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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. 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

  3. 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. ...

  4. Pediatric AML: From Biology to Clinical Management

    PubMed Central

    de Rooij, Jasmijn D. E.; Zwaan, C. Michel; van den Heuvel-Eibrink, Marry

    2015-01-01

    Pediatric acute myeloid leukemia (AML) represents 15%–20% of all pediatric acute leukemias. Survival rates have increased over the past few decades to ~70%, due to improved supportive care, optimized risk stratification and intensified chemotherapy. In most children, AML presents as a de novo entity, but in a minority, it is a secondary malignancy. The diagnostic classification of pediatric AML includes a combination of morphology, cytochemistry, immunophenotyping and molecular genetics. Outcome is mainly dependent on the initial response to treatment and molecular and cytogenetic aberrations. Treatment consists of a combination of intensive anthracycline- and cytarabine-containing chemotherapy and stem cell transplantation in selected genetic high-risk cases or slow responders. In general, ~30% of all pediatric AML patients will suffer from relapse, whereas 5%–10% of the patients will die due to disease complications or the side-effects of the treatment. Targeted therapy may enhance anti-leukemic efficacy and minimize treatment-related morbidity and mortality, but requires detailed knowledge of the genetic abnormalities and aberrant pathways involved in leukemogenesis. These efforts towards future personalized therapy in a rare disease, such as pediatric AML, require intensive international collaboration in order to enhance the survival rates of pediatric AML, while aiming to reduce long-term toxicity. PMID:26237023

  5. AML1, AML2, and AML3, the human members of the runt domain gene-family: cDNA structure, expression, and chromosomal localization

    SciTech Connect

    Levanon, D.; Negreanu, V.; Bernstein, Y.

    1994-09-15

    cDNAs corresponding to three human runt domain-containing genes, AML1, AML2, and AML3, were isolated and characterized. In addition to homology in the highly conserved runt domain, extensive sequence similarities were also observed in other parts of the proteins. All three carried an identical, putative ATP binding sit -GRSGRGKS-, and their C-terminal halves were particularly rich in proline and serine residues. While AML1 cDNAs were cloned by others, AML2 represents a new member, not previously described, of the runt domain gene family, and AML3 was identified as the human homologue of mouse PEB-P2{alpha}A. The chromosomal location of AML1 to chromosome 21q22 was confirmed, while AML2 and AML3 were mapped to chromosome regions 1p36 and 6p21, respectively. Analysis of AML1 and AML2 expression in hematopoietic cell lines revealed a distinct pattern of expression. 42 refs., 6 figs., 1 tab.

  6. 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…

  7. 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 ...

  8. 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.

  9. 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

  10. 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

  11. [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

  12. IDH2 inhibition in AML: Finally progress?

    PubMed

    Stein, Eytan M

    2015-01-01

    Isocitrate dehydrogenase (IDH) catalyzes the conversion of isocitrate to alpha ketoglutarate. IDH occurs in three isoforms, IDH1, located in the cytoplasm, IDH2 located in the mitochondria, and IDH3, which functions as part of the TCA cycle. Mutations in the active site of IDH1 at position R132 and an analogous mutation in the IDH2 gene at position R172 have been discovered. Notably, many cases of acute myeloid leukemia (AML) have mutations in R172 and R140. The impact of these mutations and early results of inhibiting mutant IDH2 with the reversible inhibitor AG-221 are discussed in this review. PMID:26590767

  13. 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

  14. 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).

  15. 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.

  16. Kommunikation mit Mitarbeitern

    NASA Astrophysics Data System (ADS)

    Spychala, Anne; Fleischmann, Jürgen

    Kommunikation ist der Austausch von Nachrichten und Informationen zwischen Mitarbeitern eines Unternehmens (O'Hair et al. 1997). Dieser Austausch kann persönlich, aber z.B. auch per Telefon, E-Mail oder durch Computersysteme erfolgen. In diesem Kapitel betrachten wir die persönliche Kommunikation zwischen Vorgesetzten und Mitarbeitern. Zur persönlichen Kommunikation mit Mitarbeitern zählen sowohl formelle Gespräche mit Mitarbeitern als auch eher informelle Gespräche zwischen Tür und Angel. Die Gespräche können dabei mit einzelnen Mitarbeitern (z.B. jährliches Mitarbeitergespräch) oder mit Gruppen von Mitarbeitern (z.B. regelmäßige Projekt- oder Teambesprechungen) stattfinden.

  17. SYK Regulates mTOR Signaling in AML

    PubMed Central

    Carnevale, Julia; Ross, Linda; Puissant, Alexandre; Banerji, Versha; Stone, Richard M.; DeAngelo, Daniel J.; Ross, Kenneth N.; Stegmaier, Kimberly

    2014-01-01

    Spleen Tyrosine Kinase (SYK) was recently identified as a new target in acute myeloid leukemia (AML); however, its mechanistic role in this disease is poorly understood. Based on the known interaction between SYK and mTOR signaling in lymphoma, we hypothesized that SYK may regulate mTOR signaling in AML. Both small-molecule inhibition of SYK and SYK-directed shRNA suppressed mTOR and its downstream signaling effectors, as well as its upstream activator, AKT. Moreover, the inhibition of multiple nodes of the PI3K signaling pathway enhanced the effects of SYK suppression on AML cell viability and differentiation. Evaluation of the collateral MAPK pathway revealed a heterogeneous response to SYK inhibition in AML with down-regulation of MEK and ERK phosphorylation in some AML cell lines but a paradoxical increase in MEK/ERK phosphorylation in RAS-mutated AML. These studies reveal SYK as a regulator of mTOR and MAPK signaling in AML and demonstrate that inhibition of PI3K pathway activity enhances the effects of SYK inhibition on AML cell viability and differentiation. PMID:23535559

  18. 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…

  19. Epigenetic Therapies in MDS and AML

    PubMed Central

    Gore, Steven D.

    2013-01-01

    The use of low dose hypomethylating agents for patients with myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML) has had made a significant impact. In the past, therapies for these diseases were limited and patients who elected to receive treatment were subject to highly toxic, inpatient chemotherapeutics, which were often ineffective. In the era of hypomethy-lating agents (azacitidine and decitabine), a patient with high grade MDS or AML with multilineage dysplasia can be offered the alternative of outpatient, relatively low-toxicity therapy. Despite the fact that CR (CR) rates to such agents remain relatively low at 15–20%, a much larger percentage of patients will have clinically significant improvements in hemoglobin, platelet, and neutrophil counts while maintaining good outpatient quality of life. As our clinical experience with azanu-cleotides expands, questions regarding patient selection, optimal dosing strategy, latency to best response and optimal duration of therapy following disease progression remain, but there is no question that for some patients these agents offer, for a time, an almost miraculous clinical benefit. Ongoing clinical trials in combination and in sequence with conventional therapeutics, with other epigenetically active agents, or in conjunction with bone marrow transplantation continue to provide promise for optimization of these agents for patients with myeloid disease. Although the mechanism(s) responsible for the proven efficacy of these agents remain a matter of some controversy, activity is thought to stem from induction of DNA hypom-ethylation, direct DNA damage, or possibly even immune modulation; there is no question that they have become a permanent part of the armamentarium against myeloid neoplasms. PMID:22956506

  20. AML1 deletion in adult mice causes splenomegaly and lymphomas.

    PubMed

    Putz, G; Rosner, A; Nuesslein, I; Schmitz, N; Buchholz, F

    2006-02-01

    AML1 (RUNX1) encodes a DNA-binding subunit of the CBF transcription factor family and is required for the establishment of definitive hematopoiesis. AML1 is one of the most frequently mutated genes associated with human acute leukemia, suggesting that genetic alterations of the gene contribute to leukemogenesis. Here, we report the analysis of mice carrying conditional AML1 knockout alleles that were inactivated using the Cre/loxP system. AML1 was deleted in adult mice by inducing Cre activity to replicate AML1 deletions found in human MDS, familial platelet disorder and rare de novo human AML. At a latency of 2 months after induction, the thymus was reduced in size and frequently populated by immature double negative thymocytes, indicating defective T-lymphocyte maturation, resulting in lymphatic diseases with 50% penetrance, including atypical hyperplasia and thymic lymphoma. Metastatic lymphomas to the liver and the meninges were observed. Mice also developed splenomegaly with an expansion of the myeloid compartment. Increased Howell-Jolly body counts indicated splenic hypofunction. Thrombocytopenia occurred due to immaturity of mini-megakaryocytes in the bone marrow. Together with mild lymphocytopenia in the peripheral blood and increased fractions of immature cells in the bone marrow, AML1 deficient mice display features of a myelodysplastic syndrome, suggesting a preleukemic state.

  1. Volasertib for AML: clinical use and patient consideration.

    PubMed

    Hao, Zhonglin; Kota, Vamsi

    2015-01-01

    Acute myeloid leukemia (AML) is a disease diagnosed mostly in patients >65 years of age. Despite its heterogeneous nature, the different types of AMLs are still managed by standard induction chemotherapy for those who can tolerate it in the beginning. For the elderly and infirm patients, however, this approach leads to unacceptably high induction mortality rate. This article reviews past and current efforts searching for low-intensiveness treatments for the elderly and infirm patients who cannot tolerate the standard induction regimen. Volasertib, currently in Phase III clinical trials in combination with cytarabine, is reviewed as a promising agent for this patient population with AML, from the viewpoints of potential compliance and efficacy.

  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. AML evolution from preleukemia to leukemia and relapse.

    PubMed

    Shlush, Liran I; Mitchell, Amanda

    2015-01-01

    Dismal outcomes of acute myeloid leukemia (AML), especially in the elderly, are mainly associated with leukemia relapse and primary no response to initial therapy. This review will focus on AML relapse, and how a better understanding of the evolutionary stages that lead to relapse might help us improve disease outcome. The fact that the relapse rate for some AMLs is so high indicates that we do not truly understand the biology of relapse or possibly that we are not implementing our current understanding into, clinical practice. Therefore, this review will also aim to explore some of the current understanding of AML relapse biology in order to identify the gaps in our knowledge and translation. Accumulating evidence suggests that the root of relapse evolves even before the time of diagnosis, meaning that the complex clonal structure of AML is created before patients present to the clinic. Some of the clones that exist at diagnosis can survive chemotherapy and give rise to relapse. Accordingly, in order to better understand the mechanisms of relapse, we must consider both early and late steps in AML evolution.

  5. 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

  6. Securinine, a Myeloid Differentiation Agent with Therapeutic Potential for AML

    PubMed Central

    Gupta, Kalpana; Chakrabarti, Amitabha; Rana, Sonia; Ramdeo, Ritu; Roth, Bryan L.; Agarwal, Munna L.; Tse, William; Agarwal, Mukesh K.; Wald, David N.

    2011-01-01

    As the defining feature of Acute Myeloid Leukemia (AML) is a maturation arrest, a highly desirable therapeutic strategy is to induce leukemic cell maturation. This therapeutic strategy has the potential of avoiding the significant side effects that occur with the traditional AML therapeutics. We identified a natural compound securinine, as a leukemia differentiation-inducing agent. Securinine is a plant-derived alkaloid that has previously been used clinically as a therapeutic for primarily neurological related diseases. Securinine induces monocytic differentiation of a wide range of myeloid leukemia cell lines as well as primary leukemic patient samples. Securinine's clinical potential for AML can be seen from its ability to induce significant growth arrest in cell lines and patient samples as well as its activity in significantly impairing the growth of AML tumors in nude mice. In addition, securinine can synergize with currently employed agents such as ATRA and decitabine to induce differentiation. This study has revealed securinine induces differentiation through the activation of DNA damage signaling. Securinine is a promising new monocytic differentiation inducing agent for AML that has seen previous clinical use for non-related disorders. PMID:21731671

  7. 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

  8. Clinical implications of novel mutations in epigenetic modifiers in AML.

    PubMed

    Abdel-Wahab, Omar; Patel, Jay; Levine, Ross L

    2011-12-01

    The studies highlighted in this article suggest that mutations in TET2 mutations may impart adverse outcome in patients with CN-AML, whereas mutations in DNMT3a may have adverse implications in a broader set of patients with AML. The data with IDH enzyme mutations are less clear, in that individual IDH1 and IDH2 mutations may have different clinical effects and the data so far have not suggested a uniform effect on outcome. Despite the exciting data indicating that mutational testing for these alterations may be clinically useful, several challenges to understanding their clinical relevance remain. First, patients may simultaneously have mutations in multiple genes described in this article (FLT3, NPM1, CEBPa, DNMT3a, IDH1/2, or TET2), and in additional genes not mentioned earlier (Ras,47 PTEN,48 PHF6,49 ASXL1,15 and RUNX145). Furthermore, comprehensive sequencing studies of well-annotated, homogeneously treated patient cohorts are needed to understand the clinical implications of integrated mutational profiling in AML. An additional challenge to using mutational analysis for TET2 and DNMT3a in clinical use is identifying a means for rapid molecular testing of these mutations. This challenge may be met by the use of non–polymerase chain reaction–based methods of target enrichment, such as hybrid capture, followed by next-generation sequencing technologies. Moreover, clinical studies evaluating the biochemical consequences of mutations in some of these genes (eg, production of 2-HG in bodily fluids from patients with IDH-mutant AML or increased hydroxymethylcytosine levels in pretreatment blast DNA in patients with TET2/IDH mutant AML) may also prove to be useful in identifying biomarkers. Alternatively, protein-based technologies such as immunohistochemistry or mass spectrometry may be used in the clinical setting to detect the mutant proteins or loss of expression of specific proteins in patients with mutations. An additional area of importance highlighted by

  9. Ten uncommon and unusual variants of renal angiomyolipoma (AML): radiologic-pathologic correlation.

    PubMed

    Schieda, N; Kielar, A Z; Al Dandan, O; McInnes, M D F; Flood, T A

    2015-02-01

    Classic (triphasic) renal angiomyolipoma (AML) is currently classified as a neoplasm of perivascular epithelioid cells. For diagnosis of AML, the use of thin-section non-contrast enhanced CT (NECT) improves diagnostic accuracy; however, identifying gross fat within a very small AML is challenging and often better performed with chemical-shift MRI. Although the presence of gross intra-tumoural fat is essentially diagnostic of AML; co-existing intra-tumoural fat and calcification may represent renal cell carcinoma (RCC). Differentiating AML from retroperitoneal sarcoma can be difficult when AML is large; the feeding vessel and claw signs are suggestive imaging findings. AML can haemorrhage, with intra-tumoural aneurysm size >5 mm a more specific predictor of future haemorrhage than tumor size >4 cm. Diagnosis of AML in the setting of acute haemorrhage is complex; comparison studies or follow-up imaging may be required. Not all AML contain gross fat and imaging features of AML without visible fat overlap with RCC; however, homogeneity, hyperdensity at NECT, low T2-weighted signal intensity and, microscopic fat are suggestive features. Patients with tuberous sclerosis often demonstrate a combination of classic and minimal fat AML, but are also at a slightly increased risk for RCC and should be imaged cautiously. Several rare pathological variants of AML exist including AML with epithelial cysts and epithelioid AML, which have distinct imaging characteristics. Classic AML, although benign, can be locally invasive and the rare epithelioid AML can be frankly malignant. The purpose of this review is to highlight the imaging manifestations of 10 uncommon and unusual variants of AML using pathological correlation.

  10. 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.

  11. 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.

  12. [Research progress of epigenetic drug decitabine in AML].

    PubMed

    Zhang, Rui; Li, Hui-Min

    2014-10-01

    Epigenetics is a gene regulation mechanism that can be reversible and heritable, but do not involve the DNA sequence changes. DNA methylation is one of the most important epigenetic modifications, which is closely correlate with tumorigenesis. Decitabine is a methylation inhibitor, which has different action mechanism and targeting characteristics from the traditional chemotherapy, representing a new therapeutic strategy. This review mainly focuses on the anti-leukemia mechanism of decitabine and its clinical efficacy for AML.

  13. 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.

  14. MIT's interferometer CST testbed

    NASA Astrophysics Data System (ADS)

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

    1990-12-01

    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.

  15. Transcriptome Profiling of Pediatric Core Binding Factor AML.

    PubMed

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

    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 = 1.5 x 10(-51) and p = 1.8 x 10(-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

  16. 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.

  17. Integrative genetic analysis of mouse and human AML identifies cooperating disease alleles

    PubMed Central

    Hatlen, Megan A.; Arora, Kanika; Vacic, Vladimir; Grabowska, Ewa A.; Liao, Willey; Riley-Gillis, Bridget; Oschwald, Dayna M.; Wang, Lan; Joergens, Jacob E.; Shih, Alan H.; Rapaport, Franck; Gu, Shengqing; Voza, Francesca; Asai, Takashi; Neel, Benjamin G.; Kharas, Michael G.; Gonen, Mithat

    2016-01-01

    t(8;21) is one of the most frequent chromosomal abnormalities observed in acute myeloid leukemia (AML). However, expression of AML1-ETO is not sufficient to induce transformation in vivo. Consistent with this observation, patients with this translocation harbor additional genetic abnormalities, suggesting a requirement for cooperating mutations. To better define the genetic landscape in AML and distinguish driver from passenger mutations, we compared the mutational profiles of AML1-ETO–driven mouse models of leukemia with the mutational profiles of human AML patients. We identified TET2 and PTPN11 mutations in both mouse and human AML and then demonstrated the ability of Tet2 loss and PTPN11 D61Y to initiate leukemogenesis in concert with expression of AML1-ETO in vivo. This integrative genetic profiling approach allowed us to accurately predict cooperating events in t(8;21)+ AML in a robust and unbiased manner, while also revealing functional convergence in mouse and human AML. PMID:26666262

  18. Transcription of the AML1/ETO chimera is guided by the P2 promoter of the AML1 gene in the Kasumi-1 cell line.

    PubMed

    Markova, Elena N; Kantidze, Omar L; Razin, Sergey V

    2012-12-01

    Chromosomal translocation t (8;21)(q22;22) is one of the most frequent cytogenetic abnormalities found in acute myeloid leukaemia (AML). It generates the AML1/ETO fusion gene, which itself supports human haematopoietic stem cell self-renewal. However, the mechanism guiding transcription of this chimeric gene remains unclear. In our work, we attempted to shed light on this essential issue. We investigated the promoter from which transcription of the AML1/ETO gene is initiated and defined the three-dimensional structure of the whole rearranged locus.

  19. 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.

  20. Isoform-Specific Potentiation of Stem and Progenitor Cell Engraftment by AML1/RUNX1

    PubMed Central

    Tsuzuki, Shinobu; Hong, Dengli; Gupta, Rajeev; Matsuo, Keitaro; Seto, Masao; Enver, Tariq

    2007-01-01

    Background AML1/RUNX1 is the most frequently mutated gene in leukaemia and is central to the normal biology of hematopoietic stem and progenitor cells. However, the role of different AML1 isoforms within these primitive compartments is unclear. Here we investigate whether altering relative expression of AML1 isoforms impacts the balance between cell self-renewal and differentiation in vitro and in vivo. Methods and Findings The human AML1a isoform encodes a truncated molecule with DNA-binding but no transactivation capacity. We used a retrovirus-based approach to transduce AML1a into primitive haematopoietic cells isolated from the mouse. We observed that enforced AML1a expression increased the competitive engraftment potential of murine long-term reconstituting stem cells with the proportion of AML1a-expressing cells increasing over time in both primary and secondary recipients. Furthermore, AML1a expression dramatically increased primitive and committed progenitor activity in engrafted animals as assessed by long-term culture, cobblestone formation, and colony assays. In contrast, expression of the full-length isoform AML1b abrogated engraftment potential. In vitro, AML1b promoted differentiation while AML1a promoted proliferation of progenitors capable of short-term lymphomyeloid engraftment. Consistent with these findings, the relative abundance of AML1a was highest in the primitive stem/progenitor compartment of human cord blood, and forced expression of AML1a in these cells enhanced maintenance of primitive potential both in vitro and in vivo. Conclusions These data demonstrate that the “a” isoform of AML1 has the capacity to potentiate stem and progenitor cell engraftment, both of which are required for successful clinical transplantation. This activity is consistent with its expression pattern in both normal and leukaemic cells. Manipulating the balance of AML1 isoform expression may offer novel therapeutic strategies, exploitable in the contexts of

  1. 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

  2. An LSC epigenetic signature is largely mutation independent and implicates the HOXA cluster in AML pathogenesis

    PubMed Central

    Jung, Namyoung; Dai, Bo; Gentles, Andrew J.; Majeti, Ravindra; Feinberg, Andrew P.

    2015-01-01

    Acute myeloid leukaemia (AML) is characterized by subpopulations of leukaemia stem cells (LSCs) that are defined by their ability to engraft in immunodeficient mice. Here we show an LSC DNA methylation signature, derived from xenografts and integration with gene expression that is comprised of 71 genes and identifies a key role for the HOXA cluster. Most of the genes are epigenetically regulated independently of underlying mutations, although several are downstream targets of epigenetic modifier genes mutated in AML. The LSC epigenetic signature is associated with poor prognosis independent of known risk factors such as age and cytogenetics. Analysis of early haematopoietic progenitors from normal individuals reveals two distinct clusters of AML LSC resembling either lymphoid-primed multipotent progenitors or granulocyte/macrophage progenitors. These results provide evidence for DNA methylation variation between AML LSCs and their blast progeny, and identify epigenetically distinct subgroups of AML likely reflecting the cell of origin. PMID:26444494

  3. Tumor suppressor DYRK1A effects on proliferation and chemoresistance of AML cells by downregulating c-Myc.

    PubMed

    Liu, Qiang; Liu, Na; Zang, Shaolei; Liu, Heng; Wang, Pin; Ji, Chunyan; Sun, Xiulian

    2014-01-01

    Acute myeloid leukemia (AML), caused by abnormal proliferation and accumulation of hematopoietic progenitor cells, is one of the most common malignancies in adults. We reported here DYRK1A expression level was reduced in the bone marrow of adult AML patients, comparing to normal controls. Overexpression of DYRK1A inhibited the proliferation of AML cell lines by increasing the proportion of cells undergoing G0/G1 phase. We reasoned that the proliferative inhibition was due to downregulation of c-Myc by DYRK1A, through mediating its degradation. Moreover, overexpression of c-Myc markedly reversed AML cell growth inhibition induced by DYRK1A. DYRK1A also had significantly lower expression in relapsed/refractory AML patients, comparing to newly-diagnosed AML patients, which indicated the role of DYRK1A in chemoresistance of AML. Our study provided functional evidences for DYRK1A as a potential tumor suppressor in AML. PMID:24901999

  4. Should minimal residual disease guide therapy in AML?

    PubMed

    Paietta, Elisabeth

    2015-01-01

    The prognostic power of minimal residual disease after therapy for acute leukemias is not in question. It is only logical that the finding of leukemic blast cells after therapy predicts for impending relapse or at least the need for additional treatment. Which level of what is called minimal residual disease (MRD) is clinically relevant, however, depends on the efficacy of the initial treatment as well as the treatment strategies available to target MRD. There are a multitude of additional factors that can alter the clinical significance of MRD, including the genotype of the patient's leukemic cells. The fact that methodologies of MRD detection are not standardized and thresholds for defining MRD positivity vary depending upon MRD detection method and the operator's skills or convictions only add to the complexity of MRD interpretation. While enormous efforts are devoted to enhancing the sensitivity of MRD detection, eg, by next-generation sequencing, improvements of methods for detecting MRD per se will not automatically lead to a more reliable estimation of total tumor burden. Most importantly, even the best assay will yield accurate MRD results only if the tissue source for MRD determination is of good quality. Another aspect of potentially crucial importance is the heterogenous distribution of leukemic cells throughout the skeleton after treatment, recently demonstrated for acute myeloid leukemia (AML) by bone marrow imaging. Once technical difficulties of MRD measurement are resolved and better MRD-targeting drugs are developed, we still need to learn about alternate proposed mechanisms to explain MRD-independent prognostication, well described in acute lymphoid leukemia, before MRD can be included routinely in the guidance of therapy in AML.

  5. Cell line OCI/AML3 bears exon-12 NPM gene mutation-A and cytoplasmic expression of nucleophosmin.

    PubMed

    Quentmeier, H; Martelli, M P; Dirks, W G; Bolli, N; Liso, A; Macleod, R A F; Nicoletti, I; Mannucci, R; Pucciarini, A; Bigerna, B; Martelli, M F; Mecucci, C; Drexler, H G; Falini, B

    2005-10-01

    We recently identified a new acute myeloid leukemia (AML) subtype characterized by mutations at exon-12 of the nucleophosmin (NPM) gene and aberrant cytoplasmic expression of NPM protein (NPMc+). NPMc+ AML accounts for about 35% of adult AML and it is associated with normal karyotype, wide morphological spectrum, CD34-negativity, high frequency of FLT3-ITD mutations and good response to induction therapy. In an attempt to identify a human cell line to serve as a model for the in vitro study of NPMc+ AML, we screened 79 myeloid cell lines for mutations at exon-12 of NPM. One of these cell lines, OCI/AML3, showed a TCTG duplication at exon-12 of NPM. This mutation corresponds to the type A, the NPM mutation most frequently observed in primary NPMc+ AML. OCI/AML3 cells also displayed typical phenotypic features of NPMc+ AML, that is, expression of macrophage markers and lack of CD34, and the immunocytochemical hallmark of this leukemia subtype, that is, the aberrant cytoplasmic expression of NPM. The OCI/AML3 cell line easily engrafts in NOD/SCID mice and maintains in the animals the typical features of NPMc+ AML, such as the NPM cytoplasmic expression. For all these reasons, the OCI/AML3 cell line represents a remarkable tool for biomolecular studies of NPMc+ AML.

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

    PubMed

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

    2016-04-04

    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.

  7. 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

  8. 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 ...

  9. A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis

    PubMed Central

    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.

    2013-01-01

    Transcription factors are frequently altered in leukaemia through chromosomal translocation, mutation or aberrant expression1. AML1-ETO, a fusion protein generated by the t(8;21) translocation in acute myeloid leukaemia (AML), is a transcription factor implicated in both gene repression and activation2. AML1-ETO oligomerization, mediated by the NHR2 domain, is critical for leukaemogenesis3–6, making it important to identify coregulatory factors that “read” the NHR2 oligomerization and contribute to leukaemogenesis4. We now show that, in leukaemic cells, AML1-ETO resides in and functions through a stable protein 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, colocalize 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 a potential therapeutic target in t(8;21)+ AML. PMID:23812588

  10. Notch pathway activation targets AML-initiating cell homeostasis and differentiation

    PubMed Central

    Ntziachristos, Panagiotis; Ndiaye-Lobry, Delphine; Oh, Philmo; Cimmino, Luisa; Zhu, Nan; Araldi, Elisa; Hu, Wenhuo; Freund, Jacquelyn; Abdel-Wahab, Omar; Ibrahim, Sherif; Skokos, Dimitris; Armstrong, Scott A.; Levine, Ross L.; Park, Christopher Y.

    2013-01-01

    Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. Here we report a novel tumor suppressor role for Notch signaling in acute myeloid leukemia (AML) and demonstrate that Notch pathway activation could represent a therapeutic strategy in this disease. We show that Notch signaling is silenced in human AML samples, as well as in AML-initiating cells in an animal model of the disease. In vivo activation of Notch signaling using genetic Notch gain of function models or in vitro using synthetic Notch ligand induces rapid cell cycle arrest, differentiation, and apoptosis of AML-initiating cells. Moreover, we demonstrate that Notch inactivation cooperates in vivo with loss of the myeloid tumor suppressor Tet2 to induce AML-like disease. These data demonstrate a novel tumor suppressor role for Notch signaling in AML and elucidate the potential therapeutic use of Notch receptor agonists in the treatment of this devastating leukemia. PMID:23359070

  11. Aberrant DNA methylation is a dominant mechanism in MDS progression to AML

    PubMed Central

    Jiang, Ying; Dunbar, Andrew; Gondek, Lukasz P.; Mohan, Sanjay; Rataul, Manjot; O'Keefe, Christine; Sekeres, Mikkael

    2009-01-01

    Myelodysplastic syndromes (MDSs) are clonal hematologic disorders that frequently represent an intermediate disease stage before progression to acute myeloid leukemia (AML). As such, study of MDS/AML can provide insight into the mechanisms of neoplastic evolution. In 184 patients with MDS and AML, DNA methylation microarray and high-density single nucleotide polymorphism array (SNP-A) karyotyping were used to assess the relative contributions of aberrant DNA methylation and chromosomal deletions to tumor-suppressor gene (TSG) silencing during disease progression. Aberrant methylation was seen in every sample, on average affecting 91 of 1505 CpG loci in early MDS and 179 of 1505 loci after blast transformation (refractory anemia with excess blasts [RAEB]/AML). In contrast, chromosome aberrations were seen in 79% of early MDS samples and 90% of RAEB/AML samples, and were not as widely distributed over the genome. Analysis of the most frequently aberrantly methylated genes identified FZD9 as a candidate TSG on chromosome 7. In patients with chromosome deletion at the FZD9 locus, aberrant methylation of the remaining allele was associated with the poorest clinical outcome. These results indicate that aberrant methylation can cooperate with chromosome deletions to silence TSG. However, the ubiquity, extent, and correlation with disease progression suggest that aberrant DNA methylation is the dominant mechanism for TSG silencing and clonal variation in MDS evolution to AML. PMID:18832655

  12. Minimally differentiated acute myelogenous leukemia (AML-M0) granulocytic sarcoma presenting in the oral cavity.

    PubMed

    Amin, Kay S; Ehsan, Aamir; McGuff, H Stan; Albright, Steven C

    2002-07-01

    Acute myelogenous leukemia with minimal differentiation (AML-M0) is a rare subtype of acute leukemia in which blasts fail to show morphologic differentiation and conventional cytochemical stains and myeloid markers are negative. Acute myelogenous leukemia (AML) presents primarily with peripheral blood and/or bone marrow involvement. Presentation in extramedullary sites, including the head and neck region, is not uncommon. Acute myelomonocytic leukemia (AML-M4) and acute monocytic leukemia (AML-M5) have had the highest incidence of associated oral infiltrates. We report a case of a 58-year-old gentleman, with no prior history of acute leukemia, presenting with a solitary palatal swelling. Initial morphologic examination favored high-grade non-Hodgkin's lymphoma (NHL). Conventional cytochemical and immunohistochemical stains were negative for lymphoid and myeloid markers. Subsequent immunophenotyping via flow cytometry performed on peripheral blood and bone marrow aspirate demonstrated myeloid lineage without lymphoid differentiation, confirming the diagnosis of AML-M0.To our knowledge, this subtype of AML-M0 has not been previously reported involving the oral cavity. With absence of morphologic differentiation, and negative findings on conventional cytochemical and immunohistochemical stains, this subtype of leukemia may be misdiagnosed as non-Hodgkin's lymphoma (NHL). Flow cytometry is useful in detecting the myeloid lineage of this leukemia. PMID:12110349

  13. Chaperonin TRiC/CCT Modulates the Folding and Activity of Leukemogenic Fusion Oncoprotein AML1-ETO.

    PubMed

    Roh, Soung-Hun; Kasembeli, Moses; Galaz-Montoya, Jesús G; Trnka, Mike; Lau, Wilson Chun-Yu; Burlingame, Alma; Chiu, Wah; Tweardy, David J

    2016-02-26

    AML1-ETO is the most common fusion oncoprotein causing acute myeloid leukemia (AML), a disease with a 5-year survival rate of only 24%. AML1-ETO functions as a rogue transcription factor, altering the expression of genes critical for myeloid cell development and differentiation. Currently, there are no specific therapies for AML1-ETO-positive AML. While known for decades to be the translational product of a chimeric gene created by the stable chromosome translocation t(8;21)(q22;q22), it is not known how AML1-ETO achieves its native and functional conformation or whether this process can be targeted for therapeutic benefit. Here, we show that the biosynthesis and folding of the AML1-ETO protein is facilitated by interaction with the essential eukaryotic chaperonin TRiC (or CCT). We demonstrate that a folding intermediate of AML1-ETO binds to TRiC directly, mainly through its β-strand rich, DNA-binding domain (AML-(1-175)), with the assistance of HSP70. Our results suggest that TRiC contributes to AML1-ETO proteostasis through specific interactions between the oncoprotein's DNA-binding domain, which may be targeted for therapeutic benefit.

  14. Isolated trisomy 13 defines a homogeneous AML subgroup with high frequency of mutations in spliceosome genes and poor prognosis.

    PubMed

    Herold, Tobias; Metzeler, Klaus H; Vosberg, Sebastian; Hartmann, Luise; Röllig, Christoph; Stölzel, Friedrich; Schneider, Stephanie; Hubmann, Max; Zellmeier, Evelyn; Ksienzyk, Bianka; Jurinovic, Vindi; Pasalic, Zlatana; Kakadia, Purvi M; Dufour, Annika; Graf, Alexander; Krebs, Stefan; Blum, Helmut; Sauerland, Maria Cristina; Büchner, Thomas; Berdel, Wolfgang E; Woermann, Bernhard J; Bornhäuser, Martin; Ehninger, Gerhard; Mansmann, Ulrich; Hiddemann, Wolfgang; Bohlander, Stefan K; Spiekermann, Karsten; Greif, Philipp A

    2014-08-21

    In acute myeloid leukemia (AML), isolated trisomy 13 (AML+13) is a rare chromosomal abnormality whose prognostic relevance is poorly characterized. We analyzed the clinical course of 34 AML+13 patients enrolled in the German AMLCG-1999 and SAL trials and performed exome sequencing, targeted candidate gene sequencing and gene expression profiling. Relapse-free (RFS) and overall survival (OS) of AML+13 patients were inferior compared to other ELN Intermediate-II patients (n=855) (median RFS, 7.8 vs 14.1 months, P = .006; median OS 9.3 vs. 14.8 months, P = .004). Besides the known high frequency of RUNX1 mutations (75%), we identified mutations in spliceosome components in 88%, including SRSF2 codon 95 mutations in 81%. Recurring mutations were detected in ASXL1 (44%) and BCOR (25%). Two patients carried mutations in CEBPZ, suggesting that CEBPZ is a novel recurrently mutated gene in AML. Gene expression analysis revealed a homogeneous expression profile including upregulation of FOXO1 and FLT3 and downregulation of SPRY2. This is the most comprehensive clinical and biological characterization of AML+13 to date, and reveals a striking clustering of lesions in a few genes, defining AML+13 as a genetically homogeneous subgroup with alterations in a few critical cellular pathways. Clinicaltrials.gov identifiers: AMLCG-1999: NCT00266136; AML96: NCT00180115; AML2003: NCT00180102; and AML60+: NCT00893373. PMID:24923295

  15. 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.

  16. Outcome of children with acute myeloid leukaemia (AML) experiencing primary induction failure in the AIEOP AML 2002/01 clinical trial.

    PubMed

    Quarello, Paola; Fagioli, Franca; Basso, Giuseppe; Putti, Maria C; Berger, Massimo; Luciani, Matteo; Rizzari, Carmelo; Menna, Giuseppe; Masetti, Riccardo; Locatelli, Franco

    2015-11-01

    Paediatric patients with acute myeloid leukaemia (AML) who fail induction due to primary resistance to chemotherapy account for a significant proportion of cases and have a particularly dismal prognosis. We report the clinical and biological data, and final outcome of 48 paediatric patients with primary-resistant AML enrolled in the Associazione Italiana di Ematologia e Oncologia Pediatrica AML 2002/01 clinical trial. These patients had a significantly higher white blood cell count at diagnosis compared to other AML patients. Cytogenetic and molecular features did not differ between patients with primary induction failure and patients allocated to the high-risk group. For the whole patient population, the probability of overall survival, event-free survival (EFS) and disease-free survival (DFS) was 21·8% ± 6·2, 20·4% ± 5·9, and 49·5% ± 11·3, respectively. Twenty-eight (58%) patients received haematopoietic stem cell transplantation (HSCT); 3 were autologous and 25 were allogeneic. Patients who underwent HSCT had improved EFS (31·2% vs. 5%, P < 0·0001). Only one of the 20 patients who did not receive HSCT is alive and disease free. The 19 patients in complete remission at time of HSCT showed significantly better DFS than the 9 with active disease (46% vs. 0%, P = 0·02). This study represents one of the largest series with long-term follow up of paediatric AML patients with primary refractory disease. Children who underwent transplantation had an encouraging long-term outcome. Disease recurrence remains the major cause of treatment failure; a better understanding of the disease biology is desirable to develop more effective treatment strategies.

  17. 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.

  18. 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

  19. Reactivating the ARF-p53 axis in AML cells by targeting ULF

    PubMed Central

    Chen, Delin; Yoon, Jong-Bok

    2010-01-01

    The tumor suppressor ARF plays an essential role in the cellular response to oncogenic stress mainly through activation of p53. Nucleophosmin (NPM), a multifunctional protein, forms a stable protein complex with ARF in the nucleolus and protects ARF from the proteasome-mediated degradation. Notably, NPM is mutated in about one third of acute myeloid leukaemia (AML) patients and these mutations lead to aberrant cytoplasmic dislocation of nucleophosmin (NPM-c). Cytoplasmic NPM mutants lose their abilities to retain ARF in the nucleolus and fail to stabilize ARF. Thus, activation of the ARF-p53 axis is significantly compromised in these AML cells. We have recently identified the ubiquitin ligase of ARF (ULF) as a key factor that controls ARF turnover in human cells. Here, we found that the steady levels of both ARF and p53 are very low in human acute myeloid leukaemia OCI-AML3 cells expressing cytoplamsic dislocated nucleophosmin (NPM-c). As expected, ARF is very unstable and rapidly degraded by proteasome. Nevertheless, ULF knockdown stabilizes ARF and reactivates p53 responses in these AML cells. These results further demonstrate that ULF is a bona fide E3 ligase for ARF and also suggest that ULF is an important target for activating the ARF-p53 axis in human AML cells. PMID:20699639

  20. Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study.

    PubMed

    Boehrer, Simone; Adès, Lionel; Braun, Thorsten; Galluzzi, Lorenzo; Grosjean, Jennifer; Fabre, Claire; Le Roux, Génèviève; Gardin, Claude; Martin, Antoine; de Botton, Stéphane; Fenaux, Pierre; Kroemer, Guido

    2008-02-15

    Erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR), induces differentiation, cell-cycle arrest, and apoptosis of EGFR-negative myeloblasts of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), as well as in EGFR-negative cell lines representing these diseases (P39, KG-1, and HL 60). This off-target effect can be explained by inhibitory effects on JAK2. Apoptosis induction coupled to mitochondrial membrane permeabilization occurred independently from phenotypic differentiation. In apoptosis-sensitive AML cells, erlotinib caused a rapid (within less than 1 hour) nucleocytoplasmic translocation of nucleophosmin-1 (NPM-1) and p14(ARF). Apoptosis-insensitive myeloblasts failed to manifest this translocation yet became sensitive to apoptosis induction by erlotinib when NPM-1 was depleted by RNA interference. Moreover, erlotinib reduced the growth of xenografted human AML cells in vivo. Erlotinib also killed CD34(+) bone marrow blasts from MDS and AML patients while sparing normal CD34(+) progenitors. This ex vivo therapeutic effect was once more associated with the nucleocytoplasmic translocation of NPM-1 and p14(ARF). One patient afflicted with both MDS and non-small cell lung cancer manifested hematologic improvement in response to erlotinib. In summary, we here provide novel evidence in vitro, ex vivo, and in vivo for the potential therapeutic efficacy of erlotinib in the treatment of high-risk MDS and AML.

  1. 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

  2. Survival benefits with transplantation in secondary AML evolving from myelodysplastic syndrome with hypomethylating treatment failure.

    PubMed

    Shin, S-H; Yahng, S-A; Yoon, J-H; Lee, S-E; Cho, B-S; Eom, K-S; Lee, S; Min, C-K; Kim, H-J; Cho, S-G; Kim, D-W; Lee, J-W; Min, W-S; Park, C-W; Kim, Y-J

    2013-05-01

    The prognosis for patients with myelodysplastic syndrome with hypomethylating treatment failure (MDS-HTF) has been known to be poor. However, the clinical outcomes and optimal treatment options for secondary AML evolving from MDS-HTF (sAML/MDS-HTF) are not well known. This retrospective analysis was conducted to evaluate the clinical outcomes and influences of treatment options on survival in 46 consecutive patients with sAML/MDS-HTF. The median OS rates were 1.4 months in the best supportive care group (n=15) and 9.4 months in the active treatment group (n=31). One-year OS rates were 13.3% and 36.8%, respectively (P=0.001). Active treatment (P<0.001), lower BM blast (<33%) at sAML (P=0.007), non-poor NCCN (National Cancer Comprehensive Network) cytogenetics (P=0.001) and good performance status (ECOG (Eastern Cooperative Oncology Group) 1) (P=0.024) were significant predictors affecting favorable OS in a multivariate analysis. Of the active treatment options, allo-SCT with prior chemotherapy (CTx) showed better OS compared with CTx only or SCT without CTx (P=0.019). Our analyses suggest that active treatment, particularly SCT following CTx, should be considered in patients with sAML/MDS-HTF if the patient is medically fit.

  3. Evaluation of IDH1G105 polymorphism as prognostic marker in intermediate-risk AML.

    PubMed

    Fasan, Annette; Haferlach, Claudia; Eder, Christiane; Alpermann, Tamara; Quante, Anne; Peters, Annette; Kern, Wolfgang; Haferlach, Torsten; Schnittger, Susanne

    2015-12-01

    Germline polymorphisms in genes mutated in acute myeloid leukemia (AML) may have prognostic impact. Therefore, the relevance of the polymorphism IDH1G105 (IDH1105(GGT) minor allele) was evaluated in the context of concomitant molecular mutations in a cohort of 507 AML cases with intermediate-risk cytogenetics. In addition, a cohort of 475 healthy controls was analyzed for this polymorphism. IDH1105(GGT) minor allele was found in 10 % of AML patients and 9 % of healthy controls. While no differences were seen with regard to cytomorphology or cytogenetics, immunophenotyping revealed significantly reduced expression of the progenitor marker CD34 in AML cases harboring IDH1105(GGT) minor allele. Cases with IDH1105(GGT) minor allele as compared to those with the IDH1105(GGC) major allele had significantly longer event-free survival (EFS) (median 16 vs 11 months, p = 0.013) which was most pronounced in the age group >60 years (median 14 vs 9 months, p = 0.007) and in the NPM1 mutated/FLT3-ITD/FLT3wt ratio <0.5 group (median 61 vs 13 months, p = 0.012). However, this association is not independent of other prognostic parameters, and we conclude that IDH1105(GGT) minor allele has to be considered in the context of the genetic background of the individual AML analyzed. PMID:26351014

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. Impaired NK cells and increased T regulatory cell numbers during cytotoxic maintenance therapy in AML.

    PubMed

    Lichtenegger, Felix S; Lorenz, Robin; Gellhaus, Katharina; Hiddemann, Wolfgang; Beck, Barbara; Subklewe, Marion

    2014-08-01

    Cyclic cytotoxic maintenance therapy can be applied to patients with AML in post-remission. We studied the immune status of AML patients in complete remission and the effect of maintenance therapy on different immune cell populations. Patients in complete remission had reduced NK, TH and Treg counts and a reduced NK activation capacity. In the course of cytotoxic maintenance therapy, NK counts further declined, while TH and Treg cells increased, with lower proliferative potential of TH cells. We conclude that immunotherapeutic approaches in post-remission have to consider reduced NK cell function and further impairment of cellular immune responses during cytotoxic therapy.

  10. 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.

  11. ELMO1 Is Upregulated in AML CD34+ Stem/Progenitor Cells, Mediates Chemotaxis and Predicts Poor Prognosis in Normal Karyotype AML

    PubMed Central

    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

  12. NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

    PubMed Central

    Bar-Natan, Michal; Haibe-Kains, Benjamin; Pilarski, Patrick M.; Bach, Christian; Pevzner, Samuel; Calimeri, Teresa; Avet-Loiseau, Herve; Lode, Laurence; Verselis, Sigitas; Fox, Edward A.; Galinsky, Ilene; Mathews, Steven; Dagogo-Jack, Ibiayi; Wadleigh, Martha; Steensma, David P.; Motyckova, Gabriela; Deangelo, Daniel J.; Quackenbush, John; Tenen, Daniel G.; Stone, Richard M.; Griffin, James D.

    2014-01-01

    Our previous studies revealed an increase in alternative splicing of multiple RNAs in cells from patients with acute myeloid leukemia (AML) compared with CD34+ bone marrow cells from normal donors. Aberrantly spliced genes included a number of oncogenes, tumor suppressor genes, and genes involved in regulation of apoptosis, cell cycle, and cell differentiation. Among the most commonly mis-spliced genes (>70% of AML patients) were 2, NOTCH2 and FLT3, that encode myeloid cell surface proteins. The splice variants of NOTCH2 and FLT3 resulted from complete or partial exon skipping and utilization of cryptic splice sites. Longitudinal analyses suggested that NOTCH2 and FLT3 aberrant splicing correlated with disease status. Correlation analyses between splice variants of these genes and clinical features of patients showed an association between NOTCH2-Va splice variant and overall survival of patients. Our results suggest that NOTCH2 and FLT3 mis-splicing is a common characteristic of AML and has the potential to generate transcripts encoding proteins with altered function. Thus, splice variants of these genes might provide disease markers and targets for novel therapeutics. PMID:24574459

  13. Quantification of TEL-AML1 transcript for minimal residual disease assessment in childhood acute lymphoblastic leukaemia.

