A exon 23- patients when treated with idarubicin, whereas patients treated with daunorubicin had similar outcome regardless the DNMT3A status. This study shows that DNMT3A mutations have no impact on outcome but could be a predictive factor for response to idarubicin and thus, could have a direct influence in the way AML patients should be managed. PMID:22081665

  19. A t(16;21)(p11;q22) in Acute Myeloid Leukemia (AML) Resulting in Fusion of the FUS/TLS and ERG Genes: A Review of the Literature.

    PubMed

    Buchanan, Justin; Tirado, Carlos A

    2016-01-01

    The t(16;21)(p11;q22) is a rare chromosomal abnormality that appears in approximately 1% of acute myeloid leukemia (AML) cases. Previously, between 50 and 60 cases have been reported. In this review, we will discuss the literature regarding t(16;21) as well as cases published. We compiled 68 cases from the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer as well as 10 additional cases in the literature, for a total of 78 cases. The t(16;21) results in the TLS(FUS)-ERG fusion protein, which is believed to function as a transcriptional activator in leukemogenesis and has been demonstrated to interfere in normal pre-mRNA splicing functions of FUS/TLS. Reverse-transcriptase polymerase chain reaction of fusion transcripts in patients, has been demonstrated to have diagnostic significance in monitoring for minimal residual disease. Cytogenetically, about half of the cases had secondary chromosomal abnormalities; we found that trisomy 8 and 10 were the most common abnormalities, occurring in 9.1% of the otal cases for each. t(16;21) in AML has been described with various morphological features, such as phagocytosis and vacuolation, and is present in multiple FAB types. Immunophenotypic characteristics such as CD33 and CD34 expression have also been noted, and several studies have examined the relation between CD56 receptor expression and t(16;21) AML. In general, t(16;21) in AML is associated with a poor prognosis and this abnormality could serve as cytogenetic indicator in determining diagnosis and prognosis. Herein, we summarize the cytogenetic features found in the the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer for t(16;21) in AML, as well as review the current literature associated with t(16;21), AML and its features. PMID:27183148

  20. Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF)1

    PubMed Central

    Bekdash, Amira; Darwish, Manal; Timsah, Zahra; Kassab, Elias; Ghanem, Hadi; Najjar, Vicky; Ghosn, Marwan; Nasser, Selim; El-Hajj, Hiba; Bazerbachi, Ali; Liu, Shihui; Leppla, Stephen H.; Frankel, Arthur E.; Abi-Habib, Ralph J.

    2015-01-01

    In this study, we attempt to target both the urokinase plasminogen activator and the mitogen-activated protein kinase pathway in acute myeloid leukemia (AML) cell lines and primary AML blasts using PrAgU2/LF, a urokinase-activated anthrax lethal toxin. PrAgU2/LF was cytotoxic to five out of nine AML cell lines. Cytotoxicity of PrAgU2/LF appeared to be nonapoptotic and was associated with MAPK activation and urokinase activity because all the PrAgU2/LF-sensitive cell lines showed both uPAR expression and high levels of MEK1/2 phosphorylation. Inhibition of uPAR or desensitization of cells to MEK1/2 inhibition blocked toxicity of PrAgU2/LF, indicating requirement for both uPAR expression and MAPK activation for activity. PrAgU2/LF was also cytotoxic to primary blasts from AML patients, with blasts from four out of five patients showing a cytotoxic response to PrAgU2/LF. Cytotoxicity of primary AML blasts was also dependent on uPAR expression and phos-MEK1/2 levels. CD34+ bone marrow blasts and peripheral blood mononuclear cells lacked uPAR expression and were resistant to PrAgU2/LF, demonstrating the lack of toxicity to normal hematological cells and, therefore, the tumor selectivity of this approach. Dose escalation in mice revealed that the maximal tolerated dose of PrAgU2/LF is at least 5.7-fold higher than that of the wild-type anthrax lethal toxin, PrAg/LF, further demonstrating the increased safety of this molecule. We have shown, in this study, that PrAgU2/LF is a novel, dual-specific molecule for the selective targeting of AML. PMID:26500025

  1. Knocking down mitochondrial iron transporter (MIT) reprograms primary and secondary metabolism in rice plants

    PubMed Central

    Vigani, Gianpiero; Bashir, Khurram; Ishimaru, Yasuhiro; Lehmann, Martin; Casiraghi, Fabio Marco; Nakanishi, Hiromi; Seki, Motoaki; Geigenberger, Peter; Zocchi, Graziano; Nishizawa, Naoko K.

    2016-01-01

    Iron (Fe) is an essential micronutrient for plant growth and development, and its reduced bioavailability strongly impairs mitochondrial functionality. In this work, the metabolic adjustment in the rice (Oryza sativa) mitochondrial Fe transporter knockdown mutant (mit-2) was analysed. Biochemical characterization of purified mitochondria from rice roots showed alteration in the respiratory chain of mit-2 compared with wild-type (WT) plants. In particular, proteins belonging to the type II alternative NAD(P)H dehydrogenases accumulated strongly in mit-2 plants, indicating that alternative pathways were activated to keep the respiratory chain working. Additionally, large-scale changes in the transcriptome and metabolome were observed in mit-2 rice plants. In particular, a strong alteration (up-/down-regulation) in the expression of genes encoding enzymes of both primary and secondary metabolism was found in mutant plants. This was reflected by changes in the metabolic profiles in both roots and shoots of mit-2 plants. Significant alterations in the levels of amino acids belonging to the aspartic acid-related pathways (aspartic acid, lysine, and threonine in roots, and aspartic acid and ornithine in shoots) were found that are strictly connected to the Krebs cycle. Furthermore, some metabolites (e.g. pyruvic acid, fumaric acid, ornithine, and oligosaccharides of the raffinose family) accumulated only in the shoot of mit-2 plants, indicating possible hypoxic responses. These findings suggest that the induction of local Fe deficiency in the mitochondrial compartment of mit-2 plants differentially affects the transcript as well as the metabolic profiles in root and shoot tissues. PMID:26685186

  2. Knocking down mitochondrial iron transporter (MIT) reprograms primary and secondary metabolism in rice plants.

    PubMed

    Vigani, Gianpiero; Bashir, Khurram; Ishimaru, Yasuhiro; Lehmann, Martin; Casiraghi, Fabio Marco; Nakanishi, Hiromi; Seki, Motoaki; Geigenberger, Peter; Zocchi, Graziano; Nishizawa, Naoko K

    2016-03-01

    Iron (Fe) is an essential micronutrient for plant growth and development, and its reduced bioavailability strongly impairs mitochondrial functionality. In this work, the metabolic adjustment in the rice (Oryza sativa) mitochondrial Fe transporter knockdown mutant (mit-2) was analysed. Biochemical characterization of purified mitochondria from rice roots showed alteration in the respiratory chain of mit-2 compared with wild-type (WT) plants. In particular, proteins belonging to the type II alternative NAD(P)H dehydrogenases accumulated strongly in mit-2 plants, indicating that alternative pathways were activated to keep the respiratory chain working. Additionally, large-scale changes in the transcriptome and metabolome were observed in mit-2 rice plants. In particular, a strong alteration (up-/down-regulation) in the expression of genes encoding enzymes of both primary and secondary metabolism was found in mutant plants. This was reflected by changes in the metabolic profiles in both roots and shoots of mit-2 plants. Significant alterations in the levels of amino acids belonging to the aspartic acid-related pathways (aspartic acid, lysine, and threonine in roots, and aspartic acid and ornithine in shoots) were found that are strictly connected to the Krebs cycle. Furthermore, some metabolites (e.g. pyruvic acid, fumaric acid, ornithine, and oligosaccharides of the raffinose family) accumulated only in the shoot of mit-2 plants, indicating possible hypoxic responses. These findings suggest that the induction of local Fe deficiency in the mitochondrial compartment of mit-2 plants differentially affects the transcript as well as the metabolic profiles in root and shoot tissues. PMID:26685186

  3. A New Tool for Inundation Modeling: Community Modeling Interface for Tsunamis (ComMIT)

    NASA Astrophysics Data System (ADS)

    Titov, V. V.; Moore, C. W.; Greenslade, D. J. M.; Pattiaratchi, C.; Badal, R.; Synolakis, C. E.; Kânoğlu, U.

    2011-11-01

    Almost 5 years after the 26 December 2004 Indian Ocean tragedy, the 10 August 2009 Andaman tsunami demonstrated that accurate forecasting is possible using the tsunami community modeling tool Community Model Interface for Tsunamis (ComMIT). ComMIT is designed for ease of use, and allows dissemination of results to the community while addressing concerns associated with proprietary issues of bathymetry and topography. It uses initial conditions from a precomputed propagation database, has an easy-to-interpret graphical interface, and requires only portable hardware. ComMIT was initially developed for Indian Ocean countries with support from the United Nations Educational, Scientific, and Cultural Organization (UNESCO), the United States Agency for International Development (USAID), and the National Oceanic and Atmospheric Administration (NOAA). To date, more than 60 scientists from 17 countries in the Indian Ocean have been trained and are using it in operational inundation mapping.

  4. MITR-III: Upgrade and relicensing studies for the MIT Research Reactor. Second annual report

    SciTech Connect

    Trosman, H.G.; Lanning, D.D.; Harling, O.K.

    1994-08-01

    The current operating license of the MIT research reactor will expire on May 7, 1996 or possibly a few years later if the US Nuclear Regulatory Commission agrees that the license period can start with the date of initial reactor operation. Driven by the imminent expiration of the operating license, a team of nuclear engineering staff and students have begun a study of the future options for the MIT Research Reactor. These options have included the range from a major rebuilding of the reactor to its decommissioning. This document reports the results of a two year intensive activity which has been supported by a $148,000 grant from the USDOE contract Number DEFG0293ER75859, approximately $100,000 of internal MIT funds and Nuclear Engineering Department graduate student fellowships as well as assistance from international visiting scientists and engineers.

  5. Immunohistochemistry and molecular analyses in myeloid sarcoma of the breast in a patient with relapse of NPM1-mutated and FLT3-mutated AML after allogeneic stem cell transplantation.

    PubMed

    Choschzick, Matthias; Bacher, Ulrike; Ayuk, Francis; Lebeau, Annette

    2010-06-01

    Myeloid sarcoma of the breast is a rare manifestation of acute myeloid leukaemia (AML). This report describes a patient who was diagnosed with AML FAB M2. Molecular analysis showed evidence of an NPM1 mutation (subtype A) and internal tandem duplications of the FLT3 gene (FLT3-ITD). Eight months after allogeneic stem cell transplantation, the patient developed a palpable mass in the left breast initially suspected as breast carcinoma. Core needle biopsy of the lesion resulted in diagnosis of myeloid sarcoma. Molecular analysis of formalin-fixed specimens of the breast tumour confirmed the known FLT3 and NPM1 gene mutations. Immunohistochemically, an aberrant cytoplasmic staining pattern for NPM1 and overexpression of FLT3 were demonstrated. The myeloid sarcoma showed complete transient resolution following treatment with the kinase inhibitor sorafenib. However, the patient developed bone marrow relapse and died in fatal cerebral haemorrhage 1 year after initial diagnosis of AML. In summary, combined molecular and immunohistochemical examination of NPM1 and FLT3 is helpful in the diagnosis of extramedullary manifestations of AML in core needle biopsies. PMID:20360144

  6. Center for Multiscale Plasma Dynamics: Report on Activities (UCLA/MIT), 2009-2010

    SciTech Connect

    Troy Carter

    2011-04-18

    The final 'phaseout' year of the CMPD ended July 2010; a no cost extension was requested until May 2011 in order to enable the MIT subcontract funds to be fully utilized. Research progress over this time included verification and validation activities for the BOUT and BOUT++ code, studies of spontaneous reconnection in the VTF facility at MIT, and studies of the interaction between Alfven waves and drift waves in LAPD. The CMPD also hosted the 6th plasma physics winter school in 2010 (jointly with the NSF frontier center the Center for Magnetic Self-Organization, significant funding came from NSF for this most recent iteration of the Winter School).

  7. 193-nm full-field step-and-scan prototype at MIT Lincoln Laboratory

    NASA Astrophysics Data System (ADS)

    Hibbs, Michael S.; Kunz, Roderick R.

    1995-05-01

    Optical lithography at a 193-nm exposure wavelength has been under development at MIT Lincoln Laboratory for several years, supported by ARPA's Advanced Lithography Program. As part of this program, a prototype 193-nm full-field step-and-scan lithographic exposure system was built and installed in the clean-room facilities of MIT Lincoln Laboratory. This exposure system has now been in use for one year, supporting a program of photoresist and lithographic process development at 193 nm. This paper describes the characteristics of the exposure system and some of the advances in 193-nm lithography that have been achieved with the system.

  8. Novel evidence that pituitary gonadotropins directly stimulate human leukemic cells-studies of myeloid cell lines and primary patient AML and CML cells

    PubMed Central

    Abdelbaset-Ismail, Ahmed; Borkowska, Sylwia; Janowska-Wieczorek, Anna; Tonn, Torsten; Rodriguez, Cesar; Moniuszko, Marcin; Bolkun, Lukasz; Koloczko, Janusz; Eljaszewicz, Andrzej; Ratajczak, Janina; Ratajczak, Mariusz Z.; Kucia, Magda

    2016-01-01

    We recently reported that normal hematopoietic stem cells express functional pituitary sex hormone (SexH) receptors. Here we report for the first time that pituitary-secreted gonadotrophins stimulate migration, adhesion, and proliferation of several human myeloid and lymphoid leukemia cell lines. Similar effects were observed after stimulation of human leukemic cell lines by gonadal SexHs. This effect seems to be direct, as the SexH receptors expressed by leukemic cells responded to stimulation by phosphorylation of MAPKp42/44 and AKTser473. Furthermore, in parallel studies we confirmed that human primary patient-derived AML and CML blasts also express several functional SexH receptors. These results shed more light on the potential role of SexHs in leukemogenesis and, in addition, provide further evidence suggesting a developmental link between hematopoiesis and the germline. PMID:26701888

  9. Novel evidence that pituitary gonadotropins directly stimulate human leukemic cells-studies of myeloid cell lines and primary patient AML and CML cells.

    PubMed

    Abdelbaset-Ismail, Ahmed; Borkowska, Sylwia; Janowska-Wieczorek, Anna; Tonn, Torsten; Rodriguez, Cesar; Moniuszko, Marcin; Bolkun, Lukasz; Koloczko, Janusz; Eljaszewicz, Andrzej; Ratajczak, Janina; Ratajczak, Mariusz Z; Kucia, Magda

    2016-01-19

    We recently reported that normal hematopoietic stem cells express functional pituitary sex hormone (SexH) receptors. Here we report for the first time that pituitary-secreted gonadotrophins stimulate migration, adhesion, and proliferation of several human myeloid and lymphoid leukemia cell lines. Similar effects were observed after stimulation of human leukemic cell lines by gonadal SexHs. This effect seems to be direct, as the SexH receptors expressed by leukemic cells responded to stimulation by phosphorylation of MAPKp42/44 and AKTser473. Furthermore, in parallel studies we confirmed that human primary patient-derived AML and CML blasts also express several functional SexH receptors. These results shed more light on the potential role of SexHs in leukemogenesis and, in addition, provide further evidence suggesting a developmental link between hematopoiesis and the germline. PMID:26701888

  10. Amplified segment in the 'Down syndrome critical region' on HSA21 shared between Down syndrome and euploid AML-M0 excludes RUNX1, ERG and ETS2.

    PubMed

    Canzonetta, Claudia; Hoischen, Alexander; Giarin, Emanuela; Basso, Guiseppe; Veltman, Joris A; Nacheva, Elisabeth; Nizetic, Dean; Groet, Jürgen

    2012-04-01

    Children with Down syndrome have a 20- to 50-fold increased risk of acute lymphocytic or myeloid leukaemia. Whole or partial gains of chromosome 21 have been described in multiple childhood leukaemias, and have recently been reported as a likely primary event in B-precursor-acute lymphoblastic leukaemia. It is unclear which amplified gene(s) on chromosome 21 play a key role in leukaemia progression. We describe a minimal amplified segment within the so-called 'Down syndrome critical region' shared between two cases of AML-M0; a Down syndrome, and a constitutionally normal individual. Interestingly, the amplified region does not include the oncogenes RUNX1, ETS2 and ERG. PMID:22221250

  11. Fabrication of water-soluble polymer-encapsulated As4S4 to increase oral bioavailability and chemotherapeutic efficacy in AML mice

    PubMed Central

    Ma, Qiang; Wang, Chuan; Li, Xiaojin; Guo, Hua; Meng, Jie; Liu, Jian; Xu, Haiyan

    2016-01-01

    Realgar (As4S4) has been demonstrated to be effective for the treatment of acute myeloid leukemia (AML); it has the advantages of no drug resistance and oral administration. Nevertheless, its poor solubility has been an obstacle to its bioavailability, requiring high-dose administration over a long period. We investigated whether crushing realgar crystals to the nanoscale and encapsulating the particles in a water-soluble polymer in one step using hot-melt extrusion would increase the bioavailability of As4S4. Raw As4S4 (r-As4S4) and water-soluble polymer were processed via co-rotating twin screw extrusion. The resulting product (e-As4S4) was characterized by SEM, XRD, and DLS. The cytotoxicity and therapeutic effects of e-As4S4 were evaluated in vivo and in vitro. The results show that e-As4S4 dissolved rapidly in water, forming a stable colloid solution. The average size of e-As4S4 particles was 680 nm, which was reduced by more than 40-fold compared with that of r-As4S4. The bioavailability of e-As4S4 was up to 12.6-fold higher than that of r-As4S4, and it inhibited the proliferation of HL-60 cells much more effectively than did r-As4S4, inducing apoptosis and significantly reducing the infiltration of HL-60 cells into the bone marrow, spleen, and liver. This in turn prolonged the survival of AML mice. PMID:27383126

  12. Comparison of the cytotoxicity of cladribine and clofarabine when combined with fludarabine and busulfan in AML cells: Enhancement of cytotoxicity with epigenetic modulators.

    PubMed

    Valdez, Benigno C; Li, Yang; Murray, David; Ji, Jie; Liu, Yan; Popat, Uday; Champlin, Richard E; Andersson, Borje S

    2015-06-01

    Clofarabine (Clo), fludarabine (Flu), and busulfan (Bu) combinations are efficacious in hematopoietic stem cell transplantation for myeloid leukemia. We sought to determine whether the more affordable drug cladribine (Clad) can provide a viable alternative to Clo, with or without panobinostat (Pano) and 5-aza-2'-deoxycytidine (DAC). Both Clad+Flu+Bu and Clo+Flu+Bu combinations showed synergistic cytotoxicity in KBM3/Bu250(6), HL60, and OCI-AML3 cell lines. Cell exposure to these drug combinations resulted in 60%-80% inhibition of proliferation; activation of the ATM pathway; increase in histone modifications; decrease in HDAC3, HDAC4, HDAC5 and SirT7 proteins; decrease in mitochondrial membrane potential; activation of apoptosis and stress signaling pathways; and downregulation of the AKT pathway. These drug combinations activated DNA-damage response and apoptosis in primary cell samples from AML patients. At lower concentrations of Clad/Clo, Flu, and Bu, inclusion of Pano and DAC enhanced cell killing, increased histone modifications and DNA demethylation, and increased the levels of P16/INK4a, P15/INK4b and P21/Waf1/Cip1 proteins. The observed DNA demethylating activity of Clad and Clo may complement DAC activity; increase demethylation of the gene promoters for SFRP1, DKK3, and WIF1; and cause degradation of β-catenin in cells exposed to Clad/Clo+Flu+Bu+DAC+Pano. The overlapping activities of Clad/Clo+Flu+Bu, Pano, and DAC in DNA-damage formation and repair, histone modifications, DNA demethylation, and apoptosis may underlie their synergism. Our results provide a basis for supplanting Clo with Clad and for including epigenetic modifiers in the pre-hematopoietic stem cell transplantation conditioning regimen for myeloid leukemia patients. PMID:25704054

  13. Fabrication of water-soluble polymer-encapsulated As4S4 to increase oral bioavailability and chemotherapeutic efficacy in AML mice.

    PubMed

    Ma, Qiang; Wang, Chuan; Li, Xiaojin; Guo, Hua; Meng, Jie; Liu, Jian; Xu, Haiyan

    2016-01-01

    Realgar (As4S4) has been demonstrated to be effective for the treatment of acute myeloid leukemia (AML); it has the advantages of no drug resistance and oral administration. Nevertheless, its poor solubility has been an obstacle to its bioavailability, requiring high-dose administration over a long period. We investigated whether crushing realgar crystals to the nanoscale and encapsulating the particles in a water-soluble polymer in one step using hot-melt extrusion would increase the bioavailability of As4S4. Raw As4S4 (r-As4S4) and water-soluble polymer were processed via co-rotating twin screw extrusion. The resulting product (e-As4S4) was characterized by SEM, XRD, and DLS. The cytotoxicity and therapeutic effects of e-As4S4 were evaluated in vivo and in vitro. The results show that e-As4S4 dissolved rapidly in water, forming a stable colloid solution. The average size of e-As4S4 particles was 680 nm, which was reduced by more than 40-fold compared with that of r-As4S4. The bioavailability of e-As4S4 was up to 12.6-fold higher than that of r-As4S4, and it inhibited the proliferation of HL-60 cells much more effectively than did r-As4S4, inducing apoptosis and significantly reducing the infiltration of HL-60 cells into the bone marrow, spleen, and liver. This in turn prolonged the survival of AML mice. PMID:27383126

  14. Residual disease detected by flow cytometry is an independent predictor of survival in childhood acute myeloid leukaemia; results of the NOPHO-AML 2004 study.

    PubMed

    Tierens, Anne; Bjørklund, Elizabeth; Siitonen, Sanna; Marquart, Hanne Vibeke; Wulff-Juergensen, Gitte; Pelliniemi, Tarja-Terttu; Forestier, Erik; Hasle, Henrik; Jahnukainen, Kirsi; Lausen, Birgitte; Jonsson, Olafur G; Palle, Josefine; Zeller, Bem; Fogelstrand, Linda; Abrahamsson, Jonas

    2016-08-01

    Early response after induction is a prognostic factor for disease outcome in childhood acute myeloid leukaemia (AML). Residual disease (RD) detection by multiparameter flow cytometry (MFC) was performed at day 15 and before consolidation therapy in 101 patients enrolled in the Nordic Society of Paediatric Haemato-Oncology AML 2004 study. A multicentre laboratory approach to RD analysis was used. Event-free survival (EFS) and overall survival (OS) was significantly different in patients with and without RD at both time points, using a 0·1% RD cut-off level. RD-negative and -positive patients after first induction showed a 5-year EFS of 65 ± 7% and 22 ± 7%, respectively (P < 0·001) and an OS of 77 ± 6% (P = 0·025) and 51 ± 8%. RD-negative and -positive patients at start of consolidation therapy had a 5-year EFS of 57 ± 7% and 11 ± 7%, respectively (P < 0·001) and an OS of 78 ± 6% and 28 ± 11%) (P < 0·001). In multivariate analysis only RD was significantly correlated with survival. RD before consolidation therapy was the strongest independent prognostic factor for EFS [hazard ratio (HR):5·0; 95% confidence interval (CI):1·9-13·3] and OS (HR:7·0; 95%CI:2·0-24·5). In conclusion, RD before consolidation therapy identifies patients at high risk of relapse in need of intensified treatment. In addition, RD detection can be performed in a multicentre setting and can be implemented in future trials. PMID:27072379

  15. Mit1 Transcription Factor Mediates Methanol Signaling and Regulates the Alcohol Oxidase 1 (AOX1) Promoter in Pichia pastoris*

    PubMed Central

    Wang, Xiaolong; Wang, Qi; Wang, Jinjia; Bai, Peng; Shi, Lei; Shen, Wei; Zhou, Mian; Zhou, Xiangshan; Zhang, Yuanxing; Cai, Menghao

    2016-01-01

    The alcohol oxidase 1 (AOX1) promoter (PAOX1) of Pichia pastoris is the most powerful and commonly used promoter for driving protein expression. However, mechanisms regulating its transcriptional activity are unclear. Here, we identified a Zn(II)2Cys6-type methanol-induced transcription factor 1 (Mit1) and elucidated its roles in regulating PAOX1 activity in response to glycerol and methanol. Mit1 regulated the expression of many genes involved in methanol utilization pathway, including AOX1, but did not participate in peroxisome proliferation and transportation of peroxisomal proteins during methanol metabolism. Structural analysis of Mit1 by performing domain deletions confirmed its specific and critical role in the strict repression of PAOX1 in glycerol medium. Importantly, Mit1, Mxr1, and Prm1, which positively regulated PAOX1 in response to methanol, were bound to PAOX1 at different sites and did not interact with each other. However, these factors cooperatively activated PAOX1 through a cascade. Mxr1 mainly functioned during carbon derepression, whereas Mit1 and Prm1 functioned during methanol induction, with Prm1 transmitting methanol signal to Mit1 by binding to the MIT1 promoter (PMIT1), thus increasingly expressing Mit1 and subsequently activating PAOX1. PMID:26828066

  16. Mit1 Transcription Factor Mediates Methanol Signaling and Regulates the Alcohol Oxidase 1 (AOX1) Promoter in Pichia pastoris.

    PubMed

    Wang, Xiaolong; Wang, Qi; Wang, Jinjia; Bai, Peng; Shi, Lei; Shen, Wei; Zhou, Mian; Zhou, Xiangshan; Zhang, Yuanxing; Cai, Menghao

    2016-03-18

    The alcohol oxidase 1 (AOX1) promoter (PAOX1) of Pichia pastoris is the most powerful and commonly used promoter for driving protein expression. However, mechanisms regulating its transcriptional activity are unclear. Here, we identified a Zn(II)2Cys6-type methanol-induced transcription factor 1 (Mit1) and elucidated its roles in regulating PAOX1 activity in response to glycerol and methanol. Mit1 regulated the expression of many genes involved in methanol utilization pathway, including AOX1, but did not participate in peroxisome proliferation and transportation of peroxisomal proteins during methanol metabolism. Structural analysis of Mit1 by performing domain deletions confirmed its specific and critical role in the strict repression of PAOX1 in glycerol medium. Importantly, Mit1, Mxr1, and Prm1, which positively regulated PAOX1 in response to methanol, were bound to PAOX1 at different sites and did not interact with each other. However, these factors cooperatively activated PAOX1 through a cascade. Mxr1 mainly functioned during carbon derepression, whereas Mit1 and Prm1 functioned during methanol induction, with Prm1 transmitting methanol signal to Mit1 by binding to the MIT1 promoter (PMIT1), thus increasingly expressing Mit1 and subsequently activating PAOX1. PMID:26828066

  17. Effectivity of a strategy in elderly AML patients to reach allogeneic stem cell transplantation using intensive chemotherapy: Long-term survival is dependent on complete remission after first induction therapy.

    PubMed

    von dem Borne, P A; de Wreede, L C; Halkes, C J M; Marijt, W A F; Falkenburg, J H F; Veelken, H

    2016-07-01

    Intensive chemotherapy followed by allogeneic stem cell transplantation (alloSCT) can cure AML. Most studies on alloSCT in elderly AML report results of highly selected patient cohorts. Hardly any data exist on the effectiveness of prospective strategies intended to bring as many patients as possible to transplant. Between 2006 and 2011 we implemented a treatment algorithm for all newly diagnosed AML patients aged 61-75 years, consisting of intensive chemotherapy cycles to induce complete remission, followed by alloSCT. 44 of 60 (73%) newly diagnosed elderly AML patients started with chemotherapy. By meticulously following our algorithm in almost all patients, we could induce complete remission (CR) in 66% of patients starting with chemotherapy, and transplant 32% of these patients in continuous CR. Main reasons for failure were early relapse (16%), early death (14%), primary refractory disease (9%), and patient or physician decision to stop treatment (16%). Patients in continuous CR after first induction benefit most with 36% long-term survival. Patients not in CR after first induction benefit less; although additional chemotherapy induces CR in 45% of these patients, only 23% are transplanted and no long-term survival is observed, mainly due to relapse. Long-term survival in the group of 44 patients is 9% (median 4.5 years after alloSCT). Considering that 27% of patients do not start with chemotherapy and 64% of patients starting with chemotherapy do not reach alloSCT, the reasons for failure presented here should be used as a guide to develop new treatment algorithms to improve long-term survival in elderly AML patients. PMID:27123833

  18. Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism.

    PubMed

    Krupka, C; Kufer, P; Kischel, R; Zugmaier, G; Lichtenegger, F S; Köhnke, T; Vick, B; Jeremias, I; Metzeler, K H; Altmann, T; Schneider, S; Fiegl, M; Spiekermann, K; Bauerle, P A; Hiddemann, W; Riethmüller, G; Subklewe, M

    2016-02-01

    Bispecific T-cell engagers (BiTEs) are very effective in recruiting and activating T cells. We tested the cytotoxicity of the CD33/CD3 BiTE antibody construct AMG 330 on primary acute myeloid leukemia (AML) cells ex vivo and characterized parameters contributing to antileukemic cytolytic activity. The E:T ratio and the CD33 expression level significantly influenced lysis kinetics in long-term cultures of primary AML cells (n=38). AMG 330 induced T-cell-mediated proinflammatory conditions, favoring the upregulation of immune checkpoints on target and effector cells. Although not constitutively expressed at the time of primary diagnosis (n=123), PD-L1 was strongly upregulated on primary AML cells upon AMG 330 addition to ex vivo cultures (n=27, P<0.0001). This phenomenon was cytokine-driven as the sole addition of interferon (IFN)-γ and tumor necrosis factor-α also induced expression. Through blockade of the PD-1/PD-L1 interaction, AMG 330-mediated lysis (n=9, P=0.03), T-cell proliferation (n=9, P=0.01) and IFN-γ secretion (n=8, P=0.008) were significantly enhanced. The combinatorial approach was most beneficial in settings of protracted AML cell lysis. Taken together, we have characterized a critical resistance mechanism employed by primary AML cells under AMG 330-mediated proinflammatory conditions. Our results support the evaluation of checkpoint molecules in upcoming clinical trials with AMG 330 to enhance BiTE antibody construct-mediated cytotoxicity. PMID:26239198

  19. How Much Have They Retained? Making Unseen Concepts Seen in a Freshman Electromagnetism Course at MIT

    ERIC Educational Resources Information Center

    Dori, Yehudit Judy; Hult, Erin; Breslow, Lori; Belcher, John W.

