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Sample records for depletion syndrome mds

  1. Adult mitochondrial DNA depletion syndrome with mild manifestations

    Directory of Open Access Journals (Sweden)

    Josef Finsterer

    2013-06-01

    Full Text Available Mitochondrial DNA depletion syndrome (MDS is usually a severe disorder of infancy or childhood, due to a reduced copy number of mtDNA molecules. MDS with only mild, non-specific clinical manifestations and onset in adulthood has not been reported. A 47-year-old Caucasian female with short stature and a history of migraine, endometriosis, Crohn’s disease, C-cell carcinoma of the thyroid gland, and a family history positive for mitochondrial disorder (2 sisters, aunt, niece, developed day-time sleepiness, exercise intolerance, and myalgias in the lower-limb muscles since age 46y. She slept 9-10 hours during the night and 2 hours after lunch daily. Clinical exam revealed sore neck muscles, bilateral ptosis, and reduced Achilles tendon reflexes exclusively. Blood tests revealed hyperlipidemia exclusively. Nerve conduction studies, needle electromyography, and cerebral and spinal magnetic resonance imaging were non-informative. Muscle biopsy revealed detached lobulated fibers with subsarcolemmal accentuation of the NADH and SDH staining. Real-time polymerase chain reaction revealed depletion of the mtDNA down to 9% of normal. MDS may be associated with a mild phenotype in adults and may not significantly progress during the first year after onset. In an adult with hypersomnia, severe tiredness, exercise intolerance, and a family history positive for mitochondrial disorder, a MDS should be considered.

  2. Genetic predisposition syndromes: when should they be considered in the work-up of MDS?

    Science.gov (United States)

    Babushok, Daria V; Bessler, Monica

    2015-03-01

    Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by cytopenias, ineffective hematopoiesis, myelodysplasia, and an increased risk of acute myeloid leukemia (AML). While sporadic MDS is primarily a disease of the elderly, MDS in children and young and middle-aged adults is frequently associated with underlying genetic predisposition syndromes. In addition to the classic hereditary bone marrow failure syndromes (BMFS) such as Fanconi Anemia and Dyskeratosis Congenita, in recent years there has been an increased awareness of non-syndromic familial MDS/AML predisposition syndromes such as those caused by mutations in GATA2, RUNX1, CEBPA, and SRP72 genes. Here, we will discuss the importance of recognizing an underlying genetic predisposition syndrome a patient with MDS, will review clinical scenarios when genetic predisposition should be considered, and will provide a practical overview of the common BMFS and familial MDS/AML syndromes which may be encountered in adult patients with MDS. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Proposed minimal diagnostic criteria for myelodysplastic syndromes (MDS) and potential pre-MDS conditions.

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    Valent, Peter; Orazi, Attilio; Steensma, David P; Ebert, Benjamin L; Haase, Detlef; Malcovati, Luca; van de Loosdrecht, Arjan A; Haferlach, Torsten; Westers, Theresia M; Wells, Denise A; Giagounidis, Aristoteles; Loken, Michael; Orfao, Alberto; Lübbert, Michael; Ganser, Arnold; Hofmann, Wolf-Karsten; Ogata, Kiyoyuki; Schanz, Julie; Béné, Marie C; Hoermann, Gregor; Sperr, Wolfgang R; Sotlar, Karl; Bettelheim, Peter; Stauder, Reinhard; Pfeilstöcker, Michael; Horny, Hans-Peter; Germing, Ulrich; Greenberg, Peter; Bennett, John M

    2017-09-26

    Myelodysplastic syndromes (MDS) comprise a heterogeneous group of myeloid neoplasms characterized by peripheral cytopenia, dysplasia, and a variable clinical course with about 30% risk to transform to secondary acute myeloid leukemia (AML). In the past 15 years, diagnostic evaluations, prognostication, and treatment of MDS have improved substantially. However, with the discovery of molecular markers and advent of novel targeted therapies, new challenges have emerged in the complex field of MDS. For example, MDS-related molecular lesions may be detectable in healthy individuals and increase in prevalence with age. Other patients exhibit persistent cytopenia of unknown etiology without dysplasia. Although these conditions are potential pre-phases of MDS they may also transform into other bone marrow neoplasms. Recently identified molecular, cytogenetic, and flow-based parameters may add in the delineation and prognostication of these conditions. However, no generally accepted integrated classification and no related criteria are as yet available. In an attempt to address this challenge, an international consensus group discussed these issues in a working conference in July 2016. The outcomes of this conference are summarized in the present article which includes criteria and a proposal for the classification of pre-MDS conditions as well as updated minimal diagnostic criteria of MDS. Moreover, we propose diagnostic standards to delineate between ´normal´, pre-MDS, and MDS. These standards and criteria should facilitate diagnostic and prognostic evaluations in clinical studies as well as in clinical practice.

  4. Management of older adults with myelodysplastic syndromes (MDS).

    Science.gov (United States)

    Luskin, Marlise R; Abel, Gregory A

    2017-12-28

    The myelodysplastic syndromes (MDS) are a varied group of hematologic neoplasms that lead to bone marrow failure, and also carry a risk of progression to acute myeloid leukemia. Patients with MDS suffer significant impairments to both their quality of life and survival. Age is the dominant risk factor for the development of MDS, with a median age at diagnosis over 70years. Consequently, patients with MDS frequently have concurrent comorbidities and/or frailty which may be coincident or related to the disease itself. Disease characteristics, degree of comorbidity, and presence of frailty all impact prognosis. Treatment of MDS focuses on supportive care, with disease-modifying approaches (chemotherapy and allogeneic hematopoietic cell transplantation) reserved for fit patients with high-risk disease. Care of patients with MDS requires understanding the disease in the context of an older population, and tailoring approaches to both disease risk and patient suitability for therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Myelodysplastic Syndrome, Unclassifiable (MDS-U) With 1% Blasts Is a Distinct Subgroup of MDS-U With a Poor Prognosis.

    Science.gov (United States)

    Margolskee, Elizabeth; Hasserjian, Robert P; Hassane, Duane; Tam, Wayne; Mathew, Susan; Ok, Chi Young; Wang, Sa A; Oak, Jean; Arber, Daniel A; Orazi, Attilio

    2017-07-01

    Three situations qualify as myelodysplastic syndrome, unclassifiable (MDS-U): (1) refractory cytopenia with dysplasia and 1% blasts in peripheral blood (BL), (2) pancytopenia with unilineage dysplasia (Pan), and (3) persistent cytopenia, less than 5% bone marrow blasts, and less than 10% dysplastic cells and presence of MDS-defining cytogenetic abnormalities (CG). We compared the clinicopathologic features and mutational profiles for these three groups. MDS-U cases were reviewed at four major academic institutions. Targeted next-generation sequencing for genes implicated in myeloid neoplasms was performed in a subset of cases. Twenty-seven patients were identified (six MDS-U BL, 13 MDS-U Pan, and eight MDS-U CG). Clonal cytogenetic abnormalities were found in six of six, seven of 13, and eight of eight cases in MDS-U BL, Pan, and CG, respectively (P > .05). Overall, four of six patients with MDS-U BL progressed to acute myeloid leukemia; no MDS-U Pan or CG patients did. The rates of progression-free survival and mortality (overall survival) were significantly higher in MDS-U BL compared with Pan and CG (P MDS-U BL is a distinct subset of MDS-U with a poor prognosis, while MDS-U Pan and CG are relatively indolent. Evaluation of peripheral blood smears in patients with MDS is essential for accurate classification and prognosis. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  6. Myelodysplastic Syndromes (MDS) and autoimmune disorders (AD): cause or consequence?

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    Braun, Thorsten; Fenaux, Pierre

    2013-12-01

    Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) are frequently associated with clinical manifestations of autoimmune disorders (AD) and inflammatory response of the immune system. AD accompanying MDS and CMML include vasculitis, seronegative polyarthritis and neutrophilic dermatosis. Rare AD including relapsing polychondritis is strongly associated with MDS as in a high proportion of those patients MDS is diagnosed during disease course. Antinuclear antibodies (ANA) are frequently found among MDS patients without clinical manifestation of AD. In a subset of patients, MDS and resulting cytopenias appear to be the consequence of auto reactive immunologic activity and may respond to immunosuppressive treatment (IST). Increased release of inflammatory cytokines like tumor necrosis factor-(TNF)-α and interferon (IF)-γ triggers apoptosis of myeloid precursor cells leading to cytopenias. Impaired function of immune cells including cytotoxic, regulatory (Treg), helper (Th17) T cells and NK cells also appears to predict response to IST, outcome and occurrence of AD. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Diagnosis, management and response criteria of iron overload in myelodysplastic syndromes (MDS): updated recommendations of the Austrian MDS platform.

    Science.gov (United States)

    Valent, Peter; Stauder, Reinhard; Theurl, Igor; Geissler, Klaus; Sliwa, Thamer; Sperr, Wolfgang R; Bettelheim, Peter; Sill, Heinz; Pfeilstöcker, Michael

    2018-02-01

    Despite the availability of effective iron chelators, transfusion-related morbidity is still a challenge in chronically transfused patients with myelodysplastic syndromes (MDS). In these patients, transfusion-induced iron overload may lead to organ dysfunction or even organ failure. In addition, iron overload is associated with reduced overall survival in MDS. Areas covered: During the past 10 years, various guidelines for the management of MDS patients with iron overload have been proposed. In the present article, we provide our updated recommendations for the diagnosis, prevention and therapy of iron overload in MDS. In addition, we propose refined treatment response criteria. As in 2006 and 2007, recommendations were discussed and formulated by participants of our Austrian MDS platform in a series of meetings in 2016 and 2017. Expert commentary: Our updated recommendations should support early recognition of iron overload, optimal patient management and the measurement of clinical responses to chelation treatment in daily practice.

  8. Cost of transfusion-dependent myelodysplastic syndrome (MDS) from a German payer?s perspective

    OpenAIRE

    2010-01-01

    Abstract No curative treatment exists for patients with myelodysplastic syndrome (MDS) besides allogeneic stem cell transplantation. Hence, palliative treatment is provided for a life time accruing high health care cost. As no study in cost of MDS exists in Germany, the objective of this study was to assess and analyze costs of transfusion-dependent low/intermediate-1-risk MDS in Germany from a payers? perspective. From seven centers, 116 low/intermediate-1-risk transfusion-depende...

  9. Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy

    DEFF Research Database (Denmark)

    Grövdal, Michael; Karimi, Mohsen; Khan, Rasheed

    2010-01-01

    This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5-azacytidine for older patients with high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS-acute myeloid leukaemia syndromes in complete remission (CR) after induction ......-IV thrombocytopenia and neutropenia occurred after 9.5 and 30% of the cycles, respectively, while haemoglobin levels increased during treatment. 5-azacytidine treatment is safe, feasible and may be of benefit in a subset of patients....

  10. Distinct mutation profile and prognostic relevance in patients with hypoplastic myelodysplastic syndromes (h-MDS).

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    Yao, Chi-Yuan; Hou, Hsin-An; Lin, Tzung-Yi; Lin, Chien-Chin; Chou, Wen-Chien; Tseng, Mei-Hsuan; Chiang, Ying-Chieh; Liu, Ming-Chih; Liu, Chia-Wen; Kuo, Yuan-Yeh; Wu, Shang-Ju; Liao, Xiu-Wen; Lin, Chien-Ting; Ko, Bor-Shen; Chen, Chien-Yuan; Hsu, Szu-Chun; Li, Chi-Cheng; Huang, Shang-Yi; Yao, Ming; Tang, Jih-Luh; Tsay, Woei; Liu, Chieh-Yu; Tien, Hwei-Fang

    2016-09-27

    Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies. Although most MDS patients have normal or increased BM cellularity (NH-MDS), some have hypocellular BM (h-MDS). The reports concerning the differences in genetic alterations between h-MDS and NH-MDS patients are limited. In this study, 369 MDS patients diagnosed according to the WHO 2008 criteria were recruited. h-MDS patients had lower PB white blood cell and blast counts, and lower BM blast percentages, than those with NH-MDS. h-MDS was closely associated with lower-risk MDS, defined by the International Prognostic Scoring System (IPSS) and revised IPSS (IPSS-R). IPSS-R could properly predict the prognosis in h-MDS (PMDS patients. The h-MDS patients had lower incidences of RUNX1, ASXL1, DNMT3A, EZH2 and TP53 mutations than NH-MDS patients. The cumulated incidence of acute leukemic transformation at 5 years was 19.3% for h-MDS and 40.4% for NH-MDS patients (P= 0.001). Further, the patients with h-MDS had longer overall survival (OS) than those with NH-MDS (P= 0.001), and BM hypocellularity remains an independent favorable prognostic factor for OS irrespective of age, IPSS-R, and gene mutations. Our findings provide evidence that h-MDS indeed represent a distinct clinico-biological subgroup of MDS and can predict better leukemia-free survival and OS.

  11. Allogeneic hematopoietic stem cell transplant in adult patients with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes.

    Science.gov (United States)

    Sharma, Prashant; Shinde, Shivani S; Damlaj, Moussab; Hefazi Rorghabeh, Mehrdad; Hashmi, Shahrukh K; Litzow, Mark R; Hogan, William J; Gangat, Naseema; Elliott, Michelle A; Al-Kali, Aref; Tefferi, Ayalew; Patnaik, Mrinal M

    2017-04-01

    MDS/MPN (myelodysplastic syndrome/myeloproliferative neoplasm) overlap syndromes are myeloid malignancies for which allogeneic hematopoietic stem cell transplant (allo-HSCT) is potentially curative. We describe transplant outcomes of 43 patients - 35 with chronic myelomonocytic leukemia, CMML (of which 17 had blast transformation, BT) and eight with MDS/MPN-unclassifiable (MDS/MPN,U). At median follow-up of 21 months, overall survival (OS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 55%, 29%, and 25% respectively in CMML without BT and 47%, 40%, and 34% respectively in CMML with BT. Higher HSCT-comorbidity index (HSCT-CI >3 versus ≤3; p = 0.015) and splenomegaly (p = 0.006) predicted worse OS in CMML without BT. In CMML with BT, engraftment failure (p = 0.006) and higher HSCT-CI (p = 0.03) were associated with inferior OS, while HSCT within 1-year of diagnosis was associated with improved OS (p = 0.045). In MDS/MPN,U, at median follow-up of 15 months, OS, CIR, and NRM were 62%, 30%, and 14%, respectively.

  12. Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene.

    Science.gov (United States)

    Bornstein, Belén; Area, Estela; Flanigan, Kevin M; Ganesh, Jaya; Jayakar, Parul; Swoboda, Kathryn J; Coku, Jorida; Naini, Ali; Shanske, Sara; Tanji, Kurenai; Hirano, Michio; DiMauro, Salvatore

    2008-06-01

    Mitochondrial DNA depletion syndrome (MDS) is characterized by a reduction in mtDNA copy number and has been associated with mutations in eight nuclear genes, including enzymes involved in mitochondrial nucleotide metabolism (POLG, TK2, DGUOK, SUCLA2, SUCLG1, PEO1) and MPV17. Recently, mutations in the RRM2B gene, encoding the p53-controlled ribonucleotide reductase subunit, have been described in seven infants from four families, who presented with various combinations of hypotonia, tubulopathy, seizures, respiratory distress, diarrhea, and lactic acidosis. All children died before 4 months of age. We sequenced the RRM2B gene in three unrelated cases with unexplained severe mtDNA depletion. The first patient developed intractable diarrhea, profound weakness, respiratory distress, and died at 3 months. The other two unrelated patients had a much milder phenotype and are still alive at ages 27 and 36 months. All three patients had lactic acidosis and severe depletion of mtDNA in muscle. Muscle histochemistry showed RRF and COX deficiency. Sequencing the RRM2B gene revealed three missense mutations and two single nucleotide deletions in exons 6, 8, and 9, confirming that RRM2B mutations are important causes of MDS and that the clinical phenotype is heterogeneous and not invariably fatal in infancy.

  13. Clinical Features and Outcomes of 666 Cases with Therapy-Related Myelodysplastic Syndrome (t-MDS).

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    El-Fattah, Mohamed Abd

    2018-01-01

    Therapy-related myelodysplastic syndrome (t-MDS) is a serious complication of chemoradiotherapy for primary diseases. This cohort was aimed to determine the clinical features and outcomes of t-MDS in comparison with de novo MDS. I retrieved data of 666 cases with t-MDS, and 29,703 cases with de novo MDS diagnosed between 2001 and 2012 from the database of U.S. National Cancer Institute. Survival curves were estimated, and Cox proportional hazards model was constructed. Compared with patients with de novo MDS, patients with t-MDS tended to be young (median age; 65 vs. 76 years, p  MDS than de novo MDS (17.2 months and 22% vs. 31 months and 32%, respectively, p  MDS cases, with a median follow-up of 16 months (range 1-143 months), 521 cases (78.2%) had died. Of which, 78 (15%) cases had died from acute myeloid leukemia, and 66 (12.7%) cases had died from solid cancers. Of the total 66 cases died from solid cancers; 19 cases (28.8%) died from cancer of lung/bronchus, 11 cases (16.7%) breast cancers, and 10 cases (15.2%) ovarian cancer. In a multivariate analysis adjusted for clinical features, calendar period and radiotherapy, the hazard of mortality was significantly low in de novo MDS compared with t-MDS (hazard ratio 0.59; p  MDS is a distinct entity of MDS in terms of clinical characteristics and prognosis.

  14. Hearing loss in a patient with the myopathic form of mitochondrial DNA depletion syndrome and a novel mutation in the TK2 gene.

    Science.gov (United States)

    Martí, Ramon; Nascimento, Andrés; Colomer, Jaume; Lara, Mari C; López-Gallardo, Ester; Ruiz-Pesini, Eduardo; Montoya, Julio; Andreu, Antoni L; Briones, Paz; Pineda, Mercè

    2010-08-01

    Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a devastating disorder of infancy caused by a significant reduction of the number of copies of mitochondrial DNA in one or more tissues. We report a Spanish patient with the myopathic form of MDS, harboring two mutations in the thymidine kinase 2 gene (TK2): a previously reported deletion (p.K244del) and a novel nucleotide duplication in the exon 2, generating a frameshift and premature stop codon. Sensorineural hearing loss was a predominant symptom in the patient and a novel feature of MDS due to TK2 mutations. The patient survived up to the age of 8.5 y, which confirms that survival above the age of 5 y is not infrequent in patients with MDS due to TK2 deficiency.

  15. Reversion of mtDNA depletion in a patient with TK2 deficiency.

    Science.gov (United States)

    Vilà, M R; Segovia-Silvestre, T; Gámez, J; Marina, A; Naini, A B; Meseguer, A; Lombès, A; Bonilla, E; DiMauro, S; Hirano, M; Andreu, A L

    2003-04-08

    Mutations in the thymidine kinase 2 (TK2) gene cause a myopathic form of the mitochondrial DNA depletion syndrome (MDS). Here, the authors report the unusual clinical, biochemical, and molecular findings in a 14-year-old patient in whom pathogenic mutations were identified in the TK2 gene. This report extends the phenotypic expression of primary TK2 deficiency and suggests that factors other than TK2 may modify expression of the clinical phenotype in patients with MDS syndrome.

  16. Iron overload in myelodysplastic syndromes (MDS).

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    Gattermann, Norbert

    2018-01-01

    Iron overload (IOL) starts to develop in MDS patients before they become transfusion-dependent because ineffective erythropoiesis suppresses hepcidin production in the liver and thus leads to unrestrained intestinal iron uptake. However, the most important cause of iron overload in MDS is chronic transfusion therapy. While transfusion dependency by itself is a negative prognostic factor reflecting poor bone marrow function, the ensuing transfusional iron overload has an additional dose-dependent negative impact on the survival of patients with lower risk MDS. Cardiac dysfunction appears to be important in this context, as a consequence of chronic anemia, age-related cardiac comorbidity, and iron overload. Another potential problem is iron-related endothelial dysfunction. There is some evidence that with increasing age, high circulating iron levels worsen the atherosclerotic phenotype. Transfusional IOL also appears to aggravate bone marrow failure in MDS, through unfavorable effects on mesenchymal stromal cells as well a hematopoietic cells, particularly erythroid precursors. Patient series and clinical trials have shown that the iron chelators deferoxamine and deferasirox can improve hematopoiesis in a minority of transfusion-dependent patients. Analyses of registry data suggest that iron chelation provides a survival benefit for patients with MDS, but data from a prospective randomized clinical trial are still lacking.

  17. Pediatric MDS: GATA screen the germline.

    Science.gov (United States)

    Stieglitz, Elliot; Loh, Mignon L

    2016-03-17

    In this issue of Blood, Wlodarski and colleagues demonstrate that as many as 72% of adolescents diagnosed with myelodysplastic syndrome (MDS) and monosomy 7 harbor germline mutations in GATA2. Although pediatric MDS is a very rare diagnosis, occurring in 0.8 to 4 cases per million, Wlodarski et al screened >600 cases of primary or secondary MDS in children and adolescents who were enrolled in the European Working Group on MDS consortium over a period of 15 years. The overall frequency of germline GATA2 mutations in children with primary MDS was 7%, and 15% in those presenting with advanced disease. Notably, mutations in GATA2 were absent in patients with therapy-related MDS or acquired aplastic anemia.

  18. Pathophysiology of MDS: genomic aberrations.

    Science.gov (United States)

    Ichikawa, Motoshi

    2016-01-01

    Myelodysplastic syndromes (MDS) are characterized by clonal proliferation of hematopoietic stem/progenitor cells and their apoptosis, and show a propensity to progress to acute myelogenous leukemia (AML). Although MDS are recognized as neoplastic diseases caused by genomic aberrations of hematopoietic cells, the details of the genetic abnormalities underlying disease development have not as yet been fully elucidated due to difficulties in analyzing chromosomal abnormalities. Recent advances in comprehensive analyses of disease genomes including whole-genome sequencing technologies have revealed the genomic abnormalities in MDS. Surprisingly, gene mutations were found in approximately 80-90% of cases with MDS, and the novel mutations discovered with these technologies included previously unknown, MDS-specific, mutations such as those of the genes in the RNA-splicing machinery. It is anticipated that these recent studies will shed new light on the pathophysiology of MDS due to genomic aberrations.

  19. Modeling Marrow Failure and MDS for Novel Therapeutics

    Science.gov (United States)

    2017-03-01

    syndrome (MDS) and leukemia is also markedly elevated in patients with inherited marrow failure syndromes compared to age-matched controls. Prognosis of...Novel Therapeutics W81XWH-16-1-0054 1. Introduction Clonal evolution is a potentially life threatening long-term complication of inherited and...The risk of early progression to myelodysplastic syndrome (MDS) and leukemia is also markedly elevated in patients with inherited marrow failure

  20. A phase 1/2 study of rigosertib in patients with myelodysplastic syndromes (MDS) and MDS progressed to acute myeloid leukemia.

    Science.gov (United States)

    Navada, Shyamala C; Fruchtman, Steven M; Odchimar-Reissig, Rosalie; Demakos, Erin P; Petrone, Michael E; Zbyszewski, Patrick S; Holland, James F; Silverman, Lewis R

    2018-01-01

    This Phase 1/2, dose-escalating study of rigosertib enrolled 22 patients with higher-risk myelodysplastic syndromes (MDS) (n=9) and acute myeloid leukemia (AML; n=13) who had relapsed or were refractory to standard therapy and for whom no second-line therapies were approved. Patients received 3- to 7-day continuous intravenous infusions of rigosertib, an inhibitor of Ras-effector pathways that interacts with the Ras-binding domains, common to several signaling proteins including Raf and PI3 kinase. Rigosertib was administered at doses of 650-1700mg/m 2 /day in 14-day cycles. Initial dose escalation followed a Fibonacci scheme, followed by recommended phase 2 dose confirmation in an expanded cohort. Rigosertib was well tolerated for up to 23 cycles, with no treatment-related deaths and 18% of patients with related serious adverse events (AEs). Common AEs were fatigue, diarrhea, pyrexia, dyspnea, insomnia, and anemia. Rigosertib exhibited biologic activity, with reduction or stabilization of bone marrow blasts and improved peripheral blood counts in a subset of patients. Ten of 19 evaluable patients (53%) demonstrated bone marrow/peripheral blood responses (n=4 MDS, n=1 AML) or stable disease (n=3 MDS, n=2 AML). Median survival was 15.7 and 2.0 months for responders and non-responders, respectively. Additional studies of rigosertib are ongoing in higher-risk MDS (NCT00854646). Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. MDS classification is improving in an era of the WHO 2016 criteria of MDS: A population-based analysis among 9159 MDS patients diagnosed in the Netherlands.

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    Dinmohamed, Avinash G; Visser, Otto; Posthuma, Eduardus F M; Huijgens, Peter C; Sonneveld, Pieter; van de Loosdrecht, Arjan A; Jongen-Lavrencic, Mojca

    2017-10-01

    Morphologic and cytogenetic assessments are required to characterize diagnostic and prognostic features of myelodysplastic syndromes (MDS). We assessed whether these assessments were performed among newly diagnosed MDS patients in the Netherlands. MDS cases were retrieved from the nationwide Netherlands Cancer Registry (N=9159; period 2001-2014) and the regional PHAROS MDS registry (N=676; period 2008-2011). The proportion of unclassified MDS decreased from 58% in 2001 to 13% in 2014. Data from the more detailed PHAROS registry revealed that the degree of bone marrow dysplasia was only reported in ∼30% of all evaluable bone marrow aspirates. Further, the International Prognostic Scoring System was undetermined in 55% of patients, primarily owing to unperformed cytogenetics in 46% of patients. The classification of MDS is improving in the Netherlands. Nevertheless, particular diagnostic and prognostic procedures that are essential for the diagnosis and subsequent treatment decision-making of MDS were not fully utilized in particular patient subsets. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Lessons from the atomic bomb about secondary MDS.

    Science.gov (United States)

    Hata, Tomoko; Imanishi, Daisuke; Miyazaki, Yasushi

    2014-12-01

    Myelodysplastic syndromes (MDSs) is a hematological neoplasm defined by ineffective hematopoiesis, dysplasia of hematopoietic cells, and risk of progression to acute leukemia. MDS occurs as de novo or secondary, and chemoradiotherapy for cancers is thought to increase the risk of MDS among patients. Recently, an epidemiological study for MDS among A-bomb survivors was performed, and it clearly demonstrated that the exposure to external radiation significantly increased the risk of MDS. Precise epidemiological data among survivors have revealed important clinical factors related to the risk of leukemias. In this review, by comparing data for secondary MDS and leukemia/MDS among survivors, several factors which would affect the risk of MDS, especially secondary MDS, are discussed.

  3. Downregulation of MMP1 in MDS-derived mesenchymal stromal cells reduces the capacity to restrict MDS cell proliferation.

    Science.gov (United States)

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

    2017-03-06

    The role of mesenchymal stromal cells (MSCs) in the pathogenesis of myelodysplastic syndromes (MDS) has been increasingly addressed, but has yet to be clearly elucidated. In this investigation, we found that MDS cells proliferated to a greater extent on MDS-derived MSCs compared to normal MSCs. Matrix metalloproteinase 1(MMP1), which was downregulated in MDS-MSCs, was identified as an inhibitory factor of MDS cell proliferation, given that treatment with an MMP1 inhibitor or knock-down of MMP1 in normal MSCs resulted in increased MDS cell proliferation. Further investigations indicated that MMP1 induced apoptosis of MDS cells by interacting with PAR1 and further activating the p38 MAPK pathway. Inhibition of either PAR1 or p38 MAPK can reverse the apoptosis-inducing effect of MMP1. Taken together, these data indicate that downregulation of MMP1 in MSCs of MDS patients may contribute to the reduced capacity of MSCs to restrict MDS cell proliferation, which may account for the malignant proliferation of MDS cells.

  4. MDS: Recent progress in molecular pathogenesis and clinical aspects.

    Science.gov (United States)

    Harada, Hironori

    2017-01-01

    Myelodysplastic syndromes (MDS) are defined as hematopoietic stem cell disorders caused by various gene abnormalities. Recent analysis using next generation sequencing has provided great progress in identifying relationships between gene mutations and clinical phenotypes of MDS. It is estimated that one or more gene mutations occur in greater than 90% of MDS patients. More than 50 gene mutations affecting RNA splicing machinery, DNA methylation, histone modifications, transcription factors, signal transduction proteins, and components of the cohesion complex participate in the pathogenesis of MDS. The sequential accumulation of additional cooperating mutations drives disease evolution from clonal hematopoiesis of indeterminate potential (CHIP) to symptomatic MDS and from MDS to acute myelogenous leukemia (AML). Mutations in RNA splicing and DNA methylation occur early and are considered founding mutations, whereas others that occur later are regarded as subclonal mutations. RUNX1 mutations are more likely to be subclonal; however, they apparently play a pivotal role in familial MDS. In addition, large alterations of chromosomes are involved in the pathogenesis of MDS. 5q- syndrome, which leads to haploinsufficiency of the located genes, has consistent clinical features. Understanding gene abnormalities of MDS patients can provide clinical information, including diagnosis, prognostic score, and prediction of response to therapy.

  5. Deoxyribonucleoside kinases in mitochondrial DNA depletion.

    Science.gov (United States)

    Saada-Reisch, Ann

    2004-10-01

    Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a heterogeneous group of mitochondrial disorders, manifested by a decreased mtDNA copy number and respiratory chain dysfunction. Primary MDS are inherited autosomally and may affect a single organ or multiple tissues. Mutated mitochondrial deoxyribonucleoside kinases; deoxyguanosine kinase (dGK) and thymidine kinase 2 (TK2), were associated with the hepatocerebral and myopathic forms of MDS respectively. dGK and TK2 are key enzymes in the mitochondrial nucleotide salvage pathway, providing the mitochondria with deoxyribonucleotides (dNP) essential for mtDNA synthesis. Although the mitochondrial dNP pool is physically separated from the cytosolic one, dNP's may still be imported through specific transport. Non-replicating tissues, where cytosolic dNP supply is down regulated, are thus particularly vulnerable to dGK and TK2 deficiency. The overlapping substrate specificity of deoxycytidine kinase (dCK) may explain the relative sparing of muscle in dGK deficiency, while low basal TK2 activity render this tissue susceptible to TK2 deficiency. The precise pathophysiological mechanisms of mtDNA depletion due to dGK and TK2 deficiencies remain to be determined, though recent findings confirm that it is attributed to imbalanced dNTP pools.

  6. Flow cytometry in the diagnosis of myelodysplastic syndromes (MDS) and the value of myeloid nuclear differentiation antigen (MNDA).

    Science.gov (United States)

    Bellos, Frauke; Kern, Wolfgang

    2014-09-25

    Background: Confirming diagnosis of myelodysplastic syndromes (MDS) is often challenging. Standard diagnostic methods are cytomorphology (CM) and cytogenetics (CG). Multiparameter flow cytometry (MFC) is upcoming in MDS diagnostic work up, comparability and investigator experience are critical. Myeloid nuclear differentiation antigen (MNDA) in myelomonocytic cells might be expressed more weakly in patients with MDS. The analysis of MNDA may thus improve diagnostic capabilities of MFC in MDS. Methods: Staining methods and antibody combinations for MFC in MDS are outlined, giving details for interpretation of results in regard to dyspoiesis. MFC results are correlated with CM and CG and with survival data. Use of myeloid nuclear differentiation antigen (MNDA) in MDS diagnostics was evaluated in 239 patients with MDS, AML, other cytopenic conditions and in 30 negative controls. Results: Strong correlation between findings in CM and MFC was found; MFC results correlated well with those of CG. Patients with higher grades of dysplasia in MFC had shorter overall survival. Percentages of granulocytes and monocytes with diminished MNDA expression (%dimG, %dimM) were higher in patients with MDS and AML. Mean fluorescence intensity (MFI) of MNDA in monocytes was lower in MDS and AML. Cut-off values for %dimG (12%) and %dimM (22%) as well as for MFI in monocytes (72) were defined discriminating between MDS and non-MDS. Conclusion: MFC adds significant information on dyspoiesis in the diagnostic work up for MDS and provides prognostic information. MNDA expression can be assessed by MFC and may facilitate evaluation of dyspoiesis when added to MDS MFC panels. © 2014 Clinical Cytometry Society. Copyright © 2014 Clinical Cytometry Society.

  7. Cytomorphology review of 100 newly diagnosed lower-risk MDS patients in the European LeukemiaNet MDS (EUMDS) registry reveals a high inter-observer concordance

    NARCIS (Netherlands)

    Swart, L. de; Smith, A.; MacKenzie, M.; Symeonidis, A.; Neukirchen, J.; Mikulenkova, D.; Vallespi, T.; Zini, G.; Paszkowska-Kowalewska, M.; Kruger, A.; Saft, L.; Fenaux, P.; Bowen, D.; Hellstrom-Lindberg, E.; Cermak, J.; Stauder, R.; Tatic, A.; Holm, M.S.; Malcovati, L.; Madry, K.; Droste, J.A.; Blijlevens, N.M.; Witte, T.J. de; Germing, U.

    2017-01-01

    The European LeukemiaNet MDS (EUMDS) registry is collecting data of myelodysplastic syndrome (MDS) patients belonging to the IPSS low or intermediate-1 category, newly diagnosed by local cytologists. The diagnosis of MDS can be challenging, and some data report inter-observer variability with regard

  8. Mammalian-target of rapamycin inhibition with temsirolimus in myelodysplastic syndromes (MDS) patients is associated with considerable toxicity: results of the temsirolimus pilot trial by the German MDS Study Group (D-MDS).

    Science.gov (United States)

    Wermke, Martin; Schuster, Claudia; Nolte, Florian; Al-Ali, Haifa-Kathrin; Kiewe, Philipp; Schönefeldt, Claudia; Jakob, Christiane; von Bonin, Malte; Hentschel, Leopold; Klut, Ina-Maria; Ehninger, Gerhard; Bornhäuser, Martin; Baretton, Gustavo; Germing, Ulrich; Herbst, Regina; Haase, Detelef; Hofmann, Wolf K; Platzbecker, Uwe

    2016-12-01

    The mammalian-target of rapamycin (also termed mechanistic target of rapamycin, mTOR) pathway integrates various pro-proliferative and anti-apoptotic stimuli and is involved in regulatory T-cell (TREG) development. As these processes contribute to the pathogenesis of myelodysplastic syndromes (MDS), we hypothesized that mTOR modulation with temsirolimus (TEM) might show activity in MDS. This prospective multicentre trial enrolled lower and higher risk MDS patients, provided that they were transfusion-dependent/neutropenic or relapsed/refractory to 5-azacitidine, respectively. All patients received TEM at a weekly dose of 25 mg. Of the 9 lower- and 11 higher-risk patients included, only 4 (20%) reached the response assessment after 4 months of treatment and showed stable disease without haematological improvement. The remaining patients discontinued TEM prematurely due to adverse events. Median overall survival (OS) was not reached in the lower-risk group and 296 days in the higher-risk group. We observed a significant decline of bone marrow (BM) vascularisation (P = 0·006) but were unable to demonstrate a significant impact of TEM on the balance between TREG and pro-inflammatory T-helper-cell subsets within the peripheral blood or BM. We conclude that mTOR-modulation with TEM at a dose of 25 mg per week is accompanied by considerable toxicity and has no beneficial effects in elderly MDS patients. © 2016 John Wiley & Sons Ltd.

  9. Deoxynucleoside salvage enzymes and tissue specific mitochondrial DNA depletion.

    Science.gov (United States)

    Wang, L

    2010-06-01

    Adequate mitochondrial DNA (mtDNA) copies are required for normal mitochondria function and reductions in mtDNA copy number due to genetic alterations cause tissue-specific mtDNA depletion syndrome (MDS). There are eight nuclear genes, directly or indirectly involved in mtDNA replication and mtDNA precursor synthesis, which have been identified as the cause of MDS. However, the tissue specific pathology of these nuclear gene mutations is not well understood. Here, mtDNA synthesis, mtDNA copy number control, and mtDNA turnover, as well as the synthesis of mtDNA precursors in relation to the levels of salvage enzymes are discussed. The question why MDS caused by TK2 and p53R2 mutations are predominantly muscle specific while dGK deficiency affected mainly liver will be addressed.

  10. Unraveling the Pathogenesis of MDS: The NLRP3 Inflammasome and Pyroptosis Drive the MDS Phenotype.

    Science.gov (United States)

    Sallman, David A; Cluzeau, Thomas; Basiorka, Ashley A; List, Alan

    2016-01-01

    Myelodysplastic syndromes (MDS) are characterized by bone marrow cytological dysplasia and ineffective hematopoiesis in the setting of recurrent somatic gene mutations and chromosomal abnormalities. The underlying pathogenic mechanisms that drive a common clinical phenotype from a diverse array of genetic abnormalities have only recently begun to emerge. Accumulating evidence has highlighted the integral role of the innate immune system in upregulating inflammatory cytokines via NF-κB activation in the pathogenesis of MDS. Recent investigations implicate activation of the NLRP3 inflammasome in hematopoietic stem/progenitor cells as a critical convergence signal in MDS with consequent clonal expansion and pyroptotic cell death though caspase-1 maturation. Specifically, the alarmin S100A9 and/or founder gene mutations trigger pyroptosis through the generation of reactive oxygen species leading to assembly and activation of the redox-sensitive NLRP3 inflammasome and β-catenin, assuring propagation of the MDS clone. More importantly, targeted inhibition of varied steps in this pathway restore effective hematopoiesis. Together, delineation of the role of pyroptosis in the clinical phenotype of MDS patients has identified novel therapeutic strategies that offer significant promise in the treatment of MDS.

  11. New proposals of the WHO working group (2016) for the diagnosis of myelodysplastic syndromes (MDS): Characteristics of refined MDS types.

    Science.gov (United States)

    Strupp, Corinna; Nachtkamp, Kathrin; Hildebrandt, Barbara; Giagounidis, Aristoteles; Haas, Rainer; Gattermann, Norbert; Bennett, John M; Aul, Carlo; Germing, Ulrich

    2017-06-01

    Based on centrally diagnosed 3528 patients in the Düsseldorf registry, we validated the new proposals for the classification of the MDS by the WHO working group: 256 patients were diagnosed as MDSSLD (7,3%), 978 MDSMLD (27,7%), 227 MDS RS SLD (6,4%); 321 MDS RS MLD (9,1%), 159 MDS del(5q) (4,5%), 481 MDSEB 1 (13,6%), 620 MDSEB 2 (17,6%), and 148 MDS-U (4,2%). 352 patients (16,9% of the non blastic types) changed the category, mainly moving from RCMD to MDS RS MLD, RCUD and RCMD to MDS del(5q). Median survival times of the refined groups differed from more than 60 months in the MDSSLD (RS) groups, 37 months in the MDSMLD (RS) groups, 79 months of the MDS del(5q) group and 21 and 11 months in the MDSEB 1 and 2 groups, respectively. The difference between the groups with regard to the risk of AML evolution was also impressing. No major changes were made with regard to the MDS-U categories. In summary, the proposals of the WHO group for the classification of MDS are thoughtful, taking into account biologic parameters of the diseases, a more precise wording, to some extend pragmatic and feasible. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Impact Of Mutation-derived Antigens In Immune Recognition Of Hematological Malignancies, Specifically Myeloid Dysplastic Syndromes (MDS)

    DEFF Research Database (Denmark)

    Saini, Sunil Kumar; Dorfmüller, S.; Bjerregaard, Anne-Mette

    2016-01-01

    Mutation-derived neoepitopes have been suggested as a major component for immune recognition of solid tumors with a high mutational load, e.g. Melanoma and Non-Small-Cell Lung Cancer (NSCLC). Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms characterized by increasing...

  13. Co-occurring Down syndrome and SUCLA2-related mitochondrial depletion syndrome.

    Science.gov (United States)

    Couser, Natario L; Marchuk, Daniel S; Smith, Laurie D; Arreola, Alexandra; Kaiser-Rogers, Kathleen A; Muenzer, Joseph; Pandya, Arti; Gucsavas-Calikoglu, Muge; Powell, Cynthia M

    2017-10-01

    Mitochondrial DNA depletion syndrome 5 (MIM 612073) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the beta subunit of the succinate-CoA ligase gene located within the 13q14 band. We describe two siblings of Hispanic descent with SUCLA2-related mitochondrial depletion syndrome (encephalomyopathic form with methylmalonic aciduria); the older sibling is additionally affected with trisomy 21. SUCLA2 sequencing identified homozygous p.Arg284Cys pathogenic variants in both patients. This mutation has previously been identified in four individuals of Italian and Caucasian descent. The older sibling with concomitant disease has a more severe phenotype than what is typically described in patients with either SUCLA2-related mitochondrial depletion syndrome or Down syndrome alone. The younger sibling, who has a normal female chromosome complement, is significantly less affected compared to her brother. While the clinical and molecular findings have been reported in about 50 patients affected with a deficiency of succinate-CoA ligase caused by pathogenic variants in SUCLA2, this report describes the first known individual affected with both a mitochondrial depletion syndrome and trisomy 21. © 2017 Wiley Periodicals, Inc.

  14. Genetics Home Reference: MPV17-related hepatocerebral mitochondrial DNA depletion syndrome

    Science.gov (United States)

    ... DNA depletion syndrome MPV17-related hepatocerebral mitochondrial DNA depletion syndrome Printable PDF Open All Close All Enable ... collapse boxes. Description MPV17 -related hepatocerebral mitochondrial DNA depletion syndrome is an inherited disorder that can cause ...

  15. [Clinical Significance of ID4 Gene Mehtylation in Demethylation-Treated MDS Cell Line and 2 MDS Patients].

    Science.gov (United States)

    Kang, Hui-Yuan; Wang, Xin-Rong; Gao, Li; Wang, Wei; Li, Mian-Yang; Wang, Li-Li; Wang, Cheng-Bin; Yu, Li

    2015-04-01

    To evaluate significance of ID4 gene mehtylation in demethylating myelodysplastic syndrome(MDS) cell Line MUTZ1 and 2 patients with MDS. The methylation-specific PCR (MS-PCR) and reverse transcription-PCR (RT-PCR) were applied to identify the methylation status and gene expression of ID4 gene in MDS cell line MUTZ1, a patient with aplastic anemia(AA) and a donor with normal bone marrow (NBM). RT-PCR was applied to detect the ID4 gene expression status in MUTZ1 cell line treated with decitabine at 3 different concentrations. Then bisulfite sequencing PCR (BSP) was applied to detect ID4 gene methylation status in 2 MDS parients treated with decitabine. The MDS cell line MUTZ-1 displayed a complete methylation of ID4 gene promoter with little mRNA expression. Inversely, bone marrow of an AA patient and NBM showed complete unmethylation of this gene with intensity mRNA expression. With the increase of decitabine concentration, ID4 gene mRNA expression was more and more increased. After decitabine treatment, ID4 gene methylation-positive frequencies of both the 2 MDS patients were much more decreased than that of the first treatment. So, ID4 gene mRNA expression inhibited by promoter hypemethylation could be recovered by using demethylation medicine. ID4 as a new potential anti-oncogene suggests that its methylation may become a marker for selection and assessment of therapeutic schedules in patients with MDS.

  16. Therapy-Related Myelodysplastic Syndrome Following Treatment for Childhood Acute Lymphoblastic Leukemia: Outcome of Patients Registered in the EWOG-MDS 98/06 Studies

    DEFF Research Database (Denmark)

    Strahm, Birgitte; Amann, Roland; De Moerloose, Barbara

    Objective: Therapy-related myelodysplastic syndrome (tMDS) following treatment of childhood acute lymphoblastic leukemia (ALL) is one of the most frequently observed secondary malignancies in survivors of childhood cancer. Allogeneic stem cell transplantation (SCT) is the only curative treatment....... This analysis was performed to asses the outcome of patients with tMDS following treatment for childhood ALL reported to the EWOG-MDS study group. Patients and Transplant Procedure: Forty-three patients (19 male/24 female) were diagnosed with tMDS between August 1989 and August 2009. The median age at diagnosis...... was 8.9 yrs (3.4–20.5). The median interval from diagnosis of ALL to the diagnosis of tMDS was 3.3 yrs (1.7–7.0). Five patients did not receive SCT and died due to progressive disease at a median of 5.6 mo after diagnosis. Thirty-eight patients were transplanted. One patient was excluded from...

  17. Cost-effectiveness of azacitidine compared with low-doses of chemotherapy (LDC in myelodysplastic syndrome (MDS

    Directory of Open Access Journals (Sweden)

    Myrna Candelaria-Hernández

    2017-06-01

    Full Text Available ABSTRACTIntroductionMyelodysplastic syndrome (MDS comprises a group of clonal hematological disorders, characterized by ineffective hematopoiesis and progressive bone marrow failure. It increases the risk of transformation to acute myeloid leukemia (AML. Therapeutic benefit should include overall survival increase (OS, hematological improvement, transfusion dependence and time to progression to AML decrease.ObjectiveAssess, from a Mexican health-care perspective, the cost-effectiveness of azacitidine compared with low-doses of chemotherapy (LDC plus best supportive care (BSC for the treatment of adult patients with intermediate-2 and high-risk MDS, who are not eligible for hematopoietic stem-cell transplantation. We developed a cost-effectiveness survival analysis model of three stages: MDS, AML, and death. OS and costs are extrapolated beyond three-year time horizon. Discount rate of 5% was applied. To estimate the model cycle probability transition to mortality state, survival curves were constructed for each treatment arm using individual patient-level data from Study AZA-001. Unitary costs are from public price list, and profiles for the management of MDS and AML were collected separately using a structured questionnaire. Probabilistic sensitivity analyses (PSA were conducted by simultaneously sampling from estimated probability distributions of model parameters.ResultsOverall survival was projected to increase by 72.26 weeks with azacitidine. Incremental expected total costs for azacitidine compared to LDC was MXN$68,045. However, the cost of the drug therapy was lower with azacitidine. The incremental cost-effectiveness ratio (ICER for azacitidine compared to LDC was MXN$48,932 per life-year gained (LYG. PSA showed that azacitidine was a highly cost-effective option in 96.49% of the simulated cases in MXN$180,000/LYG willingness-to-pay.ConclusionsCompared with LDC, azacitidine represents a cost-effective treatment alternative in patients

  18. A review of therapy-related myelodysplastic syndromes and acute myeloid leukaemia (t-MDS/AML) in Irish patients: a single centre experience.

    Science.gov (United States)

    Maung, Su W; Burke, Cathie; Hayde, Jennifer; Walshe, Janice; McDermott, Ray; Desmond, Ronan; McHugh, Johnny; Enright, Helen

    2017-07-01

    To demonstrate the incidence, characteristics, treatment and outcomes of patients with therapy-related myelodysplastic syndromes and therapy-related acute myeloid leukaemia (t-MDS/AML) in a tertiary referral centre. Patients meeting the diagnostic criteria for t-MDS/AML from 2003 to 2014 were reviewed to analyse their diagnostic features, details of antecedent disorder and treatment, approach to management and survival. 39 patients who developed t-MDS/AML were identified with incidence of 8.7%. Median age and gender distribution were similar to de novo MDS but t-MDS/AML patients had greater degree of cytopenia and adverse karyotypes. Time to development of t-MDS/AML was shortest for patients with antecedent haematological malignancy compared to solid tumours and autoimmune disorders (46, 85 and 109 months). Patients with prior acute leukaemia had the shortest latency and poor overall survival. Treatment options included best supportive care (56%), Azacitidine (31%) or intensive chemotherapy/allogeneic transplant (13%). Median OS of all patients was 14 months. Survival declined markedly after two years and 5-year OS was 13.8%. Longer survival was associated with blast count MDS/AML patients showed unique characteristics which influenced their treatment and outcomes. IPSS-R may be useful in risk-adapted treatment approaches and can predict outcomes. Survival remains poor but improved outcomes were seen with allogeneic transplantation. Azacitidine may be effective in patients unfit for intensive therapies.

  19. Connect MDS/AML: design of the myelodysplastic syndromes and acute myeloid leukemia disease registry, a prospective observational cohort study.

    Science.gov (United States)

    Steensma, David P; Abedi, Medrdad; Bejar, Rafael; Cogle, Christopher R; Foucar, Kathryn; Garcia-Manero, Guillermo; George, Tracy I; Grinblatt, David; Komrokji, Rami; Ma, Xiaomei; Maciejewski, Jaroslaw; Pollyea, Daniel A; Savona, Michael R; Scott, Bart; Sekeres, Mikkael A; Thompson, Michael A; Swern, Arlene S; Nifenecker, Melissa; Sugrue, Mary M; Erba, Harry

    2016-08-19

    Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are myeloid neoplasms in which outgrowth of neoplastic clones disrupts normal hematopoiesis. Some patients with unexplained persistent cytopenias may not meet minimal diagnostic criteria for MDS but an alternate diagnosis is not apparent; the term idiopathic cytopenia of undetermined significance (ICUS) has been used to describe this state. MDS and AML occur primarily in older patients who are often treated outside the clinical trial setting. Consequently, our understanding of the patterns of diagnostic evaluation, management, and outcomes of these patients is limited. Furthermore, there are few natural history studies of ICUS. To better understand how patients who have MDS, ICUS, or AML are managed in the routine clinical setting, the Connect MDS/AML Disease Registry, a multicenter, prospective, observational cohort study of patients newly diagnosed with these conditions has been initiated. The Connect MDS/AML Disease Registry will capture diagnosis, risk assessment, treatment, and outcomes data for approximately 1500 newly diagnosed patients from approximately 150 community and academic sites in the United States in 4 cohorts: (1) lower-risk MDS (International Prognostic Scoring System [IPSS] low and intermediate-1 risk), with and without del(5q); (2) higher-risk MDS (IPSS intermediate-2 and high risk); (3) ICUS; and (4) AML in patients aged ≥ 55 years (excluding acute promyelocytic leukemia). Diagnosis will be confirmed by central review. Baseline patient characteristics, diagnostic patterns, treatment patterns, clinical outcomes, health economics outcomes, and patient-reported health-related quality of life will be entered into an electronic data capture system at enrollment and quarterly for 8 years. A tissue substudy to explore the relationship between karyotypes, molecular markers, and clinical outcomes will be conducted, and is optional for patients. The Connect MDS/AML Disease

  20. Implication of microRNAs in the Pathogenesis of MDS

    Science.gov (United States)

    Fang, Jing; Varney, Melinda; Starczynowski, Daniel T.

    2016-01-01

    MicroRNAs (miRNAs) are significant regulators of human hematopoietic stem cells (HSC), and their deregulation contributes to hematological malignancies. Myelodysplastic syndromes (MDS) represent a spectrum of hematological disorders characterized by dysfunctional HSC, ineffective blood cell production, progressive marrow failure, and an increased risk of developing acute myeloid leukemia (AML). Although miRNAs have been primarily studied in AML, only recently have similar studies been performed on MDS. In this review, we describe the normal function and expression of miRNAs in human HSC, and describe mounting evidence that deregulation of miRNAs contributes to the pathogenesis of MDS. PMID:22571695

  1. Apoptosis-Related Gene Expression Profiling in Hematopoietic Cell Fractions of MDS Patients

    NARCIS (Netherlands)

    MC Langemeijer, Saskia; Mariani, Niccolo; Knops, Ruth; Gilissen, Christian; Woestenenk, Rob; de Witte, Theo; Huls, Gerwin; van der Reijden, Bert A.; Jansen, Joop H.

    2016-01-01

    Although the vast majority of patients with a myelodysplastic syndrome (MDS) suffer from cytopenias, the bone marrow is usually normocellular or hypercellular. Apoptosis of hematopoietic cells in the bone marrow has been implicated in this phenomenon. However, in MDS it remains only partially

  2. MDS. A disease with high radiation-risk

    International Nuclear Information System (INIS)

    Ban, Sadayuki; Sudo, Hitomi; Saegusa, Kumiko; Sagara, Masashi; Imai, Takashi

    2003-01-01

    A preliminary epidemiological study demonstrated that myelodysplastic syndrome (MDS) has an excess relative risk per sievert of 13 in atomic bomb survivors. MDS is the only other radiogenic blood disease apart from leukemia. Clinically, MDS involves dysplastic hematopoiesis and an increased risk of leukemic transformation. Because it is uncertain whether MDS pathogenesis affects lymphoid progenitor cells as well as myeloid progenitor cells, we investigated the micronucleus (MN) frequency in peripheral T lymphocytes of twenty-three atomic bomb survivors with MDS and five normal individuals. The spontaneous- and X-ray-induced-MN frequencies were significantly higher in MDS patients than in normal individuals. Interestingly, radiation sensitivity increased along with the severity of MDS clinical subtypes. Because many of the patients in this study had not been exposed to chemo- or radiation-therapy, their unusual radiosensitivities may be related to their chromosomal or genomic instability. To explain the cause of unusual radiosensitivity, we measured the expression levels of four nucleotide excision repair (NER) genes (ERCC1, ERCC3, ERCC5 and XPC) in peripheral blood mononuclear cells using a reverse transcripts-polymerase chain reaction (RT-PCR) method. The ERCC5 gene was expressed at reduced levels in only one of 10 patients with mild symptom. Reduction of NER genes was expressed in four of 11 patients with severe symptom. Immortalized lymphoid cell lines were established from B-lymphocytes infected with Epstein-Barr virus in vitro. The abrogation of radiation-induced-G2/M arrnst was observed in some of MDS-B lymphoid cell lines, but not in the normal B lymphoid cell lines. Our data suggest that the control of chromosomal stability is impaired in pluripotent stem cells of MDS patients, and that DNA repair defects and loss of G2/M arrest may be involved in the pathophysiology of disease progression. (authors)

  3. A pilot study on the usefulness of peripheral blood flow cytometry for the diagnosis of lower risk myelodysplastic syndromes: the "MDS thermometer".

    Science.gov (United States)

    Aires, Ana; Teixeira, Maria Dos Anjos; Lau, Catarina; Moreira, Cláudia; Spínola, Ana; Mota, Alexandra; Freitas, Inês; Coutinho, Jorge; Lima, Margarida

    2018-01-01

    Immunophenotypic analysis of the bone marrow (BM) cells has proven to be helpful in the diagnosis of Myelodysplastic Syndromes (MDS). However, the usefulness of flow cytometry (FCM) for the detection of myelodysplasia in the peripheral blood (PB) still needs to be investigated. The aim of this pilot study was to evaluate the value of FCM-based PB neutrophil and monocyte immunophenotyping for the diagnosis of lower risk MDS (LR-MDS). We evaluated by 8-color FCM the expression of multiple cell surface molecules (CD10, CD11b, CD11c, CD13, CD14, CD15, CD16, CD34, CD45, CD56, CD64 and HLA-DR) in PB neutrophils and monocytes from a series of 14 adult LR-MDS patients versus 14 normal individuals. Peripheral blood neutrophils from patients with LR-MDS frequently had low forward scatter (FSC) and side scatter (SSC) values and low levels of CD11b, CD11c, CD10, CD16, CD13 and CD45 expression, in that order, as compared to normal neutrophils. In addition, patients with LR-MDS commonly display a higher fraction of CD14 + CD56 + and a lower fraction of CD14 + CD16 + monocytes in the PB. Based on these results, we proposed an immunophenotyping score based on which PB samples from patients with LR-MDS could be distinguished from normal PB samples with a sensitivity 93% and a specificity of 100%. In addition, we used this score to construct the MDS Thermometer, a screening tool for detection and monitoring of MDS in the PB in clinical practice. Peripheral blood neutrophil and monocyte immunophenotyping provide useful information for the diagnosis of LR-MDS, as a complement to cytomorphology. If validated by subsequent studies in larger series of MDS patients and extended to non-MDS patients with cytopenias, our findings may improve the diagnostic assessment and avoid invasive procedures in selected groups of MDS patients.

  4. New Insights into the Pathogenesis of MDS and the rational therapeutic opportunities.

    Science.gov (United States)

    Abou Zahr, Abdallah; Bernabe Ramirez, Carolina; Wozney, Jocelyn; Prebet, Thomas; Zeidan, Amer M

    2016-01-01

    Myelodysplastic syndromes (MDS) include a heterogeneous group of acquired hematopoietic malignancies characterized by ineffective hematopoiesis, peripheral cytopenias, and a varying propensity for progression to acute myeloid leukemia. The clinical heterogeneity in MDS is a reflection of its molecular heterogeneity. Better understanding of aberrant epigenetics, dysregulation of immune responses, and del(5q) MDS has provided the rationale for well-established treatments in MDS. Further understanding of abnormal signal transduction and aberrant apoptosis pathways has led to development of new rational therapies that are in advanced phases of clinical translation. This review seeks to describe recent developments in our understanding of the pathogenesis of MDS and the potential therapeutic implications of these observations.

  5. New MDS or near MDS self-dual codes over finite fields

    OpenAIRE

    Tong, Hongxi; Wang, Xiaoqing

    2016-01-01

    The study of MDS self-dual codes has attracted lots of attention in recent years. There are many papers on determining existence of $q-$ary MDS self-dual codes for various lengths. There are not existence of $q-$ary MDS self-dual codes of some lengths, even these lengths $< q$. We generalize MDS Euclidean self-dual codes to near MDS Euclidean self-dual codes and near MDS isodual codes. And we obtain many new near MDS isodual codes from extended negacyclic duadic codes and we obtain many new M...

  6. Therapy with low-dose azacitidine for MDS in children and young adults: a retrospective analysis of the EWOG-MDS study group.

    Science.gov (United States)

    Cseh, Annamaria M; Niemeyer, Charlotte M; Yoshimi, Ayami; Catala, Albert; Frühwald, Michael C; Hasle, Henrik; van den Heuvel-Eibrink, Mary M; Lauten, Melchior; De Moerloose, Barbara; Smith, Owen P; Bernig, Toralf; Gruhn, Bernd; Kulozik, Andreas E; Metzler, Markus; Olcay, Lale; Suttorp, Meinolf; Furlan, Ingrid; Strahm, Brigitte; Flotho, Christian

    2016-03-01

    Low-dose azacitidine is efficient and safe in the therapy of malignant myeloid disorders in adults but data in children are lacking. We present a retrospective analysis of 24 children and young adults with myelodysplastic syndrome (MDS) who received azacitidine at the time of first diagnosis or relapse after allotransplant (2 children were treated with azacitidine both initially and for relapse). Diagnoses were refractory cytopenia of childhood (N = 4), advanced primary MDS (N = 9) and secondary MDS (N = 11). The median duration of treatment was four cycles. Azacitidine was well tolerated, but cytopenias led to dose reduction in five cases. Treatment was discontinued in one child because of impaired renal function. Sixteen MDS patients were treated with azacitidine at first diagnosis. One complete clinical remission was observed and one child showed complete marrow remission; six children experienced stable disease with haematological improvement. Ten children received azacitidine for relapsed MDS after transplant: of these, seven experienced stable disease for 2-30 cycles (median 3), including one patient with haematological improvement for seven cycles. In summary, azacitidine is effective in some children with MDS and appears to be a non-toxic option in palliative situations to prolong survival. © 2016 John Wiley & Sons Ltd.

  7. Molecular mechanisms of mitochondrial DNA depletion diseases caused by deficiencies in enzymes in purine and pyrimidine metabolism.

    Science.gov (United States)

    Eriksson, Staffan; Wang, Liya

    2008-06-01

    Mitochondrial DNA depletion syndrome (MDS), a reduction of mitochondrial DNA copy number, often affects muscle or liver. Mutations in enzymes of deoxyribonucleotide metabolism give MDS, for example, the mitochondrial thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) genes. Sixteen TK2 and 22 dGK alterations are known. Their characteristics and symptoms are described. Levels of five key deoxynucleotide metabolizing enzymes in mouse tissues were measured. TK2 and dGK levels in muscles were 5- to 10-fold lower than other nonproliferating tissues and 100-fold lower compared to spleen. Each type of tissue apparently relies on de novo and salvage synthesis of DNA precursors to varying degrees.

  8. To chelate or not to chelate in MDS: That is the question!

    Science.gov (United States)

    Zeidan, Amer M; Griffiths, Elizabeth A

    2018-03-08

    Myelodysplastic syndromes (MDS) are a heterogeneous group of hemopathies that exhibit physical manifestations with clinical consequences of bone marrow failure and inherent risk of progression to acute myeloid leukemia. Iron overload (IO) is common in MDS due to chronic transfusion support and disease-related alterations in iron metabolism. IO has been conclusively associated with inferior outcomes among MDS patients. Despite lack of randomized trials showing a survival impact of iron chelation therapy (ICT), ICT is recommended by experts and guidelines for select MDS patients with IO and is often used. The availability of effective oral ICT agents has reignited the controversy regarding ICT use in patients with MDS and IO. Here we summarize the studies evaluating the value of ICT in MDS and suggest a practical approach for use of these therapies. We also highlight controversies regarding use of ICT in MDS and discuss some ongoing efforts to answer these questions. Copyright © 2018 Elsevier Ltd. All rights reserved.

  9. [Combination of busulfan with increased-dose of fludarabine as conditioning regimen for MDS and MDS-AML patients with allo-HSCT].

    Science.gov (United States)

    Yuan, Jing; Ren, Hanyun; Qiu, Zhixiang; Li, Yuan; Wang, Mangju; Liu, Wei; Xu, Weilin; Sun, Yuhua; Wang, Lihong; Liang, Zeyin; Dong, Yujun; Ou, Jinping; Wang, Wensheng; Yin, Yue; Cen, Xinan; Wang, Qian

    2015-06-01

    To investigate the safety and efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS) and secondary acute myelogenous leukemia (MDS-AML) using conditioning regimen with busulfan (Bu) and increased-dose of fludarabine (ID-Flu). A total of 49 patients with MDS or MDS-AML were treated by allo-HSCT, the clinical data was analyzed retrospectively. All patients achieved hematopoietic reconstitution. Neutrophil engraftment was at 10 - 22 days (median 13 days), and platelet engraftment was at 8 - 66 days (median 16 days). The cumulative incidences of Ⅱ-Ⅳ degree acute graft-versus-host disease (GVHD), hemorrhagic cystitis (HC), and hepatic venous occlusive disease (VOD) were 28.6%, 14.3% and 2.0%, respectively. The transplant-related mortality (TRM) was only 4.1% at 100d and 8.2% at 1-92 months of followed-up (median 14 months) period. Overall survival (OS) and disease free survival (DFS) was 75.5%, 73.5%, respectively. Kaplan-Meier curve showed that 3-year OS and 3-year DFS was (71.1 ± 7.8)%, (66.7 ± 8.3)%, respectively, with a relapse incidence (RI) 16.3%. OS for MDS and MDS-AML was 81.5% and 68.2%, and RI in two settings was 3.7%, 31.8%, respectively. OS for MDS-AML at complete remission (CR) and non-CR subgroup was 83.3% and 50.0%, respectively, while cumulative RR was 16.7% and 50.0%, respectively. OS and RI except for non-CR subgroup were 82.1% and 7.7%. Univariate analysis showed that pre-HSCT disease status had correlation with OS (P=0.031), but age, decitabine in conditioning regimen, stem cell source, HLA matching, patient-donor gender, dose of mononuclear cells and GVHD had no correlation with OS. Bu/ID-Flu conditioning regimen for MDS and MDS-AML has high efficiency, fewer complications, lower toxicity and TRM. The OS and DFS were higher and RI was lower except for refractory MDS-AML patients. The regimen is valuable for clinical application.

  10. Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene.

    Science.gov (United States)

    Chanprasert, Sirisak; Wang, Jing; Weng, Shao-Wen; Enns, Gregory M; Boué, Daniel R; Wong, Brenda L; Mendell, Jerry R; Perry, Deborah A; Sahenk, Zarife; Craigen, William J; Alcala, Francisco J Climent; Pascual, Juan M; Melancon, Serge; Zhang, Victor Wei; Scaglia, Fernando; Wong, Lee-Jun C

    2013-01-01

    Mitochondrial DNA (mtDNA) depletion syndromes (MDSs) are a clinically and molecularly heterogeneous group of mitochondrial cytopathies characterized by severe mtDNA copy number reduction in affected tissues. Clinically, MDSs are mainly categorized as myopathic, encephalomyopathic, hepatocerebral, or multi-systemic forms. To date, the myopathic form of MDS is mainly caused by mutations in the TK2 gene, which encodes thymidine kinase 2, the first and rate limiting step enzyme in the phosphorylation of pyrimidine nucleosides. We analyzed 9 unrelated families with 11 affected subjects exhibiting the myopathic form of MDS, by sequencing the TK2 gene. Twelve mutations including 4 novel mutations were detected in 9 families. Skeletal muscle specimens were available from 7 out of 11 subjects. Respiratory chain enzymatic activities in skeletal muscle were measured in 6 subjects, and enzymatic activities were reduced in 3 subjects. Quantitative analysis of mtDNA content in skeletal muscle was performed in 5 subjects, and marked mtDNA content reduction was observed in each. In addition, we outline the molecular and clinical characteristics of this syndrome in a total of 52 patients including those previously reported, and a total of 36 TK2 mutations are summarized. Clinically, hypotonia and proximal muscle weakness are the major phenotypes present in all subjects. In summary, our study expands the molecular and clinical spectrum associated with TK2 deficiency. © 2013.

  11. Age-related epigenetic drift in the pathogenesis of MDS and AML.

    Science.gov (United States)

    Maegawa, Shinji; Gough, Sheryl M; Watanabe-Okochi, Naoko; Lu, Yue; Zhang, Nianxiang; Castoro, Ryan J; Estecio, Marcos R H; Jelinek, Jaroslav; Liang, Shoudan; Kitamura, Toshio; Aplan, Peter D; Issa, Jean-Pierre J

    2014-04-01

    The myelodysplastic syndrome (MDS) is a clonal hematologic disorder that frequently evolves to acute myeloid leukemia (AML). Its pathogenesis remains unclear, but mutations in epigenetic modifiers are common and the disease often responds to DNA methylation inhibitors. We analyzed DNA methylation in the bone marrow and spleen in two mouse models of MDS/AML, the NUP98-HOXD13 (NHD13) mouse and the RUNX1 mutant mouse model. Methylation array analysis showed an average of 512/3445 (14.9%) genes hypermethylated in NHD13 MDS, and 331 (9.6%) genes hypermethylated in RUNX1 MDS. Thirty-two percent of genes in common between the two models (2/3 NHD13 mice and 2/3 RUNX1 mice) were also hypermethylated in at least two of 19 human MDS samples. Detailed analysis of 41 genes in mice showed progressive drift in DNA methylation from young to old normal bone marrow and spleen; to MDS, where we detected accelerated age-related methylation; and finally to AML, which markedly extends DNA methylation abnormalities. Most of these genes showed similar patterns in human MDS and AML. Repeat element hypomethylation was rare in MDS but marked the transition to AML in some cases. Our data show consistency in patterns of aberrant DNA methylation in human and mouse MDS and suggest that epigenetically, MDS displays an accelerated aging phenotype.

  12. Inhibition of WNT signaling in the bone marrow niche prevents the development of MDS in the Apcdel/+ MDS mouse model.

    Science.gov (United States)

    Stoddart, Angela; Wang, Jianghong; Hu, Chunmei; Fernald, Anthony A; Davis, Elizabeth M; Cheng, Jason X; Le Beau, Michelle M

    2017-06-01

    There is accumulating evidence that functional alteration(s) of the bone marrow (BM) microenvironment contribute to the development of some myeloid disorders, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In addition to a cell-intrinsic role of WNT activation in leukemia stem cells, WNT activation in the BM niche is also thought to contribute to the pathogenesis of MDS and AML. We previously showed that the Apc -haploinsufficient mice ( Apc del/+ ) model MDS induced by an aberrant BM microenvironment. We sought to determine whether Apc, a multifunctional protein and key negative regulator of the canonical β-catenin (Ctnnb1)/WNT-signaling pathway, mediates this disease through modulating WNT signaling, and whether inhibition of WNT signaling prevents the development of MDS in Apc del/+ mice. Here, we demonstrate that loss of 1 copy of Ctnnb1 is sufficient to prevent the development of MDS in Apc del/+ mice and that altered canonical WNT signaling in the microenvironment is responsible for the disease. Furthermore, the US Food and Drug Administration (FDA)-approved drug pyrvinium delays and/or inhibits disease in Apc del /+ mice, even when it is administered after the presentation of anemia. Other groups have observed increased nuclear CTNNB1 in stromal cells from a high frequency of MDS/AML patients, a finding that together with our results highlights a potential new strategy for treating some myeloid disorders. © 2017 by The American Society of Hematology.

  13. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults.

    Science.gov (United States)

    Savona, Michael R; Malcovati, Luca; Komrokji, Rami; Tiu, Ramon V; Mughal, Tariq I; Orazi, Attilio; Kiladjian, Jean-Jacques; Padron, Eric; Solary, Eric; Tibes, Raoul; Itzykson, Raphael; Cazzola, Mario; Mesa, Ruben; Maciejewski, Jaroslaw; Fenaux, Pierre; Garcia-Manero, Guillermo; Gerds, Aaron; Sanz, Guillermo; Niemeyer, Charlotte M; Cervantes, Francisco; Germing, Ulrich; Cross, Nicholas C P; List, Alan F

    2015-03-19

    Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms. An international panel comprising laboratory and clinical experts in MDS/MPN was established involving 3 independent academic MDS/MPN workshops (March 2013, December 2013, and June 2014). These recommendations are the result of this collaborative project sponsored by the MDS Foundation. © 2015 by The American Society of Hematology.

  14. Comparison of clinical outcomes and prognostic utility of risk stratification tools in patients with therapy-related vs de novo myelodysplastic syndromes: a report on behalf of the MDS Clinical Research Consortium.

    Science.gov (United States)

    Zeidan, A M; Al Ali, N; Barnard, J; Padron, E; Lancet, J E; Sekeres, M A; Steensma, D P; DeZern, A; Roboz, G; Jabbour, E; Garcia-Manero, G; List, A; Komrokji, R

    2017-06-01

    While therapy-related (t)-myelodysplastic syndromes (MDS) have worse outcomes than de novo MDS (d-MDS), some t-MDS patients have an indolent course. Most MDS prognostic models excluded t-MDS patients during development. The performances of the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), MD Anderson Global Prognostic System (MPSS), WHO Prognostic Scoring System (WPSS) and t-MDS Prognostic System (TPSS) were compared among patients with t-MDS. Akaike information criteria (AIC) assessed the relative goodness of fit of the models. We identified 370 t-MDS patients (19%) among 1950 MDS patients. Prior therapy included chemotherapy alone (48%), chemoradiation (31%), and radiation alone in 21%. Median survival for t-MDS patients was significantly shorter than for d-MDS (19 vs 46 months, PMDS (PMDS had a significantly higher hazard of death relative to d-MDS in every risk model, and had inferior survival compared to patients with d-MDS within all risk group categories. AIC Scores (lower is better) were 2316 (MPSS), 2343 (TPSS), 2343 (IPSS-R), 2361 (WPSS) and 2364 (IPSS). In conclusion, subsets of t-MDS patients with varying clinical outcomes can be identified using conventional risk stratification models. The MPSS, TPSS and IPSS-R provide the best predictive power.

  15. Podocyte Depletion in Thin GBM and Alport Syndrome.

    Science.gov (United States)

    Wickman, Larysa; Hodgin, Jeffrey B; Wang, Su Q; Afshinnia, Farsad; Kershaw, David; Wiggins, Roger C

    2016-01-01

    The proximate genetic cause of both Thin GBM and Alport Syndrome (AS) is abnormal α3, 4 and 5 collagen IV chains resulting in abnormal glomerular basement membrane (GBM) structure/function. We previously reported that podocyte detachment rate measured in urine is increased in AS, suggesting that podocyte depletion could play a role in causing progressive loss of kidney function. To test this hypothesis podometric parameters were measured in 26 kidney biopsies from 21 patients aged 2-17 years with a clinic-pathologic diagnosis including both classic Alport Syndrome with thin and thick GBM segments and lamellated lamina densa [n = 15] and Thin GBM cases [n = 6]. Protocol biopsies from deceased donor kidneys were used as age-matched controls. Podocyte depletion was present in AS biopsies prior to detectable histologic abnormalities. No abnormality was detected by light microscopy at 70% podocyte depletion. Low level proteinuria was an early event at about 25% podocyte depletion and increased in proportion to podocyte depletion. These quantitative data parallel those from model systems where podocyte depletion is the causative event. This result supports a hypothesis that in AS podocyte adherence to the GBM is defective resulting in accelerated podocyte detachment causing progressive podocyte depletion leading to FSGS-like pathologic changes and eventual End Stage Kidney Disease. Early intervention to reduce podocyte depletion is projected to prolong kidney survival in AS.

  16. [mRNA expression of notch ligand-delta-like-1 and jagged-1 in mesenchymal stem cells of MDS patients].

    Science.gov (United States)

    Fei, Cheng-Ming; Gu, Shu-Cheng; Zhao, You-Shan; Guo, Juan; Li, Xiao; Chang, Chun-Kang

    2014-12-01

    This study was aimed to investigated the mRNA expression levels of Notch ligands- Delta-like-1 and Jagged-1 in bone marrow mesenchymal stem cells of patients with myelodysplastic syndrome (MDS), and to explore their relation with onset of MDS. Bone marrow mesenchymal stem cells of 38 patients with MDS and 16 normal subjects as control were collected to detect mRNA expression of Delta-like-1 and Jagged-1 by using real-time quantitative polymerase chain reaction. The results showed that the expression levels of Delta-like-1 and Jagged-1 in mesenchymal stem cells of MDS patients were significantly higher than that in normal controls (P MDS patients (r = 0.502, P MDS patients with abnormal karyotypes were significantly higher than those in MDS patients with normal karyotypes (P 0.05). It is concluded that the changes of Delta-like-1 and Jagged-1 expression level in MSC may play a role in the pathogenesis of myelodysplastic syndrome.

  17. Clinical and biological significance of isolated Y chromosome loss in myelodysplastic syndromes and chronic myelomonocytic leukemia. A report from the Spanish MDS Group.

    Science.gov (United States)

    Nomdedeu, Meritxell; Pereira, Arturo; Calvo, Xavier; Colomer, Joan; Sole, Francesc; Arias, Amparo; Gomez, Candida; Luño, Elisa; Cervera, Jose; Arnan, Montserrat; Pomares, Helena; Ramos, Fernando; Oiartzabal, Itziar; Espinet, Blanca; Pedro, Carme; Arrizabalaga, Beatriz; Blanco, María Laura; Tormo, Mar; Hernandez-Rivas, Jesus Maria; Díez-Campelo, María; Ortega, Margarita; Valcárcel, David; Cedena, Maria-Teresa; Collado, Rosa; Grau, Javier; Granada, Isabel; Sanz, Guillermo; Campo, Elias; Esteve, Jordi; Costa, Dolors

    2017-12-01

    Isolate loss of chromosome Y (-Y) in myelodysplastic syndromes (MDS) is associated to a better outcome but it is also well described as an age-related phenomenon. In this study we aimed to analyze the prognostic impact of -Y in the context of the IPSS-R cytogenetic classification, evaluate the clinical significance of the percentage of metaphases with isolated -Y, and test whether finding -Y may predispose to over-diagnose MDS in patients with borderline morphological features. We evaluated 3581 male patients from the Spanish MDS Registry with a diagnosis of MDS or chronic myelomonocytic leukemia (CMML). -Y was identified in 177 patients (4.9%). Compared with the 2246 male patients with normal karyotype, -Y group showed a reduced risk of leukemic transformation that did not translate into a survival advantage. The overall survival and the risk of leukemic transformation were not influenced by the percentage of metaphases with -Y. The -Y group was not enriched in patients with minor morphologic traits of dysplasia, suggesting that the better outcome in the -Y group cannot be explained by enrichment in cases misdiagnosed as MDS. In conclusion, our results support the current recommendation of classifying patients with -Y within the very good risk category of the IPSS-R for MDS and rule out a selection bias as a possible explanation of this better outcome. An analysis of the molecular basis of MDS with isolated -Y would be of interest as it may provide a biological basis of protection against progression to acute leukemia. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. [Establishment of Primary Adult MDS Nested Case-Control Study Cohort and Study of Risk Factors Associated with MDS Evolution to Leukemia].

    Science.gov (United States)

    Ma, Yan; Chen, Bo-Bin; Wang, Xiao-Qin; Xu, Xiao-Ping; Lin, Guo-Wei

    2015-12-01

    To establish a nested case-control study cohort in myelodysplastic syndrome (MDS) patients and investigate the clinical characteristics, WHO subtype and risk factors associated with MDS evolution to leukemia of this cohort. All patients, ≥18 years of age, provided by 24 Shanghai hospitals with initial clinical findings consistent with a hematopoietic abnormality between June 2003 and April 2007, were the candidates for inclusion in this study. The blood and bone marrow samples of every patient should be provided at baseline. Diagnosis was made by incorporating morphologic, immunophenotypic, cytogenetic and molecular features according to WHO classification criteria. Cytogenetic analysis was performed using conventional G-banding karyotyping and fluorescence in situ hybridization (FISH) techniques. Cumulative risk of evolution was estimated by Kaplan-Meier method. Prognostic factors were evaluated by univariate Log-rank method and multivariate Cox proportional hazard models. A total of 435 patients were diagnosed as MDS. The median age of MDS onset was 58(18-90) years, with 248 male patients and 187 female patients (male: female 1.33: 1). The percentage of cases with refractory cytopenia with multilineage dysplasia (RCMD) was the highest (65.5%), while that of refraetory anemia (RA) (2.3%), refractory anenia with ring sideroblast (RARS) (1.1%) and 5q-syndrome (0.5%) was lower. Trisomy 8 (+8) was the most common chromosome abnormalities (71 cases, 12.7%). The mean follow-up time was 20.3 (4.2-57.1) months. Cases were patients with evolution by the end of follow-up, while controls were patients without evolution by that time. Case group included 41 patients and control group included 342 patients. Univariate analysis showed that the age, sex, WHO subtype, WBC count, absolute neutrophil count (ANC), IPSS cytogenetic subgroup, IPSS group and bone marrow blast percentage were significant risk factors for leukemia-free survival (LFS). Multivariate analysis of COX model

  19. The need for additional genetic markers for MDS stratification: what does the future hold for prognostication?

    Science.gov (United States)

    Otrock, Zaher K.; Tiu, Ramon V.; Maciejewski, Jaroslaw P.; Sekeres, Mikkael A.

    2013-01-01

    Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal hematopoietic disorders. Metaphase cytogenetics (MC) has been the gold standard for genetic testing in MDS, but it can detect clonal cytogenetic abnormalities in only 50% of cases. New karyotyping tests include fluorescence in situ hybridization (FISH), array-based comparative genomic hybridization (aCGH), and single nucleotide polymorphism arrays (SNP-A). These techniques have increased the detected genetic abnormalities in MDS, many of which confer prognostic significance to overall and leukemia-free survival. This has eventually increased our understanding of MDS genetics. With the help of new technologies, we anticipate that the existing prognostic scoring systems will incorporate mutational data into their parameters. This review discusses the progress in MDS diagnosis through the use of array-based technologies. We also discuss the recently investigated genetic mutation in MDS, and revisit the MDS classification and prognostic scoring systems. PMID:23373781

  20. Despite differential gene expression profiles pediatric MDS derived mesenchymal stromal cells display functionality in vitro.

    Science.gov (United States)

    Calkoen, F G J; Vervat, C; van Pel, M; de Haas, V; Vijfhuizen, L S; Eising, E; Kroes, W G M; 't Hoen, P A C; van den Heuvel-Eibrink, M M; Egeler, R M; van Tol, M J D; Ball, L M

    2015-03-01

    Pediatric myelodysplastic syndrome (MDS) is a heterogeneous disease covering a spectrum ranging from aplasia (RCC) to myeloproliferation (RAEB(t)). In adult-type MDS there is increasing evidence for abnormal function of the bone-marrow microenvironment. Here, we extensively studied the mesenchymal stromal cells (MSCs) derived from children with MDS. MSCs were expanded from the bone-marrow of 17 MDS patients (RCC: n=10 and advanced MDS: n=7) and pediatric controls (n=10). No differences were observed with respect to phenotype, differentiation capacity, immunomodulatory capacity or hematopoietic support. mRNA expression analysis by Deep-SAGE revealed increased IL-6 expression in RCC- and RAEB(t)-MDS. RCC-MDS MSC expressed increased levels of DKK3, a protein associated with decreased apoptosis. RAEB(t)-MDS revealed increased CRLF1 and decreased DAPK1 expressions. This pattern has been associated with transformation in hematopoietic malignancies. Genes reported to be differentially expressed in adult MDS-MSC did not differ between MSC of pediatric MDS and controls. An altered mRNA expression profile, associated with cell survival and malignant transformation, of MSC derived from children with MDS strengthens the hypothesis that the micro-environment is of importance in this disease. Our data support the understanding that pediatric and adult MDS are two different diseases. Further evaluation of the pathways involved might reveal additional therapy targets. Copyright © 2015. Published by Elsevier B.V.

  1. Red Blood Cell Transfusion Dependency and Hyperferritinemia Are Associated with Impaired Survival in Patients Diagnosed with Myelodysplastic Syndromes: Results from the First Polish MDS-PALG Registry.

    Science.gov (United States)

    Waszczuk-Gajda, Anna; Mądry, Krzysztof; Machowicz, Rafał; Drozd-Sokołowska, Joanna; Stella-Hołowiecka, Beata; Mital, Andrzej; Obara, Agata; Szmigielska-Kapłon, Anna; Sikorska, Anna; Subocz, Edyta; Jędrzejczak, Wiesław W; Dwilewicz-Trojaczek, Jadwiga

    2016-01-01

    Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterized by ineffective hematopoiesis, cytopenias and a risk of progression to acute myeloid leukemia (AML). Anemia is the most frequent cytopenia diagnosed in patients with MDS. Regular RBC transfusions are the only treatment option for about 40% of patients. Transfusion-dependent patients develop secondary iron overload. The influence of serum ferritin (SF) concentration on survival and acute myeloid leukemia transformation in MDS patients remains controversial. The data for the Central European population is scarce and so far there is no description for Poland. The aim of this study was to perform a retrospective analysis of the relationship of SF concentration with red blood cell transfusion dependency, survival and transformation to acute myeloid leukemia. We retrospectively evaluated the data of the 819 MDS patients (58% male; median age 70 years) included in the MDS Registry of the MDS Section of the Polish Adult Leukemia Group (PALG). Analyses were performed on 190 patients diagnosed with MDS, maximal 6 months before inclusion to the registry in order to avoid selection bias (a shorter survival of higher risk MDS patients). Patients with hyperferritinemia higher than 1000 ng/L vs. patients with SF concentration lower than 1000 ng/L had a median survival of 320 days vs. 568 days, respectively (p log-rank = 0.014). The following factors were found to significantly worsen survival: RBC-transfusion dependence (p = 0.0033; HR 2.67L), platelet transfusion dependence (p = 0.0071; HR 3.321), hemoglobin concentration lower than 10 g/dL (p = 0.0036; HR 2.97), SF concentration higher than 1000 ng/L (p = 0.0023; HR = 2.94), platelet count lower than 10 G/L (p = 0.0081 HR = 5.04), acute leukemia transformation (p = 0.0081; HR 1.968). Taking into account the relatively low number of patients in previous studies exploring hyperferritinemia in MDS, the results of the first Polish

  2. Gene expression profiling in MDS and AML: potential and future avenues

    DEFF Research Database (Denmark)

    Theilgaard-Mönch, K; Boultwood, J; Ferrari, S

    2011-01-01

    Today, the classification systems for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) already incorporate cytogenetic and molecular genetic aberrations in an attempt to better reflect disease biology. However, in many MDS/AML patients no genetic aberrations have been identified yet...... with regard to diagnosis, prediction of clinical outcome, discovery of novel subclasses and identification of novel therapeutic targets and novel drugs. As many challenges remain ahead, we discuss the pitfalls of this technology and its potential including future integrative studies with other genomics...