    PubMed

    Drunat, S; Olivi, M; Brunie, G; Grandchamp, B; Vilmer, E; Bièche, I; Cavé, H

    2001-08-01

    Strategies currently used for residual disease detection in acute lymphoblastic leukaemia (ALL) rely on polymerase chain reaction (PCR) detection of immunoglobulin and T-cell receptor rearrangements. The TEL-AML1 fusion transcript, which is associated with t(12;21) (p13;q22), is found in 25% of childhood B-cell precursor ALL, and represents an interesting alternative target. We compared two methods for quantitating TEL-AML1 fusion transcripts: competitive PCR and real-time PCR. These techniques showed similar sensitivity (5 x 10(-5)) and reproducibility. Giving highly correlated results, both techniques can be conveniently used for TEL-AML1 transcript quantification. The constancy of TEL-AML1 expression was evaluated by measuring TEL-AML1 transcripts at different steps of the cell cycle, and in 21 cases of ALL at diagnosis. No major variation in TEL-AML1 expression was observed during the cell cycle or in 20/21 of the ALL patients. Residual disease was then determined after completion of induction therapy in 20 patients with a TEL-AML1-positive ALL. Seven patients out of 20 (35%) were still positive, including two patients with high level of residual blasts (close to or beyond 10(-2)). When comparison was possible, results obtained using TEL-AML1 quantification were in accordance with those obtained using T-cell receptor rearrangements analysis.

  14. 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

  15. 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

  16. Identification of ins(8;21) with AML1/ETO fusion in acute myelogenous leukemia M2 by molecular cytogenetics.

    PubMed

    Urioste, M; Martínez-Ramírez, A; Cigudosa, J C; Mateo, M S; Martínez, P; Contra, T; Benítez, J

    2002-02-01

    A high percentage of cases of acute myelogenous leukemia (AML) of the M2 subtype show a rearrangement between the AML1 and ETO genes. The detection of the AML1/ETO fusion has clinical relevance because patients with this subtype have a good prognosis. We present the results of conventional and molecular cytogenetic studies in a patient with acute myelogenous leukemia French-American-British M2 classification, who had a complex karyotype involving chromosomes 8 and 21. Dual-color fluorescence in situ hybridization (FISH) using the AML1/ETO probe demonstrated a recombination of both genes on an add(8) chromosome. The use of other FISH probes (CEP8, c-myc and TEL21) and spectral karyotyping indicated that AML1/ETO fusion occurred as a consequence of a previously undescribed ins(8;21)(q22;q22.1q22.3).

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

    PubMed Central

    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

    2016-01-01

    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

  18. 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

  19. 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

  20. 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

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

    PubMed Central

    Sergeeva, Anna; He, Hong; Ruisaard, Kathryn; St. John, Lisa; Alatrash, Gheath; Clise-Dwyer, Karen; Li, Dan; Patenia, Rebecca; Hong, Richard; Sukhumalchandra, Pariya; You, M. James; Gagea, Mihai; Ma, Qing; Molldrem, Jeffrey J.

    2016-01-01

    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, which 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, co-incubation of AML with 8F4 ex vivo prevented engraftment of all tested AML subtypes in immunodeficient NSG 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 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

  2. Outcome of myeloablative allogeneic peripheral blood hematopoietic stem cell transplantation for refractory/relapsed AML patients in NR status.

    PubMed

    Liu, Na; Ning, Hong-Mei; Hu, Liang-Ding; Jiang, Min; Xu, Chen; Hu, Jiang-Wei; Wang, Jun; Li, Yu-Hang; Li, Bo-Tao; Lou, Xiao; Yang, Fan; Chen, Jian-Lin; Su, Yong-Feng; Li, Meng; Wang, Hong-Ye; Ren, Jing; Feng, Yue-Qian; Zhang, Bin; Wang, Dan-Hong; Chen, Hu

    2015-12-01

    To further find effective method to improve the long term survival of refractory or relapsed acute myeloid leukemia (AML) patients, we retrospectively analyzed the outcomes of myeloablative hematopoietic stem cell transplantation (HSCT) for 133 consecutive patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) therapy related AML(t-AML) in not remission status. The overall 3-year OS and DFS were 40.9% and 35.6% respectively. The variables associated with improved long term DFS were a bone marrow blast cell count less than 20% and an intensified conditioning regimen. In addition, the t-AML group had higher rates of relapse and III-IV acute GVHD than the primary AML group. The unrelated donor group had similar OS and DFS with sibling groups. Our study suggested that decreasing bone marrow blast cell counts before HSCT and strengthening the conditioning regimen may improve long-term DFS for refractory/relapsed AML patients, and unrelated donor group can get similar effect when compared to the sibling group. PMID:26530539

  3. 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

  4. Exon trapping of internal and 3{prime}-terminal exons from a YAC containing the AML1 gene

    SciTech Connect

    Ally, A.; Nisson, P.E.

    1994-09-01

    The t(8;21) translocation is associated with a high percentage of acute myelogenous leukemia (AML) cases of type 2 FAB. This cytogenetic landmark has been instrumental in the positional cloning of the AML1 gene which encodes a transcription factor and spans the translocation region. Using 3{prime} RACE and exon trapping, multiple AML1 transcripts have been observed which are generated by alternative splicing 3{prime} to exon 5. Although several transcripts from the AML1 gene have been cloned, these account for only a fraction of those predicted by Northern blotting. We therefore have subjected a 240 kb YAC (C4C10) that contains the entire AML1 gene to internal and 3{prime}-terminal exon trapping in an attempt to fully characterize the transcript repetoire from AML1. Exon trapping has been shown previously to capture exonic sequence by selecting splicing signals and has been applied primarily on cosmids. We report here the development of protocols for the efficient capture of internal and 3{prime}-terminal exons from the AML1 gene directly from YAC DNA.

  5. Favorable outcome in infants with AML after intensive first- and second-line treatment: an AML-BFM study group report.

    PubMed

    Creutzig, U; Zimmermann, M; Bourquin, J-P; Dworzak, M N; Kremens, B; Lehrnbecher, T; von Neuhoff, C; Sander, A; von Stackelberg, A; Schmid, I; Starý, J; Steinbach, D; Vormoor, J; Reinhardt, D

    2012-04-01

    Infants <1 year of age have a high prevalence of prognostically unfavorable leukemias and a presumed susceptibility to treatment-related toxicities. A total of 125 infants with acute myeloid leukemia (AML) were treated in studies AML-BFM-98 (n = 59) and -2004 (n = 66). Treatment regimens of both studies were comparable, consisting of intensive induction followed by four courses (mainly high-dose cytarabine and anthracyclines). Allogeneic-hematopoietic stem-cell-transplantation (allo-HSCT) in 1st remission was optional for high-risk (HR) patients. Most infants (120/125=96%) were HR patients according to morphological, cytogenetic/molecular genetic and response criteria. Five-year overall survival was 66 ± 4%, and improved from 61 ± 6% in study-98 to 75 ± 6% in study-2004 (P(logrank) 0.14) and event-free survival rates were 44 ± 6% and 51 ± 6% (P(logrank) 0.66), respectively. Results in HR infants were similar to those of older HR children (1-<2- or 2-<10-year olds, P(logrank) 0.90 for survival). Survival rates of HSCT in 1st remission, initial partial response and after relapse were high (13/14, 2/8 and 20/30 patients, respectively). The latter contributes to excellent 5-year survival after relapse (50±8%). Despite more severe infections and pulmonary toxicities in infants, treatment-related death rate was identical to that of older children (3%). Our data indicate that intensive frontline and relapse AML treatment is feasible in infants, toxicities are manageable, and outcome is favorable. PMID:21968880

  6. 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…

  7. Dichloroacetate and Trichloroacetate Toxicity in AML12 Cells: Role of Oxidative Stress.

    PubMed

    Hassoun, Ezdihar; Mettling, Christopher

    2015-11-01

    The toxicity of the drinking water disinfection by products dichloroacetate (DCA) and trichloroacetate (TCA) was studied in the alpha mouse liver (AML12) cells at concentrations ranging between 770 and 4100 ppm and at incubation times ranging from 24 to 72 h. Cellular viability, superoxide anion (SA) and lipid peroxidation (LP) production, as well as superoxide dismutase (SOD) activity were determined. DCA and TCA resulted in time- and concentration-dependent decreases in cellular viability, and also in significant increases in SA and LP production, and in SOD activity at specific concentrations and time points. The effective toxic concentrations of the compounds in these cells were found to be 10-fold higher than those producing similar effects in the mouse liver. It has been concluded that the AML12 is a good screening system to identify toxic concentrations of the halaocetates present in the drinking water that may need further in vivo testing.

  8. Evaluation of prognostic factors in patients with relapsed AML: Clonal evolution versus residual disease

    PubMed Central

    Kim, Hyojeong; Seol, Young Mi; Song, Moo-Kon; Choi, Young Jin; Shin, Ho-Jin; Park, Sang Hyuk; Lee, Eun Yup

    2016-01-01

    Background It is widely known that the prognosis of acute myeloid leukemia (AML) depends on chromosomal abnormalities. The majority of AML patients relapse and experience a dismal disease course despite initial remission. Methods We reviewed the medical records and laboratory findings of 55 AML patients who had relapsed between 2004 and 2013 and who had been treated at the Division of Hematology of the Pusan National University Hospital. Results The event-free survival (EFS) was related to prognostic karyotype classification at the time of diagnosis and relapse (unfavorable vs. favorable or intermediate karyotypes at diagnosis, 8.2 vs. 11.9 mo, P=0.003; unfavorable vs. favorable or intermediate karyotypes at relapse, 8.2 vs. 11.9 mo, P=0.009). The overall survival (OS) was significantly correlated with karyotype classification only at diagnosis (unfavorable vs. favorable or intermediate vs. karyotypes at diagnosis, 8.5 vs. 21.8 mo, P=0.001; unfavorable vs. favorable or intermediate karyotypes at relapse, 8.5 vs. 21.2 mo, P=0.136). A change in karyotype between diagnosis and relapse, which is regarded as a factor of resistance against treatment, was not a significant prognostic factor for OS, EFS, and post-relapse survival (PRS). A Cox proportional hazards model showed that the combined use of fludarabine, cytosine arabinoside, and granulocyte colony-stimulating factor (FLAG) as a salvage regimen, was a significant prognostic factor for OS (hazard ratio=0.399, P=0.010) and the PRS (hazard ratio=0.447, P=0.031). Conclusion The karyotype classification at diagnosis predicts survival including PRS in relapsed AML patients as well as in treatment-naïve patients. We suggest that presently, administration of salvage FLAG could be a better treatment option. PMID:27722128

  9. 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

  10. Effects of T-Cell Depletion on Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in AML Patients

    PubMed Central

    Hobbs, Gabriela Soriano; Perales, Miguel-Angel

    2015-01-01

    Graft versus host disease (GVHD) remains one of the leading causes of morbidity and mortality associated with conventional allogeneic hematopoietic stem cell transplantation (HCT). The use of T-cell depletion significantly reduces this complication. Recent prospective and retrospective data suggest that, in patients with AML in first complete remission, CD34+ selected grafts afford overall and relapse-free survival comparable to those observed in recipients of conventional grafts, while significantly decreasing GVHD. In addition, CD34+ selected grafts allow older patients, and those with medical comorbidities or with only HLA-mismatched donors to successfully undergo transplantation. Prospective data are needed to further define which groups of patients with AML are most likely to benefit from CD34+ selected grafts. Here we review the history of T-cell depletion in AML, and techniques used. We then summarize the contemporary literature using CD34+ selection in recipients of matched or partially mismatched donors (7/8 or 8/8 HLA-matched), and provide a summary of the risks and benefits of using T-cell depletion. PMID:26239251

  11. Classifying Cytogenetics in Patients with AML in Complete Remission Undergoing Allogeneic Transplantation: A CIBMTR Study

    PubMed Central

    Armand, Philippe; Kim, Haesook T.; Zhang, Mei-Jie; Perez, Waleska S.; Dal Cin, Paola S.; Klumpp, Thomas R.; Waller, Edmund K.; Litzow, Mark R.; Liesveld, Jane L.; Lazarus, Hillard M.; Artz, Andrew S.; Gupta, Vikas; Savani, Bipin N.; McCarthy, Philip L.; Cahn, Jean-Yves; Schouten, Harry C.; Finke, Jürgen; Ball, Edward D.; Aljurf, Mahmoud D.; Cutler, Corey S.; Rowe, Jacob M.; Antin, Joseph H.; Isola, Luis M.; Di Bartolomeo, Paolo; Camitta, Bruce M.; Miller, Alan M.; Cairo, Mitchell S.; Stockerl-Goldstein, Keith; Sierra, Jorge; Savoie, M. Lynn; Halter, Joerg; Stiff, Patrick J.; Nabhan, Chadi; Jakubowski, Ann A.; Bunjes, Donald W.; Petersdorf, Effie W.; Devine, Steven M.; Maziarz, Richard T.; Bornhauser, Martin; Lewis, Victor A.; Marks, David I.; Bredeson, Christopher N.; Soiffer, Robert J.; Weisdorf, Daniel J.

    2011-01-01

    Cytogenetics play a major role in determining the prognosis of patients with AML. However, the existing cytogenetics classifications were developed on chemotherapy-treated patients and may not be optimal for patients undergoing allogeneic hematopoietic cell transplantation (HCT). We studied 821 adult patients reported to the CIBMTR who underwent HCT for AML in first or second CR between 1999 and 2004. We compared the ability of the 6 existing classifications to stratify patients by overall survival (OS). We then defined a new schema specifically applicable to HCT patients using this patient cohort. Under this CIBMTR schema, inv(16) is favorable, complex karyotype (4+ abnormalities) is adverse, and all other classified abnormalities are intermediate in predicting survival after HCT (5y OS 64%, 18%, and 50%, respectively, p=0.0001). This schema stratified patients into 3 groups with similar non-relapse mortality, but significantly different incidences of relapse, overall and leukemia-free survival. It applied to patients regardless of their disease status (CR1 or CR2), donor type (MRD or URD), or conditioning intensity (myeloablative or reduced intensity). This transplantation-specific classification could be adopted for prognostication purposes and to stratify patients with AML and karyotypic abnormalities entering HCT clinical trials. PMID:21810400

  12. Serum Exosome MicroRNA as a Minimally-Invasive Early Biomarker of AML

    PubMed Central

    Hornick, Noah I.; Huan, Jianya; Doron, Ben; Goloviznina, Natalya A.; Lapidus, Jodi; Chang, Bill H.; Kurre, Peter

    2015-01-01

    Relapse remains the major cause of mortality for patients with Acute Myeloid Leukemia (AML). Improved tracking of minimal residual disease (MRD) holds the promise of timely treatment adjustments to preempt relapse. Current surveillance techniques detect circulating blasts that coincide with advanced disease and poorly reflect MRD during early relapse. Here, we investigate exosomes as a minimally invasive platform for a microRNA (miRNA) biomarker. We identify a set of miRNA enriched in AML exosomes and track levels of circulating exosome miRNA that distinguish leukemic xenografts from both non-engrafted and human CD34+ controls. We develop biostatistical models that reveal circulating exosomal miRNA at low marrow tumor burden and before circulating blasts can be detected. Remarkably, both leukemic blasts and marrow stroma contribute to serum exosome miRNA. We propose development of serum exosome miRNA as a platform for a novel, sensitive compartment biomarker for prospective tracking and early detection of AML recurrence. PMID:26067326

  13. 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.

  14. Pirin downregulation is a feature of AML and leads to impairment of terminal myeloid differentiation.

    PubMed

    Licciulli, S; Cambiaghi, V; Scafetta, G; Gruszka, A M; Alcalay, M

    2010-02-01

    Terminal differentiation of blood cells requires the concerted action of a series of transcription factors that are expressed at specific stages of maturation and function in a cell-type and dosage-dependent manner. Leukemogenic oncoproteins block differentiation by subverting the normal transcriptional status of hematopoietic precursor cells. Pirin (PIR) is a putative transcriptional regulator whose expression is silenced in cells bearing the acute myeloid leukemia-1 eight-twenty-one (AML1/ETO) and promyelocytic leukemia/retinoic acid receptor (PML/RAR) leukemogenic fusion proteins. A role for PIR in myeloid differentiation has not to date been reported. In this study we show that PIR expression is significantly repressed in a large proportion of acute myeloid leukemias (AMLs), regardless of subtype or underlying karyotypic abnormalities. We show that PIR expression increases during in vitro myeloid differentiation of primary hematopoietic precursor cells, and that ablation of PIR in the U937 myelomonocytic cell line or in murine primary hematopoietic precursor cells results in impairment of terminal myeloid differentiation. Gene expression profiling of U937 cells after knockdown of PIR revealed increased expression of genes associated with the early phases of hematopoiesis, in particular, homeobox A (HOXA) genes. Our results suggest that PIR is required for terminal myeloid maturation, and its downregulation may contribute to the differentiation arrest associated with AML. PMID:20010624

  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 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

  17. 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

  18. Abdichtungen im Verbund mit Fliesen und Platten

    NASA Astrophysics Data System (ADS)

    Platts, Thomas

    Abdichtungen im Verbund mit Fliesen und Platten, im Folgenden auch als Verbundabdichtungen oder mit Kurzzeichen als AIV bezeichnet, haben sich in der Baupraxis insbesondere in Innenräumen wegen des vereinfachten konstruktiven Aufbaus gegenüber Bahnenabdichtungen nach DIN 18195-5 [14.1] in der Mehrzahl der Ausführungen durchgesetzt und bewährt. Sie können im Innen- und Außenbereich angeordnet werden und sind dadurch gekennzeichnet, dass die Nutzschicht in Boden- und Wandbereichen im Dünnbettverfahren unmittelbar auf die Abdichtung aufgebracht wird. Aufwändige Zwischenschichten oder Einbauteile wie armierter Putz, Telleranker etc. entfallen (Bild 14.1) und es lassen sich geringere Aufbauhöhen realisieren.

  19. 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.

  20. 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

  1. Depletion of the chromatin remodeler CHD4 sensitizes AML blasts to genotoxic agents and reduces tumor formation

    PubMed Central

    Sperlazza, Justin; Rahmani, Mohamed; Beckta, Jason; Aust, Mandy; Hawkins, Elisa; Wang, Shou Zhen; Zu Zhu, Sheng; Podder, Shreya; Dumur, Catherine; Archer, Kellie; Grant, Steven

    2015-01-01

    Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATPase that alters the phasing of nucleosomes on DNA and has recently been implicated in DNA double-stranded break (DSB) repair. Here, we show that depletion of CHD4 in acute myeloid leukemia (AML) blasts induces a global relaxation of chromatin that renders cells more susceptible to DSB formation, while concurrently impeding their repair. Furthermore, CHD4 depletion renders AML blasts more sensitive both in vitro and in vivo to genotoxic agents used in clinical therapy: daunorubicin (DNR) and cytarabine (ara-C). Sensitization to DNR and ara-C is mediated in part by activation of the ataxia-telangiectasia mutated pathway, which is preliminarily activated by a Tip60-dependent mechanism in response to chromatin relaxation and further activated by genotoxic agent–induced DSBs. This sensitization preferentially affects AML cells, as CHD4 depletion in normal CD34+ hematopoietic progenitors does not increase their susceptibility to DNR or ara-C. Unexpectedly, we found that CHD4 is necessary for maintaining the tumor-forming behavior of AML cells, as CHD4 depletion severely restricted the ability of AML cells to form xenografts in mice and colonies in soft agar. Taken together, these results provide evidence for CHD4 as a novel therapeutic target whose inhibition has the potential to enhance the effectiveness of genotoxic agents used in AML therapy. PMID:26265695

  2. 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.

  3. Ajoene (natural garlic compound): a new anti-leukaemia agent for AML therapy.

    PubMed

    Hassan, H T

    2004-07-01

    The reputation of garlic (Allium sativum) as an effective remedy for tumours extends back to the Egyptian Codex Ebers of 1550 b.c. Several garlic compounds including allicin and its corresponding sulfide inhibit the proliferation and induce apoptosis of several human non-leukaemia malignant cells including breast, bladder, colorectal, hepatic, prostate cancer, lymphoma and skin tumour cell lines. Ajoene (4,5,9-trithiadodeca-1,6,11-triene-9-oxide) is a garlic-derived compound produced most efficiently from pure allicin and has the advantage of a greater chemical stability than allicin. Several clinical trials and in vitro studies of ajoene have demonstrated its best-known anti-thrombosis, anti-microbial and cholesterol lowering activities. Recently, topic application of ajoene has produced significant clinical response in patients with skin basal cell carcinoma. Ajoene was shown to inhibit proliferation and induce apoptosis of several human leukaemia CD34-negative cells including HL-60, U937, HEL and OCIM-1. Also, ajoene induces 30% apoptosis in myeloblasts from chronic myeloid leukaemia patient in blast crisis. More significantly, ajoene profoundly enhanced the apoptotic effect of the two chemotherapeutic drugs: cytarabine and fludarabine in human CD34-positive resistant myeloid leukaemia cells through enhancing their bcl-2 inhibitory and caspase-3 activation activities. The two key anti-leukaemia biological actions of ajoene were the inhibition of proliferation and the induction of apoptosis. Studies have shown the anti-proliferation activity of ajoene to be associated with a block in the G2/M phase of cell cycle in human myeloid leukaemia cells. The apoptosis inducing activity of ajoene is via the mitochondria-dependent caspase cascade through a significant reduction of the anti-apoptotic bcl-2 that results in release of cytochrome c and the activation of caspase-3. Since acute myeloid leukaemia (AML) is a heterogeneous malignant disease in which disease

  4. 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.

  5. 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.

  6. AML outcome: role of nucleotide excision repair polymorphisms in intermediate risk patients

    PubMed Central

    Strom, Sara S; Estey, Elihu H; Outschoorn, Ubaldo Martinez; Guillermo, Garcia-Manero

    2010-01-01

    Purpose Acute Myeloid Leukemia (AML) is frequently associated with genetic abnormalities. Based on pre-treatment cytogenetics, patients are classified into favorable, intermediate and poor subgroups. Cytogenetics predicts treatment outcome for the favorable and poor subgroups but not for the intermediate subgroup. Polymorphisms within the nucleotide excision repair (NER) pathway may lead to inter-individual differences in DNA repair capacity (DRC) which could influence outcome. Methods We studied the role of 6 polymorphisms (ERCC1 Gln504Lys, XPD Lys751Gln, XPC Ala499Val, XPC Lys939Gln, XPG Asp1104His, and CCNH Val270Ala) within NER pathway on overall and disease-free survival among 170 adult de-novo AML patients with intermediate cytogenetics [diploid (n=117); non-diploid (n=53)], treated with induction chemotherapy. Kaplan-Meier methods and Cox proportional hazards models were performed. Results Diploid patients with the XPD AC/CC genotype survived shorter than those with the wild-type (AA) genotype (median survival 22 vs. 40 months, log-rank p = 0.03). Similarly diploid patients with XPC CT/TT genotype survived shorter than those with the wild-type (CC) genotype (median survival 15 vs. 30 months, log-rank p = 0.02). Among diploid patients, after adjusting for clinical and socio-demographic variables, patients carrying both XPD AC/CC and XPC CT/TT had a greater than two-fold increased risk of dying compared to those with the wild-type genotypes (HR=2.49; 95%CI: 1.06–5.85). No significant associations were observed for disease-free survival in AML patients. Conclusion By reduced DRC, this combined genotype may result in greater susceptibility to treatment effects decreasing overall survival. These findings could in the future help in selecting treatment strategies for patients with normal cytogenetics. PMID:20141440

  7. 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

  8. 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).

  9. 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

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

    PubMed

    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.

  11. 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

  12. Cytotoxic T cell response against the chimeric ETV6-AML1 protein in childhood acute lymphoblastic leukemia.

    PubMed

    Yotnda, P; Garcia, F; Peuchmaur, M; Grandchamp, B; Duval, M; Lemonnier, F; Vilmer, E; Langlade-Demoyen, P

    1998-07-15

    Cytotoxic T lymphocytes (CTL) are potent effector cells that could provide long term antitumor immunity if induced by appropriate vaccines. CTL recognize 8-14 amino acid-long peptides processed intracellularly and presented by MHC class I molecules. A well-characterized example of a potential tumor antigen in childhood pre-B Acute Lymphoblastic Leukemia (ALL) results from the chromosomal translocation 12;21 leading to the fusion of the ETV6 and AML1 genes. This translocation is observed in > 25% of ALL-patients. In this study, we have examined whether the chimeric ETV6-AML1 protein could serve as a tumor specific antigen for CTL in HLA-A2.1 individuals. We have identified a nonapeptide (RIAECILGM), encoded by the fusion region of the ETV6-AML1 protein, that binds to HLA-A2.1 molecules and induces specific primary CTL in peripheral blood lymphocytes from healthy donors. These CTL specifically lysed HLA-A2.1 tumor cells endogeneously expressing the ETV6-AML fusion protein. CTL with similar functional capacities were found with high frequencies and cloned from one patient's bone marrow indicating that ETV6-AML1-specific anti-ALL CTL are, at least in some patients, spontaneously stimulated and might participate to host antileukemia defense.

  13. Cytotoxic T cell response against the chimeric ETV6-AML1 protein in childhood acute lymphoblastic leukemia.

    PubMed Central

    Yotnda, P; Garcia, F; Peuchmaur, M; Grandchamp, B; Duval, M; Lemonnier, F; Vilmer, E; Langlade-Demoyen, P

    1998-01-01

    Cytotoxic T lymphocytes (CTL) are potent effector cells that could provide long term antitumor immunity if induced by appropriate vaccines. CTL recognize 8-14 amino acid-long peptides processed intracellularly and presented by MHC class I molecules. A well-characterized example of a potential tumor antigen in childhood pre-B Acute Lymphoblastic Leukemia (ALL) results from the chromosomal translocation 12;21 leading to the fusion of the ETV6 and AML1 genes. This translocation is observed in > 25% of ALL-patients. In this study, we have examined whether the chimeric ETV6-AML1 protein could serve as a tumor specific antigen for CTL in HLA-A2.1 individuals. We have identified a nonapeptide (RIAECILGM), encoded by the fusion region of the ETV6-AML1 protein, that binds to HLA-A2.1 molecules and induces specific primary CTL in peripheral blood lymphocytes from healthy donors. These CTL specifically lysed HLA-A2.1 tumor cells endogeneously expressing the ETV6-AML fusion protein. CTL with similar functional capacities were found with high frequencies and cloned from one patient's bone marrow indicating that ETV6-AML1-specific anti-ALL CTL are, at least in some patients, spontaneously stimulated and might participate to host antileukemia defense. PMID:9664088

  14. 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

  15. Erlebniseinkauf in der Innenstadt mit hoher Akzeptanz

    NASA Astrophysics Data System (ADS)

    Pangels, Rolf

    2002-03-01

    Im Oktober 2000 führte die BAG zum zehnten Mal die über die Grenzen des Einzelhandels bekannte Untersuchung "Kundenverkehr" in mehr als hundertfünfzig deutschen Städten durch. In Kooperation mit der Swiss Retail Federation sowie mit Unterstützung der femged (European Federation of Medium-size and Major Retailers) wurde die Untersuchung erstmals auch in der Schweiz und in Österreich durchgeführt. Es beteiligten sich insgesamt 463 Unternehmen an der Untersuchung, die knapp 9,5 Mio. Besucher gezählt haben und davon mehr als 360.000 Kunden nach bestimmten Parametern befragten. Die Daten für Deutschland wurden, wie in den Jahren zuvor, vom Institut für Handelsforschung an der Universität Köln ausgewertet. Die Zahlen der Untersuchung in der Schweiz und Österreich wurden von der wirtschafts- und sozialwissenschaftlichen Beratungsgesellschaft ECON-Consult in Köln zusammengetragen und analysiert.

  16. 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

  17. 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

  18. 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

  19. 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

  20. Detection of minimal residual disease in an AML patient with trisomy 8 using interphase fish.

    PubMed

    White, D L; Hutchins, C J; Turczynowicz, S; Suttle, J; Haylock, D N; Hughes, T P; Juttner, C A; To, L B

    1997-08-01

    Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) often exhibit clonal chromosomal abnormalities. Using a probe for the centromeric region of chromosome 8, fluorescence in situ hybridization (FISH) on interphase cells was used to detect trisomy 8 in an AML patient whose leukemia was characterised by the karyotype 47, XY, +8, del(9) (q21.1q32). We have demonstrated using FISH the presence of the trisomy at all stages of the patient's disease course (including remission, peripheral blood cell harvest and relapse), whereas conventional karyoptypic analysis was only able to detect the trisomy at diagnosis and clinical relapse. We have also shown using immunophenotyping, cell sorting and FISH, that the trisomic cells in this patient were restricted to the CD34+ subset of blood and bone marrow and could not be found in the CD 34-, T or B cell compartment. Overall we have shown FISH to be a rapid, quantitative method for the detection of cells with numerical chromosome abnormalities. FISH analysis of interphase cells provides valuable information on the status of the whole population, rather than just cycling cells, and can be applied successfully to monitor the level of leukemic cells.

  1. 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.

  2. Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells.

    PubMed

    El Hajj, Hiba; Dassouki, Zeina; Berthier, Caroline; Raffoux, Emmanuel; Ades, Lionel; Legrand, Olivier; Hleihel, Rita; Sahin, Umut; Tawil, Nadim; Salameh, Ala; Zibara, Kazem; Darwiche, Nadine; Mohty, Mohamad; Dombret, Hervé; Fenaux, Pierre; de Thé, Hugues; Bazarbachi, Ali

    2015-05-28

    Nucleophosmin-1 (NPM1) is the most frequently mutated gene in acute myeloid leukemia (AML). Addition of retinoic acid (RA) to chemotherapy was proposed to improve survival of some of these patients. Here, we found that RA or arsenic trioxide synergistically induce proteasomal degradation of mutant NPM1 in AML cell lines or primary samples, leading to differentiation and apoptosis. NPM1 mutation not only delocalizes NPM1 from the nucleolus, but it also disorganizes promyelocytic leukemia (PML) nuclear bodies. Combined RA/arsenic treatment significantly reduced bone marrow blasts in 3 patients and restored the subnuclear localization of both NPM1 and PML. These findings could explain the proposed benefit of adding RA to chemotherapy in NPM1 mutant AMLs, and warrant a broader clinical evaluation of regimen comprising a RA/arsenic combination.

  3. High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21.

    PubMed

    Preudhomme, C; Warot-Loze, D; Roumier, C; Grardel-Duflos, N; Garand, R; Lai, J L; Dastugue, N; Macintyre, E; Denis, C; Bauters, F; Kerckaert, J P; Cosson, A; Fenaux, P

    2000-10-15

    The AML1 gene, situated in 21q22, is often rearranged in acute leukemias through t(8;21) translocation, t(12;21) translocation, or less often t(3;21) translocation. Recently, point mutations in the Runt domain of the AML1 gene have also been reported in leukemia patients. Observations for mutations of the Runt domain of the AML1 gene in bone marrow cells were made in 300 patients, including 131 with acute myeloid leukemia (AML), 94 with myelodysplastic syndrome (MDS), 28 with blast crisis chronic myeloid leukemia (CML), 3 with atypical CML, 41 with acute lymphoblastic leukemia (ALL), and 3 with essential thrombocythemia (ET). Forty-one of the patients had chromosome 21 abnormalities, including t(8;21) in 6 of the patients with AML, t(12;21) in 8 patients with ALL, acquired trisomy 21 in 17 patients, tetrasomy 21 in 7 patients, and constitutional trisomy 21 (Down syndrome) in 3 patients. A point mutation was found in 14 cases (4.7%), including 9 (22%) of the 41 patients with AML of the Mo type (MoAML) (none of them had detectable chromosome 21 rearrangement) and 5 (38%) of the 13 myeloid malignancies with acquired trisomy 21 (1 M1AML, 2 M2AML, 1 ET, and 1 atypical CML). In at least 8 of 9 mutated cases of MoAML, both AML alleles were mutated: 3 patients had different stop codon mutations of the 2 AML1 alleles, and 5 patients had the same missense or stop codon mutation in both AML1 alleles, which resulted in at least 3 of the patients having duplication of the mutated allele and deletion of the normal residual allele, as shown by FISH analysis and by comparing microsatellite analyses of several chromosome 21 markers on diagnosis and remission samples. In the remaining mutated cases, with acquired trisomy 21, a missense mutation of AML1, which involved 2 of the 3 copies of the AML1 gene, was found. Four of the 7 mutated cases could be reanalyzed in complete remission, and no AML1 mutation was found, showing that mutations were acquired in the leukemic clone. In

  4. 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…

  5. 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.

  6. 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

  7. 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

  8. Unfälle mit Kleintransportern

    NASA Astrophysics Data System (ADS)

    Tschirschwitz, Christian

    Auf einer außerörtlichen Bundesstraße geriet ein mit vier Personen besetzter Pkw Toyota Corolla aus letztlich nicht vollständig geklärten Gründen ins Schleudern. Nachdem sich das Fahrzeug beträchtlich entgegen dem Uhrzeigersinn ausgedreht hatte, prallte ein entgegenkommender Kleintransporter VW T4 frontal an die rechte Flanke des Toyota. Der Transporter wurde gedreht, ausgehoben und durch einen Pkw Ford Escort unterfahren. Alle Fahrzeuge kamen in Kollisionsortnähe zum Endstand. Die vier Toyota-Insassen wurden getötet. Aus den anderen Fahrzeugen wurden sechs Personen überwiegend schwer verletzt. Unbeteiligte Zeugen waren nicht vorhanden.

  9. 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.

  10. 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.

  11. 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

  12. Apoptosis repressor with caspase recruitment domain is regulated by MAPK/PI3K and confers drug resistance and survival advantage to AML

    PubMed Central

    Mak, P. Y.; Mak, D. H.; Mu, H.; Shi, Y.; Ruvolo, P.; Ruvolo, V.; Jacamo, R.; Burks, J. K.; Wei, W.; Huang, X.; Kornblau, S. M.; Andreeff, M.; Carter, B. Z.

    2014-01-01

    The apoptosis repressor with caspase recruitment domain (ARC) protein is known to suppress both intrinsic and extrinsic apoptosis. We previously reported that ARC expression is a strong, independent adverse prognostic factor in acute myeloid leukemia (AML). Here, we investigated the regulation and role of ARC in AML. ARC expression is upregulated in AML cells co-cultured with bone marrow-derived mesenchymal stromal cells (MSCs) and suppressed by inhibition of MAPK and PI3K signaling. AML patient samples with RAS mutations (N = 64) expressed significantly higher levels of ARC than samples without RAS mutations (N = 371) (P = 0.016). ARC overexpression protected and ARC knockdown sensitized AML cells to cytarabine and to agents that selectively induce intrinsic (ABT-737) or extrinsic (TNF-related apoptosis inducing ligand) apoptosis. NOD-SCID mice harboring ARC-overexpressing KG-1 cells had significantly shorter survival than mice injected with control cells (median 84 versus 111 days) and significantly fewer leukemia cells were present when NOD/SCID IL2R null mice were injected with ARC knockdown as compared to control Molm13 cells (P = 0.005 and 0.03 at 2 and 3 weeks, respectively). Together, these findings demonstrate that MSCs regulate ARC in AML through activation of MAPK and PI3K signaling pathways. ARC confers drug resistance and survival advantage to AML in vitro and in vivo, suggesting ARC as a novel target in AML therapy. PMID:24337870

  13. 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.

  14. 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

  15. Hispolon induces apoptosis through JNK1/2-mediated activation of a caspase-8, -9, and -3-dependent pathway in acute myeloid leukemia (AML) cells and inhibits AML xenograft tumor growth in vivo.

    PubMed

    Hsiao, Pei-Ching; Hsieh, Yi-Hsien; Chow, Jyh-Ming; Yang, Shun-Fa; Hsiao, Michael; Hua, Kuo-Tai; Lin, Chien-Huang; Chen, Hui-Yu; Chien, Ming-Hsien

    2013-10-23

    Hispolon is an active phenolic compound of Phellinus igniarius, a mushroom that was recently shown to have antioxidant and anticancer activities in various solid tumors. Here, the molecular mechanisms by which hispolon exerts anticancer effects in acute myeloid leukemia (AML) cells was investigated. The results showed that hispolon suppressed cell proliferation in the various AML cell lines. Furthermore, hispolon effectively induced apoptosis of HL-60 AML cells through caspases-8, -9, and -3 activations and PARP cleavage. Moreover, treatment of HL-60 cells with hispolon induced sustained activation of JNK1/2, and inhibition of JNK by JNK1/2 inhibitor or JNK1/2-specific siRNA significantly abolished the hispolon-induced activation of the caspase-8/-9/-3. In vivo, hispolon significantly reduced tumor growth in mice with HL-60 tumor xenografts. In hispolon-treated tumors, activation of caspase-3 and a decrease in Ki67-positive cells were observed. Our results indicated that hispolon may have the potential to serve as a therapeutic tool to treat AML. PMID:24093560

  16. 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

  17. Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML.

    PubMed

    Vo, Thanh-Trang; Ryan, Jeremy; Carrasco, Ruben; Neuberg, Donna; Rossi, Derrick J; Stone, Richard M; Deangelo, Daniel J; Frattini, Mark G; Letai, Anthony

    2012-10-12

    Despite decades of successful use of cytotoxic chemotherapy in acute myelogenous leukemia (AML), the biological basis for its differential success among individuals and for the existence of a therapeutic index has remained obscure. Rather than taking a genetic approach favored by many, we took a functional approach to ask how differential mitochondrial readiness for apoptosis ("priming") might explain individual variation in clinical behavior. We found that mitochondrial priming measured by BH3 profiling was a determinant of initial response to induction chemotherapy, relapse after remission, and requirement for allogeneic bone marrow transplantation. Differential priming between malignant myeloblasts and normal hematopoietic stem cells supports a mitochondrial basis to the therapeutic index for chemotherapy. BH3 profiling identified BCL-2 inhibition as a targeted strategy likely to have a useful therapeutic index. BH3 profiling refines predictive information provided by conventional biomarkers currently in use and thus may itself have utility as a clinical predictive biomarker. PAPERCLIP:

  18. 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

  19. 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

  20. 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.

  1. Silencing AML1-ETO gene expression leads to simultaneous activation of both pro-apoptotic and proliferation signaling.

    PubMed

    Spirin, P V; Lebedev, T D; Orlova, N N; Gornostaeva, A S; Prokofjeva, M M; Nikitenko, N A; Dmitriev, S E; Buzdin, A A; Borisov, N M; Aliper, A M; Garazha, A V; Rubtsov, P M; Stocking, C; Prassolov, V S

    2014-11-01

    The t(8;21)(q22;q22) rearrangement represents the most common chromosomal translocation in acute myeloid leukemia (AML). It results in a transcript encoding for the fusion protein AML1-ETO (AE) with transcription factor activity. AE is considered to be an attractive target for treating t(8;21) leukemia. However, AE expression alone is insufficient to cause transformation, and thus the potential of such therapy remains unclear. Several genes are deregulated in AML cells, including KIT that encodes a tyrosine kinase receptor. Here, we show that AML cells transduced with short hairpin RNA vector targeting AE mRNAs have a dramatic decrease in growth rate that is caused by induction of apoptosis and deregulation of the cell cycle. A reduction in KIT mRNA levels was also observed in AE-silenced cells, but silencing KIT expression reduced cell growth but did not induce apoptosis. Transcription profiling of cells that escape cell death revealed activation of a number of signaling pathways involved in cell survival and proliferation. In particular, we find that the extracellular signal-regulated kinase 2 (ERK2; also known as mitogen-activated protein kinase 1 (MAPK1)) protein could mediate activation of 23 out of 29 (79%) of these upregulated pathways and thus may be regarded as the key player in establishing the t(8;21)-positive leukemic cells resistant to AE suppression.

  2. WT1 vaccination in AML and MDS: A pilot trial with synthetic analog peptides.

    PubMed

    Brayer, Jason; Lancet, Jeffrey E; Powers, John; List, Alan; Balducci, Lodovico; Komrokji, Rami; Pinilla-Ibarz, Javier

    2015-07-01

    Peptide vaccines are capable of eliciting immune responses targeting tumor-associated antigens such as the Wilms' Tumor 1 (WT1) antigen, often overexpressed in myeloid malignancies. Here, we assessed the safety, tolerability, and immunogenicity of a polyvalent WT1 peptide vaccine. Individuals with WT1-positive acute myeloid leukemia (AML) in first (CR1) or second (CR2) remission or with higher-risk myelodysplastic syndrome (MDS) following at least 1 prior line of therapy were vaccinated with a mixture of peptides derived from the WT1 protein, with sargramostim injections before vaccination to amplify immunogenicity. Six vaccinations were delivered biweekly, continuing then monthly until patients received 12 vaccinations or showed disease relapse or progression. Therapeutic efficacy was evaluated by progression-free and overall survival. Immune responses were evaluated by delayed-type hypersensitivity testing and T-cell IFNγ ELISPOT at specified intervals. In 16 patients who received at least one vaccination, 10 completed the planned course of six vaccinations and six continued for up to six additional monthly vaccinations. Vaccinations were well tolerated, with no patients discontinuing due to toxicity. One of two patients with high-risk MDS experienced a prolonged decrease in transfusion dependence. Two of 14 AML patients demonstrated relapse-free survival >1 year. Both patients were in CR2 at time of vaccination, with duration of their remission exceeding duration of their first remission, suggesting a potential benefit. Our WT1 vaccine was well-tolerated. The clinical benefit that we observed in several patients suggests engagement of a protective immune response, indicating a need for further trials.

  3. 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

  4. WT1 vaccination in AML and MDS: A pilot trial with synthetic analog peptides.

    PubMed

    Brayer, Jason; Lancet, Jeffrey E; Powers, John; List, Alan; Balducci, Lodovico; Komrokji, Rami; Pinilla-Ibarz, Javier

    2015-07-01

    Peptide vaccines are capable of eliciting immune responses targeting tumor-associated antigens such as the Wilms' Tumor 1 (WT1) antigen, often overexpressed in myeloid malignancies. Here, we assessed the safety, tolerability, and immunogenicity of a polyvalent WT1 peptide vaccine. Individuals with WT1-positive acute myeloid leukemia (AML) in first (CR1) or second (CR2) remission or with higher-risk myelodysplastic syndrome (MDS) following at least 1 prior line of therapy were vaccinated with a mixture of peptides derived from the WT1 protein, with sargramostim injections before vaccination to amplify immunogenicity. Six vaccinations were delivered biweekly, continuing then monthly until patients received 12 vaccinations or showed disease relapse or progression. Therapeutic efficacy was evaluated by progression-free and overall survival. Immune responses were evaluated by delayed-type hypersensitivity testing and T-cell IFNγ ELISPOT at specified intervals. In 16 patients who received at least one vaccination, 10 completed the planned course of six vaccinations and six continued for up to six additional monthly vaccinations. Vaccinations were well tolerated, with no patients discontinuing due to toxicity. One of two patients with high-risk MDS experienced a prolonged decrease in transfusion dependence. Two of 14 AML patients demonstrated relapse-free survival >1 year. Both patients were in CR2 at time of vaccination, with duration of their remission exceeding duration of their first remission, suggesting a potential benefit. Our WT1 vaccine was well-tolerated. The clinical benefit that we observed in several patients suggests engagement of a protective immune response, indicating a need for further trials. PMID:25802083

  5. Evidence for the involvement of the glutathione pathway in drug resistance in AML.

    PubMed

    Sargent, J M; Williamson, C; Hall, A G; Elgie, A W; Taylor, C G

    1999-01-01

    We have studied altered drug detoxification through the glutathione pathway as a possible mechanism of resistance in 38 patients with AML. GST alpha, mu and pi expressions were determined using immunocytochemistry, the median percentages of positive cells being 73% (range 0-98), 55% (range 0-99) and 97% (range 80-100) respectively. MRP expression was measured using MRPm6 MoAb and flow cytometry. Results were expressed as the ratio of fluorescence associated with MRP over that of an isotype matched control (median, 1.32; range 0.95-2.15). Statistical analyses showed a significant increase in GST alpha expression in blast cells showing in vitro resistance to doxorubicin, with a median value of 78% positive cells compared to 41% in the sensitive group (p < 0.02). There was a significant reduction, however, in GST mu expression from a median value of 60% in newly presenting patients to 40% in a group of patients who had received previous cytotoxic therapy (p < 0.02). Interestingly, patients with high GST mu expression appeared to co-express MRP (p < 0.05). In vitro drug modulation studies, comparing the cytotoxic effect of doxorubicin +/- ethacrynic acid at 6.5 microM resulted in only one significant increase in sensitivity (2.6-fold), out of 22 comparisons. These results support the theory that altered detoxification through the glutathione pathway contributes towards drug resistance in AML. Further studies using fresh blast cells are required to elucidate the importance of this mechanism for individual patients.