    2007-01-01

    The introductory freshmen electromagnetism course at MIT has been taught since 2000 using a studio physics format entitled TEAL--Technology Enabled Active Learning. TEAL has created a collaborative, hands-on environment where students carry out desktop experiments, submit web-based assignments, and have access to a host of visualizations and…

  20. When Alcohol Kills, Who Is Responsible? MIT's Inaction Blamed for Contributing to Death of a Freshman.

    ERIC Educational Resources Information Center

    Reisberg, Leo

    1998-01-01

    The alcohol-related death of a Massachusetts Institute of Technology (MIT) freshman has focused attention on problems in the institution's housing policies and fraternity system, including unclear policy about housing and long-ignored complaints about hazing and dangerous drinking in the Greek system. (MSE)

  1. The MIT-Hawaii-IRTF Joint Campaign for NEO Spectral Reconnaissance

    NASA Technical Reports Server (NTRS)

    Binzel, R. P.; Rivkin, A. S.; Thomas, C. A.; DeMeo, F. E.; Tokunaga, A.; Bus, S. J.

    2005-01-01

    We describe a new joint observing program for routine measurement of near-Earth object (NEO) spectra being conducted by MIT, the University of Hawaii, and the NASA Infrared Telescope Facility (IRTF) on Mauna Kea, Hawaii. All spectroscopic observations obtained in this campaign are being made publicly available in near-real time.

  2. Graduate Training and Potential Employment for Political Scientists: The MIT Perspective.

    ERIC Educational Resources Information Center

    Altshuler, Alan

    This paper presents ideas on ways to help graduate students in political science to become more marketable for nonacademic positions. It also includes background information on the changing employment market for Ph.D.'s. These ideas were discussed at a 1980 meeting of teachers, graduate students, and recent Ph.D.'s at MIT. The purpose of the…

  3. Rapid Confirmation of Listeria spp. with the MIT 1000 Microbial Identification System

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Methods that can rapidly confirm the identification of foodborne pathogens are highly desired. The USDA has recently entered into a collaborative research agreement with Micro Imaging Technology to evaluate their MIT 1000 microbial identification system for its ability to identify Listeria species ...

  4. NASIC at MIT; Phase 1 Report, 16 July 1973 - 28 February 1974.

    ERIC Educational Resources Information Center

    Benenfeld, Alan R.; And Others

    An experimental, pilot operation of computer-based reference search services to users on a fee-for-service basis was initiated at M.I.T. as the first module in the development of the Northeast Academic Science Information Center (NASIC) under a New England Board of Higher Education (NEBHE) program. The development encompassed, among other tasks,…

  5. Lithium-metal infused trenches (LiMIT) for heat removal in fusion devices

    NASA Astrophysics Data System (ADS)

    Ruzic, D. N.; Xu, W.; Andruczyk, D.; Jaworski, M. A.

    2011-10-01

    Observation of liquid lithium flow in metal trenches has been made using a lithium-metal infused trench (LiMIT) tile and is reported here. The flow is self-pumping and uses thermoelectric magnetohydrodynamics to remove heated lithium and replenish it at a lower temperature. Flow velocities have been measured and compared with theoretical predictions.

  6. ComMIT and Tweb Integration: Global Tsunami Modeling Done Locally

    NASA Astrophysics Data System (ADS)

    Kamb, L.; Moore, C. W.; Burger, E. F.

    2014-12-01

    Tweb is a web-based tsunami modeling research tool that was developed to provide distributed and remote access to the modeling and forecasting infrastructure developed for operational use at NOAA's Center for Tsunami Research (NCTR). ComMIT is a desktop application providing a powerful and fully functional, yet easy-to use graphical user interface to the NCTR-developed MOST tsunami forecasting model. ComMIT is a self-contained downloadable application available from NCTR for use by qualified and novice modelers alike. We have recently added functionality that allows ComMIT to retrieve the prefered model solution for tsunami events from the Tweb Web Service. A ComMIT user with access to high resolution coastal bathymetry can generate detailed inundation models for real or synthetic events for their areas of interest. Then with the push of a button, the ComMIT user can upload their model results to Tweb where a community of tsunami modelers and forecasters can see these model results displayed in Tweb, along with other operational and contributed inundation forecast models. Besides the crowdsourcing aspect of tsunami modeling that will allow tsunami forecasters to get inundation model inputs from areas they normally would not consider, these contributed flooding models could provide forecasters with an early model solution verification capability by allowing model result comparisons with local tide gauge data in areas where operational models have not been developed. In addition, with the proper training this tool is very useful for education and as a vehicle for community tsunami hazard assessment. We will illustrate the model solution and results interchange capabilities now possible with these two applications.

  7. Optimization of the matrix inversion tomosynthesis (MITS) impulse response and modulation transfer function characteristics for chest imaging

    SciTech Connect

    Godfrey, Devon J.; McAdams, H.P.; Dobbins, James T. III

    2006-03-15

    Matrix inversion tomosynthesis (MITS) uses linear systems theory, along with a priori knowledge of the imaging geometry, to deterministically distinguish between true structure and overlying tomographic blur in a set of conventional tomosynthesis planes. In this paper we examine the effect of total scan angle (ANG), number of input projections (N), and plane separation/number of reconstructed planes (NP) on the MITS impulse response (IR) and modulation transfer function (MTF), with the purpose of optimizing MITS imaging of the chest. MITS IR and MTF data were generated by simulating the imaging of a very thin wire, using various combinations of ANG, N, and NP. Actual tomosynthesis data of an anthropomorphic chest phantom were acquired with a prototype experimental system, using the same imaging parameter combinations as those in the simulations. Thoracic projection data from two human subjects were collected for corroboration of the system response analysis in vivo. Results suggest that ANG=20 deg. , N=71, NP=69 is the optimal combination for MITS chest imaging given the inherent constraints of our prototype system. MITS chest data from human subjects demonstrates that the selected imaging strategy can effectively produce high-quality MITS thoracic images in vivo.

  8. FLT3 and NPM1 mutations in a cohort of AML patients and detection of a novel mutation in tyrosine kinase domain of FLT3 gene from Western India.

    PubMed

    Ghosh, Kanjaksha; Swaminathan, Suchitra; Madkaikar, Manisha; Gupta, Maya; Kerketta, Lily; Vundinti, Baburao

    2012-11-01

    Acute myeloid leukemia (AML) is an aggressive hematological disorder characterized by the loss of ability of the hematopoietic progenitor cells to differentiate and proliferate normally leading to an accumulation of immature myeloid cells in the bone marrow. Several novel molecular genetic aberrations in FLT3 and NPM1 have been shown to have a prognostic impact in AML, particularly in those having normal karyotype. Though there is substantial amount of data on these mutations from western literature, there is surprisingly little data from Indian subcontinent on the frequency of this mutation in AML patients from India. The present study screens a large cohort of non-acute promyelocytic leukemia (APL) AML patients (207 patients) for the presence of FLT3 and NPM1 mutations and further correlates with cytogenetics, immunophenotypic characteristics and with follow-up data wherever available. During the course of study, 56 APL patients were also studied. Briefly, both FLT3 (internal tandem duplication (ITD) in 19.4% and tyrosine kinase domain (TKD) in 9%) and NPM1 mutations were detected in 28.4% of the total non-APL AML patients screened showing distinct correlations with hematologic, immunophenotypic, cytogenetics characteristics and follow-up. With regards to adult APL patients, 22.2 and 32.6% of the patients showed FLT3 and NPM1 mutation, respectively. In the pediatrics age group (<15 years), 23 and 16% of patients with APL showed FLT3 and NPM1 mutation, respectively, while in non-APL patient is this age group, 23% of patients showed both FLT3 and NPM1 mutation. NPM1 mutation was distinctly uncommon in younger age group of patients. In contrast to report elsewhere, most of our FLT3 mutation was in exon 11 rather than in exon 12. FLT3 mutation due to ITD or TKD mutation was detected in 2:1 ratio in our patients and a new TKD mutation was also detected S840G in an M5 patient who did not go into remission and had a short survival of 3 months from diagnosis. Generally

  9. Nanomedical strategy to prolong survival period, heighten cure rate, and lower systemic toxicity of S180 mice treated with MTX/MIT.

    PubMed

    Song, Ning; Zhao, Ming; Wang, Yuji; Hu, Xi; Wu, Jianhui; Jiang, Xueyun; Li, Shan; Cui, Chunying; Peng, Shiqi

    2016-01-01

    In spite of the usual combination form of methotrexate (MTX)/mitoxantrone (MIT) and various complex combination regimens of MTX/MIT with other anticancer drugs, the survival period, cure rate, and systemic toxicity still need to be improved. For this purpose, a nanostructured amino group-modified mesoporous silica nanoparticles (MSNN)-MTX/MIT was designed. In the preparation, the surface of mesoporous silica nanoparticles (MSNs) was modified with amino groups to form MSNN. The covalent modification of the amino groups on the surface of MSNN with MTX resulted in MSNN-MTX. The loading of MIT into the surface pores of MSNN-MTX produced nanostructured MSNN-MTX/MIT. Compared with the usual combination form (MTX/MIT), nanostructured MSNN-MTX/MIT increased the survival period greatly, heightened the cure rate to a great extent, and lowered the systemic toxicity of the treated S180 mice, significantly. These superior in vivo properties of nanostructured MSNN-MTX/MIT over the usual combination form (MTX/MIT) were correlated with the former selectively releasing MTX and MIT in tumor tissue and inside cancer cells in vitro. The chemical structure and the nanostructure of MSNN-MTX/MIT were characterized using infrared and differential scanning calorimeter spectra as well as transmission electron microscope images, respectively. PMID:27621591

  10. Nanomedical strategy to prolong survival period, heighten cure rate, and lower systemic toxicity of S180 mice treated with MTX/MIT

    PubMed Central

    Song, Ning; Zhao, Ming; Wang, Yuji; Hu, Xi; Wu, Jianhui; Jiang, Xueyun; Li, Shan; Cui, Chunying; Peng, Shiqi

    2016-01-01

    In spite of the usual combination form of methotrexate (MTX)/mitoxantrone (MIT) and various complex combination regimens of MTX/MIT with other anticancer drugs, the survival period, cure rate, and systemic toxicity still need to be improved. For this purpose, a nanostructured amino group-modified mesoporous silica nanoparticles (MSNN)−MTX/MIT was designed. In the preparation, the surface of mesoporous silica nanoparticles (MSNs) was modified with amino groups to form MSNN. The covalent modification of the amino groups on the surface of MSNN with MTX resulted in MSNN−MTX. The loading of MIT into the surface pores of MSNN−MTX produced nanostructured MSNN−MTX/MIT. Compared with the usual combination form (MTX/MIT), nanostructured MSNN−MTX/MIT increased the survival period greatly, heightened the cure rate to a great extent, and lowered the systemic toxicity of the treated S180 mice, significantly. These superior in vivo properties of nanostructured MSNN−MTX/MIT over the usual combination form (MTX/MIT) were correlated with the former selectively releasing MTX and MIT in tumor tissue and inside cancer cells in vitro. The chemical structure and the nanostructure of MSNN−MTX/MIT were characterized using infrared and differential scanning calorimeter spectra as well as transmission electron microscope images, respectively. PMID:27621591

  11. HLA-Identical Sibling Allogeneic Transplants versus Chemotherapy in Acute Myelogenous Leukemia with t(8;21) in First Complete Remission: Collaborative Study Between the German AML Intergroup and CIBMTR

    PubMed Central

    Schlenk, Richard F.; Pasquini, Marcelo C.; Pérez, Waleska S.; Zhang, Mei-Jie; Krauter, Jürgen; Antin, Joseph H.; Bashey, Asad; Bolwell, Brian J.; Büchner, Thomas; Cahn, Jean-Yves; Cairo, Mitchell S.; Copelan, Edward A.; Cutler, Corey S.; Döhner, Hartmut; Gale, Robert Peter; Ilhan, Osman; Lazarus, Hillard M.; Liesveld, Jane L.; Litzow, Mark R.; Marks, David I.; Maziarz, Richard T.; McCarthy, Philip L.; Nimer, Stephen D.; Sierra, Jorge; Tallman, Martin S.; Weisdorf, Daniel J.; Horowitz, Mary M.; Ganser, Arnold

    2008-01-01

    We studied the role of HLA-matched sibling hematopoietic cell transplantation (HCT) in treating t(8;21) AML in first remission. Outcomes of 118 patients receiving HCT and reported to the Center for International Blood and Marrow Transplant Research were compared with 132 similar patients receiving chemotherapy selected from eight German AML Intergroup multicenter trials. Characteristics of the cohorts were similar except that chemotherapy recipients were significantly older. To adjust for time to treatment bias, outcomes were compared using left-truncated Cox regression models. Transplants were associated with higher treatment-related mortality [relative risk (RR) 6.76, 95% confidence interval (CI) 2.95–15.45, p<0.001], lower relapse (RR 0.47, 95% CI 0.25–0.85, p=0.01) and similar relapse-free survival (p=0.2). Loss of sex chromosomes (LOS) in addition to t(8;21) negatively impacted overall survival in patients receiving chemotherapy. Patients without LOS experienced shorter survival after HCT comparing to chemotherapy (RR 3.05, p=0.02), whereas patients with LOS had similar survival regardless of postremission therapy. In both cohorts, white blood cell count (WBC) at diagnosis > 25 x109/L was associated with a higher relapse risk (RR=2.09, p=0.03), lower relapse-free (RR=1.9, p=0.008) and overall survival (RR=1.91, p=0.01). In this cohort of patients with t(8;21) AML , HCT did not improve overall survival, since reduction of relapse was offset by high transplant-related mortality. In the group without LOS, survival after chemotherapy was far superior to HCT. These results suggest that patients with t(8;21) AML without poor prognostic factors have higher rates of survival after chemotherapy as a post remission therapy compared to HCT. PMID:18215779

  12. The MIT Accelerator Laboratory for Diagnostic Development for OMEGA, Z and the NIF

    NASA Astrophysics Data System (ADS)

    Petrasso, R.; Gatu Johnson, M.; Armstrong, E.; Orozco, D.; Rinderknecht, H. G.; Rojas Herrera, J.; Rosenberg, M.; Sio, H.; Zylstra, A.; Frenje, J.; Li, C. K.; Seguin, F. H.; Hahn, K.; Jones, B.; Ruiz, C. L.; Sangster, T. C.

    2014-10-01

    The MIT Linear Electrostatic Ion Accelerator generates D-D and D-3He fusion products, which are used for development of nuclear diagnostics for OMEGA, Z, and the NIF. Fusion reaction rates around 106 s-1 are routinely achieved with this accelerator, and fluence and energy of the fusion products are accurately characterized. Diagnostics developed and calibrated at this facility include CR-39 based charged-particle spectrometers, neutron detectors, and the particle Time-Of-Flight (pTOF) CVD-diamond-based bang time detector. The accelerator is also a vital tool in the education of graduate and undergraduate students at MIT. This work was supported in part by SNL, DOE, LLE and LLNL.

  13. Executing a program on the MIT tagged-token dataflow architecture

    SciTech Connect

    Arvind; Nikhil, R.S. . Lab. for Computer Science)

    1990-03-01

    The MIT tagged-token dataflow project has an unconventional, but integrated approach to general-purpose high-performance parallel computing. Rather than extending conventional sequential languages, the authors use Id, a high-level language with fine-grained parallelism and determinacy implicit in its operational semantics. Id programs are compiled to dynamic dataflow graphs, a parallel machine language. Dataflow graphs are directly executed on the MIT tagged-token dataflow architecture (TTDA), a novel multiprocessor architecture. Dataflow research has advanced significantly in the last few years; in this paper, the authors provide an overview of our current thinking, by describing example Id programs, their compilation to dataflow graphs, and their execution on the TTDA. Finally, the authors describe related work and the status of our project.

  14. Educational Outreach at the M.I.T. Plasma Fusion Center

    NASA Astrophysics Data System (ADS)

    Censabella, V.

    1996-11-01

    Educational outreach at the MIT Plasma Fusion Center consists of volunteers working together to increase the public's knowledge of fusion and plasma-related experiments. Seeking to generate excitement about science, engineering and mathematics, the PFC holds a number of outreach activities throughout the year, such as Middle and High School Outreach Days. Outreach also includes the Mr. Magnet Program, which uses an interactive strategy to engage elementary school children. Included in this year's presentation will be a new and improved C-MOD Jr, a confinement video game which helps students to discover how computers manipulate magnetic pulses to keep a plasma confined for as long as possible. Also on display will be an educational toy created by the Cambridge Physics Outlet, a PFC spin-off company. The PFC maintains a Home Page on the World Wide Web, which can be reached at http://cmod2.pfc.mit.edu/.

  15. Mutation or loss of Wilms' tumor gene 1 (WT1) are not major reasons for immune escape in patients with AML receiving WT1 peptide vaccination

    PubMed Central

    2010-01-01

    Background Efficacy of cancer vaccines may be limited due to immune escape mechanisms like loss or mutation of target antigens. Here, we analyzed 10 HLA-A2 positive patients with acute myeloid leukemia (AML) for loss or mutations of the WT1 epitope or epitope flanking sequences that may abolish proper T cell recognition or epitope presentation. Methods All patients had been enrolled in a WT1 peptide phase II vaccination trial (NCT00153582) and ultimately progressed despite induction of a WT1 specific T cell response. Blood and bone marrow samples prior to vaccination and during progression were analyzed for mRNA expression level of WT1. Base exchanges within the epitope sequence or flanking regions (10 amino acids N- and C-terminal of the epitope) were assessed with melting point analysis and sequencing. HLA class I expression and WT1 protein expression was analyzed by flow cytometry. Results Only in one patient, downregulation of WT1 mRNA by 1 log and loss of WT1 detection on protein level at time of disease progression was observed. No mutation leading to a base exchange within the epitope sequence or epitope flanking sequences could be detected in any patient. Further, no loss of HLA class I expression on leukemic blasts was observed. Conclusion Defects in antigen presentation caused by loss or mutation of WT1 or downregulation of HLA molecules are not the major basis for escape from the immune response induced by WT1 peptide vaccination. PMID:20092642

  16. NK cell killing of AML and ALL blasts by Killer-Immunoglobulin Receptor (KIR) negative NK cells after NKG2A and LIR-1 blockade

    PubMed Central

    Godal, Robert; Bachanova, Veronika; Gleason, Michelle; McCullar, Valarie; Yun, Gong H.; Cooley, Sarah; Verneris, Michael R.; McGlave, Philip B.; Miller, Jeffrey S.

    2010-01-01

    Although NK cell alloreactivity has been dominated by studies of KIR, we hypothesized that NKG2A and LIR-1, present on 53±13% and 36±18% of normal NK cells, plays a role in NK cell killing of primary leukemia targets. KIR− cells, which comprise nearly half of the circulating NK cell population, exhibited tolerance to primary leukemia targets, suggesting signaling through other inhibitory receptors. Both AML and ALL targets could be rendered susceptible to lysis by fresh resting KIR− NK cells when inhibitory receptor-MHC class I interactions were blocked by pan-HLA antibodies demonstrating that these cells were functionally competent. Blockade of a single inhibitory receptor resulted in slight increases in killing, while combined LIR-1 and NKG2A blockade consistently resulted in increased NK cell cytotoxicity. Dual blockade of NKG2A and LIR-1 led to significant killing of targets by resting KIR− NK cells showing that this population is not hyporesponsive. Together these results suggest that alloreactivity of a significant fraction of KIR− NK cells is determined by NKG2A and LIR-1. Thus strategies to interrupt NKG2A and LIR-1 in combination with anti-KIR blockade hold promise for exploiting NK cell therapy in acute leukemia. PMID:20139023

  17. A Natural Combination Extract of Viscum album L. Containing Both Triterpene Acids and Lectins Is Highly Effective against AML In Vivo

    PubMed Central

    Delebinski, Catharina I.; Twardziok, Monika; Kleinsimon, Susann; Hoff, Florian; Mulsow, Katharina; Rolff, Jana; Jäger, Sebastian; Eggert, Angelika; Seifert, Georg

    2015-01-01

    Aqueous Viscum album L. extracts are widely used in complementary cancer medicine. Hydrophobic triterpene acids also possess anti-cancer properties, but due to their low solubility they do not occur in significant amounts in aqueous extracts. Using cyclodextrins we solubilised mistletoe triterpenes (mainly oleanolic acid) and investigated the effect of a mistletoe whole plant extract on human acute myeloid leukaemia cells in vitro, ex vivo and in vivo. Single Viscum album L. extracts containing only solubilised triterpene acids (TT) or lectins (viscum) inhibited cell proliferation and induced apoptosis in a dose-dependent manner in vitro and ex vivo. The combination of viscum and TT extracts (viscumTT) enhanced the induction of apoptosis synergistically. The experiments demonstrated that all three extracts are able to induce apoptosis via caspase-8 and -9 dependent pathways with down-regulation of members of the inhibitor of apoptosis and Bcl-2 families of proteins. Finally, the acute myeloid leukaemia mouse model experiment confirmed the therapeutic effectiveness of viscumTT-treatment resulting in significant tumour weight reduction, comparable to the effect in cytarabine-treated mice. These results suggest that the combination viscumTT may have a potential therapeutic value for the treatment AML. PMID:26244918

  18. Amount of bone marrow blasts is strongly correlated to NPM1 and FLT3-ITD mutation rate in AML with normal karyotype.

    PubMed

    Haferlach, Torsten; Bacher, Ulrike; Alpermann, Tamara; Haferlach, Claudia; Kern, Wolfgang; Schnittger, Susanne

    2012-01-01

    FLT3-ITDs are linked to higher leukocytes/blasts in acute myeloid leukemia. To evaluate the effect of NPM1 mutations, we correlated NPM1mut status with morphology in 805 adult normal karyotype AML. NPM1mut were found in 391/805 (48.6%), FLT3-ITD in 219/805 (27.2%). Frequencies of FLT3-ITD and NPM1mut cases were continuously increasing by blast decades: NPM1mut from 38/123 (30.9%) in 20-29% blast decade to 70/103 (68.0%) in 90-100% decade (p<0.001), FLT3-ITDs from 15/123 (12.2%) to 58/103 (56.3%) (p<0.001). Mean WBC count was highest in NPM1-mut/FLT3-ITD-positive and lowest in NPM1-wildtype/FLT3-ITD-negative patients (p<0.0001); similar for BM blasts. Therefore, FLT3-ITD and NPM1mut might synergistically stimulate blast proliferation. PMID:21621842

  19. Can a Female Donor for a Male Recipient Decrease Relapse Rate for Patients with AML Treated with Allogeneic Hematopoietic Stem Cell Transplantation?

    PubMed Central

    Kongtim, Piyanuch; Di Stasi, Antonio; Rondon, Gabriela; Chen, Julianne; Adekola, Kehinde; Popat, Uday; Oran, Betul; Kebriaei, Partow; Andersson, Borje S.; Champlin, Richard E.; Ciurea, Stefan O.

    2015-01-01

    The mismatched minor histocompatibility antigens present on Y chromosome (H-Y) in male recipients receiving stem cells from female donors may contribute to graft-versus-leukemia effect (GVL) and results in reduce relapse rate especially in patients with high-risk disease. We retrospectively compared the outcomes of male AML patients who received an allogeneic hematopoietic stem cell transplant (HSCT) from female donors (F-M) (174 patients) versus other gender combinations (667 patients). Median age was 50 years (range 18–74 years). For the whole group, the one-year cumulative incidence of relapse was significantly lower in F-M group (34.1% versus 41.3%, p=0.044) while non-relapse mortality (NRM) was higher (23.2% versus 15.7%, p=0.004). For patients younger than 50 years beyond first complete remission, the F-M group was associated with lower relapse rate (42.5% versus 55.2%, p=0.045) whereas NRM was not significantly different (35.8% versus 25.5%, p=0.141). Although survival was not significantly improved, transplantation from a female donor for male recipient was associated with a lower relapse rate. When relapse is most common concern for treatment failure, especially for younger patients, a female donor for a male recipient might be beneficial to decrease relapse rate post-transplant. Future studies are needed to explore how H-Y mismatch may improve survival post-transplant. PMID:25540936

  20. The prognostic significance of early treatment response in pediatric relapsed acute myeloid leukemia: results of the international study Relapsed AML 2001/01

    PubMed Central

    Creutzig, Ursula; Zimmermann, Martin; Dworzak, Michael N.; Gibson, Brenda; Tamminga, Rienk; Abrahamsson, Jonas; Ha, Shau-Yin; Hasle, Henrik; Maschan, Alexey; Bertrand, Yves; Leverger, Guy; von Neuhoff, Christine; Razzouk, Bassem; Rizzari, Carmelo; Smisek, Petr; Smith, Owen P.; Stark, Batia; Reinhardt, Dirk; Kaspers, Gertjan L.

    2014-01-01

    The prognostic significance of early response to treatment has not been reported in relapsed pediatric acute myeloid leukemia. In order to identify an early and easily applicable prognostic factor allowing subsequent treatment modifications, we assessed leukemic blast counts in the bone marrow by morphology on days 15 and 28 after first reinduction in 338 patients of the international Relapsed-AML2001/01 trial. Both day 15 and day 28 status was classified as good (≤20% leukemic blasts) in 77% of patients. The correlation between day 15 and 28 blast percentages was significant, but not strong (Spearman correlation coefficient = 0.49, P<0.001). Survival probability decreased in a stepwise fashion along with rising blast counts at day 28. Patients with bone marrow blast counts at this time-point of ≤5%, 6–10%, 11–20% and >20% had 4-year probabilities of survival of 52%±3% versus 36%±10% versus 21%±9% versus 14%±4%, respectively, P<0.0001; this trend was not seen for day 15 results. Multivariate analysis showed that early treatment response at day 28 had the strongest prognostic significance, superseding even time to relapse (< or ≥12 months). In conclusion, an early response to treatment, measured on day 28, is a strong and independent prognostic factor potentially useful for treatment stratification in pediatric relapsed acute myeloid leukemia. This study was registered with ISRCTN code: 94206677. PMID:24763401

  1. Teleoperation experiments with a Utah/MIT hand and a VPL DataGlove

    NASA Technical Reports Server (NTRS)

    Clark, D.; Demmel, J.; Hong, J.; Lafferriere, Gerardo; Salkind, L.; Tan, X.

    1989-01-01

    A teleoperation system capable of controlling a Utah/MIT Dextrous Hand using a VPL DataGlove as a master is presented. Additionally the system is capable of running the dextrous hand in robotic (autonomous) mode as new programs are developed. The software and hardware architecture used is presented and the experiments performed are described. The communication and calibration issues involved are analyzed and applications to the analysis and development of automated dextrous manipulations are investigated.

  2. The MIT high resolution X-ray spectroscopy instruments on AXAF

    NASA Technical Reports Server (NTRS)

    Canizares, C. R.; Dewey, D.; Galton, E. B.; Markert, T. H.; Smith, Henry I.; Schattenburg, M. L.; Woodgate, B. E.; Jordan, S.

    1992-01-01

    The general design and performance characteristics of MIT's two dispersive spectrometers, the Bragg Crystal Spectrometer (BCS) and the High Energy Transmission Grating Spectrometer (HETG), now being developed for the Advanced X-ray Astrophysics Facility (AXAF), are described. Particular attention is given to the development of the critical technologies incorporated into these instruments, including BCS diffractors, imaging gas flow proportional counters, and grating elements for the HETG. The principal stages and the current status of the developments are reviewed.

  3. IS THE AMPLIFICATION OF c-MYC, MLL AND RUNX1 GENES IN AML AND MDS PATIENTS WITH TRISOMY 8, 11 AND 21 A FACTOR FOR A CLONAL EVOLUTION IN THEIR KARYOTYPE?

    PubMed

    Angelova, S; Spassov, B; Nikolova, V; Christov, I; Tzvetkov, N; Simeonova, M

    2015-01-01

    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). Amplification of c-MYC, MLL and RUNX1 genes by means of fluorescence in situ hybridization (FISH) was found in 35% (7 out of 20) of AML and MDS patients with +8, +11 u +21 as single CA in their karyotype; in 63.6% of pts (7 out of 11)--with additional numerical or structural CA and in 75% (9 out of 12)--with complex karyotype. We assume that the amplification of the respective chromosomal regions in patients with +8, +11 and +21 is related to CE. Considering the amplification as a factor of CE, we established 3 patterns of karyotype development depending on the type of the initiating CA in it. Significant statistical differences were found between the three patterns regarding the karyotype distribution in the different stages of progression (p < 0.001). PMID:26214902

  4. Acceptance and Operational Test Report for Neutron and Gamma Probe Application to Tank 241-SY-101 MITs

    SciTech Connect

    CANNON, N.S.

    1999-08-12

    This Operational Test Report (OTR) presents the results of the ATP/OTP testing performed to verify that newly procured neutron and gamma probes (reduced diameter design modifications) for operation in the Tank 241-SY-101 MITs are compatible with existing LOW van instrumentation and hardware. This verification was accomplished and a set of moisture data versus elevation were obtained from the Tank 241-SY-101 MITs as part of this testing program.

  5. Magnetisches Tracking für die Navigation mit dem da Vinci® Surgical System

    NASA Astrophysics Data System (ADS)

    Nickel, Felix; Wegner, Ingmar; Kenngott, Hannes; Neuhaus, Jochen; Müller-Stich, Beat P.; Meinzer, Hans-Peter; Gutt, Carsten N.

    In dieser Studie wurde untersucht ob in einem typischen OP-Aufbau mit dem da Vinci® Telemanipulator elektromagnetisches Tracking für die Realisation eines Navigationssystems eingesetzt werden kann. Hierfür wurde in einem realen OP-Aufbau untersucht, wie stark metallische und ferromagnetisch wirksame Objekte wie Operationstisch und Telemanipulator das elektromagnetische Feld des Trackingsystems beeinflussen. Die Ergebnisse zeigen, dass der Telemanipulator nur unwesentlich die Störung des Magnetfeldes durch den OP-Tisch verstärkt. Insbesondere die Bewegung der Instrumente im Trackingvolumen verursachte keine zusätzliche relevante Störung des Magnetfeldes. Bei Begrenzung des Trackingvolumens auf eine Länge von 190 mm, Höhe von 200mm und Breite von 400 mm war der maximale Fehler in diesem Bereich an allen Messpunkten kleiner 10 mm. Der Einsatz von elektromagnetischem Tracking für die Navigation mit dem da Vinci® Surgical System ist somit in einem begrenzten Arbeitsvolumen mit hinreichender Genauigkeit möglich.

  6. MIT: A Future Mission to Investigate Magnetosphere-Ionosphere-Thermosphere Coupling with Multipoint Observations

    NASA Astrophysics Data System (ADS)

    Liu, Y.

    2015-12-01

    The Magnetosphere, Ionosphere and Thermosphere (MIT) mission is one of the Space Science Strategic Pioneer Projects of the Chinese Academy of Sciences (CAS). Its major scientific objectives focus on the heating, acceleration and transport processes of ions in the polar regions and on their impact on the ring current and radiation belts. Because of the dynamic nature of these processes that also vary with altitude, it is imperative to cover with MIT altitudes from a few 100 km to several earth radii. This will be accomplished with a novel constellation of four spacecraft in polar orbits that provide periodic simultaneous measurements in the polar regions at three different altitudes. The two Ionospheric spacecraft have a polar orbit of 500km*1500km. The other two spacecraft have symmetric polar orbits with geocentric distances of 2Re*8Re (Re is the radius of the Earth).With instrument packages covering particle and field measurements over a wide energy range on all four spacecraft we will be able to monitor and investigate all relevant processes, including ion outflow from the source region in the ionosphere, their acceleration at mid-altitudes, to their final destination in the magnetosphere. Presently, MIT is in the background study stage that will be completed in 2015, with the engineering stage planed to start in 2016, if selected.