  3. Incorporating novel approaches in the management of MDS beyond conventional hypomethylating agents.

    Science.gov (United States)

    Odenike, Olatoyosi

    2017-12-08

    In the last decade, the treatment of higher-risk myelodysplastic syndromes (MDS) has revolved around the azanucleosides, azacitidine and decitabine, which at lower doses are postulated to work predominantly via their effects on inhibition of DNA methyltransferases and consequent DNA hypomethylation. For patients who relapse after, or do not respond to, hypomethylating agent therapy, the outcome is dismal, and new agents and approaches that have the potential to alter the natural history of these diseases are desperately needed. Allogeneic stem cell transplant is the only known potentially curative approach in MDS, but its applicability has been limited by the advanced age of patients and attendant comorbidities. There is now an increasing array of new agents under clinical investigation in MDS that aim to exploit our expanding understanding of molecular pathways that are important in the pathogenesis of MDS. This review focuses on a critical appraisal of novel agents being evaluated in higher-risk MDS that go beyond the conventional hypomethylating agent therapies approved by the US Food and Drug Administration. © 2016 by The American Society of Hematology. All rights reserved.

  4. PD-1 signaling and inhibition in AML and MDS.

    Science.gov (United States)

    Haroun, Faysal; Solola, Sade A; Nassereddine, Samah; Tabbara, Imad

    2017-09-01

    Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are clinically and molecularly heterogeneous clonal myeloid disorders with a poor prognosis especially in the relapsed refractory setting and in patients above the age of 60. While allogeneic hematopoietic stem cell transplantation (ASCT) is a potentially curative approach, high relapse, morbidity, and mortality rates necessitate the development of alternative therapies. Immune checkpoint inhibitors unmask tumoral immune tolerance and have demonstrated efficacy in the treatment of chemotherapy-resistant hematologic and solid malignancies. The rationale for the investigation of those agents in AML and MDS is supported by an observed increased expression of programmed cell death 1 protein (PD-1) and ligand 1 (PD-L1) in the hematopoietic microenvironment of AML and MDS, and its association with low TP53 and a poor prognosis. Early clinical experience in combination with a hypomethylating agent has shown encouraging responses; however, larger clinical trials are needed to determine the role of checkpoint inhibition in myeloid malignancies.

  5. Epigenetically Aberrant Stroma in MDS Propagates Disease via Wnt/β-Catenin Activation.

    Science.gov (United States)

    Bhagat, Tushar D; Chen, Si; Bartenstein, Matthias; Barlowe, A Trevor; Von Ahrens, Dagny; Choudhary, Gaurav S; Tivnan, Patrick; Amin, Elianna; Marcondes, A Mario; Sanders, Mathijs A; Hoogenboezem, Remco M; Kambhampati, Suman; Ramachandra, Nandini; Mantzaris, Iaonnis; Sukrithan, Vineeth; Laurence, Remi; Lopez, Robert; Bhagat, Prafullla; Giricz, Orsi; Sohal, Davendra; Wickrema, Amittha; Yeung, Cecilia; Gritsman, Kira; Aplan, Peter; Hochedlinger, Konrad; Yu, Yiting; Pradhan, Kith; Zhang, Jinghang; Greally, John M; Mukherjee, Siddhartha; Pellagatti, Andrea; Boultwood, Jacqueline; Will, Britta; Steidl, Ulrich; Raaijmakers, Marc H G P; Deeg, H Joachim; Kharas, Michael G; Verma, Amit

    2017-09-15

    The bone marrow microenvironment influences malignant hematopoiesis, but how it promotes leukemogenesis has not been elucidated. In addition, the role of the bone marrow stroma in regulating clinical responses to DNA methyltransferase inhibitors (DNMTi) is also poorly understood. In this study, we conducted a DNA methylome analysis of bone marrow-derived stromal cells from myelodysplastic syndrome (MDS) patients and observed widespread aberrant cytosine hypermethylation occurring preferentially outside CpG islands. Stroma derived from 5-azacytidine-treated patients lacked aberrant methylation and DNMTi treatment of primary MDS stroma enhanced its ability to support erythroid differentiation. An integrative expression analysis revealed that the WNT pathway antagonist FRZB was aberrantly hypermethylated and underexpressed in MDS stroma. This result was confirmed in an independent set of sorted, primary MDS-derived mesenchymal cells. We documented a WNT/β-catenin activation signature in CD34 + cells from advanced cases of MDS, where it associated with adverse prognosis. Constitutive activation of β-catenin in hematopoietic cells yielded lethal myeloid disease in a NUP98-HOXD13 mouse model of MDS, confirming its role in disease progression. Our results define novel epigenetic changes in the bone marrow microenvironment, which lead to β-catenin activation and disease progression of MDS. Cancer Res; 77(18); 4846-57. ©2017 AACR . ©2017 American Association for Cancer Research.

  6. Myopathic mtDNA Depletion Syndrome Due to Mutation in TK2 Gene.

    Science.gov (United States)

    Martín-Hernández, Elena; García-Silva, María Teresa; Quijada-Fraile, Pilar; Rodríguez-García, María Elena; Rivera, Henry; Hernández-Laín, Aurelio; Coca-Robinot, David; Fernández-Toral, Joaquín; Arenas, Joaquín; Martín, Miguel A; Martínez-Azorín, Francisco

    2017-01-01

    Whole-exome sequencing was used to identify the disease gene(s) in a Spanish girl with failure to thrive, muscle weakness, mild facial weakness, elevated creatine kinase, deficiency of mitochondrial complex III and depletion of mtDNA. With whole-exome sequencing data, it was possible to get the whole mtDNA sequencing and discard any pathogenic variant in this genome. The analysis of whole exome uncovered a homozygous pathogenic mutation in thymidine kinase 2 gene ( TK2; NM_004614.4:c.323 C>T, p.T108M). TK2 mutations have been identified mainly in patients with the myopathic form of mtDNA depletion syndromes. This patient presents an atypical TK2-related myopathic form of mtDNA depletion syndromes, because despite having a very low content of mtDNA (TK2 gene in mtDNA depletion syndromes and expanded the phenotypic spectrum.

  7. Cytomorphology review of 100 newly diagnosed lower-risk MDS patients in the European LeukemiaNet MDS (EUMDS) registry reveals a high inter-observer concordance.

    Science.gov (United States)

    de Swart, Louise; Smith, Alex; MacKenzie, Marius; Symeonidis, Argiris; Neukirchen, Judith; Mikulenková, Dana; Vallespí, Teresa; Zini, Gina; Paszkowska-Kowalewska, Malgorzata; Kruger, Anton; Saft, Leonie; Fenaux, Pierre; Bowen, David; Hellström-Lindberg, Eva; Čermák, Jaroslav; Stauder, Reinhard; Tatic, Aurelia; Holm, Mette Skov; Malcovati, Luca; Mądry, Krzysztof; Droste, Jackie; Blijlevens, Nicole; de Witte, Theo; Germing, Ulrich

    2017-07-01

    The European LeukemiaNet MDS (EUMDS) registry is collecting data of myelodysplastic syndrome (MDS) patients belonging to the IPSS low or intermediate-1 category, newly diagnosed by local cytologists. The diagnosis of MDS can be challenging, and some data report inter-observer variability with regard to the assessment of the MDS subtype. In order to ensure that correct diagnoses were made by the participating centres, blood and bone marrow slides of 10% of the first 1000 patients were reviewed by an 11-person panel of cytomorphologists. All slides were rated by at least 3 panel members (median 8 panel members; range 3-9). Marrow slides from 98 out of 105 patients were of good quality and therefore could be rated properly according to the WHO 2001 classification, including assessment of dysplastic lineages. The agreement between the reviewers whether the diagnosis was MDS or non-MDS was strong with an intra-class correlation coefficient (ICC) of 0.85. Six cases were detected not to fit the entry criteria of the registry, because they were diagnosed uniformly as CMML or AML by the panel members. The agreement by WHO 2001 classification was strong as well (ICC = 0.83). The concordance of the assessment of dysplastic lineages was substantial for megakaryopoiesis and myelopoiesis and moderate for erythropoiesis. Our data show that in general, the inter-observer agreement was high and a very low percentage of misdiagnosed cases had been entered into the EUMDS registry. Further studies including histomorphology are warranted.

  8. Therapy-related AML/MDS after treatment of low-grade B-cell lymphoma

    International Nuclear Information System (INIS)

    Yanada, Masamitsu

    2008-01-01

    Described is the therapy-related AML (acute myelogenetic leukemia)/MDS (myelo-dysplasia syndrome), which is manifested after various treatments of low-grade B-cell lymphoma and has strongly attracted attention because of the markedly improved prognosis due to recent advantages of the therapy for the disease. AML/MDS occurs several years after chemotherapy and/or radiation therapy which cause DNA damage in hematopoietic cells, and the AML/MDS risk is known increased in patients undergone especially with autologous transplantation of those cells. AML/MDS has the feature similar to that caused either by alkylating agent or by topoisomerase-2 inhibitor, and the disease by radiation belong to the former. Yet unclear is the problem whether malignant cells causing the disease after therapy are derived from the remaining cells in the graft or in the body. Although irradiations of total body and total lymphaden as well as chemotherapy are said to be related to AML/MDS and local irradiation does not contribute to its risk, the most important factor for the disease is considered to be the autotransplantation as the recurrence occurs in 50% after it. Thus the treatment history should be taken into consideration for suppressing AML/MDS, for which follow up with consideration for the disease is required particularly after autotransplantation. (R.T.)

  9. Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells.

    Science.gov (United States)

    Geyh, S; Oz, S; Cadeddu, R-P; Fröbel, J; Brückner, B; Kündgen, A; Fenk, R; Bruns, I; Zilkens, C; Hermsen, D; Gattermann, N; Kobbe, G; Germing, U; Lyko, F; Haas, R; Schroeder, T

    2013-09-01

    Ineffective hematopoiesis is a major characteristic of myelodysplastic syndromes (MDS) causing relevant morbidity and mortality. Mesenchymal stromal cells (MSC) have been shown to physiologically support hematopoiesis, but their contribution to the pathogenesis of MDS remains elusive. We show that MSC from patients across all MDS subtypes (n=106) exhibit significantly reduced growth and proliferative capacities accompanied by premature replicative senescence. Osteogenic differentiation was significantly reduced in MDS-derived MSC, indicated by cytochemical stainings and reduced expressions of Osterix and Osteocalcin. This was associated with specific methylation patterns that clearly separated MDS-MSC from healthy controls and showed a strong enrichment for biological processes associated with cellular phenotypes and transcriptional regulation. Furthermore, in MDS-MSC, we detected altered expression of key molecules involved in the interaction with hematopoietic stem and progenitor cells (HSPC), in particular Osteopontin, Jagged1, Kit-ligand and Angiopoietin as well as several chemokines. Functionally, this translated into a significantly diminished ability of MDS-derived MSC to support CD34+ HSPC in long-term culture-initiating cell assays associated with a reduced cell cycle activity. Taken together, our comprehensive analysis shows that MSC from all MDS subtypes are structurally, epigenetically and functionally altered, which leads to impaired stromal support and seems to contribute to deficient hematopoiesis in MDS.

  10. Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN.

    Science.gov (United States)

    Jabbour, Elias; Short, Nicholas J; Montalban-Bravo, Guillermo; Huang, Xuelin; Bueso-Ramos, Carlos; Qiao, Wei; Yang, Hui; Zhao, Chong; Kadia, Tapan; Borthakur, Gautam; Pemmaraju, Naveen; Sasaki, Koji; Estrov, Zeev; Cortes, Jorge; Ravandi, Farhad; Alvarado, Yesid; Komrokji, Rami; Sekeres, Mikkael A; Steensma, David P; DeZern, Amy; Roboz, Gail; Kantarjian, Hagop; Garcia-Manero, Guillermo

    2017-09-28

    Hypomethylating agents (HMAs) improve survival in patients with higher-risk myelodysplastic syndromes (MDS) but are less well-studied in lower-risk disease. We compared the safety and efficacy of low-dose decitabine vs low-dose azacitidine in this group of patients. Adults with low- or intermediate 1-risk MDS or MDS/myeloproliferative neoplasm (MPN), including chronic myelomonocytic leukemia, according to the International Prognostic Scoring System, were randomly assigned using a Bayesian adaptive design to receive either azacitidine 75 mg/m 2 intravenously/subcutaneously daily or decitabine 20 mg/m 2 intravenously daily for 3 consecutive days on a 28-day cycle. The primary outcome was overall response rate (ORR). Between November 2012 and February 2016, 113 patients were treated: 40 (35%) with azacitidine and 73 (65%) with decitabine. The median age was 70 years; 81% of patients were intermediate 1-risk patients. The median number of cycles received was 9. The ORRs were 70% and 49% ( P = .03) for patients treated with decitabine and azacitidine, respectively. Thirty-two percent of patients treated with decitabine became transfusion independent compared with 16% of patients treated with azacitidine ( P = .2). Cytogenetic response rates were 61% and 25% ( P = .02), respectively. With a median follow-up of 20 months, the overall median event-free survival was 18 months: 20 and 13 months for patients treated with decitabine and azacitidine, respectively ( P = .1). Treatment was well tolerated, with a 6-week mortality rate of 0%. The use of low-dose HMAs is safe and effective in patients with lower-risk MDS and MDS/MPN. Their effect on the natural history of lower-risk disease needs to be further studied. This trial was registered at clinicaltrials.gov (identifier NCT01720225). © 2017 by The American Society of Hematology.

  11. SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS.

    Science.gov (United States)

    Inoue, D; Kitaura, J; Matsui, H; Hou, H-A; Chou, W-C; Nagamachi, A; Kawabata, K C; Togami, K; Nagase, R; Horikawa, S; Saika, M; Micol, J-B; Hayashi, Y; Harada, Y; Harada, H; Inaba, T; Tien, H-F; Abdel-Wahab, O; Kitamura, T

    2015-04-01

    Mutations in ASXL1 are frequent in patients with myelodysplastic syndrome (MDS) and are associated with adverse survival, yet the molecular pathogenesis of ASXL1 mutations (ASXL1-MT) is not fully understood. Recently, it has been found that deletion of Asxl1 or expression of C-terminal-truncating ASXL1-MTs inhibit myeloid differentiation and induce MDS-like disease in mice. Here, we find that SET-binding protein 1 (SETBP1) mutations (SETBP1-MT) are enriched among ASXL1-mutated MDS patients and associated with increased incidence of leukemic transformation, as well as shorter survival, suggesting that SETBP1-MT play a critical role in leukemic transformation of MDS. We identify that SETBP1-MT inhibit ubiquitination and subsequent degradation of SETBP1, resulting in increased expression. Expression of SETBP1-MT, in turn, inhibited protein phosphatase 2A activity, leading to Akt activation and enhanced expression of posterior Hoxa genes in ASXL1-mutant cells. Biologically, SETBP1-MT augmented ASXL1-MT-induced differentiation block, inhibited apoptosis and enhanced myeloid colony output. SETBP1-MT collaborated with ASXL1-MT in inducing acute myeloid leukemia in vivo. The combination of ASXL1-MT and SETBP1-MT activated a stem cell signature and repressed the tumor growth factor-β signaling pathway, in contrast to the ASXL1-MT-induced MDS model. These data reveal that SETBP1-MT are critical drivers of ASXL1-mutated MDS and identify several deregulated pathways as potential therapeutic targets in high-risk MDS.

  12. Mitochondrial DNA depletion syndrome presenting with ataxia and ...

    African Journals Online (AJOL)

    Laila Selim

    2012-07-24

    Jul 24, 2012 ... Sequencing analysis of the TK2 gene revealed no sequence variation. ... the pathogenesis of the myopathic form of mitochondrial depletion syndrome should be ..... [39,40]. However, the biochemical evidence of deficiency of.

  13. Mutational profiling in patients with MDS: ready for every-day use in the clinic?

    Science.gov (United States)

    Bacher, Ulrike; Kohlmann, Alexander; Haferlach, Torsten

    2015-03-01

    Multiple recurrent somatic mutations were identified in the majority of patients with myelodysplastic syndromes (MDS), but investigating the broad spectrum of molecular markers in MDS exceeds many laboratories' capacity when traditional molecular techniques are used. High-throughput second generation sequencing (=next-generation sequencing, NGS) has proven to be applicable for comprehensive biomarker mutation analyses allowing to increase diagnostic sensitivity and accuracy and to improve risk stratification and prognostication in addition to cytomorphology and cytogenetic analysis in patients with MDS. Amplicon deep-sequencing enables comprehensive biomarker analysis in a multitude of patients per investigation in an acceptable turn-around time and at affordable costs. Comprehensive myeloid marker panels were successfully introduced into diagnostic practice. Therefore, molecular mutation analysis is ready for use in all patients with suspected MDS, may contribute to risk stratification in possible candidates for allogeneic stem cell transplantation, and should become an integral part of clinical research studies in MDS patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. T-cell receptor Vbeta CDR3 oligoclonality frequently occurs in childhood refractory cytopenia (MDS-RC) and severe aplastic anemia

    DEFF Research Database (Denmark)

    Vries, A.C. de; Langerak, A.W.; Verhaaf, B.

    2008-01-01

    (Very) severe acquired aplastic anemia ((v)SAA) and myelodysplastic syndrome (MDS) are rare diseases in childhood. (V)SAA is a bone marrow (BM) failure syndrome characterized by immune-mediated destruction of hematopoietic progenitors. MDS is a malignant clonal stem cell disorder, of which...... the hypoplastic variant is, in case of absence of a cytogenetic clone, difficult to separate from (v)SAA. Recently, studies provided a molecular signature of autoimmunity in adult (v)SAA, by showing oligoclonality based on the length of the TCR Vbeta CDR3 region. We investigated retrospectively the frequency...... and the discriminative value of TCR Vbeta CDR3 oligoclonality in pediatric (v)SAA and MDS patients. Peripheral blood (PB) and/or BM mononuclear cell samples of pediatric patients with (v)SAA (n=38), refractory cytopenia (MDS-RC) (n=28) and 18 controls were analysed via TCR Vbeta heteroduplex PCR analysis of extracted...

  15. Relapse of nephrotic syndrome during post-rituximab peripheral blood B-lymphocyte depletion.

    Science.gov (United States)

    Sato, Mai; Kamei, Koichi; Ogura, Masao; Ishikura, Kenji; Ito, Shuichi

    2018-02-01

    Rituximab is effective against complicated childhood steroid-dependent nephrotic syndrome (SDNS). Peripheral blood B-lymphocyte (B-cell) depletion is strongly correlated with persistent remission, relapse rarely occurring during B-cell depletion; however, we have encountered several such patients. We retrospectively analyzed the characteristics and clinical course of 82 patients with SDNS treated with rituximab from January 2007 to December 2012 in our institution. Six of 82 patients (7.3%) had relapses during B-cell depletion after receiving rituximab (relapsed group). The remaining 76 patients did not have relapses during B-cell depletion (non-relapsed group). The median time to initial relapse during B-cell depletion was 85 days after receiving rituximab, which is significantly shorter than in the non-relapsed group (410 days, p = 0.0003). The median annual numbers of relapses after receiving rituximab were 2.5 and 0.9 in the relapsed and non-relapsed groups, respectively (p depletion did not differ between the two groups. Relapse during B-cell depletion after receiving rituximab suggests that various pathophysiological mechanisms play a part in childhood nephrotic syndrome.

  16. Time-dependent changes in mortality and transformation risk in MDS.

    Science.gov (United States)

    Pfeilstöcker, Michael; Tuechler, Heinz; Sanz, Guillermo; Schanz, Julie; Garcia-Manero, Guillermo; Solé, Francesc; Bennett, John M; Bowen, David; Fenaux, Pierre; Dreyfus, Francois; Kantarjian, Hagop; Kuendgen, Andrea; Malcovati, Luca; Cazzola, Mario; Cermak, Jaroslav; Fonatsch, Christa; Le Beau, Michelle M; Slovak, Marilyn L; Levis, Alessandro; Luebbert, Michael; Maciejewski, Jaroslaw; Machherndl-Spandl, Sigrid; Magalhaes, Silvia M M; Miyazaki, Yasushi; Sekeres, Mikkael A; Sperr, Wolfgang R; Stauder, Reinhard; Tauro, Sudhir; Valent, Peter; Vallespi, Teresa; van de Loosdrecht, Arjan A; Germing, Ulrich; Haase, Detlef; Greenberg, Peter L

    2016-08-18

    In myelodysplastic syndromes (MDSs), the evolution of risk for disease progression or death has not been systematically investigated despite being crucial for correct interpretation of prognostic risk scores. In a multicenter retrospective study, we described changes in risk over time, the consequences for basal prognostic scores, and their potential clinical implications. Major MDS prognostic risk scoring systems and their constituent individual predictors were analyzed in 7212 primary untreated MDS patients from the International Working Group for Prognosis in MDS database. Changes in risk of mortality and of leukemic transformation over time from diagnosis were described. Hazards regarding mortality and acute myeloid leukemia transformation diminished over time from diagnosis in higher-risk MDS patients, whereas they remained stable in lower-risk patients. After approximately 3.5 years, hazards in the separate risk groups became similar and were essentially equivalent after 5 years. This fact led to loss of prognostic power of different scoring systems considered, which was more pronounced for survival. Inclusion of age resulted in increased initial prognostic power for survival and less attenuation in hazards. If needed for practicability in clinical management, the differing development of risks suggested a reasonable division into lower- and higher-risk MDS based on the IPSS-R at a cutoff of 3.5 points. Our data regarding time-dependent performance of prognostic scores reflect the disparate change of risks in MDS subpopulations. Lower-risk patients at diagnosis remain lower risk whereas initially high-risk patients demonstrate decreasing risk over time. This change of risk should be considered in clinical decision making. © 2016 by The American Society of Hematology.

  17. Overall survival in lower IPSS risk MDS by receipt of iron chelation therapy, adjusting for patient-related factors and measuring from time of first red blood cell transfusion dependence: an MDS-CAN analysis.

    Science.gov (United States)

    Leitch, Heather A; Parmar, Ambica; Wells, Richard A; Chodirker, Lisa; Zhu, Nancy; Nevill, Thomas J; Yee, Karen W L; Leber, Brian; Keating, Mary-Margaret; Sabloff, Mitchell; St Hilaire, Eve; Kumar, Rajat; Delage, Robert; Geddes, Michelle; Storring, John M; Kew, Andrea; Shamy, April; Elemary, Mohamed; Lenis, Martha; Mamedov, Alexandre; Ivo, Jessica; Francis, Janika; Zhang, Liying; Buckstein, Rena

    2017-10-01

    Analyses suggest iron overload in red blood cell (RBC) transfusion-dependent (TD) patients with myleodysplastic syndrome (MDS) portends inferior overall survival (OS) that is attenuated by iron chelation therapy (ICT) but may be biassed by unbalanced patient-related factors. The Canadian MDS Registry prospectively measures frailty, comorbidity and disability. We analysed OS by receipt of ICT, adjusting for these patient-related factors. TD International Prognostic Scoring System (IPSS) low and intermediate-1 risk MDS, at RBC TD, were included. Predictive factors for OS were determined. A matched pair analysis considering age, revised IPSS, TD severity, time from MDS diagnosis to TD, and receipt of disease-modifying agents was conducted. Of 239 patients, 83 received ICT; frailty, comorbidity and disability did not differ from non-ICT patients. Median OS from TD was superior in ICT patients (5·2 vs. 2·1 years; P MDS, adjusting for age, frailty, comorbidity, disability, revised IPSS, TD severity, time to TD and receiving disease-modifying agents. This provides additional evidence that ICT may confer clinical benefit. © 2017 John Wiley & Sons Ltd.

  18. [SUCLA2-related encephalomyopathic mitochondrial DNA depletion syndrome: a case report and review of literature].

    Science.gov (United States)

    Liu, Zhimei; Fang, Fang; Ding, Changhong; Wu, Husheng; Lyu, Junlan; Wu, Yun

    2014-11-01

    To analyze the clinical characteristics of SUCLA2-related encephalomyopathic mitochondrial DNA depletion syndrome (MDS) in one patient, and review the latest clinical research reports. Clinical, laboratory and genetic data of one case of SUCLA2-related encephalomyopathic MDS diagnosed by department of Neurology, Beijing Children's Hospital in November, 2013 were reported, and through taking "SUCLA2" as key words to search at CNKI, Wanfang, PubMed and the Human Gene Mutation Database (HGMD) professional to date, the clinical characteristics of 24 reported cases of SUCLA2-related encephalomyopathic MDS in international literature in combination with our case were analyzed. (1) The patient was 5 years and 9 months old, born as a term small for gestational age infant whose birth weight was 2 400 g, and presented since birth with severe muscular hypotonia, feeding difficulties, failure to thrive, psychomotor retardation and hearing impairment. Until now, he still showed severe developmental retardation, together with muscular atrophy, thoracocyllosis and scoliosis, and facial features. The patient is the first born from consanguineous healthy parents, whose relationship is cousins. Laboratory tests showed urinary excretion of mild methylmalonic acid (MMA), elevated plasma lactate concentration, and increased C3-carnitine and C4-dicarboxylic-carnitine in plasma carnitine ester profiling. MRI showed brain atrophy-like and bilateral T2 hyperintensities in bilateral caudate nuclei and putamen. By Next-Generation Sequencing (NGS), we identified a novel homozygous missense mutation (c.970G > A) in the SUCLA2 in a highly conserved amino acid residue. (2) The total number was only 25 with a male to female ratio of 14: 11, and age of onset of 23 was 0-4 months. The most common clinical features in patients with SUCLA2 mutation were permanent hypotonia, muscle atrophy, psychomotor retardation and scoliosis or kyphosis. Frequent signs included hearing impairment, hyperkinesia

  19. Increased separase activity and occurrence of centrosome aberrations concur with transformation of MDS.

    Science.gov (United States)

    Ruppenthal, Sabrina; Kleiner, Helga; Nolte, Florian; Fabarius, Alice; Hofmann, Wolf-Karsten; Nowak, Daniel; Seifarth, Wolfgang

    2018-01-01

    ESPL1/separase, a cysteine endopeptidase, is a key player in centrosome duplication and mitotic sister chromatid separation. Aberrant expression and/or altered separase proteolytic activity are associated with centrosome amplification, aneuploidy, tumorigenesis and disease progression. Since centrosome alterations are a common and early detectable feature in patients with myelodysplastic syndrome (MDS) and cytogenetic aberrations play an important role in disease risk stratification, we examined separase activity on single cell level in 67 bone marrow samples obtained from patients with MDS, secondary acute myeloid leukemia (sAML), de novo acute myeloid leukemia (AML) and healthy controls by a flow cytometric separase activity assay. The separase activity distribution (SAD) value, a calculated measure for the occurrence of cells with prominent separase activity within the analyzed sample, was tested for correlation with the centrosome, karyotype and gene mutation status. We found higher SAD values in bone marrow cells of sAML patients than in corresponding cells of MDS patients. This concurred with an increased incidence of aberrant centrosome phenotypes in sAML vs. MDS samples. No correlation was found between SAD values and the karyotype/gene mutation status. During follow-up of four MDS patients we observed increasing SAD values after transformation to sAML, in two patients SAD values decreased during azacitidine therapy. Cell culture experiments employing MDS-L cells as an in vitro model of MDS revealed that treatment with rigosertib, a PLK1 inhibitor and therapeutic drug known to induce G2/M arrest, results in decreased SAD values. In conclusion, the appearance of cells with unusual high separase activity levels, as indicated by increased SAD values, concurs with the transformation of MDS to sAML and may reflect separase dysregulation potentially contributing to clonal evolution during MDS progression. Separase activity measurement may therefore be useful as a

  20. Age-related inflammatory bone marrow microenvironment induces ineffective erythropoiesis mimicking del(5q) MDS.

    Science.gov (United States)

    Mei, Y; Zhao, B; Basiorka, A A; Yang, J; Cao, L; Zhang, J; List, A; Ji, P

    2018-04-01

    Anemia is characteristic of myelodysplastic syndromes (MDS). The mechanisms of anemia in MDS are unclear. Using a mouse genetic approach, here we show that dual deficiency of mDia1 and miR-146a, encoded on chromosome 5q and commonly deleted in MDS (del(5q) MDS), causes an age-related anemia and ineffective erythropoiesis mimicking human MDS. We demonstrate that the ageing bone marrow microenvironment is important for the development of ineffective erythropoiesis in these mice. Damage-associated molecular pattern molecules (DAMPs), whose levels increase in ageing bone marrow, induced TNFα and IL-6 upregulation in myeloid-derived suppressor cells (MDSCs) in mDia1/miR-146a double knockout mice. Mechanistically, we reveal that pathologic levels of TNFα and IL-6 inhibit erythroid colony formation and differentially affect terminal erythropoiesis through reactive oxygen species-induced caspase-3 activation and apoptosis. Treatment of the mDia1/miR-146a double knockout mice with all-trans retinoic acid, which promoted the differentiation of MDSCs and ameliorated the inflammatory bone marrow microenvironment, significantly rescued anemia and ineffective erythropoiesis. Our study underscores the dual roles of the ageing microenvironment and genetic abnormalities in the pathogenesis of ineffective erythropoiesis in del(5q) MDS.

  1. MDS shows a higher expression of hTERT and alternative splice variants in unactivated T-cells.

    Science.gov (United States)

    Dong, Wen; Wu, Lei; Sun, Houfang; Ren, Xiubao; Epling-Burnette, Pearlie K; Yang, Lili

    2016-11-01

    Telomere instability and telomerase reactivation are believed to play an important role in the development of myelodysplastic syndromes (MDS). Abnormal enzymatic activity of human telomerase reverse transcriptase (hTERT), and its alternative splice variants have been reported to account for deregulated telomerase function in many cancers. In this study, we aim to compare the differences in expression of hTERT and hTERT splice variants, as well as telomere length and telomerase activity in unstimulated T-cells between MDS subgroups and healthy controls. Telomere length in MDS cases was significantly shorter than controls (n = 20, pMDS using World Health Organization classification (WHO subgroups versus control: RARS, p= 0.009; RCMD, p=0.0002; RAEB1/2, p=0.004, respectively) and the International Prognostic Scoring System (IPSS subgroups: Low+Int-1, pMDS patients (n=20) had significantly higher telomerase activity (p=0.002), higher total hTERT mRNA levels (p=0.001) and hTERT α+β- splice variant expression (pMDS (r=0.58, p=0.007). This data is in sharp contrast to data published previously by our group showing a reduction in telomerase and hTERT mRNA in MDS T-cells after activation. In conclusion, this study provides additional insight into hTERT transcript patterns and activity in peripheral T-cells of MDS patients. Additional studies are necessary to better understand the role of this pathway in MDS development and progression.

  2. GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways.

    Science.gov (United States)

    Guerenne, Laura; Beurlet, Stéphanie; Said, Mohamed; Gorombei, Petra; Le Pogam, Carole; Guidez, Fabien; de la Grange, Pierre; Omidvar, Nader; Vanneaux, Valérie; Mills, Ken; Mufti, Ghulam J; Sarda-Mantel, Laure; Noguera, Maria Elena; Pla, Marika; Fenaux, Pierre; Padua, Rose Ann; Chomienne, Christine; Krief, Patricia

    2016-01-27

    In spite of the recent discovery of genetic mutations in most myelodysplasic (MDS) patients, the pathophysiology of these disorders still remains poorly understood, and only few in vivo models are available to help unravel the disease. We performed global specific gene expression profiling and functional pathway analysis in purified Sca1+ cells of two MDS transgenic mouse models that mimic human high-risk MDS (HR-MDS) and acute myeloid leukemia (AML) post MDS, with NRASD12 and BCL2 transgenes under the control of different promoters MRP8NRASD12/tethBCL-2 or MRP8[NRASD12/hBCL-2], respectively. Analysis of dysregulated genes that were unique to the diseased HR-MDS and AML post MDS mice and not their founder mice pointed first to pathways that had previously been reported in MDS patients, including DNA replication/damage/repair, cell cycle, apoptosis, immune responses, and canonical Wnt pathways, further validating these models at the gene expression level. Interestingly, pathways not previously reported in MDS were discovered. These included dysregulated genes of noncanonical Wnt pathways and energy and lipid metabolisms. These dysregulated genes were not only confirmed in a different independent set of BM and spleen Sca1+ cells from the MDS mice but also in MDS CD34+ BM patient samples. These two MDS models may thus provide useful preclinical models to target pathways previously identified in MDS patients and to unravel novel pathways highlighted by this study.

  3. An Exercise in Extrapolation: Clinical Management of Atypical CML, MDS/MPN-Unclassifiable, and MDS/MPN-RS-T.

    Science.gov (United States)

    Talati, Chetasi; Padron, Eric

    2016-12-01

    According to the recently published 2016 World Health Organization (WHO) classification of myeloid malignancies, myelodysplastic/myeloproliferative neoplasms (MDS/MPN) include atypical chronic myeloid leukemia (aCML), MDS/MPN-unclassifiable (MDS/MPN-U), chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), and MDS/MPN ring sideroblasts with thrombocytosis (MDS/MPN-RS-T). MDS/MPN-RS-T was previously a provisional category known as refractory anemia with ring sideroblasts with thrombocytosis (RARS-T) which has now attained a distinct designation in the 2016 WHO classification. In this review, we focus on biology and management of aCML, MDS/MPN-U, and MDS/MPN-RS-T. There is considerable overlap between these entities which we attempt to further elucidate in this review. We also discuss recent advances in the field of molecular landscape that further defines and characterizes this heterogeneous group of disorders. The paucity of clinical trials available secondary to unclear pathogenesis and rarity of these diseases makes the management of these entities clinically challenging. This review summarizes some of the current knowledge of the molecular pathogenesis and suggested treatment guidelines based on the available data.

  4. GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways

    Directory of Open Access Journals (Sweden)

    Laura Guerenne

    2016-01-01

    Full Text Available Abstract Background In spite of the recent discovery of genetic mutations in most myelodysplasic (MDS patients, the pathophysiology of these disorders still remains poorly understood, and only few in vivo models are available to help unravel the disease. Methods We performed global specific gene expression profiling and functional pathway analysis in purified Sca1+ cells of two MDS transgenic mouse models that mimic human high-risk MDS (HR-MDS and acute myeloid leukemia (AML post MDS, with NRASD12 and BCL2 transgenes under the control of different promoters MRP8NRASD12/tethBCL-2 or MRP8[NRASD12/hBCL-2], respectively. Results Analysis of dysregulated genes that were unique to the diseased HR-MDS and AML post MDS mice and not their founder mice pointed first to pathways that had previously been reported in MDS patients, including DNA replication/damage/repair, cell cycle, apoptosis, immune responses, and canonical Wnt pathways, further validating these models at the gene expression level. Interestingly, pathways not previously reported in MDS were discovered. These included dysregulated genes of noncanonical Wnt pathways and energy and lipid metabolisms. These dysregulated genes were not only confirmed in a different independent set of BM and spleen Sca1+ cells from the MDS mice but also in MDS CD34+ BM patient samples. Conclusions These two MDS models may thus provide useful preclinical models to target pathways previously identified in MDS patients and to unravel novel pathways highlighted by this study.

  5. Spliceosomal gene aberrations are rare, coexist with oncogenic mutations, and are unlikely to exert a driver effect in childhood MDS and JMML

    NARCIS (Netherlands)

    S. Hirabayashi (Shinsuke); C. Flotho (Christian); J. Moetter (Jessica); M. Heuser (Michael); H. Hasle (Henrik); B. Gruhn (Bernd); T. Klingebiel (Thomas); F. Thol (Felicitas); B. Schlegelberger (Brigitte); I. Baumann (Irith); B. Strahm (Brigitte); J. Stary (Jan); F. Locatelli (Franco); M. Zecca (Marco); E. Bergstraesser (Eva); M.N. Dworzak (Michael); M.M. van den Heuvel-Eibrink (Marry); B. de Moerloose (Barbara); S. Ogawa (Susumu); C.M. Niemeyer (Charlotte); M. Wlodarski (Marcin)

    2012-01-01

    textabstractSomatic mutations of the spliceosomal machinery occur frequently in adult patients with myelodysplastic syndrome (MDS). We resequenced SF3B1, U2AF35, and SRSF2 in 371 children with MDS or juvenile myelomonocytic leukemia. We found missense mutations in 2 juvenile myelomonocytic leukemia

  6. Hypotéza o MDS kódech

    OpenAIRE

    Kesely, Michal

    2010-01-01

    In this thesis, we study some properties of MDS codes and we mainly focus on the MDS codes conjecture. In the first chapter we define MDS codes, show some examples and basic properties of MDS codes, for example a link between MDS codes and Latin squares or rectangles. Afterwards we state the MDS codes conjecture and prove it in several cases. In the third chapter we can observe the relationship between MDS codes and narcs in projective geometries. Finally we present those known cases, for whi...

  7. IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells.

    Science.gov (United States)

    Schinke, Carolina; Giricz, Orsolya; Li, Weijuan; Shastri, Aditi; Gordon, Shanisha; Barreyro, Laura; Barreryo, Laura; Bhagat, Tushar; Bhattacharyya, Sanchari; Ramachandra, Nandini; Bartenstein, Matthias; Pellagatti, Andrea; Boultwood, Jacqueline; Wickrema, Amittha; Yu, Yiting; Will, Britta; Wei, Sheng; Steidl, Ulrich; Verma, Amit

    2015-05-14

    Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Novel therapeutic targets against preleukemic stem cells need to be identified for potentially curative strategies. We conducted parallel transcriptional analysis of highly fractionated stem and progenitor populations in MDS, AML, and control samples and found interleukin 8 (IL8) to be consistently overexpressed in patient samples. The receptor for IL8, CXCR2, was also significantly increased in MDS CD34(+) cells from a large clinical cohort and was predictive of increased transfusion dependence. High CXCR2 expression was also an adverse prognostic factor in The Cancer Genome Atlas AML cohort, further pointing to the critical role of the IL8-CXCR2 axis in AML/MDS. Functionally, CXCR2 inhibition by knockdown and pharmacologic approaches led to a significant reduction in proliferation in several leukemic cell lines and primary MDS/AML samples via induction of G0/G1 cell cycle arrest. Importantly, inhibition of CXCR2 selectively inhibited immature hematopoietic stem cells from MDS/AML samples without an effect on healthy controls. CXCR2 knockdown also impaired leukemic growth in vivo. Together, these studies demonstrate that the IL8 receptor CXCR2 is an adverse prognostic factor in MDS/AML and is a potential therapeutic target against immature leukemic stem cell-enriched cell fractions in MDS and AML. © 2015 by The American Society of Hematology.

  8. Strongly-MDS convolutional codes

    NARCIS (Netherlands)

    Gluesing-Luerssen, H; Rosenthal, J; Smarandache, R

    Maximum-distance separable (MDS) convolutional codes have the property that their free distance is maximal among all codes of the same rate and the same degree. In this paper, a class of MDS convolutional codes is introduced whose column distances reach the generalized Singleton bound at the

  9. Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS

    DEFF Research Database (Denmark)

    Holm, Mette; Dybedahl, I; Holm, Mette

    2014-01-01

    This prospective phase II study evaluated the efficacy of azacitidine (Aza)+erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo+granulocyte colony stimulation factors for >8 weeks and a trans...... patients, but efficacy is limited, toxicity substantial and most responses of short duration. This treatment cannot be generally recommended in lower-risk MDS. Mutational screening revealed a high frequency of mutations....

  10. Th17 Cells Exhibit Antitumor Effects in MDS Possibly through Augmenting Functions of CD8+ T Cells.

    Science.gov (United States)

    Li, Jing; Yue, Lanzhu; Wang, Huaquan; Liu, Chunyan; Liu, Hui; Tao, Jinglian; Qi, Weiwei; Wang, Yihao; Zhang, Wei; Fu, Rong; Shao, Zonghong

    2016-01-01

    Th17 cells are a newly found subset of distinct CD4+ Th effector cells' family and are found to play an important role in cancers. Myelodysplastic syndromes (MDS) are a common malignant hematological disease. Here, we showed that both the percentage and the function of Th17 cells were elevated in low-risk MDS while being decreased in high-risk MDS. Levels of upstream molecules of Th17 cells, IL-6 and IL-23, were higher in low-risk MDS but lower in high-risk MDS patients. The abnormal percentage of Th17 cells was closely related to clinical parameters including karyotype, morphologic blast percentage of bone marrow, peripheral absolute neutrophil count, and hemoglobin concentration. Furthermore, expression rates of perforin and granzyme B in BM CD3+CD8+ cells (cytotoxic T lymphocyte, CTL) positively correlated with levels of IL-17 but negatively correlated with BM blast percentage and could be significantly increased after stimulation with human recombinant IL-17 (rhIL-17). Our results suggested that Th17 cells might play an antitumor effect in the pathogenesis of MDS through IL-17/CTL pathway.

  11. Electrolyte depletion in white-nose syndrome bats.

    Science.gov (United States)

    Cryan, Paul M; Meteyer, Carol Uphoff; Blehert, David S; Lorch, Jeffrey M; Reeder, DeeAnn M; Turner, Gregory G; Webb, Julie; Behr, Melissa; Verant, Michelle; Russell, Robin E; Castle, Kevin T

    2013-04-01

    The emerging wildlife disease white-nose syndrome is causing widespread mortality in hibernating North American bats. White-nose syndrome occurs when the fungus Geomyces destructans infects the living skin of bats during hibernation, but links between infection and mortality are underexplored. We analyzed blood from hibernating bats and compared blood electrolyte levels to wing damage caused by the fungus. Sodium and chloride tended to decrease as wing damage increased in severity. Depletion of these electrolytes suggests that infected bats may become hypotonically dehydrated during winter. Although bats regularly arouse from hibernation to drink during winter, water available in hibernacula may not contain sufficient electrolytes to offset winter losses caused by disease. Damage to bat wings from G. destructans may cause life-threatening electrolyte imbalances.

  12. Electrolyte depletion in white-nose syndrome bats

    Science.gov (United States)

    Cryan, Paul M.; Meteyer, Carol Uphoff; Blehert, David S.; Lorch, Jeffrey M.; Reeder, DeeAnn M.; Turner, Gregory G.; Webb, Julie; Behr, Melissa; Verant, Michelle L.; Russell, Robin E.; Castle, Kevin T.

    2013-01-01

    The emerging wildlife disease white-nose syndrome is causing widespread mortality in hibernating North American bats. White-nose syndrome occurs when the fungus Geomyces destructans infects the living skin of bats during hibernation, but links between infection and mortality are underexplored. We analyzed blood from hibernating bats and compared blood electrolyte levels to wing damage caused by the fungus. Sodium and chloride tended to decrease as wing damage increased in severity. Depletion of these electrolytes suggests that infected bats may become hypotonically dehydrated during winter. Although bats regularly arouse from hibernation to drink during winter, water available in hibernacula may not contain sufficient electrolytes to offset winter losses caused by disease. Damage to bat wings from G. destructans may cause life-threatening electrolyte imbalances.

  13. MDS MIC Catalog Inputs

    Science.gov (United States)

    Johnson-Throop, Kathy A.; Vowell, C. W.; Smith, Byron; Darcy, Jeannette

    2006-01-01

    This viewgraph presentation reviews the inputs to the MDS Medical Information Communique (MIC) catalog. The purpose of the group is to provide input for updating the MDS MIC Catalog and to request that MMOP assign Action Item to other working groups and FSs to support the MITWG Process for developing MIC-DDs.

  14. MDS 3.0 Frequency Report

    Data.gov (United States)

    U.S. Department of Health & Human Services — The MDS 3.0 Frequency Report summarizes information for active residents currently in nursing homes. The source of these counts is the residents MDS assessment...

  15. Differential response to hypomethylating agents based on sex: a report on behalf of the MDS Clinical Research Consortium (MDS CRC).

    Science.gov (United States)

    DeZern, Amy E; Zeidan, Amer M; Barnard, John; Hand, Wesley; Al Ali, Najla; Brown, Francis; Zimmerman, Cassie; Roboz, Gail J; Garcia-Manero, Guillermo; Steensma, David P; Komrokji, Rami S; Sekeres, Mikkael A

    2017-06-01

    First-line therapy for higher-risk myelodysplastic syndromes (MDS) includes decitabine (DAC) or azacitidine (AZA). Variables have not identified differential response rates between these. We assessed the influence of patient sex on outcomes including overall survival (OS) in 642 patients with higher-risk MDS treated with AZA or DAC. DAC-treated patients (35% of females, 31% of males) had marginally better OS than AZA-treated patients (p = .043), (median OS of 18.7 months versus 16.4 months), but the difference varied strongly by sex. Female patients treated with DAC had a longer median OS (21.1 months, 95% CI: 16.0-28.0) than female patients treated with AZA (13.2 months, 95% CI: 11.0-15.9; p = .0014), while for males there was no significant difference between HMAs (median OS 18.3 months with DAC versus 17.9 months for AZA, p = .59). The biological reason for this variability is unclear, but may be a consequence of differences in cytidine deaminase activity between men and women.

  16. Focal Adhesion Kinase as a Potential Target in AML and MDS.

    Science.gov (United States)

    Carter, Bing Z; Mak, Po Yee; Wang, Xiangmeng; Yang, Hui; Garcia-Manero, Guillermo; Mak, Duncan H; Mu, Hong; Ruvolo, Vivian R; Qiu, Yihua; Coombes, Kevin; Zhang, Nianxiang; Ragon, Brittany; Weaver, David T; Pachter, Jonathan A; Kornblau, Steven; Andreeff, Michael

    2017-06-01

    Although overexpression/activation of focal adhesion kinase (FAK) is widely known in solid tumors to control cell growth, survival, invasion, metastasis, gene expression, and stem cell self-renewal, its expression and function in myeloid leukemia are not well investigated. Using reverse-phase protein arrays in large cohorts of newly diagnosed acute myeloid leukemia (AML) and myeloid dysplastic syndrome (MDS) samples, we found that high FAK expression was associated with unfavorable cytogenetics ( P = 2 × 10 -4 ) and relapse ( P = 0.02) in AML. FAK expression was significantly lower in patients with FLT3 -ITD ( P = 0.0024) or RAS ( P = 0.05) mutations and strongly correlated with p-SRC and integrinβ3 levels. FAK protein levels were significantly higher in CD34 + ( P = 5.42 × 10 -20 ) and CD34 + CD38 - MDS ( P = 7.62 × 10 -9 ) cells compared with normal CD34 + cells. MDS patients with higher FAK in CD34 + cells tended to have better overall survival ( P = 0.05). FAK expression was significantly higher in MDS patients who later transformed to compared with those who did not transform to AML and in AML patients who transformed from MDS compared with those with de novo AML. Coculture with mesenchymal stromal cells (MSC) increased FAK expression in AML cells. Inhibition of FAK decreased MSC-mediated adhesion/migration and viability of AML cells and prolonged survival in an AML xenograft murine model. Our results suggest that FAK regulates leukemia-stromal interactions and supports leukemia cell survival; hence, FAK is a potential therapeutic target in myeloid leukemia. Mol Cancer Ther; 16(6); 1133-44. ©2017 AACR . ©2017 American Association for Cancer Research.

  17. The emerging role of immune checkpoint based approaches in AML and MDS.

    Science.gov (United States)

    Boddu, Prajwal; Kantarjian, Hagop; Garcia-Manero, Guillermo; Allison, James; Sharma, Padmanee; Daver, Naval

    2018-04-01

    The development of immune checkpoint inhibitors represents a major breakthrough in the field of cancer therapeutics. Pursuant to their success in melanoma and numerous solid tumor malignancies, these agents are being investigated in hematological malignancies including acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). Although AML/MDS have traditionally been considered to be less immunogenic than solid tumor malignancies, recent pre-clinical models suggest a therapeutic role for immune checkpoint inhibition in these diseases. CTLA-4 inhibition may be especially effective in treating late post-allogeneic stem cell transplant relapse of AML in patients with limited or no graft versus host disease. Immune checkpoint inhibition, specifically PD-1 inhibition, demonstrated limited single agent efficacy in patients with relapsed AML and with MDS post-hypomethylating therapy. Rationally designed combinations of PD-1 inhibitors with standard anti-leukemic therapy are needed. Hypomethylating agents such as azacitidine, up-regulate PD-1, PD-L1, and PD-L2 in patients with AML/MDS and up-regulation of these genes was associated with the emergence of resistance. The combination of azacitidine and PD-1/PD-L1 inhibition may be a potential mechanism to prevent or overcome resistance to 5-azacitidine. A number of such combinations are being evaluated in clinical trials with early encouraging results. Immune checkpoint inhibition is also an attractive option to improve relapse-free survival or eliminate minimal residual disease post induction and consolidation by enhancing T-cell surveillance in patients with high-risk AML. The ongoing clinical trials with checkpoint inhibitors in AML/MDS will improve our understanding of the immunobiology of these diseases and guide us to the most appropriate application of these agents in the therapy of AML/MDS.

  18. Downregulation but lack of promoter hypermethylation or somatic mutations of the potential tumor suppressor CXXC5 in MDS and AML with deletion 5q

    DEFF Research Database (Denmark)

    Treppendahl, Marianne Bach; Möllgård, L; Hellström-Lindberg, E

    2013-01-01

    During recent years mutations in epigenetic modulators have been identified in several human cancers, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)[1]. CXXC5 has been found to be necessary for retinoic acid induced differentiation of myelocytic leukemia cells, identify......During recent years mutations in epigenetic modulators have been identified in several human cancers, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)[1]. CXXC5 has been found to be necessary for retinoic acid induced differentiation of myelocytic leukemia cells...

  19. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance.

    Science.gov (United States)

    Kwok, Brian; Hall, Jeff M; Witte, John S; Xu, Yin; Reddy, Prashanti; Lin, Keming; Flamholz, Rachel; Dabbas, Bashar; Yung, Aine; Al-Hafidh, Jenan; Balmert, Emily; Vaupel, Christine; El Hader, Carlos; McGinniss, Matthew J; Nahas, Shareef A; Kines, Julie; Bejar, Rafael

    2015-11-19

    Establishing a diagnosis in patients suspected of having a myelodysplastic syndrome (MDS) can be challenging and could be informed by the identification of somatic mutations. We performed a prospective study to examine the frequency and types of mutations encountered in 144 patients with unexplained cytopenias. Based on bone marrow findings, 17% were diagnosed with MDS, 15% with idiopathic cytopenias of undetermined significance (ICUS) and some evidence of dysplasia, and 69% with ICUS and no dysplasia. Bone marrow DNA was sequenced for mutations in 22 frequently mutated myeloid malignancy genes. Somatic mutations were identified in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients and no dysplasia. In total, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis. We validated these results in a cohort of 91 lower-risk MDS and 249 ICUS cases identified over a 6-month interval. Mutations were found in 79% of those with MDS, in 45% of those with ICUS with dysplasia, and in 17% of those with ICUS without dysplasia. The spectrum of mutated genes was similar with the exception of SF3B1 which was rarely mutated in patients without dysplasia. Variant allele fractions were comparable between clonal ICUS (CCUS) and MDS as were mean age and blood counts. We demonstrate that CCUS is a more frequent diagnosis than MDS in cytopenic patients. Clinical and mutational features are similar in these groups and may have diagnostic utility once outcomes in CCUS patients are better understood. © 2015 by The American Society of Hematology.

  20. Telomere dynamics in patients with del (5q) MDS before and under treatment with lenalidomide.

    Science.gov (United States)

    Beier, Fabian; Masouleh, Behzad Kharabi; Buesche, Guntram; Ventura Ferreira, Monica S; Schneider, Rebekka K; Ziegler, Patrick; Wilop, Stefan; Vankann, Lucia; Gattermann, Norbert; Platzbecker, Uwe; Giagounidis, Aristoteles; Götze, Katharina S; Nolte, Florian; Hofmann, Wolf-Karsten; Haase, Detlef; Kreipe, Hans; Panse, Jens; Blasco, Maria A; Germing, Ulrich; Brümmendorf, Tim H

    2015-09-21

    Myelodysplastic syndrome (MDS) associated with an acquired, isolated deletion of chromosome 5q (del (5q) MDS), represent a clonal disorder of hematopoiesis and a clinically distinct entity of MDS. Treatment of del (5q) MDS with the drug lenalidomide has significantly improved quality of life leading to transfusion independence and complete cytogenetic response rates (CCR) in the majority of patients. Telomeres are located at the end of eukaryotic chromosomes and are linked to replicative history/potential as well as genetic (in) stability of hematopoietic stem cells. Here, we analyzed telomere length (TL) dynamics before and under lenalidomide treatment in the peripheral blood and/or bone marrow of del (5q) patients enrolled in the LEMON-5 study (NCT01081431). Hematopoietic cells from del (5q) MDS patients were characterized by significantly shortened TL compared to age-matched healthy controls. Telomere loss was more accelerated in patients with longer disease duration (>2 years) and more pronounced cytopenias. Sequential analysis under lenalidomide treatment revealed that previously shortened TL in peripheral blood cells was significantly "elongated" towards normal levels within the first six months suggesting a shift from clonal del (5q) cells towards normal hematopoiesis in lenalidomide treated MDS patients. Taken together our findings suggest that the development of the del (5q) clone is associated with accelerated telomere shortening at diagnosis. However, upon induction of CCR and reoccurrence of normal hematopoiesis, the lack of a persistent TL deficit argues against telomere-mediated genetic instability neither as a disease-promoting event of del (5q) MDS nor for lenalidomide mediated development of secondary primary malignancies of the hematopoietic system in responding patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Depletion of cytotoxic T-cells does not protect NUP98-HOXD13 mice from myelodysplastic syndrome but reveals a modest tumor immunosurveillance effect.

    Directory of Open Access Journals (Sweden)

    Sheryl M Gough

    Full Text Available Myelodysplastic syndrome (MDS and aplastic anemia (AA patients both present with symptoms of bone marrow failure. In many AA patients, these features are thought to result from an oligoclonal expansion of cytotoxic T-cells that destroy haematopoietic stem or progenitor cells. This notion is supported by the observation that AA patients respond to immunosuppressive therapy. A fraction of MDS patients also respond well to immunosuppressive therapy suggesting a similar role for cytotoxic T-cells in the etiology of MDS, however the role of cytotoxic T-cells in MDS remains unclear. Mice that express a NUP98-HOXD13 (NHD13 transgene develop a MDS that closely mimics the human condition in terms of dysplasia, ineffective hematopoiesis, and transformation to acute myeloid leukemia (AML. We followed a cohort of NHD13 mice lacking the Rag1 protein (NHD13/Rag1KO to determine if the absence of lymphocytes might 1 delay the onset and/or diminish the severity of the MDS, or 2 effect malignant transformation and survival of the NHD13 mice. No difference was seen in the onset or severity of MDS between the NHD13 and NHD13/Rag1KO mice. However, NHD13/Rag1KO mice had decreased survival and showed a trend toward increased incidence of transformation to AML compared to the NHD13 mice, suggesting protection from AML transformation by a modest immuno-surveillance effect. In the absence of functional Tcrb signaling in the NHD13/Rag1KO T-cell tumors, Pak7 was identified as a potential Tcrb surrogate survival signal.

  2. MECP2 Duplication Syndrome

    DEFF Research Database (Denmark)

    Signorini, Cinzia; De Felice, Claudio; Leoncini, Silvia

    2016-01-01

    Rett syndrome (RTT) and MECP2 duplication syndrome (MDS) are neurodevelopmental disorders caused by alterations in the methyl-CpG binding protein 2 (MECP2) gene expression. A relationship between MECP2 loss-of-function mutations and oxidative stress has been previously documented in RTT patients...... and murine models. To date, no data on oxidative stress have been reported for the MECP2 gain-of-function mutations in patients with MDS. In the present work, the pro-oxidant status and oxidative fatty acid damage in MDS was investigated (subjects n = 6) and compared to RTT (subjects n = 24) and healthy...... similar to those observed in RTT patients except for higher plasma F2-isoprostanes levels (P work shows unique data in patients affected by MDS. For the first...

  3. Survey of expert opinions and related recommendations regarding bridging therapy using hypomethylating agents followed by allogeneic transplantation for high-risk MDS.

    Science.gov (United States)

    Sohn, Sang Kyun; Moon, Joon Ho

    2015-08-01

    According to current guidelines on therapeutic strategies for myelodysplastic syndrome (MDS), cytoreductive therapies before allogeneic stem cell transplantation (SCT) are not widely recommended for patients with high-risk MDS or refractory anemia with excess blasts (RAEB) who are eligible for allogeneic SCT because of controversial evidence on the role of such therapies. Yet, while treatment with hypomethylating agents (HMAs) has a critical limitation in eradicating MDS clones, the use of HMA treatment as a bridge to allogeneic SCT has become a focus with the hope of improving the SCT outcome based on the chance of achieving complete remission or reducing the blast percentage safely and effectively before allogeneic SCT. However, a consensus needs to be established on the use of HMAs as a bridging therapy for high-risk MDS or RAEB. Thus, the Korean AML/MDS working party group surveyed 34 Korean MDS experts on their bridging therapies for high-risk MDS. Accordingly, this paper presents the survey questionnaire and resulting data, along with a summary of the consensus and related recommendations regarding strategies using HMA treatment and allogeneic SCT based on reported studies and the current survey results. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. EVI and MDS/EVI are required for adult intestinal stem cell formation during postembryonic vertebrate development.

    Science.gov (United States)

    Okada, Morihiro; Shi, Yun-Bo

    2018-01-01

    The gene ectopic viral integration site 1 (EVI) and its variant myelodysplastic syndrome 1 (MDS)/EVI encode zinc-finger proteins that have been recognized as important oncogenes in various types of cancer. In contrast to the established role of EVI and MDS/EVI in cancer development, their potential function during vertebrate postembryonic development, especially in organ-specific adult stem cells, is unclear. Amphibian metamorphosis is strikingly similar to postembryonic development around birth in mammals, with both processes taking place when plasma thyroid hormone (T3) levels are high. Using the T3-dependent metamorphosis in Xenopus tropicalis as a model, we show here that high levels of EVI and MDS/EVI are expressed in the intestine at the climax of metamorphosis and are induced by T3. By using the transcription activator-like effector nuclease gene editing technology, we have knocked out both EVI and MDS/EVI and have shown that EVI and MDS/EVI are not essential for embryogenesis and premetamorphosis in X. tropicalis On the other hand, knocking out EVI and MDS/EVI causes severe retardation in the growth and development of the tadpoles during metamorphosis and leads to tadpole lethality at the climax of metamorphosis. Furthermore, the homozygous-knockout animals have reduced adult intestinal epithelial stem cell proliferation at the end of metamorphosis (for the few that survive through metamorphosis) or during T3-induced metamorphosis. These findings reveal a novel role of EVI and/or MDS/EVI in regulating the formation and/or proliferation of adult intestinal adult stem cells during postembryonic development in vertebrates.-Okada, M., Shi, Y.-B. EVI and MDS/EVI are required for adult intestinal stem cell formation during postembryonic vertebrate development. © FASEB.

  5. CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets.

    Science.gov (United States)

    Gleason, Michelle K; Ross, Julie A; Warlick, Erica D; Lund, Troy C; Verneris, Michael R; Wiernik, Andres; Spellman, Stephen; Haagenson, Michael D; Lenvik, Alexander J; Litzow, Mark R; Epling-Burnette, Pearlie K; Blazar, Bruce R; Weiner, Louis M; Weisdorf, Daniel J; Vallera, Daniel A; Miller, Jeffrey S

    2014-05-08

    Myelodysplastic syndromes (MDS) are stem cell disorders that can progress to acute myeloid leukemia. Although hematopoietic cell transplantation can be curative, additional therapies are needed for a disease that disproportionally afflicts the elderly. We tested the ability of a CD16xCD33 BiKE to induce natural killer (NK) cell function in 67 MDS patients. Compared with age-matched normal controls, CD7(+) lymphocytes, NK cells, and CD16 expression were markedly decreased in MDS patients. Despite this, reverse antibody-dependent cell-mediated cytotoxicity assays showed potent degranulation and cytokine production when resting MDS-NK cells were triggered with an agonistic CD16 monoclonal antibody. Blood and marrow MDS-NK cells treated with bispecific killer cell engager (BiKE) significantly enhanced degranulation and tumor necrosis factor-α and interferon-γ production against HL-60 and endogenous CD33(+) MDS targets. MDS patients had a significantly increased proportion of immunosuppressive CD33(+) myeloid-derived suppressor cells (MDSCs) that negatively correlated with MDS lymphocyte populations and CD16 loss on NK cells. Treatment with the CD16xCD33 BiKE successfully reversed MDSC immunosuppression of NK cells and induced MDSC target cell lysis. Lastly, the BiKE induced optimal MDS-NK cell function irrespective of disease stage. Our data suggest that the CD16xCD33 BiKE functions against both CD33(+) MDS and MDSC targets and may be therapeutically beneficial for MDS patients.

  6. Are the MDS-UPDRS-based composite scores clinically applicable?

    Science.gov (United States)

    Makkos, Attila; Kovács, Márton; Aschermann, Zsuzsanna; Harmat, Márk; Janszky, József; Karádi, Kázmér; Kovács, Norbert

    2018-02-28

    The International Parkinson and Movement Disorder Society-sponsored UPDRS (MDS-UPDRS) is a powerful clinical outcome measure. To evaluate the feasibility of various MDS-UPDRS-based composite scores and determine their minimal clinically important difference threshold values. Overall, 1,113 paired investigations of 452 patients were reviewed implementing three different techniques simultaneously. Based on the ordinal regression modeling, the MDS-UPDRS II+III, MDS-UPDRS I+II+III, and the total score of MDS-UPDRS are clinically applicable outcome measures. Any improvement greater than 4.9 points or any worsening more than 4.2 points on MDS-UPDRS II+III represent a minimal, yet clinically meaningful, change. In reference to MDS-UPDRS I+II+III, the smallest changes considered clinically relevant were 6.7 and 5.2 points for improvement and deterioration, respectively. The thresholds for the total score of MDS-UPDRS were 7.1 points for improvement and 6.3 points for worsening. Our findings support the application of various MDS-UPDRS-based composite scores. © 2018 International Parkinson and Movement Disorder Society. © 2018 International Parkinson and Movement Disorder Society.

  7. PP2A: The Achilles Heal in MDS with 5q Deletion

    Directory of Open Access Journals (Sweden)

    David eSallman

    2014-09-01

    Full Text Available Myelodysplastic syndromes (MDS represent a hematologically diverse group of myeloid neoplasms, however, one subtype characterized by an isolated deletion of chromosome 5q (del(5q is pathologically and clinically distinct. Patients with del(5q MDS share biological features that account for the profound hypoplastic anemia and unique sensitivity to treatment with lenalidomide. Ineffective erythropoiesis in del(5q MDS arises from allelic deletion of the ribosomal processing S-14 (RPS14 gene, which leads to MDM2 sequestration with consequent p53 activation and erythroid cell death. Since its approval in 2005, lenalidomide has changed the natural course of the disease. Patients who achieve transfusion independence and/or a cytogenetic response with lenalidomide have a decreased risk of progression to AML and an improved overall survival compared to non-responders. Elucidation of the mechanisms of action of lenalidomide in del(5q MDS has advanced therapeutic strategies for this disease. The selective cytotoxicity of lenalidomide in del(5q clones derives from inhibition of a haplodeficient phosphatase whose catalytic domain is encoded within the common deleted region on chromosome 5q, i.e., protein phosphatase 2A (PP2Acα. PP2A is a highly conserved, dual specificity phosphatase that plays an essential role in regulation of the G2/M checkpoint. Inhibition of PP2Acα results in cell cycle arrest and apoptosis in del(5q cells. Targeted knockdown of PP2Acα using siRNA is sufficient to sensitize non-del(5q clones to lenalidomide. Through its inhibitory effect on PP2A, lenalidomide stabilizes MDM2 to restore p53 degradation in erythroid precursors, with subsequent arrest in G2/M. Unfortunately, the majority of patients with del(5q MDS develop resistance to lenalidomide over time associated with PP2Acα overexpression. Targeted inhibition of PP2A with a more potent inhibitor has emerged as an attractive therapeutic approach for patients with del(5q MDS.

  8. Interaction mediated by the putative tip regions of MdsA and MdsC in the formation of a Salmonella-specific tripartite efflux pump.

    Directory of Open Access Journals (Sweden)

    Saemee Song

    Full Text Available To survive in the presence of a wide range of toxic compounds, gram-negative bacteria expel such compounds via tripartite efflux pumps that span both the inner and outer membranes. The Salmonella-specific MdsAB pump consists of MdsB, a resistance-nodulation-division (RND-type inner membrane transporter (IMT that requires the membrane fusion protein (MFP MdsA, and an outer membrane protein (OMP; MdsC or TolC to form a tripartite efflux complex. In this study, we investigated the role of the putative tip regions of MdsA and its OMPs, MdsC and TolC, in the formation of a functional MdsAB-mediated efflux pump. Comparative analysis indicated that although sequence homologies of MdsA and MdsC with other MFPs and OMPs, respectively, are extremely low, key residues in the putative tip regions of these proteins are well conserved. Mutagenesis studies on these conserved sites demonstrated their importance for the physical and functional interactions required to form an MdsAB-mediated pump. Our studies suggest that, despite differences in the primary amino acid sequences and functions of various OMPs and MFPs, interactions mediated by the conserved tip regions of OMP and MFP are required for the formation of functional tripartite efflux pumps in gram-negative bacteria.

  9. Tissue-Specific Upregulation of MDS/EVI Gene Transcripts in the Intestine by Thyroid Hormone during Xenopus Metamorphosis

    Science.gov (United States)

    Hasebe, Takashi; Fu, Liezhen; Heimeier, Rachel A.; Das, Biswajit; Ishizuya-Oka, Atsuko; Shi, Yun-Bo

    2013-01-01

    Background Intestinal remodeling during amphibian metamorphosis resembles the maturation of the adult intestine during mammalian postembryonic development when the adult epithelial self-renewing system is established under the influence of high concentrations of plasma thyroid hormone (T3). This process involves de novo formation and subsequent proliferation and differentiation of the adult stem cells. Methodology/Principal Findings The T3-dependence of the formation of adult intestinal stem cell during Xenopus laevis metamorphosis offers a unique opportunity to identify genes likely important for adult organ-specific stem cell development. We have cloned and characterized the ectopic viral integration site 1 (EVI) and its variant myelodysplastic syndrome 1 (MDS)/EVI generated via transcription from the upstream MDS promoter and alternative splicing. EVI and MDS/EVI have been implicated in a number of cancers including breast, leukemia, ovarian, and intestinal cancers. We show that EVI and MDS/EVI transcripts are upregulated by T3 in the epithelium but not the rest of the intestine in Xenopus laevis when adult stem cells are forming in the epithelium. Conclusions/Significance Our results suggest that EVI and MDS/EVI are likely involved in the development and/or proliferation of newly forming adult intestinal epithelial cells. PMID:23383234

  10. Impact of azacitidine on red blood cell alloimmunisation in myelodysplastic syndrome.

    Science.gov (United States)

    Ortiz, Sebastián; Orero, Maria T; Javier, Karla; Villegas, Carolina; Luna, Irene; Pérez, Pedro; Roig, Mónica; López, María; Costa, Sofía; Carbonell, Félix; Collado, Rosa; Ivars, David; Linares, Mariano

    2017-09-01

    The incidence of alloimmunisation in myelodysplastic syndromes (MDS) during the era of supportive treatment ranges from 9 to 56%. However, it is unknown if the widespread use of hypomethylating agents has changed the risk of immunisation. The aim of this study is to evaluate the impact of azacitidine (AZA) therapy on red blood cell (RBC) alloimmunisation in transfused patients with MDS, myelodysplastic syndromes/myeloproliferative syndromes (MDS/MPS) and secondary acute myeloid leukaemia (AML). We have analysed retrospectively all patients with MDS, MDS/MPS and secondary AML from MDS, who received their first transfusion in our hospital between January 1995 and December 2014. We have assessed the impact of age, sex, RBC and platelets units transfused, and AZA treatment on developing alloantibodies. In our study, the number of RBC units transfused increased the risk of developing alloantibodies. However aging and the treatment with AZA were associated with a lower rate of alloimmunisation. Patients with MDS, MDS/MPS and secondary AML who received treatment with AZA developed RBC antibodies at a lower rate than control group. We suggest that aging and immunosuppression due to AZA therapy could develop an immunological tolerance with a weak response to allotransfusions.

  11. Rescue of TET2 Haploinsufficiency in Myelodysplastic Syndrome Patients Using Turbo Cosubstrate

    Science.gov (United States)

    2017-07-01

    prevalent in a number of myeloid malignancies such as MDS-myeloproliferative neoplasms (MDS-MPN) and acute myeloid leukemia derived from MDS and MDS...Myelodysplastic syndromes (MDS), MDS-myeloproliferative neoplasms (MDS-MPN), Acute myeloid leukemia (AML), 5-methylcytosine (5mC), Mutation...normal initially, with age, develop diverse myeloid malignancies similar to humans. The objective in this project is to develop effective strategies

  12. SF3B1-initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells.

    Science.gov (United States)

    Mortera-Blanco, Teresa; Dimitriou, Marios; Woll, Petter S; Karimi, Mohsen; Elvarsdottir, Edda; Conte, Simona; Tobiasson, Magnus; Jansson, Monika; Douagi, Iyadh; Moarii, Matahi; Saft, Leonie; Papaemmanuil, Elli; Jacobsen, Sten Eirik W; Hellström-Lindberg, Eva

    2017-08-17

    Mutations in the RNA splicing gene SF3B1 are found in >80% of patients with myelodysplastic syndrome with ring sideroblasts (MDS-RS). We investigated the origin of SF3B1 mutations within the bone marrow hematopoietic stem and progenitor cell compartments in patients with MDS-RS. Screening for recurrently mutated genes in the mononuclear cell fraction revealed mutations in SF3B1 in 39 of 40 cases (97.5%), combined with TET2 and DNMT3A in 11 (28%) and 6 (15%) patients, respectively. All recurrent mutations identified in mononuclear cells could be tracked back to the phenotypically defined hematopoietic stem cell (HSC) compartment in all investigated patients and were also present in downstream myeloid and erythroid progenitor cells. While in agreement with previous studies, little or no evidence for clonal ( SF3B1 mutation) involvement could be found in mature B cells, consistent involvement at the pro-B-cell progenitor stage was established, providing definitive evidence for SF3B1 mutations targeting lymphomyeloid HSCs and compatible with mutated SF3B1 negatively affecting lymphoid development. Assessment of stem cell function in vitro as well as in vivo established that only HSCs and not investigated progenitor populations could propagate the SF3B1 mutated clone. Upon transplantation into immune-deficient mice, SF3B1 mutated MDS-RS HSCs differentiated into characteristic ring sideroblasts, the hallmark of MDS-RS. Our findings provide evidence of a multipotent lymphomyeloid HSC origin of SF3B1 mutations in MDS-RS patients and provide a novel in vivo platform for mechanistically and therapeutically exploring SF3B1 mutated MDS-RS. © 2017 by The American Society of Hematology.

  13. Health-related quality of life in lower-risk MDS patients compared with age- and sex-matched reference populations: a European LeukemiaNet study.

    Science.gov (United States)

    Stauder, Reinhard; Yu, Ge; Koinig, Karin A; Bagguley, Tim; Fenaux, Pierre; Symeonidis, Argiris; Sanz, Guillermo; Cermak, Jaroslav; Mittelman, Moshe; Hellström-Lindberg, Eva; Langemeijer, Saskia; Holm, Mette Skov; Mądry, Krzysztof; Malcovati, Luca; Tatic, Aurelia; Germing, Ulrich; Savic, Aleksandar; van Marrewijk, Corine; Guerci-Bresler, Agnès; Luño, Elisa; Droste, Jackie; Efficace, Fabio; Smith, Alex; Bowen, David; de Witte, Theo

    2018-03-06

    In myelodysplastic syndromes (MDS), health-related quality of life (HRQoL) represents a relevant patient-reported outcome, which is essential in individualized therapy planning. Prospective data on HRQoL in lower-risk MDS remain rare. We assessed HRQOL by EQ-5D questionnaire at initial diagnosis in 1690 consecutive IPSS-Low/Int-1 MDS patients from the European LeukemiaNet Registry. Impairments were compared with age- and sex-matched EuroQol Group norms. A significant proportion of MDS patients reported moderate/severe problems in the dimensions pain/discomfort (49.5%), mobility (41.0%), anxiety/depression (37.9%), and usual activities (36.1%). Limitations in mobility, self-care, usual activities, pain/discomfort, and EQ-VAS were significantly more frequent in the old, in females, and in those with high co-morbidity burden, low haemoglobin levels, or red blood cells transfusion need (p MDS patients (p MDS-related restrictions in the dimension mobility were most prominent in males, and in older people (p MDS experience a pronounced reduction in HRQoL and a clustering of restrictions in distinct dimensions of HRQoL as compared with reference populations.

  14. Design and rationale of the QUAZAR Lower-Risk MDS (AZA-MDS-003) trial: a randomized phase 3 study of CC-486 (oral azacitidine) plus best supportive care vs placebo plus best supportive care in patients with IPSS lower-risk myelodysplastic syndromes and poor prognosis due to red blood cell transfusion-dependent anemia and thrombocytopenia.

    Science.gov (United States)

    Garcia-Manero, Guillermo; Almeida, Antonio; Giagounidis, Aristoteles; Platzbecker, Uwe; Garcia, Regina; Voso, Maria Teresa; Larsen, Stephen R; Valcarcel, David; Silverman, Lewis R; Skikne, Barry; Santini, Valeria

    2016-01-01

    CC-486 is an oral formulation of the epigenetic modifier azacitidine. In an expanded phase 1 trial, CC-486 demonstrated clinical and biological activity in patients with International Prognostic Scoring System (IPSS) lower-risk (low- and intermediate-1-risk) myelodysplastic syndromes (MDS) with poor prognostic features including anemia and/or thrombocytopenia who may have required red blood cell or platelet transfusions. The overall response rate was 40 %, including hematologic improvement in 28 % of patients and RBC transfusion independence sustained for 56 days in 47 % of patients with baseline transfusion dependence. Based on the results of this study, the randomized, placebo-controlled phase 3 QUAZAR Lower-Risk MDS trial (AZA-MDS-003) was initiated. The design and rationale for this trial comparing CC-486 with placebo for the treatment of patients with IPSS lower-risk MDS with poor prognostic features are described. Patients must have IPSS lower-risk MDS with red blood cell (RBC) transfusion-dependent anemia and thrombocytopenia. Eligible patients are randomized 1:1 to receive 300 mg of CC-486 or placebo once daily for the first 21 days of 28-day treatment cycles. Disease status assessments occur at the end of cycle 6 and patients may continue to receive treatment unless there is evidence of progressive disease, lack of efficacy, or unacceptable toxicity. The primary endpoint is RBC transfusion independence for ≥ 84 days, assessed according to International Working Group 2006 criteria. Secondary endpoints include overall survival, hematologic response including platelet response and erythroid response, RBC transfusion independence for ≥ 56 days, duration of RBC transfusion independence, time to RBC transfusion independence, rate of acute myeloid leukemia (AML) progression, time to AML progression, clinically significant bleeding events, safety, health-related quality of life, and healthcare resource utilization. This study will provide data

  15. Cytogenetic studies of Brazilian pediatric myelodysplastic syndrome cases: challenges and difficulties in a large and emerging country.

    Science.gov (United States)

    Velloso, E D R P; Chauffaille, M L; Peliçario, L M; Tanizawa, R S S; Toledo, S R C; Gaiolla, R D; Lopes, L F

    2013-01-01

    Myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematopoietic stem cell diseases affecting children. Cytogenetics plays an important role in the diagnosis of these diseases. We report here the experience of the Cytogenetic Subcommittee of the Brazilian Cooperative Group on Pediatric Myelodysplastic Syndromes (BCG-MDS-PED). We analyzed 168 cytogenetic studies performed in 23 different cytogenetic centers; 84 of these studies were performed in patients with confirmed MDS (primary MDS, secondary MDS, JMML, and acute myeloid leukemia/MDS+Down syndrome). Clonal abnormalities were found in 36.9% of the MDS cases and cytogenetic studies were important for the detection of constitutional diseases and for differential diagnosis with other myeloid neoplasms. These data show the importance of the Cooperative Group for continuing education in order to avoid a late or wrong diagnosis.

  16. Myelodysplastic changes mimicking MDS following treatment for osteosarcoma

    DEFF Research Database (Denmark)

    Løhmann, Ditte

    -MDS/AML) is a feared long-term complication of paediatric cancer including osteosarcoma. Few develop t-MDS/AML, but it is not known how many have significant haematological changes after finishing treatment for osteosarcoma. In this study we reviewed biochemistry from a consecutive series of children for up to two...... years after finishing treatment. We included all children (n=14) who where diagnosed from October 2006 to January 2011 at our department and treated according to the EURAMOS-1 protocol. Four patients relapsed and died before the end of the study period. We found noteworthy changes in MCV, platelets...... for osteosarcoma developed haematological abnormalities similar to early MDS but few developed t-MDS/AML. Close monitoring of patients recovering from osteosarcoma is essential. Keywords: Osteosarcoma, t-MDS/AML, Haematological abnormalities, Children...

  17. Cytogenetic studies of Brazilian pediatric myelodysplastic syndrome cases: challenges and difficulties in a large and emerging country

    Directory of Open Access Journals (Sweden)

    E.D.R.P. Velloso

    2013-01-01

    Full Text Available Myelodysplastic syndromes (MDS and juvenile myelomonocytic leukemia (JMML are rare hematopoietic stem cell diseases affecting children. Cytogenetics plays an important role in the diagnosis of these diseases. We report here the experience of the Cytogenetic Subcommittee of the Brazilian Cooperative Group on Pediatric Myelodysplastic Syndromes (BCG-MDS-PED. We analyzed 168 cytogenetic studies performed in 23 different cytogenetic centers; 84 of these studies were performed in patients with confirmed MDS (primary MDS, secondary MDS, JMML, and acute myeloid leukemia/MDS+Down syndrome. Clonal abnormalities were found in 36.9% of the MDS cases and cytogenetic studies were important for the detection of constitutional diseases and for differential diagnosis with other myeloid neoplasms. These data show the importance of the Cooperative Group for continuing education in order to avoid a late or wrong diagnosis.

  18. Therapy Related AML/MDS Following Treatment for Childhood Cancer: Experience from a Tertiary Care Centre in North India.

    Science.gov (United States)

    Vyas, Chintan; Jain, Sandeep; Kapoor, Gauri

    2018-01-01

    Therapy-related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS) is a devastating late effect of cancer treatment. There is limited data on incidence of t-AML/MDS from India. We retrospectively studied pediatric t AML/MDS at our institute between January 1996 and December 2015. Among 1285 children, 8 patients developed t-AML with a median age of 15.5 years. Overall incidence of t-AML/MDS was 0.62% [0.99% (4/402) in solid tumours and 0.45% (4/883) in leukemia/lymphoma, P  = 0.26] with 6390 patient years of follow up. Primary malignancy included sarcoma [bone (2), soft tissue (2)], B-non-Hodgkin lymphoma (2) and acute lymphoblastic leukemia (2). The median cumulative equivalent doses of cyclophosphamide, doxorubicin and etoposide were 6.8, 270 and 2.5 gm/m 2 respectively. Two patients received radiotherapy [rhabdomyosarcoma (50 Gy), synovial sarcoma (45 Gy)]. The median latency period to develop t-AML/MDS was 24 months (range 16.5-62 months). Most common FAB morphology was M4/M5 (7/8) and cytogenetic abnormality was MLL rearrangement (4/8). Five patients opted for treatment, 4 achieved remission out of which 2 patients are alive and disease free. Short latency periods, absence of pre-leukemic phase and 11q23 translocations were characteristic in the patients with t-AML/MDS. In view of poor outcome with conventional therapy, novel strategies and prevention need to be considered.

  19. Prognostic classification of MDS is improved by the inclusion of FISH panel testing with conventional cytogenetics.

    Science.gov (United States)

    Kokate, Prajakta; Dalvi, Rupa; Koppaka, Neeraja; Mandava, Swarna

    2017-10-01

    Cytogenetics is a critical independent prognostic factor in myelodysplastic syndromes (MDS). Conventional cytogenetics (CC) and Fluorescence in situ hybridization (FISH) Panel Testing are extensively used for the prognostic stratification of MDS, although the FISH test is not yet a bona fide component of the International Prognostic Scoring System (IPSS). The present study compares the utility of CC and FISH to detect chromosomal anomalies and in prognostic categorization. GTG-Banding and FISH Panel Testing specifically for -5/-5q, -7/-7q, +8 and -20q was performed on whole blood or bone marrow samples from 136 patients with MDS. Chromosomal anomalies were found in 40 cases by CC, including three novel translocations. FISH identified at least one anomaly in 54/136 (39.7%) cases. More than one anomaly was found in 18/54 (33.3%) cases, therefore, overall FISH identified 75 anomalies of which 32 (42.6%) were undetected by CC. FISH provided additional information in cases with CC failure and in cases with a normal karyotype. Further, in ten cases with an abnormal karyotype, FISH could identify additional anomalies, increasing the number of abnormalities per patient. Although CC is the gold standard in the cytogenetic profiling of MDS, FISH has proven to be an asset in identifying additional abnormalities. The number of anomalies per patient can predict the prognosis in MDS and hence, FISH contributed towards prognostic re-categorization. The FISH Panel testing should be used as an adjunct to CC, irrespective of the adequacy of the number of metaphases in CC, as it improves the prognostic classification of MDS. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    NARCIS (Netherlands)

    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.

    2016-01-01

    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

  1. Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS

    Science.gov (United States)

    Schneider, Rebekka K.; Ademà, Vera; Heckl, Dirk; Järås, Marcus; Mallo, Mar; Lord, Allegra M.; Chu, Lisa P.; McConkey, Marie E.; Kramann, Rafael; Mullally, Ann; Bejar, Rafael; Solé, Francesc; Ebert, Benjamin L.