  6. 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.

  7. The Runt domain of AML1 (RUNX1) binds a sequence-conserved RNA motif that mimics a DNA element

    PubMed Central

    Fukunaga, Junichi; Nomura, Yusuke; Tanaka, Yoichiro; Amano, Ryo; Tanaka, Taku; Nakamura, Yoshikazu; Kawai, Gota; Sakamoto, Taiichi; Kozu, Tomoko

    2013-01-01

    AML1 (RUNX1) is a key transcription factor for hematopoiesis that binds to the Runt-binding double-stranded DNA element (RDE) of target genes through its N-terminal Runt domain. Aberrations in the AML1 gene are frequently found in human leukemia. To better understand AML1 and its potential utility for diagnosis and therapy, we obtained RNA aptamers that bind specifically to the AML1 Runt domain. Enzymatic probing and NMR analyses revealed that Apt1-S, which is a truncated variant of one of the aptamers, has a CACG tetraloop and two stem regions separated by an internal loop. All the isolated aptamers were found to contain the conserved sequence motif 5′-NNCCAC-3′ and 5′-GCGMGN′N′-3′ (M:A or C; N and N′ form Watson–Crick base pairs). The motif contains one AC mismatch and one base bulged out. Mutational analysis of Apt1-S showed that three guanines of the motif are important for Runt binding as are the three guanines of RDE, which are directly recognized by three arginine residues of the Runt domain. Mutational analyses of the Runt domain revealed that the amino acid residues used for Apt1-S binding were similar to those used for RDE binding. Furthermore, the aptamer competed with RDE for binding to the Runt domain in vitro. These results demonstrated that the Runt domain of the AML1 protein binds to the motif of the aptamer that mimics DNA. Our findings should provide new insights into RNA function and utility in both basic and applied sciences. PMID:23709277

  8. 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.

  9. 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.

  10. 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

  11. Cannabidiol stimulates Aml-1a-dependent glial differentiation and inhibits glioma stem-like cells proliferation by inducing autophagy in a TRPV2-dependent manner.

    PubMed

    Nabissi, Massimo; Morelli, Maria Beatrice; Amantini, Consuelo; Liberati, Sonia; Santoni, Matteo; Ricci-Vitiani, Lucia; Pallini, Roberto; Santoni, Giorgio

    2015-10-15

    Glioma stem-like cells (GSCs) correspond to a tumor cell subpopulation, involved in glioblastoma multiforme (GBM) tumor initiation and acquired chemoresistance. Currently, drug-induced differentiation is considered as a promising approach to eradicate this tumor-driving cell population. Recently, the effect of cannabinoids (CBs) in promoting glial differentiation and inhibiting gliomagenesis has been evidenced. Herein, we demonstrated that cannabidiol (CBD) by activating transient receptor potential vanilloid-2 (TRPV2) triggers GSCs differentiation activating the autophagic process and inhibits GSCs proliferation and clonogenic capability. Above all, CBD and carmustine (BCNU) in combination overcome the high resistance of GSCs to BCNU treatment, by inducing apoptotic cell death. Acute myeloid leukemia (Aml-1) transcription factors play a pivotal role in GBM proliferation and differentiation and it is known that Aml-1 control the expression of several nociceptive receptors. So, we evaluated the expression levels of Aml-1 spliced variants (Aml-1a, b and c) in GSCs and during their differentiation. We found that Aml-1a is upregulated during GSCs differentiation, and its downregulation restores a stem cell phenotype in differentiated GSCs. Since it was demonstrated that CBD induces also TRPV2 expression and that TRPV2 is involved in GSCs differentiation, we evaluated if Aml-1a interacted directly with TRPV2 promoters. Herein, we found that Aml-1a binds TRPV2 promoters and that Aml-1a expression is upregulated by CBD treatment, in a TRPV2 and PI3K/AKT dependent manner. Altogether, these results support a novel mechanism by which CBD inducing TRPV2-dependent autophagic process stimulates Aml-1a-dependent GSCs differentiation, abrogating the BCNU chemoresistance in GSCs.

  12. 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.

  13. 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.

  14. 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

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

    PubMed Central

    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

  16. 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

  17. Treatment of relapsed undifferentiated acute myeloid leukemia (AML-M0) with Ayurvedic therapy

    PubMed Central

    Prakash, Balendu

    2011-01-01

    A 16-year-old boy was detected with acute myeloid leukemia (AML – M0) with bone marrow pathology showing 85% blasts in February 07, 1997. He received two cycles of induction chemotherapy (3+7 protocol) with daunomycin and cytosar, following which he achieved incomplete remission with bone marrow aspirate showing 14% blasts. Subsequently, the patient received two cycles of high-dose cytosine arabinoside Ara-C and achieved remission. However, his disease relapsed on August 29, 1997. Peripheral blood smear showed 6% blast cells and bone marrow showed 40% blast cells. The patient refused further chemotherapy and/or bone marrow transplant and volunteered for Ayurvedic therapy (AYT) advocated by the author from September 09, 1997. Bone marrow studies done after six months of AYT indicated that the disease was in remission. The AYT was continued for five years and stopped. Thereafter, the patient received intermittent maintenance AYT for three months in the next two years. At present, the patient is normal and healthy and has completed 12 years of disease-free survival with AYT. PMID:21897645

  18. 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

  19. A Jehovah's Witness with Acute Myeloid Leukemia Successfully Treated with an Epigenetic Drug, Azacitidine: A Clue for Development of Anti-AML Therapy Requiring Minimum Blood Transfusions

    PubMed Central

    Yamamoto, Yumi; Kawashima, Akihito; Kashiwagi, Eri

    2014-01-01

    Therapy for acute leukemia in Jehovah's Witnesses patients is very challenging because of their refusal to accept blood transfusions, a fundamental supportive therapy for this disease. These patients are often denied treatment for fear of treatment-related death. We present the first Jehovah's Witness patient with acute myeloid leukemia (AML) treated successfully with azacitidine. After achieving complete remission (CR) with one course of azacitidine therapy, the patient received conventional postremission chemotherapy and remained in CR. In the case of patients who accept blood transfusions, there are reports indicating the treatment of AML patients with azacitidine. In these reports, azacitidine therapy was less toxic, including hematoxicity, compared with conventional chemotherapy. The CR rate in azacitidine-treated patients was inadequate; however, some characteristics could be useful in predicting azacitidine responders. The present case is useful for treating Jehovah's Witnesses patients with AML and provides a clue for anti-AML therapy requiring minimum blood transfusions. PMID:25371835

  20. 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.

  1. [Clinical curative efficacy of inducing remission for the newly diagnosed aged AML patients by chemotherapy with IA and DA regimens].

    PubMed

    Tian, Dong-Hua; Gan, Si-Lin; Xing, Hai-Zhou; Liu, Yan-Fang; Xie, Xin-Sheng; Sun, Hui

    2014-10-01

    This study was aimed to explore the clinical efficacy and toxicity of idarubicin (IA regimen) and daunoru-bicin combined with cytarabine (DA regimen) for treating aged patients with AML as induction chemotherapy. The clinical data of 60 newly diagnosed AML aged patients treated with IA or DA regimen were analyzed retrospectively. IA regimen group included 22 patients (8 male and 14 females with median age of 66 yrs), while the DA regimen group included 38 patients (20 males and 18 females with median age of 64 yrs). The complete remission rate, total effective rate and adverse effects after one chemotherapy course were compared. The results showed that the CR rate in IA regimen group was 63.63%, which was significantly higer than that in DA regimen group (31.58%) (P < 0.05). The total effective rate was 63.63% and 36.84% respectively in IA and DA regimen groups, there was significant difference between the two groups (P < 0.05). Both the hematological and non-hematological adverse effects were observed and no difference was found in the two regimen groups, neither in myelosupression (P > 0.05), the major hematological adverse effects, nor in non-hematological adverse effects (P > 0.05). It is concluded that for aged AML patients, IA regimen can achieve a higher CR rate and higher total effective rate than that in DA regimen without increase of adverse effects after one induction chemotherapy course.

  2. 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

  3. Results of the AIEOP AML 2002/01 multicenter prospective trial for the treatment of children with acute myeloid leukemia.

    PubMed

    Pession, Andrea; Masetti, Riccardo; Rizzari, Carmelo; Putti, Maria Caterina; Casale, Fiorina; Fagioli, Franca; Luciani, Matteo; Lo Nigro, Luca; Menna, Giuseppe; Micalizzi, Concetta; Santoro, Nicola; Testi, Anna Maria; Zecca, Marco; Biondi, Andrea; Pigazzi, Martina; Rutella, Sergio; Rondelli, Roberto; Basso, Giuseppe; Locatelli, Franco

    2013-07-11

    We evaluated the outcome of 482 children with acute myeloid leukemia (AML) enrolled in the Associazione Italiana di Ematologia e Oncologia Pediatrica AML 2002/01 trial. Treatment was stratified according to risk group; hematopoietic stem cell transplantation (HSCT) was used in high-risk (HR) children. Patients with core binding factor leukemia achieving complete remission (CR) after the first induction course were considered standard risk (SR; 99 patients), whereas the others (n = 383) were assigned to the HR group. Allogeneic (ALLO) or autologous (AUTO) HSCT was employed, respectively, in 141 and 102 HR patients after consolidation therapy. CR, early death, and induction failure rates were 87%, 3%, and 10%, respectively. Relapse occurred in 24% of patients achieving CR. The 8-year overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 68%, 55%, and 63%, respectively. OS, EFS, and DFS for SR and HR patients were 83%, 63%, and 66% and 64%, 53%, and 62%. DFS was 63% and 73% for HR patients given AUTO-HSCT and ALLO-HSCT, respectively. In multivariate analysis, risk group, white blood cell >100 × 10(9)/L at diagnosis, and monosomal karyotype predicted poorer EFS. Risk-oriented treatment and broad use of HSCT result in a long-term EFS comparing favorably with previously published studies on childhood AML.

  4. Mapping of the mouse homolog of the human runt domain gene, AML2, to the distal region of mouse chromosome 4

    SciTech Connect

    Avraham, K.B.; Copeland, N.G.; Jenkins, N.A.

    1995-01-20

    AML2 is a runt domain belonging to a group of transcription factors that appear to play a role in Drosophila embryogenesis and mammalian oncogenic transformation. AML2 maps to human chromosome 1p36, a region involved in the t(1;3)(p36;q21) translocation found in association with myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), and acute nonlymphocytic leukemia. 9 refs., 1 fig.

  5. Preleukemic TEL-AML1-positive clones at cell level of 10(-3) to 10(-4) do not persist into adulthood.

    PubMed

    Olsen, Marianne; Madsen, Hans O; Hjalgrim, Henrik; Gregers, Jannie; Rostgaard, Klaus; Schmiegelow, Kjeld

    2006-11-01

    The TEL-AML1 translocation, t(12;21)(p13;q22), is one of the most frequent genetic aberrations in childhood B-cell precursor acute lymphoblastic leukemia (ALL), where it occurs in 25% of all cases. In contrast, the translocation is seen in only 3% of adult ALL cases. Evidence suggests that the TEL-AML1 translocation occurs in utero in 1% of all newborn children at cell levels of 10 to 10. In this study, we explore the prevalence of TEL-AML1-positive cells in 2 cohorts of healthy blood donors by real-time and nested reverse transcription-polymerase chain reaction. Overall, TEL-AML1-positive cells were demonstrated in 10 of 2005 healthy donors, that is, a prevalence of 0.5% (95% confidence interval, 0.2-0.3%). The level of TEL-AML1-positive cells was estimated to 10 to 10. The observed prevalence of TEL-AML1-positive cells in healthy adults is of the same order of magnitude as the prevalence reported in healthy newborns, but the observed cell level of 10 to 10 is much lower. These data indicates that prenatal TEL-AML1 subclones does not persist throughout adult life at cell levels of 10 to 10. The findings are compatible with the risk of t(12;21)(p13;q22) ALL correlating with the total number of TEL-AML1-positive cells in peripheral blood in both childhood and adulthood. PMID:17114960

  6. Subclones with the t(9;22)/BCR-ABL1 rearrangement occur in AML and seem to cooperate with distinct genetic alterations.

    PubMed

    Bacher, Ulrike; Haferlach, Torsten; Alpermann, Tamara; Zenger, Melanie; Hochhaus, Andreas; Beelen, Dietrich W; Uppenkamp, Michael; Rummel, Mathias; Kern, Wolfgang; Schnittger, Susanne; Haferlach, Claudia

    2011-03-01

    In AML, cooperation of mutations suppressing differentiation ('class-II-mutations') with 'class-I-mutations' increasing cell proliferation is frequent. In rare cases of myeloid malignancies, the BCR-ABL1 fusion was reported to cooperate as class-I-mutation with class-II-mutations, but most cases had to be classified as blast phase of chronic myeloid leukaemia (CML). We identified five cases of Philadelphia positive subclones in AML occurring in coincidence with other genetic lesions: 1:220 patients with inv(16)/CBFB-MYH11 (0·5%), 2:272 AML cases with t(8;21)/RUNX1-RUNX1T1 (0·7%), 1:1029 NPM1-mutated AML (0·1%), and one patient with s-AML following MDS with a 5q-deletion. Four patients had m-BCR (e1a2) BCR-ABL1 transcripts; one case only had an M-BCR (b3a2) breakpoint. These cases allow some interesting conclusions: The BCR-ABL1 rearrangement apparently can cooperate with the NPM1 mutation similar to other class-I-mutations. The identification of Philadelphia positive subclones in <1% of patients with CBF-leukaemias fits well with previous observations that most CBF-AML are accompanied by activating mutations in genes enhancing proliferation. Since we observed the occurrence of the Philadelphia positive subclones at diagnosis, at relapse, or throughout the disease, the time point of the emergence of Philadelphia subclones seems variable in AML. Clinical research should further concentrate on Philadelphia positive subclones in AML to assess the clinical impact. PMID:21275954

  7. Up-regulation of anti-apoptotic genes confers resistance to the novel anti-leukaemic compound PEP005 in primary AML cells

    PubMed Central

    Hampson, Peter; Wang, Keqing; Ersvær, Elisabeth; McCormack, Emmet; Schüler, Julia; Fiebig, Heinz-Herbert; Gjertsen, Bjørn Tore; Bruserud, Øystein; Lord, Janet M.

    2014-01-01

    We showed previously that PEP005 induced apoptosis in leukaemic cell lines and blasts from patients with acute myeloid leukaemia (AML). Here we assess the anti-leukeamic effects of PEP005 in vivo and determine the mechanism of resistance of PEP005 non-responsive cells. We used 2 human xenograft mouse models of AML to assess the anti-leukaemic effects of PEP005 in vivo. Expression microarray analysis of primary AML blasts following treatment with PEP005 was used to determine patterns of gene expression that conferred resistance. PEP005 significantly reduced tumour burden in two human leukaemia mouse xenograft models. We also assessed responsiveness of 33 AML samples to PEP005, with 78% of the samples entering apoptosis at 100nM. Resistance to PEP005 was not restricted to a particular AML subtype. Expression microarray analysis of resistant samples following treatment with PEP005 revealed a significant up regulation of the anti-apoptotic genes Bcl-2A1, Mcl-1, and PHLDA1 which was verified using RT-PCR. We conclude that PEP005 shows broad efficacy against AML subtypes and that up regulation of anti-apoptotic genes underlies resistance to this agent and could be used to screen for patients unlikely to benefit from a therapeutic regime involving PEP005. PMID:25594060

  8. SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML.

    PubMed

    Kung Sutherland, May S; Walter, Roland B; Jeffrey, Scott C; Burke, Patrick J; Yu, Changpu; Kostner, Heather; Stone, Ivan; Ryan, Maureen C; Sussman, Django; Lyon, Robert P; Zeng, Weiping; Harrington, Kimberly H; Klussman, Kerry; Westendorf, Lori; Meyer, David; Bernstein, Irwin D; Senter, Peter D; Benjamin, Dennis R; Drachman, Jonathan G; McEarchern, Julie A

    2013-08-22

    Outcomes in acute myeloid leukemia (AML) remain unsatisfactory, and novel treatments are urgently needed. One strategy explores antibodies and their drug conjugates, particularly those targeting CD33. Emerging data with gemtuzumab ozogamicin (GO) demonstrate target validity and activity in some patients with AML, but efficacy is limited by heterogeneous drug conjugation, linker instability, and a high incidence of multidrug resistance. We describe here the development of SGN-CD33A, a humanized anti-CD33 antibody with engineered cysteines conjugated to a highly potent, synthetic DNA cross-linking pyrrolobenzodiazepine dimer via a protease-cleavable linker. The use of engineered cysteine residues at the sites of drug linker attachment results in a drug loading of approximately 2 pyrrolobenzodiazepine dimers per antibody. In preclinical testing, SGN-CD33A is more potent than GO against a panel of AML cell lines and primary AML cells in vitro and in xenotransplantation studies in mice. Unlike GO, antileukemic activity is observed with SGN-CD33A in AML models with the multidrug-resistant phenotype. Mechanistic studies indicate that the cytotoxic effects of SGN-CD33A involve DNA damage with ensuing cell cycle arrest and apoptotic cell death. Together, these data suggest that SGN-CD33A has CD33-directed antitumor activity and support clinical testing of this novel therapeutic in patients with AML.

  9. Prognostic significance of the BAALC isoform pattern and CEBPA mutations in pediatric acute myeloid leukemia with normal karyotype: a study by the Japanese Childhood AML Cooperative Study Group.

    PubMed

    Mizushima, Yasuhiro; Taki, Tomohiko; Shimada, Akira; Yui, Yoshihiro; Hiraumi, Yoshimi; Matsubara, Hiroshi; Watanabe, Motonobu; Watanabe, Ken-ichiro; Kamitsuji, Yuri; Hayashi, Yasuhide; Tsukimoto, Ichiro; Kobayashi, Ryoji; Horibe, Keizo; Tawa, Akio; Nakahata, Tatsutoshi; Adachi, Souichi

    2010-06-01

    High BAALC (brain and acute leukemia, cytoplasmic) gene expression may indicate an adverse prognosis for adults who have acute myeloid leukemia (AML) and a normal karyotype, but its prognostic significance for pediatric AML cases is unclear. Whether different BAALC isoform patterns are of prognostic significance is also unclear. Newly diagnosed AML patients with normal karyotype who were treated by the Japanese Childhood AML Cooperative Treatment Protocol AML 99 were analyzed in terms of their BAALC expression levels (n = 29), BAALC isoforms (n = 29), and CEBPA mutations (n = 49). Eleven and 18 patients exhibited high and low BAALC expression, respectively, but these groups did not differ significantly in terms of overall survival (54.6 vs. 61.1%, P = 0.55) or event-free survival (61.4 vs. 50.0%, P = 0.82). Three of these 29 patients (10.3%) expressed the exon 1-5-6-8 BAALC isoform along with the expected 1-6-8 isoform and had adverse clinical outcomes. Novel CEBPA mutations were also identified in four of 49 patients (8.2%). All four patients have maintained complete remission for at least 5 years. Thus, 1-5-6-8 isoform expression may be associated with an adverse prognosis in pediatric AML with normal karyotype. CEBPA mutations may indicate a favorable prognosis.

  10. 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

  11. 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.

  12. 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

  13. 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

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

    PubMed Central

    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

  15. 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

  16. 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.…

  17. 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…

  18. High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients.

    PubMed

    Barjesteh van Waalwijk van Doorn-Khosrovani, Sahar; Erpelinck, Claudia; van Putten, Wim L J; Valk, Peter J M; van der Poel-van de Luytgaarde, Sonja; Hack, Ronald; Slater, Rosalyn; Smit, Elisabeth M E; Beverloo, H Berna; Verhoef, Gregor; Verdonck, Leo F; Ossenkoppele, Gert J; Sonneveld, Pieter; de Greef, Georgine E; Löwenberg, Bob; Delwel, Ruud

    2003-02-01

    The proto-oncogene EVI1 encodes a DNA binding protein and is located on chromosome 3q26. The gene is aberrantly expressed in acute myeloid leukemia (AML) patients carrying 3q26 abnormalities. Two mRNAs are transcribed from this locus: EVI1 and a fusion of EVI1 with MDS1 (MDS1-EVI1), a gene located 5' of EVI1. The purpose of this study was to investigate which of the 2 gene products is involved in transformation in human AML. To discriminate between EVI1 and MDS1-EVI1 transcripts, distinct real-time quantitative polymerase chain reaction (PCR) assays were developed. Patients with 3q26 abnormalities often showed high EVI1 and MDS1-EVI1 expression. In a cohort of 319 AML patients, 4 subgroups could be distinguished: EVI1(+) and MDS1-EVI1(-) (6 patients; group I), EVI1(+) and MDS1-EVI1(+) (26 patients; group II), EVI1(-) and MDS1-EVI1(+) (12 patients; group III), and EVI1(-) and MDS1-EVI1(-) (275 patients; group IV). The only 4 patients with a 3q26 aberration belonged to groups I and II. Interestingly, high EVI1 and not MDS1-EVI1 expression was associated with unfavorable karyotypes (eg, -7/7q-) or complex karyotypes. Moreover, a significant correlation was observed between EVI1 expression and 11q23 aberrations (mixed lineage leukemia [MLL] gene involvement). Patients from groups I and II had significantly shorter overall and event-free survival than patients in groups III and IV. Our data demonstrate that high EVI1 expression is an independent poor prognostic marker within the intermediate- risk karyotypic group.

  19. Rac1 signaling protects monocytic AML cells expressing the MLL-AF9 oncogene from caspase-mediated apoptotic death.

    PubMed

    Hinterleitner, C; Huelsenbeck, J; Henninger, C; Wartlick, F; Schorr, A; Kaina, B; Fritz, G

    2013-08-01

    We investigated the relevance of signaling mechanisms regulated by the Ras-homologous GTPase Rac1 for survival of acute myeloid leukemia (AML) cells harbouring the MLL-AF9 oncogene due to t(9;11)(p21;q23) translocation. Monocytic MLL-AF9 expressing cells (MM6, THP-1) were hypersensitive to both small-molecule inhibitors targeting Rac1 (EHT 1864, NSC 23766) (IC50EHT ~12.5 μM) and lipid lowering drugs (lovastatin, atorvastatin) (IC50Lova ~7.5 μM) as compared to acute myelocytic leukemia (NOMO-1, HL60) and T cell leukemia (Jurkat) cells (IC50EHT >30 μM; IC50Lova >25 μM). Hypersensitivity of monocytic cells following Rac1 inhibition resulted from caspase-driven apoptosis as shown by profound activation of caspase-8,-9,-7,-3 and substantial (~90 %) decrease in protein expression of pro-survival factors (survivin, XIAP, p-Akt). Apoptotic death was preceded by S139-posphorylation of histone H2AX (γH2AX), a prototypical surrogate marker of DNA double-strand breaks (DSBs). Taken together, abrogation of Rac1 signaling causes DSBs in acute monocytic leukemia cells harbouring the MLL-AF9 oncogene, which, together with downregulation of survivin, XIAP and p-Akt, results in massive induction of caspase-driven apoptotic death. Apparently, Rac1 signaling is required for maintaining genetic stability and maintaining survival in specific subtypes of AML. Hence, targeting of Rac1 is considered a promising novel strategy to induce lethality in MLL-AF9 expressing AML. PMID:23624644

  20. Core binding factor acute myeloid leukemia (CBF-AML) in México: a single institution experience.

    PubMed

    Ruiz-Delgado, Guillermo J; Macías-Gallardo, Julio; Lutz-Presno, Julia; Garcés-Eisele, Javier; Hernández-Arizpe, Ana; Montes-Montiel, Maryel; Ruiz-Argüelles, Guillermo J

    2011-01-01

    Twenty one patients with CBF-AML presented prospectively in the Centro de Hematología y Medicina Interna de Puebla (Puebla, México) between February 1995 and March 2010, 14 with the t(8;21)(q22;q22) and 7 with the inv(16)(p13;q22)/t(16;16)(p13;q22); they represent 13% of all cases of AML. The median age of the patients was 24 years (range 1 to 61). Seven of 14 patients with t(8;21)(q22;q22) had an M2 morphology whereas 3/7 with the inv(16) had an M4 morphology; in addition to the myeloid markers identified by flow-cytometry (surface CD13, surface CD33, and cytoplasmic myeloperoxidase) lymphoid markers were identified in the blast cells of 8/14 cases of the t(8;21) patients, but in no patient with the inv(16). Nineteen patients were treated with combined chemotherapy and 16 (84%) achieved a complete molecular remission. Seven patients were auto or allografted. Relapses presented in 10/16 patients. The median probability of overall survival (OS) has not been reached being above 165 months, whereas the 165-month probability of OS and leukemia-free survival was 52%; despite a tendency for a better outcome of patients with the t(8;21), there were no significant differences in survival of patients with either the t(8;21) or the inv(16). In this single institution experience in México, we found that the CBF variants of AML have a similar prevalence as compared with Caucasian populations, that the co-expression of lymphoid markers in the blast cells was frequent in the t(8;21) and that these two AML subtypes were associated with a relatively good long-term prognosis. Further studies are needed to describe with more detail the precise biological features of these molecular subtypes of acute leukemia.

  1. The shortest isoform of C/EBPβ, liver inhibitory protein (LIP), collaborates with Evi1 to induce AML in a mouse BMT model.

    PubMed

    Watanabe-Okochi, Naoko; Yoshimi, Akihide; Sato, Tomohiko; Ikeda, Toshiyuki; Kumano, Keiki; Taoka, Kazuki; Satoh, Yumiko; Shinohara, Akihito; Tsuruta, Takako; Masuda, Akiko; Yokota, Hiromitsu; Yatomi, Yutaka; Takahashi, Koki; Kitaura, Jiro; Kitamura, Toshio; Kurokawa, Mineo

    2013-05-16

    Ecotropic viral integration site 1 (Evi1) is one of the master regulators in the development of acute myeloid leukemia (AML) and myelodysplastic syndrome. High expression of Evi1 is found in 10% of patients with AML and indicates a poor outcome. Several recent studies have indicated that Evi1 requires collaborative factors to induce AML. Therefore, the search for candidate factors that collaborate with Evi1 in leukemogenesis is one of the key issues in uncovering the mechanism of Evi1-related leukemia. Previously, we succeeded in making a mouse model of Evi1-related leukemia using a bone marrow transplantation (BMT) system. In the Evi1-induced leukemic cells, we identified frequent retroviral integrations near the CCAAT/enhancer-binding protein β (C/EBPβ) gene and overexpression of its protein. These findings imply that C/EBPβ is a candidate gene that collaborates with Evi1 in leukemogenesis. Cotransduction of Evi1 and the shortest isoform of C/EBPβ, liver inhibitory protein (LIP), induced AML with short latencies in a mouse BMT model. Overexpression of LIP alone also induced AML with longer latencies. However, excision of all 3 isoforms of C/EBPβ (LAP*/LAP/LIP) did not inhibit the development of Evi1-induced leukemia. Therefore, isoform-specific intervention that targets LIP is required when we consider C/EBPβ as a therapeutic target.

  2. Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51

    PubMed Central

    Edwards, Holly; Caldwell, J. Timothy; Chen, Wei; Inaba, Hiroto; Xu, Xuelian; Buck, Steven A.; Taub, Jeffrey W.; Baker, Sharyn D.; Ge, Yubin

    2013-01-01

    Acute myeloid leukemia (AML) remains a challenging disease to treat and urgently requires new therapies to improve its treatment outcome. In this study, we investigated the molecular mechanisms underlying the cooperative antileukemic activities of panobinostat and cytarabine or daunorubicin (DNR) in AML cell lines and diagnostic blast samples in vitro and in vivo. Panobinostat suppressed expression of BRCA1, CHK1, and RAD51 in AML cells in a dose-dependent manner. Further, panobinostat significantly increased cytarabine- or DNR-induced DNA double-strand breaks and apoptosis, and abrogated S and/or G2/M cell cycle checkpoints. Analogous results were obtained by shRNA knockdown of BRCA1, CHK1, or RAD51. Cotreatment of NOD-SCID-IL2Rγnull mice bearing AML xenografts with panobinostat and cytarabine significantly increased survival compared to either cytarabine or panobinostat treatment alone. Additional studies revealed that panobinostat suppressed the expression of BRCA1, CHK1, and RAD51 through downregulation of E2F1 transcription factor. Our results establish a novel mechanism underlying the cooperative antileukemic activities of these drug combinations in which panobinostat suppresses expression of BRCA1, CHK1, and RAD51 to enhance cytarabine and daunorubicin sensitivities in AML cells. PMID:24244429

  3. Real-time quantitative PCR detection of WT1 gene expression in children with AML: prognostic significance, correlation with disease status and residual disease detection by flow cytometry.

    PubMed

    Trka, J; Kalinová, M; Hrusák, O; Zuna, J; Krejcí, O; Madzo, J; Sedlácek, P; Vávra, V; Michalová, K; Jarosová, M; Starý, J

    2002-07-01

    The clinical significance of WT1 gene expression at diagnosis and during therapy of AML has not yet been resolved. We analysed WT1 expression at presentation in an unselected group of 47 childhood AML patients using real-time quantitative reverse-transcription PCR. We also showed that within the first 30 h following aspiration RQ-RT-PCR results were not influenced by transportation time. We observed lower levels of WT1 transcript in AML M5 (P = 0.0015); no association was found between expression levels and sex, initial leukocyte count and karyotype-based prognostic groups. There was significant correlation between very low WT1 expression at presentation and excellent outcome (EFS P = 0.0014). Combined analysis of WT1 levels, three-colour flow cytometry residual disease detection and the course of the disease in 222 samples from 28 children with AML showed remarkable correlation. Fourteen patients expressed high WT1 levels at presentation. In eight of them, who suffered relapse or did not reach complete remission, dynamics of WT1 levels clearly correlated with the disease status and residual disease by flow cytometry. We conclude that very low WT1 levels at presentation represent a good prognostic factor and that RQ-RT-PCR-based analysis of WT1 expression is a promising and rapid approach for monitoring of MRD in approximately half of paediatric AML patients.

  4. 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.

  5. NK cell expression of natural cytotoxicity receptors may determine relapse risk in older AML patients undergoing immunotherapy for remission maintenance

    PubMed Central

    Martner, Anna; Rydström, Anna; Riise, Rebecca E.; Aurelius, Johan; Brune, Mats; Foà, Robin; Hellstrand, Kristoffer; Thorén, Fredrik B.

    2015-01-01

    In a phase IV trial, eighty-four patients (age 18–79) with acute myeloid leukemia (AML) in first complete remission (CR) received cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose human recombinant interleukin-2 (IL-2) to prevent relapse in the post-consolidation phase. Aspects of natural killer (NK) cell biology were analyzed before and during immunotherapy with focus on outcome in older patients. In younger (<60 years old, n = 37) and older patients (>60 years old, n = 47), treatment with HDC/IL-2 resulted in an expansion of CD56bright and CD16+ NK cells in blood along with an increased NK cell expression of the natural cytotoxicity receptors (NCR) NKp30 and NKp46. In older patients, a high expression of NKp30 or NKp46 on CD16+ NK cells before and during therapy predicted leukemia-free and overall survival. These results suggest that NK cell functions determine relapse risk and survival in older AML patients and point to biomarkers of efficacy in protocols for remission maintenance. PMID:26544512

  6. 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

  7. The novel structure make LDM effectively remove CD123+ AML stem cells in combination with interleukin 3

    PubMed Central

    Zhang, Yanjun; Liu, Rong; Fan, Dongmei; Shi, Rizan; Yang, Ming; Miao, Qingfang; Deng, Zhao-Qun; Qian, Jun; Zhen, Yongsu; Xiong, Dongsheng; Wang, Jianxiang

    2015-01-01

    CD123 became a therapeutic target for acute myelocytic leukemia(AML) because of its overexpression only on AML stem cells. It is α subunit of interleukin-3 (multi-CSF, IL3) receptor. Lidamycin(LDM) is a novel antibiotic composed of an apoprotein (LDP) and a chromophore (AE). We cloned, expressed and isolated IL3LDP fusion protein first then assembled with AE in vitro. We found that131/132 amino acids of IL3 were the key factors for IL3 fusion protein stability and I131L/F132L mutation effectively improved the IL3 fusion protein stability. The toxicity of IL3LDM to CD123+ tumor cells was 2–10 times compared to LDM alone and 10000 times compared to ADR. Meanwhile, IL3LDM impaired the colony-forming ability of CD123+ stem-like cells but not to CD123 negative normal cord blood cells. Three drug delivery methods in vivo were adopted: prophylactic treatment and single/multiple-dosing administration. The tumor-free survival extended to 120 d and cancer cell invasion significantly decreased after IL3LDM continuous multiple treated. Moreover, IL3LDM had been shown to modulate apoptosis by arrested cell cycle in G2/M phase. Therefore, IL3LDM is expected to be a new drug for leukemia target therapy. PMID:26186454

  8. 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.

  9. The Runx-PU.1 pathway preserves normal and AML/ETO9a leukemic stem cells.

    PubMed

    Staber, Philipp B; Zhang, Pu; Ye, Min; Welner, Robert S; Levantini, Elena; Di Ruscio, Annalisa; Ebralidze, Alexander K; Bach, Christian; Zhang, Hong; Zhang, Junyan; Vanura, Katrina; Delwel, Ruud; Yang, Henry; Huang, Gang; Tenen, Daniel G

    2014-10-01

    Runx transcription factors contribute to hematopoiesis and are frequently implicated in hematologic malignancies. All three Runx isoforms are expressed at the earliest stages of hematopoiesis; however, their function in hematopoietic stem cells (HSCs) is not fully elucidated. Here, we show that Runx factors are essential in HSCs by driving the expression of the hematopoietic transcription factor PU.1. Mechanistically, by using a knockin mouse model in which all three Runx binding sites in the -14kb enhancer of PU.1 are disrupted, we observed failure to form chromosomal interactions between the PU.1 enhancer and its proximal promoter. Consequently, decreased PU.1 levels resulted in diminished long-term HSC function through HSC exhaustion, which could be rescued by reintroducing a PU.1 transgene. Similarly, in a mouse model of AML/ETO9a leukemia, disrupting the Runx binding sites resulted in decreased PU.1 levels. Leukemia onset was delayed, and limiting dilution transplantation experiments demonstrated functional loss of leukemia-initiating cells. This is surprising, because low PU.1 levels have been considered a hallmark of AML/ETO leukemia, as indicated in mouse models and as shown here in samples from leukemic patients. Our data demonstrate that Runx-dependent PU.1 chromatin interaction and transcription of PU.1 are essential for both normal and leukemia stem cells.

  10. 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

  11. 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

  12. Activated leukemic oncogenes AML1-ETO and c-kit: role in development of acute myeloid leukemia and current approaches for their inhibition.

    PubMed

    Rulina, A V; Spirin, P V; Prassolov, V S

    2010-12-01

    Acute myeloid leukemia (AML) is a malignant blood disease caused by different mutations that enhance the proliferative activity and survival of blood cells and affect their differentiation and apoptosis. The most frequent disorders in AML are translocations between chromosomes 21 and 8 leading to production of a chimeric oncogene, AML1-ETO, and hyperexpression of the receptor tyrosine kinase KIT. Mutations in these genes often occur jointly. The presence in cells of two activated oncogenes is likely to trigger their malignization. The current approaches for treatment of oncologic diseases (bone marrow transplantation, radiotherapy, and chemotherapy) have significant shortcomings, and thus many laboratories are intensively developing new approaches against leukemias. Inhibiting expression of activated leukemic oncogenes based on the principle of RNA interference seems to be a promising approach in this field.

  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.

  14. 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.

  15. Cell cycle status in AML blast cells from peripheral blood, bone marrow aspirates and trephines and implications for biological studies and treatment.

    PubMed

    Sellar, Rob S; Fraser, Laura; Khwaja, Asim; Gale, Rosemary E; Marafioti, Teresa; Akarca, Ayse; Hubank, Mike; Brooks, Tony; Stoeber, Kai; Williams, Gareth; Linch, David C

    2016-07-01

    Using immunohistochemistry and flow cytometry to define phases of the cell cycle, this study shows that a high proportion of acute myeloid leukaemia (AML) blasts obtained from trephine biopsies are cycling, whereas >95% of peripheral blood-derived blasts are arrested in G1 . Results obtained from bone marrow aspirates are more similar to those from blood rather than from trephine biopsies. These differences were confirmed by gene expression profiling in a patient with high count AML. This has implications for cell cycle and other biological studies using aspirates rather than trephine biopsies and for the use of cell mobilising agents before chemotherapy. PMID:27061724

  16. The Kubo-Greenwood expression and 2d MIT transport

    NASA Astrophysics Data System (ADS)

    Castner, Theodore

    2010-03-01

    The 2d MIT in GaAs heterostructures (p- and n-type)features a mobility that drops continuously as the reduced density x= n/nc-1 is decreased. The Kubo-Greenwood result [1] predicts μ = (eɛh/hnc)α^2(x) where α is a normalized DOS. α(x)is obtained from the data [p-type, Gao et al. [2]; n-type Lilly et al. [3

  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. 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

  19. Outcome in 146 patients with paediatric acute myeloid leukaemia treated according to the AML99 protocol in the period 2003-06 from the Japan Association of Childhood Leukaemia Study.

    PubMed

    Imamura, Toshihiko; Iwamoto, Shotaro; Kanai, Rie; Shimada, Akira; Terui, Kiminori; Osugi, Yuko; Kobayashi, Ryoji; Tawa, Akio; Kosaka, Yoshiyuki; Kato, Koji; Hori, Hiroki; Horibe, Keizo; Oda, Megumi; Adachi, Souichi

    2012-10-01

    The acute myeloid leukaemia (AML) 99 trial conducted previously in Japan for the treatment of de novo paediatric AML showed excellent results, with a 5-year overall survival (OS) and event-free survival (EFS) of 75·6% and 61·6%, respectively. To examine reproducibility of these results in another cohort, the outcome of 146 newly diagnosed AML paediatric patients prospectively registered in the Japan Association of Childhood Leukaemia Study (JACLS) from 2003 to 2006 was compared to that of 240 patients in the original AML 99 clinical trial. The 5-year EFS and OS achieved in the new cohort was 66·7 ± 4·0% and 77·7 ± 8·0% respectively, which were comparable to those obtained in the original AML 99 clinical trial, although less frequent core-binding factor (CBF) AML (29·5% vs. 37%) and an almost equal frequency of allogeneic haematopoietic stem cell transplantation (allo-HSCT) during first complete remission (16·5% vs. 19%) were observed. The 5-year EFS in patients with a normal karyotype (NK) (n = 35, 54·9 ± 15·1%) was inferior in the present cohort when compared to the original AML99 trial. This study confirmed the excellent outcome of the original AML99 protocol.

  20. 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

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

    PubMed

    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.

  2. 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

  3. AML1/ETO accelerates cell migration and impairs cell-to-cell adhesion and homing of hematopoietic stem/progenitor cells

    PubMed Central

    Saia, Marco; Termanini, Alberto; Rizzi, Nicoletta; Mazza, Massimiliano; Barbieri, Elisa; Valli, Debora; Ciana, Paolo; Gruszka, Alicja M.; Alcalay, Myriam

    2016-01-01

    The AML1/ETO fusion protein found in acute myeloid leukemias functions as a transcriptional regulator by recruiting co-repressor complexes to its DNA binding site. In order to extend the understanding of its role in preleukemia, we expressed AML1/ETO in a murine immortalized pluripotent hematopoietic stem/progenitor cell line, EML C1, and found that genes involved in functions such as cell-to-cell adhesion and cell motility were among the most significantly regulated as determined by RNA sequencing. In functional assays, AML1/ETO-expressing cells showed a decrease in adhesion to stromal cells, an increase of cell migration rate in vitro, and displayed an impairment in homing and engraftment in vivo upon transplantation into recipient mice. Our results suggest that AML1/ETO expression determines a more mobile and less adherent phenotype in preleukemic cells, therefore altering the interaction with the hematopoietic niche, potentially leading to the migration across the bone marrow barrier and to disease progression. PMID:27713544

  4. Dual inhibition of AKT/FLT3-ITD by A674563 overcomes FLT3 ligand-induced drug resistance in FLT3-ITD positive AML

    PubMed Central

    Wang, Wenchao; Yu, Kailin; Liu, Xiaochuan; Zou, Fengming; Zhao, Zheng; Wu, Jiaxin; Liu, Juan; Liu, Feiyang; Wang, Li; Stone, Richard M.; Galinksy, Ilene A.; Griffin, James D.; Zhang, Shanchun; Weisberg, Ellen L.; Liu, Jing; Liu, Qingsong

    2016-01-01

    The FLT3-ITD mutation is one of the most prevalent oncogenic mutations in AML. Several FLT3 kinase inhibitors have shown impressive activity in clinical evaluation, however clinical responses are usually transient and clinical effects are rapidly lost due to drug resistance. One of the resistance mechanisms in the AML refractory patients involves FLT3-ligand induced reactivation of AKT and/or ERK signaling via FLT3 wt kinase. Via a screen of numerous AKT kinase inhibitors, we identified the well-established orally available AKT inhibitor, A674563, as a dual suppressor of AKT and FLT3-ITD. A674563 suppressed FLT3-ITD positive AML both in vitro and in vivo. More importantly, compared to other FLT3 inhibitors, A674563 is able to overcome FLT3 ligand-induced drug resistance through simultaneous inhibition of FLT3-ITD- and AKT-mediated signaling. Our findings suggest that A674563 might be a potential drug candidate for overcoming FLT3 ligand-mediated drug resistance in FLT3-ITD positive AML. PMID:27074558

  5. 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

  6. Multilineage dysplasia does not influence prognosis in CEBPA-mutated AML, supporting the WHO proposal to classify these patients as a unique entity.

    PubMed

    Bacher, Ulrike; Schnittger, Susanne; Macijewski, Katja; Grossmann, Vera; Kohlmann, Alexander; Alpermann, Tamara; Kowarsch, Andreas; Nadarajah, Niroshan; Kern, Wolfgang; Haferlach, Claudia; Haferlach, Torsten

    2012-05-17

    In 2008, the World Health Organization introduced CEBPA (encoding the CCAAT/enhancer binding protein)-mutated acute myeloid leukemia (AML) as a provisional entity. However, the classification of CEBPA-mutated AML with multilineage dysplasia (MLD; ≥ 50% dysplastic cells in 2-3 lineages) remains to be clarified. In the present study, we investigated 108 CEBPA-mutated AML patients for the impact of MLD, karyotype, and additional mutations. MLD(+) patients differed from MLD(-) patients only by lower mean WBC counts, not by biologic characteristics, cytogenetic risk profiles, or additional mutations. Survival was better for female patients, patients < 60 years of age, for intermediate versus adverse karyotypes, and, in the case of FLT3-ITD negativity, biallelic versus monoallelic/homozygous CEBPA mutations. In contrast, 2-year overall survival and event-free survival did not differ significantly between MLD(+) and MLD(-) patients. By univariable Cox regression analysis, sex, age, WBC count, and cytogenetic risk category were related to overall survival, but MLD was not. Therefore, because dysplasia is not relevant for this subtype, CEBPA-mutated AML patients should be characterized only according to mutation status, cytogenetic risk group, or additional mutations. PMID:22442349

  7. Role of Misfolded N-CoR Mediated Transcriptional Deregulation of Flt3 in Acute Monocytic Leukemia (AML)-M5 Subtype

    PubMed Central

    Nin, Dawn Sijin; Kok, Wai Kay; Li, Feng; Takahashi, Shinichiro; Chng, Wee Joo; Khan, Matiullah

    2012-01-01

    The nuclear receptor co-repressor (N-CoR) is a key component of the generic multi-protein complex involved in transcriptional control. Flt3, a key regulator of hematopoietic cell growth, is frequently deregulated in AML (acute myeloid leukemia). Here, we report that loss of N-CoR-mediated transcriptional control of Flt3 due to misfolding, contributes to malignant growth in AML of the M5 subtype (AML-M5). An analysis of hematopoietic genes in AML cells led to the identification of Flt3 as a transcriptional target of N-CoR. Flt3 level was inversely related to N-CoR status in various leukemia cells. N-CoR was associated with the Flt3 promoter in-vivo, and a reporter driven by the Flt3 promoter was effectively repressed by N-CoR. Blocking N-CoR loss with Genistein; an inhibitor of N-CoR misfolding, significantly down-regulated Flt3 levels regardless of the Flt3 receptor mutational status and promoted the differentiation of AML-M5 cells. While stimulation of the Flt3 receptor with the Flt3 ligand triggered N-CoR loss, Flt3 antibody mediated blockade of Flt3 ligand-receptor binding led to N-CoR stabilization. Genetic ablation of N-CoR potentiated Flt3 ligand induced proliferation of BA/F3 cells. These findings suggest that N-CoR-induced repression of Flt3 might be crucial for limiting the contribution of the Flt3 signaling pathway on the growth potential of leukemic cells and its deregulation due to N-CoR loss in AML-M5, could contribute to malignant growth by conferring a proliferative advantage to the leukemic blasts. Therapeutic restoration of N-CoR function could thus be a useful approach in restricting the contribution of the Flt3 signaling pathway in AML-M5 pathogenesis. PMID:22514634

  8. Mitotic crossover promotes leukemogenesis in children born with TEL-AML1 via the generation of loss of heterozygosity at 12p.