  7. May 1, 1989- A Critical Turning Point in the Cold Fusion Saga: APS, MIT and the Real Story

    NASA Astrophysics Data System (ADS)

    Mallove, Sc. D.; Eugene, F.; Chubb, Talbot

    2001-04-01

    As Chief Science Writer at the MIT News Office from 1987 through 1991, and as an engineer (MIT, S.B. 1969, S.M. 1970) familiar with heat measurements and the various other experiment claims, I was in a position to ascertain the true facts surrounding: the media and Press Conference events at MIT before and after May 1, 1989; the ill-fated calorimetric experiment performed by the MIT Plasma Fusion Center; and the MIT Administration's so-called investigation of this experiment. This activity led to wide-spread disparagement of the Fleischmann-Pons claims. A reconstruction of these events will be outlined, together with original supporting evidence that confirm that the "standard story" of how cold fusion was "debunked" at the May 1, 1989 APS meeting in Baltimore is not only wrong, but catastrophically so(Eugene Mallove, Fire from Ice: Searching for the Truth Behind the Cold Fusion Furor. (John Wiley & Sons, 1991))^,(Infinite Energy Magazine, Issue #24, March/April 1999, 10th Anniversary of Cold Fusion issue. (Includes time-lines and 55-page "MIT Special Report") ).

  8. Teaching practical leadership in MIT satellite development class: CASTOR and Exoplanet projects

    NASA Astrophysics Data System (ADS)

    Babuscia, Alessandra; Craig, Jennifer L.; Connor, Jane A.

    2012-08-01

    For more than a decade, the Aeronautics and Astronautics Department at MIT has offered undergraduate students the opportunity of conceiving, developing, implementing and operating new spacecraft's missions. During a three term class, junior and senior students experience all the challenges of a true engineering team project: design, analysis, testing, technical documentation development, team management, and leadership. Leadership instruction is an important part of the curricula; through the development of leadership skills, students learn to manage themselves and each other in a more effective way, increasing the overall productivity of the team. Also, a strong leadership education is a key factor in improving the abilities of future engineers to be effective team members and leaders in the companies and agencies in which they will work. However, too often leadership instruction is presented in an abstract way, which does not provide students with suggestions for immediate applicability. As a consequence, students underestimate the potential that leadership education can have on the development of their projects. To counteract that effect, a new approach for teaching "practical" leadership has been developed. This approach is composed of a set of activities developed to improve students' leadership skills in the context of a project. Specifically, this approach has been implemented in the MIT satellite development class. In that class, students experienced the challenges of building two satellites: CASTOR and Exoplanet. These two missions are real space projects which will be launched in the next two years, and which involve cooperation with different entities (MIT, NASA, and Draper). Hence, the MIT faculty was interested in developing leadership activities to improve the productivity of the teams in a short time. In fact, one of the key aspects of the approach proposed is that it can be quickly implemented in a single semester, requiring no more than 4 h of

  9. A Novel Ubiquitin-Specific Protease, UBP43, Cloned from Leukemia Fusion Protein AML1-ETO-Expressing Mice, Functions in Hematopoietic Cell Differentiation

    PubMed Central

    Liu, Li-Qin; Ilaria, Robert; Kingsley, Paul D.; Iwama, Atsushi; van Etten, Richard A.; Palis, James; Zhang, Dong-Er

    1999-01-01

    Using PCR-coupled subtractive screening-representational difference analysis, we have cloned a novel gene from AML1-ETO knockin mice. This gene is highly expressed in the yolk sac and fetal liver of the knockin mice. Nucleotide sequence analysis indicates that its cDNA contains an 1,107-bp open reading frame encoding a 368-amino-acid polypeptide. Further protein sequence and protein translation analysis shows that it belongs to a family of ubiquitin-specific proteases (UBP), and its molecular mass is 43 kDa. Therefore, we have named this gene UBP43. Like other ubiquitin proteases, the UBP43 protein has deubiquitinating enzyme activity. Protein ubiquitination has been implicated in many important cellular events. In wild-type adult mice, UBP43 is highly expressed in the thymus and in peritoneal macrophages. Among nine different murine hematopoietic cell lines analyzed, UBP43 expression is detectable only in cell lines related to the monocytic lineage. Furthermore, its expression is regulated during cytokine-induced monocytic cell differentiation. We have investigated its function in the hematopoietic myeloid cell line M1. UBP43 was introduced into M1 cells by retroviral gene transfer, and several high-expressing UBP43 clones were obtained for further study. Morphologic and cell surface marker examination of UBP43/M1 cells reveals that overexpression of UBP43 blocks cytokine-induced terminal differentiation of monocytic cells. These data suggest that UBP43 plays an important role in hematopoiesis by modulating either the ubiquitin-dependent proteolytic pathway or the ubiquitination state of another regulatory factor(s) during myeloid cell differentiation. PMID:10082570

  10. A novel ubiquitin-specific protease, UBP43, cloned from leukemia fusion protein AML1-ETO-expressing mice, functions in hematopoietic cell differentiation.

    PubMed

    Liu, L Q; Ilaria, R; Kingsley, P D; Iwama, A; van Etten, R A; Palis, J; Zhang, D E

    1999-04-01

    Using PCR-coupled subtractive screening-representational difference analysis, we have cloned a novel gene from AML1-ETO knockin mice. This gene is highly expressed in the yolk sac and fetal liver of the knockin mice. Nucleotide sequence analysis indicates that its cDNA contains an 1,107-bp open reading frame encoding a 368-amino-acid polypeptide. Further protein sequence and protein translation analysis shows that it belongs to a family of ubiquitin-specific proteases (UBP), and its molecular mass is 43 kDa. Therefore, we have named this gene UBP43. Like other ubiquitin proteases, the UBP43 protein has deubiquitinating enzyme activity. Protein ubiquitination has been implicated in many important cellular events. In wild-type adult mice, UBP43 is highly expressed in the thymus and in peritoneal macrophages. Among nine different murine hematopoietic cell lines analyzed, UBP43 expression is detectable only in cell lines related to the monocytic lineage. Furthermore, its expression is regulated during cytokine-induced monocytic cell differentiation. We have investigated its function in the hematopoietic myeloid cell line M1. UBP43 was introduced into M1 cells by retroviral gene transfer, and several high-expressing UBP43 clones were obtained for further study. Morphologic and cell surface marker examination of UBP43/M1 cells reveals that overexpression of UBP43 blocks cytokine-induced terminal differentiation of monocytic cells. These data suggest that UBP43 plays an important role in hematopoiesis by modulating either the ubiquitin-dependent proteolytic pathway or the ubiquitination state of another regulatory factor(s) during myeloid cell differentiation. PMID:10082570

  11. Isoforms of p38MAPK gamma and delta contribute to differentiation of human AML cells induced by 1,25-dihydroxyvitamin D3

    PubMed Central

    Zhang, Jing; Harrison, Jonathan S; Studzinski, George P.

    2010-01-01

    Inhibition of p38MAPK alpha/beta is known to enhance 1,25-dihydroxyvitamin (1,25D)-induced monocytic differentiation, but the detailed mechanism of this effect was not clear. We now show that the enhancement of differentiation becomes apparent with slow kinetics (12-24h). Interestingly, the inhibition of p38MAPK alpha/beta by their selective inhibitor SB202190 (SB) leads to an upregulated expression of p38MAPK isoforms gamma and delta in 1,25D-treated AML cells, in cell lines and in primary culture. Although the expression and activating phosphorylations of p38MAPK alpha are also increased by an exposure of the cells to SB, its kinase activity is blocked by SB, as shown by reduced levels of phosphorylated Hsp27, a downstream target of p38MAPK alpha. A positive role of p38MAPKs in 1,25D-induced differentiation is shown by the inhibition of differentiation by antisense oligonucleotides to all p38MAPK isoforms. Other principal branches of MAPK pathways showed early (6h) activation of MEK/ERK by SB, followed by activation of JNK1/2 pathway and enhanced expression and/or activation of PU.1, ATF-2 differentiation-related transcription factors. Taken together with previous reports, the results indicate that 1,25D-induced differentiation is enhanced by the activation of at least three branches of MAPK pathways (ERK1/2; p38MAPK gamma/delta; JNK1/2). This activation may result from the removal of feedback inhibition of an upstream regulator of those pathways, when p38MAPK alpha and beta are inhibited by SB. PMID:20804750

  12. Comparing Analytic Methods for Longitudinal GWAS and a Case-Study Evaluating Chemotherapy Course Length in Pediatric AML. A Report from the Children's Oncology Group.

    PubMed

    Vujkovic, Marijana; Aplenc, Richard; Alonzo, Todd A; Gamis, Alan S; Li, Yimei

    2016-01-01

    Regression analysis is commonly used in genome-wide association studies (GWAS) to test genotype-phenotype associations but restricts the phenotype to a single observation for each individual. There is an increasing need for analytic methods for longitudinally collected phenotype data. Several methods have been proposed to perform longitudinal GWAS for family-based studies but few methods are described for unrelated populations. We compared the performance of three statistical approaches for longitudinal GWAS in unrelated subjectes: (1) principal component-based generalized estimating equations (PC-GEE); (2) principal component-based linear mixed effects model (PC-LMEM); (3) kinship coefficient matrix-based linear mixed effects model (KIN-LMEM), in a study of single-nucleotide polymorphisms (SNPs) on the duration of 4 courses of chemotherapy in 624 unrelated children with de novo acute myeloid leukemia (AML) genotyped on the Illumina 2.5 M OmniQuad from the COG studies AAML0531 and AAML1031. In this study we observed an exaggerated type I error with PC-GEE in SNPs with minor allele frequencies < 0.05, wheras KIN-LMEM produces more than expected type II errors. PC-MEM showed balanced type I and type II errors for the observed vs. expected P-values in comparison to competing approaches. In general, a strong concordance was observed between the P-values with the different approaches, in particular among P < 0.01 where the between-method AUCs exceed 99%. PC-LMEM accounts for genetic relatedness and correlations among repeated phenotype measures, shows minimal genome-wide inflation of type I errors, and yields high power. We therefore recommend PC-LMEM as a robust analytic approach for GWAS of longitudinal data in unrelated populations. PMID:27547214

  13. Toll-like receptor 9, NOD2 and IL23R gene polymorphisms influenced outcome in AML patients transplanted from HLA-identical sibling donors.

    PubMed

    Elmaagacli, A H; Steckel, N; Ditschkowski, M; Hegerfeldt, Y; Ottinger, H; Trenschel, R; Koldehoff, M; Beelen, D W

    2011-05-01

    We evaluated the influence of gene polymorphisms of TLR9 (T1237C; T1486C), IL23R (A1142G), and NOD2 SNP8 (R702W), SNP12 (G908R) and SNP13 (1007fs) on outcome of hematopoietic SCT in a homogenous group of 142 AML patients after non-T-cell-depleted myeloablative transplantation from HLA-identical sibling donors. In our retrospective study, we found that TLR9 gene variant at 1486 influenced transplant outcome. Estimated 5-year OS in patients with the CC gene variant of TLR9 was 70.2% compared with 44.8% (P<0.027) in patients with TC/TT of TLR9 gene. No significant influences on 5-year OS were found for gene polymorphisms of NOD2 or IL23R (A1142G) in this study group. The 5-year treatment-related mortality was lowest in patients with CC gene variant of TLR9 (7.8 vs 23.1%; NS). Acute GVHD grade III-IV was higher in patients with NOD2 gene variants (28 vs 12.8%; P=0.065). In contrast, patients transplanted from donors with the gene variant of IL23R had no occurrence of severe acute GVHD grade III-IV (0 vs 18.4%; P<0.048). However, multivariate analysis confirmed the influence of NOD2 gene variants on the occurrence of acute GVHD grade II-IV after transplant. These results suggest that the gene variants of TLR9, NOD2 and Il23R had influence on the outcome of transplant. PMID:20622911

  14. The identification of a novel TP53 cancer susceptibility mutation through whole genome sequencing of a patient with therapy-related AML

    PubMed Central

    Link, Daniel C.; Schuettpelz, Laura G.; Shen, Dong; Wang, Jinling; Walter, Matthew J.; Kulkarni, Shashikant; Payton, Jacqueline E.; Ivanovich, Jennifer; Goodfellow, Paul J.; Le Beau, Michelle; Koboldt, Daniel C.; Dooling, David J.; Fulton, Robert S.; Bender, R. Hugh F.; Fulton, Lucinda L.; Delehaunty, Kimberly D.; Fronick, Catrina C.; Appelbaum, Elizabeth L.; Schmidt, Heather; Abbott, Rachel; O'Laughlin, Michelle; Chen, Ken; McLellan, Michael D.; Varghese, Nobish; Nagarajan, Rakesh; Heath, Sharon; Graubert, Timothy A.; Ding, Li; Ley, Timothy J.; Zambetti, Gerard P.; Wilson, Richard K.; Mardis, Elaine R.

    2011-01-01

    Context The identification of patients with inherited cancer susceptibility syndromes facilitates early diagnosis, prevention, and treatment. However, in many cases of suspected cancer susceptibility, the family history is unclear and genetic testing of common cancer susceptibility genes is unrevealing. Objective To apply whole-genome sequencing to a patient with suspected cancer susceptibility (and lacking a clear family history of cancer and no BRCA1 and BRCA2 mutations) to identify rare or novel germline variants in cancer susceptibility genes. Design, Setting, and Participant Skin (normal) and bone marrow (leukemia) DNA were obtained from a patient with early-onset breast and ovarian cancer and therapy-related acute myeloid leukemia (t-AML), and analyzed with: 1) whole genome sequencing using paired end reads; 2) SNP genotyping; 3) RNA expression profiling; and 4) spectral karyotyping. Main Outcome Measures Structural variants, copy number alterations, single nucleotide variants and small insertions and deletions (indels) were detected and validated using the above platforms. Results Whole genome sequencing revealed a novel, heterozygous 3 Kb deletion removing exons 7-9 of TP53 in the patient’s normal skin DNA, which was homozygous in the leukemia DNA as a result of uniparental disomy. In addition, a total of 28 validated somatic single nucleotide variations or indels in coding genes, 8 somatic structural variants, and 12 somatic copy number alterations were detected in the patient’s leukemia genome. Conclusions Whole genome sequencing can identify novel, cryptic variants in cancer susceptibility genes in addition to providing unbiased information on the spectrum of mutations in a cancer genome. PMID:21505135

  15. Comparing Analytic Methods for Longitudinal GWAS and a Case-Study Evaluating Chemotherapy Course Length in Pediatric AML. A Report from the Children's Oncology Group

    PubMed Central

    Vujkovic, Marijana; Aplenc, Richard; Alonzo, Todd A.; Gamis, Alan S.; Li, Yimei

    2016-01-01

    Regression analysis is commonly used in genome-wide association studies (GWAS) to test genotype-phenotype associations but restricts the phenotype to a single observation for each individual. There is an increasing need for analytic methods for longitudinally collected phenotype data. Several methods have been proposed to perform longitudinal GWAS for family-based studies but few methods are described for unrelated populations. We compared the performance of three statistical approaches for longitudinal GWAS in unrelated subjectes: (1) principal component-based generalized estimating equations (PC-GEE); (2) principal component-based linear mixed effects model (PC-LMEM); (3) kinship coefficient matrix-based linear mixed effects model (KIN-LMEM), in a study of single-nucleotide polymorphisms (SNPs) on the duration of 4 courses of chemotherapy in 624 unrelated children with de novo acute myeloid leukemia (AML) genotyped on the Illumina 2.5 M OmniQuad from the COG studies AAML0531 and AAML1031. In this study we observed an exaggerated type I error with PC-GEE in SNPs with minor allele frequencies < 0.05, wheras KIN-LMEM produces more than expected type II errors. PC-MEM showed balanced type I and type II errors for the observed vs. expected P-values in comparison to competing approaches. In general, a strong concordance was observed between the P-values with the different approaches, in particular among P < 0.01 where the between-method AUCs exceed 99%. PC-LMEM accounts for genetic relatedness and correlations among repeated phenotype measures, shows minimal genome-wide inflation of type I errors, and yields high power. We therefore recommend PC-LMEM as a robust analytic approach for GWAS of longitudinal data in unrelated populations. PMID:27547214

  16. MitProNet: A Knowledgebase and Analysis Platform of Proteome, Interactome and Diseases for Mammalian Mitochondria

    PubMed Central

    Mao, Song; Chai, Xiaoqiang; Hu, Yuling; Hou, Xugang; Tang, Yiheng; Bi, Cheng; Li, Xiao

    2014-01-01

    Mitochondrion plays a central role in diverse biological processes in most eukaryotes, and its dysfunctions are critically involved in a large number of diseases and the aging process. A systematic identification of mitochondrial proteomes and characterization of functional linkages among mitochondrial proteins are fundamental in understanding the mechanisms underlying biological functions and human diseases associated with mitochondria. Here we present a database MitProNet which provides a comprehensive knowledgebase for mitochondrial proteome, interactome and human diseases. First an inventory of mammalian mitochondrial proteins was compiled by widely collecting proteomic datasets, and the proteins were classified by machine learning to achieve a high-confidence list of mitochondrial proteins. The current version of MitProNet covers 1124 high-confidence proteins, and the remainders were further classified as middle- or low-confidence. An organelle-specific network of functional linkages among mitochondrial proteins was then generated by integrating genomic features encoded by a wide range of datasets including genomic context, gene expression profiles, protein-protein interactions, functional similarity and metabolic pathways. The functional-linkage network should be a valuable resource for the study of biological functions of mitochondrial proteins and human mitochondrial diseases. Furthermore, we utilized the network to predict candidate genes for mitochondrial diseases using prioritization algorithms. All proteins, functional linkages and disease candidate genes in MitProNet were annotated according to the information collected from their original sources including GO, GEO, OMIM, KEGG, MIPS, HPRD and so on. MitProNet features a user-friendly graphic visualization interface to present functional analysis of linkage networks. As an up-to-date database and analysis platform, MitProNet should be particularly helpful in comprehensive studies of complicated

  17. Using MFACE as input in the UAM to specify the MIT dynamics

    NASA Astrophysics Data System (ADS)

    Prokhorov, B. E.; Förster, M.; He, M.; Namgaladze, A. A.; Holschneider, M.

    2014-08-01

    The magnetosphere-ionosphere-thermosphere (MIT) dynamic system significantly depends on the highly variable solar wind conditions, in particular, on changes of the strength and orientation of the interplanetary magnetic field (IMF). The solar wind and IMF interactions with the magnetosphere drive the MIT system via the magnetospheric field-aligned currents (FACs). The global modeling helps us to understand the physical background of this complex system. With the present study, we test the recently developed high-resolution empirical model of field-aligned currents MFACE (a high-resolution Model of Field-Aligned Currents through Empirical orthogonal functions analysis). These FAC distributions were used as input of the time-dependent, fully self-consistent global Upper Atmosphere Model (UAM) for different seasons and various solar wind and IMF conditions. The modeling results for neutral mass density and thermospheric wind are directly compared with the CHAMP satellite measurements. In addition, we perform comparisons with the global empirical models: the thermospheric wind model (HWM07) and the atmosphere density model (Naval Research Laboratory Mass Spectrometer and Incoherent Scatter Extended 2000). The theoretical model shows a good agreement with the satellite observations and an improved behavior compared with the empirical models at high latitudes. Using the MFACE model as input parameter of the UAM model, we obtain a realistic distribution of the upper atmosphere parameters for the Northern and Southern Hemispheres during stable IMF orientation as well as during dynamic situations. This variant of the UAM can therefore be used for modeling the MIT system and space weather predictions.

  18. Sampling Technique for Robust Odorant Detection Based on MIT RealNose Data

    NASA Technical Reports Server (NTRS)

    Duong, Tuan A.

    2012-01-01

    This technique enhances the detection capability of the autonomous Real-Nose system from MIT to detect odorants and their concentrations in noisy and transient environments. The lowcost, portable system with low power consumption will operate at high speed and is suited for unmanned and remotely operated long-life applications. A deterministic mathematical model was developed to detect odorants and calculate their concentration in noisy environments. Real data from MIT's NanoNose was examined, from which a signal conditioning technique was proposed to enable robust odorant detection for the RealNose system. Its sensitivity can reach to sub-part-per-billion (sub-ppb). A Space Invariant Independent Component Analysis (SPICA) algorithm was developed to deal with non-linear mixing that is an over-complete case, and it is used as a preprocessing step to recover the original odorant sources for detection. This approach, combined with the Cascade Error Projection (CEP) Neural Network algorithm, was used to perform odorant identification. Signal conditioning is used to identify potential processing windows to enable robust detection for autonomous systems. So far, the software has been developed and evaluated with current data sets provided by the MIT team. However, continuous data streams are made available where even the occurrence of a new odorant is unannounced and needs to be noticed by the system autonomously before its unambiguous detection. The challenge for the software is to be able to separate the potential valid signal from the odorant and from the noisy transition region when the odorant is just introduced.

  19. Estimates of intakes and internal doses from ingestion of {sup 32}P at MIT and NIH

    SciTech Connect

    Stabin, M.G.; Toohey, R.E.

    1996-06-01

    A researcher at Massachusetts Institute of Technology (MIT) became internally contaminated with {sup 32}P, probably due to an intentional act. The incident occurred on or about 14 August 1995. Subsequent measurement of activity in urine and a single whole body count were used to estimate the individual`s intake, with the assumption of ingestion as the route of intake. Two separate Sets of urine data were analyzed-one supplied by MIT and one from independent analyses of urine samples conducted at Oak Ridge Institute for Science and Education (ORISE); the former data set contained 35 samples, the latter 49. In addition, the results of 35 whole body counts, provided by MIT from a chair-type counter calibrated for 32p, were used to obtain a separate estimate of intake. The kinetic model for 32P proposed in ICRP Publication 30 and implemented in NUREG/CR-4884 was used to interpret the data. The data were analyzed using both the weighted and unweighted least squares techniques. All of the intake estimates were in very good agreement with each other, ranging from 18-22 MBq. Based on the dose model in ICRP 30, this would indicate a committed effective dose equivalent of 38-46 mSv. The incident was helpful in assessing the value of the least squares techniques in determining estimates of intake and dose. The ICRP model tended to slightly overestimate the whole body retention data and underestimate the urinary excretion at later times. Further results obtained by visual best fit and development of an individual-specific kinetic and dose model will also be discussed. This incident was quite similar to another case of ingestion of 32p that occurred at the National Institute of Health (NIH) on 28 June 1995. Dose assessment for the NIH case will also be presented if the data are available for public release.

  20. MIT extraction method for measuring average subchannel axial velocities in reactor assemblies

    SciTech Connect

    Hawley, J.T.; Chiu, C.; Todreas, N.E.

    1980-08-01

    The MIT extraction method for obtaining flow split data for individual subchannels is described in detail. An analysis of the method is presented which shows that isokinetic values of the subchannel flow rates are obtained directly even though the method is non-isokinetic. Time saving methods are discussed for obtaining the average value of the interior region flow split parameter. An analysis of the method at low bundle flow rates indicates that there is no inherent low flow rate limitation on the method and suggests a way to obtain laminar flow split data.

  1. Lasers, their development, and applications at M.I.T. Lincoln Laboratory

    NASA Technical Reports Server (NTRS)

    Rediker, R. H.; Melngailis, I.; Mooradian, A.

    1984-01-01

    A historical account of the work on lasers at MIT Lincoln Laboratory is presented. Highlighted are the efforts that led to the coinvention of the semiconductor laser and the Laboratory's later role in establishing the feasibility of GaInAsP/InP semiconductor lasers for use in fiber telecommunications at 1.3-1.5 micron wavelengths. Descriptions of other important developments include tunable lead-salt semiconductor and solid-state lasers for spectroscopy and LIDAR applications, respectively, as well as ultrastable CO2 lasers for coherent infrared radar.

  2. Considerations on Beam Quality Control in MIT X-Ray FEL

    SciTech Connect

    Wang, D.; Graves, W.; Wang, D.; Zwart, T.; Emma, P.; Wu, J.; Huang, G.; /LBL, Berkeley

    2006-03-15

    The x-ray FEL at MIT is one example of a design for a new generation linac-based light source. Such a new machine requires very high quality electron beams. Besides the usual requirements on beam parameters such as emittance, energy spread, peak current, there are new challenges emerging in the design studies, e.g., the arrival timing of electron beam must reach precision below tens of femtoseconds level to ensure the laser seed overlaps the desired sections of electron bunch in the multiple-stage HGHG process. In this paper we report the progress on design optimization towards high quality and low sensitivity beams.

  3. 50 years of helium liquefaction at the MIT Cryogenic Engineering Laboratory

    NASA Astrophysics Data System (ADS)

    Smith, Joseph L.

    2002-05-01

    The evolution of the helium liquefaction facility of the MIT Cryogenic Engineering Laboratory and the history of its operation over the last 50 years are described. Professor Samuel C. Collins created the liquid-helium facility based on his earlier developments. The chronology of the laboratory helium liquefiers is given with a brief description of each one. The current facility based on the Model 2000 liquefier is described and operating experience is given. The reasons for the very high availability of the liquefaction system are developed.

  4. Von Donuts und Zucker: Mit Neutronen biologische Makromoleküle erforschen

    NASA Astrophysics Data System (ADS)

    May, Roland P.

    2003-05-01

    Für die Erforschung von Biomolekülen bieten Neutronen einzigartige Eigenschaften. Vor allem ihre unterschiedliche Wechselwirkung mit dem natürlichen Wasserstoff und seinem schweren Isotop Deuterium ermöglicht tiefe Einblicke in Struktur, Funktion und Dynamik von Proteinen, Nukleinsäuren und Biomembranen. Bei vielen Fragestellungen zur Strukturaufklärung gibt es kaum oder keine Alternative zum Neutron. Das Institut Laue-Langevin trägt Bahnbrechendes zum Erfolg der Neutronen-Methoden in der Biologie bei.

  5. Messsysteme für die Bildgebung mit Röntgenstrahlung

    NASA Astrophysics Data System (ADS)

    Krieger, Hanno

    Nach einem kurzen Überblick über die heute verwendeten Detektorsysteme zur Erzeugung von Röntgenbildern in der Projektionsradiografie folgt die ausführliche Darstellung der klassischen Kombination von Röntgenfilm und Verstärkungsfolien. Der nächste Abschnitt befasst sich mit den Ausführungen zu Bildverstärkern, den Speicherfolien und den anderen digitalen Festkörperdetektoren. Der Dosisbedarf eines bildgebenden Systems kann bei Film-Folien- Kombinationen durch die Angabe von Empfindlichkeitsklassen definiert werden, bei den digitalen Detektoren geschieht dies mit Hilfe der Dosisindikatoren (Exposure Indicator EI, Abweichungsindikator DI). Im zweiten großen Abschnitt dieses Kapitels werden die Grundlagen der Computertomografie erläutert. Dazu werden zunächst die CT-Gerätegenerationen und die CT-Detektoren besprochen. Nach einer Erläuterung der Rechenverfahren zur Bilderzeugung folgt die Definition der Hounsfield-Einheiten. Den Abschluss bildet eine ausführliche Darstellung der Bildartefakte bei der Computertomografie.

  6. MitBASE : a comprehensive and integrated mitochondrial DNA database. The present status

    PubMed Central

    Attimonelli, M.; Altamura, N.; Benne, R.; Brennicke, A.; Cooper, J. M.; D’Elia, D.; Montalvo, A. de; Pinto, B. de; De Robertis, M.; Golik, P.; Knoop, V.; Lanave, C.; Lazowska, J.; Licciulli, F.; Malladi, B. S.; Memeo, F.; Monnerot, M.; Pasimeni, R.; Pilbout, S.; Schapira, A. H. V.; Sloof, P.; Saccone, C.

    2000-01-01

    MitBASE is an integrated and comprehensive database of mitochondrial DNA data which collects, under a single interface, databases for Plant, Vertebrate, Invertebrate, Human, Protist and Fungal mtDNA and a Pilot database on nuclear genes involved in mitochondrial biogenesis in Saccharomyces cerevisiae. MitBASE reports all available information from different organisms and from intraspecies variants and mutants. Data have been drawn from the primary databases and from the literature; value adding information has been structured, e.g., editing information on protist mtDNA genomes, pathological information for human mtDNA variants, etc. The different databases, some of which are structured using commercial packages (Microsoft Access, File Maker Pro) while others use a flat-file format, have been integrated under ORACLE. Ad hoc retrieval systems have been devised for some of the above listed databases keeping into account their peculiarities. The database is resident at the EBI and is available at the following site: http://www3.ebi.ac.uk/Research/Mitbase/mitbase.pl . The impact of this project is intended for both basic and applied research. The study of mitochondrial genetic diseases and mitochondrial DNA intraspecies diversity are key topics in several biotechnological fields. The database has been funded within the EU Biotechnology programme. PMID:10592207

  7. Acute myelogenous leukemia (AML) -- children

    MedlinePlus

    ... Leung WH, Pounds S, Cao X, e t al. Definition of cure in childhood acute myeloid leukemia. Cancer . 2014 Aug ... MD, Medical Oncologist, Fresno, CA. Review provided by VeriMed Healthcare Network. Also reviewed by ...

  8. Rearrangement between the MYH11 gene at 16p13 and D12S158 at 12p13 in a case of acute myeloid leukemia M1 (AML-M1).

    PubMed

    La Starza, R; Wlodarska, I; Matteucci, C; Falzetti, D; Baens, M; Martelli, M F; Van den Berghe, H; Marynen, P; Mecucci, C

    1998-09-01

    A case of acute myeloid leukemia (AML) M1 with bone marrow eosinophilia was characterized by cytogenetics and fluorescence in situ hybridization (FISH). A complex karyotype including a der(12)t(12;17)(p12-13;q11) and a der(16)t(16;20)(p13;p11) was found at diagnosis. FISH studies with probes for chromosome 16 and for the short arm of chromosome 12 showed even more complex rearrangements. Analysis with a panel of probes for 12p showed that D12S158 spanned the breakpoint on the der(12). Unexpectedly, FISH signals were found on the der(12) and on the der(6) at band p13, the site of juxtaposition between the short arm of chromosome 16 and chromosome 20. Moreover, both YAC 854E2, containing the MYH11 gene, and cosmid ZIT133, encompassing the MYH11 breakpoint in inv(16) and t(16;16) of AML-M4 with eosinophilia, demonstrated fluorescent signals on the normal 16, on the der(16), and on the der(12). These data clearly support a reciprocal exchange between D12S158 at 12p13.3 and the MYH11 gene at 16p13. In addition, experiments with two PAC clones for the CBFB gene at 16q22 excluded the presence of a masked inv(16). An interstitial deletion, independent from the translocation and flanked by VWF and KRAS2, was also detected on the der(12). PMID:9713991

  9. Blockade of adaptive defensive changes in cholesterol uptake and synthesis in AML by the addition of pravastatin to idarubicin + high-dose Ara-C: a phase 1 study

    PubMed Central

    Banker, Deborah E.; Stirewalt, Derek; Shen, Danny; Lemker, Elizabeth; Verstovsek, Srdan; Estrov, Zeev; Faderl, Stefan; Cortes, Jorge; Beran, Miloslav; Jackson, C. Ellen; Chen, Wenjing; Estey, Elihu; Appelbaum, Frederick R.