    2014-01-01

    Summary The Casein kinase 1A1 gene (CSNK1A1) is a putative tumor suppressor gene located in the common deleted region for del(5q) myelodysplastic syndrome (MDS). We generated a murine model with conditional inactivation of Csnk1a1 and found that Csnk1a1 haploinsufficiency induces hematopoietic stem cell expansion and a competitive repopulation advantage whereas homozygous deletion induces hematopoietic stem cell failure. Based on this finding, we found that heterozygous inactivation of Csnk1a1 sensitizes cells to a CSNK1 inhibitor relative to cells with two intact alleles. In addition, we identified recurrent somatic mutations in CSNK1A1 on the non-deleted allele of patients with del(5q) MDS. These studies demonstrate that CSNK1A1 plays a central role in the biology of del(5q) MDS and is a promising therapeutic target. PMID:25242043

  2. Relationship between the non-motor items of the MDS-UPDRS and Quality of Life in patients with Parkinson's disease.

    Science.gov (United States)

    Skorvanek, Matej; Rosenberger, Jaroslav; Minar, Michal; Grofik, Milan; Han, Vladimir; Groothoff, Johan W; Valkovic, Peter; Gdovinova, Zuzana; van Dijk, Jitse P

    2015-01-01

    The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a newly developed comprehensive tool to assess Parkinson's disease (PD), which covers a wider range of non-motor PD manifestations than the original UPDRS scale. The aim of this study was to assess the relationship between the MDS-UPDRS and Quality of Life (QoL) and to analyze the relationship between individual MDS-UPDRS non-motor items and QoL. A total of 291 PD patients were examined in a multicenter Slovak study. Patients were assessed by the MDS-UPDRS, HY scale and PDQ39. Data were analyzed using the multiple regression analyses. The mean participant age was 68.0 ± 9.0 years, 53.5% were men, mean disease duration was 8.3 ± 5.3 years and mean HY was 2.7 ± 1.0. In a multiple regression analysis model the PDQ39 summary index was related to MDS-UPDRS parts II, I and IV respectively, but not to part III. Individual MDS-UPDRS non-motor items related to the PDQ39 summary index in the summary group and in the non-fluctuating patients subgroup were pain, fatigue and features of dopamine dysregulation syndrome (DDS). In the fluctuating PD patient subgroup, PDQ39 was related to pain and Depressed mood items. Other MDS-UPDRS non-motor items e.g. Anxious mood, Apathy, Cognitive impairment, Hallucinations and psychosis, Sleep problems, Daytime sleepiness and Urinary problems were related to some PDQ39 domains. The overall burden of NMS in PD is more important in terms of QoL than motor symptoms. Individual MDS-UPDRS non-motor items related to worse QoL are especially pain and other sensations, fatigue and features of DDS. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. An improved resource management model based on MDS

    Science.gov (United States)

    Yuan, Man; Sun, Changying; Li, Pengfei; Sun, Yongdong; He, Rui

    2005-11-01

    GRID technology provides a kind of convenient method for managing GRID resources. This service is so-called monitoring, discovering service. This method is proposed by Globus Alliance, in this GRID environment, all kinds of resources, such as computational resources, storage resources and other resources can be organized by MDS specifications. However, this MDS is a theory framework, particularly, in a small world intranet, in the case of limit of resources, the MDS has its own limitation. Based on MDS, an improved light method for managing corporation computational resources and storage resources is proposed in intranet(IMDS). Firstly, in MDS, all kinds of resource description information is stored in LDAP, it is well known although LDAP is a light directory access protocol, in practice, programmers rarely master how to access and store resource information into LDAP store, in such way, it limits MDS to be used. So, in intranet, these resources' description information can be stored in RDBMS, programmers and users can access this information by standard SQL. Secondly, in MDS, how to monitor all kinds of resources in GRID is not transparent for programmers and users. In such way, it limits its application scope, in general, resource monitoring method base on SNMP is widely employed in intranet, therefore, a kind of resource monitoring method based on SNMP is integrated into MDS. Finally, all kinds of resources in the intranet can be described by XML, and all kinds of resources' description information is stored in RDBMS, such as MySql, and retrieved by standard SQL, dynamic information for all kinds of resources can be sent to resource storage by SNMP, A prototype resource description, monitoring is designed and implemented in intranet.

  4. Immune Mechanisms in Myelodysplastic Syndrome

    Directory of Open Access Journals (Sweden)

    Andreas Glenthøj

    2016-06-01

    Full Text Available Myelodysplastic syndrome (MDS is a spectrum of diseases, characterized by debilitating cytopenias and a propensity of developing acute myeloid leukemia. Comprehensive sequencing efforts have revealed a range of mutations characteristic, but not specific, of MDS. Epidemiologically, autoimmune diseases are common in patients with MDS, fueling hypotheses of common etiological mechanisms. Both innate and adaptive immune pathways are overly active in the hematopoietic niche of MDS. Although supportive care, growth factors, and hypomethylating agents are the mainstay of MDS treatment, some patients—especially younger low-risk patients with HLA-DR15 tissue type—demonstrate impressive response rates after immunosuppressive therapy. This is in contrast to higher-risk MDS patients, where several immune activating treatments, such as immune checkpoint inhibitors, are in the pipeline. Thus, the dual role of immune mechanisms in MDS is challenging, and rigorous translational studies are needed to establish the value of immune manipulation as a treatment of MDS.

  5. Valuation of transfusion-free living in MDS: results of health utility interviews with patients

    Directory of Open Access Journals (Sweden)

    Lübbert Michael

    2009-09-01

    Full Text Available Abstract Background This study measured how myelodysplastic syndrome (MDS patients value transfusion independence (TI, reduced transfusions (RT and transfusion-dependence (TD using health utility assessment methodology. Methods 47 MDS patients were interviewed, US (n = 8, France (n = 9, Germany (n = 9 and the UK (n = 21, to elicit the utility value of TI, RT and TD. Health states were developed based on literature; patient forum discussions; and were validated by a hematologist. Face-to-face interviews used the feeling thermometer Visual Analogue Scale (VAS and the Time Trade-Off (TTO method to value the health states on a 0 (dead to 1 (perfect health scale. Socio-demographic, clinical, and quality-of-life (EQ-5D characteristics were surveyed to describe the patient sample. Results and Discussion The mean age was 67 years (range: 29-83; 45% male, 70% retired; 40% had secondary/high school education, or higher (32%, and 79% lived with family, a partner or spouse, or friends. The mean time from MDS diagnosis was 5 years (range:1-23. Most patients (87% received previous transfusions and 49% had received a transfusion in the last 3 months. Mean EQ-5D index score was 0.78; patients reported at least some problem with mobility (45%, usual activities (40%, pain/discomfort (47%, and anxiety/depression (34%. Few patients had difficulty understanding the VAS (n = 3 and TTO (n = 4 exercises. Utility scores for TI were higher than for RT (0.84 vs. 0.77; p Conclusion Patients value TI, suggesting an important role for new treatments aiming to achieve greater TI in MDS. These results can be used in preference-based health economic evaluation of new MDS treatments, such as in future cost-utility studies.

  6. Mediators of the association of major depressive syndrome and anxiety syndrome with postpartum smoking relapse.

    Science.gov (United States)

    Correa-Fernández, Virmarie; Ji, Lingyun; Castro, Yessenia; Heppner, Whitney L; Vidrine, Jennifer Irvin; Costello, Tracy J; Mullen, Patricia Dolan; Cofta-Woerpel, Ludmila; Velasquez, Mary M; Greisinger, Anthony; Cinciripini, Paul M; Wetter, David W

    2012-08-01

    Based on conceptual models of addiction and affect regulation, this study examined the mechanisms linking current major depressive syndrome (MDS) and anxiety syndrome (AS) to postpartum smoking relapse. Data were collected in a randomized clinical trial from 251 women who quit smoking during pregnancy. Simple and multiple mediation models of the relations of MDS and AS with postpartum relapse were examined using linear regression, continuation ratio logit models, and a bootstrapping procedure to test the indirect effects. Both MDS and AS significantly predicted postpartum smoking relapse. After adjusting for MDS, AS significantly predicted relapse. However, after adjusting for AS, MDS no longer predicted relapse. Situationally based self-efficacy, expectancies of controlling negative affect by means other than smoking, and various dimensions of primary and secondary tobacco dependence individually mediated the effect of both MDS and AS on relapse. In multiple mediation models, self-efficacy in negative/affective situations significantly mediated the effect of MDS and AS on relapse. The findings underscore the negative impact of depression and anxiety on postpartum smoking relapse and suggest that the effects of MDS on postpartum relapse may be largely explained by comorbid AS. The current investigation provided mixed support for affect regulation models of addiction. Cognitive and tobacco dependence-related aspects of negative and positive reinforcement significantly mediated the relationship of depression and anxiety with relapse, whereas affect and stress did not. The findings emphasize the unique role of low agency with respect to abstaining from smoking in negative affective situations as a key predictor of postpartum smoking relapse. © 2012 American Psychological Association

  7. Progress in the diagnosis of and therapy for MDS.

    Science.gov (United States)

    Nannya, Yasuhito

    2016-01-01

    The WHO classification system of MDS 4 th edition was recently updated. This revision includes nomenclature changes, reflecting the policy of the revision team to emphasize morphological features over cytopenias. Other changes are 1) taking SF3B1 mutation status into account for the definition criteria of MDS-RS (ring sideroblasts), 2) allowing for one additional cytogenetic abnormality (excluding -7/del (7q)) to be diagnosed as 'MDS with isolated del (5q)', 3) sub-classifying MDS-U according to the reasons for being included in this category, and 4) changing the diagnostic rules for myeloid neoplasms with erythroid blast predominance. This session also deals with recent topics in hematopoietic stem cell transplantation (HSCT) as an example of progress in therapy for MDS. Although HSCT is the only curative therapy for MDS, high treatment related mortality precludes its applicability especially for elderly patients, for whom demethylating agents are an alternative. Recently, reports on both well-designed retrospective or prospective studies have validated the advantage of HSCT over demethylating agents for patients of comparatively advanced age with higher risk MDS. Optimal intensity of conditioning regimens for HSCT is another controversial topic for which preliminary results of randomized controlled trials have been released and will be introduced in this session.

  8. MDS clinical diagnostic criteria for Parkinson's disease in China.

    Science.gov (United States)

    Li, Jun; Jin, Miao; Wang, Li; Qin, Bin; Wang, Kang

    2017-03-01

    The Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (MDS-PD Criteria) was introduced by the Movement Disorder Society in 2015 for research purposes. However, its use for clinical diagnosis of Parkinson disease still needs further revision. This study compares the UK-Criteria versus MDS-PD Criteria in the clinical diagnosis of Parkinson disease referred to the China-Japan Friendship Hospital of Beijing, China. To compare the MDS-PD Criteria with the UK-Criteria and discuss the feasibility of the clinical application of MDS-PD Criteria as a general guide to clinical diagnosis of PD in Chinese PD patients. 150 patients of neurology clinic of China-Japan Friendship Hospital of Beijing were recruited in our research. They were divided into three groups: UK-Criteria group, MDS-PD Criteria group and a combined group of UK and MDS-PD Criteria. Clinical history was collected while physical and auxiliary examinations were done by a trained neurologist according to the corresponding criteria. An interrater reliability analysis using the Kappa statistic claimed substantial agreement (κ = 0.626) between the MDS-PD Criteria and the UK-Criteria. The differences between the diagnostic results of these two criteria were statistically significant by paired Chi-square test (p = 0.000). It was found that levodopa-induced dyskinesia had a good positive predictive value, while early bulbar impairment and inspiratory dysfunction presented a negative predictive value. The MDS-PD Criteria emphasize the importance of non-motor symptoms, keeping the motor symptoms as the core for the clinical diagnosis of PD, and establish categories of diagnosis features and levels of certainty which are more complete and organized to be used and replicated by non specialized physicians to evaluated patients with Parkinsonism. The higher sensitivity of MDS-PD Criteria compared with UK-Criteria is worth being widely used in clinical work.

  9. Multidimensional assessment of patient condition and mutational analysis in peripheral blood, as tools to improve outcome prediction in myelodysplastic syndromes: A prospective study of the Spanish MDS group.

    Science.gov (United States)

    Ramos, Fernando; Robledo, Cristina; Pereira, Arturo; Pedro, Carmen; Benito, Rocío; de Paz, Raquel; Del Rey, Mónica; Insunza, Andrés; Tormo, Mar; Díez-Campelo, María; Xicoy, Blanca; Salido, Eduardo; Sánchez-Del-Real, Javier; Arenillas, Leonor; Florensa, Lourdes; Luño, Elisa; Del Cañizo, Consuelo; Sanz, Guillermo F; María Hernández-Rivas, Jesús

    2017-09-01

    The International Prognostic Scoring System and its revised form (IPSS-R) are the most widely used indices for prognostic assessment of patients with myelodysplastic syndromes (MDS), but can only partially account for the observed variation in patient outcomes. This study aimed to evaluate the relative contribution of patient condition and mutational status in peripheral blood when added to the IPSS-R, for estimating overall survival and the risk of leukemic transformation in patients with MDS. A prospective cohort (2006-2015) of 200 consecutive patients with MDS were included in the study series and categorized according to the IPSS-R. Patients were further stratified according to patient condition (assessed using the multidimensional Lee index for older adults) and genetic mutations (peripheral blood samples screened using next-generation sequencing). The change in likelihood-ratio was tested in Cox models after adding individual covariates. The addition of the Lee index to the IPSS-R significantly improved prediction of overall survival [hazard ratio (HR) 3.02, 95% confidence interval (CI) 1.96-4.66, P < 0.001), and mutational analysis significantly improved prediction of leukemic evolution (HR 2.64, 1.56-4.46, P < 0.001). Non-leukemic death was strongly linked to patient condition (HR 2.71, 1.72-4.25, P < 0.001), but not to IPSS-R score (P = 0.35) or mutational status (P = 0.75). Adjustment for exposure to disease-modifying therapy, evaluated as a time-dependent covariate, had no effect on the proposed model's predictive ability. In conclusion, patient condition, assessed by the multidimensional Lee index and patient mutational status can improve the prediction of clinical outcomes of patients with MDS already stratified by IPSS-R. © 2017 Wiley Periodicals, Inc.

  10. TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomide-resistant patients

    Science.gov (United States)

    Caceres, Gisela; McGraw, Kathy; Yip, Bon Ham; Pellagatti, Andrea; Johnson, Joseph; Zhang, Ling; Liu, Kenian; Zhang, Lan Min; Fulp, William J.; Lee, Ji-Hyun; Al Ali, Najla H.; Basiorka, Ashley; Smith, Larry J.; Daugherty, F. Joseph; Littleton, Neil; Wells, Richard A.; Sokol, Lubomir; Wei, Sheng; Komrokji, Rami S.; Boultwood, Jacqueline; List, Alan F.

    2013-01-01

    Stabilization of p53 in erythroid precursors in response to nucleosomal stress underlies the hypoplastic anemia in myelodysplastic syndromes (MDS) with chromosome 5q deletion [del(5q)]. We investigated whether cenersen, a clinically active 20-mer antisense oligonucleotide complementary to TP53 exon10, could suppress p53 expression and restore erythropoiesis in del(5q) MDS. Cenersen treatment of ribosomal protein S-14-deficient erythroblasts significantly reduced cellular p53 and p53-up-regulated modulator of apoptosis expression compared with controls, accompanied by a significant reduction in apoptosis and increased cell proliferation. In a two-stage erythroid differentiation assay, cenersen significantly suppressed nuclear p53 in bone marrow CD34+ cells isolated from patients with del(5q) MDS, whereas erythroid burst recovery increased proportionally to the magnitude of p53 suppression without evidence of del(5q) clonal suppression (r = −0.6; P = 0.005). To explore the effect of p53 suppression on erythropoiesis in vivo, dexamethasone, a glucocorticoid receptor-dependent p53 antagonist, was added to lenalidomide treatment in eight lower-risk, transfusion-dependent, del(5q) MDS patients with acquired drug resistance. Transfusion independence was restored in five patients accompanied by expansion of erythroid precursors and decreased cellular p53 expression. We conclude that targeted suppression of p53 could support effective erythropoiesis in lenalidomide-resistant del(5q) MDS. PMID:24043769

  11. Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease.

    Science.gov (United States)

    Tobiasson, Magnus; Abdulkadir, Hani; Lennartsson, Andreas; Katayama, Shintaro; Marabita, Francesco; De Paepe, Ayla; Karimi, Mohsen; Krjutskov, Kaarel; Einarsdottir, Elisabet; Grövdal, Michael; Jansson, Monika; Ben Azenkoud, Asmaa; Corddedu, Lina; Lehmann, Sören; Ekwall, Karl; Kere, Juha; Hellström-Lindberg, Eva; Ungerstedt, Johanna

    2017-04-25

    Azacitidine (Aza) is first-line treatment for patients with high-risk myelodysplastic syndromes (MDS), although its precise mechanism of action is unknown. We performed the first study to globally evaluate the epigenetic effects of Aza on MDS bone marrow progenitor cells assessing gene expression (RNA seq), DNA methylation (Illumina 450k) and the histone modifications H3K18ac and H3K9me3 (ChIP seq). Aza induced a general increase in gene expression with 924 significantly upregulated genes but this increase showed no correlation with changes in DNA methylation or H3K18ac, and only a weak association with changes in H3K9me3. Interestingly, we observed activation of transcripts containing 15 endogenous retroviruses (ERVs) confirming previous cell line studies. DNA methylation decreased moderately in 99% of all genes, with a median β-value reduction of 0.018; the most pronounced effects seen in heterochromatin. Aza-induced hypomethylation correlated significantly with change in H3K9me3. The pattern of H3K18ac and H3K9me3 displayed large differences between patients and healthy controls without any consistent pattern induced by Aza. We conclude that the marked induction of gene expression only partly could be explained by epigenetic changes, and propose that activation of ERVs may contribute to the clinical effects of Aza in MDS.

  12. Azacitidine improves outcome in higher-risk MDS patients with chromosome 7 abnormalities: a retrospective comparison of GESMD and GFM registries.

    Science.gov (United States)

    Díez-Campelo, María; Lorenzo, Jose I; Itzykson, Raphael; Rojas, Silvia M; Berthon, Céline; Luño, Elisa; Beyne-Rauzy, Odile; Perez-Oteyza, Jaime; Vey, Norbert; Bargay, Joan; Park, Sophie; Cedena, Teresa; Bordessoule, Dominique; Muñoz, Juan A; Gyan, Emmanuel; Such, Esperanza; Visanica, Sorin; López-Cadenas, Félix; de Botton, Stéphane; Hernández-Rivas, Jesús M; Ame, Shanti; Stamatoullas, Aspasia; Delaunay, Jacques; Salanoubat, Celia; Isnard, Françoise; Guieze, Romain; Pérez Guallar, Joan; Badiella, Llorenc; Sanz, Guillermo; Cañizo, Consuelo; Fenaux, Pierre

    2018-05-01

    Treatment with azacitidine (AZA) has been suggested to be of benefit for higher-risk myelodysplastic syndrome (HR-MDS) patients with chromosome 7 abnormalities (Abn 7). This retrospective study of 235 HR-MDS patients with Abn 7 treated with AZA (n = 115) versus best supportive care (BSC; n = 120), assessed AZA treatment as a time-varying variable in multivariable analysis. A Cox Regression model with time-interaction terms of overall survival (OS) at different time points confirmed that, while chromosome 7 cytogenetic categories (complex karyotype [CK] versus non-CK) and International Prognostic Scoring System risk (high versus intermediate-2) retained poor prognosis over time, AZA treatment had a favourable impact on OS during the first 3 years of treatment compared to BSC (Hazard ratio [HR] 0·5 P MDS and cytogenetic abnormalities involving chromosome 7, especially for those with CK. © 2018 John Wiley & Sons Ltd.

  13. IER3 Expression in Childhood Myelodysplastic Syndrome

    DEFF Research Database (Denmark)

    de Vries, Andrica; Zwaan, Christian M.; Danen van Ooschot, Astrid

    Background: Childhood myelodysplastic syndrome (MDS) is a rare disease accounting for less than 5% of all hematological malignancies. In about 50% of the MDS cases an abnormal karyotype is found by conventional karyotyping, of which chromosome 6 is involved in 10%. The immediate-early-response 3...

  14. Bone marrow MRI in patients with myelodysplastic syndromes

    International Nuclear Information System (INIS)

    Chen Zhao; Guo You; Wang Renfa; Zou Mingli; Liu Wenli; Xia Liming; Wang Chengyuan

    2004-01-01

    Objective: To observe the MR imaging of bone marrow in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and to reveal the rule of bone marrow infiltration and the role of MRI in diagnosing and predicting the prognosis of myelodysplastic syndromes. Methods: Thirty patients received MRI after the diagnosis based on clinic and FAB subtype study, including 16 with MDS and 14 with AML. MR image was obtained by T 1 -weighted spin echo and shot time inversion recovery in pelvis and femur. The examining results of morphology and blood routine were collected at the same time. 30 age-matched volunteers were selected as controls. Results: The MRI appearance was classified into their patterns based on scope of focus. MRI patterns from grade 1 to grade 3 was observed in patients with MDS. All patients with AML distributed in grade 2 to grade 3. The distribution of patterns had no significant difference between MDS and AML (P>0.05). The marrow ratio had significant difference among MDS, AML, and controls (P<0.05). The MRI grade was consistent with the clinic diagnostic indexes. Conclusion: MRI can provide a better understanding of the difference between MDS and AML. MRI can estimate the extent of disease in the marrow as a whole. MRI of bone marrow can provide imaging basis in diagnosis and predicting the prognosis for patients with MDS

  15. Mitochondrial DNA Depletion Syndrome is Expressed in Amniotic Fluid Cell Cultures

    OpenAIRE

    Blake, Julian C.; Taanman, Jan-Willem; Morris, Andrew M. M.; Gray, R. George F.; Cooper, J. Mark; McKiernan, Patrick J.; Leonard, James V.; Schapira, Anthony H. V.

    1999-01-01

    Mitochondrial DNA depletion syndrome is an autosomal inherited disease associated with grossly reduced cellular levels of mitochondrial DNA in infancy. Most patients are born after a full and uncomplicated pregnancy, are normal at birth, but develop symptoms in the early neonatal period. These observations have led to the suggestion that the patients have a defect affecting the control of mitochondrial DNA copy number after birth. Using immunocytochemical techniques, we demonstrated that the ...

  16. [Application of Next Generation Sequencing for AML/MDS Diagnosis and Treatment].

    Science.gov (United States)

    Cheng, Huan-Chen; Liu, Sheng-Wei; Liu, Yu; Zhao, Xue-Fei; Li, Wei; Qiu, Lin; Ma, Jun

    2017-12-01

    To detect the mutations of AML/MDS- related genes by using next generation sequencing (NGS), to analyze the mutation levels of each genes in the AML/MDS and the sensitivity of NGS, and to evaluate the feasibility of gene mutations for monitoring the MRD and predicating the progression of diseases. The specimens were collected from primary AML (68 cases) and MDS (57 cases) patients from August 2015 to June 2016 in the Harbin Institute of Hematology and Oncology. The mutations of 22 related genes were detected by using AML/MDS-NGS chips. TET2 gene showed the highest mutation rate in AML (55.9%) and MDS (56.1%). The gene mutations were as follows: CEBPA (11.8%), DNMT3A (7.4%), C-KIT (7.4%) and FLT3-ITD (7.4%) in AML, and U2AF1 (10.5%) and SRSF2 (10.5%) in MDS. All the genes had specific mutation sites except TP53 and CEBPA. The mutations of FLT3, C-KIT and CEBPA became negative in the 5 AML patients in remission when compared with those at primary attack, but the mutation rate of TET2 gene was not obviously changed, whereas the mutation rate of the 5 MDS patients was not significantly changed. The new gene mutations appeared in 3 MDS patients with disease progression, but the mutation rate was not changed significantly in the disease progression. The gene mutation rate still has not been changed significantly even after remission. Both AML and MDS have their own specific mutated genes and sites. Some gene mutations, such as CEBPA, can be used as an effective indicator to monitoring MRD in AML patients, but those only used for the evaluation of the disease progression and prognosis in MDS patients.

  17. Minimal clinically important difference on the Motor Examination part of MDS-UPDRS.

    Science.gov (United States)

    Horváth, Krisztina; Aschermann, Zsuzsanna; Ács, Péter; Deli, Gabriella; Janszky, József; Komoly, Sámuel; Balázs, Éva; Takács, Katalin; Karádi, Kázmér; Kovács, Norbert

    2015-12-01

    Recent studies increasingly utilize the Movement Disorders Society Sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS). However, the minimal clinically important difference (MCID) has not been fully established for MDS-UPDRS yet. To assess the MCID thresholds for MDS-UPDRS Motor Examination (Part III). 728 paired investigations of 260 patients were included. At each visit both MDS-UPDRS and Clinician-reported Global Impression-Improvement (CGI-I) scales were assessed. MDS-UPDRS Motor Examination (ME) score changes associated with CGI-I score 4 (no change) were compared with MDS-UPDRS ME score changes associated with CGI-I score 3 (minimal improvement) and CGI-I score 5 (minimal worsening). Both anchor- and distribution-based techniques were utilized to determine the magnitude of MCID. The MCID estimates for MDS-UPDRS ME were asymmetric: -3.25 points for detecting minimal, but clinically pertinent, improvement and 4.63 points for observing minimal, but clinically pertinent, worsening. MCID is the smallest change of scores that are clinically meaningful to patients. These MCID estimates may allow the judgement of a numeric change in MDS-UPDRS ME on its clinical importance. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Handling missing values in the MDS-UPDRS.

    Science.gov (United States)

    Goetz, Christopher G; Luo, Sheng; Wang, Lu; Tilley, Barbara C; LaPelle, Nancy R; Stebbins, Glenn T

    2015-10-01

    This study was undertaken to define the number of missing values permissible to render valid total scores for each Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part. To handle missing values, imputation strategies serve as guidelines to reject an incomplete rating or create a surrogate score. We tested a rigorous, scale-specific, data-based approach to handling missing values for the MDS-UPDRS. From two large MDS-UPDRS datasets, we sequentially deleted item scores, either consistently (same items) or randomly (different items) across all subjects. Lin's Concordance Correlation Coefficient (CCC) compared scores calculated without missing values with prorated scores based on sequentially increasing missing values. The maximal number of missing values retaining a CCC greater than 0.95 determined the threshold for rendering a valid prorated score. A second confirmatory sample was selected from the MDS-UPDRS international translation program. To provide valid part scores applicable across all Hoehn and Yahr (H&Y) stages when the same items are consistently missing, one missing item from Part I, one from Part II, three from Part III, but none from Part IV can be allowed. To provide valid part scores applicable across all H&Y stages when random item entries are missing, one missing item from Part I, two from Part II, seven from Part III, but none from Part IV can be allowed. All cutoff values were confirmed in the validation sample. These analyses are useful for constructing valid surrogate part scores for MDS-UPDRS when missing items fall within the identified threshold and give scientific justification for rejecting partially completed ratings that fall below the threshold. © 2015 International Parkinson and Movement Disorder Society.

  19. Myelodysplastic syndromes in Chernobyl clean-up workers.

    Science.gov (United States)

    Gluzman, Daniil F; Sklyarenko, Lilia M; Koval, Stella V; Rodionova, Nataliia K; Zavelevich, Michael P; Ivanivskaya, Tetiana S; Poludnenko, Liudmyla Yu; Ukrainskaya, Nataliia I

    2015-10-01

    The studies of the recent decades posed the question of the association between radiation exposure and myelodysplastic syndromes (MDS). This association has been proved in secondary MDS originating upon exposure to chemotherapeutics and/or radiation therapy. The long-term study in Japanese atomic (A)-bomb survivors demonstrated the significant linear dose-response for MDS confirming the link between radiation exposure and this form of hematopoietic malignancies. All these findings provide the strong basis for studying MDS in the persons exposed to radiation following the Chernobyl disaster, especially those in the cohort of Chernobyl clean-up workers of 1986-1987. The data on MDS among Chernobyl clean-up workers (1986-1987) diagnosed in 1996-2012 at the reference laboratory of RE Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology are summarized. MDS cases were diagnosed in 23 persons (21 males and 2 females) having been exposed to radiation as clean-up workers of 1986-1987. Refractory anemia (RA) has been detected in 13, refractory anemia with ring sideroblasts (RARS)-in 2, and refractory anemia with excess blasts (RAEB)-in 8 patients. The median age of those MDS patients was 62.0 years. In addition, 5 cases of chronic myelomonocytic leukemia (CMML) were recorded in the group of Chernobyl clean-up workers with the median time of 14.8 years from 1986-1987 to diagnosis. The association between radiation exposure and MDS is discussed. The suggested life-long risk for myelodysplastic syndromes among A-bomb survivors in Japan highlights the importance of the continuing follow-up studies in the affected populations in the post-Chernobyl period.

  20. RECENT ADVANCES IN THE 5Q- SYNDROME

    Directory of Open Access Journals (Sweden)

    Andrea Pellagatti

    2015-05-01

    Full Text Available The 5q- syndrome is the most distinct of the myelodysplastic syndromes (MDS and patients with this disorder have a deletion of chromosome 5q [del(5q] as the sole karyotypic abnormality. Several genes mapping to the commonly deleted region of the 5q- syndrome have been implicated in disease pathogenesis in recent years. Haploinsufficiency of the ribosomal gene RPS14 has been shown to cause the erythroid defect in the 5q- syndrome. Loss of the microRNA genes miR-145 and miR-146a has been associated with the thrombocytosis observed in 5q- syndrome patients. Haploinsufficiency of CSNK1A1 leads to hematopoietic stem cell expansion in mice and may play a role in the initial clonal expansion in patients with 5q- syndrome. Moreover, a subset of patients harbor mutation of the remaining CSNK1A1 allele. Mouse models of the 5q- syndrome, which recapitulate the key features of the human disease, indicate that a p53-dependent mechanism underlies the pathophysiology of this disorder. Importantly, activation of p53 has been demonstrated in the human 5q- syndrome. Recurrent TP53 mutations have been associated with an increased risk of disease evolution and with decreased response to the drug lenalidomide in del(5q MDS patients. Potential new therapeutic agents for del(5q MDS include the translation enhancer L-leucine.

  1. Disease: H00469 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H00469 Mitochondrial DNA depletion syndrome (MDS) Mitochondrial DNA depletion synd...n mitochondrial DNA in the affected tissues. The manifestations vary from tissue-specific mtDNA depletion to...5400 221350 615084 615418 615471 617156 PMID:20444604 ... AUTHORS ... Suomalainen A, Isohanni P ... TITLE ... Mitochondrial DNA depletion...drial transcription factor A, cause neonatal liver failure associated with mtDNA depletion. ... JOURNAL ... Mol Genet Metab 119:91-9 (2016) DOI:10.1016/j.ymgme.2016.07.001

  2. [Progress of cytogenetic detection in myelodysplastic syndromes].

    Science.gov (United States)

    Zhou, Qing-Bing; Hu, Xiao-Mei; Liu, -Feng; Ma, Rou

    2011-12-01

    In recent years, significant progresses have been got in study on pathogenesis, treatment and prognosis of myelodysplastic syndromes (MDS), especially on use of new technology, that has great importance for cytogenetics of MDS. Recently, the progress of cytogenetic detection in MDS is very remarkable. Based on the metaphase cytogenetics (MC) method, prognostic significance of cytogenetics in MDS was clarified gradually. For example, people have known the prognostic significance of 12 p-, 11 q-, +21, t(11(q23)), although these genetic abnormalities are rare in the MDS. In addition, chromosome mutation emerged in the process of MDS may indicate the poor prognosis. On the other hand, with the use of SNP-A and aCGH in the study of genetics, MDS cytogenetic abnormality detection rate has been further improved and can reach to 78%. At the same time, some of MDS patients with the "normal karyotype" detected by MC have new hidden aberrations through the SNP or CGH detection, and these patients have a poorer prognosis. In this review, the advances of study on cytogenetic detection for MDS based on MC and SNP-A or aCGH methods are summarized.

  3. Explicit MDS Codes with Complementary Duals

    DEFF Research Database (Denmark)

    Beelen, Duals Peter; Jin, Lingfei

    2018-01-01

    In 1964, Massey introduced a class of codes with complementary duals which are called Linear Complimentary Dual (LCD for short) codes. He showed that LCD codes have applications in communication system, side-channel attack (SCA) and so on. LCD codes have been extensively studied in literature....... On the other hand, MDS codes form an optimal family of classical codes which have wide applications in both theory and practice. The main purpose of this paper is to give an explicit construction of several classes of LCD MDS codes, using tools from algebraic function fields. We exemplify this construction...

  4. Outcome of Allogeneic Stem Cell Transplantation for Patients Transformed to Myelodysplastic Syndrome or Leukemia from Severe Aplastic Anemia: A Report from the MDS Subcommittee of the Chronic Malignancies Working Party and the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation

    NARCIS (Netherlands)

    Hussein, A.A.; Halkes, C.M.; Socie, G.; Tichelli, A.; Borne, P.A. von dem; Schaap, M.N.; Foa, R.; Ganser, A.; Dufour, C.; Bacigalupo, A.; Locasciulli, A.; Aljurf, M.; Peters, C.; Robin, M.; Biezen, A.A. van; Volin, L.; Witte, T.J. de; Marsh, J.; Passweg, J.R.; Kroger, N.; et al.,

    2014-01-01

    One hundred and forty patients who had undergone hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) transformation after treatment of severe aplastic anemia (SAA) were identified in the European Group for Blood and Marrow

  5. Construction of new quantum MDS codes derived from constacyclic codes

    Science.gov (United States)

    Taneja, Divya; Gupta, Manish; Narula, Rajesh; Bhullar, Jaskaran

    Obtaining quantum maximum distance separable (MDS) codes from dual containing classical constacyclic codes using Hermitian construction have paved a path to undertake the challenges related to such constructions. Using the same technique, some new parameters of quantum MDS codes have been constructed here. One set of parameters obtained in this paper has achieved much larger distance than work done earlier. The remaining constructed parameters of quantum MDS codes have large minimum distance and were not explored yet.

  6. Impact of chromosome alterations, genetic mutations and clonal hematopoiesis of indeterminate potential (CHIP) on the classification and risk stratification of MDS.

    Science.gov (United States)

    Ganguly, Bani Bandana; Banerjee, Debasis; Agarwal, Mohan B

    2018-03-01

    The advent of technological development has undoubtedly advanced biological and molecular inputs for better understanding the heterogeneous hematopoietic pre-malignant disorder of the stem cells known as myelodysplastic syndromes (MDS). Chromosomal rearrangements, including del(3q/5q/7q/11q/12p/20q), loss of 5/7/Y, trisomy 8/19, i(17q), etc. frequently detected in MDS with variable frequencies and combinations, are the integral components of the 5-tier risk-stratification and WHO-2016 classification. Observations on mutations in genes involved in RNA-splicing, DNA methylation, chromatin modification, transcription factor, signal transduction/kinases, RAS pathway, cohesin complex, DNA repair and other pathways have given insights in independent effects and biological interaction of co-occurrence on disease-phenotype and treatment outcome. However, recent concepts of clonal hematopoiesis of indeterminate potential (CHIP) and idiopathic cytopenia of undetermined significance (ICUS) have urged a re-definition of mutational events in non-clonal cytopenia and non-MDS healthy elderly but with a higher risk of overt leukemia. Considering gene mutations, chromosomal alterations, CHIP, ICUS and their significance in classification and risk-scoring certainly presents a comprehensive picture of disease-phenotype towards better understanding of MDS-pathogenesis, its evolution to AML and its response to therapeutic agents. The present review summarizes chromosomal and gene mutations, co-existence of mutational complexity, and WHO-2016 classification and risk-stratifications of MDS to facilitate a better understanding of its pathogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Some Families of Asymmetric Quantum MDS Codes Constructed from Constacyclic Codes

    Science.gov (United States)

    Huang, Yuanyuan; Chen, Jianzhang; Feng, Chunhui; Chen, Riqing

    2018-02-01

    Quantum maximal-distance-separable (MDS) codes that satisfy quantum Singleton bound with different lengths have been constructed by some researchers. In this paper, seven families of asymmetric quantum MDS codes are constructed by using constacyclic codes. We weaken the case of Hermitian-dual containing codes that can be applied to construct asymmetric quantum MDS codes with parameters [[n,k,dz/dx

  8. Age-related changes of healthy bone marrow cell signaling in response to growth factors provide insight into low risk MDS.

    Science.gov (United States)

    Kornblau, Steven M; Cohen, Aileen C; Soper, David; Huang, Ying-Wen; Cesano, Alessandra

    2014-11-01

    Single Cell Network Profiling (SCNP) is a multiparametric flow cytometry-based assay that quantifiably and simultaneously measures changes in intracellular signaling proteins in response to in vitro extracellular modulators at the single cell level. Myelodysplastic syndrome (MDS) is a heterogeneous clonal disorder of hematopoietic stem cells that occurs in elderly subjects and is characterized by dysplasia and ineffective hematopoiesis. The functional responsiveness of MDS bone marrow (BM) hematopoietic cells, including functionally distinct myeloid and erythroid precursor subsets, to hematopoietic growth factors (HGF) and the relationship of modulated signaling to disease characteristics is poorly understood. SCNP was used first to examine the effects of age on erythropoietin (EPO) and granulocyte colony stimulating factor (GCSF)-induced signaling in myeloid, nucleated red blood cells (nRBC), and CD34 expressing cell subsets in healthy BM (n = 15). SCNP was then used to map functional signaling profiles in low risk (LR) MDS (n = 7) for comparison to signaling in samples from healthy donors and to probe signaling associations within clinically defined subgroups. In healthy BM samples, signaling responses to HGF were quite homogeneous (i.e., tightly regulated) with age-dependent effects observed in response to EPO but not to GCSF. Despite the relatively small number of samples assayed in the study, LR MDS could be classified into distinct subgroups based on both cell subset frequency and signaling profiles. As a correlate of underlying genetic abnormalities, signal transduction analyses may provide a functional and potentially clinically relevant classification of MDS. Further evaluation in a larger cohort is warranted. © 2013 Clinical Cytometry Society.

  9. Construction of MDS self-dual codes from orthogonal matrices

    OpenAIRE

    Shi, Minjia; Sok, Lin; Solé, Patrick

    2016-01-01

    In this paper, we give algorithms and methods of construction of self-dual codes over finite fields using orthogonal matrices. Randomization in the orthogonal group, and code extension are the main tools. Some optimal, almost MDS, and MDS self-dual codes over both small and large prime fields are constructed.

  10. Two cases of therapy-related myelodysplastic syndrome after concurrent oral cancer chemoradiotherapy

    International Nuclear Information System (INIS)

    Doi, Katsuyuki; Asano, Takanori; Kinoshita, Takashi

    2010-01-01

    Therapy-related myelodysplastic syndrome (t-MDS) and therapy-related leukemia (TRL) are reported increasingly often, and we report two cases of T-MDS after concurrent chemoradiotherapy (CCRT) with oral cancer. Patients underwent CCRT with cisplatin (CDDP) or carboplatin (CBDCA). The interval between primary CCRT and t-MDS was 11 months in 1 case and 14 years in the other. Chromosomal analysis indicated abnormal karyotypes. Platinum has a relatively lower t-MDS risk than alkylating agents or topoisomerase II inhibitors, but our experience supports concurrent use of radiotherapy with platinum affects the risk of t-MDS. If pancytopenia is detected after CCRT, bone marrow and cytogenetic examinations should be conducted to rule out t-MDS. (author)

  11. Monitoring the grid with the Globus Toolkit MDS4

    International Nuclear Information System (INIS)

    Schopf, Jennifer M; Pearlman, Laura; Miller, Neill; Kesselman, Carl; Foster, Ian; D'Arcy, Mike; Chervenak, Ann

    2006-01-01

    The Globus Toolkit Monitoring and Discovery System (MDS4) defines and implements mechanisms for service and resource discovery and monitoring in distributed environments. MDS4 is distinguished from previous similar systems by its extensive use of interfaces and behaviors defined in the WS-Resource Framework and WS-Notification specifications, and by its deep integration into essentially every component of the Globus Toolkit. We describe the MDS4 architecture and the Web service interfaces and behaviors that allow users to discover resources and services, monitor resource and service states, receive updates on current status, and visualize monitoring results. We present two current deployments to provide insights into the functionality that can be achieved via the use of these mechanisms

  12. Mediators of the Association of Major Depressive Syndrome and Anxiety Syndrome with Postpartum Smoking Relapse

    Science.gov (United States)

    Correa-Fernandez, Virmarie; Ji, Lingyun; Castro, Yessenia; Heppner, Whitney L.; Vidrine, Jennifer Irvin; Costello, Tracy J.; Mullen, Patricia Dolan; Cofta-Woerpel, Ludmila; Velasquez, Mary M.; Greisinger, Anthony; Cinciripini, Paul M.; Wetter, David W.

    2012-01-01

    Objective: Based on conceptual models of addiction and affect regulation, this study examined the mechanisms linking current major depressive syndrome (MDS) and anxiety syndrome (AS) to postpartum smoking relapse. Method: Data were collected in a randomized clinical trial from 251 women who quit smoking during pregnancy. Simple and multiple…

  13. MDS Nordion - a Canadian success story

    International Nuclear Information System (INIS)

    Boyd, F.

    1998-01-01

    MDS Nordion,the world leading supplier of radioisotopes, had its beginnings as a small division of the crown company Eldorado Mining and Refining Ltd. in the late 1940's. With the end of World War II, Eldorado found itself with a supply of radium left over from the production of uranium during the war and set up a small group in Ottawa to sell it. Most of the stock of radium was disposed of when the development of the NRX reactor made reactor produced radioisotopes possible. The company turned to selling these radioisotopes and soon focused on Cobalt 60 for its use in cancer therapy. In 1952, the group transferred to AECL (Atomic Energy of Canada Ltd.), as part of the Commercial Products Division. In 1988, as part of the federal government's move to privatization, the organization was split into two companies, Theratronics, which manufactures the cancer therapy machines and other equipment for the use of radioisotopes, and Nordion International, which continued the primary business of processing, packaging, selling radioisotopes. In 1991 Nordion International was sold to MDS Inc., a large international group of companies in the life and sciences fields with headquarters in Toronto. The name was changed to MDS Nordion in December 1996

  14. [Inhibitory Effect of Decitabine on Proliferation of MDS-L Cells and Its Mechanism].

    Science.gov (United States)

    Wu, Dong; Zhang, Yao; Zhao, You-Shan; Guo, Juan; Chang, Chun-Kang

    2017-10-01

    To investigate the inhibitory effect of decitabine (DAC) in various dosages on the proliferention of MDS-RAEB cell line MDS-L and its mechanism. LC-MS/MS method was used to test the blood DAC concentration of 2 groups of MDS patients being treated with DAC 20 and 15 mg/m 2 ×5 d. In according to the various blood DAC concentration levels, the MDS-L cells were treated with different DAC dosages for 24, 48, 72 and 96 h, respectively. The CCK-8 method was applied to determine the cell proliferation, the flow cytometry was used to analyze the cell cycle and cell apoptosis changes, the P15 INK4B DNA methylation status was measured by methylation specific PCR using EZ DNA Methylation-Gold Kit. The blood DAC concentration of MDS patients treated with DAC 20 mg/m 2 ×5 d was 174.08±80.15(84.7-311) ng/ml, which was significantly higher than 89.87±32.94(43.2-165)ng/ml for the group treated with 15 mg/m 2 ×5 d (P=0.014). DAC could notably inhibit the proliferation of MDS-L cells, and the effect was in dose- and- time-dependent manner(r=0.786). However, when DAC concentration was ≥0.1 µg/ml, the proliferation inhibition rates were not significantly different between various dosages. After DAC treatment, MDS-L cells in G 1 phase increased notably, while cells in S phase decreased significantly. Also, the P15 INK4B DNA methylation status of MDS-L cells decreased after being treated with DAC for 96 h, but the difference was not significant between various dosages. DAC can significantly suppress MDS-L cell proliferation, block MDS-L cells in G 1 phase and induce the apoptosis at low concentration (0.1-0.2 µg/ml).

  15. IER3 Expression in Childhood Myelodysplastic Syndrome

    DEFF Research Database (Denmark)

    de Vries, Andrica; Zwaan, Christian M.; Danen van Ooschot, Astrid

    Background: Childhood myelodysplastic syndrome (MDS) is a rare disease accounting for less than 5% of all hematological malignancies. In about 50% of the MDS cases an abnormal karyotype is found by conventional karyotyping, of which chromosome 6 is involved in 10%. The immediate-early-response 3...... (IER3) gene, which is located on chromosome 6p21, encodes for a glycoprotein that plays a role in the regulation of apoptosis and cell cycle progression. Recently, it was shown that IER3 gene aberrations frequently occur in adult MDS patients, which are not restricted to patients with chromosome 6...... aberrations and that low IER3 expression was associated with a worse outcome. Therefore, we investigated the frequency and prognostic impact of IER3 expression in childhood MDS. Methods: IER3 mRNA expression was determined by quantitative real-time PCR in 58 childhood MDS patients of which 17 carried...

  16. Sequential acquisition of mutations in myelodysplastic syndromes.

    Science.gov (United States)

    Makishima, Hideki

    2017-01-01

    Recent progress in next-generation sequencing technologies allows us to discover frequent mutations throughout the coding regions of myelodysplastic syndromes (MDS), potentially providing us with virtually a complete spectrum of driver mutations in this disease. As shown by many study groups these days, such driver mutations are acquired in a gene-specific fashion. For instance, DDX41 mutations are observed in germline cells long before MDS presentation. In blood samples from healthy elderly individuals, somatic DNMT3A and TET2 mutations are detected as age-related clonal hematopoiesis and are believed to be a risk factor for hematological neoplasms. In MDS, mutations of genes such as NRAS and FLT3, designated as Type-1 genes, may be significantly associated with leukemic evolution. Another type (Type-2) of genes, including RUNX1 and GATA2, are related to progression from low-risk to high-risk MDS. Overall, various driver mutations are sequentially acquired in MDS, at a specific time, in either germline cells, normal hematopoietic cells, or clonal MDS cells.

  17. The biology of myelodysplastic syndromes: unity despite heterogeneity

    Directory of Open Access Journals (Sweden)

    Azra Raza

    2010-06-01

    Full Text Available Myelodysplastic syndromes (MDS traditionally have been grouped together as a disease entity based on clinical phenomena seen in association. Despite the similarities, there is great heterogeneity among the syndromes. Recent insights have shown, however, that there exists a biologically cohesive theme that unifies and thereby validates the conceptual interconnectedness. The first suggestion that such a relationship existed where biology could directly explain the observed cytopenias was the finding of excessive premature apoptosis of hematopoietic cells in MDS marrows. This apoptosis was mediated by paracrine as well as autocrine factors implicating both the seed and the soil in the pathology of the disease. Pro-inflammatory cytokines in the marrow microenvironment were mainly the paracrine mediators of apoptosis, but how the clonal cells committed suicide because of autocrine stimulation had remained a mystery for more than a decade. It has been shown now that deregulation of ribosome biogenesis can initiate a stress response in the cell through the p53 signaling pathway. Congenital anemias had been associated with mutations in ribosomal protein genes. The surprise came with the investigation of 5q- syndrome patients where haplo-insufficiency of the ribosomal protein gene RPS14 was found to be the cause of this MDS subtype. Similar ribosomal deregulation was shown to be present in all varieties of MDS patients, serving as another unifying characteristic. In addition to these findings, there are other DNA-related abnormalities such as uniparental disomy, mutations in the TET2 gene, and epigenetic phenomena that are associated with and occur across all types of MDS. This paper summarizes the themes unifying this heterogeneous group of diseases.

  18. Aberrant Methylation-Mediated Suppression of APAF1 in Myelodysplastic Syndrome.

    Science.gov (United States)

    Zaker, Farhad; Nasiri, Nahid; Amirizadeh, Naser; Razavi, Seyed Mohsen; Yaghmaie, Marjan; Teimoori-Toolabi, Ladan; Maleki, Ali; Bakhshayesh, Masoumeh

    2017-04-01

    Background: Myelodysplastic syndromes (MDSs) include a diverse group of clonal bone marrow disorders characterized by ineffective hematopoiesis and pancytopenia. It was found that down regulation of APAF1, a putative tumor suppressor gene (TSG), leads to resistance to chemotherapy and disease development in some cancers. In this study, we investigated the relation of APAF1 methylation status with its expression and clinicopathological factors in myelodysplastic syndrome (MDS) patients. Materials and Methods: Methylation Sensitive-High Resolution Melting Curve Analysis (MS-HRM) was employed in studying the methylation of CpG islands in the APAF1promoter region in MDS. Gene expression was analyzed by using real time RT-PCR. Results: 42.6% of patient samples were methylated in promoter region of APAF1analyzed, while methylation of the gene was not seen in controls (P<0.05). Methylation of APAF1was significantly associated with the suppression of its mRNA expression (P=0.00). The methylation status of APAF1in advanced-stage MDS patients (80%) was significantly higher than that of the early-stage MDS patients (28.2%) (P=0.001). The difference in frequency of hypermethylatedAPAF1 gene was significant between good (37.5%) and poor (85.71%) cytogenetic risk groups (P=0.043). In addition, a higher frequency of APAF1hypermethylation was observed in higher-risk MDS group (69.2%) compared to lower-risk MDS group (34.14%) (P=0.026). Conclusion: Our study indicated that APAF1hypermethylation in MDS was associated to high-risk disease classified according to the IPSS, WHO and cytogenetic risk.

  19. 657del5 mutation of the NBS1 gene in myelodysplastic syndrome

    Directory of Open Access Journals (Sweden)

    Bunjevacki Vera

    2014-01-01

    Full Text Available Myelodysplastic syndromes (MDS are clonal hematologic stem cell disorders with an as yet unknown molecular pathology. Genetic instability has been proposed as a cause of MDS. Mutations in the NBS1 gene, whose product nibrin (p95 is involved in DNA damage repair and cell-cycle control, might be associated with an elevated predisposition to the development of MDS. The aim of the study was to examine truncating 5 bp deletion (657del5, the most frequent NBS1 gene mutation in Slavic populations, in MDS patients. Among 71 MDS patients, we found one case that was heterozygous for the NBS1 657del5 mutation. To the best of our knowledge, this is the first report of a NBS1 mutation in MDS. [Projekat Ministarstva nauke Republike Srbije, br. 175091

  20. [VALIDATION OF THE HUNGARIAN MDS-UPDRS: WHY DO WE NEED A NEW PARKINSON SCALE?].

    Science.gov (United States)

    Horvath, Krisztina; Aschermann Zsuzsanna; Acs, Péter; Bosnyák, Edit; Deli, Gabriella; Pál, Endre; Késmárki, Ildikó; Horváth Réka; Takács, Katalin; Komoly, Sámuel; Bokor, Magdolna; Rigó, Eszter; Lajtos, Júlia; Klivényi, Péter; Dibó, György; Vécsei, László; Takáts, Annamária; Tóth, Adrián; Imre, Piroska; Nagy, Ferenc; Herceg, Mihály; Hidasi, Eszter; Kovács, Norbert

    2014-03-30

    The Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) has been published in 2008 as the successor of the original UPDRS. The MDS-UPDRS organizing team developed guidelines for the development of official non-English translations consisting of four steps: translation/back-translation, cognitive pretesting, large field testing, and clinimetric analysis. The aim of this paper was to introduce the new MDS-UPDRS and its validation process into Hungarian. Two independent groups of neurologists translated the text of the MDS-UPDRS into Hungarian and subsequently back-translated into English. After the review of the back-translated English version by the MDS-UPDRS translation administration team, cognitive pretesting was conducted with ten patients. Based on the results of the initial cognitive pretesting, another round was conducted. For the large field testing phase, the Hungarian official working draft version of MDS-UPDRS was tested with 357 patients with Parkinson's disease (PD). Confirmatory factor analyses (CFA) determined whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Hungarian Official Draft Version. To become an official translation, the Comparative Fit Index (CFI) had to be ≥ 0.90 compared to the English-language version. For all four parts of the Hungarian MDS-UPDRS, the CFI was ≥ 0.94. The overall factor structure of the Hungarian version was consistent with that of the English version based on the high CFIs for all the four parts of the MDS-UPDRS in the CFA; therefore, this version was designated as the "OFFICIAL GUNGARIAN VERSION OF THE MDS-UPDRS'.

  1. Simultaneous Presentation of Giant Cell Arteritis and Myelodysplastic Syndrome in an Elderly Japanese Man.

    Science.gov (United States)

    Senjo, Hajime; Higuchi, Takakazu; Morimoto, Masaya; Koyamada, Ryosuke; Yanaoka, Chisun; Okada, Sadamu

    2018-05-18

    An 81-year-old Japanese man presented with constitutional symptoms and anemia and was diagnosed with giant cell arteritis (GCA) and myelodysplastic syndrome (MDS) simultaneously. His symptoms and anemia improved promptly with steroids; however, the MDS rapidly progressed to overt leukemia. While MDS patients are at an increased risk of autoimmune diseases, an association with GCA has rarely been reported. This case illustrates the importance of considering GCA as a cause of anemia in elderly patients if MDS is already diagnosed, even in countries where the prevalence of GCA is very low. The simultaneous development of GCA and MDS suggests a common pathogenetic link between these two diseases.

  2. Measuring depression in nursing home residents with the MDS and GDS: an observational psychometric study

    Directory of Open Access Journals (Sweden)

    Fries Brant E

    2005-01-01

    Full Text Available Abstract Background The objective of this study was to examine the Minimum Data Set (MDS and Geriatric Depression Scale (GDS as measures of depression among nursing home residents. Methods The data for this study were baseline, pre-intervention assessment data from a research study involving nine nursing homes and 704 residents in Massachusetts. Trained research nurses assessed residents using the MDS and the GDS 15-item version. Demographic, psychiatric, and cognitive data were obtained using the MDS. Level of depression was operationalized as: (1 a sum of the MDS Depression items; (2 the MDS Depression Rating Scale; (3 the 15-item GDS; and (4 the five-item GDS. We compared missing data, floor effects, means, internal consistency reliability, scale score correlation, and ability to identify residents with conspicuous depression (chart diagnosis or use of antidepressant across cognitive impairment strata. Results The GDS and MDS Depression scales were uncorrelated. Nevertheless, both MDS and GDS measures demonstrated adequate internal consistency reliability. The MDS suggested greater depression among those with cognitive impairment, whereas the GDS suggested a more severe depression among those with better cognitive functioning. The GDS was limited by missing data; the DRS by a larger floor effect. The DRS was more strongly correlated with conspicuous depression, but only among those with cognitive impairment. Conclusions The MDS Depression items and GDS identify different elements of depression. This may be due to differences in the manifest symptom content and/or the self-report nature of the GDS versus the observer-rated MDS. Our findings suggest that the GDS and the MDS are not interchangeable measures of depression.

  3. Measuring depression in nursing home residents with the MDS and GDS: an observational psychometric study

    Science.gov (United States)

    Koehler, Melissa; Rabinowitz, Terry; Hirdes, John; Stones, Michael; Carpenter, G Iain; Fries, Brant E; Morris, John N; Jones, Richard N

    2005-01-01

    Background The objective of this study was to examine the Minimum Data Set (MDS) and Geriatric Depression Scale (GDS) as measures of depression among nursing home residents. Methods The data for this study were baseline, pre-intervention assessment data from a research study involving nine nursing homes and 704 residents in Massachusetts. Trained research nurses assessed residents using the MDS and the GDS 15-item version. Demographic, psychiatric, and cognitive data were obtained using the MDS. Level of depression was operationalized as: (1) a sum of the MDS Depression items; (2) the MDS Depression Rating Scale; (3) the 15-item GDS; and (4) the five-item GDS. We compared missing data, floor effects, means, internal consistency reliability, scale score correlation, and ability to identify residents with conspicuous depression (chart diagnosis or use of antidepressant) across cognitive impairment strata. Results The GDS and MDS Depression scales were uncorrelated. Nevertheless, both MDS and GDS measures demonstrated adequate internal consistency reliability. The MDS suggested greater depression among those with cognitive impairment, whereas the GDS suggested a more severe depression among those with better cognitive functioning. The GDS was limited by missing data; the DRS by a larger floor effect. The DRS was more strongly correlated with conspicuous depression, but only among those with cognitive impairment. Conclusions The MDS Depression items and GDS identify different elements of depression. This may be due to differences in the manifest symptom content and/or the self-report nature of the GDS versus the observer-rated MDS. Our findings suggest that the GDS and the MDS are not interchangeable measures of depression. PMID:15627403

  4. Utility of 5-Methylcytosine Immunohistochemical Staining to Assess Global DNA Methylation and Its Prognostic Impact in MDS Patients

    Science.gov (United States)

    Chandra, Dinesh; Tyagi, Seema; Singh, Jasdeep; Deka, Roopam; Manivannan, Prabhu; Mishra, Pravas; Pati, Hara Prasad; Saxena, Renu

    2017-12-29

    Background: DNA methylation plays a vital role in the pathogenesis of the myelodysplastic syndrome (MDS), a heterogeneous group of clonal hematopoietic stem cell (HSC) disorders. It is reported to be an independent prognostic factor affecting overall survival (OS). Our aim was to analyze the role of global DNA methylation using an anti-5-methylcytosine (5-MC) antibody by immunohistochemistry (IHC) of bone marrow biopsy (BM Bx) specimens in MDS patients, assessing correlations with various clinical and biological prognostic factors. Material and methods: A total of 59 MDS cases, classified as per the World Health Organization (WHO) 2008 guidelines, were evaluated over a period of 4 years. Clinical data were retrieved from departmental case records and anti-5-MC expression was analyzed with formalin fixed paraffin embedded sections of BM Bx specimens of MDS patients and controls. Results: The median age at diagnosis was 52 years (15-85years). Patients were categorized into low risk (59%) and high risk (41%) according to International Prognostic Scoring System (IPSS). The median follow-up time was 10 months (1 to 37 months). We generated a methylation score (M-score) using anti-5-MC and with the derived cut-off of 30.5 from the receiver operator curve (ROC), there was a significant difference between the two groups in the percentage of BM blasts (p=0.01), WHO sub-type (p=0.01), IPSS (p=0.004), progression to AML (p=0.04) on univariate analysis. Interestingly, patients showing a high M-score (M-score ≥ 30.5) demonstrated a significantly shorter OS and progression to AML. However, on multivariate analysis, only BM blasts (p=0.01) and IPSS (p=0.02) remained independent variables for progression to AML and OS respectively. Conclusion: Immunostaining with anti-5-MC antibody with BM Bx samples is a simple and cost effective technique to detect global methylation, a powerful tool to predict overall survival in patients with MDS. Creative Commons Attribution License

  5. Radiotherapy- and Chemotherapy-Induced Myelodysplasia Syndrome

    Science.gov (United States)

    Sun, Li-Min; Lin, Cheng-Li; Lin, Ming-Chia; Liang, Ji-An; Kao, Chia-Hung

    2015-01-01

    Abstract This study explored which kinds of cancer are related to a higher incidence of subsequent myelodysplastic syndrome (MDS) after radiotherapy (RT) and chemotherapy (CT). We performed a nested case–control study by using data from the Taiwanese National Health Insurance (NHI) system. The case group included cancer patients who developed MDS. For the control group, 4 cancer patients without MDS were frequency-matched with each MDS case by age, sex, year of cancer diagnosis, and MDS index year. A multivariable logistic regression analysis was conducted, and odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. Overall, cancer patients who received RT or CT exhibited secondary MDS more frequently than did those who did not (RT: OR = 1.53; 95% CI = 1.33–1.77; CT: OR = 1.51; 95% CI = 1.25–1.82). Analysis by cancer site showed that RT increased the risk of MDS for patients with stomach, colorectal, liver, breast, endometrial, prostate, and kidney cancers. By contrast, CT was more likely to increase the risk of MDS for patients with lung, endometrial, and cervical cancers. Further analysis revealed that RT and CT seemed to have a positive interaction. The major limitation of this study was the lack of certain essential data in the NHI Research Database, such as data regarding cancer stage and treatment dose details. This population-based nested case–control study determined that RT and CT predisposed patients in Taiwan to the development of MDS. This effect was more prominent when both modalities were used. PMID:25929909

  6. Risk stratification in myelodysplastic syndromes: is there a role for gene expression profiling?

    Science.gov (United States)

    Zeidan, Amer M; Prebet, Thomas; Saad Aldin, Ehab; Gore, Steven David

    2014-04-01

    Evaluation of: Pellagatti A, Benner A, Mills KI et al. Identification of gene expression-based prognostic markers in the hematopoietic stem cells of patients with myelodysplastic syndromes. J. Clin. Oncol. 31(28), 3557-3564 (2013). Patients with myelodysplastic syndromes (MDS) exhibit wide heterogeneity in clinical outcomes making accurate risk-stratification an integral part of the risk-adaptive management paradigm. Current prognostic schemes for MDS rely on clinicopathological parameters. Despite the increasing knowledge of the genetic landscape of MDS and the prognostic impact of many newly discovered molecular aberrations, none to date has been incorporated formally into the major risk models. Efforts are ongoing to use data generated from genome-wide high-throughput techniques to improve the 'individualized' outcome prediction for patients. We here discuss an important paper in which gene expression profiling (GEP) technology was applied to marrow CD34(+) cells from 125 MDS patients to generate and validate a standardized GEP-based prognostic signature.

  7. Comparison of childhood myelodysplastic syndrome, AML FAB M6 or M7, CCG 2891: report from the Children's Oncology Group.

    Science.gov (United States)

    Barnard, Dorothy R; Alonzo, Todd A; Gerbing, Robert B; Lange, Beverly; Woods, William G

    2007-07-01

    Myelodysplastic syndromes (MDS), acute erythroleukemia (FAB M6), and acute megakaryocytic leukemia (FAB M7) have overlapping features. Children without Down syndrome or acute promyelocytic leukemia who were newly diagnosed with primary myelodysplastic syndrome or acute myeloid leukemia (AML) M6 or M7 were compared to children with de novo AML M0-M5. All children were entered on the Children's Cancer Group therapeutic research study CCG 2891. The presentation and outcomes of the 132 children diagnosed with MDS (60 children), AML FAB M6 (19 children), or AML FAB M7 (53 children) were similar. Children with AML FAB M7 were diagnosed at a significantly younger age (P = 0.001). Children with MDS, M6, or M7 had significantly lower white blood cell (WBC) counts (P = 0.001), lower peripheral blast counts (P M6 and AML M7 resemble MDS in presentation, poor induction success rates, and outcomes.

  8. Prognostic factors in de novo myelodysplastic syndrome in young and middle-aged people

    Directory of Open Access Journals (Sweden)

    Наталья Николаевна Климкович

    2015-01-01

    Full Text Available We spent multivariate analysis of clinical and laboratory parameters for the prediction of de-novo myelodysplastic syndromes (MDS patients aged 18-60 years. The results of clinical application of prognostic systems in MDS show that there is a large variability within individual risk groups, especially at low-risk MDS. So now hematologists conduct research aimed at identifying additional adverse risk MDS. This is done so that patients with low-risk MDS embodiments and unfavorable prognosis could benefit from early therapeutic intervention, and not only be clinician monitored until disease progression. We found that additional adverse risk factors for the development of MDS are the expression of CD95 in bone marrow ≤40 % and FLT3≥60 %. The expression level of CD95 in bone marrow cells≤40 % and FLT3≥60 % can be considered as a prognostic marker progression of MDS and time start specific therapy

  9. On depleted uranium: gulf war and Balkan syndrome.

    Science.gov (United States)

    Duraković, A

    2001-04-01

    The complex clinical symptomatology of chronic illnesses, commonly described as Gulf War Syndrome, remains a poorly understood disease entity with diversified theories of its etiology and pathogenesis. Several causative factors have been postulated, with a particular emphasis on low level chemical warfare agents, oil fires, multiple vaccines, desert sand (Al-Eskan disease), botulism, Aspergillus flavus, Mycoplasma, aflatoxins, and others, contributing to the broad scope of clinical manifestations. Among several hundred thousand veterans deployed in the Operation Desert Storm, 15-20% have reported sick and about 25,000 died. Depleted uranium (DU), a low-level radioactive waste product of the enrichment of natural uranium with U-235 for the reactor fuel or nuclear weapons, has been considered a possible causative agent in the genesis of Gulf War Syndrome. It was used in the Gulf and Balkan wars as an armor-penetrating ammunition. In the operation Desert Storm, over 350 metric tons of DU was used, with an estimate of 3-6 million grams released in the atmosphere. Internal contamination with inhaled DU has been demonstrated by the elevated excretion of uranium isotopes in the urine of the exposed veterans 10 years after the Gulf war and causes concern because of its chemical and radiological toxicity and mutagenic and carcinogenic properties. Polarized views of different interest groups maintain an area of sustained controversy more in the environment of the public media than in the scientific community, partly for the reason of being less than sufficiently addressed by a meaningful objective interdisciplinary research.

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

    Directory of Open Access Journals (Sweden)

    Udit Bhaskar Bhatnagar

    2016-01-01

    Full Text Available 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.

  11. 75 FR 16512 - Willstaff Staffing Agency, Willstaff Crystal, Inc., and MDS Industrial Resources, Inc., Working...

    Science.gov (United States)

    2010-04-01

    ... Agency, Willstaff Crystal, Inc., and MDS Industrial Resources, Inc., Working On-Site at Tyler Pipe... MDS Industrial Resources, Inc., working on-site at Tyler Pipe Company, Waterworks Division, South... Staffing Agency, Willstaff Crystal, Inc., and MDS Industrial Resources, Inc., working on-site at Tyler Pipe...

  12. Myelodysplastic syndromes and the role of iron overload.

    Science.gov (United States)

    Harvey, R Donald

    2010-04-01

    The epidemiology of myelodysplastic syndromes (MDS) and iron overload, recent clinical findings that highlight the importance of actively managing iron overload, and recommendations for initiating and maintaining iron chelation therapy (ICT) are summarized. MDS are a variety of hematological disorders with differing time courses. Disease morbidities are primarily due to cytopenias and evolution to acute myeloid leukemia. Iron overload is a serious complication in patients with MDS due to the long-term use of red blood cell transfusions in patients with symptomatic anemia. Clinical consequences of iron overload include end-organ damage and dysfunction, an increased frequency of transplant-related complications, and reduced survival rates. To prevent these complications, recommendations for initiating and maintaining ICT should be followed by clinicians caring for patients with MDS and iron overload. As current therapeutic options for patients with MDS do not always reduce the transfusion burden, many patients will still need long-term transfusion therapy. Strategies for the management of iron overload in MDS should be considered early in the disease course and in appropriate patients in order to prevent negative clinical outcomes associated with excessive iron accumulation.

  13. Parkinson's disease severity levels and MDS-Unified Parkinson's Disease Rating Scale.

    Science.gov (United States)

    Martínez-Martín, Pablo; Rodríguez-Blázquez, Carmen; Mario Alvarez; Arakaki, Tomoko; Arillo, Víctor Campos; Chaná, Pedro; Fernández, William; Garretto, Nélida; Martínez-Castrillo, Juan Carlos; Rodríguez-Violante, Mayela; Serrano-Dueñas, Marcos; Ballesteros, Diego; Rojo-Abuin, Jose Manuel; Chaudhuri, Kallol Ray; Merello, Marcelo

    2015-01-01

    Severity of PD is usually assessed by means of the motor and disability-based Hoehn and Yahr staging (HY), or clinician and patient global perceptions. Scores of more detailed assessments, as the MDS-UPDRS, have not been translated to a grading that allows assignment of score sections to severity levels. The objective of the present study is to determine cut-off points for PD severity levels based on the MDS-UPDRS. International, observational study. Applied assessments were: HY, MDS-UPDRS, Clinical Impression for Severity Index, and Clinical and Patient Global Impression of Severity. The coincidence in severity level (mild, moderate, severe) of at least two clinical classifications plus the patient's gradation was considered "the criterion of severity". Cut-off values for each MDS-UPDRS subscale was determined by triangulation of: 1) percentile 90 of the subscale total score; 2) receiver operating characteristic (ROC) analysis; and 3) ordinal logistic regression (OLR) model. Sample was composed of 452 consecutive PD patients without dementia, 55.3% males, age 65.1 ± 10.7 years and PD duration 8.7 ± 6.3 years. All HY stages were represented. The "criterion", classified 275 patients (60.8% of the sample) as: mild PD, 149 (54.2%); moderate, 82 (29.8%); and severe, 44 (16%). The following MDS-UPDRS cut-off points between mild/moderate and moderate/severe levels were found: Part 1: 10/11 and 21/22; Part 2: 12/13 and 29/30; Part 3: 32/33 and 58/59; and Part 4: 4/5 and 12/13. Cut-off points to classify PD patients as mild, moderate, or severe on the basis of their MDS-UPDRS scores are proposed. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Entanglement-assisted quantum MDS codes from negacyclic codes

    Science.gov (United States)

    Lu, Liangdong; Li, Ruihu; Guo, Luobin; Ma, Yuena; Liu, Yang

    2018-03-01

    The entanglement-assisted formalism generalizes the standard stabilizer formalism, which can transform arbitrary classical linear codes into entanglement-assisted quantum error-correcting codes (EAQECCs) by using pre-shared entanglement between the sender and the receiver. In this work, we construct six classes of q-ary entanglement-assisted quantum MDS (EAQMDS) codes based on classical negacyclic MDS codes by exploiting two or more pre-shared maximally entangled states. We show that two of these six classes q-ary EAQMDS have minimum distance more larger than q+1. Most of these q-ary EAQMDS codes are new in the sense that their parameters are not covered by the codes available in the literature.

  15. Long Term Care Minimum Data Set (MDS)

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Long-Term Care Minimum Data Set (MDS) is a standardized, primary screening and assessment tool of health status that forms the foundation of the comprehensive...

  16. New recurrent deletions in the PPARgamma and TP53 genes are associated with childhood myelodysplastic syndrome

    DEFF Research Database (Denmark)

    Silveira, Cássia G T; Oliveira, Fábio M; Valera, Elvis T

    2009-01-01

    Myelodysplastic syndrome (MDS) is a rare hematological malignancy in children. It was performed FISH analysis in 19 pediatric MDS patients to investigate deletions involving the PPARgamma and TP53 genes. Significant losses in the PPARgamma gene and deletions in the tumor suppressor gene TP53 were...

  17. Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance

    OpenAIRE

    Akman, Hasan O.; Dorado, Beatriz; López, Luis C.; García-Cazorla, Ángeles; Vilà, Maya R.; Tanabe, Lauren M.; Dauer, William T.; Bonilla, Eduardo; Tanji, Kurenai; Hirano, Michio

    2008-01-01

    Mitochondrial DNA (mtDNA) depletion syndrome (MDS), an autosomal recessive condition, is characterized by variable organ involvement with decreased mtDNA copy number and activities of respiratory chain enzymes in affected tissues. MtDNA depletion has been associated with mutations in nine autosomal genes, including thymidine kinase (TK2), which encodes a ubiquitous mitochondrial protein. To study the pathogenesis of TK2-deficiency, we generated mice harboring an H126N Tk2 mutation. Homozygous...

  18. Quality of life, physical function and MRI T2* in elderly low-risk MDS patients treated to a haemoglobin level of ≥120 g/L with darbepoetin alfa ± filgrastim or erythrocyte transfusions

    DEFF Research Database (Denmark)

    Nilsson-Ehle, Herman; Birgegård, Gunnar; Samuelsson, Jan

    2011-01-01

    Anaemia in low-risk myelodysplastic syndromes (MDS) is associated with reduced quality of life (QoL). Response to treatment with erythropoietin ± granulocyte colony-stimulating factor (G-CSF) is associated with improved QoL, but whether transfusion therapy with higher haemoglobin (Hb) target levels...... has similar effects is unknown. The objective for this prospective phase II Nordic multicentre trial was to assess QoL, response rate and physical function in elderly anaemic MDS patients treated to a target Hb level of >120 g/L....

  19. Outcome of patients treated for myelodysplastic syndromes without deletion 5q after failure of lenalidomide therapy

    OpenAIRE

    Prebet, Thomas; Toma, Andrea; Cluzeau, Thomas; Sekeres, Mikkael A.; Vey, Norbert; Park, Sophie; Al Ali, Najla; Sugrue, Marie M.; Komrokji, Rami; Fenaux, Pierre; Gore, Steven D.

    2017-01-01

    Anemia is a key survival prognostic factor in lower-risk myelodysplastic syndromes (MDS). Lenalidomide (LEN) can correct anemia in 25% of MDS patients without deletion 5q (del5q). As this therapy will inevitably fail, understanding the outcome of these patients will facilitate development of subsequent treatment strategies. To answer this question, an international retrospective study focused on LEN-treated lower-risk, non-del5q, MDS patients was performed. We analyzed the overall survival af...

  20. Quantitative Detection of ID4 Gene Aberrant Methylation in the Differentiation of Myelodysplastic Syndrome from Aplastic Anemia

    Directory of Open Access Journals (Sweden)

    Mian-Yang Li

    2015-01-01

    Full Text Available Background: The diagnosis of myelodysplastic syndrome (MDS, especially hypoplastic MDS, and MDS with low blast counts or normal karyotype may be problematic. This study characterized ID4 gene methylation in patients with MDS and aplastic anemia (AA. Methods: The methylation status of ID4 was analyzed by bisulfite sequencing polymerase chain reaction (PCR and quantitative real-time methylation-specific PCR (MethyLight PCR in 100 patients with MDS and 31 patients with AA. Results: The MDS group had a higher ID4 gene methylation positivity rate (22.22% and higher methylation levels (0.21 [0-3.79] than the AA group (P < 0.05. Furthermore, there were significant differences between the hypoplastic MDS and AA groups, the MDS with low blast count and the AA groups, and the MDS with normal karyotype and the AA groups. The combination of genetic and epigenetic markers was used in much more patients with MDS (62.5% [35/56] than the use of genetic markers only (51.79% [29/56]. Conclusions: These results showed that the detection of ID4 methylation positivity rates and levels could be a useful biomarker for MDS diagnosis.

  1. New q-ary quantum MDS codes with distances bigger than q/2

    Science.gov (United States)

    He, Xianmang; Xu, Liqing; Chen, Hao

    2016-07-01

    The construction of quantum MDS codes has been studied by many authors. We refer to the table in page 1482 of (IEEE Trans Inf Theory 61(3):1474-1484, 2015) for known constructions. However, there have been constructed only a few q-ary quantum MDS [[n,n-2d+2,d

  2. MR imaging findings of the femoral marrow in myelodysplastic syndrome

    International Nuclear Information System (INIS)

    Tanaka, Osamu; Takagi, Shojiro; Matsuura, Katsuhiko; Ichikawa, Tamaki; Kobayashi, Yasuyuki; Nagai, Jun

    1995-01-01

    MR imaging of the femoral marrow was performed in 30 patients with myelodysplastic syndrome (MDS), 11 cases of which evolved to acute myeloid leukemia (AML). The MRI appearance was classified into five patterns: fatty marrow; faint signal; nodular pattern; heterogeneous infiltration; and diffuse infiltration. For each type of MDS, MRI patterns of the femoral marrow were evaluated and compared with those in normal subjects as well as in patients with aplastic anemia. Signal intensity alteration, a low signal on T1-weighted SE image and a high signal on STIR image, began in the proximal femoral marrow almost symmetrically in patients with MDS. The area of abnormal signal intensity tended to gradually extend towards the distal portion of the femur as the disease progressed. MRI patterns of the femoral marrow correlated with marrow cellularity, and diffuse marrow infiltration was noted in patients with a more advanced type of MDS or with severe anemia. There were limitations to making an accurate diagnosis of the MDS type on the basis of the MRI pattern. Progression of the MRI appearance in the course of MDS was thought to be a sign suggesting evolution to AML. It was difficult to differentiate hypoplastic MDS from aplastic anemia, although the nodular pattern was commonly seen in the latter disease. (author)

  3. MR imaging findings of the femoral marrow in myelodysplastic syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Osamu; Takagi, Shojiro; Matsuura, Katsuhiko; Ichikawa, Tamaki; Kobayashi, Yasuyuki; Nagai, Jun [Jichi Medical School, Minamikawachi, Tochigi (Japan)

    1995-10-01

    MR imaging of the femoral marrow was performed in 30 patients with myelodysplastic syndrome (MDS), 11 cases of which evolved to acute myeloid leukemia (AML). The MRI appearance was classified into five patterns: fatty marrow; faint signal; nodular pattern; heterogeneous infiltration; and diffuse infiltration. For each type of MDS, MRI patterns of the femoral marrow were evaluated and compared with those in normal subjects as well as in patients with aplastic anemia. Signal intensity alteration, a low signal on T1-weighted SE image and a high signal on STIR image, began in the proximal femoral marrow almost symmetrically in patients with MDS. The area of abnormal signal intensity tended to gradually extend towards the distal portion of the femur as the disease progressed. MRI patterns of the femoral marrow correlated with marrow cellularity, and diffuse marrow infiltration was noted in patients with a more advanced type of MDS or with severe anemia. There were limitations to making an accurate diagnosis of the MDS type on the basis of the MRI pattern. Progression of the MRI appearance in the course of MDS was thought to be a sign suggesting evolution to AML. It was difficult to differentiate hypoplastic MDS from aplastic anemia, although the nodular pattern was commonly seen in the latter disease. (author).

  4. Therapy related myelodysplastic syndrome: A case report and review of literature

    Directory of Open Access Journals (Sweden)

    Smita Sonawane

    2011-01-01

    Full Text Available Therapy related myeloid neoplasm is directly related to previous cytotoxic chemotherapy or radiation therapy. We present a 47-year-old lady who developed therapy related myelodysplastic syndrome (MDS 2.5 years after she received four cycles of chemotherapy and local radiation therapy for carcinoma breast. She presented with bicytopenia with trilineage dyspoiesis in the peripheral blood, bone marrow aspirate and biopsy. Fluorescent in-situ hybridization studies did not reveal any of the common abnormalities associated with MDS. A diagnosis of therapy related MDS was rendered. Different studies have shown that patients treated with alkylating agents and ionizing radiation present as MDS with a latent period of 3-10 years. Our patient developed MDS within 2.5 years of starting chemotherapy and radiotherapy and did not reveal any of the conventional cytogenetic abnormalities. It highlights the importance of simple tests like a complete blood count and peripheral blood smear examination in follow-up of the patients treated with chemotherapy.

  5. Independent Validation of the SEND-PD and Correlation with the MDS-UPDRS Part IA

    Directory of Open Access Journals (Sweden)

    Mayela Rodríguez-Violante

    2014-01-01

    Full Text Available Introduction. Neuropsychiatric symptoms in Parkinson’s disease can be assessed by the MDS-UPDRS part IA. The Scale for Evaluation of Neuropsychiatric Disorders in Parkinson’s disease (SEND-PD has been recently developed to assess the severity of some neuropsychiatric symptoms. The objective of this study is to compare the performance of the SEND-PD with the corresponding items of the MDS-UPDRS part IA. Methods. Patients with Parkinson’s disease were evaluated using the MDS-UPDRS and the SEND-PD by independent raters. Partial SEND-PD and neuropsychiatric MDS-UPDRS part IA were constructed with equivalent items for comparison. Results. A total of 260 consecutive patients were included. Overall, 61.2% of the patients did not report any psychotic symptom and 83.5% did not report any ICD symptom. On the other hand, 78.5% of the patients did report at least one symptom related to apathy, depression, or anxiety. The partial SEND-PD score was 2.9±3.1 (range from 0 to 16. The neuropsychiatric MDS-UPDRS part IA score was 2.9±3 (range from 0 to 14. The correlation coefficient between corresponding items ranged from 0.67 to 0.98 and between both summary indexes was rs=0.93 (all, P<0.001. Conclusion. A high association between equivalent items of the SEND-PD and the MDS-UPDRS was found.

  6. Acquired Elliptocytosis as a Manifestation of Myelodysplastic Syndrome with Ring Sideroblasts and Multilineage Dysplasia

    Directory of Open Access Journals (Sweden)

    Jacob D. Kjelland

    2017-01-01

    Full Text Available Acquired elliptocytosis is a known but rarely described abnormality in the myelodysplastic syndromes (MDS. Here we report the case of an elderly male who was admitted to the hospital with chest pain, dyspnea, and fatigue and was found to be anemic with an elliptocytosis that had only recently been noted on peripheral smears of his blood. After bone marrow biopsy he was diagnosed with MDS with ring sideroblasts and multilineage dysplasia and acquired elliptocytosis. Here we report a rare case of acquired elliptocytosis cooccurring with MDS with ring sideroblasts and multilineage dysplasia.

  7. Should elderly patients with higher-risk myelodysplastic syndromes undergo allogeneic hematopoietic stem cell transplantation?

    Science.gov (United States)

    Zeidan, Amer M; Gore, Steven D

    2013-10-01

    Myelodysplastic syndromes (MDS) include a group of hematopoietic malignancies characterized by dysplastic changes, ineffective hematopoiesis and variable risk of leukemic progression. At diagnosis, 86% of MDS patients are ≥60 years. Azacitidine, the only drug that prolongs life in high-risk (HR)-MDS patients, adds a median of only 9.5 months to life. Allogeneic stem cell transplantation (alloSCT) remains the only potentially curative approach. Despite recent improvements including use of reduced intensity conditioning (RIC) that decrease transplant-related mortality, alloSCT continues to be used rarely in elderly MDS. There is paucity of data regarding outcomes of RIC alloSCT in elderly MDS patients, especially in direct comparison with azanucleosides. In this paper, the authors discuss the recent Markov decision analysis by Koreth et al. in which investigators demonstrated superior survival of patients with HR-MDS aged 60-70 years who underwent RIC alloSCT in comparison with those who were treated with azanucleosides.

  8. MDS-UPDRS to assess non-motor symptoms after STN DBS for Parkinson's disease.

    Science.gov (United States)

    Jafari, Nickey; Pahwa, Rajesh; Nazzaro, Jules M; Arnold, Paul M; Lyons, Kelly E

    2016-01-01

    To determine if the non-motor sections of the Movement Disorder Society's (MDS) version of the Unified Parkinson's Disease Rating Scale (UPDRS) could supplement the original UPDRS as a patient completed assessment of changes in non-motor symptoms in Parkinson's disease (PD) patients after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS). Thirty PD patients who underwent bilateral STN DBS were assessed using the total UPDRS and the non-motor sections of the MDS-UPDRS prior to surgery and one year following surgery. This study focuses on non-motor symptoms as assessed by Part I of the UPDRS and Part 1A and 1B of the MDS-UPDRS. One year following surgery, no individual non-motor symptoms or the total mentation score of the UPDRS were significantly changed. In comparison, the MDS-UPDRS showed significant improvements in sleep and urinary problems and a trend towards improvement in anxiety, constipation, daytime sleepiness, fatigue and pain. This study provides evidence that the MDS-UPDRS non-motor sections, when completed by the patients, can supplement the original version of the UPDRS as an effective method of measuring changes in non-motor symptoms after DBS. It also reinforces the benefits of bilateral STN DBS on non-motor symptoms of PD.