    PubMed

    Ivanovski, Ivan; Garavelli, Livia; Djurić, Olivera; Ćirović, Aleksandar; Škorić, Dejan; Ivanovski, Petar I

    2015-01-01

    TEL-AML1 (ETV6-RUNX1) fusion gene which is formed prenatally in 1% of the newborns, is a common genetic abnormality in childhood Bcell precursor acute lymphoblastic leukemia. But only one child out of a hundred children born with this fusion gene develops leukemia (bottleneck phenomenon) later in its life, if contracts the second mutation. In other words, out of a hundred children born with TEL-AML1 only one child is at risk for leukemia development, which means that TEL-AML1 fusion gene is not sufficient for overt leukemia. There is a stringent requirement for a second genetic abnormality for leukemia development and this is the real or the ultimate cause of the leukemia bottleneck phenomenon. In most cases of TEL-AML1+ leukemia, the translocation t(12;21) is complemented with the loss of the normal TEL gene, not involved in the translocation, on the contralateral 12p. The loss of the normal TEL gene, i.e. loss of heterozygosity at 12p, occurs postnatally during the mitotic proliferation of TEL-AML1+ cell in the mitotic crossing over process. Mitotic crossing over is a very rare event with a frequency rate of 10-6 in a 10 kb region. The exploration and identification of the environmental exposure(s) that cause(s) proliferation of the TELAML1+ cell in which approximately 106 mitoses are generated to cause 12p loss of heterozygosity, i.e. TEL gene deletion, may contribute to the introduction of preventive measures for leukemia. PMID:26429121

  9. 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.

  10. Real-time control of the MIT vehicle emulation system

    NASA Technical Reports Server (NTRS)

    Durfee, William K.; Idris, Husni R.; Dubowsky, Steven

    1991-01-01

    The MIT vehicle emulation system (VES) is an experimental facility designed to facilitate the study of controlling robots fixed to nonstationary bases. This includes assembly and repair manipulators attached to space vehicles, or to the space shuttle arm, as well as manipulators fixed to the bed of moving ground vehicles. Controlling manipulators under these conditions for endpoint force and positioning tasks requires both the development of new theory, and the development of a testbed for verifying theoretical results through experimentation. A description is presented of the technical details of the real-time controller for the second generation VES system.

  11. 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.}

  12. 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

  13. Brennraumdruckregelung von Dieselmotoren mit homogener Kompressionszündung (HCCI)

    NASA Astrophysics Data System (ADS)

    Kohlhase, Martin

    In den letzten Jahren ist die Zahl der neu zugelassenen Dieselfahrzeuge stark gestiegen. Diese Entwicklung ist zum einen darauf zurückzuführen, dass der Dieselmotor im Vergleich zum Ottomotor einen besseren thermischen Wirkungsgrad aufweist. Einhergehend damit ist der Kraftstoffverbrauch und somit der CO2-Ausstoß im Gegensatz zum Ottomotor deutlich geringer. Zum anderen hat der Dieselmotor im Bereich Fahrspaß und -komfort durch Einzug der Direkteinspritzung basierend auf Common-Rail-Systemen und durch effiziente Abgasturbolader mit variabler Turbinengeometrie (VTG) deutlich an Akzeptanz gewonnen.

  14. 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.

  15. 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

  16. MIT Lincoln Laboratory: Physics and Technology in the National Interest

    NASA Astrophysics Data System (ADS)

    Ralston, Richard

    2001-03-01

    This year, MIT is celebrating the 50th anniversary of the founding of Lincoln Laboratory, which was formed at the request of the DoD with the initial goal of developing a national air defense system. In its 50 years, the Laboratory staff have made significant contributions in diverse areas including radar imaging, satellite communications, digital signal processing, computer science, semiconductor materials and solid state physics. The Laboratory has been true to its mission statement, which places strong emphasis on the application of advanced electronics to R&D in the national interest. Much of the technology is transitioned to U.S. industry for both government and commercial use. Annually more than 500 publications and meeting speeches are given, and cooperative developments with industry have targeted technology transitions ranging from next-generation photolithographic tools to microchip lasers. The Laboratory staff have been granted over 400 patents, and license to this intellectual property is at the core of many of the over 70 spin-off companies. MIT employs 2,300 people at Lincoln, including 1,200 professionals with degrees in physics, math, computer science, materials science and the engineering disciplines. Two-fifths of the professional staff are at the doctoral level; over two-thirds hold advanced degrees. This presentation will describe recent examples of research challenges for physicists in a multidisciplinary project-oriented environment.

  17. MIT nuclear reactor laboratory high school teaching program

    SciTech Connect

    Olmez, I. )

    1991-11-01

    For the last 6 years, the Massachusetts Institute of Technology (MIT) Nuclear Reactor Laboratory's academic and scientific staff{sup a} have been conducting evening seminars for precollege science teachers, parents, and high school students from the New England area. These seminars, as outlined in this paper, are intended to give general information on nuclear technologies with specific emphasis on radiation physics, nuclear medicine, nuclear chemistry, and ongoing research activities at the MIT research reactor. The ultimate goal is to create interest or build on the already existing interest in science and technology by, for example, special student projects. Several small projects have already been completed ranging from environmental research to biological reactions with direct student involvement. Another outcome of these seminars was the change in attitudes of science teachers toward nuclear technology. Numerous letters have been received from the teachers and parents stating their previous lack of knowledge on the beneficial aspects of nuclear technologies and the subsequent inclusion of programs in their curriculum for educating students so that they may also develop a more positive attitude toward nuclear power.

  18. 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.

  19. 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…

  20. 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…

  1. 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…

  2. 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…

  3. 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.

  4. 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…

  5. Extramedullary relapse of AML with t(9;11)(p22;q23) associated with clonal evolution from trisomy 8 into tetrasomy 8.

    PubMed

    Takahashi, Tohru; Tsukuda, Hiroyuki; Kimura, Hirokazu; Yoshimoto, Mitsuru; Tsujisaki, Masayuki

    2010-01-01

    This report describes a patient with extramedullary relapse of acute myeloid leukemia (AML) without involving bone marrow. A 57-year-old man was diagnosed as having acute monoblastic leukemia with t(9;11)(p22;q23) and trisomy 8. Ten months after achieving complete response (CR) with chemotherapy, masses developed in his left forearm and in the back of his thigh, preceded by enigmatic peripheral neurological symptoms. Aspiration from the forearm showed leukemic relapse, and fluorescence in situ hybridization (FISH) revealed that the majority of the cells had 11q23 anomaly and tetrasomy 8. Bone marrow or meningeal relapse was not observed. To our knowledge, this is the first case report of clonal evolution associated with the development of myeloid sarcoma as a relapse in AML. PMID:20190481

  6. 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

  7. Treatment and long-term results in children with acute myeloid leukaemia treated according to the AIEOP AML protocols.

    PubMed

    Pession, A; Rondelli, R; Basso, G; Rizzari, C; Testi, A M; Fagioli, F; De Stefano, P; Locatelli, F

    2005-12-01

    Since 1982, four consecutive studies on childhood acute myeloid leukaemia (AML) (namely LAM-82, -87, -87M and -92) have been conducted in Italy by the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) group. The induction therapy of the first three studies consisted of daunorubicin and cytarabine structured in a 3+7 backbone. In the most recent protocol (LAM92), patients received two induction courses including idarubicin, cytarabine and etoposide. Patients with acute promyelocytic leukaemia (20% of diagnoses) were included in LAM-87 and 87M studies. Postremissional therapy significantly changed over time, with an ever-increasing role given to stem cell transplantation (SCT). The long-term outcome of patients enrolled in the LAM-82, 87 and 87M studies was comparable, whereas that of children treated according to LAM-92 study was significantly better (P<0.005). Either allogeneic or autologous SCT was employed as consolidation therapy in more than 75% of cases enrolled in this latter study. Patients enrolled in the LAM-92 study were stratified in standard and high-risk groups with different outcome (67 vs 47%, respectively, P=0.04). Altogether, the results obtained in these four studies have permitted a progressive refinement of treatment, contributing to the structure of the ongoing LAM-2002 protocol that stratifies patients according to the presence of definite genetic anomalies and response to induction therapy.

  8. 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.

  9. Energy Flow in the Magnetosphere-Ionosphere-Thermosphere (MIT) System

    NASA Astrophysics Data System (ADS)

    Huang, C. Y.; Huang, Y.; Su, Y. J.; Sutton, E. K.; Hairston, M. R.

    2015-12-01

    The conventional model of energy input and dissipation in the IT system assumes that the auroral zone is the primary locus for these processes. Recent work has revealed that, contrary to this traditional view, the polar cap can play a significant role in energy transfer during magnetic storms. DMSP measurements of DC Poynting flux shows high levels of electromagnetic energy entering the polar cap at all local times (LTs) in both hemispheres during storms. An analysis of ion temperature observations at DMSP altitudes shows that the largest temperature increases occur at polar latitudes during magnetic activity. Finally, observations of neutral densities from the CHAMP, GRACE and GOCE spacecraft show that the highest frequency of occurrence of heated neutrals occurs close to the poles in both hemispheres. These results demand a revision of the standard paradigm for MIT coupling.

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

    PubMed

    Harrington, Kimberly H; Gudgeon, Chelsea J; 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.

  11. 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

  12. High prognostic value of minimal residual disease detected by flow-cytometry-enhanced fluorescence in situ hybridization in core-binding factor acute myeloid leukemia (CBF-AML).

    PubMed

    Wang, Libing; Gao, Lei; Xu, Sheng; Gong, Shenglan; Liu, Min; Qiu, Huiying; Xu, Xiaoqian; Ni, Xiong; Chen, Li; Lu, Shuqing; Chen, Jie; Song, Xianmin; Zhang, Weiping; Yang, Jianmin; Hu, Xiaoxia; Wang, Jianmin

    2014-10-01

    Acute myeloid leukemia (AML) is generally regarded as a disorder of stem cells, known as leukemic initiating cells (LICs), which initiate the disease and contribute to relapses. Although the phenotype of these cells remains unclear in most patients, they are enriched within the CD34(+)CD38(-) population. In core-binding factor (CBF) AML, the cytogenetic abnormalities also exist in LIC. The aim of this study was to determine the prognostic power of minimal residual disease (MRD) measured by fluorescence in situ hybridization (FISH) in CD34(+)CD38(-) cells sorted by flow cytometry at different periods during therapy. Thirty-six patients under 65 years of age with de novo CBF-AML treated with intensive chemotherapy were retrospectively included in this study. Correlations with relapse-free survival (RFS) and overall survival were evaluated with univariate and multivariate analyses. FISH efficiently identified LICs in the CD34(+)CD38(-) population. The presence of FISH(+)CD34(+)CD38(-) cells before consolidation was negatively associated with cumulative incidence of relapse (64 vs 18 %, P = .012), which showed prognostic value for RFS (12 vs 68 %, P = .008) and OS (11 vs 75 %, P = .0005), and retained prognostic significance for RFS in multivariate analysis. The detection of FISH(+)CD34(+)CD38(-) cells before consolidation therapy significantly correlated with long-term survival. Fluorescence-activated cell sorting (FACS)-FISH could be potentially adopted as a MRD monitor approach in clinical practice to identify CBF-AML patients at risk of treatment failure during therapy.

  13. [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…

  14. 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

  15. The addition of arsenic trioxide to low-dose Ara-C in older patients with AML does not improve outcome.

    PubMed

    Burnett, A K; Hills, R K; Hunter, A; Milligan, D; Kell, J; Wheatley, K; Yin, J; McMullin, M-F; Cahalin, P; Craig, J; Bowen, D; Russell, N

    2011-07-01

    Most patients with acute myeloid leukaemia (AML) are older, with many unsuitable for conventional chemotherapy. Low-dose Ara-C (LDAC) is superior to best supportive care but is still inadequate. The combination of arsenic trioxide (ATO) and LDAC showed promise in an unrandomised study. We report a randomised trial of LDAC versus LDAC+ATO. Patients with AML according to WHO criteria or myelodysplastic syndrome with >10% blasts, considered as unfit for conventional chemotherapy, were randomised between subcutaneous Ara-C (20 mg b.d. for 10 days) and the same LDAC schedule with ATO (0.25 mg/kg) on days 1-5, 9 and 11, for at least four courses every 4 to 6 weeks. Overall 166 patients were entered; the trial was terminated on the advice of the DMC, as the projected benefit was not observed. Overall 14% of patients achieved complete remission (CR) and 7% CRi. Median survival was 5.5 months and 19 months for responders (CR: not reached; CRi: 14 months; non-responders: 4 months). There were no differences in response or survival between the arms. Grade 3/4 cardiac and liver toxicity, and supportive care requirements were greater in the ATO arm. This randomised comparison demonstrates that adding ATO to LDAC provides no benefit for older patients with AML.

  16. Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML.

    PubMed

    Falini, Brunangelo; Bolli, Niccolò; Shan, Jing; Martelli, Maria Paola; Liso, Arcangelo; Pucciarini, Alessandra; Bigerna, Barbara; Pasqualucci, Laura; Mannucci, Roberta; Rosati, Roberto; Gorello, Paolo; Diverio, Daniela; Roti, Giovanni; Tiacci, Enrico; Cazzaniga, Giovanni; Biondi, Andrea; Schnittger, Suzanne; Haferlach, Torsten; Hiddemann, Wolfgang; Martelli, Massimo F; Gu, Wei; Mecucci, Cristina; Nicoletti, Ildo

    2006-06-01

    We recently identified aberrant cytoplasmic expression of nucleophosmin (NPM) as the immunohistochemical marker of a large subgroup of acute myeloid leukemia (AML) (about one-third of adult AML) that is characterized by normal karyotype and mutations occurring at the exon-12 of the NPM gene. In this paper, we have elucidated the molecular mechanism underlying the abnormal cytoplasmic localization of NPM. All 29 AML-associated mutated NPM alleles so far identified encode abnormal proteins which have acquired at the C-terminus a nuclear export signal (NES) motif and lost both tryptophan residues 288 and 290 (or only the residue 290) which determine nucleolar localization. We show for the first time that both alterations are crucial for NPM mutant export from nucleus to cytoplasm. In fact, the cytoplasmic accumulation of NPM is blocked by leptomycin-B and ratjadones, specific exportin-1/Crm1-inhibitors, and by reinsertion of tryptophan residues 288 and 290, which respectively relocate NPM mutants in the nucleoplasm and nucleoli. NPM leukemic mutants in turn recruit the wild-type NPM from nucleoli to nucleoplasm and cytoplasm. These findings indicate that potential therapeutic strategies aimed to retarget NPM to its physiological sites will have to overcome 2 obstacles, the new NES motif and the mutated tryptophan(s) at the NPM mutant C-terminus.

  17. Targeted i.v. BU and fludarabine (t-i.v. BU/Flu) provides effective control of AML in adults with reduced toxicity.

    PubMed

    Pidala, J; Kim, J; Anasetti, C; Kharfan-Dabaja, M A; Field, T; Perkins, J; Ayala, E; Perez, L; Fernandez, H

    2011-05-01

    Myeloablative doses of BU and fludarabine followed by allogeneic hematopoietic cell transplantation offer effective therapy for AML. We anticipated that pharmacokinetic targeting of i.v. BU to 5300 μM/L min/day × 4 (targeted i.v. BU and fludarabine (t-i.v. BU/Flu)) would limit nonrelapse mortality (NRM) in adults up to 70 years of age. We assessed the safety and efficacy of t-i.v. BU/Flu in a series of 100 adults (median age 48, range 22-69 years) with AML in the first CR (CR1) with high risk of treatment failure (n=49), second CR (CR2, n=25), relapsed disease (REL, n=9), primary induction failure (PIF, n=16) and untreated (n=1). NRM was 3% at 100 days and 15% at 1 year. The cumulative incidence of relapse was 30.6% for CR1, 41.7% for CR2, 55.6% for REL and 58.6% for PIF. OS for primary AML in CR1 was 66% (95% confidence interval (CI): 46-80%) at 1 year, and 62% (95% CI: 42-77%) at 2 years. On multivariable modeling, remission status, moderate/severe chronic GVHD and day-90 BM chimerism ≥90% predicted improved OS. Importantly, there was no effect of age. t-i.v. BU/Flu provides effective disease control with encouraging NRM in patients up to age of 70 years. PMID:20711242

  18. 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

  19. MDS/AML-associated cytogenetic abnormalities in multiple myeloma and monoclonal gammopathy of undetermined significance: evidence for frequent de novo occurrence and multipotent stem cell involvement of del(20q).

    PubMed

    Nilsson, Therese; Nilsson, Lars; Lenhoff, Stig; Rylander, Lars; Astrand-Grundström, Ingbritt; Strömbeck, Bodil; Höglund, Mattias; Turesson, Ingemar; Westin, Jan; Mitelman, Felix; Jacobsen, Sten E W; Johansson, Bertil

    2004-11-01

    Multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are characterized cytogenetically by 14q32 rearrangements, -13/13q-, and various trisomies. Occasionally, karyotypic patterns characteristic of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) occur in MM, often signifying therapy-related (t)-MDS/t-AML. Comparison of cytogenetic features in all published MMs (n = 993) and t-MDS/t-AML post-MM (n = 117) revealed significant differences in complexity and ploidy levels and in most genomic changes. Thus, these features often can be used to distinguish between MM and t-MDS/t-AML. Rarely, myeloid-associated aberrations are detected in MM without any signs of MDS/AML. To characterize such abnormalities in MM/MGUS, we ascertained all 122 MM and 26 MGUS/smoldering MM (SMM) cases analyzed in our department. Sixty-six (54%) MMs and 8 (31%) MGUS/SMMs were karyotypically abnormal, of which 6 (9%) MMs and 3 (38%) MGUS/SMMs displayed myeloid abnormalities, that is, +8 (1 case) and 20q- (8 cases) as the sole anomalies, without any evidence of MDS/AML. One patient developed AML, whereas no MDS/AML occurred in the remaining 8 patients. In one MGUS with del(20q), fluorescence in situ hybridization analyses revealed its presence in CD34+CD38- (hematopoietic stem cells), CD34+CD38+ (progenitors), CD19+ (B cells), and CD15+ (myeloid cells). The present data indicate that 20q- occurs in 10% of karyotypically abnormal MM/MGUS cases and that it might arise at a multipotent progenitor/stem cell level. PMID:15334545

  20. The 3;21 translocation in myelodysplasia results in a fusion transcript between the AML1 gene and the gene for EAP, a highly conserved protein associated with the Epstein-Barr virus small RNA EBER 1.

    PubMed Central

    Nucifora, G; Begy, C R; Erickson, P; Drabkin, H A; Rowley, J D

    1993-01-01

    In the 8;21 translocation, the AML1 gene, located at chromosome band 21q22, is translocated to chromosome 8 (q22), where it is fused to the ETO gene and transcribed as a chimeric gene. AML1 is the human homolog of the recently cloned mouse gene pebp2 alpha B, homologous to the DNA binding alpha subunit of the polyoma enhancer factor pebp2. AML1 is also involved in a translocation with chromosome 3 that is seen in patients with therapy-related acute myeloid leukemia and myelodysplastic syndrome and in chronic myelogenous leukemia in blast crisis. We have isolated a fusion cDNA clone from a t(3;21) library derived from a patient with therapy-related myelodysplastic syndrome; this clone contains sequences from AML1 and from EAP, which we have now localized to band 3q26. EAP has previously been characterized as a highly expressed small nuclear protein of 128 residues (EBER 1) associated with Epstein-Barr virus small RNA. The fusion clone contains the DNA binding 5' part of AML1 that is fused to ETO in the t(8;21) and, in addition, at least one other exon. The translocation replaces the last nine codons of AML1 with the last 96 codons of EAP. The fusion does not maintain the correct reading frame of EAP and may not lead to a functional chimeric protein. Images Fig. 1 Fig. 2 Fig. 4 Fig. 5 Fig. 6 PMID:8395054

  1. Differential methylation in CN-AML preferentially targets non-CGI regions and is dictated by DNMT3A mutational status and associated with predominant hypomethylation of HOX genes.

    PubMed

    Qu, Ying; Lennartsson, Andreas; Gaidzik, Verena I; Deneberg, Stefan; Karimi, Mohsen; Bengtzén, Sofia; Höglund, Martin; Bullinger, Lars; Döhner, Konstanze; Lehmann, Sören

    2014-08-01

    The extent and role of aberrant DNA methylation in promoter CpG islands (CGIs) have been extensively studied in leukemia and other malignancies. Still, CGIs represent only a small fraction of the methylome. We aimed to characterize genome-wide differential methylation of cytogenetically normal AML (CN-AML) cells compared with normal CD34(+) bone marrow cells using the Illumina 450K methylation array. Differential methylation in CN-AML was most prominent in genomic areas far from CGIs, in so called open sea regions. Furthermore, differential methylation was specifically found in genes encoding transcription factors (TFs), with WT1 being the most differentially methylated TF. Among genetic mutations in AML, DNMT3A mutations showed the most prominent association with the DNA methylation pattern, characterized by hypomethylation of CGIs (as compared with DNMT3A wild type cases). The differential methylation in DNMT3A mutant cells vs. wild type cells was predominantly found in HOX genes, which were hypomethylated. These results were confirmed and validated in an independent CN-AML cohort. In conclusion, we show that, in CN-AML, the most pronounced changes in DNA methylation occur in non-CGI regions and that DNMT3A mutations confer a pattern of global hypomethylation that specifically targets HOX genes.

  2. TEL (ETV6)-AML1 (RUNX1) initiates self-renewing fetal pro-B cells in association with a transcriptional program shared with embryonic stem cells in mice.

    PubMed

    Tsuzuki, Shinobu; Seto, Masao

    2013-02-01

    The initial steps involved in the pathogenesis of acute leukemia are poorly understood. The TEL-AML1 fusion gene usually arises before birth, producing a persistent and covert preleukemic clone that may convert to precursor B cell leukemia following the accumulation of secondary genetic "hits." Here, we show that TEL-AML1 can induce persistent self-renewing pro-B cells in mice. TEL-AML1+ cells nevertheless differentiate terminally in the long term, providing a "window" period that may allow secondary genetic hits to accumulate and lead to leukemia. TEL-AML1-mediated self-renewal is associated with a transcriptional program shared with embryonic stem cells (ESCs), within which Mybl2, Tgif2, Pim2, and Hmgb3 are critical and sufficient components to establish self-renewing pro-B cells. We further show that TEL-AML1 increases the number of leukemia-initiating cells that are generated in collaboration with additional genetic hits, thus providing an overall basis for the development of novel therapeutic and preventive measures targeting the TEL-AML1-associated transcriptional program. PMID:23135987

  3. 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

  4. 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.

  5. 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.

  6. 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

  7. Sulforaphane induces glutathione S-transferase isozymes which detoxify aflatoxin B(1)-8,9-epoxide in AML 12 cells.

    PubMed

    Gao, Shang Shang; Chen, Xiao Yan; Zhu, Ri Zhe; Choi, Byung-Min; Kim, Bok-Ryang

    2010-01-01

    The aflatoxin B(1)-8,9-epoxide (AFBO) is hepatocarcinogenic intermediate of aflatoxin B(1) (AFB(1)) and is detoxified by glutathione S-transferases (GSTs). In this study, we investigated whether sulforaphane (SFN) could increase the rate of conjugation between AFBO and glutathione (GSH) as well as which of the GST isozymes were involved in the conjugation reaction. The conjugation potential was inhibited dose dependently with curcumin, an inhibitor of GSTs. SFN induced the expression of GST A3, GST A4, GST M1, GST P1, and GST T1 in alpha mouse line (AML) 12 cells. The cells treated with SFN (10 microM) for 12 h showed a 35-fold increase in conjugation potential of AFBO with GSH compared with the vehicle-treated cell. The conjugation potential was blocked partially by transfection of cells with siRNAs against each of the GST isozymes. The activity of GST A3 had the strongest effect on the conjugation potential. SFN treatment also increased total GST activity detected with 1-chloro-2,4-dinitrobenzene (CDNB) up to 4.3-fold. The induction fold was much lower than that detected with AFBO. These results suggest that the chemopreventive effect of SFN on the decomposition of AFBO is related to the upregulation of several GST isozymes genes. The increase of GST activity by SFN was extremely specific toward the conjugation reaction of AFBO compared with CDNB. Therefore, this system for detecting GST activity seems to be an excellent method for screening chemopreventive compounds toward AFB(1) toxicity. PMID:20818711

  8. Vertebrate MitBASE: a specialised database on vertebrate mitochondrial DNA sequences.

    PubMed

    Carone, A; Malladi, S B; Attimonelli, M; Saccone, C

    1999-01-01

    Vertebrate MitBASE is a specialized database where all the vertebrate mitochondrial DNA entries from primary databases are collected, revised and integrated with new information emerging from the literature. Variant sequences are also analyzed, aligned and linked to reference sequences. Data related to the same species and fragment can be viewed over the WWW. The database has a flexible interface and a retrieval system to help non-expert users and contains information not currently available in the primary databases. Vertebrate MitBASE is now available through the MitBASE home page at URL: http://www.ebi.ac.uk/htbin/Mitbase/mitb ase.pl. This work is part of a larger project, MitBASE which is a network of databases covering the full panorama of knowledge on mitochondrial DNA from protists to human sequences.

  9. MIT Study Sees Nuclear Power as Green Weapon Against Global Warming

    NASA Astrophysics Data System (ADS)

    Dawson, Jim

    2003-12-01

    Although the public doesn't yet view nuclear power as a way to mitigate global warming, an MIT study says a global tripling of nuclear power generation could avoid nearly 2 billion tonnes of carbon emissions annually.

  10. 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.

  11. 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.

  12. 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.

  13. Research and Demonstration Program of Day Care Services for M.I.T. Employees. Interim Report.

    ERIC Educational Resources Information Center

    Arterton, Janet Bond

    A survey of day care needs of M.I.T. employees, its resulting information, and a description of the pilot program of day care services undertaken by M.I.T. are included in this report. A survey was administered to all 4,650 Institute employees in April, 1970, and enjoyed a 35% rate of response. The compiled data supports the conclusion that a…

  14. Boer-Mulders function of the pion in the MIT bag model

    NASA Astrophysics Data System (ADS)

    Lu, Zhun; Ma, Bo-Qiang; Zhu, Jiacai

    2012-11-01

    We apply the MIT bag model to study the Boer-Mulders function of the pion, a T-odd function that describes the transverse polarization distribution of the quark inside the pion. We simulate the effect of the gauge link through the “one-gluon-exchange” approximation. We consider both the quark helicity nonflip and double-flip contributions. The result in the MIT bag model is compared with those in the spectator models.

  15. 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

  16. Chemosensitivity of nonleukemic clonogenic precursors in AML patients in complete remission: association with CD34(+) mobilization and with disease-free survival.

    PubMed

    Milone, Giuseppe; Avola, Giuseppe; Leotta, Salvatore; Strano, Aurora; Camuglia, Maria Grazia; Pinto, Valeria; Mercurio, Salvatore; Poidomani, Massimo; Coppoletta, Stefania; Di Marco, Anna Lia; Consoli, Carla; Triolo, Anna; Spadaro, Andrea; Privitera, Antonella; Ragusa, Angela; Tibullo, Daniele; Di Mercurio, Sandra

    2012-01-01

    A high number of CD34(+) cells in the peripheral blood during mobilization in patients with acute myeloid leukemia (AML) in complete remission (CR) is associated with a high relapse rate. The variability in chemoresistance of normal bone marrow precursors has been hypothesized as explanation for the variable CD34 mobilization in AML. In 37 patients with AML in CR, we determined the chemosensitivity of bone marrow clonogenic precursors to maphosphamide and etoposide, which was then correlated with the degree of CD34(+) mobilization. In an enlarged set of 49 patients, we also studied the importance of chemosensitivity of marrow precursors for disease-free survival and relapse incidence. Significant correlations were demonstrated between the peak number of CD34(+) cells and residual growth of colony-forming unit granulocyte-macrophage (CFU-GM) after maphosphamide (R = 0.550; p = 0.0003) and after etoposide (R = 0.793; p = 0.0003). It was possible to identify three groups of AML patients based on chemosensitivity. The mean CD34(+) peak was 33 × 10(6)/L in the hyperchemosensitive group, 141 × 10(6)/L in the normochemosensitive (p = 0.03), and 379 × 10(6)/L in the chemoresistant group (p = 0.002). Failed CD34(+) mobilization was observed in 72% of the hyperchemosensitive group, 23% of the normochemosensitive group, and 0% of the chemoresistant group (p = 0.001). Hyperchemosensitivity of CFU-GM, together with a low platelet count, were independent factors important in the failure of CD34(+) cell mobilization. A disease-free survival significantly inferior to that of all other patients was associated with chemoresistance of CFU-GM (log rank, p = 0.030) and with chemoresistance of burst-forming unit erythroid (BFU-E) (log rank, p = 0.033). Chemoresistance of CFU-GM (p = 0.048) and BFU-E (p = 0.017) was also associated with increase relapse incidence. Nonleukemic nature of these precursors was demonstrated studying minimal residual disease from single colony cells

  17. Benchmarking on Tsunami Currents with ComMIT

    NASA Astrophysics Data System (ADS)

    Sharghi vand, N.; Kanoglu, U.

    2015-12-01

    There were no standards for the validation and verification of tsunami numerical models before 2004 Indian Ocean tsunami. Even, number of numerical models has been used for inundation mapping effort, evaluation of critical structures, etc. without validation and verification. After 2004, NOAA Center for Tsunami Research (NCTR) established standards for the validation and verification of tsunami numerical models (Synolakis et al. 2008 Pure Appl. Geophys. 165, 2197-2228), which will be used evaluation of critical structures such as nuclear power plants against tsunami attack. NCTR presented analytical, experimental and field benchmark problems aimed to estimate maximum runup and accepted widely by the community. Recently, benchmark problems were suggested by the US National Tsunami Hazard Mitigation Program Mapping & Modeling Benchmarking Workshop: Tsunami Currents on February 9-10, 2015 at Portland, Oregon, USA (http://nws.weather.gov/nthmp/index.html). These benchmark problems concentrated toward validation and verification of tsunami numerical models on tsunami currents. Three of the benchmark problems were: current measurement of the Japan 2011 tsunami in Hilo Harbor, Hawaii, USA and in Tauranga Harbor, New Zealand, and single long-period wave propagating onto a small-scale experimental model of the town of Seaside, Oregon, USA. These benchmark problems were implemented in the Community Modeling Interface for Tsunamis (ComMIT) (Titov et al. 2011 Pure Appl. Geophys. 168, 2121-2131), which is a user-friendly interface to the validated and verified Method of Splitting Tsunami (MOST) (Titov and Synolakis 1995 J. Waterw. Port Coastal Ocean Eng. 121, 308-316) model and is developed by NCTR. The modeling results are compared with the required benchmark data, providing good agreements and results are discussed. Acknowledgment: The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant

  18. Up-regulation of a HOXA-PBX3 homeobox-gene signature following down-regulation of miR-181 is associated with adverse prognosis in patients with cytogenetically abnormal AML

    PubMed Central

    Li, Zejuan; Huang, Hao; Li, Yuanyuan; Jiang, Xi; Chen, Ping; Arnovitz, Stephen; Radmacher, Michael D.; Maharry, Kati; Elkahloun, Abdel; Yang, Xinan; He, Chunjiang; He, Miao; Zhang, Zhiyu; Dohner, Konstanze; Neilly, Mary Beth; Price, Colles; Lussier, Yves A.; Zhang, Yanming; Larson, Richard A.; Le Beau, Michelle M.; Caligiuri, Michael A.; Bullinger, Lars; Valk, Peter J. M.; Delwel, Ruud; Lowenberg, Bob; Liu, Paul P.; Marcucci, Guido; Bloomfield, Clara D.; Rowley, Janet D.

    2012-01-01

    Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially. PMID:22251480

  19. 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

  20. 76 FR 31230 - Safety Zone; M.I.T.'s 150th Birthday Celebration Fireworks, Charles River, Boston, MA

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-31

    ... SECURITY Coast Guard 33 CFR Part 165 RIN 1625-AA00 Safety Zone; M.I.T.'s 150th Birthday Celebration...) Zone for the M.I.T.'s 150th Birthday Celebration Fireworks display. This safety zone is necessary to.... 165.T01-0375 to read as follows: Sec. 165.T01-0375 Safety Zone; M.I.T.'s 150th Birthday...

  1. Hypoxia inducible factor (HIF)-2α accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML.

    PubMed

    Forristal, C E; Brown, A L; Helwani, F M; Winkler, I G; Nowlan, B; Barbier, V; Powell, R J; Engler, G A; Diakiw, S M; Zannettino, A C W; Martin, S; Pattabiraman, D; D'Andrea, R J; Lewis, I D; Levesque, J P

    2015-10-01

    Hypoxia-inducible factor (HIF)-1α accumulation promotes hematopoietic stem cells' quiescence and is necessary to maintain their self-renewal. However, the role of HIF-2α in hematopoietic cells is less clear. We investigated the role of HIF-2α in leukemia and lymphoma cells. HIF-2α expression was high in subsets of human and mouse leukemia and lymphoma cells, whereas it was low in normal bone marrow leukocytes. To investigate the role of HIF-2α, we transduced human HIF-2α cDNA in mouse syngeneic models of myeloid preleukemia and a transgenic model of B lymphoma. Ectopic expression of HIF-2α accelerated leukemia cell proliferation in vitro. Mice transplanted with cells transduced with HIF-2α died significantly faster of leukemia or B lymphoma than control mice transplanted with empty vector-transduced cells. Conversely, HIF-2α knockdown in human myeloid leukemia HL60 cells decreased proliferation in vitro and significantly prolonged animal survival following transplantation. In human acute myeloid leukemia (AML), HIF-2α mRNA was significantly elevated in several subsets such as the t(15;17), inv(16), complex karyotype and favorable cytogenetic groups. However, patients with high HIF-2α expression had a trend to higher disease-free survival in univariate analysis. The different effects of HIF-2α overexpression in mouse models of leukemia and human AML illustrates the complexity of this mutliclonal disease.

  2. 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

    Wight, Andrew; Yang, Doo; Ioshikhes, Ilya; Makrigiannis, Andrew P

    2016-04-01

    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.

  3. Early clearance of peripheral blasts measured by flow cytometry during the first week of AML induction therapy as a new independent prognostic factor: a GOELAMS study.

    PubMed

    Lacombe, F; Arnoulet, C; Maynadié, M; Lippert, E; Luquet, I; Pigneux, A; Vey, N; Casasnovas, O; Witz, F; Béné, M C

    2009-02-01

    An early appreciation of treatment efficacy could be very useful in acute myeloblastic leukemia (AML), and a prognostic value has been suggested for the morphological assessment of decrease in blasts during induction therapy. More sensitive, multiparametric flow cytometry (FCM) can detect far lower blast counts, allowing for a precise and reliable calculation of blast cell decrease rate (BDR). Such a multiparametric FCM four-colours/single-tube protocol, combining CD11b, CD45-ECD and CD16-PC5, was applied to peripheral blood samples from 130 AML patients, collected daily during induction chemotherapy. Normalized blast cell percentages were used to calculate the relevant decrease slopes. Slope thresholds (<-25, -25 to -15 and >-15), or the time required to reach 90% depletion of the peripheral blast load (<5, 5 or >5 days), was strongly associated with the achievement of complete remission (P<0.0001). Log-rank test and Cox model showed that they also carried high statistical significance (P<0.0001) for disease-free survival. The prognostic value of cytogenetic features, confirmed in this series, was refined by BDR, which allowed to discriminate between good- and poor-risk patients among those with intermediate or normal karyotypes. This simple FCM protocol allows for an accurate prognostic sequential approach adapted to the determination of decrease in peripheral blast cells during induction chemotherapy.

  4. Frequency and Prognostic Impact of CEBPA Proximal, Distal and Core Promoter Methylation in Normal Karyotype AML: A Study on 623 Cases

    PubMed Central

    Fasan, Annette; Alpermann, Tamara; Haferlach, Claudia; Grossmann, Vera; Roller, Andreas; Kohlmann, Alexander; Eder, Christiane; Kern, Wolfgang; Haferlach, Torsten; Schnittger, Susanne

    2013-01-01

    The clinical impact of aberrant CEBPA promoter methylation (PM) in AML is controversially discussed. The aim of this study was to clarify the significance of aberrant CEBPA PM with regard to clinical features in a cohort of 623 cytogenetically normal (CN) de novo AML. 555 cases had wild-type CEBPA, 68 cases harbored CEBPA mutations. The distal promoter was methylated in 238/623 cases (38.2%), the core promoter in 8 of 326 cases (2.5%), whereas proximal PM was never detected. CEBPA PM and CEBPA mutations were mutually exclusive. CEBPA distal PM positive cases were characterized by reduced CEBPA mRNA expression levels and elevated white blood cell counts. CEBPA distal PM was less frequent in patients with mutations in FLT3, NPM1 and TET2 and more frequent in cases with RUNX1 and IDH2R140 mutations. Overall, no association of methylation to prognosis was seen. However CEBPA distal PM was associated with inferior outcome in cases with low FLT3-ITD ratio or TET2 mutations. A distinct gene expression profile of CEBPA distal PM positive cases compared to CEBPA mutated and CEBPA distal PM negative cases was observed. In conclusion, the presence of aberrant CEBPA PM is associated with distinct biological features but impact on outcome is weak. PMID:23383300

  5. Next-generation sequencing with a myeloid gene panel in core-binding factor AML showed KIT activation loop and TET2 mutations predictive of outcome

    PubMed Central

    Cher, C Y; Leung, G M K; Au, C H; Chan, T L; Ma, E S K; Sim, J P Y; Gill, H; Lie, A K W; Liang, R; Wong, K F; Siu, L L P; Tsui, C S P; So, C C; Wong, H W W; Yip, S F; Lee, H K K; Liu, H S Y; Lau, J S M; Luk, T H; Lau, C K; Lin, S Y; Kwong, Y L; Leung, A Y H

    2016-01-01

    Clinical outcome and mutations of 96 core-binding factor acute myeloid leukemia (AML) patients 18–60 years old were examined. Complete remission (CR) after induction was 94.6%. There was no significant difference in CR, leukemia-free-survival (LFS) and overall survival (OS) between t(8;21) (N=67) and inv(16) patients (N=29). Univariate analysis showed hematopoietic stem cell transplantation at CR1 as the only clinical parameter associated with superior LFS. Next-generation sequencing based on a myeloid gene panel was performed in 72 patients. Mutations in genes involved in cell signaling were associated with inferior LFS and OS, whereas those in genes involved in DNA methylation were associated with inferior LFS. KIT activation loop (AL) mutations occurred in 25 patients, and were associated with inferior LFS (P=0.003) and OS (P=0.001). TET2 mutations occurred in 8 patients, and were associated with significantly shorter LFS (P=0.015) but not OS. Patients negative for KIT-AL and TET2 mutations (N=41) had significantly better LFS (P<0.001) and OS (P=0.012) than those positive for both or either mutation. Multivariate analysis showed that KIT-AL and TET2 mutations were associated with inferior LFS, whereas age ⩾40 years and marrow blast ⩾70% were associated with inferior OS. These observations provide new insights that may guide better treatment for this AML subtype. PMID:27391574

  6. 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 (P AOX1) 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 P AOX1 in glycerol medium. Importantly, Mit1, Mxr1, and Prm1, which positively regulated P AOX1 in response to methanol, were bound to P AOX1 at different sites and did not interact with each other. However, these factors cooperatively activated P AOX1 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 (P MIT1), thus increasingly expressing Mit1 and subsequently activating P AOX1.

  7. A case of acute myeloid leukemia (AML) with an unreported combination of chromosomal abnormalities: gain of isochromosome 5p, tetrasomy 8 and unbalanced translocation der(19)t(17;19)(q23;p13)

    PubMed Central

    2013-01-01

    Background Acute myeloid leukemia (AML) comprises a spectrum of myeloid malignancies which are often associated with distinct chromosomal abnormalities, and the analysis of such abnormalities provides us with important information for disease classification, treatment selection and prognosis. Some chromosomal abnormalities albeit recurrent are rare such as tetrasomy 8 or isochromosome 5p. In addition, erratic chromosomal rearrangements may occur in AML, sometimes unbalanced and also accompanied by other abnormalities. Knowledge on the contribution of rare abnormalities to AML disease, progression and prognosis is limited. Here we report a unique case of acute monoblastic leukemia with gain of i(5)(p10), tetrasomy 8, an unbalanced translocation der(19)t(17;19)(q23;p13.3) and mutated NPM1. Results Bone marrow cells were examined by conventional karyotyping, fluorescence in situ hybridization (FISH) and mutation analysis at diagnosis and follow-up. At diagnosis we detected trisomy 8, an unbalanced translocation der(19)t(17;19)(q23;p13.3) and mutated NPM1. During the course of the disease we observed clonal evolution with gain of i(5)(p10), tetrasomy 8 and eventually duplication of der(19)t(17;19)(q23;p13.3). By using the der(19)t(17;19) as clonal marker, we found that i(5)(p10) and tetrasomy 8 were secondary genetic events and that tetrasomy 8 had clonally evolved from trisomy 8. Conclusions This case of acute monoblastic leukemia presents a combination of rare chromosomal abnormalities including the unbalanced translocation der(19)t(17;19)(q23;p13.3), hitherto un-reported in AML. In addition, our case supports the hypothesis of a step-wise clonal evolution from trisomy 8 to tetrasomy 8 in AML. Reporting and collecting data of rare chromosomal abnormalities will add information to AML disease, progression and prognosis, and may eventually translate to improved patient management. PMID:24079663

  8. 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

  9. MIT Clean Energy Prize: Final Technical Report May 12, 2010 - May 11, 2011

    SciTech Connect

    Snyder, Chris; Campbell, Georgina; Salony, Jason; Aulet, Bill

    2011-08-09

    The MIT Clean Energy Prize (MIT CEP) is a venture creation and innovation competition to encourage innovation in the energy space, specifically with regard to clean energy. The Competition invited student teams from any US university to submit student-led ventures that demonstrate a high potential of successfully making clean energy more affordable, with a positive impact on the environment. By focusing on student ventures, the MIT CEP aims to educate the next generation of clean energy entrepreneurs. Teams receive valuable mentoring and hard deadlines that complement the cash prize to accelerate development of ventures. The competition is a year-long educational process that culminates in the selection of five category finalists and a Grand Prize winner and the distribution of cash prizes to each of those teams. Each entry was submitted in one of five clean energy categories: Renewables, Clean Non-Renewables, Energy Efficiency, Transportation, and Deployment.

  10. 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.

  11. 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.

  12. Fusion Science Outreach at the MIT Plasma Science and Fusion Center

    NASA Astrophysics Data System (ADS)

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

    1997-11-01

    Educational Outreach at the MIT Plasma Science and Fusion Center is organized and energized by volunteers working together to increase the public's knowledge of fusion and plasma-related experiments. The PSFC holds a number of outreach activities throughout the year, such as Middle and High School Outreach Days. Included in these days is a demonstration of how magnets affect plasma using the ``Plasma Demo," an educational tool which will be on display for the first time outside the MIT area. Also featured is ``C-Mod Jr.," a video game which helps students discover how computers manipulate magnetic pulses to keep a plasma confined in the C-Mod tokamak for as long as possible. The PSFC maintains a Home Page on the World Wide Web, which can be reached at HTTP://PFC.MIT.EDU.

  13. 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).

  14. 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

  15. 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

  16. Detection and quantitation of the CBFbeta/MYH11 transcripts associated with the inv(16) in presentation and follow-up samples from patients with AML.

    PubMed

    Evans, P A; Short, M A; Jack, A S; Norfolk, D R; Child, J A; Shiach, C R; Davies, F; Tobal, K; Liu Yin, J A; Morgan, G J

    1997-03-01

    We have developed a competitor-based RT-PCR technique which will detect and quantitate the CBFbeta/MYH11 transcripts associated with inv(16)(q22;p13) and have used it to study presentation and follow-up samples of acute myeloid leukaemia (AML). The levels of the leukaemia-specific transcripts are expressed as a ratio to a ubiquitously expressed mRNA species (Abl) which controls for RNA degradation. This technique has been applied to 75 consecutive patients presenting with either de novo AML or tMDS; 6/75 patients analysed were positive for the inv(16), all were confirmed by conventional cytogenetics. The inv(16) has a strong association with M4Eo, but we found only 2/6-positive patients to have this diagnosis (two patients with M2, one patient M1 and one patient had MDS). At presentation the levels of CBFbeta/MYH11 transcripts were 0.1-10/Abl transcript (mean 3.3/Abl transcript). Seventeen follow-up samples were available on 5/6 of these patients, and on two further patients in whom stored material was available. Following the first cycle of chemotherapy the level of transcripts was at least 10(-2) lower (0.1-10 x 10(-2)/abl transcript) than their presentation sample. Subsequent samples on these patients when in remission gave transcript levels in the range (1.0 x 10(-4) - 2 x 10(-3)/abl transcript), and three long-term follow-up samples were negative. We have developed a quantitative test which opens the possibility of predicting relapse by detecting changes in the numbers of leukaemia-specific transcripts. PMID:9067575

  17. 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

  18. Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: results from Study AML-BFM 2004.