    2007-01-01

    Following exposure to cytotoxic agents, acute myeloid leukemia (AML) blasts elevate cellular cholesterol in a defensive adaptation that increases chemoresistance, but blockade of HMG-CoA reductase with statins restores chemosensitivity in vitro. This phase 1 study evaluated adding pravastatin (PV) (40-1680 mg/day, days 1-8) to idarubicin (Ida) ([12 mg/(M2 · day), days 4-6]) + high-dose cytarabine (Ara-C; HDAC) [1.5 g/(M2 · day) by CI, days 4-7] in 15 newly diagnosed and 22 salvage patients with unfavorable (n = 26) or intermediate (n = 10) prognosis cytogenetics. Compared with historical experience with Ida-HDAC, the duration of neutropenia and throbmbocytopenia and the toxicity profile were unaffected by the addition of PV. During PV loading (day 0-4) serum triglyceride and total and LDL cholesterol levels decreased in nearly all patients. Pharmacokinetic studies demonstrated higher and more sustained serum PV levels with PV doses above 1280 mg/day. CR/CRp was obtained in 11 of 15 new patients, including 8 of 10 with unfavorable cytogenetics, and 9 of 22 salvage patients. An MTD for PV + Ida-HDAC was not reached. Addition of PV to Ida-HDAC was safe, and the encouraging response rates support conducting further trials evaluating the effect of cholesterol modulation on response in AML. PMID:17158228

  10. Deletion of PdMit1, a homolog of yeast Csg1, affects growth and Ca(2+) sensitivity of the fungus Penicillium digitatum, but does not alter virulence.

    PubMed

    Zhu, Congyi; Wang, Weili; Wang, Mingshuang; Ruan, Ruoxin; Sun, Xuepeng; He, Meixian; Mao, Cungui; Li, Hongye

    2015-04-01

    GDP-mannose:inositol-phosphorylceramide (MIPC) and its derivatives are important for Ca(2+) sensitization of Saccharomyces cerevisiae and for the virulence of Candida albicans, but its role in the virulence of plant fungal pathogens remains unclear. In this study, we report the identification and functional characterization of PdMit1, the gene encoding MIPC synthase in Penicillium digitatum, one of the most important pathogens of postharvest citrus fruits. To understand the function of PdMit1, a PdMit1 deletion mutant was generated. Compared to its wild-type control, the PdMit1 deletion mutant exhibited slow radial growth, decreased conidia production and delayed conidial germination, suggesting that PdMit1 is important for the growth of mycelium, sporulation and conidial germination. The PdMit1 deletion mutant also showed hypersensitivity to Ca(2+). Treatment with 250 mmol/l Ca(2+) induced vacuole fusion in the wild-type strain, but not in the PdMit1 deletion mutant. Treatment with 250mmol/lCaCl2 upregulated three Ca(2+)-ATPase genes in the wild-type strain, and this was significantly inhibited in the PdMit1 deletion mutant. These results suggest that PdMit1 may have a role in regulating vacuole fusion and expression of Ca(2+)-ATPase genes by controlling biosynthesis of MIPC, and thereby imparts P. digitatum Ca(2+) tolerance. However, we found that PdMit1 is dispensable for virulence of P. digitatum. PMID:25725383

  11. Deletion of PdMit1, a homolog of yeast Csg1, affects growth and Ca2+ sensitivity of the fungus Penicillium digitatum, but does not alter virulence

    PubMed Central

    Zhu, Congyi; Wang, Weili; Wang, Mingshuang; Ruan, Ruoxin; Sun, Xuepeng; He, Meixian; Mao, Cungui; Li, Hongye

    2015-01-01

    GDP-mannose:inositol-phosphorylceramide (MIPC) and its derivatives are important for Ca2+ sensitization of Saccharomyces cerevisiae and for the virulence of Candida albicans, but its role in the virulence of plant fungal pathogens remains unclear. In this study, we report the identification and functional characterization of PdMit1, the gene encoding MIPC synthase in Penicillium digitatum, one of the most important pathogens of postharvest citrus fruits. To understand the function of PdMit1, a PdMit1 deletion mutant was generated. Compared to its wild-type control, the PdMit1 deletion mutant exhibited slow radial growth, decreased conidia production and delayed conidial germination, suggesting that PdMit1 is important for the growth of mycelium, sporulation and conidial germination. The PdMit1 deletion mutant also showed hypersensitivity to Ca2+. Treatment with 250 mmol/l Ca2+ induced vacuole fusion in the wild-type strain, but not in the PdMit1 deletion mutant. Treatment with 250 mmol/lCaCl2 upregulated three Ca2+-ATPase genes in the wild-type strain, and this was significantly inhibited in the PdMit1 deletion mutant. These results suggest that PdMit1 may have a role in regulating vacuole fusion and expression of Ca2+-ATPase genes by controlling biosynthesis of MIPC, and thereby imparts P. digitatum Ca2+ tolerance. However, we found that PdMit1 is dispensable for virulence of P. digitatum. PMID:25725383

  12. TAF-4 is required for the life extension of isp-1, clk-1 and tpk-1 Mit mutants

    PubMed Central

    Hufnal, Bryce; Farber, Robert; Munkácsy, Erin; Rodriguez, Amanda; Dillow, Andy; Kahlig, Erynn; Rea, Shane L.

    2013-01-01

    While numerous life-extending manipulations have been discovered in the nematode Caenorhabditis elegans, one that remains most enigmatic is disruption of oxidative phosphorylation. In order to unravel how such an ostensibly deleterious manipulation can extend lifespan, we sought to identify the ensemble of nuclear transcription factors that are activated in response to defective mitochondrial electron transport chain (ETC) function. Using a feeding RNAi approach, we targeted over 400 transcription factors and identified 15 that, when reduced in function, reproducibly and differentially altered the development, stress response, and/or fecundity of isp-1(qm150) Mit mutants relative to wild-type animals. Seven of these transcription factors – AHA-1, CEH-18, HIF-1, JUN-1, NHR-27, NHR-49 and the CREB homolog-1 (CRH-1)-interacting protein TAF-4 – were also essential for isp-1 life extension. When we tested the involvement of these seven transcription factors in the life extension of two other Mit mutants, namely clk-1(qm30) and tpk-1(qm162), TAF-4 and HIF-1 were consistently required. Our findings suggest that the Mit phenotype is under the control of multiple transcriptional responses, and that TAF-4 and HIF-1 may be part of a general signaling axis that specifies Mit mutant life extension. PMID:24107417

  13. Excellence in Research: Creative Organizational Responses at Berkeley, Harvard, MIT, and Stanford. ASHE 1985 Annual Meeting Paper.

    ERIC Educational Resources Information Center

    Gardiner, John J.

    Research environments of four leading universities were studied: University of California at Berkeley (UC-Berkeley), Harvard University, Massachusetts Institute of Technology (MIT), and Stanford University. Attention was directed to organizational responses for encouraging collaboration in research at these leading universities, as well as to…

  14. Designing Materials for the Language Lab of the Future: An Overview of the MIT Athena Language Learning Project.

    ERIC Educational Resources Information Center

    Kramsch, Claire; And Others

    1985-01-01

    Details the current status, the future plans and the reasoning behind a five-year, campus-wide educational experiment for the integration of computers into the foreign language curriculum at MIT. The project is to use artificial intelligence in natural processing and to include interactive video and interactive audio components. (Author/SED)

  15. Trouble and Triumph: German Life-Turkish Tradition in Renan Demirkan's "Schwarzer Tee mit drei Stuck Zucker"

    ERIC Educational Resources Information Center

    Ebert, Reika

    2004-01-01

    This paper explores Demirkan's narrative strategies in "Schwarzer Tee mit drei Stuck Zucker" to negotiate issues of a life between two cultures and traditions. Based on Bhabha's insights that mainstream culture needs intellectual and artistic infusion from the margins of a society in order to remain vital; and that cultural production itself is a…

  16. Use of graphics in decision aids for telerobotic control: (Parts 5-8 of an 8-part MIT progress report)

    NASA Technical Reports Server (NTRS)

    Sheridan, Thomas B.; Roseborough, James B.; Das, Hari; Chin, Kan-Ping; Inoue, Seiichi

    1989-01-01

    Four separate projects recently completed or in progress at the MIT Man-Machine Systems Laboratory are summarized. They are: a decision aid for retrieving a tumbling satellite in space; kinematic control and graphic display of redundant teleoperators; real time terrain/object generation: a quad-tree approach; and two dimensional control for three dimensional obstacle avoidance.

  17. MitBASE pilot: a database on nuclear genes involved in mitochondrial biogenesis and its regulation in Saccharomyces cerevisiae.

    PubMed

    de Pinto, B; Malladi, S B; Altamura, N

    1999-01-01

    In the framework of the EU BIOTECH PROGRAM and within the 'MITBASE: a comprehensive and integrated database on mtDNA' project, we have prepared a pilot database (MitBASE Pilot) on nuclear genes involved in mitochondrial biogenesis and its regulation in Saccharomyces cerevisiae. MitBASE Pilot includes nuclear genes encoding mitochondrial proteins as well as nuclear genes encoding products which are localised in other sub-cellular compartments but nevertheless interact with mitochondrial functions. Genes have been classified on the basis of the mitochondrial process in which they participate and the mitochondrial phenotype of the gene knockout. The structure of the MitBASE Pilot database has been conceived for a flexible organisation of the information. An intuitive visual query system has been developed which allows users to select information in different combinations, both in the query and the output format, according to their needs. MitBASE Pilot is a relational database, is maintained at the EMBL-European Bioinformatics Institute (EBI) and is available at the World Wide Web site http://www3.ebi.ac. uk/Research/Mitbase/mitbiog.pl PMID:9847161

  18. Understanding the Self-Directed Online Learning Preferences, Goals, Achievements, and Challenges of MIT OpenCourseWare Subscribers

    ERIC Educational Resources Information Center

    Bonk, Curtis J.; Lee, Mimi Miyoung; Kou, Xiaojing; Xu, Shuya; Sheu, Feng-Ru

    2015-01-01

    This research targeted the learning preferences, goals and motivations, achievements, challenges, and possibilities for life change of self-directed online learners who subscribed to the monthly OpenCourseWare (OCW) e-newsletter from MIT. Data collection included a 25-item survey of 1,429 newsletter subscribers; 613 of whom also completed an…

  19. Rapid identification of Listeria spp.: an AOAC performance test of the MIT 1000 rapid microbial identification system

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Methods that rapidly confirm the identification of foodborne pathogens are highly desired. The Micro Imaging Technology (MIT) 1000 Rapid Microbial Identification (RMID) System is a benchtop instrument that detects laser light scattered from individual bacterial cells in solution with an array of 35 ...

  20. Evaluation of the MIT RMID 1000 system for the identification of Listeria species:AOAC performance tested method 090325

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The MIT 1000 RMID System is a rapid microbial identification device that uses the principles of light scattering coupled with proprietary algorithms to identify bacteria after being cultured and placed in a vial of filtered water. This specific method is for pure culture identification of Listeria ...

  1. Draft Genome Sequences of Supercritical CO2-Tolerant Bacteria Bacillus subterraneus MITOT1 and Bacillus cereus MIT0214

    PubMed Central

    Peet, Kyle C.

    2015-01-01

    We report draft genome sequences of Bacillus subterraneus MITOT1 and Bacillus cereus MIT0214 isolated through enrichment of samples from geologic sequestration sites in pressurized bioreactors containing a supercritical (sc) CO2 headspace. Their genome sequences expand the phylogenetic range of sequenced bacilli and allow characterization of molecular mechanisms of scCO2 tolerance. PMID:25858826

  2. Integrated optomechanical analysis and testing software development at MIT Lincoln Laboratory

    NASA Astrophysics Data System (ADS)

    Stoeckel, Gerhard P.; Doyle, Keith B.

    2013-09-01

    Advanced analytical software capabilities are being developed to advance the design of prototypical hardware in the Engineering Division at MIT Lincoln Laboratory. The current effort is focused on the integration of analysis tools tailored to the work flow, organizational structure, and current technology demands. These tools are being designed to provide superior insight into the interdisciplinary behavior of optical systems and enable rapid assessment and execution of design trades to optimize the design of optomechanical systems. The custom software architecture is designed to exploit and enhance the functionality of existing industry standard commercial software, provide a framework for centralizing internally developed tools, and deliver greater efficiency, productivity, and accuracy through standardization, automation, and integration. Specific efforts have included the development of a feature-rich software package for Structural-Thermal-Optical Performance (STOP) modeling, advanced Line Of Sight (LOS) jitter simulations, and improved integration of dynamic testing and structural modeling.

  3. MIT-NASA/KSC space life science experiments - A telescience testbed

    NASA Technical Reports Server (NTRS)

    Oman, Charles M.; Lichtenberg, Byron K.; Fiser, Richard L.; Vordermark, Deborah S.

    1990-01-01

    Experiments performed at MIT to better define Space Station information system telescience requirements for effective remote coaching of astronauts by principal investigators (PI) on the ground are described. The experiments were conducted via satellite video, data, and voice links to surrogate crewmembers working in a laboratory at NASA's Kennedy Space Center. Teams of two PIs and two crewmembers performed two different space life sciences experiments. During 19 three-hour interactive sessions, a variety of test conditions were explored. Since bit rate limits are necessarily imposed on Space Station video experiments surveillance video was varied down to 50 Kb/s and the effectiveness of PI controlled frame rate, resolution, grey scale, and color decimation was investigated. It is concluded that remote coaching by voice works and that dedicated crew-PI voice loops would be of great value on the Space Station.

  4. VDI-Richtlinien - mit Technischen Regeln Wirtschaftlichkeit erhöhen und Standards setzen

    NASA Astrophysics Data System (ADS)

    Mandelartz, Johannes

    Der Verein Deutscher Ingenieure e.V. (VDI) ist ein gemeinnütziger, wirtschaftlich und politisch unabhängiger, technisch-wissenschaftlicher Verein von Ingenieuren und Naturwissenschaftlern. Mit über 137 000 persönlich zugeordneten Mitgliedern ist er eine der größten Ingenieur-Vereinigungen Europas und gilt in Deutschland als führender Sprecher der Technik und der Ingenieure. 1856 gegründet, hat er viele für die Technik wesentliche Entwicklungen in Gang gesetzt, so im Bereich der technischen Überwachung, der technischen Regelsetzung und Normung, der Arbeitsstudien, im gewerblichen Rechtsschutz und im Patentwesen. Seit seiner Gründung sieht es der VDI als seine Aufgabe, "das Zusammenwirken aller geistiger Kräfte der Technik im Bewusstsein ethischer Verantwortung zu fördern“ und die Lebensmöglichkeiten aller Menschen durch Entwicklung und sinnvoller Anwendung technischer Mittel zu verbessern.

  5. Rapid Speech Transmission Index predictions and auralizations of unusual instructional spaces at MIT's new Stata Center

    NASA Astrophysics Data System (ADS)

    Conant, David A.

    2005-04-01

    The Stata Center for Computer, Information and Intelligence Sciences, recently opened at the Massachusetts Institute of Technology, includes a variety of oddly-shaped seminar rooms in addition to lecture spaces of somewhat more conventional form. The architects design approach prohibited following conventional, well understood room-acoustical behavior yet MIT and the design team were keenly interested in ensuring that these spaces functioned exceptionally well, acoustically. CATT-Acoustic room modeling was employed to assess RASTI through multiple design iterations for all these spaces. Presented here are computational and descriptive results achieved for these rooms which are highly-regarded by faculty. They all sound peculiarly good, given their unusual form. In addition, binaural auralizations for selected spaces are provided.

  6. The standoff aerosol active signature testbed (SAAST) at MIT Lincoln Laboratory

    NASA Astrophysics Data System (ADS)

    Richardson, Jonathan M.; Aldridge, John C.

    2005-11-01

    Standoff LIDAR detection of BW agents depends on accurate knowledge of the infrared and ultraviolet optical elastic scatter (ES) and ultraviolet fluorescence (UVF) signatures of bio-agents and interferents. MIT Lincoln Laboratory has developed the Standoff Aerosol Active Signature Testbed (SAAST) for measuring ES cross sections from BW simulants and interferents at all angles including 180º (direct backscatter). Measurements of interest include the dependence of the ES and UVF signatures on several spore production parameters including growth medium, sporulation protocol, washing protocol, fluidizing additives, and degree of aggregation. Using SAAST, we have made measurements of the ES signature of Bacillus globigii (atropheaus, Bg) spores grown under different growth methods. We have also investigated one common interferent (Arizona Test Dust). Future samples will include pollen and diesel exhaust. This paper presents the details of the SAAST apparatus along with the results of recent measurements.

  7. Space applications of the MITS electron-photon Monte Carlo transport code system

    SciTech Connect

    Kensek, R.P.; Lorence, L.J.; Halbleib, J.A.; Morel, J.E.

    1996-07-01

    The MITS multigroup/continuous-energy electron-photon Monte Carlo transport code system has matured to the point that it is capable of addressing more realistic three-dimensional adjoint applications. It is first employed to efficiently predict point doses as a function of source energy for simple three-dimensional experimental geometries exposed to simulated uniform isotropic planar sources of monoenergetic electrons up to 4.0 MeV. Results are in very good agreement with experimental data. It is then used to efficiently simulate dose to a detector in a subsystem of a GPS satellite due to its natural electron environment, employing a relatively complex model of the satellite. The capability for survivability analysis of space systems is demonstrated, and results are obtained with and without variance reduction.

  8. Performance and reliability of photovoltaic modules at various MIT LL test sites

    SciTech Connect

    Forman, S. E.; Themelis, M. P.

    1980-01-01

    Between March 1977 and the present, MIT Lincoln Laboratory, in conjunction with the US Department of Energy, has placed 85 kW of photovoltaic modules at various experimental test sites in the United States. These sites range in size and function from a 25-kW System Test Facility, where all the components in a PV system are tested, down to a 0.1-kW Environmental Test Site, where modules alone undergo weathering and soil accumulation experiments. To date, 144 modules (amounting to 2.75 kW) of 4533 have experienced electrical failure. This report summarizes the performance and reliability of photovoltaic modules at two experimental test sites: a 25-kW array field at Mead, Nebraska, and a 7.5-kW array field at Arlington, Texas.

  9. MC21 analysis of the MIT PWR benchmark: Hot zero power results

    SciTech Connect

    Kelly Iii, D. J.; Aviles, B. N.; Herman, B. R.

    2013-07-01

    MC21 Monte Carlo results have been compared with hot zero power measurements from an operating pressurized water reactor (PWR), as specified in a new full core PWR performance benchmark from the MIT Computational Reactor Physics Group. Included in the comparisons are axially integrated full core detector measurements, axial detector profiles, control rod bank worths, and temperature coefficients. Power depressions from grid spacers are seen clearly in the MC21 results. Application of Coarse Mesh Finite Difference (CMFD) acceleration within MC21 has been accomplished, resulting in a significant reduction of inactive batches necessary to converge the fission source. CMFD acceleration has also been shown to work seamlessly with the Uniform Fission Site (UFS) variance reduction method. (authors)

  10. Die Struktur von schlankem Materialfluss mit Lean Production Kanban und Innovationen

    NASA Astrophysics Data System (ADS)

    Scheid, Wolf-Michael

    In der Literatur wird Materialfluss überwiegend in Spezialdisziplinen betrachtet, etwa der Steuerungslogik, der Logistiktechnik oder dem Supply Chain Management. Ein charakterisierendes Merkmal des Materialflusses ist jedoch, dass er sich aus vielfältigen Einzelbausteinen zusammensetzt, die alle harmonisch abgestimmt sein müssen. Die maximal erreichbare Effizienz wird nicht durch Höchstleistungen in dem einen oder anderen Spezialthema bestimmt, sondern durch das schwächste Glied im gesamten komplexen Netzwerk. Den Schnittstellen zwischen den betroffenen Fachbereichen in einem Unternehmen kommt hier eine ganz besondere Bedeutung zu: Erst ein harmonischer Einklang ermöglicht hohe Effektivität. Dies setzt umfassendes Verständnis für interdisziplinäre Notwendigkeiten, ein hohes Maß an Abstimmung mit den operativen Prozessen und letztlich einen einvernehmlichen Umgang und den Respekt vor den Problemstellungen des Anderen voraus.

  11. Calibrating a VPL DataGlove for teleoperating the Utah/MIT hand

    NASA Technical Reports Server (NTRS)

    Hong, Jiawei; Tan, Xiaonan

    1989-01-01

    A system able to control the Utah/MIT hand with the VPL DataGlove has been developed. To get the actual joint angles from the DataGlove sensor values, a least-squares fit is used to find the best-fit exponential curve for each sensor, and then the correlation between the sensors is reduced by the iterative correlation elimination procedure. The calibration depends both on the wearer and the particular DataGlove being used. The first-level calibration is simple and can be done under 15 min with experience. The second level is fixed and requires no adjustments. To control the hand, a mapping from the DataGlove angles to the hand angles is applied, making the hand fingertips follow the DataGlove fingertips. The hand can successfully implement various high-level tasks under the DataGlove wearer's control.

  12. MIT-Hawaii-IRTF Joint Program for Characterization of Near-Earth Objects

    NASA Astrophysics Data System (ADS)

    Tokunaga, Alan; Bus, S. J.; Binzel, R. P.; Thomas, C. A.; DeMeo, F. E.; Rivkin, A. S.

    2006-09-01

    We describe an ongoing joint observing program for routine measurement of near-Earth object (NEO) spectra being conducted on behalf of the community by MIT, the University of Hawaii, and the NASA Infrared Telescope Facility (IRTF) on Mauna Kea, Hawaii. We utilize SpeX, a low-to-medium resolution near-infrared spectrograph and imager, to obtain 0.8- to 2.5-micron spectra. Under good seeing conditions the limiting magnitude for our program is near V=17.5 magnitudes. Our program goals are to provide an ongoing source of current spectral measurements allowing broad characterization of the near-Earth object population. Particular emphasis is placed on characterizing potentially hazardous asteroids (PHAs) and enhancing our understanding of asteroid-comet-meteorite interrelationships. NEOs residing in orbits that may be accessible as spacecraft targets are also given priority. All spectroscopic observations obtained in this program are being made publicly available in near-real time via the website: http://smass.mit.edu/ and are also linked through the IRTF website: http://irtfweb.ifa.hawaii.edu/ . We have as an operational goal to process and to make available in the public domain the spectral results within a few days of the observations. Spectra for nearly 100 NEOs are presently available. This program has been granted long-term planetary status and utilizes approximately one night per month. This frequent access enables routine characterization of both newly discovered targets of opportunity and previously known near-Earth objects. There is no pre-condition for collaboration for any researcher wishing to use these data. All data obtained and released by this program may be used freely. We welcome broad community participation in target selection, observing, and data utilization. This research supported by NASA Cooperative Agreement NCC5-538.

  13. Effects of tissue heterogeneity on single-coil, scanning MIT imaging

    NASA Astrophysics Data System (ADS)

    Feldkamp, J. R.; Quirk, S.

    2016-03-01

    We recently reported on the use of a single induction coil to accomplish imaging of the electrical conductivity in human tissues via magnetic induction tomography (MIT). A key to the method was the development of a mapping equation that quantitatively relates an arbitrary electrical conductivity distribution to ohmic loss in a coil consisting of concentric circular loops in a plane. By making multiple coil loss measurements at a number of locations in the vicinity of the target (scan), this mapping equation can be used to build an algorithm for 3D image construction of electrical conductivity. Important assumptions behind the mathematical formula included uniform relative permittivity throughout all space and continuous variation in conductivity. In this paper, these two assumptions were tested in a series of experiments involving the use of human tissue phantoms created from agarose, doped with sufficient sodium chloride to yield physiological conductivities. Inclusions of doped agarose were scanned both while isolated and also while embedded in a matrix of agarose gel having lowered conductivity - to help evaluate the effects of abrupt permittivity change. The effects of discontinuous conductivity change were simulated by filling 5 cm diameter petri dishes with 1.4% aqueous KCl and placing them in a much larger, 14 cm diameter petri dish - gap distance varied from about 3 mm to 30 mm. In either case, we will show that these effects are minimal on resultant images, helping to further validate the mapping equation used to construct MIT images. Because of their simplicity, scans reported here did not include coil rotation. To acknowledge the importance of rotation, however, we have devoted a section of this work to illustrate the profound benefits of coil rotation during a scan - though virtual data are used, where coil rotation is more easily specified.

  14. Prophylaxe beim hereditären Angioödem (HAE) mit C1-Inhibitormangel.

    PubMed

    Greve, Jens; Strassen, Ulrich; Gorczyza, Marina; Dominas, Nina; Frahm, Uta-Marie; Mühlberg, Heike; Wiednig, Michaela; Zampeli, Vasiliki; Magerl, Markus

    2016-03-01

    Das hereditäre Angioödem (engl.: hereditary angioedema, HAE) ist eine seltene angeborene Erkrankung, die durch wiederkehrende Episoden subkutaner oder submuköser Ödeme charakterisiert ist. Kehlkopf-Manifestationen können lebensbedrohlich sein. In den meisten Fällen kann die Erkrankung mit einem On-Demand-Ansatz angemessen behandelt werden - in einigen Fällen ist jedoch eine Kurz- oder Langzeitprophylaxe angebracht. Attenuierte Androgene waren einmal das Standardmedikament; sie werden jedoch mit erheblichen Nebenwirkungen in Verbindung gebracht und sind in den deutschsprachigen Ländern der EU nicht mehr kommerziell erhältlich. Zurzeit werden sie von wirksameren und besser verträglichen Therapien wie C1-Esterase-Inhibitoren, dem Kallikrein-Inhibitor Ecallantid und dem B2-Rezeptorantagonisten Icatibant verdrängt, welche kürzlich auf dem Markt zugelassen wurden. Diese neuen Medikamente hatten einen erheblichen Einfluss, insbesondere auf die Indikationsstellung und das Vorgehen bei einer Langzeitprophylaxe. Nach den neuesten internationalen Konsenspapieren und unserer eigenen Erfahrung sind selbstverabreichte C1-Inhibitoren nun die erste Option bei der Langzeitprophylaxe. Die Entscheidung für eine Prophylaxe sollte nicht länger auf der Grundlage einzelner Parameter wie der Häufigkeit der Anfälle getroffen werden, sondern auf einer adäquaten allgemeinen Krankheitskontrolle, einschließlich der Lebensqualität. Zurzeit werden weitere Medikamente entwickelt, welche zu weiteren Veränderungen bei den Behandlungsalgorithmen des HAE führen könnten. PMID:26972190

  15. Entropy Generation/Availability Energy Loss Analysis Inside MIT Gas Spring and "Two Space" Test Rigs

    NASA Technical Reports Server (NTRS)

    Ebiana, Asuquo B.; Savadekar, Rupesh T.; Patel, Kaushal V.

    2006-01-01

    The results of the entropy generation and availability energy loss analysis under conditions of oscillating pressure and oscillating helium gas flow in two Massachusetts Institute of Technology (MIT) test rigs piston-cylinder and piston-cylinder-heat exchanger are presented. Two solution domains, the gas spring (single-space) in the piston-cylinder test rig and the gas spring + heat exchanger (two-space) in the piston-cylinder-heat exchanger test rig are of interest. Sage and CFD-ACE+ commercial numerical codes are used to obtain 1-D and 2-D computer models, respectively, of each of the two solution domains and to simulate the oscillating gas flow and heat transfer effects in these domains. Second law analysis is used to characterize the entropy generation and availability energy losses inside the two solution domains. Internal and external entropy generation and availability energy loss results predicted by Sage and CFD-ACE+ are compared. Thermodynamic loss analysis of simple systems such as the MIT test rigs are often useful to understand some important features of complex pattern forming processes in more complex systems like the Stirling engine. This study is aimed at improving numerical codes for the prediction of thermodynamic losses via the development of a loss post-processor. The incorporation of loss post-processors in Stirling engine numerical codes will facilitate Stirling engine performance optimization. Loss analysis using entropy-generation rates due to heat and fluid flow is a relatively new technique for assessing component performance. It offers a deep insight into the flow phenomena, allows a more exact calculation of losses than is possible with traditional means involving the application of loss correlations and provides an effective tool for improving component and overall system performance.

  16. Genetic Localization and Molecular Characterization of Two Key Genes (mitAB) Required for Biosynthesis of the Antitumor Antibiotic Mitomycin C

    PubMed Central

    Mao, Yingqing; Varoglu, Mustafa; Sherman, David H.

    1999-01-01

    Mitomycin C (MC) is an antitumor antibiotic derived biosynthetically from 3-amino-5-hydroxybenzoic acid (AHBA), d-glucosamine, and carbamoyl phosphate. A gene (mitA) involved in synthesis of AHBA has been identified and found to be linked to the MC resistance locus, mrd, in Streptomyces lavendulae. Nucleotide sequence analysis showed that mitA encodes a 388-amino-acid protein that has 71% identity (80% similarity) with the rifamycin AHBA synthase from Amycolatopsis mediterranei, as well as with two additional AHBA synthases from related ansamycin antibiotic-producing microorganisms. Gene disruption and site-directed mutagenesis of the S. lavendulae chromosomal copy of mitA completely blocked the production of MC. The function of mitA was confirmed by complementation of an S. lavendulae strain containing a K191A mutation in MitA with AHBA. A second gene (mitB) encoding a 272-amino-acid protein (related to a group of glycosyltransferases) was identified immediately downstream of mitA that upon disruption resulted in abrogation of MC synthesis. This work has localized a cluster of key genes that mediate assembly of the unique mitosane class of natural products. PMID:10094699

  17. [Prognostic significance of cytogenetic changes in patients with acute myeloid leukemia (AML). (Analysis of results in 105 patients treated at the Hemato-oncology Clinic of the University Hospital in Olomouc from 1997 to 2000].