  9. Resident Assessment Instrument/Minimum Data Set (RAI/MDS)

    Data.gov (United States)

    Department of Veterans Affairs — The Resident Assessment Instrument/Minimum Data Set (RAI/MDS) is a comprehensive assessment and care planning process used by the nursing home industry since 1990 as...

  10. Trisomy 8, a Cytogenetic Abnormality in Myelodysplastic Syndromes, Is Constitutional or Not?

    Science.gov (United States)

    Saumell, Sílvia; Solé, Francesc; Arenillas, Leonor; Montoro, Julia; Valcárcel, David; Pedro, Carme; Sanzo, Carmen; Luño, Elisa; Giménez, Teresa; Arnan, Montserrat; Pomares, Helena; De Paz, Raquel; Arrizabalaga, Beatriz; Jerez, Andrés; Martínez, Ana B; Sánchez-Castro, Judith; Rodríguez-Gambarte, Juan D; Raya, José M; Ríos, Eduardo; Rodríguez-Rivera, María; Espinet, Blanca; Florensa, Lourdes

    2015-01-01

    Isolated trisomy 8 is not considered presumptive evidence of myelodysplastic syndrome (MDS) in cases without minimal morphological criteria. One reason given is that trisomy 8 (+8) can be found as a constitutional mosaicism (cT8M). We tried to clarify the incidence of cT8M in myeloid neoplasms, specifically in MDS, and the diagnostic value of isolated +8 in MDS. Twenty-two MDS and 10 other myeloid neoplasms carrying +8 were studied. Trisomy 8 was determined in peripheral blood by conventional cytogenetics (CC) and on granulocytes, CD3+ lymphocytes and oral mucosa cells by fluorescence in situ hybridization (FISH). In peripheral blood CC, +8 was seen in 4/32 patients. By FISH, only one patient with chronic myelomonocytic leukemia showed +8 in all cell samples and was interpreted as a cT8M. In our series +8 was acquired in all MDS. Probably, once discarded cT8M by FISH from CD3+ lymphocytes and non-hematological cells, +8 should be considered with enough evidence to MDS.

  11. Trisomy 8, a Cytogenetic Abnormality in Myelodysplastic Syndromes, Is Constitutional or Not?

    Directory of Open Access Journals (Sweden)

    Sílvia Saumell

    Full Text Available Isolated trisomy 8 is not considered presumptive evidence of myelodysplastic syndrome (MDS in cases without minimal morphological criteria. One reason given is that trisomy 8 (+8 can be found as a constitutional mosaicism (cT8M. We tried to clarify the incidence of cT8M in myeloid neoplasms, specifically in MDS, and the diagnostic value of isolated +8 in MDS. Twenty-two MDS and 10 other myeloid neoplasms carrying +8 were studied. Trisomy 8 was determined in peripheral blood by conventional cytogenetics (CC and on granulocytes, CD3+ lymphocytes and oral mucosa cells by fluorescence in situ hybridization (FISH. In peripheral blood CC, +8 was seen in 4/32 patients. By FISH, only one patient with chronic myelomonocytic leukemia showed +8 in all cell samples and was interpreted as a cT8M. In our series +8 was acquired in all MDS. Probably, once discarded cT8M by FISH from CD3+ lymphocytes and non-hematological cells, +8 should be considered with enough evidence to MDS.

  12. Acquired Myelodysplasia or Myelodysplastic Syndrome: Clearing the Fog

    Directory of Open Access Journals (Sweden)

    Ethan A. Natelson

    2013-01-01

    Full Text Available Myelodysplastic syndromes (MDS are clonal myeloid disorders characterized by progressive peripheral blood cytopenias associated with ineffective myelopoiesis. They are typically considered neoplasms because of frequent genetic aberrations and patient-limited survival with progression to acute myeloid leukemia (AML or death related to the consequences of bone marrow failure including infection, hemorrhage, and iron overload. A progression to AML has always been recognized among the myeloproliferative disorders (MPD but occurs only rarely among those with essential thrombocythemia (ET. Yet, the World Health Organization (WHO has chosen to apply the designation myeloproliferative neoplasms (MPN, for all MPD but has not similarly recommended that all MDS become the myelodysplastic neoplasms (MDN. This apparent dichotomy may reflect the extremely diverse nature of MDS. Moreover, the term MDS is occasionally inappropriately applied to hematologic disorders associated with acquired morphologic myelodysplastic features which may rather represent potentially reversible hematological responses to immune-mediated factors, nutritional deficiency states, and disordered myelopoietic responses to various pharmaceutical, herbal, or other potentially myelotoxic compounds. We emphasize the clinical settings, and the histopathologic features, of such AMD that should trigger a search for a reversible underlying condition that may be nonneoplastic and not MDS.

  13. Distinct neutrophil subpopulations phenotype by flow cytometry in myelodysplastic syndromes.

    Science.gov (United States)

    Vikentiou, Myrofora; Psarra, Katerina; Kapsimali, Violetta; Liapis, Konstantinos; Michael, Michalis; Tsionos, Konstantinos; Lianidou, Evi; Papasteriades, Chryssa

    2009-03-01

    The cardinal feature of myelodysplastic syndromes (MDS) is dysplasia involving one or more myeloid cell lineages. In the present study, we used 4-color flow cytometric analysis to investigate dysgranulopoiesis in bone marrow specimens from 65 patients with MDS. The antigen expression patterns of total neutrophil granulocytes (TNG) and of the two distinct neutrophil granulocytic subpopulations (NGSs), NGS-1 (dimmer CD45 expression) and NGS-2 (stronger CD45 expression) identified on the side scatter (SS) vs. CD45-intensity plot, were studied. The neutrophil granulocytes from patients with MDS showed characteristic antigen expression aberrancies which were more pronounced in NGS-2 subpopulation. Studying separately the NGS-2 subpopulation with the CD16/MPO/LF combination, the low CD16(+)/MPO(+) and low CD16(+)/LF(+) percentages seemed to discriminate between lower-risk and higher-risk patients with MDS in most occasions. Furthermore, a detailed assessment of the NGS-1 and NGS-2 immunophenotypic patterns revealed early dysplastic changes, not otherwise observed by standard TNG analysis, especially in cases of lower-risk MDS.

  14. Multiple constitutional aetiological factors in bone marrow failure syndrome (BMFS) patients from north India.

    Science.gov (United States)

    Varma, Neelam; Varma, Subhash; Marwaha, Ram Kumar; Malhotra, Pankaj; Bansal, Deepak; Malik, Kiran; Kaur, Sukhdeep; Garewal, Gurjeevan

    2006-07-01

    A large number of patients diagnosed with bone marrow failure syndromes (BMFS), comprising aplastic anaemia (AA) and myelodysplastic syndromes (MDS), remain aetiologically uncharacterized worldover, especially in resource constrained set up. We carried out this study to identify a few constitutional causes in BMFS patients attending a tertiary care hospital in north India. Peripheral blood lymphocyte cultures were performed (with and without clastogens) in a cohort of 135 consecutive BMFS patients, in order to detect Fanconi anaemia (FA), Down's syndrome (+21), trisomy 8 (+8) and monosomy 7 (-7). Constitutional factors were detected in 17 (12.6%) patients. FA defect was observed in 24.07 percent (13/54), 16.66 percent (1/6) and 2.85 percent (1/35) paediatric aplastic anaemia, paediatric MDS and adult MDS patients respectively. Down's syndrome was detected in 5.00 percent (2/40) adult aplastic anaemia patients. None of the patients revealed trisomy 8 or monosomy 7. Presence of an underlying factor determines appropriate management, prognostication, family screening and genetic counselling of BMFS patients. Special tests required to confirm or exclude constitutional aetiological factors are not available to majority of the patients in our country. Diepoxybutane (DEB) test yielded better results than mitomycin C (MMC) test in our experience.

  15. [TOPICS-MDS: a versatile resource for generating scientific and social knowledge for elderly care].

    Science.gov (United States)

    van den Brink, Danielle; Lutomski, Jennifer E; Qin, Li; den Elzen, Wendy P J; Kempen, Gertrudis I J M; Krabbe, Paul F M; Steyerberg, Ewout W; Muntinga, Maaike; Moll van Charante, Eric P; Bleijenberg, Nienke; Olde Rikkert, Marcel G M; Melis, René J F

    2015-04-01

    Developed as part of the National Care for the Elderly Programme (NPO), TOPICS-MDS is a uniform, national database on the health and wellbeing of the older persons and caregivers who participated in NPO-funded projects. TOPICS-MDS Consortium has gained extensive experience in constructing a standardized questionnaire to collect relevant health care data on quality of life, health services utilization, and informal care use. A proactive approach has been undertaken not only to ensure the standardization and validation of instruments but also the infrastructure for external data requests. Efforts have been made to promote scientifically and socially responsible use of TOPICS-MDS; data has been available for secondary use since early 2014. Through this data sharing initiative, researchers can explore health issues in a broader framework which may have not been possible within individual NPO projects; this broader framework is highly relevant for influencing health policy. In this article, we provide an overview of the development and on-going progress of TOPICS-MDS. We further describe how information derived from TOPICS-MDS can be applied to facilitate future scientific innovations and public health initiatives to improve care for frail older persons and their caregivers.

  16. Studies on the tumor initiation/promotion potential of six middle distillates (MDs) in mouse skin.

    Science.gov (United States)

    Jungen, H; Mellert, W; Wenzel-Hartung, R

    1995-08-01

    Six middle distillates (MDs) were tested for tumor initiating/promoting activity after application to the skin of 30 male CD-1 (ICR) BR mice per group. As the control, 7,12-dimethylbenz[a]-anthracene (DMBA) was used for initiation followed by 12-O-tetradecanoylphorbol-13-acetate (TPA) for promotion. For assessing the tumor-initiating activity, 50 microliters of neat MDs was administered for 5 days with subsequent TPA promotion. In the promotion bioassay, after DMBA initiation 50 microliters of the neat MDs was administered twice weekly until Week 28. For the examination of complete carcinogenic activity, one MD was given without DMBA initiation. Hyperkeratosis, hyperplasia, and dermal inflammation, occurring during the initiation with the MDs, were completely reversible during the 2-week treatment-free period after initiation. Similar skin findings were observed during promotion with the MDs. Regarding the number of affected animals and the severity of the response, TPA was more irritating than the MDs. The initiation study revealed skin tumors for the DMBA/TPA control (30/30), MD 57,389 (14/30), MD 57,396 (5/30), MD 57,383 (4/30) and MD 57,324 (2/30). The promotion study revealed tumor induction by MDs 57,389 (9/30), 57,324 (1/30), 57,393 (1/30), and 57,396 (1/30). Two of 30 animals treated with MD 57,389 developed tumors without DMBA initiation thus indicating that it also is a complete carcinogen. MD 57,399 caused neither initiating nor promoting effects. The tumors observed were diagnosed histopathologically predominantly as squamous cell papillomas.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Mouse Drawer System (MDS): An autonomous hardware for supporting mice space research

    Science.gov (United States)

    Liu, Y.; Biticchi, R.; Alberici, G.; Tenconi, C.; Cilli, M.; Fontana, V.; Cancedda, R.; Falcetti, G.

    2005-08-01

    For the scientific community the ability of flying mice under weightless conditions in space, compared to other rodents, offers many valuable advantages. These include the option of testing a wide range of wild-type and mutant animals, an increased animal number for flight, and a reduced demand on shuttle resources and crew time. In this study, we describe a spaceflight hardware for mice, the Mouse Drawer System (MDS). MDS can interface with Space Shuttle middeck and International Space Station Express Rack. It consists of Mice Chamber, Liquid Handling Subsystem, Food Delivery Subsystem, Air Conditioning Subsystem, Illumination Subsystem, Observation Subsystem and Payload Control Unit. It offers single or paired containment for 6-8 mice with a mean weight of 40 grams/mouse for a period of up to 3 months. Animal tests were conducted in a MDS breadboard to validate the biocompatibility of various subsystems. Mice survived in all tests of short and long duration. Results of blood parameters, histology and air/waste composition analysis showed that MDS subsystems meet the NIH guidelines for temperature, humidity, food and water access, air quality, odour and waste management.

  18. Depleted uranium and the Gulf War syndrome

    International Nuclear Information System (INIS)

    1999-01-01

    Some military personnel involved in the 1991Gulf War have complained of continuing stress-like symptoms for which no obvious cause has been found. These symptoms have at times been attributed to the use of depleted uranium (DU) in shell casings which are believed to have caused toxic effects. Depleted uranium is natural uranium which is depleted in the rarer U-235 isotope. It is a heavy metal and in common with other heavy metals is chemically toxic. It is also slightly radioactive and could give rise to a radiological hazard if dispersed in finely divided form so that it was inhaled. In response to concerns, the possible effects of DU have been extensively studied along with other possible contributors to G ulf War sickness . This article looks at the results of some of the research that has been done on DU. (author)

  19. Application of FISH 7q in MDS patients without monosomy 7 or 7q deletion by conventional G-banding cytogenetics: does -7/7q- detection by FISH have prognostic value?

    Science.gov (United States)

    Ademà, Vera; Hernández, Jesús María; Abáigar, María; Lumbreras, Eva; Such, Esperanza; Calull, Anna; Dominguez, Esther; Arenillas, Leonor; Mallo, Mar; Cervera, José; Marugán, Isabel; Tormo, Mar; García, Francisca; González, Teresa; Luño, Elisa; Sanzo, Carmen; Martín, María Luisa; Fernández, Manuela; Costa, Dolors; Blázquez, Beatriz; Barreña, Beatriz; Marco, Fernando; Batlle, Ana; Buño, Ismael; Martínez-Laperche, Carolina; Noriega, Víctor; Collado, Rosa; Ivars, David; Carbonell, Félix; Vallcorba, Isabel; Melero, Josefa; Delgado, Elena; Vargas, María Teresa; Grau, Javier; Salido, Marta; Espinet, Blanca; Melero, Carme; Florensa, Lourdes; Pedro, Carmen; Solé, Francesc

    2013-04-01

    Chromosomal abnormalities are detected in 40-60% of patients with de novo myelodysplastic syndromes (MDS). This study used the FISH technique in 773 patients with de novo MDS without evidence of monosomy 7 (-7) or 7q deletion (7q-) by conventional G-banding cytogenetics (CC) to analyze their prognostic impact by FISH alone. FISH detected -7/7q- in 5.2% of patients. Presence of -7/7q- was associated with shorter overall survival than absence of such aberrations. Our results suggest that FISH 7q could be beneficial in patients with intermediate WHO morphologic risk stratification and no evidence of -7/7q- by CC. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Validity of the RAI-MDS for ascertaining diabetes and comorbid conditions in long-term care facility residents.

    Science.gov (United States)

    Lix, Lisa M; Yan, Lin; Blackburn, David; Hu, Nianping; Schneider-Lindner, Verena; Teare, Gary F

    2014-01-15

    This study assessed the validity of the Resident Assessment Instrument Minimum Data Set (RAI-MDS) Version 2.0 for diagnoses of diabetes and comorbid conditions in residents of long-term care facilities (LTCFs). Hospital inpatient, outpatient physician billing, RAI-MDS, and population registry data for 1997 to 2011 from Saskatchewan, Canada were used to ascertain cases of diabetes and 12 comorbid conditions. Prevalence estimates were calculated for both RAI-MDS and administrative health data. Sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were calculated using population-based administrative health data as the validation data source. Cohen's κ was used to estimate agreement between the two data sources. 23,217 LTCF residents were in the diabetes case ascertainment cohort. Diabetes prevalence was 25.3% in administrative health data and 21.9% in RAI-MDS data. Overall sensitivity of a RAI-MDS diabetes diagnoses was 0.79 (95% CI: 0.79, 0.80) and the PPV was 0.92 (95% CI: 0.91, 0.92), when compared to administrative health data. Sensitivity of the RAI-MDS for ascertaining comorbid conditions ranged from 0.21 for osteoporosis to 0.92 for multiple sclerosis; specificity was high for most conditions. RAI-MDS clinical assessment data are sensitive to ascertain diabetes cases in LTCF populations when compared to administrative health data. For many comorbid conditions, RAI-MDS data have low validity when compared to administrative data. Risk-adjustment measures based on these comorbidities might not produce consistent results for RAI-MDS and administrative health data, which could affect the conclusions of studies about health outcomes and quality of care across facilities.

  1. Abrupt evolution of Philadelphia chromosome-positive acute myeloid leukemia in myelodysplastic syndrome.

    Science.gov (United States)

    Fukunaga, Akiko; Sakoda, Hiroto; Iwamoto, Yoshihiro; Inano, Shojiro; Sueki, Yuki; Yanagida, Soshi; Arima, Nobuyoshi

    2013-03-01

    Myelodysplastic syndrome (MDS) is a clonal disorder arising from an alteration in multipotent stem cells, which lose the ability of normal proliferation and differentiation. Disease progression occurs in approximately 30% MDS cases. Specific chromosomal alterations seem responsible for each step in the evolution of acute myeloid leukemia (AML). Multiple genetic aberrations occur during the clonal evolution of MDS; however, few studies report the presence of the Philadelphia (Ph) chromosome. We report a rare case of Ph-positive AML, which evolved during the course of low-risk MDS. The patient, a 76-year-old man with mild leukocytopenia, was diagnosed with MDS, refractory neutropenia (RN). After 1.5 yr, his peripheral blood and bone marrow were suddenly occupied by immature basophils and myeloblasts, indicating the onset of AML. A bone marrow smear showed multilineage dysplasia, consistent with MDS evolution. Chromosomal analysis showed an additional t(9;22)(q34;q11) translocation. Because progression occurred concurrently with emergence of the Ph chromosome, we diagnosed this case as Ph-positive AML with basophilia arising from the clonal evolution of MDS. The patient was initially treated with nilotinib. A hematological response was soon achieved with disappearance of the Ph chromosome in the bone marrow. Emergence of Ph-positive AML in the course of low-risk MDS has rarely been reported. We report this case as a rare clinical course of MDS. © 2012 John Wiley & Sons A/S.

  2. [Changes of CD34(+) and CD71(+)CD45(-) cell levels in bone marrow of MDS and AA patients].

    Science.gov (United States)

    Yan, Zhen-Yu; Tian, Xu; Li, Ying; Yang, Mei-Rong; Zhang, Song; Wang, Xie-Ming; Zhang, Hai-Xia; Cheng, Nai-Yao

    2014-04-01

    This study was aimed to investigate the changes of CD34(+) and CD71(+)CD45(-) cell levels in MDS and AA patients. A total of 25 cases MDS and 43 cases of AA (18 cases SAA and 25 cases of NSAA) from January 2010 to October 2013 in the Department of Hematology, affiliated hospital of Hebei United University were enrolled in this study. The complete blood count, bone marrow smears, bone marrow biopsy, karyotype analysis and bone marrow blood cell immune genotyping (mainly the proportion of CD34(+) cells, CD71(+)CD45(-) cells in nucleated cells) were carried out for all patients; the changes of CD34(+) and CD71(+)CD45(-) cell levels in patients with MDS and AA (SAA NSAA) were compared; the differences of white blood cell count, platelet count and hemoglobin concentration in patients with count of CD71(+)CD45(-) ≥ 15% or MDS group was higher than that in AA (NSAA and SAA) group (P MDS group was higher than that in SAA (P MDS group. In MDS group with CD71(+)CD45(-) ≥ 15%, the platelet count was significantly higher than that in NSAA group (P MDS and NSAA group with CD71(+)CD45(-) 0.05). It is concluded that the count of CD34(+) cells in MDS patients is significantly higher than that in AA and SAA patients. The count of CD71(+)CD45(-) cells in MDS group is significantly higher than that of SAA group. The platelet count in MDS patients with CD71(+)CD45(-) cells ≥ 15% is significantly higher than that of the NSAA group.

  3. Impaired Expression of Focal Adhesion Kinase in Mesenchymal Stromal Cells from Low-Risk Myelodysplastic Syndrome Patients

    Directory of Open Access Journals (Sweden)

    Yuenv Wu

    2017-08-01

    Full Text Available The pathogenic role of mesenchymal stromal cells (MSCs in myelodysplastic syndromes (MDS development and progression has been investigated by numerous studies, yet, it remains controversial in some aspects (1, 2. In the present study, we found distinct features of MSCs from low-risk (LR-MDS stromal microenvironment as compared to those from healthy subjects. At the molecular level, focal adhesion kinase, a key tyrosine kinase in control of cell proliferation, survival, and adhesion process, was found profoundly suppressed in expression and activation in LR-MDS MSC. At a functional level, LR-MDS MSCs showed impaired growth and clonogenic capacity, which were independent of cellular senescence and apoptosis. The pro-adipogenic differentiation and attenuated osteogenic capacity along with reduced SDF-1 expression could be involved in creating an unfavorable microenvironment for hematopoiesis. In conclusion, our experiments support the theory that the stromal microenvironment is fundamentally altered in LR-MDS, and these preliminary data offer a new perspective on LR-MDS pathophysiology.

  4. Nuclear Nox4-Derived Reactive Oxygen Species in Myelodysplastic Syndromes

    Directory of Open Access Journals (Sweden)

    Marianna Guida

    2014-01-01

    Full Text Available A role for intracellular ROS production has been recently implicated in the pathogenesis and progression of a wide variety of neoplasias. ROS sources, such as NAD(PH oxidase (Nox complexes, are frequently activated in AML (acute myeloid leukemia blasts and strongly contribute to their proliferation, survival, and drug resistance. Myelodysplastic syndromes (MDS comprise a heterogeneous group of disorders characterized by ineffective hematopoiesis, with an increased propensity to develop AML. The molecular basis for MDS progression is unknown, but a key element in MDS disease progression is the genomic instability. NADPH oxidases are now recognized to have specific subcellular localizations, this targeting to specific compartments for localized ROS production. Local Nox-dependent ROS production in the nucleus may contribute to the regulation of redox-dependent cell growth, differentiation, senescence, DNA damage, and apoptosis. We observed that Nox1, 2, and 4 isoforms and p22phox and Rac1 subunits are expressed in MDS/AML cell lines and MDS samples, also in the nuclear fractions. Interestingly, Nox4 interacts with ERK and Akt1 within nuclear speckle domain, suggesting that Nox4 could be involved in regulating gene expression and splicing factor activity. These data contribute to the elucidation of the molecular mechanisms used by nuclear ROS to drive MDS evolution to AML.

  5. High Frequency of AML1/RUNX1 Point Mutations in Radiation-Associated Myelodysplastic Syndrome Around Semipalatinsk Nuclear Test Site

    OpenAIRE

    Dinara, ZHARLYGANOVA; Hironori, HARADA; Yuka, HARADA; Sergey, SHINKAREV; Zhaxybay, ZHUMADILOV; Aigul, ZHUNUSOVA; Naylya J., TCHAIZHUNUSOVA; Kazbek N., APSALIKOV; Vadim, KEMAIKIN; Kassym, ZHUMADILOV; Noriyuki, KAWANO; Akiro, KIMURA; Masaharu, HOSHI; Department of Radiation Biophysics, Research Institute for Radiation Biology and Medicine, Hiroshima University; Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University

    2008-01-01

    It is known that bone marrow is a sensitive organ to ionizing radiation, and many patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) have been diagnosed in radiation-treated cases and atomic bomb survivors in Hiroshima and Nagasaki. The AML1/RUNX1 gene has been known to be frequently mutated in MDS/AML patients among atomic bomb survivors and radiation therapy-related MDS/AML patients. In this study, we investigated the AML1 mutations in radiation-exposed patients wi...

  6. Significant association between polymorphism of the erythropoietin gene promoter and myelodysplastic syndrome

    Directory of Open Access Journals (Sweden)

    O'Brien Susan

    2010-11-01

    Full Text Available Abstract Background Myelodysplastic syndrome (MDS may be induced by certain mutagenic environmental or chemotherapeutic toxins; however, the role of susceptibility genes remains unclear. The G/G genotype of the single-nucleotide polymorphism (SNP rs1617640 in the erythropoietin (EPO promoter has been shown to be associated with decreased EPO expression. We examined the association of rs1617640 genotype with MDS. Methods We genotyped the EPO rS1617640 SNP in 189 patients with MDS, 257 with acute myeloid leukemia (AML, 106 with acute lymphoblastic leukemia, 97 with chronic lymphocytic leukemia, 353 with chronic myeloid leukemia, and 95 healthy controls. Results The G/G genotype was significantly more common in MDS patients (47/187; 25.1% than in controls (6/95; 6.3% or in patients with other leukemias (101/813; 12.4% (all P P = 0.03. Time to neutrophils recovery after therapy was significantly longer in MDS patients with the G/G genotype (P = 0.02. Conclusions These findings suggest a strong association between the rs1617640 G/G genotype and MDS. Further studies are warranted to investigate the utility of screening for this marker in individuals exposed to environmental toxins or chemotherapy.

  7. The Differencies in Adult and Pediatric Myelodysplastic Syndrome: A Review

    Directory of Open Access Journals (Sweden)

    Vasekova P

    2016-08-01

    Full Text Available Myelodysplastic syndrome (MDS represent very heterogenous group of clonal stem cell bone marrow disorders with ineffective haematopoesis leading to cytopenias in peripheral blood and increased risk of blastic transformation and evolution of acute myeloid leukemia. MDS is a disease of older age mostly, in children it seems to be very rare. There are several significant morphological, cytogenetic and prognostic differencies of the disease in adults and in children. Adult MDS patients most commonly manifest with symptoms of anemia, bleeding and infection are uncommon. In childhood, MDS manifests predominantly by neutropenia and thrombocytopenia. In addition, some pediatric MDS patients present also with constitutional disease’s signs and symptoms. Early and correct diagnosis in both age groups is essential for the choice of appropriate therapy and also for next life of patients. However, the diagnosis of MDS is challenging, complex and requiring close correlation of clinical symptoms, laboratory parameters and standardized examination of BM biopsies. The authors present an overview focused on biology of MDS in adults and children, on the differences in the incidence, clinical presentation and treatment. They summarize the possibilities and limits of histopathological diagnosis and differential diagnosis of the disease in different age groups. A major problem in the morphological diagnosis of MDS remains the determination, whether the myelodysplasia is due to clonal disorder. It might result also from some other factors, as significant dysplasia can also occur in reactive conditions, and vice versa, only discrete dysplasia is sometimes observed in MDS patients. Although histomorphological and immunohistochemical analysis of BM biopsy is invasive and time-consuming examination, it has its value in the diagnosis, differential diagnosis and evaluation of therapeutic effect.

  8. TOPICS-MDS: Veelzijdige bron voor wetenschappelijke en maatschappelijke kennisgeneratie ten behoeve van de ouderenzorg

    NARCIS (Netherlands)

    van den Brink, D.; Lutomski, J.E.; Qin, L.; den Elzen, W.P.J.; Kempen, G.I.J.M.; Krabbe, P.F.M.; Steyerberg, E.W.; Muntinga, M.E.; Moll van Charante, E.P.; Bleijenberg, N.; Olde Rikkert, M.G.M.; Melis, R.J.F.

    2015-01-01

    Developed as part of the National Care for the Elderly Programme (NPO), TOPICS-MDS is a uniform, national database on the health and wellbeing of the older persons and caregivers who participated in NPO-funded projects. TOPICS-MDS Consortium has gained extensive experience in constructing a

  9. Endothelial Progenitor Cell Dysfunction in Myelodysplastic Syndromes: Possible Contribution of a Defective Vascular Niche to Myelodysplasia

    Directory of Open Access Journals (Sweden)

    Luciana Teofili

    2015-05-01

    Full Text Available We set a model to replicate the vascular bone marrow niche by using endothelial colony forming cells (ECFCs, and we used it to explore the vascular niche function in patients with low-risk myelodysplastic syndromes (MDS. Overall, we investigated 56 patients and we observed higher levels of ECFCs in MDS than in healthy controls; moreover, MDS ECFCs were found variably hypermethylated for p15INK4b DAPK1, CDH1, or SOCS1. MDS ECFCs exhibited a marked adhesive capacity to normal mononuclear cells. When normal CD34+ cells were co-cultured with MDS ECFCs, they generated significant lower amounts of CD11b+ and CD41+ cells than in co-culture with normal ECFCs. At gene expression profile, several genes involved in cell adhesion were upregulated in MDS ECFCs, while several members of the Wingless and int (Wnt pathways were underexpressed. Furthermore, at miRNA expression profile, MDS ECFCs hypo-expressed various miRNAs involved in Wnt pathway regulation. The addition of Wnt3A reduced the expression of intercellular cell adhesion molecule-1 on MDS ECFCs and restored the defective expression of markers of differentiation. Overall, our data demonstrate that in low-risk MDS, ECFCs exhibit various primary abnormalities, including putative MDS signatures, and suggest the possible contribution of the vascular niche dysfunction to myelodysplasia.

  10. Aplastic Anemia and MDS International Foundation (AAMDSIF): Bone marrow failure disease scientific symposium 2016.

    Science.gov (United States)

    Zeidan, Amer M; Battiwalla, Minoo; Berlyne, Deborah; Winkler, Thomas

    2017-02-01

    Patients with acquired and inherited bone marrow failure syndromes (BMFS) have ineffective hematopoiesis due to impairments of the hematopoietic stem cell compartment. Common manifestations of BMFS include varying degrees of peripheral blood cytopenias and, sometimes, progression to acute myelogenous leukemia. Research efforts have been made all over the world to improve understanding of the pathogenesis of these diseases and their clinical implications. The Aplastic Anemia and MDS International Foundation (AAMDSIF) is an independent nonprofit organization whose mission is to help patients and family members cope with BMFS. Here, we summarize recent scientific discoveries in several BMFS that were presented at the fifth International Bone Marrow Failure Disease Scientific Symposium 2016 that AAMDSIF sponsored on March 17-18, 2016, in Rockville, Maryland. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Progression of MDS-UPDRS Scores Over Five Years in De Novo Parkinson Disease from the Parkinson's Progression Markers Initiative Cohort.

    Science.gov (United States)

    Holden, Samantha K; Finseth, Taylor; Sillau, Stefan H; Berman, Brian D

    2018-01-01

    The Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UDPRS) is a commonly used tool to measure Parkinson disease (PD) progression. Longitudinal changes in MDS-UPDRS scores in de novo PD have not been established. Determine progression rates of MDS-UPDRS scores in de novo PD. 362 participants from the Parkinson's Progression Markers Initiative, a multicenter longitudinal cohort study of de novo PD, were included. Longitudinal progression of MDS-UPDRS total and subscale scores were modeled using mixed model regression. MDS-UPDRS scores increased in a linear fashion over five years in de novo PD. MDS-UPDRS total score increased an estimated 4.0 points/year, Part I 0.25 points/year, Part II 1.0 points/year, and Part III 2.4 points/year. The expected average progression of MDS-UPDRS scores in de novo PD from this study can assist in clinical monitoring and provide comparative data for detection of disease modification in treatment trials.

  12. The Mice Drawer System (MDS experiment and the space endurance record-breaking mice.

    Directory of Open Access Journals (Sweden)

    Ranieri Cancedda

    Full Text Available The Italian Space Agency, in line with its scientific strategies and the National Utilization Plan for the International Space Station (ISS, contracted Thales Alenia Space Italia to design and build a spaceflight payload for rodent research on ISS: the Mice Drawer System (MDS. The payload, to be integrated inside the Space Shuttle middeck during transportation and inside the Express Rack in the ISS during experiment execution, was designed to function autonomously for more than 3 months and to involve crew only for maintenance activities. In its first mission, three wild type (Wt and three transgenic male mice over-expressing pleiotrophin under the control of a bone-specific promoter (PTN-Tg were housed in the MDS. At the time of launch, animals were 2-months old. MDS reached the ISS on board of Shuttle Discovery Flight 17A/STS-128 on August 28(th, 2009. MDS returned to Earth on November 27(th, 2009 with Shuttle Atlantis Flight ULF3/STS-129 after 91 days, performing the longest permanence of mice in space. Unfortunately, during the MDS mission, one PTN-Tg and two Wt mice died due to health status or payload-related reasons. The remaining mice showed a normal behavior throughout the experiment and appeared in excellent health conditions at landing. During the experiment, the mice health conditions and their water and food consumption were daily checked. Upon landing mice were sacrificed, blood parameters measured and tissues dissected for subsequent analysis. To obtain as much information as possible on microgravity-induced tissue modifications, we organized a Tissue Sharing Program: 20 research groups from 6 countries participated. In order to distinguish between possible effects of the MDS housing conditions and effects due to the near-zero gravity environment, a ground replica of the flight experiment was performed at the University of Genova. Control tissues were collected also from mice maintained on Earth in standard vivarium cages.

  13. The Mice Drawer System (MDS) experiment and the space endurance record-breaking mice.

    Science.gov (United States)

    Cancedda, Ranieri; Liu, Yi; Ruggiu, Alessandra; Tavella, Sara; Biticchi, Roberta; Santucci, Daniela; Schwartz, Silvia; Ciparelli, Paolo; Falcetti, Giancarlo; Tenconi, Chiara; Cotronei, Vittorio; Pignataro, Salvatore

    2012-01-01

    The Italian Space Agency, in line with its scientific strategies and the National Utilization Plan for the International Space Station (ISS), contracted Thales Alenia Space Italia to design and build a spaceflight payload for rodent research on ISS: the Mice Drawer System (MDS). The payload, to be integrated inside the Space Shuttle middeck during transportation and inside the Express Rack in the ISS during experiment execution, was designed to function autonomously for more than 3 months and to involve crew only for maintenance activities. In its first mission, three wild type (Wt) and three transgenic male mice over-expressing pleiotrophin under the control of a bone-specific promoter (PTN-Tg) were housed in the MDS. At the time of launch, animals were 2-months old. MDS reached the ISS on board of Shuttle Discovery Flight 17A/STS-128 on August 28(th), 2009. MDS returned to Earth on November 27(th), 2009 with Shuttle Atlantis Flight ULF3/STS-129 after 91 days, performing the longest permanence of mice in space. Unfortunately, during the MDS mission, one PTN-Tg and two Wt mice died due to health status or payload-related reasons. The remaining mice showed a normal behavior throughout the experiment and appeared in excellent health conditions at landing. During the experiment, the mice health conditions and their water and food consumption were daily checked. Upon landing mice were sacrificed, blood parameters measured and tissues dissected for subsequent analysis. To obtain as much information as possible on microgravity-induced tissue modifications, we organized a Tissue Sharing Program: 20 research groups from 6 countries participated. In order to distinguish between possible effects of the MDS housing conditions and effects due to the near-zero gravity environment, a ground replica of the flight experiment was performed at the University of Genova. Control tissues were collected also from mice maintained on Earth in standard vivarium cages.

  14. Relationship between the MDS-UPDRS and Quality of Life: A large multicenter study of 3206 patients.

    Science.gov (United States)

    Skorvanek, Matej; Martinez-Martin, Pablo; Kovacs, Norbert; Zezula, Ivan; Rodriguez-Violante, Mayela; Corvol, Jean-Christophe; Taba, Pille; Seppi, Klaus; Levin, Oleg; Schrag, Anette; Aviles-Olmos, Iciar; Alvarez-Sanchez, Mario; Arakaki, Tomoko; Aschermann, Zsuzsanna; Benchetrit, Eve; Benoit, Charline; Bergareche-Yarza, Alberto; Cervantes-Arriaga, Amin; Chade, Anabel; Cormier, Florence; Datieva, Veronika; Gallagher, David A; Garretto, Nelida; Gdovinova, Zuzana; Gershanik, Oscar; Grofik, Milan; Han, Vladimir; Kadastik-Eerme, Liis; Kurtis, Monica M; Mangone, Graziella; Martinez-Castrillo, Juan Carlos; Mendoza-Rodriguez, Amelia; Minar, Michal; Moore, Henry P; Muldmaa, Mari; Mueller, Christoph; Pinter, Bernadette; Poewe, Werner; Rallmann, Karin; Reiter, Eva; Rodriguez-Blazquez, Carmen; Singer, Carlos; Valkovic, Peter; Goetz, Christopher G; Stebbins, Glenn T

    2018-03-28

    The relationship between Health-Related Quality of Life (HRQoL) and MDS-UPDRS has not been fully studied so far. The aim of this study was to evaluate the relationship between all MDS-UPDRS components and HRQoL in a representative international cohort of PD patients. We collected demographic and disease-related data as well as MDS-UPDRS and PDQ8 scales. Data were analyzed using correlations between PDQ8 and all MDS-UPDRS items, subsequently two hierarchical multiple regressions were performed, first between the scores of the MDS-UPDRS Parts and PDQ8 and second between individual items from those Parts demonstrating significant relationship to PDQ8 scores in the first regression. LASSO regression analyses were performed to evaluate the relationship between PDQ8 and all individual MDS-UPDRS items. A total of 3206 PD patients were included in the study. In the first regression analysis, PDQ8 was significantly related to MDS-UPDRS parts I and II, but not to III and IV. In the second regression model, significant contributions to PDQ8 were found for Part I items Fatigue, Pain, Depressed mood, Apathy; and Part II items Dressing, Doing hobbies, Freezing, Speech and Tremor. In the LASSO analysis, six Part I, seven Part II, three Part III and one Part IV items contributed to PDQ8 scores. The five items most significantly related to the model were Depressed mood, Dressing, Apathy, Pain and Fatigue. This is so far the largest study related to HRQoL issues in PD. Restrictions in activities of daily living and non-motor symptoms significantly contribute to HRQoL in PD. Copyright © 2018. Published by Elsevier Ltd.

  15. MDS 2.0 Public Quality Indicator and Resident Reports

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Minimum Data Set (MDS) is part of the federally mandated process for clinical assessment of all residents in Medicare or Medicaid certified nursing homes. This...

  16. Azacitidine-lenalidomide (ViLen) combination yields a high response rate in higher risk myelodysplastic syndromes (MDS)-ViLen-01 protocol.

    Science.gov (United States)

    Mittelman, Moshe; Filanovsky, Kalman; Ofran, Yishai; Rosenbaum, Hanna; Raanani, Pia; Braester, Andrei; Goldschmidt, Neta; Kirgner, Ilya; Herishanu, Yair; Perri, Chava; Ellis, Martin; Oster, Howard S

    2016-10-01

    Azacitidine treatment is effective in higher risk MDS (HR-MDS), with less than 50 % response, lasting 2 years. Aza and lenalidomide (Len) have a potential synergistic effect. ViLen-01 phase IIa trial includes 6-month induction (Aza 75 mg/m(2)/day, days 1-5, Len 10 mg/day, days 6-21, every 28 days), 6-month consolidation (Aza 75 mg/m(2)/day, days 1-5, every 28 days), and 12-month maintenance (Len 10 mg/day, days 1-21, every 28 days). Response was evaluated according to IWG criteria. Totally, 25 patients enrolled, with an average of 76.3 years old (60-87), and 88 % with major comorbidities. Thirteen patients completed induction, 7 proceeded for consolidation, and 2 for maintenance. The overall response rate (ORR) was 72 % (18/25), with 6 (24 %) for CR, 3 (12 %) for marrow CR, and 9 (36 %) for hematologic improvement (HI). The 7 non-responding patients were on the study 3 days to 4.1 months. At 6 months, 4 of 6 evaluable patients achieved complete cytogenetic response and 2 with del (5q) at diagnosis. Adverse events (AEs) were as expected in these patients: grades III-IV, mainly hematologic-thrombocytopenia (20 patients) and neutropenia (13 patients). The common non-hematologic AEs were infections (14 patients), nausea (7), vomiting (7), diarrhea (7), and skin reactions (5). The median progression-free survival (PFS) was 12 ± 1.36 months, with median overall survival (OS) of 12 ± 1.7 months. Quality of life (FACT questionnaire) data were available for 12 patients with a tendency towards improved QoL. This trial with elderly HR-MDS patients with an expected poor prognosis demonstrates a high (72 %) response rate and a reasonable expected safety profile but a relatively short PFS and OS.

  17. Phenotypic characterization of aberrant stem and progenitor cell populations in myelodysplastic syndromes.

    Science.gov (United States)

    Ostendorf, Benjamin N; Flenner, Eva; Flörcken, Anne; Westermann, Jörg

    2018-01-01

    Recent reports have revealed myelodysplastic syndromes (MDS) to arise from cancer stem cells phenotypically similar to physiological hematopoietic stem cells. Myelodysplastic hematopoiesis maintains a hierarchical organization, but the proportion of several hematopoietic compartments is skewed and multiple surface markers are aberrantly expressed. These aberrant antigen expression patterns hold diagnostic and therapeutic promise. However, eradication of MDS requires targeting of early myelodysplasia propagating stem cells. This warrants an exact assessment of the differentiation stage at which aberrant expression occurs in transformed hematopoiesis. Here, we report results on the prospective and extensive dissection of the hematopoietic hierarchy in 20 patients with either low-risk MDS or MDS with excess blasts and compare it to hematopoiesis in patients with non-malignancy-associated cytopenia or B cell lymphoma without bone marrow infiltration. We found patients with MDS with excess blasts to exhibit characteristic expansions of specific immature progenitor compartments. We also identified the aberrant expression of several markers including ALDH, CLL-1, CD44, and CD47 to be specific features of hematopoiesis in MDS with excess blasts. We show that amongst these, aberrant CLL-1 expression manifested at the early uncommitted hematopoietic stem cell level, suggesting a potential role as a therapeutic target.

  18. Phenotypic characterization of aberrant stem and progenitor cell populations in myelodysplastic syndromes.

    Directory of Open Access Journals (Sweden)

    Benjamin N Ostendorf

    Full Text Available Recent reports have revealed myelodysplastic syndromes (MDS to arise from cancer stem cells phenotypically similar to physiological hematopoietic stem cells. Myelodysplastic hematopoiesis maintains a hierarchical organization, but the proportion of several hematopoietic compartments is skewed and multiple surface markers are aberrantly expressed. These aberrant antigen expression patterns hold diagnostic and therapeutic promise. However, eradication of MDS requires targeting of early myelodysplasia propagating stem cells. This warrants an exact assessment of the differentiation stage at which aberrant expression occurs in transformed hematopoiesis. Here, we report results on the prospective and extensive dissection of the hematopoietic hierarchy in 20 patients with either low-risk MDS or MDS with excess blasts and compare it to hematopoiesis in patients with non-malignancy-associated cytopenia or B cell lymphoma without bone marrow infiltration. We found patients with MDS with excess blasts to exhibit characteristic expansions of specific immature progenitor compartments. We also identified the aberrant expression of several markers including ALDH, CLL-1, CD44, and CD47 to be specific features of hematopoiesis in MDS with excess blasts. We show that amongst these, aberrant CLL-1 expression manifested at the early uncommitted hematopoietic stem cell level, suggesting a potential role as a therapeutic target.

  19. New polymorphisms of Xeroderma Pigmentosum DNA repair genes in myelodysplastic syndrome.

    Science.gov (United States)

    Santiago, Sabrina Pinheiro; Junior, Howard Lopes Ribeiro; de Sousa, Juliana Cordeiro; de Paula Borges, Daniela; de Oliveira, Roberta Taiane Germano; Farias, Izabelle Rocha; Costa, Marília Braga; Maia, Allan Rodrigo Soares; da Nóbrega Ito, Mayumi; Magalhães, Silvia Maria Meira; Pinheiro, Ronald Feitosa

    2017-07-01

    The association between Xeroderma Pigmentosum DNA repair genes (XPA rs1800975, XPC rs2228000, XPD rs1799793 and XPF rs1800067) polymorphisms and myelodysplastic syndrome (MDS) have not been reported. To assess the functional role between these polymorphisms and MDS, we evaluated 189 samples stratified in two groups: 95 bone marrow samples from MDS patients and 94 from healthy elderly volunteers used as controls. Genotypes for all polymorphisms were identified in DNA samples in an allelic discrimination experiment by real-time polymerase chain reaction (qPCR). We also studied the mRNA expression of XPA and XPC genes to evaluate if its polymorphisms were functional in 53 RNAm MDS patients by qPCR methodologies. To the rs2228000 polymorphism, the CT and TT polymorphic genotype were associated with increased odds ratio (OR) of more profound cytopenia (hemoglobin and neutrophils count). To the rs1799793 polymorphism, we found that the GG homozygous wild-type genotype was associated with a decreased chance of developing MDS. We observed low expression of XPA in younger patients, in hypoplastic MDS and patients with abnormal karyotype when presented AG or AA polymorphic genotypes. We also found that there was a statistically significant interaction between the presence of micromegakaryocyte on down regulation of XPC regarding the CT heterozygous genotype of the rs1800975 polymorphism. Our results suggest that new functional polymorphisms of Xeroderma Pigmentosum DNA repair genes in MDS are related to its pathogenesis and prognosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Precision Medicine in Myelodysplastic Syndromes and Leukemias: Lessons from Sequential Mutations.

    Science.gov (United States)

    Nazha, Aziz; Sekeres, Mikkael A

    2017-01-14

    Precision medicine can be simply defined as the identification of personalized treatment that matches patient-specific clinical and genomic characteristics. Since the completion of the Human Genome Project in 2003, significant advances have been made in our understanding of the genetic makeup of diseases, especially cancers. The identification of somatic mutations that can drive cancer has led to the development of therapies that specifically target the abnormal proteins derived from these mutations. This has led to a paradigm shift in our treatment methodology. Although some success has been achieved in targeting some genetic abnormalities, several challenges and limitations exist when applying precision-medicine concepts in leukemia and myelodysplastic syndromes. We review the current understanding of genomics in myelodysplastic syndromes (MDS) and leukemias and the limitations of precision-medicine concepts in MDS.

  1. Azacitidine in Lower-Risk Myelodysplastic Syndromes: A Meta-Analysis of Data from Prospective Studies.

    Science.gov (United States)

    Komrokji, Rami; Swern, Arlene S; Grinblatt, David; Lyons, Roger M; Tobiasson, Magnus; Silverman, Lewis R; Sayar, Hamid; Vij, Ravi; Fliss, Albert; Tu, Nora; Sugrue, Mary M

    2018-02-01

    After erythropoiesis-stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients with lower-risk myelodysplastic syndromes (LR-MDS). Optimal choice of these agents as front-line therapy in non-del(5q) LR-MDS is unclear. Because azacitidine clinical data mainly describe experience in higher-risk MDS, we performed a meta-analysis of patient-level data to evaluate azacitidine in patients with red blood cell (RBC) transfusion-dependent LR-MDS. We searched English-language articles for prospective phase II and III azacitidine clinical trials and patient registries published between 2000 and 2015, and Embase abstracts from 2015 conferences. Patient-level data from identified relevant studies were provided by investigators. Meta-analyses followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Efficacy endpoints were RBC transfusion independence (TI) and Clinical Benefit (RBC-TI, erythroid response, and complete or partial remission, per International Working Group 2006 criteria for MDS). Data for 233 patients from 6 clinical studies and 1 registry study met criteria for inclusion in analyses. Overall, 90.3% of patients had non-del(5q) LR-MDS. Pooled estimates from random-effects models of RBC-TI and Clinical Benefit were 38.9% and 81.1%, respectively; for the ESA-refractory subgroup, they were 40.5% and 77.3%; and for patients with isolated anemia, they were 41.9% and 82.5%. In multivariate analyses, planned use of ≥6 azacitidine treatment cycles was significantly predictive of response. Azacitidine effects in these patients, most with non-del(5q) LR-MDS, were promising and generally similar to those reported for lenalidomide in similar patients. The choice of initial therapy is important because most patients eventually stop responding to front-line therapy and alternatives are limited. Lower-risk myelodysplastic syndromes (LR-MDS) are primarily characterized by

  2. Polymorphisms of Interlukin-1β rs16944 confer susceptibility to myelodysplastic syndromes.

    Science.gov (United States)

    Yin, Congcong; He, Na; Li, Peng; Zhang, Chen; Yu, Jie; Hua, Mingqiang; Ji, Chunyan; Ma, Daoxin

    2016-11-15

    Genetic factors have been shown to be associated with Myelodysplastic syndromes (MDS) susceptibility. In recent years, the role of inflammation in the promotion of tumor growth is supported by a broad range of experimental and clinical evidence. But the relationship between polymorphisms in NOD-like receptor protein 3 (NLRP3) inflammasome and MDS is rarely reported. Thus, we conducted a case-control study, and genotyped five single nucleotide polymorphisms (SNPs) (NLRP3, IL-1β, IL-18, CARD8, and NF-κB) in MDS patients and healthy controls. The association of different genotypes with patient characteristics was analyzed. Comparing MDS patients with controls, GG genotype of IL-1β (rs16944) was observed to be associated with a significantly increased risk of MDS 78/166 (48.8%) vs 26/96 (27.0%), OR=2.1, CI (1.0-4.4). No significant association was identified regarding the rest of investigated polymorphisms and MDS susceptibility. Complex karyotypes were more frequent in patients with GG genotype of IL-1β (rs16944). Patients with IL-1β polymorphisms (rs16944) GG and GA had lower hemoglobin than those without. Patients with IL-1β polymorphisms (rs16944) GG had higher IPSS scores than those without IL-1β polymorphisms. In conclusion, our present data shows that the IL-1β polymorphisms (rs16944) GG were frequently occurred in MDS. IL-1β (rs16944) GG genotype might serve as a novel biomarker and potential targets for MDS. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance.

    Science.gov (United States)

    Akman, Hasan O; Dorado, Beatriz; López, Luis C; García-Cazorla, Angeles; Vilà, Maya R; Tanabe, Lauren M; Dauer, William T; Bonilla, Eduardo; Tanji, Kurenai; Hirano, Michio

    2008-08-15

    Mitochondrial DNA (mtDNA) depletion syndrome (MDS), an autosomal recessive condition, is characterized by variable organ involvement with decreased mtDNA copy number and activities of respiratory chain enzymes in affected tissues. MtDNA depletion has been associated with mutations in nine autosomal genes, including thymidine kinase (TK2), which encodes a ubiquitous mitochondrial protein. To study the pathogenesis of TK2-deficiency, we generated mice harboring an H126N Tk2 mutation. Homozygous Tk2 mutant (Tk2(-/-)) mice developed rapidly progressive weakness after age 10 days and died between ages 2 and 3 weeks. Tk2(-/-) animals showed Tk2 deficiency, unbalanced dNTP pools, mtDNA depletion and defects of respiratory chain enzymes containing mtDNA-encoded subunits that were most prominent in the central nervous system. Histopathology revealed an encephalomyelopathy with prominent vacuolar changes in the anterior horn of the spinal cord. The H126N TK2 mouse is the first knock-in animal model of human MDS and demonstrates that the severity of TK2 deficiency in tissues may determine the organ-specific phenotype.

  4. Hypermethylation of the VTRNA1-3 Promoter is Associated with Poor Outcome in Lower Risk Myelodysplastic Syndrome Patients

    DEFF Research Database (Denmark)

    Helbo, Alexandra Søgaard; Treppendahl, Marianne; Aslan, Derya

    2015-01-01

    Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders. MDS is frequently associated with deletions on chromosome 5q as well as aberrant DNA methylation patterns including hypermethylation of key tumor suppressors. We have previously shown that hypermethylation...... causes reactivation these genes. In normal hematopoiesis, we find that vault RNAs (vtRNAs) show differential methylation between various hematopoietic cell populations, indicating that allele-specific methylation events may occur during hematopoiesis. In addition, we show that VTRNA1-3 promoter...... hypermethylation is frequent in lower risk MDS patients and is associated with a decreased overall survival....

  5. Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes

    DEFF Research Database (Denmark)

    Musto, Pellegrino; Lanza, Francesco; Balleari, Enrico

    2005-01-01

    Thirty-seven anaemic subjects with low-to-intermediate risk myelodysplastic syndrome (MDS) received the highly glycosylated, long-acting erythropoiesis-stimulating molecule darbepoetin-alpha (DPO) at the single, weekly dose of 150 microg s.c. for at least 12 weeks. Fifteen patients (40.5%) achieved......, no excess of blasts and hypoplastic bone marrow. This study suggests that DPO, at the dose and schedule used, can be safely given in low-intermediate risk MDS and may be effective in a significant proportion of these patients....

  6. Radiotherapy- and chemotherapy-induced myelodysplasia syndrome: a nationwide population-based nested case-control study.

    Science.gov (United States)

    Sun, Li-Min; Lin, Cheng-Li; Lin, Ming-Chia; Liang, Ji-An; Kao, Chia-Hung

    2015-05-01

    This study explored which kinds of cancer are related to a higher incidence of subsequent myelodysplastic syndrome (MDS) after radiotherapy (RT) and chemotherapy (CT).We performed a nested case-control study by using data from the Taiwanese National Health Insurance (NHI) system. The case group included cancer patients who developed MDS. For the control group, 4 cancer patients without MDS were frequency-matched with each MDS case by age, sex, year of cancer diagnosis, and MDS index year. A multivariable logistic regression analysis was conducted, and odds ratios (ORs) and 95% confidence intervals (CIs) were estimated.Overall, cancer patients who received RT or CT exhibited secondary MDS more frequently than did those who did not (RT: OR = 1.53; 95% CI = 1.33-1.77; CT: OR = 1.51; 95% CI = 1.25-1.82). Analysis by cancer site showed that RT increased the risk of MDS for patients with stomach, colorectal, liver, breast, endometrial, prostate, and kidney cancers. By contrast, CT was more likely to increase the risk of MDS for patients with lung, endometrial, and cervical cancers. Further analysis revealed that RT and CT seemed to have a positive interaction. The major limitation of this study was the lack of certain essential data in the NHI Research Database, such as data regarding cancer stage and treatment dose details.This population-based nested case-control study determined that RT and CT predisposed patients in Taiwan to the development of MDS. This effect was more prominent when both modalities were used.

  7. Iron overload promotes erythroid apoptosis through regulating HIF-1a/ROS signaling pathway in patients with myelodysplastic syndrome.

    Science.gov (United States)

    Zheng, Qing-Qing; Zhao, You-Shan; Guo, Juan; Zhao, Si-da; Song, Lu-Xi; Fei, Cheng-Ming; Zhang, Zheng; Li, Xiao; Chang, Chun-Kang

    2017-07-01

    Erythroid apoptosis increases significantly in myelodysplastic syndrome (MDS) patients with iron overload, but the underlying mechanism is not fully clear. In this study, we aim to explore the effect of HIF-1a/ROS on erythroid apoptosis in MDS patients with iron overload. We found that iron overload injured cellular functions through up-regulating ROS levels in MDS/AML cells, including inhibited cell viability, increased cell apoptosis and blocked cell cycle at G0/G1 phase. Interestingly, overexpression of hypoxia inducible factor-1a (HIF-1a), which was under-expressed in iron overload models, reduced ROS levels and attenuated cell damage caused by iron overload in MDS/AML cells. And gene knockdown of HIF-1a got the similar results as iron overload in MDS/AML cells. Furthermore, iron overload caused high erythroid apoptosis was closely related with ROS in MDS patients. Importantly, the HIF-1a protein levels of erythrocytes elevated obviously after incubation with desferrioxamine (DFO) from MDS patients with iron overload, accompanied by ROS levels inhibited and erythroid apoptosis reduced. Taken together, our findings determine that the HIF-1a/ROS signaling pathway plays a key role in promoting erythroid apoptosis in MDS patients with iron overload. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Increased relative risk of myelodysplastic syndrome in atomic bomb survivors

    International Nuclear Information System (INIS)

    Oda, Kenji; Kimura, Akiro; Matsuo, Tatsuki; Tomonaga, Masao; Kodama, Kazunori; Mabuchi, Kiyohiko

    1998-01-01

    It was investigated what blood disorders except leukemia increased the relative risk with dose dependency in atomic bomb survivors. Subjects were 217 patients of atomic bomb survivors in Hiroshima and Nagasaki, who had blood disorders except leukemia and died between 1950 and 1990. Their medical records were analyzed and their diagnoses were reevaluated. Sixteen cases were diagnosed as the aplastic anemia and 12 as the myelodysplastic syndrome (MDS). In the aplastic anemia, there was no correlation between the exposure dose and the mortality. In MDS, the excess relative risk (ERR)/bone marrow exposure dose of 1 Sv was very high (13.0). These results supports the hypothesis that MDS would be broken out by the clonal abnormality of the hematopoietic stem cell and radiation exposure could cause the appearance of the abnormal stem cell clone. (K.H.)

  9. Increased relative risk of myelodysplastic syndrome in atomic bomb survivors

    Energy Technology Data Exchange (ETDEWEB)

    Oda, Kenji [Hiroshima City Hospital (Japan); Kimura, Akiro; Matsuo, Tatsuki; Tomonaga, Masao; Kodama, Kazunori; Mabuchi, Kiyohiko

    1998-12-01

    It was investigated what blood disorders except leukemia increased the relative risk with dose dependency in atomic bomb survivors. Subjects were 217 patients of atomic bomb survivors in Hiroshima and Nagasaki, who had blood disorders except leukemia and died between 1950 and 1990. Their medical records were analyzed and their diagnoses were reevaluated. Sixteen cases were diagnosed as the aplastic anemia and 12 as the myelodysplastic syndrome (MDS). In the aplastic anemia, there was no correlation between the exposure dose and the mortality. In MDS, the excess relative risk (ERR)/bone marrow exposure dose of 1 Sv was very high (13.0). These results supports the hypothesis that MDS would be broken out by the clonal abnormality of the hematopoietic stem cell and radiation exposure could cause the appearance of the abnormal stem cell clone. (K.H.)

  10. Expanded and independent validation of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS).

    Science.gov (United States)

    Martinez-Martin, Pablo; Rodriguez-Blazquez, Carmen; Alvarez-Sanchez, Mario; Arakaki, Tomoko; Bergareche-Yarza, Alberto; Chade, Anabel; Garretto, Nelida; Gershanik, Oscar; Kurtis, Monica M; Martinez-Castrillo, Juan Carlos; Mendoza-Rodriguez, Amelia; Moore, Henry P; Rodriguez-Violante, Mayela; Singer, Carlos; Tilley, Barbara C; Huang, Jing; Stebbins, Glenn T; Goetz, Christopher G

    2013-01-01

    The Movement Disorder Society-UPDRS (MDS-UPDRS) was published in 2008, showing satisfactory clinimetric results and has been proposed as the official benchmark scale for Parkinson's disease. The present study, based on the official MDS-UPDRS Spanish version, performed the first independent testing of the scale and adds information on its clinimetric properties. The cross-culturally adapted MDS-UPDRS Spanish version showed a comparative fit index ≥ 0.90 for each part (I-IV) relative to the English-language version and was accepted as the Official MDS-UPDRS Spanish version. Data from this scale, applied with other assessments to Spanish-speaking Parkinson's disease patients in five countries, were analyzed for an independent and complementary clinimetric evaluation. In total, 435 patients were included. Missing data were negligible and moderate floor effect (30 %) was found for Part IV. Cronbach's α index ranged between 0.79 and 0.93 and only five items did not reach the 0.30 threshold value of item-total correlation. Test-retest reliability was adequate with only two sub-scores of the item 3.17, Rest tremor amplitude, reaching κ values lower than 0.60. The intraclass correlation coefficient was higher than 0.85 for the total score of each part. Correlation of the MDS-UPDRS parts with other measures for related constructs was high (≥ 0.60) and the standard error of measurement lower than one-third baseline standard deviation for all subscales. Results confirm those of the original study and add information on scale reliability, construct validity, and precision. The MDS-UPDRS Spanish version shows satisfactory clinimetric characteristics.

  11. Outcomes for Patients with Chronic Lymphocytic Leukemia (CLL) and Acute Leukemia or Myelodysplastic Syndrome

    Science.gov (United States)

    Tambaro, Francesco Paolo; Garcia-Manero, Guillermo; O’Brien, Susan M.; Faderl, Stefan H.; Ferrajoli, Alessandra; Burger, Jan A.; Pierce, Sherry; Wang, Xuemei; Do, Kim-Anh; Kantarjian, Hagop M.; Keating, Michael J.; Wierda, William G.

    2016-01-01

    Acute leukemia (AL) and myelodysplastic syndrome (MDS) are uncommon in CLL. We retrospectively identified 95 patients with CLL also diagnosed with AL (n=38) or MDS (n=57), either concurrently (n=5) or subsequent (n=90) to CLL diagnosis and report their outcomes. Median number of CLL treatments prior to AL and MDS was 2(0–9) and 1(0–8), respectively; the most common regimen was purine analogue combined with alkylating agent±CD20 mAb. Twelve had no prior CLL treatment. Among 38 with AL, 33 had AML, 3 had ALL (1Ph+), 1 had biphenotypic, and 1 had extramedullary (bladder) AML. Unfavorable AML karyotype was noted in 26, intermediate-risk in 7. There was no association between survival from AL and number of prior CLL regimens or karyotype. Expression of CD7 on blasts was associated with shorter survival. Among MDS cases, all IPSS were represented; karyotype was unfavorable in 36, intermediate in 6, and favorable in 12 patients; 10 experienced transformation to AML. Shorter survival from MDS correlated with higher-risk IPSS, poor-risk karyotype, and increased number of prior CLL treatments. Overall, outcomes for patients with CLL subsequently diagnosed with AL or MDS were poor; AL/MDS occurred without prior CLL treatment. Effective therapies for these patients are desperately needed. PMID:26290497

  12. Cardiac iron overload in chronically transfused patients with thalassemia, sickle cell anemia, or myelodysplastic syndrome.

    Directory of Open Access Journals (Sweden)

    Mariane de Montalembert

    Full Text Available The risk and clinical significance of cardiac iron overload due to chronic transfusion varies with the underlying disease. Cardiac iron overload shortens the life expectancy of patients with thalassemia, whereas its effect is unclear in those with myelodysplastic syndromes (MDS. In patients with sickle cell anemia (SCA, iron does not seem to deposit quickly in the heart. Our primary objective was to assess through a multicentric study the prevalence of cardiac iron overload, defined as a cardiovascular magnetic resonance T2*8 ECs in the past year, and age older than 6 years. We included from 9 centers 20 patients with thalassemia, 41 with SCA, and 25 with MDS in 2012-2014. Erythrocytapharesis did not consistently prevent iron overload in patients with SCA. Cardiac iron overload was found in 3 (15% patients with thalassemia, none with SCA, and 4 (16% with MDS. The liver iron content (LIC ranged from 10.4 to 15.2 mg/g dry weight, with no significant differences across groups (P = 0.29. Abnormal T2* was not significantly associated with any of the measures of transfusion or chelation. Ferritin levels showed a strong association with LIC. Non-transferrin-bound iron was high in the thalassemia and MDS groups but low in the SCA group (P<0.001. Hepcidin was low in thalassemia, normal in SCA, and markedly elevated in MDS (P<0.001. Two mechanisms may explain that iron deposition largely spares the heart in SCA: the high level of erythropoiesis recycles the iron and the chronic inflammation retains iron within the macrophages. Thalassemia, in contrast, is characterized by inefficient erythropoiesis, unable to handle free iron. Iron accumulation varies widely in MDS syndromes due to the competing influences of abnormal erythropoiesis, excess iron supply, and inflammation.

  13. MDS 3.0 for Nursing Homes and Swing Bed Providers

    Data.gov (United States)

    U.S. Department of Health & Human Services — The MDS is a powerful tool for implementing standardized assessment and for facilitating care management in nursing homes (NHs) and non-critical access hospital...

  14. Despite differential gene expression profiles pediatric MDS derived mesenchymal stromal cells display functionality in vitro

    Directory of Open Access Journals (Sweden)

    F.G.J. Calkoen

    2015-03-01

    An altered mRNA expression profile, associated with cell survival and malignant transformation, of MSC derived from children with MDS strengthens the hypothesis that the micro-environment is of importance in this disease. Our data support the understanding that pediatric and adult MDS are two different diseases. Further evaluation of the pathways involved might reveal additional therapy targets.

  15. Speech-activated Myoclonus Mimicking Stuttering in a Patient with Myoclonus–Dystonia Syndrome

    Directory of Open Access Journals (Sweden)

    Peter Hedera

    2016-07-01

    Full Text Available Background: Acquired neurogenic stuttering has been considered a fairly uncommon clinical occurrence; speech-activated myoclonus is a rare entity that can mimic stuttering and is caused by a wide array of etiologies.Case Report: Here we report a patient with myoclonus–dystonia syndrome (MDS, due to an identified disease-causing mutation, who displayed speech-activated myoclonus mimicking stuttering.Discussion: In MDS, myoclonus has only infrequently been reported to affect speech. This case further expands the spectrum of conditions causing the rare clinical phenomenon of speech-activated myoclonus. 

  16. Relationship between the MDS-UPDRS domains and the health-related quality of life of Parkinson's disease patients.

    Science.gov (United States)

    Martínez-Martín, P; Rodríguez-Blázquez, C; Forjaz, M J; Alvarez-Sánchez, M; Arakaki, T; Bergareche-Yarza, A; Chade, A; Garretto, N; Gershanik, O; Kurtis, M M; Martínez-Castrillo, J C; Mendoza-Rodríguez, A; Moore, H P; Rodríguez-Violante, M; Singer, C; Tilley, B C; Huang, J; Stebbins, G T; Goetz, C G

    2014-03-01

    The Movement Disorder Society sponsored version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a comprehensive instrument for assessing Parkinson's disease (PD). The present study was aimed at determining the relationships between MDS-UPDRS components and health-related quality of life (HRQoL) evaluations in PD patients. An international, multicenter, cross-sectional study was carried out of 435 PD patients assessed with the MDS-UPDRS, Hoehn and Yahr (HY), Clinical Impression Severity for PD, EQ-5D and PD Questionnaire - eight items (PDQ-8). Spearman's rank correlation coefficients, exploratory factor analysis and multiple linear regression models (dependent variables EQ-5D and PDQ-8) were performed. The participants' age was 66.71 ± 10.32 years (51.5% men). PD duration was 8.52 ± 6.14, and median HY was 2 (range 1-5). The correlation between the EQ-5D index and the MDS-UPDRS ranged from -0.46 (Part IV) to -0.72 (Part II) and for the PDQ-8 index from 0.47 (Part III) to 0.74 (Part II). In multiple regression models with the MDS-UPDRS domains as independent variables, the main determinant for both the EQ-5D index and the PDQ-8 was Part II followed by Part I. After factorial grouping of the cardinal PD manifestations embedded in the MDS-UPDRS Parts III and IV for inclusion into multiple regression models, a factor formed by M-EDL, nM-EDL and fluctuations was the main determinant for both the EQ-5D and PDQ-8 indexes. The MDS-UPDRS component most tightly related with the HRQoL measures was a combination of motor and non-motor experiences of daily living. © 2014 The Author(s) European Journal of Neurology © 2014 EFNS.

  17. The MDS challenging behavior profile for long-term care

    NARCIS (Netherlands)

    Gerritsen, D. L.; Achterberg, W. P.; Steverink, N.; Frijters, D. H. M.; Ribbe, M. W.

    2008-01-01

    The objective was to construct a reliable and valid challenging behavior scale with items from the Minimum Data Set (MDS). Exploratory factor analyses of a sample of 656 nursing home residents yielded a 16-item Behavior Profile containing four internally consistent and valid subscales measuring

  18. Tumor suppressor microRNAs are downregulated in myelodysplastic syndrome with spliceosome mutations

    DEFF Research Database (Denmark)

    Aslan, Derya; Garde, Christian; Nygaard, Mette Katrine

    2016-01-01

    Spliceosome mutations are frequently observed in patients with myelodysplastic syndromes (MDS). However, it is largely unknown how these mutations contribute to the disease. MicroRNAs (miRNAs) are small noncoding RNAs, which have been implicated in most human cancers due to their role in post...... the most downregulated miRNAs were several tumor-suppressor miRNAs, including several let-7 family members, miR-423, and miR-103a. Finally, we observed that the predicted targets of the most downregulated miRNAs were involved in apoptosis, hematopoiesis, and acute myeloid leukemia among other cancer......- and metabolic pathways. Our data indicate that spliceosome mutations may play an important role in MDS pathophysiology by affecting the expression of tumor suppressor miRNA genes involved in the development and progression of MDS....

  19. Meeting report: Vienna 2008 Workshop of the German–Austrian Working Group for Studying Prognostic Factors in Myelodysplastic Syndromes

    OpenAIRE

    Valent , Peter; Hofmann , Wolf-Karsten; Büsche , Guntram; Sotlar , Karl; Horny , Hans-Peter; Haase , Detlef; Haferlach , Torsten; Kern , Wolfgang; Bettelheim , Peter; Baumgartner , Christian; Sperr , Wolfgang R.; Nösslinger , Thomas; Wimazal , Friedrich; Giagounidis , Aristoteles A.; Lübbert , Michael

    2009-01-01

    Abstract Criteria, scoring systems, and treatment algorithms for myelodysplastic syndromes (MDS) have been updated repeatedly in recent years. This apparently results from increased awareness and early recognition of the disease, an increasing number of new diagnostic and prognostic markers and tools, and new therapeutic options that may change the course and thus prognosis in MDS. To address these challenges and to create useful new diagnostic and prognostic parameters and scores,...

  20. Classification of Multiple Chinese Liquors by Means of a QCM-based E-Nose and MDS-SVM Classifier.

    Science.gov (United States)

    Li, Qiang; Gu, Yu; Jia, Jing

    2017-01-30

    Chinese liquors are internationally well-known fermentative alcoholic beverages. They have unique flavors attributable to the use of various bacteria and fungi, raw materials, and production processes. Developing a novel, rapid, and reliable method to identify multiple Chinese liquors is of positive significance. This paper presents a pattern recognition system for classifying ten brands of Chinese liquors based on multidimensional scaling (MDS) and support vector machine (SVM) algorithms in a quartz crystal microbalance (QCM)-based electronic nose (e-nose) we designed. We evaluated the comprehensive performance of the MDS-SVM classifier that predicted all ten brands of Chinese liquors individually. The prediction accuracy (98.3%) showed superior performance of the MDS-SVM classifier over the back-propagation artificial neural network (BP-ANN) classifier (93.3%) and moving average-linear discriminant analysis (MA-LDA) classifier (87.6%). The MDS-SVM classifier has reasonable reliability, good fitting and prediction (generalization) performance in classification of the Chinese liquors. Taking both application of the e-nose and validation of the MDS-SVM classifier into account, we have thus created a useful method for the classification of multiple Chinese liquors.

  1. Classification of Multiple Chinese Liquors by Means of a QCM-based E-Nose and MDS-SVM Classifier

    Directory of Open Access Journals (Sweden)

    Qiang Li

    2017-01-01

    Full Text Available Chinese liquors are internationally well-known fermentative alcoholic beverages. They have unique flavors attributable to the use of various bacteria and fungi, raw materials, and production processes. Developing a novel, rapid, and reliable method to identify multiple Chinese liquors is of positive significance. This paper presents a pattern recognition system for classifying ten brands of Chinese liquors based on multidimensional scaling (MDS and support vector machine (SVM algorithms in a quartz crystal microbalance (QCM-based electronic nose (e-nose we designed. We evaluated the comprehensive performance of the MDS-SVM classifier that predicted all ten brands of Chinese liquors individually. The prediction accuracy (98.3% showed superior performance of the MDS-SVM classifier over the back-propagation artificial neural network (BP-ANN classifier (93.3% and moving average-linear discriminant analysis (MA-LDA classifier (87.6%. The MDS-SVM classifier has reasonable reliability, good fitting and prediction (generalization performance in classification of the Chinese liquors. Taking both application of the e-nose and validation of the MDS-SVM classifier into account, we have thus created a useful method for the classification of multiple Chinese liquors.

  2. Current State of the Art: Management of Higher Risk Myelodysplastic Syndromes.

    Science.gov (United States)

    Komrokji, Rami S

    2016-08-01

    The higher risk myelodysplastic syndrome (MDS) patients, defined by the International Prognostic Scoring System (IPSS) as intermediate-2 or high-risk groups, compromise a third of MDS patients who have an expected survival of less than 1.5 years. Our ability to better define higher risk MDS improved with the proposal of new clinical risk models such as the revised IPSS and by integration of molecular data, including somatic gene mutations. Allogeneic hematopoietic stem-cell transplantation (AHSCT) remains the only curative option. In higher risk MDS patients, proceeding early with AHSCT is associated with maximum survival gain. The decision to pursue AHSCT is individualized according to disease risk, comorbidities, and functional status. The role of therapy before AHSCT remains controversial, and the role of post-AHSCT maintenance is evolving. Hypomethylating agents are the only medications that alter the natural history of the disease. Azacitidine is the only drug reported to improve overall survival in higher risk MDS patients. Appropriate use and assessment of response is key for assuring patients benefit of such limited options. Treatment after failure of hypomethylating agents is an unmet need. The role of detectable somatic gene mutations in prognosis and tailoring therapy continue to emerge. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Provision of TCRγδ T Cells and Memory T Cells Plus Selected Use of Blinatumomab in Naïve T-cell Depleted Haploidentical Donor Hematopoietic Cell Transplantation for Hematologic Malignancies Relapsed or Refractory Despite Prior Transplantation

    Science.gov (United States)

    2018-01-03

    Acute Lymphoblastic Leukemia (ALL); Acute Myeloid Leukemia (AML); Myeloid Sarcoma; Chronic Myeloid Leukemia (CML); Juvenile Myelomonocytic Leukemia (JMML); Myelodysplastic Syndrome (MDS); Non-Hodgkin Lymphoma (NHL)

  4. Cytokine expression patterns and mesenchymal stem cell karyotypes from the bone marrow microenvironment of patients with myelodysplastic syndromes

    Energy Technology Data Exchange (ETDEWEB)

    Xiong, H.; Yang, X.Y.; Han, J.; Wang, Q.; Zou, Z.L. [Department of Hematology, Shanghai Clinical Research Center, Chinese Academy of Sciences, Shanghai Xuhui District Central Hospital, Shanghai (China)

    2015-01-20

    The purpose of this study was to explore cytokine expression patterns and cytogenetic abnormalities of mesenchymal stem cells (MSCs) from the bone marrow microenvironment of Chinese patients with myelodysplastic syndromes (MDS). Bone marrow samples were obtained from 30 cases of MDS (MDS group) and 30 healthy donors (control group). The expression pattern of cytokines was detected by customized protein array. The karyotypes of MSCs were analyzed using fluorescence in situ hybridization. Compared with the control group, leukemia inhibitory factor, stem cell factor (SCF), stromal cell-derived factor (SDF-1), bone morphogenetic protein 4, hematopoietic stem cell (HSC) stimulating factor, and transforming growth factor-β in the MDS group were significantly downregulated (P<0.05), while interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and programmed death ligand (B7-H1) were significantly upregulated (P<0.05). For chromosome abnormality analysis, the detection rate of abnormal karyotypes (+8, -8, -20, 20q-, -Y, -7, 5q-) was 30% in the MDS group and 0% in the control group. In conclusion, the up- and downregulated expression of these cytokines might play a key role in the pathogenesis of MDS. Among them, SCF and SDF-1 may play roles in the apoptosis of HSCs in MDS; and IFN-γ, TNF-α, and B7-H1 may be associated with apoptosis of bone marrow cells in MDS. In addition, the abnormal karyotypes might be actively involved in the pathogenesis of MDS. Further studies are required to determine the role of abnormal karyotypes in the occurrence and development of MDS.

  5. Cytokine expression patterns and mesenchymal stem cell karyotypes from the bone marrow microenvironment of patients with myelodysplastic syndromes

    International Nuclear Information System (INIS)

    Xiong, H.; Yang, X.Y.; Han, J.; Wang, Q.; Zou, Z.L.

    2015-01-01

    The purpose of this study was to explore cytokine expression patterns and cytogenetic abnormalities of mesenchymal stem cells (MSCs) from the bone marrow microenvironment of Chinese patients with myelodysplastic syndromes (MDS). Bone marrow samples were obtained from 30 cases of MDS (MDS group) and 30 healthy donors (control group). The expression pattern of cytokines was detected by customized protein array. The karyotypes of MSCs were analyzed using fluorescence in situ hybridization. Compared with the control group, leukemia inhibitory factor, stem cell factor (SCF), stromal cell-derived factor (SDF-1), bone morphogenetic protein 4, hematopoietic stem cell (HSC) stimulating factor, and transforming growth factor-β in the MDS group were significantly downregulated (P<0.05), while interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and programmed death ligand (B7-H1) were significantly upregulated (P<0.05). For chromosome abnormality analysis, the detection rate of abnormal karyotypes (+8, -8, -20, 20q-, -Y, -7, 5q-) was 30% in the MDS group and 0% in the control group. In conclusion, the up- and downregulated expression of these cytokines might play a key role in the pathogenesis of MDS. Among them, SCF and SDF-1 may play roles in the apoptosis of HSCs in MDS; and IFN-γ, TNF-α, and B7-H1 may be associated with apoptosis of bone marrow cells in MDS. In addition, the abnormal karyotypes might be actively involved in the pathogenesis of MDS. Further studies are required to determine the role of abnormal karyotypes in the occurrence and development of MDS

  6. Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS: Results from the nordic NMDSG08A phase II trial

    International Nuclear Information System (INIS)

    Tobiasson, M; Dybedahl, I; Holm, M S; Karimi, M; Brandefors, L; Garelius, H; Grövdal, M; Högh-Dufva, I; Grønbæk, K; Jansson, M; Marcher, C; Nilsson, L; Kittang, A O; Porwit, A; Saft, L; Möllgård, L; Hellström-Lindberg, E

    2014-01-01

    This prospective phase II study evaluated the efficacy of azacitidine (Aza)+erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo+granulocyte colony stimulation factors for >8 weeks and a transfusion need of ⩾4 units over 8 weeks were included. Aza 75 mg m −2 d −1 , 5/28 days, was given for six cycles; non-responding patients received another three cycles combined with Epo 60 000 units per week. Primary end point was transfusion independence (TI). All patients underwent targeted mutational screen for 42 candidate genes. Thirty enrolled patients received ⩾one cycle of Aza. Ten patients discontinued the study early, 7 due to adverse events including 2 deaths. Thirty-eight serious adverse events were reported, the most common being infection. Five patients achieved TI after six cycles and one after Aza+Epo, giving a total response rate of 20%. Mutational screening revealed a high frequency of recurrent mutations. Although no single mutation predicted for response, SF3A1 (n=3) and DNMT3A (n=4) were only observed in non-responders. We conclude that Aza can induce TI in severely anemic MDS patients, but efficacy is limited, toxicity substantial and most responses of short duration. This treatment cannot be generally recommended in lower-risk MDS. Mutational screening revealed a high frequency of mutations

  7. The MDS-UPDRS Part II (motor experiences of daily living) resulted useful for assessment of disability in Parkinson's disease.

    Science.gov (United States)

    Rodriguez-Blazquez, Carmen; Rojo-Abuin, Jose Manuel; Alvarez-Sanchez, Mario; Arakaki, Tomoko; Bergareche-Yarza, Alberto; Chade, Anabel; Garretto, Nelida; Gershanik, Oscar; Kurtis, Monica M; Martinez-Castrillo, Juan Carlos; Mendoza-Rodriguez, Amelia; Moore, Henry P; Rodriguez-Violante, Mayela; Singer, Carlos; Tilley, Barbara C; Huang, Jing; Stebbins, Glenn T; Goetz, Christopher G; Martinez-Martin, Pablo

    2013-10-01

    To evaluate the motor experiences of daily living section of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS M-EDL) for assessing disability in PD patients; to determine the association between disability and quality of life; and to identify cut-off score ranges for no, mild, moderate and severe disability with this measure. International, observational, cross-sectional study of 435 PD patients, assessed with: MDS-UPDRS, Hoehn and Yahr staging, Rapid Assessment of Disability Scale, Clinical Impression of Severity Index for PD, Parkinson's Disease Questionnaire-8 and EQ-5D. Descriptive statistics, Spearman's rank correlation coefficients, Kruskal-Wallis test for group comparisons, ordinal logistic regression analysis for setting cut-off values and a step-wise multiple linear regression model were calculated. MDS-UPDRS M-EDL correlated 0.70-0.80 with other disability measures, and -0.46 to 0.74 with quality of life scales. Scores significantly increased with higher disease duration and severity (p MDS-UPDRS nM-EDL section as the main determinant of M-EDL, followed by the rest of MDS-UPDRS sections (explained variance: 59%). MDS-UPDRS M-EDL proved to be useful for assessing disability in PD. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Chromosomal instability and the abrogated G2/M arrest in x-irradiated myelodysplastic syndrome cells

    International Nuclear Information System (INIS)

    Ban, S.; Sudo, H.; Saegusa, K.; Sagara, M.; Imai, T.; Kimura, A.

    2003-01-01

    A preliminary epidemiological study demonstrated that myelodysplastic syndrome (MDS) has an excess relative risk per sievert of 13 in atomic bomb survivors in Hiroshima. MDS is the only other radiogenic blood disease apart from leukemia. Clinically, MDS involves dysplastic hematopoiesis and an increased risk of leukemic transformation. Because it is uncertain whether MDS pathogenesis affects lymphoid progenitor cells as well as myeloid progenitor cells, we investigated the karyotypes of bone marrow cells and the micronucleus (MN) frequency in peripheral T lymphocytes of twenty- three atomic bomb survivors with MDS and five normal individuals. Aneuploidy was observed in 10 of 23 patients. Chromosome aberrations were observed in 3 of 12 patients with mild symptoms, and six of 11 patients of severe symptoms. The spontaneous- and X-ray-induced-MN frequencies were significantly higher in MDS patients than in normal individuals. Interestingly, radiation sensitivity increased along with the severity of MDS clinical subtypes. Because many of the patients in this study had not been exposed to chemo- or radiation- therapy, their unusual radiosensitivity may be related to their chromosomal or genomic instability. Immortalized lymphoid cell lines were established from B-lymphocytes infected with Epstein-Barr virus in vitro. The abrogation of radiation-induced-G2/M arrest was observed in 10 of 12 MDS-B lymphoid cell lines, but not in the normal B lymphoid cell lines. Our data suggest that the control of chromosomal stability is impaired in pluripotent stem cells of MDS patients, and that the abrogated G2/M arrest may be involved in the pathophysiology of disease progression and the high radiation sensitivity of patients

  9. Impact of Nagasaki atomic bomb exposure on myelodysplastic syndrome patients who are treated with azacitidine.

    Science.gov (United States)

    Jo, Tatsuro; Horio, Kensuke; Shigematsu, Kazuto

    2015-05-01

    High-dose radiation exposure greatly increases the risk of myelodysplastic syndromes (MDS), however the clinical characteristics of MDS among atomic bomb survivors have not been thoroughly investigated to date. We designed this study to identify these characteristics. We retrospectively evaluated data from 13 atomic bomb survivors with MDS and 15 elderly patients with de novo MDS who were diagnosed between April 2011 and April 2013 at the Nagasaki Genbaku Hospital. All patients were treated with azacitidine (AZA; a hypomethylating agent) and overall survival rates were estimated. No clear difference was observed in the clinical response to AZA between the two groups. However, atomic bomb survivors had a survival disadvantage, independent of their karyotype. Minute genetic alterations caused by exposure to atomic radiation can adversely affect the response to AZA, even 66 years after the exposure. Further studies are required to clarify the mechanisms underlying this phenomenon. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  10. Impairment of FOS mRNA stabilization following translation arrest in granulocytes from myelodysplastic syndrome patients.