    PubMed

    Creutzig, Ursula; Zimmermann, Martin; Bourquin, Jean-Pierre; Dworzak, Michael N; Fleischhack, Gudrun; Graf, Norbert; Klingebiel, Thomas; Kremens, Bernhard; Lehrnbecher, Thomas; von Neuhoff, Christine; Ritter, Jörg; Sander, Annette; Schrauder, André; von Stackelberg, Arend; Starý, Jan; Reinhardt, Dirk

    2013-07-01

    Outcomes of patients with acute myeloid leukemia (AML) improve significantly by intensification of induction. To further intensify anthracycline dosage without increasing cardiotoxicity, we compared potentially less cardiotoxic liposomal daunorubicin (L-DNR) to idarubicin at a higher-than-equivalent dose (80 vs 12 mg/m(2) per day for 3 days) during induction. In the multicenter therapy-optimization trial AML-BFM 2004, 521 of 611 pediatric patients (85%) were randomly assigned to L-DNR or idarubicin induction. Five-year results in both treatment arms were similar (overall survival 76% ± 3% [L-DNR] vs 75% ± 3% [idarubicin], Plogrank = .65; event-free survival [EFS] 59% ± 3% vs 53% ± 3%, Plogrank = .25; cumulative incidence of relapse 29% ± 3% vs 31% ± 3%, P(Gray) = .75), as were EFS results for standard (72% ± 5% vs 68% ± 5%, Plogrank = .47) and high-risk (51% ± 4% vs 46% ± 4%, Plogrank = .45) patients. L-DNR resulted in significantly better probability of EFS in patients with t(8;21). Overall, treatment-related mortality was lower with L-DNR than idarubicin (2/257 vs 10/264 patients, P = .04). Grade 3/4 cardiotoxicity was rare after induction (4 L-DNR vs 5 idarubicin). Only 1 L-DNR and 3 idarubicin patients presented with subclinical or mild cardiomyopathy during follow-up. In conclusion, at the given dose, L-DNR has overall antileukemic activity comparable to idarubicin, promises to be more active in subgroups, and causes less treatment-related mortality. This trial was registered at www.clinicaltrials.gov as #NCT00111345. PMID:23704089

  19. NK cells from an AML patient have recovered in remission and reached comparable cytolytic activity to that of a healthy monozygotic twin mediated by the single-chain triplebody SPM-2

    PubMed Central

    2013-01-01

    Background The capacity of patient’s Natural Killer cells (NKs) to be activated for cytolysis is an important prerequisite for the success of antibody-derived agents such as single-chain triplebodies (triplebodies) in cancer therapy. NKs recovered from AML patients at diagnosis are often found to be reduced in peripheral blood titers and cytolytic activity. Here, we had the unique opportunity to compare blood titers and cytolytic function of NKs from an AML patient with those of a healthy monozygotic twin. The sibling’s NKs were compared with the patient’s drawn either at diagnosis or in remission after chemotherapy. The cytolytic activities of NKs from these different sources for the patient’s autologous AML blasts and other leukemic target cells in conjunction with triplebody SPM-2, targeting the surface antigens CD33 and CD123 on the AML cells, were compared. Methods Patient NKs drawn at diagnosis were compared to NKs drawn in remission after chemotherapy and a sibling’s NKs, all prepared from PBMCs by immunomagnetic beads (MACS). Redirected lysis (RDL) assays using SPM-2 and antibody-dependent cellular cytotoxicity (ADCC) assays using the therapeutic antibody RituximabTM were performed with the enriched NKs. In addition, MACS-sorted NKs were analyzed for NK cell activating receptors (NCRs) by flow cytometry, and the release of TNF-alpha and IFN-gamma from blood samples of both siblings after the addition of the triplebody were measured in ELISA-assays. Results Patient NKs isolated from peripheral blood drawn in remission produced comparable lysis as NKs from the healthy twin against the patient’s autologous bone marrow (BM) blasts, mediated by SPM-2. The NCR receptor expression profiles on NKs from patient and twin were similar, but NK cell titers in peripheral blood were lower for samples drawn at diagnosis than in remission. Conclusions Peripheral blood NK titers and ex vivo cytolytic activities mediated by triplebody SPM-2 were comparable for

  20. 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…

  1. 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…

  2. Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian multicenter therapy trials. Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster Study Group.

    PubMed

    Borkhardt, A; Cazzaniga, G; Viehmann, S; Valsecchi, M G; Ludwig, W D; Burci, L; Mangioni, S; Schrappe, M; Riehm, H; Lampert, F; Basso, G; Masera, G; Harbott, J; Biondi, A

    1997-07-15

    The molecular approach for the analysis of leukemia associated chromosomal translocations has led to the identification of prognostic relevant subgroups. In pediatric acute lymphoblastic leukemia (ALL), the most common translocations, t(9;22) and t(4;11), have been associated with a poorer clinical outcome. Recently the TEL gene at chromosome 12p13 and the AML1 gene at chromosome 21q22 were found to be involved in the translocation t(12;21)(p13;q22). By conventional cytogenetics, however, this chromosomal abnormality is barely detectable and occurs in less than 0.05% of childhood ALL. To investigate the frequency of the molecular equivalent of the t(12;21), the TEL/AML1 gene fusion, we have undertaken a prospective screening in the running German Berlin-Frankfurt-Münster (BFM) and Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) multicenter ALL therapy trials. We have analyzed 334 unselected cases of pediatric ALL patients consecutively referred over a period of 5 and 9 months, respectively. The overall incidence of the t(12;21) in pediatric ALL is 18.9%. The 63 cases positive for the TEL/AML1 chimeric products ranged in age between 1 and 12 years, and all but one showed CD10 and pre-B immunophenotype. Interestingly, one case displayed a pre-pre-B immunophenotype. Among the B-lineage subgroup, the t(12;21) occurs in 22.0% of the cases. Fifteen of 61 (24.6%) cases coexpressed at least two myeloid antigens (CD13, CD33, or CDw65) in more than 20% of the gated blast cells. DNA index was available for 59 of the 63 TEL/AML1 positive cases; a hyperdiploid DNA content (> or = 1.16) was detected in only four patients, being nonhyperdiploid in the remaining 55. Based on this prospective analysis, we retrospectively evaluated the impact of TEL/AML1 in prognosis by identifying the subset of B-lineage ALL children enrolled in the closed German ALL-BFM-90 and Italian ALL-AIEOP-91 protocols who had sufficient material for analysis. A total of 342 children

  3. 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

  4. 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.

  5. 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

  6. Coexistence of tetrasomy 8 and trisomy 8 in acute promyelocytic leukemia (AML-M3) with t(15;17)(q22;q12).

    PubMed

    Wang, Hui-Ping; Li, Guo-Xia; Qiao, Zhen-Hua; Ren, Wen-Ying; Wang, Hong-Wei

    2004-08-01

    This study was purposed to characterize the first case of acute promyelocitic leukemia (AML-M(3a)) with t(15;17), trisomy 8 and tetrasomy 8, and explore its characteristics of morphology, cytogenetics, molecular biology, immunology and clinical features. Morphological changes of peripheral blood and bone marrow smears were observed under microscope. Chromosome specimen was prepared by 24 h short-term culture of bone marrow cell, RHG-banding technique was used for karyotypic analysis. PML-RARa fusion gene transcript was detected by nested-reverse transcription-polymerase chain reaction (nested RT-PCR). Interphase fluorescence in situ hybridization (FISH) using chromosome 8 centromere specific probe were carried out to detect abnormal numbers of chromosome 8. Immunophenotypic analysis was performed by flow cytometry. The results showed that peripheral blood smear revealed 65% promyelocyte, and bone marrow aspirate was hypercellular with 72.4% promyelocyte, moderately basophilic cytoplasm with numerous azurophilic granules. Karyotype analysis demonstrated 48, XY, +8, +8, t(15;17)(q22;q12) [16]/47, XY, +8, t(15;17)(q22;q12) [3]/46, XY, t(15;17)(q22;q12) [1]. RT-PCR assay revealed PML-RARa fusion gene transcript (+). FISH showed that the percentages of cells exhibiting 1, 2, 3, 4, 5, 6 green fluorescence signals were 0.5, 7, 19, 55, 18 and 0.5, respectively. This confirmed the presence of tetrasomy 8 and trisomy 8 and also revealed a low percentage of a pentasomy 8 clone. Immunophenotypes of the blasts displayed that CD13 (96.2%), CD33 (55.9%), CYMPO (93.5%) were positive. All the lymphoid markers tested were negative. The patient survival time was just 10 days. It is concluded that tetrasomy 8 is secondary cytogenetic event after t(15;17) in this case. It may be a consequence of clonal evolution of trisomy 8. t(15;17) AML-M(3) with tetrasomy 8 heralds a poor prognosis. PMID:15363120

  7. The role of matched sibling donor allogeneic stem cell transplantation in pediatric high-risk acute myeloid leukemia: results from the AML-BFM 98 study

    PubMed Central

    Klusmann, Jan-Henning; Reinhardt, Dirk; Zimmermann, Martin; Kremens, Bernhard; Vormoor, Josef; Dworzak, Michael; Creutzig, Ursula; Klingebiel, Thomas

    2012-01-01

    Background The role of allogeneic stem cell transplantation in post-remission management of children with high-risk acute myeloid leukemia remains controversial. In the multi-center AML-BFM 98 study we prospectively evaluated the impact of allogeneic stem cell transplantation in children with high-risk acute myeloid leukemia in first complete remission. Design and Methods HLA-typed patients with high-risk acute myeloid leukemia, who achieved first complete remission (n=247), were included in this analysis. All patients received double induction and consolidation. Based on the availability of a matched-sibling donor, patients were allocated by genetic chance to allogeneic stem cell transplantation (n=61) or chemotherapy-only (i.e. intensification and maintenance therapy; n=186). The main analysis was done on an intention-to-treat basis according to this allocation. Results Intention-to-treat analysis did not show a significantly different 5-year disease-free survival (49±6% versus 45±4%, Plog rank=0.44) or overall survival (68±6% versus 57±4%, Plog rank=0.17) between the matched-sibling donor and no-matched-sibling donor groups, whereas late adverse effects occurred more frequently after allogeneic stem cell transplantation (72.5% versus 31.8%, PFischer<0.01). These results were confirmed by as-treated analysis corrected for the time until transplantation (5-year overall survival: 72±8% versus 60±4%, PMantel-Byar 0.21). Subgroup analysis demonstrated improved survival rates for patients with 11q23 aberrations allocated to allogeneic stem cell transplantation (5-year overall survival: 94±6% versus 52±7%, Plog-rank=0.01; n=18 versus 49) in contrast to patients without 11q23 aberrations (5-year overall survival: 58±8% versus 55±5%, Plog-rank=0.66). Conclusions Our analyses defined a genetic subgroup of children with high-risk acute myeloid leukemia who benefited from allogeneic stem cell transplantation in the prospective multi-center AML-BFM 98 study. For

  8. Dose intensification in acute myeloid leukaemia: greater effectiveness at lower cost. Principal report of the Medical Research Council's AML9 study. MRC Leukaemia in Adults Working Party.

    PubMed

    Rees, J K; Gray, R G; Wheatley, K

    1996-07-01

    Between 1984 and 1990, 972 patients aged 1-79 years with acute myeloid leukaemia (AML), from 85 British hospitals, were entered into the MRC's 9th AML trial. Patients were randomized between DAT 1 + 5 (daunorubicin for 1 d, with cytarabine and 6-thioguanine for 5 d) and DAT 3 + 10 (same dose drugs for 3 and 10 d respectively) as induction therapy. The 63% who achieved complete remission (CR) were randomized to receive two courses of DAT 2 + 7 alternating with two courses of either MAZE (m-AMSA, 5-azacytidine, etoposide) or COAP (cyclophosphamide, vincristine, cytarabine, prednisone). Finally, those still in CR were randomized to receive either 1 year of maintenance treatment with eight courses of cytarabine and thioguanine followed by four courses of COAP, or no further cytotoxic therapy. Resistance to induction therapy was less common with the DAT 3 + 10 regimen than with DAT 1 + 5 (13% v 23%; P = 0.0001) and hence, despite a 5% increase in the risk of induction death, the CR rate was higher (66% v 61%; P = 0.15). Moreover, CR was achieved more rapidly with DAT 3 + 10 (median 34 v 46 d; P < 0.0001) and thus patients required less time in hospital (mean 20 v 29 d) and less blood product support. 5-year relapse-free survival (28% v 23%; P = 0.05) and survival (23% v 18%; P < 0.05) were also better with DAT 3 + 10. Post-remission intensification of therapy with MAZE resulted in fewer relapses (66% v 74% at 5 years; P = 0.03) but patients allocated MAZE required considerably more supportive care and 14 (4.5%) died following 312 MAZE courses, whereas no deaths occurred following COAP. 5-year survival was not significantly higher with MAZE (37% v 31%). Finally, although 1 year of outpatient maintenance treatment appeared to delay, but not prevent, recurrence it did not improve 5-year survival which was non-significantly worse for those allocated maintenance treatment (41% v 44%). We conclude that the more intensive induction regimen, DAT 3 + 10, is not only more

  9. 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.

  10. 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/.

  11. The neurosciences research program at MIT and the beginning of the modern field of neuroscience.

    PubMed

    Adelman, George

    2010-01-15

    The interdisciplinary field, "neuroscience," began at MIT in 1962 with the founding of the Neurosciences Research Program (NRP) by Francis O. Schmitt and a group of US and international scientists - physical, biological, medical, and behavioral - interested in understanding the brain basis of behavior and mind. They organized and held specialist meetings of basic topics in neuroscience, and the journal and book publications over the next 20 years, based on these meetings, helped establish the new field.

  12. The MIT high resolution X-ray spectroscopy instruments on AXAF

    NASA Astrophysics Data System (ADS)

    Canizares, C. R.; Dewey, D.; Galton, E. B.; Markert, T. H.; Smith, Henry I.; Schattenburg, M. L.; Woodgate, B. E.; Jordan, S.

    1992-03-01

    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.

  13. 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.

  14. Gaussian frequency blending algorithm with matrix inversion tomosynthesis (MITS) and filtered back projection (FBP) for better digital breast tomosynthesis reconstruction

    NASA Astrophysics Data System (ADS)

    Chen, Ying; Lo, Joseph Y.; Baker, Jay A.; Dobbins, James T., III

    2006-03-01

    Breast cancer is a major problem and the most common cancer among women. The nature of conventional mammpgraphy makes it very difficult to distinguish a cancer from overlying breast tissues. Digital Tomosynthesis refers to a three-dimensional imaging technique that allows reconstruction of an arbitrary set of planes in the breast from limited-angle series of projection images as the x-ray source moves. Several tomosynthesis algorithms have been proposed, including Matrix Inversion Tomosynthesis (MITS) and Filtered Back Projection (FBP) that have been investigated in our lab. MITS shows better high frequency response in removing out-of-plane blur, while FBP shows better low frequency noise propertities. This paper presents an effort to combine MITS and FBP for better breast tomosynthesis reconstruction. A high-pass Gaussian filter was designed and applied to three-slice "slabbing" MITS reconstructions. A low-pass Gaussian filter was designed and applied to the FBP reconstructions. A frequency weighting parameter was studied to blend the high-passed MITS with low-passed FBP frequency components. Four different reconstruction methods were investigated and compared with human subject images: 1) MITS blended with Shift-And-Add (SAA), 2) FBP alone, 3) FBP with applied Hamming and Gaussian Filters, and 4) Gaussian Frequency Blending (GFB) of MITS and FBP. Results showed that, compared with FBP, Gaussian Frequency Blending (GFB) has better performance for high frequency content such as better reconstruction of micro-calcifications and removal of high frequency noise. Compared with MITS, GFB showed more low frequency breast tissue content.

  15. 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.

  16. MIT: A Future Mission to Investigate Magnetosphere-Ionosphere-Thermosphere Coupling with Multipoint Observations

    NASA Astrophysics Data System (ADS)

    Liu, Yong; Wang, Chi; Xu, Jiyao; Li, Xiaoyu; Klecker, Berndt

    2015-04-01

    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.

  17. MRD assessed by WT1 and NPM1 transcript levels identifies distinct outcomes in AML patients and is influenced by gemtuzumab ozogamicin

    PubMed Central

    Lambert, Juliette; Lambert, Jérôme; Nibourel, Olivier; Pautas, Cécile; Hayette, Sandrine; Cayuela, Jean-Michel; Terré, Christine; Rousselot, Philippe; Dombret, Hervé; Chevret, Sylvie; Preudhomme, Claude; Castaigne, Sylvie; Renneville, Aline

    2014-01-01

    We analysed the prognostic significance of minimal residual disease (MRD) level in adult patients with acute myeloid leukemia (AML) treated in the randomized gemtuzumab ozogamicin (GO) ALFA-0701 trial. Levels of WT1 and NPM1 gene transcripts were assessed using cDNA-based real-time quantitative PCR in 183 patients with WT1 overexpression and in 77 patients with NMP1 mutation (NPM1mut) at diagnosis. Positive WT1 MRD (defined as > 0.5% in the peripheral blood) after induction and at the end of treatment were both significantly associated with a higher risk of relapse and a shorter overall survival (OS). Positive NPM1mut MRD (defined as > 0.1% in the bone marrow) after induction and at the end of treatment also predicted a higher risk of relapse, but did not influence OS. Interestingly, the achievement of a negative NPM1mut MRD was significantly more frequent in patients treated in the GO arm compared to those treated in control arm (39% versus 7% (p=0.006) after induction and 91% versus 61% (p=0.028) at the end of treatment). However, GO did not influence WT1 MRD levels. Our study supports the prognostic significance of MRD assessed by WT1 and NPM1mut transcript levels and show that NPM1 MRD is decreased by GO treatment. PMID:25026287

  18. Stage I of Phase II study assessing efficacy, safety and tolerability of barasertib (AZD1152) versus LDAC in elderly AML patients

    PubMed Central

    Kantarjian, Hagop M; Martinelli, Giovanni; Jabbour, Elias J; Quintás-Cardama, Alfonso; Ando, Kiyoshi; Bay, Jacques-Olivier; Wei, Andrew; Gröpper, Stefanie; Papayannidis, Cristina; Owen, Kate; Pike, Laura; Schmitt, Nicola; Stockman, Paul K; Giagounidis, Aristoteles

    2013-01-01

    Background This Phase II study evaluated the efficacy, safety and tolerability of the Aurora B kinase inhibitor barasertib, compared with low-dose cytosine arabinoside (LDAC), in patients aged ≥60 years with acute myeloid leukemia (AML). Methods Patients were randomized 2:1 to open-label barasertib 1200 mg (7-day iv infusion) or LDAC 20 mg (sc twice-daily for 10 days) in 28-day cycles. The primary endpoint was objective complete response rate (OCRR: CR + CRi [Cheson criteria, additionally requiring CRi reconfirmation ≥21 days after first appearance and associated with partial recovery of platelets and neutrophils]). Secondary endpoints included overall survival (OS) and safety. Results 74 patients (barasertib, n=48; LDAC, n=26) completed ≥1 cycle. A significant improvement in OCRR was observed with barasertib (35.4% vs 11.5%; difference, 23.9% [95% CI, 2.7–39.9]; P<0.05). Although not formally sized to compare OS data, the median OS with barasertib was 8.2 months versus 4.5 months with LDAC. (HR=0.88, 95% CI, 0.49-1.58; P=0.663;). Stomatitis and febrile neutropenia were the most common adverse events with barasertib versus LDAC (71% vs 15%; 67% vs 19%, respectively). Conclusions Barasertib showed a significant improvement in OCRR versus LDAC, with a more toxic but manageable safety profile that was consistent with previous studies. Clinicaltrials.gov, NCT00952588. PMID:23605952

  19. 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

  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. 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

  2. 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.

  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. MicroSPECT/CT imaging of primary human AML engrafted into the bone marrow and spleen of NOD/SCID mice using 111In-DTPA-NLS-CSL360 radioimmunoconjugates recognizing the CD123+ / CD131- epitope expressed by leukemia stem cells.

    PubMed

    Leyton, Jeffrey V; Williams, Brent; Gao, Catherine; Keating, Armand; Minden, Mark; Reilly, Raymond M

    2014-11-01

    Engraftment of primary human acute myeloid leukemia (AML) specimens into the bone marrow (BM) of NOD/SCID mice has been used to study leukemia biology and new treatments for the disease. CSL360 is a chimeric IgG1 monoclonal antibody that recognizes CD123 (IL-3 receptor α-subchain) expressed in the absence of CD131 (β-subchain), an epitope that is displayed by leukemia stem cells (LSCs). We are studying CSL360 modified with diethylenetriaminepentaacetic acid (DTPA) for complexing 111In and 13-mer nuclear translocation sequence (NLS) peptides to enable nuclear importation in LSCs for Auger electron radioimmunotherapy (RIT) of AML. We demonstrate that microSPECT/CT imaging using 111In-DTPA-NLS-CSL360 revealed engraftment of primary human AML specimens into the BM and spleen of NOD/SCID mice. Our results suggest that microSPECT/CT imaging is a powerful tool which enables non-invasive assessment of the engraftment of AML into NOD/SCID mice and in the current study specifically probes an epitope displayed by the LSC subpopulation. The targeting of 111In-DTPA-NLS-CSL360 to sites of AML engraftment in the NOD/SCID mouse model is encouraging for future RIT studies. Ultimately, SPECT imaging could be applied in AML patients to assess the delivery of 111In-DTPA-NLS-CSL360 to sites of leukemia and be combined with Auger electron RIT using the same agent targeting the LSC population as a "theranostic" pair.

  5. Prospective pilot trial of PerMIT versus standard anticoagulation service management of patients initiating oral anticoagulation.

    PubMed

    Borgman, Mark P; Pendleton, Robert C; McMillin, Gwendolyn A; Reynolds, Kristen K; Vazquez, Sara; Freeman, Andrew; Wilson, Andrew; Valdes, Roland; Linder, Mark W

    2012-09-01

    We performed a randomised pilot trial of PerMIT, a novel decision support tool for genotype-based warfarin initiation and maintenance dosing, to assess its efficacy for improving warfarin management. We prospectively studied 26 subjects to compare PerMIT-guided management with routine anticoagulation service management. CYP2C9 and VKORC1 genotype results for 13 subjects randomly assigned to the PerMIT arm were recorded within 24 hours of enrolment. To aid in INR interpretation, PerMIT calculates estimated loading and maintenance doses based on a patient's genetic and clinical characteristics and displays calculated S-warfarin plasma concentrations based on planned or administered dosages. In comparison to control subjects, patients in the PerMIT study arm demonstrated a 3.6-day decrease in the time to reach a stabilised INR within the target therapeutic range (4.7 vs. 8.3 days, p = 0.015); a 12.8% increase in time spent within the therapeutic interval over the first 25 days of therapy (64.3% vs. 55.3%, p = 0.180); and a 32.9% decrease in the frequency of warfarin dose adjustments per INR measurement (38.3% vs. 57.1%, p = 0.007). Serial measurements of plasma S-warfarin concentrations were also obtained to prospectively evaluate the accuracy of the pharmacokinetic model during induction therapy. The PerMIT S-warfarin plasma concentration model estimated 62.8% of concentrations within 0.15 mg/l. These pilot data suggest that the PerMIT method and its incorporation of genotype/phenotype information may help practitioners increase the safety, efficacy, and efficiency of warfarin therapeutic management. PMID:22836303

  6. MitProNet: A knowledgebase and analysis platform of proteome, interactome and diseases for mammalian mitochondria.

    PubMed

    Wang, Jiabin; Yang, Jian; 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

  7. 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

  8. PKR inhibits the DNA damage response, and is associated with poor survival in AML and accelerated leukemia in NHD13 mice

    PubMed Central

    Cheng, Xiaodong; Byrne, Michael; Brown, Kevin D.; Konopleva, Marina Y.; Kornblau, Steven M.; Bennett, Richard L.

    2015-01-01

    Increased expression of the interferon-inducible double-stranded RNA-activated protein kinase (PKR) has been reported in acute leukemia and solid tumors, but the role of PKR has been unclear. Now, our results indicate that high PKR expression in CD34+ cells of acute myeloid leukemia (AML) patients correlates with worse survival and shortened remission duration. Significantly, we find that PKR has a novel and previously unrecognized nuclear function to inhibit DNA damage response signaling and double-strand break repair. Nuclear PKR antagonizes ataxia-telangiectasia mutated (ATM) activation by a mechanism dependent on protein phosphatase 2A activity. Thus, inhibition of PKR expression or activity promotes ATM activation, γ-H2AX formation, and phosphorylation of NBS1 following ionizing irradiation. PKR transgenic but not PKR null mice demonstrate a mutator phenotype characterized by radiation-induced and age-associated genomic instability that was partially reversed by short-term pharmacologic PKR inhibition. Furthermore, the age-associated accumulation of somatic mutations that occurs in the Nup98-HOXD13 (NHD13) mouse model of leukemia progression was significantly elevated by co-expression of a PKR transgene, whereas knockout of PKR expression or pharmacologic inhibition of PKR activity reduced the frequency of spontaneous mutations in vivo. Thus, PKR cooperated with the NHD13 transgene to accelerate leukemia progression and shorten survival. Taken together, these results indicate that increased nuclear PKR has an oncogenic function that promotes the accumulation of potentially deleterious mutations. Thus, PKR inhibition may be a therapeutically useful strategy to prevent leukemia progression or relapse, and improve clinical outcomes. PMID:26202421

  9. 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

  10. Regional climate projection of the Maritime Continent using the MIT Regional Climate Model

    NASA Astrophysics Data System (ADS)

    IM, E. S.; Eltahir, E. A. B.

    2014-12-01

    Given that warming of the climate system is unequivocal (IPCC AR5), accurate assessment of future climate is essential to understand the impact of climate change due to global warming. Modelling the climate change of the Maritime Continent is particularly challenge, showing a high degree of uncertainty. Compared to other regions, model agreement of future projections in response to anthropogenic emission forcings is much less. Furthermore, the spatial and temporal behaviors of climate projections seem to vary significantly due to a complex geographical condition and a wide range of scale interactions. For the fine-scale climate information (27 km) suitable for representing the complexity of climate change over the Maritime Continent, dynamical downscaling is performed using the MIT regional climate model (MRCM) during two thirty-year period for reference (1970-1999) and future (2070-2099) climate. Initial and boundary conditions are provided by Community Earth System Model (CESM) simulations under the emission scenarios projected by MIT Integrated Global System Model (IGSM). Changes in mean climate as well as the frequency and intensity of extreme climate events are investigated at various temporal and spatial scales. Our analysis is primarily centered on the different behavior of changes in convective and large-scale precipitation over land vs. ocean during dry vs. wet season. In addition, we attempt to find the added value to downscaled results over the Maritime Continent through the comparison between MRCM and CESM projection. Acknowledgements.This research was supported by the National Research Foundation Singapore through the Singapore MIT Alliance for Research and Technology's Center for Environmental Sensing and Modeling interdisciplinary research program.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. Evaluation of Dynamics of the West African Monsoon Jump Simulated by the MIT Regional Climate Model

    NASA Astrophysics Data System (ADS)

    Eltahir, Elfatih A. B.; Im, Eun-Soon

    2015-04-01

    The seasonal advance and retreat of the West African monsoon behaves abrupt northward jump of maximum rainfall from the Guinean coast to the Sahel region. Both global and regional climate models have difficulties in accurately reproducing such a behavior due to its complexity combined the dynamical and physical processes. In this study, we evaluate the performance of the MIT Regional Climate Model (MRCM) in simulating the West African monsoon. For this, 20-year long-term simulation (1989-2008) is performed using the ERAInterim reanalysis as the initial and boundary condition, and the analysis primarily focuses on the dynamics associated with abrupt phase transitions of the monsoon rainfall. We first examine detailed characteristics in terms of the onset, maximum, and retreat of the monsoon rainfall using daily precipitation. We then present the dynamical explanation behind rainfall variability from the analysis of the absolute vorticity near the tropopause and the meridional gradient of boundary-layer entropy within the dynamical theory proposed by Eltahir and Gong (1996). Acknowledgements : This research was supported by the National Research Foundation Singapore through the Singapore MIT Alliance for Research and Technology's Center for Environmental Sensing and Modeling interdisciplinary research program.

  16. Identifikationsverfahren zur Analyse von EEG-Signalen bei Epilepsie mit Reaktions-Diffusions Netzwerken

    NASA Astrophysics Data System (ADS)

    Gollas, F.; Tetzlaff, R.

    2007-06-01

    Partielle Differentialgleichungen des Reaktions-Diffusions-Typs beschreiben Phänomene wie Musterbildung, nichtlineare Wellenausbreitung und deterministisches Chaos und werden oft zur Untersuchung komplexer Vorgänge auf den Gebieten der Biologie, Chemie und Physik herangezogen. Zellulare Nichtlineare Netzwerke (CNN) sind eine räumliche Anordnung vergleichsweise einfacher dynamischer Systeme, die eine lokale Kopplung untereinander aufweisen. Durch eine Diskretisierung der Ortsvariablen können Reaktions-Diffusions-Gleichungen häufig auf CNN mit nichtlinearen Gewichtsfunktionen abgebildet werden. Die resultierenden Reaktions-Diffusions-CNN (RD-CNN) weisen dann in ihrer Dynamik näherungsweise gleiches Verhalten wie die zugrunde gelegten Reaktions-Diffusions-Systeme auf. Werden RD-CNN zur Identifikation neuronaler Strukturen anhand von EEG-Signalen herangezogen, so besteht die Möglichkeit festzustellen, ob das gefundene Netzwerk lokale Aktivität aufweist. Die von Chua eingeführte Theorie der lokalen Aktivität Chua (1998); Dogaru und Chua (1998) liefert eine notwendige Bedingung für das Auftreten von emergentem Verhalten in zellularen Netzwerken. Änderungen in den Parametern bestimmter RD-CNN könnten auf bevorstehende epileptische Anfälle hinweisen. In diesem Beitrag steht die Identifikation neuronaler Strukturen anhand von EEG-Signalen durch Reaktions-Diffusions-Netzwerke im Vordergrund der dargestellten Untersuchungen. In der Ergebnisdiskussion wird insbesondere auch die Frage nach einer geeigneten Netzwerkstruktur mit minimaler Komplexität behandelt.

  17. How Much Have They Retained? Making Unseen Concepts Seen in a Freshman Electromagnetism Course at MIT

    NASA Astrophysics Data System (ADS)

    Dori, Yehudit Judy; Hult, Erin; Breslow, Lori; Belcher, John W.

    2007-08-01

    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 simulations. These learning tools help them visualize unseen electromagnetic concepts and develop stronger intuition about related phenomena. A previous study has shown that students who took the course in the TEAL format (the experimental group) gained significantly better conceptual understanding than those who took it in the traditional lecture-recitation format (the control group). The present longitudinal study focuses on the extent to which these two research groups (experimental and control) retain conceptual understanding about a year to 18 months after finishing the course. It also examines students attitudes about whether the teaching format (TEAL or traditional) contributes to their learning in advanced courses. Our research has indicated that the long-term effect of the TEAL course on students' retention of concepts was significantly stronger than that of the traditional course. This research is significant because it documents the long-term cognitive and affective impact of the TEAL studio physics format on learning outcomes of MIT students.

  18. Acute myelogenous leukemia (AML) - children

    MedlinePlus

    ... lumps around the eyes that may be blue-green Painless lumps in the neck, armpits, stomach, groin, or other parts of the body that may be blue or purple Pinpoint spots under the skin caused by bleeding Shortness of breath Loss of appetite and eating less food

  19. Immunonutrition - the influence of early postoperative glutamine supplementation in enteral/parenteral nutrition on immune response, wound healing and length of hospital stay in multiple trauma patients and patients after extensive surgery.

    PubMed

    Lorenz, Kai J; Schallert, Reiner; Daniel, Volker

    2015-01-01

    Einleitung: Die Prognose polytraumatisierter Patienten mit schweren Schädel-Hirntraumata sowie Patienten mit ausgedehnten Kopf-Hals-chirurgischen Eingriffen hängt in der postoperativen Phase maßgeblich vom Proteinmetabolismus sowie der Prävention von septischen Komplikationen ab. Ebenso wirken sich Wundheilungsstörungen deutlich verlängernd auf den Intensivaufenthalt und die Dauer des stationären Aufenthaltes aus. Folglich sollte sich eine immunstimulierende Versorgung der Patienten im Rahmen der postoperativen Phase verbessernd auf die Immun- und Gesamtsituation des Patienten auswirken. Patienten und Methoden: In einer Studie an 15 Patienten mit ausgedehnten HNO-tumorchirurgischen Eingriffen und 7 polytraumatisierten Patienten wurden die Auswirkung einer gezielten enteralen Substitution mit Glutamin im auf die Immuninduktion, die Wundheilung sowie den stationären Aufenthalt untersucht. Die Hälfte der Patienten wurde mit einer glutaminreichen Diät ernährt, die Kontrollgruppe erhielt eine isonitrogene, isokalorische Ernährung.Ergebnisse: Zusammenfassend zeigt sich, dass sich die Anzahl der Gesamtlymphozyten, der Anteil von aktivierten CD4+DR+ T-Helferlymphozyten, die In-vitro-Stimulierbarkeit der Lymphozyten mit Mitogenen sowie die IL-2 Plasmaspiegel bei glutaminreich ernährten Patienten schneller normalisieren als bei isonitrogen-isokalorisch ernähren Patienten und dass diese Parameter gegen Ende der 2. postoperativen Woche sogar „übernormal“ sind.Zusammenfassung: Die gezielte frühenterale Substitution kritisch kranker Patienten mit einer bedarforientierten, immunstimulierenden Diät scheint uns unter dem Aspekt der Verringerung septischer Komplikationen, der schnelleren Wundheilung wie auch der Verkürzung des Intensiv- wie auch stationären Aufenthalts unbedingt gerechtfertigt.

  20. Distinct mechanisms of recognizing endosomal sorting complex required for transport III (ESCRT-III) protein IST1 by different microtubule interacting and trafficking (MIT) domains.

    PubMed

    Guo, Emily Z; Xu, Zhaohui

    2015-03-27

    The endosomal sorting complex required for transport (ESCRT) machinery is responsible for membrane remodeling in a number of biological processes including multivesicular body biogenesis, cytokinesis, and enveloped virus budding. In mammalian cells, efficient abscission during cytokinesis requires proper function of the ESCRT-III protein IST1, which binds to the microtubule interacting and trafficking (MIT) domains of VPS4, LIP5, and Spartin via its C-terminal MIT-interacting motif (MIM). Here, we studied the molecular interactions between IST1 and the three MIT domain-containing proteins to understand the structural basis that governs pairwise MIT-MIM interaction. Crystal structures of the three molecular complexes revealed that IST1 binds to the MIT domains of VPS4, LIP5, and Spartin using two different mechanisms (MIM1 mode versus MIM3 mode). Structural comparison revealed that structural features in both MIT and MIM contribute to determine the specific binding mechanism. Within the IST1 MIM sequence, two phenylalanine residues were shown to be important in discriminating MIM1 versus MIM3 binding. These observations enabled us to deduce a preliminary binding code, which we applied to provide CHMP2A, a protein that normally only binds the MIT domain in the MIM1 mode, the additional ability to bind the MIT domain of Spartin in the MIM3 mode.

  1. 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

  2. Draft Genome Sequences of Supercritical CO2-Tolerant Bacteria Bacillus subterraneus MITOT1 and Bacillus cereus MIT0214.

    PubMed

    Peet, Kyle C; Thompson, Janelle R

    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.

  3. 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 ...

  4. Interactive Web-Based and Hands-On Engineering Education: A Freshman Aerospace Design Course at MIT.

    ERIC Educational Resources Information Center

    Newman, Dava J.

    "Introduction to Aerospace and Design" is a 3-hour per week freshman elective course at Massachusetts Institute of Technology (MIT) that culminates in a Lighter-Than-Air (LTA) vehicle design competition, exposing freshmen to the excitement of aerospace engineering design typically taught in the junior or senior years. In addition to the hands-on…

  5. 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…

  6. 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 ...

  7. 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…

  8. 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)

  9. 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…

  10. Whistler mode based explanation for the fast reconnection rate measured in the mit versatile toroidal facility.

    PubMed

    Singh, Nagendra

    2011-12-01

    Despite the widely discussed role of whistler waves in mediating magnetic reconnection (MR), the direct connection between such waves and the MR has not been demonstrated by comparing the characteristic temporal and spatial features of the waves and the MR process. Using the whistler wave dispersion relation, we theoretically predict the experimentally measured rise time (τ(rise)) of a few microseconds for the fast rising MR rate in the Versatile Toroidal Facility at MIT. The rise time is closely given by the inverse of the frequency bandwidth of the whistler waves generated in the evolving current sheet. The wave frequencies lie much above the ion cyclotron frequency, but they are limited to less than 0.1% of the electron cyclotron frequency in the argon plasma. The maximum normalized MR rate R=0.35 measured experimentally is precisely predicted by the angular dispersion of the whistler waves.

  11. Oncogenic MITF dysregulation in clear cell sarcoma: defining the MiT family of human cancers.

    PubMed

    Davis, Ian J; Kim, Jessica J; Ozsolak, Fatih; Widlund, Hans R; Rozenblatt-Rosen, Orit; Granter, Scott R; Du, Jinyan; Fletcher, Jonathan A; Denny, Christopher T; Lessnick, Stephen L; Linehan, W Marston; Kung, Andrew L; Fisher, David E

    2006-06-01

    Clear cell sarcoma (CCS) harbors a pathognomonic chromosomal translocation fusing the Ewing's sarcoma gene (EWS) to the CREB family transcription factor ATF1 and exhibits melanocytic features. We show that EWS-ATF1 occupies the MITF promoter, mimicking melanocyte-stimulating hormone (MSH) signaling to induce expression of MITF, the melanocytic master transcription factor and an amplified oncogene in melanoma. Knockdown/rescue studies revealed that MITF mediates the requirement of EWS-ATF1 for CCS survival in vitro and in vivo as well as for melanocytic differentiation. Moreover, MITF and TFE3 reciprocally rescue one another in lines derived from CCS or pediatric renal carcinoma. Seemingly unrelated tumors thus employ distinct strategies to oncogenically dysregulate the MiT family, collectively broadening the definition of MiT-associated human cancers.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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)

  17. 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.

  18. 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.

  19. 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.

  20. [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

  1. 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

  2. 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

  3. The risk of developing depression when suffering from neurological diseases.

    PubMed

    Thielscher, C; Thielscher, S; Kostev, K

    2013-01-01

    Zweck der Untersuchung: Ermittlung der Häufigkeit des Auftretens von Depressionen im Gefolge von neurologischen Erkrankungen (M. Alzheimer, Demenz, Epilepsie, multiple Sklerose, M. Parkinson).Methodik: Wir beobachteten den Krankheitsverlauf von 42.914 Patienten, bei denen die genannten neurologischen Erkrankungen erstmals auftraten, über fünf Jahre, im Hinblick auf das Auftreten einer Depression.Ergebnisse: Bei 21% (männliche Patienten mit Epilepsie) bis 39% (weibliche Parkinson-Patientinnen) bzw. 44% (beide Geschlechter, Patienten unter 60 Jahren mit Alzheimer-Diagnose) der Patientinnen und Patienten wurde innerhalb von fünf Jahren zusätzlich eine Depression diagnostiziert. Schlussfolgerung: Wir empfehlen, alle Patientinnen und Patienten mit einer der genannten Erkrankungen, v. a. den besonders komorbiden, auf Depression zu untersuchen.

  4. [Evaluation of the Musical Concentration Training with Pepe (MusiKo mit Pepe) for children with attention deficits].

    PubMed

    Rothmann, Kathrin; Hillmer, Jana-Mareike; Hosser, Daniela

    2014-09-01

    Fragestellung: Die vorliegende Studie überprüft die Wirksamkeit des Musikalischen Konzentrationstrainings mit Pepe (MusiKo mit Pepe) für fünf- bis zehnjährige Kinder mit Aufmerksamkeitsproblemen. Methodik: In einem Prä-Post-Kontrollgruppendesign (N = 108) wurden Veränderungen der Aufmerksamkeitsleistung mittels der Testbatterie zur Aufmerksamkeitsprüfung für Kinder (KiTAP) sowie Veränderungen der kindlichen Lebensqualität mittels des Fragebogens für Kinder (KINDL-R) erfasst. Zusätzlich wurden Fremdbeurteilungsbögen zur Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (FBB-ADHS) sowie zur Störung des Sozialverhaltens (FBB-SSV) des Diagnostik-Systems für psychische Störungen nach ICD-10 und DSM-IV für Kinder und Jugendliche II und der Eltern- und der Lehrerfragebogen über das Verhalten von Kindern und Jugendlichen (CBCL, TRF) eingesetzt. Ergebnisse: Es zeigen sich für die am Training teilnehmenden Kinder im Vergleich zu der Kontrollgruppe über die Zeit signifikante Verbesserungen der Aufmerksamkeitsleistung sowie der Lebensqualität. Darüber hinaus ergibt sich eine signifikante Reduktion der ADHS-Symptomatik im Eltern- und Lehrerurteil sowie eine Verminderung der Internalisierenden Probleme im Elternurteil. Die Behandlungseffektivität ist unabhängig von Alter, Geschlecht, Intelligenz und Migrationshintergrund der teilnehmenden Kinder. Schlussfolgerung: Das musikbasierte Trainingsprogramm MusiKo mit Pepe stellt eine wirkungsvolle Maßnahme zur Behandlung von Aufmerksamkeitsproblemen dar, sollten sich diese Effekte in Replikationsstudien bestätigen.

  5. A Preliminary MIT-VLA Snapshot Survey Catalog: 8000 MG/PMN Sources at 4.8/8.4 GHz and 0.''3 Resolution

    NASA Astrophysics Data System (ADS)

    Fletcher, A. B.; Burke, B. F.; Conner, S. R.; Herold, L. K.; Lehar, J.; Winn, J. N.; Hewitt, J. N.; Langston, G. I.; Lawrence, C. R.; Bennett, C. L.

    1999-09-01

    A preliminary catalog of the 1981-1994 MIT-VLA Snapshot Survey for radio-loud gravitational lenses will be made available via anonymous ftp from MIT in June 1999 (ftp zenobia.mit.edu; cd pub/fletcher; get mitvla.readme). This plain text catalog contains detailed information on the VLA positions, flux densities and morphologies of ~ 6200 northern MIT-Greenbank (MG) and ~ 1800 Parkes-MIT-NRAO (PMN) radio sources at 4.8 and 8.4 GHz, and at angular resolutions ranging from 0.2 to 0.4 arcseconds. These sources represent ~ 80% of the entire 15 year MIT-VLA Snapshot Survey effort from 1981 to 1995, and are complementary to MIT's VLA-Magellan Gravitational Lens Survey of ~ 1900 flat-spectrum sources begun last year (see J. Winn et al., 1998, BAAS 30(4), p.1425, with a paper recently submitted to the ApJS). The 4.8 GHz single-dish flux densities of the ~ 8000 MIT-VLA sources range from ~ 70 mJy to ~ 5000 mJy. Though the sample is incomplete, it is consistently representative of the wide variety of source morphologies and spectral indices appearing in the MIT-VLA Snapshot Survey. This preliminary MIT-VLA catalog will be improved and checked before publication. It is meanwhile intended as a general purpose resource for the astronomical community; possible uses include (1) organizing an optical follow-up of known gravitational lens candidates within the sample (see A. Fletcher, 1998, MIT Ph.D. thesis), (2) assembling samples of new compact MG and PMN radio sources requiring further imaging using VLBI, such as compact doubles and position calibrators, (3) estimating the mean growth rate of the kiloparsec-scale extended structures in radio-loud AGN (see A. Fletcher & B. Burke, 1998, BAAS 30(4), p.1249), and (4) providing sub-arcsecond information missing from overlapping radio sky surveys made at lower angular resolution, such as the FIRST, WENSS, NVSS and Molonglo Wide Field Surveys.

  6. 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.

  7. Vibratory Loads Reduction Testing of the NASA/Army/MIT Active Twist Rotor

    NASA Technical Reports Server (NTRS)

    Wilbur, Matthew; Mirick, Paul H.; Yeager, William T., Jr.; Langston, Chester W.; Cesnik, Carlos E. S.; Shin, SangJoon

    2001-01-01

    Recent studies have indicated that controlled strain-induced blade twisting can be attained using piezoelectric active fiber composite technology, and that such advancement may provide a mechanism for reduced rotorcraft vibrations and increased rotor performance. In order to validate these findings experimentally, a cooperative effort between the 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 a four-bladed, aeroelastically-scaled, active-twist model rotor has been designed and fabricated for testing in the heavy gas test medium of the NASA Langley Transonic Dynamics Tunnel. Initial wind tunnel testing has been conducted to assess the impact of active blade twist on both fixed- and rotating-system vibratory loads in forward flight. The active twist control was found to have a pronounced effect on all system loads and was shown to generally offer reductions in fixed-system loads of 60% to 95%, depending upon flight condition, with 1.1 to 1.4 of dynamic blade twist observed. A summary of the systems developed and the vibratory loads reduction results obtained are presented in this paper.