    PubMed

    Jarosová, M; Indrák, K; Holzerová, M; Hubácek, J; Faber, E; Papajík, T; Raida, L; Szotkowski, T; Knotková, R; Hlusí, T; Jedlicková, K; Pikalová, Z; Sulovská, I

    2001-09-01

    Chromosomal aberrations are one of the most important prognostic factors in patients with acute myeloid leukemia (AML). This work present analysis of conventional cytogenetic results completed by fluorescence in situ hybridization (FISH) obtained from 105 patients in the time of diagnosis of AML. The median age of patients was 51 years (range 19-79 years), with slight predominance of women (female to male ratio 1.2:1). The evaluated group involved all patients with AML diagnosis, treated by intensive induction chemotherapy in the Department of Hematology-oncology, University Hospital, Olomouc during last 4 years with assessable cytogenetic results. Chromosomal changes were found in 63 (60%) patients. The most often affected chromosomes in succession of frequency were 8, 17, 7, 5, 11, 15, 16 a 21. Based on found specific and frequent chromosomal changes the patients were divided into 3 prognostic subgroups and the significance of chromosomal aberrations was evaluated. The subgroup of 17 patients with good prognosis consisted of a patients with acute promyelocytic leukemia with translocation t(15;17), 4 patients with t(8;21) and 4 patients with inv(16). 14 patients of 17 live in complete remission, median of overall survival (OS) is 63 weeks. The subgroup of intermediate prognosis was formed by 60 patients, 42 had normal karyotype and 18 patients had other chromosomal abnormalities. Median OS of this group was 35 weeks. The third subgroup with poor prognosis consisted of 28 patients with changes of chromosomes 3, 5, 7, 11 and complex karyotype. 64.3% of patients received complete remission and median OS was 35 weeks. Statistical evaluation of OS showed significant difference (p = 0.002) in subgroup with good prognosis versus subgroup with poor prognosis and in subgroup with good prognosis versus subgroup with intermediate prognosis (p = 0.014). Statistical significance of OS in subgroup with intermediate prognosis versus subgroup with poor prognosis was not proved (p

  18. Regulation of the miRNA expression by TEL/AML1, BCR/ABL, MLL/AF4 and TCF3/PBX1 oncoproteins in acute lymphoblastic leukemia (Review).

    PubMed

    Organista-Nava, Jorge; Gómez-Gómez, Yazmín; Illades-Aguiar, Berenice; Leyva-Vázquez, Marco Antonio

    2016-09-01

    MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs that play important regulatory roles by targeting mRNAs for cleavage or translational repression. miRNAs act in diverse biological processes including development, cell growth, apoptosis, and hematopoiesis. The miRNA expression is associated with specific cytogenetic changes and can also be used to discriminate between the different subtypes of leukemia in acute lymphoblastic leukemia with common translocations, it is shown that the miRNAs have the potential to be used for clinical diagnosis and prognosis. We reviewed the roles of miRNA here with emphasis on their function in human leukemia and the mechanisms of the TEL/AML1, BCR/ABL, MLL/AF4 and TCF3/PBX1 oncoproteins on miRNAs expression in acute lymphoblastic leukemia. PMID:27431573

  19. The influence of disease and comorbidity risk assessments on the survival of MDS and oligoblastic AML patients treated with 5-azacitidine: A retrospective analysis in ten centers of the "Rete Ematologica Lombarda".

    PubMed

    Molteni, Alfredo; Riva, Marta; Borin, Lorenza; Bernardi, Massimo; Pelizzari, Anna Maria; Freyrie, Alessandra; Porta, Matteo Della; Nichelatti, Michele; Ravano, Emanuele; Quaresmini, Giulia; Mariotti, Jacopo; Caramazza, Domenica; Ubezio, Marta; Guarco, Simona; Gigli, Federica; Greco, Rosa; Cairoli, Roberto; Morra, Enrica

    2016-03-01

    5-Azacytidine is an effective therapy in high risk MDS and oligoblastic AML. This "real life" analysis was made on 185 patients treated with 5-azacytidine in 10 centers afferent to REL ("Rete Ematologica Lombarda"), a network in Lombardia region. The aim was to assess the influence of disease and comorbidity risk assessments on the survival. The results confirm the utility of 5-azacitidine in prolonging OS regardless of advanced age and the presence of comorbidities. They also encourage an early treatment since patients with IPSS-R High risk MDS have better outcome with respect to Very High risk ones. According to the IPSS cytogenetic risk, there was no difference in the outcome between Intermediate and High risk patients. Nevertheless, a poorer cytogenetic risk, according to the IPSS-R cytogenetic stratification, negatively influenced the outcome. PMID:26852003

  20. The MIT Integrated Global System Model: A facility for Assessing and Communicating Climate Change Uncertainty (Invited)

    NASA Astrophysics Data System (ADS)

    Prinn, R. G.

    2013-12-01

    The world is facing major challenges that create tensions between human development and environmental sustenance. In facing these challenges, computer models are invaluable tools for addressing the need for probabilistic approaches to forecasting. To illustrate this, I use the MIT Integrated Global System Model framework (IGSM; http://globalchange.mit.edu ). The IGSM consists of a set of coupled sub-models of global economic and technological development and resultant emissions, and physical, dynamical and chemical processes in the atmosphere, land, ocean and ecosystems (natural and managed). Some of the sub-models have both complex and simplified versions available, with the choice of which version to use being guided by the questions being addressed. Some sub-models (e.g.urban air pollution) are reduced forms of complex ones created by probabilistic collocation with polynomial chaos bases. Given the significant uncertainties in the model components, it is highly desirable that forecasts be probabilistic. We achieve this by running 400-member ensembles (Latin hypercube sampling) with different choices for key uncertain variables and processes within the human and natural system model components (pdfs of inputs estimated by model-observation comparisons, literature surveys, or expert elicitation). The IGSM has recently been used for probabilistic forecasts of climate, each using 400-member ensembles: one ensemble assumes no explicit climate mitigation policy and others assume increasingly stringent policies involving stabilization of greenhouse gases at various levels. These forecasts indicate clearly that the greatest effect of these policies is to lower the probability of extreme changes. The value of such probability analyses for policy decision-making lies in their ability to compare relative (not just absolute) risks of various policies, which are less affected by the earth system model uncertainties. Given the uncertainties in forecasts, it is also clear that

  1. The MIT IGSM-CAM framework for uncertainty studies in global and regional climate change

    NASA Astrophysics Data System (ADS)

    Monier, E.; Scott, J. R.; Sokolov, A. P.; Forest, C. E.; Schlosser, C. A.

    2011-12-01

    The MIT Integrated Global System Model (IGSM) version 2.3 is an intermediate complexity fully coupled earth system model that allows simulation of critical feedbacks among its various components, including the atmosphere, ocean, land, urban processes and human activities. A fundamental feature of the IGSM2.3 is the ability to modify its climate parameters: climate sensitivity, net aerosol forcing and ocean heat uptake rate. As such, the IGSM2.3 provides an efficient tool for generating probabilistic distribution functions of climate parameters using optimal fingerprint diagnostics. A limitation of the IGSM2.3 is its zonal-mean atmosphere model that does not permit regional climate studies. For this reason, the MIT IGSM2.3 was linked to the National Center for Atmospheric Research (NCAR) Community Atmosphere Model (CAM) version 3 and new modules were developed and implemented in CAM in order to modify its climate sensitivity and net aerosol forcing to match that of the IGSM. The IGSM-CAM provides an efficient and innovative framework to study regional climate change where climate parameters can be modified to span the range of uncertainty and various emissions scenarios can be tested. This paper presents results from the cloud radiative adjustment method used to modify CAM's climate sensitivity. We also show results from 21st century simulations based on two emissions scenarios (a median "business as usual" scenario where no policy is implemented after 2012 and a policy scenario where greenhouse-gas are stabilized at 660 ppm CO2-equivalent concentrations by 2100) and three sets of climate parameters. The three values of climate sensitivity chosen are median and the bounds of the 90% probability interval of the probability distribution obtained by comparing the observed 20th century climate change with simulations by the IGSM with a wide range of climate parameters values. The associated aerosol forcing values were chosen to ensure a good agreement of the simulations

  2. Once Daily IV Busulfan and Fludarabine (IV Bu-Flu) Compares Favorably with IV Busulfan and Cyclophosphamide (IV BuCy2) as Pretransplant Conditioning Therapy in AML/MDS

    PubMed Central

    Andersson, Borje S.; de Lima, Marcos; Thall, Peter F.; Wang, Xuemei; Couriel, Daniel; Korbling, Martin; Roberson, Soonja; Giralt, Sergio; Pierre, Betty; Russell, James A.; Shpall, Elizabeth J.; Jones, Roy B.; Champlin, Richard E.

    2009-01-01

    Summary We postulated that fludarabine (Flu) instead of cyclophosphamide (Cy) combined with IV busulfan (Bu) as preconditioning for allogeneic hematopoietic stem cell transplantation (HSCT) would improve safety and retain antileukemic efficacy. 67 patients received BuCy2 and subsequently 148 patients received Bu-Flu. We used a Bayesian method to compare outcomes between these non-randomized patients. The groups had comparable pretreatment characteristics, except that Bu-Flu patients were older (46 vs. 39 years, p< 0.01), more often had unrelated donors (47.3% vs. 20.9%, p< 0.0003), and had shorter median follow-up (39.7 vs. 74.6 months). To account for improved supportive care and other unidentified factors that may affect outcome (“period” effects), 78 AML patients receiving Melphalan-Flu (“MF”), treated in parallel during this time (1997 to 2004) were used to estimate the period effect; The MF patients’ outcomes worsened during this period. Therefore, the period effect is unlikely to explain the greatly improved outcome with Bu-Flu. Patients transplanted with Bu-Flu in CR1 had a 3-year overall survival and event-free-survival (EFS) of 78% and 74%, respectively, while CR1 patients younger than age 41 had a 3-year EFS of 89%. These results support replacing BuCy±ATG with Bu-Flu±rabbit-ATG, and warrant a prospective comparison between allogeneic HSCT and conventional induction/consolidation chemotherapy for AML in CR1. PMID:18489993

  3. High feasibility and antileukemic efficacy of fludarabine, cytarabine, and idarubicin (FLAI) induction followed by risk-oriented consolidation: A critical review of a 10-year, single-center experience in younger, non M3 AML patients.

    PubMed

    Guolo, Fabio; Minetto, Paola; Clavio, Marino; Miglino, Maurizio; Di Grazia, Carmen; Ballerini, Filippo; Pastori, Giordana; Guardo, Daniela; Colombo, Nicoletta; Kunkl, Annalisa; Fugazza, Giuseppina; Rebesco, Barbara; Sessarego, Mario; Lemoli, Roberto Massimo; Bacigalupo, Andrea; Gobbi, Marco

    2016-08-01

    About 105 consecutive acute myeloid leukemia (AML) patients treated with the same induction-consolidation program between 2004 and 2013 were retrospectively analyzed. Median age was 47 years. The first induction course included fludarabine (Flu) and high-dose cytarabine (Ara-C) plus idarubicin (Ida), with or without gemtuzumab-ozogamicin (GO) 3 mg/m(2) (FLAI-5). Patients achieving complete remission (CR) received a second course without fludarabine but with higher dose of idarubicin. Patients not achieving CR received an intensified second course. Patients not scheduled for early allogeneic bone marrow transplantation (HSCT) where planned to receive at least two courses of consolidation therapy with Ara-C. Our double induction strategy significantly differs from described fludarabine-containing regimens, as patients achieving CR receive a second course without fludarabine, to avoid excess toxicity, and Ara-C consolidation is administrated at the reduced cumulative dose of 8 g/m(2) per cycle. Toxicity is a major concern in fludarabine containing induction, including the recent Medical Research Council AML15 fludarabine, cytarabine, idaraubicin and G-CSF (FLAG-Ida) arm, and, despite higher anti-leukemic efficacy, only a minority of patients is able to complete the full planned program. In this article, we show that our therapeutic program is generally well tolerated, as most patients were able to receive subsequent therapy at full dose and in a timely manner, with a 30-day mortality of 4.8%. The omission of fludarabine in the second course did not reduce efficacy, as a CR rate of 83% was achieved and 3-year disease-free survival and overall survival (OS) were 49.6% and 50.9%, respectively. Our experience shows that FLAI-5/Ara-C + Ida double induction followed by risk-oriented consolidation therapy can result in good overall outcome with acceptable toxicity. Am. J. Hematol. 91:755-762, 2016. © 2016 Wiley Periodicals, Inc. PMID:27084986

  4. Synergistic effect of sorafenib and cGvHD in patients with high-risk FLT3-ITD+AML allows long-term disease control after allogeneic transplantation.

    PubMed

    Tschan-Plessl, A; Halter, J P; Heim, D; Medinger, M; Passweg, J R; Gerull, S

    2015-11-01

    The multikinase inhibitor sorafenib has shown a strong anti-leukemic effect in FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML); however, remission is often transient. To better understand the role of sorafenib, we performed a retrospective analysis of all patients who received sorafenib in combination with allogeneic hematopoietic stem cell transplantation (HSCT) at our center. Seventeen patients with FLT3-ITD positive AML were treated with sorafenib in combination with allogeneic HSCT. Seven patients received sorafenib therapy pre- and posttransplant, and 10 patients were given sorafenib only posttransplant. Median duration of sorafenib treatment was 13 months (range 1-42); median dose was 600 mg (range 100-1200). Fourteen patients (82 %) achieved a complete remission (CR), while 5 patients (29 %) eventually developed progressive disease. Developing chronic graft-versus-host disease (GvHD) had a strong protective influence on the risk of sorafenib resistance (p = 0.028, HR 0.08, 95 % CI 0.01-0.76). In a total of 8 patients, sorafenib had to be stopped, paused or dose-reduced due to toxicity. In 5 patients with pronounced toxicity, we switched to an alternating dosing schedule with 1 month on/1 month off sorafenib. These patients subsequently remained in sustained complete molecular remission, with a median follow-up of 20 months. Our data indicate that sorafenib can achieve high rates of sustained remission in high-risk patients treated in combination with HSCT. PMID:26233683

  5. Whole-arm translocation of der(5;17)(p10;q10) with concurrent TP53 mutations in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS): A unique molecular-cytogenetic subgroup.

    PubMed

    Hong, Ming; Hao, Suyang; Patel, Keyur P; Kantarjian, Hagop M; Garcia-Manero, Guillermo; Yin, C Cameron; Medeiros, L Jeffrey; Lin, Pei; Lu, Xinyan

    2016-05-01

    Der(5;17)(p10;q10) is a recurrent but rare aberration reported in myeloid neoplasms (MNs). We report 48 such patients including 19 acute myeloid leukemia (AML) and 29 myelodysplastic syndrome (MDS), to characterize their clinicopathological features. There were 29 men and 19 women, with a median age of 61 years (range, 18-80). 62.5% patients had therapy-related diseases (t-MNs), 70.8% had multilineage dysplasia and 83.3% showed complex karyotypes. In 39 patients tested, FLT3, NPM1, CEBPA, KIT were all wild type and NRAS, KRAS, IDH1, APC, TET2 mutations were detected in single case(s) respectively. TP53 mutations were identified in 8 of 10 cases (80%) tested. Median disease-free survival (DFS) and overall survival (OS) were 3 and 10 months, respectively and did not differ between AML or MDS cases, or between de novo versus therapy-related cases, or between the groups with or without complex karyotypes. In 19 patients who achieved complete remission after chemotherapy, and in 9 patients who underwent stem cell transplantation, the OS was better (14 and 17.5 months, P = 0.0128 and P = 0.0086, respectively). The der(5;17)(p10;q10) represents a unique molecular-cytogenetic subgroup in t-MNs and, associated with complex karyotypes. TP53 inactivation, resulting from 17p deletion coupled with TP53 mutation, likely contributes to the poor clinical outcome of these patients. PMID:27134073

  6. First Observations of a Stellar Occultation by KBO (50000) Quaoar from MIT's George R. Wallace, Jr., Astrophysical Observatory

    NASA Astrophysics Data System (ADS)

    Sallum, Stephanie; Brothers, T.; Elliot, J. L.; Person, M. J.; Bosh, A. S.; Zangari, A.; Zuluaga, C.; Levine, S.; Bright, L.; Sheppard, S.; Tilleman, T.

    2011-05-01

    Here we report the first recorded observations of a stellar occultation by Kuiper Belt Object (KBO) (50000) Quaoar. We detected a single-chord stellar occultation by Quaoar of a magnitude 16.2 star designated 26029635 UCAC2 (2MASS ID 1275509401), which occurred on 11 February 2011 UT. The prediction of the occultation was made using long baseline astrometric observations of Quaoar from several sites as part of the MIT Planetary Astronomy Laboratory's continuing effort to improve KBO positions for occultation prediction. The successful observations were made with a Celestron C14 0.36 m telescope and an SBIG STL-1001E CCD camera on a Paramount ME robotic mount. These observations show that a relatively accessible level of astronomical equipment, of the class often used by amateur astronomers, can be used to record KBO occultations. The data were taken at MIT's George R. Wallace, Jr., Astrophysical Observatory in Westford, MA. A light curve was generated from the data using aperture photometry on the individual images and is presented here. This light curve is being analyzed by Person et al. (this meeting) to provide constraints on Quaoar's size. We also discuss various observing strategies that could be used in the future to optimize the data from this type of event. This work was supported in part by grant NNX10AB27G to MIT from NASA's Planetary Astronomy Division. Student participation was supported in part by NSF's REU program, MIT's Undergraduate Research Opportunities Program, NASA's Massachusetts Space Grant, and the George R. Wallace, Jr., Astrophysical Observatory.

  7. Acceptance and operational test procedure for neutron and gamma probe application to tank 241-SY-101 MITs

    SciTech Connect

    CANNON, N.S.

    1999-06-02

    This ATP/OTP provides procedures for testing to be performed to verify that newly procured neutron and gamma probes (reduced diameter design modifications) for operation in the Tank 241-SY-101 MlTs are compatible with existing LOW van instrumentation and hardware. A set of moisture data versus elevation will be obtained from the Tank 241-SY-101 MITs, and (optionally) from the Tank 241-AX-I01 LOW as part of this testing program.

  8. Field Measurement-Based System Identification and Dynamic Response Prediction of a Unique MIT Building

    PubMed Central

    Cha, Young-Jin; Trocha, Peter; Büyüköztürk, Oral

    2016-01-01

    Tall buildings are ubiquitous in major cities and house the homes and workplaces of many individuals. However, relatively few studies have been carried out to study the dynamic characteristics of tall buildings based on field measurements. In this paper, the dynamic behavior of the Green Building, a unique 21-story tall structure located on the campus of the Massachusetts Institute of Technology (MIT, Cambridge, MA, USA), was characterized and modeled as a simplified lumped-mass beam model (SLMM), using data from a network of accelerometers. The accelerometer network was used to record structural responses due to ambient vibrations, blast loading, and the October 16th 2012 earthquake near Hollis Center (ME, USA). Spectral and signal coherence analysis of the collected data was used to identify natural frequencies, modes, foundation rocking behavior, and structural asymmetries. A relation between foundation rocking and structural natural frequencies was also found. Natural frequencies and structural acceleration from the field measurements were compared with those predicted by the SLMM which was updated by inverse solving based on advanced multiobjective optimization methods using the measured structural responses and found to have good agreement. PMID:27376303

  9. NASA Education and Public Outreach Initiatives at the MIT Center for Space Research

    NASA Astrophysics Data System (ADS)

    Porro, I. L.

    2003-12-01

    Since its inception in 1999, the EPO office of the MIT Center for Space Research (CSR) has fostered direct participation of local scientists in educational initiatives such as teachers workshops and public tours of the Chandra Operations and Control Center. The role played by the CSR EPO office has grown significantly, thanks to the award of a number of EPO grants associated with the Chandra and HETE missions. In the past year about one-third of the CSR research staff was involved in the office's EPO initiatives: more than 500 K-12 students, about half from underrepresented groups, were included in formal education programs and informal education events attracted an estimated 900 people. Today the mission of the CSR EPO office is focused in two areas: professional development for K-12 science teachers, and educational programs in out-of-school time. To be associated with major NASA research missions is beneficial to our mission in several respects, but provides also specific challenges. We present here some of the strategies and intiatives that we have undertaken to overcome those challenges.

  10. Harvard-MIT research program in short-lived radiopharmaceuticals. Final report

    SciTech Connect

    Adelstein, S.J.

    1995-02-01

    The Harvard-MIT Research Program in Short-lived Radiopharmaceuticals was established in 1977 to foster interaction among groups working in radiopharmaceutical chemistry at Harvard Medical School, the Massachusetts Institute of Technology, and the Massachusetts General Hospital. To this was added a group at The Childrens Hospital. From these collaborations and building upon the special strengths of the participating individuals, laboratories and institutions, it was hoped that original approaches would be found for the design of new, clinically useful, radiolabeled compounds. The original thrust of this proposal included: (a) examination of the coordination chemistry of technetium as a basis for rational radiopharmaceutical design, (b) development of an ultrashort-lived radionuclide generator for the diagnosis of congenital heart disease in newborns, (c) synthesis of receptor-site-directed halopharmaceuticals, (d) improved facile labeling of complex molecules with positron-emitting radionuclides. The authors` 1986 proposal was oriented toward organs and disease, emphasizing radiolabeled agents that delineate specific functions and the distribution of receptors in brain, heart, and tumors. In 1989, they further refined their purposes and focused on two major aims: (a) synthesis and utilization of neutral technetium and rhenium complexes of high specific activity, and (b) development of new approaches to the radiolabeling of proteins, peptides, immunoglobulins, and their fragments. In 1992, the authors amended this proposal to concentrate their efforts on biologically active peptides and proteins for targeted radiodiagnosis and therapy.

  11. Field Measurement-Based System Identification and Dynamic Response Prediction of a Unique MIT Building.

    PubMed

    Cha, Young-Jin; Trocha, Peter; Büyüköztürk, Oral

    2016-01-01

    Tall buildings are ubiquitous in major cities and house the homes and workplaces of many individuals. However, relatively few studies have been carried out to study the dynamic characteristics of tall buildings based on field measurements. In this paper, the dynamic behavior of the Green Building, a unique 21-story tall structure located on the campus of the Massachusetts Institute of Technology (MIT, Cambridge, MA, USA), was characterized and modeled as a simplified lumped-mass beam model (SLMM), using data from a network of accelerometers. The accelerometer network was used to record structural responses due to ambient vibrations, blast loading, and the October 16th 2012 earthquake near Hollis Center (ME, USA). Spectral and signal coherence analysis of the collected data was used to identify natural frequencies, modes, foundation rocking behavior, and structural asymmetries. A relation between foundation rocking and structural natural frequencies was also found. Natural frequencies and structural acceleration from the field measurements were compared with those predicted by the SLMM which was updated by inverse solving based on advanced multiobjective optimization methods using the measured structural responses and found to have good agreement. PMID:27376303

  12. Hover Testing of the NASA/Army/MIT Active Twist Rotor Prototype Blade

    NASA Technical Reports Server (NTRS)

    Wilbur, Matthew L.; Yeager, William T., Jr.; Wilkie, W. Keats; Cesnik, Carlos E. S.; Shin, Sangloon

    2000-01-01

    Helicopter rotor individual blade control promises to provide a mechanism for increased rotor performance and reduced rotorcraft vibrations and noise. Active material methods, such as piezoelectrically actuated trailing-edge flaps and strain-induced rotor blade twisting, provide a means of accomplishing individual blade control without the need for hydraulic power in the rotating system. Recent studies have indicated that controlled strain induced blade twisting can be attained using piezoelectric active fiber composite technology. In order to validate these findings experimentally, a cooperative effort between NASA Langley Research Center, the Army Research Laboratory, and the MIT Active Materials and Structures Laboratory has been developed. As a result of this collaboration an aeroelastically-scaled active-twist model rotor blade has been designed and fabricated for testing in the heavy gas environment of the Langley Transonic Dynamics Tunnel (TDT). The results of hover tests of the active-twist prototype blade are presented in this paper. Comparisons with applicable analytical predictions of active-twist frequency response in hovering flight are also presented.

  13. Examination of Climate Response to Historical and Projected Forcings Over Years 850-4000 with the MIT IGSM.

    NASA Astrophysics Data System (ADS)

    Sokolov, A.; Scott, J.; Monier, E.; Schlosser, C. A.; Kicklighter, D.; Dutkiewicz, S.

    2012-04-01

    The MIT IGSM is used for a study of the climate response to various historical and projected forcings over the period 850-4000 AD. The MIT IGSM includes a zonally-averaged atmospheric model coupled to land and ocean models. Both land and ocean models simulate carbon cycle. Two configurations of the IGSM were used in the simulations; one with the MIT 3D OGCM and other with anomaly diffusing ocean model. Over the period 850-2005, a historical run with all time-varying natural and anthropogenic forcings is compared to a set of runs where only a single component of the forcing time series is varied. Over 2005-3000, climate projections as forced by four different Representation Concentration Pathways are compared. These projections are extended by decreasing forcings back to pre-industrial levels over years 3000-4000. In addition to changes in surface air temperature, carbon uptake in the ocean and land systems and changes in the oceans' large-scale circulation are a focus in analyses of these simulations. Simulations with interactive carbon cycle and prescribed carbon emissions were also carried out. Dependency of the projected changes on assumptions about climate system parameters, such as climate sensitivity, rate of oceanic heat uptake and aerosol forcing were studied using the IGSM with simplified ocean model.

  14. Structural Fine-Tuning of MIT-Interacting Motif 2 (MIM2) and Allosteric Regulation of ESCRT-III by Vps4 in Yeast.

    PubMed

    Kojima, Rieko; Obita, Takayuki; Onoue, Kousuke; Mizuguchi, Mineyuki

    2016-06-01

    The endosomal sorting complex required for transport (ESCRT) facilitates roles in membrane remodeling, such as multivesicular body biogenesis, enveloped virus budding and cell division. In yeast, Vps4 plays a crucial role in intraluminal vesicle formation by disassembling ESCRT proteins. Vps4 is recruited by ESCRT-III proteins to the endosomal membrane through the interaction between the microtubule interacting and trafficking (MIT) domain of Vps4 and the C-terminal MIT-interacting motif (MIM) of ESCRT-III proteins. Here, we have determined the crystal structure of Vps4-MIT in a complex with Vps20, a member of ESCRT-III, and revealed that Vps20 adopts a unique MIM2 conformation. Based on structural comparisons with other known MIM2s, we have refined the consensus sequence of MIM2. We have shown that another ESCRT-III protein, Ist1, binds to Vps4-MIT via its C-terminal MIM1 with higher affinity than Vps2, but lacks MIM2 by surface plasmon resonance. Surprisingly, the Ist1 MIM1 competed with the MIM2 of Vfa1, a regulator of Vps4, for binding to Vps4-MIT, even though these MIMs bind in non-overlapping sites on the MIT. These findings provide insight into the allosteric recognition of MIMs of ESCRT-III by Vps4 and also the regulation of ESCRT machinery at the last step of membrane remodeling. PMID:27075672

  15. Development of Improved Models, Stochasticity, and Frameworks for the MIT Extensible Air Network Simulation

    NASA Technical Reports Server (NTRS)

    Clarke, John-Paul

    2004-01-01

    MEANS, the MIT Extensible Air Network Simulation, was created in February of 2001, and has been developed with support from NASA Ames since August of 2001. MEANS is a simulation tool which is designed to maximize fidelity without requiring data of such a low level as to preclude easy examination of alternative scenarios. To this end, MEANS is structured in a modular fashion to allow more detailed components to be brought in when desired, and left out when they would only be an impediment. Traditionally, one of the difficulties with high-fidelity models is that they require a level of detail in their data that is difficult to obtain. For analysis of past scenarios, the required data may not have been collected, or may be considered proprietary and thus difficult for independent researchers to obtain. For hypothetical scenarios, generation of the data is sufficiently difficult to be a task in and of itself. Often, simulations designed by a researcher will model exactly one element of the problem well and in detail, while assuming away other parts of the problem which are not of interest or for which data is not available. While these models are useful for working with the task at hand, they are very often not applicable to future problems. The MEAN Simulation attempts to address these problems by using a modular design which provides components of varying fidelity for each aspect of the simulation. This allows for the most accurate model for which data is available to be used. It also provides for easy analysis of sensitivity to data accuracy. This can be particularly useful in the case where accurate data is available for some subset of the situations that are to be considered. Furthermore, the ability to use the same model while examining effects on different parts of a system reduces the time spent learning the simulation, and provides for easier comparisons between changes to different parts of the system.

  16. Idarubicin and cytarabine in combination with gemtuzumab ozogamicin (IAGO) for untreated patients with high-risk MDS or AML evolved from MDS: a phase II study from the EORTC and GIMEMA Leukemia Groups (protocol 06013).