    Science.gov (United States)

    Feng, Xiaomin; Shikama, Yayoi; Shichishima, Tsutomu; Noji, Hideyoshi; Ikeda, Kazuhiko; Ogawa, Kazuei; Kimura, Hideo; Takeishi, Yasuchika; Kimura, Junko

    2013-01-01

    Although quantitative and qualitative granulocyte defects have been described in myelodysplastic syndromes (MDS), the underlying molecular basis of granulocyte dysfunction in MDS is largely unknown. We recently found that FOS mRNA elevation under translation-inhibiting stimuli was significantly smaller in granulocytes from MDS patients than in healthy individuals. The aim of this study is to clarify the cause of the impaired FOS induction in MDS. We first examined the mechanisms of FOS mRNA elevation using granulocytes from healthy donors cultured with the translation inhibitor emetine. Emetine increased both transcription and mRNA stability of FOS. p38 MAPK inhibition abolished the emetine-induced increase of FOS transcription but did not affect FOS mRNA stabilization. The binding of an AU-rich element (ARE)-binding protein HuR to FOS mRNA containing an ARE in 3'UTR was increased by emetine, and the knockdown of HuR reduced the FOS mRNA stabilizing effect of emetine. We next compared the emetine-induced transcription and mRNA stabilization of FOS between MDS patients and healthy controls. Increased rates of FOS transcription by emetine were similar in MDS and controls. In the absence of emetine, FOS mRNA decayed to nearly 17% of initial levels in 45 min in both groups. In the presence of emetine, however, 76.7±19.8% of FOS mRNA remained after 45 min in healthy controls, versus 37.9±25.5% in MDS (Pknowledge, this is the first report demonstrating attenuation of stress-induced FOS mRNA stabilization in MDS granulocytes.

  11. The Mice Drawer System Tissue Sharing Program (MDS-TSP)

    Science.gov (United States)

    Biticchi, Roberta; Cancedda, Ranieri; Cilli, Michele; Cotronei, Vittorio; Costa, Delfina; Liu, Yi; Piccardi, Federica; Pignataro, Salvatore; Ruggiu, Alessandra; Tasso, Roberta; Tavella, Sara

    Several organs and apparatus are affected by weightless conditions and in particular by the weightless experienced during space flights. Therefore space missions are good opportunities to investigate in a whole organism the controlling cellular and molecular mechanisms. For this type of studies mice represent an excellent animal model for several reasons: reduced body size, relatively short time needed to reach adulthood, availability of strains with different genetic background and of different transgenic lines, etc. In line with the International Space Station (ISS) development, the Italian Space Agency (ASI) contracted Thales Alenia Space Italia, the largest Italian aerospace industry, to design and build a spaceflight payload for rodent research on ISS, the Mouse Drawer System (MDS -see abstract P. Cipparelli et al.). This payload meets NIH guideline for several physical parameters to maintain 6 animals in good health conditions in a space environment. Given the interest of our laboratory in the microgravity induced skeleton alterations, we focused our attention on transgenic mice over-expressing pleiotrophin (PTN) under the control of the human bone specific osteocalcin promoter. This protein is a heparin-binding cytokine with different functions. PTN is expressed by the cells in an early differentiation stage and is upregulated in tissue injury and wound repair. PTN is specifically involved in bone formation, neurite outgrowth and angiogenesis. As PTN-transgenic mice show an increased bone mass and mineralization, we decided to use this mouse model in the flight experiment and to study its potential role in counteracting bone loss in microgravity. Not all mouse strains are equally suitable for flight. After preliminary tests in the MDS breadboard at our animal facility on the behavior of different mouse strains, PTN-transgenic mice originally obtained in the BDF strain were backcrossed in the C57Bl/J10 strain before being used in this study. In order to

  12. Differential diagnosis of myelodysplastic syndrome and aplastic anemia using MRI

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Seung Eun; Park, Jung Mi; Lee, Jae Mun; Kim, Ki Tae; Kim, Dong Wook; Kim, Chun Choo; Kim, Chun Yul; Shinn, Kyung Sub [Catholic University Medical College, Seoul (Korea, Republic of)

    1995-04-15

    To assess the patterns of myelodysplastic syndrome (MDS) and aplastic anemia (AA) on MRI of the spinal bone marrow and to find the differential points between the two groups. Fourteen patients with MDS (n=7) and AA (n=7) were studied using magnetic resonance imaging. Sagittal images from the lower thoracic and lumbar vertebral marrow were evaluated on T1-weighted and STIR images. Five distinct patterns of signal intensity of the T1-weighted and STIR images were classified. T1 and T2 relaxation times and T1 marrow/fat signal intensity ratio were measured and analyzed (t-test). The cellularity of bone marrow was evaluated on histologic slides. MDS showed homogeneously low signal intensity on T1WI and high signal intensity on STIR image, indicating hypercellular marrow, whereas AA showed relative high signal intensity on T1WI and low signal intensity on STIR image, representing fatty marrow. T1 and T2 relaxation time (T1 for MDS=750.26 msec {+-} 177.50, T1 for AA=413.21 msec {+-} 167.39 ({rho} < 0.000), T2 for MDS=91.86 msec {+-} 14.16, T2 for AA=81.44 msec {+-} 15.31 ({rho} < 0.001) and T1 marrow/fat signal intensity ratio (0.22 {+-} 0.048 in MDS, 0.30 {+-} 0.083 in AA ({rho} < 0.000) revealed statistically significant difference between the two groups. Although the marrow aspiration and needle biopsy are mandatory in hematologic disease for diagnosis, there are limited in assessing the change of total marrow mass. Therefore MRI of bone marrow might be useful in distinguishing MDS from AA because of its ability of representation of total marrow mass.

  13. Differential diagnosis of myelodysplastic syndrome and aplastic anemia using MRI

    International Nuclear Information System (INIS)

    Jung, Seung Eun; Park, Jung Mi; Lee, Jae Mun; Kim, Ki Tae; Kim, Dong Wook; Kim, Chun Choo; Kim, Chun Yul; Shinn, Kyung Sub

    1995-01-01

    To assess the patterns of myelodysplastic syndrome (MDS) and aplastic anemia (AA) on MRI of the spinal bone marrow and to find the differential points between the two groups. Fourteen patients with MDS (n=7) and AA (n=7) were studied using magnetic resonance imaging. Sagittal images from the lower thoracic and lumbar vertebral marrow were evaluated on T1-weighted and STIR images. Five distinct patterns of signal intensity of the T1-weighted and STIR images were classified. T1 and T2 relaxation times and T1 marrow/fat signal intensity ratio were measured and analyzed (t-test). The cellularity of bone marrow was evaluated on histologic slides. MDS showed homogeneously low signal intensity on T1WI and high signal intensity on STIR image, indicating hypercellular marrow, whereas AA showed relative high signal intensity on T1WI and low signal intensity on STIR image, representing fatty marrow. T1 and T2 relaxation time (T1 for MDS=750.26 msec ± 177.50, T1 for AA=413.21 msec ± 167.39 (ρ < 0.000), T2 for MDS=91.86 msec ± 14.16, T2 for AA=81.44 msec ± 15.31 (ρ < 0.001) and T1 marrow/fat signal intensity ratio (0.22 ± 0.048 in MDS, 0.30 ± 0.083 in AA (ρ < 0.000) revealed statistically significant difference between the two groups. Although the marrow aspiration and needle biopsy are mandatory in hematologic disease for diagnosis, there are limited in assessing the change of total marrow mass. Therefore MRI of bone marrow might be useful in distinguishing MDS from AA because of its ability of representation of total marrow mass

  14. Clinical consequences of iron overload in patients with myelodysplastic syndromes: the case for iron chelation therapy.

    Science.gov (United States)

    Shammo, Jamile M; Komrokji, Rami S

    2018-06-14

    Patients with myelodysplastic syndromes (MDS) are at increased risk of iron overload due to ineffective erythropoiesis and chronic transfusion therapy. The clinical consequences of iron overload include cardiac and/or hepatic failure, endocrinopathies, and infection risk. Areas covered: Iron chelation therapy (ICT) can help remove excess iron and ultimately reduce the clinical consequences of iron overload. The authors reviewed recent (last five years) English-language articles from PubMed on the topic of iron overload-related complications and the use of ICT (primarily deferasirox) to improve outcomes in patients with MDS. Expert Commentary: While a benefit of ICT has been more firmly established in other transfusion-dependent conditions such as thalassemia, its role in reducing iron overload in MDS remains controversial due to the lack of prospective controlled data demonstrating a survival benefit. Orally administered chelation agents (e.g., deferasirox), are now available, and observational and/or retrospective data support a survival benefit of using ICT in MDS. The placebo-controlled TELESTO trial (NCT00940602) is currently examining the use of deferasirox in MDS patients with iron overload, and is evaluating specifically whether use of ICT to alleviate iron overload can also reduce iron overload-related complications in MDS and improve survival.

  15. Characterization and prognostic implication of 17 chromosome abnormalities in myelodysplastic syndrome.

    Science.gov (United States)

    Sánchez-Castro, Judit; Marco-Betés, Víctor; Gómez-Arbonés, Xavier; Arenillas, Leonor; Valcarcel, David; Vallespí, Teresa; Costa, Dolors; Nomdedeu, Benet; Jimenez, María José; Granada, Isabel; Grau, Javier; Ardanaz, María T; de la Serna, Javier; Carbonell, Félix; Cervera, José; Sierra, Adriana; Luño, Elisa; Cervero, Carlos J; Falantes, José; Calasanz, María J; González-Porrás, José R; Bailén, Alicia; Amigo, M Luz; Sanz, Guillermo; Solé, Francesc

    2013-07-01

    The prognosis of chromosome 17 (chr17) abnormalities in patients with primary myelodysplastic syndrome (MDS) remains unclear. The revised International Prognostic Scoring System (IPSS-R) includes these abnormalities within the intermediate cytogenetic risk group. This study assessed the impact on overall survival (OS) and risk of acute myeloid leukemia transformation (AMLt) of chr17 abnormalities in 88 patients with primary MDS. We have compared this group with 1346 patients with primary MDS and abnormal karyotype without chr17 involved. The alterations of chr17 should be considered within group of poor prognosis. The different types of alterations of chromosome 17 behave different prognosis. The study confirms the intermediate prognostic impact of the i(17q), as stated in IPSS-R. The results of the study, however, provide valuable new information on the prognostic impact of alterations of chromosome 17 in complex karyotypes. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. Hematological abnormalities in adult patients with Down's syndrome.

    LENUS (Irish Health Repository)

    McLean, S

    2012-02-01

    BACKGROUND: There is a paucity of data regarding hematological abnormalities in adults with Down\\'s syndrome (DS). AIMS: We aimed to characterize hematological abnormalities in adult patients with DS and determine their long-term significance. METHODS: We retrospectively studied a cohort of nine DS patients referred to the adult hematology service in our institution between May 2001 and April 2008. Data collected were: full blood count (FBC), comorbidities, investigations performed, duration of follow-up and outcome to most recent follow-up. RESULTS: Median follow-up was 26 months (9-71). Of the nine patients, two had myelodysplastic syndrome (MDS) at presentation. Of these, one progressed, with increasing marrow failure, and requiring support with transfusions and gCSF. The remaining eight patients, with a variety of hematological abnormalities including leukopenia, macrocytosis, and thrombocytopenia, had persistently abnormal FBCs. However there was no evidence of progression, and no patient has evolved to acute myeloid leukemia (AML). CONCLUSIONS: MDS is a complication of DS and may require supportive therapy. However, minor hematological abnormalities are common in adult DS patients, and may not signify underlying marrow disease.

  17. Development of a Minimum Data Set (MDS) for C-Section Anesthesia Information Management System (AIMS).

    Science.gov (United States)

    Sheykhotayefeh, Mostafa; Safdari, Reza; Ghazisaeedi, Marjan; Khademi, Seyed Hossein; Seyed Farajolah, Seyedeh Sedigheh; Maserat, Elham; Jebraeily, Mohamad; Torabi, Vahid

    2017-04-01

    Caesarean section, also known as C-section, is a very common procedure in the world. Minimum data set (MDS) is defined as a set of data elements holding information regarding a series of target entities to provide a basis for planning, management, and performance evaluation. MDS has found a great use in health care information systems. Also, it can be considered as a basis for medical information management and has shown a great potential for contributing to the provision of high quality care and disease control measures. The principal aim of this research was to determine MDS and required capabilities for Anesthesia information management system (AIMS) in C-section in Iran. Data items collected from several selected AIMS were studied to establish an initial set of data. The population of this study composed of 115 anesthesiologists was asked to review the proposed data elements and score them in order of importance by using a five-point Likert scale. The items scored as important or highly important by at least 75% of the experts were included in the final list of minimum data set. Overall 8 classes of data (consisted of 81 key data elements) were determined as final set. Also, the most important required capabilities were related to airway management and hypertension and hypotension management. In the development of information system (IS) based on MDS and identification, because of the broad involvement of users, IS capabilities must focus on the users' needs to form a successful system. Therefore, it is essential to assess MDS watchfully by considering the planned uses of data. Also, IS should have essential capabilities to meet the needs of its users.

  18. The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion

    DEFF Research Database (Denmark)

    Miller, Chaya; Wang, Liya; Ostergaard, Elsebet

    2011-01-01

    SUCLA2-related mitochondrial DNA (mtDNA) depletion syndrome is a result of mutations in the β subunit of the ADP-dependent isoform of the Krebs cycle succinyl-CoA synthase (SCS). The mechanism of tissue specificity and mtDNA depletion is elusive but complementation by the GDP-dependent isoform en...

  19. Results of allogeneic stem cell transplantation in the Spanish MDS registry: prognostic factors for low risk patients.

    Science.gov (United States)

    Díez Campelo, M; Sánchez-Barba, M; de Soria, V Gómez-García; Martino, R; Sanz, G; Insunza, A; Bernal, T; Duarte, R; Amigo, M L; Xicoy, B; Tormo, M; Iniesta, F; Bailén, A; Benlloch, L; Córdoba, I; López-Villar, O; Del Cañizo, M C

    2014-10-01

    Although new agents have been approved for the treatment of MDS, the only curative approach is allogeneic hematopoietic stem cell transplantation (HSCT) and thus, in particular circumstances this procedure has been proposed as a treatment option for low risk patients. We have retrospectively analyzed the results of HSCT in 291 patients from the Spanish MDS registry with special attention to low risk MDS (LR-MDS) in order to define the variables that could impact their clinical evolution after transplantation. At 2 years OS was 51% and EFS was 50% (95% CI 0.7-4.5 years for OS and 95% CI 0.1-3.9 years for EFS). Among 43 LR-MDS, transplant-related mortality was 28%. At 3 years, OS was 67% (95% CI 264.7-8927.2 days for OS) and EFS was 64% (95% CI 0-9697.2 days for EFS). In the multivariate analysis only cytogenetics retained statistical significant effect on both OS (p=.047) and EFS (p=.046). Conditioning regimen could improve outcome among this subset of patients (OS 86% and RFS 100% for patients receiving RIC regimen). The present study confirms that specific disease characteristic as well as transplant characteristics have a significant impact on transplant outcome. Regarding low risk patients a non-myeloablative conditioning would be preferable especially in cases without high-risk cytogenetics. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Minimum variance and variance of outgoing quality limit MDS-1(c1, c2) plans

    Science.gov (United States)

    Raju, C.; Vidya, R.

    2016-06-01

    In this article, the outgoing quality (OQ) and total inspection (TI) of multiple deferred state sampling plans MDS-1(c1,c2) are studied. It is assumed that the inspection is rejection rectification. Procedures for designing MDS-1(c1,c2) sampling plans with minimum variance of OQ and TI are developed. A procedure for obtaining a plan for a designated upper limit for the variance of the OQ (VOQL) is outlined.

  1. The prognostic value of monosomal karyotype (MK) in higher-risk patients with myelodysplastic syndromes treated with 5-Azacitidine. A retrospective analysis of the Hellenic (Greek) MDS Study Group.

    Science.gov (United States)

    Papageorgiou, Sotirios G; Vasilatou, Diamantina; Kontos, Christos K; Kotsianidis, Ioannis; Symeonidis, Argiris; Galanopoulos, Athanasios G; Hatzimichael, Eleftheria; Megalakaki, Aekaterini; Poulakidas, Elias; Diamantopoulos, Panagiotis; Vassilakopoulos, Theodoros; Zikos, Panagiotis; Papadaki, Helen; Mparmparousi, Despoina; Bouronikou, Eleni; Panayiotidis, Panayiotis; Viniou, Nora-Athina; Pappa, Vassiliki

    2018-04-16

    In this study, we investigated the incidence and prognostic impact of monosomal karyotype (MK) in 405 higher-risk MDS patients treated with 5-AZA. The MK was present in 66 out of 405 (16.3%) patients, most of whom had complex karyotype (CK). MK was strongly associated with CK and the cytogenetic risk defined according to IPSS-R, as well as with high-risk disease, according to IPSS (P=0.029), IPSS-R (PMDS treated with 5-AZA. Furthermore, we showed that in MDS with high or very-high IPSS-R risk score, MK can further distinguish patients with worse outcome. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

  2. Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration

    OpenAIRE

    Bartesaghi, Stefano; Betts-Henderson, Joanne; Cain, Kelvin; Dinsdale, David; Zhou, Xiaoshan; Karlsson, Anna; Salomoni, Paolo; Nicotera, Pierluigi

    2010-01-01

    Mutations of thymidine kinase 2 (TK2), an essential component of the mitochondrial nucleotide salvage pathway, can give rise to mitochondrial DNA (mtDNA) depletion syndromes (MDS). These clinically heterogeneous disorders are characterized by severe reduction in mtDNA copy number in affected tissues and are associated with progressive myopathy, hepatopathy and/or encephalopathy, depending in part on the underlying nuclear genetic defect. Mutations of TK2 have previously been associated with a...

  3. Iron overload in patients with myelodysplastic syndromes: An updated overview.

    Science.gov (United States)

    Moukalled, Nour M; El Rassi, Fuad A; Temraz, Sally N; Taher, Ali T

    2018-06-15

    Myelodysplastic syndromes (MDS) encompass a heterogeneous group of clonal hematopoietic stem cell disorders characterized by a broad clinical spectrum related to ineffective hematopoiesis leading to unilineage or multilineage cytopenias, with a high propensity for transformation to acute myeloid leukemia. Iron overload has been recently identified as one of the important conditions complicating the management of these diverse disorders. The accumulation of iron is mainly related to chronic transfusions; however, evidence suggests a possible role for ineffective erythropoiesis and increased intestinal absorption of iron, related to altered hepcidin and growth differentiation factor-15 levels in the development of hemosiderosis in patients with MDS. In addition to its suggested role in the exacerbation of ineffective erythropoiesis, multiple reports have identified a prognostic implication for the development of iron overload in patients with MDS, with an improvement in overall survival after the initiation of iron chelation therapy. This review includes a detailed discussion of iron overload in patients with MDS whether they are undergoing supportive therapy or curative hematopoietic stem cell transplantation, with a focus on the mechanism, diagnosis, and effect on survival as well as the optimal management of this highly variable complication. Cancer 2018. © 2018 American Cancer Society. © 2018 American Cancer Society.

  4. Single nucleotide polymorphism array karyotyping: a diagnostic and prognostic tool in myelodysplastic syndromes with unsuccessful conventional cytogenetic testing.

    Science.gov (United States)

    Arenillas, Leonor; Mallo, Mar; Ramos, Fernando; Guinta, Kathryn; Barragán, Eva; Lumbreras, Eva; Larráyoz, María-José; De Paz, Raquel; Tormo, Mar; Abáigar, María; Pedro, Carme; Cervera, José; Such, Esperanza; José Calasanz, María; Díez-Campelo, María; Sanz, Guillermo F; Hernández, Jesús María; Luño, Elisa; Saumell, Sílvia; Maciejewski, Jaroslaw; Florensa, Lourdes; Solé, Francesc

    2013-12-01

    Cytogenetic aberrations identified by metaphase cytogenetics (MC) have diagnostic, prognostic, and therapeutic implications in myelodysplastic syndromes (MDS). However, in some MDS patients MC study is unsuccesful. Single nucleotide polymorphism array (SNP-A) based karyotyping could be helpful in these cases. We performed SNP-A in 62 samples from bone marrow or peripheral blood of primary MDS with an unsuccessful MC study. SNP-A analysis enabled the detection of aberrations in 31 (50%) patients. We used the copy number alteration information to apply the International Prognostic Scoring System (IPSS) and we observed differences in survival between the low/intermediate-1 and intermediate-2/high risk patients. We also saw differences in survival between very low/low/intermediate and the high/very high patients when we applied the revised IPSS (IPSS-R). In conclusion, SNP-A can be used successfully in PB samples and the identification of CNA by SNP-A improve the diagnostic and prognostic evaluation of this group of MDS patients. Copyright © 2013 Wiley Periodicals, Inc.

  5. Considering Bone Marrow Blasts From Nonerythroid Cellularity Improves the Prognostic Evaluation of Myelodysplastic Syndromes.

    Science.gov (United States)

    Arenillas, Leonor; Calvo, Xavier; Luño, Elisa; Senent, Leonor; Alonso, Esther; Ramos, Fernando; Ardanaz, María Teresa; Pedro, Carme; Tormo, Mar; Marco, Víctor; Montoro, Julia; Díez-Campelo, María; Brunet, Salut; Arrizabalaga, Beatriz; Xicoy, Blanca; Andreu, Rafael; Bonanad, Santiago; Jerez, Andrés; Nomdedeu, Benet; Ferrer, Ana; Sanz, Guillermo F; Florensa, Lourdes

    2016-09-20

    WHO classification of myeloid malignancies is based mainly on the percentage of bone marrow (BM) blasts. This is considered from total nucleated cells (TNCs), unless there is erythroid-hyperplasia (erythroblasts ≥ 50%), calculated from nonerythroid cells (NECs). In these instances, when BM blasts are ≥ 20%, the disorder is classified as erythroleukemia, and when BM blasts are < 20%, as myelodysplastic syndrome (MDS). In the latter, the percentage of blasts is considered from TNCs. We assessed the percentage of BM blasts from TNCs and NECs in 3,692 patients with MDS from the Grupo Español de Síndromes Mielodisplásicos, 465 patients with erythroid hyperplasia (MDS-E) and 3,227 patients without erythroid hyperplasia. We evaluated the relevance of both quantifications on classification and prognostication. By enumerating blasts systematically from NECs, 22% of patients with MDS-E and 12% with MDS from the whole series diagnosed within WHO categories with < 5% BM blasts, were reclassified into higher-risk categories and showed a poorer overall survival than did those who remained in initial categories (P = .006 and P = .001, respectively). Following WHO recommendations, refractory anemia with excess blasts (RAEB)-2 diagnosis is not possible in MDS-E, as patients with 10% to < 20% BM blasts from TNCs fulfill erythroleukemia criteria; however, by considering blasts from NECs, 72 patients were recoded as RAEB-2 and showed an inferior overall survival than did patients with RAEB-1 without erythroid hyperplasia. Recalculating the International Prognostic Scoring System by enumerating blasts from NECs in MDS-E and in the overall MDS population reclassified approximately 9% of lower-risk patients into higher-risk categories, which indicated the survival expected for higher-risk patients. Regardless of the presence of erythroid hyperplasia, calculating the percentage of BM blasts from NECs improves prognostic assessment of MDS. This fact should be considered in future

  6. PAS positivity of erythroid precursor cells is associated with a poor prognosis in newly diagnosed myelodysplastic syndrome patients.

    Science.gov (United States)

    Masuda, Kenta; Shiga, Shuichi; Kawabata, Hiroshi; Takaori-Kondo, Akifumi; Ichiyama, Satoshi; Kamikubo, Yasuhiko

    2018-07-01

    Myelodysplastic syndrome (MDS) is a group of clonal stem cell disorders characterized by hematopoietic insufficiency. The accurate risk stratification of patients with MDS is essential for selection of appropriate therapies. We herein conducted a retrospective cohort study to examine the prognostic value of periodic acid-Schiff (PAS) reaction-positive erythroblasts in MDS patients. We examined the PAS positivity of the bone marrow erythroblasts of 144 patients newly diagnosed with MDS; 26 (18.1%) of them had PAS-positive erythroblasts, whereas 118 (81.9%) did not. The PAS-positive group showed significantly poorer karyotypes as defined in the revised International Prognostic Scoring System (IPSS-R) and higher scores in age-adjusted IPSS-R (IPSS-RA) than the PAS-negative group. Overall survival (OS) and leukemia-free survival (LFS) were also significantly shorter in the PAS-positive group than in the PAS-negative group. Similar results were obtained when only high- and very high risk groups were analyzed using IPSS-RA. This retrospective study suggested that the PAS positivity of erythroblasts is an additional prognostic factor combined with other risk scores for OS and LFS in MDS, and our results may contribute to improved clinical decision-making and rapid risk stratification.

  7. BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders.

    Science.gov (United States)

    Damm, Frederik; Chesnais, Virginie; Nagata, Yasunobu; Yoshida, Kenichi; Scourzic, Laurianne; Okuno, Yusuke; Itzykson, Raphael; Sanada, Masashi; Shiraishi, Yuichi; Gelsi-Boyer, Véronique; Renneville, Aline; Miyano, Satoru; Mori, Hiraku; Shih, Lee-Yung; Park, Sophie; Dreyfus, François; Guerci-Bresler, Agnes; Solary, Eric; Rose, Christian; Cheze, Stéphane; Prébet, Thomas; Vey, Norbert; Legentil, Marion; Duffourd, Yannis; de Botton, Stéphane; Preudhomme, Claude; Birnbaum, Daniel; Bernard, Olivier A; Ogawa, Seishi; Fontenay, Michaela; Kosmider, Olivier

    2013-10-31

    Patients with low-risk myelodysplastic syndromes (MDS) that rapidly progress to acute myeloid leukemia (AML) remain a challenge in disease management. Using whole-exome sequencing of an MDS patient, we identified a somatic mutation in the BCOR gene also mutated in AML. Sequencing of BCOR and related BCORL1 genes in a cohort of 354 MDS patients identified 4.2% and 0.8% of mutations respectively. BCOR mutations were associated with RUNX1 (P = .002) and DNMT3A mutations (P = .015). BCOR is also mutated in chronic myelomonocytic leukemia patients (7.4%) and BCORL1 in AML patients with myelodysplasia-related changes (9.1%). Using deep sequencing, we show that BCOR mutations arise after mutations affecting genes involved in splicing machinery or epigenetic regulation. In univariate analysis, BCOR mutations were associated with poor prognosis in MDS (overall survival [OS]: P = .013; cumulative incidence of AML transformation: P = .005). Multivariate analysis including age, International Prognostic Scoring System, transfusion dependency, and mutational status confirmed a significant inferior OS to patients with a BCOR mutation (hazard ratio, 3.3; 95% confidence interval, 1.4-8.1; P = .008). These data suggest that BCOR mutations define the clinical course rather than disease initiation. Despite infrequent mutations, BCOR analyses should be considered in risk stratification.

  8. Erythropoietin plus granulocyte colony-stimulating factor in the treatment of myelodysplastic syndromes. Identification of a subgroup of responders. The Spanish Erythropathology Group.

    Science.gov (United States)

    Remacha, A F; Arrizabalaga, B; Villegas, A; Manteiga, R; Calvo, T; Julià, A; Fernández Fuertes, I; González, F A; Font, L; Juncà, J; del Arco, A; Malcorra, J J; Equiza, E P; de Mendiguren, B P; Romero, M

    1999-12-01

    Anemia leading to transfusion is probably the most important problem in patients with myelodysplastic syndromes (MDS). Human recombinant erythropoietin (rHuEpo) and granulocyte colony-stimulating factor (G-CSF) have been used to treat patients with anemia of MDS, but fewer than 50% respond. The aim of this work was to evaluate the benefit of rHuEpo +/- G-CSF treatment and to isolate the response predictive variables in a group of selected patients with MDS. A non-randomized multicenter trial was carried out in 32 patients with MDS. The inclusion criteria were age >= 18 years, refractory anemia (RA) or refractory anemia with ringed sideroblasts, Hb +1 (77% of cases responded). In contrast, when this score was <= 1 only 15 % of the cases responded. Use of the Scandinavian-American response score is to be recommended in a patient-oriented approach to treating MDS cases with the Epo and G-CSF. Treatment with rHuEpo and G-CSF is safe, its main drawback being its cost. However, a long-term study evaluating the regimen's cost-benefit ratio is warranted.

  9. Progressive transfusion and growth factor independence with adjuvant sertraline in low risk myelodysplastic syndrome treated with an erythropoiesis stimulating agent and granulocyte-colony stimulating factor

    Directory of Open Access Journals (Sweden)

    Kirtan Nautiyal

    2015-01-01

    Full Text Available Refractoriness to growth factor therapy is commonly associated with inferior outcome in patients with low-risk myelodysplastic syndrome (LR-MDS who require treatment for cytopenias. However, the mechanisms leading to refractoriness are unknown. Here we describe a clinically depressed 74-year-old male with refractory cytopenia with multilineage dysplasia (RCMD and documented growth factor refractory anemia after erythropoeisis stimulating agent (ESA therapy, who attained transfusion and growth factor independence after the addition of sertraline to his medication regimen. Our case demonstrates hematological improvement-erythroid (HI-E in growth factor refractory, low risk MDS and highlights a potential mechanistic link between common inflammatory diseases and LR-MDS.

  10. The prognostic impact of mutations in spliceosomal genes for myelodysplastic syndrome patients without ring sideroblasts

    International Nuclear Information System (INIS)

    Kang, Min-Gu; Kim, Hye-Ran; Seo, Bo-Young; Lee, Jun Hyung; Choi, Seok-Yong; Kim, Soo-Hyun; Shin, Jong-Hee; Suh, Soon-Pal; Ahn, Jae-Sook; Shin, Myung-Geun

    2015-01-01

    Mutations in genes that are part of the splicing machinery for myelodysplastic syndromes (MDS), including MDS without ring sideroblasts (RS), have been widely investigated. The effects of these mutations on clinical outcomes have been diverse and contrasting. We examined a cohort of 129 de novo MDS patients, who did not harbor RS, for mutations affecting three spliceosomal genes (SF3B1, U2AF1, and SRSF2). The mutation rates of SF3B1, U2AF1, and SRSF2 were 7.0 %, 7.8 %, and 10.1 %, respectively. Compared with previously reported results, these rates were relatively infrequent. The SRSF2 mutation strongly correlated with old age (P < 0.001), while the mutation status of SF3B1 did not affect overall survival (OS), progression-free survival (PFS), or acute myeloid leukemia (AML) transformation. In contrast, MDS patients with mutations in U2AF1 or SRSF2 exhibited inferior PFS. The U2AF1 mutation was associated with inferior OS in low-risk MDS patients (P = 0.035). The SRSF2 mutation was somewhat associated with AML transformation (P = 0.083). Our findings suggest that the frequencies of the SF3B1, U2AF1, and SRSF2 splicing gene mutations in MDS without RS were relatively low. We also demonstrated that the U2AF1 and SRSF2 mutations were associated with an unfavorable prognostic impact in MDS patients without RS. The online version of this article (doi:10.1186/s12885-015-1493-5) contains supplementary material, which is available to authorized users

  11. Potential Relationship between Inadequate Response to DNA Damage and Development of Myelodysplastic Syndrome

    Directory of Open Access Journals (Sweden)

    Ting Zhou

    2015-01-01

    Full Text Available Hematopoietic stem cells (HSCs are responsible for the continuous regeneration of all types of blood cells, including themselves. To ensure the functional and genomic integrity of blood tissue, a network of regulatory pathways tightly controls the proliferative status of HSCs. Nevertheless, normal HSC aging is associated with a noticeable decline in regenerative potential and possible changes in other functions. Myelodysplastic syndrome (MDS is an age-associated hematopoietic malignancy, characterized by abnormal blood cell maturation and a high propensity for leukemic transformation. It is furthermore thought to originate in a HSC and to be associated with the accrual of multiple genetic and epigenetic aberrations. This raises the question whether MDS is, in part, related to an inability to adequately cope with DNA damage. Here we discuss the various components of the cellular response to DNA damage. For each component, we evaluate related studies that may shed light on a potential relationship between MDS development and aberrant DNA damage response/repair.

  12. Pesticide exposure as a risk factor for myelodysplastic syndromes: a meta-analysis based on 1,942 cases and 5,359 controls.

    Directory of Open Access Journals (Sweden)

    Jie Jin

    Full Text Available Pesticide exposure has been linked to increased risk of cancer at several sites, but its association with risk of myelodysplastic syndromes (MDS is still unclear. A meta-analysis of studies published through April, 2014 was performed to investigate the association of pesticide exposure with the risk of MDS.Studies were identified by searching the Web of Science, Cochrane Library and PubMed databases. Summary odds ratios (ORs with corresponding 95% confidence intervals (CIs were calculated using random- or fixed-effect models.This meta-analysis included 11 case-control studies, all of which demonstrated a correlation between pesticide exposure and a statistically significant increased risk of MDS (OR=1.95, 95% CI 1.23-3.09. In subgroup analyses, patients with pesticide exposure had increased risk of developing MDS if they were living in the Europe or Asia and had refractory anemia (RA or RA with ringed sideroblasts (RARS. Moreover, in the analysis by specific pesticides, increased risk was associated with exposure to insecticides (OR=1.71, 95% CI 1.22-2.40 but not exposure to herbicides or fungicides.This meta-analysis supports the hypothesis that exposure to pesticides increases the risk of developing MDS. Further prospective cohort studies are warranted to verify the association and guide clinical practice in MDS prevention.

  13. The development of the Older Persons and Informal Caregivers Survey Minimum DataSet (TOPICS-MDS): a large-scale data sharing initiative.

    Science.gov (United States)

    Lutomski, Jennifer E; Baars, Maria A E; Schalk, Bianca W M; Boter, Han; Buurman, Bianca M; den Elzen, Wendy P J; Jansen, Aaltje P D; Kempen, Gertrudis I J M; Steunenberg, Bas; Steyerberg, Ewout W; Olde Rikkert, Marcel G M; Melis, René J F

    2013-01-01

    In 2008, the Ministry of Health, Welfare and Sport commissioned the National Care for the Elderly Programme. While numerous research projects in older persons' health care were to be conducted under this national agenda, the Programme further advocated the development of The Older Persons and Informal Caregivers Survey Minimum DataSet (TOPICS-MDS) which would be integrated into all funded research protocols. In this context, we describe TOPICS data sharing initiative (www.topics-mds.eu). A working group drafted TOPICS-MDS prototype, which was subsequently approved by a multidisciplinary panel. Using instruments validated for older populations, information was collected on demographics, morbidity, quality of life, functional limitations, mental health, social functioning and health service utilisation. For informal caregivers, information was collected on demographics, hours of informal care and quality of life (including subjective care-related burden). Between 2010 and 2013, a total of 41 research projects contributed data to TOPICS-MDS, resulting in preliminary data available for 32,310 older persons and 3,940 informal caregivers. The majority of studies sampled were from primary care settings and inclusion criteria differed across studies. TOPICS-MDS is a public data repository which contains essential data to better understand health challenges experienced by older persons and informal caregivers. Such findings are relevant for countries where increasing health-related expenditure has necessitated the evaluation of contemporary health care delivery. Although open sharing of data can be difficult to achieve in practice, proactively addressing issues of data protection, conflicting data analysis requests and funding limitations during TOPICS-MDS developmental phase has fostered a data sharing culture. To date, TOPICS-MDS has been successfully incorporated into 41 research projects, thus supporting the feasibility of constructing a large (>30,000 observations

  14. Myeloablative radioimmunotherapies in the conditioning of patients with AML, MDS and multiple myeloma prior to stem cell transplantation; Myeloablative Radioimmuntherapien zur Konditionierung bei Patienten mit AML, MDS und multiplem Myelom vor Stammzelltransplantation

    Energy Technology Data Exchange (ETDEWEB)

    Buchmann, I. [Abt. fuer Nuklearmedizin, Universitaetsklinik Heidelberg (Germany)

    2008-06-15

    Aggressive consolidation chemotherapy and hematopoietic stem cell transplantation have improved the prognosis of patients with acute myeloid leukemia (AML), myelodyplastic syndrome (MDS) and multiple myeloma. Nevertheless, only a minor fraction of patients achieve long-term disease-free survival after stem cell transplantation with disease recurrence being the most common cause of treatment failure. In addition, therapy-related effects such as toxicity of chemotherapy and complications of stem cell transplantation increase mortality rates significantly. Myeloablative radioimmunotherapy uses radiolabeled monoclonal antibodies (mAb) with affinity for the hematopoietic marrow. It applies high radiation doses in the bone marrow but spares normal organs. Adding myeloablative radioimmunotherapy to the conditioning schemes of AML, MDS and multiple myeloma before stem cell transplantation allows for the achievement of a pronounced antileukemic/antimyeloma effect for the reduction of relapse rates without significant increase of acute organ toxicity and therapy-related mortality. In order to optimise therapy, a rational design of the nuclide-antibody combination is necessary. {sup 90}Y, {sup 188}Re and {sup 131}I are the most frequently used {beta}{sup -}-particles. Of these, {sup 90}Y is the most qualified nuclide for myeloablation. Backbone stabilised DTPA are ideal chelators to stably conjugate {sup 90}Y to antibodies so far. For myeloablative conditioning, anti-CD66-, -45- and -33-mAb are used. The anti-CD66-antibody BW250/183 binds to normal hematopoietic cells but not to leukemic blasts and myeloma cells. The {sup 90}Y-2B3M-DTPA-BW250/183 is the most suited radioimmunoconjugate for patients with an infiltration grade of leukemic blasts in the bone marrow < 25%. The specific doses (Gy/GBq) are 10.2 {+-} 1.8 (bone marrow), 2.7 {+-} 2 (liver) and < 1 (kidneys). In contrast, radiolabeled anti-CD33- and anti-CD45-antibodies bind to both, most of white blood cells and

  15. Myelodysplastic Syndromes (MDS)

    Science.gov (United States)

    ... talk about donating their baby's cord blood College football player stays true to his commitment Be the ... appointment, the transplant doctor will: Review your medical history Talk with you about your treatment options Discuss ...

  16. Directory of Open Access Journals (Sweden)

    E.D.R.P. Velloso

    2013-11-01

    Full Text Available Myelodysplastic syndromes (MDS and juvenile myelomonocytic leukemia (JMML are rare hematopoietic stem cell diseases affecting children. Cytogenetics plays an important role in the diagnosis of these diseases. We report here the experience of the Cytogenetic Subcommittee of the Brazilian Cooperative Group on Pediatric Myelodysplastic Syndromes (BCG-MDS-PED. We analyzed 168 cytogenetic studies performed in 23 different cytogenetic centers; 84 of these studies were performed in patients with confirmed MDS (primary MDS, secondary MDS, JMML, and acute myeloid leukemia/MDS+Down syndrome. Clonal abnormalities were found in 36.9% of the MDS cases and cytogenetic studies were important for the detection of constitutional diseases and for differential diagnosis with other myeloid neoplasms. These data show the importance of the Cooperative Group for continuing education in order to avoid a late or wrong diagnosis.

  17. Health and environmental impact of depleted uranium

    International Nuclear Information System (INIS)

    Furitsu, Katsumi

    2010-01-01

    Depleted Uranium (DU) is 'nuclear waste' produced from the enrichment process and is mostly made up of 238 U and is depleted in the fissionable isotope 235 U compared to natural uranium (NU). Depleted uranium has about 60% of the radioactivity of natural uranium. Depleted uranium and natural uranium are identical in terms of the chemical toxicity. Uranium's high density gives depleted uranium shells increased range and penetrative power. This density, combined with uranium's pyrophoric nature, results in a high-energy kinetic weapon that can punch and burn through armour plating. Striking a hard target, depleted uranium munitions create extremely high temperatures. The uranium immediately burns and vaporizes into an aerosol, which is easily diffused in the environment. People can inhale the micro-particles of uranium oxide in an aerosol and absorb them mainly from lung. Depleted uranium has both aspects of radiological toxicity and chemical toxicity. The possible synergistic effect of both kinds of toxicities is also pointed out. Animal and cellular studies have been reported the carcinogenic, neurotoxic, immuno-toxic and some other effects of depleted uranium including the damage on reproductive system and foetus. In addition, the health effects of micro/ nano-particles, similar in size of depleted uranium aerosols produced by uranium weapons, have been reported. Aerosolized DU dust can easily spread over the battlefield spreading over civilian areas, sometimes even crossing international borders. Therefore, not only the military personnel but also the civilians can be exposed. The contamination continues after the cessation of hostilities. Taking these aspects into account, DU weapon is illegal under international humanitarian laws and is considered as one of the inhumane weapons of 'indiscriminate destruction'. The international society is now discussing the prohibition of DU weapons based on 'precautionary principle'. The 1991 Gulf War is reportedly the first

  18. Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group.

    Science.gov (United States)

    Lübbert, Michael; Suciu, Stefan; Hagemeijer, Anne; Rüter, Björn; Platzbecker, Uwe; Giagounidis, Aristoteles; Selleslag, Dominik; Labar, Boris; Germing, Ulrich; Salih, Helmut R; Muus, Petra; Pflüger, Karl-Heinz; Schaefer, Hans-Eckart; Bogatyreva, Lioudmila; Aul, Carlo; de Witte, Theo; Ganser, Arnold; Becker, Heiko; Huls, Gerwin; van der Helm, Lieke; Vellenga, Edo; Baron, Frédéric; Marie, Jean-Pierre; Wijermans, Pierre W

    2016-01-01

    In a study of elderly AML patients treated with the hypomethylating agent decitabine (DAC), we noted a surprisingly favorable outcome in the (usually very unfavorable) subgroup with two or more autosomal monosomies (MK2+) within a complex karyotype (Lübbert et al., Haematologica 97:393-401, 2012). We now analyzed 206 myelodysplastic syndrome (MDS) patients (88 % of 233 patients randomized in the EORTC/GMDSSG phase III trial 06011, 61 of them with RAEBt, i.e. AML by WHO) with cytogenetics informative for MK status.. Endpoints are the following: complete/partial (CR/PR) and overall response rate (ORR) and progression-free (PFS) and overall survival (OS). Cytogenetic subgroups are the following: 63 cytogenetically normal (CN) patients, 143 with cytogenetic abnormalities, 73 of them MK-negative (MK-), and 70 MK-positive (MK+). These MK+ patients could be divided into 17 with a single autosomal monosomy (MK1) and 53 with at least two monosomies (MK2+). ORR with DAC in CN patients: 36.1 %, in MK- patients: 16.7 %, in MK+ patients: 43.6 % (MK1: 44.4 %, MK2+ 43.3 %). PFS was prolonged by DAC compared to best supportive care (BSC) in the CN (hazard ratio (HR) 0.55, 99 % confidence interval (CI), 0.26; 1.15, p = 0.03) and MK2+ (HR 0.50; 99 % CI, 0.23; 1.06, p = 0.016) but not in the MK-, MK+, and MK1 subgroups. OS was not improved by DAC in any subgroup. In conclusion, we demonstrate for the first time in a randomized phase III trial that high-risk MDS patients with complex karyotypes harboring two or more autosomal monosomies attain encouraging responses and have improved PFS with DAC treatment compared to BSC.

  19. Lenalidomide induces lipid raft assembly to enhance erythropoietin receptor signaling in myelodysplastic syndrome progenitors.

    Science.gov (United States)

    McGraw, Kathy L; Basiorka, Ashley A; Johnson, Joseph O; Clark, Justine; Caceres, Gisela; Padron, Eric; Heaton, Ruth; Ozawa, Yukiyasu; Wei, Sheng; Sokol, Lubomir; List, Alan F

    2014-01-01

    Anemia remains the principal management challenge for patients with lower risk Myelodysplastic Syndromes (MDS). Despite appropriate cytokine production and cellular receptor display, erythropoietin receptor (EpoR) signaling is impaired. We reported that EpoR signaling is dependent upon receptor localization within lipid raft microdomains, and that disruption of raft integrity abolishes signaling capacity. Here, we show that MDS erythroid progenitors display markedly diminished raft assembly and smaller raft aggregates compared to normal controls (p = 0.005, raft number; p = 0.023, raft size). Because lenalidomide triggers raft coalescence in T-lymphocytes promoting immune synapse formation, we assessed effects of lenalidomide on raft assembly in MDS erythroid precursors and UT7 cells. Lenalidomide treatment rapidly induced lipid raft formation accompanied by EpoR recruitment into raft fractions together with STAT5, JAK2, and Lyn kinase. The JAK2 phosphatase, CD45, a key negative regulator of EpoR signaling, was displaced from raft fractions. Lenalidomide treatment prior to Epo stimulation enhanced both JAK2 and STAT5 phosphorylation in UT7 and primary MDS erythroid progenitors, accompanied by increased STAT5 DNA binding in UT7 cells, and increased erythroid colony forming capacity in both UT7 and primary cells. Raft induction was associated with F-actin polymerization, which was blocked by Rho kinase inhibition. These data indicate that deficient raft integrity impairs EpoR signaling, and provides a novel strategy to enhance EpoR signal fidelity in non-del(5q) MDS.

  20. [Characteristic and function of peripheral blood mononuclear cells-induced macrophages in patients with myelodysplastic syndrome].

    Science.gov (United States)

    Han, Y; Wang, H Q; Fu, R; Qu, W; Ruan, E B; Wang, X M; Wang, G J; Wu, Y H; Liu, H; Song, J; Guan, J; Xing, L M; Li, L J; Jiang, H J; Liu, H; Wang, Y H; Liu, C Y; Zhang, W; Shao, Z H

    2017-08-14

    Objective: To explore characteristic and function of peripheral blood mononuclear cells (PBMNC) -induced macrophages in patients with myelodysplastic syndrome (MDS) to couple with its progression. Methods: A total of 24 MDS patients (11 low-risk patients and 13 high-risk group patients) referred to Department of Hematology of Tianjin Medical University General Hospital and normal controls were enrolled from September 2014 to December 2015. PBMNC was stimulated with GM-CSF to transform to macrophages. The morphology of macrophages was observed by microscope. The quantity of macrophages, CD206 and SIRPα on surface of macrophages were detected by flow cytometry. The phagocytic function of macrophages was analyzed by fluorescence microscopy and flow cytometry. Results: The morphology of macrophages from MDS patients was abnormal. The percentage of transformed macrophages was (5.17±3.47) % in patients with MDS, which was lower than that in controls significantly[ (66.18±13.43) %, t =3.529, P =0.001]. The expression of CD206 on macrophages from MDS patients was significantly lower than that of controls[ (9.73±2.59) % vs (51.15±10.82) %, t =4.551, P patients was significantly lower than that of controls [ (0.51±0.09) % vs (0.77±0.06) %, t =2.102, P =0.043]. The phagocytic index and the percentage of phagocytic of macrophages from MDS patients were significantly lower than those of macrophages from normal controls[0.45±0.08 vs 0.92±0.07, t =-6.253, P =0.008; (23.69±3.22) % vs (42.75±2.13) %, t =-6.982, P =0.006 respectively]by flow cytometry. The phagocytic index of MDS patients was significantly lower than that of controls (0.24±0.04 vs 0.48±0.96, t =3.464, P =0.001) by fluorescence microscopy. Conclusion: The quantity, recognization receptors and phagocytosis of PBMNC-induced macrophages decreased in MDS patients.

  1. Prognostic value of trisomy 8 as a single anomaly and the influence of additional cytogenetic aberrations in primary myelodysplastic syndromes.

    Science.gov (United States)

    Saumell, Sílvia; Florensa, Lourdes; Luño, Elisa; Sanzo, Carmen; Cañizo, Consuelo; Hernández, Jesus M; Cervera, José; Gallart, Miguel A; Carbonell, Félix; Collado, Rosa; Arenillas, Leonor; Pedro, Carme; Bargay, Joan; Nomdedeu, Benet; Xicoy, Blanca; Vallespí, Teresa; Raya, José M; Belloch, Luis; Sanz, Guillermo F; Solé, Francesc

    2012-11-01

    Trisomy 8 is the most common chromosomal gain in myelodysplastic syndromes (MDS), however, little is known about the features of MDS with isolated trisomy 8 and the influence of additional cytogenetic aberrations. We determined the characteristics and prognostic factors of 72 patients with trisomy 8 as a single anomaly and analysed also the impact of other aberrations added to trisomy 8 in another 62 patients. According to our study, MDS with isolated trisomy 8 was more frequent in men, with more than one cytopenia in most patients (62%) and having about 4% bone marrow blasts. The multivariate analysis demonstrated that platelet count and percentage bone marrow blasts had the strongest impact on overall survival (OS). The median OS for isolated trisomy 8, trisomy 8 plus one aberration (tr8 + 1), plus two (tr8 + 2) and plus three or more aberrations (tr8 + ≥3) was 34·3, 40, 23·4 and 5·8 months, respectively (P < 0·001). Trisomy 8 confers a poorer prognosis than a normal karyotype in MDS patients with ≥5% bone marrow blasts. This study supports the view that MDS with isolated trisomy 8 should be included in the intermediate cytogenetic risk group. © 2012 Blackwell Publishing Ltd.

  2. Myeloablative radioimmunotherapies in the conditioning of patients with AML, MDS and multiple myeloma prior to stem cell transplantation

    International Nuclear Information System (INIS)

    Buchmann, I.

    2008-01-01

    Aggressive consolidation chemotherapy and hematopoietic stem cell transplantation have improved the prognosis of patients with acute myeloid leukemia (AML), myelodyplastic syndrome (MDS) and multiple myeloma. Nevertheless, only a minor fraction of patients achieve long-term disease-free survival after stem cell transplantation with disease recurrence being the most common cause of treatment failure. In addition, therapy-related effects such as toxicity of chemotherapy and complications of stem cell transplantation increase mortality rates significantly. Myeloablative radioimmunotherapy uses radiolabeled monoclonal antibodies (mAb) with affinity for the hematopoietic marrow. It applies high radiation doses in the bone marrow but spares normal organs. Adding myeloablative radioimmunotherapy to the conditioning schemes of AML, MDS and multiple myeloma before stem cell transplantation allows for the achievement of a pronounced antileukemic/antimyeloma effect for the reduction of relapse rates without significant increase of acute organ toxicity and therapy-related mortality. In order to optimise therapy, a rational design of the nuclide-antibody combination is necessary. 90 Y, 188 Re and 131 I are the most frequently used β - -particles. Of these, 90 Y is the most qualified nuclide for myeloablation. Backbone stabilised DTPA are ideal chelators to stably conjugate 90 Y to antibodies so far. For myeloablative conditioning, anti-CD66-, -45- and -33-mAb are used. The anti-CD66-antibody BW250/183 binds to normal hematopoietic cells but not to leukemic blasts and myeloma cells. The 90 Y-2B3M-DTPA-BW250/183 is the most suited radioimmunoconjugate for patients with an infiltration grade of leukemic blasts in the bone marrow 90 Y-anti-CD45-mAb YAML568 are 6.4 ± 1.2 (bone marrow), 3.9 ± 1.4 (liver) and 1.1 ± 0.4 (kidneys). CD45 is expressed also on the extramedullar clonogenic myeloma progenitor cell that circulates in the peripheral blood. Thus, the conditioning of

  3. Microcephaly, microtia, preauricular tags, choanal atresia and developmental delay in three unrelated patients: a mandibulofacial dysostosis distinct from Treacher Collins syndrome.

    NARCIS (Netherlands)

    Wieczorek, D.; Gener, B.; Gonzalez, M.J.; Seland, S.; Fischer, S.; Hehr, U.; Kuechler, A.; Hoefsloot, L.H.; Leeuw, N. de; Gillessen-Kaesbach, G.; Lohmann, D.R.

    2009-01-01

    Treacher Collins syndrome (TCS, OMIM 154500) is a well-defined mandibulofacial dysostosis characterized by symmetric facial anomalies consisting of malar hypoplasia, coloboma of the lower eyelid, dysplastic ears, micrognathia, cleft palate and deafness. Other mandibulofacial dysostoses (MDs) such as

  4. Immune Mechanisms in Myelodysplastic Syndrome

    DEFF Research Database (Denmark)

    Glenthøj, Andreas; Ørskov, Andreas Due; Hansen, Jakob Werner

    2016-01-01

    diseases are common in patients with MDS, fueling hypotheses of common etiological mechanisms. Both innate and adaptive immune pathways are overly active in the hematopoietic niche of MDS. Although supportive care, growth factors, and hypomethylating agents are the mainstay of MDS treatment, some patients......-especially younger low-risk patients with HLA-DR15 tissue type-demonstrate impressive response rates after immunosuppressive therapy. This is in contrast to higher-risk MDS patients, where several immune activating treatments, such as immune checkpoint inhibitors, are in the pipeline. Thus, the dual role of immune...... mechanisms in MDS is challenging, and rigorous translational studies are needed to establish the value of immune manipulation as a treatment of MDS....

  5. Causes of death in 2877 patients with myelodysplastic syndromes.

    Science.gov (United States)

    Nachtkamp, Kathrin; Stark, Romina; Strupp, Corinna; Kündgen, Andrea; Giagounidis, Aristoteles; Aul, Carlo; Hildebrandt, Barbara; Haas, Rainer; Gattermann, Norbert; Germing, Ulrich

    2016-05-01

    Patients with myelodysplastic syndromes face a poor prognosis. The exact causes of death have not been described properly in the past. We performed a retrospective analysis of causes of death using data of 3792 patients in the Düsseldorf registry who have been followed up for a median time of 21 months. Medical files as well as death certificates were screened and primary care physicians were contacted. Death after AML evolution, infection, and bleeding was considered to be clearly disease-related. Further categories of causes of death were heart failure, other possibly disease-related reasons, such as hemochromatosis, disease-independent reasons as well as cases with unclear causes of death. Median age at the time of diagnosis was 71 years. At the time of analysis, 2877 patients (75.9 %) had deceased. In 1212 cases (42.1 %), the exact cause of death could not be ascertained. From 1665 patients with a clearly documented cause of death, 1388 patients (83.4 %) succumbed directly disease-related (AML (46.6 %), infection (27.0 %), bleeding (9.8 %)), whereas 277 patients (16.6 %) died for reasons not directly related with myelodysplastic syndromes (MDS), including 132 patients with cardiac failure, 77 non-disease-related reasons, 23 patients with solid tumors, and 45 patients with possibly disease-related causes like hemochromatosis. Correlation with IPSS, IPSS-R, and WPSS categories showed a proportional increase of disease-related causes of death with increasing IPSS/IPSS-R/WPSS risk category. Likewise, therapy-related MDS were associated with a higher percentage of disease-related causes of death than primary MDS. This reflects the increasing influence of the underlying disease on the cause of death with increasing aggressiveness of the disease.

  6. Safety and efficacy of the CD95-ligand inhibitor asunercept in transfusion-dependent patients with low and intermediate risk MDS.

    Science.gov (United States)

    Boch, Tobias; Luft, Thomas; Metzgeroth, Georgia; Mossner, Maximilian; Jann, Johann-Christoph; Nowak, Daniel; Meir, Franziska La; Schumann, Christiane; Klemmer, Jennifer; Brendel, Susanne; Fricke, Harald; Kunz, Claudia; Weiß, Christel; Hofmann, Wolf-Karsten; Nolte, Florian

    2018-05-01

    In low risk MDS, increased apoptosis of erythroid progenitors mediated via CD95 (Fas) activation has been described to result in peripheral cytopenia. Blockade of the CD95 system can improve erythropoiesis in MDS. Asunercept (APG101) is a fusion protein consisting of the extracellular domain of human CD95 and the Fc domain of human IgG1 blocking the interaction between CD95 and its ligand. Here we report on results from a phase I study in 20 transfusion-dependent low and intermediate risk MDS patients treated with intravenous asunercept (EudraCT 2012-003027-37). Primary objectives were safety and tolerability as well as pharmacodynamic effects. Secondary objectives were hematologic improvement, incidence and time to leukemic progression as well as overall survival. Frequency and severity of adverse events were in range of what could be expected in a patient cohort comprising of elderly MDS patients. Two patients experienced a serious adverse event with a suspected relationship to asunercept. The incidence of disease progression was low. In the 20 patients a decrease of the transfusion need from a mean of 10,8 (±5,1) pRBCs during the 12 weeks treatment phase to a mean of 10,0 (±4,2) pRBCs at the end of the study was observed. In conclusion, asunercept was well tolerated and showed efficacy in transfusion-dependent low and intermediate risk MDS patients. Further clinical investigation is warranted, particularly in combination with erythropoiesis stimulating agents (ESAs). Copyright © 2018. Published by Elsevier Ltd.

  7. Peptide Vaccination Against Cancer Testis Antigens in Combination With Azacitidine for Patients With Myelodysplastic Syndrome and Acute Myeloid Leukemia

    DEFF Research Database (Denmark)

    Holmberg, S.; Ortved Gang, A.; Svane, I.M.

    2016-01-01

    Myelodysplastic Syndrome (MDS) is a clonal disorder and characterized by increasing bone marrow failure due to accumulation of genetic and epigenetic changes in hematopoietic stem cells. Patients with high-risk disease have a poor prognosis and a high risk of progression to Acute Myeloid Leukemia...

  8. Deferasirox in iron-overloaded patients with transfusion-dependent myelodysplastic syndromes: Results from the large 1-year EPIC study

    DEFF Research Database (Denmark)

    Gattermann, Norbert; Finelli, Carlo; Porta, Matteo Della

    2010-01-01

    The prospective 1-year EPIC study enrolled 341 patients with myelodysplastic syndromes (MDS); although baseline iron burden was >2500ng/mL, approximately 50% were chelation-naïve. Overall median serum ferritin decreased significantly at 1 year (p=0.002). Decreases occurred irrespective of whether...

  9. Impact of socioeconomic status on disease phenotype, genomic landscape and outcomes in myelodysplastic syndromes.

    Science.gov (United States)

    Mastaglio, Francesca; Bedair, Khaled; Papaemmanuil, Elli; Groves, Michael J; Hyslop, Ann; Keenan, Norene; Hothersall, Eleanor J; Campbell, Peter J; Bowen, David T; Tauro, Sudhir

    2016-07-01

    Genetic and epigenetic alterations contribute to the biological and clinical characteristics of myelodysplastic syndromes (MDS), but a role for socioeconomic environment remains unclear. Here, socioeconomic status (SES) for 283 MDS patients was estimated using the Scottish Index of Multiple Deprivation tool. Indices were assigned to quintile categorical indicators ranked from SES1 (lowest) to SES5 (highest). Clinicopathological features and outcomes between SES quintiles containing 15%, 20%, 19%, 30% and 16% of patients were compared. Prognostic scores identified lower-risk MDS in 82% of patients, with higher-risk disease in 18%. SES quintiles did not associate with age, gender, cytogenetics, International Prognostic scores or, in sub-analysis (n = 95), driver mutations. The odds ratio of a diagnosis of refractory anaemia was greater than other MDS sub-types in SES5 (OR 1·9, P = 0·024). Most patients (91%) exclusively received supportive care. SES did not associate with leukaemic transformation or cause of death. Cox regression models confirmed male gender (P < 0·05), disease-risk (P < 0·0001) and age (P < 0·01) as independent predictors of leukaemia-free survival, with leukaemic transformation an additional determinant of overall survival (P = 0·07). Thus, if access to healthcare is equitable, SES does not determine disease biology or survival in MDS patients receiving supportive treatment; additional studies are required to determine whether outcomes following disease-modifying therapies are influenced by SES. © 2016 John Wiley & Sons Ltd.

  10. In vivo measurements of the T1 relaxation processes in the bone marrow in patients with myelodysplastic syndrome

    International Nuclear Information System (INIS)

    Jensen, K.E.; Nielsen, H.; Thomsen, C.; Soerensen, P.G.; Karle, H.; Christoffersen, P.; Henriksen, O.; Hvidovre Hospital, Copenhagen; Hvidovre Hospital, Copenhagen

    1989-01-01

    Nine patients with myelodysplastic syndrome (MDS) were examined with magnetic resonance imaging and in vivo T1 relaxation time measurements of the vertebral bone marrow in a 1.5 tesla whole body scanner. Two patients underwent transformation to acute myeloid leukemia and were evaluated at follow-up examinations. At the time of diagnosis the T1 relaxation times of the vertebral bone marrow were significantly prolonged compared with normal values. The T1 relaxation times of the vertebral bone marrow in patients with MDS showed significantly lower values compared with patients with acute leukemia and did not differ from patients with polycythemia vera. (orig.)

  11. Myelodysplastic syndromes and acute myeloid leukemia in cats infected with feline leukemia virus clone33 containing a unique long terminal repeat.

    Science.gov (United States)

    Hisasue, Masaharu; Nagashima, Naho; Nishigaki, Kazuo; Fukuzawa, Isao; Ura, Shigeyoshi; Katae, Hiromi; Tsuchiya, Ryo; Yamada, Takatsugu; Hasegawa, Atsuhiko; Tsujimoto, Hajime

    2009-03-01

    Feline leukemia virus (FeLV) clone33 was obtained from a domestic cat with acute myeloid leukemia (AML). The long terminal repeat (LTR) of this virus, like the LTRs present in FeLV from other cats with AML, differs from the LTRs of other known FeLV in that it has 3 tandem direct 47-bp repeats in the upstream region of the enhancer (URE). Here, we injected cats with FeLV clone33 and found 41% developed myelodysplastic syndromes (MDS) characterized by peripheral blood cytopenias and dysplastic changes in the bone marrow. Some of the cats with MDS eventually developed AML. The bone marrow of the majority of cats with FeLV clone33 induced MDS produced fewer erythroid and myeloid colonies upon being cultured with erythropoietin or granulocyte-macrophage colony-stimulating factor (GM-SCF) than bone marrow from normal control cats. Furthermore, the bone marrow of some of the cats expressed high-levels of the apoptosis-related genes TNF-alpha and survivin. Analysis of the proviral sequences obtained from 13 cats with naturally occurring MDS reveal they also bear the characteristic URE repeats seen in the LTR of FeLV clone33 and other proviruses from cats with AML. Deletions and mutations within the enhancer elements are frequently observed in naturally occurring MDS as well as AML. These results suggest that FeLV variants that bear URE repeats in their LTR strongly associate with the induction of both MDS and AML in cats.

  12. Wormhole Detection Based on Ordinal MDS Using RTT in Wireless Sensor Network

    Directory of Open Access Journals (Sweden)

    Saswati Mukherjee

    2016-01-01

    Full Text Available In wireless communication, wormhole attack is a crucial threat that deteriorates the normal functionality of the network. Invasion of wormholes destroys the network topology completely. However, most of the existing solutions require special hardware or synchronized clock or long processing time to defend against long path wormhole attacks. In this work, we propose a wormhole detection method using range-based topology comparison that exploits the local neighbourhood subgraph. The Round Trip Time (RTT for each node pair is gathered to generate neighbour information. Then, the network is reconstructed by ordinal Multidimensional Scaling (MDS followed by a suspicion phase that enlists the suspected wormholes based on the spatial reconstruction. Iterative computation of MDS helps to visualize the topology changes and can localize the potential wormholes. Finally, a verification phase is used to remove falsely accused nodes and identify real adversaries. The novelty of our algorithm is that it can detect both short path and long path wormhole links. Extensive simulations are executed to demonstrate the efficacy of our approach compared to existing ones.

  13. The drift-flux correlation package MDS

    International Nuclear Information System (INIS)

    Hoeld, A.

    2001-01-01

    Based on the SONNENBURG drift-flux correlation, developed at GRS/Garching (Germany), a comprehensive drift-flux correlation package (MDS) has been established. Its aim is to support thermal-hydraulic mixture-fluid models, models being used for the simulation of the steady state and transient behaviour of characteristic thermal-hydraulic parameters of single- or two-phase fluids flowing along coolant channels of different types (being, e.g., parts of NPP-s, steam generators etc.). The characteristic properties of this package with respect to the behaviour at co- and counter-current flow, its inverse solutions needed for steady state simulations, its behaviour when approaching the lower or upper boundary of a two-phase region, its verification and behaviour with respect to other correlations will be discussed. An adequate driver code, MDSDRI, has been established too, allowing to test the package very thoroughly out of the complex thermal-hydraulic codes. (author)

  14. The drift-flux correlation package MDS

    Energy Technology Data Exchange (ETDEWEB)

    Hoeld, A. [Bernaysstr. 16A, Munich, F.R. (Germany)

    2001-07-01

    Based on the SONNENBURG drift-flux correlation, developed at GRS/Garching (Germany), a comprehensive drift-flux correlation package (MDS) has been established. Its aim is to support thermal-hydraulic mixture-fluid models, models being used for the simulation of the steady state and transient behaviour of characteristic thermal-hydraulic parameters of single- or two-phase fluids flowing along coolant channels of different types (being, e.g., parts of NPP-s, steam generators etc.). The characteristic properties of this package with respect to the behaviour at co- and counter-current flow, its inverse solutions needed for steady state simulations, its behaviour when approaching the lower or upper boundary of a two-phase region, its verification and behaviour with respect to other correlations will be discussed. An adequate driver code, MDSDRI, has been established too, allowing to test the package very thoroughly out of the complex thermal-hydraulic codes. (author)

  15. Investigation of 305 patients with myelodysplastic syndromes and 20q deletion for associated cytogenetic and molecular genetic lesions and their prognostic impact.

    Science.gov (United States)

    Bacher, Ulrike; Haferlach, Torsten; Schnittger, Susanne; Zenger, Melanie; Meggendorfer, Manja; Jeromin, Sabine; Roller, Andreas; Grossmann, Vera; Krauth, Maria-Theresa; Alpermann, Tamara; Kern, Wolfgang; Haferlach, Claudia

    2014-03-01

    In patients with myelodysplastic syndromes (MDS), sole 20q deletion [del(20q)] is a recurrent favourable abnormality. We studied additional molecular and cytogenetic lesions and their prognostic impact in 305 MDS patients with del(20q) (229 males/76 females; 29-90 years). All patients were investigated by cytomorphology and chromosome banding analysis (CBA), subsets by fluorescence in situ hybridization, molecular mutation screening, and array comparative genomic hybridization (aCGH). By aCGH (n = 30), the minimal common deleted region (CDR) was flanked by PTPRT (20q13·11) and EYA2 (20q13·12). 210 (68·9%) patients had 'early MDS' without blast increase, 95 (31·1%) 'advanced' MDS with blast increase (5-19%). Additional chromosomal abnormalities (ACAs) were detected in 88/305 (28·9%) patients. Patients with advanced MDS more frequently had ACAs (P = 0·003) and had a higher mean number of ACAs (P = 0·020) and of molecular mutations (P = 0·060). Spliceosome mutations were frequent (U2AF1: n = 31/155; 20·0%; SRSF2: n = 31/159; 19·5%; SF3B1mut: n = 8/159; 5·0%). ASXL1mut (25/153; 16·3%) were associated with advanced MDS (P = 0·001). Presence of ≥3 ACAs (P = 0·003) and ASXL1mut (P = 0·002) were associated with worse 2-year survival. In conclusion, the cytogenetic subgroup of MDS with del(20q) has a good prognosis but may be further subclassified by additional cytogenetic and molecular lesions. U2AF1mut is overrepresented in MDS with del(20q), and ASXL1mut is prognostically adverse. © 2013 John Wiley & Sons Ltd.

  16. A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome.

    Science.gov (United States)

    Kirschbaum, Mark; Gojo, Ivana; Goldberg, Stuart L; Bredeson, Christopher; Kujawski, Lisa A; Yang, Allen; Marks, Peter; Frankel, Paul; Sun, Xing; Tosolini, Alessandra; Eid, Joseph E; Lubiniecki, Gregory M; Issa, Jean-Pierre

    2014-10-01

    Patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) may respond to treatment with epigenetic-modifying agents. Histone deacetylase inhibitors may synergize with hypomethylating agents. This phase 1 dose-escalation study was designed to determine the maximum tolerated dose, recommended phase 2 dose, safety and tolerability of vorinostat plus decitabine in patients with relapsed/refractory AML, newly-diagnosed AML, or intermediate- to high-grade MDS. Thirty-four patients received concurrent therapy with decitabine plus vorinostat and 37 received sequential therapy with decitabine followed by vorinostat. Twenty-nine patients had relapsed/refractory AML, 31 had untreated AML and 11 had MDS. The target maximum administered dose (MAD) of decitabine 20 mg/m(2) daily for 5 d plus vorinostat 400 mg/d for 14 d was achieved for concurrent and sequential schedules, with one dose-limiting toxicity (Grade 3 QTc prolongation) reported in the sequential arm. Common toxicities were haematological and gastrointestinal. Responses were observed more frequently at the MAD on the concurrent schedule compared with the sequential schedule in untreated AML (46% vs. 14%), relapsed/refractory AML (15% vs. 0%) and MDS (60% vs. 0%). Decitabine plus vorinostat given concurrently or sequentially appears to be safe and well-tolerated. Concurrent therapy shows promising clinical activity in AML or MDS, warranting further investigation. © 2014 John Wiley & Sons Ltd.

  17. The Role of mDia1 in the Aberrant Innate Immune Signaling in del(5q) Myelodysplastic Syndromes

    Science.gov (United States)

    2017-10-01

    chromosome 5q (del(5q)). There are two common deleted regions (CDRs) identified on 5q: a distal locus that is often deleted in 5q- syndrome with good ...chromosome 5q being the most common . Our recently published work demonstrated that loss of mDia1, a protein with its encoding genes located at chromosome 5...is the most common cytogenetic abnormality in patients with myelodysplastic syndromes (MDS). We discovered in 2014 that CD14 was aberrantly

  18. CMS MDS 3.0 Section M Skin Conditions in Long-term Care: Pressure Ulcers, Skin Tears, and Moisture-Associated Skin Damage Data Update.

    Science.gov (United States)

    Ayello, Elizabeth A

    2017-09-01

    The purpose of this learning activity is to provide information about the updates to the Centers for Medicare & Medicaid Services (CMS) MDS 3.0 Section M, Skin Conditions documentation in long-term care. This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. After participating in this educational activity, the participant should be better able to:1. Explain the use of the CMS MDS 3.0 tool for documenting skin problems in long-term care.2. Demonstrate examples of proper documentation for specific skin problems. This manuscript reviews some of the key parts of the October 2016 revised Long-term Care Resident Assessment Instrument manual for Minimum Data Set (MDS) 3.0 Section M Skin Conditions. It also reports the Centers for Medicare & Medicaid's publicly reported frequency data in long-term care for selected items on the MDS 3.0 Section M Skin Conditions. Percentages and trends of pressure ulcers/injuries, skin tears, and moisture-associated skin damage are assessed.

  19. Longitudinal Analysis of DNA Methylation in CD34+ Hematopoietic Progenitors in Myelodysplastic Syndrome

    DEFF Research Database (Denmark)

    Wong, Yan Fung; Micklem, Chris N; Taguchi, Masataka

    2014-01-01

    Myelodysplastic syndrome (MDS) is a disorder of hematopoietic stem cells (HSCs) that is often treated with DNA methyltransferase 1 (DNMT1) inhibitors (5-azacytidine [AZA], 5-aza-2'-deoxycytidine), suggesting a role for DNA methylation in disease progression. How DNMT inhibition retards disease...... regulators not expressed within the hematopoietic compartment and was distinct from that observed between healthy hematopoietic cell types. After AZA treatment, we observed only limited DNA demethylation at sites that varied between patients. This suggests that a subset of the stem cell population...... is resistant to AZA and provides a basis for disease relapse. Using gene expression data from patient samples and an in vitro AZA treatment study, we identified differentially methylated genes that can be activated following treatment and that remain silent in the CD34+ stem cell compartment of high-risk MDS...

  20. Sustained trilineage recovery and disappearance of abnormal chromosome clone in a patient with myelodysplastic syndrome following combination therapy with cytokines (granulocyte colony-stimulating factor and erythropoietin) and high-dose methylprednisolone.

    Science.gov (United States)

    Imai, Y; Fukuoka, T; Nakatani, A; Ohsaka, A; Takahashi, A

    1996-04-01

    We report a case of hypoplastic myelodyplastic syndrome (MDS) (refractory anemia (RA)) in which sustained trilineage haematological response and persistent disappearance of an abnormal chromosome clone were achieved after treatment with combination therapy of cytokines (granulocyte colony-stimulating factor (G-CSF) and erythropoietin (Epo)) and methylprednisolone (mPSL) pulse dose. The patient's haematological recovery was rapid and maintained even after cessation of the therapy. In addition, the predominant chromosome clone 13q- in bone marrow cells disappeared in the fourth week. The patient's improved bone marrow haemopoiesis and disappearance of the abnormal chromosome has continued to the present, 13 months after treatment. The occurrence of both trilineage response and abnormal chromosome disappearance in MDS patients treated with cytokine(s) or steroids is rare. Combination therapy might therefore be advantageous in MDS.

  1. In vivo measurements of the T1 relaxation processes in the bone marrow in patients with myelodysplastic syndrome. A magnetic resonance imaging study

    Energy Technology Data Exchange (ETDEWEB)

    Jensen, K.E.; Nielsen, H.; Thomsen, C.; Soerensen, P.G.; Karle, H.; Christoffersen, P.; Henriksen, O. (Hvidovre Hospital, Copenhagen (Denmark). Dept. of Magnetic Resonance; Hvidovre Hospital, Copenhagen (Denmark). Dept. of Hematology; Hvidovre Hospital, Copenhagen (Denmark). Dept. of Pathology)

    Nine patients with myelodysplastic syndrome (MDS) were examined with magnetic resonance imaging and in vivo T1 relaxation time measurements of the vertebral bone marrow in a 1.5 tesla whole body scanner. Two patients underwent transformation to acute myeloid leukemia and were evaluated at follow-up examinations. At the time of diagnosis the T1 relaxation times of the vertebral bone marrow were significantly prolonged compared with normal values. The T1 relaxation times of the vertebral bone marrow in patients with MDS showed significantly lower values compared with patients with acute leukemia and did not differ from patients with polycythemia vera. (orig.).

  2. Meta-Analytical Online Repository of Gene Expression Profiles of MDS Stem Cells

    Science.gov (United States)

    2015-12-01

    lymphoid cell percentages in these samples. We observed that most of the MDS samples had lymphoid and neutrophil percentages that were in the normal...pathways involved in chemokine signaling, cytokine-cytokine receptor interaction, innate immunity signaling, hematopoietic cell lineage regulation, and...transcription factors are important for survival of cancer stem cells .2,34-36 IL8 is also an important regulator of innate immunity. Recent data have shown

  3. Lenalidomide for the Treatment of Low- or Intermediate-1-Risk Myelodysplastic Syndromes Associated with Deletion 5q Cytogenetic Abnormality: An Evidence Review of the NICE Submission from Celgene

    NARCIS (Netherlands)

    H.M. Blommestein (Hedwig); N. Armstrong (Nigel); S. Ryder; S. Deshpande (Sohan); G. Worthy (Gill); C. Noake; R. Riemsma (Rob); J. Kleijnen (Jos); J.L. Severens (Hans); M.J. Al (Maiwenn)

    2016-01-01

    textabstractThe National Institute for Health and Care Excellence (NICE) invited the manufacturer of lenalidomide (Celgene) to submit evidence of the clinical and cost effectiveness of the drug for treating adults with myelodysplastic syndromes (MDS) associated with deletion 5q cytogenetic

  4. Developments in the treatment of transfusion-dependent anemia in patients with myelodysplastic syndromes: epidemiology, etiology, genetics, and targeted therapies

    Directory of Open Access Journals (Sweden)

    Raza A

    2014-07-01

    Full Text Available Azra Raza, Nicholas Iverson, Abdullah M AliThe MDS Center, Columbia University, New York, NY, USAAbstract: Myelodysplastic syndromes are malignant hematopoietic stem cell disorders that present with variable cytopenias and predominantly affect the elderly. Treatment options are limited, with allogeneic transplant being the only potentially curative strategy. Recent mutational profiling studies have led to cataloguing of driver and passenger mutations most commonly affecting the epigenetic regulators and genes involved in RNA splicing. Despite improved understanding of the disease biology, these emerging molecular insights have not led to identification of novel therapeutic strategies. Although several drugs approved in the last decade improve the cytopenias, the relief is temporary, most likely due to the sequential activation of clones. Future advances depend upon identification of signaling pathways in dominant clones and targeting these with agents that might be known but need to be matched to suit the needs of individual patients in a longitudinal, dynamic fashion. Myelodysplastic syndromes are ideally suited for the development of such personalized medicine.Keywords: cancer, epigenetics, iron, MDS, myelodysplasia, splicing

  5. [Marked hemosiderosis in myelodysplastic syndrome].

    Science.gov (United States)

    Klinz, C

    1999-01-29

    A 68-year-old man was admitted because of symptoms of lumbar pain. He was known to have chronic anemia with ring sideroblasts and diabetes melitus and to be in heart failure. Three months before he had been given 7 units of red cell concentrate. On admission the outstanding features were brown discoloration of the skin, absent body hair, tachycardia, hepatomegaly and small testicles. He had a normocytic anemia, hyperglycemia and raised transaminases, hypogonadism and vitamin D3 deficiency. The serum levels of iron, transferrin saturation and feritin were markedly elevated. Liver iron content/g dried liver was 4.2 g (by biomagnetometer). Radiology of the lumbar vertebrae showed osteoporosis and sonography confirmed hepatomegaly. The known myelodysplastic syndrome (MDS) had fed to secondary hemosiderosis with heart failure, liver involvement, diabetes mellitus, hypogonadism and osteoporosis. Symptomatic treatment was unsuccessfully complemented by desferoxamine (up to 4 g/12 h) to release iron. But very good iron excretion was then achieved with deferiprone (3 x 1 g/d). The patient later died of the sequelae of hemosiderosis. Even when they have not required transfusions, patients with long-standing MDS should be examined regularly for the possible development of secondary hemosiderosis so that iron-chelating agents can be administered as needed.

  6. Isotopes and innovation: MDS Nordion's first fifty years, 1946-1996

    International Nuclear Information System (INIS)

    Litt, P.

    2000-01-01

    Few people realize that Canada leads in the world in the production of radio isotopes, the raw material of nuclear medicine and high-tech scanners, and in their use in medicine and industry. In Isotopes and Innovation the author gives an in-depth look at MDS Nordion, a company that started as the radium sales department of Eldorado Mining and Refining, the Canadian uranium producer that was a key strategic resource for the Allies during the race to build the nuclear bomb, and went on to become the world?s leading producer of radioisotopes. When radium began to be used as a cancer treatment, Eldorado quickly became familiar with the medical marketplace and adept at developing products that could solve clinical problems and, more important, save lives. When Canadian nuclear reactors at Chalk River began producing radioisotopes that outperformed radium, Eldorado's radium sales department was transferred to a new crown corporation, Atomic Energy of Canada Limited, created to manage Canada's nuclear research establishment. The new company developed many useful applications for radioisotopes, including cobalt-60 cancer therapy machines and industrial sterilization plants. Bought by Medical Data Services Inc. in the early 1990s, MDS Nordion was a runaway success, creator and sole proprietor of several market-leading products. Isotopes and Innovation describes how a company capitalized on the byproducts of Canada's unique nuclear research program to attain a commanding international position in extremely specialized and demanding high-tech markets, a saga in which innovative research and enterprising global marketing have brought commercial success and saved countless lives around the world

  7. High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia.

    Science.gov (United States)

    Pasquet, Marlène; Bellanné-Chantelot, Christine; Tavitian, Suzanne; Prade, Naïs; Beaupain, Blandine; Larochelle, Olivier; Petit, Arnaud; Rohrlich, Pierre; Ferrand, Christophe; Van Den Neste, Eric; Poirel, Hélène A; Lamy, Thierry; Ouachée-Chardin, Marie; Mansat-De Mas, Véronique; Corre, Jill; Récher, Christian; Plat, Geneviève; Bachelerie, Françoise; Donadieu, Jean; Delabesse, Eric

    2013-01-31

    Congenital neutropenia is a group of genetic disorders that involve chronic neutropenia and susceptibility to infections. These neutropenias may be isolated or associated with immunologic defects or extra-hematopoietic manifestations. Complications may occur as infectious diseases, but also less frequently as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Recently, the transcription factor GATA2 has been identified as a new predisposing gene for familial AML/MDS. In the present study, we describe the initial identification by exome sequencing of a GATA2 R396Q mutation in a family with a history of chronic mild neutropenia evolving to AML and/or MDS. The subsequent analysis of the French Severe Chronic Neutropenia Registry allowed the identification of 6 additional pedigrees and 10 patients with 6 different and not previously reportedGATA2 mutations (R204X, E224X, R330X, A372T, M388V, and a complete deletion of the GATA2 locus). The frequent evolution to MDS and AML in these patients reveals the importance of screening GATA2 in chronic neutropenia associated with monocytopenia because of the frequent hematopoietic transformation, variable clinical expression at onset, and the need for aggressive therapy in patients with poor clinical outcome. Mutations of key transcription factor in myeloid malignancies.

  8. Therapy-related acute myeloid leukemia and myelodysplastic syndrome: a clinical and morphologic study of 65 cases

    International Nuclear Information System (INIS)

    Michels, S.D.; McKenna, R.W.; Arthur, D.C.; Brunning, R.D.

    1985-01-01

    This study consists of 65 patients (pts) who developed a myelodysplastic syndrome (MDS) (39 pts) or acute myeloid leukemia (AML) (26 pts) following chemotherapy and/or radiotherapy; the interval from the onset of therapy to bone marrow abnormality ranged from 11 to 192 months (median, 58). Thirty-three patients had been previously treated for lymphoproliferative diseases, 29 for carcinoma, and three for a nonneoplastic disorder. Approximately 30% of the cases presenting in the MDS phase evolved to AML in one to 12 months (median, 3.5). The AML in 49% of the cases was not readily classified according to French-American-British (FAB) criteria; the primary difficulty in classification related to the involvement of multiple cell lines. Among the cases that could be classified, all FAB types were represented except for M1; M2 was the most frequent type. Clonal chromosome abnormalities were found in marrow specimens from 22 of 24 (92%) patients studied with G banding; 11 had abnormalities of chromosomes 5 and/or 7. The median survival for all patients was four months with no significant difference between those treated and not treated with antileukemic therapy. The median survival was three months for the patients presenting with AML, six months for the patients with AML following an MDS, and four months for the patients with an MDS that did not evolve to AML. The findings in the present study suggest that there are three stages of therapy-related panmyelosis: (1) pancytopenia with associated myelodysplastic changes, (2) a frank MDS, and (3) overt AML. Many patients will present in the stage of overt AML that differs from de novo AML primarily by the high incidence of trilineage involvement, difficulty in classification, frequent cytogenetic abnormalities, and poor response to antileukemic therapy

  9. Impact of baseline cytogenetic findings and cytogenetic response on outcome of high-risk myelodysplastic syndromes and low blast count AML treated with azacitidine.