  8. 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.

  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. A Truck, a Plasma and a Pickle: On the Road with MIT's Traveling Plasma Lab

    NASA Astrophysics Data System (ADS)

    Thomas, Paul

    2004-11-01

    For the past 12 years MIT's Mr. Magnet community outreach program has brought the excitement of magnetism into New England's local schools. Averaging 60-70 school visits each year, Mr. Magnet has become a popular school assembly choice. Paul Thomas, the program's creator, has recently expanded the program to offer a one-hour lecture on the principles of plasma science, geared toward middle schools and high schools. The behavior of particles of matter and light in a plasma is complex. Rather than attempt to convey a complete understanding of their quantum nature in a single lecture, Paul Thomas focuses on presenting just enough information to excite a student's imagination. Using a glow discharge plasma, an emission spectrometer, and such ubiquitous substances as nail polish remover, local dirt and a pickle, students discover, by experiment, the unique properties of the plasma state. Equal parts teacher and showman, Paul explains the basic science of plasma while engaging students with hands-on experiments. Paul Thomas will showcase some of his plasma experiments ``live on stage.'' He will explain some of the mechanics involved with traveling to schools, and how he succeeds in engaging students in science exploration. His goal is to spark curiosity, which may lead a student to study science in college or pursue science as a career. He hopes also to encourage APS-DPP members who may wish to establish educational outreach programs for their local communities.

  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. 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

  13. Polymorphisms XbaI (rs693) and EcoRI (rs1042031) of the ApoB gene are associated with carotid plaques but not with carotid intima-media thickness in patients with diabetes mellitus type 2.

    PubMed

    Nikolajevic Starcevic, Jovana; Santl Letonja, Marija; Praznikar, Zala J; Makuc, Jana; Vujkovac, Andreja C; Petrovic, Daniel

    2014-05-01

    Hintergrund: Apolipoprotein B ist eine wichtige strukturelle Komponente der atherogenetischen Lipoproteine (LDL, VLDL und IDL). Genetische Variationen des ApoB-Gens können verschiedene Effekte auf Plasmakonzentrationen des ApoB und auf den Lipidspiegel haben, was dann die Atherogenese beeinflusst. Primäres Ziel der Studie war die Analyse der Assoziation der Polymorphismen XbaI (rs693) und EcoRI (rs1042031) mit Plasmakonzentrationen von ApoB, dem Lipidspiegel und verschiedenen atherosklerotischen Phänotypen bei Patienten mit Diabetes mellitus Typ 2. Patienten und Methoden: 595 Patienten mit Diabetes mellitus Typ 2 (399 mit Statin-Therapie und 196 Patienten ohne Statin-Therapie) und 200 Personen ohne Diabetes mellitus Typ 2 (Kontrollgruppe). Die Intima-Media-Dicke (IMD) der A. carotis und die Charakteristika der atherosklerotischen Plaques wurden mit Ultraschall analysiert. Biochemische Untersuchungen wurden mit standardmäßigen biochemischen Methoden durchgeführt. Die XbaI (rs693) und EcoRI (rs1042031) Genotypen wurden mittels Real-Time PCR analysiert. Ergebnisse: Die Genotyp-Verteilung und die allelische Häufigkeit von XbaI und EcoRI Polymorphismen unterschieden sich nicht zwischen Patienten mit und ohne Diabetes mellitus. Es wurden keine signifikanten Unterschiede der Plasmakonzentrationen von ApoA1, ApoB, Cholesterinspiegel, hs-CRP, Fibrinogen und der IMD bei Patienten mit Diabetes mellitus Typ 2 mit verschiedenen Genotypen festgestellt, auch unter Berücksichtigung der Statintherapie. Das Risiko der Atherosklerose der Karotiden wird bei Patienten mit X + X + Genotyp im Vergleich zu Patienten ohne diesen Genotyp (OR = 1.74, p = 0.03)höher und bei Diabetiker mit E-Allelen (OR = 0.48, p = 0.02) niedriger. Es gab keine Assoziation zwischen XbaI / EcoRI Polymorphismen und IMD oder instabilen atherosklerotischen Plaques bei Patienten mit Diabetes mellitus Typ 2. Schlussfolgerungen: Das Risiko der Atherosklerose der Karotiden wird höher bei Patienten mit

  14. 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.

  15. Autolytic activity of human calpain 7 is enhanced by ESCRT-III-related protein IST1 through MIT-MIM interaction.

    PubMed

    Osako, Yohei; Maemoto, Yuki; Tanaka, Ryohei; Suzuki, Hironori; Shibata, Hideki; Maki, Masatoshi

    2010-11-01

    Calpain 7, a mammalian ortholog of yeast Cpl1/Rim13 and fungal PalB, is an atypical calpain that lacks a penta-EF-hand domain. Previously, we reported that a region containing a tandem repeat of microtubule-interacting and transport (MIT) domains in calpain 7 interacts with a subset of endosomal sorting complex required for transport (ESCRT)-III-related proteins, suggesting involvement of calpain 7 in the ESCRT system. Although yeast and fungal calpains are thought to be involved in alkaline adaptation via limited proteolysis of specific transcription factors, proteolytic activity of calpain 7 has not been demonstrated yet. In this study, we investigated the interaction between calpain 7 and a newly reported ESCRT-III family member, increased sodium tolerance-1 (IST1), which possesses two different types of MIT-interacting motifs (MIM1 and MIM2). We found that glutathione-S-transferase (GST)-fused tandem MIT domains of calpain 7 (calpain 7MIT) pulled down FLAG-tagged IST1 expressed in HEK293T cells. Coimmunoprecipitation assays with various deletion or point mutants of epitope-tagged calpain 7 and IST1 revealed that both repetitive MIT domains and MIMs are required for efficient interaction. Direct MIT-MIM binding was confirmed by a pulldown experiment with GST-fused IST1 MIM and purified recombinant calpain 7MIT. Furthermore, we found that the GST-MIM protein enhances the autolysis of purified Strep-tagged monomeric green fluorescent protein (mGFP)-fused calpain 7 (mGFP-calpain 7-Strep). The autolysis was almost completely abolished by 10 mmN-ethylmaleimide but only partially inhibited by 1 mm leupeptin or E-64. The putative catalytic Cys290-substituted mutant (mGFP-calpain 7(C290S)-Strep) showed no autolytic activity. These results demonstrate for the first time that human calpain 7 is proteolytically active, and imply that calpain 7 is activated in the ESCRT system. PMID:20849418

  16. 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.

  17. 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.

  18. Comparative costs of the Mouse Inoculation Test (MIT) and Virus Isolation in Cell Culture (VICC) for use in rabies diagnosis in Brazil.

    PubMed

    Bones, Vanessa C; Gameiro, Augusto H; Castilho, Juliana G; Molento, Carla F M

    2015-05-01

    The decision to use laboratory animals rather than in vitro methods is frequently based on the financial costs involved, so the objective of our study was to compare the costs of performing the Mouse Inoculation Test (MIT) and Virus Isolation in Cell Culture (VICC) for use in rabies diagnosis in Brazil. Based on observations of laboratory routines at the Pasteur Institute, São Paulo, we listed the fixed cost (FC) and variable cost (VC) items necessary to perform both tests. Considering that 200 MITs are equivalent to 350 VICC assays, in terms of facilities and staff-hours needed per month, we calculated, for both tests, the average total cost per sample, the costs of the implementation of the laboratory structure, and the costs of routine use. With regard to absolute values, the total cost was mainly influenced by FC items, as they represented 60% of the cost for the MIT and 86% of the cost for VICC. A sample analysed by the MIT costs around 205% more than one analysed by using VICC. The MIT costs 74% and 406% more than VICC, when implementation costs and routine use per month, respectively, are taken into account. Our results can assist in the resolution of costing disputes that could hinder the replacement of animals for rabies diagnosis in Brazil. The method demonstrated here might also be useful for cost comparisons in other situations where animal use still continues when validated alternatives exist.

  19. 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

  20. 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

  1. 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

  2. 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.

  3. Reduced-toxicity conditioning with treosulfan, fludarabine and ATG as preparative regimen for allogeneic stem cell transplantation (alloSCT) in elderly patients with secondary acute myeloid leukemia (sAML) or myelodysplastic syndrome (MDS).

    PubMed

    Kröger, N; Shimoni, A; Zabelina, T; Schieder, H; Panse, J; Ayuk, F; Wolschke, C; Renges, H; Dahlke, J; Atanackovic, D; Nagler, A; Zander, A

    2006-02-01

    We investigated a dose-reduced conditioning regimen consisting of treosulfan and fludarabine followed by allogeneic stem cell transplantation (SCT) in 26 patients with secondary AML or MDS. Twenty patients were transplanted from matched or mismatched unrelated donors and six from HLA-identical sibling donors. The median age of the patients was 60 years (range, 44-70). None of the patients was eligible for a standard myeloablative preparative regimen. No graft-failure was observed, and leukocyte and platelet engraftment were observed after a median of 16 and 17 days, respectively. Acute graft-versus-host disease (GvHD) grade II-IV was seen in 23% and severe grade III GvHD in 12% of the patients. No patients experienced grade IV acute GvHD. Chronic GvHD was noted in 36% of the patients, which was extensive disease in 18%. The 2-year cumulative incidence of relapse was 21%. The relapse rate was higher in patients beyond CR1 or with intermediate two or high risk MDS (P = 0.02). The treatment-related mortality at day 100 was 28%. The 2-year estimated overall and disease-free survival was 36-34%, respectively. No difference in survival was seen between unrelated and related SCT.

  4. High PRDM16 expression identifies a prognostic subgroup of pediatric acute myeloid leukaemia correlated to FLT3-ITD, KMT2A-PTD, and NUP98-NSD1: the results of the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 trial.

    PubMed

    Shiba, Norio; Ohki, Kentaro; Kobayashi, Tohru; Hara, Yusuke; Yamato, Genki; Tanoshima, Reo; Ichikawa, Hitoshi; Tomizawa, Daisuke; Park, Myoung-Ja; Shimada, Akira; Sotomatsu, Manabu; Arakawa, Hirokazu; Horibe, Keizo; Adachi, Souichi; Taga, Takashi; Tawa, Akio; Hayashi, Yasuhide

    2016-02-01

    Recent reports described the NUP98-NSD1 fusion as an adverse prognostic marker for acute myeloid leukaemia (AML) and PRDM16 (also known as MEL1) as the representative overexpressed gene in patients harbouring NUP98-NSD1 fusion. PRDM16 gene expression levels were measured via real-time polymerase chain reaction in 369 paediatric patients with de novo AML, of whom 84 (23%) exhibited PRDM16 overexpression (PRDM16/ABL1 ratio ≥0·010). The frequencies of patients with high or low PRDM16 expression differed widely with respect to each genetic alteration, as follows: t(8;21), 4% vs. 96%, P < 0·001; inv(16), 0% vs. 100%, P < 0·001; KMT2A (also termed MLL)- partial tandem duplication, 100% vs. 0%, P < 0·001; NUP98-NSD1, 100% vs. 0%, P < 0·001. The overall survival (OS) and event-free survival (EFS) among PRDM16-overexpressing patients were significantly worse than in patients with low PRDM16 expression (3-year OS: 51% vs. 81%, P < 0·001, 3-year EFS: 32% vs. 64%, P < 0·001) irrespective of other cytogenetic alterations except for NPM1. PRDM16 gene expression was particularly useful for stratifying FLT3-internal tandem duplication-positive AML patients (3-year OS: high = 30% vs. low = 70%, P < 0·001). PRDM16 overexpression was highly recurrent in de novo paediatric AML patients with high/intermediate-risk cytogenetic profiles and was independently associated with an adverse outcome.

  5. 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.

  6. 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…

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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 ...

  12. AML Therapy With Irradiated Allogeneic Cells

    ClinicalTrials.gov

    2016-07-08

    Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  13. 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" ...

  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. Sub-micrometer aerosol particles in the upper troposphere/lowermost stratosphere as measured by CARIBIC and modeled using the MIT-CAM3 global climate model

    NASA Astrophysics Data System (ADS)

    Ekman, Annica M. L.; Hermann, Markus; Groß, Peter; Heintzenberg, Jost; Kim, Dongchul; Wang, Chien

    2012-06-01

    In this study, we compare modeled (MIT-CAM3) and observed (CARIBIC) sub-micrometer nucleation (N4-12, 4 ≤ d ≤ 12 nm) and Aitken mode (N12, d > 12 nm) particle number concentrations in the upper troposphere and lowermost stratosphere (UT/LMS). Modeled and observed global median N4-12 and N12 agree fairly well (within a factor of two) indicating that the relatively simplified binary H2SO4-H2O nucleation parameterization applied in the model produces reasonable results in the UT/LMS. However, a comparison of the spatiotemporal distribution of sub-micrometer particles displays a number of discrepancies between MIT-CAM3 and CARIBIC data: N4-12is underestimated by the model in the tropics and overestimated in the extra-topics. N12 is in general overestimated by the model, in particular in the tropics and during summer months. The modeled seasonal variability of N4-12 is in poor agreement with CARIBIC data whereas it agrees rather well for N12. Modeled particle frequency distributions are in general narrower than the observed ones. The model biases indicate an insufficient diffusive mixing in MIT-CAM3 and a too large vertical transport of carbonaceous aerosols. The overestimated transport is most likely caused by the constant supersaturation threshold applied in the model for the activation of particles into cloud droplets. The annually constant SO2 emissions in the model may also partly explain the poor representation of the N4-12seasonal cycle. Comparing the MIT-CAM3 with CARIBIC data, it is also clear that care has to be taken regarding the representativeness of the measurement data and the time frequency of the model output.

  16. Early results from the MIT millimeter and sub-millimeter balloon-borne anisotropy measurement. [of cosmic microwave background radiation

    NASA Technical Reports Server (NTRS)

    Meyer, Stephan S.; Cheng, Edward S.; Page, Lyman A.

    1991-01-01

    The MIT balloon-borne bolometric search for Cosmic Microwave Background Radiation (CMBR) anisotropies places the most stringent constraints to date on fluctuations in the CMBR. Four maps of half of the Northern Hemisphere at 1.8, 1.1, 0.63 and 0.44 mm wavelength, have a beam size of 3.8 deg with a 1 sigma sensitivity of less than 0.1 mK (thermodynamic) per FOV in each of the first two channels. Analysis of the sky map at 1.8 mm wavelength using a likelihood ratio test for galactic latitudes of 15 deg and greater yields a 95 percent confidence level (CL) upper limit on fluctuations of the CMBR at DeltaT/T less than or equal to 1.6 x 10 exp -5 with a statistical power of 92 percent for Gaussian fluctuations at a correlation angle of 13 deg. Between 3 deg and 22 deg, the upper limit for fluctuations is DeltaT/T less than or equal to 4.0 x 10 exp -5 (95 percent CL).

  17. VizieR Online Data Catalog: The MIT-Green Bank 5GHz Survey (Bennett+, 1986-91)

    NASA Astrophysics Data System (ADS)

    Bennett, C. L.; Lawrence, C. R.; Burke, B. F.; Hewitt, J. N.; Mahoney, J.

    1999-04-01

    The MIT-Green Bank 5 GHz survey catalog was produced from four separate surveys with the National Radio Astronomy Observatory (NRAO) 91m transit telescope (Bennett et al., 1986ApJS...61....1B (MG1); Langston et al., 1990ApJS...72..621L (MG2); Griffith et al., 1990ApJS...74..129G (MG3); Griffith et al. 1991ApJS...75..801G (MG4)). The sky coverage of the various surveys is: 00h < RAB < 24h, -00d30'13" < DECB < +19d29'47" for MG1; 04h < RAJ < 21h, +17.0d < DECJ < +39d09' for MG2; 16h30m < RAB < 05h, +17d < DECB < +39d09' for MG3; and 15h30m < RAB < 02h30m, +37.00d < DECB < +50d58'48" for MG4; where RAB and DECB refer to B1950 coordinates, and RAJ and DECJ refer to J2000 coordinates. The catalog contains 20344 sources detected with a signal-to-noise ratio greater than 5 and 3836 possible detections (MG1) with a signal-to-noise ratio less than 5. Spectral indices are computed for MG1 sources also identified in the Texas 365 MHz survey (Douglas et al. 1980), and for MG1-MG4 sources also identified in the NRAO 1400 MHz Survey (Condon and Broderick 1985). (1 data file).

  18. VizieR Online Data Catalog: The MIT-Green Bank 5GHz Survey (Bennett+, 1986-91)

    NASA Astrophysics Data System (ADS)

    Bennett, C. L.; Lawrence, C. R.; Burke, B. F.; Hewitt, J. N.; Mahoney, J.

    2003-08-01

    The MIT-Green Bank 5GHz survey catalog was produced from four separate surveys with the National Radio Astronomy Observatory (NRAO) 91m transit telescope (Bennett et al., 1986ApJS...61....1B (MG1); Langston et al., 1990ApJS...72..621L (MG2); Griffith et al., 1990ApJS...74..129G (MG3); Griffith et al. 1991ApJS...75..801G (MG4)). The sky coverage of the various surveys is: 00h < RAB < 24h, -00d30'13" < DECB < +19d29'47" for MG1; 04h < RAJ < 21h, +17.0d < DECJ < +39d09' for MG2; 16h30m < RAB < 05h, +17d < DECB < +39d09' for MG3; and 15h30m < RAB < 02h30m, +37.00d < DECB < +50d58'48" for MG4; where RAB and DECB refer to B1950 coordinates, and RAJ and DECJ refer to J2000 coordinates. The catalog contains 20344 sources detected with a signal-to-noise ratio greater than 5 and 3836 possible detections (MG1) with a signal-to-noise ratio less than 5. Spectral indices are computed for MG1 sources also identified in the Texas 365MHz survey (Douglas et al. 1980), and for MG1-MG4 sources also identified in the NRAO 1400MHz Survey (Condon and Broderick 1985). (1 data file).

  19. 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.

  20. Upgrade of the MIT Linear Electrostatic Ion Accelerator (LEIA) for nuclear diagnostics development for Omega, Z and the NIF.

    PubMed

    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; Gatu Johnson, M; Frenje, J A; Séguin, F H; Li, C K; Petrasso, R D; Ruiz, C L; Leeper, R J

    2012-04-01

    The MIT Linear Electrostatic Ion Accelerator (LEIA) generates DD and D(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(7) s(-1) and 10(6) s(-1) for DD and D(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.

  1. 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.

  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/.

  3. 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

  4. VizieR Online Data Catalog: MGIV (Fourth MIT-Green Bank) 5GHz Survey (Griffith+ 1991)

    NASA Astrophysics Data System (ADS)

    Griffith, M.; Langston, G.; Heflin, M.; Conner, S.; Burke, B.

    1998-10-01

    The MIT-Green Bank IV (MG IV) 5 GHz survey covers 0.504 sr of sky in the right ascension range 15.5 to 2.5 hours, between +37.00 and +50.98 degrees declination (B1950). The final MG IV catalog contains 3427 sources detected with a signal-to-noise ratio greater than 5. The catalog was produced from two separate north and south surveys with the National Radio Astronomy Observatory (NRAO) 91m transit telescope. The north survey was produced from data collected while scanning the telescope north from +39.0 to +50.98 degrees declination and the south survey from data collected from scans from +48.98 to +37.00 degrees declination. The completeness and reliability of the final source list is checked by examination of north and south source lists in a twice observed comparison region, lying between +39.15 and +48.83 degrees declination and excluding the area between +/-10 degrees Galactic latitude. The comparison region covers 0.270 sr of sky and contains 1094 sources. In this region, the MG IV catalog contains 423 sources brighter than 90 mJy and is shown to be 99.1 +/- 1.2% complete at this flux density level. Spectral indices are computed for sources identified in the NRAO 1400 MHz Survey (published by Condon and Broderick in 1985). A comparison of the spectral index distributions between +/- 10 and outside of +/- 10 degrees Galactic latitude is presented. (1 data file).

  5. Retrospective analysis of a VACM (vacuum-assisted closure and mesh-mediated fascial traction) treatment manual for temporary abdominal wall closure - results of 58 consecutive patients.

    PubMed

    Beltzer, Christian; Eisenächer, Alexander; Badendieck, Steffen; Doll, Dietrich; Küper, Markus; Lenz, Stefan; Krapohl, Björn Dirk

    2016-01-01

    Einleitung: Das optimale Behandlungskonzept eines temporären Bauchdeckenverschlusses (temporary abdominal closure, TAC) bei kritisch kranken viszeralchirurgischen Patienten mit offenem Abdomen („open abdomen“, OA) ist weiterhin unklar. Durch eine VACM-Therapie (vacuum-assisted closure and mesh-mediated fascial traction) scheinen sich gegenüber anderen Verfahren des TAC höhere Faszienverschlussraten (delayed primary fascial closure rate, FCR) realisieren zu lassen. Material und Methoden: Patienten unserer Klinik (n=58), welche in den Jahren 2005 bis 2008 mittels eines VAC/VACM-Behandlungsmanuals behandelt wurden, wurden retrospektiv analysiert. Ergebnisse: Die FCR aller Patienten betrug insgesamt 48,3% (95%-Konfidenzintervall: 34,95–61,78). Bei Patienten, bei denen im Verlauf ein Vicryl-Netz auf Faszienebene implantiert wurde (VACM-Therapie), konnte eine FCR von 61,3% realisiert werden. Die Letalität der mittels VACM therapierten Patienten betrug 45,2% (95%-KI: 27,32–63,97).Schlussfolgerung: Die Ergebnisse der eigenen Untersuchung bestätigen bisherige Studienergebnisse, die eine akzeptable FCR bei non-trauma-Patienten durch Anwendung der VACM-Therapie zeigen konnten. Die VACM-Therapie scheint aktuell Therapiekonzept der ersten Wahl bei Patienten mit OA und Indikation zum TAC zu sein.

  6. Konstruieren von Pkw-Karosserien: Grundlagen, Elemente und Baugruppen, Vorschriftenübersicht, Beispiele mit CATIA V4 und V5

    NASA Astrophysics Data System (ADS)

    Grabner, Jörg; Nothhaft, Richard

    Die Faszination, die vom Auto ausgeht, ist und bleibt ungebrochen. Entsprechend interessant ist es, sich vor dem Hintergrund konventioneller Konstruktionstechniken über die virtuelle Produktentwicklung von Pkw-Karosserien an modernen CAD-Arbeitsplätzen informieren zu können. Die Autoren führen in die Grundlagen ein und zeigen anhand von Beispielen und zahlreichen Abbildungen, wie mit dem System CATIA der Rohbau sowie die Ausstattung innen und au=C3=9Fen konstruiert werden. Darüber hinaus wird das so genannte "Package" an Beispielen beschrieben, also das Management und die Harmonisierung der Anforderungen an die Bauräume (z.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. Guillain-Barré syndrome: clinical profile and management.

    PubMed

    Sudulagunta, Sreenivasa Rao; Sodalagunta, Mahesh Babu; Sepehrar, Mona; Khorram, Hadi; Bangalore Raja, Shiva Kumar; Kothandapani, Shyamala; Noroozpour, Zahra; Aheta Sham, Mohammed; Prasad, Nagendra; Sunny, Sony Parethu; Mohammed, Munawar Dhanish; Gangadharappa, Rekha; Nidsale Sudarshan, Ranjitha

    2015-01-01

    Einführung: Das Guillain-Barré-Syndrom (GBS) ist eine fulminant verlaufende Polyradiculoneuropathie, die akut, meist schwer verlaufend, auf der Basis eines Autoimmunprozesses auftritt. Die Ätiologie der Erkrankung wird nicht ganz verstanden, die Prognose ist bei früher Diagnose und Therapie gewöhnlich gut. Eine retrospektive Studie wurde durchgeführt, um das klinische Profil, die Epidemiologie, die Laborwerte, die Elektrodiagnose, die Behandlungsarten und die Prognose von Patienten mit GBS auszuwerten.Methode: Die klinischen Daten von 1.166 Patienten, die zwischen Januar 2003 und Januar 2014 mit GBS überwiesen oder in den Ambulanzen vorgestellt wurden, wurden ausgewertet. Ergebnisse: Geschlechtsspezifische Unterschiede wurden nicht beobachtet. Etwa 35% der Patienten waren älter als 50 Jahre. Die Analyse zeigte schlecht eingestellten Diabetes mellitus (HBA1c = 8,1 ± 2,11%). Die saisonale Abhängigkeit der GBS ist deutlich, im Winter wurden 484 (41,5%) gefunden und 449 (38,5%) Patienten mit GBS wurden künstlich beatmet. 48 (4,11%) der Patienten verstarben an GBS. Die neurologischen Untersuchungen ergaben bei 407 (34,9%) der Patienten Beteiligung der cranialen Nerven, faciale Lähmungen bei 401 (34,39%) und Ataxien bei 88 (7,54%) der Patienten. Die meisten Patienten, die mit Plasmapherese behandelt wurden, hatten einen niedrigeren sozioökonomischen Status. Die mittlere Proteinkonzentration im Liquor war 113,8 ± 11,8 mg/dl. Störungen der Nervenleitung, indirekt bestimmt über den H-Reflex, wurden bei 891 (90,64%) der Patienten beobachtet. Keine Unterschiede hinsichtlich Komplikationen und Endergebnis wurden festgestellt zwischen den Behandlungen mit intravenöser Gabe von Immunglobulinen und Plasmaaustausch.Schlussfolgerung: GBS tritt vorwiegend in den Wintermonaten auf, der „Peak-Flow-Test“ kann ein Indikator für eine erforderliche künstliche Beatmung und für die Prognose sein. Eine Verminderung oder Blockierung der Nervenleitung ist die

  12. L'ostéome ostéoïde de l'extrémité inférieur du radius: à propos d'un cas, localisation rare et revue de la littérature

    PubMed Central

    Abdelhafid, Derfoufi; Moncef, Erraji; Abdessamad, Kharraji; Najib, Abdeljaouad; Hicham, Yacoubi

    2016-01-01

    L'ostéome ostéoïde est une tumeur osseuse bénigne, mais douloureuse et dont le traitement consiste en l'exérèse chirurgicale totale. Nous rapportons, dans ce travail le cas d'une jeune patiente présentant un ostéome ostéoïde de l'extrémité inférieur du radius. PMID:27642387

  13. MIT's 3.091 and NSDL Materials Digital Library: Investigating the Role of Digital Libraries in Freshmen Introductory Science Courses with No Lab Component

    NASA Astrophysics Data System (ADS)

    Sadoway, Donald; Bartolo, Laura

    2005-03-01

    One example of the reality facing science educators is the practical impossibility of providing meaningful laboratory experience in large introductory undergraduate science courses. The Materials Digital Library (MatDL), as part of the National Science Foundation (NSF) National Science Digital Library (NSDL) program, investigates issues associated with the delivery of content in materials science and its cognate areas. The focus of the current work is to investigate the feasibility of using data archived in digital libraries to provide freshmen in large introductory science classes a virtual laboratory experience that meets many of the educational objectives of classical laboratory offerings. Also, the question of scalability and broader applicability, e.g., to freshman physics, is under study. The results of a new pilot project launched this academic year will be reported. The virtual laboratory is associated with ``Introduction to Solid State Chemistry 3.091,'' a course that over half the freshman class at MIT choose to satisfy the chemistry requirement but which lacks a laboratory component.

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. Uran-Anreicherung mit Lasern

    NASA Astrophysics Data System (ADS)

    Meyer-Kretschmer, G.; Jetter, H.

    1983-01-01

    In uranium enrichment a substantial cost reduction seems to be possible with laser-based processes. Two different approaches are under investigation, the atomic-vapor process and the molecular process with UF6. The specific problems are discussed and the laser parameters are estimated. After intensive development activities in the past ten years the laser processes seem now to be ready for technical realization.

  1. 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

  2. More great saphenous vein valves - less varicose veins?

    PubMed

    Gräub, Anna-Barbara; Naef, Markus; Wagner, Hans E; Mouton, Wolfgang G

    2014-07-01

    Hintergrund: Die Bedeutung der Anzahl der Venenklappen und derer degenerativen Veränderungen sind bei der Krampfadererkrankungen weder umfassend dokumentiert noch erforscht. Ziel dieser prospektiven Studie ist die quantitative und qualitative Erfassung und Beschreibung der Venenklappen bei Venenerkrankungen der CEAP Stadien C2 bis C6. Patienten und Methoden: Innerhalb von zwei Jahren wurden 152 Patienten (entsprechend 223 Beinen) mit Primäroperation der Vena saphena magna in die Studie eingeschlossen. Bei allen Patienten wurde das CEAP Stadium präoperativ für jedes Bein bestimmt (C2 bis C6). Die Klappen wurden nach der Entfernung der Vena saphena magna quantitativ und qualitativ erfasst. Die qualitative Erfassung erfolgte makroskopisch mittels sechs Klappenerkrankungsklassen (0 bis 5). Ergebnisse: Es bestand eine negative Korrelation zwischen dem Patientenalter und der Anzahl der Klappen (p = 0.0035). Die C-Klasse der CEAP-Einteilung stieg mit zunehmendem Patientenalter. Es fand sich keine statistisch signifikante Korrelation zwischen der Anzahl der Klappen pro Meter und der C-Klasse der CEAP-Einteilung. Bei allen CEAP-Klassen wurden zwischen vier und fünf Klappen pro Meter gezählt. Die Klappenerkrankungsklasse war positiv zur CEAP-Klasse korreliert, wenn auch die Klappenerkrankungsklasse die CEAP-Klasse nie überschritt (p < 0.05). Schlussfolgerungen: Die Venenklappenklasse korreliert in unserer Studie mit der klinischen CEAP-Klasse; die Anzahl der Klappen korreliert nicht mit der klinischen CEAP-Klasse.

  3. La place du clou Telegraph court dans le traitement des fractures de l'extrémité supérieure de l'humérus: à propos de 19 cas

    PubMed Central

    karabila, Mohamed Amine; Hmouri, Ismail; Mhamdi, Younes; Azouz, Mohamed; Madani, Tarik; Kharmaz, Mohamed; Ouadaghiri, Mohamed; Lamrani, Moulay Omar; Bardouni, Ahmed; Lahlou, Abdou; Mahfoud, Mustapha; Berrada, Mohamed Saleh; Montbarbon, Éric; Beaudouin, Emmanuel

    2016-01-01

    La fracture de l'extrémité supérieure de l'humérus est la troisième fracture en fréquence chez les sujets âgés et leur répartition est bimodale touchant préférentiellement le sujet âgé ostéoporotique après un traumatisme à faible énergie ou plus rarement le sujet jeune par mécanisme à forte cinétique. Le traitement des fractures complexes de l'humérus proximal est le sujet de nombreuses controverses Le clou Telegraph constitue une approche thérapeutique très efficace pour les fractures déplacées de l'extrémité supérieure de l'humérus, de technique chirurgicale facile mais avec une courbe d'apprentissage et permettant un protocole de rééducation dans l'immédiat de l'intervention. C'est un matériel d'enclouage antérograde de 15 cm de long, plein verrouillé en proximal et en distal, le verrouillage proximal est assuré par 4 vis spongieuses, de filetage long, stables dans le clou et cela confère une solidité tout-à-fait remarquable à ce montage alors que le verrouillage distal est assuré au niveau du V deltoïdien en zone avasculaire et là où il n'y a pas de passage nerveux. L’étude présentée concerne 19 patients traités par un clou Telegraph court dans le traitement des fractures de l'extrémité supérieure de l'humérus entre 2013 et 2015 et elle a pour but d'analyser les résultats radio-cliniques et d’évaluer la répercussion de cette technique sur la fonction de l’épaule. Le clou Telegraph proposé depuis plus de 12 ans à peu près, a rencontré et continue de rencontrer un réel succès. Il permet de traiter très efficacement les fractures simples type 2 et 3, mais aussi les fractures impactées en valgus à 4 fragments. L'ostéosynthèse par clou Telegraph est une solution efficace, rapide et reproductible dans le traitement chirurgical des fractures de l'extrémité supérieur de l'humérus même en cas des fractures complexes et permet une reprise rapide de la mobilité de l’épaule. PMID:27583100

  4. Quantitative detection of Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae in patients with new influenza A (H1N1)/2009 and influenza A/2010 virus infection.

    PubMed

    Safaeyan, Firouzeh; Nahaei, Mohammad Reza; Seifi, Sirus Jedary; Kafil, Hossein Samadi; Sadeghi, Javid

    2015-01-01

    Einleitung: Die Virusgrippe ist eine saisonale Infektionskrankheit, die mit ausgeprägterer Morbidität und Mortalität einhergeht. In den USA werden jährlich mehr als 35.000 Todesfälle und 200.000 Krankenhausbehandlungen erfasst. Die mit der viralen Primärinfektion assoziierte bakterielle Superinfektion oder Ko-Infektion verursacht schwere Krankheitsverläufe speziell bei Hochrisikogruppen wie alten Menschen und Kleinkindern. Zielsetzung: Die Zielsetzung der Studie bestand in der quantitativen Bestimmung von S. aureus, S. pneumoniae and H. influenzae bei Patienten mit saisonaler Influenza A bzw. pandemischer Influenza A (H1N1) und Symptomen respiratorischer Infektionen, im Vergleich zu je einer Kontrollgruppe. Methode: Insgesamt wurden von April 2009 bis April 2010 625 Patienten mit Verdacht auf eine respiratorische Infektion untersucht, davon 58 Patienten mit Nachweis von Influenza A (H1N1). Vom November 2010 bis zum Februar 2011 wurden 158 Patienten mit respiratorischen Symptomen auf das Vorkommen der saisonalen Influenza A untersucht, davon erwiesen sich 25 als positiv. Zur Ermittlung der bakteriellen Kolonisation wurden parallel 62 gesunde Personen untersucht (Kontrollgruppe). Bei der verwendeten Real-time PCR wurde als Cutoff zur Unterscheidung von Koloniation und Infektion im Respirationstrakt 10(4) CFU/ml eingeführt. Ergebnisse:S. aureus, S. pneumoniae und H. influenzae wurden bei 12%, 26% bzw. 33% der Patienten mit Nachweis von Influenzavirus A (H1N1) gefunden; die Häufigkeit in der Kontrollgruppe betrug 9%, 19% bzw. 31%. Bei der saisonalen Influenza A waren bei 12%, 24% bzw. 32% die Erreger nachweisbar, in der parallelen Kontrollgruppe bei 5%, 11% bzw. 10%. Schlussfolgerung: Die Ergebnisse zeigen, dass der Serotyp der pandemischen Influenza A (H1N1) die Inzidenz der bakteriellen Superinfektion für die drei untersuchten Bakterienspecies nicht erhöht hat. Die quantitative Detektion einer sekundären bakteriellen Infektion mittels Real-time PCR ist

  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. Reconstructive kidney surgery for organ-preserving therapy of renal tumors.

    PubMed

    Hamza, Amir; Günther, Manuel; Behrendt, Wolf; Tietze, Stefan; Beige, Joachim

    2015-01-01

    Hintergrund: Ziel dieser Studie war es, Unterschiede in verschiedenen klinischen Endpunkten bei Patienten mit rekonstruktiver Nierenchirurgie mittels Nierenteilresektion bei malignen Tumoren bis zu 4 cm beziehungsweise größer als 4 cm zu evaluieren.Material und Methoden: Insgesamt wurden 170 Patienten mit einer Nierenteilresektion bei malignen Tumoren in die Studie eingeschlossen. Es wurde retrospektiv anhand der klinikinternen Unterlagen sowie eines Fragebogens zur Erhebung der Follow-up-Daten die klinischen Endpunkte erfasst. Wichtige klinische Endpunkte waren die postoperative Nierenfunktion, intra- und postoperative Komplikationen, die Lokalrezidivrate sowie das Gesamtüberleben.Ergebnisse: Die Lokalrezidivrate betrug 6,1% bei Tumoren bis 4 cm bzw. 14,9% bei Tumoren größer als 4 cm. Im Vergleich zu T1a-Tumoren ist bei mehr als 4 cm großen Nierentumoren nach einer Nierenteilresektion mit einer schlechteren postoperativen Nierenfunktion (p=0,007) sowie mit einer höheren Gesamtkomplikationsrate zu rechnen (p=0,048). Insbesondere zeigte sich hier neben einem höheren Risiko einer transfusionspflichtigen Nachblutung (p=0,012) auch ein höheres Risiko einer hypertensiver Entgleisung im postoperativen Verlauf (p=0,022). Zudem war das Gesamtüberleben bei Tumoren bis 4 cm signifikant besser (p=0,003). Schlussfolgerung: Den Ergebnissen unserer retrospektiven Studie nach, die 170 Pateinen mit Nierenteilresektion bei malignen Tumoren einschloss, ist die Nierenteilresektion ein onkologisch sicheres Operationsverfahren mit geringen Lokalrezidivraten. Allerdings ist bei Tumoren >4 cm mit einer schlechteren postoperativen Nierenfunktion, mit einer höheren Komplikationsrate sowie mit einem schlechterem Gesamtüberleben zu rechnen.

  7. Kontrollierte therapeutische Systeme (Controlled drug delivery systems)

    NASA Astrophysics Data System (ADS)

    Ha, Suk-Woo; Wintermantel, Erich

    Es gibt eine grosse Anzahl von Arzneistoffen, die nicht mit der höchsten Effizienz eingesetzt werden können, weil das geeignete therapeutische System (drug delivery system) für die optimale Applikation fehlt. Viele Arzneistoffe setzen eine häufige Anwendung voraus und sind oft mit mehr oder weniger starken Nebenwirkungen oder aber mit Beeinträchtigungen von Arbeits- und Lebensrhythmus der Patienten verbunden. Der therapeutische Erfolg einer medikamentösen Behandlung setzt eine korrekte Diagnose, die Wahl der richtigen Wirksubstanz sowie ihr Vorliegen in geeigneter Darreichungsform voraus. Zudem muss ein genauer Verabreichungsplan erstellt werden, dessen Einhaltung seitens der Patienten eine wesentliche Voraussetzung für die optimale Wirkung des Arzneistoffes ist. Das Mass, mit dem eine Wirksubstanz therapeutisch voll genutzt werden kann, korreliert direkt mit der Darreichungsform, in der sie angewandt wird. Da viele hochwirksame Arzneimittel bereits existieren, hat sich, neben Neuentwicklungen, das Interesse im vergangenen Jahrzehnt der Optimierung von Arzneimittelwirkungen durch neue Darreichungsformen zugewandt.

  8. 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

  9. 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

    2016-08-15

    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

  10. Tissue plasminogen activator as a novel diagnostic aid in acute pulmonary embolism.

    PubMed

    Flores, Julio; García-Avello, Angel; Alonso, Esther; Ruíz, Antonio; Navarrete, Olga; Alvarez, Concepción; Lozano, Cristina; Arribas, Ignacio

    2014-11-01

    Hintergrund: Wir haben die diagnostische Wertigkeit des Gewebeplasminogen Aktivators (tPA) bei akuter Lungenembolie (PE) mit einer ELISA Methode untersucht und sie mit einem ELISA D-dimer (VIDAS D-dimer) verglichen. Patienten und Methoden: 127 aufeinander folgende ambulante Patienten mit klinischem Verdacht auf PE wurden getestet. Die Diagnose einer PE basierte auf dem klinischen Wahrscheinlichkeitsvortest und einem strengen Bildgebungsprotokoll. Plasmaproben wurden bei der Registrierung entnommen. Die diagnostische Genauigkeit für tPA und D-dimer wurde durch die Fläche unter der Kurve (ROC) bestimmt. Die Empfindlichkeit, Genauigkeit und Voraussagewahrscheinlichkeit wurden berechnet. Ergebnisse: PE wurde bei 41 Patienten (32 %) bestätigt. Die Flächen unter den ROC-Kurven waren 0.86 für D-dimer und 0.71 für tPA. Positive und negative prädiktive Werte für D-dimer bei einem Cut off Wert von 500 ng/mL und tPA bei einem Cut off Wert von 8.5 ng/mL waren 95 % (95 % CI, 88–100 %)/95 und 95 % (95 % CI, 88–100 %)/94 % (95 % CI, 86–100 %). Die diagnostische Brauchbarkeit, um eine PE auszuschließen, war 28.3 % (95 % CI, 21–37 %) für D-dimer und 24.4 % (95 % CI, 17–33 %) für tPA. Schlussfolgerungen: Der tPA mit einem Cut off Wert von 8.5 ng/mL hat eine hohe Empfindlichkeit und einen negativen Vorhersagewert für den Ausschluss einer PE, der einem VIDAS D-dimer mit einem Cut off Wert von 500 ng/mL ähnlich ist, obwohl der diagnostische Nutzen für den D-dimer etwas höher war.

  11. 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.

  12. Testen komplexer digitaler Schaltungen mit Python

    NASA Astrophysics Data System (ADS)

    Reichör, S.; Hueber, G.; Hagelauer, R.; Lindorfer, M.

    2004-05-01

    Die Verifikation von digitalen Schaltungen nimmt heutzutage einen bedeutenden Stellenwert ein. In diesem Paper wird ein Weg beschrieben, der die Erstellung und Wartung von funktionalen Testbenches für digitale Designs unterstützt. Für viele Projekte übersteigt der zeitliche Aufwand für das Testen den Aufwand für die Implementierung der Schaltung. In vielen Fällen beträgt der Aufwand für das Testen bereits 70% des Entwicklungsaufwands (Bergeron, 2000). Typischerweise wird die Testbench auch in der gewählten Hardwarebeschreibungssprache (VHDL oder Verilog) implementiert. Diese Sprachen stellen jedoch nicht die beste Wahl für Verifikationsbelange dar. Gründe dafür sind darin zu suchen, dass diese Sprachen wichtige Konzepte aus den Softwaresprachen (wie z.B. Objektorientierung) nicht kennen. Weiters stehen komfortable Softwarebibliotheken (Zufallszahlengenerierung, Stringverarbeitung, etc.) den Hardwaresprachen nicht zur Verfügung. In diesem Paper wird der Einsatz der Programmiersprache Python (PythonHomepage, 2003; Beazley, 2001) für die Verifikation vorgeschlagen, um die benötigte Zeit für die Funktionalen Tests zu reduzieren.

  13. MIT Adopts a Quiet Global Strategy

    ERIC Educational Resources Information Center

    Fischer, Karin

    2012-01-01

    Back in the 1960s and 1970s, the Massachusetts Institute of Technology was in the university-building business. The elite institute is back in the university-building business. In addition to the thousands of faculty research collaborations around the globe, the university over the past five years has once more engaged in ambitious efforts to…

  14. 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

  15. 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.

  16. 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).

  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. Biotechnology Process Engineering Center at MIT Home

    Science.gov Websites

    ... o PICTo &3;&24;&2;d &17;&2; &1;, &1;, &1; &4;MSWD &30; &1; , &18;&7;&15;Times New Roman &3;&7; 2 . &4; (&1;Z&1;w&1;< &6; &1; - &8; &22; Q )&28;&1;h &6; - &8; &22; )&25;&1;t &6; &2; - &8; &1; &22; ...

  19. 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)

  20. Clinical practice and self-awareness as determinants of empathy in undergraduate education: a qualitative short survey at three medical schools in Germany.

    PubMed

    Ahrweiler, Florian; Scheffer, Christian; Roling, Gudrun; Goldblatt, Hadass; Hahn, Eckhart G; Neumann, Melanie

    2014-01-01

    Ziel der Studie: Ärztliche Empathie ist ein Outcome-relevantes Ziel der medizinischen Ausbildung. Faktoren, die die ärztliche Empathie fördern oder hemmen, sind jedoch vor allem in Deutschland noch nicht ausreichend erforscht. In der vorliegenden Studie untersuchten wir die Sichtweise deutscher Medizinstudentinnen und -studenten auf die Faktoren, die ihre Empathie fördern und hemmen und darauf, in welcher Beziehung ihre Erfahrungen zu den jeweiligen Curricula standen. Methoden: Es wurde eine qualitative Kurzumfrage an drei Universitäten durchgeführt: an der Ruhr-Universität Bochum, an der Universität zu Köln und an der Universität Witten/Herdecke. Die Studierenden wurden gebeten, einen anonymen Fragebogen mit offenen Fragen über Ausbildungsinhalte und Situationen während ihres Medizinstudiums auszufüllen, die einen positiven oder negativen Einfluss auf ihre Empathie hatten. Die Daten wurden mit einer qualitativen Inhaltsanalyse nach Green und Thorogood ausgewertet.Ergebnisse: Insgesamt nahmen 115 Studierende an der Umfrage teil. Die Befragten gaben an, dass eine praxisorientierte Ausbildung mit Patientenkontakt sowie Lehre mit Bezug zur klinischen Praxis und der Sichtweise der Patienten ihre Empathie förderten, während das Fehlen dieser Faktoren ihre Empathie hemmte. Auch die persönliche Reaktion der Studierenden auf die Patienten, wie Sympathie für oder Abneigung gegen Patienten, Vorurteile und die innere Haltung wurden als Einflussfaktoren auf ihre Empathie betrachtet. Obwohl jede Universität einen anderen Ansatz bei der Vermittlung sozialer Kompetenzen verfolgt, ergaben sich aus den Antworten der jeweiligen Studierenden keine relevanten Unterschiede bezüglich möglicher Einflussfaktoren von Empathie. Schlussfolgerung: Mehr Lehre mit Praxisbezug und häufigerer Patientenkontakt könnten sich fördernd auf die Empathie der Studierenden auswirken. Sie benötigen Unterstützung bei der Entwicklung einer therapeutischen Beziehung zum Patienten

  1. Virtual patients in continuing medical education and residency training: a pilot project for acceptance analysis in the framework of a residency revision course in pediatrics.