    PubMed

    de Witte, Theo; Suciu, Stefan; Meert, Liv; Halkes, Constantijn; Selleslag, Dominik; Bron, Dominique; Amadori, Sergio; Willemze, Roel; Muus, Petra; Baron, Frédéric

    2015-12-01

    The primary objective of this trial was to assess the feasibility, toxicity profile, and antitumor activity of gemtuzumab ozogamicin (GO) combined with a chemotherapy remission-induction regimen in adults with untreated high-risk myelodysplastic syndrome (HR-MDS) or secondary acute myeloid leukemia (sAML). In this phase II trial, 30 patients with median age of 58 years received 1 day of GO as a 1-h infusion at the dose level of 5 mg/m(2) on day 7 of the remission-induction course further consisting of a continuous infusion of cytarabine 100 mg/m(2)/day for 10 days and idarubicin 12 mg/m(2)/day on days 1, 3, and 5. A consolidation course, consisting of intermediate-dose cytarabine (A) and idarubicin (I) followed by hematopoietic stem cell transplantation (HSCT) was planned for patients in complete remission (CR). The primary endpoints were response rate (CR/CRi) and severe toxicity rate. The secondary endpoint(s) were survival and progression-free survival (PFS) from start of treatment. Thirteen patients (43 %) achieved CR (eight patients) or CR with incomplete hematopoietic recovery (CRi) (five patients). In patients who achieved CR or CRi, the median time to recovery of neutrophils to 0.5 × 10(9)/l and of platelets to >50 × 10(9)/l was 29 and 30 days, respectively. Grade 3 to 4 severe toxicities occurred in nine patients. The most prominent was liver toxicity, as shown by elevated bilirubin levels in 16 patients and one case of nonfatal veno-occlusive disease (VOD). All 13 patients with CR/CRi received consolidation therapy, which was followed by allogeneic HSCT in five patients and autologous HSCT in three patients. According to the statistical design of the study, the idarubicin and cytarabine in combination with gemtuzumab ozogamicin (IAGO) regimen did not show sufficient activity to warrant further exploration of this regimen in adult patients with HR-MDS or sAML. PMID:26410352

  17. The MitCHAP-60 disease is due to entropic destabilization of the human mitochondrial Hsp60 oligomer.

    PubMed

    Parnas, Avital; Nadler, Michal; Nisemblat, Shahar; Horovitz, Amnon; Mandel, Hanna; Azem, Abdussalam

    2009-10-01

    The 60-kDa heat shock protein (mHsp60) is a vital cellular complex that mediates the folding of many of the mitochondrial proteins. Its function is executed in cooperation with the co-chaperonin, mHsp10, and requires ATP. Recently, the discovery of a new mHsp60-associated neurodegenerative disorder, MitCHAP-60 disease, has been reported. The disease is caused by a point mutation at position 3 (D3G) of the mature mitochondrial Hsp60 protein, which renders it unable to complement the deletion of the homologous bacterial protein in Escherichia coli (Magen, D., Georgopoulos, C., Bross, P., Ang, D., Segev, Y., Goldsher, D., Nemirovski, A., Shahar, E., Ravid, S., Luder, A., Heno, B., Gershoni-Baruch, R., Skorecki, K., and Mandel, H. (2008) Am. J. Hum. Genet. 83, 30-42). The molecular basis of the MitCHAP-60 disease is still unknown. In this study, we present an in vitro structural and functional analysis of the purified wild-type human mHsp60 and the MitCHAP-60 mutant. We show that the D3G mutation leads to destabilization of the mHsp60 oligomer and causes its disassembly at low protein concentrations. We also show that the mutant protein has impaired protein folding and ATPase activities. An additional mutant that lacks the first three amino acids (N-del), including Asp-3, is similarly impaired in refolding activity. Surprisingly, however, this mutant exhibits profound stabilization of its oligomeric structure. These results suggest that the D3G mutation leads to entropic destabilization of the mHsp60 oligomer, which severely impairs its chaperone function, thereby causing the disease. PMID:19706612

  18. The MitCHAP-60 Disease Is Due to Entropic Destabilization of the Human Mitochondrial Hsp60 Oligomer*

    PubMed Central

    Parnas, Avital; Nadler, Michal; Nisemblat, Shahar; Horovitz, Amnon; Mandel, Hanna; Azem, Abdussalam

    2009-01-01

    The 60-kDa heat shock protein (mHsp60) is a vital cellular complex that mediates the folding of many of the mitochondrial proteins. Its function is executed in cooperation with the co-chaperonin, mHsp10, and requires ATP. Recently, the discovery of a new mHsp60-associated neurodegenerative disorder, MitCHAP-60 disease, has been reported. The disease is caused by a point mutation at position 3 (D3G) of the mature mitochondrial Hsp60 protein, which renders it unable to complement the deletion of the homologous bacterial protein in Escherichia coli (Magen, D., Georgopoulos, C., Bross, P., Ang, D., Segev, Y., Goldsher, D., Nemirovski, A., Shahar, E., Ravid, S., Luder, A., Heno, B., Gershoni-Baruch, R., Skorecki, K., and Mandel, H. (2008) Am. J. Hum. Genet. 83, 30–42). The molecular basis of the MitCHAP-60 disease is still unknown. In this study, we present an in vitro structural and functional analysis of the purified wild-type human mHsp60 and the MitCHAP-60 mutant. We show that the D3G mutation leads to destabilization of the mHsp60 oligomer and causes its disassembly at low protein concentrations. We also show that the mutant protein has impaired protein folding and ATPase activities. An additional mutant that lacks the first three amino acids (N-del), including Asp-3, is similarly impaired in refolding activity. Surprisingly, however, this mutant exhibits profound stabilization of its oligomeric structure. These results suggest that the D3G mutation leads to entropic destabilization of the mHsp60 oligomer, which severely impairs its chaperone function, thereby causing the disease. PMID:19706612

  19. Measuring Neutron Spectrum at MIT Research Reactor Utilizing He-3 Bonner Cylinder Approach with an Unfolding Analysis

    NASA Astrophysics Data System (ADS)

    Leder, Alexander; Ricochet Collaboration

    2016-03-01

    The Ricochet experiment seeks to measure Coherent (neutral-current) Elastic Neutrino-Nucleus Scattering (CENNS) using dark matter style detectors placed near a neutrino source, possibly the MIT research reactor (MITR), which offers a high continuous neutrino flux at high energies. Currently, Ricochet is characterizing the backgrounds at MITR. The main background is the neutrons emitted simultaneously from the core. To characterize this background, we wrapped a Bonner cylinder around a 3He thermal neutron detector, whose data was then unfolded to produce a neutron energy spectrum across several orders of magnitude. We discuss the resulting spectrum as well its implications for deploying Ricochet in the future.

  20. A New Instrument for the IRTF: the MIT Optical Rapid Imaging System (MORIS)

    NASA Astrophysics Data System (ADS)

    Gulbis, Amanda A. S.; Elliot, J. L.; Rojas, F. E.; Bus, S. J.; Rayner, J. T.; Stahlberger, W. E.; Tokunaga, A. T.; Adams, E. R.; Person, M. J.

    2010-10-01

    NASA's 3-m Infrared Telescope Facility (IRTF) on Mauna Kea, HI plays a leading role in obtaining planetary science observations. However, there has been no capability for high-speed, visible imaging from this telescope. Here we present a new IRTF instrument, MORIS, the MIT Optical Rapid Imaging System. MORIS is based on POETS (Portable Occultation Eclipse and Transit Systems; Souza et al., 2006, PASP, 118, 1550). Its primary component is an Andor iXon camera, a 512x512 array of 16-micron pixels with high quantum efficiency, low read noise, low dark current, and full-frame readout rates of between 3.5 Hz (6 e /pixel read noise) and 35 Hz (49 e /pixel read noise at electron-multiplying gain=1). User-selectable binning and subframing can increase the cadence to a few hundred Hz. An electron-multiplying mode can be employed for photon counting, effectively reducing the read noise to sub-electron levels at the expense of dynamic range. Data cubes, or individual frames, can be triggered to nanosecond accuracy using a GPS. MORIS is mounted on the side-facing widow of SpeX (Rayner et al. 2003, PASP, 115, 362), allowing simultaneous near-infrared and visible observations. The mounting box contains 3:1 reducing optics to produce a 60 arcsec x 60 arcsec field of view at f/12.7. It hosts a ten-slot filter wheel, with Sloan g×, r×, i×, and z×, VR, Johnson V, and long-pass red filters. We describe the instrument design, components, and measured characteristics. We report results from the first science observations, a 24 June 2008 stellar occultation by Pluto. We also discuss a recent overhaul of the optical path, performed in order to eliminate scattered light. This work is supported in part by NASA Planetary Major Equipment grant NNX07AK95G. We are indebted to the University of Hawai'i Institute for Astronomy machine shop, in particular Randy Chung, for fabricating instrument components.

  1. The Ashima/MIT Mars GCM and argon in the martian atmosphere

    NASA Astrophysics Data System (ADS)

    Lian, Yuan; Richardson, Mark I.; Newman, Claire E.; Lee, Christopher; Toigo, Anthony D.; Mischna, Michael A.; Campin, Jean-Michel

    2012-04-01

    We investigate the ability of modern general circulation models (GCMs) to simulate transport in the martian atmosphere using measurements of argon as a proxy for the transport processes. Argon provides the simplest measure of transport as it is a noble gas with no sinks or sources on seasonal timescales. Variations in argon result solely from 'freeze distillation', as the atmosphere condenses at the winter poles, and from atmospheric transport. Comparison of all previously published models when rescaled to a common definition of the argon enhancement factor (EF) suggest that models generally do a poor job in predicting the peak enhancement in southern winter over the winter pole - the time when the capability of the model transport approaches are most severely tested. Despite observed peak EF values of ˜6, previously published model predictions peaked at EF values of only 2-3. We introduce a new GCM that provides a better treatment of mass conservation within the dynamical core, includes more sophisticated tracer transport approaches, and utilizes a cube-sphere grid structure thus avoiding the grid-point convergence problem at the pole that exists for most current Mars GCMs. We describe this model - the Ashima Research/Massachusetts Institute of Technology Mars General Circulation Model (Ashima/MIT Mars GCM) and use it to demonstrate the significant sensitivity of peak EF to the choices of transport approach for both tracers and heat. We obtain a peak EF of 4.75 which, while over 50% higher than any prior model, remains well short of the observed value. We show that the polar EF value in winter is primarily determined by the competition between two processes: (1) mean meridional import of lower-latitude air not enriched in argon and (2) the leakage of enriched argon out of the polar column by eddies in the lowest atmospheric levels. We suggest possibilities for improving GCM representation of the CO2 cycle and the general circulation that may further improve the

  2. Mit castor satellite: Design, implementation, and testing of the communication system

    NASA Astrophysics Data System (ADS)

    Babuscia, Alessandra; McCormack, Matthew Michael; Munoz, Michael; Parra, Spencer; Miller, David W.

    2012-12-01

    Cathode Anode Satellite Thruster for Orbital Reposition (CASTOR) is an orbital manoeuvre and transfer micro-satellite bus developed at MIT Space System Laboratory. The technical objective of the mission is achieving 1 km/s of delta-V over a 1 year mission in Low Earth Orbit (LEO). This will be accomplished using a novel electric propulsion system, the Diverging Cusped Field Thruster (DCFT), which enables high efficiency orbital changes of the ESPA-ring class satellite. CASTOR is capable of improving rapid access to space capabilities by providing an orbital transfer platform with a very high performance to mass ratio, thus greatly reducing launch costs and allowing for highly efficient orbital manoeuvre. Furthermore, CASTOR is highly scalable and modular, allowing it to be adapted to a wide range of scales and applications. CASTOR is developed as part of the University Nanosatellite Program (UNP) funded by Air Force Research Laboratory (AFRL). In order to accomplish CASTOR mission objective, a highly optimized, scalable, light weight, and low cost communication system needed to be developed. These constraints imply the development of trade studies to select the final communication system architecture able to maximize the amount of data transmitted, while guaranteeing reliability, redundancy and limited mass, power consumption, and cost. A special attention is also required to guarantee a reliable communication system in cases of tumbling, or in case of strong Doppler shift which is inevitable due to the high delta-V capabilities of the vehicle. In order to accomplish all the mission requirements, different features have been introduced in the design of the communication system for this mission. Specifically, customized patch antennas have been realized, and a customized communication protocol has been designed and implemented. The communication subsystem has been validated through an intense testing campaign which included software tests in the laboratory, hardware

  3. First results from the ‘Violin-Mode’ tests on an advanced LIGO suspension at MIT

    NASA Astrophysics Data System (ADS)

    Lockerbie, N. A.; Carbone, L.; Shapiro, B.; Tokmakov, K. V.; Bell, A.; Strain, K. A.

    2011-12-01

    This paper describes the first results from ‘Violin-Mode’ measurements made on the four suspension fibres of a fully suspended 40 kg test mass. These measurements were made at the LIGO lab, Gravitational Wave Observatory test facility, at MIT. Here, an aluminium-alloy (dummy) test mass, simulating an advanced LIGO (Laser Interferometer Gravitational Wave Observatory) test mass/mirror, had been suspended in air from a test suspension by four fused-silica suspension fibres, each measuring 400 µm in diameter × 600 mm long. Violin-Mode measurements were made on these highly tensioned fibres by retrofitting a prototype system of four novel shadow sensors to the test suspension, one per fibre, these sensors having, collectively, a displacement sensitivity of (6.9 ± 1.3) × 10-11 m (rms) Hz-1/2, at 500 Hz, over a measuring span of ±0.1 mm. Violin-Mode fundamental resonances were detected in all four fibres: with frequencies ˜ 485 Hz when the test mass was supported lightly from below, and at ˜500 Hz when it was fully suspended. In the latter case the Violin-Mode detection took place whilst the test mass, together with its suspension fibres, was undergoing relatively large-amplitude ‘pendulum-mode’ motion, at ˜0.6 Hz. This motion was measured to have a peak-peak amplitude at one of the suspension fibres of up to ˜140 µm (35 µm, rms)—the shadow sensors each having subsidiary outputs for monitoring such low-frequency, large amplitude, motion. Under fully suspended conditions, a calibrated Violin-Mode ‘free-oscillation’ amplitude of 430 ± 20 picometres, rms, was measured at 500.875 Hz, in the same suspension fibre which was found to be undergoing, simultaneously, the ˜140 µm peak-peak motion. Over the bandwidth monitored (dc to 3.2 kHz), Violin-Mode harmonics up to the sixth were recorded in an evoked response. It was concluded that the prototype system had demonstrated amply its practical viability as a detector of Violin-Mode resonances in the

  4. Molecular cytogenetic investigations in a novel complex variant of t(8;21)(q22;q22) with ins(15;21)(q15;q22.2q22.3) in a patient with AML-M2 subtype.

    PubMed

    Kokate, Prajakta; Ahmad, Firoz; Dalvi, Rupa; Das, Bibhu Ranjan; Mandava, Swarna

    2008-07-01

    Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease characterized by the aberrant proliferation of myeloid stem cells, reduced apoptosis and blockage in cellular differentiation. The present report describes the results of hematological, cytogenetic, and fluorescence in situ hybridization (FISH) analysis in a 25-year-old man diagnosed with AML-M2. Cytogenetic as well as FISH analysis revealed a complex translocation involving four chromosomes, with the karyotype 45,-Y,der(X)t(X;8)(p21;q22),der(8)t(8;21)(q22;q22),ins(15;21)(q15;q22.2q22.3),der(21)t(8;21)(q22;q22). The breakpoints at 8q22 and 21q22 suggested a rearrangement of the RUNX1T1 (alias ETO) and RUNX1 (previously AML1) genes, respectively. Using a dual-color FISH test with RUNX1T1 and RUNX1 probes, we demonstrated an RUNX1/RUNX1T1 fusion signal on the derivative chromosome 8, establishing this translocation as a novel complex variant of t(8;21)(q22;q22). PMID:18558290

  5. The MIT HEDP Accelerator Facility for education and advanced diagnostics development for OMEGA, Z and the NIF

    NASA Astrophysics Data System (ADS)

    Petrasso, R.; Gatu Johnson, M.; Armstrong, E.; Han, H. W.; Kabadi, N.; Lahmann, B.; Orozco, D.; Rojas Herrera, J.; Sio, H.; Sutcliffe, G.; Frenje, J.; Li, C. K.; Séguin, F. H.; Leeper, R.; Ruiz, C. L.; Sangster, T. C.

    2015-11-01

    The MIT HEDP Accelerator Facility utilizes a 135-keV linear electrostatic ion accelerator, a D-T neutron source and two x-ray sources for development and characterization of nuclear diagnostics for OMEGA, Z, and the NIF. The ion accelerator generates D-D and D-3He fusion products through acceleration of D ions onto a 3He-doped Erbium-Deuteride target. Fusion reaction rates around 106 s-1 are routinely achieved, and fluence and energy of the fusion products have been accurately characterized. The D-T neutron source generates up to 6 × 108 neutrons/s. The two x-ray generators produce spectra with peak energies of 35 keV and 225 keV and maximum dose rates of 0.5 Gy/min and 12 Gy/min, respectively. Diagnostics developed and calibrated at this facility include CR-39 based charged-particle spectrometers, neutron detectors, and the particle Time-Of-Flight (pTOF) and Magnetic PTOF CVD-diamond-based bang time detectors. The accelerator is also a vital tool in the education of graduate and undergraduate students at MIT. This work was supported in part by SNL, DOE, LLE and LLNL.

  6. MIT jar test of the natural polymer chitosan with fresh pond water from the Cambridge Water Department, November-December 1992

    SciTech Connect

    Murcott, S.; Harleman, D.R.F.

    1993-01-01

    The purpose of the MIT (Massachusetts Institute of Technology) jar tests of chitosan using CWD (Cambridge Water Department Treatment Plant) water was to demonstrate the effectiveness of chitosan as a coagulant in drinking water applications. The approach was to compare the performance of the natural organic coagulant, chitosan, to the performance of alum and other chemical coagulants in terms of the parameters turbidity, color, pH and alkalinity. Twenty-five jar tests were conducted during November and December, 1992, at Parsons Laboratory, MIT, Cambridge, Massachusetts.

  7. A combined polarizing microscope, XRD, SEM, and specific gravity study of the petrified woods of volcanic origin from the Çamlıdere-Çeltikçi-Güdül fossil forest, in Ankara, Turkey

    NASA Astrophysics Data System (ADS)

    Hatipoğlu, Murat; Türk, Necdet

    2009-03-01

    The fossil forest in the Çamlıdere-Çeltikçi-Güdül region of the province of Ankara in Turkey has a large number of petrified coniferous and oak tree remains. Petrification occurred in volcanic ashes and tuffs with permineralization, and Fe, Mg, Ca and Ni ions played important roles in the substitution of Si for C. However, the petrified wood samples are heterogeneous in colouration, weight, toughness, and durability, despite being obtained from the same source. Those features are very important for end-users because petrified woods, if cut and polished, are used widely as both decorative indoor tiles and gemstone objects, but heterogeneous materials suffer large wastage while they are being worked and used. Chemical analyses, specific gravity measurements, polarizing microscope studies, X-ray diffraction patterns, and scanning electron image evaluations were performed to classify and identify the homogenous material of the petrified woods relating to its physical and mineralogical characteristics. The different characteristics of the petrified wood samples are due to their varying inner structures, which depend on the replacement silica-building phases and their ratios, and silica particle sizes. Thin sections and XRD patterns revealed that petrified woods in the region were silicified by replacement with both chalcedonic quartz components, including chalcedony (length-fast quartz), moganite and orthorhombic-silica (length-slow quartz), and opalline quartz components including opal-CT and opal-C (length-slow quartz). The scanning electron microscope images were shown that the internal structures of the petrified woods consist of mostly submicron-sized (100-800 nm), and partially nano-sized (60-120 nm) silica-building particles. So, the petrified wood samples can be firstly classified into five main-groups based on their colourations and specific gravity values, then, into three sub-groups based on the principal chalcedonic and opalline quartz silica

  8. Potent graft-versus-leukemia effect after reduced-intensity allogeneic SCT for intermediate-risk AML with FLT3-ITD or wild-type NPM1 and CEBPA without FLT3-ITD.

    PubMed

    Labouré, Gaëlle; Dulucq, Stéphanie; Labopin, Myriam; Tabrizi, Reza; Guérin, Estelle; Pigneux, Arnaud; Lafarge, Xavier; Leguay, Thibaut; Bouabdallah, Krimo; Dilhuydy, Marie-Sarah; Duclos, Cédric; Lascaux, Axelle; Marit, Gérald; Mahon, François-Xavier; Boiron, Jean-Michel; Milpied, Noël; Vigouroux, Stéphane

    2012-12-01

    To investigate the role of reduced-intensity allogeneic (RIC-allo) stem cell transplant (SCT) as postremission therapy in adult intermediate-risk patients with acute myelogenous leukemia (AML) with FLT3-ITD or wild-type NPM1 and CEBPA without FLT3-ITD, we conducted a single-center retrospective study between January 2001 and December 2010. Sixty-six patients were included: 37 treated with RIC-alloSCT and 29 with nonallogeneic SCT therapies. Both groups were comparable concerning age, WBC count at diagnosis, gender, karyotype, genotype, and number of courses of chemotherapy to reach complete remission (CR1). Median follow-up after CR1 was 37 months (range, 11-112 months) and 48 months (range, 9-83 months) in the allo and no-allo groups, respectively. In the allo versus no-allo groups, the 3-year cumulative incidence of relapse (CIR) rates were 25% ± 8% versus 61% ± 9%; P = .005. The 3-year nonrelapse mortality (NRM), overall survival (OS), and relapse-free survival (RFS) were 22% ± 7% versus 4% ± 4% (P = .005), 52% ± 9% versus 44% ± 10% (P = .75), and 53% ± 9% versus 35% ± 9% (P = .28), respectively. Multivariate analysis indicated that CIR was reduced by allo (hazard ratio [HR], 0.32; P = .01). A landmark analysis performed at day 185 after CR1 confirmed a lower CIR after allo. RIC-allo reduces the risk of relapse, suggesting a potent graft-versus-leukemia (GVL) effect in these patients at a high risk of relapse. PMID:22766221

  9. The Effect of Multiple Intelligences Theory (MIT)-based Instruction on Attitudes towards the Course, Academic Success, and Permanence of Teaching on the Topic of "Respiratory Systems"

    ERIC Educational Resources Information Center

    Koksal, Mustafa Serdar; Yel, Mustafa

    2007-01-01

    Studies on the effective teaching of biology have been continuously increasing since the 1800s. New teaching approaches have been purposed and tried out along the way. The multiple intelligences theory (MIT)-based approaches which give more importance to individual in educational settings can provide alternatives for meeting this requirement. An…

  10. Reconstitution and Upgrade of the Thermal Neutron Irradiation Facility in the Basement Medical Room of the MIT Research Reactor

    SciTech Connect

    Harling, Otto, K.; Riley, Kent, J.; Binns, Peter J.

    2004-12-31

    The M-011 thermal neutron beam has been reconstituted and upgraded to provide a high intensity and high quality facility for preclinical and certain clinical studies. Intensities of thermal neutrons in the beam range from 5.0-8.5 x 109 n cm-2 s-1. Beam contamination is at a low level where it has no practical influence on beam performance. New computer controlled dose and beam monitoring systems have been implemented which assure precise dose delivery and redundant safety interlocks. An additional beam shutter and massive shielding in the back of the medical room have been added which significantly reduce room background and now permit staff entry without the necessity for lowering the reactor power. This system is needed for BNCT research by the MIT group as well as other US groups. This need became acute with the closure of the BMRR which previously had the only high quality thermal neutron irradiation facility for BNCT in the USA.

  11. Enhancing undergraduate education in aerospace engineering and planetary sciences at MIT through the development of a CubeSat mission

    NASA Astrophysics Data System (ADS)

    Smith, Matthew W.; Miller, David W.; Seager, Sara

    2011-09-01

    CubeSats are a class of nanosatellites that conform to a standardized 10 cm x 10 cm x 10 cm, 1 kg form factor. This miniaturization, along with a standardized deployment device for launch vehicles, allows CubeSats to be launched at low cost by sharing the trip to orbit with other spacecraft. Part of the original motivation for the CubeSat platform was also to allow university students to participate more easily in space technology development and to gain hands-on experience with flight hardware. The Department of Aeronautics and Astronautics along with the Department of Earth, Atmospheric, and Planetary Studies (EAPS) at the Massachusetts Institute of Technology (MIT) recently completed a three semester-long course that uses the development of a CubeSat-based science mission as its core teaching method. Serving as the capstone academic experience for undergraduates, the goal of this class is to design and build a CubeSat spacecraft that serves a relevant science function, such as the detection of exoplanets transiting nearby stars. This project-based approach gives students essential first hand insights into the challenges of balancing science requirements and engineering design. Students are organized into subsystem-specific teams that refine and negotiate requirements, explore the design trade space, perform modeling and simulation, manage interfaces, test subsystems, and finally integrate prototypes and flight hardware. In this work we outline the heritage of capstone design/build classes at MIT, describe the class format in greater detail, and give results on the ability to meet learning objectives using this pedagogical approach.

  12. The MIT/WHOI Joint Program in Oceanography and Applied Ocean Science and Engineering: An Ongoing Experiment in Graduate Education and the Sverdrup, Johnson and Fleming Influence.

    NASA Astrophysics Data System (ADS)

    Farrington, J. W.

    2002-12-01

    On May 8, 1968 Paul M. Fye, President of Woods Hole Oceanographic Institution and Howard W. Johnson, President of Massachusetts Institute of Oceanography, signed a Memorandum of Agreement of one and one-half pages in which both partner institutions "have each approved the creation of a Joint Graduate Program in Oceanography for which there will be established appropriate graduate degrees to be conferred jointly by the Massachusetts Institute of Technology and Woods Hole Oceanographic Institution." The partnership brought together the MIT experience with formal graduate education in sciences and engineering involving classroom instruction and more traditional academic advising with the less formal one to one "apprenticeship" or European tutorial style of education at WHOI. During the first year the graduate program involved only the physical sciences with the MIT home being in the Earth, Atmospheric and Planetary Sciences Department. Ocean Engineering was added the following year with the MIT home being the Ocean Engineering Department. Biological Oceanography was added in 1970 with the MIT home being the Biology Department. The existing graduate curricula of the home departments at MIT, the inclusion of ocean engineering, and the fact that several of the early program instructors and advisers at WHOI entered oceanography after formal graduate training in more traditional disciplines such as chemistry, geology, physics, biology and mathematics was not conducive to an automatic adoption of the Sverdrup, Johnson and Fleming paradigm of core courses that predominated in other leading graduate programs in oceanography. Despite this caveat, the Sverdrup, Johnson and Fleming paradigm has influenced the learning environment in the Joint Program. Taking into account lessons learned in the process, some suggestions for the future of graduate education in ocean sciences and ocean engineering will be presented.

  13. Defining the dose of gemtuzumab ozogamicin in combination with induction chemotherapy in acute myeloid leukemia: a comparison of 3 mg/m2 with 6 mg/m2 in the NCRI AML17 Trial.

    PubMed

    Burnett, Alan; Cavenagh, Jamie; Russell, Nigel; Hills, Robert; Kell, Jonathan; Jones, Gail; Nielsen, Ove Juul; Khwaja, Asim; Thomas, Ian; Clark, Richard

    2016-06-01

    Arecent source data meta-analysis of randomized trials in adults assessing the immunoconjugate gemtuzumab ozogamicin combined with standard chemotherapy in acute myeloid leukemia showed a significant survival benefit in patients without an adverse karyotype. It is not clear whether the optimal dose should be 3 mg/m(2) or 6 mg/m(2) In this study, we randomized 788 patients to a single dose of gemtuzumab ozogamicin 3 mg/m(2) or 6 mg/m(2) with the first course of induction therapy. We found that the rate of complete remission was higher with 3 mg/m(2) [82% vs 76%; odds ratio 1.46 (1.04-2.06); P=0.03], but this was balanced by a higher rate of complete remission with incomplete peripheral blood count recovery in the 6 mg/m(2) treatment (10% vs 7%) resulting in similar overall response rate [89% vs 86%; hazard ratio 1.34 (0.88-2.04); P=0.17]. There was no overall difference in relapse or survival at four years between the arms: 46% vs 54%; hazard ratio 1.17 (0.94-1.45), P=0.5, and 50% versus 47%; hazard ratio 1.10 (0.90-1.34), P=0.3, respectively. The 30- and 60-day mortality was significantly higher in the 6 mg/m(2) recipients: 7% versus 3%; hazard ratio 2.07 (1.11-3.87), P=0.02, and 9% versus 5%; hazard ratio 1.99 (1.17-3.39), P=0.01, respectively, which in addition was associated with a higher rate of veno-occlusive disease (5.6% vs 0.5%; P<0.0001). Our conclusion from this trial is that there is no advantage in using a single dose of 6 mg/m(2) of gemtuzumab ozogamicin in combination with induction chemotherapy when compared with a 3 mg/m(2) dose, with respect to response, disease-free and overall survival, either overall, or in any disease subgroup. (AML17 was registered as ISRCTN55675535). PMID:26921360

  14. Defining the dose of gemtuzumab ozogamicin in combination with induction chemotherapy in acute myeloid leukemia: a comparison of 3 mg/m2 with 6 mg/m2 in the NCRI AML17 Trial

    PubMed Central

    Burnett, Alan; Cavenagh, Jamie; Russell, Nigel; Hills, Robert; Kell, Jonathan; Jones, Gail; Nielsen, Ove Juul; Khwaja, Asim; Thomas, Ian; Clark, Richard

    2016-01-01

    Arecent source data meta-analysis of randomized trials in adults assessing the immunoconjugate gemtuzumab ozogamicin combined with standard chemotherapy in acute myeloid leukemia showed a significant survival benefit in patients without an adverse karyotype. It is not clear whether the optimal dose should be 3 mg/m2 or 6 mg/m2. In this study, we randomized 788 patients to a single dose of gemtuzumab ozogamicin 3 mg/m2 or 6 mg/m2 with the first course of induction therapy. We found that the rate of complete remission was higher with 3 mg/m2 [82% vs. 76%; odds ratio 1.46 (1.04–2.06); P=0.03], but this was balanced by a higher rate of complete remission with incomplete peripheral blood count recovery in the 6 mg/m2 treatment (10% vs. 7%) resulting in similar overall response rate [89% vs. 86%; hazard ratio 1.34 (0.88–2.04); P=0.17]. There was no overall difference in relapse or survival at four years between the arms: 46% vs. 54%; hazard ratio 1.17 (0.94–1.45), P=0.5, and 50% versus 47%; hazard ratio 1.10 (0.90–1.34), P=0.3, respectively. The 30- and 60-day mortality was significantly higher in the 6 mg/m2 recipients: 7% versus 3%; hazard ratio 2.07 (1.11–3.87), P=0.02, and 9% versus 5%; hazard ratio 1.99 (1.17–3.39), P=0.01, respectively, which in addition was associated with a higher rate of veno-occlusive disease (5.6% vs. 0.5%; P<0.0001). Our conclusion from this trial is that there is no advantage in using a single dose of 6 mg/m2 of gemtuzumab ozogamicin in combination with induction chemotherapy when compared with a 3 mg/m2 dose, with respect to response, disease-free and overall survival, either overall, or in any disease subgroup. (AML17 was registered as ISRCTN55675535.) PMID:26921360

  15. Amyloid precursor protein cooperates with c-KIT mutation/overexpression to regulate cell apoptosis in AML1-ETO-positive leukemia via the PI3K/AKT signaling pathway.

    PubMed

    Yu, Guopan; Yin, Changxin; Jiang, Ling; Zheng, Zhongxin; Wang, Zhixiang; Wang, Chunli; Zhou, Hongsheng; Jiang, Xuejie; Liu, Qifa; Meng, Fanyi

    2016-09-01

    It has been reported that amyloid precursor protein (APP) promotes cell proliferation and metastasis in various types of solid cancers. In our previous study, we showed that APP is highly expressed and regulates leukemia cell migration in AML1‑ETO-positive (AE) leukemia. Whether APP is involved in the regulation of AE leukemia cell proliferation or apoptosis is unclear. In the present study we focused on the correlation of APP with c-KIT mutation/overexpression and cell proliferation and apoptosis in AE leukemia. APP and c-KIT expression detected by quantitative real-time (qPCR) method, and c-KIT mutations screened using PCR in bone marrow cells from 65 patients with AE leukemia before their first chemotherapy, were simultaneously assessed. Furthermore, the Kasumi-1 cell line was chosen as the cell model, and the APP gene was knocked down using siRNA technology. The correlation of cell cycle distribution and apoptosis and c-Kit expression with APP expression levels, as well as the regulation of the PI3K/AKT signaling pathway by APP were analyzed in the Kasumi-1 cell line. The results showed that peripheral white blood cell counts (P=0.008) and bone marrow cellularity (P=0.031), but not bone marrow blasts, were correlated with APP expression. Moreover, the patients with APP high expression had a significantly higher incidence of c-KIT mutations (P<0.001) and increased levels of c-KIT expression (P=0.001) and poorer disease outcome. In the Kasumi-1 cell line, as compared with the wild-type and negative control cells, cell apoptosis, both early (P<0.001) and late (P<0.001), was significantly increased when the APP gene was knocked down, concomitant with reduced levels of anti-apoptotic protein Bcl-2 and increased levels of caspase-3 and -9, however, no apparent change was observed in the cell cycle distribution (P>0.05). Moreover, the knockdown of APP markedly decreased c-KIT expression at both the transcription (as evidenced by qPCR analysis) and translation

  16. Cancer Statistics: Acute Myeloid Leukemia (AML)

    MedlinePlus

    ... at a Glance Show More At a Glance Estimated New Cases in 2016 19,950 % of All New Cancer Cases 1.2% Estimated Deaths in 2016 10,430 % of All Cancer ... Common Is This Cancer? Common Types of Cancer Estimated New Cases 2016 Estimated Deaths 2016 1. Breast ...