    Science.gov (United States)

    Sébert, Marie; Komrokji, Rami S; Sekeres, Mikkael A; Prebet, Thomas; Cluzeau, Thomas; Santini, Valeria; Gyan, Emmanuel; Sanna, Alessandro; Ali, Najla HAl; Hobson, Sean; Eclache, Virginie; List, Alan; Fenaux, Pierre; Adès, Lionel

    2017-12-01

    Karyotype according to the revised IPSS is a strong independent prognostic factor for overall survival (OS) in myelodysplastic syndromes (MDS), however established in untreated patients. The prognostic impact of cytogenetics and cytogenetic response (CyR) in MDS patients receiving azacitidine (AZA) remains uncertain. We examined the prognostic value of baseline cytogenetics and CyR for overall response rate (ORR) and OS in 702 AZA-treated higher risk MDS and low blast count acute myeloid leukemia (AML), including 493 (70%) with abnormal karyotype. None of the cytogenetic abnormalities had significant impact on ORR (43.9%) or complete response (15.35%), except 3q abnormalities and complex karyotypes, which were associated with a lower ORR. OS differed significantly across all R-IPSS cytogenetic subgroups (pcytogenetics. CyR was achieved in 32% of the 281 evaluable patients with abnormal cytogenetics, was complete (CCyR) in 71 (25.3%) patients. We found no correlation between hematological response and cytogenetic response and 21% of the patients with CCyR did not achieve morphological response. In the 281 patients, we found no impact of CyR on survival, but when restricting to MDS (ie: <20% marrow blasts) achievement of CCyR was associated with better OS. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Multi-color CD34⁺ progenitor-focused flow cytometric assay in evaluation of myelodysplastic syndromes in patients with post cancer therapy cytopenia.

    Science.gov (United States)

    Tang, Guilin; Jorgensen, L Jeffrey; Zhou, Yi; Hu, Ying; Kersh, Marian; Garcia-Manero, Guillermo; Medeiros, L Jeffrey; Wang, Sa A

    2012-08-01

    Bone marrow assessment for myelodysplastic syndrome (MDS) in a patient who develops cytopenia(s) following cancer therapy is challenging. With recent advances in multi-color flow cytometry immunophenotypic analysis, a CD34(+) progenitor-focused 7-color assay was developed and tested in this clinical setting. This assay was first performed in 73 MDS patients and 53 non-MDS patients (developmental set). A number of immunophenotypic changes were differentially observed in these two groups. Based on the sensitivity, specificity and reproducibility, a core panel of markers was selected for final assessment that included increased total CD34(+) myeloblasts; decreased stage I hematogones; altered CD45/side scatter; altered expression of CD13, CD33, CD34, CD38, CD117, and CD123; aberrant expression of lymphoid or mature myelomonocytic antigens on CD34(+) myeloblasts; and several marked alterations in maturing myelomonocytic cells. The data were translated into a simplified scoring system which was then used in 120 patients with cytopenia(s) secondary to cancer therapy over a 2-year period (validation set). With a median follow-up of 11 months, this assay demonstrated 89% sensitivity, 94% specificity, and 92% accuracy in establishing or excluding a diagnosis of MDS. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. Depleted uranium

    International Nuclear Information System (INIS)

    Huffer, E.; Nifenecker, H.

    2001-02-01

    This document deals with the physical, chemical and radiological properties of the depleted uranium. What is the depleted uranium? Why do the military use depleted uranium and what are the risk for the health? (A.L.B.)

  12. Proposal for refining the definition of dysgranulopoiesis in acute myeloid leukemia and myelodysplastic syndromes.

    Science.gov (United States)

    Goasguen, Jean E; Bennett, John M; Bain, Barbara J; Brunning, Richard; Vallespi, Maria-Teresa; Tomonaga, Masao; Zini, Gina; Renault, Alain

    2014-04-01

    Studies of morphology of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) refer to the definitions produced by the French-American-British (FAB) group and by the World Health Organization expert group. To clarify some points regarding the dysgranulopoiesis that are still unclear we analyzed a series of 98 neutrophils from MDS patients with regard to granularity, nuclear segmentation, the appearance of the chromatin, the presence of giant neutrophils, and the presence of nuclear chromatin extensions. We found that cells with at least 2/3 reduction of the content of granules, Pelger-like neutrophils, dysplastic non-Pelger cells, neutrophils with abnormal clumping of the chromatin, and macropolycytes could be recognized as dysplastic and included in the 10% count recommended by these two classifications. In addition, we suggest that neutrophils with more than 4 nuclear projections could be recognized as a relevant dysplastic feature. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Increasing the effectiveness of hematopoiesis in myelodysplastic syndromes: erythropoiesis-stimulating agents and transforming growth factor-β superfamily inhibitors.

    Science.gov (United States)

    Mies, Anna; Platzbecker, Uwe

    2017-07-01

    Patients with lower-risk myelodysplastic syndromes (MDS) are mainly affected by chronic anemia and fatigue. Treatment strategies aim to improve anemia and quality of life, as well as iron overload due to red blood cell transfusion support. To promote proliferation and differentiation of erythropoiesis, erythropoiesis-stimulating agents (ESAs) such as erythropoietin (EPO) and mimetics are applied as first-line therapy in a large fraction of lower-risk MDS patients. In general, ESAs yield favorable responses in about half of the patients, although responses are often short-lived. In fact, many ESA-refractory patients harbor defects in late-stage erythropoiesis downstream of EPO action. Novel transforming growth factor (TGF)-β superfamily inhibitors sotatercept and luspatercept represent a promising approach to alleviate anemia by stimulating erythroid differentiation. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. In vivo measurements of the T1 relaxation processes in the bone marrow in patients with myelodysplastic syndrome. A magnetic resonance imaging study

    DEFF Research Database (Denmark)

    Jensen, K E; Nielsen, H; Thomsen, C

    1989-01-01

    Nine patients with myelodysplastic syndrome (MDS) were examined with magnetic resonance imaging and in vivo T1 relaxation time measurements of the vertebral bone marrow in a 1.5 tesla whole body scanner. Two patients underwent transformation to acute myeloid leukemia and were evaluated at follow-...... not differ from patients with polycythemia vera....

  15. Impact of iron overload and potential benefit from iron chelation in low-risk myelodysplastic syndrome.

    Science.gov (United States)

    Shenoy, Niraj; Vallumsetla, Nishanth; Rachmilewitz, Eliezer; Verma, Amit; Ginzburg, Yelena

    2014-08-07

    Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal bone marrow disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias, and potential for malignant transformation. Lower/intermediate-risk MDSs are associated with longer survival and high red blood cell (RBC) transfusion requirements resulting in secondary iron overload. Recent data suggest that markers of iron overload portend a relatively poor prognosis, and retrospective analysis demonstrates that iron chelation therapy is associated with prolonged survival in transfusion-dependent MDS patients. New data provide concrete evidence of iron's adverse effects on erythroid precursors in vitro and in vivo. Renewed interest in the iron field was heralded by the discovery of hepcidin, the main serum peptide hormone negative regulator of body iron. Evidence from β-thalassemia suggests that regulation of hepcidin by erythropoiesis dominates regulation by iron. Because iron overload develops in some MDS patients who do not require RBC transfusions, the suppressive effect of ineffective erythropoiesis on hepcidin may also play a role in iron overload. We anticipate that additional novel tools for measuring iron overload and a molecular-mechanism-driven description of MDS subtypes will provide a deeper understanding of how iron metabolism and erythropoiesis intersect in MDSs and improve clinical management of this patient population. © 2014 by The American Society of Hematology.

  16. Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration.

    Science.gov (United States)

    Bartesaghi, Stefano; Betts-Henderson, Joanne; Cain, Kelvin; Dinsdale, David; Zhou, Xiaoshan; Karlsson, Anna; Salomoni, Paolo; Nicotera, Pierluigi

    2010-05-01

    Mutations of thymidine kinase 2 (TK2), an essential component of the mitochondrial nucleotide salvage pathway, can give rise to mitochondrial DNA (mtDNA) depletion syndromes (MDS). These clinically heterogeneous disorders are characterized by severe reduction in mtDNA copy number in affected tissues and are associated with progressive myopathy, hepatopathy and/or encephalopathy, depending in part on the underlying nuclear genetic defect. Mutations of TK2 have previously been associated with an isolated myopathic form of MDS (OMIM 609560). However, more recently, neurological phenotypes have been demonstrated in patients carrying TK2 mutations, thus suggesting that loss of TK2 results in neuronal dysfunction. Here, we directly address the role of TK2 in neuronal homeostasis using a knockout mouse model. We demonstrate that in vivo loss of TK2 activity leads to a severe ataxic phenotype, accompanied by reduced mtDNA copy number and decreased steady-state levels of electron transport chain proteins in the brain. In TK2-deficient cerebellar neurons, these abnormalities are associated with impaired mitochondrial bioenergetic function, aberrant mitochondrial ultrastructure and degeneration of selected neuronal types. Overall, our findings demonstrate that TK2 deficiency leads to neuronal dysfunction in vivo, and have important implications for understanding the mechanisms of neurological impairment in MDS.

  17. Delayed globin synthesis leads to excess heme and the macrocytic anemia of Diamond Blackfan anemia and del(5q) myelodysplastic syndrome.

    Science.gov (United States)

    Yang, Zhantao; Keel, Siobán B; Shimamura, Akiko; Liu, Li; Gerds, Aaron T; Li, Henry Y; Wood, Brent L; Scott, Bart L; Abkowitz, Janis L

    2016-05-11

    Diamond Blackfan anemia (DBA) and myelodysplastic syndrome (MDS) with isolated del(5q) are severe macrocytic anemias; although both are associated with impaired ribosome assembly, why the anemia occurs is not known. We cultured marrow cells from DBA (n = 3) and del(5q) MDS (n = 6) patients and determined how heme (a toxic chemical) and globin (a protein) are coordinated. We show that globin translation initiates slowly, whereas heme synthesis proceeds normally. This results in insufficient globin protein, excess heme and excess reactive oxygen species in early erythroid precursors, and CFU-E (colony-forming unit-erythroid)/proerythroblast cell death. The cells that can more rapidly and effectively export heme or can slow heme synthesis preferentially survive and appropriately mature. Consistent with these observations, treatment with 10 μM succinylacetone, a specific inhibitor of heme synthesis, improved the erythroid cell output of DBA and del(5q) MDS marrow cultures by 68 to 95% (P = 0.03 to 0.05), whereas the erythroid cell output of concurrent control marrow cultures decreased by 4 to 13%. Our studies demonstrate that erythropoiesis fails when heme exceeds globin. Our data further suggest that therapies that decrease heme synthesis (or facilitate heme export) could improve the red blood cell production of persons with DBA, del(5q) MDS, and perhaps other macrocytic anemias. Copyright © 2016, American Association for the Advancement of Science.

  18. Mechanisms of resistance to decitabine in the myelodysplastic syndrome.

    Directory of Open Access Journals (Sweden)

    Taichun Qin

    Full Text Available The DNA methylation inhibitor 5-aza-2'-deoxycytidine (DAC is approved for the treatment of myelodysplastic syndromes (MDS, but resistance to DAC develops during treatment and mechanisms of resistance remain unknown. Therefore, we investigated mechanisms of primary and secondary resistance to DAC in MDS.We performed Quantitative Real-Time PCR to examine expression of genes related to DAC metabolism prior to therapy in 32 responders and non-responders with MDS as well as 14 patients who achieved a complete remission and subsequently relapsed while on therapy (secondary resistance. We then performed quantitative methylation analyses by bisulfite pyrosequencing of 10 genes as well as Methylated CpG Island Amplification Microarray (MCAM analysis of global methylation in secondary resistance.Most genes showed no differences by response, but the CDA/DCK ratio was 3 fold higher in non-responders than responders (P<.05, suggesting that this could be a mechanism of primary resistance. There were no significant differences at relapse in DAC metabolism genes, and no DCK mutations were detected. Global methylation measured by the LINE1 assay was lower at relapse than at diagnosis (P<.05. On average, the methylation of 10 genes was lower at relapse (16.1% compared to diagnosis (18.1% (P<.05. MCAM analysis showed decreased methylation of an average of 4.5% (range 0.6%-9.7% of the genes at relapse. By contrast, new cytogenetic changes were found in 20% of patients.Pharmacological mechanisms are involved in primary resistance to DAC, whereas hypomethylation does not prevent a relapse for patients with DAC treatment.

  19. Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series

    Directory of Open Access Journals (Sweden)

    Mella Olav

    2009-07-01

    Full Text Available Abstract Background Chronic fatigue syndrome (CFS is a disease of unknown aetiology. A patient with CFS had unexpected, marked recovery of CFS symptoms lasting for five months during and after cytotoxic chemotherapy for Hodgkin's disease. We reasoned that the transient CFS recovery was related to methotrexate treatment, which induces immunomodulation in part through B-cell depletion. Methods In a case series, this patient and two additional CFS patients were B-cell depleted by infusion of the monoclonal anti-CD20 antibody rituximab. Results All three had improvement of all CFS symptoms. Patients 1 and 2 had major amelioration from 6 weeks after intervention, patient 3 slight improvement from the same time, but then improved markedly from 26 weeks after intervention. The symptomatic effect lasted until weeks 16, 18 and 44, respectively. At relapse, all were retreated with a single (patient 1 or double rituximab infusion (patients 2 and 3. Again, all three had marked symptom improvement, mimicking their first response. After new symptom recurrence, patients 1 and 2 were given weekly oral methotrexate, patient 1 having effect also from this agent. Patients 1 and 2 were again treated for a third rituximab infusion after new relapse, again with a marked clinical benefit. No unexpected toxicity was seen. Conclusion These observations suggest that B-lymphocytes are involved in CFS pathogenesis for a subset of patients. Benefit for all CFS symptoms, the delayed symptom relief following B-cell depletion, the kinetics of relapses, and the effect also from methotrexate treatment, provide suggestive evidence that B-cells play a significant role in the ongoing clinical features, and that CFS may be amenable to therapeutic interventions aimed at modifying B-cell number and function. More systematic investigations of this therapeutic strategy, and of its biological basis, are now needed.

  20. Emerging roles of the spliceosomal machinery in myelodysplastic syndromes and other hematological disorders.

    Science.gov (United States)

    Visconte, V; Makishima, H; Maciejewski, J P; Tiu, R V

    2012-12-01

    In humans, the majority of all protein-coding transcripts contain introns that are removed by mRNA splicing carried out by spliceosomes. Mutations in the spliceosome machinery have recently been identified using whole-exome/genome technologies in myelodysplastic syndromes (MDS) and in other hematological disorders. Alterations in splicing factor 3 subunit b1 (SF3b1) were the first spliceosomal mutations described, immediately followed by identification of other splicing factor mutations, including U2 small nuclear RNA auxillary factor 1 (U2AF1) and serine arginine-rich splicing factor 2 (SRSF2). SF3b1/U2AF1/SRSF2 mutations occur at varying frequencies in different disease subtypes, each contributing to differences in survival outcomes. However, the exact functional consequences of these spliceosomal mutations in the pathogenesis of MDS and other hematological malignancies remain largely unknown and subject to intense investigation. For SF3b1, a gain of function mutation may offer the promise of new targeted therapies for diseases that carry this molecular abnormality that can potentially lead to cure. This review aims to provide a comprehensive overview of the emerging role of the spliceosome machinery in the biology of MDS/hematological disorders with an emphasis on the functional consequences of mutations, their clinical significance, and perspectives on how they may influence our understanding and management of diseases affected by these mutations.

  1. Emerging roles of the spliceosomal machinery in myelodysplastic syndromes and other hematologic disorders

    Science.gov (United States)

    Visconte, V; Makishima, H; Maciejewski, JP; Tiu, RV

    2013-01-01

    In humans, the majority of all protein-coding transcripts contain introns that are removed by mRNA splicing carried out by spliceosomes. Mutations in the spliceosome machinery have recently been identified using whole exome/genome technologies in myelodysplastic syndromes (MDS) and in other hematologic disorders. Alterations in Splicing Factor 3 Subunit b1 (SF3b1) were the first spliceosomal mutations described, immediately followed by identification of other splicing factor mutations, including U2 Small Nuclear RNA Auxillary Factor 1 (U2AF1) and Serine Arginine Rich Splicing Factor 2 (SRSF2). SF3b1/U2AF1/SRSF2 mutations occur at varying frequencies in different disease subtypes, each contributing to differences in survival outcomes. However, the exact functional consequences of these spliceosomal mutations in the pathogenesis of MDS and other hematologic malignancies remain largely unknown and subject to intense investigation. For SF3b1, a gain of function mutation may offer the promise of new targeted therapies for diseases that carry this molecular abnormality that can potentially lead to cure. This review aims to provide a comprehensive overview of the emerging role of the spliceosome machinery in the biology of MDS/hematologic disorders with an emphasis on the functional consequences of mutations, their clinical significance, and perspectives on how they may influence our understanding and management of diseases affected by these mutations. PMID:22678168

  2. [Cystinosis : Diagnosis, cystine-depleting therapy, and transition].

    Science.gov (United States)

    Kaufeld, Jessica; Weber, Lutz T; Kurschat, Christine; Canaan-Kuehl, Sima; Brand, Eva; Oh, Jun; Pape, Lars

    2018-04-18

    This article presents a case of cystinosis in a young man. Diagnosis of the disease and the problem of transition to adult care are described. Cystinosis is a rare lysosomal storage disease with first manifestation in early childhood presenting as renal Fanconi syndrome. Without treatment, the disease leads to severe health impairment. Due to the rarity of the disease, a correct diagnosis is often delayed. Without treatment, cystinosis often leads to end-stage renal failure, blindness, hypothyroidism, diabetes mellitus, and rickets. Cystine-depleting therapy with cysteamine significantly improves mortality and quality of life.

  3. MR imaging of the bone marrow in myeloid leukemia and myelodysplastic syndrome. Comparison of the lumbar spine and femur

    International Nuclear Information System (INIS)

    Tanaka, Osamu; Kobayashi, Yasuyuki; Ichikawa, Tamaki; Matsuura, Katsuhiko; Nagai, Jun; Takagi, Shojiro

    1995-01-01

    MR imaging of the lumber spine and the femur was performed with T1-weighted SE sequence and comparison of the MRI findings of the lumber vertebral body and the femoral marrow was made in 15 patients with acute myeloid leukemia (AML), 5 chronic myelogenous leukemia (CML), and 9 myelodysplastic syndrome (MDS). The MRI appearance of the bone marrow was classified into four patterns: 1) fatty marrow; 2) faint signal; 3) heterogeneous infiltration; and 4) diffuse infiltration. The MRI of the lumber vertebral body showed a diffuse marrow infiltration pattern in over the half of the cases of AML and MDS. On the MRI of the femoral marrow, the signal intensity alteration, a low signal on T1-weighted SE image, began in the proximal femurs almost symmetrically. The abnormal low signal intensity area tended to gradually extend towards the distal portion of the femoral marrow with progression of the disease in the patients with AML and MDS. M2 type of AML tended to be demonstrated as a faint signal pattern, which was significantly different from the other types of AML. In all the cases of CML, a diffuse cellular infiltration pattern was noted with total replacement of the fatty marrow on both lumbar spinal and femoral MRI, and the femoral marrow involvement was more downwardly extended than AML. We concluded that MRI of the femoral marrow was more efficient than that of the lumbar spine in the assessment of myeloid leukemia and MDS. (author)

  4. Evaluation of renal uptake on 111InCl3 bone marrow scintigraphy in patients with aplastic anemia and myelodysplastic syndrome

    International Nuclear Information System (INIS)

    Koizumi, Mitsuru; Goto, Masafumi; Nomura, Toshiharu; Watari, Tsutomu; Saito, Kenji

    1993-01-01

    High renal uptake on bone marrow scan with indium-111 chloride is often shown in patients with bone marrow abnormality. We evaluated the renal uptake on bone marrow scan in 27 cases of aplastic anemia, 20 cases of myelodysplastic syndrome (MDS) and 10 cases of other diseases. The high renal uptake was observed in patients not only with aplastic anemia but also with MDS. The renal uptake correlated with blood transfusion units, unsaturated iron binding capacity (UIBC), blood pool imaging and bone marrow uptake. The renal uptake correlated with UIBC better than with the blood transfusion units. Following mechanism of the renal uptake is proposed that frequent blood transfusion makes low UIBC, and the low UIBC causes the failure to chelate indium with transferrin. The fast blood clearance of un-chelated indium via kidneys is followed. Hypoplastic bone marrow may also play an important role for the high renal uptake because all patients with the high renal uptake could not be explained by above mentioned mechanism. Caution should be paid to the scans with the high renal uptake because both aplastic anemia and MDS patients show the high renal uptake. (author)

  5. Radioimmunotherapy for treatment of acute myeloid leukaemia and myelodysplastic syndrome. Conceptual chances

    International Nuclear Information System (INIS)

    Buchmann, I.; Helisch, A.; Bartenstein, P.; Meyer, R.G.; Herr, W.

    2005-01-01

    The prognosis of patients with acute myeloid leukaemia (AML) has improved considerably by introduction of aggressive consolidation chemotherapy and haematopoietic stem cell transplantation (SCT). Nevertheless, only 20-30% of patients with AML achieve long-term disease-free survival after SCT. The most common cause of treatment failure is relapse. Additionally, mortality rates are significantly increased by therapy-related causes such as toxicity of chemotherapy and complications of SCT. Including radioimmunotherapies in the treatment of AML and myelodyplastic syndrome (MDS) allows for the achievement of a pronounced antileukaemic effect for the reduction of relapse rates on the one hand. On the other hand, no increase of acute toxicity and later complications should be induced. These effects are important for the primary reduction of tumour cells as well as for the myelblative conditioning before SCT. This paper provides a systematic and critical review of the currently used radionuclides and immunoconjugates for the treatment of AML and MDS and summarizes the literature on primary tumour cell reductive radioimmunotherapies on the one hand and conditioning radioimmunotherapies before SCT on the other hand. (orig.)

  6. Increased incidence of myelodysplastic syndrome and acute myeloid leukemia following breast cancer treatment with radiation alone or combined with chemotherapy: a registry cohort analysis 1990-2005

    International Nuclear Information System (INIS)

    Kaplan, Henry G; Malmgren, Judith A; Atwood, Mary K

    2011-01-01

    Our objective was to measure myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) risk associated with radiation and/or chemotherapy breast cancer (BC) treatment. Our study cohort was composed of BC patients diagnosed from 1990 to 2005 and followed up for blood disorders, mean length of follow up = 7.17 years, range 2-18 years. 5790 TNM stage 0-III patients treated with surgery alone, radiation and/or chemotherapy were included. Patients without surgery (n = 111), with stem cell transplantation (n = 98), unknown or non-standard chemotherapy regimens (n = 94), lost to follow up (n = 66) or 'cancer status unknown' (n = 67) were excluded. Rates observed at our community based cancer care institution were compared to SEER incidence data for rate ratio (RR) calculations. 17 cases of MDS/AML (10 MDS/7 AML) occurred during the follow up period, crude rate .29% (95% CI = .17, .47), SEER comparison RR = 3.94 (95% CI = 2.34, 6.15). The RR of MDS in patients age < 65 comparing our cohort incidence to SEER incidence data was 10.88 (95% CI = 3.84, 24.03) and the RR of AML in patients age < 65 was 5.32 (95% CI = 1.31, 14.04). No significant increased risk of MDS or AML was observed in women ≥ 65 or the surgery/chemotherapy-only group. A RR of 3.32 (95% CI = 1.42, 6.45) was observed in the surgery/radiation-only group and a RR of 6.32 (95% CI = 3.03, 11.45) in the surgery/radiation/chemotherapy group. 3 out of 10 MDS cases died of disease at an average 3.8 months post diagnosis and five of seven AML cases died at an average 9 months post diagnosis. An elevated rate of MDS and AML was observed among breast cancer patients < 65, those treated with radiation and those treated with radiation and chemotherapy compared to available population incidence data. Although a small number of patients are affected, leukemia risk associated with treatment and younger age is significant

  7. Wheat Mds-1 encodes a heat-shock protein and governs susceptibility towards the Hessian fly gall midge

    Science.gov (United States)

    Plant pests including insects must manipulate plants in order to utilize the nutrition and environment of the host. Here, we show that the heat-shock protein gene Mayetiola destructor susceptibility gene-1 (Mds-1) is a major susceptibility gene in wheat that allows the gall midge M. destructor, com...

  8. Sensibility analysis of fuel depletion using different nuclear fuel depletion codes

    Energy Technology Data Exchange (ETDEWEB)

    Martins, F.; Velasquez, C.E.; Castro, V.F.; Pereira, C.; Silva, C. A. Mello da, E-mail: felipmartins94@gmail.com, E-mail: carlosvelcab@hotmail.com, E-mail: victorfariascastro@gmail.com, E-mail: claubia@nuclear.ufmg.br, E-mail: clarysson@nuclear.ufmg.br [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Departamento de Engenharia Nuclear

    2017-07-01

    Nowadays, the utilization of different nuclear codes to perform the depletion and criticality calculations has been used to simulated nuclear reactors problems. Therefore, the goal is to analyze the sensibility of the fuel depletion of a PWR assembly using three different nuclear fuel depletion codes. The burnup calculations are performed using the codes MCNP5/ORIGEN2.1 (MONTEBURNS), KENO-VI/ORIGEN-S (TRITONSCALE6.0) and MCNPX (MCNPX/CINDER90). Each nuclear code performs the burnup using different depletion codes. Each depletion code works with collapsed energies from a master library in 1, 3 and 63 groups, respectively. Besides, each code uses different ways to obtain neutron flux that influences the depletions calculation. The results present a comparison of the neutronic parameters and isotopes composition such as criticality and nuclides build-up, the deviation in results are going to be assigned to features of the depletion code in use, such as the different radioactive decay internal libraries and the numerical method involved in solving the coupled differential depletion equations. It is also seen that the longer the period is and the more time steps are chosen, the larger the deviation become. (author)

  9. Sensibility analysis of fuel depletion using different nuclear fuel depletion codes

    International Nuclear Information System (INIS)

    Martins, F.; Velasquez, C.E.; Castro, V.F.; Pereira, C.; Silva, C. A. Mello da

    2017-01-01

    Nowadays, the utilization of different nuclear codes to perform the depletion and criticality calculations has been used to simulated nuclear reactors problems. Therefore, the goal is to analyze the sensibility of the fuel depletion of a PWR assembly using three different nuclear fuel depletion codes. The burnup calculations are performed using the codes MCNP5/ORIGEN2.1 (MONTEBURNS), KENO-VI/ORIGEN-S (TRITONSCALE6.0) and MCNPX (MCNPX/CINDER90). Each nuclear code performs the burnup using different depletion codes. Each depletion code works with collapsed energies from a master library in 1, 3 and 63 groups, respectively. Besides, each code uses different ways to obtain neutron flux that influences the depletions calculation. The results present a comparison of the neutronic parameters and isotopes composition such as criticality and nuclides build-up, the deviation in results are going to be assigned to features of the depletion code in use, such as the different radioactive decay internal libraries and the numerical method involved in solving the coupled differential depletion equations. It is also seen that the longer the period is and the more time steps are chosen, the larger the deviation become. (author)

  10. Aplicación del Escalamiento Multidimensional (MDS al análisis del discurso mediático. El caso de la cobertura periodística a los ‘escraches’

    Directory of Open Access Journals (Sweden)

    Xabier Albizu Landa

    2014-06-01

    Full Text Available En el presente artículo se discuten las posibilidades que ofrece la técnica de análisis multivariante conocida como Escalamiento Multidimensional (MDS para el análisis del discurso periodístico y la determinación de los frames presentes en este. En una primera parte se repasan las tradiciones de los análisis de framing y de la aplicación del MDS. En una segunda parte se presenta un caso práctico en el que el MDS es utilizado para la determinación de los frames presentes en la cobertura periodística a los escraches protagonizados en la primavera de 2013 por el movimiento contra los desahucios.

  11. "When the going gets tough, who keeps going?" Depletion sensitivity moderates the ego-depletion effect.

    Science.gov (United States)

    Salmon, Stefanie J; Adriaanse, Marieke A; De Vet, Emely; Fennis, Bob M; De Ridder, Denise T D

    2014-01-01

    Self-control relies on a limited resource that can get depleted, a phenomenon that has been labeled ego-depletion. We argue that individuals may differ in their sensitivity to depleting tasks, and that consequently some people deplete their self-control resource at a faster rate than others. In three studies, we assessed individual differences in depletion sensitivity, and demonstrate that depletion sensitivity moderates ego-depletion effects. The Depletion Sensitivity Scale (DSS) was employed to assess depletion sensitivity. Study 1 employs the DSS to demonstrate that individual differences in sensitivity to ego-depletion exist. Study 2 shows moderate correlations of depletion sensitivity with related self-control concepts, indicating that these scales measure conceptually distinct constructs. Study 3 demonstrates that depletion sensitivity moderates the ego-depletion effect. Specifically, participants who are sensitive to depletion performed worse on a second self-control task, indicating a stronger ego-depletion effect, compared to participants less sensitive to depletion.

  12. When the Going Gets Tough, Who Keeps Going? Depletion Sensitivity Moderates the Ego-Depletion Effect

    Directory of Open Access Journals (Sweden)

    Stefanie J. Salmon

    2014-06-01

    Full Text Available Self-control relies on a limited resource that can get depleted, a phenomenon that has been labeled ego-depletion. We argue that individuals may differ in their sensitivity to depleting tasks, and that consequently some people deplete their self-control resource at a faster rate than others. In three studies, we assessed individual differences in depletion sensitivity, and demonstrate that depletion sensitivity moderates ego-depletion effects. The Depletion Sensitivity Scale (DSS was employed to assess depletion sensitivity. Study 1 employs the DSS to demonstrate that individual differences in sensitivity to ego-depletion exist. Study 2 shows moderate correlations of depletion sensitivity with related self-control concepts, indicating that these scales measure conceptually distinct constructs. Study 3 demonstrates that depletion sensitivity moderates the ego-depletion effect. Specifically, participants who are sensitive to depletion performed worse on a second self-control task, indicating a stronger ego-depletion effect, compared to participants less sensitive to depletion.

  13. Evaluation of renal uptake on [sup 111]InCl[sub 3] bone marrow scintigraphy in patients with aplastic anemia and myelodysplastic syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Koizumi, Mitsuru; Goto, Masafumi; Nomura, Toshiharu; Watari, Tsutomu; Saito, Kenji (Dokkyo Univ. School of Medicine, Mibu, Tochigi (Japan))

    1993-04-01

    High renal uptake on bone marrow scan with indium-111 chloride is often shown in patients with bone marrow abnormality. We evaluated the renal uptake on bone marrow scan in 27 cases of aplastic anemia, 20 cases of myelodysplastic syndrome (MDS) and 10 cases of other diseases. The high renal uptake was observed in patients not only with aplastic anemia but also with MDS. The renal uptake correlated with blood transfusion units, unsaturated iron binding capacity (UIBC), blood pool imaging and bone marrow uptake. The renal uptake correlated with UIBC better than with the blood transfusion units. Following mechanism of the renal uptake is proposed that frequent blood transfusion makes low UIBC, and the low UIBC causes the failure to chelate indium with transferrin. The fast blood clearance of un-chelated indium via kidneys is followed. Hypoplastic bone marrow may also play an important role for the high renal uptake because all patients with the high renal uptake could not be explained by above mentioned mechanism. Caution should be paid to the scans with the high renal uptake because both aplastic anemia and MDS patients show the high renal uptake. (author).

  14. MDS system increases drilling safety and efficiency

    Energy Technology Data Exchange (ETDEWEB)

    Chevallier, J.; Turner, L. (Sedco Forex, Paris (FR))

    1989-09-01

    There's a great deal of data recorded during drilling operations on rigs these days, but it is seldom well utilized. The operator's company person relies upon mud loggers for collecting and recording most information. The methods used to process and display this information are often inadequate for those who need it the most the driller and toolpusher. Drilling contractor personnel usually have only rudimentary displays of drilling parameters, and practically no serious method of analysis except for daily paper reports. These are cumbersome to use and provide only incomplete data, after the fact. The MDS system, presented in this article, is a new information and alarm network, which rectifies this situation by bringing to the rig, for the first time, the latest in sensor and computer technologies. This system acquires key drilling data on the rig floor, pump room, and return line, and displays it in a clear graphical format to both the driller and the toolpusher in real time. It also provides the toolpusher with a workstation for easy access to the same information for evaluation and planning of the drilling program.

  15. [Distribution of abnormal cell clone with deletion of chromosome 20q in marrow cell lineages and apoptosis cells in myelodysplastic syndrome].

    Science.gov (United States)

    Qin, Ling; Wang, Chun; Qin, You-Wen; Xie, Kuang-Cheng; Yan, Shi-Ke; Gao, Yan-Rong; Wang, Xiao-Rui; Zhao, Chu-Xian

    2008-06-01

    This study was aimed to investigate the distribution of abnormal clone in marrow cell lineages and apoptosis cells in myelodysplastic syndrome (MDS) with deletion of chromosome 20q. Monoclonal antibodies recognizing myeloid precursors (CD15), erythroid precursors (GPA), T cells (CD3(+)CD56(-)CD16(-)), B cells (CD19), NK cells (CD3(-)CD56(+)CD16(+)) were used to sort bone marrow cells in a MDS patient with del (20q) by fluorescence activated cell sorting (FACS). Annexin V-FITC and PI were used to sort bone marrow Annexin V(+)PI(-) and Annexin V(-)PI(-) cells by FACS. The sorted positive cells were detected by interphase dual-color fluorescence in situ hybridization (D-FISH) using a LSI D20S108 probe (Spectrum Orange) and a Telvysion TM 20p probe (Spectrum Green). FACS and FISH analysis were also performed on the samples from 4 cases with normal karyotype. The results showed that the proportions of MDS clone in the myeloid and erythroid precursors were 70.50% and 93.33% respectively, in the RAEB-1 patient with del (20q) and were obviously higher than that in control group (5.39% and 6.17%). The proportions of abnormal clone in T, B and NK cells were 3.23%, 4.32% and 5.77% respectively and were less than that in control group (5.76%, 4.85%, 6.36%). The percentage of apoptotic cells in the bone marrow nucleated cells was 16.09%. The proportions of MDS clone in Annexin V(+)PI(-) and Annexin V(-)PI(-) cells were 32.48% and 70.11%, respectively. It is concluded that most myeloid and erythroid precursors are originated from the abnormal clone in MDS with del (20q). A little part of apoptotic cells are derived from the abnormal clone.

  16. Neutrophil depletion improves diet-induced non-alcoholic fatty liver disease in mice.

    Science.gov (United States)

    Ou, Rongying; Liu, Jia; Lv, Mingfen; Wang, Jingying; Wang, Jinmeng; Zhu, Li; Zhao, Liang; Xu, Yunsheng

    2017-07-01

    Non-alcoholic fatty liver disease is highly associated with morbidity and mortality in population. Although studies have already demonstrated that the immune response plays a pivotal role in the development of non-alcoholic fatty liver disease, the comprehensive regulation is unclear. Therefore, present study was carried out to investigate the non-alcoholic fatty liver disease development under neutrophil depletion. To achieve the aim of the study, C57BL/6 J mice were fed with high fat diet for 6 weeks before treated with neutrophil deplete antibody 1A8 or isotype control (200 μg/ mouse every week) for another 4 weeks. Treated with 1A8 antibody, obese mice exhibited better whole body metabolic parameters, including reduction of body weight gain and fasting blood glucose levels. Neutrophil depletion also effectively reduced hepatic structural disorders, dysfunction and lipid accumulation. Lipid β-oxidative markers, phosphorylated-AMP-activated protein kinase α and phosphorylated-acetyl-CoA carboxylase levels were increased in 1A8 antibody-treated obese mouse group. The mitochondrial number and function were also reversed after 1A8 antibody treatment, including increased mitochondrial number, reduced lipid oxidative damage and enhanced mitochondrial activity. Furthermore, the expression of inflammatory cytokines, tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1 were obviously reduced after neutrophil depletion, accompanied with decreased F4/80 mRNA level and macrophage percentage in liver. The decreased NF-κB signaling activity was also involved in the beneficial effect of neutrophil depletion. Taken together, neutrophil depletion could attenuate metabolic syndromes and hepatic dysfunction.

  17. Hematopoietic stem cell transplantation in children and young adults with secondary myelodysplastic syndrome and acute myelogenous leukemia after aplastic anemia.

    Science.gov (United States)

    Yoshimi, Ayami; Strahm, Brigitte; Baumann, Irith; Furlan, Ingrid; Schwarz, Stephan; Teigler-Schlegel, Andrea; Walther, Joachim-Ulrich; Schlegelberger, Brigitte; Göhring, Gudrun; Nöllke, Peter; Führer, Monika; Niemeyer, Charlotte M

    2014-03-01

    Secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/sAML) are the most serious secondary events occurring after immunosuppressive therapy in patients with aplastic anemia. Here we evaluate the outcome of hematopoietic stem cell transplantation (HSCT) in 17 children and young adults with sMDS/sAML after childhood aplastic anemia. The median interval between the diagnosis of aplastic anemia and the development of sMDS/sAML was 2.9 years (range, 1.2 to 13.0 years). At a median age of 13.1 years (range, 4.4 to 26.7 years), patients underwent HSCT with bone marrow (n = 6) or peripheral blood stem cell (n = 11) grafts from HLA-matched sibling donors (n = 2), mismatched family donors (n = 2), or unrelated donors (n = 13). Monosomy 7 was detected in 13 patients. The preparative regimen consisted of busulfan, cyclophosphamide, and melphalan in 11 patients and other agents in 6 patients. All patients achieved neutrophil engraftment. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and that of chronic GVHD was 70%. Relapse occurred in 1 patient. The major cause of death was transplant-related complication (n = 9). Overall survival and event-free survival at 5 years after HSCT were both 41%. In summary, this study indicates that HSCT is a curative therapy for some patients with sMDS/sAML after aplastic anemia. Future efforts should focus on reducing transplantation-related mortality. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  18. Outcome of patients treated for myelodysplastic syndromes with 5q deletion after failure of lenalidomide therapy

    OpenAIRE

    Prebet, Thomas; Cluzeau, Thomas; Park, Sophie; Sekeres, Mikkael A.; Germing, Ulrich; Ades, Lionel; Platzbecker, Uwe; Gotze, Katharina; Vey, Norbert; Oliva, Esther; Sugrue, Mary M.; Bally, Cecile; Kelaidi, Charikleia; Al Ali, Najla; Fenaux, Pierre

    2017-01-01

    While lenalidomide (LEN) is the standard of care for the lower-risk myelodysplastic syndromes (MDS) patients with deletion 5q, 35% will not respond to or do not tolerate the drug. Moreover, most of the patients will lose their response after a few years. Defining the outcome of patients with LEN failure and determining the impact of subsequent therapies is therefore important to develop alternative strategies. Based on an international collaboration, we were able to compile a total of 392 pat...

  19. Toward a new task assignment and path evolution (TAPE) for missile defense system (MDS) using intelligent adaptive SOM with recurrent neural networks (RNNs).

    Science.gov (United States)

    Wang, Chi-Hsu; Chen, Chun-Yao; Hung, Kun-Neng

    2015-06-01

    In this paper, a new adaptive self-organizing map (SOM) with recurrent neural network (RNN) controller is proposed for task assignment and path evolution of missile defense system (MDS). We address the problem of N agents (defending missiles) and D targets (incoming missiles) in MDS. A new RNN controller is designed to force an agent (or defending missile) toward a target (or incoming missile), and a monitoring controller is also designed to reduce the error between RNN controller and ideal controller. A new SOM with RNN controller is then designed to dispatch agents to their corresponding targets by minimizing total damaging cost. This is actually an important application of the multiagent system. The SOM with RNN controller is the main controller. After task assignment, the weighting factors of our new SOM with RNN controller are activated to dispatch the agents toward their corresponding targets. Using the Lyapunov constraints, the weighting factors for the proposed SOM with RNN controller are updated to guarantee the stability of the path evolution (or planning) system. Excellent simulations are obtained using this new approach for MDS, which show that our RNN has the lowest average miss distance among the several techniques.

  20. Isotopes and innovation: MDS Nordion's first fifty years, 1946-1996

    Energy Technology Data Exchange (ETDEWEB)

    Litt, P

    2000-07-01

    Few people realize that Canada leads in the world in the production of radio isotopes, the raw material of nuclear medicine and high-tech scanners, and in their use in medicine and industry. In Isotopes and Innovation the author gives an in-depth look at MDS Nordion, a company that started as the radium sales department of Eldorado Mining and Refining, the Canadian uranium producer that was a key strategic resource for the Allies during the race to build the nuclear bomb, and went on to become the world?s leading producer of radioisotopes. When radium began to be used as a cancer treatment, Eldorado quickly became familiar with the medical marketplace and adept at developing products that could solve clinical problems and, more important, save lives. When Canadian nuclear reactors at Chalk River began producing radioisotopes that outperformed radium, Eldorado's radium sales department was transferred to a new crown corporation, Atomic Energy of Canada Limited, created to manage Canada's nuclear research establishment. The new company developed many useful applications for radioisotopes, including cobalt-60 cancer therapy machines and industrial sterilization plants. Bought by Medical Data Services Inc. in the early 1990s, MDS Nordion was a runaway success, creator and sole proprietor of several market-leading products. Isotopes and Innovation describes how a company capitalized on the byproducts of Canada's unique nuclear research program to attain a commanding international position in extremely specialized and demanding high-tech markets, a saga in which innovative research and enterprising global marketing have brought commercial success and saved countless lives around the world.

  1. Mitochondrial DNA copy number threshold in mtDNA depletion myopathy.

    Science.gov (United States)

    Durham, S E; Bonilla, E; Samuels, D C; DiMauro, S; Chinnery, P F

    2005-08-09

    The authors measured the absolute amount of mitochondrial DNA (mtDNA) within single muscle fibers from two patients with thymidine kinase 2 (TK2) deficiency and two healthy controls. TK2 deficient fibers containing more than 0.01 mtDNA/microm3 had residual cytochrome c oxidase (COX) activity. This defines the minimum amount of wild-type mtDNA molecules required to maintain COX activity in skeletal muscle and provides an explanation for the mosaic histochemical pattern seen in patients with mtDNA depletion syndrome.

  2. Deuterium-depleted water

    International Nuclear Information System (INIS)

    Stefanescu, Ion; Steflea, Dumitru; Saros-Rogobete, Irina; Titescu, Gheorghe; Tamaian, Radu

    2001-01-01

    Deuterium-depleted water represents water that has an isotopic content smaller than 145 ppm D/(D+H) which is the natural isotopic content of water. Deuterium depleted water is produced by vacuum distillation in columns equipped with structured packing made from phosphor bronze or stainless steel. Deuterium-depleted water, the production technique and structured packing are patents of National Institute of Research - Development for Cryogenics and Isotopic Technologies at Rm. Valcea. Researches made in the last few years showed the deuterium-depleted water is a biological active product that could have many applications in medicine and agriculture. (authors)

  3. Ego depletion in visual perception: Ego-depleted viewers experience less ambiguous figure reversal.

    Science.gov (United States)

    Wimmer, Marina C; Stirk, Steven; Hancock, Peter J B

    2017-10-01

    This study examined the effects of ego depletion on ambiguous figure perception. Adults (N = 315) received an ego depletion task and were subsequently tested on their inhibitory control abilities that were indexed by the Stroop task (Experiment 1) and their ability to perceive both interpretations of ambiguous figures that was indexed by reversal (Experiment 2). Ego depletion had a very small effect on reducing inhibitory control (Cohen's d = .15) (Experiment 1). Ego-depleted participants had a tendency to take longer to respond in Stroop trials. In Experiment 2, ego depletion had small to medium effects on the experience of reversal. Ego-depleted viewers tended to take longer to reverse ambiguous figures (duration to first reversal) when naïve of the ambiguity and experienced less reversal both when naïve and informed of the ambiguity. Together, findings suggest that ego depletion has small effects on inhibitory control and small to medium effects on bottom-up and top-down perceptual processes. The depletion of cognitive resources can reduce our visual perceptual experience.

  4. Relationship between the non-motor items of the MDS-UPDRS and Quality of Life in patients with Parkinson's disease

    NARCIS (Netherlands)

    Skorvanek, Matej; Rosenberger, Jaroslav; Minar, Michal; Grofik, Milan; Han, Vladimir; Groothoff, Johan W.; Valkovic, Peter; Gdovinova, Zuzana; van Dijk, Jitse P.

    2015-01-01

    The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a newly developed comprehensive tool to assess Parkinson's disease (PD), which covers a wider range of non-motor PD manifestations than the original UPDRS scale. The aim of this study was to assess the relationship

  5. Donor-Cell Origin High-Risk Myelodysplastic Syndrome Synchronous with an Intracranial Meningioma-Like Tumor, 8 Years after Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    G. Brás

    2017-01-01

    Full Text Available Secondary neoplasias are well known consequences of radiotherapy or chemotherapy for a primary cancer. In this report, we describe two rare secondary neoplasias occurring in the same patient: a meningioma-like intracranial tumor and high-risk myelodysplastic syndrome (MDS of donor-cells origin, both diagnosed simultaneously, 8 years after an allogeneic hematopoietic stem cell transplantation (allo-HSCT for chronic lymphocytic leukemia (CLL. Due to an engraftment failure during the first allo-HSCT of a matched related donor for CLL treatment, the salvage treatment was a second allo-HSCT. At the moment of meningioma-like tumor diagnosis, the patient was pancytopenic due to high-risk MDS, so it was decided to postpone a surgical intervention until hematological improvement. For the high-risk MDS of donor-cells origin the chosen treatment was induction with intensive chemotherapy. Due to refractory disease, the patient was treated with 5-azacitidine and donor-lymphocytes infusion with no response and, finally, a third allo-HSCT of a matched unrelated donor was performed. The patient died 6 months after the third allo-HSCT, in cytogenetic remission but without hematological recovery, due to an intracranial hemorrhage with origin in the meningioma-like tumor.

  6. “When the going gets tough, who keeps going?” Depletion sensitivity moderates the ego-depletion effect

    Science.gov (United States)

    Salmon, Stefanie J.; Adriaanse, Marieke A.; De Vet, Emely; Fennis, Bob M.; De Ridder, Denise T. D.

    2014-01-01

    Self-control relies on a limited resource that can get depleted, a phenomenon that has been labeled ego-depletion. We argue that individuals may differ in their sensitivity to depleting tasks, and that consequently some people deplete their self-control resource at a faster rate than others. In three studies, we assessed individual differences in depletion sensitivity, and demonstrate that depletion sensitivity moderates ego-depletion effects. The Depletion Sensitivity Scale (DSS) was employed to assess depletion sensitivity. Study 1 employs the DSS to demonstrate that individual differences in sensitivity to ego-depletion exist. Study 2 shows moderate correlations of depletion sensitivity with related self-control concepts, indicating that these scales measure conceptually distinct constructs. Study 3 demonstrates that depletion sensitivity moderates the ego-depletion effect. Specifically, participants who are sensitive to depletion performed worse on a second self-control task, indicating a stronger ego-depletion effect, compared to participants less sensitive to depletion. PMID:25009523

  7. Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome.

    Science.gov (United States)

    Maslak, P; Chanel, S; Camacho, L H; Soignet, S; Pandolfi, P P; Guernah, I; Warrell, R; Nimer, S

    2006-02-01

    Epigenetic mechanisms underlying tumorigenesis have recently received much attention as potential therapeutic targets of human cancer. We designed a pilot study to target DNA methylation and histone deacetylation through the sequential administration of 5-azacytidine followed by sodium phenylbutyrate (PB) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Ten evaluable patients (eight AML, two MDS) were treated with seven consecutive daily subcutaneous injections of 5-azacytidine at 75 mg/m2 followed by 5 days of sodium PB given intravenously at a dose of 200 mg/kg. Five patients (50%) were able to achieve a beneficial clinical response (partial remission or stable disease). One patient with MDS proceeded to allogeneic stem cell transplantation and is alive without evidence of disease 39 months later. The combination regimen was well tolerated with common toxicities of injection site skin reaction (90% of the patients) from 5-azacytidine, and somnolence/fatigue from the sodium PB infusion (80% of the patients). Correlative laboratory studies demonstrated the consistent reacetylation of histone H4, although no relationship with the clinical response could be demonstrated. Results from this pilot study demonstrate that a combination approach targeting different mechanisms of transcriptional modulation is clinically feasible with acceptable toxicity and measurable biologic and clinical outcomes.

  8. Myelodysplastic syndromes: advantages of a combined cytogenetic and molecular diagnostic workup.

    Science.gov (United States)

    Ciabatti, Elena; Valetto, Angelo; Bertini, Veronica; Ferreri, Maria Immacolata; Guazzelli, Alice; Grassi, Susanna; Guerrini, Francesca; Petrini, Iacopo; Metelli, Maria Rita; Caligo, Maria Adelaide; Rossi, Simona; Galimberti, Sara

    2017-10-03

    In this study we present a new diagnostic workup for the myelodysplastic syndromes (MDS) including FISH, aCGH, and somatic mutation assays in addition to the conventional cytogenetics (CC). We analyzed 61 patients by CC, FISH for chromosome 5, 7, 8 and PDGFR rearrangements, aCGH, and PCR for ASXL1, EZH2, TP53, TET2, RUNX1, DNMT3A, SF3B1 somatic mutations. Moreover, we quantified WT1 and RPS14 gene expression levels, in order to find their possible adjunctive value and their possible clinical impact. CC analysis showed 32% of patients with at least one aberration. FISH analysis detected chromosomal aberrations in 24% of patients and recovered 5 cases (13.5%) at normal karyotype (two 5q- syndromes, one del(7) case, two cases with PDGFR rearrangement). The aGCH detected 10 "new" unbalanced cases in respect of the CC, including one with alteration of the ETV6 gene. After mutational analysis, 33 patients (54%) presented at least one mutation and represented the only marker of clonality in 36% of all patients. The statistical analysis confirmed the prognostic role of CC either on overall or on progression-free-survival. In addition, deletions detected by aCGH and WT1 over-expression negatively conditioned survival. In conclusion, our work showed that 1) the addition of FISH (at least for chr. 5 and 7) can improve the definition of the risk score; 2) mutational analysis, especially for the TP53 and SF3B1, could better define the type of MDS and represent a "clinical warning"; 3) the aCGH use could be probably applied to selected cases (with suboptimal response or failure).

  9. Using peripheral blood circulating DNAs to detect CpG global methylation status and genetic mutations in patients with myelodysplastic syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Iriyama, Chisako [Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan); Tomita, Akihiro, E-mail: atomita@med.nagoya-u.ac.jp [Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan); Hoshino, Hideaki; Adachi-Shirahata, Mizuho [Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan); Furukawa-Hibi, Yoko; Yamada, Kiyofumi [Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Nagoya (Japan); Kiyoi, Hitoshi; Naoe, Tomoki [Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan)

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer Circulating DNAs (CDs) can be used to detect genetic/epigenetic abnormalities in MDS. Black-Right-Pointing-Pointer Epigenetic changes can be detected more sensitively when using plasma DNA than PBMNC. Black-Right-Pointing-Pointer Mutation ratio in CDs may reflect the ratio in stem cell population in bone marrow. Black-Right-Pointing-Pointer Using CDs can be a safer alternate strategy compared to bone marrow aspiration. -- Abstract: Myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder. Several genetic/epigenetic abnormalities are deeply associated with the pathogenesis of MDS. Although bone marrow (BM) aspiration is a common strategy to obtain MDS cells for evaluating their genetic/epigenetic abnormalities, BM aspiration is difficult to perform repeatedly to obtain serial samples because of pain and safety concerns. Here, we report that circulating cell-free DNAs from plasma and serum of patients with MDS can be used to detect genetic/epigenetic abnormalities. The plasma DNA concentration was found to be relatively high in patients with higher blast cell counts in BM, and accumulation of DNA fragments from mono-/di-nucleosomes was confirmed. Using serial peripheral blood (PB) samples from patients treated with hypomethylating agents, global methylation analysis using bisulfite pyrosequencing was performed at the specific CpG sites of the LINE-1 promoter. The results confirmed a decrease of the methylation percentage after treatment with azacitidine (days 3-9) using DNAs from plasma, serum, and PB mono-nuclear cells (PBMNC). Plasma DNA tends to show more rapid change at days 3 and 6 compared with serum DNA and PBMNC. Furthermore, the TET2 gene mutation in DNAs from plasma, serum, and BM cells was quantitated by pyrosequencing analysis. The existence ratio of mutated genes in plasma and serum DNA showed almost equivalent level with that in the CD34+/38- stem cell population in BM. These data suggest that genetic

  10. Using peripheral blood circulating DNAs to detect CpG global methylation status and genetic mutations in patients with myelodysplastic syndrome

    International Nuclear Information System (INIS)

    Iriyama, Chisako; Tomita, Akihiro; Hoshino, Hideaki; Adachi-Shirahata, Mizuho; Furukawa-Hibi, Yoko; Yamada, Kiyofumi; Kiyoi, Hitoshi; Naoe, Tomoki

    2012-01-01

    Highlights: ► Circulating DNAs (CDs) can be used to detect genetic/epigenetic abnormalities in MDS. ► Epigenetic changes can be detected more sensitively when using plasma DNA than PBMNC. ► Mutation ratio in CDs may reflect the ratio in stem cell population in bone marrow. ► Using CDs can be a safer alternate strategy compared to bone marrow aspiration. -- Abstract: Myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder. Several genetic/epigenetic abnormalities are deeply associated with the pathogenesis of MDS. Although bone marrow (BM) aspiration is a common strategy to obtain MDS cells for evaluating their genetic/epigenetic abnormalities, BM aspiration is difficult to perform repeatedly to obtain serial samples because of pain and safety concerns. Here, we report that circulating cell-free DNAs from plasma and serum of patients with MDS can be used to detect genetic/epigenetic abnormalities. The plasma DNA concentration was found to be relatively high in patients with higher blast cell counts in BM, and accumulation of DNA fragments from mono-/di-nucleosomes was confirmed. Using serial peripheral blood (PB) samples from patients treated with hypomethylating agents, global methylation analysis using bisulfite pyrosequencing was performed at the specific CpG sites of the LINE-1 promoter. The results confirmed a decrease of the methylation percentage after treatment with azacitidine (days 3–9) using DNAs from plasma, serum, and PB mono-nuclear cells (PBMNC). Plasma DNA tends to show more rapid change at days 3 and 6 compared with serum DNA and PBMNC. Furthermore, the TET2 gene mutation in DNAs from plasma, serum, and BM cells was quantitated by pyrosequencing analysis. The existence ratio of mutated genes in plasma and serum DNA showed almost equivalent level with that in the CD34+/38- stem cell population in BM. These data suggest that genetic/epigenetic analyses using PB circulating DNA can be a safer and painless alternative to using BM

  11. Azacitidine in the 'real-world': an evaluation of 1101 higher-risk myelodysplastic syndrome/low blast count acute myeloid leukaemia patients in Ontario, Canada.

    Science.gov (United States)

    Mozessohn, Lee; Cheung, Matthew C; Fallahpour, Saber; Gill, Tripat; Maloul, Asmaa; Zhang, Liying; Lau, Olivia; Buckstein, Rena

    2018-06-01

    The outcome of myelodysplastic syndrome (MDS) patients with uniformly higher-risk disease treated with azacitidine (AZA) in the 'real-world' remains largely unknown. We evaluated 1101 consecutive higher-risk MDS patients (International Prognostic Scoring System intermediate-2/high) and low-blast count acute myeloid leukaemia (AML; 21-30% blasts) patients treated in Ontario, Canada. By dosing schedule, 24·7% received AZA for seven consecutive days, 12·4% for six consecutive days and 62·9% by 5-2-2. Overall, median number of cycles was 6 (range 1-67) and 8 (range 6-14) when restricted to the 692 (63%) patients who received at least 4 cycles. The actuarial median survival was 11·6 months [95% confidence interval (CI) 10·7-12·4) for the entire cohort and 18·0 months (landmark analysis; 95% CI 16·6-19·1 months) for those receiving at least 4 cycles. There was no difference in overall survival (OS) between the 3 dosing schedules (P = 0·87). In our large 'real-world' evaluation of AZA in higher-risk MDS/low-blast count AML, we demonstrated a lower than expected OS. Reassuringly, survival did not differ by dosing schedules. The OS was higher in the 2/3 of patients who received at least 4 cycles of treatment, reinforcing the necessity of sustained administration until therapeutic benefits are realised. This represents the largest 'real-world' evaluation of AZA in higher-risk MDS/low-blast count AML. © 2018 John Wiley & Sons Ltd.

  12. Halo Star Lithium Depletion

    International Nuclear Information System (INIS)

    Pinsonneault, M. H.; Walker, T. P.; Steigman, G.; Narayanan, Vijay K.

    1999-01-01

    The depletion of lithium during the pre-main-sequence and main-sequence phases of stellar evolution plays a crucial role in the comparison of the predictions of big bang nucleosynthesis with the abundances observed in halo stars. Previous work has indicated a wide range of possible depletion factors, ranging from minimal in standard (nonrotating) stellar models to as much as an order of magnitude in models that include rotational mixing. Recent progress in the study of the angular momentum evolution of low-mass stars permits the construction of theoretical models capable of reproducing the angular momentum evolution of low-mass open cluster stars. The distribution of initial angular momenta can be inferred from stellar rotation data in young open clusters. In this paper we report on the application of these models to the study of lithium depletion in main-sequence halo stars. A range of initial angular momenta produces a range of lithium depletion factors on the main sequence. Using the distribution of initial conditions inferred from young open clusters leads to a well-defined halo lithium plateau with modest scatter and a small population of outliers. The mass-dependent angular momentum loss law inferred from open cluster studies produces a nearly flat plateau, unlike previous models that exhibited a downward curvature for hotter temperatures in the 7Li-Teff plane. The overall depletion factor for the plateau stars is sensitive primarily to the solar initial angular momentum used in the calibration for the mixing diffusion coefficients. Uncertainties remain in the treatment of the internal angular momentum transport in the models, and the potential impact of these uncertainties on our results is discussed. The 6Li/7Li depletion ratio is also examined. We find that the dispersion in the plateau and the 6Li/7Li depletion ratio scale with the absolute 7Li depletion in the plateau, and we use observational data to set bounds on the 7Li depletion in main-sequence halo

  13. Fluorescence in situ hybridization of TP53 for the detection of chromosome 17 abnormalities in myelodysplastic syndromes.

    Science.gov (United States)

    Sánchez-Castro, Judit; Marco-Betés, Víctor; Gómez-Arbonés, Xavier; García-Cerecedo, Tomás; López, Ricard; Talavera, Elisabeth; Fernández-Ruiz, Sara; Ademà, Vera; Marugan, Isabel; Luño, Elisa; Sanzo, Carmen; Vallespí, Teresa; Arenillas, Leonor; Marco Buades, Josefa; Batlle, Ana; Buño, Ismael; Martín Ramos, María Luisa; Blázquez Rios, Beatriz; Collado Nieto, Rosa; Vargas, Ma Teresa; González Martínez, Teresa; Sanz, Guillermo; Solé, Francesc

    2015-01-01

    Conventional G-banding cytogenetics (CC) detects chromosome 17 (chr17) abnormalities in 2% of patients with de novo myelodysplastic syndromes (MDS). We used CC and fluorescence in situ hybridization (FISH) (LSI p53/17p13.1) to assess deletion of 17p in 531 patients with de novo MDS from the Spanish Group of Hematological Cytogenetics. FISH detected - 17 or 17p abnormalities in 13 cases (2.6%) in whom no 17p abnormalities were revealed by CC: 0.9% of patients with a normal karyotype, 0% in non-informative cytogenetics, 50% of patients with a chr17 abnormality without loss of 17p and 4.7% of cases with an abnormal karyotype not involving chr17. Our results suggest that applying FISH of 17p13 to identify the number of copies of the TP53 gene could be beneficial in patients with a complex karyotype. We recommend using FISH of 17p13 in young patients with a normal karyotype or non-informative cytogenetics, and always in isolated del(17p).

  14. Response to lenalidomide in myelodysplastic syndromes with del(5q): influence of cytogenetics and mutations.

    Science.gov (United States)

    Mallo, Mar; Del Rey, Mónica; Ibáñez, Mariam; Calasanz, M José; Arenillas, Leonor; Larráyoz, M José; Pedro, Carmen; Jerez, Andrés; Maciejewski, Jaroslaw; Costa, Dolors; Nomdedeu, Meritxell; Diez-Campelo, María; Lumbreras, Eva; González-Martínez, Teresa; Marugán, Isabel; Such, Esperanza; Cervera, José; Cigudosa, Juan C; Alvarez, Sara; Florensa, Lourdes; Hernández, Jesús M; Solé, Francesc

    2013-07-01

    Lenalidomide is an effective drug in low-risk myelodysplastic syndromes (MDS) with isolated del(5q), although not all patients respond. Studies have suggested a role for TP53 mutations and karyotype complexity in disease progression and outcome. In order to assess the impact of complex karyotypes on treatment response and disease progression in 52 lenalidomide-treated patients with del(5q) MDS, conventional G-banding cytogenetics (CC), single nucleotide polymorphism array (SNP-A), and genomic sequencing methods were used. SNP-A analysis (with control sample, lymphocytes CD3+, in 30 cases) revealed 5q losses in all cases. Other recurrent abnormalities were infrequent and were not associated with lenalidomide responsiveness. Low karyotype complexity (by CC) and a high baseline platelet count (>280 × 10(9) /l) were associated with the achievement of haematological response (P = 0·020, P = 0·013 respectively). Unmutated TP53 status showed a tendency for haematological response (P = 0·061). Complete cytogenetic response was not observed in any of the mutated TP53 cases. By multivariate analysis, the most important predictor for lenalidomide treatment failure was a platelet count <280 × 10(9) /l (Odds Ratio = 6·17, P = 0·040). This study reveals the importance of a low baseline platelet count, karyotypic complexity and TP53 mutational status for response to lenalidomide treatment. It supports the molecular study of TP53 in MDS patients treated with lenalidomide. © 2013 John Wiley & Sons Ltd.

  15. "When the going gets tough, who keeps going?" Depletion sensitivity moderates the ego-depletion effect

    NARCIS (Netherlands)

    Salmon, Stefanie J.; Adriaanse, Marieke A.; De Vet, Emely; Fennis, Bob M.; De Ridder, Denise T D

    2014-01-01

    Self-control relies on a limited resource that can get depleted, a phenomenon that has been labeled ego-depletion. We argue that individuals may differ in their sensitivity to depleting tasks, and that consequently some people deplete their self-control resource at a faster rate than others. In

  16. "When the going gets tough, who keeps going?" : Depletion sensitivity moderates the ego-depletion effect

    NARCIS (Netherlands)

    Salmon, Stefanie J.; Adriaanse, Marieke A.; De Vet, Emely; Fennis, Bob M.; De Ridder, Denise T. D.

    2014-01-01

    Self-control relies on a limited resource that can get depleted, a phenomenon that has been labeled ego-depletion. We argue that individuals may differ in their sensitivity to depleting tasks, and that consequently some people deplete their self-control resource at a faster rate than others. In

  17. The modality effect of ego depletion: Auditory task modality reduces ego depletion.

    Science.gov (United States)

    Li, Qiong; Wang, Zhenhong

    2016-08-01

    An initial act of self-control that impairs subsequent acts of self-control is called ego depletion. The ego depletion phenomenon has been observed consistently. The modality effect refers to the effect of the presentation modality on the processing of stimuli. The modality effect was also robustly found in a large body of research. However, no study to date has examined the modality effects of ego depletion. This issue was addressed in the current study. In Experiment 1, after all participants completed a handgrip task, one group's participants completed a visual attention regulation task and the other group's participants completed an auditory attention regulation task, and then all participants again completed a handgrip task. The ego depletion phenomenon was observed in both the visual and the auditory attention regulation task. Moreover, participants who completed the visual task performed worse on the handgrip task than participants who completed the auditory task, which indicated that there was high ego depletion in the visual task condition. In Experiment 2, participants completed an initial task that either did or did not deplete self-control resources, and then they completed a second visual or auditory attention control task. The results indicated that depleted participants performed better on the auditory attention control task than the visual attention control task. These findings suggest that altering task modality may reduce ego depletion. © 2016 Scandinavian Psychological Associations and John Wiley & Sons Ltd.

  18. Depletion of NADP(H) due to CD38 activation triggers endothelial dysfunction in the postischemic heart.

    Science.gov (United States)

    Reyes, Levy A; Boslett, James; Varadharaj, Saradhadevi; De Pascali, Francesco; Hemann, Craig; Druhan, Lawrence J; Ambrosio, Giuseppe; El-Mahdy, Mohamed; Zweier, Jay L

    2015-09-15

    In the postischemic heart, coronary vasodilation is impaired due to loss of endothelial nitric oxide synthase (eNOS) function. Although the eNOS cofactor tetrahydrobiopterin (BH4) is depleted, its repletion only partially restores eNOS-mediated coronary vasodilation, indicating that other critical factors trigger endothelial dysfunction. Therefore, studies were performed to characterize the unidentified factor(s) that trigger endothelial dysfunction in the postischemic heart. We observed that depletion of the eNOS substrate NADPH occurs in the postischemic heart with near total depletion from the endothelium, triggering impaired eNOS function and limiting BH4 rescue through NADPH-dependent salvage pathways. In isolated rat hearts subjected to 30 min of ischemia and reperfusion (I/R), depletion of the NADP(H) pool occurred and was most marked in the endothelium, with >85% depletion. Repletion of NADPH after I/R increased NOS-dependent coronary flow well above that with BH4 alone. With combined NADPH and BH4 repletion, full restoration of NOS-dependent coronary flow occurred. Profound endothelial NADPH depletion was identified to be due to marked activation of the NAD(P)ase-activity of CD38 and could be prevented by inhibition or specific knockdown of this protein. Depletion of the NADPH precursor, NADP(+), coincided with formation of 2'-phospho-ADP ribose, a CD38-derived signaling molecule. Inhibition of CD38 prevented NADP(H) depletion and preserved endothelium-dependent relaxation and NO generation with increased recovery of contractile function and decreased infarction in the postischemic heart. Thus, CD38 activation is an important cause of postischemic endothelial dysfunction and presents a novel therapeutic target for prevention of this dysfunction in unstable coronary syndromes.

  19. The Toxicity of Depleted Uranium

    Directory of Open Access Journals (Sweden)

    Wayne Briner

    2010-01-01

    Full Text Available Depleted uranium (DU is an emerging environmental pollutant that is introduced into the environment primarily by military activity. While depleted uranium is less radioactive than natural uranium, it still retains all the chemical toxicity associated with the original element. In large doses the kidney is the target organ for the acute chemical toxicity of this metal, producing potentially lethal tubular necrosis. In contrast, chronic low dose exposure to depleted uranium may not produce a clear and defined set of symptoms. Chronic low-dose, or subacute, exposure to depleted uranium alters the appearance of milestones in developing organisms. Adult animals that were exposed to depleted uranium during development display persistent alterations in behavior, even after cessation of depleted uranium exposure. Adult animals exposed to depleted uranium demonstrate altered behaviors and a variety of alterations to brain chemistry. Despite its reduced level of radioactivity evidence continues to accumulate that depleted uranium, if ingested, may pose a radiologic hazard. The current state of knowledge concerning DU is discussed.

  20. The DVB Channel Coding Application Using the DSP Development Board MDS TM-13 IREF

    Directory of Open Access Journals (Sweden)

    M. Slanina

    2004-12-01

    Full Text Available The paper deals with the implementation of the channel codingaccording to DVB standard on DSP development board MDS TM-13 IREF andPC. The board is based on Philips Nexperia media processor andintegrates hardware video ADC and DAC. The program libraries featuresused for MPEG based video compression are outlined and then thealgorithms of channel decoding (FEC protection against errors arepresented including the flowchart diagrams. The paper presents thepartial hardware implementation of the simulation system that coversselected phenomena of DVB baseband processing and it is used for realtime interactive demonstration of error protection influence ontransmitted digital video in laboratory and education.

  1. Miliary tuberculosis with no pulmonary involvement in myelodysplastic syndromes: a curable, yet rarely diagnosed, disease: case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Krambovitis Elias

    2008-03-01

    Full Text Available Abstract Background Although tuberculosis is not uncommon among patients with myelodysplastic syndrome (MDS, only a few reports of such patients suffering from miliary tuberculosis (MT exist. MT often presents as a fever of unknown origin and it is a curable disease, yet fatal if left untreated. Case presentation We report a case of MT with no clinical or laboratory indications of pulmonary involvement in a patient with MDS, and review the relevant literature. Mycobacterium tuberculosis was isolated from the liquid culture of a bone marrow aspirate. Conclusion Even if the initial diagnostic investigation for a fever of obscure etiology is negative, MT should not be excluded from the differential diagnosis list. Since it is a curable disease, persistent and vigorous diagnostic efforts are warranted. In suspected cases, mycobacterial blood cultures should be collected as soon as possible after hospital admission and early bone marrow aspirate with mycobacterial cultures is advocated.

  2. Molecular insight into mitochondrial DNA depletion syndrome in two patients with novel mutations in the deoxyguanosine kinase and thymidine kinase 2 genes.

    Science.gov (United States)

    Wang, Liya; Limongelli, Anna; Vila, Maya R; Carrara, Franco; Zeviani, Massimo; Eriksson, Staffan

    2005-01-01

    Thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) are the two key enzymes in mitochondrial DNA (mtDNA) precursor synthesis. Deficiencies in TK2 or dGK activity, due to genetic alteration, have been shown to cause tissue-specific depletion of mtDNA. In the case of TK2 deficiency, affected individuals suffer severe myopathy and, in the case of dGK deficiency, devastating liver or multi-systemic disease. Here, we report clinical and biochemical findings from two patients with mtDNA depletion syndrome. Patient A was a compound heterozygote carrying the previously reported T77M mutation and a novel mutation (R161K) in the TK2 gene. Patient B carried a novel mutation (L250S) in the dGK gene. The clinical symptoms of patient A included muscular weakness and exercise intolerance due to a severe mitochondrial myopathy associated with a 92% reduction in mtDNA. There was minimal involvement of other organs. Patient B suffered from rapidly progressive, early onset fatal liver failure associated with profoundly decreased mtDNA levels in liver and, to a lesser extent, in skeletal muscle. Site-directed mutagenesis was used to introduce the mutations detected in patients A and B into the TK2 and dGK cDNAs, respectively. We then characterized each of these recombinant enzymes. Catalytic activities of the three mutant enzymes were reduced to about 2-4% for TK2 and 0.5% for dGK as compared to the wild-type enzymes. Altered competition between dCyd and dThd was observed for the T77M mutant. The residual activities of the two mitochondrial enzymes correlated directly with disease development.

  3. Targeted impairment of thymidine kinase 2 expression in cells induces mitochondrial DNA depletion and reveals molecular mechanisms of compensation of mitochondrial respiratory activity

    International Nuclear Information System (INIS)

    Villarroya, Joan; Lara, Mari-Carmen; Dorado, Beatriz; Garrido, Marta; Garcia-Arumi, Elena; Meseguer, Anna; Hirano, Michio; Vila, Maya R.

    2011-01-01

    Highlights: → We impaired TK2 expression in Ost TK1 - cells via siRNA-mediated interference (TK2 - ). → TK2 impairment caused severe mitochondrial DNA (mtDNA) depletion in quiescent cells. → Despite mtDNA depletion, TK2 - cells show high cytochrome oxidase activity. → Depletion of mtDNA occurs without imbalance in the mitochondrial dNTP pool. → Nuclear-encoded ENT1, DNA-pol γ, TFAM and TP gene expression is lowered in TK2 - cells. -- Abstract: The mitochondrial DNA (mtDNA) depletion syndrome comprises a clinically heterogeneous group of diseases characterized by reductions of the mtDNA abundance, without associated point mutations or rearrangements. We have developed the first in vitro model to study of mtDNA depletion due to reduced mitochondrial thymidine kinase 2 gene (TK2) expression in order to understand the molecular mechanisms involved in mtDNA depletion syndrome due to TK2 mutations. Small interfering RNA targeting TK2 mRNA was used to decrease TK2 expression in Ost TK1 - cells, a cell line devoid of endogenous thymidine kinase 1 (TK1). Stable TK2-deficient cell lines showed a reduction of TK2 levels close to 80%. In quiescent conditions, TK2-deficient cells showed severe mtDNA depletion, also close to 80% the control levels. However, TK2-deficient clones showed increased cytochrome c oxidase activity, higher cytochrome c oxidase subunit I transcript levels and higher subunit II protein expression respect to control cells. No alterations of the deoxynucleotide pools were found, whereas a reduction in the expression of genes involved in nucleoside/nucleotide homeostasis (human equilibrative nucleoside transporter 1, thymidine phosphorylase) and mtDNA maintenance (DNA-polymerase γ, mitochondrial transcription factor A) was observed. Our findings highlight the importance of cellular compensatory mechanisms that enhance the expression of respiratory components to ensure respiratory activity despite profound depletion in mtDNA levels.

  4. Genetics Home Reference: RRM2B-related mitochondrial DNA depletion syndrome, encephalomyopathic form with renal ...

    Science.gov (United States)

    ... Additional NIH Resources (1 link) National Institute of Neurological Disorders and Stroke: Mitochondrial Myopathy Information Page Educational Resources (7 links) Cincinnati Children's Hospital: Mitochondrial Diseases Disease InfoSearch: Mitochondrial DNA depletion ...

  5. Investigation of porosity and fractal properties of the sintered metal and semiconductor layers in the MDS capacitor structure

    Directory of Open Access Journals (Sweden)

    Skatkov Leonid

    2012-01-01

    Full Text Available MDS capacitor (metal - dielectric - semiconductor is a structure in which metal plate is represented by compact bulk-porous pellets of niobium sintered powder, and semiconductor plate - by pyrolytic layer of MnO2. In the present paper we report the results of investigation of microporosity of sintered Nb and pyrolytic MnO2 and also the fractal properties of semiconductor layer.

  6. Management of depleted uranium

    International Nuclear Information System (INIS)

    2001-01-01

    Large stocks of depleted uranium have arisen as a result of enrichment operations, especially in the United States and the Russian Federation. Countries with depleted uranium stocks are interested in assessing strategies for the use and management of depleted uranium. The choice of strategy depends on several factors, including government and business policy, alternative uses available, the economic value of the material, regulatory aspects and disposal options, and international market developments in the nuclear fuel cycle. This report presents the results of a depleted uranium study conducted by an expert group organised jointly by the OECD Nuclear Energy Agency and the International Atomic Energy Agency. It contains information on current inventories of depleted uranium, potential future arisings, long term management alternatives, peaceful use options and country programmes. In addition, it explores ideas for international collaboration and identifies key issues for governments and policy makers to consider. (authors)

  7. Treatment strategies in patients with AML or high-risk myelodysplastic syndrome relapsed after Allo-SCT.

    Science.gov (United States)

    Sauer, T; Silling, G; Groth, C; Rosenow, F; Krug, U; Görlich, D; Evers, G; Albring, J; Besoke, R; Mesters, R M; Müller-Tidow, C; Kessler, T; Büchner, T; Berdel, W E; Stelljes, M

    2015-04-01

    Non-relapse mortality after Allo-SCT has significantly decreased over the last years. Nevertheless, relapse remains a major cause for post SCT mortality in patients with AML and high-risk myelodysplastic syndrome (MDS). In this retrospective single-center analysis, we have analyzed the treatment outcomes of 108 patients with AML or MDS, who relapsed after Allo-SCT. Seventy of these patients (65%) were treated with salvage therapies containing chemotherapy alone, allogeneic cell-based treatment or the combination of both. Thirty-eight patients (35%) received palliative treatment. Median OS after diagnosis of relapse was 130 days. Compared with patients who received chemotherapy alone, response to salvage therapy was significantly improved in patients treated with a combination of chemo- and allogeneic cell-based therapy (CR rate 57% vs 13%, P=0.002). Among risk factors concerning pretreatment characteristics, disease status before first Allo-SCT, and details of transplantation, only the time interval from Allo-SCT to relapse was an independent predictor of response to salvage therapy and OS. These data confirmed that time to relapse after transplantation is an important prognostic factor. Up to now, only patients eligible for treatment regimens containing allogeneic cell-based interventions achieved relevant response rates.

  8. Aging- and Senescence-associated Changes of Mesenchymal Stromal Cells in Myelodysplastic Syndromes.

    Science.gov (United States)

    Mattiucci, Domenico; Maurizi, Giulia; Leoni, Pietro; Poloni, Antonella

    2018-01-01

    Hematopoietic stem and progenitor cells reside within the bone marrow (BM) microenvironment. By a well-balanced interplay between self-renewal and differentiation, they ensure a lifelong supply of mature blood cells. Physiologically, multiple different cell types contribute to the regulation of stem and progenitor cells in the BM microenvironment by cell-extrinsic and cell-intrinsic mechanisms. During the last decades, mesenchymal stromal cells (MSCs) have been identified as one of the main cellular components of the BM microenvironment holding an indispensable role for normal hematopoiesis. During aging, MSCs diminish their functional and regenerative capacities and in some cases encounter replicative senescence, promoting inflammation and cancer progression. It is now evident that alterations in specific stromal cells that comprise the BM microenvironment can contribute to hematologic malignancies, and there is growing interest regarding the contribution of MSCs to the pathogenesis of myelodysplastic syndromes (MDSs), a clonal hematological disorder, occurring mostly in the elderly, characterized by ineffective hematopoiesis and increased tendency to acute myeloid leukemia evolution. The pathogenesis of MDS has been associated with specific genetic and epigenetic events occurring both in hematopoietic stem cells (HSCs) and in the whole BM microenvironment with an aberrant cross talk between hematopoietic elements and stromal compartment. This review highlights the role of MSCs in MDS showing functional and molecular alterations such as altered cell-cycle regulation with impaired proliferative potential, dysregulated cytokine secretion, and an abnormal gene expression profile. Here, the current knowledge of impaired functional properties of both aged MSCs and MSCs in MDS have been described with a special focus on inflammation and senescence induced changes in the BM microenvironment. Furthermore, a better understanding of aberrant BM microenvironment could

  9. Comparative Analysis of VERA Depletion Problems

    International Nuclear Information System (INIS)

    Park, Jinsu; Kim, Wonkyeong; Choi, Sooyoung; Lee, Hyunsuk; Lee, Deokjung

    2016-01-01

    Each code has its own solver for depletion, which can produce different depletion calculation results. In order to produce reference solutions for depletion calculation comparison, sensitivity studies should be preceded for each depletion solver. The sensitivity tests for burnup interval, number of depletion zones, and recoverable energy per fission (Q-value) were performed in this paper. For the comparison of depletion calculation results, usually the multiplication factors are compared as a function of burnup. In this study, new comparison methods have been introduced by using the number density of isotope or element, and a cumulative flux instead of burnup. In this paper, optimum depletion calculation options are determined through the sensitivity study of the burnup intervals and the number of depletion intrazones. Because the depletion using CRAM solver performs well for large burnup intervals, smaller number of burnup steps can be used to produce converged solutions. It was noted that the depletion intra-zone sensitivity is only pin-type dependent. The 1 and 10 depletion intra-zones for the normal UO2 pin and gadolinia rod, respectively, are required to obtain the reference solutions. When the optimized depletion calculation options are used, the differences of Q-values are found to be a main cause of the differences of solutions. In this paper, new comparison methods were introduced for consistent code-to-code comparisons even when different kappa libraries were used in the depletion calculations

  10. Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome

    International Nuclear Information System (INIS)

    Chen, T-C; Hou, H-A; Chou, W-C; Tang, J-L; Kuo, Y-Y; Chen, C-Y; Tseng, M-H; Huang, C-F; Lai, Y-J; Chiang, Y-C; Lee, F-Y; Liu, M-C; Liu, C-W; Liu, C-Y; Yao, M; Huang, S-Y; Ko, B-S; Hsu, S-C; Wu, S-J; Tsay, W; Chen, Y-C; Tien, H-F

    2014-01-01

    Recently, mutations of the additional sex comb-like 1 (ASXL1) gene were identified in patients with myelodysplastic syndrome (MDS), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, ASXL1 mutations were identified in 106 (22.7%) of the 466 patients with primary MDS based on the French-American-British (FAB) classification and 62 (17.1%) of the 362 patients based on the World Health Organization (WHO) classification. ASXL1 mutation was closely associated with trisomy 8 and mutations of RUNX1, EZH2, IDH, NRAS, JAK2, SETBP1 and SRSF2, but was negatively associated with SF3B1 mutation. Most ASXL1-mutated patients (85%) had concurrent other gene mutations at diagnosis. ASXL1 mutation was an independent poor prognostic factor for survival. Sequential studies showed that the original ASXL1 mutation remained unchanged at disease progression in all 32 ASXL1-mutated patients but were frequently accompanied with acquisition of mutations of other genes, including RUNX1, NRAS, KRAS, SF3B1, SETBP1 and chromosomal evolution. On the other side, among the 80 ASXL1-wild patients, only one acquired ASXL1 mutation at leukemia transformation. In conclusion, ASXL1 mutations in association with other genetic alterations may have a role in the development of MDS but contribute little to disease progression

  11. Iron overload and chelation therapy in myelodysplastic syndromes.

    Science.gov (United States)

    Temraz, Sally; Santini, Valeria; Musallam, Khaled; Taher, Ali

    2014-07-01

    Iron overload remains a concern in MDS patients especially those requiring recurrent blood transfusions. The consequence of iron overload may be more relevant in patients with low and intermediate-1 risk MDS who may survive long enough to experience such manifestations. It is a matter of debate whether this overload has time to yield organ damage, but it is quite evident that cellular damage and DNA genotoxic effect are induced. Iron overload may play a critical role in exacerbating pre-existing morbidity or even unmask silent ones. Under these circumstances, iron chelation therapy could play an integral role in the management of these patients. This review entails an in depth analysis of iron overload in MDS patients; its pathophysiology, effect on survival, associated risks and diagnostic options. It also discusses management options in relation to chelation therapy used in MDS patients and the impact it has on survival, hematologic response and organ function. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  12. Molecular dissection of a contiguous gene syndrome: Frequent submicroscopic deletions, evolutionarily conserved sequences, and a hypomethylated island in the Miller-Dieker chromosome region

    International Nuclear Information System (INIS)

    Ledbetter, D.H.; Ledbetter, S.A.; vanTuinen, P.