    PubMed

    Lehmann, Ronny; Hanebeck, Benjamin; Oberle, Stephan; Simon, Anke; Choukair, Daniela; Tönshoff, Burkhard; Huwendiek, Sören

    2015-01-01

    Zielsetzung: Virtuelle Patienten (VPs) sind eine E-Learning-Ressource, welche klinische Entscheidungsfindung an Fallbeispielen schult. Wichtig für ihre erfolgreiche Integration ist dabei die Verbindung mit Präsenzveranstaltungen im Sinne von „Blended Learning“. Bisher gibt es kaum Untersuchungen zum Einsatz von VPs in der Fort- und Weiterbildung. In der vorliegenden Pilot-Studie wurde der Einsatz von VPs im Rahmen eines pädiatrischen Weiterbildungsrepetitoriums untersucht. Methodik: Im Rahmen des Repetitoriums der Deutschen Gesellschaft für Kinder- und Jugendmedizin 2009 in Heidelberg wurden den ca. 200 Teilnehmenden eines pädiatrisch-nephrologischen Fachvortrags zum Thema „nephrotisches und nephritisches Syndrom im Kindesalter“ zwei VPs als Nachbereitung vor Ort zur Verfügung gestellt. Anhand eines Online-Fragebogens wurden verschiedene Aspekte der Lernerfahrung mit VPs, der Verknüpfung mit dem Fachvortrag sowie der Meinung hinsichtlich des Einsatzes von VPs allgemein in der Weiterbildung evaluiert. Ergebnisse: Der Rücklauf an auswertbaren Fragebögen betrug N=40 (ca. 21%), beungünstigt durch ein technisches Problem mit der Firewall vor Ort. Die Teilnehmenden empfanden die Fallbearbeitung als lohnende Lernerfahrung mit guter Vorbereitung für die Diagnostik und Therapie bei realen Patienten/innen mit entsprechenden Beschwerden. Insbesondere wurden die Falldarstellung, die Interaktivität und die Möglichkeit der wiederholten Übung unabhängig von Zeit und Ort positiv hervorgehoben. Gefragt zum grundsätzlichen Einsatz von VPs in der Weiterbildung wurden diese als geeignete Lernmodalität bewertet und der Wunsch nach mehr solcher Angebote geäußert. Schlussfolgerung: VPs können im Bereich der ärztlichen Weiterbildung eine sinn- und wertvolle Ergänzung zu den bisherigen Angeboten bieten.

  2. Pseudarthrose de l'extrémité inférieure du fémur traitée par mégaprothèse: à propos d'un cas et revue de la littérature

    PubMed Central

    Elidrissi, Mohammed; Hammou, Nassereddine; Shimi, Mohammed; Elibrahimi, Abdelhalim; Elmrini, Abdelmajid

    2013-01-01

    Les pseudarthroses de l'extrémité distale du fémur sont relativement rares du fait de la qualité de la vascularisation de cette région. La prise en charge d'une telle complication pose un certain nombre de difficultés. Le traitement chirurgical fait appel à plusieurs techniques conservatrices, le traitement par prothèse peut s'avérer utile quand la perte de substance est importante chez le sujet âgé. L'objectif de ce travail est de discuter l'intérêt de la mégaprothèse du genou dans le traitement de la pseudarthrose de l'extrémité distale du fémur, à travers l’étude de l'observation d'une patiente et revue de la littérature. Il s'agit d'une patiente âgée de 62 ans qui présente une pseudarthrose de l'extrémité distale du fémur gauche. Sur le plan clinique la patiente présente des douleurs du genou gauche, avec gène fonctionnelle importante. Le score de l'IKS préopératoire était de 60. Elle a bénéficié d'un remplacement prothétique par une mégaprothèse du genou. En postopératoire la flexion du genou était à 90°, le score de l'IKS était de 130. A travers l’étude de cette observation, et la revue de la littérature, nous pensons que l'utilisation de mégaprothèse du genou, constitue une solution efficace et durable pour le traitement des pseudarthroses du fémur distal et particulièrement chez le sujet âgé. Cette technique permet de répondre aux impératifs d'un tel aléa de la consolidation: lutter contre la douleur et garantir une mobilité satisfaisante permettant de répondre aux besoins de la vie quotidienne du patient et ainsi améliorer sa qualité de vie. PMID:24396555

  3. The causal representation of outpatients with Crohn's disease: is there a link between psychological distress and clinical disease activity?

    PubMed

    Banovic, Ingrid; Gilibert, Daniel; Andronikof, Anne; Jebrane, Ahmed; Ajdukovic, Ivan; Cosnes, Jaques

    2013-01-01

    Zielsetzung: Aufgrund des fluktuierenden Charakters des Morbus Crohn (Crohn’s disease, (CD)) müssen Patienten mit der Veränderlichkeit ihres Gesundheitszustandes zurechtkommen. Die wahrgenommene, persönliche Kontrollierbarkeit ist ein wichtiges Element der Anpassungsfähigkeit an die Herausforderungen des Krankheitsbildes. In dieser Arbeit wird untersucht, ob wahrgenommene Kontrolle als Prädiktor klinischer Aktivität der Krankheit und psychologischer Belastung (Depression, Angst) angesehen werden kann.Methode: Der HADS (Hospital Anxiety Depression Scale), die Kausale Dimensonsskala und der CGI (Clinical Global Impression, Einschätzung der wahrgenommenen Schwere) wurden an 160 CD-Patienten erhoben. Entzündungsindikatoren (CRP), Krankheitsdauer und klinische Aktivität der Krankheit wurden ebenfalls erhoben.Ergebnisse: Insgesamt scheinen die Patienten ihre Krankheit weder als persönlich ausgeprägt kontrollierbar noch unkontrollierbar zu empfinden. Während die psychologische Belastung bei klinisch aktivem Symptombild höher ist, erweist sich die Beziehung zwischen den Variablen als komplex. Das Gefühl persönlicher Kontrolle weist einen Zusammenhang zu der klinischen Aktivität der Krankkheit auf (p=0,0001), wie auch die Wahrnehmung der Stabilität der CD (p<0,0001) und die Globalität des Einflusses der Krankheit auf das Leben (p=0,001). Ungeachtet dessen zeigte sich die wahrgenommene persönliche Kontrolle nicht als prädiktiv für den Aktivitätsstatus der Krankheit. Schließlich zeigte sich ein Zusammenhang psychologischer Belastung mit der Wahrnehmung der Kontrollierbarkeit der Krankheit durch das medizinische Team (p=0,00001) und der Globalität der Krankheitsfolgen für das Leben (p<0,005)Schlussfolgerung: Psychologische Behandlungen sollten diese Dimensionen berücksichtigen, um das Wohlbefinden und die Gesundheit der Patienten zu verbessern.

  4. The Effects of Hemodynamic Shear Stress on Stemness of Acute Myelogenous Leukemia (AML)

    NASA Astrophysics Data System (ADS)

    Raddatz, Andrew; Triantafillu, Ursula; Kim, Yonghyun (John)

    2015-11-01

    Cancer stem cells (CSCs) have recently been identified as the root cause of tumors generated from cancer cell populations. This is because these CSCs are drug-resistant and have the ability to self-renew and differentiate. Current methods of culturing CSCs require much time and money, so cancer cell culture protocols, which maximize yield of CSCs are needed. It was hypothesized that the quantity of Acute myelogenous leukemia stem cells (LSCs) would increase after applying shear stress to the leukemia cells based on previous studies with breast cancer in bioreactors. The shear stress was applied by pumping the cells through narrow tubing to mimic the in vivo bloodstream environment. In support of the hypothesis, shear stress was found to increase the amount of LSCs in a given leukemia population. This work was supported by NSF REU Site Award 1358991.

  5. Metformin+Cytarabine for the Treatment of Relapsed/Refractory AML

    ClinicalTrials.gov

    2016-08-31

    Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  6. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults.

    PubMed

    Young, Andrew L; Challen, Grant A; Birmann, Brenda M; Druley, Todd E

    2016-01-01

    Clonal haematopoiesis is thought to be a rare condition that increases in frequency with age and predisposes individuals to haematological malignancy. Recent studies, utilizing next-generation sequencing (NGS), observed haematopoietic clones in 10% of 70-year olds and rarely in younger individuals. However, these studies could only detect common haematopoietic clones->0.02 variant allele fraction (VAF)-due to the error rate of NGS. To identify and characterize clonal mutations below this threshold, here we develop methods for targeted error-corrected sequencing, which enable the accurate detection of clonal mutations as rare as 0.0003 VAF. We apply these methods to study serially banked peripheral blood samples from healthy 50-60-year-old participants in the Nurses' Health Study. We observe clonal haematopoiesis, frequently harbouring mutations in DNMT3A and TET2, in 95% of individuals studied. These clonal mutations are often stable longitudinally and present in multiple haematopoietic compartments, suggesting a long-lived haematopoietic stem and progenitor cell of origin. PMID:27546487

  7. Acute Hemolysis with Renal Failure due to Clostridium Bacteremia in a Patient with AML

    PubMed Central

    Medrano-Juarez, R. M.; Sotello, D.; D'Cuhna, L.; Payne, J. D.

    2016-01-01

    We present a case of acute hemolytic anemia, renal failure, and Clostridium perfringens bacteremia in a patient with acute myelogenous leukemia. The high fatality of C. perfringens bacteremia requires that clinicians recognize and rapidly treat patients at risk for this infection. Although other hemolytic processes are in the differential diagnosis of these events, the presence of high fever, chills, and rapidly positive blood cultures may help narrow the diagnosis. Most cases of C. perfringens bacteremia have a concomitant coinfection, which makes broad spectrum empiric therapy essential. There is a high mortality rate of C. perfringens infections associated with leukemia. PMID:27774325

  8. A case of chronic myeloid leukaemia presenting as megakaryocytic blast crisis (AML M7)

    PubMed Central

    Karkuzhali, Ponnuswamy; Shanthi, Velusamy; Usha, Thiruvengadam

    2013-01-01

    Acute megakaryocytic leukaemia (AMeL) is a rare subtype of acute myeloid leukaemia, which can be frequently misdiagnosed as acute myelofibrosis or myelosclerosis [1]. Chronic myeloid leukaemia (CML) presenting primarily as megakaryocytic blast crisis is very rare, with very few case reports published to date [2, 3]. This case report describes a 36-year-old woman who presented with anaemia and massive splenomegaly with peripheral blood and bone marrow showing features of AMeL. Reverse transcriptase polymerase chain reaction and gel-electrophoretic study of peripheral blood leucocytes demonstrated breakpoint cluster region–Abelson oncogene translocation encoding for p210 fusion protein. Megakaryocytic blast crisis as the primary presentation of CML is very rare and requires clinical correlation and additional cytogenetic studies to determine the diagnosis. PMID:24282446

  9. Retinoic acid synergizes ATO-mediated cytotoxicity by precluding Nrf2 activity in AML cells

    PubMed Central

    Valenzuela, M; Glorieux, C; Stockis, J; Sid, B; Sandoval, J M; Felipe, K B; Kviecinski, M R; Verrax, J; Calderon, P Buc

    2014-01-01

    Background: Standard therapy for acute promyelocytic leukaemia (APL) includes retinoic acid (all-trans retinoic acid (ATRA)), which promotes differentiation of promyelocytic blasts. Although co-administration of arsenic trioxide (ATO) with ATRA has emerged as an effective option to treat APL, the molecular basis of this effect remains unclear. Methods: Four leukaemia cancer human models (HL60, THP-1, NBR4 and NBR4-R2 cells) were treated either with ATO alone or ATO plus ATRA. Cancer cell survival was monitored by trypan blue exclusion and DEVDase activity assays. Gene and protein expression changes were assessed by RT-PCR and western blot. Results: ATO induced an antioxidant response characterised by Nrf2 nuclear translocation and enhanced transcription of downstream target genes (that is, HO-1, NQO1, GCLM, ferritin). In cells exposed to ATO plus ATRA, the Nrf2 nuclear translocation was prevented and cytotoxicity was enhanced. HO-1 overexpression reversed partially the cytotoxicity by ATRA-ATO in HL60 cells. The inhibitory effects of ATRA on ATO-mediated responses were not observed in either the ATRA-resistant NB4-R2 cells or in NB4 cells pre-incubated with the RARα antagonist Ro-41-52-53. Conclusions: The augmented cytotoxicity observed in leukaemia cells following combined ATO-ATRA treatment is likely due to inhibition of Nrf2 activity, thus explaining the efficacy of combined ATO-ATRA treatment in the APL therapy. PMID:25003661

  10. Select microtubule inhibitors increase lysosome acidity and promote lysosomal disruption in acute myeloid leukemia (AML) cells.

    PubMed

    Bernard, Dannie; Gebbia, Marinella; Prabha, Swayam; Gronda, Marcela; MacLean, Neil; Wang, Xiaoming; Hurren, Rose; Sukhai, Mahadeo A; Cho, Eunice E; Manolson, Morris F; Datti, Alessandro; Wrana, Jeffrey; Minden, Mark D; Al-Awar, Rima; Aman, Ahmed; Nislow, Corey; Giaever, Guri; Schimmer, Aaron D

    2015-07-01

    To identify new biological vulnerabilities in acute myeloid leukemia, we screened a library of natural products for compounds cytotoxic to TEX leukemia cells. This screen identified the novel small molecule Deoxysappanone B 7,4' dimethyl ether (Deox B 7,4), which possessed nanomolar anti-leukemic activity. To determine the anti-leukemic mechanism of action of Deox B 7,4, we conducted a genome-wide screen in Saccharomyces cerevisiae and identified enrichment of genes related to mitotic cell cycle as well as vacuolar acidification, therefore pointing to microtubules and vacuolar (V)-ATPase as potential drug targets. Further investigations into the mechanisms of action of Deox B 7,4 and a related analogue revealed that these compounds were reversible microtubule inhibitors that bound near the colchicine site. In addition, Deox B 7,4 and its analogue increased lysosomal V-ATPase activity and lysosome acidity. The effects on microtubules and lysosomes were functionally important for the anti-leukemic effects of these drugs. The lysosomal effects were characteristic of select microtubule inhibitors as only the Deox compounds and nocodazole, but not colchicine, vinca alkaloids or paclitaxel, altered lysosome acidity and induced lysosomal disruption. Thus, our data highlight a new mechanism of action of select microtubule inhibitors on lysosomal function. PMID:25832785

  11. Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin for Older Patients With Relapsed or Refractory AML

    ClinicalTrials.gov

    2015-01-22

    Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia

  12. Treatment for Relapsed/Refractory AML Based on a High Throughput Drug Sensitivity Assay

    ClinicalTrials.gov

    2016-05-10

    Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Chronic Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts

  13. Geotechnical properties of Kentucky`s AML landslides and slope failure evaluation

    SciTech Connect

    Iannacchione, A.T.; Bhatt, S.K.; Sefton, J.

    1995-12-31

    A large body of geotechnical data, obtained from the U.S. Office of Surface Mining Reclamation and Enforcement (OSM) and the Kentucky Division of Abandoned Lands, is analyzed in this paper. The analysis includes causes of subsurface failures, phreatic levels, soil profiles, and soil composition data. Soil properties calculated from laboratory procedures and stability analysis techniques were also reviewed. Employing prudent engineering practices and parameters, seven failed slopes were subjected to back analysis for estimating realistic factors of safety. Important factors affecting landslides in eastern Kentucky are presented with appropriate examples.

  14. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults

    PubMed Central

    Young, Andrew L.; Challen, Grant A.; Birmann, Brenda M.; Druley, Todd E.

    2016-01-01

    Clonal haematopoiesis is thought to be a rare condition that increases in frequency with age and predisposes individuals to haematological malignancy. Recent studies, utilizing next-generation sequencing (NGS), observed haematopoietic clones in 10% of 70-year olds and rarely in younger individuals. However, these studies could only detect common haematopoietic clones—>0.02 variant allele fraction (VAF)—due to the error rate of NGS. To identify and characterize clonal mutations below this threshold, here we develop methods for targeted error-corrected sequencing, which enable the accurate detection of clonal mutations as rare as 0.0003 VAF. We apply these methods to study serially banked peripheral blood samples from healthy 50–60-year-old participants in the Nurses' Health Study. We observe clonal haematopoiesis, frequently harbouring mutations in DNMT3A and TET2, in 95% of individuals studied. These clonal mutations are often stable longitudinally and present in multiple haematopoietic compartments, suggesting a long-lived haematopoietic stem and progenitor cell of origin. PMID:27546487

  15. Evolving Strategies in the Treatment of Tuberous Sclerosis Complex-associated Angiomyolipomas (TSC-AML).

    PubMed

    Kapoor, Anil; Girard, Louis; Lattouf, Jean-Baptiste; Pei, York; Rendon, Ricardo; Card, Paul; So, Alan

    2016-03-01

    Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder characterized by the development of numerous benign tumors that occur in multiple organ systems throughout the lifetime of the affected individuals. Renal angiomyolipomas occur in up to 80% of TSC patients, and chronic kidney disease from increasing tumor burden is the primary cause of TSC-related mortality. Our review evaluates evidence for localized and systemic therapy in the management of TSC-angiomyolipomas. Urologists or nephrologists experienced in TSC disease should coordinate the care of TSC patients with renal involvement to improve care and reduce costs. PMID:26723178

  16. The longitudinal curriculum "social and communicative competencies" within Bologna-reformed undergraduate medical education in Basel.

    PubMed

    Kiessling, Claudia; Langewitz, Wolf

    2013-01-01

    Hintergrund: Mit der Umstellung auf die Bachelor-/Masterstruktur wurde in Basel (Schweiz) ein longitudinales Curriculum „soziale und Kommunikative Kompetenzen“ (SOKO) in das Medizinstudium implementiert. Projektbeschreibung: Ziel ist es, den Studierenden grundlegende Techniken einer patientenzentrierten Kommunikation in dem Sinne zu vermitteln, dass die Studierenden in der Lage sind, Informationen zu erheben und Informationen an Patientinnen und Patienten weiterzugeben, um sie als gut informierte Partner am Entscheidungsprozess zu beteiligen. Das SOKO Curriculum umfasst aus Sicht der Studierenden 57 Unterrichtsstunden. In Vorlesungen und kleinen Gruppen kommen vom 1. bis 3. Bachelor- und im 1. Masterstudienjahr Rollenspiele, Videofeedback, Simulationspatienten und der Kontakt mit realen Patienten als didaktische Methoden zum Einsatz. Die Lernziele werden in den summativen klinisch-praktischen OSCE-Prüfungen abgeprüft.Schlussfolgerungen: In Basel konnte mit der Umstellung auf die Bologna-Struktur ein longitudinales SOKO-Curriculum implementiert werden, das kumulatives Lernen erlaubt, auf die Inhalte des sonstigen Studiums Bezug nimmt und regelmäßig in den OSCEs abgeprüft wird. Zurzeit wird ein Großteil der Lehre durch die Psychosomatik des Unispital Basels geleistet. Für die Zukunft wird entscheidend sein, nachhaltige Strukturen in der gesamten Fakultät und im gesamten Unispital zu verankern, um dauerhaft eine hohe Qualität des Unterrichts und der Prüfungen sicherzustellen.

  17. Decitabine and Midostaurin in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-04-25

    Acute Myeloid Leukemia (AML) With Multilineage Dysplasia Following Myelodysplastic Syndrome, in Adults; AML (Adult) With 11q23 (MLL) Abnormalities; AML (Adult) With Del(5q); AML (Adult) With Inv(16)(p13;q22); AML (Adult) With t(16;16)(p13;q22); AML (Adult) With t(8;21)(q22;q22); Secondary AML (Adult); Untreated AML (Adult)

  18. IMP3 can predict aggressive behaviour of lung adenocarcinoma

    PubMed Central

    2012-01-01

    with IMP3 overexpression more often had distant metastases than patients with negative IMP3, 55.5% versus 33.3% (P = 0.033). Non solid subtypes with IMP3 overexpression developed distant metastasis more common than non solid subtypes with negative IMP3, 72% versus 35% (P = 0.028). Conclusions Expression of IMP3 correlates with solid subtype and with distant metastases regardless of histological subtype of lung adenocarcinoma. Virtual slides http://www.diagnosticpathology.diagnomx.eu/vs/1966211581795258 Zusammenfassung Hintergrund Das Lungenkarzinom kommt meistens als nicht resektabler Tumor vor und die Diagnose kann nur in kleinen Biopsaten oder zytologisch gestellt werden. In der Gruppe der nicht kleinzelligen Lungenkarzinome kann der nicht anders spezifizierte Adenokarzinom Phänotyp mit Hilfe der Antikörper TTF-1 und Napsin A diagnostiziert werden. Die Expression des onkoföetalen Proteins IMP3 ist bei humanen Karzinomen mit agressivem Verhalten und metastatischem Potential verbunden. In dieser Studie korreliert die Expression von IMP3 mit TTF-1, Napsin A, histologischem Typ und klinischem Staging des Lungenkarzinoms. Wir waren daran interessiert, ob Fernmetastasen mit IMP3 Überexpression assoziiert sind, unabhängig von der histologischen Subtyp von Adenokarzinom. Methode In der retrospektiven Studie wurden die von 2006 bis 2009 im Klinischem Krankenhaus Split, Kroatien diagnostizerte Adenokarzinome der Lunge von 105 Patienten analysiert. Die klinischen Daten stammten aus der Abteilung für Pulmologie und im Falle des Todes vom Todesregister. Die Paraffinblöcke der primären Lungenbiopsate dieser Patienten wurden im Institut für Pathologie mit der indirekter Enzym - Immunohistochemie mittels Kombination der Antikörper gegen IMP3, Napsin A und TTF1 untersucht. 15 Fälle aus der Analyse aufgrund unzureichender Material ausgeschlossen. Es wurde eine statistische Untersuchung durchgeführt und Werte weniger als 0.05 P wurden als statistisch signifikant

  19. [Quality of involuntary hospital administration in Switzerland].

    PubMed

    Jäger, Matthias; Ospelt, Isabelle; Kawohl, Wolfram; Theodoridou, Anastasia; Rössler, Wulf; Hoff, Paul

    2014-05-21

    Fragestellung: Diese Studie hat zum Ziel, die vor Einführung des neuen Kindes- und Erwachsenenschutzrechts per Januar 2013 bestehende Praxis der Fürsorgerischen Freiheitsentziehung (FFE) anhand formaler und inhaltlicher Kriterien der Zuweisungsschreiben zu untersuchen. Hinweise auf Unterschiede zwischen Zuweisern mit verschiedenen professionellen Hintergründen sollen überprüft und die eingewiesenen Personen charakterisiert werden. Methode: Retrospektive Auswertung der Zuweisungsformulare und der Krankenakten sämtlicher per FFE in die Psychiatrische Universitätsklinik Zürich eingetretenen Patienten in einem Zeitraum von sechs Monaten (n=489). Resultate: Es bestehen erhebliche Mängel bezüglich formaler und insbesondere inhaltlicher Qualitätskriterien. Psychiatrische Fachärzte erstellen die Zeugnisse mit der höchsten Qualität, gefolgt von Notärzten sowie Spitälern und Hausärzten. Die Patienten dieser Zuweisergruppen unterscheiden sich bezüglich soziodemographischer und klinischer Variablen. Schlussfolgerungen: Die formale und insbesondere inhaltliche Qualität der Zwangseinweisungen ist angesichts der schwerwiegenden ethischen und juristischen Konsequenzen für die betroffene Person verbesserungsbedürftig. Die Auswirkungen der neuen Gesetzgebung auf die Qualität der Zuweisungen sollten überprüft werden, sodass etwaige Defizite in der Anwendung freiheitsbeschränkender Massnahmen in der Aus- und Weiterbildungspraxis adressiert werden können.

  20. [The treatment needs of migrant children according to child and adolescent psychiatrists from medical clinics and in private practice].

    PubMed

    Siefen, Georg; Kirkcaldy, Bruce; Adam, Hubertus; Schepker, Renate

    2015-03-01

    Fragestellung: Wie reagiert das kinder- und jugendpsychiatrische Versorgungssystem in Deutschland auf die steigende Zahl von Kindern und Jugendlichen mit Migrationshintergrund? Methodik: Mit einem weiterentwickelten Fragebogen für psychiatrische Kliniken wurden leitende Ärzte kinder- und jugendpsychiatrischer Kliniken über die Bundesarbeitsgemeinschaft der Leitenden Klinikärzte für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie (BAG) nach Bedingungen und Entwicklungsmöglichkeiten der Versorgung von Migrantenkindern und -jugendlichen befragt. Außerdem erhielt eine «random representative» Stichprobe niedergelassener Kinder- und Jugendpsychiater über den Berufsverband für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie in Deutschland e. V. (BKJPP) einen adaptierten Bogen. Ergebnisse: Mit 100 Kinder- und Jugendpsychiatern in eigener Praxis wurden nur etwa 1/8 der Niedergelassenen aber mit 55 Leitenden Ärzten 1/3 und damit eine repräsentative Stichprobe der Chefärzte kinder- und jugendpsychiatrischer Kliniken und Tageskliniken befragt. Jede dritte Klinik hat migrantenspezifische Angebote. In Klinik und Praxis werden zu selten kompetente Dolmetscher eingesetzt. Behandlungsprobleme bei Migrantenkindern und -jugendlichen ergeben sich aus dem Krankheitsverständnis der Eltern, des Patienten und sprachlichen Verständigungsproblemen. Kulturelle Vielfalt wird als bereichernd wahrgenommen. Migrationshintergrund und Gender der Kinder- und Jugendpsychiater beeinflussen die Migrantenbehandlung. Schlussfolgerungen: Durch konkrete Schritte wie die Finanzierung von Dolmetscherkosten müssen der Prozess der «kulturellen Öffnung» unterstützt und die Versorgung von Migrantenkindern und -jugendlichen weiter verbessert werden.

  1. Education 2.0 -- how has social media and Web 2.0 been integrated into medical education? A systematical literature review.

    PubMed

    Hollinderbäumer, Anke; Hartz, Tobias; Uckert, Frank

    2013-01-01

    Zielsetzung: Die Studierenden sind mit einem hohen multimedialen Bezug aufgewachsen. Die von ihnen genutzten Kommunikationswege sind schneller, spontaner und unabhängig von Ort und Zeit geworden. Diese neuen webbasierten Informations- und Kommunikationswege werden von Studierenden, Lehrenden und Patienten in vielfältigen Weisen genutzt. Universitäten, die diese Tools in der Lehre einsetzten, berichten über viele positive Auswirkungen auf das Lernverhalten der Studierenden. In einer systematischen Literaturübersicht wird zusammengestellt, für welche Lehr- und Lernformen Social Media und Web 2.0 Tools in der derzeitigen medizinischen Ausbildung eingesetzt werden.Methode: Es wurde eine systematische Literaturrecherche über die letzten 5 Jahre mit MeSH in PubMed durchgeführt. Ergebnis: Unter den 20 identifizierten Publikationen konnte nur ein deutscher Artikel identifiziert werden. Mehrheitlich stammen die Artikel aus USA und England. Neuere Veröffentlichungen befassen sich mit dem konkreten Einsatz der Tools in der Lehre. Hierzu zählen Social Networking, Podcasts, Blogs, Wikis, YouTube, Twitter und Skype.Schlussfolgerung: Die Einbindung von Web 2.0 und Social Media stellt die heutige Form des selbstbestimmten Lernens dar. Es stimuliert die Reflektion und bindet die Lernenden aktiv, ein Wissen zu konstruieren. Mit diesen neuen Tools lernen Studierende Fertigkeiten, die sie sowohl im sozialen als auch im beruflichen Kontext benötigen.

  2. Terror mit Atomwaffen: reale Gefahr? Nukleare und Radiologische Waffen

    NASA Astrophysics Data System (ADS)

    Harigel, Gert G.

    2006-01-01

    Können Terroristen sich nukleare Massenvernichtungswaffen beschaffen? Dazu müssten sie ausreichende Mengen an waffenfähigem, spaltbarem Material stehlen. Selbst der Bau einer primitiven Atombombe erfordert einen hohen technischen Aufwand und Spezialisten. Wahrscheinlicher ist deshalb der Diebstahl einer kleinen taktischen Kernwaffe. Alternativ könnten Terroristen sich radioaktives Material aus zivilen Quellen beschaffen und daraus eine Schmutzige Bombe bauen. Eine solche radiologische Waffe wäre keine echte Massenvernichtungswaffe, doch ihre psychologische Wirkung könnte stark sein. Das macht sie für Terroristen attraktiv, weswegen diese Gefahr ernst genommen werden muss.

  3. MIT and Itinerant Ferromagnetism in the Half Heuslers

    NASA Astrophysics Data System (ADS)

    Drymiotis, Fivos; Balicas, Luis; Fisk, Zachary

    2002-03-01

    We have performed a single crystal study on selected members of the half Heusler family of compounds. In particular we have studied the evolution from the non-magnetic TiCoSb, to what we find to be, ferromagnetic VCoSb and paramagnetic TiFeSb. We have also studied the transition from the non-magnetic TiNiSn to the ferromagnetic TiCoSn. Resistance, magnetization and heat capacity measurements were performed on members of the series. Contrary to band structure calculations, we have found that TiCoSb is metallic but very close to a metal-insulator transition. Preliminary measurements indicate the opening of a gap with applied pressure. In the case of VCoSb and TiCoSn the onset of ferromagnetism seems to be of Stoner type and the transition to the magnetic metallic state is accompanied by lattice parameter changes.

  4. Harvard-MIT research program in short-lived radiopharmaceuticals

    SciTech Connect

    Adelstein, S.J.

    1991-01-01

    This report presents research on radiopharmaceuticals. The following topics are discussed: antibody labeling with positron-emitting radionuclides; antibody modification for radioimmune imaging; labeling antibodies; evaluation of technetium acetlyacetonates as potential cerebral blood flow agents; and studies in technetium chemistry. (CBS)

  5. Systeme mit veränderlicher Teilchenzahl, Gasentartung

    NASA Astrophysics Data System (ADS)

    Heintze, Joachim

    Bisher haben wir die Zustandsgrößen ν (Zahl der Mole) und N (Zahl der Teilchen im System) als konstant betrachtet. In diesem Kapitel wollen wir untersuchen, wie sich Veränderungen von ν bzw. von N beschreiben lassen. Dazu werden wir eine neue thermodynamische Größe einführen, das chemische Potential μ. Als Beispiele für die Veränderung von Teilchenzahlen werden wir diffusive Prozesse und chemische Reaktionen betrachten. Am Ende des Kapitels werden wir die quantenmechanische Gasentartung diskutieren, bei der das chemische Potential ebenfalls eine Rolle spielt. Wir werden feststellen, dass es nicht schwierig ist, einige Eigenschaften dieses interessanten Materiezustands zu verstehen. Wir behandeln das Thema bereits hier und nicht erst in der Quantenphysik am Ende des Buches, weil es in die Wärmelehre gehört und weil auf dieser Grundlage die elektrischen Eigenschaften von Metallen in Bd. III/9 leicht diskutiert werden können.

  6. Managing Organization Vitality. M.S. Thesis - MIT, Cambridge

    NASA Technical Reports Server (NTRS)

    Chandler, G. P., Jr.

    1976-01-01

    The three major objectives are: (1) to measure the extent to which the organization renewal techniques have been adopted by organizations in both the private and public sectors; (2) to determine the overall results of these applications; and (3) to test a number of specific hypotheses regarding situational determinants of the success of this approach. It appears that top management involvement is the single most crucial determinant of the success of organization renewal. Organization renewal has considerable potential for increasing the commitment of individuals, and can have a significant positive influence on the results of the organization.

  7. The 2d MIT: The Pseudogap and Fermi Liquid Theory

    NASA Astrophysics Data System (ADS)

    Castner, T. G.

    2005-06-01

    Fermi liquid theory for the 2d metal-insulator transition is extended to include the correlation gap in the density-of-states. The results are consistent with the scaling form g=gce[on(To/T)] at T larger than a characteristic T* ∝ xTc (Tc=Ec= mobility edge). The two-component model n1+nloc=n=nc(1+x) for n>nc is required and the theory explains the T-dependence of the data of Hanein et al. for p-type GaAs.

  8. Kommunikationsschulung mit englischen Werbetexten (Communication Training Using English Advertising Material)

    ERIC Educational Resources Information Center

    Thiering, Christian

    1975-01-01

    Using English airline advertisements, the article shows how, at Secondary Grade 2, such material can be used to encourage active communication by the students. Advertising material is found more productive than traditional text analysis. (Text is in German.) (IFS/WGA)

  9. Development and testing of the MIT acoustic levitation test facilities

    NASA Astrophysics Data System (ADS)

    Lupi, Victor D.; Hansman, R. J.

    1991-08-01

    Two acoustic levitation test facilities have been developed for cloud physics experimentation. These facilities utilize acoustic standing wave energy to suspend both solid and liquid objects in a contact-free environment. In the still-air facility, the air in the test section is essentially motionless, whereas in the ventilated facility, a small vertical wind tunnel creates a steady flow through the test section. Temperature control is available in both facilities, and relative humidity can be adjusted in the still-air facility. It was observed that liquid samples deform, to first order, into shapes characteristic of freely falling raindrops when subjected to the acoustic standing wave. It was also determined that the presence of an acoustic field in the test section does not significantly affect molecular diffusion processes. Water-droplet freezing experiments were conducted in both facilities to demonstrate the capability to support samples during a change of phase.

  10. Heuristic control of the Utah/MIT dextrous robot hand

    NASA Technical Reports Server (NTRS)

    Bass, Andrew H., Jr.

    1987-01-01

    Basic hand grips and sensor interactions that a dextrous robot hand will need as part of the operation of an EVA Retriever are analyzed. What is to be done with a dextrous robot hand is examined along with how such a complex machine might be controlled. It was assumed throughout that an anthropomorphic robot hand should perform tasks just as a human would; i.e., the most efficient approach to developing control strategies for the hand would be to model actual hand actions and do the same tasks in the same ways. Therefore, basic hand grips that human hands perform, as well as hand grip action were analyzed. It was also important to examine what is termed sensor fusion. This is the integration of various disparate sensor feedback paths. These feedback paths can be spatially and temporally separated, as well as, of different sensor types. Neural networks are seen as a means of integrating these varied sensor inputs and types. Basic heuristics of hand actions and grips were developed. These heuristics offer promise of control dextrous robot hands in a more natural and efficient way.

  11. Optimierung und Charakterisierung einer transportablen optischen Gitteruhr mit Ytterbium

    NASA Astrophysics Data System (ADS)

    Mura, Gregor

    2015-08-01

    This thesis deals with the improvement and the characterization of a transportable optical lattice clock with ytterbium. Building on results of former theses from T. Franzen [1] and C. Abou Jadoudeh [2] numerous improvements were needed to increase the overall stability of the whole apparatus. The improved stability should lead to a more accurate characterization of the system and a better mobility. Finally, the apparatus should be transported to the Instituto Nationale di Ricerca Metrologica (INRIM) in Torino (Italy) in the course of the Space Optical Clocks 2 (SOC2) project.(Abridged)

  12. Measurements of Aerodynamic Damping in the MIT Transonic Rotor

    NASA Technical Reports Server (NTRS)

    Crawley, E. F.

    1981-01-01

    A method was developed and demonstrated for the direct measurement of aerodynamic forcing and aerodynamic damping of a transonic compressor. The method is based on the inverse solution of the structural dynamic equations of motion of the blade disk system in order to determine the forces acting on the system. The disturbing and damping forces acting on a given blade are determined if the equations of motion are expressed in individual blade coordinates. If the structural dynamic equations are transformed to multiblade coordinates, the damping can be measured for blade disk modes, and related to a reduced frequency and interblade phase angle. In order to measure the aerodynamic damping in this way, the free response to a known excitation is studied.

  13. CU Trianguli - ein EA-Stern mit verdoppelter Periode

    NASA Astrophysics Data System (ADS)

    Maintz, Gisela

    2016-02-01

    CU Tri was obseved at my private observatory. It was found that the period given by Antipin 2008 must be doubled. New elements are given as: 2456948.4491 + 5.156766 * E. The secundary minimum is 0.07 mag less bright than the primary. It is at phase 0.5. This paper makes use of data from the DR1 of the WASP data (Butters et al. 2010) as provided by the WASP consortium, and the computing and storage facilities at the CERIT Scientific Cloud, reg. no. CZ.1.05/3.2.00/08.0144

  14. Publishing Practices of NIH-Funded Faculty at MIT

    ERIC Educational Resources Information Center

    Crummett, Courtney; Duranceau, Ellen Finnie; Gabridge, Tracy A.; Green, Remlee S.; Kajosalo, Erja; Noga, Michael M.; Silver, Howard J.; Stout, Amy

    2010-01-01

    Faculty and researchers who receive substantial funding from NIH were interviewed about their publication practices. Qualitative data was collected from interviews of eleven faculty members and one researcher representing six academic departments who received NIH funding. Interview responses were analyzed to identify a representative publication…

  15. Harvard--MIT research program in short-lived radiopharmaceuticals

    SciTech Connect

    Not Available

    1991-03-01

    This report describes progress on five projects. The first project showed a 1000 fold concentration of the cationic complex {sup 99m}Tc (MIBI) in heart cell mitochondria vs heart cell cytoplasm, as determined by high resolution electron probe microanalysis. Additional technetium-99m based complexes are being developed and tested. The second project involves evaluating technetium acetylacteonates as potential indicators of cerebral blood flow. An intermediate in the synthesis of a technetium porphyrin complex has been synthesized; an oxotechnetium(V)-2,4-pentanedione complex has been prepared and is currently being characterized. The third project involves using radio labelled antibodies for diagnosis and treatment of cancer. An early discovery was that chloramine-T based iodination protocols resulted in a reversal of the charge on mouse lgGs. Immunoperoxidase-labelled monoclonal antibody MOv 18 was shown to bind specifically to the most frequent ovarian aderon carcinomas, and not to healthy tissue, making this antibody a good candidate for immunotherapy or immunodetection. Work on a specific immunotherapy protocol suffered a setback when one reagent, a {sup 125}I-biotin complex, proved to be unstable in vivo. The fourth project involves labelling antibodies with positron emitting radionuclides. Radiofluorination was accomplished through reductive alkylation of {sup 18}F-aldehyde, or pentafluorophenyl esters. Radioiodination was accomplished using alkyl-tin derivation exchange. The fifth project examined antibody modification for use in radioimmune imaging. Technetium-99m-labelled lgG was shown to be biologically equivalent to Indium-III-labelled lgG for imaging focal sites of inflamation. Also, Indium III labelling of small bioactive peptides was examined as a means of imaging important physiological processes. 44 refs., 2 figs.

  16. Advanced Global Atmospheric Gases Experiment (AGAGE): MIT Contribution

    NASA Technical Reports Server (NTRS)

    Kurylo, Michael

    2003-01-01

    We describe in detail the instrumentation and calibrations used in the ALE, GAGE and AGAGE experiments and present a history of the majority of the anthropogenic ozone- depleting and climate-forcing gases in air based on these experiments. Beginning in 1978, these three successive automated high frequency in-situ experiments have documented the long-term behavior of the measured concentrations of these gases over the past twenty years, and show both the evolution of latitudinal gradients and the high frequency variability due to sources and circulation. We provide estimates of the long-term trends in total chlorine contained in long- lived halocarbons involved in ozone depletion. We summarize interpretations of these measurements using inverse methods to determine trace gas lifetimes and emissions. Finally, we provide a combined observational and modeled reconstruction of the evolution of chlorocarbons by latitude in the atmosphere over the past sixty years which can be used as boundary conditions for interpreting trapped air in glaciers and oceanic measurements of chlorocarbon tracers of the deep oceanic circulation. Some specific conclusions are: (a) International compliance with the Montreal Protocol is so far resulting in chlorofluorocarbon and chlorocarbon mole fractions comparable to target levels, (b) Mole fractions of total chlorine contained in long-lived halocarbons (CCl2F2, CCl3F, CH3CCl3, CCl4, CHClF2, CCl2FCClF2, CH3Cl, CH2Cl2, CHCl3, CCl2=CCl2) in the lower troposphere reached maximum values of about 3.6 ppb in 1993 and are beginning to slowly decrease in the global lower atmosphere, (c) The chlorofluorocarbons have atmospheric lifetimes consistent with destruction in the stratosphere being their principal removal mechanism, (d) Multi-annual variations in chlorofluorocarbon and chlorocarbon emissions deduced from ALUGAGWAGAGE data are consistent approximately with variations estimated independently from industrial production and sales data where available (CCl2F2 (CFC-12) and CCl2FCClF2 (CFC-113) show the greatest discrepancies), (e) The mole fractions of the hydrochlorofluorocarbons and hydrofluorocarbons, which are replacing the regulated halocarbons, are rising very rapidly in the atmosphere but, with the exception of the much longer manufactured CHClF2 (HCFC-22), they are not yet at levels sufficient to contribute significantly to atmospheric chlorine loading. These replacement species could in the future provide independent estimates of the global weighted-average OH concentration provided their industrial emissions are accurately documented, (f) In the future, analysis of pollution events measured using high frequency in-situ measurements of chlorofluorocarbons and their replacements may enable emission estimates at the regional level which, together with industrial end-use data, are of sufficient accuracy to be capable of identifying regional non-compliance with the Montreal Protocol.

  17. Workstations as Roommates: Project Athena and Student Life at MIT.

    ERIC Educational Resources Information Center

    Jackson, Gregory A.

    1988-01-01

    A study of Massachusetts Institute of Technology student living groups equipped with powerful computer workstations suggests that the intervention enhances rather than degrades the living groups socially, a few residents benefit substantially while most benefit only modestly, and individual benefits fail to offset potential organizational costs.…

  18. Reversible effect of all-trans-retinoic acid on AML12 hepatocyte proliferation and cell cycle progression

    EPA Science Inventory

    The role of all-trans-retinoic acid (atRA) in the regulation of cellular proliferation and differentiation is well documented. Numerous studies have established the cancer preventive propertiesofatRAwhichfunctionstoregulate levels ofcellcycleproteinsessentialfortheGliS transition...

  19. Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts

    PubMed Central

    Cartellieri, M; Feldmann, A; Koristka, S; Arndt, C; Loff, S; Ehninger, A; von Bonin, M; Bejestani, E P; Ehninger, G; Bachmann, M P

    2016-01-01

    The adoptive transfer of CD19-specific chimeric antigen receptor engineered T cells (CAR T cells) resulted in encouraging clinical trials in indolent B-cell malignancies. However, they also show the limitations of this fascinating technology: CAR T cells can lead to even life-threatening off-tumor, on-target side effects if CAR T cells crossreact with healthy tissues. Here, we describe a novel modular universal CAR platform technology termed UniCAR that reduces the risk of on-target side effects by a rapid and reversible control of CAR T-cell reactivity. The UniCAR system consists of two components: (1) a CAR for an inert manipulation of T cells and (2) specific targeting modules (TMs) for redirecting UniCAR T cells in an individualized time- and target-dependent manner. UniCAR T cells can be armed against different tumor targets simply by replacement of the respective TM for (1) targeting more than one antigen simultaneously or subsequently to enhance efficacy and (2) reducing the risk for development of antigen-loss tumor variants under treatment. Here we provide ‘proof of concept' for retargeting of UniCAR T cells to CD33- and/or CD123-positive acute myeloid leukemia blasts in vitro and in vivo. PMID:27518241

  20. Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts.

    PubMed

    Cartellieri, M; Feldmann, A; Koristka, S; Arndt, C; Loff, S; Ehninger, A; von Bonin, M; Bejestani, E P; Ehninger, G; Bachmann, M P

    2016-01-01

    The adoptive transfer of CD19-specific chimeric antigen receptor engineered T cells (CAR T cells) resulted in encouraging clinical trials in indolent B-cell malignancies. However, they also show the limitations of this fascinating technology: CAR T cells can lead to even life-threatening off-tumor, on-target side effects if CAR T cells crossreact with healthy tissues. Here, we describe a novel modular universal CAR platform technology termed UniCAR that reduces the risk of on-target side effects by a rapid and reversible control of CAR T-cell reactivity. The UniCAR system consists of two components: (1) a CAR for an inert manipulation of T cells and (2) specific targeting modules (TMs) for redirecting UniCAR T cells in an individualized time- and target-dependent manner. UniCAR T cells can be armed against different tumor targets simply by replacement of the respective TM for (1) targeting more than one antigen simultaneously or subsequently to enhance efficacy and (2) reducing the risk for development of antigen-loss tumor variants under treatment. Here we provide 'proof of concept' for retargeting of UniCAR T cells to CD33- and/or CD123-positive acute myeloid leukemia blasts in vitro and in vivo. PMID:27518241

  1. 30 CFR 874.17 - AML agency procedures for reclamation projects receiving less than 50 percent government funding.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR ABANDONED MINE LAND RECLAMATION GENERAL... abandoned mine land reclamation project as government-financed construction under part 707 of this chapter...) Characterize the site in terms of mine drainage, active slides and slide-prone areas, erosion and...