  17. Acute Myeloid Leukemia (AML) (For Parents)

    MedlinePlus

    ... Diseases & Conditions Pregnancy & Baby Nutrition & Fitness Emotions & Behavior School & Family Life First Aid & Safety Doctors & Hospitals Q& ... What to Say Vaccines: Which Ones & When? Smart School Lunches Emmy-Nominated Video "Cerebral Palsy: Shannon's Story" ...

  18. Realisierung eines verzerrungsarmen Open-Loop Klasse-D Audio-Verstärkers mit SB-ZePoC

    NASA Astrophysics Data System (ADS)

    Schnick, O.; Mathis, W.

    2007-06-01

    In den letzten Jahren hat die Entwicklung von Klasse-D Verstärkern für Audio-Anwendungen ein vermehrtes Interesse auf sich gezogen. Eine Motivation hierfür liegt in der mit dieser Technik extrem hohen erzielbaren Effizienz von über 90%. Die Signale, die Klasse-D Verstärker steuern, sind binär. Immer mehr Audio-Signale werden entweder digital gespeichert (CD, DVD, MP3) oder digital übermittelt (Internet, DRM, DAB, DVB-T, DVB-S, GMS, UMTS), weshalb eine direkte Umsetzung dieser Daten in ein binäres Steuersignal ohne vorherige konventionelle D/A-Wandlung erstrebenswert erscheint. Die klassischen Pulsweitenmodulationsverfahren führen zu Aliasing-Komponenten im Audio-Basisband. Diese Verzerrungen können nur durch eine sehr hohe Schaltfrequenz auf ein akzeptables Maß reduziert werden. Durch das von der Forschungsgruppe um Prof. Mathis vorgestellte SB-ZePoC Verfahren (Zero Position Coding with Separated Baseband) wird diese Art der Signalverzerrung durch Generierung eines separierten Basisbands verhindert. Deshalb können auch niedrige Schaltfrequenzen gewählt werden. Dadurch werden nicht nur die Schaltverluste, sondern auch Timing-Verzerrungen verringert, die durch die nichtideale Schaltendstufe verursacht werden. Diese tragen einen großen Anteil zu den gesamten Verzerrungen eines Klasse-D Verstärkers bei. Mit dem SB-ZePoC Verfahren lassen sich verzerrungsarme Open-Loop Klasse-D Audio-Verstärker realisieren, die ohne aufwändige Gegenkopplungsschleifen auskommen. Class-D amplifiers are suiteble for amplification of audio signals. One argument is their high efficiency of 90% and more. Today most of the audio signals are stored or transmitted in digital form. A digitally controlled Class-D amplifier can be directly driven with coded (modulated) data. No separate D/A conversion is needed. Classical modulation schemes like Pulse-Width-Modulation (PWM) cause aliasing. So a very high switching rate is required to minimize the aliasing component within the signal

  19. Solution of the inverse problem of magnetic induction tomography (MIT) with multiple objects: analysis of detectability and statistical properties with respect to the reconstructed conducting region.

    PubMed

    Merwa, Robert; Brunner, Patricia; Missner, Andreas; Hollaus, Karl; Scharfetter, Hermann

    2006-05-01

    Magnetic induction tomography (MIT) is a technique to image the passive electrical properties (i.e. conductivity, permittivity, permeability) of biological tissues. The inverse eddy current problem is nonlinear and ill-posed, thus a Gauss-Newton one-step method in combination with four different regularization schemes is used to obtain stable solutions. Simulations with 16 excitation coils, 32 receiving coils and different spherical perturbations inside a homogeneous cylinder were computed. In order to compare the statistical properties of the reconstructed results a Monte Carlo study with a SNR of 40 dB and 20 dB was carried out. Simulated conductivity perturbations inside a homogeneous cylinder can be localized and resolved and the results prove the feasibility of difference imaging with MIT. PMID:16636415

  20. Massachusetts Beryllium Screening Program for Former Workers of Wyman-Gordon, Norton Abrasives, and MIT/Nuclear Metals

    SciTech Connect

    Pepper, L. D.

    2008-05-21

    The overall objective of this project was to provide medical screening to former workers of Wyman-Gordon Company, Norton Abrasives, and MIT/Nuclear Metals (NMI) in order to prevent and minimize the health impact of diseases caused by site related workplace exposures to beryllium. The program was developed in response to a request by the U.S. Department of Energy (DOE) that had been authorized by Congress in Section 3162 of the 1993 Defense Authorization Act, urging the DOE to carry out a program for the identification and ongoing evaluation of current and former DOE employees who are subjected to significant health risks during such employment." This program, funded by the DOE, was an amendment to the medical surveillance program for former DOE workers at the Nevada Test Site (NTS). This program's scope included workers who had worked for organizations that provided beryllium products or materials to the DOE as part of their nuclear weapons program. These organizations have been identified as Beryllium Vendors.

  1. Upgrade of the MIT Linear Electrostatic Ion Accelerator (LEIA) for nuclear diagnostics development for Omega, Z and the NIF

    SciTech Connect

    Sinenian, N.; Manuel, M. J.-E.; Zylstra, A. B.; Rosenberg, M.; Waugh, C. J.; Rinderknecht, H. G.; Casey, D. T.; Sio, H.; Ruszczynski, J. K.; Zhou, L.; Johnson, M. Gatu; Frenje, J. A.; Seguin, F. H.; Li, C. K.; Petrasso, R. D.; Ruiz, C. L.; Leeper, R. J.

    2012-04-15

    The MIT Linear Electrostatic Ion Accelerator (LEIA) generates DD and D{sup 3}He fusion products for the development of nuclear diagnostics for Omega, Z, and the National Ignition Facility (NIF). Significant improvements to the system in recent years are presented. Fusion reaction rates, as high as 10{sup 7} s{sup -1} and 10{sup 6} s{sup -1} for DD and D{sup 3}He, respectively, are now well regulated with a new ion source and electronic gas control system. Charged fusion products are more accurately characterized, which allows for better calibration of existing nuclear diagnostics. In addition, in situ measurements of the on-target beam profile, made with a CCD camera, are used to determine the metrology of the fusion-product source for particle-counting applications. Finally, neutron diagnostics development has been facilitated by detailed Monte Carlo N-Particle Transport (MCNP) modeling of neutrons in the accelerator target chamber, which is used to correct for scattering within the system. These recent improvements have resulted in a versatile platform, which continues to support the existing nuclear diagnostics while simultaneously facilitating the development of new diagnostics in aid of the National Ignition Campaign at the National Ignition Facility.

  2. mit-o-matic: a comprehensive computational pipeline for clinical evaluation of mitochondrial variations from next-generation sequencing datasets.

    PubMed

    Vellarikkal, Shamsudheen Karuthedath; Dhiman, Heena; Joshi, Kandarp; Hasija, Yasha; Sivasubbu, Sridhar; Scaria, Vinod

    2015-04-01

    The human mitochondrial genome has been reported to have a very high mutation rate as compared with the nuclear genome. A large number of mitochondrial mutations show significant phenotypic association and are involved in a broad spectrum of diseases. In recent years, there has been a remarkable progress in the understanding of mitochondrial genetics. The availability of next-generation sequencing (NGS) technologies have not only reduced sequencing cost by orders of magnitude but has also provided us good quality mitochondrial genome sequences with high coverage, thereby enabling decoding of a number of human mitochondrial diseases. In this study, we report a computational and experimental pipeline to decipher the human mitochondrial DNA variations and examine them for their clinical correlation. As a proof of principle, we also present a clinical study of a patient with Leigh disease and confirmed maternal inheritance of the causative allele. The pipeline is made available as a user-friendly online tool to annotate variants and find haplogroup, disease association, and heteroplasmic sites. The "mit-o-matic" computational pipeline represents a comprehensive cloud-based tool for clinical evaluation of mitochondrial genomic variations from NGS datasets. The tool is freely available at http://genome.igib.res.in/mitomatic/. PMID:25677119

  3. Effect of Adding a Regenerator to Kornhauser's MIT "Two-Space" (Gas-Spring+Heat Exchanger) Test Rig

    NASA Technical Reports Server (NTRS)

    Ebiana, Asuquo B.; Gidugu, Praveen

    2008-01-01

    This study employed entropy-based second law post-processing analysis to characterize the various thermodynamic losses inside a 3-space solution domain (gas spring+heat exchanger+regenerator) operating under conditions of oscillating pressure and oscillating flow. The 3- space solution domain is adapted from the 2-space solution domain (gas spring+heat exchanger) in Kornhauser's MIT test rig by modifying the heat exchanger space to include a porous regenerator system. A thermal nonequilibrium model which assumes that the regenerator porous matrix and gas average temperatures can differ by several degrees at a given axial location and time during the cycle is employed. An important and primary objective of this study is the development and application of a thermodynamic loss post-processor to characterize the major thermodynamic losses inside the 3-space model. It is anticipated that the experience gained from thermodynamic loss analysis of the simple 3-space model can be extrapolated to more complex systems like the Stirling engine. It is hoped that successful development of loss post-processors will facilitate the improvement of the optimization capability of Stirling engine analysis codes through better understanding of the heat transfer and power losses. It is also anticipated that the incorporation of a successful thermal nonequilibrium model of the regenerator in Stirling engine CFD analysis codes, will improve our ability to accurately model Stirling regenerators relative to current multidimensional thermal-equilibrium porous media models.

  4. Modeling water resource systems within the framework of the MIT Integrated Global System Model: IGSM-WRS

    NASA Astrophysics Data System (ADS)

    Strzepek, Kenneth; Schlosser, Adam; Gueneau, Arthur; Gao, Xiang; Blanc, Élodie; Fant, Charles; Rasheed, Bilhuda; Jacoby, Henry D.

    2013-07-01

    Through the integration of a water resource system (WRS) component, the MIT Integrated Global System Model (IGSM) framework has been enhanced to study the effects of climate change on managed water-resource systems. Development of the WRS involves the downscaling of temperature and precipitation from the zonal representation of the IGSM to regional (latitude-longitude) scale, and the translation of the resulting surface hydrology to runoff at the scale of river basins, referred to as assessment subregions (ASRs). The model of water supply is combined with analysis of water use in agricultural and nonagricultural sectors and with a model of water system management that allocates water among uses and over time and routes water among ASRs. Results of the IGSM-WRS framework include measures of water adequacy and ways it is influenced by climate change. Here we document the design of WRS and its linkage to other components of the IGSM and present tests of consistency of model simulation with the historical record.

  5. The MIT/OSO 7 catalog of X-ray sources - Intensities, spectra, and long-term variability

    NASA Technical Reports Server (NTRS)

    Markert, T. H.; Laird, F. N.; Clark, G. W.; Hearn, D. R.; Sprott, G. F.; Li, F. K.; Bradt, H. V.; Lewin, W. H. G.; Schnopper, H. W.; Winkler, P. F.

    1979-01-01

    This paper is a summary of the observations of the cosmic X-ray sky performed by the MIT 1-40-keV X-ray detectors on OSO 7 between October 1971 and May 1973. Specifically, mean intensities or upper limits of all third Uhuru or OSO 7 cataloged sources (185 sources) in the 3-10-keV range are computed. For those sources for which a statistically significant (greater than 20) intensity was found in the 3-10-keV band (138 sources), further intensity determinations were made in the 1-15-keV, 1-6-keV, and 15-40-keV energy bands. Graphs and other simple techniques are provided to aid the user in converting the observed counting rates to convenient units and in determining spectral parameters. Long-term light curves (counting rates in one or more energy bands as a function of time) are plotted for 86 of the brighter sources.

  6. Vfa1 binds to the N-terminal microtubule-interacting and trafficking (MIT) domain of Vps4 and stimulates its ATPase activity.

    PubMed

    Vild, Cody J; Xu, Zhaohui

    2014-04-11

    The endosomal sorting complexes required for transport (ESCRT) are responsible for multivesicular body biogenesis, membrane abscission during cytokinesis, and retroviral budding. They function as transiently assembled molecular complexes on the membrane, and their disassembly requires the action of the AAA-ATPase Vps4. Vps4 is regulated by a multitude of ESCRT and ESCRT-related proteins. Binding of these proteins to Vps4 is often mediated via the microtubule-interacting and trafficking (MIT) domain of Vps4. Recently, a new Vps4-binding protein Vfa1 was identified in a yeast genetic screen, where overexpression of Vfa1 caused defects in vacuolar morphology. However, the function of Vfa1 and its role in vacuolar biology were largely unknown. Here, we provide the first detailed biochemical and biophysical study of Vps4-Vfa1 interaction. The MIT domain of Vps4 binds to the C-terminal 17 residues of Vfa1. This interaction is of high affinity and greatly stimulates the ATPase activity of Vps4. The crystal structure of the Vps4-Vfa1 complex shows that Vfa1 adopts a canonical MIT-interacting motif 2 structure that has been observed previously in other Vps4-ESCRT interactions. These findings suggest that Vfa1 is a novel positive regulator of Vps4 function. PMID:24567329

  7. Genomic insights into growth and survival of supercritical-CO2 tolerant bacterium MIT0214 under conditions associated with geologic carbon dioxide sequestration

    NASA Astrophysics Data System (ADS)

    Peet, K. C.; Freedman, A. J.; Hernandez, H.; Thompson, J. R.

    2011-12-01

    Carbon capture and storage (CCS) of CO2 has the potential to significantly reduce the emissions of greenhouse gasses associated with fossil fuel combustion. The largest potential for storing captured CO2 in the United Sates is in deep geologic saline formations. Currently, little is known about the effects of CO2 storage on biologically active microbial communities found in the deep earth biosphere. Therefore, to investigate how deep earth microbial communities will be affected by the storage of CO2 we have enriched for a microbial consortium from the saline formation waters of the Frio 2 project site (Texas Gulf Coast) that is capable of growth in nutrient media under a supercritical CO2 headspace (Hernandez, et al). The cultivation of actively growing cells in an environment containing scCO2 is unexpected based on previous experimental evidence of microbial sterilization attributed to the acidic, desiccating, and solvent-like properties of scCO2. We have isolated strain MIT0214 from this supercritical CO2 based enrichment and have sequenced its genome using the Illumina platform followed by de novo assembly of reads and targeted Sanger sequencing to reduce gaps in the draft assembly. The genome of strain MIT0214 is approximately 5,551,062 base pairs with 35% GC-content and is most similar to nonpathogenic Bacillus cereus strain ATCC 14597. Annotation of the draft assembly of the MIT0214 genome by the Rapid Annotation using Subsystem Technology (RAST) server revealed 5538 coding sequences where 4145 of the coding sequences were assigned putative functions. These functions were enriched in cell wall and capsule formation, phage/prophage and plasmids, gene regulation and signaling, and nitrogen and sulfur metabolism relative to the genome of the most closely-related surface-isolated B. cereus reference (ATCC 14597) and in total 773,416 bp of the MIT0214 genome content was distinct from the B. cereus reference. Notably, this set of distinct sequences were most

  8. Transplant outcomes of the triple-negative NPM1/FLT3-ITD/CEBPA mutation subgroup are equivalent to those of the favourable ELN risk group, but significantly better than the intermediate-I risk group after allogeneic transplant in normal-karyotype AML.

    PubMed

    Ahn, Jae-Sook; Kim, Hyeoung-Joon; Kim, Yeo-Kyeoung; Jung, Sung-Hoon; Yang, Deok-Hwan; Lee, Je-Jung; Kim, Nan Young; Choi, Seung Hyun; Jung, Chul Won; Jang, Jun-Ho; Kim, Hee Je; Moon, Joon Ho; Sohn, Sang Kyun; Won, Jong-Ho; Kim, Sung-Hyun; Kim, Dennis Dong Hwan

    2016-03-01

    The prognostic significance of molecular mutations (FLT3-ITD, NPM1, and CEBPA mutations) was examined in patients with normal-karyotype acute myeloid leukaemia (NK-AML) after allogeneic haematopoietic cell transplantation (HCT). In total, 115 patients received allogeneic HCT for NK-AML and were evaluated for FLT3-ITD, NPM1, and CEBPA mutations in diagnostic samples and for long-term outcomes following HCT, retrospectively. The prevalences of FLT3-ITD(pos), NPM1 (mut), and CEBPA (dm) (double mutations) were 32.2, 43.5, and 24.6 %, respectively. The triple-negative group (NPM1 (wild)/FLT3-ITD(neg)/non-CEBPA (dm)) showed a similar transplant outcome to those in the favourable European LeukemiaNet (ELN) risk group for overall survival (OS) (60.9 vs. 63.7 %; p = 0.810), but a more favourable OS than others in the intermediate-I risk group (40.0 %; p = 0.034). Also, the triple-negative group showed a similar relapse rate at 5 years compared with those in the favourable risk group (9.7 vs. 15.5 %; p = 0.499), but a lower rate of relapse than the others in the intermediate-I risk group (15.5 vs. 48.6 %; p = 0.004). The 5-year relapse incidences were 4.0 % (NPM1 (mut)/FLT3-ITD(neg)), 14.7 % (CEBPA (dm)), 15.5 % (NPM1 (wild)/FLT3-ITD(neg)/non-CEBPA (dm)), 39.1 % (NPM1 (mut)/FLT3-ITD(pos)/non-CEBPA (dm)), and 66.7 % (NPM1 (wild)/FLT3-ITD(pos)/non-CEBPA (dm)). Thus, the triple-negative (NPM1 (wild)/FLT3-ITD(neg)/non-CEBPA (dm)) group showed favourable long-term outcomes after allogeneic HCT in NK-AML, similar to those of the favourable risk group by the ELN risk classification. PMID:26692090

  9. Impact on long-term OS of conditioning regimen in allogeneic BMT for children with AML in first CR: TBI+CY versus BU+CY: a report from the Société Française de Greffe de Moelle et de Thérapie Cellulaire.

    PubMed

    de Berranger, E; Cousien, A; Petit, A; Peffault de Latour, R; Galambrun, C; Bertrand, Y; Salmon, A; Rialland, F; Rohrlich, P-S; Vannier, J-P; Lutz, P; Yakouben, K; Duhamel, A; Bruno, B; Michel, G; Dalle, J-H

    2014-03-01

    Allogeneic hematopoietic SCT (HSCT) appears to be an efficient tool to cure high-risk AML in first CR but the choice between BU-based or TBI-based conditioning regimens still remains controversial. In order to analyze the impact of conditioning regimen on long-term survival, we conducted a retrospective analysis from French registry data including all consecutive patients under 18 years old (n=226) from 1980 to 2004 transplanted for AML in CR1 from sibling (n=142) or matched unrelated donors and given either TBI-1200 cGy and CY 120 mg/kg (TBI-Cy, n=84) or BU 16 mg/kg and CY 200 mg/kg (BuCy200, n=142). Patient subgroups were comparable for all criteria except for median age at diagnosis and HSCT and for donor type. Both 5-year OS and disease-free survival (DFS) were significantly better in BuCy200 group (P=0.02 and 0.005, respectively). In multivariate analysis, both HLA matching and BuCy200 appeared as good prognostic factors for treatment-related mortality and DFS. Grade 2-4 acute GvHD and chronic GvHD rates were statistically higher in TBI-Cy group than in Bu-Cy200 one with a RR at 2 (P=0.002). In total, Bu-Cy200 conditioning regimen gives better outcome compared with TBI-Cy irrespective of the stem cell source and the donor type. PMID:24317131

  10. Recent KBO (Pluto/Charon and beyond, including Quaoar) Occultation Observations by the Williams College Team as part of the Williams-MIT Collaboration

    NASA Astrophysics Data System (ADS)

    Pasachoff, Jay M.; Babcock, B. A.; Davis, A. B.; Pandey, S.; Lu, M.; Rogosinski, Z.; Person, M. J.; Bosh, A. S.; Zangari, A. M.; Zuluaga, C. A.; Gulbis, A. S.; Naranjo, O.; Navas, G.; Zerpa, L.; Villarreal, J.; Rojo, P.; Förster, F.; Servajean, E.

    2013-10-01

    The Williams College-MIT collaboration has observed numerous occultations of stars by Pluto/Charon and other Kuiper-belt objects (www.stellaroccultations.info), since its establishment three decades ago with an attempted discovery of Neptune's rings in 1983. In this paper, we describe several recent occultation observations, both successful and (for reasons of path uncertainties and/or weather) unsuccessful. Light curves made or arranged by Williams College faculty and students were used together with light curves by MIT colleagues and others to study Pluto's atmosphere and Charon's size, to discover one of the highest-known solar-system albedos (KBO 55636), and to attempt to study 1000-km-diameter Quaoar. Observations discussed include light curves for KBO 55636 on 9 October 2009 from Hawaii; Pluto on 3/4 July 2010 from Chile, 22 May 2011 from Williamstown, Massachusetts, 23 June 2011 from Hawaii (in support of SOFIA observations of Pluto's atmosphere, discussed in an article in press in AJ and of the pair of Pluto/Charon occultations of the same star), and 4 May 2013 (Bosh et al., this conference) and 15 July 2013 from Williamstown; Charon on 15 June 2013 from Williamstown; Quaoar from a picket fence ranging from Chile through Venezuela (with a detection there) to Massachusetts on July 8/9 and in South Africa on 12 July 2013. This work was supported in part by NASA Planetary Astronomy grants NNX08AO50G and NNH11ZDA001N to Williams College, NNX10AB27G to MIT, and USRA grant #8500-98-003 to Lowell Observatory. We thank Steven P. Souza at Williams; Steven Levine at Lowell Obs.; Jennifer G. Winters (GSU) in Chile; Richard Rojas/Jorge Moreno in Venezuela; Scott Sheppard; Federica Bianco; David Osip; and others. ZR (Vassar '14) was a Keck Northeast Astronomy Consortium Summer Fellow at Williams College, supported by an NSF/REU grant to the Keck Northeast Astronomy Consortium. ES: partial support from Programa Nacional de Becas de Postgrado (CONICYT Grant 21110496). FF

  11. Assessment of MIT and UCB wall condensation tests and of the pre-release RELAP5/MOD3.2 code condensation models

    SciTech Connect

    Shumway, R.W.

    1995-01-01

    In recent years, a new class of reactor designs has been proposed that utilize passive safety systems. General Electric has developed a Simplified Boiling Water Reactor (SBWR) design that relies on such passive systems. The SBWR has two passive cooling systems that involve energy transfer by condensation. These are the isolation condenser system (ICS) and the passive containment cooling systems (PCCS). It is important that such heat transfer phenomena be correctly understood and quantified. The General Electric Company has sponsored tests at the Massachusetts Institute of Technology (MIT) and at the University of California at Berkeley (UCB) to obtain data simulating PCCS conditions. Data was obtained with pure steam, steam-air mixtures and steam-helium mixtures. INEL has been contracted by the NRC to evaluate these tests and assess existing condensation heat transfer correlations against the test data. This report assesses the relevance of the tests to SBWR conditions and shows RELAP5/MOD3.2 predictions of the tests.

  12. Adjustable impedance, force feedback and command language aids for telerobotics (parts 1-4 of an 8-part MIT progress report)

    NASA Technical Reports Server (NTRS)

    Sheridan, Thomas B.; Raju, G. Jagganath; Buzan, Forrest T.; Yared, Wael; Park, Jong

    1989-01-01

    Projects recently completed or in progress at MIT Man-Machine Systems Laboratory are summarized. (1) A 2-part impedance network model of a single degree of freedom remote manipulation system is presented in which a human operator at the master port interacts with a task object at the slave port in a remote location is presented. (2) The extension of the predictor concept to include force feedback and dynamic modeling of the manipulator and the environment is addressed. (3) A system was constructed to infer intent from the operator's commands and the teleoperation context, and generalize this information to interpret future commands. (4) A command language system is being designed that is robust, easy to learn, and has more natural man-machine communication. A general telerobot problem selected as an important command language context is finding a collision-free path for a robot.

  13. Development of the system for visualization of electric conductivity distribution in human brain and its activity by the magnetic induction tomography (MIT) method

    NASA Astrophysics Data System (ADS)

    Sapetsky, S.; Cherepenin, V.; Korjenevsky, A.; Kornienko, V.; Vartanov, A.

    2010-04-01

    Currently rapid development of functional activity researches of human brain sets the problem of reliable and non-invasive detection of mental processes and states. At present we know some traditional methods of rapid and contactless acquisition of brain activity characteristics, such as functional tomography (fMRI) and magnetoencephalography. But these methods have low temporal resolution, complicated and ambiguous association of measured values with information processes in brain. So possibility of MIT application is investigated. Estimation of possibility of such changes registration is performed. Investigations of magnetic field configuration, schematics of transmit-receive modules and numerical algorithms are in progress. It may allow us to register high speed conductivity changes in brain tissues.

  14. Edelgase als Tracer für Wechselwirkungen von Krusten- und Mantelfluiden mit diamantführenden Gesteinen des östlichen Baltischen Schildes

    NASA Astrophysics Data System (ADS)

    Wiersberg, Thomas

    2001-11-01

    In der vorliegenden Arbeit werden anhand der Edelgaszusammensetzung von Kimberliten und Lamproiten sowie ihrer gesteinsbildenden Minerale die Wechselwirkungen dieser Gesteine mit Fluiden diskutiert. Die untersuchten Proben stammen vom östlichen Baltischen Schild, vom Kola-Kraton (Poria Guba und Kandalaksha) und vom karelischen Kraton (Kostamuksha). Edelgasanalysen nach thermischer oder mechanischer Gasextraktion von 23 Gesamtgesteinsproben und 15 Mineralseparaten ergeben folgendes Bild: Helium- und Neon-Isotopendaten der Fluideinschlüsse von Lamproiten aus Kostamuksha lassen auf den Einfluss einer fluiden Phase krustaler Herkunft schliessen. Diese Wechselwirkungen fanden wahrscheinlich schon während des Magmenaufstiegs statt, denn spätere Einflüsse krustaler Fluide auf die Lamproite und ihr Nebengestein (Quarzit) sind gering, wie anhand der C/36Ar-Zusammensetzung gezeigt wird. Auch sind die mit verschiedenen Datierungsmethoden (Rb-Sr, Sm-Nd, K-Ar) an Mineralseparaten und teilweise an Gesamtgestein ermittelten Alter konsistent und machen eine metamorphe Überprägung unwahrscheinlich. Aufgrund der Verteilung der primordialen Edelgasisotope zwischen Fluideinschlüssen und Gesteinsmatrix ist ein langsamer Magmenaufstieg anzunehmen, was die Möglichkeit der Kontamination mit einem krustalen Fluid während des Magmenaufstiegs erhöht. Die Gasextraktion aus Mineralseparaten erfolgte thermisch, wodurch eine Freisetzung der Gase ausschließlich aus Fluideinschlüssen nicht möglich ist. Hierbei zeigen Amphibol und Klinopyroxen, separiert aus Kostamuksha-Lamproiten, in ihrer Neon-Isotopenzusammensetzung im Vergleich zur krustalen Zusammensetzung (Kennedy et al., 1990) ein leicht erhöhtes Verhältnis von 20Ne/22Ne, was ein Hinweis auf Mantel-Neon sein könnte. Kalifeldspäte, Quarz und Karbonate enthalten dagegen nur Neon krustaler Zusammensetzung. Phlogopite haben sehr kleine Verhältnisse von 20Ne/22Ne und 21Ne/22Ne, zurückzuführen auf in-situ-Produktion von 22Ne

  15. Parameter Tuning and Calibration of RegCM3 with MIT-Emanuel Cumulus Parameterization Scheme over CORDEX East Asian Domain

    SciTech Connect

    Zou, Liwei; Qian, Yun; Zhou, Tianjun; Yang, Ben

    2014-10-01

    In this study, we calibrated the performance of regional climate model RegCM3 with Massachusetts Institute of Technology (MIT)-Emanuel cumulus parameterization scheme over CORDEX East Asia domain by tuning the selected seven parameters through multiple very fast simulated annealing (MVFSA) sampling method. The seven parameters were selected based on previous studies, which customized the RegCM3 with MIT-Emanuel scheme through three different ways by using the sensitivity experiments. The responses of model results to the seven parameters were investigated. Since the monthly total rainfall is constrained, the simulated spatial pattern of rainfall and the probability density function (PDF) distribution of daily rainfall rates are significantly improved in the optimal simulation. Sensitivity analysis suggest that the parameter “relative humidity criteria” (RH), which has not been considered in the default simulation, has the largest effect on the model results. The responses of total rainfall over different regions to RH were examined. Positive responses of total rainfall to RH are found over northern equatorial western Pacific, which are contributed by the positive responses of explicit rainfall. Followed by an increase of RH, the increases of the low-level convergence and the associated increases in cloud water favor the increase of the explicit rainfall. The identified optimal parameters constrained by the total rainfall have positive effects on the low-level circulation and the surface air temperature. Furthermore, the optimized parameters based on the extreme case are suitable for a normal case and the model’s new version with mixed convection scheme.

  16. An integrated assessment modelling framework for uncertainty studies in global and regional climate change: the MIT IGSM-CAM (version 1.0)

    NASA Astrophysics Data System (ADS)

    Monier, E.; Scott, J. R.; Sokolov, A. P.; Forest, C. E.; Schlosser, C. A.

    2013-03-01

    This paper describes an integrated assessment modelling framework for uncertainty studies in global and regional climate change. In this framework, the Massachusetts Institute of Technology (MIT) Integrated Global System Model (IGSM), an integrated assessment model that couples an earth system model of intermediate complexity to a human activity model, is linked to the National Center for Atmospheric Research (NCAR) Community Atmosphere Model (CAM). Since the MIT IGSM-CAM framework (version 1.0) incorporates a human activity model, it is possible to analyse uncertainties in emissions resulting from both uncertainties in the economic model parameters and uncertainty in future climate policies. Another major feature is the flexibility to vary key climate parameters controlling the climate system response: climate sensitivity, net aerosol forcing and ocean heat uptake rate. Thus, the IGSM-CAM is a computationally efficient framework to explore the uncertainty in future global and regional climate change associated with uncertainty in the climate response and projected emissions. This study presents 21st century simulations based on two emissions scenarios (unconstrained scenario and stabilization scenario at 660 ppm CO2-equivalent) and three sets of climate parameters. The chosen climate parameters provide a good approximation for the median, and the 5th and 95th percentiles of the probability distribution of 21st century global climate change. As such, this study presents new estimates of the 90% probability interval of regional climate change for different emissions scenarios. These results underscore the large uncertainty in regional climate change resulting from uncertainty in climate parameters and emissions, especially when it comes to changes in precipitation.