    1989-01-01

    The Miller-Dieker syndrome (MDS), composed of characteristic facial abnormalities and a severe neuronal migration disorder affecting the cerebral cortex, is caused by visible or submicroscopic deletions of chromosome band 17p13. Twelve anonymous DNA markers were tested against a panel of somatic cell hybrids containing 17p deletions from seven MDS patients. All patients, including three with normal karyotypes, are deleted for a variable set of 5-12 markers. Two highly polymorphic VNTR (variable number of tandem repeats) probes, YNZ22 and YNH37, are codeleted in all patients tested and make molecular diagnosis for this disorder feasible. By pulsed-field gel electrophoresis, YNZ22 and YNH37 were shown to be within 30 kilobases (kb) of each other. Cosmid clones containing both VNTR sequences were identified, and restriction mapping showed them to be 100 kb were completely deleted in all patients, providing a minimum estimate of the size of the MDS critical region. A hypomethylated island and evolutionarily conserved sequences were identified within this 100-kb region, indications of the presence of one or more expressed sequences potentially involved in the pathophysiology of this disorder. The conserved sequences were mapped to mouse chromosome 11 by using mouse-rat somatic cell hybrids, extending the remarkable homology between human chromosome 17 and mouse chromosome 11 by 30 centimorgans, into the 17p telomere region

  13. Mayo Alliance Prognostic Model for Myelodysplastic Syndromes: Integration of Genetic and Clinical Information.

    Science.gov (United States)

    Tefferi, Ayalew; Gangat, Naseema; Mudireddy, Mythri; Lasho, Terra L; Finke, Christy; Begna, Kebede H; Elliott, Michelle A; Al-Kali, Aref; Litzow, Mark R; Hook, C Christopher; Wolanskyj, Alexandra P; Hogan, William J; Patnaik, Mrinal M; Pardanani, Animesh; Zblewski, Darci L; He, Rong; Viswanatha, David; Hanson, Curtis A; Ketterling, Rhett P; Tang, Jih-Luh; Chou, Wen-Chien; Lin, Chien-Chin; Tsai, Cheng-Hong; Tien, Hwei-Fang; Hou, Hsin-An

    2018-06-01

    To develop a new risk model for primary myelodysplastic syndromes (MDS) that integrates information on mutations, karyotype, and clinical variables. Patients with World Health Organization-defined primary MDS seen at Mayo Clinic (MC) from December 28, 1994, through December 19, 2017, constituted the core study group. The National Taiwan University Hospital (NTUH) provided the validation cohort. Model performance, compared with the revised International Prognostic Scoring System, was assessed by Akaike information criterion and area under the curve estimates. The study group consisted of 685 molecularly annotated patients from MC (357) and NTUH (328). Multivariate analysis of the MC cohort identified monosomal karyotype (hazard ratio [HR], 5.2; 95% CI, 3.1-8.6), "non-MK abnormalities other than single/double del(5q)" (HR, 1.8; 95% CI, 1.3-2.6), RUNX1 (HR, 2.0; 95% CI, 1.2-3.1) and ASXL1 (HR, 1.7; 95% CI, 1.2-2.3) mutations, absence of SF3B1 mutations (HR, 1.6; 95% CI, 1.1-2.4), age greater than 70 years (HR, 2.2; 95% CI, 1.6-3.1), hemoglobin level less than 8 g/dL in women or less than 9 g/dL in men (HR, 2.3; 95% CI, 1.7-3.1), platelet count less than 75 × 10 9 /L (HR, 1.5; 95% CI, 1.1-2.1), and 10% or more bone marrow blasts (HR, 1.7; 95% CI, 1.1-2.8) as predictors of inferior overall survival. Based on HR-weighted risk scores, a 4-tiered Mayo alliance prognostic model for MDS was devised: low (89 patients), intermediate-1 (104), intermediate-2 (95), and high (69); respective median survivals (5-year overall survival rates) were 85 (73%), 42 (34%), 22 (7%), and 9 months (0%). The Mayo alliance model was subsequently validated by using the external NTUH cohort and, compared with the revised International Prognostic Scoring System, displayed favorable Akaike information criterion (1865 vs 1943) and area under the curve (0.87 vs 0.76) values. We propose a simple and contemporary risk model for MDS that is based on a limited set of genetic and clinical variables

  14. SPAG6 regulates cell apoptosis through the TRAIL signal pathway in myelodysplastic syndromes.

    Science.gov (United States)

    Li, Xinxin; Yang, Bihui; Wang, Li; Chen, Liping; Luo, Xiaohua; Liu, Lin

    2017-05-01

    Myelodysplastic syndromes (MDSs) are a group of malignant clone hematopoietic stem-cell diseases, and the evolution and progression of MDS depend on the abnormal apoptosis of bone marrow cells. Our previous studies have indicated that sperm-associated antigen 6 (SPAG6), located in the uniparental disomy regions of myeloid cells, is overexpressed in patients with MDS as compared to controls, and SPAG6 can inhibit apoptosis of SKM-1. However, the concrete mechanism is still unclear. In the present study, it was found that the TNF-related apoptosis-inducing ligand (TRAIL)signal pathway was activated when the expression of SPAG6 was inhibited by SPAG6-shRNA lentivirus in SKM-1 cells. Additionally, the results of flow cytometry, Cell Counting Kit-8 assay and western blot analysis implied that the TRAIL signal pathway could be inhibited by a high expression of SPAG6. However, SPAG6 cannot influence the expression of TRAIL death receptors, except for FADD. Additionally the interaction between FADD and TRAIL death receptors also increased in SKM-1 cells infected with SPAG6-shRNA lentivirus. Thus, our study demonstrates that SPAG6 may regulate apoptosis in SKM-1 through the TRAIL signal pathway, indicating that SPAG6 could be a potential therapeutic target.

  15. Ozone-depleting Substances (ODS)

    Data.gov (United States)

    U.S. Environmental Protection Agency — This site includes all of the ozone-depleting substances (ODS) recognized by the Montreal Protocol. The data include ozone depletion potentials (ODP), global warming...

  16. Copy number neutral loss of heterozygosity at 17p and homozygous mutations of TP53 are associated with complex chromosomal aberrations in patients newly diagnosed with myelodysplastic syndromes.

    Science.gov (United States)

    Svobodova, Karla; Zemanova, Zuzana; Lhotska, Halka; Novakova, Milena; Podskalska, Lucie; Belickova, Monika; Brezinova, Jana; Sarova, Iveta; Izakova, Silvia; Lizcova, Libuse; Berkova, Adela; Siskova, Magda; Jonasova, Anna; Cermak, Jaroslav; Michalova, Kyra

    2016-03-01

    Complex karyotypes are seen in approximately 20% of patients with myelodysplastic syndromes (MDS) and are associated with a high risk of transformation to acute myeloid leukemia and poor outcomes in patients. Copy number neutral loss of heterozygosity (CN-LOH, i.e., both copies of a chromosomal pair or their parts originate from one parent) might contribute to increased genomic instability in the bone-marrow cells of patients with MDS. The pathological potential of CN-LOH, which arises as a clonal aberration in a proportion of somatic cells, consists of tumor suppressor gene and oncogene homozygous mutations. The aim of our study was to evaluate the frequency of CN-LOH at 17p in bone-marrow cells of newly diagnosed MDS patients with complex chromosomal aberrations and to assess its correlation with mutations in the TP53 gene (17p13.1). CN-LOH was detected in 40 chromosomal regions in 21 (29%) of 72 patients analyzed. The changes in 27 of the 40 regions identified were sporadic. The most common finding was CN-LOH of the short arm of chromosome 17, which was detected in 13 (18%) of 72 patients. A mutational analysis confirmed the homozygous mutation of TP53 in all CN-LOH 17p patients, among which two frameshift mutations are not registered in the International Agency for Research on Cancer TP53 Database. CN-LOH 17p correlated with aggressive disease (median overall survival 4 months) and was strongly associated with a complex karyotype in the cohort studied, which might cause rapid disease progression in high-risk MDS. No other CN-LOH region previously recorded in MDS or AML patients (1p, 4q, 7q, 11q, 13q, 19q, 21q) was detected in our cohort of patients with complex karyotype examined at the diagnosis of MDS. The LOH region appeared to be balanced (i.e., with no DNA copy number change) when examined with conventional and molecular cytogenetic methods. Therefore, a microarray that detects single-nucleotide polymorphisms is an ideal method with which to identify and

  17. Anti-ceramide antibody prevents the radiation gastrointestinal syndrome in mice

    Science.gov (United States)

    Rotolo, Jimmy; Stancevic, Branka; Zhang, Jianjun; Hua, Guoqiang; Fuller, John; Yin, Xianglei; Haimovitz-Friedman, Adriana; Kim, Kisu; Qian, Ming; Cardó-Vila, Marina; Fuks, Zvi; Pasqualini, Renata; Arap, Wadih; Kolesnick, Richard

    2012-01-01

    Radiation gastrointestinal (GI) syndrome is a major lethal toxicity that may occur after a radiation/nuclear incident. Currently, there are no prophylactic countermeasures against radiation GI syndrome lethality for first responders, military personnel, or remediation workers entering a contaminated area. The pathophysiology of this syndrome requires depletion of stem cell clonogens (SCCs) within the crypts of Lieberkühn, which are a subset of cells necessary for postinjury regeneration of gut epithelium. Recent evidence indicates that SCC depletion is not exclusively a result of DNA damage but is critically coupled to ceramide-induced endothelial cell apoptosis within the mucosal microvascular network. Here we show that ceramide generated on the surface of endothelium coalesces to form ceramide-rich platforms that transmit an apoptotic signal. Moreover, we report the generation of 2A2, an anti-ceramide monoclonal antibody that binds to ceramide to prevent platform formation on the surface of irradiated endothelial cells of the murine GI tract. Consequently, we found that 2A2 protected against endothelial apoptosis in the small intestinal lamina propria and facilitated recovery of crypt SCCs, preventing the death of mice from radiation GI syndrome after high radiation doses. As such, we suggest that 2A2 represents a prototype of a new class of anti-ceramide therapeutics and an effective countermeasure against radiation GI syndrome mortality. PMID:22466649

  18. Therapy with recombinant human erythropoietin in patients with myelodysplastic syndromes.

    Science.gov (United States)

    Stone, R M; Bernstein, S H; Demetri, G; Facklam, D P; Arthur, K; Andersen, J; Aster, J C; Kufe, D

    1994-10-01

    We conducted a Phase I-II trial of recombinant human erythropoietin-beta (rhEPO) in patients with myelodysplastic syndrome (MDS). Patients with anemia and pathologically confirmed MDS were eligible for the study. Treatment consisted of rhEPO by subcutaneous injection thrice weekly for 6 weeks at one of three dose levels (100 U/kg (three patients), 200 U/kg (three patients) and 400 U/kg (14 patients)). Ferrous sulfate (325 mg po tid) was also administered if the transferrin saturation was below 30% (two patients). Patients were monitored with weekly CBC, white cell differential, and reticulocyte counts. Bone marrow examinations were performed at the conclusion of the treatment period and after a 2 week washout period. Patients who responded to therapy were continued on rhEPO at the same dose for 6 additional months. Response criteria included: 50% reduction in transfusion requirements compared with the 6 week pre-study period; doubling of reticulocyte count that was maintained on two determinations at least 1 week apart; or an increase in hemoglobin by at least 1.2 gm/dl without transfusions. Pre-treatment factors potentially predictive of response were analyzed by univariate analysis and in a multivariate fashion by classification and regression trees. Seven of the twenty patients sustained an untransfused rise in serum hemoglobin > or = 1.2 gm/dl. Four of the sixteen patients (including three of seven patients experiencing a rise in serum hemoglobin) who were transfusion-dependent prior to the study achieved a reduction or elimination of their transfusion requirements. Five of thirteen patients who received rhEPO during the extension phase had a continued response. A low baseline erythropoietin level (< 50 mU/ml) was the best predictor of hemoglobin response when controlling for other variables. rhEPO has a role in the treatment of certain patients with MDS, particularly in those whose endogenous serum erythropoietin levels are not markedly elevated.

  19. Use of 60 ppm deuterium depleted water in companionship animals

    International Nuclear Information System (INIS)

    Balint, Emilia; Manolescu, N.; Cranganu, D.; Militaru, Manuela; Pop, Aneta; Codreanu, M.; Panait, Marieta; Lastofka, D.

    2004-01-01

    There are presented the results of studies on the effects of deuterium depleted water in companionship animals. Based on these results, a new product was realized, 'Aqua Forte' that is a deuterium depleted potable water (60 ppm deuterium) with beneficial effects in animal's health maintaining. Aqua forte has prophylactic properties (in preventing diseases related to immune system) and therapeutic properties, as adjuvant in various therapeutic programs. The mechanism of action takes place at the cellular metabolism level by replacing the constitutional and free water of 150 ppm deuterium, this resulting in the stimulation of the immune cellular system and also of resistance at the onset of some pathological states. The non-specific stimulation implies performing both the humoral mediated immune reactions and of those cellularly mediated. Aqua forte is recommended in: - the feeding of the young weaned animals, the action being of growth stimulation, and increasing of the resistance against some diseases specific to the age; - as an adjuvant in some chronic diseases (hepatitis, pancreatitis, dermatological diseases, osteoarthropaties, hepato-renal syndrome, renal insufficiency, after surgical interventions, in antitumoral therapy); - in the feeding of the old animals for the quality of life improvement. (authors)

  20. “When the going gets tough, who keeps going?” Depletion sensitivity moderates the ego-depletion effect

    NARCIS (Netherlands)

    Salmon, S.J.; Adriaanse, M.A.; Vet, de E.W.M.L.; Fennis, B.M.; Ridder, de D.T.D.

    2014-01-01

    Self-control relies on a limited resource that can get depleted, a phenomenon that has been labeled ego-depletion. We argue that individuals may differ in their sensitivity to depleting tasks, and that consequently some people deplete their self-control resource at a faster rate than others. In

  1. Therapy-related myelodysplastic syndrome after successful treatment of acute promyelocytic leukemia: case report and literature review

    Directory of Open Access Journals (Sweden)

    Cîrstea Mihaela

    2017-04-01

    Full Text Available In the 2016 revision of the World Health Organization classification the term therapy-related myeloid neoplasia (t-MN defines a subgroup of acute myeloid leukemia (AML comprising patients who develop myelodysplastic syndrome (MDS-t or acute myeloid leukemia (AML-t after treatment with cytotoxic and/or radiation therapy for various malignancies or autoimmune disorders. We report the case of a 36 year old patient with t-MN (t-MDS after achieving complete remission (CR of a PML-RARA positive acute promyelocytic leukemia (APL at 32 months after diagnosis. Initially classified as low risk APL and treated according to the AIDA protocol - induction and 3 consolidation cycles - the patient achieved a complete molecular response in September 2013 and started maintenance therapy. On follow-up PML-RARA transcript remained negative. In January 2016 leukopenia and thrombocytopenia developed and a peripheral blood smear revealed hypogranular and agranular neutrophils. Immunophenotyping in the bone marrow aspirate identified undifferentiated blast cells that did not express cytoplasmic myeloperoxidase. The cytogenetic study showed normal karyotype. The molecular biology tests not identified PMLRARA transcript. A diagnosis of t-MDS (AREB-2 - WHO 2008 was established. Treatment of AML was started with 2 “3+7” regimens and 1 MEC cycle. Two months from diagnosis, while in CR, an allogeneic HSCT from an unrelated HLA compatible donor was performed after myeloablative regimen. An unfavorable clinical evolution was followed by death on day 9 after transplantation. The occurrence of t-MNs during CR of APL represents a particular problem in terms of follow-up and differential diagnosis of relapse and constitutes a dramatic complication for a disease with a favorable prognosis.

  2. Gene expression deregulation in postnatal skeletal muscle of TK2 deficient mice reveals a lower pool of proliferating myogenic progenitor cells.

    Directory of Open Access Journals (Sweden)

    João A Paredes

    Full Text Available Loss of thymidine kinase 2 (TK2 causes a heterogeneous myopathic form of mitochondrial DNA (mtDNA depletion syndrome (MDS in humans that predominantly affects skeletal muscle tissue. In mice, TK2 deficiency also affects several tissues in addition to skeletal muscle, including brain, heart, adipose tissue, kidneys and causes death about 3 weeks after birth. We analysed skeletal muscle and heart muscle tissues of Tk2 knockout mice at postnatal development phase and observed that TK2 deficient pups grew slower and their skeletal muscles appeared significantly underdeveloped, whereas heart was close to normal in size. Both tissues showed mtDNA depletion and mitochondria with altered ultrastructure, as revealed by transmission electron microscopy. Gene expression microarray analysis showed a strong down-regulation of genes involved in cell cycle and cell proliferation in both tissues, suggesting a lower pool of undifferentiated proliferating cells. Analysis of isolated primary myoblasts from Tk2 knockout mice showed slow proliferation, less ability to differentiate and signs of premature senescence, even in absence of mtDNA depletion. Our data demonstrate that TK2 deficiency disturbs myogenic progenitor cells function in postnatal skeletal muscle and we propose this as one of the causes of underdeveloped phenotype and myopathic characteristic of the TK2 deficient mice, in addition to the progressive mtDNA depletion, mitochondrial damage and respiratory chain deficiency in post-mitotic differentiated tissue.

  3. Gene expression deregulation in postnatal skeletal muscle of TK2 deficient mice reveals a lower pool of proliferating myogenic progenitor cells.

    Science.gov (United States)

    Paredes, João A; Zhou, Xiaoshan; Höglund, Stefan; Karlsson, Anna

    2013-01-01

    Loss of thymidine kinase 2 (TK2) causes a heterogeneous myopathic form of mitochondrial DNA (mtDNA) depletion syndrome (MDS) in humans that predominantly affects skeletal muscle tissue. In mice, TK2 deficiency also affects several tissues in addition to skeletal muscle, including brain, heart, adipose tissue, kidneys and causes death about 3 weeks after birth. We analysed skeletal muscle and heart muscle tissues of Tk2 knockout mice at postnatal development phase and observed that TK2 deficient pups grew slower and their skeletal muscles appeared significantly underdeveloped, whereas heart was close to normal in size. Both tissues showed mtDNA depletion and mitochondria with altered ultrastructure, as revealed by transmission electron microscopy. Gene expression microarray analysis showed a strong down-regulation of genes involved in cell cycle and cell proliferation in both tissues, suggesting a lower pool of undifferentiated proliferating cells. Analysis of isolated primary myoblasts from Tk2 knockout mice showed slow proliferation, less ability to differentiate and signs of premature senescence, even in absence of mtDNA depletion. Our data demonstrate that TK2 deficiency disturbs myogenic progenitor cells function in postnatal skeletal muscle and we propose this as one of the causes of underdeveloped phenotype and myopathic characteristic of the TK2 deficient mice, in addition to the progressive mtDNA depletion, mitochondrial damage and respiratory chain deficiency in post-mitotic differentiated tissue.

  4. Ego Depletion Impairs Implicit Learning

    Science.gov (United States)

    Thompson, Kelsey R.; Sanchez, Daniel J.; Wesley, Abigail H.; Reber, Paul J.

    2014-01-01

    Implicit skill learning occurs incidentally and without conscious awareness of what is learned. However, the rate and effectiveness of learning may still be affected by decreased availability of central processing resources. Dual-task experiments have generally found impairments in implicit learning, however, these studies have also shown that certain characteristics of the secondary task (e.g., timing) can complicate the interpretation of these results. To avoid this problem, the current experiments used a novel method to impose resource constraints prior to engaging in skill learning. Ego depletion theory states that humans possess a limited store of cognitive resources that, when depleted, results in deficits in self-regulation and cognitive control. In a first experiment, we used a standard ego depletion manipulation prior to performance of the Serial Interception Sequence Learning (SISL) task. Depleted participants exhibited poorer test performance than did non-depleted controls, indicating that reducing available executive resources may adversely affect implicit sequence learning, expression of sequence knowledge, or both. In a second experiment, depletion was administered either prior to or after training. Participants who reported higher levels of depletion before or after training again showed less sequence-specific knowledge on the post-training assessment. However, the results did not allow for clear separation of ego depletion effects on learning versus subsequent sequence-specific performance. These results indicate that performance on an implicitly learned sequence can be impaired by a reduction in executive resources, in spite of learning taking place outside of awareness and without conscious intent. PMID:25275517

  5. Ego depletion impairs implicit learning.

    Directory of Open Access Journals (Sweden)

    Kelsey R Thompson

    Full Text Available Implicit skill learning occurs incidentally and without conscious awareness of what is learned. However, the rate and effectiveness of learning may still be affected by decreased availability of central processing resources. Dual-task experiments have generally found impairments in implicit learning, however, these studies have also shown that certain characteristics of the secondary task (e.g., timing can complicate the interpretation of these results. To avoid this problem, the current experiments used a novel method to impose resource constraints prior to engaging in skill learning. Ego depletion theory states that humans possess a limited store of cognitive resources that, when depleted, results in deficits in self-regulation and cognitive control. In a first experiment, we used a standard ego depletion manipulation prior to performance of the Serial Interception Sequence Learning (SISL task. Depleted participants exhibited poorer test performance than did non-depleted controls, indicating that reducing available executive resources may adversely affect implicit sequence learning, expression of sequence knowledge, or both. In a second experiment, depletion was administered either prior to or after training. Participants who reported higher levels of depletion before or after training again showed less sequence-specific knowledge on the post-training assessment. However, the results did not allow for clear separation of ego depletion effects on learning versus subsequent sequence-specific performance. These results indicate that performance on an implicitly learned sequence can be impaired by a reduction in executive resources, in spite of learning taking place outside of awareness and without conscious intent.

  6. Ego depletion impairs implicit learning.

    Science.gov (United States)

    Thompson, Kelsey R; Sanchez, Daniel J; Wesley, Abigail H; Reber, Paul J

    2014-01-01

    Implicit skill learning occurs incidentally and without conscious awareness of what is learned. However, the rate and effectiveness of learning may still be affected by decreased availability of central processing resources. Dual-task experiments have generally found impairments in implicit learning, however, these studies have also shown that certain characteristics of the secondary task (e.g., timing) can complicate the interpretation of these results. To avoid this problem, the current experiments used a novel method to impose resource constraints prior to engaging in skill learning. Ego depletion theory states that humans possess a limited store of cognitive resources that, when depleted, results in deficits in self-regulation and cognitive control. In a first experiment, we used a standard ego depletion manipulation prior to performance of the Serial Interception Sequence Learning (SISL) task. Depleted participants exhibited poorer test performance than did non-depleted controls, indicating that reducing available executive resources may adversely affect implicit sequence learning, expression of sequence knowledge, or both. In a second experiment, depletion was administered either prior to or after training. Participants who reported higher levels of depletion before or after training again showed less sequence-specific knowledge on the post-training assessment. However, the results did not allow for clear separation of ego depletion effects on learning versus subsequent sequence-specific performance. These results indicate that performance on an implicitly learned sequence can be impaired by a reduction in executive resources, in spite of learning taking place outside of awareness and without conscious intent.

  7. Exposure to nature counteracts aggression after depletion.

    Science.gov (United States)

    Wang, Yan; She, Yihan; Colarelli, Stephen M; Fang, Yuan; Meng, Hui; Chen, Qiuju; Zhang, Xin; Zhu, Hongwei

    2018-01-01

    Acts of self-control are more likely to fail after previous exertion of self-control, known as the ego depletion effect. Research has shown that depleted participants behave more aggressively than non-depleted participants, especially after being provoked. Although exposure to nature (e.g., a walk in the park) has been predicted to replenish resources common to executive functioning and self-control, the extent to which exposure to nature may counteract the depletion effect on aggression has yet to be determined. The present study investigated the effects of exposure to nature on aggression following depletion. Aggression was measured by the intensity of noise blasts participants delivered to an ostensible opponent in a competition reaction-time task. As predicted, an interaction occurred between depletion and environmental manipulations for provoked aggression. Specifically, depleted participants behaved more aggressively in response to provocation than non-depleted participants in the urban condition. However, provoked aggression did not differ between depleted and non-depleted participants in the natural condition. Moreover, within the depletion condition, participants in the natural condition had lower levels of provoked aggression than participants in the urban condition. This study suggests that a brief period of nature exposure may restore self-control and help depleted people regain control over aggressive urges. © 2017 Wiley Periodicals, Inc.

  8. Immunological studies in acquired immunodeficiency syndrome. Functional studies of lymphocyte subpopulations

    DEFF Research Database (Denmark)

    Hofmann, B; Ødum, Niels; Platz, P

    1985-01-01

    The lymphocyte transformation response in vitro to mitogens (phytohaemagglutinin, concanavalin A, and pokeweed mitogen) and antigens (purified protein derivative and tetanus) was studied in three patients with acquired immunodeficiency syndrome (AIDS), three patients with pre-AIDS, and six healthy...... controls before and after depletion of T4- or T8-positive cells. In controls, T8-depleted lymphocytes responded as well as peripheral blood mononuclear cells (PBMC) when monocytes were added, whereas T4-depleted cells gave about 50% of this response to mitogens and no response at all to antigens....... No evidence of suppression was seen when various mixtures of T4- and T8-depleted cells were made. In particular, there was a virtually linear relationship between the percentage of T8-depleted cells and the response to antigens. The PBMC of all AIDS and pre-AIDS patients had very low or absent responses...

  9. Aberrations of chromosome 8 in myelodysplastic syndromes: Clinical and biological significance

    Directory of Open Access Journals (Sweden)

    Marisavljević Dragomir

    2006-01-01

    Full Text Available Introduction: Rearrangements of any single chromosome in human karyotype have been reported in patients with pMDS. Objective: To examine the role of aberrations of chromosome 8 in pathogenesis, clinical presentation and progression of myelodysplastic syndromes. Method: Cytogenetic analysis of bone marrow cells was carried out by direct method and by means of 24- and/or 48-hour unstimulated cell culture. Chromosomes were obtained by modified method of HG-bands. Results: On presentation, 109 out of 271 successfully karyotyped patients (40,2% had abnormal karyotypes. Among them, 22 patients (10.9% had aberrations of chromosome 8. Ten patients had trisomy 8 as "simple" aberration whilst additional three cases had trisomy 8 included in "complex" karyotypes (≥3 chromosomes. Cases with constitutional trisomy 8 mosaicism (CT8M were excluded using the chromosome analyses of PHA-stimulated blood cultures. On the contrary, monosomy (seven patients or deletion of chromosome 8 (two patients were exclusively found in "complex" karyotypes. During prolonged cytogenetic follow-up, trisomy 8 was not recorded in evolving karyotypes. In contrast, trisomy 8 disappeared in two cases during subsequent cytogenetic studies, i.e. 23 and 72 months from diagnosis, accompanied in one patient with complete hematological remission. No difference regarding age, sex, cytopenia, blood and marrow blast count or response to treatment was found between patients with trisomy 8 as the sole aberration compared to those with normal cytogenetics. Median survival of patients with trisomy 8 as the sole aberration was 27 months, as compared to 32 months in patients with normal cytogenetics (p=0.468, whilst median survival of patients with aberrations of chromosome 8 included in "complex" karyotypes was only 4 months. Conclusion: Aberrations of chromosome 8 are common in patients with pMDS. The presence of a clone with trisomy 8 is not always the sign of disease progression or poor

  10. Kinetics of depletion interactions

    NARCIS (Netherlands)

    Vliegenthart, G.A.; Schoot, van der P.P.A.M.

    2003-01-01

    Depletion interactions between colloidal particles dispersed in a fluid medium are effective interactions induced by the presence of other types of colloid. They are not instantaneous but built up in time. We show by means of Brownian dynamics simulations that the static (mean-field) depletion force

  11. Outcome of acute myeloid leukemia and high-risk myelodysplastic syndrome according to health insurance status.

    Science.gov (United States)

    Al-Ameri, Ali; Anand, Ankit; Abdelfatah, Mohamed; Kanaan, Zeyad; Hammonds, Tracy; Haller, Nairmeen; Cherry, Mohamad

    2014-12-01

    Age, cytogenetic status, and molecular features are the most important prognostic factors in acute myeloid leukemia (AML). This study aimed to analyze the outcomes of patients with AML or high-risk myelodysplastic syndrome (MDS) according to insurance status. A retrospective chart review was performed, covering all patients with AML and high-risk MDS evaluated and treated at Akron General Medical Center between 2002 and 2012. A Cox regression model was analyzed to account for survival over time, adjusted for insurance type, while controlling for patient age at diagnosis and patient risk of mortality. A total of 130 adult patients (age ≥ 18 years) were identified. Insurance information was available for 97 patients enrolled in the study; 3 were excluded because of self-pay status. Cox regression analysis with insurance type as the predictor found that overall survival declines over time and that the rate of decline may be influenced by insurance type (χ(2)(2) = 6.4; P = .044). The likelihood of survival in patients with Medicaid or Medicare without supplemental insurance was .552 (95% CI, .338-.903; P = .018) times the likelihood in patients who had Medicare with supplemental insurance. To explain the difference, variables of age, gender, and risk of mortality were added to the model. Age and risk of mortality were found to be significant predictors of survival. The addition of insurance type to the model did not significantly contribute (χ(2)(3) = 3.83; P = .147). No significant difference in overall survival was observed when patients with AML or high-risk MDS were analyzed according to their health insurance status. The overall survival was low in this study compared with the national average. Early referral to a specialized center or possible clinical trial enrollment may be a good alternative to improve outcome. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Health-Related Quality of Life, Treatment Satisfaction, Adherence and Persistence in β-Thalassemia and Myelodysplastic Syndrome Patients with Iron Overload Receiving Deferasirox: Results from the EPIC Clinical Trial

    Directory of Open Access Journals (Sweden)

    John Porter

    2012-01-01

    Full Text Available Treatment of iron overload using deferoxamine (DFO is associated with significant deficits in patients' health-related quality of life (HRQOL and low treatment satisfaction. The current article presents patient-reported HRQOL, satisfaction, adherence, and persistence data from β-thalassemia (n=274 and myelodysplastic syndrome (MDS patients (n=168 patients participating in the Evaluation of Patients' Iron Chelation with Exjade (EPIC study (NCT00171821; a large-scale 1-year, phase IIIb study investigating the efficacy and safety of the once-daily oral iron chelator, deferasirox. HRQOL and satisfaction, adherence, and persistence to iron chelation therapy (ICT data were collected at baseline and end of study using the Medical Outcomes Short-Form 36-item Health Survey (SF-36v2 and the Satisfaction with ICT Questionnaire (SICT. Compared to age-matched norms, β-thalassemia and MDS patients reported lower SF-36 domain scores at baseline. Low levels of treatment satisfaction, adherence, and persistence were also observed. HRQOL improved following treatment with deferasirox, particularly among β-thalassemia patients. Furthermore, patients reported high levels of satisfaction with deferasirox at end of study and greater ICT adherence, and persistence. Findings suggest deferasirox improves HRQOL, treatment satisfaction, adherence, and persistence with ICT in β-thalassemia and MDS patients. Improving such outcomes is an important long-term goal for patients with iron overload.

  13. Fully Depleted Charge-Coupled Devices

    International Nuclear Information System (INIS)

    Holland, Stephen E.

    2006-01-01

    We have developed fully depleted, back-illuminated CCDs that build upon earlier research and development efforts directed towards technology development of silicon-strip detectors used in high-energy-physics experiments. The CCDs are fabricated on the same type of high-resistivity, float-zone-refined silicon that is used for strip detectors. The use of high-resistivity substrates allows for thick depletion regions, on the order of 200-300 um, with corresponding high detection efficiency for near-infrared and soft x-ray photons. We compare the fully depleted CCD to the p-i-n diode upon which it is based, and describe the use of fully depleted CCDs in astronomical and x-ray imaging applications

  14. Deuterium - depleted water. Achievements and perspectives

    International Nuclear Information System (INIS)

    Titescu, Gh.; Stefanescu, I.; Saros-Rogobete, I.

    2001-01-01

    Deuterium - depleted water represents water that has an isotopic content lower than 145 ppm D/(D+H) which is the natural isotopic content of water. The research conducted at ICSI Ramnicu Valcea, regarding deuterium - depleted water were completed by the following patents: - technique and installation for deuterium - depleted water production; - distilled water with low deuterium content; - technique and installation for the production of distilled water with low deuterium content; - mineralized water with low deuterium content and technique to produce it. The gold and silver medals won at international salons for inventions confirmed the novelty of these inventions. Knowing that deuterium content of water has a big influence on living organisms, beginning with 1996, the ICSI Ramnicu Valcea, deuterium - depleted water producer, co-operated with Romanian specialized institutes for biological effects' evaluation of deuterium - depleted water. The role of natural deuterium in living organisms was examined by using deuterium - depleted water instead of natural water. These investigations led to the following conclusions: 1. deuterium - depleted water caused a tendency towards the increase of the basal tone, accompanied by the intensification of the vasoconstrictor effects of phenylefrine, noradrenaline and angiotensin; the increase of the basal tone and vascular reactivity produced by the deuterium - depleted water persists after the removal of the vascular endothelium; -2. animals treated with deuterium - depleted water showed an increase of the resistance both to sublethal and to lethal gamma radiation doses, suggesting a radioprotective action by the stimulation of non-specific immune defence mechanism; 3, deuterium - depleted water stimulates immune defence reactions, represented by the opsonic, bactericidal and phagocyte capacity of the immune system, together with increase in the numbers of polymorphonuclear neutrophils; 4. investigations regarding artificial

  15. Dendritic cells (DCs) can be successfully generated from leukemic blasts in individual patients with AML or MDS: an evaluation of different methods.

    Science.gov (United States)

    Kremser, Andreas; Dressig, Julia; Grabrucker, Christine; Liepert, Anja; Kroell, Tanja; Scholl, Nina; Schmid, Christoph; Tischer, Johanna; Kufner, Stefanie; Salih, Helmut; Kolb, Hans Jochem; Schmetzer, Helga

    2010-01-01

    Myeloid-leukemic cells (AML, MDS, CML) can be differentiated to leukemia-derived dendritic cell [DC (DCleu)] potentially presenting the whole leukemic antigen repertoire without knowledge of distinct leukemia antigens and are regarded as promising candidates for a vaccination strategy. We studied the capability of 6 serum-free DC culture methods, chosen according to different mechanisms, to induce DC differentiation in 137 cases of AML and 52 cases of MDS. DC-stimulating substances were cytokines ("standard-medium", "MCM-Mimic", "cytokine-method"), bacterial lysates ("Picibanil"), double-stranded RNA ["Poly (I:C)"] or a cytokine bypass method ("Ca-ionophore"). The quality/quantity of DC generated was estimated by flow cytometry studying (co) expressions of "DC"antigens, costimulatory, maturation, and blast-antigens. Comparing these methods on average 15% to 32% DC, depending on methods used, could be obtained from blast-containing mononuclear cells (MNC) in AML/MDS cases with a DC viability of more than 60%. In all, 39% to 64% of these DC were mature; 31% to 52% of leukemic blasts could be converted to DCleu and DCleu-proportions in the suspension were 2% to 70% (13%). Average results of all culture methods tested were comparable, however not every given case of AML could be differentiated to DC with 1 selected method. However performing a pre-analysis with 3 DC-generating methods (MCM-Mimic, Picibanil, Ca-ionophore) we could generate DC in any given case. Functional analyses provided proof, that DC primed T cells to antileukemia-directed cytotoxic cells, although an anti-leukemic reaction was not achieved in every case. In summary our data show that a successful, quantitative DC/DCleu generation is possible with the best of 3 previously tested methods in any given case. Reasons for different functional behaviors of DC-primed T cells must be evaluated to design a practicable DC-based vaccination strategy.

  16. Simulations and observations of plasma depletion, ion composition, and airglow emissions in two auroral ionospheric depletion experiments

    International Nuclear Information System (INIS)

    Yau, A.W.; Whalen, B.A.; Harris, F.R.; Gattinger, R.L.; Pongratz, M.B.; Bernhardt, P.A.

    1985-01-01

    In an ionospheric depletion experiment where chemically reactive vapors such as H 2 O and CO 2 are injected into the O + dominant F region to accelerate the plasma recombination rate and to reduce the plasma density, the ion composition in the depleted region is modified, and photometric emissions are produced. We compare in situ ion composition, density, and photometric measurements from two ionospheric depletion experiments with predictions from chemical modeling. The two injections, Waterhole I and III, were part of an auroral perturbation experiment and occurred in different ambient conditions. In both injections a core region of greater than fivefold plasma depletion was observed over roughly-equal5-km diameter within seconds of the injection, surrounded by an outer region of less drastic and slower depletion. In Waterhole I the plasma density was depleted tenfold over a 30-km diamter region after 2 min. The ambient O + density was drastically reduced, and the molecular O + 2 abundance was enhanced fivehold in the depletion region. OH airglow emission associated with the depletion was observed with a peak emission intensity of roughly-equal1 kR. In Waterhole III the ambient density was a decade lower, and the plasma depletion was less drastic, being twofold over 30 km after 2 min. The airglow emissions were also much less intense and below measurement sensitivity (30 R for the OH 306.4-nm emission; 50 R for the 630.0-nm emission)

  17. DNA (cytosine-5-methyltransferase 3B (DNMT 3B polymorphism and risk of Down syndrome offspring

    Directory of Open Access Journals (Sweden)

    Cláudia Melo de Moura

    2018-01-01

    Full Text Available Down syndrome (DS is the most common form of human genetic mental retardation. Several polymorphisms in genes coding folic acid cycle enzymes have been associated to the risk of bearing a DS child; however, the results are controversial. S-adenosyl-l-methionine (SAM is an important intermediate of folic acid pathway and acts as methyl donor and substrate for DNA (cytosine-5-methyltransferase 3B (DNMT3B – EC 2.1.1.37 de novo methylation processes during embryogenesis. Recent studies suggest that a functional polymorphism of DNMT 3B in maternal genotype may be associated with a decreased risk of having a DS child. We herein investigate the association of this polymorphism with the occurrence of DS in a Brazilian population. We have genotyped 111 mothers of DS infants (MDS and 212 control mothers (CM through PCR-RFLP. The observed genotypic frequencies were CC = 0.22; CT = 0.49 and TT = 0.29 in CM, and CC = 0.30; CT = 0.52 and TT = 0.18 in MDS. Allelic frequencies were C = 0.47 and T = 0.53 in CM and C = 0.56 and T = 0.44 in MDS. No deviation of HWE was observed, and both DNMT 3B rs2424913 genotype (χ2 = 4.53; DF = 1; P = 0.03 and allelic (χ2 = 4.90; DF = 1; P = 0.03 frequencies show significant differences between MDS and CM. The presence of the mutant DNMT 3B T allele decreases 30% the risk of bearing a DS child (OR = 0.69; 95% CI: 0.50–0.96; P = 0.03, and the risk is diminished up to 45% in association with the homozygous genotype (OR = 0.54; 95% CI: 0.31–0.96; P = 0.04. Our results suggest that women harboring the single nucleotide polymorphism DNMT 3B rs2424913 have a decreased risk of a DS pregnancy, and further studies are necessary to confirm this protective effect.

  18. Effect of 90-day space flight (MDS-ISS) on immunological parameters in mice: lymphocyte distribution and function

    Science.gov (United States)

    Roberts, Arthur; Lhuillier, Andrew; Liu, Yi; Ruggiu, Alessandra; Shi, Yufang

    Elucidation of the effects of space flight on the immune system of astronauts and other animal species is important for the survival and success of manned space flight, especially long-term missions. Space flight exposes astronauts to microgravity, galactic cosmic radiation (GCR), and various psycho-social stressors. Blood samples from astronauts returning from space flight have shown changes in the numbers and types of circulating leukocytes. Similarly, normal lym-phocyte homeostasis has been shown to be severely affected in mice using ground-based models of microgravity and GCR exposure, as demonstrated by profound effects on several immuno-logical parameters examined by other investigators and ourselves. In particular, lymphocyte numbers are significantly reduced and subpopulation distribution is altered in the spleen, thy-mus, and peripheral blood following hindlimb unloading (HU) in mice. Lymphocyte depletion was found to be mediated through corticosteroid-induced apoptosis, although the molecular mechanism of apoptosis induction is still under investigation. The proliferative capacity of TCR-stimulated lymphocytes was also inhibited after HU. We have similarly shown that mice exposed to high-energy 56Fe ion radiation have decreased lymphocyte numbers and perturba-tions in proportions of various subpopulations, including CD4+ and CD8+ T cells, and B cells in the spleen, and maturation stages of immature T cells in the thymus. To compare these ground-based results to the effects of actual space-flight, fresh spleen and thymus samples were recently obtained from normal and transgenic mice immediately after 90 d. space-flight in the MDS, and identically-housed ground control mice. Total leukocyte numbers in each organ were enumerated, and subpopulation distribution was examined by flow cytometric analysis of CD3, CD4, CD8, CD19, CD25, DX-5, and CD11b. Splenic T cells were stimulated with anti-CD3 and assessed for proliferation after 2-4 d., and production of

  19. HFE gene mutation and oxidative damage biomarkers in patients with myelodysplastic syndromes and its relation to transfusional iron overload: an observational cross-sectional study.

    Science.gov (United States)

    De Souza, Geane Felix; Ribeiro, Howard Lopes; De Sousa, Juliana Cordeiro; Heredia, Fabíola Fernandes; De Freitas, Rivelilson Mendes; Martins, Manoel Ricardo Alves; Gonçalves, Romélia Pinheiro; Pinheiro, Ronald Feitosa; Magalhães, Silvia Maria Meira

    2015-04-03

    A relation between transfusional IOL (iron overload), HFE status and oxidative damage was evaluated. An observational cross-sectional study involving 87 healthy individuals and 78 patients with myelodysplastic syndromes (MDS) with and without IOL, seen at University Hospital of the Federal University of Ceará, Brazil, between May 2010 and September 2011. IOL was defined using repeated measures of serum ferritin ≥1000 ng/mL. Variations in the HFE gene were investigated using PCR/restriction fragment length polymorphism (RFLP). The biomarkers of oxidative stress (plasmatic malonaldehyde (MDA), glutathione peroxidase (GPx) and superoxide dismutase (SOD)) were determined by spectrophotometry. The HFE gene variations were identified in 24 patients (30.77%) and 5 volunteers (5.74%). The H63D variant was observed in 35% and the C282Y variant as heterozygous in 5% of patients with MDS with IOL. One patient showed double heterozygous variant (C282Y/H63D) and serum ferritin of 11,649 ng/mL. In patients without IOL, the H63D variant was detected in 29.34%. Serum MDA levels were highest in patients with MDS with IOL, with a significant difference when compared with patients without IOL and healthy volunteers, pointing to the relationship between IOL and oxidative stress. The GPx and SOD were also significantly higher in these patients, indicating that lipid peroxidation increase was followed by an increase in antioxidant capacity. Higher ferritin levels were observed in patients with HFE gene variation. 95.7% of patients with MDS with the presence of HFE gene variations had received more of 20 transfusions. We observed a significant increase in MDA levels in patients with MDS and IOL, suggesting an increased lipid peroxidation in these patients. The accumulation of MDA alters the organisation of membrane phospholipids, contributing to the process of cellular degeneration. Results show that excess iron intensifies the process of cell damage through oxidative stress

  20. Too Depleted to Try? Testing the Process Model of Ego Depletion in the Context of Unhealthy Snack Consumption.

    Science.gov (United States)

    Haynes, Ashleigh; Kemps, Eva; Moffitt, Robyn

    2016-11-01

    The process model proposes that the ego depletion effect is due to (a) an increase in motivation toward indulgence, and (b) a decrease in motivation to control behaviour following an initial act of self-control. In contrast, the reflective-impulsive model predicts that ego depletion results in behaviour that is more consistent with desires, and less consistent with motivations, rather than influencing the strength of desires and motivations. The current study sought to test these alternative accounts of the relationships between ego depletion, motivation, desire, and self-control. One hundred and fifty-six undergraduate women were randomised to complete a depleting e-crossing task or a non-depleting task, followed by a lab-based measure of snack intake, and self-report measures of motivation and desire strength. In partial support of the process model, ego depletion was related to higher intake, but only indirectly via the influence of lowered motivation. Motivation was more strongly predictive of intake for those in the non-depletion condition, providing partial support for the reflective-impulsive model. Ego depletion did not affect desire, nor did depletion moderate the effect of desire on intake, indicating that desire may be an appropriate target for reducing unhealthy behaviour across situations where self-control resources vary. © 2016 The International Association of Applied Psychology.

  1. The Toxicity of Depleted Uranium

    OpenAIRE

    Briner, Wayne

    2010-01-01

    Depleted uranium (DU) is an emerging environmental pollutant that is introduced into the environment primarily by military activity. While depleted uranium is less radioactive than natural uranium, it still retains all the chemical toxicity associated with the original element. In large doses the kidney is the target organ for the acute chemical toxicity of this metal, producing potentially lethal tubular necrosis. In contrast, chronic low dose exposure to depleted uranium may not produce a c...

  2. A sequential erythropoietin and GM-CSF schedule offers clinical benefits in the treatment of anaemia in myelodysplastic syndromes.

    Science.gov (United States)

    Bernell, P; Stenke, L; Wallvik, J; Hippe, E; Hast, R

    1996-08-01

    In order to reduce anaemia in patients with myelodysplastic syndromes (MDS) a stepwise treatment protocol including erythropoietin (EP) and granulocyte-macrophage colony-stimulating factor (GM-CSF) was designed. Thirty-seven MDS patients (stages I-III) with symptomatic anaemia were first given EPO 10,000 U s.c. 3 times weekly for 6 weeks. Those not responding, i.e. increased their haemoglobin levels > 15 g/l, proceeded into the second phase of the study where GM-CSF (200 micrograms/d. s.c. on weeks 1-6) was combined with EPO (10,000 U s.c. 3 times weekly on weeks 5-14). Following the initial EPO treatment phase, 14 of the 37 patients (38%) responded with increased haemoglobin levels. Responders were significantly different from non-responders in that their pre-treatment values of s-EPO, s-LDH and bone marrow blast cell counts were lower, their baseline haemoglobin levels higher and their transfusion dependency less pronounced. Eighteen of the 23 non-responders proceeded into the second phase, 13 of those were evaluable having completed the entire schedule. Three of the 13 initially EPO resistant patients (23%) responded to the GM-CSF/EPO combination with increased haemoglobin levels, suggesting a positive synergy between the two cytokines. Thus, the overall response rate to the present protocol was 46% (17 of 37 cases), but only a limited subset of the patients did clearly benefit from the combined GM-CSF/EPO administration. Therefore, we believe this step-wise approach to multiple growth factor treatment in MDS, starting with EPO alone and reserving the combination for refractory cases, has considerable advantages, taking into account both medical and socio-economical aspects.

  3. Thymidine Kinase 2 Deficiency-Induced mtDNA Depletion in Mouse Liver Leads to Defect beta-Oxidation

    OpenAIRE

    Zhou, Xiaoshan; Kannisto, Kristina; Curbo, Sophie; von Dobeln, Ulrika; Hultenby, Kjell; Isetun, Sindra; Gåfvels, Mats; Karlsson, Anna

    2013-01-01

    Thymidine kinase 2 (TK2) deficiency in humans causes mitochondrial DNA (mtDNA) depletion syndrome. To study the molecular mechanisms underlying the disease and search for treatment options, we previously generated and described a TK2 deficient mouse strain (TK2(-/-)) that progressively loses its mtDNA. The TK2(-/-) mouse model displays symptoms similar to humans harboring TK2 deficient infantile fatal encephalomyopathy. Here, we have studied the TK2(-/-) mouse model to clarify the pathologica...

  4. Constitutional t(5;7)(q11;p15) rearranged to acquire monosomy 7q and trisomy 1q in a patient with myelodysplastic syndrome transforming to acute myelocytic leukemia.

    Science.gov (United States)

    Ganly, Peter; McDonald, Margaret; Spearing, Ruth; Morris, Christine M

    2004-03-01

    We report the case of a 61-year-old woman who presented with a myelodysplastic syndrome (MDS) and a t(5;7)(q11.2;p15) in her bone marrow cells. Subsequent analysis of phytohemagglutinin-stimulated peripheral blood lymphocytes and cultured skin fibroblasts showed that the translocation was constitutional. Disruption of chromosome bands 5q11.2 and 7p15 has been described recurrently in MDS and acute myelocytic leukemia (AML) and, although the age of onset was not earlier than usual, it is nonetheless possible that genes interrupted by this translocation may been a predisposing factor for her condition. With progression to AML, a further rearrangement of the constitutional der(7)t(5;7) occurred, involving chromosome arm 1q. Fluorescence in situ hybridization (FISH) with whole-chromosome paints showed that the result of the second rearrangement, a t(1;7)(q32.1;q32), was observed, leading to trisomy of the segment 1q32.1 approximately qter and monosomy of the segment 7q32.1 approximately qter. The acquired imbalances, particularly loss of 7q, are commonly associated with MDS/AML and a poor prognosis; however, this patient remained in remission after treatment for more than two years before AML relapse, perhaps because the affected regions fall outside of the critical regions of imbalance.

  5. Cytogenetic abnormalities in a series of 1,029 patients with primary myelodysplastic syndromes: a report from the US with a focus on some undefined single chromosomal abnormalities.

    Science.gov (United States)

    Pozdnyakova, Olga; Miron, Patricia M; Tang, Guilin; Walter, Otto; Raza, Azra; Woda, Bruce; Wang, Sa A

    2008-12-15

    Conventional karyotype has an established role in myelodysplastic syndrome (MDS) and is included in the International Prognostic Scoring System (IPSS) for patient risk stratification and treatment selection. Although some chromosomal abnormalities have been well characterized, the significance of several miscellaneous, infrequent, single chromosomal abnormalities remains to be defined. In addition, the emerging therapeutic agents may change the natural course of disease in patients with MDS and the cytogenetic impact on risk stratification. Clinicopathologic data were retrieved on 1029 patients who had a diagnosis of primary MDS and had available cytogenetic data (karyotype) on file. Cytogenetic abnormalities were identified in 458 patients (45%) and occurred most frequently in patients who had refractory anemia with excess blasts (62%). Overall, the 3 cytogenetic risk groups defined by the IPSS -- good, intermediate, and poor -- effectively stratified the patients' overall survival (OS) (64 months, 31 months, and 12 months, respectively; P < .001). With the exception of gain of chromosome 8, single cytogenetic abnormalities within the intermediate group were extremely infrequent in the series but demonstrated variable OS ranging from 10 months for patients who had isochromosome (17q) to 69 months for patients who had deletion of 12p [del(12p)], suggesting different prognostic significance. In the poor cytogenetic risk group, patients with isolated del(7q) and derivative (1;7)(q10;p10) had a significantly better median OS than patients who had either loss of chromosome 7 or a complex karyotype (P < .05). The current data generated from a large cohort of patients with primary MDS indicated that some specific cytogenetic abnormalities carry different risk than their IPSS cytogenetic risk-group assignment, especially in the new treatment era. Because of the extreme low frequency, additional combined studies are needed to better categorize some rare single cytogenetic

  6. Deuterium-depleted water. Romanian achievements and perspective

    International Nuclear Information System (INIS)

    Stefanescu, Ion; Saros-Rogobete, Irina; Titescu, Gheorghe

    2001-01-01

    Deuterium-depleted water has an isotopic content smaller than 145 ppm D/(D+H) which is the natural isotopic content of water. Beginning with 1996 ICSI Rm. Valcea, deuterium-depleted water producer, co-operated with Romanian specialized institutes for biological effect's evaluation of deuterium-depleted water. These investigations lead to the following conclusions: - Deuterium-depleted water caused a tendency towards the increase of the basal tonus, accompanied by the intensification of the vasoconstrictor effects of phenylefrine, noradrenaline and angiotensin; the increase of the basal tonus and vascular reactivity produced by the deuterium-depleted water persist after the removal of the vascular endothelium; - Animals treated with deuterium-depleted water showed an increase of the resistance both to sublethal and to lethal gamma radiation doses, suggesting a radioprotective action; - Deuterium-depleted water stimulates immune defence reactions and increases the numbers of polymorphonuclear neutrophils; - Investigations regarding artificial reproduction of fish with deuterium-depleted water fecundated solutions confirmed favourable influence in embryo growth stage and resistance in subsequent growth stages; - It was studied germination, growth and quantitative character's variability in plants; one can remark the favourable influence of deuterium-depleted water on biological process in plants in various ontogenetic stages; - The deuterium depletion in seawater produces the diminution of the water spectral energy related to an increased metabolism of Tetraselmis Suecica. (authors)

  7. Depletion of white adipose tissue in cancer cachexia syndrome is associated with inflammatory signaling and disrupted circadian regulation.

    Directory of Open Access Journals (Sweden)

    Maria Tsoli

    Full Text Available Involuntary weight loss in patients with cancer is the hallmark of cancer cachexia. The etiology of cachexia is multifactorial involving loss of skeletal muscle and adipose tissue associated with high systemic levels of acute phase proteins and inflammatory cytokines. While muscle wasting overtly impacts on cancer patient quality of life, loss of lipid depots represents a sustained energy imbalance. In this study fat depletion was examined in Colon-26 model of cancer cachexia, which is a widely used rodent model of this syndrome. We investigated diurnal expression of circadian rhythm regulators as well as key mediators of energy metabolism and cytokine signaling. Mice bearing the C26 tumour exhibited reduced adipose mass, elevated adipose tissue lipolysis and a 5-fold increase in plasma levels of free fatty acids. These changes were associated with activated IL-6 signaling in WAT through a 3-fold increase in phosphorylated STAT3 and high SOCS3 gene expression levels. In addition perturbations in circadian regulation of lipid metabolism were also observed. Lipid catabolism did not appear to be influenced by the classical PKA pathway activating the lipase HSL. ATGL protein levels were elevated 2-fold in cachectic mice while 4-fold increase phosphorylated ACC and a 2-fold decrease in phosphorylated 4EBP1 was observed indicating that lipid metabolism is modulated by the ATGL & AMPK/mTOR pathways. This study provides evidence for activation of cytokine signaling and concomitant alterations in circadian rhythm and regulators of lipid metabolism in WAT of cachectic animals.

  8. Donation intensity and metabolic syndrome in active whole-blood donors

    NARCIS (Netherlands)

    Peffer, K.; Verbeek, A.L.M.; Swinkels, D.W.; Geurts-Moespot, A.J.; den Heijer, M.; Atsma, F.

    2015-01-01

    Background and Objectives: Increased iron and metabolic syndrome (MetS) go hand in hand. Frequent blood donation depletes iron stores. This study investigates whether high-intensity blood donation is associated with lower MetS prevalence compared with low-intensity blood donation, and whether iron

  9. Iron overload in lower international prognostic scoring system risk patients with myelodysplastic syndrome receiving red blood cell transfusions: Relation to infections and possible benefit of iron chelation therapy.

    Science.gov (United States)

    Wong, Colleen A C; Wong, Shannon A Y; Leitch, Heather A

    2018-04-01

    An increased incidence of infections and infectious mortality has been reported in myelodysplastic syndromes (MDS) patients receiving red blood cell (RBC) transfusions. We examined incidence of infections requiring antibiotics, antifungal or antiviral medications in transfused lower International Prognostic Scoring System (IPSS) risk MDS patients and whether this differed with iron chelation therapy (ICT). 138 transfused MDS patients were lower IPSS risk. 59 received ICT; median duration was 13 months. There was no significant difference between groups in neutrophil count at first RBC transfusion or first infection. Infections included: bacterial, n = 88; viral; fungal; and mycobacterial; n = 2 each. In ICT and non-ICT patients, respectively, infections were (number [%]): patients, 23 (40.0%) and 22 (27.8%); episodes (median [range]), 2 (1-6) and 2 (1-5); hospitalizations, 16 (27.1%) and 8 (10.1%); and deaths, 0 (0%) and 1 (1.3%), p = NS for all. Median overall survival (OS) from first RBC transfusion was superior in ICT patients, p = 0.01, and remained significant in a multivariate analysis (MVA), p = 0.003. Median time to first infection (TTI) was 27 and 7.8 months, respectively, p < 0.0001, and ICT remained significant for TTI in an MVA, p = 0.02, hazard ratio 0.3. For ICT patients with blast count <5%, TTI was significantly superior (p = 0.004). In this retrospective analysis, for lower IPSS risk MDS patients receiving RBC transfusions, though number and type of infections were similar between groups and despite similar neutrophil counts, time to first infection was significantly longer in ICT patients (p < 0.0001). These results should be confirmed in larger, prospective analyses. Copyright © 2018 Elsevier Ltd. All rights reserved.

  10. Statistical implications in Monte Carlo depletions - 051

    International Nuclear Information System (INIS)

    Zhiwen, Xu; Rhodes, J.; Smith, K.

    2010-01-01

    As a result of steady advances of computer power, continuous-energy Monte Carlo depletion analysis is attracting considerable attention for reactor burnup calculations. The typical Monte Carlo analysis is set up as a combination of a Monte Carlo neutron transport solver and a fuel burnup solver. Note that the burnup solver is a deterministic module. The statistical errors in Monte Carlo solutions are introduced into nuclide number densities and propagated along fuel burnup. This paper is towards the understanding of the statistical implications in Monte Carlo depletions, including both statistical bias and statistical variations in depleted fuel number densities. The deterministic Studsvik lattice physics code, CASMO-5, is modified to model the Monte Carlo depletion. The statistical bias in depleted number densities is found to be negligible compared to its statistical variations, which, in turn, demonstrates the correctness of the Monte Carlo depletion method. Meanwhile, the statistical variation in number densities generally increases with burnup. Several possible ways of reducing the statistical errors are discussed: 1) to increase the number of individual Monte Carlo histories; 2) to increase the number of time steps; 3) to run additional independent Monte Carlo depletion cases. Finally, a new Monte Carlo depletion methodology, called the batch depletion method, is proposed, which consists of performing a set of independent Monte Carlo depletions and is thus capable of estimating the overall statistical errors including both the local statistical error and the propagated statistical error. (authors)

  11. To change or not to change - translating and culturally adapting the paediatric version of the Moral Distress Scale-Revised (MDS-R).

    Science.gov (United States)

    Af Sandeberg, Margareta; Wenemark, Marika; Bartholdson, Cecilia; Lützén, Kim; Pergert, Pernilla

    2017-02-20

    Paediatric cancer care poses ethically difficult situations that can lead to value conflicts about what is best for the child, possibly resulting in moral distress. Research on moral distress is lacking in paediatric cancer care in Sweden and most questionnaires are developed in English. The Moral Distress Scale-Revised (MDS-R) is a questionnaire that measures moral distress in specific situations; respondents are asked to indicate both the frequency and the level of disturbance when the situation arises. The aims of this study were to translate and culturally adapt the questionnaire to the context of Swedish paediatric cancer care. In doing so we endeavoured to keep the content in the Swedish version as equivalent to the original as possible but to introduce modifications that improve the functional level and increase respondent satisfaction. The procedure included linguistic translation and cultural adaptation of MDS-R's paediatric versions for Physicians, Nurses and Other Healthcare Providers to the context of Swedish paediatric cancer care. The process of adjustment included: preparation, translation procedure and respondent validation. The latter included focus group and cognitive interviews with healthcare professionals in paediatric cancer care. To achieve a Swedish version with a good functional level and high trustworthiness, some adjustments were made concerning design, language, cultural matters and content. Cognitive interviews revealed problems with stating the level of disturbance hypothetically and items with negations caused even more problems, after having stated that the situation never happens. Translation and cultural adaptation require the involvement of various types of specialist. It is difficult to combine the intention to keep the content as equivalent to the original as possible with the need for modifications that improve the functional level and increase respondent satisfaction. The translated and culturally adapted Swedish MDS-R seems

  12. Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease.

    Science.gov (United States)

    Berg, Daniela; Postuma, Ronald B; Bloem, Bastiaan; Chan, Piu; Dubois, Bruno; Gasser, Thomas; Goetz, Christopher G; Halliday, Glenda M; Hardy, John; Lang, Anthony E; Litvan, Irene; Marek, Kenneth; Obeso, José; Oertel, Wolfgang; Olanow, C Warren; Poewe, Werner; Stern, Matthew; Deuschl, Günther

    2014-04-01

    With advances in knowledge disease, boundaries may change. Occasionally, these changes are of such a magnitude that they require redefinition of the disease. In recognition of the profound changes in our understanding of Parkinson's disease (PD), the International Parkinson and Movement Disorders Society (MDS) commissioned a task force to consider a redefinition of PD. This review is a discussion article, intended as the introductory statement of the task force. Several critical issues were identified that challenge current PD definitions. First, new findings challenge the central role of the classical pathologic criteria as the arbiter of diagnosis, notably genetic cases without synuclein deposition, the high prevalence of incidental Lewy body (LB) deposition, and the nonmotor prodrome of PD. It remains unclear, however, whether these challenges merit a change in the pathologic gold standard, especially considering the limitations of alternate gold standards. Second, the increasing recognition of dementia in PD challenges the distinction between diffuse LB disease and PD. Consideration might be given to removing dementia as an exclusion criterion for PD diagnosis. Third, there is increasing recognition of disease heterogeneity, suggesting that PD subtypes should be formally identified; however, current subtype classifications may not be sufficiently robust to warrant formal delineation. Fourth, the recognition of a nonmotor prodrome of PD requires that new diagnostic criteria for early-stage and prodromal PD should be created; here, essential features of these criteria are proposed. Finally, there is a need to create new MDS diagnostic criteria that take these changes in disease definition into consideration. © 2014 International Parkinson and Movement Disorder Society.

  13. Depletion of CD4+ T cells precipitates immunopathology in immunodeficient mice infected with a noncytocidal virus

    DEFF Research Database (Denmark)

    Christensen, Jan Pravsgaard; Bartholdy, C; Wodarz, D

    2001-01-01

    investigated whether CD4(+) Th cells are required to establish and maintain this new equilibrium. The absence of IFN-gamma does not impair the generation of IL-2-producing CD4(+) cells, and depletion of these cells precipitates severe CD8(+) T cell-mediated immunopathology in IFN-gamma(-/-) mice, indicating...... an important role of CD4(+) T cells in preventing this syndrome. Analysis of organ virus levels revealed a further impairment of virus control in IFN-gamma(-/-) mice following CD4(+) cell depletion. Initially the antiviral CTL response did not require CD4(+) cells, but with time an impaired reactivity toward...... especially the glycoprotein 33--41 epitope was noted. Enumeration of epitope-specific (glycoprotein 33--41 and nucleoprotein 396--404) CD8(+) T cells by use of tetramers gave similar results. Finally, limiting dilution analysis of CTL precursors reveal an impaired capacity to sustain this population in CD4...

  14. Depletion of elements in shock-driven gas

    International Nuclear Information System (INIS)

    Gondhalekar, P.M.

    1985-01-01

    The depletion of elements in shocked gas in supernova remnants and in interstellar bubbles is examined. It is shown that elements are depleted in varying degrees in gas filaments shocked to velocities up to 200 km s -1 and that large differences in depletions are observed in gas filaments shocked to similar velocities. In the shocked gas the depletion of an element appears to be correlated with the electron density (or the neutral gas density) in the filaments. This correlation, if confirmed, is similar to the correlation between depletion and mean density of gas in the clouds in interstellar space. (author)

  15. Dynamic MRI of the lumbar spine for the evaluation of microcirculation during anti-angiogenetic therapy in patients with myelodysplastics syndromes

    International Nuclear Information System (INIS)

    Scherer, A.; Wittsack; Strupp, C.; Engelbrecht, V.

    2002-01-01

    Material and Methods: In 20 healthy normal persons and 28 MDS patients a dynamic contrast-enhanced MRI (d-MRI) of the lumbar spine was performed. After the initial d-MRI-investigation 24 of the 28 MDS patients received an antiangiogenetic therapy with thalidomide. With an average of 4.2 months after the beginning of therapy a d-MRI-follow-up examination in 9 of these patients was performed. The amplitude and exchange-rate constant were calculated and a statistical comparison of these values between healthy persons and MDS patients as well as a correlation with the clinical course was executed. Results: Compared with the normal controls the MDS patients showed a higher amplitude (normal persons: 14.4±5.2, MDS: 24.8±8.1) and exchange-rate constant (normal persons: 0.124±0.042, MDS: 0.136±0.036). In 7 of 9 MDS patients undergoing thalidomide therapy a reduction of the amplitude and exchange rate constant values was evident in the d-MRI follow-up examinations. Clinically these patients showed a therapy response with complete or partial disease remission. (orig.) [de

  16. Depleted uranium: A DOE management guide

    International Nuclear Information System (INIS)

    1995-10-01

    The U.S. Department of Energy (DOE) has a management challenge and financial liability in the form of 50,000 cylinders containing 555,000 metric tons of depleted uranium hexafluoride (UF 6 ) that are stored at the gaseous diffusion plants. The annual storage and maintenance cost is approximately $10 million. This report summarizes several studies undertaken by the DOE Office of Technology Development (OTD) to evaluate options for long-term depleted uranium management. Based on studies conducted to date, the most likely use of the depleted uranium is for shielding of spent nuclear fuel (SNF) or vitrified high-level waste (HLW) containers. The alternative to finding a use for the depleted uranium is disposal as a radioactive waste. Estimated disposal costs, utilizing existing technologies, range between $3.8 and $11.3 billion, depending on factors such as applicability of the Resource Conservation and Recovery Act (RCRA) and the location of the disposal site. The cost of recycling the depleted uranium in a concrete based shielding in SNF/HLW containers, although substantial, is comparable to or less than the cost of disposal. Consequently, the case can be made that if DOE invests in developing depleted uranium shielded containers instead of disposal, a long-term solution to the UF 6 problem is attained at comparable or lower cost than disposal as a waste. Two concepts for depleted uranium storage casks were considered in these studies. The first is based on standard fabrication concepts previously developed for depleted uranium metal. The second converts the UF 6 to an oxide aggregate that is used in concrete to make dry storage casks

  17. Thymidine kinase 2 enzyme kinetics elucidate the mechanism of thymidine-induced mitochondrial DNA depletion.

    Science.gov (United States)

    Sun, Ren; Wang, Liya

    2014-10-07

    Mitochondrial thymidine kinase 2 (TK2) is a nuclear gene-encoded protein, synthesized in the cytosol and subsequently translocated into the mitochondrial matrix, where it catalyzes the phosphorylation of thymidine (dT) and deoxycytidine (dC). The kinetics of dT phosphorylation exhibits negative cooperativity, but dC phosphorylation follows hyperbolic Michaelis-Menten kinetics. The two substrates compete with each other in that dT is a competitive inhibitor of dC phosphorylation, while dC acts as a noncompetitive inhibitor of dT phosphorylation. In addition, TK2 is feedback inhibited by dTTP and dCTP. TK2 also phosphorylates a number of pyrimidine nucleoside analogues used in antiviral and anticancer therapy and thus plays an important role in mitochondrial toxicities caused by nucleoside analogues. Deficiency in TK2 activity due to genetic alterations causes devastating mitochondrial diseases, which are characterized by mitochondrial DNA (mtDNA) depletion or multiple deletions in the affected tissues. Severe TK2 deficiency is associated with early-onset fatal mitochondrial DNA depletion syndrome, while less severe deficiencies result in late-onset phenotypes. In this review, studies of the enzyme kinetic behavior of TK2 enzyme variants are used to explain the mechanism of mtDNA depletion caused by TK2 mutations, thymidine overload due to thymidine phosphorylase deficiency, and mitochondrial toxicity caused by antiviral thymidine analogues.

  18. The value of rituximab treatment in primary Sjögren's syndrome

    NARCIS (Netherlands)

    Verstappen, Gwenny M.; van Nimwegen, Jolien F.; Vissink, Arjan; Kroese, Frans G. M.; Bootsma, Hendrika

    The rationale for B cell depletion therapy with rituximab in primary Sjogren's syndrome relies upon the well-established role of B cell hyperactivity in immunopathogenesis. In line with this notion, several biomarkers of B cell activity are significantly affected by treatment, both in the target

  19. Are relative depletions altered inside diffuse clouds?

    International Nuclear Information System (INIS)

    Joseph, C.L.

    1988-01-01

    The data of Jenkins, Savage, and Spitzer (1986) were used to analyze interstellar abundances and depletions of Fe, P, Mg, and Mn toward 37 stars, spanning nearly 1.0 (dex) in mean line-of-sight depletion. It was found that the depletions of these elements are linearly correlated and do not show evidence of differences in the rates of depletion or sputtering from one element to another. For a given level of overall depletion, the sightline-to-sightline rms variance in the depletion for each of these elements was less than 0.16 (dex), which is significantly smaller than is the element-to-element variance. The results suggest that, for most diffuse lines of sight, the relative abundances of these elements are set early in the lifetime of the grains and are not altered significantly thereafter. 53 references

  20. Uncovering Clinical Features of De Novo Philadelphia Positive Myelodysplasia.

    Science.gov (United States)

    Armas, Aristides; Chen, Chen; Mims, Martha; Rivero, Gustavo

    2017-01-01

    Myelodysplastic syndrome (MDS) is cytogenetically heterogeneous and retains variable risk for acute myeloid leukemia transformation. Though not yet fully understood, there is an association between genetic abnormalities and defects in gene expression. The functional role for infrequent cytogenetic alteration remains unclear. An uncommon chromosomic abnormality is the presence of the Philadelphia (Ph) chromosome. Here, we report a patient with Ph+ MDS treated with low dose Dasatinib who achieved hematologic response for 7 months. In addition, we also examined the English literature on all de novo Ph + MDS cases between 1996 and 2015 to gain insight into clinical features and outcome.

  1. Azacitidine front-line in 339 patients with myelodysplastic syndromes and acute myeloid leukaemia: comparison of French-American-British and World Health Organization classifications

    Directory of Open Access Journals (Sweden)

    Lisa Pleyer

    2016-04-01

    Full Text Available Abstract Background The MDS-IWG and NCCN currently endorse both FAB and WHO classifications of MDS and AML, thus allowing patients with 20–30 % bone marrow blasts (AML20–30, formerly MDS-RAEB-t to be categorised and treated as either MDS or AML. In addition, an artificial distinction between AML20–30 and AML30+ was made by regulatory agencies by initially restricting approval of azacitidine to AML20–30. Thus, uncertainty prevails regarding the diagnosis, prognosis and optimal treatment timing and strategy for patients with AML20–30. Here, we aim to provide clarification for patients treated with azacitidine front-line. Methods The Austrian Azacitidine Registry is a multicentre database (ClinicalTrials.gov: NCT01595295. For this analysis, we selected 339 patients treated with azacitidine front-line. According to the WHO classification 53, 96 and 190 patients had MDS-RAEB-I, MDS-RAEB-II and AML (AML20–30: n = 79; AML30+: n = 111, respectively. According to the FAB classification, 131, 101 and 111 patients had MDS-RAEB, MDS-RAEB-t and AML, respectively. Results The median ages of patients with MDS and AML were 72 (range 37–87 and 77 (range 23–93 years, respectively. Overall, 80 % of classifiable patients (≤30 % bone marrow blasts had intermediate-2 or high-risk IPSS scores. Most other baseline, treatment and response characteristics were similar between patients diagnosed with MDS or AML. WHO-classified patients with AML20–30 had significantly worse OS than patients with MDS-RAEB-II (13.1 vs 18.9 months; p = 0.010, but similar OS to patients with AML30+ (10.9 vs 13.1 months; p = 0.238. AML patients that showed MDS-related features did not have worse outcomes compared with patients who did not (13.2 vs 8.9 months; p = 0.104. FAB-classified patients with MDS-RAEB-t had similar survival to patients with AML30+ (12.8 vs 10.9 months; p = 0.376, but significantly worse OS than patients with MDS-RAEB (10

  2. Interstellar depletion anomalies and ionization potentials

    International Nuclear Information System (INIS)

    Tabak, R.G.

    1979-01-01

    Satellite observations indicate that (1) most elements are depleted from the gas phase when compared to cosmic abundances, (2) some elements are several orders of magnitude more depleted than others, and (3) these depletions vary from cloud to cloud. Since the most likely possibility is that the 'missing' atoms are locked into grains, depletions occur either by accretion onto core particles in interstellar clouds or earlier, during the period of primary grain formation. If the latter mechanism is dominant, then the most important depletion parameter is the condensation temperature of the elements and their various compounds. However, this alone is not sufficient to explain all the observed anomalies. It is shown that electrostatic effects - under a wide variety of conditions- can enormously enhance the capture cross-section of the grain. It is suggested that this mechanism can also account for such anomalies as the apparent 'overabundance' of the alkali metals in the gas phase. (orig.)

  3. An International MDS/MPN Working Group’s perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms

    Science.gov (United States)

    Mughal, Tariq I.; Cross, Nicholas C.P.; Padron, Eric; Tiu, Ramon V.; Savona, Michael; Malcovati, Luca; Tibes, Raoul; Komrokji, Rami S.; Kiladjian, Jean-Jacques; Garcia-Manero, Guillermo; Orazi, Attilio; Mesa, Ruben; Maciejewski, Jaroslaw P.; Fenaux, Pierre; Itzykson, Raphael; Mufti, Ghulam; Solary, Eric; List, Alan F.

    2015-01-01

    In the 2008 WHO classification, chronic myeloid malignancies that share both myelodysplastic and myeloproliferative features define the myelodysplastic/myeloproliferative group, which includes chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia, refractory anemia with ring sideroblasts and thrombocytosis, and myelodysplastic/myeloproliferative unclassified. With the notable exception of refractory anemia with ring sideroblasts and thrombocytosis, there is much overlap among the various subtypes at the molecular and clinical levels, and a better definition of these entities, an understanding of their biology and an identification of subtype-specific molecular or cellular markers are needed. To address some of these challenges, a panel comprised of laboratory and clinical experts in myelodysplastic/myeloproliferative was established, and four independent academic MDS/MPN workshops were held on: 9th March 2013, in Miami, Florida, USA; 6th December 2013, in New Orleans, Louisiana, USA; 13th June 2014 in Milan, Italy; and 5th December 2014 in San Francisco, USA. During these meetings, the current understanding of these malignancies and matters of biology, diagnosis and management were discussed. This perspective and the recommendations on molecular pathogenesis, diagnosis and clinical characterization for adult onset myelodysplastic/myeloproliferative is the result of a collaborative project endorsed and supported by the MDS Foundation. PMID:26341525

  4. The Chemistry and Toxicology of Depleted Uranium

    Directory of Open Access Journals (Sweden)

    Sidney A. Katz

    2014-03-01

    Full Text Available Natural uranium is comprised of three radioactive isotopes: 238U, 235U, and 234U. Depleted uranium (DU is a byproduct of the processes for the enrichment of the naturally occurring 235U isotope. The world wide stock pile contains some 1½ million tons of depleted uranium. Some of it has been used to dilute weapons grade uranium (~90% 235U down to reactor grade uranium (~5% 235U, and some of it has been used for heavy tank armor and for the fabrication of armor-piercing bullets and missiles. Such weapons were used by the military in the Persian Gulf, the Balkans and elsewhere. The testing of depleted uranium weapons and their use in combat has resulted in environmental contamination and human exposure. Although the chemical and the toxicological behaviors of depleted uranium are essentially the same as those of natural uranium, the respective chemical forms and isotopic compositions in which they usually occur are different. The chemical and radiological toxicity of depleted uranium can injure biological systems. Normal functioning of the kidney, liver, lung, and heart can be adversely affected by depleted uranium intoxication. The focus of this review is on the chemical and toxicological properties of depleted and natural uranium and some of the possible consequences from long term, low dose exposure to depleted uranium in the environment.

  5. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study.

    Directory of Open Access Journals (Sweden)

    Øystein Fluge

    Full Text Available Chronic fatigue syndrome (CFS is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients.In this double-blind, placebo-controlled phase II study (NCT00848692, 30 CFS patients were randomised to either Rituximab 500 mg/m(2 or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV was not detected in any of the patients. The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67% in the Rituximab group and in two out of 15 patients (13% in the Placebo group (p = 0.003. Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8-44. Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed, with differences between the Rituximab and Placebo groups between 6-10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening.The delayed responses starting from 2-7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact

  6. Time-on-task effects in children with and without ADHD: depletion of executive resources or depletion of motivation?

    Science.gov (United States)

    Dekkers, Tycho J; Agelink van Rentergem, Joost A; Koole, Alette; van den Wildenberg, Wery P M; Popma, Arne; Bexkens, Anika; Stoffelsen, Reino; Diekmann, Anouk; Huizenga, Hilde M

    2017-12-01

    Children with attention-deficit/hyperactivity disorder (ADHD) are characterized by deficits in their executive functioning and motivation. In addition, these children are characterized by a decline in performance as time-on-task increases (i.e., time-on-task effects). However, it is unknown whether these time-on-task effects should be attributed to deficits in executive functioning or to deficits in motivation. Some studies in typically developing (TD) adults indicated that time-on-task effects should be interpreted as depletion of executive resources, but other studies suggested that they represent depletion of motivation. We, therefore, investigated, in children with and without ADHD, whether there were time-on-task effects on executive functions, such as inhibition and (in)attention, and whether these were best explained by depletion of executive resources or depletion of motivation. The stop-signal task (SST), which generates both indices of inhibition (stop-signal reaction time) and attention (reaction time variability and errors), was administered in 96 children (42 ADHD, 54 TD controls; aged 9-13). To differentiate between depletion of resources and depletion of motivation, the SST was administered twice. Half of the participants was reinforced during second task performance, potentially counteracting depletion of motivation. Multilevel analyses indicated that children with ADHD were more affected by time-on-task than controls on two measures of inattention, but not on inhibition. In the ADHD group, reinforcement only improved performance on one index of attention (i.e., reaction time variability). The current findings suggest that time-on-task effects in children with ADHD occur specifically in the attentional domain, and seem to originate in both depletion of executive resources and depletion of motivation. Clinical implications for diagnostics, psycho-education, and intervention are discussed.

  7. Fanconi syndrome due to prolonged use of low-dose adefovir

    Directory of Open Access Journals (Sweden)

    Xiao-Bing Wang

    2015-01-01

    Full Text Available Fanconi syndrome results from a generalized abnormality of the proximal tubules of the kidney and owing to phosphate depletion can cause hypophosphatemic osteomalacia. Adefovir dipivoxyl (ADV effectively suppresses hepatitis B virus replication but exhibits nephrotoxicity when administered at a low dosage. We report two cases of Fanconi syndrome induced by ADV at 10 mg/day to call for regular screening for evidence of proximal tubular dysfunction and detailed bone metabolic investigations for prompt detection of ADV nephrotoxicity is critically important to ensure timely drug withdrawal before the development of irreversible tubulointerstitial injury.

  8. Inspecting Targeted Deep Sequencing of Whole Genome Amplified DNA Versus Fresh DNA for Somatic Mutation Detection: A Genetic Study in Myelodysplastic Syndrome Patients.

    Science.gov (United States)

    Palomo, Laura; Fuster-Tormo, Francisco; Alvira, Daniel; Ademà, Vera; Armengol, María Pilar; Gómez-Marzo, Paula; de Haro, Nuri; Mallo, Mar; Xicoy, Blanca; Zamora, Lurdes; Solé, Francesc

    2017-08-01

    Whole genome amplification (WGA) has become an invaluable method for preserving limited samples of precious stock material and has been used during the past years as an alternative tool to increase the amount of DNA before library preparation for next-generation sequencing. Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell disorders characterized by presenting somatic mutations in several myeloid-related genes. In this work, targeted deep sequencing has been performed on four paired fresh DNA and WGA DNA samples from bone marrow of MDS patients, to assess the feasibility of using WGA DNA for detecting somatic mutations. The results of this study highlighted that, in general, the sequencing and alignment statistics of fresh DNA and WGA DNA samples were similar. However, after variant calling and when considering variants detected at all frequencies, there was a high level of discordance between fresh DNA and WGA DNA (overall, a higher number of variants was detected in WGA DNA). After proper filtering, a total of three somatic mutations were detected in the cohort. All somatic mutations detected in fresh DNA were also identified in WGA DNA and validated by whole exome sequencing.

  9. Specification for the VERA Depletion Benchmark Suite

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kang Seog [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2015-12-17

    CASL-X-2015-1014-000 iii Consortium for Advanced Simulation of LWRs EXECUTIVE SUMMARY The CASL neutronics simulator MPACT is under development for the neutronics and T-H coupled simulation for the pressurized water reactor. MPACT includes the ORIGEN-API and internal depletion module to perform depletion calculations based upon neutron-material reaction and radioactive decay. It is a challenge to validate the depletion capability because of the insufficient measured data. One of the detoured methods to validate it is to perform a code-to-code comparison for benchmark problems. In this study a depletion benchmark suite has been developed and a detailed guideline has been provided to obtain meaningful computational outcomes which can be used in the validation of the MPACT depletion capability.

  10. Development of the point-depletion code DEPTH

    International Nuclear Information System (INIS)

    She, Ding; Wang, Kan; Yu, Ganglin

    2013-01-01

    Highlights: ► The DEPTH code has been developed for the large-scale depletion system. ► DEPTH uses the data library which is convenient to couple with MC codes. ► TTA and matrix exponential methods are implemented and compared. ► DEPTH is able to calculate integral quantities based on the matrix inverse. ► Code-to-code comparisons prove the accuracy and efficiency of DEPTH. -- Abstract: The burnup analysis is an important aspect in reactor physics, which is generally done by coupling of transport calculations and point-depletion calculations. DEPTH is a newly-developed point-depletion code of handling large burnup depletion systems and detailed depletion chains. For better coupling with Monte Carlo transport codes, DEPTH uses data libraries based on the combination of ORIGEN-2 and ORIGEN-S and allows users to assign problem-dependent libraries for each depletion step. DEPTH implements various algorithms of treating the stiff depletion systems, including the Transmutation trajectory analysis (TTA), the Chebyshev Rational Approximation Method (CRAM), the Quadrature-based Rational Approximation Method (QRAM) and the Laguerre Polynomial Approximation Method (LPAM). Three different modes are supported by DEPTH to execute the decay, constant flux and constant power calculations. In addition to obtaining the instantaneous quantities of the radioactivity, decay heats and reaction rates, DEPTH is able to calculate the integral quantities by a time-integrated solver. Through calculations compared with ORIGEN-2, the validity of DEPTH in point-depletion calculations is proved. The accuracy and efficiency of depletion algorithms are also discussed. In addition, an actual pin-cell burnup case is calculated to illustrate the DEPTH code performance in coupling with the RMC Monte Carlo code

  11. Erythrocyte depletion from bone marrow: performance evaluation after 50 clinical-scale depletions with Spectra Optia BMC.