  2. 30 CFR 874.17 - AML agency procedures for reclamation projects receiving less than 50 percent government funding.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR ABANDONED MINE LAND RECLAMATION GENERAL... abandoned mine land reclamation project as government-financed construction under part 707 of this chapter...) Characterize the site in terms of mine drainage, active slides and slide-prone areas, erosion and...

  3. 30 CFR 874.17 - AML agency procedures for reclamation projects receiving less than 50 percent government funding.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR ABANDONED MINE LAND RECLAMATION GENERAL... abandoned mine land reclamation project as government-financed construction under part 707 of this chapter...) Characterize the site in terms of mine drainage, active slides and slide-prone areas, erosion and...

  4. Increased risk of acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) in a county of Hesse, Germany.

    PubMed

    Kolb, G; Becker, N; Scheller, S; Zugmaier, G; Pralle, H; Wahrendorf, J; Havemann, K

    1993-01-01

    The incidence of acute and chronic myelogenous leukemia has been compared for the two neighbouring regions of Marburg and Giessen in Hesse (Germany). The investigation was based on the incident cases of the years 1983-1989 which have been diagnosed in the hematological departments of the universities of the two regions. The epidemiological evaluation of the data has been carried out in terms of a historical follow-up study, and shows an increased relative risk for the region around Marburg with a particular elevation for one community within this region. Potential determinants are discussed and focus on trinitrotoluene (TNT) and decomposition products which are known to contaminate the soil of this community, in some places severely, due to insufficient removal of remnants of the TNT production in large underground plants during World War II.

  5. 30 CFR 874.17 - AML agency procedures for reclamation projects receiving less than 50 percent government funding.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., vegetation, toxic materials, and hydrologic balance; (2) Ensure that the reclamation project is conducted in accordance with the provisions of 30 CFR subchapter R; (3) Develop specific-site reclamation...

  6. 30 CFR 874.17 - AML agency procedures for reclamation projects receiving less than 50 percent government funding.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., vegetation, toxic materials, and hydrologic balance; (2) Ensure that the reclamation project is conducted in accordance with the provisions of 30 CFR subchapter R; (3) Develop specific-site reclamation...

  7. [Beweggründe von Krebspatienten für und gegen die Inanspruchnahme der Misteltherapie].

    PubMed

    Gschwendtner, Kathrin M; Holmberg, Christine; Weis, Joachim

    2016-01-01

    Einleitung: Die Misteltherapie ist im deutschsprachigen Raum ein häufig angewandtes komplementärmedizinisches Verfahren (KM) in der Onkologie. Diese Studie hatte das Ziel, die Beweggründe für oder gegen eine Inanspruchnahme der Misteltherapie zu untersuchen und Themenfeldern zuzuordnen. Patienten und Methoden: Es wurden qualitative leitfadengestützte Interviews mit Krebspatienten geführt. Der Interviewleitfaden fragte nach der Inanspruchnahme von KM, der Motivation zur Inanspruchnahme, Informationsverhalten und -bedürfnissen zu KM sowie nach der Krebserkrankung. Um die Beweggründe für die Inanspruchnahme oder Nichtinanspruchnahme der Misteltherapie zu verstehen, wurden die Interviews inhaltsanalytisch ausgewertet. Ergebnisse: Insgesamt wurden Interviews mit 88 Krebspatienten geführt, davon nutzen 18 (20,5%) die Misteltherapie. Die Beweggründe für oder gegen eine Inanspruchnahme der Misteltherapie ließen sich den 2 Themenfeldern «Wahrgenommene Indikation» und «Abwägungen bei der Entscheidungsfindung» zuordnen. Diskussion und Schlussfolgerungen: Mit der Misteltherapie wird sowohl ein Einfluss auf das Tumorwachstum als auch eine supportive Wirkung assoziiert. Anwender sehen die Misteltherapie als sicheres Verfahren; Nichtnutzer befürchten eher Neben- oder Wechselwirkungen. Die Empfehlung von Fachpersonal spielt eine wichtige Rolle bei der Inanspruchnahme. Zum Teil waren die Nichtnutzer interessiert an der Anwendung der Misteltherapie, befanden sich jedoch noch im Klärungsprozess.

  8. Reconstructive surgery for male stress urinary incontinence: Experiences using the ATOMS(®) system at a single center.

    PubMed

    Krause, Jens; Tietze, Stefan; Behrendt, Wolf; Nast, Jenifer; Hamza, Amir

    2014-01-01

    Fragestellung: Es erfolgt die Darstellung der Probleme und Komplikationsraten mit dem ATOMS(®)-Schlingensystem an Hand von eigenen Ergebnissen, um aktuelle Behandlungsmöglichkeiten von männlicher Stressinkontinenz zu analysieren. Material und Methode: In dem definiertem Zeitraum (4/2010 bis 4/2014) wurde bei 36 Patienten ein ATOMS(®)-System in unserer Klinik implantiert. Die Evaluation erfolgte prä- und postoperativ mithilfe des internationalen Fragebogens zur Inkontinenz (ICIQ SF). Es erfolgte die Erweiterung des Fragebogen mit Fragen über die postoperative perineale Schmerzsymptomatik, die generelle Zufriedenheit mit Operationsergebnis und über die Bereitschaft zur Therapieweiterempfehlung an den besten Freund.Ergebnisse: Unsere Daten zeigen eine relativ hohe Explantationsrate, jedoch eine hohe Patientenzufriedenheit. Die Explantation war in den meisten Fällen aufgrund einer Spätinfektion des Implantats oder aufgrund anderer symptomatische Faktoren notwendig. Im Vergleich zu anderen Studien zeigte sich unmittelbar postoperativ eine geringere Infektionsrate. Schlussfolgerung: Ein nicht invasives, unkompliziertes adjustierbares System zur Linderung der männlichen Stressinkontinenz bleibt eine Herausforderung. Obwohl unterschiedliche Systeme zur Behandlung der männlichen Stressinkontinenz verfügbar sind, scheint es, dass ein artifizieller Sphincter mehr Vorteile gegenüber dem ATOMS(®)-Systems besitzt. Dies könnte jedoch auch aufgrund zahlreicher, gut dokumentierter und langfristiger Daten über den artifiziellen Sphincter begründet werden.

  9. [Beweggründe von Krebspatienten für und gegen die Inanspruchnahme der Misteltherapie].

    PubMed

    Gschwendtner, Kathrin M; Holmberg, Christine; Weis, Joachim

    2016-01-01

    Einleitung: Die Misteltherapie ist im deutschsprachigen Raum ein häufig angewandtes komplementärmedizinisches Verfahren (KM) in der Onkologie. Diese Studie hatte das Ziel, die Beweggründe für oder gegen eine Inanspruchnahme der Misteltherapie zu untersuchen und Themenfeldern zuzuordnen. Patienten und Methoden: Es wurden qualitative leitfadengestützte Interviews mit Krebspatienten geführt. Der Interviewleitfaden fragte nach der Inanspruchnahme von KM, der Motivation zur Inanspruchnahme, Informationsverhalten und -bedürfnissen zu KM sowie nach der Krebserkrankung. Um die Beweggründe für die Inanspruchnahme oder Nichtinanspruchnahme der Misteltherapie zu verstehen, wurden die Interviews inhaltsanalytisch ausgewertet. Ergebnisse: Insgesamt wurden Interviews mit 88 Krebspatienten geführt, davon nutzen 18 (20,5%) die Misteltherapie. Die Beweggründe für oder gegen eine Inanspruchnahme der Misteltherapie ließen sich den 2 Themenfeldern «Wahrgenommene Indikation» und «Abwägungen bei der Entscheidungsfindung» zuordnen. Diskussion und Schlussfolgerungen: Mit der Misteltherapie wird sowohl ein Einfluss auf das Tumorwachstum als auch eine supportive Wirkung assoziiert. Anwender sehen die Misteltherapie als sicheres Verfahren; Nichtnutzer befürchten eher Neben- oder Wechselwirkungen. Die Empfehlung von Fachpersonal spielt eine wichtige Rolle bei der Inanspruchnahme. Zum Teil waren die Nichtnutzer interessiert an der Anwendung der Misteltherapie, befanden sich jedoch noch im Klärungsprozess. PMID:27606463

  10. Digitale Subtraktion von kontrastiertem Stuhlmaterial für die virtuelle CT-Koloskopie

    NASA Astrophysics Data System (ADS)

    Mostarkic, Zvonimir; Gündel, Lutz; Freisleben, Bernd

    In der virtuellen Koloskopie mittels CT-Daten werden Stuhlreste durch oral zugeführte Kontrastmittel hervorgehoben, um diese vom umliegenden Darmgewebe des Patienten abzugrenzen. Eine eindeutige 3D Befundung wird für den Radiologen ermöglicht, nachdem die Stuhlreste aus den Bilddaten entfernt und die Darmwände für den virtuellen Darmdurchflug nicht verdeckt werden. In diesem Beitrag wird ein Verfahren vorgestellt, welches ermöglicht, Stuhl- und Flüssigkeitsreste nachträglich aus Computertomographien zu subtrahieren, ohne dabei falscherweise Darmgewebe zu entfernen. Zum einen kommen dabei adaptive Schwellwerte zum Einsatz, die aus dem Histogramm des CTDatensatzes gewonnen werden, und zum anderen werden mit einer Eigenwertanalyse der Hesse'schen Matrix Darmfaltenperforationen vermieden.

  11. One-day point prevalence of emerging bacterial pathogens in a nationwide sample of 62 German hospitals in 2012 and comparison with the results of the one-day point prevalence of 2010.

    PubMed

    Wegner, Christian; Hübner, Nils-Olaf; Gleich, Sabine; Thalmaier, Ulrike; Krüger, Colin M; Kramer, Axel

    2013-01-01

    .550 angefragten Krankenhäusern beteiligten sich 62 (4%). Die Daten von 56 Krankenhäusern (3,6%) waren auswertbar, davon 26 der Regelversorgung, 20 der Schwerpunktversorgung und 10 der Maximalversorgung. MRSA stand unabhängig vom Versorgungs- und Stationstyp in der Häufigkeit an erster Stelle mit 1,53% [CI95: 1,32–1,75], gefolgt von CDAD 1,30% [CI95: 1,11–1,50], ESBL-EC 0,97% [CI95: 0,80–1,14] und ESBL-KP 0,27% [CI95: 0,18–0,36]. Wie erwartet war die Prävalenz aller MRE am höchsten in Intensivtherapieeinheiten und verglichen mit chirurgischen Stationen relativ hoch in internistischen Stationen. Während die Krankenhäuser der Maximalversorgung ausnahmslos eine hauptamtliche Hygienefachkraft beschäftigten, war das bei Schwerpunkt- und Regelversorgern nur in etwa 70% der Fall. Überraschenderweise verfügten zwei der zehn Krankenhäuser der Maximalversorgung weder über einen hauptamtlichen Krankenhaushygieniker, noch über einen nebenamtlich beschäftigten.Diskussion: Mit mehr als 13.000 Patienten von 56 bundesweit verteilten Krankenhäusern schloss die Umfrage im Vergleich zur ersten Erhebung 2010 mehr als dreimal so viel Patienten ein. Damit werden nicht nur wertvolle Hinweise zur Epidemiologie gefährlicher nosokomialer Pathogene erhalten, sondern die Studie trägt auch dazu bei, dass die Prävalenzen mit den Ergebnissen früherer Erhebungen verglichen werden können. Einige Krankenhäuser verfügten über keinerlei Hygienefachpersonal. Dies steht in Übereinstimmung mit einer anderen in dieser Ausgabe veröffentlichten Analyse.

  12. Self-image and perception of mother and father in psychotic and borderline patients.

    PubMed

    Armelius, K; Granberg

    2000-02-01

    Psychotic and borderline patients rated their self-image and their perception of their mother and father using the Structural Analysis of Social Behavior model (SASB). The borderline patients had more negative images of themselves and their parents, especially their fathers, than did the psychotic patients and the normal subjects, while the psychotic patients' ratings did not differ much from those of the normal subjects. The self-image was related to the images of both parents for borderline patients and normal subjects, while for the psychotic patients only the image of the mother was important for the self-image. In addition, the psychotic patients did not differentiate between the poles of control and autonomy in the introjected self-image. It was concluded that borderline patients are characterized by negative attachment, while psychotic patients are characterized by poor separation from the mother and poor differentiation between autonomy and control. The paper also discusses how this may influence the patients' relations to others. Psychotische und Borderline Patienten beurteilten ihr Selbstbild und ihre Wahrnehmung von Mutter und Vater mit Hilfe der strukturalen Analyse sozialen Verhaltens (SASB). Die Borderline Patienten hattten negativere Selbstbilder und Elternbilder (speziell Vaterbilder) als die psychotischen Patienten und gesunde Personen. Die Beurteilungen der psychotischen Patienten unterschieden sich dagegen nicht besonders von jenen Gesunder. Das Selbstbild stand in Beziehung zu beiden Elternbildern bei den Borderline Patienten und den Gesunden, während bei den psychotischen Patienten nur das Mutterbild für das Selbstbild bedeutsam war. Außerdem konnte bei den psychotischen Patienten nicht zwischen den Polen der Kontrolle und Autonomie bzgl. der introjizierten Selbstbilder differenziert werden. Aus den Ergebnissen wird gefolgert, dass Borderline Patienten durch eine negative Bindung charackterisiert sind, psychotische Patienten dagegen durch

  13. Self-image and perception of mother and father in psychotic and borderline patients.

    PubMed

    Armelius, K; Granberg

    2000-02-01

    Psychotic and borderline patients rated their self-image and their perception of their mother and father using the Structural Analysis of Social Behavior model (SASB). The borderline patients had more negative images of themselves and their parents, especially their fathers, than did the psychotic patients and the normal subjects, while the psychotic patients' ratings did not differ much from those of the normal subjects. The self-image was related to the images of both parents for borderline patients and normal subjects, while for the psychotic patients only the image of the mother was important for the self-image. In addition, the psychotic patients did not differentiate between the poles of control and autonomy in the introjected self-image. It was concluded that borderline patients are characterized by negative attachment, while psychotic patients are characterized by poor separation from the mother and poor differentiation between autonomy and control. The paper also discusses how this may influence the patients' relations to others. Psychotische und Borderline Patienten beurteilten ihr Selbstbild und ihre Wahrnehmung von Mutter und Vater mit Hilfe der strukturalen Analyse sozialen Verhaltens (SASB). Die Borderline Patienten hattten negativere Selbstbilder und Elternbilder (speziell Vaterbilder) als die psychotischen Patienten und gesunde Personen. Die Beurteilungen der psychotischen Patienten unterschieden sich dagegen nicht besonders von jenen Gesunder. Das Selbstbild stand in Beziehung zu beiden Elternbildern bei den Borderline Patienten und den Gesunden, während bei den psychotischen Patienten nur das Mutterbild für das Selbstbild bedeutsam war. Außerdem konnte bei den psychotischen Patienten nicht zwischen den Polen der Kontrolle und Autonomie bzgl. der introjizierten Selbstbilder differenziert werden. Aus den Ergebnissen wird gefolgert, dass Borderline Patienten durch eine negative Bindung charackterisiert sind, psychotische Patienten dagegen durch

  14. PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation.

    PubMed

    Kong, Y; Zhang, J; Claxton, D F; Ehmann, W C; Rybka, W B; Zhu, L; Zeng, H; Schell, T D; Zheng, H

    2015-07-31

    Prognosis of leukemia relapse post allogeneic stem cell transplantation (alloSCT) is poor and effective new treatments are urgently needed. T cells are pivotal in eradicating leukemia through a graft versus leukemia (GVL) effect and leukemia relapse is considered a failure of GVL. T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3). To evaluate whether T-cell exhaustion and inhibitory pathways are involved in leukemia relapse post alloSCT, we performed phenotypic and functional studies on T cells from peripheral blood of acute myeloid leukemia patients receiving alloSCT. Here we report that PD-1(hi)TIM-3(+) cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1(hi)TIM-3(+) T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing TN and TEMRA subsets. Importantly, increase of PD-1(hi)TIM-3(+) cells occurs before clinical diagnosis of leukemia relapse, suggesting their predictive value. Results of our study provide an early diagnostic approach and a therapeutic target for leukemia relapse post transplantation.

  15. Acid neutralizing capacity and leachate results for igneous rocks, with associated carbon contents of derived soils, Animas River AML site, Silverton, Colorado

    USGS Publications Warehouse

    Yager, Douglas B.; Stanton, Mark R.; Choate, LaDonna M.; Burchell,

    2009-01-01

    Mine planning efforts have historically overlooked the possible acid neutralizing capacity (ANC) that local igneous rocks can provide to help neutralize acidmine drainage. As a result, limestone has been traditionally hauled to mine sites for use in neutralizing acid drainage. Local igneous rocks, when used as part of mine life-cycle planning and acid mitigation strategy, may reduce the need to transport limestone to mine sites because these rocks can contain acid neutralizing minerals. Igneous hydrothermal events often introduce moderately altered mineral assemblages peripheral to more intensely altered rocks that host metal-bearing veins and ore bodies. These less altered rocks can contain ANC minerals (calcite-chlorite-epidote) and are referred to as a propylitic assemblage. In addition, the carbon contents of soils in areas of new mining or those areas undergoing restoration have been historically unknown. Soil organic carbon is an important constituent to characterize as a soil recovery benchmark that can be referred to during mine cycle planning and restoration.
    This study addresses the mineralogy, ANC, and leachate chemistry of propylitic volcanic rocks that host polymetallic mineralization in the Animas River watershed near the historical Silverton, Colorado, mining area. Acid titration tests on volcanic rocks containing calcite (2 – 20 wt %) and chlorite (6 – 25 wt %), have ANC ranging from 4 – 146 kg/ton CaCO3 equivalence. Results from a 6-month duration, kinetic reaction vessel test containing layered pyritic mine waste and underlying ANC volcanic rock (saturated with deionized water) indicate that acid generating mine waste (pH 2.4) has not overwhelmed the ANC of propylitic volcanic rocks (pH 5.8). Sequential leachate laboratory experiments evaluated the concentration of metals liberated during leaching. Leachate concentrations of Cu-Zn-As-Pb for ANC volcanic rock are one-to-three orders of magnitude lower when compared to leached solution from mine waste used in the kinetic reaction vessel test. This finding suggests that mine waste and not ANC rock may generate the majority of leachable metals in a field scenario.
    The organic carbon content of naturally reclaimed soils derived from weathering of propylitically-altered andesite was determined in catchments where ANC studies were initiated. Soils were found to have total carbon concentrations (TOC) that exceed global average soil TOC abundances by as much as 1.5 – 5 times. These data support an environmental management system involving use of ANC rocks as part of life-cycle mine planning to reduce post-mine closure acid mitigation measures. Carbon contents of undisturbed soils in mined catchments can possibly be used to validate post-reclamation success and help quantify carbon sequestration for CO2 emission offset trading as carbon markets mature.

  16. Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6.

    PubMed

    Uras, Iris Z; Walter, Gina J; Scheicher, Ruth; Bellutti, Florian; Prchal-Murphy, Michaela; Tigan, Anca S; Valent, Peter; Heidel, Florian H; Kubicek, Stefan; Scholl, Claudia; Fröhling, Stefan; Sexl, Veronika

    2016-06-01

    Up to 30% of patients with acute myeloid leukemia have constitutively activating internal tandem duplications (ITDs) of the FLT3 receptor tyrosine kinase. Such mutations are associated with a poor prognosis and a high propensity to relapse after remission. FLT3 inhibitors are being developed as targeted therapy for FLT3-ITD(+) acute myeloid leukemia; however, their use is complicated by rapid development of resistance, which illustrates the need for additional therapeutic targets. We show that the US Food and Drug Administration-approved CDK4/6 kinase inhibitor palbociclib induces apoptosis of FLT3-ITD leukemic cells. The effect is specific for FLT3-mutant cells and is ascribed to the transcriptional activity of CDK6: CDK6 but not its functional homolog CDK4 is found at the promoters of the FLT3 and PIM1 genes, another important leukemogenic driver. There CDK6 regulates transcription in a kinase-dependent manner. Of potential clinical relevance, combined treatment with palbociclib and FLT3 inhibitors results in synergistic cytotoxicity. Simultaneously targeting two critical signaling nodes in leukemogenesis could represent a therapeutic breakthrough, leading to complete remission and overcoming resistance to FLT3 inhibitors. PMID:27099147

  17. Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6

    PubMed Central

    Uras, Iris Z.; Walter, Gina J.; Scheicher, Ruth; Bellutti, Florian; Prchal-Murphy, Michaela; Tigan, Anca S.; Valent, Peter; Heidel, Florian H.; Kubicek, Stefan; Scholl, Claudia; Fröhling, Stefan

    2016-01-01

    Up to 30% of patients with acute myeloid leukemia have constitutively activating internal tandem duplications (ITDs) of the FLT3 receptor tyrosine kinase. Such mutations are associated with a poor prognosis and a high propensity to relapse after remission. FLT3 inhibitors are being developed as targeted therapy for FLT3-ITD+ acute myeloid leukemia; however, their use is complicated by rapid development of resistance, which illustrates the need for additional therapeutic targets. We show that the US Food and Drug Administration–approved CDK4/6 kinase inhibitor palbociclib induces apoptosis of FLT3-ITD leukemic cells. The effect is specific for FLT3-mutant cells and is ascribed to the transcriptional activity of CDK6: CDK6 but not its functional homolog CDK4 is found at the promoters of the FLT3 and PIM1 genes, another important leukemogenic driver. There CDK6 regulates transcription in a kinase-dependent manner. Of potential clinical relevance, combined treatment with palbociclib and FLT3 inhibitors results in synergistic cytotoxicity. Simultaneously targeting two critical signaling nodes in leukemogenesis could represent a therapeutic breakthrough, leading to complete remission and overcoming resistance to FLT3 inhibitors. PMID:27099147

  18. Epigenetische Aspekte bei Karzinomen der Kopf-Hals-Region

    PubMed Central

    Schmezer, Peter; Plass, Christoph

    2009-01-01

    Zusammenfassung Plattenepithelkarzinome der Kopf-Hals-Region (HNSCC) zählen seit Jahren zu den weltweit häufigsten Krebsarten. Trotz vieler Bemühungen hat sich das 5-Jahres-Überleben bei Patienten mit HNSCC kaum verbessert. Um einen Fortschritt zu erzielen, ist es notwendig, die der Erkrankung zugrunde liegenden biologischen Prozesse besser zu verstehen. Neben den bekannten genetischen Veränderungen haben molekular-zytogenetische Untersuchungen bei HNSCC gezeigt, dass es weitere Veränderungen gibt, die mit Vermehrung und Verlust chromosomaler Bereiche einhergehen, für die jedoch die krankheitsverursachenden Gene bisher nicht identifiziert wurden. Darüberhinaus haben jüngste Forschungsergebnisse verdeutlicht, dass epigenetische Modifikationen wie die DNA Methylierung eine wichtige Rolle spielen. So konnte gezeigt werden, dass bei HNSCC eine Reihe von Genen (z.B. das Tumorsuppressorgen CDKN2A sowie DAPK1, MGMT, TIMP3, TCF21, und C/EBPα) hypermethylierte Bereiche in regulatorischen DNA Sequenzen aufweisen, wodurch ihre Expression verringert oder unterbunden wird. Die Hypermethylierung solcher Gene könnte als Biomarker zur Früherkennung von HNSCC genutzt werden und nicht zuletzt dadurch zur Verbesserung von Prävention und Therapieerfolg beitragen. PMID:18483718

  19. Homeopathy as elective in undergraduate medical education--an opportunity for teaching professional core skills.

    PubMed

    Lehmann, Bianca; Krémer, Brigitte; Werwick, Katrin; Herrmann, Markus

    2014-01-01

    Zielsetzung: In der Evaluation des seit sechs Jahren regelmäßig stattfindenden klinischen Wahlfachs Homöopathie am Institut für Allgemeinmedizin der Universität Magdeburg wurden sowohl die studentische Einschätzung des Seminarkonzepts und der -durchführung als auch die Bedeutung für die professionelle Sozialisation der Studierenden erfragt.Methodik: Im Rahmen des seit dem Wintersemester 2008/2009 jährlich stattfindenden Wahlfachs wurden für drei Veranstaltungen leitfadengestützte Gruppendiskussionen mit insgesamt 30 Teilnehmern des Wahlfachs durchgeführt. Die Auswertung dieser erfolgte in Anlehnung an die qualitative Inhaltsanalyse nach Mayring.Ergebnisse: Seminarkonzept und -durchführung haben sich bewährt. Die Lern- und Erlebenserfahrungen durch das Wahlfach, v.a. hinsichtlich eines holistischen, individualisierten Blicks auf die Person des Patienten sowie der Bedeutung einer partnerschaftlichen Arzt-Patient-Beziehung, werden von den Studierenden – unabhängig von ihrer persönlichen Einstellung zur Homöopathie – als positiv gewertet. Diese Einschätzung erfolgt gerade auch mit Blick auf ihre bisherige konventionell medizinisch geprägte Ausbildung.Schlussfolgerung: Das Wahlfach vermittelt den Studierenden neben dem spezifischen Fachwissen für eine integrative Medizin auch wichtige ärztliche Basiskompetenzen, welche unabhängig von einer komplementärmedizinischen Ausrichtung von Bedeutung sind.

  20. Theory in practice instead of theory versus practice--curricular design for task-based learning within a competency oriented curriculum.

    PubMed

    Rotthoff, Thomas; Schneider, Matthias; Ritz-Timme, Stefanie; Windolf, Joachim

    2015-01-01

    Zielsetzung: Medizinstudierende sollen bereits während ihres Studiums ärztliches Denken und Handeln intensiv trainieren und ihre klinische Expertise in theoretischer und praktischer Hinsicht entwickeln. Methodik: Ausgehend von den Erkenntnissen der Lehr- und Lernforschung wurde ein Curriculum für die klinisch-praktische Ausbildung im Modellstudiengang Düsseldorf entwickelt, welches auf das arbeitsplatzbezogene Lehren, Lernen und Prüfen fokussiert. Ergebnisse: Das Curriculum basiert für Studierende im 3, 4 und 5. Studienjahr wesentlich auf dem Lernen an Behandlungsanlässen von Patienten in multidisziplinären Bereichen der ambulanten und stationären Versorgung. Für dieses Lehrformat wurden 123 Behandlungsanlässe definiert und deren Verknüpfbarkeit mit Krankheitsbildern aus den verschiedenen Fachdisziplinen geprüft. Ausgehend vom Behandlungsanlass eines konkreten Falles, erarbeiten sich die Studierenden das zugrundeliegende Krankheitsbild sowie das differentialdiagnostische und therapeutische Vorgehen und vertiefen dabei das notwendige Wissen in den Grundlagenfächern. Zur Lernunterstützung wurden Studienbücher von den Kliniken erstellt. Das Lernen ist eingebunden in kompetenzorientiertes und arbeitsplatzbezogenes Lernen und Prüfen mit einer intensiven Kontaktzeit zwischen Studierenden und Ärzten.Schlussfolgerung: Das Konzept ermöglicht die Integration von Theorie in die Praxis sowie die Integration von Wissen aus den Grundlagen-, klinisch-theoretischen und klinischen Fächern in das ärztliche Denken und Handeln.

  1. Microbial contamination of mobile phones in a health care setting in Alexandria, Egypt.

    PubMed

    Selim, Heba Sayed; Abaza, Amani Farouk

    2015-01-01

    Zielsetzung: Es sollte die mikrobielle Kontamination von Mobiltelefonen in einer universitären Gesundheitseinrichtung untersucht werden.Methode: Abstrichproben wurden von 40 Mobiltelefonen von Patienten und Mitarbeitern im Universitätskrankenhaus in Alexandria entnommen. Die mikrobiologische Analyse wurde im mikrobiologischen Labor des Instituts für Public Health durchgeführt. Die Quantifizierung erfolgte sowohl durch direkte Ausbringung auf die Platte als auch durch Anlage von Subkulturen zur Differenzierung. Methicillin-resistente Staphylococcus aureus (MRSA) wurden mittels Plättchendiffusionsmethode nach Bauer und Kirby identifiziert. Isolierte Gram-negative Organismen wurden auf Vorkommen von ESBL-Bildung mittels der Doppeldiffusionsmethode gemäß Empfehlung des Clinical and Laboratory Standards Institute untersucht.Ergebnisse: Alle untersuchten Mobiltelefone waren entweder mit einer oder mehreren bakteriellen Arten kontaminiert. Am häufigsten wurden MRSA (53%) und Koagulase-negative Staphylokokken (50%) nachgewiesen. Als mittlere Anzahl von KbE ergaben sich 357 KbE mit einem Median von130 KbE/ml pro Mobiltelefon im Plattengussverfahren. Die korrespondierenden Werte betrugen 2.192 bzw. 1.720 KbE/Mobiltelefon im Direktausstrich.Schlussfolgerung: Mobiltelefone stellen ein Risiko in Gesundheitseinrichtungen zur Weiterverbreitung nosokomialer Pathogen einschließlich MRSA dar. Auf der Oberfläche von Mobiltelefonen kann die mikrobielle Kontamination methodisch einfach nachgewiesen werden.

  2. Improving Rates of Influenza Vaccination Through Electronic Health Record Portal Messages, Interactive Voice Recognition Calls and Patient-Enabled Electronic Health Record Updates: Protocol for a Randomized Controlled Trial

    PubMed Central

    Sreedhara, Meera; Goff, Sarah L; Fisher, Lloyd D; Preusse, Peggy; Jackson, Madeline; Sundaresan, Devi; Garber, Lawrence D; Mazor, Kathleen M

    2016-01-01

    Background Clinical decision support (CDS), including computerized reminders for providers and patients, can improve health outcomes. CDS promoting influenza vaccination, delivered directly to patients via an electronic health record (EHR) patient portal and interactive voice recognition (IVR) calls, offers an innovative approach to improving patient care. Objective To test the effectiveness of an EHR patient portal and IVR outreach to improve rates of influenza vaccination in a large multispecialty group practice in central Massachusetts. Methods We describe a nonblinded, randomized controlled trial of EHR patient portal messages and IVR calls designed to promote influenza vaccination. In our preparatory phase, we conducted qualitative interviews with patients, providers, and staff to inform development of EHR portal messages with embedded questionnaires and IVR call scripts. We also provided practice-wide education on influenza vaccines to all physicians and staff members, including information on existing vaccine-specific EHR CDS. Outreach will target adult patients who remain unvaccinated for more than 2 months after the start of the influenza season. Using computer-generated randomization and a factorial design, we will assign 20,000 patients who are active users of electronic patient portals to one of the 4 study arms: (1) receipt of a portal message promoting influenza vaccines and offering online appointment scheduling; (2) receipt of an IVR call with similar content but without appointment facilitation; (3) both (1) and (2); or (4) neither (1) nor (2) (usual care). We will randomize patients without electronic portals (10,000 patients) to (1) receipt of IVR call or (2) usual care. Both portal messages and IVR calls promote influenza vaccine completion. Our primary outcome is percentage of eligible patients with influenza vaccines administered at our group practice during the 2014-15 influenza season. Both outreach methods also solicit patient self-report on influenza vaccinations completed outside the clinic or on barriers to influenza vaccination. Self-reported data from both outreach modes will be uploaded into the EHR to increase accuracy of existing provider-directed EHR CDS (vaccine alerts). Results With our proposed sample size and using a factorial design, power calculations using baseline vaccination rate estimates indicated that 4286 participants per arm would give 80% power to detect a 3% improvement in influenza vaccination rates between groups (α=.05; 2-sided). Intention-to-treat unadjusted chi-square analyses will be performed to assess the impact of portal messages, either alone or in combination with the IVR call, on influenza vaccination rates. The project was funded in January 2014. Patient enrollment for the project described here completed in December 2014. Data analysis is currently under way and first results are expected to be submitted for publication in 2016. Conclusions If successful, this study’s intervention may be adapted by other large health care organizations to increase vaccination rates among their eligible patients. ClinicalTrial ClinicalTrials.gov NCT02266277; https://clinicaltrials.gov/ct2/show/NCT02266277 (Archived by WebCite at http://www.webcitation.org/6fbLviHLH). PMID:27153752

  3. Acute myeloid leukemia presenting as galactorrhea

    PubMed Central

    Nambiar, K. Rakul; Devi, R. Nandini

    2016-01-01

    Acute myeloid leukemia (AML) presents with symptoms related to pancytopenia (weakness, infections, bleeding diathesis) and organ infiltration with leukemic cells. Galactorrhea is an uncommon manifestation of AML. We report a case of AML presenting with galactorrhea. PMID:27695173

  4. Acute myeloid leukemia presenting as galactorrhea

    PubMed Central

    Nambiar, K. Rakul; Devi, R. Nandini

    2016-01-01

    Acute myeloid leukemia (AML) presents with symptoms related to pancytopenia (weakness, infections, bleeding diathesis) and organ infiltration with leukemic cells. Galactorrhea is an uncommon manifestation of AML. We report a case of AML presenting with galactorrhea.

  5. Engineering Outreach through College Pre-Orientation Programs: MIT Discover Engineering

    ERIC Educational Resources Information Center

    Thompson, Mary Kathryn; Consi, Thomas R.

    2007-01-01

    Freshmen Pre-Orientation Programs (FPOPs) can be powerful outreach tools for incoming college students and provide an exciting introduction to the field of engineering. The benefits reach not only the first year students, but also the upperclassmen who help to run the programs and the departments that sponsor them. A family of three engineering…

  6. Das heissschlagverdichten — ein neues verfahren zur herstellung keramischer brennstofftabletten mit engen formtoleranzen

    NASA Astrophysics Data System (ADS)

    Hrovat, M.; Mühling, G.; Rachor, L.; Vollath, D.; Zimmermann, H.

    1984-05-01

    The hot impact densification (HID) is a new powerful method for producing ceramic fuel pellets for nuclear reactors. Green ceramic bodies are directly processed to pellets by high speed shaping in the plastic temperature region of ceramic material. Opposed to the well established press sintering procedure it can be heated, densified, and cooled by orders of magnitude faster. Therefore, at high throughputs, small equipment dimensions become possible. The fuel pellets produced meet all requirements, particular the dimensional tolerances achieved are very closed, consequently circular grinding is omitted. Furthermore, the relatively high temperature level of the impact pressing favors the mixed crystal formation of uranium and plutonium oxide. This improves the solubility of the fuel in nitric acid, an essential point at reprocessing. A prototype facility is designed so that automatic fabrication in continuous operation will be possible. The target working cycle for a fuel pellet is in the range of some seconds.

  7. Making Big Data Useful for Health Care: A Summary of the Inaugural MIT Critical Data Conference

    PubMed Central

    2014-01-01

    With growing concerns that big data will only augment the problem of unreliable research, the Laboratory of Computational Physiology at the Massachusetts Institute of Technology organized the Critical Data Conference in January 2014. Thought leaders from academia, government, and industry across disciplines—including clinical medicine, computer science, public health, informatics, biomedical research, health technology, statistics, and epidemiology—gathered and discussed the pitfalls and challenges of big data in health care. The key message from the conference is that the value of large amounts of data hinges on the ability of researchers to share data, methodologies, and findings in an open setting. If empirical value is to be from the analysis of retrospective data, groups must continuously work together on similar problems to create more effective peer review. This will lead to improvement in methodology and quality, with each iteration of analysis resulting in more reliability. PMID:25600172

  8. MIT Laboratory for Computer Science Progress Report 26. Final technical report, July 1988-June 1989

    SciTech Connect

    Dertouzos, M.L.

    1989-06-01

    Contents: advanced network architecture; clinical decision making; computer architecture group; computation structures; information mechanics; mercury; parallel processing; programming methodology; programming systems research; spoken language systems; systematic program development; theory of computation; theory of distributed systems.

  9. Less noise, more hacking: how to deploy principles from MIT's hacking medicine to accelerate health care.

    PubMed

    DePasse, Jacqueline W; Carroll, Ryan; Ippolito, Andrea; Yost, Allison; Santorino, Data; Chu, Zen; Olson, Kristian R

    2014-07-01

    Medical technology offers enormous potential for scalable medicine--to improve the quality and access in health care while simultaneously reducing cost. However, current medical device innovation within companies often only offers incremental advances on existing products, or originates from engineers with limited knowledge of the clinical complexities. We describe how the Hacking Medicine Initiative, based at Massachusetts Institute of Technology has developed an innovative "healthcare hackathon" approach, bringing diverse teams together to rapidly validate clinical needs and develop solutions. Hackathons are based on three core principles; emphasis on a problem-based approach, cross-pollination of disciplines, and "pivoting" on or rapidly iterating on ideas. Hackathons also offer enormous potential for innovation in global health by focusing on local needs and resources as well as addressing feasibility and cultural contextualization. Although relatively new, the success of this approach is clear, as evidenced by the development of successful startup companies, pioneering product design, and the incorporation of creative people from outside traditional life science backgrounds who are working with clinicians and other scientists to create transformative innovation in health care. PMID:25096225

  10. Riding the Crest of the E-Commerce Wave: Transforming MIT's Campus Computer Resale Operation.

    ERIC Educational Resources Information Center

    Hallisey, Joanne

    1998-01-01

    Reengineering efforts, vendor consolidation, and rising costs prompted the Massachusetts Institute of Technology to convert its computer resale store to an online catalog that allows students, faculty, and staff to purchase equipment and software through a World Wide Web interface. The transition has been greeted with a mixed reaction. The next…

  11. 2012 ARPA-E Energy Innovation Summit Keynote Presentation (Susan Hockfield, MIT)

    ScienceCinema

    Hockfield, Susan (President, Massachusetts Institute of Technology)

    2016-07-12

    The third annual ARPA-E Energy Innovation Summit was held in Washington D.C. in February, 2012. The event brought together key players from across the energy ecosystem - reseachers, entrepeneurs, investors, corporate executives, and government officials - to share ideas for developing and deploying the next generation of energy technologies. Susan Hockfield, President of the Massachusetts Institute of Technology, gave the first keynote address of the third day's sessions on February 29.

  12. MIT modular x-ray source systems for the study of plasma diagnostics

    SciTech Connect

    Coleman, J.W.; Wenzel, K.W.; Petrasso, R.D.; Lo, D.H.; Li, C.K.; Lierzer, J.R.; Wei, T. )

    1992-10-01

    Two new x-ray source systems are now on line at our facility. Each provides an {ital e}-beam to 25 kV. Targets are interchangeable between machines, and four x-ray detectors may be used simultaneously with a target. The gridded {ital e}-gun of the RACEHORSE system gives a 0.5--1.0-cm pulsable spot on target. The nongridded {ital e}-gun of the SCORPION system provides a 0.3-mm or smaller dc microspot on target. RACEHORSE is being used to study and characterize type-II diamond photoconductors for use in diagnosing plasmas, while SCORPION is being used to develop a slitless spectrograph using photographic film. Source design details and some RACEHORSE results are presented.

  13. The Mit Abu El Kom Solar demonstration project in Egypt. Phase A: Solar thermal installations

    NASA Astrophysics Data System (ADS)

    Reinmuth, F.

    1981-09-01

    Maintenance-free solar installations were tested under unfavorable operating conditions in a village in Egypt. Thirty-five simple domestic hot water installations, designed as natural circulation systems of a collector surface of 2 sqm each and a 120 liter boiler mounted on the roof were examined. These installations were completely mounted and commissioned. The performance and efficiency of the systems were satisfactory.

  14. MIT's role in project Apollo. Volume 2: Optical, radar, and candidate subsystems

    NASA Technical Reports Server (NTRS)

    1972-01-01

    The development of optical, radar, and candidate subsystems for Project Apollo is discussed. The design and development of the optical subsystems for both the Apollo command and lunar spacecraft are described. Design approaches, problems, and solutions are presented. The evolution of radar interfaces with the GN&C system is discussed; these interfaces involved both hardware and software in a relatively complex interrelationship. The design and development of three candidate subsystems are also described. The systems were considered for use in Apollo, but were not incorporated into the final GN&C system. The three subsystems discussed are the star tracker-horizon photometer, the map and data viewer and the lunar module optical rendezvous system.

  15. Dr. Robert S. Harris: nutritionist, oral science researcher, and visionary MIT educator.

    PubMed

    Navia, J M

    1998-03-01

    Efforts in dental research and training have received the contribution of individuals who had no formal training in dentistry, yet they understood the dental field and the educational needs of those who would be engaged in dental research, teaching, and service in industry and academia. Dr. Robert S. Harris (1904-1983) was such a man. What follows is a personal remembrance of his character, his research accomplishments, and his successful educational endeavors in the dental field. PMID:9496916

  16. Kindern das Wort Geben ein interkulturell-kreativer Arbeitsansatz, aufgezeigt an der Arbeit mit tibetischen Migrantenkindern

    NASA Astrophysics Data System (ADS)

    Rabkin, Gabriele

    2001-03-01

    Promotion of creativity in the cause of peace and international understanding is a fundamental part of the UNESCO programme to build a culture of peace. A central aspect of this undertaking consists in encouraging children to express themselves freely on this subject in writing and art. An approach has been developed to stimulate children's creativity and to create a link between creative expression and education for intercultural understanding. This article is divided into two parts. The first explains the pedagogical and psychological concepts behind this approach. The second describes a project in which these concepts were applied. It focuses on a minority dispersed over many parts of the world, namely children of Tibetan families. The description is accompanied by commentaries of the Fourteenth Dalai Lama, arising from a personal audience granted to the author in 1999.

  17. Geodetic and Astrometric Measurements with Very-Long-Baseline Interferometry. Ph.D. Thesis - MIT

    NASA Technical Reports Server (NTRS)

    Robertson, D. S.

    1975-01-01

    The use of very-long-baseline interferometry (VLBI) observations for the estimation of geodetic and astrometric parameters is discussed. Analytic models for the dependence of delay and delay rate on these parameters are developed and used for parameter estimation by the method of weighted least squares. Results are presented from approximately 15,000 delay and delay-rate observations, obtained in a series of nineteen VLBI experiments involving a total of five stations on two continents. The closure of baseline triangles is investigated and found to be consistent with the scatter of the various baseline-component results. Estimates are made of the wobble of the earth's pole and of the irregularities in the earth's rotation rate. Estimates are also made of the precession constant and of the vertical Love number, for which a value of 0.55 + or - 0.05 was obtained.

  18. Research in volcanic geology, petrology and planetary science at MIT, 1969 to 1974

    NASA Technical Reports Server (NTRS)

    Mcgetchin, T. R.

    1974-01-01

    The behavior of volcanoes was studied by geologic mapping, petrologic investigations of lava and xenoliths, physical measurements, and theoretical modelling. Field observations were conducted in Alaska (Nunivak Island), Iceland, Hawaii (Mauna Kea), Italy (Etna, Stromboli), and Arizona. The results are discussed and compared with known data for lunar and planetary gelogy. Field methods used for the volcano research are cited and a list is given of all participating scientists and students. Publications and abstracts resulting from the research are also listed.

  19. Less noise, more hacking: how to deploy principles from MIT's hacking medicine to accelerate health care.

    PubMed

    DePasse, Jacqueline W; Carroll, Ryan; Ippolito, Andrea; Yost, Allison; Santorino, Data; Chu, Zen; Olson, Kristian R

    2014-07-01

    Medical technology offers enormous potential for scalable medicine--to improve the quality and access in health care while simultaneously reducing cost. However, current medical device innovation within companies often only offers incremental advances on existing products, or originates from engineers with limited knowledge of the clinical complexities. We describe how the Hacking Medicine Initiative, based at Massachusetts Institute of Technology has developed an innovative "healthcare hackathon" approach, bringing diverse teams together to rapidly validate clinical needs and develop solutions. Hackathons are based on three core principles; emphasis on a problem-based approach, cross-pollination of disciplines, and "pivoting" on or rapidly iterating on ideas. Hackathons also offer enormous potential for innovation in global health by focusing on local needs and resources as well as addressing feasibility and cultural contextualization. Although relatively new, the success of this approach is clear, as evidenced by the development of successful startup companies, pioneering product design, and the incorporation of creative people from outside traditional life science backgrounds who are working with clinicians and other scientists to create transformative innovation in health care.

  20. Harvard-MIT research program in short-lived radiopharmaceuticals. Technical progress report, 1991

    SciTech Connect

    Adelstein, S.J.

    1991-12-31

    This report presents research on radiopharmaceuticals. The following topics are discussed: antibody labeling with positron-emitting radionuclides; antibody modification for radioimmune imaging; labeling antibodies; evaluation of technetium acetlyacetonates as potential cerebral blood flow agents; and studies in technetium chemistry. (CBS)