  17. An integrated assessment modeling framework for uncertainty studies in global and regional climate change: the MIT IGSM-CAM (version 1.0)

    NASA Astrophysics Data System (ADS)

    Monier, E.; Scott, J. R.; Sokolov, A. P.; Forest, C. E.; Schlosser, C. A.

    2013-12-01

    This paper describes a computationally efficient framework for uncertainty studies in global and regional climate change. In this framework, the Massachusetts Institute of Technology (MIT) Integrated Global System Model (IGSM), an integrated assessment model that couples an Earth system model of intermediate complexity to a human activity model, is linked to the National Center for Atmospheric Research (NCAR) Community Atmosphere Model (CAM). Since the MIT IGSM-CAM framework (version 1.0) incorporates a human activity model, it is possible to analyze uncertainties in emissions resulting from both uncertainties in the underlying socio-economic characteristics of the economic model and in the choice of climate-related policies. Another major feature is the flexibility to vary key climate parameters controlling the climate system response to changes in greenhouse gases and aerosols concentrations, e.g., climate sensitivity, ocean heat uptake rate, and strength of the aerosol forcing. The IGSM-CAM is not only able to realistically simulate the present-day mean climate and the observed trends at the global and continental scale, but it also simulates ENSO variability with realistic time scales, seasonality and patterns of SST anomalies, albeit with stronger magnitudes than observed. The IGSM-CAM shares the same general strengths and limitations as the Coupled Model Intercomparison Project Phase 3 (CMIP3) models in simulating present-day annual mean surface temperature and precipitation. Over land, the IGSM-CAM shows similar biases to the NCAR Community Climate System Model (CCSM) version 3, which shares the same atmospheric model. This study also presents 21st century simulations based on two emissions scenarios (unconstrained scenario and stabilization scenario at 660 ppm CO2-equivalent) similar to, respectively, the Representative Concentration Pathways RCP8.5 and RCP4.5 scenarios, and three sets of climate parameters. Results of the simulations with the chosen

  18. First Results from the MIT Optical Rapid Imaging System (MORIS) on the IRTF: A Stellar Occultation by Pluto and a Transit by Exoplanet XO-2b

    NASA Astrophysics Data System (ADS)

    Gulbis, A. A. S.; Bus, S. J.; Elliot, J. L.; Rayner, J. T.; Stahlberger, W. E.; Rojas, F. E.; Adams, E. R.; Person, M. J.; Chung, R.; Tokunaga, A. T.; Zuluaga, C. A.

    2011-04-01

    We present a high-speed, visible-wavelength imaging instrument: MORIS (the MIT Optical Rapid Imaging System). MORIS is mounted on the 3 m Infrared Telescope Facility (IRTF) on Mauna Kea, Hawaii. Its primary component is an Andor iXon camera, a nearly 60" square field of view with high quantum efficiency, low read noise, low dark current, and full-frame readout rates ranging from as slow as desired to a maximum of between 3.5 Hz and 35 Hz (depending on the mode; read noise of 6 e- pixel-1 and 49 e- pixel-1 with electron-multiplying gain = 1, respectively). User-selectable binning and subframing can increase the cadence to a few hundred hertz. An electron-multiplying mode can be employed for photon counting, effectively reducing the read noise to subelectron levels at the expense of dynamic range. Data cubes, or individual frames, can be triggered to several-nanosecond accuracy using the Global Positioning System. MORIS is mounted on the side-facing exit window of SpeX, allowing simultaneous near-infrared and visible observations. Here, we describe the components, setup, and measured characteristics of MORIS. We also report results from the first science observations: the 2008 June 24 stellar occultation by Pluto and an extrasolar planetary transit by XO-2b. The Pluto occultation of a 15.8R magnitude star has a signal-to-noise ratio of 35 per atmospheric scale height and a midtime error of 0.32 s. The XO-2b transit reaches photometric precision of 0.5 mmag in 2 minutes and has a midtime timing precision of 23 s.

  19. Grundsätze über die Anlagen neuer Sternwarten mit Beziehung auf die Sternwarte der Universität Göttingen. Von Georg Heinrich Borheck

    NASA Astrophysics Data System (ADS)

    Beuermann, Klaus; Borheck, Georg Heinrich

    Die Göttinger Sternwarte, Wirkungsstätte des berühmten Gelehrten Carl Friedrich Gauß, ist ein bedeutendes Baudenkmal. Im Jahre 2005 wird sie gemeinsam von der Georg-August-Universität und der Akademie der Wissenschaften zu Göttingen renoviert, um dann als repräsentatives Gebäude der Universität und Arbeitsstätte der Akademie zu dienen. Die Nutzung der historischen Räume für Ausstellungen macht diesen imposanten Bau erstmals der Öffentlichkeit zugänglich. Die Sternwarte war bei ihrer Errichtung vor 200 Jahren ein nach seinerzeit neuesten wissenschaftlichen Erkenntnissen konzipierter Bau, der die Universität Göttingen in eine der vordersten Stellen Europa rückte. Auch aufgrund ihrer Architektur ist sie ein großer Wurf des Göttinger Universitätsbaumeisters Georg Heinrich Borheck. Durch die Kriegswirren der Napoleonischen Zeit zerschlug sich Borhecks Versuch einer Publikation seiner Beschreibung des Baus der Göttinger Sternwarte 1805. Doch seine Schrift ist auch heute noch aktuell und wird mit diesem Band erstmals einer breiten Öffentlichkeit zugängig gemacht. Er zeigt die Grundsätze, nach denen damals öffentliche Bauten konzipiert wurden, erläutert die Bedeutung des Baus aus kunst- und wissenschaftshistorischer Sicht und informiert über die Pläne zur Restaurierung der Sternwarte in einem separaten Beitrag und im Geleitwort des Präsidenten der Georg-August Universität Prof. Dr. Dr. h. c. Kurt von Figura.

  20. Intraoperative Schnellschnittuntersuchungen parapylorischer Lymphknoten bei der pyloruserhaltenden Pankreaskopfresektion: Gibt es eine klinische Relevanz?

    PubMed Central

    Riediger, Hartwig; Schulz, Antje; Adam, Ulrich; Krüger, Colin M.

    2014-01-01

    Zusammenfassung Hintergrund Die pyloruserhaltende Pankreaskopfresektion (PPPD) ist als onkologisches Standardverfahren etabliert. Lokal fortgeschrittene Tumoren können eine erweiterte Resektion erforderlich machen. Ebenso soll früheren Arbeiten zufolge bei Tumornachweis in den parapylorischen Lymphknoten (PLK) eine distale Magenresektion im Sinne einer klassischen Whipple-Operation indiziert sein. Entsprechend diesen Empfehlungen haben wir intraoperative Schnellschnittuntersuchungen der PLK in unseren Routineablauf integriert. Im Rahmen dieser Studie haben wir die klinische Relevanz dieses Vorgehens hinterfragt. Methoden Bei 105 onkologischen Patienten im Zeitraum von 2006-2012 bestand die Indikation zur PPPD. In allen Fällen erfolgte eine intraoperative Schnellschnittuntersuchung der PLK. Die Patienten wurden bezüglich Primärtumor, Anzahl der untersuchten Lymphknoten (LK) (gesamt und parapylorisch) sowie Auswirkungen auf das operative Konzept untersucht. Es handelt sich um eine retrospektive Studie, die auf prospektiv erhobenen Daten unserer Pankreasdatenbank basiert. Ergebnisse Die Primärtumoren waren 72 Pankreaskopfkarzinome und 33 extrapankreatische Karzinome (Gallengangskarzinom, Ampullenkarzinom, Duodenalkarzinom). 73 Patienten waren nodalpositiv. Insgesamt wurden 2391 LK untersucht, von denen 325 parapylorisch lokalisiert waren. Die intraoperative Schnellschnittuntersuchung erbrachte lediglich bei 4 Patienten mit Pankreaskopfkarzinom jeweils einen positiven PLK; daraufhin erfolgte eine distale Magenresektion. In keinem der distalen Magenresektate waren Tumorresiduen nachweisbar. Lokale chirurgisch-technische Probleme im Sinne von Durchblutungsstörungen des Magens ergaben sich durch die regionale Lymphadenektomie nicht. PLK waren nur beim Pankreaskarzinom positiv. In der Subgruppe der nodalpositiven Patienten mit Pankreaskopfkarzinom hatten 8% der Patienten einen positiven PLK. Schlussfolgerung Die regionale parapylorische Lymphadenektomie ist beim

  1. Indian Creek-AML: Coal slurry reclamation (Kansas case history)

    SciTech Connect

    Witthar, S.R.

    1998-12-31

    Black and Veatch, assisted by Jack Nawrot, developed conceptual and final designs and provided construction assistance to create grasslands and wetlands in order to reclaim an abandoned coal mine for the state of Kansas. The mine included spoils, a coal refuse dump, and slurry pond in the Indian Creek drainage basin in east central Kansas. The Indian Creek flowed from an off-site abandoned mine and through the coal slurry pond where its waters became more polluted. The intent of the reclamation project was to improve water quality and create a wildlife refuge. The coal refuse was covered and seeded with a diversity of vegetation including several grasses and legume. The slurry pond was developed into a series of large wetland cells to improve water quality. Prior to reclamation, the water leaving the site had a typical pH of 3.3, ranging from 2.4 to 5.6, an iron content which typically over 22 mg/L and ranging over 100 mg/L, and contained large amounts of coal slurry. The acid sediment in the slurry killed fish and caused visible damage to a new large concrete box culvert several miles downstream of the site. Post-reclamation water quality leaving the Indian Creek site showed immediate improvement even before vegetation was reestablished. The existing wetland treatment systems have been successfully treating water for over seven years with the pH of the water leaving the wetlands above 7 and soluble iron content less than 1 mg/L. Fish in the constructed wetlands support waterfowl which now nest onsite.

  2. ALACARTE User Interface - AML Code and Demonstration Maps

    USGS Publications Warehouse

    Fitzgibbon, Todd T.; Wentworth, Carl M.

    1991-01-01

    Compilations begun in other digital systems can be imported for completion as digital databases in ARC/INFO. The digital files that represent a geologic map can be used to prepare near-publication-quality color plots of the maps with full symbology or to create high-quality printing negatives. These files also constitute a digital database that can be used for computer-based query and analysis as well as for digital distribution of the map and associated data.

  3. Stabile Expression von Sulfotransferasen - allein oder in Kombination mit Cytochrom P450 - in Zelllinien für Mutagenitätsuntersuchungen

    NASA Astrophysics Data System (ADS)

    Pabel, Ulrike

    2003-10-01

    -dimethylaminoazobenzol; 0,1 µM für 2-Aminoanthracen; 10 µM für 2,4-Diaminotoluol). Die stärkste Aktivierung von 2-Acetylaminofluoren und 3′-Methyl-4-dimethylaminoazobenzol erfolgte in der Zelllinie, die CYP1A2 und SULT1A2 koexprimierte; die stärkste Aktivierung von 2,4-Diaminotoluol und 2-Aminoanthracen erfolgte in der Zelllinie, die CYP1A2 und SULT1A1 koexprimierte. Sowohl SULT1A1 als auch SULT1A2 sind im Menschen genetisch polymorph. Ein unterschiedlich starkes Aktivierungspotenzial der Alloenzyme könnte eine individuell unterschiedliche Suszeptibilität für die durch aAA ausgelöste Kanzerogenese bedingen. In HPRT-Mutationsuntersuchungen mit rekombinanten Zellen zeigten die allelischen Varianten der SULT1A2 starke Unterschiede in ihrem Aktivierungpotenzial. Nur in der Zelllinie, die das Alloenzym SULT1A2*1 mit CYP1A2 koexprimierte, wurde 2-Acetylaminofluoren zum Mutagen aktiviert. Zur Aktivierung von 3′-Methyl-4-dimethylaminoazobenzol waren jedoch sowohl das Alloenzym SULT1A2*1 als auch das Alloenzym SULT1A2*2 in der Lage. Die Alloenzyme der SULT1A1 zeigten ein ähnlich gutes Aktivierungspotenzial für aAA. In früheren Studien wurde gezeigt, dass die SULT1C1 der Ratte eine wichtige Rolle bei der Aktivierung der aAA in dieser Spezies spielt. Dahingegen war die humane SULT1C1 nicht in der Lage die untersuchten aAA zu aktivieren. Die Kenntnis solcher Spezieunterschiede könnte wichtig sein um unterschiedliche Organotropismen aAA in Menschen und Tiermodellen zu erklären, da SULT mit starker Gewebespezifität exprimiert werden und das Expressionsmuster für die einzelnen SULT-Formen in Menschen und Ratten sich stark unterscheidet. Aromatic amines and amides (aAA) represent a group of chemicals with great toxicological importance due to their wide distribution in the environment and their carcinogenic potency. The carcinogenicity of aAA is mediated by the mutagenic action of highly reactive metabolites. They are frequently formed by N-hydroxylation of the exocyclic

  4. From Uhuru at CfA to SAS-3 at MIT: Looking for X-Ray Binaries in all the Right Places

    NASA Astrophysics Data System (ADS)

    Cominsky, Lynn R.

    2013-01-01

    My career in X-ray astronomy started almost accidentally, when in 1975 I was hired fresh out of college as a “data aide” for the Uhuru satellite, in Riccardo Giacconi’s group at the Harvard-Smithsonian Center for Astrophysics. Working first for Mel Ulmer, and later for Bill Forman and Christine Jones, I learned the fundamentals of data analysis, and helped produce the Fourth Uhuru catalog of X-ray sources (Forman et al. 1978), as well as studying transient X-ray sources (Cominsky et al. 1978). Christine was the first woman scientist I had ever met, and with her encouragement, I applied to graduate school to continue on in X-ray astronomy. Lured down the street to MIT by the chance to work on SAS-3, I eagerly learned how to operate the satellite from a control room in the Center for Space Research. The SAS-3 group was led by Prof. George Clark, and it was my good luck that he was around during the holiday break in January 1978 when everyone else in the group was at an AAS meeting in Hawaii. A source I recognized from my Uhuru work, 4U0115+63, had reappeared, and I knew that it was likely to be a pulsar. With the help of George and Project Scientist Bill Mayer, I managed to send the commands to stop SAS-3 and point at the source. The 3.6 second pulsations were so strong that they could be seen in the raw data! This discovery made the New York Times, as 4U0115+63 was the first transient x-ray source shown to be in a binary system (Cominsky et al. 1978, Rappaport et al. 1978). Another personal SAS-3 highlight included working on Prof. Walter Lewin’s “World-wide Burst Watch” - coordinated multi-wavelength observations of x-ray burst sources which led to the discoveries of slightly delayed but coincident optical bursts (Grindlay et al. 1978, McClintock et al. 1979). Although live operations of SAS-3 ended when it re-entered on April 9, 1979, many years of additional data analysis remained. And later, as a continuation of work I began in my Ph.D. Thesis on X

  5. Checkpoint-Inhibitoren in der Immuntherapie: Ein Meilenstein in der Behandlung des malignen Melanoms.

    PubMed

    Wilden, Sophia M; Lang, Berenice M; Mohr, Peter; Grabbe, Stephan

    2016-07-01

    Seit Jahrzehnten ist bekannt, dass Tumoren vom Immunsystem erkannt und zerstört werden können. Diese, vor allem in Tierversuchen gewonnene Erkenntnis konnte jedoch in der Vergangenheit nicht zum Nutzen unserer Patienten umgesetzt werden, da immunonkologische Therapieansätze in den letzten Jahrzehnten in der Anwendung beim Menschen stets versagt haben. Daher hat, mit Ausnahme der adjuvanten Interferontherapie, keines dieser Verfahren den Einzug in die klinische Versorgung gefunden. Langzeitüberleben unter guter Lebensqualität war dabei sehr wenigen Patienten vorbehalten. Mit den neuen immunologischen Therapieansätzen wird jedoch sowohl das Langzeitüberleben als auch die Lebensqualität onkologischer Patienten neu definiert. Auf die neuen "Immun-Checkpoint-Inhibitoren" spricht erstmals ein relevanter Teil der behandelten Patienten an und diese zeigen in der Regel langandauernde Remissionen bis hin zur Heilung. Schon jetzt ist klar, dass die Immuntherapie in Zukunft eine der wesentlichen Therapiesäulen bei der Behandlung des metastasierten Melanoms und auch vieler anderer fortgeschrittener Tumoren bilden wird. In dieser Übersicht werden die wichtigsten neuen Therapiemodalitäten besprochen und sowohl deren Wirkprinzip als auch klinische Daten zum Therapieansprechen und zu erwartenden Nebenwirkungen der Therapie referiert. PMID:27373243

  6. Safety Study of AG-120 or AG-221 in Combination With Induction and Consolidation Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 and/or IDH2 Mutation

    ClinicalTrials.gov

    2016-04-27

    Newly Diagnosed Acute Myeloid Leukemia (AML); Untreated AML; AML Arising From Myelodysplastic Syndrome (MDS); AML Arising From Antecedent Hematologic Disorder (AHD); AML Arising After Exposure to Genotoxic Injury

  7. Therapeutisches Management kutaner und genitaler Warzen.

    PubMed

    Ockenfels, Hans Michael

    2016-09-01

    Mindestens 10 % der Bevölkerung erkranken während ihres Lebens an einer Infektion mit humanen Papillomaviren (HPV), welche sich klinisch anhand der Ausbildung kutaner oder genitaler Warzen manifestiert. Obwohl Warzen ubiquitär sind, existieren keine definierten Behandlungen. Warzen zeigen, insbesondere in den ersten sechs Monaten, eine erhöhte Selbstheilungsrate. Dieser Umstand erschwert die Interpretation von Studien, da häufig Patienten mit Neuinfektionen zusammen mit Patienten mit Altinfektionen behandelt werden. Lokalisationen, Größe und Dicke der Warzen sind ebenfalls in den meisten Fällen nicht berücksichtigt. Ziel dieses Übersichtsartikels ist eine Analyse des vorliegenden Studienmaterials, unter der für den klinischen Alltag so wichtigen Berücksichtigung von Subtypen und Lokalisationen. Insbesondere die Abgrenzung zwischen frischen und chronisch-therapieresistenten Verrucae vulgares spiegelt sich in einem Therapiealgorithmus wider. Bei genitalen Warzen wird der Therapiealgorithmus deutlicher durch das Ausmaß der infizierten Fläche als durch das Alter der Warzen bestimmt. Bei immunkompetenten Personen muss es mit den hier aufgezeigten therapeutischen Methoden immer das Ziel sein, eine komplette Abheilung zu erzielen. PMID:27607029

  8. Desorptions- und Reaktionskinetik der Erdalkalien Calcium und Strontium mit Chlor an Wolfram. Part II: Kinetics of the Elementary Steps of the Surface Reaction M + Cl MCl (M = Ca, Sr)

    NASA Astrophysics Data System (ADS)

    Biedermann, B.; Wassmuth, H. W.

    Mit Hilfe gepulster Atom-bzw. Molekularstrahlen wurde die Desorptionskinetik von Strontium, Calcium und Chlor sowie die Desorptionskinetik der sich auf einer heißen Wolframoberfläche bildenden SrCl-und CaCl- Moleküle untersucht. Als Aktivierungsenergien zur Desorption erhielten wir: = (3,76 +/- 0,05) eV, =(3,32 +/- 0,07) eV, =(4,16 +/- 0,05) eV sowie =(4,2 +/- 0,3) eV und =(3,9 +/- 0, 3)eV.In Kombination mit den im stationären Zustand erhaltenen Ergebnissen aus Teil I [1] läßt sich damit ein Einblick in die Kinetik der Reaktion M + Cl = MCl auf der wolframoberfläche gewinnen und die Temperaturabhängigkeit der Ratenkonstanten der Dissoziation und der Rekombination bestimmen. FuUr die Dissoziationsenergie DSMCl von SrCl bzw. CaCl an der Wolfram-Oberfläche erhielten wir (0,5 +/- 0,5) eV bzw. (0,3 +/- 0,5) eV; die MCl-Moleküle sind an der Oberfläche also praktisch nur durch die Aktivierungsschwelle zur Dissoziation SMCl stabilisiert, die wir für SrCl zu (2,8 +/- 0,5) eV und für CaCl zu (2,3 +/- 0,5) eV bestimmten.Translated AbstractDesorption- and Reactionkinetics of the Alkaline Earth Elements Calcium and Strontium with Chlorine on a Tungsten Surface - Part II: Kinetics of the Elementary Steps of the Surface Reaction M + Cl MCl (M = Ca, Sr)Utilizing pulsed molecular-beam-technique the kinetics of desorption of Strontium, Calcium, and Chlorine as well as that of the molecules SrCl and CaCl, which are formed at the hot tungsten surface, was investigated. Thereby, the following values were obtained for the activation energies of desorption: = (3.76 +/- 0.05) eV, = (3.32 +/- 0.07) eV, = (4.16 +/- 0.05) eV, = (4.2 +/- 0.3) eV and = (3.9 +/- 0.3) eV.Combining these results with the steady-state-results from part I [1] the temperature dependency of the rate constants of dissociation and recombination of MCl-molecules at the tungsten surface could be determined. The values obtained for the dissociation energies

  9. Supply Chain Management (SCM) mit Kanban

    NASA Astrophysics Data System (ADS)

    Beer, Anja; Dickmann, Eva; Dickmann, Philipp; Gerth, Wolf-Michael; Graßy, Mario; Herron, Colin; Schmidt, Peter; Seidl, Florian; Wittmann, Claus-Eduard

    Nach Schätzungen von Mercer Management Consulting und dem Fraunhofer Institut wird der Wertschöpfungsanteil in der Automobilindustrie von durchschnittlich 35 % im Jahr 2002 auf 23 % im Jahr 2015 sinken [Merc 04]. Der Trend, die Produktionstiefe oder allgemeiner, die Wertschöpfungstiefe, zu reduzieren, hat zur Folge, dass die Kaufteile den größeren Teil der Wertschöpfung einnehmen. Die Optimierungspotentiale und der Einfluss auf die Kosten wandern immer mehr zu den Lieferanten, vor allem bei größeren Unternehmen oder Konzernen. Lieferanten-Philosophien, die auf oberflächlichen Verbindungen zu Lieferanten aufbauen, um immer optimal und schnell den günstigsten Teilepreis zu erhalten, haben sich in vielen Sparten oder Produktbereichen, z. B. im Maschinenbau, im besten Fall als kurzfristig erfolgreich erwiesen. Kooperative und nachhaltige Strategien sind der erfolgversprechendere Weg, zumindest mittelbis langfristig. In der Realität wird sehr wenig in Supply Chain-Konzepte investiert und die Umsetzungen sind daher vielmals oberflächlich.

  10. MIT Haystack Observatory Analysis Center Report

    NASA Technical Reports Server (NTRS)

    Niell, Arthur

    2004-01-01

    The data from twenty years of the NCEP numerical weather model have been used to calculate the IMF hydrostatic mapping function for several sites distributed in latitude from -66 degrees to +78 degrees. Comparison of heights estimated with the NMF hydrostatic mapping function demonstrates that using NMFh results in height errors at annual and semi-annual periods with amplitudes as large as approximately 8 mm and 4 mm, respectively, when data down to 5 degrees are included. The errors are smallest at the equator and increase towards the poles.

  11. BEAMS Lab at MIT: Status report

    PubMed Central

    Liberman, Rosa G.; Skipper, Paul L.; Tannenbaum, Steven R.

    2009-01-01

    The Biological Engineering Accelerator Mass Spectrometry (BEAMS) Lab at the Massachusetts Institute of Technology is a facility dedicated to incorporating AMS into life sciences research. As such, it is focused exclusively on radiocarbon and tritium AMS and makes use of a particularly compact instrument of a size compatible with most laboratory space. Recent developments at the BEAMS Lab were aimed to improve different stages of the measurement process, such as the carbon sample injection interface, the simultaneous detection of tritium and hydrogen and finally, the overall operation of the system. Upgrades and results of those efforts are presented here. PMID:20383276

  12. Story I: Impella - Eine Erfolgsgeschichte mit Achterbahnfahrt

    NASA Astrophysics Data System (ADS)

    Sieß, Thorsten; Nix, Christoph; Michels, Dirk

    An der Entwicklung von Blutpumpen hatte man im Aachener Helmholtz-Institut für Biomedizinische Technik (HIA) schon seit längerem gearbeitet. Aber was der Forscher Thorsten Sieß da zu Beginn der 90er Jahre vorhat, das ist etwas ganz Besonderes. Nicht umsonst hat die Deutsche Forschungsgesellschaft (DFG) Mittel für 4 Jahre zugeschossen. Sieß ist dabei, eine so genannte minimal-invasive Technik zur Blutförderung zu entwickeln - und das geht weit über den damaligen Stand der Technik hinaus.

  13. MIT Experiments with Joint Venture Contract.

    ERIC Educational Resources Information Center

    American School and University, 1981

    1981-01-01

    A new dormitory at Massachusetts Institute of Technology was constructed using a joint venture contract with safeguards and incentives that brought university, architect, and building contractor into a closer and more productive relationship than under conventional contract arrangements. (Author/MLF)

  14. Biotechnology Process Engineering Center at MIT Home

    Science.gov Websites

    ... &22; )&25;&2;tt &6; - &8; &22; )&28; p:www.w3. &6; - &8; &22; (&2;&6;&3;&1;o &6; - &8; &22; )&25; rgTRREC )&1;- &6; &1; - &8; &22; Q )&17;&1;h &6; - &8; &22; )&25;&1;t &6; &2; - &8; &1; &22; )&14;&1;m &6; &1; - ...

  15. Investigation of air transportation technology at MIT

    NASA Technical Reports Server (NTRS)

    Simpson, R. W.

    1983-01-01

    A summary of the research done by the Massachusetts Institute of Technology is addressed including Loran-C for guidance in flying approaches, an air traffic control simulator for the Manned Vehicle Simulation Research Facility, and an air traffic collision model theory.

  16. MIT-NASA Workshop: Transformational Technologies

    NASA Technical Reports Server (NTRS)

    Mankins, J. C. (Editor); Christensen, C. B.; Gresham, E. C.; Simmons, A.; Mullins, C. A.

    2005-01-01

    As a space faring nation, we are at a critical juncture in the evolution of space exploration. NASA has announced its Vision for Space Exploration, a vision of returning humans to the Moon, sending robots and eventually humans to Mars, and exploring the outer solar system via automated spacecraft. However, mission concepts have become increasingly complex, with the potential to yield a wealth of scientific knowledge. Meanwhile, there are significant resource challenges to be met. Launch costs remain a barrier to routine space flight; the ever-changing fiscal and political environments can wreak havoc on mission planning; and technologies are constantly improving, and systems that were state of the art when a program began can quickly become outmoded before a mission is even launched. This Conference Publication describes the workshop and featured presentations by world-class experts presenting leading-edge technologies and applications in the areas of power and propulsion; communications; automation, robotics, computing, and intelligent systems; and transformational techniques for space activities. Workshops such as this one provide an excellent medium for capturing the broadest possible array of insights and expertise, learning from researchers in universities, national laboratories, NASA field Centers, and industry to help better our future in space.

  17. MIT January Operational Internship Experience 2011

    NASA Technical Reports Server (NTRS)

    DeLatte, Danielle; Furhmann, Adam; Habib, Manal; Joujon-Roche, Cecily; Opara, Nnaemeka; Pasterski, Sabrina Gonzalez; Powell, Christina; Wimmer, Andrew

    2011-01-01

    This slide presentation reviews the 2011 January Operational Internship experience (JOIE) program which allows students to study operational aspects of spaceflight, how design affects operations and systems engineering in practice for 3 weeks. Topics include: (1) Systems Engineering (2) NASA Organization (3) Workforce Core Values (4) Human Factors (5) Safety (6) Lean Engineering (7) NASA Now (8) Press, Media, and Outreach and (9) Future of Spaceflight.

  18. Umsetzung der Unternehmensstrategie mit der Balanced Scorecard

    NASA Astrophysics Data System (ADS)

    Crespo, Isabel; Bergmann, Lars; Portmann, Stefan; Lacker, Thomas; Lacker, Michael; Fleischmann, Jürgen; Kozó, Hans

    Die Balanced Scorecard (BSC) ist ein Ansatz zum strategischen Management, der neben der Ausrichtung des Unternehmens auf finanzielle Zielwerte ebenso großes Gewicht auf so genannte weiche Faktoren legt, die den wirtschaftlichen Erfolg eines Unternehmens erst ermöglichen. Das entscheidende Merkmal der Balanced Scorecard ist dabei, dass sie ein ausgewogenes System strategischer Ziele herstellt, welches das Unternehmen hinsichtlich der vier Perspektiven Finanzen, Kunden, interne Prozesse und Mitarbeiter und Potenziale strategisch ausrichtet (Kaplan u. Norton 1997).

  19. Hydraulische Charakterisierung eines urbanen Karstgrundwasserleiters mit Pumpversuchen

    NASA Astrophysics Data System (ADS)

    Spitzberg, Stefan; Ufrecht, Wolfgang

    2014-03-01

    Quantitatively defining the characteristics of groundwater flow in karst aquifers is still a difficult challenge, which requires the application of different methods and approaches, of which hydraulic tests are just one. Computer based acquisition of field data and the development of advanced evaluation methods have led to huge improvements in hydraulic testing and interpretation. However, although the so called diagnostic plot is particularly suited to gain detailed information of involved karst subsystems, these improvements have been scarcely reflected in the analysis of pumping tests in karst aquifers up to now. Against this background a systematic analysis of pumping tests from the Upper Muschelkalk in the urban area of Stuttgart was performed considering the 1st derivative of pressure with respect to time. The insights gained demonstrate the power of the diagnostic plot especially when interpreting pumping well data from karst aquifers.

  20. Miles In Trail (MIT) Restrictions: A Perspective

    NASA Technical Reports Server (NTRS)

    Kopardekar, Parimal; Green, Steven; Roherty, Tom; Aston, John

    2003-01-01

    Miles-in-trail restrictions are issued to meet the airport and/or airspace capacity. The purpose of this paper is to review the currently practiced miles-in-trail operations for traffic flow management at a typical en route Air Traffic Control Center. The paper describes roles and considerations of both traffic management coordinators and the controllers in planning, coordination, execution, and monitoring of miles-in-trail restrictions. The paper addresses the type of decisions that traffic management coordinators must make and the different information required to plan and monitor miles-in-trail restrictions. The implications of miles-in-trail restrictions on controller workload are also addressed. Using the Cleveland center as an example, the paper also identified some challenging traffic situations that required miles-in-trail restrictions on a regular basis. The paper is expected to benefit the research and development community as it provides the current challenges in traffic flow management and strengths and weakness of miles-in-trail operations.