    Science.gov (United States)

    Kim-Wanner, Soo-Zin; Bug, Gesine; Steinmann, Juliane; Ajib, Salem; Sorg, Nadine; Poppe, Carolin; Bunos, Milica; Wingenfeld, Eva; Hümmer, Christiane; Luxembourg, Beate; Seifried, Erhard; Bonig, Halvard

    2017-08-11

    Red blood cell (RBC) depletion is a standard graft manipulation technique for ABO-incompatible bone marrow (BM) transplants. The BM processing module for Spectra Optia, "BMC", was previously introduced. We here report the largest series to date of routine quality data after performing 50 clinical-scale RBC-depletions. Fifty successive RBC-depletions from autologous (n = 5) and allogeneic (n = 45) BM transplants were performed with the Spectra Optia BMC apheresis suite. Product quality was assessed before and after processing for volume, RBC and leukocyte content; RBC-depletion and stem cell (CD34+ cells) recovery was calculated there from. Clinical engraftment data were collected from 26/45 allogeneic recipients. Median RBC removal was 98.2% (range 90.8-99.1%), median CD34+ cell recovery was 93.6%, minimum recovery being 72%, total product volume was reduced to 7.5% (range 4.7-23.0%). Products engrafted with expected probability and kinetics. Performance indicators were stable over time. Spectra Optia BMC is a robust and efficient technology for RBC-depletion and volume reduction of BM, providing near-complete RBC removal and excellent CD34+ cell recovery.

  12. Tryptophan depletion affects compulsive behaviour in rats

    DEFF Research Database (Denmark)

    Merchán, A; Navarro, S V; Klein, A B

    2017-01-01

    investigated whether 5-HT manipulation, through a tryptophan (TRP) depletion by diet in Wistar and Lister Hooded rats, modulates compulsive drinking in schedule-induced polydipsia (SIP) and locomotor activity in the open-field test. The levels of dopamine, noradrenaline, serotonin and its metabolite were......-depleted HD Wistar rats, while the LD Wistar and the Lister Hooded rats did not exhibit differences in SIP. In contrast, the TRP-depleted Lister Hooded rats increased locomotor activity compared to the non-depleted rats, while no differences were found in the Wistar rats. Serotonin 2A receptor binding...

  13. Nuances of Morphology in Myelodysplastic Diseases in the Age of Molecular Diagnostics.

    Science.gov (United States)

    Shaver, Aaron C; Seegmiller, Adam C

    2017-10-01

    Morphologic dysplasia is an important factor in diagnosis of myelodysplastic syndrome (MDS). However, the role of dysplasia is changing as new molecular genetic and genomic technologies take a more prominent place in diagnosis. This review discusses the role of morphology in the diagnosis of MDS and its interactions with cytogenetic and molecular testing. Recent changes in diagnostic criteria have attempted to standardize approaches to morphologic diagnosis of MDS, recognizing significant inter-observer variability in assessment of dysplasia. Definitive correlates between cytogenetic/molecular and morphologic findings have been described in only a small set of cases. However, these genetic and morphologic tools do play a complementary role in the diagnosis of both MDS and other myeloid neoplasms. Diagnosis of MDS requires a multi-factorial approach, utilizing both traditional morphologic as well as newer molecular genetic techniques. Understanding these tools, and the interplay between them, is crucial in the modern diagnosis of myeloid neoplasms.

  14. Revisiting Antarctic Ozone Depletion

    Science.gov (United States)

    Grooß, Jens-Uwe; Tritscher, Ines; Müller, Rolf

    2015-04-01

    Antarctic ozone depletion is known for almost three decades and it has been well settled that it is caused by chlorine catalysed ozone depletion inside the polar vortex. However, there are still some details, which need to be clarified. In particular, there is a current debate on the relative importance of liquid aerosol and crystalline NAT and ice particles for chlorine activation. Particles have a threefold impact on polar chlorine chemistry, temporary removal of HNO3 from the gas-phase (uptake), permanent removal of HNO3 from the atmosphere (denitrification), and chlorine activation through heterogeneous reactions. We have performed simulations with the Chemical Lagrangian Model of the Stratosphere (CLaMS) employing a recently developed algorithm for saturation-dependent NAT nucleation for the Antarctic winters 2011 and 2012. The simulation results are compared with different satellite observations. With the help of these simulations, we investigate the role of the different processes responsible for chlorine activation and ozone depletion. Especially the sensitivity with respect to the particle type has been investigated. If temperatures are artificially forced to only allow cold binary liquid aerosol, the simulation still shows significant chlorine activation and ozone depletion. The results of the 3-D Chemical Transport Model CLaMS simulations differ from purely Lagrangian longtime trajectory box model simulations which indicates the importance of mixing processes.

  15. Identification of a common microdeletion cluster in 7q21.3 subband among patients with myeloid leukemia and myelodysplastic syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Asou, Hiroya; Matsui, Hirotaka; Ozaki, Yuko; Nagamachi, Akiko; Nakamura, Megumi; Aki, Daisuke [Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553 (Japan); Inaba, Toshiya, E-mail: tinaba@hiroshima-u.ac.jp [Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553 (Japan)

    2009-05-29

    Monosomy 7 and interstitial deletions in the long arm of chromosome 7 (-7/7q-) is a common nonrandom chromosomal abnormality found frequently in myeloid disorders including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and juvenile myelomonocytic leukemia (JMML). Using a short probe-based microarray comparative genomic hybridization (mCGH) technology, we identified a common microdeletion cluster in 7q21.3 subband, which is adjacent to 'hot deletion region' thus far identified by conventional methods. This common microdeletion cluster contains three poorly characterized genes; Samd9, Samd9L, and a putative gene LOC253012, which we named Miki. Gene copy number assessment of three genes by real-time PCR revealed heterozygous deletion of these three genes in adult patients with AML and MDS at high frequency, in addition to JMML patients. Miki locates to mitotic spindles and centrosomes and downregulation of Miki by RNA interference induced abnormalities in mitosis and nuclear morphology, similar to myelodysplasia. In addition, a recent report indicated Samd9 as a tumor suppressor. These findings indicate the usefulness of the short probe-based CGH to detect microdeletions. The three genes located to 7q21.3 would be candidates for myeloid tumor-suppressor genes on 7q.

  16. Thymidine kinase 2 deficiency-induced mtDNA depletion in mouse liver leads to defect β-oxidation.

    Directory of Open Access Journals (Sweden)

    Xiaoshan Zhou

    Full Text Available Thymidine kinase 2 (TK2 deficiency in humans causes mitochondrial DNA (mtDNA depletion syndrome. To study the molecular mechanisms underlying the disease and search for treatment options, we previously generated and described a TK2 deficient mouse strain (TK2(-/- that progressively loses its mtDNA. The TK2(-/- mouse model displays symptoms similar to humans harboring TK2 deficient infantile fatal encephalomyopathy. Here, we have studied the TK2(-/- mouse model to clarify the pathological role of progressive mtDNA depletion in liver for the severe outcome of TK2 deficiency. We observed that a gradual depletion of mtDNA in the liver of the TK2(-/- mice was accompanied by increasingly hypertrophic mitochondria and accumulation of fat vesicles in the liver cells. The levels of cholesterol and nonesterified fatty acids were elevated and there was accumulation of long chain acylcarnitines in plasma of the TK2(-/- mice. In mice with hepatic mtDNA levels below 20%, the blood sugar and the ketone levels dropped. These mice also exhibited reduced mitochondrial β-oxidation due to decreased transport of long chain acylcarnitines into the mitochondria. The gradual loss of mtDNA in the liver of the TK2(-/- mice causes impaired mitochondrial function that leads to defect β-oxidation and, as a result, insufficient production of ketone bodies and glucose. This study provides insight into the mechanism of encephalomyopathy caused by TK2 deficiency-induced mtDNA depletion that may be used to explore novel therapeutic strategies.

  17. Thymidine kinase 2 deficiency-induced mtDNA depletion in mouse liver leads to defect β-oxidation.

    Science.gov (United States)

    Zhou, Xiaoshan; Kannisto, Kristina; Curbo, Sophie; von Döbeln, Ulrika; Hultenby, Kjell; Isetun, Sindra; Gåfvels, Mats; Karlsson, Anna

    2013-01-01

    Thymidine kinase 2 (TK2) deficiency in humans causes mitochondrial DNA (mtDNA) depletion syndrome. To study the molecular mechanisms underlying the disease and search for treatment options, we previously generated and described a TK2 deficient mouse strain (TK2(-/-)) that progressively loses its mtDNA. The TK2(-/-) mouse model displays symptoms similar to humans harboring TK2 deficient infantile fatal encephalomyopathy. Here, we have studied the TK2(-/-) mouse model to clarify the pathological role of progressive mtDNA depletion in liver for the severe outcome of TK2 deficiency. We observed that a gradual depletion of mtDNA in the liver of the TK2(-/-) mice was accompanied by increasingly hypertrophic mitochondria and accumulation of fat vesicles in the liver cells. The levels of cholesterol and nonesterified fatty acids were elevated and there was accumulation of long chain acylcarnitines in plasma of the TK2(-/-) mice. In mice with hepatic mtDNA levels below 20%, the blood sugar and the ketone levels dropped. These mice also exhibited reduced mitochondrial β-oxidation due to decreased transport of long chain acylcarnitines into the mitochondria. The gradual loss of mtDNA in the liver of the TK2(-/-) mice causes impaired mitochondrial function that leads to defect β-oxidation and, as a result, insufficient production of ketone bodies and glucose. This study provides insight into the mechanism of encephalomyopathy caused by TK2 deficiency-induced mtDNA depletion that may be used to explore novel therapeutic strategies.

  18. Successful Combination of Sequential Gene Therapy and Rescue Allo-HSCT in Two Children with X-CGD - Importance of Timing.

    Science.gov (United States)

    Siler, Ulrich; Paruzynski, Anna; Holtgreve-Grez, Heidi; Kuzmenko, Elena; Koehl, Ulrike; Renner, Eleonore D; Alhan, Canan; de Loosdrecht, Arjan A van; Schwäble, Joachim; Pfluger, Thomas; Tchinda, Joelle; Schmugge, Markus; Jauch, Anna; Naundorf, Sonja; Kühlcke, Klaus; Notheis, Gundula; Güngor, Tayfun; Kalle, Christof V; Schmidt, Manfred; Grez, Manuel; Seger, Reinhard; Reichenbach, Janine

    2015-01-01

    We report on a series of sequential events leading to long-term survival and cure of pediatric X-linked chronic granulomatous disease (X-CGD) patients after gamma-retroviral gene therapy (GT) and rescue HSCT. Due to therapyrefractory life-threatening infections requiring hematopoietic stem cell transplantation (HSCT) but absence of HLAidentical donors, we treated 2 boys with X-CGD by GT. Following GT both children completely resolved invasive Aspergillus nidulans infections. However, one child developed dual insertional activation of ecotropic viral integration site 1 (EVI1) and signal transducer and activator of transcription 3 (STAT3) genes, leading to myelodysplastic syndrome (MDS) with monosomy 7. Despite resistance to mismatched allo-HSCT with standard myeloablative conditioning, secondary intensified rescue allo-HSCT resulted in 100 % donor chimerism and disappearance of MDS. The other child did not develop MDS despite expansion of a clone with a single insertion in the myelodysplasia syndrome 1 (MDS1) gene and was cured by early standard allo-HSCT. The slowly developing dominance of clones harboring integrations in MDS1-EVI1 may guide clinical intervention strategies, i.e. early rescue allo-HSCT, prior to malignant transformation. GT was essential for both children to survive and to clear therapy-refractory infections, and future GT with safer lentiviral self-inactivated (SIN) vectors may offer a therapeutic alternative for X-CGD patients suffering from life-threatening infections and lacking HLA-identical HSC donors.

  19. An exploratory phase 2 study of investigational Aurora A kinase inhibitor alisertib (MLN8237 in acute myelogenous leukemia and myelodysplastic syndromes

    Directory of Open Access Journals (Sweden)

    Stuart L. Goldberg

    2014-01-01

    Full Text Available Alisertib (MLN8237 is an investigational, oral, selective, Aurora A kinase (AAK inhibitor. In this phase 2 trial, 57 patients with acute myeloid leukemia (AML or high-grade myelodysplastic syndrome received alisertib 50 mg BID for 7 days in 21-day cycles. Responses in 6/35 AML patients (17% response rate with an additional 49% stable disease, 34% transfusion independence included 1 complete response lasting >1 year. No responses were observed in MDS patients. Adverse events >30% included diarrhea, fatigue, nausea, febrile neutropenia, and stomatitis. Results suggest modest activity in AML, supporting further research to better understand how AAK inhibition may induce leukemic cell senescence.

  20. ANATOMY OF DEPLETED INTERPLANETARY CORONAL MASS EJECTIONS

    Energy Technology Data Exchange (ETDEWEB)

    Kocher, M.; Lepri, S. T.; Landi, E.; Zhao, L.; Manchester, W. B. IV, E-mail: mkocher@umich.edu [Department of Climate and Space Sciences and Engineering, University of Michigan, 2455 Hayward Street, Ann Arbor, MI 48109-2143 (United States)

    2017-01-10

    We report a subset of interplanetary coronal mass ejections (ICMEs) containing distinct periods of anomalous heavy-ion charge state composition and peculiar ion thermal properties measured by ACE /SWICS from 1998 to 2011. We label them “depleted ICMEs,” identified by the presence of intervals where C{sup 6+}/C{sup 5+} and O{sup 7+}/O{sup 6+} depart from the direct correlation expected after their freeze-in heights. These anomalous intervals within the depleted ICMEs are referred to as “Depletion Regions.” We find that a depleted ICME would be indistinguishable from all other ICMEs in the absence of the Depletion Region, which has the defining property of significantly low abundances of fully charged species of helium, carbon, oxygen, and nitrogen. Similar anomalies in the slow solar wind were discussed by Zhao et al. We explore two possibilities for the source of the Depletion Region associated with magnetic reconnection in the tail of a CME, using CME simulations of the evolution of two Earth-bound CMEs described by Manchester et al.

  1. β2-glycoprotein-1 autoantibodies from patients with antiphospholipid syndrome are sufficient to potentiate arterial thrombus formation in a mouse model

    Science.gov (United States)

    Arad, Ariela; Proulle, Valerie; Furie, Richard A.; Furie, Barbara C.

    2011-01-01

    Antiphospholipid syndrome is characterized by thrombosis, recurrent fetal loss, and the presence of the lupus anticoagulant, anticardiolipin antibodies, or anti–β2-glycoprotein-1 (anti–β2-GP1) antibodies. Although anti–β2-GP1 antibodies have been documented as a biomarker for diagnosis of antiphospholipid syndrome, their direct role in the pathogenesis of thrombosis is unknown. We have demonstrated using intravital microscopy that anti–β2-GP1 autoantibodies purified from the sera of patients with antiphospholipid syndrome complicated by thrombosis greatly amplify thrombus size after laser-induced vessel wall injury in live mice. Anti–β2-GP1 autoantibodies from 3 patients with antiphospholipid syndrome were affinity-purified using human β2-GP1 bound to agarose. The effects of purified anti–β2-GP1 IgG autoantibodies, of anti–β2-GP1–depleted IgG, and of IgG from normal human sera on thrombus formation were measured in mice after arterial injury in the cremaster muscle. Before injury, purified anti–β2-GP1 IgG autoantibodies, anti–β2-GP1 antibody–depleted IgG, or IgG from normal human sera were infused. Increasing amounts of purified anti–β2-GP1 autoantibodies increased thrombus size in a dose-dependent manner, whereas neither anti–β2-GP1 antibody-depleted IgG nor IgG from normal serum affected thrombus size. These results indicate that anti–β2-GP1 IgG autoantibodies in antiphospholipid syndrome patient sera are not only a marker of antiphospholipid syndrome but are directly involved in the pathogenesis of thrombosis. PMID:21245481

  2. Recurrence formulas for evaluating expansion series of depletion functions

    International Nuclear Information System (INIS)

    Vukadin, Z.

    1991-01-01

    A high-accuracy analytical method for solving the depletion equations for chains of radioactive nuclides is based on the formulation of depletion functions. When all the arguments of the depletion function are too close to each other, series expansions of the depletion function have to be used. However, the high-accuracy series expressions for the depletion functions of high index become too complicated. Recursion relations are derived which enable an efficient high-accuracy evaluation of the depletion functions with high indices. (orig.) [de

  3. Report on outcomes of hypomethylating therapy for analyzing prognostic value of Revised International Prognostic Scoring System for patients with lower-risk myelodysplastic syndromes.

    Science.gov (United States)

    Lee, Yoo Jin; Park, Sung Woo; Lee, In Hee; Ahn, Jae Sook; Kim, Hyeoung Joon; Chung, Joo Seop; Shin, Ho Jin; Lee, Won Sik; Lee, Sang Min; Joo, Young Don; Kim, Hawk; Lee, Ho Sup; Kim, Yang Soo; Cho, Yoon Young; Moon, Joon Ho; Sohn, Sang Kyun

    2016-10-01

    The outcomes for patients with lower-risk myelodysplastic syndromes (LR-MDS) by the International Prognostic Scoring System (IPSS) vary widely. For more precise prognostication, this study evaluates the prognostic value of revised IPSS with the response to hypomethylating therapy (HMT). Using the Korean MDS Working Party database, treatment outcomes for 236 patients with HMT were retrospectively evaluated. The patients were then reclassified into very low/low (VL/L), intermediate (INT), and high (H) risk groups according to IPSS-R. According to the HMT response, the 3-year overall survival (OS) did not differ between the response group (37.9 ± 9.1 %) and the stable group (52.9 ± 6.6 %, p = 0. 782). When reclassifying according to IPSS-R, 42 patients (20.8 %) were reclassified into the H risk group. Most of them did not have benefit from continued HMT and progressed to secondary failure. The median OS was 59.0 months (range, 40.0-77.9 months) for the VL/L risk group, 31 months (range, 22.7-439.3 months) for the INT risk group, and 20.0 months (range, 15.9-24.1 months) for the H risk group (p risk group according to IPSS-R (HR = 3.054, p risk according to IPSS-R (HR = 4.912, p = 0.003), and transformation to AML (HR = 2.158, p = 0.002). If IPSS-R reclassifies LR-MDS patients as H risk, these patients should be considered for early allo-HCT, regardless of the current benefits from HMT.

  4. Transient Treg depletion enhances therapeutic anti‐cancer vaccination

    Science.gov (United States)

    Aston, Wayne J.; Chee, Jonathan; Khong, Andrea; Cleaver, Amanda L.; Solin, Jessica N.; Ma, Shaokang; Lesterhuis, W. Joost; Dick, Ian; Holt, Robert A.; Creaney, Jenette; Boon, Louis; Robinson, Bruce; Lake, Richard A.

    2016-01-01

    Abstract Introduction Regulatory T cells (Treg) play an important role in suppressing anti‐ immunity and their depletion has been linked to improved outcomes. To better understand the role of Treg in limiting the efficacy of anti‐cancer immunity, we used a Diphtheria toxin (DTX) transgenic mouse model to specifically target and deplete Treg. Methods Tumor bearing BALB/c FoxP3.dtr transgenic mice were subjected to different treatment protocols, with or without Treg depletion and tumor growth and survival monitored. Results DTX specifically depleted Treg in a transient, dose‐dependent manner. Treg depletion correlated with delayed tumor growth, increased effector T cell (Teff) activation, and enhanced survival in a range of solid tumors. Tumor regression was dependent on Teffs as depletion of both CD4 and CD8 T cells completely abrogated any survival benefit. Severe morbidity following Treg depletion was only observed, when consecutive doses of DTX were given during peak CD8 T cell activation, demonstrating that Treg can be depleted on multiple occasions, but only when CD8 T cell activation has returned to base line levels. Finally, we show that even minimal Treg depletion is sufficient to significantly improve the efficacy of tumor‐peptide vaccination. Conclusions BALB/c.FoxP3.dtr mice are an ideal model to investigate the full therapeutic potential of Treg depletion to boost anti‐tumor immunity. DTX‐mediated Treg depletion is transient, dose‐dependent, and leads to strong anti‐tumor immunity and complete tumor regression at high doses, while enhancing the efficacy of tumor‐specific vaccination at low doses. Together this data highlight the importance of Treg manipulation as a useful strategy for enhancing current and future cancer immunotherapies. PMID:28250921

  5. EPRI depletion benchmark calculations using PARAGON

    International Nuclear Information System (INIS)

    Kucukboyaci, Vefa N.

    2015-01-01

    Highlights: • PARAGON depletion calculations are benchmarked against the EPRI reactivity decrement experiments. • Benchmarks cover a wide range of enrichments, burnups, cooling times, and burnable absorbers, and different depletion and storage conditions. • Results from PARAGON-SCALE scheme are more conservative relative to the benchmark data. • ENDF/B-VII based data reduces the excess conservatism and brings the predictions closer to benchmark reactivity decrement values. - Abstract: In order to conservatively apply burnup credit in spent fuel pool criticality analyses, code validation for both fresh and used fuel is required. Fresh fuel validation is typically done by modeling experiments from the “International Handbook.” A depletion validation can determine a bias and bias uncertainty for the worth of the isotopes not found in the fresh fuel critical experiments. Westinghouse’s burnup credit methodology uses PARAGON™ (Westinghouse 2-D lattice physics code) and its 70-group cross-section library, which have been benchmarked, qualified, and licensed both as a standalone transport code and as a nuclear data source for core design simulations. A bias and bias uncertainty for the worth of depletion isotopes, however, are not available for PARAGON. Instead, the 5% decrement approach for depletion uncertainty is used, as set forth in the Kopp memo. Recently, EPRI developed a set of benchmarks based on a large set of power distribution measurements to ascertain reactivity biases. The depletion reactivity has been used to create 11 benchmark cases for 10, 20, 30, 40, 50, and 60 GWd/MTU and 3 cooling times 100 h, 5 years, and 15 years. These benchmark cases are analyzed with PARAGON and the SCALE package and sensitivity studies are performed using different cross-section libraries based on ENDF/B-VI.3 and ENDF/B-VII data to assess that the 5% decrement approach is conservative for determining depletion uncertainty

  6. Haploidentical Allogeneic Transplant With Post-transplant Infusion of Regulatory T-cells

    Science.gov (United States)

    2017-04-03

    Leukemia, Acute; Chronic Myelogenous Leukemia (CML); Myelodysplastic Syndrome (MDS); Non-Hodgkin Lymphoma (NHL); Chronic Lymphocytic Leukemia (CLL); Acute Myelogenous Leukemia (AML); Acute Lymphoblastic Leukemia (ALL)

  7. Depletion sensitivity predicts unhealthy snack purchases.

    Science.gov (United States)

    Salmon, Stefanie J; Adriaanse, Marieke A; Fennis, Bob M; De Vet, Emely; De Ridder, Denise T D

    2016-01-01

    The aim of the present research is to examine the relation between depletion sensitivity - a novel construct referring to the speed or ease by which one's self-control resources are drained - and snack purchase behavior. In addition, interactions between depletion sensitivity and the goal to lose weight on snack purchase behavior were explored. Participants included in the study were instructed to report every snack they bought over the course of one week. The dependent variables were the number of healthy and unhealthy snacks purchased. The results of the present study demonstrate that depletion sensitivity predicts the amount of unhealthy (but not healthy) snacks bought. The more sensitive people are to depletion, the more unhealthy snacks they buy. Moreover, there was some tentative evidence that this relation is more pronounced for people with a weak as opposed to a strong goal to lose weight, suggesting that a strong goal to lose weight may function as a motivational buffer against self-control failures. All in all, these findings provide evidence for the external validity of depletion sensitivity and the relevance of this construct in the domain of eating behavior. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Isotopic depletion with Monte Carlo

    International Nuclear Information System (INIS)

    Martin, W.R.; Rathkopf, J.A.

    1996-06-01

    This work considers a method to deplete isotopes during a time- dependent Monte Carlo simulation of an evolving system. The method is based on explicitly combining a conventional estimator for the scalar flux with the analytical solutions to the isotopic depletion equations. There are no auxiliary calculations; the method is an integral part of the Monte Carlo calculation. The method eliminates negative densities and reduces the variance in the estimates for the isotope densities, compared to existing methods. Moreover, existing methods are shown to be special cases of the general method described in this work, as they can be derived by combining a high variance estimator for the scalar flux with a low-order approximation to the analytical solution to the depletion equation

  9. Iron overload may promote alteration of NK cells and hematopoietic stem/progenitor cells by JNK and P38 pathway in myelodysplastic syndromes.

    Science.gov (United States)

    Hua, Yanni; Wang, Chaomeng; Jiang, Huijuan; Wang, Yihao; Liu, Chunyan; Li, Lijuan; Liu, Hui; Shao, Zonghong; Fu, Rong

    2017-08-01

    The objective of the study was to examine levels of intracellular iron, reactive oxygen species (ROS) and the expression of JNK and p38MAPK in NK cells and hematopoietic stem/progenitor cells (HSPCs) in MDS patients, and explore potential mechanisms by which iron overload (IOL) promotes MDS progression. Thirty-four cases of MDS and six cases of AML transformed from MDS (MDS/AML) were included. HSPCs and NK cells were isolated by magnetic absorption cell sorting. We used flow cytometry to detect the levels of ROS and intracellular JNK and P38 in NK cells and HSPCs. Total RNA and protein were extracted from NK cells and CD34 + cells to examine the expression of JNK and p38MAPK using RT-PCR and Western blotting. Intracellular iron concentration was detected. Data were analyzed by SPSS 21 statistical software. Intracellular iron concentration and ROS were increased in both NK cells and HSPCs in MDS patients with iron overload (P overload had higher JNK expression and lower p38 expression in NK cells, and higher p38 expression in HSPCs compared with non-iron overload group. IOL may cause alterations in NK cells and HSPCs through the JNK and p38 pathways, and play a role in the transformation to AML from MDS.

  10. Microscopic to macroscopic depletion model development for FORMOSA-P

    International Nuclear Information System (INIS)

    Noh, J.M.; Turinsky, P.J.; Sarsour, H.N.

    1996-01-01

    Microscopic depletion has been gaining popularity with regard to employment in reactor core nodal calculations, mainly attributed to the superiority of microscopic depletion in treating spectral history effects during depletion. Another trend is the employment of loading pattern optimization computer codes in support of reload core design. Use of such optimization codes has significantly reduced design efforts to optimize reload core loading patterns associated with increasingly complicated lattice designs. A microscopic depletion model has been developed for the FORMOSA-P pressurized water reactor (PWR) loading pattern optimization code. This was done for both fidelity improvements and to make FORMOSA-P compatible with microscopic-based nuclear design methods. Needless to say, microscopic depletion requires more computational effort compared with macroscopic depletion. This implies that microscopic depletion may be computationally restrictive if employed during the loading pattern optimization calculation because many loading patterns are examined during the course of an optimization search. Therefore, the microscopic depletion model developed here uses combined models of microscopic and macroscopic depletion. This is done by first performing microscopic depletions for a subset of possible loading patterns from which 'collapsed' macroscopic cross sections are obtained. The collapsed macroscopic cross sections inherently incorporate spectral history effects. Subsequently, the optimization calculations are done using the collapsed macroscopic cross sections. Using this approach allows maintenance of microscopic depletion level accuracy without substantial additional computing resources

  11. Depleted depletion drives polymer swelling in poor solvent mixtures.

    Science.gov (United States)

    Mukherji, Debashish; Marques, Carlos M; Stuehn, Torsten; Kremer, Kurt

    2017-11-09

    Establishing a link between macromolecular conformation and microscopic interaction is a key to understand properties of polymer solutions and for designing technologically relevant "smart" polymers. Here, polymer solvation in solvent mixtures strike as paradoxical phenomena. For example, when adding polymers to a solvent, such that all particle interactions are repulsive, polymer chains can collapse due to increased monomer-solvent repulsion. This depletion induced monomer-monomer attraction is well known from colloidal stability. A typical example is poly(methyl methacrylate) (PMMA) in water or small alcohols. While polymer collapse in a single poor solvent is well understood, the observed polymer swelling in mixtures of two repulsive solvents is surprising. By combining simulations and theoretical concepts known from polymer physics and colloidal science, we unveil the microscopic, generic origin of this collapse-swelling-collapse behavior. We show that this phenomenon naturally emerges at constant pressure when an appropriate balance of entropically driven depletion interactions is achieved.

  12. Is Ego Depletion Real? An Analysis of Arguments.

    Science.gov (United States)

    Friese, Malte; Loschelder, David D; Gieseler, Karolin; Frankenbach, Julius; Inzlicht, Michael

    2018-03-01

    An influential line of research suggests that initial bouts of self-control increase the susceptibility to self-control failure (ego depletion effect). Despite seemingly abundant evidence, some researchers have suggested that evidence for ego depletion was the sole result of publication bias and p-hacking, with the true effect being indistinguishable from zero. Here, we examine (a) whether the evidence brought forward against ego depletion will convince a proponent that ego depletion does not exist and (b) whether arguments that could be brought forward in defense of ego depletion will convince a skeptic that ego depletion does exist. We conclude that despite several hundred published studies, the available evidence is inconclusive. Both additional empirical and theoretical works are needed to make a compelling case for either side of the debate. We discuss necessary steps for future work toward this aim.

  13. Depletion-induced biaxial nematic states of boardlike particles

    International Nuclear Information System (INIS)

    Belli, S; Van Roij, R; Dijkstra, M

    2012-01-01

    With the aim of investigating the stability conditions of biaxial nematic liquid crystals, we study the effect of adding a non-adsorbing ideal depletant on the phase behavior of colloidal hard boardlike particles. We take into account the presence of the depletant by introducing an effective depletion attraction between a pair of boardlike particles. At fixed depletant fugacity, the stable liquid-crystal phase is determined through a mean-field theory with restricted orientations. Interestingly, we predict that for slightly elongated boardlike particles a critical depletant density exists, where the system undergoes a direct transition from an isotropic liquid to a biaxial nematic phase. As a consequence, by tuning the depletant density, an easy experimental control parameter, one can stabilize states of high biaxial nematic order even when these states are unstable for pure systems of boardlike particles. (paper)

  14. Self-Regulatory Capacities Are Depleted in a Domain-Specific Manner.

    Science.gov (United States)

    Zhang, Rui; Stock, Ann-Kathrin; Rzepus, Anneka; Beste, Christian

    2017-01-01

    Performing an act of self-regulation such as making decisions has been suggested to deplete a common limited resource, which impairs all subsequent self-regulatory actions (ego depletion theory). It has however remained unclear whether self-referred decisions truly impair behavioral control even in seemingly unrelated cognitive domains, and which neurophysiological mechanisms are affected by these potential depletion effects. In the current study, we therefore used an inter-individual design to compare two kinds of depletion, namely a self-referred choice-based depletion and a categorization-based switching depletion, to a non-depleted control group. We used a backward inhibition (BI) paradigm to assess the effects of depletion on task switching and associated inhibition processes. It was combined with EEG and source localization techniques to assess both behavioral and neurophysiological depletion effects. The results challenge the ego depletion theory in its current form: Opposing the theory's prediction of a general limited resource, which should have yielded comparable effects in both depletion groups, or maybe even a larger depletion in the self-referred choice group, there were stronger performance impairments following a task domain-specific depletion (i.e., the switching-based depletion) than following a depletion based on self-referred choices. This suggests at least partly separate and independent resources for various cognitive control processes rather than just one joint resource for all self-regulation activities. The implications are crucial to consider for people making frequent far-reaching decisions e.g., in law or economy.

  15. Context Matters: Distinct Disease Outcomes as a Result of Crebbp Hemizygosity in Different Mouse Bone Marrow Compartments.

    Directory of Open Access Journals (Sweden)

    Ting Zhou

    Full Text Available Perturbations in CREB binding protein (CREBBP are associated with hematopoietic malignancies, including myelodysplastic syndrome (MDS. Mice hemizygous for Crebbp develop myelodysplasia with proliferative features, reminiscent of human MDS/myeloproliferative neoplasm-unclassifiable (MDS/MPN-U, and a proportion goes on to develop acute myeloid leukemia (AML. We have also shown that the Crebbp+/- non-hematopoietic bone marrow microenvironment induces excessive myeloproliferation of wild-type cells. We now report that transplantation of unfractionated Crebbp+/- bone marrow into wild-type recipients resulted in either early-onset AML or late-onset MDS and MDS/MPN-U. In contrast, purified Lin-Sca-1+c-Kit++ cells primarily gave rise to MDS with occasional transformation to AML. Furthermore, Crebbp+/- common myeloid progenitors and granulocyte/macrophage progenitors could trigger skewed myelopoiesis, myelodysplasia and late-onset AML. Surprisingly, the phenotypically abnormal cells were all of wild-type origin. MDS, MPN and AML can thus all be transferred from Crebbp+/- BM to wild-type hosts but fractionated bone marrow does not recapitulate the full disease spectrum of whole bone marrow, indicating that not only mutational status but also cellular context contribute to disease outcome. This has important consequences for structuring and interpreting future investigations into the underlying mechanisms of myeloid malignancies as well as for their treatment.

  16. Depleted Uranium and Human Health.

    Science.gov (United States)

    Faa, Armando; Gerosa, Clara; Fanni, Daniela; Floris, Giuseppe; Eyken, Peter V; Lachowicz, Joanna I; Nurchi, Valeria M

    2018-01-01

    Depleted uranium (DU) is generally considered an emerging pollutant, first extensively introduced into environment in the early nineties in Iraq, during the military operation called "Desert Storm". DU has been hypothesized to represent a hazardous element both for soldiers exposed as well as for the inhabitants of the polluted areas in the war zones. In this review, the possible consequences on human health of DU released in the environment are critically analyzed. In the first part, the chemical properties of DU and the principal civil and military uses are summarized. A concise analysis of the mechanisms underlying absorption, blood transport, tissue distribution and excretion of DU in the human body is the subject of the second part of this article. The following sections deal with pathological condition putatively associated with overexposure to DU. Developmental and birth defects, the Persian Gulf syndrome, and kidney diseases that have been associated to DU are the arguments treated in the third section. Finally, data regarding DU exposure and cancer insurgence will be critically analyzed, including leukemia/lymphoma, lung cancer, uterine cervix cancer, breast cancer, bladder cancer and testicular cancer. The aim of the authors is to give a contribution to the debate on DU and its effects on human health and disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Translocations (5;17) and (7;17) in patients with de novo or therapy-related myelodysplastic syndromes or acute nonlymphocytic leukemia. A possible association with acquired pseudo-Pelger-Hut anomaly and small vacuolated granulocytes

    International Nuclear Information System (INIS)

    La, J.L.Z.; Zandecki, M.; Fenaux, P.; Le Baron, F.; Bauters, F.; Cosson, A.; Deminatti, M.

    1990-01-01

    Twelve patients [two with de novo myelodysplastic syndrome (MDS), four with secondary MDS, five with de novo acute nonlymphocytic leukemia (ANLL), one with secondary ANLL] showed a 17p deletion resulting from translocations involving 17p: t(5;17)(p11;p11) in four cases, t(7;17)(p11;p11) in six cases, complex (5;17)(q23;p12) translocation with dicentric chromosome in one case, and t(17;?)(p11-12;?) in the remaining patient. All these structural anomalies were observed in hypodiploid clones associated with total or partial monosomy of chromosomes 5 and 7 (12 cases), monosomy 12 (five cases), monosomy 3 (four cases), and monosomy 4 (three cases). Median survival was only 3.3 months (range 3 days to 8 months). Striking features were observed in bone marrow mature granulocytes: all but one case had a pseudo-Pelger-Hut anomaly in a significant number of granulocytes, and eight patients had granulocytes with reduced size and clear cytoplasmic vacuoles. Careful cytological review of 51 patients with MDS or ANLL and various cytogenetic anomalies was performed for comparison: vacuolated granulocytes were a very uncommon finding. On the other hand, eight patients had a pseudo-Pelger-Hut anomaly, which correlated significantly with total monosomy 17 in these patients. A possible correlation between cytological anomalies and cytogenetic data is discussed, and the role of 17p in the nuclear segmentation of granulocytes is stressed

  18. Annotating function to differentially expressed LincRNAs in myelodysplastic syndrome using a network-based method.

    Science.gov (United States)

    Liu, Keqin; Beck, Dominik; Thoms, Julie A I; Liu, Liang; Zhao, Weiling; Pimanda, John E; Zhou, Xiaobo

    2017-09-01

    Long non-coding RNAs (lncRNAs) have been implicated in the regulation of diverse biological functions. The number of newly identified lncRNAs has increased dramatically in recent years but their expression and function have not yet been described from most diseases. To elucidate lncRNA function in human disease, we have developed a novel network based method (NLCFA) integrating correlations between lncRNA, protein coding genes and noncoding miRNAs. We have also integrated target gene associations and protein-protein interactions and designed our model to provide information on the combined influence of mRNAs, lncRNAs and miRNAs on cellular signal transduction networks. We have generated lncRNA expression profiles from the CD34+ haematopoietic stem and progenitor cells (HSPCs) from patients with Myelodysplastic syndromes (MDS) and healthy donors. We report, for the first time, aberrantly expressed lncRNAs in MDS and further prioritize biologically relevant lncRNAs using the NLCFA. Taken together, our data suggests that aberrant levels of specific lncRNAs are intimately involved in network modules that control multiple cancer-associated signalling pathways and cellular processes. Importantly, our method can be applied to prioritize aberrantly expressed lncRNAs for functional validation in other diseases and biological contexts. The method is implemented in R language and Matlab. xizhou@wakehealth.edu. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  19. Maximizing percentage depletion in solid minerals

    International Nuclear Information System (INIS)

    Tripp, J.; Grove, H.D.; McGrath, M.

    1982-01-01

    This article develops a strategy for maximizing percentage depletion deductions when extracting uranium or other solid minerals. The goal is to avoid losing percentage depletion deductions by staying below the 50% limitation on taxable income from the property. The article is divided into two major sections. The first section is comprised of depletion calculations that illustrate the problem and corresponding solutions. The last section deals with the feasibility of applying the strategy and complying with the Internal Revenue Code and appropriate regulations. Three separate strategies or appropriate situations are developed and illustrated. 13 references, 3 figures, 7 tables

  20. Dysfunctional Hematopoietic Stem Cell Biology: Underlying Mechanisms and Potential Therapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Anja Geiselhart

    2012-01-01

    Full Text Available Fanconi anemia (FA is the most common inherited bone marrow failure syndrome. FA patients suffer to varying degrees from a heterogeneous range of developmental defects and, in addition, have an increased likelihood of developing cancer. Almost all FA patients develop a severe, progressive bone marrow failure syndrome, which impacts upon the production of all hematopoietic lineages and, hence, is thought to be driven by a defect at the level of the hematopoietic stem cell (HSC. This hypothesis would also correlate with the very high incidence of MDS and AML that is observed in FA patients. In this paper, we discuss the evidence that supports the role of dysfunctional HSC biology in driving the etiology of the disease. Furthermore, we consider the different model systems currently available to study the biology of cells defective in the FA signaling pathway and how they are informative in terms of identifying the physiologic mediators of HSC depletion and dissecting their putative mechanism of action. Finally, we ask whether the insights gained using such disease models can be translated into potential novel therapeutic strategies for the treatment of the hematologic disorders in FA patients.

  1. Disrupted Signaling through the Fanconi Anemia Pathway Leads to Dysfunctional Hematopoietic Stem Cell Biology: Underlying Mechanisms and Potential Therapeutic Strategies

    Science.gov (United States)

    Geiselhart, Anja; Lier, Amelie; Walter, Dagmar; Milsom, Michael D.

    2012-01-01

    Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. FA patients suffer to varying degrees from a heterogeneous range of developmental defects and, in addition, have an increased likelihood of developing cancer. Almost all FA patients develop a severe, progressive bone marrow failure syndrome, which impacts upon the production of all hematopoietic lineages and, hence, is thought to be driven by a defect at the level of the hematopoietic stem cell (HSC). This hypothesis would also correlate with the very high incidence of MDS and AML that is observed in FA patients. In this paper, we discuss the evidence that supports the role of dysfunctional HSC biology in driving the etiology of the disease. Furthermore, we consider the different model systems currently available to study the biology of cells defective in the FA signaling pathway and how they are informative in terms of identifying the physiologic mediators of HSC depletion and dissecting their putative mechanism of action. Finally, we ask whether the insights gained using such disease models can be translated into potential novel therapeutic strategies for the treatment of the hematologic disorders in FA patients. PMID:22675615

  2. Spectrum of myeloid neoplasms and immune deficiency associated with germline GATA2 mutations

    OpenAIRE

    Mir, Muhammad A; Kochuparambil, Samith T; Abraham, Roshini S; Rodriguez, Vilmarie; Howard, Matthew; Hsu, Amy P; Jackson, Amie E; Holland, Steven M; Patnaik, Mrinal M

    2015-01-01

    Guanine-adenine-thymine-adenine 2 (GATA2) mutated disorders include the recently described MonoMAC syndrome (Monocytopenia and Mycobacterium avium complex infections), DCML (dendritic cell, monocyte, and lymphocyte deficiency), familial MDS/AML (myelodysplastic syndrome/acute myeloid leukemia) (myeloid neoplasms), congenital neutropenia, congenital lymphedema (Emberger's syndrome), sensorineural deafness, viral warts, and a spectrum of aggressive infections seen across all age groups. While c...

  3. Long-term groundwater depletion in the United States

    Science.gov (United States)

    Konikow, Leonard F.

    2015-01-01

    The volume of groundwater stored in the subsurface in the United States decreased by almost 1000 km3 during 1900–2008. The aquifer systems with the three largest volumes of storage depletion include the High Plains aquifer, the Mississippi Embayment section of the Gulf Coastal Plain aquifer system, and the Central Valley of California. Depletion rates accelerated during 1945–1960, averaging 13.6 km3/year during the last half of the century, and after 2000 increased again to about 24 km3/year. Depletion intensity is a new parameter, introduced here, to provide a more consistent basis for comparing storage depletion problems among various aquifers by factoring in time and areal extent of the aquifer. During 2001–2008, the Central Valley of California had the largest depletion intensity. Groundwater depletion in the United States can explain 1.4% of observed sea-level rise during the 108-year study period and 2.1% during 2001–2008. Groundwater depletion must be confronted on local and regional scales to help reduce demand (primarily in irrigated agriculture) and/or increase supply.

  4. Mal de Debarquement Syndrome: A Rare Entity—A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Veronica Nwagwu

    2015-01-01

    Full Text Available Mal de Debarquement Syndrome (MDS is a rare, understudied, underdiagnosed, and self-limiting condition. Etiology and incidence are unknown. It is characterized by abnormal sensation of motion/balance reported after travel by air, land, and sea; being reexposed to motion/activity relieves it. Symptoms may last from minutes to years. Workup though required reveals no findings; it is a diagnosis of exclusion. While no efficacious treatment exists, amitriptyline and benzodiazepines as well as supportive therapy have proved to be useful. We have described a 40-year-old Caucasian female who presented for the evaluation of persistent rocking and swaying sensation after a ship cruise which lasted for one week. Patient was treated with benzodiazepines after extensive workup and is now stable. A high index of suspicion is required to make a diagnosis.

  5. Depletion sensitivity predicts unhealthy snack purchases

    NARCIS (Netherlands)

    Salmon, Stefanie J.; Adriaanse, Marieke A.; Fennis, Bob M.; De Vet, Emely; De Ridder, Denise T D

    2016-01-01

    The aim of the present research is to examine the relation between depletion sensitivity - a novel construct referring to the speed or ease by which one's self-control resources are drained - and snack purchase behavior. In addition, interactions between depletion sensitivity and the goal to lose

  6. Real depletion in nodal diffusion codes

    International Nuclear Information System (INIS)

    Petkov, P.T.

    2002-01-01

    The fuel depletion is described by more than one hundred fuel isotopes in the advanced lattice codes like HELIOS, but only a few fuel isotopes are accounted for even in the advanced steady-state diffusion codes. The general assumption that the number densities of the majority of the fuel isotopes depend only on the fuel burnup is seriously in error if high burnup is considered. The real depletion conditions in the reactor core differ from the asymptotic ones at the stage of lattice depletion calculations. This study reveals which fuel isotopes should be explicitly accounted for in the diffusion codes in order to predict adequately the real depletion effects in the core. A somewhat strange conclusion is that if the real number densities of the main fissionable isotopes are not explicitly accounted for in the diffusion code, then Sm-149 should not be accounted for either, because the net error in k-inf is smaller (Authors)

  7. Uranium: myths and realities the depleted uranium; Uranio: Mitos y realidades. El caso del uranio emprobrecido

    Energy Technology Data Exchange (ETDEWEB)

    Sanchez, G.

    2001-07-01

    Uranium is an element whose name causes worry. The uranium properties are very unknown for people. However the element plays an important roll in the Earth as responsible of numerous natural phenomena, which are vital for life evolution. An example of the low knowledge about uranium has been the Balkan syndrome. A relation between cancers and the use of depleted uranium in ammunition in the Balkan War has been pretended to be established. From the beginning, this hypothesis could have been discarded as it has been confirmed and stated in recent reports of UNEP Commissions who have studied this matter. (Author)

  8. Gas generation matrix depletion quality assurance project plan

    International Nuclear Information System (INIS)

    1998-01-01

    The Los Alamos National Laboratory (LANL) is to provide the necessary expertise, experience, equipment and instrumentation, and management structure to: Conduct the matrix depletion experiments using simulated waste for quantifying matrix depletion effects; and Conduct experiments on 60 cylinders containing simulated TRU waste to determine the effects of matrix depletion on gas generation for transportation. All work for the Gas Generation Matrix Depletion (GGMD) experiment is performed according to the quality objectives established in the test plan and under this Quality Assurance Project Plan (QAPjP)

  9. Immunoglobulins of patients with Cushing's syndrome due to pigmented adrenocortical micronodular dysplasia stimulate in vitro steroidogenesis

    NARCIS (Netherlands)

    Wulffraat, N. M.; Drexhage, H. A.; Wiersinga, W. M.; van der Gaag, R. D.; Jeucken, P.; Mol, J. A.

    1988-01-01

    The putative stimulation of adrenal steroid production by immunoglobulins (Igs) of five patients with pigmented adrenocortical micronodular dysplasia and clinical Cushing's syndrome was investigated. Ascorbate depletion, a process linked to steroid production, was measured by a cyto-chemical

  10. 75 FR 62843 - Advisory Council on Blood Stem Cell Transplantation; Notice of Meeting

    Science.gov (United States)

    2010-10-13

    ..., Myelodysplastic Syndromes (MDS) coverage, Medicare reimbursement for costs for allogeneic or autologous... http://www.acbsct.com or submitted by facsimile to Lux Consulting Group, Inc., the logistical support...

  11. Hsp90 depletion goes wild

    OpenAIRE

    Siegal, Mark L; Masel, Joanna

    2012-01-01

    Abstract Hsp90 reveals phenotypic variation in the laboratory, but is Hsp90 depletion important in the wild? Recent work from Chen and Wagner in BMC Evolutionary Biology has discovered a naturally occurring Drosophila allele that downregulates Hsp90, creating sensitivity to cryptic genetic variation. Laboratory studies suggest that the exact magnitude of Hsp90 downregulation is important. Extreme Hsp90 depletion might reactivate transposable elements and/or induce aneuploidy, in addition to r...

  12. Regret causes ego-depletion and finding benefits in the regrettable events alleviates ego-depletion.

    Science.gov (United States)

    Gao, Hongmei; Zhang, Yan; Wang, Fang; Xu, Yan; Hong, Ying-Yi; Jiang, Jiang

    2014-01-01

    This study tested the hypotheses that experiencing regret would result in ego-depletion, while finding benefits (i.e., "silver linings") in the regret-eliciting events counteracted the ego-depletion effect. Using a modified gambling paradigm (Experiments 1, 2, and 4) and a retrospective method (Experiments 3 and 5), five experiments were conducted to induce regret. Results revealed that experiencing regret undermined performance on subsequent tasks, including a paper-and-pencil calculation task (Experiment 1), a Stroop task (Experiment 2), and a mental arithmetic task (Experiment 3). Furthermore, finding benefits in the regret-eliciting events improved subsequent performance (Experiments 4 and 5), and this improvement was mediated by participants' perceived vitality (Experiment 4). This study extended the depletion model of self-regulation by considering emotions with self-conscious components (in our case, regret). Moreover, it provided a comprehensive understanding of how people felt and performed after experiencing regret and after finding benefits in the events that caused the regret.

  13. Is gas in the Orion nebula depleted

    International Nuclear Information System (INIS)

    Aiello, S.; Guidi, I.

    1978-01-01

    Depletion of heavy elements has been recognized to be important in the understanding of the chemical composition of the interstellar medium. This problem is also relevant to the study of H II regions. In this paper the gaseous depletion in the physical conditions of the Orion nebula is investigated. The authors reach the conclusion that very probably no depletion of heavy elements, due to sticking on dust grains, took place during the lifetime of the Orion nebula. (Auth.)

  14. Refeeding syndrome: clinical and nutritional relevance.

    Science.gov (United States)

    Viana, Larissa de Andrade; Burgos, Maria Goretti Pessoa de Araújo; Silva, Rafaella de Andrade

    2012-01-01

    Feedback syndrome is characterized clinically by neurological alterations, respiratory symptoms, arrhythmias and heart failure few days after refeeding. It happens due to severe electrolyte changes, such as hypophosphatemia, hypomagnesemia and hypokalemia associated with metabolic abnormalities that may occur as a result of nutritional support (oral, enteral or parenteral) in severely malnourished patients. To evaluate its causes and the preventive dietary measures aiming to reduce the morbimortality. Was conducted literature review in SciELO, LILACS, Medline / PUBMED, Cochrane Library and government websites in Portuguese, English and Spanish. The survey was about the last 15 years, selecting the headings: refeeding syndrome, malnutrition, hypophosphatemia, hypokalemia, hypomagnesemia. The monitoring of metabolic parameters and electrolyte levels before starting nutritional support and periodically during feeding should be based on protocols and the duration of therapy. Patients at high risk and other metabolic complications should be followed closely, and depletion of minerals and electrolytes should be replaced before starting the diet. A multidisciplinary team of nutrition therapy can guide and educate other health professionals in prevention, diagnosis and treatment of the syndrome.

  15. Nature gives us strength: exposure to nature counteracts ego-depletion.

    Science.gov (United States)

    Chow, Jason T; Lau, Shun

    2015-01-01

    Previous research rarely investigated the role of physical environment in counteracting ego-depletion. In the present research, we hypothesized that exposure to natural environment counteracts ego-depletion. Three experiments were conducted to test this hypothesis. In Experiment 1, initially depleted participants who viewed pictures of nature scenes showed greater persistence on a subsequent anagram task than those who were given a rest period. Experiment 2 expanded upon this finding by showing that natural environment enhanced logical reasoning performance after ego-depleting task. Experiment 3 adopted a two- (depletion vs. no-depletion) -by-two (nature exposure vs. urban exposure) factorial design. We found that nature exposure moderated the effect of depletion on anagram task performance. Taken together, the present studies offer a viable and novel strategy to mitigate the negative impacts of ego-depletion.

  16. Temporary CD8(+) T-cell depletion in pigs does not exacerbate infection with porcine reproductive and respiratory syndrome virus (PRRSV)

    DEFF Research Database (Denmark)

    Lohse, Louise; Nielsen, Jens; Eriksen, Lis

    2004-01-01

    Several studies have demonstrated a consistent increase in the CD8(+) T-cell subset of pigs following infection with porcine reproductive and respiratory virus (PRRSV). Consequently, it has been suggested that CD8(+) T-cells may play an important role in protection against this infection. In order...... increased disease nor influenced the ability to clear virus in the treated pigs......., confirmed the depletion effect of specific mAb therapy. Almost complete depletion of cell subsets expressing the CD8(+) antigen was obtained on day 2 and 5 post infection (PI) with nadir less than 1 % of peripheral blood mononuclear cells (PBMC). One week PI, an increase in T-cell subsets was observed...

  17. Lithium depletion and rotation in main-sequence stars

    International Nuclear Information System (INIS)

    Balachandran, S.

    1990-01-01

    Lithium abundances were measured in nearly 200 old disk-population F stars to examine the effects of rotational braking on the depletion of Li. The sample was selected to be slightly evolved off the main sequence so that the stars have completed all the Li depletion they will undergo on the main sequence. A large scatter in Li abundances in the late F stars is found, indicating that the Li depletion is not related to age and spectral type alone. Conventional depletion mechanisms like convective overshoot and microscopic diffusion are unable to explain Li depletion in F stars with thin convective envelopes and are doubly taxed to explain such a scatter. No correlation is found between Li abundance and the present projected rotational velocity and some of the most rapid rotators are undepleted, ruling out meridional circulation as the cause of Li depletion. There is a somewhat larger spread in Li abundances in the spun-down late F stars compared to the early F stars which should remain rotationally unaltered on the main sequence. 85 refs

  18. Validation of the Care-Related Quality of Life Instrument in different study settings: findings from The Older Persons and Informal Caregivers Survey Minimum DataSet (TOPICS-MDS).

    Science.gov (United States)

    Lutomski, J E; van Exel, N J A; Kempen, G I J M; Moll van Charante, E P; den Elzen, W P J; Jansen, A P D; Krabbe, P F M; Steunenberg, B; Steyerberg, E W; Olde Rikkert, M G M; Melis, R J F

    2015-05-01

    Validity is a contextual aspect of a scale which may differ across sample populations and study protocols. The objective of our study was to validate the Care-Related Quality of Life Instrument (CarerQol) across two different study design features, sampling framework (general population vs. different care settings) and survey mode (interview vs. written questionnaire). Data were extracted from The Older Persons and Informal Caregivers Minimum DataSet (TOPICS-MDS, www.topics-mds.eu ), a pooled public-access data set with information on >3,000 informal caregivers throughout the Netherlands. Meta-correlations and linear mixed models between the CarerQol's seven dimensions (CarerQol-7D) and caregiver's level of happiness (CarerQol-VAS) and self-rated burden (SRB) were performed. The CarerQol-7D dimensions were correlated to the CarerQol-VAS and SRB in the pooled data set and the subgroups. The strength of correlations between CarerQol-7D dimensions and SRB was weaker among caregivers who were interviewed versus those who completed a written questionnaire. The directionality of associations between the CarerQol-VAS, SRB and the CarerQol-7D dimensions in the multivariate model supported the construct validity of the CarerQol in the pooled population. Significant interaction terms were observed in several dimensions of the CarerQol-7D across sampling frame and survey mode, suggesting meaningful differences in reporting levels. Although good scientific practice emphasises the importance of re-evaluating instrument properties in individual research studies, our findings support the validity and applicability of the CarerQol instrument in a variety of settings. Due to minor differential reporting, pooling CarerQol data collected using mixed administration modes should be interpreted with caution; for TOPICS-MDS, meta-analytic techniques may be warranted.

  19. Department of Energy depleted uranium recycle

    International Nuclear Information System (INIS)

    Kosinski, F.E.; Butturini, W.G.; Kurtz, J.J.

    1994-01-01

    With its strategic supply of depleted uranium, the Department of Energy is studying reuse of the material in nuclear radiation shields, military hardware, and commercial applications. the study is expected to warrant a more detailed uranium recycle plan which would include consideration of a demonstration program and a program implementation decision. Such a program, if implemented, would become the largest nuclear material recycle program in the history of the Department of Energy. The bulk of the current inventory of depleted uranium is stored in 14-ton cylinders in the form of solid uranium hexafluoride (UF 6 ). The radioactive 235 U content has been reduced to a concentration of 0.2% to 0.4%. Present estimates indicate there are about 55,000 UF 6 -filled cylinders in inventory and planned operations will provide another 2,500 cylinders of depleted uranium each year. The United States government, under the auspices of the Department of Energy, considers the depleted uranium a highly-refined strategic resource of significant value. A possible utilization of a large portion of the depleted uranium inventory is as radiation shielding for spent reactor fuels and high-level radioactive waste. To this end, the Department of Energy study to-date has included a preliminary technical review to ascertain DOE chemical forms useful for commercial products. The presentation summarized the information including preliminary cost estimates. The status of commercial uranium processing is discussed. With a shrinking market, the number of chemical conversion and fabrication plants is reduced; however, the commercial capability does exist for chemical conversion of the UF 6 to the metal form and for the fabrication of uranium radiation shields and other uranium products. Department of Energy facilities no longer possess a capability for depleted uranium chemical conversion

  20. Depleted UF6 programmatic environmental impact statement

    International Nuclear Information System (INIS)

    1997-01-01

    The US Department of Energy has developed a program for long-term management and use of depleted uranium hexafluoride, a product of the uranium enrichment process. As part of this effort, DOE is preparing a Programmatic Environmental Impact Statement (PEIS) for the depleted UF 6 management program. This report duplicates the information available at the web site (http://www.ead.anl.gov/web/newduf6) set up as a repository for the PEIS. Options for the web site include: reviewing recent additions or changes to the web site; learning more about depleted UF 6 and the PEIS; browsing the PEIS and related documents, or submitting official comments on the PEIS; downloading all or part of the PEIS documents; and adding or deleting one's name from the depleted UF 6 mailing list

  1. Disproportionately severe calcinosis cutis in an 88-year-old patient with CREST syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Buchowski, J.M.; Ahn, N.U.; Ahn, U.M. [Dept. of Orthopaedic Surgery, Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States); McCarthy, E.F. [Dept. of Orthopaedic Surgery, Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States); Dept. of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (United States); Mehta, M.B. [Clinical Associates, Good Samaritan Hospital, Baltimore, MD (United States)

    2001-08-01

    An 88-year-old woman with CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias) presented with hyperglycemia, intravascular depletion, and atrial fibrillation. The patient was found to have unusually severe calcinosis cutis in both legs extending from the knees to the ankles bilaterally, as well as Raynaud's phenomenon, sclerodactyly, and telangiectasias. The patient was normocalcemic and normophosphatemic. Although subcutaneous calcification is often seen with CREST syndrome, this case is unusual in that the area of involvement was much larger than previously described. Furthermore, the amount of calcinosis was disproportionately severe and was the major cause of symptoms and disability compared with the other components of the syndrome. (orig.)

  2. Radiosensitization of CHO cells by the combination of glutathione depletion and low concentrations of oxygen: The effect of different levels of GSH depletion

    International Nuclear Information System (INIS)

    Clark, E.P.; Epp, E.R.; Zachgo, E.A.; Biaglow, J.E.

    1984-01-01

    Recently, the authors have examined the effect of GSH depletion by BSO on CHO cells equilibrated with oxygen at various concentrations (0.05-4.0%) and irradiated with 50 kVp x-rays. This is of interest because of the uncertain radiosensitizing effect GSH depletion may have on cells equilibrated with low oxygen concentrations. GSH depletion (0.1 mM BSO/24 hrs reduced [GSH] ≅ 10% of control) enhanced the radiosensitizing action of moderate (0.4-4.0%) concentrations of oxygen, i.e., GSH depletion reduced the [O/sub 2/] necessary to achieve an equivalent ER by ≅ 2-3 fold. However, GSH depletion was much more effective as a rediosensitizer when cells were equilibrated with low (<0.4%) concentrations of oxygen, i.e., GSH depletion reduced the [O/sub 2/] necessary to achieve an equivalent ER by 8-10 fold. Furthermore, while the addition of exogenous 5 mM GSH restored the ER to that observed when GSH was not depleted, the intracellular [GSH] was not increased. The results of these studies carried out at different levels of GSH depletion are presented

  3. Simultaneous analysis of the expression of 14 genes with individual prognostic value in myelodysplastic syndrome patients at diagnosis: WT1 detection in peripheral blood adversely affects survival.

    Science.gov (United States)

    Santamaría, Carlos; Ramos, Fernando; Puig, Noemi; Barragán, Eva; de Paz, Raquel; Pedro, Carme; Insunza, Andrés; Tormo, Mar; Del Cañizo, Consuelo; Diez-Campelo, María; Xicoy, Blanca; Salido, Eduardo; Sánchez del Real, Javier; Hernández, Montserrat; Chillón, Carmen; Sanz, Guillermo F; García-Sanz, Ramón; San Miguel, Jesús F; González, Marcos

    2012-12-01

    Several studies have evaluated the prognostic value of the individual expression of certain genes in patients with myelodysplastic syndromes (MDS). However, none of them includes their simultaneous analysis by quantitative polymerase chain reaction (PCR). We evaluated relative expression levels of 14 molecular markers in 193 peripheral blood samples from untreated MDS patients using real-time PCR. Detectable WT1 expression levels, low TET2, and low IER3 gene expression were the only markers showing in univariate analysis a poor prognostic value for all treatment-free (TFS), progression-free (PFS), and overall survival (OS). In multivariate analysis, molecular parameters associated with a shorter TFS were: WT1 detection (p = 0.014), low TET2 (p = 0.002), and low IER3 expression (p = 0.025). WT1 detection (p = 0.006) and low TET2 (p = 0.006) expression were associated with a shorter PFS when multivariate analysis was carried out by including only molecular markers. Molecular values with an independent value in OS were: WT1 detection (p = 0.003), high EVI1 expression (p = 0.001), and undetectatable p15-CDKN2B (p = 0.037). WT1 expressers were associated with adverse clinical-biological features, high IPSS and WPSS scoring, and unfavorable molecular expression profile. In summary, detectable WT1 expression levels, and low TET2 and low IER3 expression in peripheral blood showed a strong association with adverse prognosis in MDS patients at diagnosis. However, WT1 was the only molecular marker displaying an independent prognostic value in both OS and TFS.

  4. How Ego Depletion Affects Sexual Self-Regulation: Is It More Than Resource Depletion?

    Science.gov (United States)

    Nolet, Kevin; Rouleau, Joanne-Lucine; Benbouriche, Massil; Carrier Emond, Fannie; Renaud, Patrice

    2015-12-21

    Rational thinking and decision making are impacted when in a state of sexual arousal. The inability to self-regulate arousal can be linked to numerous problems, like sexual risk taking, infidelity, and sexual coercion. Studies have shown that most men are able to exert voluntary control over their sexual excitation with various levels of success. Both situational and dispositional factors can influence self-regulation achievement. The goal of this research was to investigate how ego depletion, a state of low self-control capacity, interacts with personality traits-propensities for sexual excitation and inhibition-and cognitive absorption, to cause sexual self-regulation failure. The sexual responses of 36 heterosexual males were assessed using penile plethysmography. They were asked to control their sexual arousal in two conditions, with and without ego depletion. Results suggest that ego depletion has opposite effects based on the trait sexual inhibition, as individuals moderately inhibited showed an increase in performance while highly inhibited ones showed a decrease. These results challenge the limited resource model of self-regulation and point to the importance of considering how people adapt to acute and high challenging conditions.

  5. Defects in maintenance of mitochondrial DNA are associated with intramitochondrial nucleotide imbalances.

    Science.gov (United States)

    Ashley, Neil; Adams, Susan; Slama, Abdelhamid; Zeviani, Massimo; Suomalainen, Anu; Andreu, Antonio L; Naviaux, Robert K; Poulton, Joanna

    2007-06-15

    Defects in mtDNA maintenance range from fatal multisystem childhood diseases, such as Alpers syndrome, to milder diseases in adults, including mtDNA depletion syndromes (MDS) and familial progressive external ophthalmoplegia (AdPEO). Most are associated with defects in genes involved in mitochondrial deoxynucleotide metabolism or utilization, such as mutations in thymidine kinase 2 (TK2) as well as the mtDNA replicative helicase, Twinkle and gamma polymerase (POLG). We have developed an in vitro system to measure incorporation of radiolabelled dNTPs into mitochondria of saponin permeabilized cells. We used this to compare the rates of mtDNA synthesis in cells from 12 patients with diseases of mtDNA maintenance. We observed reduced incorporation of exogenous alpha (32)P-dTTP in fibroblasts from a patient with Alpers syndrome associated with the A467T substitution in POLG, a patient with dGK mutations, and a patient with mtDNA depletion of unknown origin compared to controls. However, incorporation of alpha (32)P-dTTP relative to either cell doubling time or alpha (32)P-dCTP incorporation was increased in patients with thymidine kinase deficiency or PEO as the result of TWINKLE mutations compared with controls. The specific activity of newly synthesized mtDNA depends on the size of the endogenous pool diluting the exogenous labelled nucleotide. Our result is consistent with a deficiency in the intramitochondrial pool of dTTP relative to dCTP in cells from patients with TK2 deficiency and TWINKLE mutations. Such DNA precursor asymmetry could cause pausing of the replication complex and hence exacerbate the propensity for age-related mtDNA mutations. Because deviations from the normal concentrations of dNTPs are known to be mutagenic, we suggest that intramitochondrial nucleotide imbalance could underlie the multiple mtDNA mutations observed in these patients.

  6. The new MCNP6 depletion capability

    International Nuclear Information System (INIS)

    Fensin, M. L.; James, M. R.; Hendricks, J. S.; Goorley, J. T.

    2012-01-01

    The first MCNP based in-line Monte Carlo depletion capability was officially released from the Radiation Safety Information and Computational Center as MCNPX 2.6.0. Both the MCNP5 and MCNPX codes have historically provided a successful combinatorial geometry based, continuous energy, Monte Carlo radiation transport solution for advanced reactor modeling and simulation. However, due to separate development pathways, useful simulation capabilities were dispersed between both codes and not unified in a single technology. MCNP6, the next evolution in the MCNP suite of codes, now combines the capability of both simulation tools, as well as providing new advanced technology, in a single radiation transport code. We describe here the new capabilities of the MCNP6 depletion code dating from the official RSICC release MCNPX 2.6.0, reported previously, to the now current state of MCNP6. NEA/OECD benchmark results are also reported. The MCNP6 depletion capability enhancements beyond MCNPX 2.6.0 reported here include: (1) new performance enhancing parallel architecture that implements both shared and distributed memory constructs; (2) enhanced memory management that maximizes calculation fidelity; and (3) improved burnup physics for better nuclide prediction. MCNP6 depletion enables complete, relatively easy-to-use depletion calculations in a single Monte Carlo code. The enhancements described here help provide a powerful capability as well as dictate a path forward for future development to improve the usefulness of the technology. (authors)

  7. The New MCNP6 Depletion Capability

    International Nuclear Information System (INIS)

    Fensin, Michael Lorne; James, Michael R.; Hendricks, John S.; Goorley, John T.

    2012-01-01

    The first MCNP based inline Monte Carlo depletion capability was officially released from the Radiation Safety Information and Computational Center as MCNPX 2.6.0. Both the MCNP5 and MCNPX codes have historically provided a successful combinatorial geometry based, continuous energy, Monte Carlo radiation transport solution for advanced reactor modeling and simulation. However, due to separate development pathways, useful simulation capabilities were dispersed between both codes and not unified in a single technology. MCNP6, the next evolution in the MCNP suite of codes, now combines the capability of both simulation tools, as well as providing new advanced technology, in a single radiation transport code. We describe here the new capabilities of the MCNP6 depletion code dating from the official RSICC release MCNPX 2.6.0, reported previously, to the now current state of MCNP6. NEA/OECD benchmark results are also reported. The MCNP6 depletion capability enhancements beyond MCNPX 2.6.0 reported here include: (1) new performance enhancing parallel architecture that implements both shared and distributed memory constructs; (2) enhanced memory management that maximizes calculation fidelity; and (3) improved burnup physics for better nuclide prediction. MCNP6 depletion enables complete, relatively easy-to-use depletion calculations in a single Monte Carlo code. The enhancements described here help provide a powerful capability as well as dictate a path forward for future development to improve the usefulness of the technology.

  8. Allogeneic hematopoietic stem cell transplantation for primary myelodysplastic syndrome Transplante alogênico de células progenitoras hematopoiéticas para síndrome mielodisplásica primária

    Directory of Open Access Journals (Sweden)

    Carlos R. Medeiros

    2004-01-01

    Full Text Available Characteristics and outcomes of 52 patients with myelodysplastic syndrome (MDS who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT were analyzed. Median age was 30 years (range 2-61 years and median time from diagnosis to allo-HSCT was 10 months (range 1-161 months. Thirty-six patients had advanced MDS or acute myeloid leukemia following MDS at transplant. Conditioning with busulfan and cyclophosphamide was administered to 73% of patients, and the median value of graft dose was 2.595 x 10(8 of total nucleated cells/kg. Overall survival and disease free survival at 4 years were 36% and 33%, respectively. Nineteen patients were alive, with a median follow-up of 3.8 years. Twelve patients relapsed and only one is alive, after donor lymphocyte infusion. Interval II occurred in 19 patients. Donor type (identical related versus non-related/partially matched related influenced the incidence of acute GVHD (P = 0.03. Eleven patients developed chronic GVHD and previous acute GVHD was a risk factor (P = 0.03. Thirty-three patients died, 22 (67% secondary to transplant-related complications. Patients with MDS should undergo allo-HSCT earlier, mainly if they have a compatible donor and are young.Características e resultados de 52 pacientes com síndrome mielodisplásica (MDS submetidos a transplante alogênico de células progenitoras hematopoiéticas (TCPH foram analisados. A idade mediana foi de 30 anos (variação de 2-61 anos e o tempo mediano entre o diagnóstico e transplante foi de dez meses (variação de 1-161 meses. Trinta e seis pacientes tinham MDS avançada ou leucemia mielóide aguda secundária a MDS ao transplante. O condicionamento com busulfano e ciclo­fosfamida foi recebido por 73% dos pacientes, e a dose celular mediana do enxerto foi de 2.56 x 10(8 células nucleadas/kg. A sobrevida global e a sobrevida livre de doença aos quatro anos foi de 36% e 33%, respectivamente. Dezenove pacientes estavam vivos, com um

  9. Plasmonic Nanoprobes for Stimulated Emission Depletion Nanoscopy.

    Science.gov (United States)

    Cortés, Emiliano; Huidobro, Paloma A; Sinclair, Hugo G; Guldbrand, Stina; Peveler, William J; Davies, Timothy; Parrinello, Simona; Görlitz, Frederik; Dunsby, Chris; Neil, Mark A A; Sivan, Yonatan; Parkin, Ivan P; French, Paul M W; Maier, Stefan A

    2016-11-22

    Plasmonic nanoparticles influence the absorption and emission processes of nearby emitters due to local enhancements of the illuminating radiation and the photonic density of states. Here, we use the plasmon resonance of metal nanoparticles in order to enhance the stimulated depletion of excited molecules for super-resolved nanoscopy. We demonstrate stimulated emission depletion (STED) nanoscopy with gold nanorods with a long axis of only 26 nm and a width of 8 nm. These particles provide an enhancement of up to 50% of the resolution compared to fluorescent-only probes without plasmonic components irradiated with the same depletion power. The nanoparticle-assisted STED probes reported here represent a ∼2 × 10 3 reduction in probe volume compared to previously used nanoparticles. Finally, we demonstrate their application toward plasmon-assisted STED cellular imaging at low-depletion powers, and we also discuss their current limitations.

  10. Ecological considerations of natural and depleted uranium

    International Nuclear Information System (INIS)

    Hanson, W.C.

    1980-01-01

    Depleted 238 U is a major by-product of the nuclear fuel cycle for which increasing use is being made in counterweights, radiation shielding, and ordnance applications. This paper (1) summarizes the pertinent literature on natural and depleted uranium in the environment, (2) integrates results of a series of ecological studies conducted at Los Alamos Scientific Laboratory (LASL) in New Mexico where 70,000 kg of depleted and natural uranium has been expended to the environment over the past 34 years, and (3) synthesizes the information into an assessment of the ecological consequences of natural and depleted uranium released to the environment by various means. Results of studies of soil, plant, and animal communities exposed to this radiation and chemical environment over a third of a century provide a means of evaluating the behavior and effects of uranium in many contexts

  11. Mantle depletion and metasomatism recorded in orthopyroxene in highly depleted peridotites

    DEFF Research Database (Denmark)

    Scott, James; Liu, Jingao; Pearson, D. Graham

    2016-01-01

    Although trace element concentrations in clinopyroxene serve as a useful tool for assessing the depletion and enrichment history of mantle peridotites, this is not applicable for peridotites in which the clinopyroxene component has been consumed (~ 25% partial melting). Orthopyroxene persists in ...

  12. NOMAD: a nodal microscopic analysis method for nuclear fuel depletion

    International Nuclear Information System (INIS)

    Rajic, H.L.; Ougouag, A.M.

    1987-01-01

    Recently developed assembly homogenization techniques made possible very efficient global burnup calculations based on modern nodal methods. There are two possible ways of modeling the global depletion process: macroscopic and microscopic depletion models. Using a microscopic global depletion approach NOMAD (NOdal Microscopic Analysis Method for Nuclear Fuel Depletion), a multigroup, two- and three-dimensional, multicycle depletion code was devised. The code uses the ILLICO nodal diffusion model. The formalism of the ILLICO methodology is extended to treat changes in the macroscopic cross sections during a depletion cycle without recomputing the coupling coefficients. This results in a computationally very efficient method. The code was tested against a well-known depletion benchmark problem. In this problem a two-dimensional pressurized water reactor is depleted through two cycles. Both cycles were run with 1 x 1 and 2 x 2 nodes per assembly. It is obvious that the one node per assembly solution gives unacceptable results while the 2 x 2 solution gives relative power errors consistently below 2%

  13. The study of necessity of verification-methods for Depleted Uranium

    International Nuclear Information System (INIS)

    Park, J. B.; Ahn, S. H.; Ahn, G. H.; Chung, S. T.; Shin, J. S.

    2006-01-01

    ROK has tried to establish management system for depleted uranium from 2004, and ROK achieved some results in this field including management software, management skill, and the list of company using the nuclear material. But, the studies for the depleted uranium are insufficient exclude the studies of KAERI. In terms of SSAC, we have to study more about whether the depleted uranium is really dangerous material or not and how is the depleted uranium diverted to the nuclear weapon. The depleted uranium was controlled by the item counting in the national system for the small quantity nuclear material. We don't have unique technical methods to clarify the depleted uranium on-the-spot inspection not laboratory scale. Therefore, I would like to suggest of the necessity of the verification methods for depleted uranium. Furthermore, I would like to show you the methods of the verification of the depleted uranium in national system up to now

  14. Tissue specific distribution of pyrimidine deoxynucleoside salvage enzymes shed light on the mechanism of mitochondrial DNA depletion.

    Science.gov (United States)

    Wang, L; Eriksson, S

    2010-06-01

    Deficiency in thymidine kinase 2 (TK2) activity due to genetic alterations caused tissue specific mitochondrial DNA (mtDNA) depletion syndrome with symptoms resembling these of AIDS patients treated with nucleoside analogues. Mechanisms behind this mitochondrial effects is still not well understood. With rat as a model we isolated mitochondrial and cytosolic fractions from major organs and studied enzymes involved in thymidine (dT) and deoxycytidine (dC) phosphorylation by using ionic exchange column chromatography. A cytosolic form of TK2 was identified in all tested tissues in addition to mitochondrial TK2. TK1 was detected in liver and spleen cytosolic extracts while dCK was found in liver, spleen and lung cytosolic extracts. Thus, the nature of dT and dC salvage enzymes in each tissue type was determined. In most tissues TK2 is the only salvage enzyme present except liver and spleen. These results may help to explain the mechanisms of mitochondrial toxicity of antiviral nucleoside analogues and mtDNA depletion caused by TK2 deficiency.

  15. Hematopoietic growth factors for the treatment of myelodysplastic syndromes

    DEFF Research Database (Denmark)

    Hansen, P B; Penkowa, M; Johnsen, H E

    1998-01-01

    with milder forms of MDS combined with low prestudy endogenous S-Epo levels. The possible synergistic effect of combining rhEpo with rhG-CSF or rhGM-CSF has been studied with erythropoietic response rates of about 40%. The safety of the cytokine administration seems acceptable with no significant stimulation...... of leukemic myelopoiesis and subsequent progression into overt acute myeloid leukemia. In conclusion, combinations of hematopoietic growth factors may be of clinical benefit in some patients with MDS. However, due to the cost and unpredictable clinical outcome there is a need for extended laboratory research...

  16. The enhancements and testing for the MCNPX depletion capability

    International Nuclear Information System (INIS)

    Fensin, M. L.; Hendricks, J. S.; Anghaie, S.

    2008-01-01

    Monte Carlo-linked depletion methods have gained recent interest due to the ability to more accurately model true system physics and better track the evolution of temporal nuclide inventory by simulating the actual physical process. The integration of INDER90 into the MCNPX Monte Carlo radiation transport code provides a completely self-contained Monte- Carlo-linked depletion capability in a single Monte Carlo code that is compatible with most nuclear criticality (KCODE) particle tracking features in MCNPX. MCNPX depletion tracks all necessary reaction rates and follows as many isotopes as cross section data permits in order to achieve a highly accurate temporal nuclide inventory solution. We describe here the depletion methodology dating from the original linking of MONTEBURNS and MCNP to the first public release of the integrated capability (MCNPX 2. 6.B, June, 2006) that has been reported previously. Then we further detail the many new depletion capability enhancements since then leading to the present capability. The H.B. Robinson benchmark calculation results are also reported. The new MCNPX depletion capability enhancements include: (1) allowing the modeling of as large a system as computer memory capacity permits; (2) tracking every fission product available in ENDF/B VII. 0; (3) enabling depletion in repeated structures geometries such as repeated arrays of fuel pins; (4) including metastable isotopes in burnup; and (5) manually changing the concentrations of key isotopes during different time steps to simulate changing reactor control conditions such as dilution of poisons to maintain criticality during burnup. These enhancements allow better detail to model the true system physics and also improve the robustness of the capability. The H.B. Robinson benchmark calculation was completed in order to determine the accuracy of the depletion solution. Temporal nuclide computations of key actinide and fission products are compared to the results of other

  17. Acupuncture for polycystic ovarian syndrome

    Science.gov (United States)

    Jo, Junyoung; Lee, Yoon Jae; Lee, Hyangsook

    2017-01-01

    Abstract Background: This systematic review aimed at summarizing and evaluating the evidence from randomized controlled trials (RCTs) using acupuncture to treat polycystic ovarian syndrome (PCOS), specifically focusing on ovulation rate, menstrual rate, and related hormones. Methods: Fifteen databases were searched electronically through February 2016. Our review included RCTs of women with PCOS; these RCTs compared acupuncture with sham acupuncture, medication, or no treatment. Two reviewers independently extracted data. Data were pooled and expressed as mean differences (MDs) for continuous outcomes and risk ratios for dichotomous outcomes, with 95% confidence intervals (CIs) using a random-effects model. Results: We found a low level of evidence that acupuncture is more likely to improve ovulation rate (MD 0.35, 95% CI: 0.14–0.56) and menstruation rate (MD 0.50, 95% CI: 0.32–0.68) compared with no acupuncture. We found statistically significant pooled benefits of acupuncture treatment as an adjunct to medication in luteinizing hormone (LH), LH/follicular stimulating hormone (FSH) ratio, testosterone, fasting insulin, and pregnancy rates, but the level of evidence was low/very low. Conclusion: There is limited evidence to judge the efficacy and safety of acupuncture on key reproductive outcomes in women with PCOS. Large-scale, long-term RCTs with rigorous methodological input are needed. PMID:28591042

  18. Negative effect of DNA hypermethylation on the outcome of intensive chemotherapy in older patients with high-risk myelodysplastic syndromes and acute myeloid leukemia following myelodysplastic syndrome

    DEFF Research Database (Denmark)

    Grövdal, Michael; Khan, Rasheed; Aggerholm, Anni

    2007-01-01

    was designed to assess the effect of methylation status on the outcome of conventional induction chemotherapy. EXPERIMENTAL DESIGN: Sixty patients with high-risk MDS or acute myeloid leukemia following MDS were treated with standard doses of daunorubicin and 1-beta-d-arabinofuranosylcytosine. Standard.......008), and CDH methylation retained its prognostic value also in the multivariate analysis. Hypermethylation was associated with increased CD34 expression, but not with other known predictive factors for response, such as cytogenetic profile. CONCLUSIONS: We show for the first time a significant effect...

  19. Síndromes mielodisplásicas e mielodisplásicas/mieloproliferativas Myelodysplastic syndromes and diseases with myelodysplastic and myeloproliferative features

    Directory of Open Access Journals (Sweden)

    José Vassallo

    2009-08-01

    Full Text Available As síndromes mielodisplásicas (SMD representam um grupo heterogêneo de doenças hematológicas caracterizadas por hematopoese ineficaz e risco aumentado de evolução para leucemia mieloide aguda. Neste artigo educativo são apresentados aspectos gerais da sua fisiopatologia, diagnóstico, apresentação histopatológica e seu papel no diagnóstico diferencial, classificação e estratificação prognóstica. Ressalta-se a importância da avaliação clínica e laboratorial, que inclui avaliação do sangue periférico e medula óssea: morfologia - aspirado medular e biópsia óssea -, citogenética, imunofenotipagem, além de dados evolutivos. O diagnóstico definitivo, em especial nos casos de baixo risco, deve considerar a exclusão de causas não clonais que podem, através de alterações dismielopoéticas reativas, simular a mielodisplasia, tais como infecções virais, principalmente pelo HIV. A nova classificação revisada da Organização Mundial da Saúde (OMS-2008 é apresentada e discutida.Myelodysplastic syndromes (MDS represent a heterogeneous group of hematologic disorders characterized by ineffective hematopoiesis and an increased risk of developing acute myeloid leukemia. In this educational article the general aspects of the physiopathology, diagnosis, and histopathological features of MDS and their role in differential diagnosis, classification and prognostic categorization are presented. The importance of clinical and laboratory evaluations, including peripheral blood and bone marrow analyses, including morphology - aspirate and core biopsy, cytogenetics, immunophenotype and careful serial follow-up is emphasized. Definite diagnosis of MDS, especially in low-risk subtypes, should consider the exclusion of disorders with reactive bone marrow alterations, such as viral infections for example HIV. The new revised World Health Organization (WHO-2008 classification is presented and discussed.

  20. A study of megakaryocyte morphology in bone marrow aspiration smears of cases of thrombocytopenia

    Directory of Open Access Journals (Sweden)

    Shashikala Vinayakamurthy

    2017-01-01

    Full Text Available Background: Thrombocytopenia may be encountered in various hematological and nonhematological conditions and may be associated with dysplastic megakaryocytes which is a feature of myelodysplastic syndrome (MDS, even though they can be observed in non-MDS hematological conditions. Objective: To study the morphological variations of megakaryocytes on bone marrow aspiration smears in non-MDS-related thrombocytopenia in a Medical College in Bengaluru, Karnataka. Materials and Methods: It was a prospective study of 86 cases of non-MDS thrombocytopenia whose bone marrow aspirates were studied morphologically. Results: The most common cause of thrombocytopenia was acute leukemia followed by other systemic malignancies, megaloblastic anemia, and idiopathic thrombocytopenic purpura. Both dysplastic and nondysplastic features were observed in the above-mentioned conditions. The most common dysplastic feature was nuclear segmentation followed by micromegakaryocytes and hypogranular forms. Among nondysplastic features, the most common were immature forms, bare nuclei, and hypolobation. Emperipolesis and cytoplasmic vacuoles were noted in a case of pyrexia of unknown origin. Conclusion: Dysplastic megakaryocytes are common in non-MDS-related thrombocytopenia and their mere presence should not lead to the diagnosis of MDS. Hence, proper diagnosis should be made on megakaryocyte morphology, patient's clinical findings, and other hematological parameters. This understanding can improve the diagnostic accuracy for wide range of hematological disorders.